Petechiae in Children – the PiC Study

Cite this article as:
Tessa Davis. Petechiae in Children – the PiC Study, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.30782

Today the Lancet has published the long-awaited results of the Petechiae in Children (PiC) study. Team DFTB got our hands on a pre-publication copy to read, summarise, and analyse for you. So let’s get to it.

This PERUKI study by Waterfield et al. is a prospective, multicentre cohort study:

Waterfield T, Maney J-A, Fairley D, Lyttle MD, McKenna JP, Roland D, Corr M, McFetridge L, Mitchell H, Woolfall K, Lynn F, Patenall B, Shields MD, Validating clinical practice guidelines for the management of children with non-blanching rashes in the UK (PiC): a prospective, multicentre cohort study, The Lancet, 2020

Why is this study needed?

We are all somewhat terrified of children with fever and a non-blanching rash. We don’t want to miss meningococcal sepsis. Current guidelines are based on data from before the introduction of the Meningococcal B (2015) and C (1999) vaccines and consider a prevalence of 10-20% of meningococcal infection in children with fever and non-blanching rash.

Who were the patients?

The paper looked at children under 18 years old presenting to 37 Paediatric Emergency Departments in the UK over a 16 month period. Children were included if they had a fever (>38oC) and new onset of a non-blanching rash or features suggestive of meningococcal infection. Children were excluded if they had a pre-existing haematological condition or if they already had a diagnosis of Henoch-Schonlein purpura.

1513 patients were screened. 179 were excluded due to not meeting the criteria, not consenting, or a language barrier. Five that were enrolled had incomplete data leaving 1329 children were enrolled and included – the median age was 24 months, and 59% were male. Most children were vaccinated with 73% having had at least one dose of the Meningococcal B vaccine, and 77% having had at least one dose of the Meningococcal C vaccine.

What was the intervention?

There was no intervention here. Included patients were recruited at the point of meeting the criteria, using ‘recruitment prior to consent‘ and then consent was obtained soon after (usually within 24 hours). Data were collected contemporaneously: patient symptoms, blood test results, and treatment. A positive case was identified by being positive on PCR, or with a positive growth from another body sample (e.g. blood culture, or CSF). Patients were also checked for re-attendance to the hospital within 7 days. Results were also confirmed with the Public Health Agency – as meningococcal disease is a notifiable condition, this was a good method of picking up any missed cases.

What were the outcomes measured?

The primary outcome was assessing the performance of eight clinical guidelines on identifying children with invasive meningococcal disease (NICE meningitis (CG102); NICE sepsis (NG51); London; Chester; Bristol; Nottingham; Newcastle-Birmingham-Liverpool; and Glasgow).

The secondary outcomes were: performance of the eight guidelines in identifying children with other bacterial infections; and also looking at a cost comparison of each of the eight guidelines.

What were the results?

Of all 1334 children, 86% had a blood test and 45% had antibiotics. For patients admitted to hospital, the median length of stay was one night. 11 patients were admitted to PICU (2%) and two patients died (<1%).

Eight of these 11 PICU patients had N. meningitidis as did both of the patients who died. Seven patients had invasive bacterial infection (five with pneumococcal infection, one with E. Coli, and one with Group A Strep).

19 (1%) of patients in the cohort had meningococcal disease. 17 of these had N. meningitidis B, one had N. meningitidis C, and one had N. meningitidis W. Overall there were 26 patients (2%) with invasive bacterial infection (19 with meningococcal disease and 7 with an invasive bacterial infection).

346 patients (26%) did not have standard testing, and of these 19 patients (5%) had one unplanned re-attendance within seven days. However, none of these required readmission, antibiotics, or bacterial infection.

And how did the guidelines do?

All eight guidelines identified all of the 19 cases of meningococcal disease and all 26 cases of invasive bacterial infection (so the sensitivity of all of them is 100%). Specificity varied though. The NICE sepsis guideline stratified every patient as having a bacterial infection and therefore had a specificity of zero, making it the lowest specificity out of all the guidelines (closely followed by NICE meningitis guidelines with a specificity of 1%). This strategy clearly has cost implications too which is why the two NICE guidelines were also the most expensive per patient (£660.41 for the NICE sepsis guidelines).

Coming out top of the guideline ranking was the Barts Health NHS Trust guideline with a sensitivity of 100%, a specificity of 36%, and a cost of £490.29. This makes it the most accurate and also the cheapest.

Here’s the Barts Health NHS Trust guideline:

What about when we don’t follow the guidelines?

In practice, the guidelines were adhered to in 46% of the patients in the cohort. Deviation from guidelines resulted in fewer antibiotics being given. However, it also resulted in two patients being discharged with early meningococcal disease (they were subsequently treated and did not need PICU admission). Clinician decision-making increased the specificity (i.e. clinicians treated fewer people with antibiotics who didn’t have an invasive bacterial infection), but unfortunately reduced the sensitivity to 89%. Clinician decision-making did have the lowest cost per patient.

You’ve heard the facts, but how good was the paper?

As Ken Milne says…let’s get nerdy (and consider the CASP checklist for cohort studies)

Yes.

Research without prior consent was used to avoid recruitment delaying any treatment plans. However consent was obtained as soon as possible after inclusion in the study (usually within 24 hours).

Yes. Objective measurements were used for a blood test and PCR results. Risk factors for meningococcal disease are subjective and were based on contemporaneous clinical assessment – but this is what we do in practice so is a good reflection.

Yes. Note, however, that two patients with meningococcal disease were not included – one was not enrolled and the other was deemed by local staff to be inappropriate for inclusion.

Yes.

Yes, and also results were also checked with the Public Health Agency which would have allowed pick up of any missed meningococcal positive results.

There is a 1% prevalence of meningococcal disease in a mainly immunised population of children with fever and a non-blanching rash. The Barts Health NHS Trust guideline was the most accurate out of all the guidelines and with the lowest cost per patient.

Yes.

Yes. However, they would not be transferrable to populations with lower rates of vaccine uptake or a higher disease prevalence. The data was not shared on whether those with meningococcal disease were unimmunised or not, and therefore it would be prudent to be more cautious if your patient is not vaccinated.

Previous data was from prior to the meningococcal vaccination so this is the first and largest study since then.

What did the authors conclude and what can we take away from this study?

Since the advent of a vaccination programme and increased vaccine uptake, the rates of meningococcal disease are lower. Although previous data suggested 10-20% of children with fever and a non-blanching rash had meningococcal disease, in fact this study shows that only 1% had meningococcal disease.

Using a cautious guideline like NICE results in a lower specificity and higher cost. Tailored guidelines can increase the specificity and reduce the cost per patient without compromising on 100% sensitivity. The Barts Health NHS Trust guideline was the top performing guideline.

And finally, a comment from the authors themselves:

From Tom Waterfield:

The Petechiae in Children study represents the best available evidence regarding the assessment and management of febrile children with non-blanching rashes in the UK and clearly demonstrates that a lighter touch, tailored approach, is favourable to a test/treat all approach as currently advised by NICE. Moving to a tailored approach will reduce the need for invasive procedures, improve antimicrobial stewardship and save money. 

In vaccinated populations where the prevalence of invasive meningococcal disease is low the presence of Petechiae alone should no longer be viewed as a red flag and should not be used to justify immediate treatment with broad spectrum antibiotics. The emphasis and teaching should shift away from worrying about all non-blanching rashes with greater emphasis on the importance of identifying purpuric rashes as they confer the greatest risk of invasive meningococcal disease. 

Finally the PiC study demonstrates the importance of well designed prospective research studies in identifying risk factors for sepsis. Traditional approaches utilising retrospective reporting of symptoms from convenience samples of children with sepsis results in an over estimation the risks. This in turn leads to the development of overly aggressive clinical practice guidelines that are poorly adhered to. 

Note from Tessa: I am an employee of Barts Health but was not involved in the PiC study or in writing the Barts Health NHS Trust guideline.

Gastroenteritis

Cite this article as:
Angharad Griffiths. Gastroenteritis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28790

Conor is a 10 kg, 13 month-old boy who’s presented to the ED with a 24-hour history of diarrhoea and vomiting.  He has had 5 episodes of non-bloody, non-bilious vomits. Since waking up this morning has two episodes of loose/watery non-bloody malodorous stools. They have not ‘flooded’ the nappy but were quite large.  He is taking sips of fluid (mixtures of water, milk, and juice being offered) and has only eaten half a digestive biscuit so far today.  He has had a fairly large wet nappy last night, but not since, though it’s now difficult to tell as his last nappy was dirty.  He is alert and looking around while being carried but is upset on leaving his mother’s arms.  He cries with tears, has a normal heart rate but his mother is worried about his dry lips.  She was told by a healthcare worker neighbour that he will “need a drip”. CRT, HR, and BP are normal.  His temperature is 37.8.  His nappy is dry and has been on for 3 hours now.  His capillary glucose measurement is 3.2.  You decide he’s probably mildly dehydrated.

Introduction

Gastroenteritis (GE) is the presence or diarrhoea or vomiting (or both) that may or may not be accompanied by fever, abdominal pain and anorexia.  Diarrhoea is the passage of excessively liquidy or frequent stools with liquid high water content.  Although often felt to be a common minor illness presentation, it is a major cause of childhood mortality and morbidity, causing millions of deaths worldwide in children in low and middle-income countries; of all child deaths from gastroenteritis 78% occur in Africa and South-East Asia. 

Gastroenteritis accounts for a huge proportion of GP and ED presentations. In Europe, acute gastroenteritis the third commonest cause of hospital admission, accounting for between 4-17% of admissions.  In Australia, gastroenteritis caused by rotavirus alone accounts for 115,000 GP visits, 22,000 ED visits and 10,000 hospital admissions a year, with an estimated cost of 30m Australian Dollars (£12m, €18m).  In the UK, 20% of GP consultations in the under 5’s are for GE.

It is imperative that the child with gastroenteritis is differentiated from more sinister causes of vomiting.  The presence of diarrhoea is reassuring but doesn’t exclude other intra-abdominal causes.  The same can be said for pain out of proportion with gastroenteritis, distension, peritoneal signs or localised tenderness.

Most cases are not associated with complications but when complications do occur, the commonest are electrolyte disturbance and metabolic acidosis.  Supplementary fluids through oral or intravenous routes are the most effective way to avoid these complications.

Gastroenteritis in low and middle-income countries can present differently, has different aetiologies, is often managed differently, and is a larger burden to healthcare systems in general than in high-income countries.  This post will focus on gastroenteritis in high-income countries. For more information about comparisons of guidelines across the world; Vecchio et al (2016) is an interesting read.

This is not meant to provide a clinical practice guideline; rather an overview of the illness.  Many (if not all!) paediatric emergency departments or general paediatric units have their own guidelines.

Pathophysiology

Worldwide, the commonest causes are viral pathogens, most commonly rotaviruses and noroviruses.  Viral infections cause damage to the small bowel enterocytes with resultant low-grade fevers and watery diarrhoea – classically without blood.  Rotavirus strains are seasonal and vary within different geographical areas.  The peak age for these infections is between 6 months and 2 years.  Children with poor nutrition are at higher risk of acquiring gastroenteritis and developing dehydration and complications.

Children with bacterial gastroenteritis are more likely to have bloody stool.
Escherichia coli and Shigella dysenteriae can be complicated by haemolytic uraemic syndrome (HUS).  This is an acute onset, microangiopathic haemolytic anaemia, thrombocytopaenia, acute renal impairment and multisystem involvement.  (Just to confuse things, HUS can present in the absence of bloody diarrhoea.)

Pathogens can be generalised into four groups:

  • Viral (70% of cases): Rotavirus, Norovirus, Adenovirus, Enterovirus
  • Bacterial (10-20% of cases): Campylobacter jejuni, Salmonella spp, Escherichia coli, Shigella spp, Yersinia enterocolitica.
  • Protozoa (unusual, accounting for <10%): Cryptosporidium, Giardia lamblia, Entamoeba histolytica
  • Helminths (very unusual): Strongyloides stercoralis

Transmission

Pathogens are spread mainly via the faeco-oral route, acquired by ingesting contaminated food or drink.  Water may be contaminated with bacteria, viruses, or protozoa. Undercooked (or inappropriately stored/cooked) meats and seafood are common culprits of bacterial pathogens.  Bacterial contaminants can produce toxins (e.g. Bacillus cereus in re-warmed rice or Staphylococcus aureus in ice-cream).

Pathogens causing gastroenteritis can also be transmitted without the patient being symptomatic.

Assessment

Gastroenteritis is a clinical diagnosis.  Enquire about sick/infectious contacts and potential sources (recent travel, food).  Enquire about the frequency of symptoms and intake of fluids.  Note the frequency of urination.  Note other things that may cause diarrhoea e.g. recent use of enteral antibiotics or chronic constipation with overflow diarrhoea the presenting feature. 

In the presence of signs such as high fever, long duration of symptoms, severe abdominal pain or bilious vomiting; review the diagnosis and do not immediately label as gastroenteritis.

Oral hydration fluids

Most children are not dehydrated and can tolerate oral fluids and so can be managed at home.  Take a look at Nikki Abela’s DFTB19 talk on top tips for a high yield dehydration assessment.

When children are only mildly to moderately dehydrated, as a general rule they can be treated with oral / enteral rehydration with low osmolality oral rehydration solution (ORS).  Worldwide, ORS is recognised as first line therapy and treating mild to moderate dehydration with enteral rehydration is supported by the WHO, European Society for Paediatric Gastroenterology and the American Academy of Paediatrics. The WHO recommends a low osmolality (hypo-osmolar) solution, usually containing sodium, potassium, chloride, carbohydrate (glucose) and a base.  Low osmolarity solutions reduce the need for IV fluids, reduce stool output and reduce vomiting frequency.

But… a major limitation to the use of ORS is its taste – and this is where apple juice comes in. For minimally dehydrated patients, half-strength apple juice is associated with fewer treatment failures compared to ORS and could suit as a more palatable alternative.  Take a look at a sweet summary (pun intended!) of the “apple juice trial”.

Breastfeeding should continue and a child can be supplemented with ORS if this is needed.  Children can go back to a normal diet after the illness has passed.

Enteral (oral / NG) versus IV hydration

Most studies show that enteral rehydration with ORS is just as effective as IV hydration in mild to moderate dehydration with a 2006 Cochrane analysis concluding that enteral rehydration is as effective if not better than IV rehydration with fewer adverse events and a shorter hospital stay.  It is also less invasive (even with NG placement) and anecdotally satisfaction is greater amongst parents.  It is very safe.

Enteral rehydration only fails in approximately 1 in 20-25 children.

Barriers to oral rehydration include unfamiliarity with the benefits, misconception that it takes longer than IV therapy, and that it has a high failure rate.

Contraindications to enteral rehydration include haemodynamic instability, abdominal distension, concern over ileus, absent bowel sounds, or impaired airway reflexes.

IV therapy is more invasive and involves placing and maintaining IV access.  There are also iatrogenic complications including electrolyte disturbance should inappropriate fluids / composition / volume / rate be used. 

But… in severely dehydrated children, put away the ORS and apple juice. They will need IV rehydration as first line.

Antiemetics

How can we support enteral fluids? Well, children who receive Ondansetron are less likely to vomit, have greater oral intake and are less likely to require IV hydration.  A Cochrane review demonstrates that Ondansetron also increases the proportion of children who stop vomiting when compared to placebo [RR1.4] and reduces the proportion of children needing IV therapy (and therefore admission rate) [RR 0.41].  Median length of stay is also shorter in the ED. 

Reported side effects are rare with very few reported side effects other than a few cases of increased frequency of diarrhoea.

Antiemetics alleviate vomiting by acting on the ChemoReceptor Trigger Zone and vomiting centre.  Ondansetron is a 5HT3 receptor antagonist.  This class of antiemetics have fewer adverse effects (than dopamine antagonists, anticholinergics, antihistamines and corticosteroids) and can be safely used in children.  The NICE guideline discusses its off-licence use (at time of publication it’s licence was for post-operative nausea and vomiting and chemotherapy induced vomiting).

Ondansetron prolongs the QT interval.  Recommendations are it should be avoided in those with long QT and should be used in caution where there may be electrolyte imbalance (severe dehydration) or on other QT-prolonging medication.

Ondansetron is relatively cheap  £1.71 for 10 4mg tablets and is available in oro-dispersible form (though these are much more expensive at £36 for 10x4mg tablets) and liquid (£36.82 for 40mg [50ml] bottle).

Probiotics

An ESPGHAN working group position paper on the use of probiotics in acute paediatric gastroenteritis concludes that:

  • Effects seen in clinical trial are probiotic strain specific (this makes ‘trial-life’ difficult to replicate in ‘real-life’).
  • A lack of evidence now doesn’t mean that there won’t be evidence sometime in the future. 
  • Safety profile of certain strains cannot be extrapolated to other strains.
  • Studies that report benefits in certain doses in certain settings have insufficient evidence to support a health benefit at lower doses and different setting.

…the jury’s still out.

Other therapies

Antibiotics and anti-diarrhoeal agents aren’t routinely recommended in the management of paediatric gastroenteritis.

For gastroenteritis in high income countries, the WHO does not recommend adding zinc to a treatment regimen (it is for gastroenteritis in low and middle income countries). 

Investigations

Routine lab testing in mild and moderate gastroenteritis is of little value in these patients and should be avoided unless clinically indicated.

This goes for stool samples too.  Stool cultures are not routinely indicated in immunocompetent children with non-bloody diarrhoea.

Confirmation of viral gastroenteritis after the child has been discharged from the ED, and likely on the road to recovery at home, adds very little to (A) the clinical diagnosis of viral gastroenteritis in the ED, (B) the management plan and (C) the clinical outcome. 

Should the investigation influence management, then stool sampling may be of benefit.  This could be applicable where an outbreak may be suspected in school or creche, where there may be a public health benefit.

Stool samples should be sent in cases of bloody diarrhoea, immunodeficiency and recent foreign travel.

How about tests for dehydration? Sadly there is no one test that correlates clinically with dehydration. Urine specific gravity in infants is unreliable because the kidney reaches adult concentrating abilities after the age of 1.  Also, the child often doesn’t begin urinating until rehydration has begun.

And glucose? Well, almost 10% of GE patients aged 1 month to 5 years in high income countries present with hypoglycaemia.  Risk factors for hypoglycaemia on presentation include a longer duration of vomiting and increased frequency of vomiting.  It would be reasonable to consider point of care glucose testing at triage for young children as identifying hypoglycaemia on clinical ground alone is difficult in this age group. 

Prevention

The key to reducing the burden (and generally for an all-round happier life!) is in the prevention of acute gastroenteritis.  Rotavirus vaccination is now commonplace thought the antibodies, the UK & Ireland and other countries around the world.  It is very effective.

In the home and in the ED…Handwashing, handwashing, handwashing!

Vaccination leads to a profound reduction in presentations and admissions and a fall in overall seasonal workload, often within the first year after the introduction of universal vaccination against rotavirus.  Even though only those under 1 year old are generally vaccinated, it has been shown to contribute to a significant herd effect with fewer cases than expected in older children. In Scotland, where initial vaccine uptake was 93- 94% during the first 2 years, annual rotavirus confirmed gastroenteritis cases fell by 84.7%, bed days reduced by 91% (from 325 to just 29), without any documented cases of intussusception.  Reductions were seen across all age groups despite only infants receiving the vaccine.  Similar results can be seen in other areas of the UK and Ireland.

The not to miss bits

  • Do not assume isolated vomiting in a child is gastroenteritis.  Consider other causes -these very widely from inborn errors of metabolism to diabetes mellitus, surgical obstruction to urinary tract infections. If you’d like to hear more, check out Dani’s talk on vomiting in children in DFTB Essentials.
  • Beware chronic diarrhoea in an infant – do they have malabsorption or is this a presentation of IBD or an immunodeficiency?
  • Beware the non-thriving child with diarrhoea.
  • And beware chronic diarrhoea.

But what happened to Conor?

Conor was given a cup of Dioralyte ORS and his favourite beaker filled with Dioralyte.  His mum was encouraged to give him syringes of 5 mls of Dioralyte frequently or for him to take sips from his beaker and was asked to document on a piece of paper how many he received.  He vomited after 30 minutes of this therapy.

You give him a dose of Ondansetron and place an NG tube and give him 100mls (10ml/kg) over 1 hour after deciding he does not need rapid rehydration but slightly more than normal maintenance.  He then receives maintenance volumes of Dioralyte via his NG, which he tolerates well and then starts to take his own sips from his beaker.

He does not vomit in the ED again, has one episode of loose stools, passes urine, and is tolerating fluids orally.  He’s smiling at you! You feel he can be discharged and council his mum regarding regular fluid intake, choice of fluids, of any red flags, and encouraged to return in the event of any concern.

Conor’s Dad calls to say that Conor’s 3 year old sister at home is now vomiting too!  But it’s OK – He’s not too worried about her and Conor’s Mum has advised his Dad to start giving her regular sips of Dioralyte at home…

References

Colletti JE, Brown KM, Sharieff GQ, Barata IA, Ishimine P. The Management of Children with Gastroenteritis and Dehydration in the Emergency Department. J Emerg Med [Internet]. 2010;38(5):686–98. Available from: https://dx.doi.org/10.1016/j.jemermed.2008.06.015

Elliott EJ. Acute gastroenteritis in children. Br Med J. 2007;334(7583):35–40.

Vecchio A Lo, Dias A, Berkley JA, Boey C, Cohen MB, Cruchet S, et al. Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children. Gastroenterology. 2016;63(2):226–35.

Freedman SB, Willan AR, Boutis K, Schuh S. Effect of dilute apple juice and preferred fluids vs electrolyte maintenance solution on treatment failure among children with mild gastroenteritis: A randomized clinical trial. JAMA – J Am Med Assoc. 2016;315(18):1966–74.

BK F, A H, JC C. Enteral vs Intravenous regydration therapy for children with gastroenteritis: A meta-analysis of randomized controlled trials. Arch Paediatr Adolesc. 2004;158(1):483–90.

Hartling L, Bellemare S, Wiebe N, Kf R, Tp K, Wr C, et al. Oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children (Review). 2006;

Fedorowicz Z, Jagannath V, Carter B. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. [Internet]. Cochrane database of systematic reviews. 2011. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005506.pub5/full

NICE. Management of vomiting omiting in children and y young oung people with gastroenteritis : ondansetron. NICE GUIDELINES. 2014. p. 1–20.

Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, et al. Use of Probiotics for Management of Acute Gastroenteritis : A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. 2014;58(4):531–9.

Forrest R, Jones L, Willocks L, Hardie A, Templeton K. Impact of the introduction of rotavirus vaccination on paediatric hospital admissions , Lothian , Scotland : a retrospective observational study. 2017;323–7.

MARLOW RD, MUIR P, VIPOND I, TROTTER CL FA. Assessing the impacts from the first year of rotavirus vaccination in the UK. Arch Dis Child. 2015;100(Supl 3):A30.

Picture of house

Hospital in the Home

Cite this article as:
Jo Lawrence. Hospital in the Home, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28959

Elise is about to have her 8th birthday and has planned a small party at home with her family and two best friends.  Elise also has acute lymphoblastic leukaemia and is in the middle of chemotherapy treatment.  Her next dose of methotrexate is due the day after her birthday but requires pre-hydration the day before….

Thomas is in year 3 and loves playing foursquare at lunch with his friends. He also has CF and requires regular tune-ups of 2 weeks IV antibiotics and physiotherapy…..

MaryKate is an 8 month old and the youngest of 5 children.  She has poor oral feeding due to a complex medical background and requires nasogastric top-ups. Her parents have been told that she could wean from the tube if she participated in an intensive multidisciplinary program but are reluctant to attend hospital due to the significant disruption on family routine…..  

Is there a way Elise could enjoy her birthday at home, Thomas stay active at school and MaryKate receive the treatment she needs without significant family disruption?

What is Hospital in the Home?

Hospital in the Home (HITH) refers to hospital level care provided in the home environment. 

As we look at managing our growing population with a fixed number of hospital beds this is one area of healthcare that is set to boom!  

When admitted to HITH, clinicians visit the home and provide the acute care interventions required in 1-2 visits per day.  The advantages of this model of care on hospital flow and access are readily apparent.  Less obvious, although equally critical, are the substantial benefits for the family and patient.  Being treated in a safe place surrounded by familiar faces eases the stress and anxiety experienced by the child. Cost-savings for families obviously include not having to fork out for travel and hospital parking, but the real cost-savings occur for families because both parents no longer have to take carers leave – one for the hospitalized child, the other for the siblings. On average, HITH ends up being one-third of the cost of hospitalization for families1. In addition, HITH avoids disruption to family routines and unwanted separation.

So what can Hospital in the Home do?

Pretty much anything!  As long as the patient is clinically stable (not heading for ICU) and can have their care needs delivered in up to 2 visits per day, then it can be done.  

Traditionally Hospital in the Home models have centred around IV antibiotics and little else, but that has dramatically changed over the past few years. 

Here are some of the common things that paediatric HITHs are currently doing2:

  • Diabetes education
  • Eczema dressings
  • Subcutaneous infusions
  • Chemotherapy
  • Pre and post-hydration for chemotherapy
  • TPN hook ons and hook offs
  • Wound dressings
  • NG feed support
  • Cardiac monitoring
  • CF tunes ups
  • Physiotherapy 
  • IV antibiotics 

Baseline criteria regarding distance from hospital and safety of home environment exist but solutions exist for almost situations.

Although most centres service a certain distance from hospital, care can often be outsourced for children who live more rurally.  The care continues to be managed by the tertiary hospital but provided by local care teams – a superb option.

In cases where a barrier exists for staff to enter the home, creative solutions can be found by meeting children at school, in parks or family member’s homes.  

What has changed with Covid-19?

Whilst paediatric hospitals in general saw a fall in patient presentations, HITH referrals have sky-rocketed.  Doctors and families have experienced renewed interest in moving vulnerable patients out of hospital walls and away from the potential of cross-infection.  Stricter visitor restrictions meant hospitalisation had an even greater impact on family life and the driver to manage care at home wherever possible has grown.

Most of this growth has been through increasing the proportion of eligible children referred rather than creating new pathways.  A couple of children have been admitted for observation of Covid-19 infection, but these cases have been few and far between.

However, as with every area of healthcare delivery, the biggest changes for HITH have been moving with the technology.  Education visits, medical and nursing reviews and physiotherapy have all been converted to telehealth where safe to do so.

Vaccination for influenza was offered to all patients admitted to HITH and was accepted by 70% of eligible patients.  65% of these were being vaccinated for the first time against flu3.  In an environment where routine vaccinations have been falling4, this is a powerful demonstration of the opportunities that exist within HITH.

Infants with bronchiolitis have been managed through HITH before5 but the care pathway has never stuck due to barriers accessing cylinders on the same day and clinician confidence.  A new model has been rolled out overcoming these barriers through utilising oxygen concentrators and remote monitoring.

With time, our use of remote monitoring and ability to feed vital signs directly into the Electronic Medical Record, will allow massive expansion of HITH services.   Predictive modelling from large EMR datasets will allow more accurate prediction of which children are likely to be safely transferred to the home environment.  Realtime data and predictive modelling will enhance clinician and family confidence and enable us to fully realise the benefits of HITH to hospitals and families.  

So what about our friends Elise, Thomas and MaryKate….

Elise is able to receive her pre-hydration at home on her birthday.  She celebrates her birthday in her parent’s bed with her sister beside her, both building her new lego sets.  Her best friends visit and her mother prepares a special meal and bakes a special cake.  She is able to go to bed that night, knowing the HITH nurses will visit every day over the following week to administer her chemotherapy and post-hydration and she has avoided another week in hospital.

The HITH nurses visit Thomas daily before school to connect his longline to a Baxter antibiotic infusion. Before and after school he performs physiotherapy via telehealth.  At school, he wears his antibiotic in a backpack and can continue to play 4 square at lunch.

MaryKate is visited by the HITH dietitian and speech therapy who provide feeding advice and a regime that fits around the family routine. They can see where MaryKate sits for meals and how her meals are prepared first hand and are able to offer some helpful suggestions. The team are also able to visit MaryKate at her daycare and ensure her routine is consistent. In between visits, MaryKate is reviewed via telehealth by the allied health team.  She makes significant oral progress and by the end of 2 weeks, her tube is no longer required.

Haemolytic Uraemic Syndrome

Cite this article as:
Jennifer Watt. Haemolytic Uraemic Syndrome, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.26233

What is HUS?

Haemolytic Uraemic Syndrome is a combination of findings which involves the triad of:

  • Microangiopathic haemolytic anaemia with red blood cell fragmentation on blood film
  • Acute renal failure
  • Thrombocytopenia

 What causes HUS?

About 90% of cases follow an infection, most commonly with entero-haemorrhagic E. Coli (EHEC). Other infective causes to be considered include Shigella and Streptococcus pneumoniae.

These infections are commonly contracted by the ingestion of contaminated food or water sources. In the US and UK, E. Coli 0.157 forms part of the natural intestinal microflora of cattle and sheep, therefore infection can be caused by direct contact with animal faeces. This can take place at farms or petting zoos, or via undercooked contaminated meat or dairy products.

The other 10-15% of cases represent atypical HUS and are due to a variety of causes, which will not be discussed here.

How do children present?

In children infected with EHEC about 10-15% of them will go on to develop HUS.

The common presentation includes bloody diarrhoea +/- cramping abdominal pain, fever and/or vomiting. The average onset of HUS after development of diarrhoea is about 7-10 days, with children under the age of 5 at highest risk.

Dependent on the extent of HUS progression, children may present with pallor, oedema, lethargy, or reduced urine output.

How to approach the examination

As with any unwell child, an A to E assessment is critical to rule out any immediate, life threatening complications.

Specific attention should be paid to assessing their fluid status, especially for evidence of dehydration.

*Although they may be oedematous, it is important to assess if they are intra-vascularly dry.

Things to examine for:

  • Prolonged capillary refill time
  • Observations: Tachycardia; hypotension or hypertension
  • Are they are cool peripherally?
  • Assess fontanelle tension (if applicable)
  • Dry mucus membranes/reduced skin turgor
  • Oedema (common locations in children include lower limbs, sacral and peri-orbital)

Is there evidence of neurological sequelae?

  • Irritable/restlessness
  • Confusion
  • Reduced GCS

Key investigations to perform

A. Initial blood samples:

  • Full blood count with blood film to assess for RBC fragmentation
  • Coagulation
  • Group and Save +/- cross match if haemoglobin low
  • Biochemistry: U&Es, calcium, phosphate, magnesium, bicarbonate
  • Glucose
  • CRP
  • Liver function including albumin
  • Amylase/Lipase (hospital dependent)
  • LDH
  • Blood gas
  • Blood cultures

B. Stool MC&S + E. Coli PCR

C. Urinalysis + MC&S

How to approach the management of HUS

Management should always be discussed with your local paediatric nephrologist in order to individualise/optimise management.

This is a generalised framework for the approach to management. Treatment involves supportive therapy to allow time for the infection to clear and the HUS process to cease.

1. Fluid Management:

  • IV access
  • Assess fluid status
  • Monitor for electrolyte disturbances and correct as per local guidelines
  • Daily weight, In/Out fluid balance, close monitoring of patient observations

*Fluid rehydration should be administered cautiously and in the setting of oliguria/anuria and oedema, fluids given should not exceed insensible loss + urine output.

*Evidence has shown that children presenting to hospital with dehydration in the prodromal phase of EHEC-induced HUS have a higher risk of developing an oliguric AKI and the requirement for dialysis. The administration of isotonic fluid in this phase has shown to be nephroprotective. 

2. Hypertension:

  • Can be secondary to fluid overload or as a result of the HUS process
  • Trial of diuretics or if receiving dialysis, fluid can be offloaded
  • If unresponsive to diuretics, consider a vasodilator (For example, amlodipine/ nifedipine *hospital dependent)

3. Anaemia:

  • Target Haemoglobin: 70-100g/L
  • Avoid excessive transfusion due to the associated risk of development of hyperkalaemia or fluid overload

4. Thrombocytopenia:

  • Consideration for platelet transfusion if platelets <10 x109
  • If undergoing surgery may require platelets > 50 x 109

5. Abdominal pain/vomiting:

  • Secondary to colitis
  • Regular paracetamol for pain relief
  • Avoid opiates if possible due to constipating side effects

*NSAIDS like Ibuprofen should not be prescribed*

6. Nutrition:

  • All patients should be reviewed by a dietician
  • NG tube and feeding regime

7. Dialysis (Peritoneal Dialysis or Haemodialysis) Indications:

  • Intractable acidosis
  • Diuretic resistant fluid overload
  • Electrolyte abnormalities Hyperkalaemia
  • Symptoms of uraemia

In children with HUS, peritoneal dialysis is the preferred treatment option as it is a gentler form of dialysis.

Haemodialysis is indicated for children with severe colitis, severe electrolyte abnormalities and those with neurological complications.

 HUS Complications

  • AKI:  Oliguria/anuria; hyperkalaemia; hypertension
  • Neurological: Irritable, confusion, seizures
  • Bleeding Risk
  • Cardiac: Hypertensive cardiomyopathy/myocarditis
  • Gastrointestinal: Severe colitis with bleeding/perforation
  • Pancreatitis
  • Pulmonary oedema

Selected references

Mayer CL, Leibowitz CS, Kurosawa S and Stearns-Kurosawa DJ. Shiga Toxins and the Pathophysiology of Hemolytic Uremic Syndrome in Humans and Animals. Toxins (Basel). Nov 2012. [Cited June 2020]; 4 (11): 1261-1287. doi: 10.3390/toxins4111261

Kausman. J 517 Haemolytic uraemia syndrome. Royal Hospital for Children- Nephrology. Dec 2013. [Cited June 2020]; Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509707/

Hughes D. Management and investigation of bloody diarrhoea and haemolytic uraemic syndrome [draft].  GG&C Paediatric Guidelines- Kidney Diseases. Oct 30 2019. [Cited June 2020]; Available from: https://www.clinicalguidelines.scot.nhs.uk/ggc-paediatric-guidelines/ggc-guidelines/kidney-diseases/management-and-investigation-of-bloody-diarrhoea-and-haemolytic-uraemic-syndrome-draft/

Balestracci A et al. Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr Nephrol. 2012. [ Cited June 2020];27: 1407-1410. Doi: 10.1007/s00467-012-2158-0

Scheiring J. Andreoli SP. Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Ped Neprhrol. 2008. [Cited June 2020]; 23: 1749-1760. Doi: 10.1007/s00467-008-0935-6

Grisaru Silviu. Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovasc Dis. 2014 [Cited June 2020]; 7: 231-239. Doi: 10.2147/IJNRD.S41837.

Malaria

Cite this article as:
Phoebe Williams. Malaria, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24980

A child is brought into Emergency with fever and lethargy, having returned from visiting relatives in India over the school holidays. You work your way through the considerations of fever in a returned traveler, and within hours the lab calls to report the presence of malaria parasites evident in the blood film. What next?

 

Despite significant gains in combatting malaria over the past 100 years, the malaria parasite continues to cause significant morbidity and mortality globally, responsible for 230 million clinical infections and almost half a million deaths each year. That’s 1,100 deaths a day, of which 745 occur in children < 5 years. To put that into perspective, I write this at a time when COVID-2019 has caused 14,000 deaths: and while this is a number that will grow exponentially and is an important pandemic rightly gaining significant attention, it is worth considering that in the past fortnight alone, malaria has killed the same number of people. While we focus our efforts on a new infectious disease, it’s paramount that other major killers aren’t ignored. Historically, resource diversion from investment in new pandemics has had significant consequences – such as the measles epidemic that killed 6,000 children in the Democratic Republic of Congo in 2019, when the bulk of healthcare funding was focused on combating Ebola.

Malaria is a regressive disease – that is, one that affects the poorest people in the world the most. In this era of global connectedness, it is important that we realize that we all have a role to play in ensuring this completely preventable and treatable disease is tackled in our generation, as malaria traps entire nations in poverty through its impact on growth, development, morbidity, and mortality.

 

Transmission and Epidemiology

Malaria transmission occurs across large areas of Africa, Latin America, South Asia, Southeast Asia, the Middle East, Eastern Europe, the South Pacific and parts of the Caribbean.

Malaria in humans is caused by a protozoan parasite of the genus Plasmodium, and includes the species Plasmodium falciparum, P. vivax, P. ovale, or P. malariae. Plasmodium knowlesi (thought to be previously only capable of infecting monkeys) has also recently been documented causing death in humans in South East Asia. The parasite is transmitted either via the Anopheles mosquito or from a mother to an infant via the placenta.

Every febrile or anaemic child returning from a malaria-endemic region within the past 12 months should always be investigated for malaria, regardless of whether they have previously lived in a there (and presume themselves to be ‘immune’) or took chemoprophylaxis.

 

Clinical presentation

Malaria presents with an influenza-like syndrome, with malaise, headache, myalgia, nausea, and rigors (which may occur intermittently, and correspond to the rupture of schizonts in the erythrocytic stage of the parasite’s lifecycle).

It is important to distinguish uncomplicated malaria from severe malaria, as their treatment (and risk of morbidity and mortality) differs significantly. Severe malaria was previously considered only to occur secondary to P. falciparum, although there are increasing case reports of patients with P. vivax or P. knowlesi malaria presenting severely ill.

The definition of severe malaria is the presence of one or more of the following clinical or laboratory features:

  • impaired consciousness +/- seizures (cerebral malaria)
  • severe dehydration or hypovolaemic shock
  • clinical or metabolic acidosis
  • hypoglycaemia
  • severe anaemia (Hb < 50g/L)
  • oliguria or acute kidney injury
  • jaundice
  • a blood parasite count of >100,000/uL (indicating more than 2% of red blood cells are parasitized).

Falciparum spp.

Diagnosis

The biggest challenges in diagnosing malaria are:-

(i) thinking to test for it – as if you’re seeing a patient in a health setting like Australia or the UK where malaria is not endemic, you may well not think of it unless you’ve specifically asked for the exposure history

(ii) falsely diagnosing malaria infection as the sole cause of a child’s illness in an endemic region. The latter is a common reason that bacteraemia and other causes of meningitis are missed in regions of the world where malaria is prevalent. Many children in these settings may have a low-level parasitaemia persistently present that may not be the cause of their clinical illness, and important empiric antimicrobials or further investigations are missed.

Unfortunately, there is no one diagnostic test that can distinguish between parasitaemia causing clinical malaria, and a febrile illness due to another cause in a patient who also has asymptomatic parasitaemia.

Until recently, clinical diagnosis was the prime method of diagnosing malaria. That is, a child presenting with a constellation of symptoms predictive of malaria in a malaria-endemic region was presumptively considered to have malaria. However, to improve diagnostic accuracy and prevent the promotion of artemisinin resistance by ensuring the rational use of anti-malarial medications, parasitological diagnosis is now essential.

The gold standard diagnosis remains microscopy, if staff and facilities are available to perform this. A thick blood film allows the presence and density (percentage of parasitized erythrocytes) to be confirmed, while the thin film determines the Plasmodium species. The sensitivity and specificity of these tests are laboratory-dependant, and relies on astute scientists being familiar with the laboratory diagnosis of malaria.

Rapid diagnostic tests (RDTs) (lateral flow immunochromatographic tests, often reported as an ‘ICT’ result) are an alternative way of quickly establishing the presence of malaria. They work by detecting specific malaria antigens within 15 minutes on a card that resembles a pregnancy test. However, RDTs are less sensitive at detecting low numbers of parasitaemia (an important prognostic factor) and are also insensitive at detecting most species aside from P. falciparum. RDTs can also mislead a clinician in their diagnosis, as parasitaemia in a child living in a malaria-endemic region may not necessarily reflect infection, and other diagnoses (such as sepsis) are often missed if the diagnosis is assumed to just be malaria secondary to a positive RDT.

 

Why do some guidelines tell me I need to do three separate tests?

A single negative blood film, or negative antigen test, does not completely exclude the diagnosis of malaria due to the imperfect nature of these tests. Simultaneously, parasitaemia may be low, or antibiotics being taken for other reasons may have enough antimalarial activity to modify or suppress malaria symptoms and parasite load (this is particularly common with trimethoprim-sulfamethoxazole, tetracyclines and quinolones). A number of organizations, therefore, recommend repeating blood films with fever spikes (to correlate with schizont rupture) until a positive test is returned, or until 3 negative films are confirmed, in patients with a high pre-test probability. This is not necessary for patients in whom the diagnosis of malaria is unlikely.

Importantly, peripheral films will not identify parasites which have sequestered (such as into the placenta in malaria in pregnancy, or deep into the capillary system of the brain in severe malaria), so bear in mind that the peripheral blood smear may reflect a low parasite density relative to the true parasite burden. P falciparum, P. malariae and P. knowlesi infect mature erythrocytes so tend to exhibit higher parasite densities; while P. vivax and P. ovale infect only young erythrocytes, so the parasite density for these species tends to be lower.

Once a diagnosis of uncomplicated or severe malaria has been made and treatment commenced, serial blood smears need to be examined to monitor the parasitological response and ensure resolution of infection. If resources allow, this is usually performed daily until negative (or until day 7 if well enough for discharge prior to complete parasitaemia clearance). In severe malaria, parasite density tends to be monitored more frequently (every 12 hours during the first 2-3 days). The mean time for parasite density clearance is 48-72 hours, although prolonged clearance times may occur in malaria acquired in SE Asia.

 

Management

Uncomplicated malaria can be treated orally, provided the child can tolerate oral therapy. An artemesin-based combination therapy (artemether+lumefantrine, known by the tradename ‘Coartem’) is the treatment of choice for uncomplicated malaria, with additional considerations:

  1. For P. falciparum malaria acquired in Thailand, Vietnam, Cambodia, Laos or Myanmar: any patients with parasitaemia beyond 3 days may have P. falciparum with resistance to artemisinin-based therapy; call your friendly ID team for advice regarding other treatment options.
  2. For P. falciparum in patients being treated where ongoing malaria transmission is possible (including Northern Australia): add a single dose of primaquine to eliminate the transmissible stages of P. falciparum to prevent ongoing transmission of parasite from humans to mosquitoes. However, ensure you rule out the presence of G6PD deficiency in the patient first (in whom primaquine can cause severe haemolysis).
  3. For P. vivax and P. ovale malaria: These species can exist as dormant parasites (hypnozoites) in the liver that can reactive and result in malaria relapses, so require concurrent treatment with primaquine (again, only after G6PD deficiency has been excluded). If the patient has G6PD deficiency, once again, call your friendly ID team for subspecialist advice.

For the treatment of severe malaria, start parenteral therapy as soon as possible. Alongside managing the ABCDEFGs (particularly focusing on careful correction of fluid and glucose levels), commence parenteral Artesunate as soon as possible. For travelers from regions of Asia where resistance may be present (Thailand, Vietnam, Cambodia, Laos or Myanmar), combination therapy with IV artesunate + IV quinine is recommended (commencing each drug as quickly as they are available).

Adjunctive therapy with ceftriaxone and paracetamol is recommended, as bacteraemia is a common co-occurrence in severe malaria, and paracetamol can reduce the risk of haemolytic acute kidney injury.  Patients can switch from IV to oral treatment (with Coartem) once they have clinically improved and can tolerate oral therapy. Ideally, a FBC should be performed weekly for 4 weeks after completion of therapy to monitor for delayed haemolysis or the recrudescence of malaria parasites.

 

The Bottom Line

  • Malaria continues to kill 750 children per day, every day.
  • Always consider malaria in a febrile or anaemic child returning from a malaria-endemic country in the past 12 months.
  • The diagnosis of malaria requires parasitological confirmation (microscopy with thick and thin films, or a rapid diagnostic test); however these tests have imperfect sensitivity and specificity so may need to be repeated (with fever spikes, ideally) if you have a negative initial result in a child with a high pre-test probability.
  • Simultaneously, its important to consider dual diagnoses in children who are sick. Parasitaemia is not necessarily indicative of clinical malaria in children who are living in malaria-endemic regions and in children who present particularly unwell, malaria and bacteraemia can often coexist.
  • The most important initial aspect to management is differentiating uncomplicated from severe malaria. Oral therapy is appropriate for uncomplicated therapy, while urgent parenteral therapy is required for severe malaria.
  • Artemesinin-based therapy is the cornerstone of management for malaria.
  • With prompt diagnosis and treatment, the morbidity and mortality of malaria can be significantly diminished and outcomes are usually excellent.

 

Selected reference

Plewes, K. et al. Aceteminophen as a renoprotective adjunctive treatment in patients with severe and moderately severe Falciparum malaria: A randomized, controlled, open-label trial. Clinical Infectious Diseases; 2018; 67(7); 991-999.

Centers for Disease Control and Prevention (CDC). Malaria treatment (US) guidelines for clinicians. Atlanta, GA. Last updated: July 2018. www.cdc.gov/malaria/diagnosis_treatment/treatment.html

White, NJ. The treatment of malaria. NEJM, 1996; 335:800

World Health Organization (WHO): Malaria. Update in: International travel and health. Geneva; www.who.int/ith/en/

Malaria. In: Therapeutic guidelines, Australia. eTG complete [digital]. Melbourne: Therapeutic Guidelines Limited; 2019 Jun. <https://www.tg.org.au>

Dhiman, S. Are malaria elimination efforts on the right track? An analysis of gains achieved and challenges ahead. Infectious Diseases of Poverty; 2019; 8(14).

The World Health Organization (WHO): The World Malaria Report 2019. [Online], Available: https://www.who.int/malaria/publications/world-malaria-report-2019/en/ 

Guillain-Barre Syndrome

Cite this article as:
Aoife Fox. Guillain-Barre Syndrome, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.25051

A 2-year-old girl, Amy, attends the emergency department. Her father says that for the last 24 hours she has been refusing to walk. Prior to this, she was running amuck without difficulty. In the ED, you notice that she is now having difficulty crawling. She has no significant medical history but did have fever along with a runny nose and cough 2 weeks prior to her attendance which her parents managed with paracetamol at home.

 

What is Guillain-Barré Syndrome?

Guillain-Barré Syndrome (GBS) is a group of acute immune-mediated polyneuropathies.  It most commonly presents as an acute monophasic, paralyzing illness provoked by a preceding infection.

It is the most common cause of acute flaccid paralysis in children. The annual incidence is 0.34 to 1.34 cases per 100,000 in under the 18s, which makes it less common in children than in adults. It rarely occurs in children younger than 2 years, but when it does affect younger children because GBS is way off our radars, this can make it really tricky to diagnose. Boys are affected more often than girls.

 

What causes it?

It’s thought that an immune response cross-reacts with the myelin or axon of peripheral nerves due to molecular mimicry. Similar peptide sequences between the body’s own peptides and foreign peptides sometimes cause the immune system to get confused and attack its own tissues.  You probably knew that myasthenia gravis is due to auto-antibodies against the acetylcholine receptor but did you know that the receptor shares a 7 amino acid sequence with HSV, the herpes simplex virus? It’s thought that exposure to HSV may be the precipitant for myasthenia gravis.

Approximate 2/3 of patients give a history of an antecedent respiratory tract or GI infection. Campylobacter infection is the most commonly identified precipitant and can be demonstrated in as many as 30% of cases. Other infectious precipitants include CMV, EBV, Mycoplasma pneumoniae, and influenza-like illnesses.

Other suggested triggers include immunization, although there is no clear causal relationship several cases suggest an association, as well as one with trauma and surgery.

What about Guillain Barre and COVID?

There have been several case studies reporting GBS associated with SARS-CoV-2 during the COVID-19 pandemic. Given the small number of cases, it is unclear whether severe neurological deficits are typical features of COVID-19 associated GBS. An answer to the diagnostic conundrum of whether the respiratory compromise in COVID19-associated-GBS is due to coronavirus or muscle weakness is yet to be answered.

 

How can I recognize it?

GBS classically begins with paraesthesia in the extremities – fingers and toes –  followed by lower extremity symmetric, or modestly asymmetric, weakness that ascends up the body. In severe cases, the muscles of respiration are affected, in about 10-20% of children.

Cranial neuropathy can also occur, most commonly affecting facial nerves, causing bilateral facial weakness.

Autonomic dysfunction occurs in approximately half of children with GBS: cardiac dysrhythmias, orthostatic hypotension, hypertension, paralytic ileus, bladder dysfunction, sweating.

Physical exam typically reveals:

  • Symmetric weakness
  • Diminished or absent reflexes
  • Gait abnormalities
  • Sensory symptoms include pain, paraesthesia (reflecting nerve irritability)

Generally, children have shorter clinical courses and more complete recoveries in comparison to adults. A child’s function typically deteriorates for 2-4 weeks followed by a slow return of function over the coming weeks to months.

 

On examination, you find a quiet child who is otherwise acting appropriately. She is afebrile and the rest of her vitals are within normal limits. No bruises or rashes are observed on her skin and there is no evidence of trauma. Cardiovascular, respiratory, abdominal and ENT exams are unremarkable. Her extremities are warm and well perfused with normal pulses. There is no bony tenderness or deformities on palpation of her limbs. On neurological examination, she is moving all 4 limbs spontaneously. However, she will not bear weight or stand. Both her lower limbs are weak on exam. Her grip strength is reduced and when given a toy, it falls. Both upper and lower extremity reflexes are absent.

 

Subtypes

GBS most commonly presents in the classical way above: a mixed motor and sensory polyneuropathy with lower limb pain and ascending weakness. This is the classic Acute Inflammatory Demyelinating  Polyradiculopathy (AIDP), which accounts for 85 to 90% of cases in the developed world. But, there are a few other subtypes of GBS you should be aware of.

Acute Motor Axonal Neuropathy (AMAN), is a purely motor from of GBS, occurring mainly in Asia, Central and South America and associated with a preceding Campylobacter infection. Its clinical features are similar to AIDP, but respiratory failure is more common.

Acute Motor-Sensory Axonal Neuropathy (AMSAN) is similar to AMAN but with more sensory symptoms. The course tends to be prolonged and severe but is pretty uncommon in children.

Miller-Fisher syndrome is characterized by an external ophthalmoplegia, ataxia and muscle weakness with areflexia. It affects adults more commonly than children but should definitely be on your radar in a child presenting with cranial nerve and lower limb neurology.

 

How can it be diagnosed?

The initial diagnosis of GBS is based on the history and clinical exam – be suspicious of a child with lower limb weakness, weak reflexes and a preceding illness. Use investigations to confirm your suspicion.

CSF

CSF protein above 45mg/dL with a normal WCC count is present in 50-66% of patients in the first week after symptoms onset and ≥75% of patients in the third week. This disconnect between protein and white cells is called albuminocytologic dissociation.

Gadolinium-enhanced MRI of Spine

MRI will show contrast enhancement of the spinal nerve roots, cauda equina or cranial nerve roots. These changes aren’t specific to the GBS, but can be helpful in the correct clinical setting.

Nerve conduction studies

This is the most specific and sensitive test available for GBS, abnormal in up to 90% of cases. The test can be technically difficult in small children.

Antibodies

Antibodies against GQ1b (the ganglioside component of a nerve) are present in the vast majority of patients with Miller-Fisher syndrome.

 

In the emergency department, you send baseline bloods (FBC, U&E, LFTs and CRP) which are all normal and organize a CT head under sedation which is unremarkable. After getting consent from her parents you perform a lumbar puncture. The CSF appears clear. It has no red blood cells, 2 white blood cells and CSF glucose is within the normal limits but her protein is mildly elevated. No organisms were seen on gram stain and cultures had no growth after 5-days. You refer her to the neurology team for further investigation.

 

What else could it be?

The differential diagnosis of GBS is long.

 

Brain

  • Bilateral strokes
  • Acute disseminated encephalomyelitis
  • Acute cerebellar ataxia syndrome
  • Psychogenic symptoms

Spine

  • Anterior spinal artery syndrome
  • Compressive myelopathy
  • Transverse myelitis
  • Poliomyelitis
  • Infectious causes of acute myelitis

Peripheral nervous system

  • Chronic inflammatory demyelinating polyneuropathy
  • Critical illness polyneuropathy
  • Infection-related radiculitis (e.g. HIV, CMV, Lyme disease)
  • Thiamine deficiency
  • Toxins: biologic toxins (diphtheria), heavy metals (arsenic)
  • Vasculitis
  • Metabolic and electrolyte disorders (e.g. hypoglycaemia, hypophosphatemia)

Neuromuscular junction

  • Botulism
  • Myasthenia gravis
  • Neuromuscular blocking agents

Muscle

  • Acute inflammatory myopathies (e.g. dermatomyositis, polymyositis)
  • Acute viral myositis
  • Acute rhabdomyolysis
  • Critical illness myopathy
  • Metabolic myopathies (e.g. hypokalaemia, hyperkalaemia)
  • Mitochondrial myopathies

 

What is the treatment?

The mainstay of treatment is supportive management including close monitoring of motor, autonomic and respiratory function as well as pain management and prevention of immobility complications, such as pressure ulcers. ICU admission for mechanical ventilation will be required in 10-20% of kids. This is more likely to be needed in children with:

  • rapidly increasing weakness,
  • bulbar dysfunction,
  • bilateral facial weakness or

In addition IV immunoglobulin (IVIG) and plasmapheresis (plasma exchange) can be used in children with severe, progressive GBS (i.e. worsening respiratory status or need for mechanical ventilation, rapidly progressing weakness, inability to walk unaided or significant bulbar weakness).

IVIG  is typically preferred to plasmapheresis in children due to its better safety record and ease of administration

Plasmapheresis can be useful in bigger children where technically it is more feasible to perform. However, there are no reliable studies to suggest one has better efficacy than the other in children.

 

During her admission, Amy has a Gadolinium-enhanced MRI of the spine and nerve conduction studies which are consistent with the acute inflammatory demyelinating polyradiculopathy (ADIP) subtype of GBS. She is given IVIG. She does not develop any respiratory complications. On discharge after three weeks, her weakness is greatly improved and completely resolves over the next two months.

 

Bottom line

  • Clinical examination is key – do not forget to examine reflexes!
  • Always ask about recent viral illnesses.
  • GBS is the most common cause of acute flaccid paralysis in children and 10-20% will require mechanical ventilation.

 

Selected references

Bloch SA, Akhavan M, Avarello J. Weakness and the Inability to Ambulate in a 14-Month-Old Female: A Case Report and Concise Review of Guillain-Barre Syndrome. Case Rep Emerg Med [Internet]. 2013 [cited 2020 Apr 11];2013. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572648/

 Yuki N, Hartung H-P. Guillain–Barré Syndrome. New England Journal of Medicine [Internet]. 2012 Jun 14 [cited 2020 Apr 5];366(24):2294–304. Available from: https://doi.org/10.1056/NEJMra1114525

Rudant J, Dupont A, Mikaeloff Y, Bolgert F, Coste J, Weill A. Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study. Neurology. 2018 25;91(13):e1220–7.

Hicks CW, Kay B, Worley SE, Moodley M. A clinical picture of Guillain-Barré syndrome in children in the United States. J Child Neurol. 2010 Dec;25(12):1504–10.

Dimachkie MM, Barohn RJ. Guillain-Barré Syndrome and Variants. Neurol Clin [Internet]. 2013 May [cited 2020 Apr 5];31(2):491–510. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939842/

Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. The Lancet [Internet]. 2016 Aug 13 [cited 2020 Apr 5];388(10045):717–27. Available from: https://www.sciencedirect.com/science/article/pii/S0140673616003391

Ryan MM. Pediatric Guillain-Barré syndrome. Curr Opin Pediatr. 2013 Dec;25(6):689–93.

Hughes RAC, Wijdicks EFM, Barohn R, Benson E, Cornblath DR, Hahn AF, et al. Practice parameter: Immunotherapy for Guillain–Barré syndrome. Neurology. 2003 Sep 23;61(6):736.

Acute COVID management in children – evidence summary

Cite this article as:
Michaela Waak + Cameron Graydon. Acute COVID management in children – evidence summary, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.25071

This post is a rapid review of pertinent paediatric literature regarding the management of COVID-19 disease. The papers have been reviewed by Michaela Waak and Cameron Graydon as part of the Don’t Forget the Bubbles team. This is not a systematic review, but includes relevant published online content available in the English language as of April 24th 2020. Please note some references are pre-prints, editorials or draft society documents and have not undergone peer review. This has been highlighted in the review of the article.

The review is divided into paediatric acute management, critical care management, and emerging therapies.

We will aim to add more papers as more literature becomes available. If you have suggestions for literature to add please email hello@dontforgetthebubbles.com 

Executive Summary (Updated 2nd May)

Currently, there is a paucity of data in children on optimal management because of the lower prevalence of serious cases. There are small case series’ and anecdotal reports that younger infants, medically complex and obese teenagers are at higher risk of severe disease with a possibility of genetic susceptibility. As a result of the lack of trials, only protocols for COVID-19 respiratory management and resuscitation have been published for children. The overarching principles are that best practice care should not be altered by pandemic-related concerns, other aetiologies should be looked for and broad consideration must be given to reduction in health care worker exposure.

 

Acute management

The acute management for mild and moderate respiratory illness should include home or hospital-based monitoring for clinical deterioration and for the prevention of transmission. Symptomatic and supportive care for respiratory symptoms should follow local protocols with the early consideration of a trial of prone positioning of the patient. Minimal data exists either to confirm or refute, indications or safety concerns for non-invasive respiratory support. It should be considered on an individual basis in the context of disease severity, trajectory and local resources available for protection of healthcare workers (such as negative pressure rooms, PPE) titrating to the lowest possible flow to maintain a target saturation.

Management of cutaneous, cardiac and neurological disease/complications could follow published adult evidence until paediatric published and peer-reviewed experience evolves.

There are increasing reports of cutaneous and neurological manifestations that have been hypothesised to be related to endothelial dysfunction and a hyper-coagulable state.

Additionally, reports are emerging of a constellation of findings giving a picture similar to the cardiovascular, cutaneous and gastrointestinal presentation of Kawasaki’s disease but with shock, some requiring mechanical support.  It seems to be occurring in a geographically and ethnically non-uniform distribution perhaps suggesting a genetic susceptibility. Laboratory features of raised BNP, troponin, IL-6, ferritin, d-dimers and lymphopaenia should be looked for early and consideration given to immuno-modulatory medications.  The timing of the onset of symptoms relative to positive rt-PCR and serology tests suggests an immune mediated pathophysiology – it is unsure at the moment of the exact pathophysiology but hypotheses involve direct viral effects, cytokine storm, immune complexes, abnormal T-cell or immunoglobulin responses.  The different presentations may represent a number of different immune-mediated syndromes. Treatment strategy is supportive, with consideration of immuno-modulators – some centres are treating as they would for Kawasaki’s with aspirin and IVIG.

 

Critical care management

The critical care considerations including patient and staff safety, infrastructure, patient flow, planning for PPE, and intra-and inter-hospital transfer should follow published hospital, national and international guidelines, and recommendations. Best practice care considerations for ventilated patients are of utmost importance, now more than ever, and Pediatric Acute Lung Injury Consensus Conference (PALICC) recommendations should be followed for paediatric ARDS (PARDS). This includes regular re-evaluation of the lung dynamics – which have been noted to have unexpected compliance characteristics in adults. Similar considerations apply for the neonatal critical care units where guideline summaries suggest no deviation from best-practice care especially where shared decision-making with parents is possible.

In the face of the current controversy regarding acute interventions including best practice and safety considerations surrounding resuscitation and ECLS support, national guidelines that consider international guidance statements should be followed with local best practice care support.

In the absence of sufficient data on paediatric resuscitation in positive or possible COVID-19 patients, rapid response recommendations have been formulated by the Resuscitation Council United Kingdom, American Heart Association, Advanced Paediatric Life Support, and ILCOR. ILCOR has recently published, in draft, a review of the evidence to assess which aspects of resuscitation are aerosol-generating procedures. Chest compressions, assisted ventilation, and advanced airway manoeuvres are all considered potentially aerosol-generating procedures requiring appropriate PPE, whereas defibrillation can be performed wearing droplet precautions, and most organisations suggest  covering the patient’s mouth and nose.

Paediatric extracorporeal membrane oxygenation (ECMO) for patients with COVID-19 has not been reported in the literature yet, at least two patients have been successfully weaned in Europe and form part of the ELSO registry data and increasing use in the US. It seems likely, as the pandemic progresses, that patients with indications for ECMO may also have COVID-19 infection. It is not known how this might impact upon ECMO outcomes. ELSO recommends standardisation of indications, management, data collection, and containment and consideration of ECMO support for refractory ARDS or sepsis on a case-by-case basis with consideration for capacity and resource availability.

 

Emerging Therapies

Emerging therapies include convalescent plasma, IVIG, antivirals (eg remdesivir), chloroquines, and selective cytokine blockade (eg Tocilizumab), and are currently undergoing rapid review. The pace of change and the paucity of data may mean that potential treatments and management strategies could outpace current paradigms for research and development. Novel management and data collection should be conducted in the setting of best practice trials. If relevant clinical trials are available nationally or internationally, strong consideration should be given to enrolling patients rather than prescribing off-label use.

References

PICU COVID data

First authorLast authorJournalDate of PublicationPaper link
S Balasubramanian A V RamananINDIAN PEDIATRICS 7 May 2020https://indianpediatrics.net/CONVID29.03.2020/SA-00159.pdf
Ye, Y Guyatt, G H CMAJ4 May 2020https://www.cmaj.ca/content/cmaj/early/2020/05/04/cmaj.200648.full.pdf
Al GiwaProbst, M AEB medicine3 May 2020https://www.ebmedicine.net/topics/infectious-disease/COVID-19
Health Policy TeamRCPCHRCPCH website1 May 2020https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf
van den Berg, JTerheggen, UESPNIC online28 Apr 2020https://espnic-online.org/Media/Files/ESPNIC-ESPR-COVID19-Transport-Consensus-recommendations-040420202
Lynch, JSultan, SIDSA guidelines website27 Apr 2020https://www.idsociety.org/practice-guideline/covid-19-guideline-infection-prevention/
Joseph, T Moslehi, M AInternational pulmonologist’s consensus group on COVID26 Apr 2020https://www.unah.edu.hn/dmsdocument/9674-consenso-internacional-de-neumologos-sobre-covid-19-version-ingles
Marini, J JGattinoni, LJAMA24 Apr 2020https://jamanetwork.com/journals/jama/fullarticle/2765302
Shen, K-LWang, X-FWorld Journal of Pediatrics24 Apr 2020https://link.springer.com/article/10.1007/s12519-020-00362-4
Cstagnoli, RLicari, AJAMA Pediatrics22 Apr 2020https://jamanetwork.com/journals/jamapediatrics/fullarticle/2765169
K ChiotisMM NakamuraJ Pediatric Infect Dis Soc22 Apr 2020https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa045/5823622
Yuki, KKoutsogiannaki, SClin Immunol20 Apr 2020https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169933/
Chiotos, K.Nakamura, MJ Pediatric Infect Dis Soc18 Apr 2020https://academic.oup.com/jpids/article-pdf/doi/10.1093/jpids/piaa045/33112599/piaa045.pdf
APLS AustraliaRetrieved from the APLS Australia website14 Apr 2020https://apls.org.au/sites/default/files/uploadedfiles/APLS%20Australia%20Statement%20on%20Paediatric%20Resuscitation%20during%20the%20COVID-19%20pandemic%20v1.0.pdf
Matava, CTFiadjoe, JEAnesthesia & Analgesia13 Apr 2020https://journals.lww.com/anesthesia-analgesia/Abstract/publishahead/Pediatric_Airway_Management_in_COVID_19_patients__.95683.aspx
Matthai, J Sobhan, PIndian Pediatr. 12 Apr 2020https://indianpediatrics.net/CONVID29.03.2020/SA-00162.pdf
MatthaiSobhanInd Pediatrics12 Apr 2020https://www.ncbi.nlm.nih.gov/pubmed/32279064
Mimouni, FMendlovic, JJournal of Perinatology10 Apr 2020https://www.nature.com/articles/s41372-020-0665-6
Morray, B. H.Sathanandam, S. K.J Invasive Cardiol9 Apr 2020https://www.invasivecardiology.com/sites/invasivecardiology.com/files/articles/images/Morray%202020%20Apr%209%20AOP%20wm.pdf
MorraySathanandam J Invasive Cardiol9 Apr 2020https://www.invasivecardiology.com/articles/resource-allocation-and-decision-making-pediatric-and-congenital-cardiac-catheterization-during-novel-coronavirus-sars-cov-2-covid-19-pandemic-us-multi-institutional-perspective
BalasubramanianRamananInd Pediatrics9 Apr 2020https://www.ncbi.nlm.nih.gov/pubmed/32273490
Edelson, DTopjian, ACirculation9 Apr 2020https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047463
Thampi, SOng, JPaediatr Anaesth8 Apr 2020https://onlinelibrary.wiley.com/doi/epdf/10.1111/pan.13863
Phua, JDu, BLancet Resp Med6 Apr 2020https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30161-2.pdf
Ashokka, BChoolani, MAmerican Journal of Obstetrics and Gynecology3 Apr 2020https://www.ajog.org/article/S0002-9378(20)30430-0/fulltext
AshokkaChoolaniAm J Obs & Gyn3 Apr 2020https://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930430-0
Wilson, KRello, J American Thoracic Society3 Apr 2020https://www.thoracic.org/professionals/clinical-resources/disease-related-resources/covid-19-guidance.pdf
Misra, D. PZimba, O.Clin Rheumatol 202031 Mar 2020https://link.springer.com/article/10.1007/s10067-020-05073-9
DP MisraO ZimbaClin Rheum31 Mar 2020https://link.springer.com/article/10.1007%2Fs10067-020-05073-9#author-information
Hasan, AFergie, JCureus31 Mar 2020https://www.cureus.com/articles/29784-coronavirus-disease-covid-19-and-pediatric-patients-a-review-of-epidemiology-symptomatology-laboratory-and-imaging-results-to-guide-the-development-of-a-management-algorithm
Cooper, KPerkins, GD International Liaison Committee on Resuscitation (ILCOR)30 Mar 2020https://costr.ilcor.org/document/covid-19-infection-risk-to-rescuers-from-patients-in-cardiac-arrest
Chandrasekharan, PLakshminrusimha, SAmerican Journal of Perinatology30 Mar 2020https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0040-1709688.pdf
Cook, T MHiggs, AAnaesthesia27 Mar 2020https://onlinelibrary.wiley.com/doi/full/10.1111/anae.15054
Ford, NDoherty, MJIAS26 Mar 2020https://onlinelibrary.wiley.com/doi/epdf/10.1002/jia2.25489
Mimouni Mendlovic J Perinatology25 Mar 2020https://www.nature.com/articles/s41372-020-0665-6.pdf
Al Giwa, LLBDuca, AEmerg Med Pract24 Mar 2020https://www.ebmedicine.net/topics/infectious-disease/COVID-19
Kneyber, MRimsensberger, PEuropean Society for Paediatric and Neonatal Intensive Care23 Mar 2020https://scp.com.co/wp-content/uploads/2020/04/2020-ESPNIC-PEMVECC-COVID-19-practice-recommendations.pdf.pdf
Molloy, EBearer, CFPediatric Research23 Mar 2020https://www.nature.com/articles/s41390-020-0881-y_reference.pdf
Wang, YZhu, L-QWorld Journal of Pediatrics 12 Mar 2020https://link.springer.com/content/pdf/10.1007/s12519-020-00353-5.pdf
Shen, K-LYang, K-LWorld Journal of Pediatrics5 Feb 2020https://link.springer.com/content/pdf/10.1007/s12519-020-00344-6.pdf

Critical care management

Ziehr DR, Alladina J, Petri CR, et al. Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study [published online ahead of print, 2020 Apr 29]. Am J Respir Crit Care Med. 2020;10.1164/rccm.202004-1163LE. doi:10.1164/rccm.202004-1163LE

Boston group peer reviewed publication of a retrospective case series (66 patients intubated during March 11-30). Description of the hospital recommendations included not to use high-flow nasal cannula or non-invasive ventilation, favouring volume-cycled ventilation with a target tidal volume below 6 cc/kg ideal body weight. Early prone ventilation was promoted for patients with a P/F ratio <200 and PEEP was titrated as per ARDSnet table, titration by best compliance, or oesophageal manometry. 85% of patients met the Berlin definition of ARDS. They conclude that their findings differ from earlier series describing near-normal respiratory system compliance and lack of recruitability in early presentations of COVID-19 respiratory failure. Their cohort was managed with established ARDS therapies including low tidal volume ventilation, conservative fluid administration, and prone ventilation. Minimum follow-up was 30 days, overall mortality was 16.7% and most patients were successfully extubated and discharged from the ICU.

 

Marini JJ, Gattinoni L. Management of COVID-19 Respiratory Distress. JAMA. Published online April 24, 2020. doi:10.1001/jama.2

Expert opinion paper on ARDS by two Italian authors. The concept of two phenotypes, the traditional “baby lung” classic ARDS pathophysiology versus CARDS with “type L” and high compliance and “type H” with low compliance is described. The table contains suggestions for respiratory management at different time periods (before intubation, during mechanical ventilation, after intubation and weaning phase). These hypotheses have been debated in the literature – based on findings by the Boston group, published as a cohort study by the American Thoracic Society – suggests that management should follow published ARDS management strategies and diagnostic criteria.  Discussion around the Boston cohort has included that they may be patients presenting later in their disease process.

 

Chandrasekharan P et al (April 8, 2020), Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected or Confirmed SARS-CoV-2 Infection., American Journal of Perinatology, https://doi.org/ 10.1055/s-0040-1709688. ISSN 0735-1631.

This peer-reviewed and published guideline summary article has been authored by international neonatologists (US and Europe).

It outlines the precautions and steps to be taken before, during, and after resuscitation of a newborn born to a COVID-19 mother. Three optional variations of current standards are proposed and involve shared decision making with parents for perinatal management, resuscitation of the newborn, disposition, nutrition, and post-discharge care. The authors highlight that availability of resources may also drive the application of these guidelines.

Key points involve:

  • Unclear risk of vertical transmission (transmission from family members/providers to neonates is possible).
  • Importance of appropriate PPE (airborne vs. droplet/contact precautions for providers to prevent transmission)
  • Parent engagement (shared decision-making: options for rooming-in, skin-to-skin contact, and breastfeeding)

This summary article highlights the key features of current recommendations including options when shared decision making is possible, the tables and diagrams add to the practical scenarios.

 

Edelson et al. Interim Guidance for Life Support for COVID-19. From the Emergency Cardiovascular Care Committee and Get With the Guidelines®-Resuscitation Adult and Pediatric Task Forces of the American Heart Association in Collaboration with the American Academy of Pediatrics, American Association for Respiratory Care, American College of Emergency Physicians, The Society of Critical Care Anesthesiologists, and American Society of Anesthesiologists: Supporting Organizations: American Association of Critical Care Nurses and National EMS Physicians, Originally published 9 Apr 2020 https://doi.org/10.1161/CIRCULATIONAHA.120.047463

This publication contains interim guidance on resuscitation for COVID19 suspected or positive patients including in the paediatric and neonatal setting. It is produced by the AHA in collaboration with several other American societies. General principles include the provision of best practice care balanced with reduction in provider exposure. The main considerations include donning of appropriate PPE before entering the scene and limiting personnel, prioritization of oxygenation and ventilation strategies with lower aerosolization risk (including the application of viral filters) and person-centered consideration of the appropriateness of starting and continuing resuscitation (goals of care for the individual patient).

Specific considerations are given for children and neonates. In cases of out of hospital cardiac arrest – lay rescuers of children should perform chest compressions and consider mouth to mouth ventilation if willing and able, especially if the household members have been exposed to the victim at home. If a face mask is available, it can be placed on the victim or the rescuer if bystanders are unable or unwilling to perform mouth-to-mouth. 

Neonatal resuscitations – Routine initial care, avoid suctioning of the airway. Endotracheal medications such as surfactant and epinephrine (adrenaline) are considered aerosol-generating procedures. Intravenous delivery of epinephrine via a low-lying umbilical venous catheter is the preferred route of administration during neonatal resuscitation.

The provided figures and tables complement this concise guidance statement and are well worth the read for any acute care provider.

 

Couper K et al, COVID-19 infection risk to rescuers from patients in cardiac arrest; on behalf of the International Liaison Committee on Resuscitation. International Liaison Committee on Resuscitation. 2020. “COVID-19 Infection Risk to Rescuers from Patients in Cardiac Arrest.” https://costr.ilcor.org/document/covid-19-infection-risk-to-rescuers-from-patients-in-cardiac-arrest. Draft version accessed 12th April 2020

This document contains the ILCOR Draft Treatment Recommendations in the pre-published form.

The main suggestions read:

  • We suggest that chest compressions and cardiopulmonary resuscitation have the potential to generate aerosols (weak recommendation, very low certainty evidence)
  • We suggest that in the current COVID-19 pandemic lay rescuers consider chest compressions and public access defibrillation (good practice statement).
  • We suggest that in the current COVID-19 pandemic, lay rescuers who are willing, trained and able to do so, consider providing rescue breaths to infants and children in addition to chest compressions (good practice statement).
  • We suggest that in the current COVID-19 pandemic, healthcare professionals should use personal protective equipment for aerosol-generating procedures during resuscitation (weak recommendation, very low certainty evidence).
  • We suggest it may be reasonable for healthcare providers to consider defibrillation before donning personal protective equipment for aerosol-generating procedures in situations where the provider assesses the benefits may exceed the risks (good practice statement).

 

APLS Australia,   Statement    on    Paediatric    Resuscitation    during    the    COVID-19    Pandemic, retrieved from the APLS Australia website on 14th April 2020

APLS Australia has released recommendations that are consistent with ANZCOR and ILCOR guidelines. 

While recognising the concerns of health care providers regarding the risk of transmission of coronavirus they stress the importance any delays have to outcomes. Risk to rescuers is increased (chest compressions and positive pressure ventilation have the potential to generate aerosols) but the underlying principles for CPR remain unchanged. They stress that efforts to anticipate deterioration will allow opportunity for early PPE donning in order to minimise delays.

They also recognise that healthcare systems will need to consider: availability and distribution of appropriate PPE; education of the workforce in appropriate PPE donning and disposal techniques; appropriate resources and personnel to provide on-going care for children resuscitated after cardiac arrest; paediatric resus simulation in the local environments; and for staff to become familiar with and adhere to local guidelines which describe the PPE that should be worn for aerosol generating procedures. 

 Treatment recommendations are given for three situations: 

Out-of-hospital recommendations: 

  • Health care professionals and lay rescuers who are willing, trained and able to do so, should continue to deliver rescue breaths to children in addition to chest compressions.  
  • If rescuers are untrained or unwilling to perform rescue breaths, chest compression only CPR is preferable to no CPR. 

ALS in hospital recommendations:

  • Healthcare professionals should use PPE for aerosol-generating procedures during resuscitation in children with confirmed or suspected COVID 19 infection.  
  • People in the room should be minimised consistent with appropriate care.  
  • Risk associated with aerosol-generating procedures (AGPs) should (where practical) be minimised by:  
    1. Addition of viral filters on all airway devices (BVM, SGA, ETT) where available 
    2. Preferentially allocating the most experienced clinician to manage the airway 
    3. Recognising that a cuffed endotracheal tube (ETT) is preferable to a supraglottic airway (LMA or I-Gel), which is preferable to bag-valve-mask (BVM) ventilation (optimally using a two-person technique, with an oropharyngeal airway, to minimise leak) to minimise aerosol production 
    4. Healthcare professionals should anticipate potential clinical deterioration in high risk patients and don appropriate PPE in preparation for resuscitation 

 Pre-hospital and Rapid Response Teams recommendations: 

  • Use PPE for aerosol-generating procedures during resuscitation in children with confirmed or suspected COVID 19 infection. 
  • To don appropriate PPE prior to arrival at the scene in anticipation of the need to perform aerosol generating procedures during resuscitation.  
  • For early communication with the teams to where they are transferring the patients to allow them to prepare and use appropriate PPE. 

 

Kevin C. Wilson, Sanjay H. Chotirmall, Chunxue Bai, and Jordi Rello on behalf of the International Task Force on COVID‐19.  COVID‐19: Interim Guidance on Management Pending Empirical Evidence, From an American Thoracic Society‐led International Task Force.

The American Thoracic Society convened an international group of experts to develop Consensus on Science with Treatment Recommendations (CoSTR) in the absence of high-grade evidence as of 3rd April.  These recommendations are published as an open-access document on the ATS website.

The main suggestions refer to ARDS rescue management interventions:

  • prone positioning in patients with refractory hypoxemia and COVID-19 pneumonia (i.e. acute respiratory distress syndrome [ARDS])
  • consideration for extracorporeal membrane oxygenation (ECMO) in patients who have refractory hypoxemia, COVID-19 pneumonia (i.e. ARDS), and have failed prone ventilation, and
  • to prescribe hydroxychloroquine (or chloroquine) to hospitalized patients with COVID-19 pneumonia if all of the following apply: a) shared decision-making is possible, b) data can be collected for interim comparisons of patients who received hydroxychloroquine (or chloroquine) versus those who did not, c) the illness is sufficiently severe to warrant investigational therapy, and d) the drug is not in short supply

While referencing adult patients, consideration should be given to the broader applicability of adult recommendations, particularly to our young adult patients.

 

Practice recommendations for the management of children with suspected or proven COVID-19 infections; Paediatric Mechanical Ventilation Consensus Conference (PEMVECC) Section Respiratory Failure – European Society for Paediatric and Neonatal Intensive Care

This consensus statement issued by the European Society for Paediatric and Neonatal Intensive Care in March 2020 is published through the ESPNIC COVID-19 resource webpage.

This is a pragmatic and very useful guide for clinicians caring for COVID-19 positive children with respiratory symptoms.

Main recommendations include:

  • Monitoring respiratory failure severity by the SpO2/FiO2 ratio for noninvasive ventilation; oxygenation index for invasive ventilation.
  • The definition of paediatric ARDS remains unchanged, recommendations for non-invasive and invasive ventilation initiation and settings and PARDS management recommendations including for neuromuscular blockade, prone positioning, escalation of therapies for refractory hypoxemia and caring for the invasively ventilated child are highlighted.

Of note: These recommendations do not suggest deviation from best-practice care as per previously published PALICC guidelines. In fact, critically appraising the data coming from adult practice, before making use of these in paediatric practice is strongly recommended.

 

Jason Phua et al (April 6,2020), Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations, Lancet Respir Med 2020, https://doi.org/10.1016/S2213-2600(20)30161-2

This is a summary article published for the Asian Critical Care Clinical Trials Group. It highlights the epidemiological and clinical features of critically ill COVID-19 patients as of April 2nd, 2020 and emphasizes the evolving case fatality rate in adults of 5.2% compared to 9.6% for SARS and 34.4% for MERS.

Key recommendations include that clinicians should have a high index of suspicion, and a low threshold for diagnostic testing, for COVID-19 as clinical features are non-specific. They should cautiously evaluate unanswered clinical management questions, including the role of non-invasive ventilation, high-flow nasal cannula, corticosteroids, and various repurposed and experimental therapies.

Surge options and preparations are highlighted as important. These include optimizing infrastructure, supplies, staff protection from nosocomial transmission and the promotion of mental wellbeing. Table 3 focuses on evolving therapies and highlights the general lack of peer-reviewed published safety data.

Even though it is mainly based on adult data and authored by the Asian trials group, this article highlights important management and safety considerations for the paediatric setting.

 

Acute management

Shen KL, Yang YH, Jiang RM, et al. Updated diagnosis, treatment and prevention of COVID-19 in children: experts’ consensus statement (condensed version of the second edition) [published online ahead of print, 2020 Apr 24]. World J Pediatr. 2020;1‐8. doi:10.1007/s12519-020-00362-4

Peer reviewed and published paper summarising the chinese guidelines for management of children with COVID-19 disease authored by 30 Chinese experts from 11 national medical academic institutions. Epidemiology is summarised and case definitions clarified. Early warning signs of more severe cases are specified (increased respiratory rate, persistent high fever, lethargy, decreased blood lymphozytes, increased liver enzymes, metabolic acidosis, increased D-dimers, desaturation, extrapulmonary complications, co-infection with other viruses/bacteria). Glucocorticosteroids are recommended for 5 days for severe ARDS. Other treatments including antivirals and convalescent plasma are recommended only as part of clinical trials.

 

Lynch J, Sultan S. Infectious Diseases Society of America Guidelines on Infection Prevention in Patients with Suspected or Known COVID-19; Published by IDSA, 4/27/2020, posted online at www.idsociety.org/COVID19guidelines/ip

This guideline by an American MDT expert panel will be updated online. It contains an executive summary, background, definitions and recommendations based on a literature review and expert consensus on the use of PPE for HCP providing care for patients with suspected or known COVID-19. Recommendations on use of N95 masks and respirators, shoe covers, double vs single glove, face shields and surgical masks. The algorithm provided shows a clear process of what PPE to use in which settings and use either a surgical mask or N95 (or N99 or PAPR) respirator as part of appropriate PPE depending on the procedure related risks.

 

Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A, Higgs A. Consensus guidelines for managing the airway in patients with COVID-19: Guidelines from the Difficult Airway Society, the Association of Anaesthetists the Intensive Care Society, the Faculty of Intensive Care Medicine and the Royal College of Anaesthetists. Anaesthesia. 2020;75(6):785‐799. doi:10.1111/anae.15054
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This peer reviewed published article by a UK anaesthetic expert group aims to provide clinicians with figures and text to be adapted locally for safe provision of airway management in patients with COVID-19 disease drawing on published literature and immediately available information from clinicians and experts. Topics covered include the prevention of contamination of healthcare workers, the choice of staff involved in airway management, the training required, and the selection of equipment namely for emergency tracheal intubation; predicted or unexpected difficult tracheal intubation; cardiac arrest, anaesthetic care; and tracheal extubation. The overarching principle suggested is SAS – safe (for staff and patient), accurate (avoid unreliable, unfamiliar or repeated technique) and swift (timely, without rush or delay). The flowcharts, figures, photos and diagrams provided summarise and highlight the crucial principles and practical suggestions. The panel agreed on eight recommendations and provided narrative summaries of other interventions undergoing evaluations.

 

Castagnoli R, Votto M, Licari A, et al. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review. JAMA Pediatr. Published online April 22, 2020. doi:10.1001/jamapediatrics.2020.1467

This published and peer reviewed paper from a respected Italian group is a systematic review that assesses and summarises clinical features and management of children with SARS-CoV-2 infection. They included eighteen studies with 1065 participants that reflected research performed in China, except for 1 clinical case in Singapore. Mild respiratory symptoms (fever, dry cough, and fatigue) or asymptomatic children were most commonly described. CXR or CT showed bronchial thickening and ground-glass opacities, and these findings were also reported in asymptomatic patients. No deaths were reported in children aged 0 to 9 years. Available data about therapies were limited. Antibiotics and supportive care were most commonly described, most patients did not require oxygen therapy. They conclude that many therapeutic questions in children with COVID-19 remain unanswered, so in the interim, paediatric knowledge stems from the management of other respiratory infectious diseases.

 

van den Berg J, Terheggen U. European consensus recommendations for neonatal and paediatric retrievals of positive or suspected COVID-19 infants and children, European Society of Paediatric and Neonatal Intensive Care (ESPNIC)

This expert statement published on the ESPNIC website and endorsed by the European society of paediatric research (ESPR) describes procedures and precautions for safe retrievals of infants and children with confirmed or suspected COVID-19. Keypoints include case definitions, PPE suggestions, Airway management, respiratory support recommendations, special considerations for neonates and parents and decontamination recommendations for the transport vehicle.

The summary recommendations regarding respiratory support read:

  • “Use high-efficiency particulate air (HEPA) filters on expiratory and inspiratory hose of ventilator
  • NIV including CPAP and HFNC increases risk of aerosol spread of viral particles
  • Use any form of NIV with caution, if so, best provided by a ventilator with filters / closed circuits systems and under full PPE
  • Consider early intubation

 

The Royal College of Paedaitrics and Child Health publish guidelines on management of ” Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19 (PMISTAC)

This guidance document published on the Royal College of Paediatrics and Child Health website provides the first case definition and recommendation document raising awareness to clinicians and has been developed after expert review of the cases. In rare instances children that test positive for COVID-19 can present with a multisystem inflammatory syndrome that shows features of Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndromes. Early recognition by paediatricians and specialist referral including to critical care is essential. A clinical management summary is provided and includes health care worker protection, early management, monitoring, and general treatment principles. An MDT approach involving PICU and paediatric infectious diseases, immunology, rheumatology is suggested. Candidate antiviral therapies should only be given in the context of a clinical trial if available (e.g. RECOVERY trial) and all children should be considered for recruitment in research studies such as DIAMONDS and ISARIC-CCP. Any child being considered for antiviral therapy should be discussed at an MDT, Immunomodulatory therapy should be discussed with paediatric ID and/or clinicians with appropriate experience in their use (e.g. rheumatology, immunology, haematology) on a case by case basis and used in the context of a trial if eligible and available.

 

Ye, G Guyatt . Treatment of patients with non severe and severe coronavirus disease 2019: an evidence based guideline. CMAJ 2020.doi: 10.1503/cmaj.200648; early-released April 29, 2020

Published and peer reviewed paper from an international expert panel that included two consumers concludes:

“Given the largely very low-quality evidence regarding benefits of the treatments that the panel considered, and given the panel’s inferences regarding patient values and preferences, the panel made almost exclusively weak recommendations against use of the interventions included in this guideline. The research community should interpret the weak recommendations that this guideline offers as a call to urgently undertake rigorous RCTs of the candidate interventions.” It is designed as a “living guideline” that is updated as evidence evolves.”

In summary current recommendations read:

  • Available evidence is either indirect (from studies of influenza, severe acute respiratory syndrome and Middle East Respiratory Syndrome), from observational studies, or RCTs limited in sample size and rigour, permitting only weak recommendations and very large uncertainty.
  • The panel made only 1 weak recommendation in favour of treatment: use of corticosteroids in patients with acute respiratory distress syndrome (ARDS), based on indirect evidence.
  • The panel made weak recommendations against use of corticosteroids in patients without ARDS, against use of convalescent plasma and against several antiviral drugs that have been suggested as potential treatments for COVID-19.
  • Rigorous randomised trials are urgently needed to establish the benefits and risk of candidate interventions.

 

Giwa AL, Desai A, Duca A. Novel 2019 coronavirus SARS-CoV-2 (COVID-19): An updated overview for emergency clinicians. Emerg Med Pract. 2020;22(5):1‐28.

This is a second updated paper from Giwa et al. – authors in Italy and New York.  While some of the information is already out of date it gives an excellent and comprehensive summary of pathology, infection control management, evaluation, imaging and treatment options.

 

Balasubramanian et al. Coronavirus Disease (COVID-19) in Children – What We Know So Far and What We Do Not? INDIAN PEDIATRICS; APRIL 09, 2020 [E-PUB AHEAD OF PRINT]

Literature Review published in the Indian Journal of Pediatrics

Summary findings:

Pediatric COVID-19 infection usually mild or asymptomatic and with better prognosis (mortality rare)

Hypotheses of reasons for milder disease: differences in immune system function, differences in the expression/function of the cellular receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – Angiotensin converting enzyme 2 (ACE2)

COVID-19 in immunosuppressed children

No severe cases reported (may be protected by their weaker immune response), no data available on severity of COVID-19 infection in children with malnutrition, rheumatic heart disease or HIV

Children with COVID-19

Early management: supportive therapy (adequate nutrition, fluid /electrolyte management O2 supplementation, communication with parents, alleviating anxiety

Severely affected children: Respiratory management as per Pediatric Lung Injury Consensus Conference Group (PARD)

Decision to start antiviral or immunomodulatory treatment should be made carefully in consultation with experts in pediatric infectious disease and immunology and ideally as part of a trial (Hydrochloroquine only without Azitromycin, Lopinavir/Ritonavir, Tolizizumab, Anakinra)

Neonatal management (newborns of COVID-19 infected mothers):

  • Only essential personnel attending with full PPE, follow standard neonatal resuscitation measures, self-inflating mask to be used if positive pressure ventilation required,
  • newborn tested at 24 and 48 hours of life, until 2 consecutive negative tests
  • Antivirals/hydroxychloroquine/steroids or intravenous immunoglobulin (IVIG) should not be administered
  • Breastfeeding encouraged with the mother wearing a mask
  • vaccinations prior to discharge from the hospital

 

Matthai et al. for The Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition.    Coronavirus Disease (COVID-19) and the Gastrointestinal System in Children. Accessed 12 April 2020 (This is a preprint version of an article submitted for publication in Indian Pediatrics)

This is a review article pertaining to COVID and the GI system in paediatrics.

Similar to the respiratory mucosa, angiotensin converting enzyme-2 (ACE-2) receptor and transmembrane serine protease 2 (TMPRSS2) co-express in the gastrointestinal tract, which facilitates viral entry into the tissue. Less than 10% of children with infection develop diarrhea and vomiting. Prolonged rt-PCR positivity in the stool has raised the possibility of feco-oral transmission though they note that there has only been one case of active virus cultured from a stool specimen. It is unclear whether prolonged persistence of RNA in the stool is secondary to its continued positivity in bronchoalveolar sputum, even when nasopharyngeal mucosa swabs are negative.

They suggest upper GI endoscopy carries a higher risk of aerosols then lower GI endoscopy and acute upper or lower GI bleeding, esophageal obstruction, foreign body ingestion etc. may require endoscopy without delay, but should be done with full personal protection equipment including the N95 mask.

A mild rise in bilirubin and transaminases is seen in approximately 25% and more common, approximately 50% with severe disease. Consideration should be given to hypoxic and drug related liver injury (Remdesivir, Tocilizumab) aetiologies.

Available evidence is that IBD and liver transplant patients do not have an increased risk of developing Covid-19 and should stay on their immunomodulating medications. They recommend in an established COVID-19 infection, to continue calcineurin inhibitors targeting a lower trough levels and lower the dose of mycophenolate or azathioprine. Patients on high dose steroids, should have it reduced to a minimum dose based on body weight to prevent adrenal insufficiency.

Children on treatment for chronic liver diseases like Wilson disease, autoimmune hepatitis, Hepatitis B and C should continue their treatment protocols.

 

Morray BH et al. Resource Allocation and Decision Making for Pediatric and Congenital Cardiac Catheterization During the Novel Coronavirus SARS-CoV-2 (COVID-19) Pandemic: A U.S. Multi-Institutional Perspective. J Invasive Cardiol. 2020 Apr 9. pii: JIC20200409-2. [Epub ahead of print] PMID: 32269177

This article is a review of congenital cardiac catheterization practices in 56 US pediatric cardiac centers and highlighted the differences between institutions in high prevalence areas and low prevalence areas.

Noting a large decrease in activity across all centers they discuss the general approach and urgency of cases.

They classified cases in Table 3, but briefly:

1A (urgent/emergent) – haemodynamic instability

  • Pericardiocentesis; atrial septostomy for TGA; atrial septal decompression for HLHS; atrial septal decompression on ECMO; Impella (Abiomed) placement; thrombectomy for symptomatic PE with significant RV strain; coiling of AP collaterals/bronchial arteries due to hemoptysis. 1B (urgent/emergent) – to enable evaluation or discharge
  • PDA/RVOT stenting for decreased pulmonary blood flow; balloon valvuloplasty of critical or severe AS/PS; perforation of PV for PA/IVS; PDA closure in premature infants; biopsy in OHT for acute rejection; surveillance after recent OHT.

2 (semi-elective) – a delay in procedure (>30 days) could be detrimental

  • Pulmonary vein stenosis and significant RV dysfunction; heart failure and a large PDA or muscular VSD/s; increasing aortic valve/pulmonary valve gradients that already meet the threshold for intervention; venous interventions to treat occlusions/ stenoses to alleviate symptoms.

3 (elective) – can be delayed >30d

  • Secundum ASD; PDA without significant heart failure; moderate pulmonary aortic valve stenosis; pulmonary valve dysfunction awaiting pulmonary valve replacement; presurgical catheterization (pre-Fontan catheterization); routine surveillance biopsy post OHT.

There was broad consensus for delaying certain cases, and with the understanding that some cases through delay could change their relative urgency.

They recommend a local action plan should be developed for the neonate born to a positive or possible COVID mother.

They further discuss in detail the concerns in the current pandemic relating to medical resource preservation, minimizing exposure risk and resource reallocation/repurposing.

 

Thampi S et al, Special considerations for the management of COVID-19 pediatric patients in the operating room and pediatric intensive care unit in a tertiary hospital in Singapore. Paediatr Anaesth. 2020 Apr 8. doi: 10.1111/pan.13863

This article is based on a single centre experience at the National University Hospital in Singapore, a mixed adult and paediatric tertiary hospital.

General measures, as well as specific strategies in the operating rooms and paediatric intensive care unit (PICU), are presented.

PPE-related measures discussed included mask fitting and doffing/donning exercises and simulation medicine as well as powered air-purifying respirator PARP training, especially for staff who failed N95 mask fitting. With these PPE measures in place no nosocomial infections were observed. Anaesthesia considerations included a limitation on the number of accompanying adults, PPE considerations, having the most senior available operator manage the airway, the use of closed breathing systems, in-line suction and minimization of circuit disconnections as well as strict disinfection guidelines. These measures were similar in the PICU setting but also included recommendations on the use of negative pressure rooms and simulation training for emergency situations and airway management.

Limitations of this article include that it reflects accepted care in a single centre only and does not refer to the more widely accepted principle that best practice care should be provided to children during the pandemic including safe bag-mask ventilation in the event of clnical deterioration or arrest.

 

Ashokka, et al.  Care of the Pregnant Woman with COVID-19 in Labor and Delivery: Anesthesia, Emergency cesarean delivery, Differential diagnosis in the acutely ill parturient, Care of the newborn, and Protection of the healthcare personnel. 3 April 2020 (Journal Pre-proof American Journal of Obstetrics and Gynaecology) https://doi.org/10.1016/j.ajog.2020.04.005 

This is a review article with a summary of recommendations based on evidence to date.  The main recommendations:

Pertaining to staff are:

  • all healthcare staff attending to women in active labor need to don full personal protective equipment (PPE)

Pertaining care of the newborn:

  • no proven vertical transmission during pregnancy
  • possibility of acquiring the infection post-delivery

Advised against:

  • delayed cord clamping
  • skin to skin bonding between mothers and newborns

Can be considered:

  • breast feeding

Care of the unwell newborn

  • Designated NICU room with full infectious precautions

 

Mimouni et al. Mendlovic Perinatal aspects on the covid-19 pandemic: a practical resource for perinatal–neonatal specialists. Journal of Perinatology 25th Mar 2020 https://doi.org/10.1038/s41372-020-0665-6

They summarise

  • Vertical transmission from maternal infection during the third trimester probably does not occur or likely it occurs very rarely.
  • Consequences of COVID-19 infection among women during early pregnancy remain unknown.
  • We cannot conclude if pregnancy is a risk factor for more severe disease in women with COVID-19.
  • Little is known about disease severity in neonates, and from very few samples, the presence of SARS-CoV-2 has not been documented in human milk.
  • Links to websites of organizations with updated COVID-19 information are provided.
  • Infographics summarize an approach to the pregnant woman or neonate with suspected or confirmed COVID-19.

 

Al Giwa, LLB et al, Novel 2019 Coronavirus SARS-CoV-2 (COVID-19): An Updated Overview for Emergency Clinicians Publication Date March 23, 2020. Pub Med ID: 32207910

This is a peer-reviewed article dated 23rd March summarising COVID-19 data and experience from United States and Italian physicians. They provide a comprehensive review of the epidemiology, virology, pathophysiology, and management with an adult emergency department perspective.

The Italian experience in the emergency department is described – the first wave of upper airway symptoms, then patients with persistent fever and finally patients with interstitial pneumonia. Lung ultrasound was more sensitive than CXR and a useful screening tool and is discussed in some detail. Some patients presented with only gastro-intestinal symptoms and in small cohorts in California where 22% of adults and in Wuhan 40%  of children had co-infection with another virus.

Reference is made to the immunopathogenesis of COVID-19 (cytokine storm) and its implication in the rapid clinical deterioration seen. The release of inflammatory cytokines/chemokines initiates a positive feedback loop that leads to ARDS, multi-organ failure and death with histopathological features of virus-induced hemophagocytic lymphohistiocytosis. Elevated ferritin and IL-6 were associated with severe disease in adults in China.

They note the joint statement from multiple cardiology bodies highlighting there is “no clinical or scientific evidence to suggest that treatment with ACEI’s and ARB’s should be discontinued because of the COVID-19 infection.”

Even though mainly based on adult data some consideration should be given to the broader applicability in the young adult/paediatric context.

 

Hasan A, Mehmood N, Fergie J (March 31, 2020) Coronavirus Disease (COVID-19) and Pediatric Patients: A Review of Epidemiology, Symptomatology, Laboratory and Imaging Results to Guide the Development of a Management Algorithm. Cureus 12(3): e7485. doi:10.7759/cureus.7485

This is a review article from authors in the United States and has undergone peer-review.  Standard sections include epidemiology, symptomatology, imaging, labs, transmission, and a proposed management algorithm.

The algorithm recommends consideration for use of Remdesivir (which has no published in vivo data in paediatrics currently and is the subject of ongoing clinical trials) and use of procalcitonin to assess for superimposed bacterial infection (a recent systematic review by Kamat et al. did not support its use for differentiation of viral and bacterial, while a meta-analysis by Lippi suggested the higher PCT in severe COVID-19 patients might suggest bacterial infection). Serial PCTs may add to the clinical picture.

Given the limited evidence the suggestions should be taken with caution, especially in settings where clinical trials are available.

 

Matava, Clyde T, et al. On behalf of the PeDI-Collaborative Pediatric Airway Management in COVID-19 patients – Consensus Guidelines from the Society for Pediatric Anesthesia’s Pediatric Difficult Intubation Collaborative and the Canadian Pediatric Anesthesia Society, Anesthesia & Analgesia: April 13, 2020 – Volume Publish Ahead of Print – Issue – doi: 10.1213/ANE.0000000000004872  

Given challenges to medical systems and clinicians globally due to COVID-19’s rapid spread – namely clinicians required to care for patients with a highly contagious disease without evidence-based guidelines, this consensus guideline was created. The well-established and accepted nominal group technique, a structured, multistep, facilitated, group meeting technique used to generate and prioritise responses to a specific question was virtually adapted by the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from six countries, to arrive at this published and peer reviewed guideline based on expert opinion and early data about the disease. 

They are endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society 

Overarching goals during care: 

  • minimizing aerosolized respiratory secretions  
  • minimizing the number of clinicians in contact with a patient recognizing that undiagnosed asymptomatic patients may shed the virus and infect healthcare workers 

 The main recommendations are summarised here: 

  • administering anxiolytic premedications 
  • intravenous anaesthetic inductions preferred over gas inductions, but child temperament needs to be considered 
  • tracheal intubation using video laryngoscopes and cuffed endotracheal tubes
  • use of in-line suction catheters 
  • modifying workflow to recover patients from anesthesia in the operating room 
  • Anesthesiologists should consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19 
  • Airway procedures should be done in negative pressure rooms when available 
  • Adequate time should be allowed for operating room cleaning and air filtration between surgical cases 

 Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic 

 

Emerging therapies

Immune modulation (contributed by Dr Alberto Pinzon)

ANTI-CYTOKINES 

SARS-CoV-2 induced pneumonia is characterised by hyperactivation of effector T-cells and excessive production of inflammatory cytokines, particularly IL-6 (Cheng C, Zhang XR, et al. Advances in the Research of Cytokine Storm Mechanism Induced by Coronavirus Disease 2019 and the Corresponding Immunotherapies. Zhonghua Shao Shang Za Zhi:36:e005. In Chinese). Other pro-inflammatory cytokines (i.e., IL-1, TNF and IFN-g) are likely to contribute to this cytokine storm leading to progressive immunopathology, cytopaenias, plasma leakage, increased vascular permeability and disseminated intravascular coagulation. Consequently, anti-cytokine therapy has been postulated to confer protection against severe SARS-CoV-2 disease by reversing this hyperinflammatory response (Monteleone, G, Sarzi-Puttini P.C et al. Preventing COVID-19-induced pneumonia with anti-cytokine therapy. The Lancet Rheumatology.doi:10.1016/s2665-9913(20)300092-8.)

Preliminary evidence suggest that IL-6 inhibition with Tocilizumab (anti IL-6R) can reverse the detrimental inflammatory response in severe cases of SARS-CoV-2-pneumonia. An unpublished report from China including 21 patients, 17 with severe and 4 with critical illness showed that most patients had a marked improvement in oxygen requirement and CT changes within the first week of treatment.  Interestingly, all patients survived despite the severity of their disease (Xu X et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Unpublished study. 2020 [https://chinaxiv.org]). Another unpublished study in 21 Italian patients with severe SARS-CoV-2-pneumonia showed that Siltuximab (anti IL-6) was able to afford improvement in 33 % of patients while also stabilising a further 43% of patients. Nonetheless, 24% of the patients worsened, suggesting that cytokine blockade appears more effective if used earlier in the disease course (Gritti G, Raimondi F et al. Use of Siltuximab in patients with COVID-19 Pneumonia Requiring Ventilatory Support. Unpublished study. 2020 [https://www.medrxiv.org])

Multiple trials evaluating anti-cytokines and immune modulators are currently underway in Europe, the US and Asia including Tocilizumab and Sarilumab (anti-IL6R), Siltuximab (anti IL-6),Anakinra (anti-IL-1), interferon beta-1, Sirolimus as well JAK/STAT inhibitors (Baricitinib/Ruxolitinib/Tofacitinib). The use of anti-cytokines should be in the context of a randomised controlled trial and thus if a clinical trial is available, consider enrolling patients rather than prescribing off-label use.

The REMAP-CAP trial (Randomised, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) driven by the Australian and New Zealand Intensive Care Society has implemented the Pandemic Appendix to the Core protocol to respond to COVID-19. Specific domains including: no immune-modulation, interferon beta-1, and Anakinra (anti IL-1) arms have already been approved. An amendment is also planned to add Tocilizumab (anti IL-6R) and Sarilumab (anti IL-6R) as interventions.

CONVALESCENT SERUM

The successful use of convalescent serum against coronavirus infection had been previously demonstrated in patients infected by SARS-CoV (Cheng Y, Wong R, et al. Use of Convalescent Plasma Therapy in SARS Patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005) as well as MERS-CoV. The anticipated mechanism of protection would be viral neutralisation although other mechanisms such as antibody-dependent cellular cytotoxicity and phagocytosis may be possible. In the case of COVID-19, a small study of 5 Chinese patients with severe disease in showed that convalescent serum containing neutralising antibodies improved the clinical status of all patients (Shen C, Wang Z, et al. Treatment of 5 Critically Ill Patients With COVID-19 with Convalescent Plasma. JAMA, 2020). Interestingly, a recent study of 222 Chinese patients identified risk factors for severe SARS-CoV-2-pneumonia a high neutrophil count, a low lymphocyte count and a high SARS-Cov-2-specific IgG level (Zhang B, Zhou X, et al. Immune phenotyping based on neutrophil to lymphocyte ratio and IgG levels predicts disease severity and outcome for patients with COVID-19). While these data highlight the detrimental effect of hyperinflammation with dysregulated cell counts, it also brings into focus the potential role for high non-neutralising antibody titres and thus antibody dependent enhancement (ADE) of viral entry as a contributor to disease severity. As such, convalescent serum is likely useful only in the subset of patients with poor neutralising antibody responses.

Further clinical trials of convalescent plasma are currently registered and some are underway for patients with severe or life-threatening COVID-19 disease in Europe, Latin America and the US. The FDA has in fact, approved its use under the Emergency Investigational New Drug whereby requestors must procure the convalescent serum from individual blood banks. Considerations including risk of pathogen transmission as well as adverse reactions (allergic, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI)) should be discussed prior to consenting patients for this treatment.  If a clinical trial is available please consider enrolling patients rather than prescribing off-label use.

INTRAVENOUS IMMUNOGLOBULIN

High dose intravenous immunoglobulin (IVIg) has long been utilised as an immune modulator in autoimmune and inflammatory diseases given its ability to modulate Fc receptors and antigen-presenting cells, inhibit the complement cascade as well as neutralise cytokines and regulate activated lymphocytes. High dose IVIg has been shown to be beneficial in SARS-CoV, MERS-CoV and influenza infections. Therefore, high dose IVIg has been proposed to modulate the severe hyperinflammatory responses associated with SARS-Cov-2. A preliminary report of three Chinese patients treated with IVIg at the early stage of clinical deterioration suggested a beneficial role despite the concomitant use of antivirals and steroids. (Cao, W, Liu X, et al. High-dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients with Coronavirus Disease 2019. Open Forum Infectious Disease. 2020).

Further trials are currently registered and underway in Europe and Asia. At present no clinical trials assessing the role of IVIg are available in Australia. If a clinical trial becomes available please consider enrolling patients rather than prescribing off-label use.

 

Yuki, K., Fujiogi, M., & Koutsogiannaki, S. (2020). COVID-19 pathophysiology: A review. Clinical immunology (Orlando, Fla.), 215, 108427. Advance online publication. 20 Apr 2020 https://doi.org/10.1016/j.clim.2020.108427

This is a recent review of the current knowledge about COVID-19 and consideration of the potential explanation of the different symptomatology between children and adults.

It has an excellent summary of the pathophysiology going into detail regarding the spike protein and subsequent activation of a fusion peptide through protease cleavage. A furin cleavage site, which has been associated with pathogenicity of viruses, is present on COVID-19. They discuss the immuno-pathogenesis especially with respect to the cellular response.

They discuss hypotheses regarding the differing clinical findings between adults and children:

  • Expression of ACE2 may differ
  • Qualitatively different response – ?immunosenescence or differing inflammatory response.

 

Ford N, Vitoria M, Rangaraj A, Norris SL, Calmy A, Doherty M. Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID-19: initial assessment. J Int AIDS Soc. 26 March 2020. 2020;23(4):e25489. doi:10.1002/jia2.25489

This is a systematic review of the clinical outcomes of using antiretroviral drugs for the prevention and treatment of the related coronaviruses – SARS, MERS and COVID-19. Studies regarding Lopinivir/ritonavir predominated. The certainty of the evidence for the randomised trials was low. In the observational studies 3 out of 361 patients who received LPV/r died; the certainty of evidence was very low. Three studies reported a possible protective effect of LPV/r as post-exposure prophylaxis. Again, the certainty of the evidence was very low due to uncertainty due to limited sample size.

They concluded on the basis of the available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID-19.

 

INTERNATIONAL PULMONOLOGIST’S CONSENSUS ON COVID-19; first edition Book; Editors: T Joseph and M Ashkan

This consensus statement by international authors from the US, Europe and Asia and edited by the chair of the paediatric section in World Association for Bronchology and Interventional pulmonology summarises recommendations regarding the mode of mode of transmission, epidemiology, clinical features, diagnosis, initial management, treatment options, prognostic features and prevention of patients presenting with COVID-19 disease. A summary of currently available drug treatments is summarised in table format. Critical care management is divided into respiratory management and supportive therapies. They conclude that there is presently no standardised treatment or vaccination available therefore a need for containment and prevention.

 

K Chiotis et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020 Apr 22. pii: piaa045. doi: 10.1093/jpids/piaa045. [Epub ahead of print] PMID: 32318706

A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions convened to develop a set of guidance statements, recognizing the lack of clinical trials and generally low quality evidence.

Their key points are supportive care is sufficient for nearly all pediatric patients with COVID-19 given the overwhelming tendency toward mild illness in children. No agent has been identified with proven efficacy against SARS-CoV-2. They suggest a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, they suggest remdesivir as the preferred agent. Hydroxychloroquine can be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.

They addressed 4 questions:

  1. Are antiviral agents indicated in children with COVID-19?
  • Supportive care is the mainstay – if they are to be considered enroll in study and with ID support
  1. What criteria define the pediatric population in whom antiviral use may be considered?
  • They suggest antiviral agents be considered only in children with positive virologic COVID-19 testing (or with very high suspicion and no prompt testing available), and that clinical criteria, specifically respiratory support requirements, be used to define scenarios in which use of antiviral agents are considered. If patients have mild or moderate disease they should be managed without antivirals. Patients with severe disease consideration should be given to disease trajectory and comorbidities that may confer increased risk. For critical disease (new or increased need for noninvasive or invasive mechanical ventilation, or there is sepsis or multi-organ failure) can be considered on a case by case basis.
  1. Does presence of any underlying medical condition or characteristic warrant different criteria for antiviral use based on increased risk of COVID-19-related morbidity or mortality?
  • There are no definitive data to support any specific risk factor for severe COVID19 in children but they suggest consideration of immunosuppression – particularly T-cell deficiency or dysfunction, obesity, chronic cardiac or respiratory disease and diabetes.
  1. What agents are preferred if antiviral therapy is offered to children with COVID-19?
  • If an antiviral is used, the panel suggests use of remdesivir as the preferred agent.
  • If used, they stress compliance with local institutional and regulatory policies for experimental therapies, with appropriate monitoring for toxicity and the input of a pediatric ID consultant.

 

DP Misra et al. Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets Clinical Rheumatology.  doi.org/10.1007/s10067-020-05073-9   31 Mar 2020

In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2(ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored.

Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation maybe considered during infection episodes as per standard practices. Development of a vaccine maybe the only effective long-term protection against this disease.

 

Eleanor J. Molloy et al, COVID-19 in Children and Altered Inflammatory Responses, Pediatric Research doi:10.1038/s41390-020-0881-y

This summary article highlights that severe COVID-19 infection is characterized by a massive pro-inflammatory response (cytokine storm) that can result in ARDS and multi-organ dysfunction (MODS). It suggests that patients with severe COVID-19 should be screened for HLH (increasing ferritin, decreasing platelet counts, rising ESR) to identify the subgroup of patients where anti-inflammatory treatment could improve mortality.
Therapeutic options discussed include steroids, IVIG, selective cytokine blockade (anakinra or tocilizumab), Remdesivir, hydroxychloroquine, and Janus kinase (JAK) inhibitors.

The sepsis model describes two different phases, first the cytokine storm which is followed by a period of potentially prolonged immunosuppression. The second phase is quoted as the major cause of sepsis-related fatalities.

It is suggested that anti-inflammatory therapies administered in the second phase might be deleterious and that the individualized immune response would be useful to guide therapy.

Further understanding of the differences in immune responses in different age groups is also referred to as the basis for future targeted immunotherapies.

This article provides a useful summary of the pathophysiological basis and practical implications of immunomodulatory therapies in children.

 

Kun‑Ling Shenet al, Diagnosis and treatment of 2019 novel coronavirus infection in children: a pressing issue. World Journal of Pediatrics, https://doi.org/10.1007/s12519-020-00344-6

This is an editorial from the 1st Feb discussing Interferon therapy.

Interferons are a group of low-molecular weight glycoproteins that modulate the responses of the immune system and form one of the first-line innate immune defences against viruses. There are three groups – alpha, beta, and gamma – that affect different immune responses, primarily through inducing antiviral effector proteins and activating cellular immunity to clear the virus.  There is some evidence from two Chinese studies looking at respiratory viruses showing inhibition with atomized interferon. They also reference evidence of SARS-CoV infection being inhibited by an alpha-interferon in a simian model.

 

Yan Wang, Li‑Qin Zhu Pharmaceutical care recommendations for antiviral treatments in children with coronavirus disease 2019. 2 March 2020, World Journal of Pediatrics https://doi.org/10.1007/s12519-020-00353-5

This is a viewpoint paper from two authors in China. They discuss interferon-alpha, Lopinavir/ritonavir (LPVr), ribavirin, umifenovir, and chloroquine. Suggested dosing regimens are provided in a table.

Chinese expert statements recommend IFN-alpha for children in high-risk populations who have a close history of contact with suspected infected patients or those with only upper respiratory tract symptoms in the early phase. They describe contraindications to the regime as being liver function test abnormalities, CrCl reduced below 50ml/min, mental illness, severe or unstable heart disease, aplastic anaemia, and suggest caution in infants less than 2-months of age.

Ribavarin, chloroquine, and umifenovir are discussed but no recommendations are given for use.

Umifenovir is currently only available in Russia and China.

Aerosol Generating Procedures

Cite this article as:
Tagg, A. Aerosol Generating Procedures, Don't Forget the Bubbles, 2020. Available at:
https://dontforgetthebubbles.com/aerosol-generating-procedures/

As more cases of Covid19 present to health care facilities across the world, there seems to be some confusion as to what is an aerosol-generating procedure. Turning up to work is not without risk with a large number of healthcare workers in Italy and Ireland. diagnosed with COVID19. There is a case report of asymptomatic carriage lasting up to 16 days so we need to be careful whether the child in front of us has been diagnosed with COVID19 or not.

A lot of the data we have comes from the 2003 SARS epidemic and the H5N1 influenza outbreaks. There are always going to be a number of confounding variables when looking at these reports – whether the HCW was wearing appropriate PPE (or had access to it), how good their hand-washing was, how close together patients are – but nosocomial infections do occur.

First off,  we are going to take a look at what an aerosol is, then how aerosols and droplets relate to some common, and uncommon, things we do in paediatrics.

 

Aerosol or droplet?

Let’s define some terms before we get started – not as easy as it sounds, it turns out.

A  respiratory droplet is a fluid bundle of infectious particles that travels from the respiratory tract of the infected individual onto the mucosal surface of another, rather than floating down the respiratory tract. Small droplets are between 5-20μm and tend to hang up around the glottis. Large droplets are > 20μm and are probably too big to follow airflow. They tend to obey the laws of gravity and so settle on nearby surfaces when you sneeze. If you inadvertently touch the same surface then touch your face you can potentially transmit the infection. This is why we wash our hands. In healthcare, droplet precautions include a surgical mask, eyewear, disposable gown, and gloves. The surgical mask acts as a physical barrier to droplets that are too large to be inhaled.

A droplet nucleus is what is left once the liquid rapidly evaporates from a droplet. They are in the order of 10μm in diameter and are in the respirable range. This is generally defined as any particle less than 10μm. The inspirable range is defined as anything between 10 – 100μm in size.

An aerosol is a liquid (or solid) suspended in the air – think mist and fog. These small particles are less than 5μm and so are in the respirable range (rather than the inspirable range like droplets) and can enter the lower respiratory tract. They are affected by diffusion rather than gravity so tend to hang around for a while.  Measles is one such airborne disease. A recent letter in the NEJM suggests that SARS-CoV-2 can remain viable in aerosols for at least 3 hours, though the WHO’s guidance is clear that it should be managed with droplet and contact precautions UNLESS you are performing an aerosolising procedure.

Consider them on the continuum of aerosol -> small droplets -> large droplets -> puddles. Aerosols and small droplets have the ability to travel fair distances, especially if powered by a blast of oxygen or expired air. Larger droplets tend to obey the laws of gravity and settle on surfaces.

 

Just breathing, coughing and sneezing

But even putting an oxygen mask on the patient may not protect you. Hui et al. (2006) used fancy laser beams and smoke to detect just how far a single breath might travel.  With a standard oxygen mask on the patient and a flow rate of 4l/min, a tidal volume of 500mls, and 12 breaths a minute the smoke plume traveled approximately 0.45m. In most experiments, scientists use smoke as a stand-in for the more nebulous breath of air. Non-biological aerosols will behave differently depending on the airflow and ventilation in the room and have a constant density. Mathematical modelling would suggest that the further from the source a sample is taken then the lower the potential infectivity until a state of equilibrium is reached. Fortunately, the air is exchanged in most hospital rooms on a regular basis.

A patient that is coughing and sneezing can produce large, short-range droplets and small, long-range aerosols. The aerosols produced by coughing are heavier than the smoke used in experiments so hopefully, they may not be able to travel as far. Experimental data will tend to over-estimate the spread of droplets.

Thompson et al (2013) took 99 air samples around presumptive AGPs. 26.1% of them contained viral RNA. But the baseline level of contamination, when no AGPs (as defined by WHO 2009) were performed was 10.5%. Just because a procedure might generate an aerosol, it does not hold true that the aerosol can cause an infection.

Most of the data we have comes from the fast SARS-CoV epidemic in 2002-2003. Tran et al. tried to find all of the papers related to HCW infection and aerosol-generating procedures. They found 10 – 5 non-randomized cohort studies and 5 retrospective cohort studies. They then created pooled estimates of odds ratios.

Judson and Munster usefully categorized AGPs into those that mechanically create and disperse aerosols and those that make the patient wriggle and cough. Or you could think of them, as suggested by Brewster et al. (2020) as those procedures that require gas flow and those that require no extrinsic gas flow.

 

 

Bag-valve-mask ventilation and CPR

High risk 

A paediatric cardiac arrest is uncommon. When it occurs your first move* should be to open the airway and provide rescue breaths. In this time of COVID19, I doubt anyone is going to be doing mouth-to-mouth/nose ventilation. They are going to reach for an appropriately sized bag-valve-mask. Just like when placing a standard oxygen mask, there is a transverse movement of droplets even with a reasonable seal. The addition of an HME filter does appear to attenuate some of this, as demonstrated by Chan et al.(2018).

Adapted from Chan MT, Chow BK, Lo T, Ko FW, Ng SS, Gin T, Hui DS. Exhaled air dispersion during bag-mask ventilation and sputum suctioning-Implications for infection control. Scientific reports. 2018 Jan 9;8(1):1-8.

 

Adult CPR guidelines are advocating for chest compression-only CPR in the community and rapid intubation pre-compressions if circumstances allow. There has been little guidance on paediatric CPR from the ALSG but a number of enterprising teams are looking at it.

Possible cases of SARS transmission by CPR have been reported (Christian et al. 2004) but BVM ventilation took place during the cases and this may be the most important factor for possible viral transmission.

 

Intubation

High risk 

Anything, where the clinician is inches away from the respiratory tract of the patient, is going to be a high-risk procedure. There have been huge collaborative efforts worldwide creating COVID intubation algorithms. They share a lot of commonalities.

  • The most experienced operator performs the procedure – this is not a time for learning
  • No bag-valve-mask ventilation prior to intubation
  • Use of videolaryngoscopy to maximize the distance between intubator and patient
  • Minimum number of staff present

This is my favourite paediatric intubation resource from Queensland Children’s Hospital.

 

Nebulizing a medication

High risk / Unclear evidence

There are few indications for nebulizing medication. Bronchodilators are best delivered by MDI and spacer when possible but in cases of severe asthma or perhaps, more commonly, in croup, a nebulizer chamber may be the way to go. The UK guidelines do not consider the delivery of nebulized medications as an AGP. The rationale behind this is that the aerosol is derived from a non-patient source. Even if they do have the disease the medication sticks to the mucus membranes and so will not get released into the general environs. There seems to be a lack of global consensus on this.

Nebulizers generate small particles, between 1-5microns in diameter, in order to get down into the bronchioles and not just be deposited in the oropharynx. Viable COVID19 viral RNA has been detected in aerosol form 3 hours after delivery by nebulizer in experimental conditions but this does not prove infectivity, just infectious potential.

In 2009 O’Neill et al. performed air sampling studies for common patient activities, including making the bed and providing nebulized therapy, as well as some more invasive treatments (bronchoscopy and suctioning). Although small numbers they found an increase in influenza particle numbers (from baseline) of up to 70,000/cm³.

 

High Flow Nasal Cannula

High risk 

In adult practice, high flow oxygen delivery is anything over 6l/min. In paediatrics, it is 2l/kg/min up to the adult maximum of 60l/min. In one of my favourite studies to date (and certainly in keeping with the DFTB ethos) five anaesthetists gargled 10mls of red food dye, inhaled to their vital capacity and then coughed. They then repeated the experiment using blue food dye and HFNC at 60l/min and compared the distance traveled. They showed a baseline cough distance of 2.48m increasing up to 2.91m with high flow. Of course, children have a much smaller vital capacity.

This is in contradiction to the data from Hui et al. (2019). They used a human-patient-simulator (as opposed to humans in the above study), smoke and lasers. With a properly fitted mask flow forward flow was increased to ~26 cm with 5cm of CPAP and to around 33cm with 20cm of CPAP. With HFNC the exhalation distance increased from 6.5cm (10l/min) to ~17cm (60l/min). When the mask became loose or disconnected smoke was detected up to ~62cm laterally.  So why the big difference in the studies? It is the cough that causes the problem.

This video from Sick Kids in Toronto says more than any words ever could.

Whether you believe in the benefits of high-flow or not, pushing oxygen through the nose at 2l/kg/min and out through the mouth can create an aerosol spread of snot and virus. We would advise that it is only be used in cases where low flow oxygen therapy has failed. It also makes sense then, that it should only be started in the place where the patient is going to end up. It would not be wise to start a patient on HFNCO2 then wheel them through the hospital leaving a cloud of viral particles in their wake like some overactive Bisto Kid. And if you are going to do it with a coughing patient then it would be sensible to put a standard face mask on first.

 

Non-invasive ventilation (CPAP or BiPAP)

High risk 

High flow nasal cannula seems to have superseded non-invasive ventilation in many cases, though CPAP is regularly used in neonatal practice. There is very little evidence for maternal transmission of COVID19 and one might suppose that full PPE is then not warranted. However, you need to consider where the baby has come from.

Open suctioning and chest physiotherapy

High risk 

Removal of nasal foreign body

Medium to high risk

There are lots of ways to remove a nasal foreign body but all of them will generate snot. The old standby – the mother’s kiss – is, realistically, no more dangerous for the parent than living in close proximity. If your pre-encounter probability of infection with SARS-CoV-2 is low, i.e. there is little community transmission, then the risk to the provider is probably low.

Nitrous oxide

Medium to high risk 

Respiratory illness is a contra-indication to nitrous sedation but given that there is a degree of asymptomatic carriage it is not impossible that we might need to use it. With children not going to school and being told to stay away from their friends, there is going to be a spike in trampoline and bunk-bed related injuries. Again consideration should be made as to the possibility of community transmission. Logically holding a continuous flow mask on an uncooperative toddler would expose a HCW to higher risk than being a room Sith a cooperative patient using a demand system with appropriately attached to suction.

Examining the throat

Medium to high risk 

In normal times, no paediatric examination is complete without looking in the ears, nose, and throat, no matter how hard it might be. You can argue that looking at tonsils might not be overly helpful, given that the inter-rate variability is pretty high but there are other things to look for too – emerging teeth, Koplik spots, ulcers. But does a look in the throat put us at risk?

The Royal College of Paediatric and Child Health concurs, and in a statement put out on the 24th of March suggest that we only look in the throat if it is essential. If we have to do it we should be wearing appropriate protection (glove, gown, surgical face mask). If a child is at particularly high risk then they recommend empiric antibiotics.

Even ENT experts, like Eric Levi, recognize the unique risks that fiddling around near the upper respiratory tract hold.

Inserting a nasogastric tube

Medium to high risk

The combined Colleges of Surgeons of Great Britain and Ireland suggest that insertion of a nasogastric tube in an adult is an AGP, probably as it may induce coughing.

Taking a nasopharyngeal swab

Low to moderate risk 

The CDC state that collecting a nasopharyngeal swab doesn’t need to take place in an isolation room but should at least be performed in a single room with a closed door. The health care practitioner should wear an N95 mask or equivalent, coupled with eye protection, gloves, and gown. Given how far the swab has to travel up the nasopharynx nobody should be surprised that it might make someone sneeze.

The current Australian guidance contains slightly different advice.

 

We can also add things like IV access, suprapubic aspiration and performance of a lumbar puncture to this list of LOW-risk procedures.

And let’s not forget our surgical and dental colleagues

Surgical procedures

Clearly, some surgical procedures are more dangerous than others. Eric Levi. advocates for a risk assessment before any procedure takes place, starting with ‘Does it need to be done now?” Take a look at his post on how he is modifying his operative technique in order to reduce risk to himself and his colleagues.

On the 25th of March, the combined Colleges of Surgeons of Great Britain and Ireland recommended against laparoscopic surgery due to the potential for aerosol formation. Endoscopy, at either end, also has the potential for the creation of fomites and aerosolizing droplets and so should be carried out with extreme caution.

Dental procedures

There are very few dental procedures that need to be performed as an emergency but given that high-speed drills can lead to aerosolization have a care for our dental colleagues that may also be exposed in the course of duty.

The guidance for these procedures is common sense. Don’t perform them if you don’t have to. This is not the time for some minor dental procedures. If they have to be carried out then it should happen in the appropriate space with the appropriate staff. This means in a single room (ideally) with the minimum number of staff wearing appropriate PPE.

 

These are our thoughts, based on the current evidence, and we’d love you to persuade us otherwise in the comments below.

*Clearly the first step of the algorithm is D for Danger. That means putting on your PPE.

Selected references

Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA. 2020 Mar 26.

Brewster DJ, Chrimes NC, Do TB, Fraser K, Groombridge CJ, Higgs A, Humar MJ, Leeuwenburg TJ, McGloughlin S, Newman FG, Nickson CP. Consensus statement: Safe Airway Society principles of airway management and tracheal intubation specific to the COVID-19 adult patient group.

Brown JS, Gordon T, Price O, Asgharian B. Thoracic and respirable particle definitions for human health risk assessment. Particle and fibre toxicology. 2013 Dec 1;10(1):12.

Davies A, Thompson G, Walker J, Bennett A. A review of the risks and disease transmission associated with aerosol generating medical procedures. J Infect Prev 2009; 10:122–6.

van Doremalen N, Bushmaker T, Morris D, Holbrook M, Gamble A, Williamson B, Tamin A, Harcourt J, Thornburg N, Gerber S, Lloyd-Smith J. Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1. medRxiv. 2020 Jan 1.

Hui DS, Ng SS. Recommended hospital preparations for future cases and outbreaks of novel influenza viruses. Expert Review of Respiratory Medicine. 2020 Jan 2;14(1):41-50.

Hui DS, Ip M, Tang JW, Wong AL, Chan MT, Hall SD, Chan PK, Sung JJ. Airflows around oxygen masks: A potential source of infection. Chest. 2006 Sep 1;130(3):822-6.

Judson SD, Munster VJ. Nosocomial Transmission of Emerging Viruses via Aerosol-Generating Medical Procedures. Viruses. 2019 Oct;11(10):940.

Kam KQ, Yung CF, Cui L, Lin Tzer Pin R, Mak TM, Maiwald M, Li J, Chong CY, Nadua K, Tan NW, Thoon KC. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clinical Infectious Diseases. 2020 Feb 28.

Liu Y, Ning Z, Chen Y, Guo M, Liu Y, Gali NK, Sun L, Duan Y, Cai J, Westerdahl D, Liu X. Aerodynamic Characteristics and RNA Concentration of SARS-CoV-2 Aerosol in Wuhan Hospitals during COVID-19 Outbreak. bioRxiv. 2020 Jan 1

Macintyre CR, Seale H, Yang P, Zhang Y, Shi W, Almatroudi A, Moa A, Wang X, Li X, Pang X, Wang Q. Quantifying the risk of respiratory infection in healthcare workers performing high-risk procedures. Epidemiology & Infection. 2014 Sep;142(9):1802-8.

Noti JD, Lindsley WG, Blachere FM, Cao G, Kashon ML, Thewlis RE, McMillen CM, King WP, Szalajda JV, Beezhold DH. Detection of infectious influenza virus in cough aerosols generated in a simulated patient examination room. Clinical Infectious Diseases. 2012 Jun 1;54(11):1569-77.

Seto WH. Airborne transmission and precautions: facts and myths. Journal of Hospital Infection. 2015 Apr 1;89(4):225-8.

Shiu EY, Leung NH, Cowling BJ. Controversy around airborne versus droplet transmission of respiratory viruses: implication for infection prevention. Current opinion in infectious diseases. 2019 Aug 1;32(4):372-9.

Somogyi R, Vesely AE, Azami T, Preiss D, Fisher J, Correia J, Fowler RA. Dispersal of respiratory droplets with open vs closed oxygen delivery masks: implications for the transmission of severe acute respiratory syndrome. Chest. 2004 Mar 1;125(3):1155-7.

Tang JW, Li Y, Eames I, Chan PKS, Ridgway GL. Factors involved in the aerosol transmission of infection and control of ventilation in healthcare premises. J Hosp Infect 2006;64:100-14.

Tellier, R., Li, Y., Cowling, B.J. et al. Recognition of aerosol transmission of infectious agents: a commentary. BMC Infect Dis 19, 101 (2019). https://doi.org/10.1186/s12879-019-3707-y

Thompson KAPappachan JVBennett AM, et al. EASE study consortium. Influenza aerosols in UK hospitals during the H1N1 (2009) pandemic–the risk of aerosol generation during medical procedures. PLoS One. 2013;8:e56278.

Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PloS one. 2012;7(4).

World Health Organization. Infection prevention and control during health care when novel coronavirus (‎‎‎ nCoV)‎‎‎ infection is suspected: interim guidance, January 2020. World Health Organization; 2020

Intubation

Cheung JC, Ho LT, Cheng JV, Cham EY, Lam KN. Staff safety during emergency airway management for COVID-19 in Hong Kong. The Lancet Respiratory Medicine. 2020 Feb 24.

Nebulizing a medication

O’Neil CA, Li J, Leavey A, Wang Y, Hink M, Wallace M, Biswas P, Burnham CA, Babcock HM. Characterization of aerosols generated during patient care activities. Clinical Infectious Diseases. 2017 Oct 1.

Amirav I, Newhouse MT. RE: Transmission of Corona Virus by Nebulizer-a serious, underappreciated risk!.

High Flow Nasal Cannula

Hui DS, Chow BK, Lo T, Tsang OT, Ko FW, Ng SS, Gin T, Chan MT. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. European Respiratory Journal. 2019 Apr 1;53(4):1802339.

Leung CCJoynt GMGomersall CD, et al. Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial contamination in critically ill pneumonia patients: a randomized controlled crossover trial. J Hosp Infect. 2019;101(1):8487.

Loh NH, Tan Y, Taculod J, Gorospe B, Teope AS, Somani J, Tan AY. The impact of high-flow nasal cannula (HFNC) on coughing distance: implications on its use during the novel coronavirus disease outbreak. Canadian Journal of Anesthesia/Journal canadien d’anesthésie. 2020 Mar 18:1-2.

Non-invasive ventilation

Singh A, Sterk PJ. Noninvasive ventilation and the potential risk of transmission of infection. European Respiratory Journal. 2008 Sep 1;32(3):816-.

Bag-Valve-Mask Ventilation

Chan MT, Chow BK, Lo T, Ko FW, Ng SS, Gin T, Hui DS. Exhaled air dispersion during bag-mask ventilation and sputum suctioning-Implications for infection control. Scientific reports. 2018 Jan 9;8(1):1-8.

Christian MD, Loutfy M, McDonald LC, Martinez KF, Ofner M, Wong T, Wallington T, Gold WL, Mederski B, Green K, Low DE. Possible SARS coronavirus transmission during cardiopulmonary resuscitation. Emerging infectious diseases. 2004 Feb;10(2):287.

Suctioning

Inserting a nasogastric tube

Nitrous oxide

Taking a naso-pharyngeal swab

Examining the throat

Lu D, Wang H, Yu R, Zhao Y. Integrated infection control strategy to minimize nosocomial infection of corona virus disease 2019 among ENT healthcare workers. Journal of Hospital Infection. 2020 Feb 27.

Tang JW, Nicolle AD, Klettner CA, Pantelic J, Wang L, Suhaimi AB, Tan AY, Ong GW, Su R, Sekhar C, Cheong DD. Airflow dynamics of human jets: sneezing and breathing-potential sources of infectious aerosols. PLoS One. 2013;8(4).

Removal of foreign bodies

Surgical spread

Ong J, Cross GB, Dan YY. The prevention of nosocomial SARS-CoV2 transmission in endoscopy: a systematic review of recommendations within gastroenterology to identify best practice. medRxiv. 2020 Jan 1.

Dental spread

Divya R, Senthilnathan KP, Kumar MP, Murugan PS. Evaluation of aerosol and splatter contamination during minor oral surgical procedures. Drug Invention Today. 2019 Sep 1;12(9).

Sabino-Silva R, Jardim AC, Siqueira WL. Coronavirus COVID-19 impacts to dentistry and potential salivary diagnosis. Clinical Oral Investigations. 2020 Feb 20:1-3.

An evidence summary of Paediatric COVID-19 literature

Cite this article as:
Boast A, Munro A, Goldstein H. An evidence summary of Paediatric COVID-19 literature, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.24063

This post is a rapid literature review of pertinent paediatric literature regarding COVID-19 disease. We are proud to have joined forces with the UK Royal College of Paediatrics and Child Health to provide systematic search, and selected reviews of all the COVID-19 literature relevant to children and young people.

Our search and review methods have changed as the pace and utility of the published literature has evolved over time. Our process involved a formal literature search (methods can be found here), followed by identification of all papers relevant to children/young people, then reading of every article by one of our team of doctors. Initially we produced a written review of all publications, however on April 17th 2020 we moved to a more selective review process. All articles were read in full, then if high enough quality, determined by consensus and involvement of a clinical academic, a written review was also produced.

As of June 30th 2020, we have again revised our process as the urgent need for rapid evidence synthesis has lessened, and the volume of research published remains extremely high, with much of it adding little to the current body of knowledge. Our search criteria has therefore narrowed, and of the articles identified as relevant, only those felt to be of exceptional quality or impact (as determined by consensus with involvement of a clinical academic) are selected for written review.

Our team of reviewers includes Alasdair Munro, Alison Boast, Henry Goldstein, Grace Leo, Dani Hall, Daniel Yeoh, Tessa Davis, Melody Redman, Sarah Sloan, Tricia Barlow, Anne Bean, Maeve Kelleher, Victoria Dachtler, Irnthu Premadeva, Lilian Nyirongo, Esther Alderson, Sunil Bhopal, Aimee Donald and Rachel Harwood.

Here we present the top 10 papers from each category (Paediatric clinical cases, Epidemiology and transmission, and Neonates). At the top is an Executive summary followed by all New and noteworthy studies.

If you have feedback please email us at hello@dontforgetthebubbles.com

Epidemiology

Around the world, children have made up a minority of confirmed cases of COVID-19 during the first wave of the pandemic, usually contributing to between 1 – 5% of total case numbers. This almost certainly represents some undercounting of children in total case numbers as many countries have focussed on testing the most unwell. As countries have become better at shielding elderly populations and moved to community testing, the proportion of cases detected in children has increased (although predominantly in older children aged 10 – 19 years).

Countries which have produced representative population seroprevalence studies (including Switzerland, Spain and Italy) have found proportionately far fewer children have been infected than adults (young children <10 years in particular).

More detailed information has emerged into childhood severity of COVID-19. A large number of children may be asymptomatic, but the true proportion is unknown. Critical illness is very rare (~1%). In data from China, the USA and Europe, there is a “U shaped” risk gradient, with infants and older adolescents appear most likely to be hospitalised and to suffer from more severe disease. Deaths in children remain extremely rare from COVID-19, with only 4 deaths in the UK as of May 2020 in children <15 years.

Transmission

Precise details regarding paediatric transmission are still being ascertained, however important trends are emerging. Low case numbers in children suggest a more limited role than was initially feared. Contact tracing data from Asia, the USA, Europe and Israel have all demonstrated a significantly lower attack rate in children than adults, including testing of asymptomatic household contacts on both PCR and serology, indicated young children in particular are approximately half as likely as adults to acquire the infection given equivalent exposure.

The role of children in passing the disease to others is unknown, in particular given unknown numbers of asymptomatic cases. Notably, the China/WHO joint commission could not recall episodes during contact tracing where transmission occurred from a child to an adult. Studies of multiple family clusters have revealed children were unlikely to be the index case, in Guangzhou, China, Israel, the USA, Switzerland and internationally. Limited data on positive cases in schools have not demonstrated significant transmission, except within adolescent populations. Studies of younger children in schools have found low rates of transmission, but with very low case numbers. Household studies with children as index cases have so far been heavily biased by either shared exposure (children and their contacts becoming infected simultaneously) or increased exposure of caregiver to their symptomatic children post infection.

Studies of viral loads in children have generally found comparable levels of virus to adults, with no consistent or clinically relevant variation by age or symptom burden. Several studies have now shown that SARS-CoV-2 can be detected by PCR in the stool of affected children for several weeks after symptoms have resolved. Studies have confirmed there can also be live virus found in the stool of infected individuals. How much virus is present, and the extent to which faecal-oral transmission may be possible is yet to be confirmed.

Clinical features

A significant proportion of children with COVID-19 do not appear to develop any symptoms, or have subclinical symptoms, but it remains uncertain what this proportion is. The most detailed paediatric population data from China showed 13% of confirmed cases had no symptoms (cases detected by contact tracing). Considering both confirmed and suspected cases, 32% of children aged 6-10yrs were asymptomatic. Data from Italian emergency departments found 21% of SARS-CoV-2 positive children to be asymptomatic. Importantly, these studies did not follow up children to determine if they later developed symptoms, so the true proportion of asymptomatic children is unknown.

Possibly the most reliable data comes from serological screening with symptom surveys, suggesting approximately 50% of children may be asymptomatic, and only 10 – 15% will exhibit symptoms consistent with COVID-19 case definitions (cough, fever, shortness of breath). These studies are subject to recall bias.

Clinical features in symptomatic children are somewhat different to adults. Children tend to have more mild illness. The most common presenting features are cough and fever, occurring in over half of symptomatic patients. Upper respiratory tract symptoms such as rhinorrhoea and sore throat are also relatively common, occurring in 30-40% of patients. It is not uncommon for children to have diarrhoea and/or vomiting (around 10% of cases), even in some cases as their sole presenting features. Several case series of rashes resembling chill blains (often occurring on feet/toes) have been reported from Europe, contemporaneously associated with the COVID-19 outbreak but with few cases simultaneously confirmed to be infected

Blood tests also show slightly different features to adults. Lymphocytopaenia is relatively rare in children, with the majority having normal or sometimes raised lymphocyte counts. Inflammatory markers such as CRP and Procalcitonin are often raised but only very mildly. Slight elevations in liver transaminases appear to be common.

Radiographic features in children are also somewhat different to their adult counterparts. Chest X-rays are often normal, and many CT chest scans are also normal. When present abnormalities are often less severe, however a reasonable number of children have bilateral pneumonia. Changes may be found on CT even in asymptomatic children. Common features in abnormal CT scans include mild, bilateral ground glass opacities, but with less peripheral predominance than is reportedly found in adults.

There appears to be little in the way of clinical signs in children to differentiate COVID-19 from other childhood respiratory virus infections, or other benign childhood illnesses.

PIMS-TS/MIS-C

A new hyperinflammatory syndrome resembling Kawasaki shock, which appears to be a delayed immune response to COVID-19 has been described. It is known as PIMS-TS in Europe and MIS-C in the USA. Published reports from London, Italy, France and the USA in a cohort of children with evidence of past COVID-19 infection have presented with early symptom of abdominal pain, vomiting and diarrhoea, with persistent high-grade fever and commonly progression on to shock with cardiac involvement. High inflammatory markers, myocarditis, macularpapular rashes and non-suppurative conjunctivitis are common. Respiratory involvement is notably absent. Investigations are underway to ascertain a link and mechanism of disease. Most cases recover quickly, but there have been deaths reported.

Consistent with adult literature, children from a Black, Asian and Minority Ethnic (BAME) background seem to be at higher risk of severe disease from acute COVID-19 infection, and are significantly overrepresented in case reports of PIMS-TS

Newborns

A large number of cases of infants born to mothers with COVID-19 have now been reported, including several hundreds from the UK. Mothers and their babies in general appear to do well. There is a small but notable increase in the rates of preterm birth, and signals of increase in rates of foetal loss/stillborn delivery. There have been a few cases of infants delivered to mothers with COVID-19, who had elevated SARS- CoV-2 IgM. This may indicate intrauterine transmission, however swab PCR from these children has been negative and false positives with IgM tests are not uncommon. There have been case reports of newborns and very young infants testing positive including several within 12 hours of age, however they have mostly not suffered any complications of the disease and required minimal respiratory support. Evidence has been found of viral invasion into placenta, indicating possible intrauterine transmission. Vertical transmission however remains rare, occurring in approximately 2% of cases of maternal infection.

When tested, breast milk has usually been negative for SARS-CoV-2, but there have been a small number of instances where it has tested positive. It is unclear if this positive result reflects live, infectious virus, and whether the source was the mother or infants who subsequently also test positive for the virus. The vast majority of newborns have not acquired COVID-19 themselves. 

Children with co-morbidities

There is a growing body of evidence reflecting a small increased risk of children with comorbidities to be hospitalised or need intensive care from COVID-19. A pan European consortium found children with chronic lung disease, congenital heart disease, neurological disease or malignancy had 3 times higher odds of needing admission to PICU; whilst this is an increased relative risk, the absolute risk remains small.  Studies from PICU admissions in the US and Italy also found the majority have some comorbidities, most commonly respiratory, cardiac or complex neurodisability. These are groups for whom there is already a background increased risk of complications from all respiratory viruses. The rates of complications from SARS-CoV-2 infection do not appear disproportionate to those from other respiratory viruses from this early data.

Conclusion

COVID-19 appears to affect children less often, and with less severity, including frequent asymptomatic or subclinical infection. There is evidence of critical illness, but it is rare. The role of children in transmission is unclear, but consistent evidence is demonstrating a lower likelihood of acquiring infection, and lower rates of children bringing infections into households. Changes in laboratory or radiographic parameters are slightly different to adults, and changes usually mild. There is some evidence of vertical transmission to neonates which appears predominantly perinatal but evidence of intrauterine infection does exist. Evidence suggests only a small increased risk to pregnant mothers and newborns compared to other groups. Children with respiratory, cardiac and complex neurodisability appear more likely to suffer complications, however not obviously more than would be expected from infection with other respiratory viruses.

Weisberg, S.P., Connors, T.J., Zhu, Y. et al. Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum. Nature Immunology (2020). https://doi.org/10.1038/s41590-020-00826-9

This study, published online on 5th November 2020, investigates the SARS-CoV-2 antibody response and its protective capacity in 32 adult and 47 paediatric patients seen at New York-Presbyterian/Columbia University Irving Medical Center hospital and the Morgan Stanley Children’s Hospital of New York during the height of the COVID-19 pandemic in New York City from March to June 2020.  Children with SARS-CoV-2 infection are often asymptomatic and rarely have severe respiratory symptoms, but may very rarely present with multisystem inflammatory syndrome in children (MIS-C), typically 2-4 weeks after infection with SARS-CoV-2.  Adults are more likely to experience respiratory symptoms of varying severity, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (particularly in older adults and those with comorbidities such as diabetes).  The authors aimed to investigate the immune response after SARS-Co-2 infection in adults and children with a range of clinical presentations, by analysing antibodies specific for the major SARS-CoV-2 antigens, including the S protein (which binds the cellular receptor for viral entry) and the N protein (necessary for viral replication).  They also analysed the neutralising activity of these antibodies in blocking viral infection, which correlates with their protective capacity (only a small fraction of antibodies raised against viral antigens will have neutralising activity).

Study population:  There were 4 patient cohorts in the study (2 adult and 2 paediatric, one each of mild and severe disease in each age group) totalling 79 individuals, defined as having been SARS-CoV-2-infected based on symptoms, positive PCR and/or serology:

1.  19/79 (24%) adult convalescent plasma donors (CPDs): recovered from mild COVID-19 respiratory disease without hospitalisation and recruited from the community via web tool as part of convalescent plasma trial (telephone screening to determine eligibility as plasma donors), median age 45 yrs (range 28-69), 10/19 (53%) male, ethnicity: 53% white, 32% Asian, 11% Pacific Islander, 5% Hispanic/Latin American, 5% other/unknown.  Median time from onset of symptoms consistent with COVID-19 to sampling during the outpatient donation of blood: 24 days (IQR 19-37).

2.  13/79 (16%) adults hospitalised with severe COVID-19 ARDS (COVID-ARDS): median age 62 yrs (range 19-84), male 11/13 (85%), ethnicity: 31% Hispanic/Latin American, 23% Black/African American, 15% white, 38% other/unknown.  Co-morbidities: diabetes 4/13 (31%), hypertension 4/13 (31%), current/former smoker 3/13 (23%), COPD 2/13 (15%), chronic neurological disease/dementia 1/13 (8%).  Median time from onset of respiratory/COVID-19 symptoms to sampling (after diagnosis of ARDS requiring intubation and admission to ICU): 16 days (IQR 14-21).  30-day in-hospital mortality 6/13 (46%), 4 patients remained hospitalised.

3.  16/79 (20%) children hospitalised with MIS-C (paediatric MIS-C): median age 11 yrs (range 4-17), male 7/16 (44%), ethnicity: 44% Black/African American, 44% white, 25% Hispanic/Latin American, 6% other/unknown.  Asthma 4/16 (25%) (no other co-morbidities).  Median time after the onset of symptoms of MIS-C to sampling on admission to PICU: 6 days (IQR 4-7).  30-day in-hospital mortality 0%, 1/16 (6%) developed respiratory failure/ARDS.

4.  31/79 (39%) children infected with SARS-CoV-2 who didn’t develop MIS-C (paediatric non-MIS-C): median age 11 yrs (range 3-18), male 17/31 (55%), ethnicity: 48% white, 42% Hispanic/Latin American, 13% Black/Latin American, 23% other/unknown.  Co-morbidities: asthma 1/31 (3%), chronic kidney disease 1, hypertension 1.  Clinical presentation: surgical 9/31 (29%), COVID-19 symptoms 7/31 (23%), psychiatric 4/31 (13%), trauma 3/31 (10%), fever (non-COVID) 2/31 (6%), other 6/31 (19%).  Asymptomatic 15/31 (48%).  Median time from symptom onset or from confirmed COVID-19 exposure (reportable data for 16 individuals) to sampling during clinical care (including routine screening for admission and procedures): 29 days (IQR 17-44).  30-day in-hospital mortality 0%, 1/31 (3%) developed respiratory failure/ARDS.  These samples were obtained from the Columbia University Biobank after screening for appropriate age and exclusion of confounders such as immune deficiency, malignancy and genetic abnormality.

SARS-CoV-2 specific antibodies for each cohort:  Blood samples were collected from all 4 cohorts during the same 60 day time window.  Levels of antibodies to SARS-CoV-2 S (spike) and N (nucleocapsid) proteins were measured in patient plasma samples (and in a negative control pre-pandemic plasma) using serial dilutions in an indirect ELISA assay to detect anti-S IgG, anti-S IgM, anti-S IgA and anti-N IgG.  Detailed results and graphs are reported in the article, together with statistical comparisons between cohorts.  Anti-S antibodies were present as IgM (primary response), IgG (prominent in serum) and IgA (prominent in secretions) classes in adult CPDs and COVID-ARDS, with a significantly higher concentration in COVID-ARDS patients for all classes.  By contrast, anti-S antibody titres and isotype predominance in both paediatric cohorts (MISC-C and non-MIS-C) were similar to each other and to the adult CPDs, showing predominant anti-S IgG, low titres of anti-S IgM (similar to the negative control) and variable titres of anti-S IgA antibodies.  The specificity of anti-S IgG for SARS-CoV-2 S protein compared to other coronavirus strains was assessed using a cell-based ELISA: plasma IgG from subject samples (but not pre-pandemic control plasma) bound SARS-CoV-2 protein and the common circulating D614G S protein variant but did not significantly bind S protein from SARS-CoV-1 or MERS coronaviruses.  Anti-N IgG titres were significantly lower in both paediatric cohorts compared to the two adult cohorts.  The low titres of anti-N IgG in children were similar in MIS-C and non-MIS-C cohorts.  The higher titres of anti-N IgG in adults were similar in CPDs and COVID-ARDS cohorts, suggesting that production of anti-N antibody is age- but not symptom-dependent.

Effect of age on antibodies in each cohort:  No significant correlation between age and anti-S IgG in adults or paediatric MIS-C cohort; modest but significant negative correlation between age and anti-S IgG in paediatric non-MIS-C cohort (younger children having higher anti-S titres than teens).  A significant correlation between age and anti-N IgG in adult CPDs (younger adults having lower anti-N titres than older adults).  Both paediatric cohorts had low anti-N titres across all ages.

Effect of time post-symptom onset on antibodies in each cohort:  Significant correlation between anti-S IgG titres and increased time post-symptom onset for both paediatric cohorts and the adult COVID-ARDS cohort, suggesting an evolving response over time.  No correlation between anti-S IgM and time post-symptom onset in any cohort.

Neutralising activity of antibodies in each cohort:  A pseudovirus assay was used to measure neutralising activity.  Both paediatric cohorts exhibited significantly lower neutralising activity than the two adults cohorts, with no difference between MIS-C and non-MIS-C cohorts.  Plasma from adult COVID-ARDS patients showed the highest neutralising activity.  No correlation between age and neutralising activity in either adult cohort.  The significant decline of neutralising activity with age in the paediatric non-MIS-C cohort, similar to the decrease in anti-S IgG observed during the teenage years.  Neutralising activity within each cohort did not correlate with time post-symptom onset except in the adult COVID-ARDS cohort.  10/16 (62.5%) MIS-C patients maintained the same anti-S IgG titres and neutralising activity when followed up 2-4 weeks post-hospital discharge based on paired analysis, suggesting that lower levels of functional antibody responses in paediatric SARS-CoV-2 infection compared to adults is age-associated and not related to infection course.

Additional analysis to better define how antibody responses relate to age and disease severity:  Multivariable linear regression analysis was performed to control for the effects of demographic and clinical covariates.  Consistent with the grouped analysis, analysis of all paediatric and adult data showed that the paediatric age group was a significant predictor of lower SARS-CoV-2 neutralising activity, anti-S IgM and anti-N IgG, independent of time post-symptom onset, clinical syndrome or sex.  ARDS was a significant independent predictor of higher neutralising activity, anti-S IgG and anti-S IgM.

Observations:  Self-selection bias may apply to the CPDs cohort since they volunteered via the internet to be plasma donors.  Timing of onset of symptoms was subjective and the paediatric non-MIS-C cohort included 48% asymptomatic patients whose symptom onset to sampling time interval was calculated based on days since confirmed COVID-19 exposure (with reportable data for only half the cohort).  The paediatric MIS-C cohort symptom onset to sampling time interval is based on the onset of MIS-C symptoms, not potential initial COVID-19 symptoms or COVID-19 exposure.  Samples from COVID-ARDS and MIS-C patients were obtained within 24-36 hours of being admitted to ICU/PICU or intubated for respiratory failure; this was not always before the initiation of therapeutic interventions.  Treatments received by the 13 COVID-ARDS patients included: convalescent plasma 4/13 (31%) (1/13 sampled post-treatment), hydrocortisone 6/13 (46%) (1/13 sampled post-treatment), methylprednisolone 9/13 (69%) (8/13 sampled post-treatment), monoclonal antibodies 7/13 (54%) (6/13 sampled post-treatment), remdesevir 6/13 (40%) (2/13 sampled post-treatment).  16 MIS-C patients: hydrocortisone 3/16 (19%) (3/13 sampled post-treatment), intravenous immunoglobulin 14/16 (88%) (6/16 sampled post-treatment), methylprednisolone 15/16 (94%) (10/16 sampled post-treatment), monoclonal antibodies 3/16 (1/16 sampled post-treatment), remdesevir 1/16 (1/16 sampled post-treatment).  31 non-MISC-C patients: intravenous immunoglobulin 2/31 (6%) (both sampled before treatment), methylprednisolone 1/31 (3%) (1/31 sampled post-treatment), remdesevir 1/31 (3%) (1/31 sampled post-treatment).

Conclusions:  This study demonstrates quantitative and qualitative differences between children and adults in the anti-SARS-CoV-2-specific antibody response in both mild and severe disease.  The anti-SARS-CoV-2 antibody response in children was found to be predominantly anti-S IgG antibodies, with low neutralising activity compared to adults.  Children with and without MIS-C had similar antibody profiles (suggesting that the adaptive immune response is not in itself associated with MIS-C pathogenesis), in contrast to the adult cohorts, where those with the most severe disease had higher abundance, breadth and neutralising activity of anti-SARS-CoV-2 antibodies compared to adults who recovered from mild disease.  Anti-N antibody titres were low in children compared to adults, which is consistent with a milder course of infection in children (release of N proteins requires lysis of virally infected cells).  This effect was also seen in the adult CPDs cohort, where anti-N antibodies increased with age, consistent with an increase in severe and prolonged disease in older adults.  Testing platforms using anti-N IgG to identify previous infection may have decreased sensitivity in children since children were shown to predominantly generate IgG antibodies specific for the S protein, but not the N protein.  Age was the major factor distinguishing antibody profiles (independent of sex, disease severity and time post-symptom onset).  The authors note the opportunity to study primary immune responses across all ages afforded by the sudden and widespread emergence of SARS-CoV-2 as a new pathogen; the majority of primary exposures to common viral respiratory pathogens occur in infancy and childhood so that virus-specific immune memory is established by adulthood, and therefore differences between primary immune responses in children and adults are currently unknown.  The authors postulate that the reduced functional adaptive antibody response in children compared to adults may be due to efficient immune-mediated viral clearance resulting in fewer respiratory symptoms and less severe disease.  Children may have more naïve T cells available to respond to new pathogens or more recently acquired T cell memory to related coronaviruses due to more recent and frequent respiratory illnesses.  Defining the nature of the antibody response to SARS-CoV-2 infection as a function of age and disease severity will improve age-targeted screening and protection in the form of therapeutics and vaccines. 

Kevin W. Ng, Nikhil Faulkner, Georgina H. Cornish, Preexisting and de novo humoral immunity to SARS-CoV-2 in humans, Science, Nov 6th 2020, https://doi.org/10.1126/science.abe1107

It has been hypothesised that pre-existing immunity from previous seasonal “common cold” human coronavirus (HCoV) infection may provide individuals with some protection from SARS-CoV-2. In theory, cross-reactive antibodies may account for some of the variation in clinical severity within populations, including the relatively mild course of disease amongst children.

In this paper from the UK, serum samples from uninfected adults and children were examined for cross-reactive antibodies to SARS-CoV-2 using a flow-cytometry-based assay. 

The presence, level, and target(s) of cross-reactive antibodies were assessed along with the ability of the antibodies to neutralise the virus in the laboratory.

Of initial samples from 302 uninfected adults, 5.3% (n=16) had detectable IgG to SARS-CoV-2. These antibodies cross-reacted with the S2 subunit SARS-CoV-2 spike protein (S2 is relatively conserved among coronaviruses compared with the S1 subunit) but not the receptor-binding domain (RBD) which is key in allowing binding to cells to facilitate infection. The level of SARS-CoV-2 cross-reactive antibodies correlated with the level of HCoV IgG and IgA in uninfected individuals, supporting a link between previous HCoV infection and cross-protection. Notably, cross-reactive antibodies were found in individuals both with and without evidence of recent HCoV infection, suggesting that other factors such as frequency of HCoV infection may be important for SARS-CoV-2 cross-protection. 

Remarkably, 43.8% (21/48) of SARS-CoV-2 uninfected children (1-16yo) had SARS-CoV-2 cross-reactive antibodies (IgG), compared with 2.3% (1/43) of young adults (17-25yo). Amongst children 6-16yo, almost two thirds (62%) had detectable cross-reactive antibodies. This observation is in keeping with the known age distribution of HCoV infection frequency which peaks in children and adolescents. Importantly, sera containing cross-reactive antibodies from uninfected patients demonstrated the ability to neutralise the virus in vitro, preventing viral entry into cells. 

This interesting data support the hypothesis that pre-existing cross-reactive antibodies from previous HCoV infection are present in some individuals and may protect against COVID-19. The degree and duration of individual protection conferred by pre-existing cross-reactive antibodies along with any impact on the onward transmission of SARS-CoV-2 remain uncertain. The higher prevalence of these pre-existing antibodies in children and adolescents may be an important factor in explaining the milder course of SARS-CoV-2 infection in this age group.

Pray IW, Gibbons-Burgener SN, Rosenberg AZ, et al. COVID-19 Outbreak at an Overnight Summer School Retreat ― Wisconsin, July–August 2020. MMWR Morb Mortal Wkly Rep 2020;69:1600–1604. October 30, 2020 DOI: http://dx.doi.org/10.15585/mmwr.mm6943a4

This is a study of an outbreak of COVID-19 which occurred at a boys’ faith-based overnight summer school retreat in Wisconsin, USA between July 2 and August 11, 2020.

The retreat was attended by 152 people: 127 male students aged 14-17 years; 21 counsellors aged 17-24 years; and 4 staff aged 21-45 years.

A single student, who received a negative SARS-CoV-2 RT-PCR test result <1 week before the retreat and experienced symptoms 1 day after arriving, was the likely source of introduction, resulting in infection of 76% of attendees. 

At the retreat, students and counsellors were not required to wear masks or social distance, and students mixed freely. Classes were outdoors with students seated <2 m apart. Teachers wore masks. The sleeping residences for the 127 students were tightly spaced, with shared bathrooms and common areas. Counsellors and staff members resided separately. 

Extensive and rapid transmission of SARS-CoV-2 occurred, especially amongst the students, of whom 100 were affected; 15 counsellors and 1 staff member were also affected. 24 attendees had previous positive serologic results. The attack rate in the susceptible attendees who were not positive was 91%.

Confirmed COVID-19 cases were defined by a positive SARS-CoV-2 RT-PCR test result and occurred in 64 of the 127 students (52%); in 14 of the 21 counsellors (67%); and in none of the staff members. Probable cases were defined by an illness meeting clinical criteria for COVID-19 with symptom onset during the retreat and occurred in 36 students (28%), 1 counsellor (5%) and 1 staff member (25%).

Only one person was asymptomatic. The remainder had mild to moderate symptoms. None required admission to hospital and no deaths occurred.

Conclusions

The authors conclude that SARS-CoV-2 can spread rapidly among adolescents and young adults in a setting with inadequate COVID-19 mitigation measures. They observed that of 24 attendees who had documented evidence of antibodies to SARS-CoV-2 before arrival, none tested positive for SARS-CoV-2 RT-PCR at the retreat, suggesting a possible protective effect. The authors recommend that a robust COVID-19 mitigation plan developed in collaboration with public health authorities is important for preventing and containing similar outbreaks at overnight camps and residential schools. 

Cai, J., X. Wang, J. Zhao, Y et al.  “Comparison of Clinical and Epidemiological Characteristics of Asymptomatic and Symptomatic SARS-CoV-2 Infection in Children.” Virol Sin: 1-8. https://doi.org/10.1007/s12250-020-00312-4

Chinese researchers are ahead of the rest of the world in Covid-19 research, not just because the pandemic struck them first, but also because they immediately set about the detailed and systematic investigation of their cases. This important paper gives extensive data on all 49 children with SARS-CoV-2 infection confirmed by RT-PCR in Shanghai between 19th January and 30th April 2020. Of these 21 (43%) were asymptomatic. 38 (78%) were imported from outside China (mostly from Europe and the US), and their policy of screening all new arrivals might explain this high proportion. There will have been many more domestic asymptomatic cases that were never detected, so this is not an estimate of population prevalence. None of the asymptomatic cases subsequently became symptomatic.  43% had had contact with confirmed or suspected Covid-19 cases, mostly household.

All these children (mean age 11.5 +/-5.1 years) were admitted to hospital, even if asymptomatic until two nasopharyngeal PCR swabs were negative 24 hours apart. They were then followed up for 2 weeks. None became seriously ill. The most common symptoms, as expected, were cough (43%) and fever (33%), which was mostly < 39˚C and lasted a mean 2.5 days; but significant numbers had a sore throat (16%) and rhinorrhoea (14%). 40/49 underwent chest CT scanning and/or chest X-ray, including, controversially, some of the asymptomatic children. Lung lesions – ground-glass opacities and patchy infiltrates – were found in 20 of these, including 5 who had no symptoms. Only 1 progressed to clinical pneumonia, treated with Azithromycin. Blood tests were largely unremarkable: most had normal cell counts and CRP levels.

They also did sequential IgG and IgM SARS-CoV-2 specific antibody tests: 28% of the symptomatic children had positive antibodies at diagnosis, rising to 36% after 14 days. By contrast, 67% of the asymptomatic group were antibody positive at diagnosis, perhaps because they had unknowingly had the infection for longer. 

An important epidemiological observation was viral shedding: nasopharyngeal swabs remained PCR positive for around 14 days, with little difference between the symptomatic and asymptomatic groups. They also tested stool sequentially for viral RNA: surprisingly, this remained PCR positive for much longer: mean 31 (+/- 19) days in those with symptoms, and 28 (+/-13) days in those without. None had diarrhoea at any stage.

The public health implications of this are significant: asymptomatic children remain PCR- positive just as long as those with symptoms. Also, we do not yet know to what extent faecal-oral transmission might occur. In the meantime, we should be encouraging good toilet hygiene for all.

Forbes, K et al, Association between living with children and outcomes from COVID-19: an OpenSAFELY cohort study of 12 million adults in England, medRxiv, November 2nd 2020, https://doi.org/10.1101/2020.11.01.20222315

Study Question: Does living with children alter the risk in adults of SARS-CoV-2 infection and its outcome compared to not living with children?

Background: This study addresses the issue of the role of children in the transmission of SARS-CoV-2.

Methods: This was a large, population-based cohort study involving 40% of the population in England. The exposure was children in the household, classified into 3 subgroups: no children under 18 years in household, any child aged 0 to 11 years in the household and no children in the 0 – 11 age group in the household but at least one or more children aged 12 to 18 years in the household.

There were 5 outcomes:

  1. Evidence of SARS-CoV-2 infection recorded in primary care defined as a code indicating either a clinical diagnosis a positive swab test or sequelae from COVID-19
  2. Hospital admission with ICD-10 code indicating COVID-19 in the primary diagnosis field
  3. ICU admission with COVID-19 
  4. COVID-19 related death 
  5. Post hoc non-COVID-19 death from death certificate 

This study was done through OpenSAFELY, a data analytics platform created on behalf of NHS England to address urgent COVID-19 research questions. It links the Primary Care records of 24 million people (40% of England’s population) currently registered with GP surgeries which use The Phoenix Partnership (TPP) SystmOne software. The records are linked to Secondary Uses Service (SUS) hospital admissions, to Intensive Care National Audit & Research Centre (ICNARC) COVID-19-related Intensive Care Unit (ICU) admissions and to the Office for National Statistics (ONS) mortality records. The study population included all adults aged ≥18 years, registered and active for three months, in an English TPP general practice on 1st February 2020.

Multivariate Cox regression Hazard Ratios (HRs) were obtained from data from 1st Feb to 3rd Aug 2020 for each of the 5 outcomes, comparing adults living with and without children in the household, allowing for clustering, stratifying by geographic area to allow for regional variation in infection rates.  HRs were adjusted for: age, sex, ethnicity, number adults in the household, IMD, BMI, smoking, hypertension or high blood pressure, chronic respiratory disease, asthma, cancer, chronic liver disease, stroke or dementia, other neurological diseases, reduced kidney function, end-stage renal disease, solid organ transplant, asplenia, rheumatoid, lupus or psoriasis, other immunosuppressive condition. 

Results: there were 9,157,814 adults aged ≤65 years and 2,567,671 aged >65y (after exclusions of households with less than 3 months at the GP practice, households without ID, households with more than 10 people and care homes, households missing basic demographics (age, sex, ethnicity)). 

Number of children under 18 years: 5738498

28% of ≤65s lived with children under 11y and 9% lived with children aged 12-18 years.

2.3% of >65s lived with children under 11y and 1.1% lived with children aged 12-18 years

Risk in adults aged ≤65 years:

  • who live with children aged 0 to 11 years: 

There was no association with increased risk of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission. There was a reduction in the risk of dying from COVID-19 (HR 0.75, 95%CI 0.62 – 0.92).

  • who live with children aged 12 to 18 years:

There was a small increase in recorded infection (HR 1.08, 95%CI 1.03-1.13), but no association with hospital, ICU admission or death from COVID-19.

Risk in adults aged >65 years:

  • who live with children aged 0 to 11 years: 

There was no evidence of association with any outcome.

  • who live with children aged 12 to 18 years:

There was no evidence of association with any outcome.

Living with children of any age was associated with a lower risk of dying from non-COVID-19 causes in the ≤65 years but no association was seen in the >65 group.

Extensive sensitivity analyses which included for example, assumptions on the distribution of high- risk occupations, didn’t materially alter the results from the comorbidity adjusted models, although there were higher recorded infections in the period three weeks after school closures. However, there was no increased risk for any of the other outcomes. There was no evidence of a “dose-response” related to the number of children in the household.

Interpretation: the data shows that at a population level, transmission from school-age children does not result in an increased risk of serious outcomes from COVID-19 among the adults they live with. Crucially, this study found no evidence of severe outcomes of COVID-19 comparing periods before and after school closures.

Comments: this is a carefully conducted, large scale population-based study. It is powered enough to look at several outcomes and has taken into account many potential confounders as well as looking for important interactions.  

Chris Gale, Maria A Quigley, Anna Placzek, Marian Knight, Shamez Ladhani, Elizabeth S Draper, Don Sharkey, Cora Doherty, Helen Mactier, Jennifer J Kurinczuk, Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance, Lancet Child Adolesc Health, November 9th 2020, https://doi.org/10.1016/S2352-4642(20)30342-4 

The aim of this prospective study, reported by an eminent group of perinatal epidemiologists and academic clinicians, was to measure the population-level incidence, characteristics, transmission and outcomes of SARS-CoV-2 infection in neonates in the UK who received inpatient treatment for the infection in hospital. The data collection period was two months (1st March 2020 – 30th April 2020).

The data sources for identification of infected babies were the British Paediatric Surveillance Unit linked to national testing, the obstetrics surveillance database and paediatric intensive care (PIC) audit data. The defined outcomes included the UK incidence of (hospital-based) neonatal SARS-CoV-2, the incidence of severe neonatal SARS-CoV-2 disease, the proportion of these babies who acquired the infection by “vertical” transmission, the proportion who acquired the infection nosocomially and the clinical outcomes for infected babies.

A total of 66 infected babies met the inclusion criteria, giving an incidence of 5·6 [95% CI 4·3–7·1] per 10,000 live births during those two months. Of these, 28 (42%) had severe neonatal SARS-CoV-2 infection (incidence 2·4 [1·6–3·4] per10000 livebirths) and 16 (24%) were preterm. The criteria for “severe” follow the initial Dong et al paper, with any 2 of temperature >37.5, apnoea, cough, tachypnoea, respiratory distress, oxygen requirement, poor feeding, vomiting or diarrhoea, plus one of low WCC, low lymphocytes, or CRP >5mg/L and: abnormal chest x-ray.

The most common signs at presentation were hyperthermia and poor feeding or vomiting but respiratory signs were also reported to be common. Of those tested, 55% had a raised serum lactate (>2mmol/L), 29% had a CRP >5mg/L and 9% had a low lymphocyte count.

With regard to ethnicity:

– 36 (55%) babies were from white ethnic groups (incidence 4·6 [3·2–6·4] per 10,000 livebirths) – 14 (21%) were from Asian ethnic groups (incidence 15·2 [8·3–25·5] per 10000 livebirths) – 8 (12%) were from Black ethnic groups (incidence 18·0 [7·8–35·5] per 10000 livebirths)
– 7 (11%) were from mixed/other ethnic groups (incidence 5·6 [2·2–11·5] per 10000 livebirths). 

With regard to route of transmission: 

– 17 (26%) babies were born to mothers with known perinatal SARS-CoV-2 infection
– 2 (3%) were considered to have possible vertically acquired infection (SARS-CoV-2-positive
                 sample within 12 hours of birth where the mother was also positive)
– 8 (12%) babies had suspected nosocomially acquired infection. 

With regard to outcome:

– median length of stay was 7 days (IQR* 2-55) for babies admitted to a neonatal unit and 2 days  (IQR* 0-4) for those admitted to a PIC unit
– 58 (88%) babies had been discharged home by July 28, 2020
– 7 (11%) were still admitted on July 28th
– 1 (2%) had died of a cause unrelated to SARS-CoV-2 infection
– 42% of neonates met the criteria for severe disease compared with 6% of older children,   indicating that disease severity is greater in infected neonates.

A number of limitations of this study are acknowledged by the authors, including the limited range of data available from the surveillance sources; the cross-sectional nature of the data; the low frequency of testing of neonates at 12 hours which compromises the estimation of vertical transmission; the absence of longitudinal data relating to the relationship between breastfeeding and SARS-CoV-2; the inability to estimate overall infection rates in the population as the study was confined to hospital patients.

Key messages from this study are: the high proportion of babies from Black, Asian, or minority ethnic groups requires further investigation; separation of newborn babies from their SARS-CoV-2 positive mothers is not justified; disease severity appears to be greater in neonates than older children. 

Woolworth, KR et al. Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 2020.  MMWR Morb Mortal Wkly Rep 2020;69:1635–1640. DOI: http://dx.doi.org/10.15585/mmwr.mm6944e2

This is a large cohort study of pregnant women with SARS-CoV-2 in the USA gathered through the SET-NET notifiable disease network covering multiple jurisdictions across the country. 5,252 pregnant women testing positive for SARS-CoV-2 were reported on.

Among the 3,912 infants with known gestational age born to women with SARS-CoV-2 infection, 12.9% were preterm (<37 weeks), higher than a US national estimate of 10.2%. The authors state that the data is preliminary and describe primarily women with second and third-trimester infection, and their findings are subject to change pending the completion of pregnancy for all women in the cohort and enhanced efforts to improve reporting of gestational age. This finding is consistent with other CDC reports describing higher proportions of preterm births among women hospitalized at the time of SARS-CoV-2 infection and includes outcomes for women hospitalized as well as those not hospitalized at the time of infection (representing a population including persons with less severe illness). Studies comparing pregnant women with and without COVID-19 are needed to assess the actual risk of preterm birth.

Non-Hispanic Black and Hispanic women were disproportionally represented in this surveillance cohort. Racial and ethnic disparities exist for maternal morbidity, mortality, and adverse birth outcomes and the higher incidence and increased severity of COVID-19 among women. This means national rates of preterm birth might not be directly comparable. 

Further surveillance efforts, including reporting by additional jurisdictions to improve representativeness, and careful analysis of outcomes by race and ethnicity, will permit more direct and targeted public health action. 

Information regarding the frequency and severity of perinatal (potentially including in utero, peripartum, and postnatal) infection is lacking.  The American Academy of Paediatrics and CDC recommends testing all infants born to mothers with suspected or confirmed COVID-19 however, testing results were infrequently reported in this cohort. 

Perinatal infection was uncommon, affecting only 16/610 (2.6%) infants known to have been tested for SARS-CoV-2 and occurred primarily among infants born to women with infection within 1 week of delivery. 

Among the infants with positive test results, one half were born preterm, which might reflect higher rates of screening in the ICU. These findings also support the growing evidence that although severe COVID-19 does occur in neonates the majority of term neonates experience an asymptomatic infection or mild disease, however, information on long term outcomes among exposed infants is unknown.

Knight, K. Bunch, N. Vousden et al. Characteristics and outcomes of pregnant women hospitalised with confirmed SARS-CoV 2 infection in the UK: A national cohort study using UK obstetric surveillance system. Nuffield Department of Population Health, UKOSS Publications 11th May 2020, https://doi.org/10.1101/2020.05.08.20089268

As a pre print this study should be interpreted with caution until it has undergone peer review.

This is a prospective observational national cohort study carried out across all 194 consultant-led maternity units in the UK. It captured data from women admitted to hospital with confirmed SARS CoV 2 between 01/03/20 and 14/04/20, with tests having been carried out only if the woman was symptomatic. 427 women were studied and compared to a historical control sample of 694 women admitted between 01/11/17 – 31/10/18 (a historical sample was chosen to avoid confounding by including asymptomatic or minimally symptomatic carriers of COVID). The total number of maternities in the study period was 86293 and therefore the incidence of admission the SARS CoV 2 confirmed women was 4.9 per 1000 maternities. The median gestation at admission was 34 weeks (IQR 29-38 weeks), with 81% of admissions in the 3rd trimester. The results showed that there was a statistically significant risk of admission with SARS CoV 2 patients who had the following factors:

From a Black and Minority Ethnicity group: adjusted OR 4.49 (3.37-6.00). Even after sensitivity analysis which excluded women from London, West Midlands and North West England which had high rates of general infection OR 3.67 (2.55-5.28)

Overweight: adjusted OR 1.91 (1.37-2.68)

Obese: adjusted OR 2.20 (1.56-3.10)

Pre-existing medical condition (asthma, hypertension, cardiac disease or diabetes): adjusted OR 1.52 (1.12-2.06)

Maternal age ≥ 35: adjusted OR 1.35 (1.01-1.81)

Being a current smoker reduced the risk of admission, with adjusted OR 0.3 (0.17-0.51).

The odds ratio for each significant factor outlined above was adjusted for the other significant factors which became confounding variables. There were 40 admission to level 3 critical care with 4 requiring ECMO. There were 5 maternal deaths recorded, 3 of whom had been admitted to critical care. SARS CoV 2 associated maternal mortality was 5.6 (1.3-13.1) per 100,000. Only 9 women were treated with antivirals (oseltamivir, lopinavir/ritonavir and/or remdesivir). 61 women were given corticosteroids for the maturation of fetal lung.

247 women in this cohort gave birth (singleton/multip proportion not stated) to a live infant (n=243) or had a pregnancy loss (n=4). 59% of women gave birth via c-section with 20% under general anaesthetic compared to 29% of the control group with 7% of women delivering under GA. There were 63 (26%) preterm births (<37 weeks) and 29 of these were documented as being secondary to COVID 19 infection; the other reasons stated were iatrogenic, fetal compromise and other obstetric conditions. This is compared to 8.9% of births in the control group being born preterm. There were 5 neonatal deaths, including 3 stillbirth; in two of the cases of stillbirths, it is unclear whether COVID 19 infection contributed to death. The rate of pregnancy loss, still birth, livebirth and neonatal death was not statistically different between the groups. The NICU admission rate was 26% (majority for prematurity) and 5% in the cohort and comparison groups, respectively. 12 infants tested positive for SARS CoV 2, with 6 being within the first 12 hours of life (early). 1 in the early positive and 5 in the later positive groups were admitted to NICU.

This is a national study reporting on the largest cohort of SARS CoV 2 positive pregnant women admitted to hospitals with symptoms. There is likely to be an underestimation of the true effect size presented in this report as analysis was carried out in only those patient in whom data was returned and not on the entire cohort of admissions in the specified time period.  The results convincingly show important risk factors (maternal age, black and minority ethnicity, BMI, and pre-existing medical condition) for admission and thus confers the severe of infection in these risk groups. The black and minority ethnicity risk factor, which existed even after the sensitivity analysis, requires urgent further analysis and study as it was the biggest risk factor and one which has not been demonstrated to be the case in other coronavirus strains. The supposed protective factor of current smoker status is not explained in this report but could reflect lower current prevalence of smoking in pregnancy in general compared to the prevalence at the time of the historical sample. The report also highlights that most of the admission with SARS CoV 2 was in the second and third trimester thus providing weight for the precautions currently being taken in this group of women. However, they also correctly identify that there may be a sampling bias as those in the first trimester may be being admitted to hospital via routes other than the maternity services. There was a higher rate of preterm deliveries (statistical significance unknown) which is difficult to interpret but raises questions as to what extent the maternal infection may cause fetal compromise triggering preterm birth.

2% of babies tested positive for SARS CoV 2 suggesting a risk of vertical transmission, especially since 3 of the positive cases were pre-labour, c-section delivered babies. However, the IgG or IgM status of the infants is unknown and there were no placental, umbilical cord, etc samples taken/reported. The discussion states that mothers and infants were kept together with infection control measures (surgical face masks) and the low rates of neonatal infection supports continuation of this practice. However, 6 of the 12 infants testing positive for SARS CoV2 required neonatal unit admission, majority of whom were classed as late infections as they tested positive after 12 hours of life. There is no information provided on the reason for these admissions and what support and/or treatment was required during this time. It is important to point out that the report does not specially say that all other infants born to this cohort of mothers were tested for SARS CoV 2 and found to be negative. Further questions are raised in the two cases of stillbirth which may have been caused by COVID 19. There is also no clarification on the characteristics of the cases of neonatal death (e.g. were they preterm, was mother critically ill in ITU, etc) which would have added greatly to the analysis of this report.

Although this study does not provide enough detail to draw firm conclusions, it provides an important basis for further avenues where research is needed.

Zeng L, Xia S, Yuan W et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatr. Published online March 26, 2020. doi:10.1001/jamapediatrics.2020.0878

This is a cohort study following 33 neonates born to COVID-19 positive mothers, recruited Wuhan Children’s Hospital, Hubei Province, China, between January 2020 and February 2020. The authors describe three cases of early-onset neonatal COVID-19, which they suggest implies vertical transmission. However, amniotic fluid, cord blood and maternal breast milk of the mothers of all 3 positive neonates were negative for SARS-CoV-2, therefore it is unclear whether the infection was transmitted vertically or environmentally.

Three of the 33 neonates tested positive for COVID-19 on day 2 of life (positive nasopharyngeal or anal swabs). All 3 were born by caesarean section, two at term and the third at 31+2 for premature rupture of membranes and foetal distress.

Clinical features: The two term COVID-19 positive neonates had fever, although the authors don’t define what temperature they consider fever. These two neonates were also lethargic, but neither had respiratory distress. Neonate 3 was the most unwell, although this may be due to prematurity, poor condition at birth and sepsis rather than COVID-19. He was born at 31+2, required resuscitation at birth and had poor Apgars of 3, 4 and 5 at 1, 5 and 10 minutes, requiring non-invasive ventilation for respiratory distress. His blood cultures were positive for Enterobacter agglomerates.

Bloods: Neonate 1 (fever and lethargy) had normal bloods except raised procalcitonin (0.09 microgram/L). Neonate 2 (fever, lethargy and vomiting) had a leucocytosis, lymphocytopenia and elevated CK. Neonate 3 (premature with sepsis) had leucocytosis, thrombocytopenia and coagulopathy with prolonged PT (21 sec) and APTT (81.9 sec).

Radiology: All 3 had radiological evidence of pneumonia on CXR.

The authors state that because strict infection control and infection prevention procedures were implemented during delivery, SARS-CoV-2 isolated from their upper respiratory tracts or anuses was therefore maternal in origin. However, although it is stated in the illustration that one neonate was immediately quarantined after birth, it’s not clear whether this was the case for the other two babies. Plus, the negative amniotic fluid and cord blood does raise the question as to whether these neonates were truly infected in utero or not.

Yu, Nan et al Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study, The Lancet Infectious Diseases, Volume 0, Issue 0, Published:March 24, 2020 DOI:https://doi.org/10.1016/S1473-3099(20)30176-6

This is a retrospective study of 7 pregnant mothers infected with COVID-19 between Jan 1st and Feb 8th at Tongji Hospital in Wuhan, China. They were all at term (range 37/40 – 41+2/40). The mothers were all symptomatic, mainly with fever, cough, shortness of breath and diarrhoea. They all delivered via emergency caesarian section. All mothers did well.

The babies were all born with normal apgars. 4 babies were discharged home and not tested for SARS-CoV-2 and never developed symptoms (including at 28d follow up phone call. 3 children were tested, of which one was positive at age 36hrs (reported in separate study, Wang et.al Clinical infectious Diseases, but did well with no fever or cough and mild shortness of breath). The other 2 tested negative and were later discharged without complication.

Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; 395 :809–15. doi:10.1016/S0140-6736(20)30360-3

This retrospective case series looks at 9 pregnant women who were positive for COVID19 in Wuhan University Hospital between Jan 20th and Jan 31st. They all underwent a caesarean section (between 36 and 39+4 gestation). All newborn babies were well with good APGARS and, importantly, tests from 6 (3 not tested) patients were negative for SARS-CoV-2 in all amniotic fluid, cord blood, neonatal throat swabs, and breastmilk samples. There was no evidence of vertical transmission.

Dong L, Tian J, Songming H et al. Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4621

This is a case report that would suggest that vertical transmission of COVID-19 can occur. A 34+2 primiparous woman was diagnosed with COVID-19 (she was symptomatic with fever and respiratory difficulty and had classic CT chest findings and a positive nasopharyngeal swab for SARS-CoV-2). She was treated with antiviral medications, antibiotics and corticosteroids.

Her female infant was delivered by caesarean section 4 weeks after the onset of her mother’s symptoms in good condition with Apgars of 9 and 10. Although the infant’s nasopharyngeal swabs were negative, her IgM antibodies against SARS-CoV-2 were raised at 2 hours post delivery and cytokine levels were elevated. The risk of environmental infection was minimised: the caesarean was performed in a negative pressure room, the mother wore an N95 mask and did not hold her infant and the infant was immediately isolated in NICU. Maternal vaginal secretions were negative for SARS-CoV-2, which would also suggest the infection did not happen at birth. As IgM antibodies do not cross the placenta, the infant’s elevated IgM antibody levels suggest that she was infected in utero. Moreover, IgM antibodies usually do not appear until 3 to 7 days after infection. The infant also had raised IgG antibodies, but IgG is transferred placentally so this may reflect maternal or infant infection. The mother’s breast milk was negative for SARS-CoV-2 1 week following delivery.

Zeng H, Xu C, Fan J, et al. Antibodies in Infants Born to Mothers With COVID-19 Pneumonia. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4861

This report outlines the course of 6 mothers who were symptomatic for COVID-19 in their last trimester, and gave birth to 6 liveborn infants. This study is notable for antibody testing of both mothers and infants. The accuracy of the antibody tests are suspiciously high given current struggles to produce adequate tests around the world, and should be treated with a high degree of caution.

All 6 infants were born in good condition, and all tested negative for SARS-CoV-2 viral throat swabs and blood PCR. Unsurprisingly all infants had elevated IgG or SARS-CoV-2 (as this crosses the placenta), but notably 2 infants had raised IgM (39.9AU/ml and 16.25AU/ml). This raises the possibility of intrauterine infection, similar to another case of an infant with raised IgM (Dong et al JAMA). Issues with cross reactivity of IgM are well described, and so whilst full validation of these tests is awaited internationally, this should be treated with caution.

Liu, Yangli et al. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy.Journal of Infection, Volume 0, Issue 0 https://doi.org/10.1016/j.jinf.2020.02.028

This is a small case series of 13 pregnant women with confirmed SARS-CoV-2 infection between December 8 2019 and February 25 2020, in China. Two women were <28 weeks at presentation, the remainder were in the third trimester. One infant was stillborn, the 12 remaining infants (92%) were well at birth with no complications. None were positive for SARS-CoV2 or had ‘serological evidence’ of vertical transmission. The method of testing neonates was not clearly defined. The stillborn neonate had a mother who was severely unwell on Extracorporeal Membrane Oxygenation (ECMO) at the time of delivery.

Five of the 10 patients (50%) were delivered by emergency cesarean section due to pregnancy complications including fetal distress (30%), premature rupture of the membrane (10%) and stillbirth (10%). Interestingly, six patients (46%) had preterm labour between 32- 36 weeks of gestation.

Han, M. S., M. W. Seong, E. Y. Heo, J. H. Park, N. Kim, S. Shin, S. I. Cho, S. S. Park and E. H. Choi (2020). “Sequential analysis of viral load in a neonate and her mother infected with SARS-CoV-2.” Clin Infect Dis. https://doi.org/10.1093/cid/ciaa447

This is a case report of a 27 day-old female neonate with confirmed SARS-CoV-2 infection. Over the course of a short and reasonably mild illness, samples were tested from the nasopharynx, oropharynx, plasma, urine, stool and saliva. SARS-CoV-2 RNA was detected in all samples. Early in the infection, viral load was highest in the nasopharynx and oropharynx, decreasing to undetectable at day 17. Viral load in stool, however, remained high throughout, despite cessation of gastrointestinal symptoms. This was in contrast to the mother’s stool sample in which viral load was undetectable earlier.

Groß, C. Conzelmann, J. A. Müller, S. Stenger, K. Steinhart, F. Kirchhoff and J. Münch. Detection of SARS-CoV-2 in human breastmilk. Lancet, May 21st 2020, https://doi.org/10.1016/S0140-6736(20)31181-8

This report is presented as a letter.

The study primarily relates to the SARS­CoV­2 content of the breast milk of two “nursing mothers” who shared a room postnatally, with their babies, and who developed swab-positive mild Covid-19 infection after birth – three days and six days respectively. The gestation and birthweights of the babies are not reported but they seem to have been full term, well at birth and initially well for the first few days following delivery.

The babies developed abnormal respiratory signs, one with jaundice, at 8 days and 11 days respectively, both becoming swab positive for SARS­CoV­2 at about the same ages and both being admitted to a Neonatal Unit. One infant, who also tested positive for RSV, subsequently required mechanical ventilation. It is stated that one infant recovered but the outcome for the ventilated infant is not given.

The patient identification and recruitment processes are not described.

Breast milk was collected, after feeds and after nipple disinfection, from each mother starting at eight days and four days respectively after development of Covid-19 symptoms. Samples were collected on postnatal days 12-15 for the first mother and 10, 12, 13, 14 and 25 for the second. Testing for SARS­CoV­2 RNA was performed using RT­qPCR.  Information on the method of nipple disinfection is not provided.

A separate laboratory-based study investigated the effect of breast milk on viral recovery rates by “spiking” breast milk with serial dilutions of a SARS­CoV­2 stock.

The main findings of potential importance are:

  1. The breast milk of one of the mothers tested positive for SARS­CoV­2 RNA at 10-13 days after birth. Testing of breast milk from the other mother was negative.
  2. Quantification using Ct values corresponded to 1∙32 × 10⁵ copies per mL in whole milk and 9∙48 × 10⁴ copies per mL in skimmed milk.
  3. An 89∙2% reduction in recovery rate in whole milk and 51∙5% in skimmed milk, suggesting that the actual viral loads in whole milk of the mother could be even higher than detected.

This study provides the first report of the detection of viral RNA in human breast milk collected from a mother who had clinical signs of Covid-19 confirmed by PCR testing of swabs. This does not provide evidence that the RNA was indicative of infectious virus or that transmission of the virus to the baby occurred via breastmilk. Further studies will be necessary to attempt to culture virus from breast milk and assess risk of transmission, which to date has seemed low.

Li, M., L. Chen, J. Zhang, C. Xiong and X. Li (2020). “The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study.” PLoS One 15(4): e0230295. https://doi.org/10.1371/journal.pone.0230295

The study explores the presence of Angiotensin-converting enzyme 2 (ACE2) within the placenta and the developing baby. It demonstrates significant expression of RNA coding the for ACE2 protein at several points of the maternal-foetal interface, as well as variable expression in a number of foetal organs. This theoretically provides a potential route for vertical transmission, placental dysfunction and pregnancy complications. The authors call for further clinical analysis to establish this potential.

Swann Olivia V, Holden Karl A, Turtle Lance, Pollock Louisa, Fairfield Cameron J, Drake Thomas M et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. August 27th 2020, https://doi.org/10.1136/bmj.m3249

This large prospective observational study from 260 hospitals in the UK examines the clinical characteristics of children (<19yo) hospitalised with laboratory confirmed SARS-CoV-2 infection between 17th January and 3rd July 2020; as part of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK cohort. The main outcome measures were admission to critical care, in-hospital mortality and MIS-C.

Results; A total of 651 children admitted to 138 hospitals were included; median age was 4.6 (IQR 0.3-13.7); 35% were <12 months of age. Of patients with recorded ethnicity 57% were white, 12% south asian and 10% black. 56% were male and 42% had identified co-morbidities. 

Symptoms; The most common symptoms were fever (70%), cough (35%) nausea / vomiting (32%) and dyspnoea (30%). Three distinct clusters of symptoms were identified: – a discreet respiratory illness – cough, fever, dyspnoea, coryza and wheeze – a mucocutaneous enteric illness – headache, myalgia, sore throat, vomiting, abdominal pain, diarrhoea, fatigue, rash, lymphadenopathy and conjunctivitis – a rarer neurological illness – seizures and confusion

Critical care and mortality; Critical care admission occurred in 18% (116/632); 8% received inotropic support; 9% received non-invasive and invasive ventilation respectively. Children of black ethnicity had higher odds of critical care admission (OR 2.82). Infants <1mo (OR 3.21, 95% CI 1.36-7.66) and children 10-14 yo (OR 3.23, 95% CI 1.55-6.99) were also more likely to be admitted to critical care. Co-morbidities including prematurity, respiratory and cardiac co-morbidities and obesity were more common in those with critical care admission compared with those receiving ward care. Six (1%) of patients died in hospital, all had serious comorbidities; 89% of children had been discharged alive and 10% remained in hospital at the time of reporting.

MIS-C; Based on the preliminary WHO case definition, 11% (52/456) of admitted children fulfilled diagnostic criteria for MIS-C. Children with MIS-C were older than those without (median 10.7 yo vs 1.6 yo) and were more likely to be of non-white ethnicity (64% vs 42%); obesity was also more common amongst those with MIS-C (10% vs 2%). Children with MIS-C were more likely to require critical care admission (73% vs 15%), receive inotropes (51%), invasive (27%) and non-invasive (35%) ventilation. There were no deaths due to MIS-C.

Of children with MIS-C differences were noted between those who were SARS-CoV-2 PCR positive (acute phase of infection – 56%) and those who were antibody positive (post-acute phase of infection – 44%). Antibody positive MIS-C patients were more likely to be of non-white ethnicity (90% vs 45%), less likely to be obese (0% vs 19%), and more likely to have conjunctivitis (71% vs 16%) and abdominal pain (95% vs 44%) compared to those who were PCR positive. Dyspnoea was more common in PCR positive patients (52% vs 14%). Cardiac complications were also more common in the antibody positive group (75% vs 35%).

Conclusion; The findings of this large prospective study are consistent with previous studies indicating that children represent a small proportion of hospitalised cases of COVID-19 (0.9% here), that outcomes in children are generally favourable and that death due to COVID-19 in children is rare. Similar to previous studies, fever and cough were the most common symptoms, although gastrointestinal symptoms (35%) were more common in this cohort; the identification of a mucocutaneous-enteric symptom cluster with overlap with WHO MIS-C criteria is a novel finding here. Children of black ethnicity were over-represented in overall cases, as well as amongst children admitted to critical care units, consistent with adult data from the UK. Similarly, obesity was associated with increased risk of critical care admission. 

The association of MIS-C with older age and non-white ethnicity are consistent with previous studies. In addition to current WHO criteria, fatigue, headache, myalgia, sore throat and low platelet count were all associated with MIS-C.  The demographic and clinical differences identified between MIS-C patients who were antibody positive compared with those who were PCR positive suggest a spectrum of clinical presentation that varies according to phase of infection and immune response.

Götzinger, F., B. Santiago-García, A. Noguera-Julián, et al.  “COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.” Lancet Child Adolesc Health. 

This European multicentre cohort study recruited centres from the Paediatric Tuberculosis Network European Trials Groups, to look at 582 cases of paediatric (<18 years old) SARS-CoV-2 infection in 21 countries with 77 healthcare centres. Centres from five additional countries reported no SARS-CoV-2 cases at the time of the study. The breakdown of centres included 454 (78%) tertiary, 54 (9%) secondary and 74 (13%) primary healthcare providers.

Cases were collected retrospectively from identified cases prior to 1st April and prospectively between 1-24th April. The diagnosis was made based on RT-PCR of SARS-CoV-2 alone. The age group of the population was young, with a median age of 5 (IQR 0.5-12) and 230 (40%) under 2 years of age. Just over half were male (n=311, 53%).

Index case data was included from the history, with parents being the suspected case for 324 patients (56%) and siblings accounting for 24 cases (4%). However, a large number of cases (n=234, 40%) were either from someone outside of the immediate family or of unknown transmission.

The most common symptoms were fever (n=379, 65%) and respiratory symptoms (n=313, 54% URTI and n=143, 25% LRTI). 128 (2%) had gastrointestinal (GI) symptoms and 40 (7%) had GI symptoms without respiratory symptoms. Asymptomatic patients accounted for 16% of all cases (92). There was confirmed viral co-infection in 5% (n=29) of patients. The study did not capture laboratory values. A chest x-ray was performed in 34% (n=198) of patients. Almost half of the x-rays showed findings consistent with pneumonia and ten (5%) of ARDS.

Of the patients included in the study, a quarter (145) had pre-existing medical conditions. Twenty-nine patients had pre-existing respiratory conditions (asthma accounting for 16) and malignancy was known in 27 patients. The study collected data on antiviral treatments administered however numbers were small and depended on local practice.


Across the cohort 363 patients (62%) required hospital admission, 48 (8%) required ICU admission. Factors increasing risk of ICU admission (n=48) were found to be age <1 month (n=7/48, 14.6%) the presence of any pre-existing medical condition (n=25/48 52%) and presence of lower respiratory tract infection signs at time of presentation (n=35/48, 73%). Mechanical ventilation was required for 25 patients (4%) and ECMO was needed in one patient. Data on treatments given included antivirals: hydroxychloroquine (n=40, 7%), remdesivir (n=17, 3%), lopinavir-ritonavir (n=6, 1%) and oseltamivir (n=3, 1%). Other immunomodulators used were corticosteroids in 22 (4%), IvIG in 7 (1%), tocilizumab (n=4, 1%), anakinra (n=3, 1%) and siltuximab (n=1).

There were 4 deaths (0.69%), all of which were in children older than 10 years of age. Of the four deaths, one was an out of hospital cardiac arrest and two had pre-existing medical conditions; one patient had a stem cell transplant 15 months prior and another patient was managed palliatively due to their pre-existing illness. By the end of the study period, 553 patients had made a full recovery and 25 patients had ongoing symptoms.

This is one of the first multi-national European studies of SARS-CoV-2 in children. Common symptoms included respiratory and fever but gastrointestinal symptoms were present in over one-fifth of cases. Although eight percent of children required ICU admission, the case fatality rate was low at 0.69%. Children at greater risk of intensive care admission had pre-existing medical conditions, were less than 1 month old or presented with lower respiratory tract symptoms. Asymptomatic infection occurred in 16% of cases. Given that at the time of the study, there were varying practices for screening criteria, it is likely that the true proportion of asymptomatic patients is higher (and true case fatality rate lower)

Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi:10.1056/NEJMc2005073

This retrospective study examines the clinical characteristics of children with confirmed COVID-19 diagnosed at Wuhan Children’s hospital. There were 1391 children tested between Jan 28th and Feb 26th 2020 due to confirmed contact with a case of COVID-19. Of these, 171 were confirmed to have SARSCoV-2.  The median age was 6.7yrs, and there was a relatively even spread amongst age groups. Children were predominantly male (104/171, 60.8%).

Clinical features: 83/171 had cough, 79/171 had pharyngeal inflammation (sore throat), 71/171 had fever. 15/171 had diarrhoea and 13/171 had rhinorrhoea. 49/171 were tachypnoeic on admission and 72/171 were tachycardia. Only 4/171 had Oxygen saturations <92% during hospitalization. 0/31 infants <1yr were asymptomatic in this cohort, with rates of asymptomatic infection increasing with age. There were higher rates of pneumonia in infants (25/6), but their definition is unclear. We also have no information regarding co-infection with other viruses or bacteria.

Radiology: Not delineated into CXR or CT, but descriptions sound like CT findings. The most common was bilateral ground-glass opacity (56/171) followed by unilateral patchy shadowing (32/171) and bilateral patchy shadowing (21/171). There were several children with radiographic pneumonia who were asymptomatic.

Bloods: The supplementary appendix contains lab results. Only 6/171 patients had lymphopaenia, the vast majority were in normal range (Med 2.9×109/L, IQR 2.2 – 4.4). CRP was elevated (>10mg/L) in 33/171 (Med 4, IQR 1.3 – 8) of which 27/33 had pneumonia.

Outcomes: 3 patients required ITU admission and intubation. All 3 had comorbidities, including hydronephrosis, leukaemia, and intussusception. The child with intussusception suffered multiorgan failure and died after 4 weeks. The cause of death is not clear from the report. As of writing 149 patients had been discharged with 21 stable in the general wards.

Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi:10.1056/NEJMc2007617

This report covered confirmed COVID-19 infections in children under 18 years of age who presented to a research collaboration of 17 paediatric emergency departments in Italy between March 3rd and March 27th. The median age was 3.3 years and 57/100 were male. Children under 1 year were overrepresented (40%) followed by children >10yrs (24%).

Helpfully, the authors categorize their patients according to criteria from Dong et. al (see review in theEpidemiology top 10): Asymptomatic 21%, Mild 58%, Moderate 19%, Severe 1%, and Critical 1%. Only 12% of patients appeared ill on assessment. Interestingly only 4% of patients had oxygen saturations <94%. Only 38% of children needed admission for the severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below

Clinical features: Fever 54%, Cough 44%, Feeding difficulty 23%, Sore throat 4%, Rhinorrhoea 22%, Diarrhoea 9%, vomiting 10%.

Bloods: Largely unremarkable (although reports of lymphopenia unclear – state 14 patients lymphopenic but that this is 28%? – perhaps only 50 children had bloods, but this is not reported). Procalcitonin <0.5ng/L in 29/23 patients.

Radiology: Chest x-rays were performed for 35 children, of which 14/35 had interstitial abnormalities, 6/35 consolidation, and 1/35 pleural effusion: remaining 15/35 normal.

Comorbidities: There were 27/100 children with comorbidities – although it appears most had a mild illness (did not require respiratory support). This included 6 with cystic fibrosis, 4 neurological, 4 haematological, 4 with a syndrome, 3 with prematurity, 2 with cardiac conditions, 2 immunological, 2 ontological, and 1 metabolic disease.

Of the few patients that required respiratory support (9/100) a significant number had comorbidities (6/9), although the range was broad. This included two children with “epileptic encephalopathy”, one of whom also had CHARGE syndrome, a child with autism, a child with a VSD, a child with propionic acidemia, and a child with thrombocytopenia and frequent respiratory infections.

In comparison to Dong et al, the CDC data, and Lu et al, most features are broadly comparable. Some notable differences are a significantly larger number of infants in the Italian data (40% <1yr compared to 18% in Lu, 12% in Dong and 15.5% in CDC) and a slightly higher number of asymptomatic children (21% compared to 16% Lu, 13% Dong and 1.3% CDC). This most likely represents differences in the population cohorts presenting for testing among the different studies – comparison between cohorts is always difficult due to broad differences in the denominators used. There is no apparent difference in severity according to age in this Italian data set, whereas CDC noted increased hospitalization in children <1yr and Dong et al noted higher rates of severe or critical illness in infants <1yr.

Broadly speaking, this study confirms findings from China and the USA regarding the presence of significantly milder illness in children with COVID-19, including many asymptomatic children. A note is made of overrepresentation of children with comorbidities in this cohort (similar to the CDC data), although most of these still had mild illness. It is unclear if these children become more unwell, or are more likely to present to be tested.

DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics.  https://doi.org/10.1016/j.jpeds.2020.05.007

This is a retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at the Children’s National Hospital, Washington DC US. Children and young adults were detected because of presentation with symptoms at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalized, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features were associated with hospitalization, or critical care.  

This hospital served as a regional centre providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. The overall patient age range was from 0.1 – 34.2 years, with a median of 9.6 years. Of the total group 12/177 were > 20 years of age, and 37/177 were between the ages of 15 – 20years. 

Age: There was no significant difference in age between the hospitalized and non-hospitalized patients, however in the hospitalized cohort, the critically unwell group were significantly older than the non-critically unwell hospitalized group (17.3 years versus 3.6 years; P =.04) 

Sex: There was equal representation (n = 177 52% male, 48% female), as well as in the hospitalised cohort (n=44 50% male, 50% female). However, males made up 67% of the critically ill cohort (n =9, 67% male, 33% female); but this was not statistically significant (p=0.26)

Race/ethnicity: data not provided, authors describe plans to do so in follow up analysis 

Underlying conditions: 39% of positive patients had an underlying condition (classified as asthma, diabetes, neurological, obesity, cardiac, haematological, oncological). Though asthma was the most common underlying condition (35/177 20%), it was not more common in hospitalized patients (7/44 16%), nor of those admitted, or those who were critically unwell (2/9, 22%). Though the numbers were small, specific underlying conditions such as neurological, cardiac, haematological, or oncological issues were more common in the hospitalised cohort than the non hospitalised cohort. They were not more common in the hospitalized critically ill compared with the hospitalised non critically ill. The authors noted there was no underlying condition present in 96/177 (55%) of overall SARS-CoV-2 infected patients overall, 16/44 (37%) of hospitalized patients and in 2/9 (22%) of critically ill patients.

Symptoms:  76% of infected patients presented with respiratory symptoms (rhinorrhea, congestion, sore throat, cough, or shortness of breath) with or without fever. Fever was present in 116/177 (66%) but was not more common in the infected hospitalized cohort (34/44, 77%) compared with the non-hospitalized cohort (82/133, 62%; p=0.46). 

Shortness of breath was more common in the hospitalized cohort (11/44, 26%) compared with non-hospitalized (16/133, 12%; p=0.04). Patients in the critically ill cohort were not more likely to have a fever or any other specific symptom compared with the non-critically ill cohort.

Critical Care: 9 patients required critical care. This represented 5% (9/177) of the total cohort and 20% (9/44) of admitted patients. 4 required intubation (3 ARDS, 2 multiple organ failure); 3 required BiPAP, 1 RAM cannula, and one high flow nasal cannula oxygenation. One patient had features consistent with the recently emerged Kawasaki disease-like presentation with hyper-inflammatory state, hypotension, and profound myocardial depression; a 4 year male with no underlying conditions. 

Summary:  A very clear description of 177 patients with SARS-CoV-2, in one large centre in Washington DC. 25% of patients needed hospitalisation and 5% needed critical care. Older teenagers and adults who required admission were overrepresented in requiring critical care. Though underlying conditions were more common in hospitalized patients, they were not significantly more common in the hospitalized patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalized patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of the recently described hyperinflammatory state. 

de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6

This study examines the demographic and clinical risk factors for testing positive for SARS-CoV-2 amongst patients within a large primary care network in the UK. This included tests done through Public Health England and the UK National Health Service (NHS) between January 28th and April 4th 2020 with clinical and sociodemographic data extracted from patients’ primary care medical records.

Overall 587 of 3802 patient tests returned a positive result for SARS-CoV-2. Of children 4.6% (23/499) tested positive compared with 17.1% (564/3303) of adults.

In a multivariate logistic regression, adults had significantly higher odds of a positive test compared with children; those aged 40-64 (aOR 5.36, 95% CI 3.28-8.76) and >75 (aOR 5.23, 95% CI 3.00-9.09) were at highest risk.
Male sex (aOR 1.55, 95% CI 1.27-1.89), social deprivation (aOR 2.03, 95% CI 1.51-2.71), and black ethnicity (aOR 4.75, 95% CI 2.65-8.51) were also associated with an increased risk of a positive SARS-CoV -2 test. Of clinical factors, only chronic kidney disease (aOR 1.91, 95% CI 1.31-2.78) and obesity (aOR 1.41, 95% CI 1.04-1.91) were significantly associated with testing positive. Surprisingly, active smoking was associated with lower odds of a positive test (aOR 0.49, 95% CI 0.34-0.71) possibly due to presentation confounding (i.e. presence of cough in chronic smokers prompting increased testing in this group).


This is the first study to utilise primary care data to assess risk factors for testing positive for SARS-CoV-2 in the community. The risk factors identified are similar to those associated with severe COVID-19 in hospitalised patients including increased age, male sex and obesity. The higher odds of a positive test in adults compared with children here are consistent with other studies suggesting children are at lower risk of SARS-CoV-2 infection compared with adults.

González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06146-8

The Spanish Paediatric Intensive Care Society have published their findings of 50 children admitted to 47 PICUs in Spain between 1st March 2020 and 1st May 2020 with SARS-CoV-2. More than 90% of PICUs in Spain were represented in this national database. During the study period there were no deaths from SARS-CoV-2 in children admitted to PICU in the participating PICUs.

The authors divided the children into two groups: those requiring ventilation and those not requiring ventilation, to assess for different characteristics between these groups. Fourteen (28%) of the children were ventilated.  Twenty-seven (54%) of the 50 children in the study had suspected PIMS-TS; these children were less likely to require mechanical ventilation (4 of the 27 required ventilation) than those without PIMS-TS. Statistical significance between the two groups was found for age (median age of 2.8 years in the ventilated group, compared to 8.6 years in the non-ventilated group); co-morbidities (12, 24%, of the 50 children had comorbidities; 8 of these were ventilated); and clinical presentation with respiratory difficulties or an ARDS-type picture.

Overall, of the 50 children, 23 (46%) had haemodynamic instability, 20 (40%) had respiratory difficulties and 1 (2%) had neurological symptoms. Shock was present in half of the children (25, 50%), renal failure in 8 (15%) and cardiac dysfunction in 17 (34%). 

Across the 50 children, white cell count (median 9.26, IQR 5.64-14.46), lymphocytes (median 1.02, IQR 0.42-2.59) and CRP (median 13.9, IQR 4.9-27) were not statistically different between ventilated and non-ventilated children.

These are the preliminary findings from this national registry of children with SARS-CoV-2 admitted to PICU in Spain. Further results and analysis will provide more information regarding critically unwell children with COVID-19.

M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065

This study at a paediatric hospital in Rome tracked SARS-CoV-2 shedding (nasopharyngeal, faecal, urinary and conjunctival) by following a cohort of 22 children during their hospital stay, collecting clinical and microbiological data. 

Study design:  The study ran from 16th March to 12th April in the COVID centre at Bambino Gesu Pediatric Hospital and collected data on 22 in-patients with an initial positive nasopharyngeal swab (either prior to admission or on admission).  RT-PCR for SARS-CoV-2 RNA on nasopharyngeal and conjunctival swabs and stool and urine samples were repeated every 2-3 days for each child while they were inpatients until they had two consecutive negative results in the absence of new symptoms.  Kaplan-Meier analysis was used to estimate the duration of symptoms and viral shedding for symptomatic patients: patients whose last swab/sample was still positive were censored at the date of the last swab.

Study population:  15/22 (68%) male, 7/22 (32%) female.  Median age 7 years (range 8 days to 17.5 years).  4/22 neonates (1/4 tested because mother positive and 3/4 tested because midwife positive).  2/22 comorbidity (Angelman syndrome, suspected genetic syndrome and autism).  13/22 patients were discharged before the end of the study period (median inpatient stay 7 days, range 3-15 days).  

Symptoms:  4/22 (18%) asymptomatic (including 2/4 neonates, the other 2/4 had low-grade fever and poor feeding).  18 symptomatic patients: 15/18 (83%) fever, 10/18 (55%) respiratory symptoms, 7/18 (39%) diarrhoea and vomiting, 3/18 (17%) seizure.  Symptoms had resolved in all 18 before discharge from hospital.  The median duration of symptoms was 8 days (range 2-21 days).  15/22 had a positive stool sample at admission: of these 7/15 (47%) had respiratory symptoms and 3/15 (20%) had diarrhoea and vomiting.

Viral shedding:  At diagnosis: 22/22 (100%) had positive nasopharyngeal swab (by definition), 15/22 (68%) had positive stool sample, 1/22 (5%) had positive urine sample (re-test 2 and 5 days later was negative; another patient had initial negative urine test but repeat 3 days later was positive) and 2/22 (9%) had positive conjunctival swab (both were negative 2-3 days later).  A detailed table charting the dates of inpatient stay, onset, and end of symptoms and positive/negative swabs/samples for each patient is supplied: the full screen of faecal, urinary and conjunctival sampling was performed at variable intervals after the initial positive nasopharyngeal swab (up to 5 days later in several cases).  For symptomatic patients:  (1) from date of symptom onset to negative nasopharyngeal swab: median 8 days (range 2-17 days) and (2) from date of symptom onset to negative stool sample: median 14 days (range 10-15 days).  The estimate of the persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab was 52% and for stool sample 31%.

The authors note the need to confirm the clinical relevance of faecal SARS-CoV-2 shedding in terms of the risk of transmission via the faeco-oral route.

Galván Casas, C., Català, A., Carretero Hernández, et al. (2020), Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. Accepted Author Manuscript. doi:10.1111/bjd.19163

This article from a team in Spain aimed to classify cutaneous manifestations of COVID-19 and relate them to other clinical findings. 

From 3rd of April 2020 to 16th of April 2020 they collected 429 cases but excluded 54 leaving a sample of 375 patients. A standardised questionnaire was used, photographs were taken and the questionnaires and photographs were independently reviewed by 4 dermatologists.

Data was collected by Spanish dermatologists from across the country most of whom had been redeployed from their usual dermatology posts.

Patients with an eruption of recent onset (previous 2 weeks) and no clear explanation, plus suspected or confirmed COVID-19 were included.

They describe 5 cutaneous manifestations.

Acral areas of Erythema-oedema with some vesicles or pustules: 19% of cases. These were more likely in children.

Other vesicular eruptions: 9%. May also affect the limbs and have a haemorrhagic content, and become larger or diffuse.

Urticarial lesions: 19%. Mostly distributed in the trunk or disperse. A few cases were palmar.

Other maculopapular: 47%. Some showed perifollicular distribution and varying degrees of scaling, Some had been described as similar to pityriasis rosea.

Livedo or necrosis: 6%

Strengths of this study are the large number of patients recruited and that four dermatologists independently reviewed the images. It adds to the understanding of skin manifestations of COVID-19, which may give additional information when trying to make a clinical diagnosis of COVID-19 if other symptoms are non-specific, also the cutaneous manifestations may persist for some time once other symptoms have resolved.

A weakness is the authors did not specify the age of the patients involved so the usefulness for paediatric patients is limited. Also, in some areas, diagnosis of COVID-19 infection could only be made clinically, based on symptoms as the ability to test patients was limited during the height of the pandemic. 

Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041

In this study, 244 children with SARS-CoV-2 infection from Wuhan, China are compared to 44 children diagnosed with SARS (SARS-CoV-1) in in Hong Kong in 2003. 

The clinical details of this series of patients from Wuhan, previously described elsewhere, are compared with those of children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 months vs 160 months). Compared with SARS-CoV-1 patients, children with SARS CoV-2 were less likely to have symptoms (20.9% asymptomatic vs 0% of SARS-CoV-1), including fever (40.2% vs 97.7%), myalgia (37.6% vs 0.8%), and chills (32.6% vs 3.7%). 

Fewer children with SARS-CoV-2 required supplemental oxygen (4.7% vs 18.6%) and few in either cohort required mechanical ventilation (1.6% vs 2.3%). A single death occurred in a patient with SARS-CoV-2 (a 10 mo with intussusception) and no cases of PIMS-TS / MIS-C were identified amongst the 244 SARS-CoV-2 infected children from Wuhan.

The most striking difference is the milder clinical illness and relative lack of symptoms in children with SARs-CoV-2 compared with those with SARS-CoV-1. The lack of asymptomatic infections in SARS-CoV-1 is also notable, similar to findings in adults. Whilst the role of asymptomatic patients in the spread of SARS-CoV-2 is unresolved, the milder clinical illness in the majority of patients along with the demonstrated earlier peak in viral shedding relative to symptom onset and resultant role of pre-symptomatic transmission are likely major reasons for the continuing widespread transmission of SARS-CoV-2, where the outbreak of SARS-CoV-1 in 2003 was more readily contained.

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Please note that whilst all papers have been reviewed for the database and consideration of the overall updates, only selected papers which added new information at the time of publication had a formal review written. The sublists below also include the top ten papers for convenience.

Larger Cohort Clinical Papers 

Götzinger, F., B. Santiago-García, A. Noguera-Julián, et al.  “COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.” Lancet Child Adolesc Health. https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30177-2/fulltext

This European multi centre cohort study recruited from participating centres from  the Paediatric Tuberculosis Network European Trials Groups, to look at 582 cases of paediatric (<18 years old) SARS-CoV-2 infection in 21 countries with 77 healthcare centres. Centres from five additional countries reported no SARS-CoV-2 cases at the time of the study. The breakdown of centres included 454 (78%) tertiary, 54 (9%) secondary and 74 (13%) primary healthcare providers.

Cases were collected retrospectively from known cases prior to 1st April and prospectively between 1-24th April. Diagnosis was made on RT-PCR of SARS-CoV-2 alone. The age group of the population was young, with a median age of 5 (IQR 0.5-12) and 230 (40%) under 2 years of age. Just over half were male (n=311, 53%).

Index case data from history was included, with parents being the suspected index case for 324 patients (56%) and siblings accounting for 24 cases (4%). However a large number of cases (n=234, 40%) were either from someone outside of the immediate family or of unknown transmission.

The most common symptoms patients presented in were fever (n=379, 65%) and respiratory symptoms (n=313, 54% URTI and n=143, 25% LRTI). 128 (2%) had gastrointestinal (GI) symptoms and 40 (7%) had GI symptoms without respiratory symptoms. Asymptomatic patients accounted for 16% of all cases (92). There was confirmed viral co-infection in 5% (n=29) of patients. The study did not capture laboratory values. Chest x-ray was performed in 34% (n=198) of patients. Almost half of the x-rays showed findings consistent with pneumonia and ten (5%) of ARDS.

Of the patients in the study, a quarter (145) had pre-existing medical conditions. Twenty nine patients had pre-existing respiratory conditions (asthma accounting for 16) and malignancy was known in 27 patients. The study collected data on antiviral treatments administered however numbers were small and depended on local practice.

Across the cohort 363 patients (62%) required hospital admission, 48 (8%) required ICU admission. Factors increasing risk of ICU admission (n=48) were found to be age <1 month (n=7/48, 14.6%) the presence of any pre-existing medical condition (n=25/48 52%) and presence of lower respiratory tract infection signs at time of presentation (n=35/48, 73%). Mechanical ventilation was required by 25 patients (4%) and echo was used for 1 patient. Data on treatments given included antivirals: hydroxychloroquine (n=40, 7%), remdesivir (n=17, 3%), lopinavir-ritonavir (n=6, 1%) and oseltamivir (n=3, 1%). Other immunomodulators used were corticosteroids in 22 (4%), IvIG in 7 (1%), tocilizumab (n=4, 1%), anakinra (n=3, 1%) and siltuximab (n=1).

There were 4 deaths (0.69%), all of which were in children >10 years of age. Of the four deaths, one was an out of hospital cardiac arrest and two had pre-existing medical conditions; one patient had a stem cell transplant 15 months prior and another patient was managed palliatively due to their pre-existing illness. By time of end study 553 patients had made a full recovery and 25 patients had ongoing symptoms.

Overall, this is one of the first multi-national European studies of SARS-CoV-2 in children. Common symptoms included respiratory and fever but gastrointestinal symptoms were present in over one fifth of cases. Although eight percent of children required ICU admission, the case fatality rate was low at 0.69%. Children at greater risk of intensive care admission had pre-existing medical conditions, were less than 1 month old, or presented with lower respiratory tract symptoms. Asymptomatic infection occurred in 16% of cases. Given that at the time of the study, there were varying practices for screening criteria, it is likely that the true proportion of asymptomatic patients is higher (and true case fatality rate lower)

Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med 2020;:NEJMc2005073. doi:10.1056/NEJMc2005073

This retrospective study examines the clinical characteristics of children with confirmed COVID-19 diagnosed at Wuhan Children’s hospital. There were 1391 children tested between Jan 28th and Feb 26th 2020 due to known contact with a case of COVID-19, of these 171 were confirmed to have SARSCoV-2.  Median age was 6.7yrs, and there was a relatively even spread amongst age groups. Children were predominantly male (104/171, 60.8%).

Clinical features: 83/171 had cough, 79/171 had pharyngeal inflammation (sore throat), 71/171 had fever. 15/171 had diarrhoea and 13/171 had rhinorrhoea. 49/171 were tachypnoeic on admission and 72/171 were tachycardia. Only 4/171 had Oxygen saturations <92% during hospitalisation. 0/31 infants <1yr were asymptomatic in this cohort, with rates of asymptomatic infection increasing with age. There were higher rates of pneumonia in infants (25/6), but the definition of this is unclear. We also have no information regarding co-infection with other viruses or bacteria.

Radiology: Not delineated into CXR or CT, but descriptions sound like CT findings. The most common was bilateral ground glass opacity (56/171) followed by unilateral patchy shadowing (32/171) and bilateral patchy shadowing (21/171). There were several children with radiographic pneumonia who were asymptomatic.

Bloods: The supplementary appendix contains lab results. Only 6/171 patients had lymphopaenia, the vast majority were in normal range (Med 2.9×109/L, IQR 2.2 – 4.4). CRP was elevated (>10mg/L) in 33/171 (Med 4, IQR 1.3 – 8) of which 27/33 had pneumonia.

Outcomes: 3 patients required ITU admission and intubation. All 3 had comorbidities, including hydronephrosis, leukaemia and intussusception. The child with intussusception suffered multiorgan failure and died after 4 weeks. The cause of death is not clear from the report. As of writing 149 patients had been discharged with 21 stable in the general wards.

Parri N, Lenge M, Buonsenso D; Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with Covid-19 in Pediatric Emergency Departments in Italy [published online ahead of print, 2020 May 1]. N Engl J Med. doi:10.1056/NEJMc2007617

This report is of confirmed COVID-19 infections in children under 18 years of age who presented to a research collaboration of 17 paediatric emergency departments in Italy between March 3rd and March 27th. The median age was 3.3 years and 57/100 were male. Children under 1 year were overrepresented (40%) followed by children >10yrs (24%).

Helpfully they categorise their patients according to criteria from Dong et. al (see review in Epidemiology top 10): Asymptomatic 21%, Mild 58%, Moderate 19%, Severe 1% and Critical 1%. Only 12% of patients appeared ill on assessment. Interestingly only 4% of patients had Oxygen saturations <94%. Only 38% of children needed admission for severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below

Clinical features: Fever 54%, Cough 44%, Feeding difficulty 23%, Sore throat 4%, Rhinorrhoea 22%, Diarrhoea 9%, vomiting 10%.

Bloods: Largely unremarkable (although reports of lymphopenia unclear – state 14 patients lymphopenic but that this is 28%? – perhaps only 50 children had bloods, but this is not reported). Procalcitonin <0.5ng/L in 29/23 patients.

Radiology: Chest x-rays performed for 35 children, of which 14/35 had interstitial abnormalities, 6/35 consolidation and 1/35 pleural effusion: remaining 15/35 normal.

Comorbidities: There were 27/100 children with comorbidities – although it appears most had mild illness (did not require respiratory support). This included 6 with cystic fibrosis, 4 neurological, 4 haematological, 4 with a syndrome, 3 with prematurity, 2 with cardiac conditions, 2 immunological, 2 oncological and 1 metabolic disease.

Of the few patients who required respiratory support (9/100) a significant number had comorbidities (6/9), although the rage was broad. This included 2 children with “epileptic encephalopathy”, one of whom also had CHARGE syndrome, a child with autism, a child with a VSD, a child with propionic acidemia, and a child with thrombocytopenia and frequent respiratory infections.

One of the strengths of this study is comparisons across other studies of clinical features of COVID-19 in children. In comparison to Dong et al, CDC data and Lu et al, most features are broadly comparable. Some notable differences are a significantly larger number of infants in the Italian data (40% <1yr compared to 18% in Lu, 12% in Dong and 15.5% in CDC) and a slightly higher number of asymptomatic children (21% compared to 16% Lu, 13% Dong and 1.3% CDC). This most likely represents differences in which population cohorts presented for testing among the different studies – comparisons between cohorts is always difficult currently due to broad differences in the demoninators used. Notably there is no apparent difference in severity according to age in this Italian data, whereas CDC noted increased hospitalisation in children <1yr and Don’t et al noted higher rates of severe or critical illness in infants <1yr.

Broadly speaking this study confirms findings from China and the USA regarding significantly milder illness in children than adults with COVID-19, including many asymptomatic children. Note is made of overrepresentation of children with comorbidities in this cohort (similar to CDC data), although most of these still had mild illness – it is unclear if these children become more unwell, or are more likely to present to be tested.

DeBiasi RL, Song X, Delaney M, Bell M, Smith K, Pershad J, et al. Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region. The Journal of Pediatrics.  https://doi.org/10.1016/j.jpeds.2020.05.007

This is retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at Children’s National Hospital, Washington DC US. Children and young adults were detected through symptomatic presentation at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalised, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features associated with hospitalisation, or critical care.  

Of note this hospital served as a regional centre for providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. Overall patient age range was from 0.1 – 34.2 years, with a median of 9.6years. Of the total group 12/177 were > 20 years of age, and 37/177 were between age of 15 – 20years. 

Age: There was no significant difference in age between the hospitalised and non-hospitalised patients, however in the hospitalised cohort, the critically unwell group were significantly older than the non-critically unwell hospitalised group (17.3 years versus 3.6 years; P =.04) 

Sex: There was equal representation in total cohort showed (n = 177 52% male, 48% female), as well as the hospitalised cohort (n=44 50% male, 50% female). However males made up 67% of the critically ill cohort (n =9, 67% male, 33% female); but this was not statistically significant (p=0.26)

Race/ethnicity: data not provided, authors describe plans to do so in follow up analysis 

Underlying conditions: 39% of positive patients had an underlying condition (classified as asthma, diabetes, neurological, obesity, cardiac, haematological, oncological). Though asthma was the most common underlying condition (35/177 20%), it was not more common in hospitalised patients (7/44 16%), nor of those admitted, those who were critically unwell (2/9, 22%). Though the numbers where small, specific underlying conditions such as neurological, cardiac, haematological, or oncological underlying conditions were more common in the hospitalised cohort than the non hospitalised cohort. But were not more common in the hospitalised critically ill compared with the hospitalised non critically ill. The authors noted there was no underlying condition present in 96/177 (55%) of overall SARS-CoV-2 infected patients overall, 16/44 (37%) of hospitalized patients and in 2/9 (22%) of critically ill patients.

Symptoms:  76% of infected patients presented with respiratory symptoms (rhinorrhea, congestion, sore throat, cough or shortness of breath) with or without fever. Fever was present in 116/177 (66%) but was not more common in the infected hospitalized cohort (34/44, 77%) compared with the non-hospitalized cohort (82/133, 62%; p=0.46). 

Shortness of breath was more common in the hospitalized cohort (11/44, 26%) compared with non-hospitalized (16/133, 12%; p=0.04). Patients in the critically ill cohort were not more likely to have fever or any other specific symptom compared with the non-critically ill cohort.

Critical Care: 9 patients required critical care; which represented 5% (9/177) of total cohort and 20% (9/44) of admitted patients. 4 required intubation (3 ARDS, 2 multiple organ failure); 3 required BiPAP, 1 RAM cannula and 1 High flow nasal cannula. One patient had features consistent with the recently emerged Kawasaki disease-like presentation with hyper-inflammatory state, hypotension and profound myocardial depression; a 4 year male with no underlying conditions. 

Summary:  A very clear description of 177 patients with Sars CoV 2, in one large centre in Washington DC. 25% of patients needed hospitalisation and 5 % needed critical care. Older teenagers and adults who required admission, were then overrepresented in requiring critical care. Though underlying conditions were more common in hospitalised patients, they were not significantly more common in the hospitalised patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalised patients than non-hospitalised patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of recently described hyperinflammatory state. 

de Lusignan, S., J. Dorward, A. Correa, N et al, (2020). “Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study.” Lancet Infect Dis. May 15th 2020, https://doi.org/10.1016/S1473-3099(20)30371-6

This study examines the demographic and clinical risk factors for testing positive for SARS-CoV-2 amongst patients within a large primary care network in the UK. This included tests done through Public Health England and the UK National Health Service (NHS) between January 28th and April 4th 2020 with clinical and sociodemographic data extracted from patients’ primary care medical records.

Overall 587 of 3802 patient tests returned a positive result for SARS-CoV-2. Of children 4.6% (23/499) tested positive compared with 17.1% (564/3303) of adults.

In multivariate logistic regression, adults had significantly higher odds of a positive test compared with children; those aged 40-64 (aOR 5.36, 95% CI 3.28-8.76) and >75 (aOR 5.23, 95% CI 3.00-9.09) were at highest risk.
Male sex (aOR 1.55, 95% CI 1.27-1.89), social deprivation (aOR 2.03, 95% CI 1.51-2.71) and black ethnicity (aOR 4.75, 95% CI 2.65-8.51) were also associated with an increased risk of a positive SARS-CoV -2 test. Of clinical factors, only chronic kidney disease (aOR 1.91, 95% CI 1.31-2.78) and obesity (aOR 1.41, 95% CI 1.04-1.91) were significantly associated with testing positive. Surprisingly active smoking was associated with lower odds of a positive test (aOR 0.49, 95% CI 0.34-0.71) possibly due to presentation confounding (i.e. presence of cough in chronic smokers prompting increased testing in this group).


This is the first study to utilise primary care data to assess risk factors for testing positive for SARS-CoV-2 in the community. The risk factors identified are similar to those associated with severe COVID-19 in hospitalised patients including increased age, male sex and obesity. The higher odds of a positive test in adults compared with children here are consistent with other studies suggesting children are at lower risk of SARS-CoV-2 infection compared with adults.

Parri, N., A. M. Magistà, F. Marchetti, et al, (2020). “Characteristic of COVID-19 infection in pediatric patients: early findings from two Italian Pediatric Research Networks.” Eur J Pediatr: 1-9. https://doi.org/10.1007/s00431-020-03683-8

This study is published as a short communication describing the clinical presentations and outcomes in children with identified Covid-19 in 61 centres in Italy between 3rd and 26 March 2020.

Study Design: A retrospective study coordinated by the CONFIDENCE and COVID-19 Italian Paediatric Study Network’s involving 53(86.9%) hospitals and 8(13.1%) outpatient centres in 10 mainly northern regions. All children (0-18 years) diagnosed positive on screening and testing for Covid-19 by nasal/nasopharyngeal RT-PCR assay were entered into the study. Clinical, laboratory and imaging data was collected on standardised forms. 

Study Population: 130 children and adolescents recruited (112 hospital;18 outpatient). <2 years 41 (31.5%), 2-9 years 35 (26.9%)’10-17 years 45 (34.6%). Male 73 (56.2%). Female 57(43.8%) p=0.47.

Comorbidities 34 (26.2%) most frequent cardiovascular, respiratory and neuromuscular. No information on ethnicity. One patients data unobtainable.

Disease Severity: The majority of subjects were categorised as being asymptomatic or having mild disease 98/130 (75.4%). 11 (8.5%) were moderate severity, 11 severe and 9 (6.9%).critical. 75 (57.7%)were hospitalised  with 15.(11,5%) needing respiratory support (5 needing oxygen, 2 non invasive ventilation and 2 mechanical ventilation). 9 cases were admitted to ICU with 6 being less than 6 months. 3 of the latter were less than 2 months and did not require respiratory support. Children less than 6 months had an increased risk of critical disease than older children: 6/35 (17.1%) vs 3/86 (3.5%) p=0.34. OR 5.6 CI 1.3 to 29.1.

Symptoms: Common symptoms were fever 67(51.5%), dry cough 38(29.2%) and productive cough 16(12.3%). Other symptoms were rhinorrhoea25(19.2%), respiratory distress 17(13%), vomiting 15(11.5%);diarrhoea 10(7.6%); sore throat 9(6.9%). Thoracic pains (3%), somnolence, febrile convulsions (1.5%) and lower limb pains (1.5%) were reported as novel symptoms.

Oxygen saturation at presentation:  91-92% 1(0.8%). <90 1(0.8)

 Radiology: 41 (31.5%) of children had CXRs. These were normal in 15 (36.6%). The commonest abnormalities were ground-glass opacities in 17 (41.5%). Focal consolidation was seen in 4 (9.8%).

Laboratory:  71 children were reported to have had laboratory tests. The authors report leukopenia (WCC %<5.5×109) and lymphopenia (<1.2×109) in 7/19 patients and 3/19 patients, respectively. They report elevation in aspartate transaminase >50U/l in 11/60 (18.3%) and alanine tranasaminase >45U/l in 8/68 (11.8%).

Outcomes: There were no deaths and all children were reported to have recovered.

Comment: The study obtained data on all but one child found Covid-19 positive in this largely hospital based population. The authors acknowledge that there is a bias toward more ill patients with their population than community studies and this may explain the 57.7% admission rate. Also this is reflected in the amount of comorbidity. However, the majority of patients were either asymptomatic or had mild disease and small numbers required respiratory support or ITU. The authors identify the increased likelihood of critical disease in those less than 6 months and their being the majority of ICU cases. They also comment on new presenting symptoms (thoracic pain, somnolence, febrile convulsions and lower limb pains).

de Ceano-Vivas M, Martín-Espín I, del Rosal T, et al. SARS-CoV-2 infection in ambulatory and hospitalised Spanish children, Arch Dis Child, doi:10.1136 / archdischild-2020-319366 

Study design: A retrospective case series of all children seen at a tertiary centre, who were found to have positive PCR for SARS-CoV-2.  Testing for SARS-CoV-2 was only conducted in those children who had respiratory symptoms and “criteria for hospitalisation” or who had “underlying chronic pathology”. Children with mild symptoms were not tested even if there was a confirmed case in the household. Comparisons were made between the characteristics of those admitted to hospital and those treated as outpatients. The study was conducted between March 11th and April 9th 2020 at Hospital La Paz, Madrid, Spain.

Inclusion criteria: All children who underwent PCR for SARS-CoV-2 in nasopharyngeal smear, N=349.  Of whom 58 (16.6%) had a positive PCR and were the cases analysed.

Key findings: Of the 58 cases: Male 37 (63.8%), Median age 35.5 months (range 3.3-146), Underlying conditions 23 (39.7%), Temperature >39.7degC 41 (70.7%), Cough 42 (72.4%), Rhinorrhoea 33 (56.9%), Breathing difficulty 10 (17.2%), Vomiting 9 (15.5%), Headache 8 (13.8%), Loss of taste 1 (1.7%), Anosmia 1 (1.7%). 

Radiology: 40 (69%) had a CXR of which 35 (87.5%) were abnormal: Perihilar infiltrates, ground-glass pattern, lobar or multilobar consolidation. 

Bloods: 43 (74.1%) had a blood test, median WCC 9145/mm3, median lymphocyte count 2390/mm3. 

Outcomes: 33 were hospitalised and 25 were treated as outpatients. Of the inpatients, 14 (42.4%) received oxygen therapy for a median of 3 days. 5 were admitted to the PICU (15% of those hospitalised): 3 with severe COVID-19, 1 with a hypertensive crisis and 1 with diabetic ketoacidosis.  31 (53.4%) were treated with hydroxychloroquine, 3 patients were treated with remdesivir. 2 patients with an inflammatory syndrome were also treated with tocilizumab. There was 1 death of a 5/12 old infant with dilated cardiomyopathy and Hurler’s syndrome. The comparisons between the inpatient and outpatient group provide almost no additional useful information.

Comment: As the authors concede, the retrospective nature of the study is a significant weakness. Patients were selected for testing on the basis of symptoms and/or underlying conditions and many other children who could have been infected were never tested. The study is useful in describing the range of symptoms, treatment and outcome in the large selected group of children who tested positive for SARS-CoV-2. It does not, however, add anything new to what is already known about the condition in children.

Chen C. Coronavirus Disease-19 Among Children outside Wuhan, China [Internet]. Lancet Child and Adolescent medicine; Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3546071

A pre-print, the information should be treated with caution until it has undergone peer review. This is a prospective case series of 31 paediatric cases of COVID-19 diagnosed at the Shenzen Third Peoples hospital between Jan 16th and Feb 19th 2020. This made up 7.9% of all cases diagnosed in Shenzen. They were all confirmed by PCR. None had been exposed to the seafood market in Wuhan. The patients received nebulised interferon and, IV ribavirin or oral lopinovir/ritonavir. The median age was 6.75, with most patients (41.9%) aged 5-9. Followed by 0-4yrs (32.2%) and 10-14yrs (19.4%). 41.9% were male.

Clinical features: 12/31 Children were asymptomatic. Fever was observed in 14/31, Cough in 13/41, Sore throat in 2/31, Rhinorrhoea in 22/31 and diarrhoea in 2/31. Median duration of fever was 2 days, with a range of  1–9 days. Bloods: Lymphopaenia was not observed. Lymphocytosis occurred in 17/31 patients. CRP was elevated in 4/31 patients. Radiology: On admission 64.5% of CT were normal, with 25% having unilateral pneumonia and 9.7% having bilateral. During hospitalization one child developed a unilateral pneumonia whose radiography was initially normal. Outcome: 23 children had been discharged at the time of writing, and the remainder were well and afebrile.

Garazzino S, Montagnani C, Dona D, et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020; 25(18). https://dx.doi.org/10.2807%2F1560-7917.ES.2020.25.18.2000600

This rapid communication reports the preliminary results of an Italian multicentre study involving 11 of 13 exclusively paediatric hospitals and 51 of 390 paediatric units across Italy (mainly in central and northern Italy).  Retrospective data collection began on 25 March 2020.

Study design:  Data to 10 April 2020 collected by participating physicians and hospitals for all paediatric patients (aged 1 day to 17 years) with at least one RT-PCR SARS-CoV-2 positive nasal/pharyngeal swab AND adequate follow-up considered necessary by the clinician to define the final outcome (usually 2 wks).

Findings:  Data collected for 168 children and adolescents with documented COVID-19: 

Gender:  94/168 male (55.9%) and 74/168 female (44.1%)

Age:  median 2.3 yrs (IQR 0.3-9.6 yrs, range 1 day-17.7 yrs, mean 5 yrs.  <1 yr:  66/168 (39.3%), of which 15/168 neonates (6.9%). 1-5 yrs:  38/168 (22.6%). 6-10 yrs:  24/168 (14.3%). 11-17 yrs:  40/168 (23.8%)

Hospitalised: 110/168 (65.1%): <1 yr:  52/66 (78.8%). 1-5 yrs:  24/38 (63.2%). 6-10 yrs:  13/24 (54.2%). 11-17 yrs:  21/40 (52.5%)

Comorbidities:  33/168 (19.6%):  chronic lung disease 7, congenital malformations or complex genetic syndromes 14, cancer 4, epilepsy 5, gastrointestinal disorders 2, metabolic disorders 1, immunosuppression 4, immunocompromise 3.  The hospitalisation rate was similar between children with comorbidities (23/33, 70%) and those without (87/135, 64%).

Source of infection:  Close contact with a COVID-19 infected person outside the family was rarely reported.  113/168 (67.3%) of children had at least one parent who tested positive for SARS-CoV-2 infection.  Symptom onset in relatives preceded symptoms in the infected child by 1 to 14 days in 88/113 (77.8%).

Symptoms:  4/168 (2.4%) asymptomatic. Fever (37.5 to 39°C) 138/168 (82.1%), cough 82/168 (48.8%), rhinitis 45/168 (26.8%), diarrhoea 22/168 (13.1%), dyspnoea 16/168 (9.5%), pharyngitis 9/168 (5.4%), vomiting 9/168 (5.4%), conjunctivitis 6/168 (3.6%), chest pain 4/168 (2.4%), fatigue 3/168 (1.8%), non-febrile seizures 3/168 (1.8%, all 3 had a known history of epilepsy), febrile seizures 2/168 (1.2%, 1 with a history of febrile seizures and 1 with first episode of febrile seizures as onset of COVID-19).

Blood results:  Of the children who had blood tests, 47/121 (38.8%) had CRP > 0.5 mg/dl.  Other abnormal findings were rare.

Complications:  33/168 (19.6%) developed complications: interstitial pneumonia 26/168 (15.5%), severe acute respiratory illness 14/168 (8.3%),  peripheral vasculitis 1/168 (0.6%)

No child underwent a chest CT scan; pneumonia was assessed using X-ray or ultrasound in 75/168.  

Co-infection:  Documented in 10/168 (5.9%), including 3 RSV, 3 rhinovirus, 2 EBV, 1 influenza A, 1 non-SARS coronavirus infection, 1 Strep pneumoniae.

Treatment:  16/168 (9.5%) required non-invasive oxygen treatment.  2 were admitted to ICU for mechanical ventilation (1 preterm neonate and a 2-month-old with congenital heart disease).  49/168 (29.2%) children (those with more severe illness) received experimental SARS-CoV-2 treatments, including lopinavir/ritonavir, hydroxychloroquine and/or azithromycin/clarithromycin, systemic steroids.

All children, including those with comorbidities, recovered fully and there were no sequelae reported at the time of submission.  This paediatric data is in contrast to the high number of cases and case-fatality rate seen in adults in Italy.  Children comprised a marginal percentage of those hospitalised in Italy with SARS-CoV-2 infection.

Zhang C, Gu J, Chen Q, et al. Clinical Characteristics of 34 Children with Coronavirus Disease-2019 in the West of China: a Multiple-center Case Series. doi:10.1101/2020.03.12.20034686

A pre-print, the information should be treated with caution until it has undergone peer review.

This is a further retrospective case study looking at 34 children with confirmed COVID-19 between Jan 1st and Feb 25th 2020 in 4 hospitals in Western China. They were aged 1 month to 12 years.

Clinical features: The most common symptom was fever (26/34) followed by cough (20/34), followed by vomiting (4/34) and diarrhoea (4/34). A significant number had co-infections (16/34) including Mycoplasma pneumoniae (9/34), influenza A or B (12/34) and 2/34 were mononucleosis. One child had a nephroblastoma and one had asthma. The median incubation period was 10 days (IQR 7.75 – 25.25) and median 3 days (IQ 2 – 4) from admission to fever resolution

Bloods: Lymphocytosis was most common (17/34). CRP was not significantly elevated (median 7.56ml/L, IQR 1.21 – 15.13), but was >5 for 20/34, and procalcitonin was not significantly elevated either (0.6, 0.03 – 0.07)

Radiography: On chest CT 14/34 had patchy shadows bilaterally, 14/34 unilaterally, and 6 had normal CT chest.

Qiu, Haiyan et al, Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. The Lancet Infectious Diseases, Volume 0, Issue 0 DOI:https:// doi.org/10.1016/S1473-3099(20)30198-5

Qui and colleagues retrospectively identified 36 children with an EMR diagnosis of COVID-19, during the period Jan 17 through March 1st, at three hospitals in Zhejiang, China, a province 900km to the east of Wuhan. Diagnosis was made by COVID-19 RT PCR for all patients presenting with fever, cough and radiographic presentation, or if there was a history of exposure to an infected individual.

For the mild cohort, 28% of patients were asymptomatic, with moderate cases more likely to have fever of 38oC or higher (47%), cough (24%), vomiting or diarrhoea (10%) or headache (10%). More than half (53%) of patients had ground-glass opacities on CT scan, meeting the case definition for Moderate illness. Key laboratory values of note include lymphopaenia, leukocytopaenia and increased procalcitonin as all associated with moderate illness. No patients in this cohort were hypoxaemic as a result of their pneumonia.

The authors also draw comparisons between adults and children with COVID-19 (less severe illness, less likely to have abnormal investigations), as well as comparing the clinical features and severity of COVID-19 with SARS (milder symptoms and severity) and H1N1 influenza (fewer symptoms, more frequent pneumonia) in children. Wisely, Qui & colleagues note the high rate of findings that are not clinically obvious, and the high proportion of asymptomatic cases make for very challenging case identification in the absence of clear epidemiologic information. “This finding suggests a dangerous situation if community-acquired infections occur.”

Zheng F, Liao C, Fan Q-H, et al. Clinical Characteristics of Children with Coronavirus Disease 2019 in Hubei, China. Curr Med Sci 2020;:1–6. doi:10.1007/ s11596-020-2172-6

This is a retrospective case series of 25 children <14 years of age hospitalised with COVID-19 from 10 hospitals across the Hubei province between February 1st and February 10th 2020. It is unclear how the cases were ascertained. 14/25 were male (54%) and the median age was 3yrs (IQR 2-9yrs). Most patients were <3 years (40%). 2 patients had a background of repaired congenital heart disease (both infants), although we have no more detail than this. Both of these children went on to develop critical illness.

Clinical features: 13/25 (52%) had fever, 11/25 (44%) had cough, 3/25 (12%) had diarrhoea, and 2/25 (8%) had nasal congestion, vomiting, breathlessness or abdominal pain. 

Bloods: Inflammatory markers were not particularly raised, with a median CRP of 14.5mg/L (IQR 0.93 – 25). 10/25 (40%) patients had lymphopenia.

Radiology: CT chest was normal in 8/24 (32%) with unilateral involvement in 5/24 (20%) and bilateral in 12/24 (48%). Changes typically showed patchy shadows. Younger children appeared more likely to have bilateral lung findings than older children. 

Co-infection: Other organisms identified included Mycoplasma pneumoniae (3/25, 12%), Influenza B (2/25, 8%) and one of the 2 critically ill children had Enterobacter aerogenes.

PICU Clinical Papers

González-Dambrauskas S, Vásquez-Hoyos P, Camporesi A, et al. Pediatric critical care and COVID19. Pediatrics. 2020; doi: 10.1542/peds.2020-1766

In preprint, González-Dambrauskas et al describe 17 children with COVID-19 admitted to international PICUs in Chile, Colombia, Italy, Spain and USA, in April 2020. These are interim results from the CAKE (Critical Coronavirus And Kids Epidemiologic) Study, recruiting between April and December 2020 from almost 60 PICUS in 20 countries. As well as describing the clinical details of each child in detail, this paper also describes four children with myocarditis associated with covid-19.

The 17 children predominantly presented with cough and fever (53% had cough, 76% had fever). Comorbidities were common in 71% of children, including underlying respiratory, cardiac, renal, liver or neurological disorders. Six children (35%) had gastrointestinal (GI) symptoms at presentation. 

Of the four children with myocarditis, all were based in Europe, none had previous cardiac disease, and all presented with fever and GI symptoms. One also had a rash and conjunctivitis. These children all developed myocarditis early in their clinical picture, with average duration of symptoms prior to presentation of 3.5 days. All four children received IVIG. Three of these children also required inotropic support; one child also developed ARDS and acute kidney in addition to myocarditis, requiring non-invasive ventilation but not renal replacement therapy. None of the four children with myocarditis required mechanical ventilation. All four children survived to discharge home, with a mean hospital length of stay of 13.5 days.

González Cortés, R., García-Salido, A., Roca Pascual, D. et al. A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06146-8

The Spanish Paediatric Intensive Care Society have published their findings of 50 children admitted to 47 PICUs in Spain between 1st March 2020 and 1st May 2020 with SARS-CoV-2. More than 90% of PICUs in Spain were represented in this national database. During the study period there were no deaths from SARS-CoV-2 in children admitted to PICU in the participating PICUs.

The authors divided the children into two groups: those requiring ventilation and those not requiring ventilation, to assess for different characteristics between these groups. Fourteen (28%) of the children were ventilated.  Twenty-seven (54%) of the 50 children in the study had suspected PIMS-TS; these children were less likely to require mechanical ventilation (4 of the 27 required ventilation) than those without PIMS-TS. Statistical significance between the two groups was found for age (median age of 2.8 years in the ventilated group, compared to 8.6 years in the non-ventilated group); co-morbidities (12, 24%, of the 50 children had comorbidities; 8 of these were ventilated); and clinical presentation with respiratory difficulties or an ARDS-type picture.

Overall, of the 50 children, 23 (46%) had haemodynamic instability, 20 (40%) had respiratory difficulties and 1 (2%) had neurological symptoms. Shock was present in half of the children (25, 50%), renal failure in 8 (15%) and cardiac dysfunction in 17 (34%). 

Across the 50 children, white cell count (median 9.26, IQR 5.64-14.46), lymphocytes (median 1.02, IQR 0.42-2.59) and CRP (median 13.9, IQR 4.9-27) were not statistically different between ventilated and non-ventilated children.

These are the preliminary findings from this national registry of children with SARS-CoV-2 admitted to PICU in Spain. Further results and analysis will provide more information regarding critically unwell children with COVID-19.

Grasselli, G et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. doi:10.1001/jama.2020.5394 Published online April 6, 2020.

This is a retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the regional ICU coordinator of the Lombardy ICU Network, and treated at one of the ICUs of the 72 hospitals in the network. Patients were recruited between 20/02/2020 and 18/03/2020 with follow-up on 25/03/2020. Data was collected via telephone. Of the nearly 1600 patients referred for ICU admission, only 4 were between 0 and 20 years of age, with a median age of 16 and interquartile range of 14 to 19 years of age. Three of the four patients (75%) were male and three of the four had comorbidities (specific details not given).

Two required mechanical ventilation. It’s important to note that the patients in this study were those admitted to ICU and not patients on medical wards, in the ED or in the community so the high percentage of ventilated patients in this study is not a reflection of the other patients in the region with SARS-CoV-2. These two patients had relatively low oxygen requirements with an FiO2 of 30% and 50%; relatively low PEEPs of 5 and 14 mmHg; and favourable PaO2/FiO2 ratios of 195 and 323, placing these two patients in the mild to moderate ARDS severity scores (for more information on PaO2/FiO2 ratios have a look at the LITFL explanation at https://litfl. com/pao2-fio2-ratio/). None of the four patients in the 0-20 year old category received ECMO. Information on disposition was only available for two of the four patients. None of these patients died. Two remained on ICU on 25/03/2020 at time of follow-up.

What can we take from this study? As the study recruited patients admitted to ICU, the numbers of adolescent patients in this case series is low at only four, with an age range of 16 to 19. The data was collected retrospectively via telephone making it difficult to draw robust conclusions. However, we can see that compared to the older groups of patients in the study, ventilation requirements were lower. Three of the four adolescent patients had comorbidities, which might suggest that children and adolescents without comorbidities in the Lombardy region were less severely unwell and did not require ICU admission.

Oualha, M., M. Bendavid, L. Berteloot, et al.  “Severe and fatal forms of COVID-19 in children.” Archives de Pediatrie, June 4th 2020, https://doi.org/10.1016/j.arcped.2020.05.010

This paper describes the clinical presentation and course of the 27 children and young people with COVID who required paediatric intensive care in and around Paris  at the height of the coronavirus peak in France. The total population of all ages of the Ile de France , the region for which this centre is responsible for tertiary paediatric referrals, is around 12 million. During the time covered by the study, there were around 5000 COVID deaths in France, with the Ile de France region being the hardest hit.

This study focuses on 27 children unwell enough to need high dependency care during active COVID infection. The criteria for admission were oxygen requirement > 1L/min or underlying disease. The cohort of 27 were admitted within days of onset of first symptoms and 24 were positive for COVID-19 by PCR of nasal swabs. This is consistent with active virus, rather than PIMS-TS, the Kawasaki like post-COVID syndrome.

 24 had respiratory disease, mostly with radiological or CT findings consistent with COVID.  6 had cardiovascular disease and 4 renal problems.  

9 required invasive ventilation with median duration 5 days.  10 received non-invasive ventilation and 23 were treated with oxygen. 4 received catecholamines, one ECMO and one renal replacement therapy.  The median length of hospital stay was 6 days.

Mean laboratory findings in the group were of elevated CRP, procalcitonin, fibrinogen and D-dimers, consistent with an inflammatory and prothrombotic state.  Neutrophil and lymphocyte counts were normal. T cell subsets and cytokine levels were not measured.

70% had underlying conditions, but the spectrum was different from adult experience, with neurological and respiratory problems or sickle cell disease being most common.

Three of the five who died had previously been in good health. A teenage girl whose clinical course was suggestive of the cytokine storm seen in adults died within hours of admission. A teenage boy and a 6 year old girl co-infected with other pathogens both died after long PICU stays. 

This description confirms that severe illness is rare in children with COVID and shows that even those admitted for HDU care had a shorter illness and better prognosis than that seen in adults. Nonetheless, occasional children do suffer a prolonged illness with multi-organ dysfunction.

Lanyon, N., P. du Pré, T. Thiruchelvam, S. Ray, M. Johnson and M. J. Peters (2020). “Critical paediatric COVID-19: varied presentations but good outcomes.” Arch Dis Child. https://dx.doi.org/10.1136/archdischild-2020-319602

In this letter from Great Ormond Street Hospital for Children, London, 24 children, who tested positive for Covid-19, were admitted to the intensive care unit between 26th March 2020 and 31st May 2020. Thirteen of these had PIMS-TS. This letter describes the clinical features of the remaining 11.

These 11 had a median age of 5 years (range 0.4-11), 9 were boys, 9 had pre-existing medical conditions, and 4 came from the BAME community. The primary presenting feature was cough 6, apnoea 3, fever 10, gastrointestinal 6 and seizures 3

In all 11 inflammatory markers were raised, median ferritin 898 (range 254-1991), CRP 158 (27-449), LDH 1594 (802-4264) D-Dimer 158 (27-449). 4 children fulfilled the criteria for paediatric acute respiratory distress syndrome, the remaining 7 were admitted to PICU for other reason than respiratory failure. A variety of different forms of respiratory support were provided, invasive mechanical ventilation 9, prone position 4, inhaled pulmonary vasodilators 4, HFOV 2 and ECMO none. 5 children received remdesivir and 6 prophylactic anticoagulation.

All 11 children survived to hospital discharge. The authors conclude “While children can present to PICU with a pattern of illness similar to adult COVID-19 disease this is rare and three quarters of them had risk factors for respiratory infection. A larger number were found to be SARS-COV-2 coincidentally.”

Clinical Dermatology COVID-19

Colmenero, I., C. Santonja, M. Alonso-Riano, et al. “SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases.” The British journal of dermatology. June 20th 2020, https://doi.org/10.1111/bjd.19327

Anecdotally, chilblains seem to be associated with Covid-19 in children and young adults. This case series from Madrid describes 7 children (age 11-17) presenting with chilblains on their toes during the pandemic. None had underlying conditions likely to cause chilblains, and in Spain, cold weather wasn’t responsible. The chilblains looked typical, caused only minor pain and itching, and all resolved spontaneously. All had skin biopsies, which showed a variety of inflammatory and vasculitic changes on histology, typical of chilblains: they also looked specifically for SARS-CoV-2 particles in the endothelium of the dermal vessels using immunohistochemistry and electron microscopy and found the virus in all of them.

What is remarkable is that all the children were systemically well, had either mild or no respiratory symptoms; and of the 6 that had nasal and pharyngeal swabs, all were negative for SARS-CoV-2 PCR. Only 4/7 had Covid-19 positive household contacts.

The implication is that children can harbour demonstrably invasive coronavirus with minimal symptoms and negative swabs. This has epidemiological as well as clinical significance. 

In conclusion, the presence of SARS-CoV-2 in the endothelium of dermal vessels in skin biopsies of children and adolescents with acute chilblains confirms that these lesions are a manifestation of COVID-19.  Their clinical and histopathological features are similar to those of chilblains of other aetiologies, and virus-induced vascular damage could explain their pathophysiology.  Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a role in the pathogenesis of severe forms of the disease. More studies are needed to understand the reasons why previously healthy children, adolescents and young adults present

Locatelli AG, Robustelli Test E, Vezzoli P, Carugno A, Moggio E, Consonni L, Gianatti A, Sena P. Histologic features of long-lasting chilblain‐like lesions in a pediatric COVID‐19 patient. Journal of the European Academy of Dermatology and Venereology.09 May 2020.  doi: 10.1111/jdv.16617. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16617

This retrospective single case report describes clinical and pathological signs of chilblain-like lesions whilst the patient was asymptomatic. He did not have any signs of autoimmune conditions including on histological examination. The lesions persisted for several weeks whilst he remained positive for SARS-CoV-2 on nasopharyngeal swab. The authors highlight young people with this sign could be carriers of the virus.

A 16-year-old male patient attended Papa Giovanni XXIII Hospital, Italy. His nasopharyngeal swab was positive for SARS-CoV-2. His mother was admitted to hospital for SARS-CoV-2 management following his presentation. 

Clinical features: Diarrhoea and dysgeusia were experienced 3 days prior to the onset of skin lesions described as “multiple asymptomatic erythematous oedematous partially eroded macules and plaques on dorsal aspects of the fingers”. A lesion was also noted on second toe. 

Radiology: None discussed. 

Bloods: “Routine bloods autoimmunity, cryoglobulins, viral serologies all negative or within normal limits”

Treatments: None 

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.  

Other features of interest: Histopathological examination demonstrated oedema of the papillary dermis, superficial and deep lymphocytic infiltrate in the perivascular and strong peri-eccrine pattern. Images are provided.  

Recalcati, S., T. Barbagallo, L. A. Frasin, F. Prestinari, A. Cogliardi, M. C. Provero, E. Dainese, A. Vanzati and F. Fantini (2020). “Acral cutaneous lesions in the Time of COVID-19.” J Eur Acad Dermatol Venereol.

This pre-print Letter to the Editor reports on a series of unusual dermatological manifestations presenting to the Dermatologic Unit in Alessandro Manzoni Hospital, Italy in March and April 2020. The authors observed 14 cases, of which 11 were children with a mean age of 14.4 years and a range of 13-18 years. Of the 14 cases, 6 (43%) were male. 3 pairs of cases were siblings.

None of the cases had systemic symptoms (other than mild itch in 3 cases), there was no association with cold exposure, co-morbidities or drug intake, and there was no family history of COVID-19 related symptoms. 3 cases reported cough and fever 3 weeks prior to the onset of the lesions.

The authors believe that these dermatological findings are related to COVID-19 due to the rapid outbreak and clustering of these unusual skin lesions occurring at the same time as the COVID-19 outbreak. In support of this they report multiple similar cases being described from other areas affected by the pandemic. They hypothesise that the skin lesions may represent late manifestations of COVID-19 infection in young, healthy subjects, possibly due to an immunologic response targeting the cutaneous vessels. They accept that this hypothesis cannot be tested until a reliable serological test for antibody response to COVID-19 has been developed.

Clinical features: Acral eruption of erythemato-violaceous papules and macules, with possible bullous evolution or digital swelling. Lesions were found on the feet in 8 cases, hands in 4 cases, and on both sites in 2 cases. 2 children developed erythemato-papular targetoid lesions on the hands and elbows after a few days.

Histology: Lesions on fingers showed diffuse dense lymphoid infiltrate of the superficial and deep dermis, with a prevalent perivascular pattern and signs of endothelial activation. Targetoid lesions on elbows showed mild superficial perivascular dermatitis.

Bloods: Normal FBC, CRP, LDH and D-dimer. Serology was negative for EBV, CMV, Coxsackie and Parvovirus B19.

Outcomes: In all cases the lesions resolved without treatment after 2-4 weeks.

It is worth noting that this study is limited both by the small number of cases, but more particularly by the lack of evidence linking these skin lesions with a proven COVID-19 infection.

Piccolo, V., I. Neri, C. Filippeschi, T et al (2020). “Chilblain-like lesions during COVID-19 epidemic: a preliminary study on 63 patients.” J Eur Acad Dermatol Venereol published online 24th April 2020 https://doi.org/10.1111/jdv.16526

This is a report of chilblain like lesions observed during the COVID-19 pandemic, collected through a survey issued to Italian dermatologists and Paediatricians. This is a preliminary report as data collection still ongoing. 

Importantly – very few patients in this cohort were tested for COVID-19 (11/63) and only 2 of these patients were positive. It is therefore difficult to extrapolate these findings to paediatric COVID-19 specifically, but is worth being aware of. 

63 patients have been reported on with a median age of 14 years (IQR 12 – 16yrs) with feet alone being bar far the most commonly affected area (85/7%) followed by feet and hands together (7%). In uploaded pictures from 54 patients, erythematous-oedematous lesions were most common (31/54) followed by blistering lesions (23/54) and pain and itch were common, although a quarter of lesions were “asymptomatic”. Median time of onset of rash to diagnosis was 10 days. The lesions were generally stable and no other cutaneous signs observed. GI symptoms were the most common co-existing (11.1%) with surprisingly low levels of respiratory symptoms (7.9%).

This is basically a description of a common skin manifestation which coincided with COVID-19, and looked like it could be infectious in origin. Few patients tested, and even fewer positive. An interesting series worth bearing in mind given increasing reports of skin manifestation of COVID-19.

Radiology Findings COVID-19

Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults [published online ahead of print, 2020 Mar 5]. Pediatr Pulmonol. 2020;10.1002/ppul.24718. doi:10.1002/ppul.24718

A case series of 20 paediatric patients with COVID-19 infection identified with COVID-19 NAT on pharyngeal swabs from Wuhan Children’s Hospital. It reviews the clinical information and co-infections.

Clinical features: two thirds had a clear contact history. Incubation 24hrs28 days of life. 13/20 had a cough, 12/20 had a fever. Bloods: 11/20 had (N) CRP, i.e. less than 3mg/L and 80% had PCT >0.05.

Radiology: On CT: Subpleural findings were seen in all 20 patients. 50% had bilateral findings, with a further 6/20 with unilateral findings. Consolidation with a halo in 50% of cases, considered as atypical signs in paediatric patien. Chloral hydrate was the primary sedative for CTs These were predominantly mild cases in the paediatric patients, with CXR adding little diagnostically. An early chest CT exam seemed to be necessary. 9/20 had coinfection, most commonly with mycoplasma (4/9) – although the ‘flu B,’flu A or RSV accounted for almost all of the remainder

Despite this, the physical chest symptoms were mild, with retraction in one case, and another case with cyanosis.

The average length of stay 12.9 days. Some patients were managed on the basis of their  CT alone. These are similar to those seen in adults.

Görkem, S. B. and B. Çetin (2020). “COVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT.” Diagn Interv Radiol. June 5th 2020, DOI 10.5152/dir.2020.20361 

This is a case report of a 15 year old girl with Covid-19 from Turkey in an Epublished letter ahead of print with an early description of the “reversed halo sign”(RHS) on chest CT scan in. RHS is described  as a central ground glass opacity (due to septal alveolar inflammation) surrounded by denser granulomatous airspace consolidation in the shape of a crescent or ring. It was identified in adult Covid -19 patients in early studies from Wuhan. 

The patient presented with abdominal pain (epigastric tenderness). She had no respiratory symptoms and was apyrexial. Covid-19 was identified on nasopharyngeal swab. WCC 4.01×109, lymphocytes 1.92×109, CRP 1.6 mg/l rising to 10 mg/l after five days. Oxygen saturation remained above 95% in air.

Initial abdominal CT identified bilateral patchy alveolar infiltrates in the lower lobes and so an unenhanced low-dose thorax CT was performed. This identified multi focal RHS lesions within bilateral upper, middle and lower lobes. There were multiple multisegmental peripherally located alveolar infiltrations and scattered ground glass opacities.

The patient received hydroxychloroquine. Interestingly, she did not develop any respiratory symptoms, making an uneventful recovery and was discharged after 8 days.

RHS is a distinctive sign on chest CT. As well as occurring in pneumonia (including community acquired pneumonia) it can also be associated with fungal infections, immunosuppression, pneumocystis, TB, sarcoidosis, pulmonary neoplasms and pulmonary infarction. Therefore it can pose diagnostic challenges and management is guided by the clinical history. Although RHS is recognised in the adult Covid-19 literature this is a first report in a paediatric patient.

Denina, M., C. Scolfaro, E. Silvestro, G. Pruccoli, F. Mignone, M. Zoppo, U. Ramenghi and S. Garazzino (2020). “Lung Ultrasound in Children With COVID-19.” Pediatrics. 21. https://doi.org/10.1542/peds.2020-1157

Between March 18th and 26th 2020 8 children (age range 3 months to 10 years), 5 of whom were boys were admitted to Regina Margherita Children’s Hospital, Turin with Covid 19 respiratory tract infections. All 8 children had linear array chest ultrasound during routine medical examination. Although the number of patients analysed was small, the high concordance between radiologic and LUS findings suggested that ultrasound may be a reasonable method to detect lung abnormalities in children with COVID-19. The advantage of LUS was that the investigation could be done at the bedside, thus preventing transport of a potential infectious patient through a hospital

Li W, Cui H, Li K, Fang Y, Li S. Chest computed tomography in children with COVID-19 respiratory infection [published online ahead of print, 2020 Mar 11]. Pediatr Radiol. 2020;10.1007/s00247-020-04656-7. doi:10.1007/s00247-02004656-7

This study describes five children with confirmed COVID-19 who had CT chest scans in a large tertiary level hospital in China. Three of the five children had patchy ground-glass opacities on their CT scans but these changes were less severe than those seen in infected adults. The treatment is not detailed in the paper, so presented as published in this summary.

Case 1: 17 month old asymptomatic male. Bloods: CRP 9.4, WCC 9.2. Radiology: CT chest performed on day 4 showed patchy ground glass opacities. Repeat CT on day 9 after treatment had normalised (antiviral, anti-infective, immunoglobulin, interferon and Lianhua qingwen granules). No CXR.

Case 2: 10 month old asymptomatic female. Bloods: CRP 0.9, WCC 14.8. Radiology: Day 2 scan: normal. Not repeated. No CXR.

Case 3: 3 year old male with coryza, productive cough, sore throat and fever after 3 days. Bloods: CRP 0.7, WCC 15.0. Radiology: Day 9 CT showed patchy ground-glass opacities. Repeat CT on day 16 had normalised after treatment (antiviral, anti-infective, immunoglobulin). No CXR. 

Case 4: 4 year old asymptomatic male. Bloods: CRP 0.2, WCC 6.6. Radiology: Day 2 CT chest showed patchy ground-glass opacities. Repeat CT on day 7 had normalised after treatment (montelukast, immunoglobulin). No CXR.

Case 5: 6 year old asymptomatic male. Bloods: CRP 0.6, WCC 5.3. Radiology: 

Day 3 CT was normal. No CXR.

Liu H, Liu F, Li J, Zhang T, Wang D, Lan W. Clinical and CT Imaging Features of the COVID-19 Pneumonia: Focus on Pregnant Women and Children [published online ahead of print, 2020 Mar 11]. J Infect. 2020;S0163-4453(20)30118-3. doi:10.1016/j.jinf.2020.03.007

This study is a review of CT imaging findings in children and pregnant women in a hospital in the Hubei Province. Four children with confirmed COVID-19 infection were included in the study. The bottom line is that pulmonary CT changes in children were mild, with either focal ground glass opacification or focal consolidation. Although CT has been reported as a useful screening tool in adults with suspected COVID-19 infection, the CT changes of the four children were non-specific; the authors conclude that exposure history and clinical symptoms are more helpful for screening in swab-negative children than CT. 41 pregnant women with either laboratory-confirmed or clinically-diagnosed COVID-19 infection were included in the study. All pregnant women had mild courses of their COVID-19 illnesses. Six of the 16 laboratory-confirmed pregnant women and 10 of the 25 clinically diagnosed pregnant women delivered during the study period. There were no cases of vertically transmitted COVID-19 in the neonates born to these pregnant women.

Case 1: 5 year old female with fever, cough and fatigue. No lymphadenopathy. Bloods: low WCC with raised lymphocytes and decreased neutrophil ratio. Normal CRP. CT: normal. Follow-up CT 9 days later remained normal.

Case 2: 11 month old male with fever and cough. No lymphadenopathy Bloods: normal WCC with raised lymphocyte count and decreased neutrophil ratio. Normal CRP. CT chest: single consolidation without peripheral predominance (unlike reported findings in adults).

Case 3: 9 year old female with fever but no cough. No lymphadenopathy. Bloods: normal WCC, low lymphocytes and normal neutrophil ratio. Normal CRP. CT chest: single ground glass opacity without peripheral predominance (unlike reported findings in adults).

Case 4: 2 month old male with cough but no fever. No lymphadenopathy. This infant was coinfected with RSV. Bloods: normal WCC with normal lymphocytes and normal neutrophil ratio. CRP raised (does not say how high). CT chest: multiple focal consolidations and pleural effusion. This infant’s CT findings were more severe than the other three children, thought to be due to coinfection with RSV.

Cardiology Papers

Del Barba, P., D. Canarutto, E. Sala, G. Frontino, M. P. Guarneri, C. Camesasca, C. Baldoli, A. Esposito and G. Barera (2020). “COVID-19 cardiac involvement in a 38-day old infant.” Pediatr Pulmonol. June 18th 2020, https://doi.org/10.1002/ppul.24895

First (single) case report of an infant with biochemical and echocardiographic evidence of mild cardiac involvement due to SARS-CoV-2 infection.  The 38 day old male infant presented to hospital on 27/03/20.  Neither the centre nor the country is identified but is likely to be in Italy.  Pregnancy had been unremarkable.  No delivery details given.  Baby was formula fed.  Both mother and father were +ve for SARS-CoV-2.  He presented with a fever of 37.6oC and rhinitis but no respiratory distress and did not require oxygen therapy.  Nasal and nasopharygeal swabs were +ve for SARS-CoV-2.  Haemoglobin, lymphocyte count, CRP, ESR, electrolytes, liver transaminases, INR and PTT were normal.  Abnormal results: LDH “mildly increased”, platelet count 525,000/μl, procalcitonin 3.28ng/ml, troponin T 8.2ng/dl, creatine kinase-MB 9.8μg/L, D-dimer 13.3 μg/ml, pro-brain natriuretic hormone 208pg/ml, fibrinogen 1.28g/L.  CXR showed increased bronchovascular markings but no parenchymal changes (CT not done).  A resting heart rate of 140bpm and a transient peak rate of 200bpm were the only cardiac signs (serial ECGs and 24hr recording).  First echocardiogram showed no abnormalities but cardiac MR scan showed a “minimal amount” of pericardial effusion with no myocardial edema.  Follow up echo 3 days after the first confirmed a 2mm effusion.  A panel of other viruses linked to pulmonary and/or cardiac problems in infants was negative.  He required no treatment and was discharged after 14 days.  Swabs were -ve 21 and 22 days after presentation.

Selman Kesici, Hayrettin Hakan Aykan, Diclehan Orhan, Benan Bayrakci, Fulminant COVID-19-related myocarditis in an infant, European Heart Journal, June 12th 2020, ehaa515, https://doi.org/10.1093/eurheartj/ehaa515

Clinical Features: 2 year old previously healthy male in contact with Covid19, hospitalized with nausea, vomiting and lethargy. On Day 2 of admission deteriorated with Respiratory distress, filiform pulse and blood pressure was not measurable. There was hepatomegaly. Child was intubated in PICU, while preparing for ECMO went into cardiac arrest. 30 minutes of CPR was performed. During ECMO biopsy of myocardium was taken.

Radiology: Initial CXR – bilateral interstitial infiltrates. Day 2: CXR Cardiomegaly with pleural effusion. ECHO: Severe heart failure

Bloods: Initial bloods negative for inflammatory markers but Troponin was elevated 30 times normal on Day 2.

PCR for viruses were negative including RT PCR for Sars_COV_2

Myocardial Biopsy showed local inflammation, Positive for RT_PCR for COVID 19

Conclusion: Single case report showing the effect of COVID 19 causing heart failure secondary to Myocarditis without Kawasaki like Syndrome

Trogen, B., F. J. Gonzalez and G. F. Shust (2020). “COVID-19-Associated Myocarditis in an Adolescent.” The Pediatric Infectious Disease Journal. 03. June 3rd 2020, doi: 10.1097/INF.0000000000002788

This case report details the admission to PICU of a 17-year-old obese male (BMI 30kg/m2) with spondylolysis and a distant history of asthma (not requiring medication for > 5 yrs) who presented to a hospital in New York City during the third week of April with septic shock, after a week’s history of fever, GI symptoms and neck pain.

Clinical features:  7 day history of fever and neck pain and a 6 day history of diarrhoea and vomiting (non-bloody, non-bilious).  No neck stiffness, headache, photophobia or respiratory symptoms.  At presentation he was febrile, tachycardic and hypotensive (79/66 mmHg) with diffuse abdominal pain.  His cardiovascular status remained labile after initial fluid resuscitation and he was admitted to PICU.

Initial bloods:  Lymphocytes 0.9 x 103/μL, CRP 167 mg/L, ferritin 1275 ng/mL, D-dimer 1218 ng/mL, initial Troponin I level 2.97 ng/mL rising to 6.17 ng/mL 2 hrs later, brain natriuretic peptide 2124 pg/mL, sodium 128 mmol/L, creatinine 1.25 mg/dL, creatine kinase 761 U/L, LDH 346 U/L, INR 1.5, IL-6 28 pg/mL

Microbiology:  Nasopharyngeal swab RT-PCR SARS-CoV-2 positive.  Other respiratory and GI pathogen PCRs negative, including enterovirus, adenovirus, CMV, EBV, HHV-6, parvovirus B19.

Radiology:  Abdominal USS essentially normal.  CXR: low lung volumes, normal cardiothymic silhouette and mild, hazy ground glass opacities at the lower lobes bilaterally.  

ECG:  T-wave inversion particularly in inferior leads.

Cardiac imaging:  Initial transthoracic echocardiogram: LV ejection fraction mildly depressed with no obvious intracardiac clots or pericardial effusion.  Cardiac MRI: normal sized LV & RV, LVEF 40%, RVEF 39%, area of mid-wall late gadolinium enhancement at inferior LV-RV junction corresponding to area of increased T2 signal as well as an area of hypokinesia, consistent with myocarditis.  

Treatment in PICU:  Blood pressure normalised on day 1, but remained febrile and tachycardic until day 4.  Required 2 days of oxygen via NC.  Received anticoagulation, paracetamol/ibuprofen and 48 hrs of piperacillin/tazobactam until blood cultures reported negative.  No other anti-inflammatories or IVIg given.  Initially started on hydroxychloroquine which was stopped on day 3 when serial ECG demonstrated prolonged QTc interval not present initially.  Serial Troponin I and BNP levels normalised by discharge.

Outcome:  Discharged on day 5 with 2 week course of anticoagulation (apixaban).  Echocardiogram at follow-up one week after discharge demonstrated normal ejection fraction (59%) with qualitatively improved function.  However, tissue Doppler imaging signals of the mitral valve annulus were still abnormally diminished with low global longitudinal strain rate, consistent with residual myocardial dysfunction.  Repeat ECG showed persistent T-wave inversion in lead III.

The authors conclude with a discussion of the possible mechanisms of cardiac injury secondary to COVID-19, including viral entry via the ACE2 receptor causing direct damage to myocardiocytes, immune-mediated injury secondary to cytokine release or T-cell dysregulation, microvascular damage, endothelial shedding/dysfunction, hypoxia-mediated injury and abnormal coagulation, including DIC, increasing the risk of thrombosis and ischaemic events.

Ocular Manifestation

Valente, P., G. Iarossi, M. Federici, et al. Ocular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report. J aapos. June 10th 2020, https://doi.org/10.1016/j.jaapos.2020.05.002

27 paediatric patients were identified between 16/03/2020 – 15/04/2020, from Bambino Gesù Children’s Hospital, Rome, Italy. It was not clear how patients were identified/recruited. The mean age was 84 months (range=8 days to 210 months). 74% were male (n=20); 26% were female (n=7).

Clinical features present:
– Cough and/or dyspneoa = 15 patients (56%);
– Vomiting and/or diarrhoea = 8 patients (30%);
– Ocular manifestations consistent with viral conjunctivitis = 4 patients (15%);
In the abstract it states that “At admission, all patients showed ocular manifestations”, however there is no other reference to further information in the paper.

Radiology/bloods: N/a

Other investigations:
Nasopharyngeal swab to COVID-19 tested positive in all 27 patients.
Of the 4 patients with apparent viral conjunctivitis, 1 patient resulted positive for SARS-CoV-2 on RT-PCR from conjunctival swab.
Of the other patients (n=23), two more patients had positive findings for SARS-CoV-2 in their conjunctival swab without developing clinical signs of conjunctivitis.

Outcomes: 27 (100%) discharges. 

Other salient features: Some preliminary evidence to suggest that SARS-CoV-2 shedding is low in eye secretions/tears.

Testing/Viral Studies

M. A. De Ioris, A. Scarselli, M. L. Ciofi Degli Atti, et al. Dynamic viral SARS-CoV-2 RNA shedding in in children: preliminary data and clinical consideration of Italian regional center. J Pediatric Infect Dis Soc. May 23rd 2020, https://doi.org/10.1093/jpids/piaa065

This study at a paediatric hospital in Rome tracked SARS-CoV-2 shedding (nasopharyngeal, faecal, urinary and conjunctival) by following a cohort of 22 children during their hospital stay, collecting clinical and microbiological data. 

Study design:  The study ran from 16th March to 12th April in the COVID centre at Bambino Gesu Pediatric Hospital and collected data on 22 inpatients with an initial positive nasopharyngeal swab (either prior to admission or on admission).  RT-PCR for SARS-CoV-2 RNA on nasopharyngeal and conjunctival swabs and stool and urine samples were repeated every 2-3 days for each child while they were inpatients until they had two consecutive negative results in the absence of new symptoms.  Kaplan-Meier analysis was used to estimate the duration of symptoms and viral shedding for symptomatic patients: patients whose last swab/sample was still positive were censored at the date of the last swab.

Study population:  15/22 (68%) male, 7/22 (32%) female.  Median age 7 years (range 8 days to 17.5 years).  4/22 neonates (1/4 tested because mother positive and 3/4 tested because midwife positive).  2/22 comorbidity (Angelman syndrome, suspected genetic syndrome and autism).  13/22 patients were discharged before the end of the study period (median inpatient stay 7 days, range 3-15 days).  

Symptoms:  4/22 (18%) asymptomatic (including 2/4 neonates, the other 2/4 had low grade fever and poor feeding).  18 symptomatic patients: 15/18 (83%) fever, 10/18 (55%) respiratory symptoms, 7/18 (39%) diarrhoea and vomiting, 3/18 (17%) seizure.  Symptoms had resolved in all 18 before discharge from hospital.  Median duration of symptoms was 8 days (range 2-21 days).  15/22 had a positive stool sample at admission: of these 7/15 (47%) had respiratory symptoms and 3/15 (20%) had diarrhoea and vomiting.

Viral shedding:  At diagnosis: 22/22 (100%) had positive nasopharyngeal swab (by definition), 15/22 (68%) had positive stool sample, 1/22 (5%) had positive urine sample (re-test 2 and 5 days later was negative; another patient had initial negative urine test but repeat 3 days later was positive) and 2/22 (9%) had positive conjunctival swab (both were negative 2-3 days later).  A detailed table charting the dates of inpatient stay, onset and end of symptoms and positive/negative swabs/samples for each patient is supplied: the full screen of faecal, urinary and conjunctival sampling was performed at variable intervals after the initial positive nasopharyngeal swab (up to 5 days later in several cases).  For symptomatic patients:  (1) from date of symptom onset to negative nasopharyngeal swab: median 8 days (range 2-17 days) and (2) from date of symptom onset to negative stool sample: median 14 days (range 10-15 days).  Estimate of persistence of viral shedding at day 14 from symptom onset for nasopharyngeal swab 52% and for stool sample 31%.

The authors note the need to confirm the clinical relevance of faecal SARS-CoV-2 shedding in terms of the risk of transmission via the faeco-oral route.

Xu, Y, Li X. Zhu, B. et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med (2020). https://doi.org/10.1038/s41591-020-0817-4

This study presents the results of widespread screening for COVID-19 in Guangzhou in China. 745 children were screened of which 10 were positive for COVID-19. Their ages ranged from 2 months to 15 years.

Clinical features: 6/10 had a fever over 38oC.  5/10 had a cough. 4/10 had a sore throat. 2/10 had rhinorrhoea and 2/10 had diarrhoea.

Radiography: 7/10 had coarse lung markings on CXR with no pneumonia, and 3/10 were normal. CT scans revealed ground glass or patchy opacities in 5/10.

Bloods: Basically normal in all cases

They made note that rectal swabs were frequently positive and that these swabs were positive for a longer duration than nasal swabs.  The authors suggest on this basis that faecal-oral transmission may be possible, however this is very uncertain and will require further research to elucidate.

Yuan, C., H. Zhu, Y. Yang, X. Cai, F. Xiang, H. Wu, C. Yao, Y. Xiang and H. Xiao (2020). “Viral loads in throat and anal swabs in children infected with SARS-CoV-2.” Emerg Microbes Infect: https://doi.org/10.1080/22221751.2020.1771219

This is a retrospective review of RT-PCR testing results of 2138 paediatric patients with suspected SARS-CoV-2 infection at Wuhan Children’s Hospital in Hubei, China, from 1 January to 18 March 2020.  All children were tested using throat swabs (TS); a subset of 212 were also tested using anal swabs (AS).  Changes in viral load in both throat and anal swabs were monitored in 13 patients.

Findings:  217/2138 (10%) confirmed cases on EITHER throat or anal swab.

78/217 confirmed cases had both types of swab: 24/78 (31%) positive for both TS & AS, 37/78 (47%) TS pos/AS neg, 17/78 (22%) TS neg/AS pos.  For those cases where the TS and AS results didn’t match (i.e. TS pos/AS neg or TS neg/AS pos):

Asymptomatic:  12/37 (32%) TS pos & 10/17 (59%) AS pos

GI symptoms:  7/37 (19%) TS pos & 6/17 (35%) AS pos

Cough:  16/37 (43%) TS pos & 4/17 (24%) AS pos

Fever:  20/37 (54%) TS pos & 5/17 (29%) AS pos

CT evidence of pneumonia:  25/37 (68%) TS pos & 10/17 (59%) AS pos

Time from positive to negative for PCR assay:  7 days for TS pos & 6 days for AS pos

The viral loads detected on throat swabs and anal swabs showed no difference.

Zhao, W., Y. Wang, Y. Tang, W. Zhao, Y. Fan, G. Liu, R. Chen, R. Song, W. Zhou, Y. Liu and F. Zhang (2020). “Characteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge.” Clin Pediatr,May 28th https://doi.org/10.1177%2F0009922820928057

In this study from Beijing, China, serial nasopharyngeal swabs were performed on children discharged between January 21st and April 18th 2020 following hospital admission with confirmed SARS-CoV-2 infection. Criteria for hospital discharge included clinical improvement and 2 negative RT-PCR tests for SARS-CoV-2 on consecutive nasopharyngeal swabs. Follow up swabs were performed fortnightly following discharge; the authors report on children with subsequent positive RT-PCR on follow up.

In total 14 children were followed, 7 of whom had a subsequent positive SARS-CoV-2 PCR result, none of whom had significant symptoms at the time (one with a temperature of 37.5). There were no significant clinical or laboratory differences between the group with subsequent positive tests compared with those who remained negative.

The authors refer to those who have subsequent positive SARS-CoV-2 PCR as having “reactivation” of infection. This is a misnomer as the persistent shedding of viral RNA has been well recognised in adult studies<https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25952>. This includes a large cohort of over 200 patients from Korea <https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030> with positive tests following negative PCR results, similar to the children in this study. Importantly no onward transmission from these “re-positive” cases was found amongst 790 contacts in the Korean cohort, suggesting the viral RNA detected in patients with prolonged shedding is not viable. Indeed in a recent in vitro study<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> including 90 SARS-CoV-2 PCR positive samples, only samples taken within 8 days of symptoms onset were capable of infecting cells. This is in keeping with contact tracing data<https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2765641> suggesting peak transmissibility occurs before and immediately after symptom onset with limited transmission beyond 5 days of symptom onset.

The likely explanation of the “reactivation” described here is prolonged shedding of non-viable viral RNA with an interim “false negative” samples prior to hospital discharge. Given the available data, it is unlikely that these “re-positive” discharged patients represent an infection risk to others

Xing Y, Ni W, Wu Q, et al. Prolonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase. doi:10.1101/2020.03.11.20033159

A pre-print, the information should be treated again with caution until it has undergone peer review.

This study of 3 paediatric patients with COVID-19 from Qingdao, China (aged 1.5, 5 and 6 years) all had fevers and none were severe. All children had elevated lymphocytes (>4.4 x 109/L) and 2 of 3 had abnormalities on chest CT (consolidation in one and ground glass changes in the other). The primary point made in the paper is that whilst respiratory swabs were negative within 2 weeks after children became afebrile, stool remained positive for over 4 weeks.

Pandey U, Yee R, Precit M, et al Pediatric COVID-19 in Southern California: clinical features and viral genetic diversity, medRXiv, June 2nd 2020, https://doi.org/10.1101/2020.05.28.20104539

A study of 35 children age range 18 days to 18.5 years (median12.5), 57% of whom were boys, seen over an 8 week period in Southern California. Patients were identified by nasopharyngeal swabs submitted to Los Angeles Children’s Hospital between 11 March 2020 and 11 May 2020. 37% were hospitalised with a median inpatient stay of 4 days. Symptoms were diverse with fever and cough being the most common, 1/3 were symptomless. Whole genome sequencing was undertaken on Covid-19 samples. There was an association between disease severity and viral load. Children < 5 years age had a higher viral load and all were symptomatic. There was limited variation in the viral genome though a calculated evolutionary rate was like other RNA viruses. No correlation was identified between disease severity and genetic variation.

Zachariah, P., K. C. Halabi, C. L. Johnson, S. Whitter, J. Sepulveda and D. A. Green (2020). “Symptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children.” Clin Infect Dis, May 20th 2020, https://doi.org/10.1093/cid/ciaa608

This research letter details the viral loads of children with confirmed SARS-CoV-2 infection from Columbia University Irving Medical Centre in New York. All children admitted and discharged between March 14th to April 24th 2020 were included, timing of test relative to onset of symptoms, clinical severity along with viral load were compared between infants <1yo and children >1yo.
Of 57 patients with positive SARSCoV-2 PCR, 20 (35%) were under 1yo. Compared with older children, viral load was higher amongst infants <1yo (mean cycle threshold 21.05 vs 27.25, p<0.01 – where lower cycle threshold=greater viral load). Infants were tested earlier on average (2 vs 3.8 days from symptom onset) and fewer had severe disease compared with older children (5% vs 32.4%).

In this small hospital-based study symptomatic infants appear were found to have higher viral loads and milder disease compared with older children. This is in contrast to data from some adult studies where a higher viral load correlated with more severe illness.
Amongst several possible explanations for this observation are that:
– infants were more likely to be tested early in illness when viral load peaks<https://www.nature.com/articles/s41591-020-0869-5> – declining thereafter
– thresholds for hospital presentation may differ between infants and older children
– test performance and sample quality may differ between infants and older children
– there may possibly be differences in host biology according to age
Although some data suggest that higher SARS-CoV-2 viral load is associated with the presence of viable virus<https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa638/5842165> / in vitro infectivity, the exact implications of the findings here in terms of risk of transmission from infants compared with older children is unclear. Further studies examining SARS-CoV-2 viral load dynamics and correlation with clinical course in children are required to better understand potential variation between different age groups.

Haematology and Immunology Focus

Odièvre, M. H., C. de Marcellus, H. Ducou Le Pointe, S. Allali, A. S. Romain, J. Youn, J. Taytard, N. Nathan and H. Corvol (2020). “Dramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome.” May 1st 2020, Am J Hematol. https://doi.org/10.1002/ajh.25855

The authors of this case study are based at two hospitals in Paris; in this correspondence they describe the treatment of a 16 year old girl with homozygous sickle cell disease (SCD) admitted to ICU with acute chest syndrome (ACS) and pulmonary emboli complicating COVID-19 pneumonia, in particular the use of Tocilizumab, a humanised anti-IL-6 monoclonal antibody (usual indications include use as immunosuppressant therapy in rheumatoid arthritis and giant cell arteritis in adults and juvenile idiopathic arthritis in children).

Course of SCD prior to admission:  The patient had a history of recurrent vaso-occlusive crises and abnormal transcranial dopplers between the ages of 5 and 11 years old, necessitating treatment with exchange transfusions.  At 11 years of age she was commenced on daily hydroxyurea with resolution of vaso-occlusive events.  She had no history of ACS or pulmonary hypertension; respiratory function and chest radiography were previously normal.

Presentation with COVID-19-19:  She presented with isolated fever, with nasophyaryngeal swabs subsequently confirmed as RT-PCR SARS-CoV-2 positive.  7 days later she developed acute chest pain associated with respiratory distress (SpO2 85%).

Radiology:  CT pulmonary angiogram (CTPA) showed bilateral pulmonary emboli and bilateral consolidation with right-sided halo sign.

Treatment in ICU:  Included non-invasive ventilation, anticoagulation and red cell exchange transfusion followed by simple transfusion (lowest Hb 64 g/L).  Based on recent experience in adult SCD patients with COVID-19 disease she also received a single infusion of Tocilizumab (8 mg/kg).  The authors report rapid clinical improvement after Tocilizumab with repeat CTPA 5 days later showing complete resolution of pulmonary emboli and consolidation on the right and decrease on the left.  She was discharged from hospital 11 days after admission to continue oral anticoagulation for 6 weeks.

Conclusions:  Inflammatory cytokines such as IL-6 and TNF-α are elevated in COVID-19.  COVID-19 pneumonia can cause ACS in SCD patients; there have been several recent reports of successful treatment using Tocilizumab.

Tsao HS, Chason HM, Fearon DM. Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics. 2020 May 1. doi: 10.1542/peds.2020-1419. Pre-publication version.   

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2. 

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. 

A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2. 

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.  

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].  

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.  

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain. 

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.  

Wu, H., H. Zhu, C. Yuan, C. Yao, W. Luo, X. Shen, J. Wang, J. Shao and Y. Xiang (2020). “Clinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China.” JAMA Netw Open 3(6): e2010895. doi:10.1001/jamanetworkopen.2020.10895

In this retrospective case series from Wuhan, China, the clinical and immunological characteristics of children admitted to hospital with confirmed SARS-CoV-2 infection are examined. Details are provided for the 148 children with mild or moderate disease.

The median age was 84 months (IQR 18-123). Fever (40.5%) and cough (44.6%) and vomiting or diarrhoea (21.6%) were the most common symptoms. SARS-CoV-2 PCR became negative at a median of 7 days (IQR 4-11 days).
Lymphopenia was present in only 4.5% of patients; CD 4 lymphopenia in 1.9%. Elevation in CRP (32.4%) and procalcitonin (47.3% elevated; median 0.05 (IQR 0.04-0.08)) was observed in fewer than half of patients. Liver transaminases and LDH were significantly higher in moderate versus mild cases but the vast majority of levels fell within normal range.
Levels of inflammatory cytokines including IL2, IL6, TNG-a and IFN.y were largely normal; the authors note that one patient with severe disease had elevated IL-6 (3869 pg/mL). IL-10 was increased in 14%.
No deaths occurred amongst mild and moderate cases and all 148 patients were discharged.

In this large case series of children with mild or moderated SARS-CoV-2 infection, laboratory measures of inflammation were largely normal. Specifically the significant elevations in IL-6, D-dimer, and ferritin characteristic of severe COVID-19 in adults and also PIMS-TS / MIS-C in children were absent in these milder cases. The authors postulate that the relative preservation of CD4 T-cells and the higher levels of IL-10 compared with adults with severe COVID-19 may indicate these as important components of a protective immune response.
As yet our understanding of the drivers of variation in individual immune response to SARS-CoV-2 remains incomplete.

Venturini E,  Palmas G, Galli L. Severe neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection. 2020 May 19. doi 10.1016/j.paeds 2020.04.051 [Epub ahead of print]

This case report from the Meyer Children University Hospital, Florence, published as a letter describes two infants with SARS-CoV-2 with transient severe neutropenia (<0.5 x109/l)

Clinical Features: The two female infants, aged 23 days and 39 days were admitted with mild respiratory symptoms and low grade fever. Nasopharyngeal swans were positive for Covid-19. There was no clinical deterioration in their condition during admission.

Radiology: not described

Treatment: not described.

Haematology: leukocytes and neutrophils normal on admission. At 5 days neutrophil counts fell to 0.244 x 109/lnand 0.482 x 109/l. Subsequently both improved.

Apart from age and gender there is no other demographic information nor any on treatments.

Although neutropenia is described in 6% of cases of Covid-19, severe neutropenia has not been described. In the report cases it was not associated with any change in clinical state. The authors suggest consideration of performing FBCs 5 to 7 days into the illness to identify neutropenia.

It requires further studies to see if these findings are replicated and whether they are clinically significant. The severity of the neutropenia could be age dependent reflecting bone marrow maturity as one patient was in the neonatal range and the other just beyond it. 

Chen, J., Z. Z. Zhang, Y. K. Chen, et al (2020). “The clinical and immunological features of pediatric COVID-19 patients in China.” Genes and Diseases. https://doi.org/10.1016/j.gendis.2020.03.008

This early study from Chongqing, China describes the features of 12 children diagnosed with COVID-19. All had a mild course of illness. CT imaging was abnormal in 10 of 12 with patchy ground glass opacity the most common finding. Lymphopenia was present in 2 children.
The authors also compare the “immune profile” (including lymphocyte counts, immunoglobulins, complement, CRP and IL6 levels) of the 12 children with a group of 20 adults patients. Aside from a lower CRP in children (mean 11.5 vs 23.3mg/L) and expected age-related differences in absolute lymphocyte numbers, there were no significant differences between the groups.

Other Interesting Clinical Papers

Xiong, X., G. T. Chua, S. Chi et al. A Comparison Between Chinese Children Infected with COVID-19 and with SARS. J Pediatr. June 18th 2020, https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.041

In this study, 244 children with SARS-CoV-2 infection from Wuhan, China are compared to 44 children diagnosed with SARS (SARS-CoV-1) in in Hong Kong in 2003. 

The clinical details of this series of patients from Wuhan, previously described elsewhere, are compared with those of those of children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 montsh vs 160 months). Compared with SARS-CoV-1 patients, children with SARS CoV-2 were less likely to have symptoms (20.9% asymptomatic vs 0% of SARS-CoV-1), including fever (40.2% vs 97.7%), myalgia (37.6% vs 0.8%), and chills (32.6% vs 3.7%). 

Fewer children with SARS-CoV-2 required supplemental oxygen (4.7% vs 18.6%) and few in either cohort required mechanical ventilation (1.6% vs 2.3%). A single death occurred in a patient with SARS-CoV-2 (a 10 mo with intussusspection) and no cases of PIMS-TS / MIS-C were identified amongst the 244 SARS-CoV-2 infected children from Wuhan.

The most striking difference is the milder clinical illness and relative lack of symptoms in children with SARs-CoV-2 compared with those with SARS-CoV-1. The lack of asymptomatic infections in SARS-CoV-1 is also notable, similar to findings in adults. Whilst the role of asymptomatic patients in the spread of SARS-CoV-2 is unresolved, the milder clinical illness in the majority of patients along with the demonstrated earlier peak in viral shedding relative to symptom onset and resultant role of pre-symptomatic transmission are likely major reasons for the continuing widespread transmission of SARS-CoV-2, where the outbreak of SARS-CoV-1 in 2003 was more readily contained.

Li Y, Wang H, Wang F, Du H, Liu X, Chen P, Wang Y, Lu X, Comparison of Hospitalized Patients with pneumonia caused by COVID-19 and influenza A in children under 5 years, International Journal of Infectious Diseases (2020) https://doi.org/10.1016/j.ijid.2020.06.026

This study is from Wuhan children’s hospital, China. It is a retrospective one reviewing the clinical history, radiology and laboratory results of 57children under 5, with confirmed pneumonia on CT or radiography within 72 hours of admission, with COVID-19 diagnosed by detecting SARS-CoV-2 in throat swabs. The comparison group was 59 children aged under 5 who were admitted with influenza A pneumonia. Influenza A was diagnosed by direct immunofluorescence assay.

The 57 COVID-19 pneumonia children were consecutively admitted between 28th January and 11th March 2020; the 59 influenza A pneumonia children were consecutively admitted between 14th December 2019 and 30th February 2020(?).

The median age of the COVID-19 patients was 18.7+/- 16.7 months. The median age of the Influenza A patients was 21.8+/-16.7 months with no statistical difference. There was slightly higher proportion of males in each group 61.4% for COVID-19 vs 66.1% for the influenza A group with no statistical difference.

Clinical features: 31(54.4%) of the COVID-19 patients presented with fever compared to 50(84.7%) influenza A patients, P<0.001. 40(70.2%) of the COVID-19 patients presented with cough compared to 50(84.7%) in the influenza A group, p<0.001. Dyspnoea occurred in only 2(3.5%) COVID-19 patients and 5(8.5%) influenza A patients, p=NS. Gastrointestinal symptoms occurred in 8(14.1%) of the COVID-19 patients and 21(35.6%) of the influenza A patients, p=NS. Convulsions occurred in only 1 COVID-19 child and 3 influenza A children, p=NS. During hospitalization 1 COVID-19 child required supplementary oxygen and two required intensive care, compared to 7 influenza A children requiring supplementary oxygen and 4 intensive care, p=NS.

Radiology: CT chest imaging with ground glass appearance was more commonly found in COVID-19 pneumonia children 42.1% vs15% influenza A pneumonia children, p=0.03. Consolidation was more common in influenza A children (25%) compared to COVID-19 patients (5.2%), P = 0.02.

Haematology and Biochemistry

Haematology investigations showed COVID-19 patients had significantly lower levels of leukocytes and neutrophils but significantly higher lymphocyte levels compared with influenza A patients (7.87 vs. 9.89 ×109/L, P = 0.02; 2.43 vs. 5.16 ×109/L, P < 0.001; 4.58 vs. 3.56 ×109/L; P = 0.006.

Lower levels of C-reactive protein (CRP) were observed in COVID-19 patients than influenza A patients (3.7 vs. 15.1 mg/L, P = 0.001.

There were no significant routine biochemistry differences between the two groups except potassium which was significantly lower in the COVID-19 group.

Significantly lower levels of D-dimer and prothrombin time (PT) were found in COVID-19 patients than influenza A patients (0.34 vs. 1.94, P < 0.001; 10.8 vs. 11.2 mm/h, P = 0.014).

There were no deaths reported in this study.

Conclusion: The authors concluded that children under 5 with COVID-19 pneumonia compared to children with influenza A pneumonia showed milder clinical symptoms and a significantly increased lymphocytosis with a more prevalent ground glass CT chest appearance compared to influenza A pneumonia children under 5. There were no reported deaths or serious complications from COVID-19 in this study.

The study shows COVID-19 pneumonia is milder than influenza A pneumonia in a series children under 5. The influenza A patients were not typed and came from a different but overlapping time period during the winter months. Comorbidities were also not mentioned in either group.

Lu, Y., Y. Li, W. Deng, M. Liu, Y. He, L. Huang, M. Lv, J. Li and H. Du (2020). “Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan.” The Pediatric infectious disease journal. 05. doi: 10.1097/INF.0000000000002729

This retrospective study analysed demographic, clinical, laboratory, radiological and therapeutic data from the electronic medical records of 110 children hospitalised with “mild/ordinary” COVID-19 (classified as per the National Health Commission of People’s Republic of China National Recommendations for Diagnosis and Treatment of COVID-19, 7th edition) at Wuhan Children’s Hospital in Hubei, China between 30th January and 10th March 2020.  Inclusion criteria: throat or nasopharyngeal swabs RT-PCR SARS-CoV-2 positive and patient discharged from hospital after recovery (an initial cohort of 127 children was reduced to 110 after exclusion of 2 critical cases and 15 children in whom the onset of disease could not be accurately determined).

Study design:  Timings of onset of illness, most recent exposure (presumably to SARS-CoV-2-confirmed or symptomatic contacts, although this isn’t specified), diagnosis and discharge from hospital were recorded.  Patients were discharged only once they had two consecutive RT-PCR SARS-CoV-2 negative swab results (separated by at least 24 hours).  The authors calculated the duration of viral shedding for (a) symptomatic patients (81/110, 74%) as time from onset of illness to discharge and for (b) asymptomatic patients (29/110, 26%) as time from date of most recent exposure OR abnormal chest radiological imaging (reason for imaging not specified in these asymptomatic patients) to discharge.  This definition of duration of viral shedding, with starting point presumably in most cases a retrospective parent-reported start of symptoms or exposure to an infectious contact, and end point two negative swabs leading to discharge from hospital, makes interpreting the duration figures problematic.  Viral shedding in urine and faeces was not measured.

Clinical features:  Median age of the 110 children was 6 years (IQR 2-9); 59/110 male (54%), 51/110 female (46%).  Symptoms included: cough and dyspnoea 57/110 (52%), fever 56/110 (51%), GI (including diarrhoea, vomiting, poor feeding, anorexia, abdominal pain) 26/110 (24%), rhinorrhoea 10/110 (9%).

Radiology:  64/103 (62%) had unspecified chest imaging reported as demonstrating pneumonia (55/75 symptomatic (73%) and 9/28 asymptomatic (32%)).

Bloods:  Leucocytes < 4.0 x 109/L in 6/110 (5%) (all 6 were symptomatic).  Leucocytes > 10.5 x 109/L in 12/110 (11%) (9 symptomatic & 3 asymptomatic).  Lymphocyte ranges not specified.  Haemoglobin < 110 g/L in 13/110 (12%) (all 13 symptomatic).  Fibrinogen < 2.0 g/L in 34/90 (38%) (20 symptomatic & 14 asymptomatic).  Hs-CRP > 3.0 mg/L in 21/110 (19%) (18 symptomatic & 3 asymptomatic).  Procalcitonin > 0.05 ng/mL in 52/110 (47%) (43 symptomatic & 9 asymptomatic).  AST > 50.0 U/L in 19/110 (17%) (all 19 symptomatic).

Treatment:  None of the patients required oxygen therapy.  All of them received antiviral therapy, mostly commonly nebulised interferon-α.  According to the data table 22/110 received Chinese medicine therapy, although no details are given and it’s not clear if this was pre-hospitalisation.  Median duration of hospital stay was 10 days (IQR 8-13).

Conclusions:  The median duration of viral shedding using the definitions above was 15 days overall (IQR 11-20 days, range 5-37 days): 17 days (IQR 12-23) in symptomatic patients and 11 days (IQR 9-13) in asymptomatic patients.  Symptomatic infection, fever, pneumonia and lymphocyte counts < 2.0 x 109/L were reported to be associated with prolonged duration of shedding. 

Xiao, Z., X. Xie, W. Guo, Z. Luo, J. Liao, F. Wen, Q. Zhou, L. Han and T. Zheng (2020). “Examining the incubation period distributions of COVID-19 on Chinese patients with different travel histories.” Journal of infection in developing countries 14(4): 323-327. doi:10.3855/jidc.12718

Although all ages are affected by COVID-19, this paper makes it clear that the number of infected children is tiny compared to those in adults. The authors analyse incubation periods by age, finding that this increases in length in adults from aged 20 to 70+. The findings regarding children are more difficult to interpret due to small case numbers and therefore large confidence intervals, but it appears that 6 to 20 year olds may have a longer incubation period than young adults aged 20 to 60. The results for 0-5 year olds are fairly inconclusive. The authors then examine incubation in relation to travel history, finding that those who were affected by local community spread had longer incubation periods than those who had contracted the virus directly in Wuhan. They conclude that the virulence of the virus may decrease with intergenerational transmission, but that more work is needed.

Zhang, B., S. Liu, Y. Dong, L. Zhang, Q. Zhong, Y. Zou and S. Zhang (2020). “Positive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19).” Journal of Infection April 23rd 2020, https://doi.org/10.1016/j.jinf.2020.04.023

In this case series from Dongguan, China, three normally fit & well children aged 14y, 13y and 10m were followed up after positive throat swab for SARS-CoV-2. All three had a subsequent negative throat swab within approximately 7 days, and fully recovered, however 7-9 days later all three had rectal swabs which were positive. These findings raise the question of whether apparently well COVID-19 patients continue to carry and possibly shed the virus. If this was found to be the case in larger and more comprehensive studies, there may be an argument for introduction of strategies to increase avoidance of transmission via the faecal-oral route.

Nathan, N., B. Prevost and H. Corvol (2020). “Atypical presentation of COVID-19 in young infants.” The Lancet 395(10235): 1481.  https://doi.org/10.1016/S0140-6736(20)30980-6

This correspondence in the Lancet describes the clinical features of 5 infants with COVID-19 who were admitted to a Paris hospital during the first week after imposed population quarantine in France (from 17th March 2020).  At this time at Trousseau Hospital, children needing admission with fever or respiratory symptoms (or both) were admitted to a dedicated SARS-CoV-2 infection unit: during this week 14 infants under the age of 3 months were admitted and of these 5 out of 14 were confirmed SARS-CoV-2 positive on nasopharyngeal swabs.

Age/gender of infants:  All 5 of these previously healthy infants with COVID-19 were boys; ages ranged from 1.6 to 2.7 months (median 2.1).  All of their parents had mild signs of viral infection (including fever, cough, rhinitis), which could have been indicative of undiagnosed COVID-19.

Clinical features at presentation:  5/5 fever (range 37.4 to 38.5 °C), 4/5 neurological signs (drowsiness/hypotonia/abnormal “moaning” cry), 4/5 mottled skin, 4/5 runny nose, 4/5 cough, 0/5 dyspnoea, 5/5 normal SpO2, 0/5 digestive symptoms.

Investigations:  FBC, CRP & procalcitonin largely unremarkable, with the exception of lymphopaenia in 2/5.  Lumbar punctures in 4/5 babies with abnormal neurology reported normal (including negative for RT-PCR SARS-CoV-2).  Chest X-rays performed in 4/5 essentially normal.

Outcomes:  All 5 showed rapid clinical improvement and received no drugs other than paracetamol.  Inpatient stays ranged from 1 to 3 days and duration of fever ranged from 1 to 5 days (max 39°C).  The infants were followed up for 2 weeks post-discharge with a daily phone call from a paediatrician using a standardised questionnaire.

Conclusion:  This encouraging report of a small cohort of SARS-CoV-2 positive infants under the age of 3 months presenting with fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.

Wu, Q., Y. Xing, L. Shi, W. Li, Y. Gao, S. Pan, Y. Wang, W. Wang and Q. Xing (2020). “Co-infection and Other Clinical Characteristics of COVID-19 in Children.” Pediatrics. May 1st 2020, DOI: https://doi.org/10.1542/peds.2020-0961

This retrospective study from 2 hospitals in China examines the clinical and epidemiological characteristics of 74 children with confirmed SARS CoV-2 infection. Consistent with other studies, the majority of children experienced a mild course of illness with only one severe case requiring non-invasive ventilation. All recovered.

Cough was present in 32%, fever in 27% and 40% were asymptomatic at the time of testing. Lymphopenia was present in only 5% of cases. Abnormal CT imaging was observed in 50%, but only 12% showed typical changes of COVID-19.

Of those tested for other respiratory pathogens 19 of 34 had co-infection. Mycoplasma pneumoniae (16) and RSV (3) were the most common pathogens. It is not clear how these pathogens were identified. The significance of Mycoplasma in particular is not entirely clear as asymptomatic upper respiratory tract carriage<https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001444> in children is well recognised; similarly in interpreting serology, false positives<https://onlinelibrary.wiley.com/doi/full/10.1111/j.1469-0691.2004.00993.x> can be problematic.

For cases where exposure history was available 65/68 were household contacts of a confirmed adult case. There was no evidence of transmission from children to others.

This data is consistent with larger paediatrics studies demonstrating a milder course of COVID-19 in children compared with adults. Notably co-infection was not uncommon, illustrating that the presence of another respiratory pathogen should not preclude SARS-CoV-2 testing in children.

Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775

This is a paper from New York, USA, looking at the presenting characteristics, comorbidities, and outcomes of 5700 patients who were hospitalized with Covid-19. These were patients who were admitted to one of 12 Northwell Health acute care hospitals between 01/03/2020 and 04/04/2020. Clinical outcomes were monitored until 04/04/2020. All patients who were sufficiently medically ill to require hospital admission with confirmed severe acute respiratory syndrome coronavirus 2 infection by positive result on PCR testing of an NPA were included. The median age of patients was 63 years (IQR 52-75), 39.7% were female. 

There were only 59 patients under 10yo, and 15 patients between 10-20 years of age in this study.

The results below unless specified are for patients of all ages. 

At presentations, 30.7% of patients had a temperature of over 380C. 20% had oxygen saturations of less than 90%. 43.1% of patients were considered tachycardic with a heart rate of over 100. 

The majority of patients white cell count and differentials were within normal range. The mean white blood cell count was 7 (IQR 5.2-9.5). Neutrophil count 5.3 (IQR 3.7-7.7), however some patients were mildly lymphopenic, median 0.88 (IQR 0.6-1.2). 

Most patients had a low CRP, the mean result was 16 (IQR 6.4-26.9). Most patients had a raised ferritin, the mean result was 798 (IQR 411-1515), with 15-400 being considered normal range. Of note lactate dehydrogenase was tested in 70% of the patients and was significantly raised in most patients, the mean being 404 (IQR 300-551) with the normal considered to be 50-242.

A venous lactate was recorded in 44% of patients and all results were normal- <2. 

The most common comorbidities were hypertension (56.6%), obesity (41.7%) and diabetes (33.8%). 

At the study end point 2634 patients had been discharged or had died during hospitalisation. Of these 14.2% were treated in ICU, 12.2% of them received mechanical ventilation, and 21% of these patients died. At the end point of the study of those patients who had received mechanical ventilation 3.3% were discharged alive, 24.5% died, 72.2% were still in hospital. There were no deaths in the 34 patients under 18 age group out of those who had reached discharge end point. There were still 25 patients under 20 years hospitalised at the time of the paper. 

Of the patients who died, those with diabetes were more likely to have received mechanical ventilation or care in the ICU compared to those who did not have diabetes. Interestingly of those who died, those with hypertension were less likely to have received invasive mechanical ventilation than those without hypertension. 

As most patients were still in the hospital at the endo point of the study (53.8%) this biases rates toward including patients who died early in their hospital course. The researchers point out that as these patients complete their hospital course, reported mortality rates will decline. 

This study was slightly limited by the fact that the data was collected from the electronic heath record database and not the medical notes, from which a greater level of detail may have been established, however it was using this method that allowed for such a large number of patients to have been included and reviewed over a relatively short space of time. It is also limited by the fact that the study population only included patients from within the New York metropolitan area which may underrepresent some ethnic minorities. 

Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units. JAMA Pediatr. Published online May 11, 2020. doi:10.1001/jamapediatrics.2020.1948

This is a cross-sectional study of children admitted to 46 PICUs in North America. 48 children were admitted during the collection period (March 14 to April 3 2020). All had confirmed COVID-19 infection on PCR from a nasal swab.

Most patients presented with respiratory symptoms, but there were other presentations – three with DKA, and one with vaso-occlusive crisis (sickle cell). 86% of these patients had at least one comorbidity. 69% were severely or critically ill on admission, and 25% needed vasoactive drugs. 81% of patients needed respiratory support that exceeded their baseline.
61% had a range of therapies, including Hydroxychloroquine, Azithromycin, Remdisivir, and Tocilizumab. These were used as single agents or in combination with other therapies.
The overall mortality rate was 4.2% (both patients who died had pre-existing comorbidities and developed multisystem organ failure). 32% were still hospitalised at the time of publication (including one patient still receiving ECMO). 65% had been discharged.

This study reinforces what is known about the decreased burden of disease from COVID-19 in children compared with adults. Critically ill children had a less severe course of illness and better hospital outcomes than in adults. Children commonly had medically complex comorbidities. Overall the mortality is much lower in children (4.2%) than has been reported in adults (50-62%)

Lazzerini, Marzia et al, Delayed access or provision of care in Italy resulting from fear of COVID-19, The Lancet Child & Adolescent Health, Volume 0, Issue 0, Published April 9th 2020, https://doi.org/10.1016/S2352-4642(20)30108-5

This is a report of case studies during the COVID-19 pandemic in Italy of children whose presentations were thought to have been delayed due to parental fears of coming to the hospital. They report from 5 hospitals between March 1st and March 27th 2020, where paediatric presentations were reduced between 73–88%.

During this period, in the week of March 23rd to 27th 12 children are identified whose parents reported avoiding accessing hospital due to concerns over SARS-CoV-2 infection . 6 of these were admitted to PICU and there were 4 deaths. The cases include 2 children with DKA, 2 with acute leukaemia, 2 children with cerebral palsy and complex needs, 1 with pneumonia and febrile convulsions, 1 with pyelonephritis, 1 with pyloric stenosis, 1 with a Wilm’s tumour, 1 with vomiting and hypoglycaemia and 1 with a congenital syndrome on dialysis.

This case series highlights the concerns of many paediatricians that more deaths will be seen in children from collateral damage born from the COVID-19 response, than will die of COVID-19. Delayed presentations is a major concern around the world currently, and whilst these cases certainly raise concerns, evidence is needed to ascertain the true presence and extent of this problem.

Preßler, J., S. Fill Malfertheiner, M. Kabesch, H. Buntrock-Döpke, S. Häusler, A. Ambrosch and S. Wellmann (2020). “Postnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study.” Pediatr Allergy Immunol. 9th June 2020, https://doi.org/10.1111/PAI.13302 

This letter to the editor in Pediatric Allergy and Immunology presents data on 61 deliveries where there had been varying degrees of unprotected parental contact with SARS-CoV-2-infected midwives, nurses and doctors during the first week (precontainment) of a COVID-19 outbreak affecting 36 staff members in a large maternity and perinatal centre in Bavaria, Germany.  Two previous papers in the same journal, published 22 April 2020 and 15 May 2020, have reported on containment strategies, symptoms, SARS-CoV-2 RT-PCR tests and antibody responses (IgG and IgA) in hospital staff during the outbreak.  The index case was a midwife returning from holiday in Ischgl, Austria on 8 March 2020, who became unwell during a nightshift on 9 March at Regensburg University Hospital obstetric clinic; the first positive SARS-CoV-2 RT-PCR test result was received on 15 March and at that point contact tracing, testing and containment measures were introduced.

Study design:  66 families were identified with an infant born at the clinic during the week of 9 to 15 March where parents had had unprotected contact with SARS-CoV-2-infected medical staff; of these, 61 families consented to a prospective cohort study involving serial symptom interview, serial SARS-CoV-2 RT-PCR screening in throat rinsing fluid (parents) and faeces (infants) and serum IgA and IgG antibody studies (parents and infants) 4-5 weeks post-partum.  Serum and breast milk were also tested using a different antibody assay to verify antibody responses.  The authors note in their paper of 15 May 2020 that IgM antibody testing would have been useful, but that validated and certified IgM tests were not available to them at that time.

Key neonatal findings:  The median gestational age at delivery was 39.3 weeks.  Infants in the study received skin-to-skin care, rooming-in and breastfeeding in line with the hospital’s usual practice.  The authors state that antepartum infections can be excluded and that any neonatal infections probably occurred via postnatal horizontal transmission in the family setting.  16/61 families reported parental symptoms consistent with COVID-19 within 2 weeks postpartum (one or both parents), although only 5/16 symptomatic families had COVID-19 confirmed based on RT-PCR and antibody evidence.  3 infants of these 5 symptomatic PCR-positive families developed non-specific signs of infection, including fever, dyspnoea and compromised circulation, at 5, 10 and 26 days old, and were admitted to NICU.  Details of treatment are not supplied, but symptoms resolved for all 3 within a few days.  Blood cultures and tests for non-SARS-CoV-2 viruses were negative.  2/3 symptomatic neonates had PCR positive faeces (one of these still had PCR positive faeces at 4-5 weeks) and 1 asymptomatic neonate also had PCR positive faeces at 4-5 weeks. None of the 3 SARS-CoV-2 PCR positive neonates nor the uninfected neonates had elevated or even borderline antibodies [note that there is some minor disparity between results summarised in the text and the detailed figure showing results in individual families].  Only one mother had IgG-positive breast milk (serum IgG also positive at 4-5 weeks, serum IgA negative, PCR positive at 1 week but not at 4-5 weeks, infant symptomatic at day 5 with negative faecal PCR at 1 week/4-5 weeks and negative serum IgG/IgA at 4-5 weeks).  

Small cohort <10 children and Single Case Reports

Ji L, Chao S, Want Y et al. Clinical features of pediatric patients with COVID-19: a report of two family cluster cases. World J Pediatr. 2020 Mar 16. doi: 10.1007/s12519-020-00356-2. [Epub ahead of print] https://dx.doi.org/10.1007/ s12519-020-00356-2

This is a review of two confirmed paediatric cases of COVID-19 (both from oropharyngeal swabs) from two family clusters with recent travel to Wuhan. One child presented with fever and the other with diarrhoea.

Case one: 15-year-old boy presenting with a one-day history of fever. Clinical features: Temperature 37.9oC, pharyngeal congestion. Normal lung auscultation. Laboratory findings: mildly elevated white cell count at 11.82 x109/L, predominantly neutrophils (67.3%) and 25.7% lymphocytes. His CRP was mildly elevated at 35 mg/L. Radiological findings: normal unenhanced CT chest. Outcome: Symptomatic treatment. Symptoms disappeared after two days. Family information: both parents also tested positive for SARSCoV2.

Case two: 9-year-old boy presented with mild diarrhoea but no cough and no fever. Normal examination. Laboratory findings: normal white cell count and normal CRP. Radiological findings: normal unenhanced CT chest. Outcome. Treated with oral probiotic and symptoms disappeared after 2 days. Family information: Family members had negative COVID-19 swabs but were symptomatic. His mother presented with fever and cough with bilateral peripheral ground glass opacifications on CT chest. The child’s father and two-year old sister had normal CT chests but had mild symptoms consistent with COVID-19: his father had a cough for four days and his twoyear-old sister had a transient two-day low-grade fever.

Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med 2020;:NEJMc2003717. doi:10.1056/ NEJMc2003717

This letter to the editor describes a case series from Tongji hospital in Wuhan, China, taken from a cohort of 366 hospitalized children between January 7th and 15th 2020. 6 children were PCR Positive for COVID-19. Of the 6 patients, age range 1-7 years. All had fever >39oC, cough and 4/6 had vomiting. All had lymphocytopenia, with 4/6 leukopenia and 3/6 with neutropenia. One child  required an ICU admission, receiving pooled donor IVIG. The median recovery time was  7.5 days. Authors surmise COVID-19 occurs in children with some moderate-severe episodes of illness.

Pan X, Chen D, Xia Y, et al. Asymptomatic cases in a family cluster with SARS-CoV-2 infection, The Lancet Infectious Diseases, 2020, https://doi. org/10.1016/S1473-3099(20)30114-6.

This case study looks at another family cluster of COVID-19 involving asymptomatic patients. It involved a 3yr old boy who was positive for SARS-CoV-2 despite having no symptoms, normal bloods and a normal CT.

Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang Z. Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. Published online February 14, 2020. doi:10.1001/jama.2020.2131

This is a case series of, from Dec 8 2019 to Feb 6 2020, from China of 9 infants – all of whom had been hospitalised. Clinical presentation: 4/9 fever, 2/9 mild URTI symptoms, 1/9 were asymptomatic. All had family members that were COVID-19 positive. There were no severe complications or ICU admissions.

Jiehao Cai, Jing Xu, Daojiong Lin et al, A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features, Clinical Infectious Diseases, ciaa198, https://doi.org/10.1093/cid/ciaa198

This retrospective study examines 10 children diagnosed with confirmed COVID-19 between 19th Jan and 3rd February 2020 at the Children’s hospital in Shanghai. The age range is from 3 months to 11 years. None had comorbidities. There were no severe cases.

Clinical features: The assumed incubation period (time from exposure to index case to developing symptoms) was between 2 – 10 days, but median (and mode) 7 days. With regard to symptoms, 7/10 had fever >38oC,  6/10 had a cough, 4/10 had a sore throat, 3/10 had nasal congestion, 2/10 had rhinorrhea and 2/10 were sneezing.

Radiology: The chest x-ray was normal in 6/10.  The rest had unilateral opacities.

Bloods: Lymphocyte counts were normal in 9/10, raised in one case. CRP ranged from 0.5mg/L to 35mg/L but was <10 for 7/10. Procalcitonin was normal (<0.25) in all children. 2 patients had a mild elevation of ALT (100U/L) or AST (142U/L and 51U/L)

Detection of SARS-CoV-2: Virus was found in NP/throat swabs in all patients, and the duration of shedding ranged from 6-22 days (Median 12 days). Stool shedding was prolonged, over 30 days in one patient. No urine was positive, and no serum positive.

Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series BMJ 2020; 368 :m606

This study looks at a group of 62 patients with COVID-19 in a province outside of Wuhan (Hubei). 2 of these were children, aged 10 and 11. There is a lot of clinical data in the paper but it is not broken down by age, so we cannot make any inference on behalf of the paediatric patients.

Kai-Qian Kam, Chee Fu Yung, Lin Cui et al, A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load, Clinical Infectious Diseases, ciaa201, https://doi.org/10.1093/cid/ciaa201

This was a case report of a single 6-month-old with a positive nasopharyngeal swab until D16 of admission to hospital. There had been household transmission. There was a positive NPA with rt-PCR on D1 of admission although the child was asymptomatic – daily swabs remained positive until D17. The child was febrile once during the course of admission although they remained asymptomatic. Blood and stool tests were positive on D2.  They had essentially normal investigations except for a neutropenia.

Cui Y, Tian M, Huang D, et al. A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis Published Online First: 17 March 2020. doi:10.1093/infdis/jiaa113

This is a case report of a 55 day old with SARS-CoV-2 who was admitted to hospital in China on February 2, 2020. She was treated with inhaled intereron-alpha-1b, amoxicillin, reduced glutathione, ursodeoxycholic acid, and traditional Chinese medicine lotus qingwen. The child was initially well, although her respiratory status worsened on day 2-6, and she required supplemental oxygen via nasal cannulae. Anal swabs on day 11 and 13 were positive on day 11-13 despite negative pharyngeal swabs.

Note is made in the title of this study that the infant sustained liver injury and heart damage. This is on the basis of marginally elevated liver tranaminases and cardiac troponin measurements, for which it is unclear why the tests were performed. There is no indication of any clinical compromise demonstrated. It should be noted that a significant proportion of the child’s care (including investigations) would not be considered standard practice in UK/US/Aus paediatric medicine.

Paret M, Lighter J, Pellett Madan R, Raabe VN, Shust GF, Ratner AJ. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress [published online ahead of print, 2020 Apr 17]. Clin Infect Dis. 2020;ciaa452. doi:10.1093/cid/ciaa452

This is a case series of two infants presenting with fever to a hospital in New York during on week in March 2020. Neither presented with respiratory symptoms, and both had Sars Cov2 infection confirmed without other aetiology despite febrile infant work ups. 

First; a 25-day old full-term male infant, presented with fever, irritability and facial rash. Parents had sore throat and subjective fever but had not sought medical attention for themselves. Full routine work up with CSF, blood, urine samples and routine respiratory PCR panel was taken. SARS CoV2 PCR positive on nasal swab.  Treated empirically until cultures negative at 48 hours, recovered well. 

Second; a 56-day old ex 35-week male infant, presents with fever only. He had no other symptoms, and no sick contacts. Bloods, urine and routine respiratory PCR panel was taken. Infant did not have lumbar puncture. SARS CoV2 PCR was positive on nasal swab. Treated empirically until cultures negative at 36 hours. 

Authors discuss the need to maintain high index of suspicion for SARS-CoV-2 infection in febrile infants during a community outbreak, and the importance of strict infection control measures in paediatric emergency department. 

Zhu, L., J. Wang, R. Huang, L. Liu, H. Zhao, C. Wu and C. Zhu (2020). “Clinical characteristics of a case series of children with coronavirus disease 2019.” Pediatr Pulmonol 8th April 2020 https://doi.org/10.1002/ppul.24767

This is a case series of ten paediatrics patients aged 1 – 17 years with confirmed Covid 19. These cases were retrospectively selected from 3 hospitals in Jiangsu, a coastal province approx 700 km east of Wuhan. Cases were collect from 24th January 2020 to 22nd February 2020. All cases were confirmed by RT-PCR anal or throat swabs. 70% of children presented with symptoms, and 30% were asymptomatic, but were screened due to contact with confirmed family member.

The most common symptoms on presentation were fever (40%), cough, (20%) and headache (20%). There was no report of whether children had underlying conditions. All children had a CT chest completed. Half of the cohort had CT changes. There were 2 cases of bilateral pneumonia, and 3 cases of unilateral pneumonia, 2 of which were in asymptomatic patients.  Bloods were unremarkable, one child aged 1 year had Lymphocytosis, all others had normal lymphocyte counts. CRP was not raised in any child. Only one patient in the cohort required oxygen, and there were no ICU admissions. Five children were treated with antiviral medication including lopinavir/ritonavir (n=4) interferon α‐2b (n = 4), and oseltamivir (n = 1). 

Of note, 5 children were still in hospital at the end of the case series. 

Canarutto, D., A. Priolo, G. Russo, M. Pitea, M. C. Vigone and G. Barera (2020). “COVID-19 infection in a paucisymptomatic infant: Raising the index of suspicion in epidemic settings.” Pediatr Pulmonol. https://doi.org/10.1002/ppul.24754

This early single case report from Milan, Italy describes an infant with a mild case of COVID-19 who recovered without need for intervention. His father, the implied household index, had an upper airway infection with conjunctivitis without confirmatory testing.
Patient: 32 day old boy, presented to hospital symptomatic
Clinical Features: Cough, fever, rhinitis
Radiology: CXR normal
Bloods: reactive lymphocytes on film, monocytosis (1400/L) and neutrpenia (900/uL), CRP normal
Outcomes: Resolution of fever by day 3 of hospitalisation, full recovery without need for supportive therapy. Breast feeding maintained.

Shen Q, Guo W, Guo T, Li J, He W, Ni S, Ouyang X, Liu J, Xie Y, Tan X, Zhou Z. Novel coronavirus infection in children outside of Wuhan, China. Pediatric pulmonology. 2020 Apr 7.p1-6 DOI: 10.1002/ppul.24762

This retrospective study examines the clinical characteristics of children admitted to Public Health centre of Changsha, Hunan, China. There were 9 children admitted during the study period 08/01/2019 and 19/02/2020 who tested positive for COVID-19. All had a confirmed contact case with COVID-19. Median age was 8 years, with a minimum age 1 year and oldest was 12 years. Children were predominantly female (6/9, 66%). There was no information provided about co-morbidities.   

Clinical features: 2/9 were asymptomatic, 1/9 had cough, 4/9 had fever, 1/9 had sore throat and 2/9 had diarrhoea. 

Radiology: 2 patients had chest CT that were described as ground glass opacities. No further information was provided about the indications.   

Bloods: 1/9 had lymphocytosis in whom other infectious causes were excluded. 1/9 had raised CRP, 4/9 raised ESR, 1/9 raised LDH, 2/9 had raised AST with 0/9 ALT abnormalities. All abnormalities were mild. 

Treatments: All (9/9) children were treated10/2.5 mg/kg lopinavir/ritonavir twice daily, orally. 5/9 children received 10 mg/kg azithromycin once a day. One child received meprednisone and immune globulin therapy for febrile convulsion. No additional information regarding treatments were provided.  

All children required oxygen therapy. None required intensive care or mechanical ventilation.

Outcomes: At the end of data collection 3/9 remained under hospital care and were positive for COVID-19. The remainder (6/9) were discharged from hospital. The time spent in hospital varied between 11 and 22 days (median 13.5 IQR 10.75-14 days). 

Other salient features: 6/9 children were RT-PCR negative at discharge. The time between initial contact and a negative test varied between 9 and 20 days (median 13.5 IQR 10.75-14 days).  

All averages were calculated by the reviewer from the data provided within the article. 

Han, Y. N., Z. W. Feng, L. N. Sun, X. X. Ren, H. Wang, Y. M. Xue, Y. Wang and Y. Fang (2020). “A comparative-descriptive analysis of clinical characteristics in 2019-Coronavirus-infected children and adults.” J Med Virol. 6th April 2020. https://doi.org/10.1002/jmv.25835

This retrospective study compares the clinical characteristics of 25 adults and 7 children with acute respiratory disease confirmed as COVID-19. Cases were retrospectively identified from patients admitted to Xian Eighth Hospital in Shaanxi, China, between 31st January and 16th February 2020. The mean age of the children was 1.3 years with a range of 2 months to 13 years, and 4 (57%) were male. None had any co-morbidities.

Clinical features: 5/7 (71%) children had cough, 3/7 (43%) had shortness of breath, 5/7 (71%) had fever, 1/7 (14%) had sore throat and 4/7 (57%) had diarrhoea and/or vomiting.

Radiology: 5/7 (71%) children had “positive findings suggestive of pneumonia” reported on CXR and/or CT. Examples of these findings were ground glass opacities and segmental consolidation in bilateral lung fields, particularly peripherally.

Bloods: No children had a low lymphocyte count (<0.8). Raised lymphocyte counts were not mentioned but raised WCC was reported in 2/7 (29%) children. 2/7 (29%) had a raised CRP (>10). 4/7 (57%) had a raised AST (>50) or ALT (>37). 5/7 (71%) had increased Brain Natriuretic Peptide (>125). 4/7 (57%) had a raised CK Isoenzyme (>30).

Outcomes: All 7 cases in children were classified as mild and recovered within 1-2 weeks. None of the children were admitted to intensive care and none died.

Comparison of clinical characteristics in adults and children: Children were more likely than adults to have diarrhoea and/or vomiting (57% vs. 8%, p=0.012). Adults more frequently had a reduced WCC, compared to a raised WCC in children, and raised CK isoenzyme was less common in adults.

Kamali Aghdam M, Jafari N, Eftekhari K. Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report [published online ahead of print, 2020 Apr 1]. Infect Dis (Lond). 2020;1–3. doi:10.1080/23744235.2020.1747 634 Accessed from: https://www.tandfonline.com/doi/full/10.1080/23744235.2 020.1747634 on 4th April

This brief case report from Iran is of a 15 day old male from Mousavi Hospital in Zanjan, Iran. Date of admission was not available. Symptoms were fever and lethargy with his parents having fever and cough. He initially appeared tachycardic and febrile with sats of 93% on RA. He was given Vancomycin, Amikacin and Oseltamivir. SARS-CoV-2 was detected on RT-PCR. His parents were not tested as they did not meet the testing criteria at the time (hospitalisation). 

Radiology: Chest X-ray had nil findings

Bloods: WCC 6.7, Lymphocytes 36%, Neutrophils 42% and CRP 1 (normal). 

Comorbidities: There was an incidental finding of patent foramen ovale on Echo. 

Outcome: He had improvement by day 2 of admission and was cleared for discharge on day 6.

Su L, Ma X, Yu H, et al. The different clinical characteristics of coronavirus disease cases between children and their families in China – the character of children with COVID-19. Emerg Microbes Infect. 2020;9(1):707–713. doi:10.10 80/22221751.2020.1744483

This study from the Jinan Infectious Disease Hospital retrospectively reviewed cases of nucleic acid-positive SARS-CoV-2 patients between 24th January to 24th February 2020 (detected using the (ORF1ab/N) nucleic acid detection kit by Bio-germ, Shanghai, China). Nine children and members of their family totalling 14 adults were included. Note that two family members missed enrollment as they were at another hospital. Of the 9 children, 6 were female (66%). The age group ranged from 11 months to 9 years and 9 months old (mean age 4.5 years).  For eight of the nine children, there was history of their parents having travelled frequently, being in contact with someone from Wuhan or having worked or visited Wuhan.  Of note, five of the discharged children were readmitted to hospital because their stool showed positive results in SARS-CoV-2 PCR. 

Clinical Features (children): 3 of the 9 children had fever (33%) and one had cough (11.2%). Imaging (children): On chest x-ray and CT, two children had findings consistent with bronchitis (22.2%), one had bronchial pneumonia (11.1%) and a further one had pulmonary consolidation and ground glass opacity. From the two example images included,, findings appear to be bilateral but this was not specified in the body of the text. Bloods (children): 8 of 9 children (88.9%) had normal or decreased white blood cell counts. Six children (66.7%) had increased CK-MB. ALT, AST. All children had a normal CRP, PCT, ESR and IL-6. Clinical Features (adults): Of the 14 adults, 8 (57.1%) had fever, five had cough (35.7%), three had chest tightness or pain (21.4%), a further three had fatigue (21.4%) and one reported a sore throat (7.1%). Imaging (adults):  Ten (71.4%) had abnormal imaging mainly pulmonary consolidation, with 7 (50%) having nodular shadow and 7 (50%) having ground glass opacities. Bloods (adults): Four (28.6%) had reduced whice cell count with seven (50%) having lymphocytopaenia. 

Lou XX, Shi CX, Zhou CC, et al. Three children who recovered from novel coronavirus 2019 pneumonia. J Paediatr Child Health Published Online First: 22 March 2020. doi:10.1111/jpc.14871

This is a case series of 3 children diagnosed with COVID-19 and admitted in the Zhengzhou University Children’s hospital in Henan Province, China (dates not provided). They were 2 sisters aged 6 and 8yrs, and a 6m old infant. The children were all infected by a family member, although the family of the 6m infant had no link to Wuhan.

Clinical features: All 3 had a fever, 2 had nasal congestion and rhinitis alongside fatigue, diarrhoea, and headache. The 6yr old girl had a cough. 

Radiology: All 3 patients had CT scans with bilateral infiltrates

Bloods: Not reported

Outcomes: No children required intensive care/intubation or had any severe complications. All have been discharged. The 2 sisters were treated with nebulized interferon.

Mixed co-morbidities

Issitt R, Booth J, Bryant W, Spiridou A, Taylor A, DuPre P, Ramnarayan P, Hartley J, Borja MC, Moshal K, Dunn H. Coronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population. medRxiv. 2020 Jan 1. Doi https://doi.org/10.1101/2020.05.20.20107904

A retrospective cohort study published by Great Ormond Street Hospital (GOSH), London, UK suggested children who are defined as vulnerable in the COVID-19 pandemic era do not appear to be at significantly increased risk of being admitted to hospital with COVID-19. In addition, the vulnerable group have similar outcomes to those who are COVID-19 negative. However, the authors do identify children undergoing chemotherapy or radiotherapy are ‘over-represented’ in the vulnerable group.

Data was collected from the institution’s electronic health record system. The inclusion criteria were any patient admitted between 01/03/2020 and 15/05/2020 who was admitted with features suggestive of COVID-19 based on the attending clinician’s interpretation, of undefined grade, including fever, cough and “systemic symptoms”. Children were defined as COVID-19 positive by a positive PCR test for nucleic acid in respiratory or blood specimens performed at the referring or presenting hospital or a documented positive familial test. Patients were classified as vulnerable if they fulfilled the high risk shielded list from NHS digital or the institutions local policy that was not provided. Due to the nature of the specialist paediatric services the population of children were highly selected.

166 children fulfilled the criteria; 65 (38.7%) were COVID positive and 101 (60.8%) were negative. The average age for COVID positive group was 9 years [IQR 0.9-14] with 38 (58.5%) males. This compared to the COVID-19 negative group with an average age of 1 year [0.1-5.75], 58 (55.4%) male. The COVID-19 positive patients were significantly older (p<0.001). Differences in ethnicity frequency was statistically significant for Asian ethnicity: 12 (8.5%) COVID-19 positive compared to 6 (5.9%) in the COVID-19 negative group (p=0.02).

The number of vulnerable children who were COVID-19 positive totalled 31 (47.7%) compared to 73 who were COVID-19 negative (72.3%), demonstrating a lower number of vulnerable children were positive for COVID-19, (p=0.002).    

Clinical features: Breakdown of symptoms were not provided

Radiology: N/A

Bloods (For those COVID-19 positive):

ALT 41.5 U/L [IQR 29-74], Albumin 32 g/L [IQR 27-36], AntiDNAse 310U/mL [80.8-402], AntiStreptolysin O 285 IU/mL [134-384], AST 70 U/L [43-100], CRP 28 mg/L [10-74], CK 63.5 U/L [35-214], Creatinine 23 umol/L [14-46], D-dimer 1876 ug/L [1043-3618], Ferritin 788 ug/L [445-1863], Fibrinogen 3.65 g/L [2.4-4.8], Interleukin-6 50 pg/ml [50-152], Interleukin-10 50pg/mL, LDH 848 U/L [654-1136],  BNP 3550 pg/ml [626-6992], Lymphocytes 1.44 X10^9/L [0.64-2.49], Neutrophils 3.90X10^9/L [1.46-8.6], WBC 8X10^9/L [3.38-13.2], Troponin I 54 ng/L [13-157], Prothrombin time 12 seconds [11.3-13],  bilirubin 6 umol/L [3-10], Triglycerides 2.48 mmol/L [1.65-3.56].

The results highlight the difference in results between the COVID positive and negative groups but do not define further differences between vulnerable and non-vulnerable groups. These include a statistically higher average CRP (p=0.002, fibrinogen (p<0.001), albumin (p0.02) neutrophil (p<0.001) and white blood cell count (p<0.001) and a lower LDH (p=0.002),

Treatments: Patient were treated following national or speciality specific guidance. No further information was provided.

Outcomes: Mortality for those who were COVID-19 was 1 (1.5%) who was in the vulnerable group. Additional comments described the primary focus of treatment was aspiration pneumonia. This compared to 4 (4%) in the non-COVID-9 group, all of whom were in the vulnerable group. The difference in mortality rates was not statistically significant.

There was no difference in the proportion of vulnerable patients based on their COVID-19 status: 61% of vulnerable patients who were COVID-19 positive compared to 64.3% who were negative, (p = 0.84). Overall, comparing all patients, a significantly lower proportion of COVID-19 positive patients required mechanical ventilation (27.7%) than COVID-19 negative patients (57.4%), (p<0.001). The individual number of patients were not provided.

The average ICU length of stay for those with COVID-19 was 4 days [2.4-10.6]. For those in the vulnerable subgroup the average was 11 days [3.7-15.1]. The significance of the difference between the vulnerable and non-vulnerable group was not described. However, vulnerable non-COVID-19 patients had a 6 [2.8-12.2] day stay in ICU. The difference between vulnerable COVID-19 positive and negative groups demonstrated no significance (p=0.3). 

The average total hospital stay for vulnerable patients with COVID-19 was 16.2 days [3.8-20.8]. This compared to vulnerable COVID-19 negative patient were in hospital for 12.3 days [5.2-19.8]. The difference in duration was not significant (p=0.94). 

Other salient features: Breaking down conditions that comprises vulnerable children there was a significant increased number of children with cancer undergoing active chemotherapy or radiotherapy who were admitted to hospital with symptoms and COVID-19 positive status compared to with symptoms but COVID-19 negative [7 VS 3 (p=0.01)].  There was no statistical differences between the COVID-19 positive and negative categories with on the national transplant, transplant medication, haematological cancer, respiratory and rare genetic, metabolic and autoimmune conditions lists or local severe respiratory conditions, rare diseases immunosuppressive therapies and other potential factors lists.

Oncology

Gampel, B. Troullioud Lucas, AG. Broglie, T. et al. (2020 Jun 26). “COVID-19 disease in New York City pediatric hematology and oncology patients.” Pediatr Blood Cancer: e28420. June 26th 2020, https://doi.org/10.1002/pbc.28420

This retrospective observational study provides some insight into the impact of COVID-19 on haematology/oncology patients. There were some limitations in the data collection process as testing was performed for different reasons at the two different sites that are considered. However, we see that between 10/03/2020 – 06/04/2020,  19 out of 174 tested children (each of whom had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation) tested positive for COVID-19. Of these, 11 required hospitalisation. Five required PICU and one sadly died.


Method of data collection: All patients 21 years old or younger who underwent clinical laboratory COVID‐19 testing at two New York haem/onc centres were included. All patients had underlying haematological/oncological disorder or were undergoing haematopoietic stem cell transplantation. Informed consent was waived.


The two centres tested differently: “MSK tested all symptomatic patients and screened all patients prior to admission, procedures requiring sedation, and planned myelosuppressive chemotherapy. NYP tested only those patients for whom a positive test would alter management, including those who were symptomatic, likely COVID‐19 exposed, or with planned disposition to a chronic care facility.”
Features specific to children:19 out of 174 tested positive. Of these: 68% had fever, 47% had cough and 37% had dyspnea. 11 patients required hospitalisation and 4 patients required supplemental oxygen. 2 patients required mechanical ventilation and a further 3 were also admitted to PICU (all male). 3 patients received ‘COVID-19-directed therapy’ (with hydroxychloroquine and azithromycin)
1 patient died (“a child with sickle cell disease without a significant history of prior complications. Although this patient demonstrated pulmonary disease, his death may have been preceded by an acute cardiac event. Autopsy was refused…”). The authors make note that 64% of COVID+ oncology patients experienced treatment delays, showing the harms to these patients may not come primarily from COVID-19 disease itself

Ferrari, A., M. Zecca, C. Rizzari, F. et al (2020). “Children with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy.” Pediatr Blood Cancer: e28410. 

This letter to the editor describes the findings of 6 paediatric haematology and oncology centres in Lombardy during the 8 weeks after the COVID-19 pandemic began in Italy. Between 20th February 2020 and 15th April 2020. 286 patients were tested for COVID-19 when accessing services at these centres: 74 were symptomatic, 25 had close contact with a diagnosed case and 187 were tested for screening purposes. Of these, 21 cases tested positive for COVID-19, with a median age of 6 years (range 1-17 years) and 48% were male.

Of the 21 cases 10 had leukaemia, 5 had soft tissue or bone sarcoma, 2 had lymphoma, two had hepatoblastoma, 1 had a CNS tumour and 1 had colon carcinoma. 15 patients were currently receiving treatment while 6 had completed treatment and were receiving follow up.

Clinical features: 1 patient (who had existing neurological respiratory impairment) developed aspiration pneumonia requiring respiratory support, and 1 developed atypical bilateral pneumonia with mild symptoms.

Outcomes: There were no deaths related to COVID-19 infection. Cancer treatment was modified in 10 cases (delaying chemotherapy, reducing drug doses and postponing surgery).

The authors observe that despite the overwhelming rate of COVID-19 in the general population in the region at the time, relatively few paediatric cancer patients were symptomatic, or tested positive for the virus, and that severe illness was rare. They suggest that these results may indicate that paediatric anti-cancer treatments could continue without major adjustments, especially as alterations may reduce their efficacy.

Of note, these centres experienced a reduction in newly diagnosed cancer cases to 55% of the expected rate, which may reflect delayed access to healthcare services.

Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in Children With Cancer in New York City. JAMA Oncol. Published online May 13, 2020. doi:10.1001/jamaoncol.2020.2028

This research letter reports the results of SARS-CoV-2 screening of patients and caregivers from one of the largest paediatric cancer centres in the US (Memorial Sloan Kettering Cancer Center, New York) in a region with very high levels of community SARS-CoV-2 transmission.

From March 10th to April 12th 2020, inpatients and outpatients with either symptoms of or exposure to SARS-CoV-2 infection underwent RT-PCR testing. Asymptomatic patients were also tested prior to admission, deep sedation and or myelosuppressive chemotherapy, as were caregivers of children being admitted.

Overall 11% (20/178) of paediatric patients returned a positive SARS-CoV-2 result; including 29.3% in the symptomatic / exposed group and 2.5% in the asymptomatic group. In contrast 14.7% (10/76) of asymptomatic caregivers were positive. Despite close contact, 5 of the 10 children of caregivers with SARS-CoV-2 were uninfected.
Only 1 of the 20 paediatric patients required hospitalisation for COVID-19 symptoms, without need for critical care.

This data provides reassurance that children with cancer may not be more vulnerable to complications of SARS-CoV-2 infection compared to other children. The lack of specific clinical detail in this report limits the ability to draw more definitive conclusions regarding risk.
The lower rate of asymptomatic carriage in children relative to their caregivers provides further evidence that children, including paediatric cancer patients, may be less susceptible to SARS-CoV-2 infection compared with adults.
Clearly infection control strategies must consider the risk of nosocomial spread from infected caregivers as well as paediatric patients, particularly in areas with high levels of community transmission.

Cesaro, S., F. Compagno, D. Zama, L. Meneghello, N. Giurici, E. Soncini, D. Onofrillo, F. Mercolini, R. Mura, K. Perruccio, R. De Santis, A. Colombini, A. Barone, L. Sainati, V. Baretta and M. G. Petris (2020). “Screening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy.” Pediatr Blood Cancer: e28466, https://doi.org/10.1002/pbc.28466

Observational study of nasopharyngeal presence of SARS-CoV-2 in a cohort of 282 paediatric oncology patient presenting for scheduled care at 14 specialist centres in Italy between 20/02/20 and 19/04/20.  Median age for oncology cases (n=247) was 7 years (range 0-17.9) and for stem cell transplant (SCT) patients (n=35) was 9.6 years (range 0.3-17.6). 10/334 swabs from the oncology group were +ve and 0/56 from the SCT group. Only 2/10 NPS +ve patients had any symptoms (both “mild fever”). Chemotherapy was paused for all NPS +ve patients until 2 clear swabs were obtained 24 hours apart.  No adverse outcomes were recorded up to the study end but follow up was only reported up to 30/04/20. This study demonstrates that paediatric oncology patients can remain asymtomatic whilst carrying SARS-CoV-2 in the nasopharynx, and recover spontaneously, without any apparent increased rate of adverse outcomes. Researchers raise the question of whether routine chemotherapy needs to be paused for asymptomatic NP carriage of SARS-CoV-2 but present no evidence for the safety of this course of action.

Flores V, Miranda R, Merino L, et al. SARS-CoV-2 infection in children with febrile neutropenia [published online ahead of print, 2020 Jun 12]. Ann Hematol. 2020;1-2. doi:10.1007/s00277-020-04115-1

This letter to Annals of Hematology offers a brief description of three children with ALL who presented with febrile illness and were found to be SARS-CoV2 PCR positive. The letter is of note as sadly one of the children died during this illness following cardiac arrest; the authors offer the paper to highlight the occurrence of SARS CoV2 in febrile neutropenic patients; however it prompts further analysis of those cases of severe infection in the context of immunosuppression.

The patients were identified at a centre in Mexico however the time period is not known. The three patients were aged 4yrs, 8yrs and 9yrs. All had ALL, two receiving consolidation chemotherapy and one on immunosuppression with mycophenolate and prednisolone. The latter patient had undergone HSCT for ALL, the time since HSCT was not provided, however this patient was admitted from the community suggesting she wasn’t in the immediate post-transplant period. All patients developed neutropenia either at time of fever or quickly following it and similarly evolved to have ‘respiratory symptoms’. All had negative blood cultures however results of other virology is not provided. Over-all pre-covid health status is not provided within the letter and this might be helpful in understanding the severity of symptoms in the patient who died.

The child who died was 8 years old and presented with febrile neutropenia, they were on mycophenolate and prednisolone following HSCT for ALL. The child quickly developed respiratory distress and required invasive mechanical ventilation; a heamodynamic deterioration led to cardiac arrest and resuscitation measures failed.

The distinguishing features of this child was her immunosuppression and history of HSCT, she was also more profoundly lymphopenic and thrombocytopenic. All other laboratory values were variable between all three patients. Further information on her overall cardiorespiratory status pre-SARS-CoV-2 would be helpful to understand her vulnerabilities and to guide management of children presenting with similar comorbidities in the future.

Sieni, E. Pegoraro, F. Casini, T. Tondo, A. Bortone, B. Moriondo, M. Azzari, C. Galli, L. Favre, C. Favourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression. British Journal of Haematology. 2020 May 5. https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16781

This retrospective single case report discusses the progression and treatment of a child with high risk acute myeloid leukaemia having undertaken the third chemotherapy cycle of the induction phase following AIEOP LAM 2013 protocol.

13-month-old female patient attended routine clinic at Myers Hospital, Florence, Italy following completion of the chemotherapy. Routine investigations revealed a low white cell count, haemoglobin and platelet count which necessitated admission for transfusions. The need for admission was the initial reason for testing for SARS-CoV-2. RT-PCR was performed for nasal and pharyngeal swabs. Faecal PCR testing was also positive.   

Clinical features: Fever starting on day 3 (the combination of fever and low WCC suggested neutropenic sepsis), vomiting and diarrhoea with negative stool culture.

Radiology: CXR on day 3 showed bilateral reticular markings. A repeat prior to discharge demonstrated “no significant modification from baseline”.

Bloods: Day 0 showed low WCC (80/mmc), haemoglobin (7.9g/dL) and platelet (5000/mmc) count. The elevated CRP was highest at day 5 (7.2mg/dL) and normalised by day 10 (<0.5mg/dL). Additional laboratory investigations included LDH which was highest by day 13 (401  IU/L) and ferratin maximally raised on day 9 (3000 mg/mL). Immunoglobulins were low throughout the illness. On day 3 the results were: IgG 258 mg/dL, IgA 18.7 mg/dL, IgM 7 mg/dL. IL-1β, IL-6, IL-10, TNFα and cardiac enzymes were normal.

Blood microbiology was negative.

Additional  laboratory  investigations, including  cytokines  (IL-1β,  IL-6,  IL-10  and  TNFα)  and  cardiac  enzymes,  were  normal;  lactate dehydrogenase  slightly  increased  (up  to  401  IU/L  at  day  13),  whereas  ferritin  values  showed moderate elevation from day 9

Treatments: Treatment for neutropenic sepsis with piperacillin-tazobactam and fluconazole was commenced on day 3 due to fever. Hydroxychloroquine day 3-11. On day 4 lopinavir/ritonavir stopping day 12

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge. 

Other features of interest: There was a undetectable viral plasma load by day 16, however nasal swab for SARS-CoV-2  remained positive beyond discharge at day 26. There is no data to suggest a negative test to publication date. 

It is unclear if the low WCC, anaemia and thrombocytopenia requiring transfusion was due to the chemotherapy, underlying acute myeloid leukaemia or COVID-19 infection, however, on discharge these values had normalised and were maintained by day 26.   

Summary: This case describes a high-risk young patient with acute myeloid leukaemia undergoing chemotherapy presenting with febrile neutropenia. Whilst the symptoms were initially vague, subsequent investigations suggested the underlying cause was SARS-CoV-2. Early anti-viral treatments were commenced. Given the patient’s immunosuppression the authors discuss fears regarding seroconversion, viral dissemination and inflammatory responses which did not occur.  

Hrusak, O., T. Kalina, J. Wolf, A. et al. (2020). “Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.” European Journal of Cancer 132: 11-16. https://doi.org/10.1016/j.ejca.2020.03.021

This is the report of a data from an international survey of paediatric haematology and oncology clinicians to assess the frequency and severity of SARS-CoV-2 infection amongst children with cancer. The survey, conducted from 16th-17th March 2020, had over 35 respondents from 25 countries. Of an estimated 10,000 patients at risk and over 200 tested, 9 children were positive for SARS-CoV-2. Clinical details are provided for 8 cases, 6 of whom had solid tumours and 2 with acute lymphoblastic leukaemia. 7 had mild or asymptomatic disease, 1 patient required low flow oxygen. Fever was the presenting symptom in 6 patients and one patient also had diarrhoea. All 7 patients with outcome data available made a full recovery.

The interpretation of these data is clearly limited by the study design as well as the relatively early stage of the pandemic during which the survey was conducted. Notwithstanding these limitations, the absence of severe COVID-19 cases in this report provides some early reassurance. More detailed clinical studies are needed to draw firm conclusions about the risk of severe disease in children receiving chemotherapy.

D’Antiga L. (2020), Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transpl. Accepted Author Manuscript. doi:10.1002/lt.25756

This letter is from a liver transplant centre in Lombardy, Italy, reporting their experience of patients (including children) with immunosuppression and COVID-19. They have had 3 children post liver transplant test positive for SARS-CoV-2, and none have developed clinical pulmonary disease. They believe due to the widespread nature of infection that many other of their patients may also be infected, but not developed clinically apparent disease.

This provides the first official reports of vulnerable paediatric populations with COVID-19, which so far does not appear to be any more severe than the rest of the population in that age bracket. Further data is awaited.

Balduzzi, A, Brivio, E, and Rovelli, A et al, Lessons After the Early Management of the COVID-19 Outbreak in a Pediatric Transplant and Hemato-Oncology Center Embedded within a COVID-19 Dedicated Hospital in Lombardia, Italy. Estote Parati. (Be Ready.) (3/19/2020). Available at SSRN: https://ssrn. com/abstract=3559560 or https://dx.doi.org/10.2139/ssrn.3559560

This report from a paediatric haematology unit in Lombardia, Italy, includes the Italian experience of COVID-19 in children with malignancy so far. At their particular unit, they have had no children with malignancy test positive for COVID-19 (they admit this is dependent on testing criteria, requiring hospitalisation at their institute). They are aware of 5 cases of paediatric cancer patients who have had COVID-19 and have all suffered a mild course, with 3 managed at home and 2 in hospital.

This small case series provides further reassurance for at risk paediatric populations.

Cardiac disease

Lee, H., B. S. Mantell, M. E. Richmond, S. P. Law, W. A. Zuckerman, L. J. Addonizio, T. M. Lee and I. D. Lytrivi (2020). “Varying Presentations of COVID-19 in Young Heart Transplant Recipients: A Case Series.” Pediatr Transplant: e13780. https://doi.org/10.1111/petr.13780

This is a peer reviewed prepublication case report on the experience of Covid-19 among a population of young heart transplant patients from a tertiary centre, Columbia University Irving Medical Centre, New York.

Period Covered: first 3 months of the New York Covid pandemic

Hospital/Region Covered: the tertiary transplantation programme is one of the largest in the USA covering “hundreds” of patients.

Identification of Patients: 4 patients under the care of the hospital for heart transplantation are included. Case 1 was admitted after referral from secondary care with Covid symptoms and an oxygen requirement.. Cases 2 and 4 presented from home and case 3 was diagnosed during a planned admission for heart biopsy.

Age/Gender:  there is a wide age range: case 1 (F)15 years, case 2 (F)25 years, case3 (M)13 months, case 4(F) 29 months.

Comorbidities and immunosuppression: The authors highlight the questions of whether the comorbidities (including immunosuppression) associated with heart transplantation lead to worse outcomes with Covid infection? Also whether immunosuppression has a protective or aggravating effect on outcome and how regimes should be managed?

Two patients (1 and2)also had renal transplants. Case 2 had connective tissue disease (elevated IL-2).

All patients were on various combinations of immunosuppressants (1,2 and 3 on steroids).In only one case (1) was this withheld during infection because of neutropenia.

Clinical Features: 3 patients (1,2,3) had  symptoms of acute Covid-19 and were nasal/nasopharyngeal positive. Case 1 required supplemental oxygen but no other treatment for 3 days and was then discharged.Cases 2 and 3 did not require admission. Cough: 3/3. Fever: 3/3.Sore throat: 1/3. Abdominal pain: 1/3. All remained well on follow up.

Patient 4 is likely to have had Covid-19 4 weeks prior to admission (symptoms and family history). She presented with a probable post Covid anaemia and hepatitis. She had a rash (acral papular) She was negative on nasal and hepatic Covid assay. Her liver biopsy was consistent with viral hepatitis. Her Covid serology was positive and other viral hepatitis serology negative. She received a blood transfusion

Reported Imaging: CXR:1/4. Normal. Cardiac echo:2/4. No deterioration.

Laboratory: Case1: WCC low 1460/ul, neutropenia (800/ul). ?secondary to immunosuppression or Covid.  Elevated inflammatory markers: CRP, ferritin.  D-dimer, pro- BNP elevated.

Case 2:  no report. Case 3: normal FBC, CRP and LFTs.

Case 4: Hb 6.2 g/dl. Peak ALT elevated 1807 U/L. Peak AST 1070 U/L.

Comment: The centre maintains surveillance (telehealth) of most of it’s patients. Despite possible risk factors of comorbidities and immunosuppression only 4 cases presented. In the acute cases the illness was either mild (2,3) or moderate (1). This is the first report from a paediatric transplant centre and it will be necessary to examine the experience in other centres worldwide.

Case 4 developed hepatitis, anaemia and a rash 4 weeks after probable Covid infection. It is possible that this was Covid related.  Viral hepatitis has been reported in a child post liver transplant with acute Covid infection.

Respiratory disease

Poli, P., S. Timpano, M. Goffredo, R. Padoan and R. Badolato. “Asymptomatic case of Covid-19 in an infant with cystic fibrosis.” Journal of Cystic Fibrosis, April 14th 2020, https://doi.org/10.1016/j.jcf.2020.03.017

This is the first case report of confirmed SARS-CoV-2 infection in a child with cystic fibrosis. The 1 month-old, from Italy, was diagnosed with CF on newborn screening. SARS-CoV-2 infection was confirmed on nasopharyngeal swab PCR as part of contact tracing following exposure to COVID-19 through his grandfather.
The infant remained asymptomatic throughout follow up and did not require hospital admission.
This is one of a limited number of reports of SARS-CoV-2 infection in people with CF. A better understanding of the course of illness in this group will likely emerge with data from ongoing collaborative studies.

Inflammatory Bowel Disease

Turner D, Huang Y, Martín-de-Carpi J, et al. COVID-19 and Paediatric Inflammatory Bowel Diseases: Global Experience and Provisional Guidance (March 2020) from the Paediatric IBD Porto group of ESPGHAN [published online ahead of print, 2020 Mar 31]. J Pediatr Gastroenterol Nutr. 2020; doi:10.1097/MPG.0000000000002729

This article outlines the experience from Asia and Europe so far of children with inflammatory bowel disease given the COVID-19 pandemic. This is of particular interest because many of these children receive immunosuppression as part of their treatment, and so could be considered high risk for complications of the disease.

It appears to have been routine practice to suspend treatment for IBD during the outbreak of COVID-19, which resulted in a large number of relapses. No children with IBD contracted COVID-19 in China in the period covered by the survey.

In South Korea treatment for IBD was not suspended. They also have had no cases of COVID-19 in children with IBD.

In the PORTO IBD group of ESPGHAN (covering Europe, some centres in Canada and Israel) treatment was not suspended in 31/32 centres. 7 children with IBD, who were on immunosuppression, had COVID-19. They all suffered a mild illness with no flare of their IBD. There is an additional child case from an international IBD database identified who also experiences mild symptoms (no hospitalisation required).

This survey provides further reassurance that treatment with immunosuppression does not appear to significantly increase the risk of severe disease from COVID-19 in children.

Brenner, E. J., R. C. Ungaro, R. B. Gearry et al “Corticosteroids, but not TNF Antagonists, are Associated with Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results from an International Registry.” Gastroenterology https://doi.org/10.1053/j.gastro.2020.05.032

This is a pre-proof article and therefore has not yet undergone final editing and review.

This is an article from America (Carolina) aiming to characterise the clinical course of COVID-19 on patients with inflammatory bowel disease (IBD) and evaluate the association between demographics, clinical characteristics and immunosuppressant treatments of COVID-19 outcomes.

The authors created a surveillance database and healthcare providers were encouraged to voluntarily report all cases of Polymerase Chain Reaction (PCR)-confirmed COVID-19 patients with IBD.  A website was developed to enable international contributions. Contributors were asked to report cases a minimum of 7 days from symptom onset and after sufficient time had passed to observe disease course through to resolution of acute illness or death.

525 patients from 33 countries were reported. 7% had severe COVID-19, 31% were hospitalised, 3% of patients died.  The median age of patient was 41 years (from 5 to 90). The majority of patients had Crohns Disease (59.4%) and IBD disease activity was classed as remission in 58.9% of cases. The most common class of treatment was TNF antagonist therapy (43.4% of patients).

63.5% of patients had no comorbidities other than IBD. Most patients who died had other co-morbidities.  Only 3 paediatric patients (10% of paediatric cases) required hospitalization. After controlling for all other covariates use of systemic corticosteroids and ASA/sulfasalazine use were strongly associated with more serious outcomes after infection with COVID-19 but there was no significant association seen between TNF antagonist use and adverse outcomes.

The authors observed an age-standardized mortality ration of approximately 1.5-1.9 as compared to the general populations of China, Italy and the U.S.

They state it is reassuring that the most commonly used treatment- TNF antagonists- appears not to lead to increased adverse outcome for patients infected with COVID-19.

This study has strength in that it includes data from many countries although how comparable that data can be between countries is debatable. The authors did not look at dosing regimens or what was done in terms of continuing or postponing treatment which may well have varied from one country to another. There may also be some bias towards patients who were unwell enough to present to hospital, there may have been other patients who were infected but not unwell enough to require hospital treatment/testing  for COVID-19 who would not have been included in this study population.

Renal disease

Schwierzeck, V., J. C. Konig, J. Kuhn, A. Mellmann, C. L. Correa-Martinez, H. Omran, M. Konrad, T. Kaiser and S. Kampmeier (2020). “First reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit.” Clin Infect Dis, https://doi.org/10.1093/cid/ciaa491

This paper presents the results of an outbreak investigation following a member of staff on a paediatric dialysis unit developing confirmed COVID-19. Detailed contact tracing was carried out and found that 48 cases in total were involved – this included 13 patients, 28 healthcare workers and seven ‘accompanying persons’. Of note, of the 3 traced who children tested positive for SARS-CoV-2, only one had symptoms; given these children’s high-risk status, their asymptomatic presentations are noteable. The paper discusses hygiene measures put in place to avoid further spread.

Transplant related disease

Lagana SM, De Michele S, Lee MJ, Emond JC, Griesemer AD, Tulin-Silver SA, Verna EC, Martinez M, Lefkowitch JH. COVID-19 Associated Hepatitis Complicating Recent Living Donor Liver Transplantation. Archives of Pathology & Laboratory Medicine. 2020 Apr 17. doi: 10.5858/arpa.2020-0186-SA.

This retrospective single case report examines the histopathological features of liver associated COVID-19 in a child admitted to Columbia University Medical Centre, USA. The female child, 6 months old, was admitted for a liver transplant for treatment of biliary atresia. COVID-19 was diagnosed in the donor on post-operative day 2 and confirmed in the patient day 4 post-operatively. The type of test used was not described.

Clinical features: Increased work of breathing requiring CPAP, fever and diarrhoea were developed on post-operative day 4.

Radiology: CXR on post-operative day 4 was described as “no significant changes compared to prior exam with only patchy areas of atelectasis in irregularly aerated lungs”. CXR on day 6 demonstrated “patchy lung opacities bilaterally, mildly increased in the right upper lobe and left lung base”.

Bloods: Deranged LFTs exacerbated from baseline on post-operative day 1: AST (maximum 908U/L from 163U/L), ALT (maximum 980U/L from 215U/L), GGT (maximum 473U/L from 174U/L), ALP (maximum 578U/L from 388U/L).

Treatments: Treated with hydroxychloroquine from day 4 post-operative. She required CPAP for an undefined time period. Undefined immunosuppressant treatment was provided for acute transplant rejection, however liver enzymes worsened when commenced.

Outcomes: Remains on a hospital ward without supplemental oxygen.

A liver biopsy was performed on post-operative day 7 demonstrating portal tract expansion through a mixed inflammatory infiltrate which consisted of lymphocytes, rare plasma cells, and interspersed eosinophils, lymphocytic cholangitis, reactive changes in the interlobular bile ducts and mild portal venulitis. These were interpreted as acute cellular rejection.

Other findings of moderate acute hepatitis including an “azonal pattern of clusters of apoptotic hepatocytes” and singly dispersed apoptotic hepatocytes. Other features of interest include large fragments of cytoplasmic debris described as “crumbling” hepatocytes, few mitotic figures, regions of Kupffer cell prominence with sinusoidal and central vein endotheliitis. The authors commented that the extent of hepatocyte apoptosis and large clusters were unusual and not a usual feature of acute cellular rejection (ACR). Central endotheliitis may also be a feature of COVID-19 hepatitis, with the presence of more Kupffer cells and less plasma cells than ACR.

Summary: COVID-19 hepatitis likely presents as a moderate acute hepatitis with prominent clusters of “crumbling” apoptotic hepatocytes. Other features may be lymphohistiocytic inflammation of sinusoidal and central vein endothelium, with the presence of more Kupffer and less plasma cells when compared to ACR.

Angeletti, A., A. Trivelli, A. Magnasco, S. Drovandi, F. Sanguineri, M. Santaniello, G. Ferrando, R. Forno, G. Cipresso, G. Tripodi, L. V. Riella, P. Cravedi and G. M. Ghiggeri (2020). “Risk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study.” Clin Transplant. 2020 May 12. doi: 10.1111/ctr.13889. [Epub ahead of print]

Giannina Gaslini Children’s Hospital, Italy undertook this prospective observational study of patients, who received a kidney transplant between January 2010 and March 2020, with stable graft function and were taking chronic immunosuppressant therapy. They were interviewed weekly between 24th February and 12th April 2020 for 7 weeks, using a 12-point structure questionnaire contained in the appendix, to evaluate the health status of themselves and their cohabitants. The data for adults and children were combined presenting a median age of 20 (2-30) years. The demographics were reported as a combined total; 93 were male.

2 patients, an adult (information not included) and 1 girl aged 13, had co-habitants who were positive for SARS-CoV-2. The 13-year-old had a kidney transplant aged 9 years old. At the time of study, she was taking a combination of steroid, calcineurin inhibitor (CNI and mycophenolate mofetil (MMF) and had investigations including a white cell count and haemoglobin within normal limits.

She tested negative for SARS-CoV-2 using a nasopharyngeal swab (test not declared) and did not develop any symptoms in the subsequent 21 days, declared as the incubation period. Anti-SARS-CoV-2 antibodies were also negative at an undefined time point.

Clinical features: No patients developed any clinical symptoms.

Radiology: None discussed.

Bloods: None discussed for patients who were positive for SARS-CoV-2.

Treatments: None.

Outcomes: None.

Other salient features: The authors recommend avoiding altering the immunosuppressive therapy in young transplant recipients who do not have symptoms of SARS-CoV-2 including those who are exposed to positive close contact. Despite observing a relatively large population of kidney transplant recipients, a small number, 2 (1 child) were exposed to SARS-CoV-2, upon which has the conclusions are based.

Morand, A., B. Roquelaure, P. Colson, S. Amrane, E. Bosdure, D. Raoult, J. C. Lagier and A. Fabre (2020). “Child with liver transplant recovers from COVID-19 infection. A case report.” Archives de Pediatrie. https://doi.org/10.1016/j.arcped.2020.05.004

This a case report form France of a 2-and-a-half-year-old girl who recovered from COVID-19 infection, 5 months after a liver transplant; she had co-infection with Epstein-Barr virus (EBV).

The child had received a living donor transplant (father) as she had developed portal hypertension post Kasai portoentemrostoy performed at 53 days of age for biliary atresia.

She had been discharged home 20 days post procedure on tacrolimus immunosuppression therapy and had no immunization against EBV before transplantation.

On day 96 post transplant she was found to have primary EBV infection linked to the transplant- her father was EBV positive- but was asymptomatic of this.

The first developed rhinitis which developed into a fever, cough and tachypnoea.  In the few days before this her mother had been hospitalized with pneumonia and found to be COVID-19 positive on nasopharyngeal swab. On day three of the illness the child was referred to hospital where she was found to be positive for COVID-19 on NPA.

On admission she was tachypnoeic with no other signs of respiratory distress, her CRP was low (3). A chest CT showed focal alveolar condensation of the ligula and a stable mediastinal enlargement. Her liver function tests had deteriorated (GGT and AST). An US of the liver showed aggravation of the transplanted biliary tract stenosis and an elevated EBV blood viral load. She was managed symptomatically, and she did not receive any COVID-19 specific treatment.

She recovered from COVID-19 infection despite the high level of immunosuppression caused by her tacrolimus treatment.  NPA test samples became negative on day 11. The authors report they reduced the dose of tacrolimus but do not state at which point in the illness nor for how long. They do not state how long it took for her LFTs to return to previous levels nor if there were any consequences of the raised EBV viral load.

The authors suggest liver transplantation is not associated with COVID-19 symptom severity development even when there is high level immunosuppression on tacrolimus. Moreover COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.

It is difficult to draw conclusions based on one case study. Particularly as other studies have shown the severity of COVID-19 is increased when present with other co-morbidities. This particular patient, due to the nature of her original liver insult and the fact that she is a young patient, did not have other co-morbidities, this is often not the case for other patients who have required a liver transplantation.

 Other co-morbidities

Genovese, G., Colonna, C. and Marzano, A.V. (2020), Varicella‐like exanthem associated with COVID‐19 in an 8‐year‐old girl: A diagnostic clue?. Pediatr Dermatol. Accepted Author Manuscript. doi:10.1111/pde.14201

This single case report describes an 8 year old girl presenting on a hospital in Milan, Lombardy region, Italy, on 21 March 2020 with a painless, non-pruritic papulovesicular rash on the trunk developing 3 days after onset of a mild cough. The rash was predominantly papular with  some vesicles with crusting, similar in appearance to chickenpox. Limbs, face, genitalia and mucous membranes were spared. She developed a mild fever 5 days after the onset of the rash, and tested positive for SARS-CoV-2. She had bloods including FBC, renal function, liver function and CRP, all of which were normal with the exception of a mild thrombocytopenia with platelets of 105 x 109/L, which subsequently normalised. The rash lasted 7 days, by which time systemic symptoms had resolved. The young girl had a history of varicella infection a year previously.

The authors quote other case reports of cutaneous manifestations associated with COVID-19: petechial rash, widespread urticaria and varicella-like rash predominantly involving the trunk. Although unable to confirm that the rash was definitely associated with COVID-19, they feel it is likely given the child’s previous history of varicella infection and lack of pruritis to suggest the lesions were insect bites. They suggest papulovesicular eruptions be included in the spectrum of exanthems possibly associated with COVID-19.

Yung, C. F., Kam, K., Nadua, K. D. et al.  Novel coronavirus 2019 transmission risk in educational settings. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaa794

A study of contact tracing of 3 clusters of confirmed COVID-19 within schools in Singapore. Only close contacts of the affected students were placed into quarantine for 14 days, not complete year groups/schools/or classes. Target health measures implemented included terminal cleaning and interventions to reduce mixing (examples were cancelling of extra-curricular activities and staggered break times). For 3rd incident in day care, the school was closed due to increasing cases amongst staff, and all students were tested regardless of exposure/symptoms.

Case 1: 12yr male in secondary school infected at home (sibling of case 2). Attended on day 1 of symptom and subsequently quarantined. 8 classmates developed compatible symptoms, all tested negative.

Case 2: 5yr male in primary school. Attended on day 1 of symptoms and quarantined. 34 classmates developed compatible symptoms, all tested negative.

Case 3: Multiple adult staff members in pre-school involved in cluster. 70% of all students tested, all negative.

These findings are consistent with the small number of other studies of transmission within a school setting so far, which have demonstrated infrequent transmission from children.

Heavey, L., G. Casey, C. Kelly, D. Kelly and G. McDarby (2020). “No evidence of secondary transmission of COVID-19 from children attending school in Ireland, 2020.” Euro Surveill 25(21). May 28th 2020, https://doi.org/10.2807/1560-7917.ES.2020.25.21.2000903

This is an epidemiological study describing cases of Covid-19 in Irish school setting in March 2020. Cases were identified by screening all cases of SARS-CoV-2 notified to public health departments in the Republic of Ireland, to identify children under the age of 18 years, and adults who had attended the school setting.

Six cases were identified, 3 school going children, and 3 adults (1 a teacher, and 2 who conducted educational session in a school). 5 out of 6 cases presented symptomatically with fever or cough, the final case was asymptomatic and screened due to a household cluster.  Contact-tracing records were reviewed to identify cases of secondary transmission.

A total of 1155 contact of these six cases were identified. In the school setting, among 924 child contacts and 101 adult contacts identified, there were no confirmed cases of COVID-19. The only documented transmission that occurred from this cohort was from an adult case to other adults working environment outside school.

In conclusion no case of onward transmission to other children or adults within the school occurred. In the case of children, no onward transmission was detected at all.  Furthermore, no onward transmission from the three identified adult cases to children was identified.

Limitations of the study, was only symptomatic contacts were tested, and so asymptomatic secondary cases were not captured. Also, in Ireland, when a case was identified, all children and staff within the school were excluded thus limiting the potential for further transmission within the school setting once a case was identified. All Irish schools closed on March 12th 2020 and remain closed.

Somekh, E., A. Gleyzer, E. Heller, M. Lopian, L. Kashani-Ligumski, S. Czeiger, Y. Schindler, J. B. Lessing and M. Stein (2020). “The Role of Children in the Dynamics of Intra Family Coronavirus 2019 Spread in Densely Populated Area.” Pediatr Infect Dis J. doi: 10.1097/INF.0000000000002783

This is a brief study of the transmission dynamics within households in Bnei Brak, an area of Isreal with high population density and high proportion of young people (almost 50% of its population are <18yrs). They assessed 13 family clusters and tested every member of their households by PCR, regardless of the presence or absence of symptoms. The index case was identified by date of onset of symptoms (this is standard practice but does leave open the possibility of mis-classifying the index case if they were truly asymptomatic).

The results were as follows; Excluding index cases, 58.3% of adults tested positive, 32.5% of children aged 5 – 17 tested positive, and 11.8% of children aged <5yrs tested positive. In 12/13 families the index case was an adult. The other case was a 14yr old male.

This evidence is consistent with almost all other household contact tracing studies which have demonstrated a significantly lower secondary attack rate in children compared to adults. A strength is the clear documentation that all household members were tested regardless of symptoms, and for clarity the index case was not included in the rates of infection making secondary AR better defined.

Qin-Long Jing, Ming-Jin Liu, Jun Yuan et al, Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study, The Lancet, June 17th 2020, https://doi.org/10.1016/S1473-3099(20)30471-0

This is study from Guangzhou, China documenting the attack rate amongst 1964 close contacts and 134 secondary or tertiary cases of 215 confirmed COVID-19 cases from January 7th to February 18th 2020.

There were 103 non-primary cases amongst 784 household contacts giving an attack rate of 13.1% overall. Notably children (<20yo) had a lower non-primary household attack rate of 5.2%.
In statistical transmission modelling to estimate true secondary attack rates, children (<20yo) had a lower odds of infection compared with adults >60yo (OR 0.23, 95% CI 0.11-0.46)

Only 10/215 (5%) of primary cases were children.

Although the criteria for testing contacts in this study are not entirely clear, the results suggests that children are less susceptible to SARS-CoV-2 infection compared with adults with similar exposure. This is in keeping with other reports from Asia (Zhang), Israel (Somekh) and the USA (Rosenberg).

Eli S Rosenberg, Elizabeth M Dufort, Debra S Blog et al. New York State Coronavirus 2019 Response Team, COVID-19 Testing, Epidemic Features, Hospital Outcomes, and Household Prevalence, New York State—March 2020, Clinical Infectious Diseases, ciaa549, https://doi.org/10.1093/cid/ciaa549

This epidemiological study examined the first 229 positive cases diagnosed in New York State outside of the city of New York from 2nd March to 12th March 2020 and described their outcomes. In addition, from the 5th March to the 17th March, they screened any household contacts of the positive patient. There was one ‘source’ patient under 5 years of age and 7 ‘source’ patients from 5 to <18 years of age. Household screening identified a further 42 children with COVID-19. No children <18 years of age required hospitalisation but it appears they only had complete data on 18/50 positive children.

Household contact with positive patients of any age found that likelihood of the contact being positive for SARS-CoV-2 increased with the contact’s age. Of the 25 children screened <5 years of age, 5 (20%) were positive and of the 131 screened age 5 to <18 years 37 (28.2%) were positive, compared to 16/29 (55%) of contacts aged 65+ years (p 0.002). This supports previous studies which shows a lower prevalence of SARS-CoV-2 infection in children <18 years. Unfortunately it does not described whether the household contacts of the 50 source children were positive for the infection too which could contribute to the discussion about whether children spread SARS-CoV-2 as effectively as adults and would require completion of the missing data and more in-depth analysis of the findings.

Zhang J, Litvinova M, Liang Y, et al, Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China, Science, 29th April 2020, DOI: 10.1126/science.abb8001

This fascinating study assesses contacts and infection risk in China (Wuhan and Shanghai) using 3 arms:

Surveys conducted within cities studying contacts between individuals, finding that during lockdown all contact except for those within households ceased – backing up evidence that about 90% of infections during this period occurred by household transmission

Most importantly for us – an age stratified model of susceptibility to acquiring infection was produced by assessing the data from the Hunan CDC, whereby every positive case found in Hunan had recent contacts placed under quarantine for 14 days and was tested for COVID-19. They estimated odds ratios for age groups to become infected, and performed statistical adjustment for clustering and correlation structures of contacts exposed t the same index case (generalized linear mixed model regression). Their finding was that susceptibility to infection increased with age, lowest in children 0-14 years (OR 0.34, 95% CI 0.24 – 0.49 – reference participants aged 15 – 64yrs).

Finally using the above data they estimated the effects of non-pharmceutical interventions on reducing spread of COVID-19. They found that closing schools was likely to significantly impact the R0 but not enoght to be a useful measure on its own. They describe social distancing as implemented in China, to be a sufficient measure to control COVID-19

This is the latest, and one of the most comprehensive of a number of studies to demonstrate significantly lower attack rate in children to adults, suggesting decreased susceptibility to infection.

Li, W., B. Zhang, J. Lu, S. Liu, Z. Chang, P. Cao, X. Liu, P. Zhang, Y. Ling, K. Tao and J. Chen (2020). “The characteristics of household transmission of COVID-19.” Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 17. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa450/5821281

This retrospective study calculated secondary attack rates of COVID-19 amongst 392 household contacts of 105 SARS-CoV-2 RT-PCR positive index cases hospitalised at Zaoyang First People’s Hospital (250 km from Wuhan) and Chibi People’s Hospital (150 km from Wuhan) between 1st January and 20th February 2020.

Study design:  Households were eligible for the study if the index case was the only member of the household with a clear history of exposure to Wuhan, its residents or high-risk sites in the 14 days before onset of illness (the assumption then being that the only exposure of household contacts to SARS-CoV-2 was via the index case).  Once index cases were confirmed, household contacts were quarantined for 14 days in local government sites and monitored daily, with at least 2 nasopharyngeal swabs (taken at the beginning and mid-point of quarantine).  Variables analysed retrospectively in this study (using medical notes and telephone interviews) included household size, age/gender/symptoms of index cases and household contacts, time between onset of illness of the index case and hospitalisation (range 0-11 days) and spouse/non-spouse relationships. 

Key paediatric findings:  100 of the 392 household contacts were under 18 years of age (median 6.5 yrs, IQR 4-11 yrs); of these, only 4 children became infected (all male, 1 aged 0-5 yrs, 3 aged 6-17 yrs).  This secondary attack rate of 4% for children compares with 21% for the adult household contacts (60 out of 292 infected) and 16% overall (64 out of 392).

Of interest:  14 of the 105 index cases self-quarantined within the home immediately after onset of symptoms before hospitalisation (wearing masks, eating and residing separately from the rest of the household); in these households there was a 0% secondary attack rate, versus 18% in those households where the index case didn’t self-quarantine before hospitalisation.  In households where the index case was afebrile, 13% of household contacts became infected, versus 19% where the index case had fever.  In households where the index case had no cough, approximately the same proportion of household contacts became infected as in households where the index case had a cough (17% vs 16%).  9 of the infected household contacts were asymptomatic (14%), but this figure isn’t broken down by age in the article.  [Note: there are some discrepancies between calculations in the text and data tables; data from tables used here.

This article provides further reassurance to the growing body of evidence of lower attack rates of COVID-19 in children as compared to adults, as well as a signal that symptomatic patients are higher risk of transmitting the virus than those who do not develop symptoms.

Wang, Z., W. Ma, X. Zheng, G. Wu and R. Zhang (2020). “Household Transmission of SARS-CoV-2.” The Journal of infection. 10. https://doi.org/10.1016/j.jinf.2020.03.040

This is a retrospective case series of 85 patients admitted to Union Hospital in Wuhan City, Hubei Province, China and their households, one household per index case.  The aim was to attempt to determine the transmission rate of SARS-CoV-2 among household members.

All patients were confirmed infected with SARS-CoV-2 with real-time reverse transcription polymerase chain reaction (RT-PCR) assays on throat swabs. The admission dates were February 13 and February 14, 2020. The city had been under lockdown measures since the 23rd of January.

The composition of these 85 households was 107 (45%) male adults, 115 (48%) female adults and 18 (7%) children.

64 (60%) of 107 male adults and 66 (58%) of 115 female adults were confirmed infected with SARS-CoV-2, only 2 (11%) of 18 children became positive. As a whole, there were totally 240 cases in these 85 households, with 132 (55%) of them were confirmed with SARS-CoV-2 infection and 57 (24%) cases were negative in RT-PCR assays.

The researchers found there was a secondary transmission rate of 30% and this increased to 50% for households with 2 contacts, they compared this to previous studies on other two coronavirus pneumonia epidemics which reported secondary transmission rates among household contacts of 5% for Middle East respiratory syndrome coronavirus (MERS-CoV) and 10.2% for severe acute respiratory syndrome coronavirus (SARS-CoV). The researchers concluded this demonstrated the need for stringent quarantining of household contacts.

This research did have some limitations. The researchers did not clarify what criteria they were using to guide testing nor did they quantify exactly how long they followed up household contacts for. It reproduces similar studies which have found significantly lower attack rates in children.

Zhu Y, Bloxham CJ, Hulme KD, et al. Children are unlikely to have been the primary source of household SARS-CoV-2 infections. medRxiv 2020;:2020.03.26.20044826. doi:10.1101/2020.03.26.20044826

A pre-print, the information should be treated with caution until it has undergone peer review.

This study includes a review of symptom frequency in children, but most interestingly examines available case series in the literature of family clusters of COVID-19 to determine what contribution is made of children to the chain of transmission. Clusters were taken from China, Singapore, the USA, South Korea and Vietnam, totalling 31 household transmission clusters. Of these cases, only 3 (9.7%) had a child as the index case. Considering a worst case scenario (whereby ALL infected children were the index case in their family and had been mislabelled as a secondary in some studies), still children would only account for 6/28 (21%) infection clusters. They compare this to the H5N1 epidemic where children were the index case in 54% of household clusters. This provides further evidence that children appear to have a fairly limited role in the transmission of COVID-19, which has implications for non-pharmaceutical interventions such as school closures.

Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study, Lancet Infectious Disease, April 27th 2020, https://doi.org/10.1016/S1473-3099(20)30287-5

This was a fairly impressive study looking at contact tracing of 1286 contacts of 391 patients with COVID-19. Only 20 (5.1%) of the initial 391 cases were children, of which 2/3 were asymptomatic. They discovered a secondary attack rate of 15% for household contacts and 9.6% overall. The most important finding is that the rate of infection in children <10 years (7.4%) was similar to the population average (7.9%). The findings of this study suggested that children were becoming infected at a similar rate to adults but were much less likely to be asymptomatic. As no repeat testing was performed, it is unclear if these children were truly asymptomatic, or presymptomatic. Subsequent studies have consistently shown lower attack rates in children, and the reason for this discrepancy is unknown.

Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al. Prevalence of SARSCoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 2020. https://doi.org/10.1016/ S0140-6736(20)31483-5

Introduction: Spain was one of the countries in Europe hit hardest by the Covid 19 pandemic. These are the first wave results from the Seroepidemiological Survey of SARS-CoV-2 Virus Infection in Spain (Encuesta Seroepidemiológica de la Infección por el Virus SARS-CoV-2 en España; ENE-COVID). This is an epidemiological study with an aim to estimate the sero-prevalence of Sars Cov2 in Spain through symptom checking, point of care antibody testing, and serology.

Methods: 35 883 households across Spain were selected through stratified two stage sampling and invited to take part. This is the result of the first wave of sampling which was conducted from April 27 to May 11, 2020. Participants within selected households answered a questionnaire on history of symptoms compatible with COVID-19 and risk factors. “Asymptomatic” was no symptoms, “paucisymptomatic” (1–2 symptoms without anosmia or ageusia), and symptomatic (anosmia or ageusia, or at least three symptoms among fever; chills; severe tiredness; sore throat; cough; shortness of breath; headache; or nausea, vomiting, or diarrhoea). Participants were contacted by phone and then invited to go to local primary care centre for testing or have a home visit. All participants were offered point-of-care antibody test (Orient Gene Biotech COVID-19 IgG/IgM Rapid Test Cassette; Zhejiang Orient GeneBiotech, Zhejiang, China, SARS-CoV-2 spike protein) and, if agreed, donated a blood sample for additional testing with a chemiluminescent microparticle immunoassay (SARS-CoV-2 IgG for use with ARCHITECT; Abbott Laboratories, Abbott Park, IL, USA, SARS-CoV-2 nucleoprotein). Sensitivity of the test was deemed any test positive (point of care/ serum), with specificity both tests positive. Of note Spain was under lockdown at the time of this study.

Results: Of 95 699 eligible individuals, 66 805 study participants took part, with 61 075 receiving point of care testing and 51 958 the immunoassay. Overall seroprevalence was 5.0% (CI 4.7–5.4) by the point-of-care test and 4.6% (CI 4.3–5.0) by immunoassay. In 7 provinces in the central part of Spain, including Madrid, seroprevalence was greater than 10% by both methods. Seroprevalence was similar for females and males. Seroprevalence was lower in the oldest age groups (≥85 years) compared with other adults. With regards occupation it was highest in health-care workers, 10.2% (7.9 – 13) than in other occupations these results were supported by the immunoassay.
In those who reported a contact with a confirmed case, seroprevalence was greater in those
who had a confirmed case in their household (range 31.4% to 37.4% between the two tests), in their workplace 9.9–10.6%, among their non-cohabitating family members and friends 13.2–13.7%, or among their caregivers and cleaning staff 12.4–13.5%

Symptoms: For both tests seroprevalence was highest in those with a confirmed Sars-CoV-2 PCR more than 14 days before testing (88·6–90·1%). Among those with a positive test, the proportion of individuals who reported anosmia or three or more symptoms compatible with COVID-19 was 49.1%
for the point-of-care test and 54. 2% for the immunoassay. In 32.7% (CI 30.2–35.4) of point-of-care test and 28.5% (CI 25.6–31.6) participants were asymptomatic.

Results in children: 11,422 children (<19 years) had a point of care test, with 6,527 also having an immunoassay. The proportion of paediatric participants having serology was lower than that of adults, though not unsurprising given the need for extra phlebotomy. Overall seroprevalence for those < 19 years was 3·4% (2·9–3·9) for point of care testing, and 6527 3·8% (3·2–4·6) for immunoassay.
Looking at specific age ranges for point-of-care test seroprevalence was < 1 year, 1.1% (0.3–3.5): 1- 4 years 2.1 %(1.3–3.4); 5 – 9 years 3.1% (2.2–4.2); 10-14 years 4.0% (3.1–5.0); and 15 – 19 years, 3.7% (2.9–4.8). The same pattern but slightly higher percentages were seen with immunoassay <1 year 0.0% (0.0–11.9); 1- 5 years 3.5% (1.7–6.8): 5 – 9 years 3.6% (2.3–5.7); 10 – 14 years 4.1% (3.1–5.5); and 15 – 19 years 3.8 (2.8–5.0). This paper did not give data on symptoms separately in age groups.

Conclusion: Population seroprevalence is lower than expected in areas of high endemic SARS-CoV-2, and is lowest in children. Close contact with people, particularly in the same household increases viral transmission. Over 30% of those with seroprevalence were asymptomatic. This highlights the importance of rapid identification and isolation with those with confirmed SARS-CoV-2, however isolation and separation for other household members may not be realistic in poorer or urban areas.

Gabriele Pagani, Federico Conti, Andrea Giacomelli et al, Seroprevalence of SARS-CoV-2 IgG significantly varies with age: results from a mass population screening (SARS-2-SCREEN-CdA). medRxiv June 24th 2020, https://doi.org/10.1101/2020.06.24.20138875

In this brief report of a SARS-CoV-2 serosurvey from Castiglione D’Adda in Italy, the results of a logistic regression model based on the random sampling of 509 subjects from the region (total population 4550) following the peak of transmission in the region are detailed. Prior to this serosurvey testing was limited to severely symptomatic cases.

The exact number of children included is not provided but the age related prevalence was significantly lower in children – 9.1% (0-5yo), 10.1% (5-10yo), 11.2% (10-15yo), 12.5% (15-20yo) – compared with overall seroprevalence of 22.6%.

The methodological details are limited in this report but the data are consistent with serosurvey data from elsewehere in Europe suggesting that children are less susceptible to SARS-CoV-2 infection compared with adults. 

Stringhini, S., A. Wisniak, G. Piumatti, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study.” Lancet. June 11th 2020, https://doi.org/10.1016/S0140-6736(20)31304-0

Methods: This study takes a representative population sample from Geneva, Switzerland (already identified by a pre-existing health study) and invites them to attend blood tests looking for antibodies against the SARS-CoV-2 virus over time. The purpose is to monitor what proportion of the population are infected and see how it changes during the course of the pandemic (5 weeks in this study). Participants could only attend once, and were invited by email with a telephone follow up. The only exclusion criteria was living in a prison or care home. Antibodies were measured using a commercial assay (ELISA for S1 domain of spike protein IgG). They performed in house validation of the assay using a couple of techniques (the results of the immunofluorescence validation were factored in to the sensitivity analysis of the model used later in the study)

Analysis: The statistical analysis performed was a Bayesian regression which had a random effect for households and factored in age/sex as well as the test performance to extrapolate the sample results on to population estimates of seropositivity. They calculated the relative risk (RR) of age groups having been infected with age 20 – 49yrs as the reference group.

Results: 5492 people were invited and the final analysis included 2766 people (3426 of the rest were non-responders or awaiting an appointment). 455 children participated. Seropositivity in the population increased between weeks 1 and 2 (4.8% to 8.5%), with no statistically significant difference thereafter (final estimate 10.8%).

The most significant result is that of the children<10yrs in the study, only 1/115 children tested positive (although a further 8 had an equivocal result). This made the RR of infection for children <10yrs 0.32 (0.11 – 0.63) compared to adults aged 20 – 49yrs. There was no statistically significant difference between children aged 10 – 19 yrs (OR 0.86, 0.57–1.22). Another important factor was strong association between household contacts (unsurprisingly). This is important, as there were also lower rates of infection seen in the elderly (>65 yrs OR 0.5, 0.28–0.78) but only 3% of these participants had a positive household contact. Of the 123 children aged 5-9yrs, 17% of them had a positive household contact.

This study adds to a growing body of evidence that younger children (particularly those under 10yrs) may be less susceptible to acquiring infection than adults. The RR of 0.3 despite a relatively high proportion having positive household contacts is in contrast to the elderly, whose low infectivity rate may be explained by reduces exposure (additionally, a relatively high number of elderly will have been hospitalised or passed away from infection during the study, meaning they will not be counted in these statistics).

Considerations: Schools were closed for the duration of this study period which will have reduced community exposure of young children. In addition, almost all validation of antibody assays has been in adults so far. There were a notable number of equivocal results in the young children, but the significance of this is unclear. The results are however consistent with the largest seroprevalence study to date, from Spain.

Lavezzo, E., Franchin, E., Ciavarella, C. et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo’. Nature (2020). https://doi.org/10.1038/s41586-020-2488-1

This paper outlines the strategy of a small town in Italy which immediately shutdown for 14 days following their first death from COVID-19 on Feb 21st 2020. They subsequently screened 86% of the population for SARS-CoV-2 using nasopharyngeal swabs, then screened again 2 weeks later (71.5% of the population).

At the start of the lockdown 2.6% (95% CI 2.1 – 3.3%) of the population tested positive, but 0 of 217 children aged 0 – 10 tested positive (0%), and only 3/250 aged 11 – 20 (1.2%) tested positive. By the end of the lockdown, 0/157 (0%) children aged 0 – 10 tested positive, and 2/210 (1%) children aged 11- 20 tested positive. Many of the children aged 0 -10 lived with infected individuals. They also noted >40% of people who tested positive were asymptomatic. They note a significant number of infections appeared to have come from asymptomatic individuals during contact tracing. They also note these asymptomatic individuals never developed symptoms, and had similar viral loads to symptomatic patients (as determined by the cycle threshold from RT-PCR). It should be noted the definition of symptoms was restricted to ECDC definitions of COVID-19 related symptoms, and given the wide variation of non-classic symptoms which have been described (rashes, malaise, joint aches, rhinorroea, GI symptoms etc), this likely significantly undercounts the number of patients who truly developed symptoms.

This study has relatively small numbers, but again appears to provide evidence for several important features of paediatric infection: primarily that children appear significantly less likely to become infected than adults. It presents evidence for asymptomatic transmission, and against the theory of viral load correlation with symptom burden.

Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, Melsted P, Norddahl GL, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med, Published April 14th 2020, doi:10.1056/NEJMoa2006100.

This study describes the entry and spread of SARS-CoV-2 through Iceland. Importantly, this is the first epidemiological report to include SARS-CoV-2 screening of the general population and likely represents the most complete national epidemiological data published to date.

Study design: This report includes all confirmed SARS-CoV-2 infections in Iceland identified through either: targeted testing (January 31st to March 31st 2020) – 9199 predominantly symptomatic patients with travel to a high risk country or contact with a confirmed case; population screening (March 13th to April 1st 2020) – 13080 volunteers screened from the general population (without high-risk travel or contact with a confirmed case). Most patients in the population screening cohort were asymptomatic, with a minority with predominantly mild URTI symptoms. A subsequent period of random population screening from April 1st-4th excluded children.

SARS-CoV-2 real-time PCR was performed on combined oropharyngeal and nasopharyngeal samples. All confirmed cases were isolated and close contacts placed in quarantine for 14 days.

Key paediatric findings – there is comparative data provided on the 1412 children <10 years of age tested: of 564 children <10 years old tested in the targeted testing cohort, 6.7% (38) were positive – compared with 13.7% of persons >10 years old; of 848 children <10 years old tested in the population screening cohort, 0% (0) were positive – compared with 0.8% of persons >10 years old.

Details on severity of infection, hospitalisation rates and age specific symptom profiles are not included.

Discussion: The first SARS-CoV-2 infection in Iceland was confirmed on 28th February 2020. The dynamics of new cases has transitioned from imported infections initially to ongoing community spread. To date just over 0.5% of the population have had confirmed infection. Whilst physical distancing measures have been put into place including limiting gatherings to a maximum of 20 people, elementary schools have remained open. Iceland has amongst the highest national rates of SARS-CoV-2 testing per capita, with 6% of the population tested as described here. As a result this report provides the most accurate and complete national epidemiological data published to date.

The lower rate of positive tests in childen <10 year olds adds support the hypothesis that children are less susceptible to SARS-CoV-2 infection compared to adults. Similarly the lack of positive tests amongst >800 children screened goes against the theory that the low reported rates of COVID-19 in children are due to a large number of undocumented/asymptomatic paediatric cases. This finding, particularly, has important implications in decision-making around patient flow and isolation in general paediatric care, suggesting that routine testing and isolation of asymptomatic children may be of low yield in similar settings. Clearly a single PCR screening test at one time point has an insufficient negative predictive value to exclude infection. As such, serological studies will be important in providing a clearer picture of the extent of SARS-CoV-2 infection in children.

Conclusion: Children under 10 yo appear to be less likely to develop SARSCoV-2 infection compared with people >10 yo. In settings with moderate levels of SARS-CoV-2 infection (0.5% population with confirmed infection in this setting), screening of asymptomatic children without overseas travel or contact with a known case is of very low yield.

Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 April 2020. DOI: https://dx.doi. org/10.15585/mmwr.mm6914e4

This is the first USA CDC report of COVID-19 looking specifically at children, examining confirmed cases nationally between FEbruary 12th and April 2nd. Due to the extremely disparate nature of public health reporting in the USA, the data quality and availability for this report is highly variable. There is no information as to the basis on which tests were performed, whether for presentation to hospital, symptomology or due to contact tracing. This cohort is therefore likely extremely heterogeneous. Of the nearly 150,000 confirmed cases in the US at this time, 2,572 (1.7%) were in children. New York City had 33% of paediatric cases. The median age was 11y and males account for 57%. Nearly 33% of cases were in children aged 15 – 17yrs, 15% in children <1y, 11% in children ages 1 – 4y and 15% in children 5 – 9y. 91% of cases had xposure to a known COVID-19 case.

Data on signs/symptoms was only available for 11% of cases. Fever, cough OR shortness of breath were present in 73% of cases, with fever in 56%, cough in 54%, shortness of breath in 13%, rhinorrhoea 7.2%, sore throat 24%, vomiting 11% and diarrhoea 13%. They have not reported on “asymptomatic” cases due to incomplete reporting on symptoms.CU admission was documented for 2% of cases. Hospitalisation was most common in infants (62%), with little difference between other age groups in regards to hospitalisation or ICU admission. From low numbers infants id not appear significantly more likely to be admitted to ICU. Underlying conditions were present in 23% of cases, most commonly respiratory (such as asthma), followed by cardiac conditions and immunosuppression. There are 3 deaths reported, but review is ongoing to determine whether COVID-19 was the cause. This patchy data from the US is useful as it closely resembles data from Chinese cohorts of children in regards to low frequency of severity and adverse outcomes. It confirms available data suggesting lower frequency of common symptoms in children as compared to adults.

Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics 2020:e20200702. doi:10.1542/peds.2020-0702

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also  some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.

This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Felstein, L.R. et al (2020) Multisystem Inflammatory Syndrome in U.S. Children and Adolescents, NEJM. epub 29 June 2020, DOI:10.1056/NEJMoa2021680.

This retrospective and prospective multi-centre cohort study from 53 participating hospitals in 26 states looked at 234 patients under 21 years of age that met criteria for multi system inflammatory syndrome in children (MIS-C), between March 15 and May 20th

The median age of the patients was 8.3years old and 62% (115) were male. Fifty one patients (27%) had an underlying medical condition. In terms of confirmation of SARS_CoV-2 infection – 70% were positive for RT-PCR and/or antibody testing.  Of a small subgroup of 14 patients with Covid-19 symptoms before MIS-C, the median time between Covid-19 symptom to MIS-C was 25 days (6-51 days).
Criteria for MIS-C were based on CDC guidelines (in brief, requiring hospitalisation, at least two systems involved, fever of at least 24 hours and either lab confirmed SARS_CoV-2 infection (via RT-PCR or antibody testing) or an epidemiological link to a person with Covid-19 within 4 weeks before onset of symptoms).
Although MIS-C criteria was at least 2 system involvement, 71% had involvement of four organ systems or more. The most frequent systems in order were gastrointestinal (92%) followed by cardiovascular (80%), haematological (76%) and respiratory (70%). Blood changes observed included lymphocytopaenia in 80% of patients, and an elevated CRP in 91%.
Looking at similarity and overlap with Kawasaki disease, 40% of patients had either fever for at least 5 days and 4-5 of Kawasaki’s disease-like features or 2-3 Kawasaki’s disease-like features with additional lab or echocardiographic findings. Common symptoms similar to Kawasaki disease bilateral conjunctival infection in 103 (55%), oral mucosal changes in 78 (42%), peripheral extremity change in 69 (37%), rash in 110 (59%), cervical lymphadenoapthy (>1.5cm diameter) in 18 (10%). Differences between MIS-C and Kawasaki’s disease groups include an older age group and a different cardiovascular involvement (more likely myocardial dysfunction) in MIS-C patients.
The majority of patients required ICU admission (n=148, 80%) with one in five patients needing invasive mechanical ventilation. Eight patients received ECMO support. Treatment included IVIG in 77% and systemic glucocorticoids in 49%. There were four deaths (two of which had received ECMO). At the time of writing the paper, 70% of patients had fully recovered with 28% still in hospital.

Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. DOI: 10.1056/NEJMoa2021756.

This is a case series of 99 children (<21 years of age) from New York State with multisystem inflammatory syndrome in children (MIS-C). Of note some of these cases have been reported in small series (Cheung et al JAMA 2020). New York State Department of Health required hospitals that provide paediatric medical or surgical care to report potential cases of Kawasaki’s disease, toxic shock syndrome, or myocarditis or who were suspected to have MIS-C among persons younger than 21 years of age admitted since March 1, 2020, through the NYSDOH Health Emergency Response Data System. The clinical and laboratory characteristics of these reports were studied. Between March 1 and May 10 2020 191 cases were reported of which 95 met the criteria for MIS-C and 4 further were suspected.

Case definition: Confirmed cases were defined by the presence of both clinical and laboratory criteria. Suspected cases had clinical and epidemiological criteria.

Clinical criteria were children <21 years of age with fever and needing hospitalisation with either; 1 or more of hypotension or shock, features of severe cardiac illness, or other severe organ failure. Or 2 or more of; maculopapular rash, non-purulent conjunctivitis, mucocutaneous inflammatory signs or acute GI symptoms with an absence of other cause.

Laboratory criteria:

1. General Criteria; Two or more of raised inflammatory markers and

2. Either positive SARS CoV2 RNA at time of presentation or within 4 weeks or detection of specific antibody.

Epidemiological criteria: In 6 weeks prior to exposure close contact with a person with confirmed or clinically consistent Sars CoV2 infection or travel to or resident in an area with ongoing community transmission. 

Baseline characteristics: 53 (54%) were male. Age range was 0-5 years (31%), 6 to 12 year (42%) and  13 to 20 years (26%). 78 patients had data on race with 29 (37%) were white, 31 (40%) were black, 4 (5%) were Asian, and 14 (18%) were of other races. 36 patients had a preexisting condition, 29 had obesity.  24  (24%) had a Covid-19–compatible illness a median of 21 days (interquartile range, 10 to 31) before hospitalization, 38 (38%) had exposure to a person with confirmed Covid-19, and 22 (22%) had direct contact with a person who had clinical Covid 19.

Symptoms : Described in detail in the study. Prevalence of dermatologic symptoms was highest among children 0 to 5 years of age, and the prevalence of myocarditis (diagnoses and clinical) was highest among the adolescents.

Treatment : Of 99 patients, 79 were treated in ICU. 69 had IVIG, 63 received systemic glucocorticoids, 48  received both systemic glucocorticoids and IVIG. 9 patients had coronary aneurysm

Outcome : As of May 15, a total of 76 patients (77%) had been discharged and 21 (21%) were still hospitalised. Unfortunately 2 patients died in the hospital. Both were intubated and ventilated, once received ECMO. Neither received IVIG, systemic glucocorticoids, or immunomodulators.

Kaushik, S., S. I. Aydin, K. R. Derespina et al, “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with SARS-CoV-2 Infection: A Multi-institutional Study from New York City.” J Pediatr.  https://doi.org/10.1016/j.jpeds.2020.06.045

This retrospective observational study details clinical characteristics, therapies and outcomes of a multicentre cohort of 33 children with Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 admitted to PICUs at 3 tertiary care children’s hospitals in New York City between 23 April and 23 May 2020.

Study design:  Patients aged 1 month to 21 years admitted to 3 NYC PICUs (at Children’s Hospital at Montefiore, Mount Sinai Kravis Children’s Hospital and Jacobi Medical Center) with confirmed SARS-CoV-2 infection (positive nasopharyngeal swab RT-PCR or antibody assay) meeting criteria for MIS-C (US CDC case definition, formalised on 14 May 2020, used: age < 21 yrs presenting with fever, laboratory evidence of inflammation and evidence of clinically severe illness requiring hospitalisation, with ³ 2 organ involvement, plus no alternative plausible diagnosis, plus positive for current/recent SARS-CoV-2 infection or COVID-19 exposure within 4 wks prior to onset of symptoms).  During the study period there were additional suspected patients with similar presentations and management without confirmed SARS-CoV-2 infection/exposure who were excluded; only cases with confirmed infection by RT-PCR/antibody assay were included. 

Study population:  33 children met the inclusion criteria at the 3 centres.  Median age 10 years (IQR 6-13), 20/33 male (61%), median BMI 18.6 kg/m2 (IQR 15.9-22.9), 2/33 obese (6%, BMI > 30 kg/m2).  15/33 Hispanic/Latino (45%), 13/33 black (39%), 3/33 white (9%), 1/33 Asian (3%), 1/33 other (3%).  16/33 comorbidities (48%) (most common comorbidity was asthma).  8/33 (24%) had had contact with an ill person, 5/33 (15%) had had contact with a confirmed COVID-19 case.

Clinical features:  Fever 31/33 (94%), mucocutaneous involvement 7/33 (21%), conjunctivitis 12/33 (36%), rash 14/33 (42%), abdominal pain 21/33 (64%), nausea/vomiting 23/33 (70%), diarrhoea 16/33 (48%), dyspnoea 11/33 (33%), dizziness 3/33 (9%).  Duration of symptoms prior to admission 4.5 days (IQR 3-6).  21/33 (64%) were hypotensive on admission.

Admission blood results:  Medians (IQR in brackets): WBC 11,000/mL (8450-14,400), lymphocytes 1,100/mL (600-1,300), CRP 250 mg/L (156-302), ESR 53 mm/hr (28-77), procalcitonin 5.4 ng/mL (1.8-16.7), ferritin 568 ng/mL (340-954), fibrinogen 627 mg/dL (455-782), D-dimer 3.7 mg/mL FEU (2.4-5.1), BNP 388 pg/mL (75-1086), pro-BNP 4328 pg/mL (2117-13370), troponin T 0.08 ng/mL (0.02-0.17), IL-6 200 pg/mL (56.4-330), IL-8 41.7 pg/mL (25.1-54.4), creatinine 0.6 mg/dL (0.4-1.1).

CXRs:  Cardiomegaly 10/33 (30%), focal or bilateral pulmonary opacities 11/33 (33%).

Echocardiograms:  Performed in 32/33 (97%).  Pericardial effusion 15/32 (47%), median LVEF 47% (IQR 40-53).  LVEF < 30% 4/32 (13%), LVEF 30-50% 17/32 (53%), LVEF > 50% 11/32 (34%).  24/32 had a second echocardiogram prior to discharge: of those with initial LVEF < 50%, 20/21 (95%) had recovery of ventricular function with normal EF.  Median pre-discharge LVEF 58% (IQR 55-62).  A detailed table is supplied for the 21 patients with LVEF < 50%, including BNP/troponin levels, drug treatment by patient and the 8/21 who had prominent coronary arteries on echo.

Treatment in PICU:  18/33 received IVIg (55%), 17/33 corticosteroids (52%), 12/33 tocilizumab (35%), 7/33 remdesivir (21%), 4/33 Anakinra (12%), convalescent plasma therapy 1/33 (3%), 17/33 vasopressor/inotropes (52%) (median duration of vasopressor use 72 hrs (IQR 48-110), norepinephrine most commonly used agent), 8/33 aspirin (24%), 21/33 diuretics (64%).  Anticoagulation was used in all patients:  prophylactic dose enoxaparin 5/33 (15%), therapeutic dose enoxaparin 27/33 (82%), therapeutic dose unfractionated heparin 1/33 (3%).  Empiric antibiotic coverage for < 48 hrs in 14/33 (42%) and > 48 hrs in 15/33 (45%).  5/33 (15%) required invasive mechanical ventilation.  2/33 (6%) required mechanical circulatory support: 1 ECMO (5-yr-old) and 1 intra-aortic balloon pump (20-yr-old).

Outcomes:  32/33 (97%) patients were discharged home with median PICU stay of 4.7 days (IQR 4-8) and hospital stay of 7.8 days (IQR 6-10).  1/33 (3%) died (ischaemic brain infarction with subarachnoid haemorrhage on day 6 of ECMO).

The authors conclude that rapid, complete clinical and myocardial recovery was almost universal in their study.  They hypothesise that this novel COVID-19 MIS-C is predominantly an antibody-mediated or other immune cell-mediated cytokine storm, with some contribution from direct myocardial injury.  They note the lower morbidity in their cohort relative to recent European studies

Capone, C. A., A. Subramony, T. Sweberg, J. et al. “Characteristics, Cardiac involvement, and Outcomes of Multisystem Inflammatory Disease of Childhood (MIS-C) Associated with SARS-CoV-2 Infection.” J Pediatr. https://dx.doi.org/10.1016%2Fj.jpeds.2020.06.044

This is a single-centre retrospective case series of 33 sequentially hospitalized febrile paediatric patients with CDC case definition for Multisystem Inflammatory Disease of Childhood (MIS-C) and WHO criteria for Multisystem Inflammatory Syndrome (MIS) admitted to Cohen Children’s Medical Center, Queens, NY from April 17, 2020 through May 13, 2020. All cases were positive for SARS-CoV-2 by detection of serum antibodies or nucleic acid from a nasopharyngeal specimen. Patients with COVID-like lower respiratory tract involvement were excluded. The peak of hospitalizations occurred approximately five weeks after the peak of hospitalizations with acute COVID-19. Patients were predominantly male (20, 61%) and non-Hispanic (24, 73%) with a median age of 8.6 years (IQR 5.5-12.6). Most patients were previously healthy but a higher proportion were overweight (2,6%) or obese (12, 39%) compared with the regional childhood obesity rate of 18%. 

Patients presented with a median of 4 days (IQR 3-5) of fever and almost all (32, 97%) had gastrointestinal symptoms (including diarrhoea, vomiting and abdominal pain) as well as other organ system involvement. 21 (64%) patients fulfilled complete criteria for KD and most patients with complete KD criteria, had shock (16, 76%). 

All patients had negative blood cultures and multiplex nucleic acid amplification test for multiple respiratory pathogens except 1 patient in whom influenza virus detected. 26 (79%) patients needed intensive care and 6 (18%) required mechanical ventilation. 58% had myocardial dysfunction and 76% required vasoactive medications. Coronary artery aneurysm was identified in 5 (15%) and dilation was detected in 3 (9%) patients. 

All patients were treated with IVIG, 88% received aspirin, and 70% were given a corticosteroid and 42% were given Enoxaparin. 24% of patients exhibited a partial response to these treatments and received a biologic modifying medication (Anakinra, Tocilizumab, Infliximab). Most patients demonstrated rapid clinical improvement. No patients died. Median length of hospital stay was 4 days (IQR 4, 8). At hospital discharge, mild cardiac dysfunction was still present in 9 of 19 patients. 

This case series shares similarities with smaller international case series reported as Kawasaki-like disease and hyperinflammatory shock syndrome. In all these studies, most patients had antibodies against SARS-COV2 virus, suggestive of a post-infectious, immunologically mediated pathophysiology. The authors suggest that the latent period between the peak of paediatric cases of COVID-19 and MIS-C suggests that MIS-C has a post-infectious, possibly immunologically mediated pathogenesis.

Despite clinical similarities with KD, differences include the predominance of gastrointestinal symptoms, an older age range (8.6 year in MIS-C patients compared with a median age of 2.5 years for patients with KD), markedly elevated inflammatory markers, higher proportion of patients with shock and/or impaired cardiac function (76%) than in other KD studies (less than 3% shock reported), and the lack of thrombotic events in the case series patients. This suggests that MIS-C may be a syndrome distinct from KD. Acute COVID-19 with “cytokine storm” further complicates differentiation of these presentations.  

Further study is needed to shed light on the pathophysiology, treatment options, and outcomes of MIS-C.

Whittaker, E., A. Bamford, J. Kenny, et al. “Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2.” Jama. doi:10.1001/jama.2020.10369

This paper provides a detailed description of the clinical and laboratory features of 58 children diagnosed with PIMS-TS from 8 hospitals in England between March 23rd and May 16th 2020. All children fulfilling the UK, WHO or CDC criteria for PIMS-TS / MIS-C were included; evidence of SARS-CoV-2 infection was not required for inclusion. Features of this group were compared with previous data from children with Kawasaki Disease (KD), KD shock syndrome (KDSS) and toxic shock syndrome (TSS).

Of the 58 patients, 45 (78%) had evidence of SARS-CoV-2 infection (RT-PCR (15) and or IgG (40)). 33 (57%) were female. 22 (38%) were of black race, 18 (31%) asian. The majority were previously well; only 7 had co-morbidities (3 with asthma, 1 epilepsy, 1 neuro-disability, 1 sickle cell trait, 1 alopecia)

All patients had fever (range 3-19 days). Gastrointestinal symptoms were common (abdominal pain (53%), diarrhoea (52%), vomiting (45%)) whilst respiratory symptoms were relatively uncommon (21%) and 15 (26%) had headache. 

Only 13 (22%) of patients fulfilled criteria for KD; 8 (14%) had coronary artery aneurysm, 26 (45%) conjunctival injection, 30 (52%) rash, 17 (29%) mucous membrane changes, 9 (16%) lymphadenopathy, and 9 (16%) swollen hands and feet. Half of patients developed shock. 

Laboratory findings were consistent with marked inflammation (mean CRP 229 mg/L (IQR 156-338), ferritin 610 μg/L (359-1280), fibrinogen 5.7 g/L (4.4-7), D-dimer 3578 ng/mL (2085-8235)) with neutrophilia (13 x 10^9 (10-19)). Evidence of myocardial injury was common with troponin elevated in 34/50 (68%) and NT ProBNP in 24/29 (83%). Low haemaglobin (92 g/L (83-103)), lymphocyte (0.8 x 10^9 (0.5-1.5) and platelet levels (151 x 10^9 (104-210)) were also observed. 

Half of patients were admitted to a critical care unit; 25 (43%) requiring mechanical ventilation, 27 (47%) inotropes and 3 (5%) ECMO. A range of treatments were given including IVIG (71%), steroids (64%), anakinra (5%) and infliximab (14%). 13 (22%) recovered without immunomodulatory treatment, whilst 60% received >/= 2 and  16% >/= 3 agents. To the last date of follow up only one child had passed away. 

The authors suggest three clinical patterns of PIMS-TS based on the patients included in this series: 

  (1) persistent fever and elevated inflammatory markers (without KD, shock or organ failure) – 23 patients here

  (2) fever and shock, often with myocardial dysfunction – 29 patients 

  (3) children fulfilling criteria for KD – 7 patients (13 if aneurysm included in criteria). 

Compared with children with KD, KDSS and TSS, children with PIMS-TS were older (median age 9 (IQR 5.7-14)) with higher CRP and lower haemaglobin. Compared with those with KD and KDSS, PIMS-TS patients in this series had higher neutrophil count, ferritin and troponin with lower platelet and lymphocyte counts. Compared with pre-COVID-KD cases children with PIMS-TS KD were older and had higher markers of inflammation and myocardial injury. 

This is the most detailed clinical report of PIMS-TS to date. The findings here demonstrate a syndrome with a wide spectrum of signs, symptoms and severity with some overlap with KD, KDSS and TSS. PIMS-TS is characterised by marked inflammation with myocardial dysfunction and often shock necessitating ICU admission for inotropic support, mechanical ventilation and, in a small number of patients, ECMO. Treatment with immunomodulatory agents similar to those used in KD has been employed and only one death had occurred at the time of the report. Differences in clinical and laboratory profile compared with KD, KDSS and TSS, suggests= that PIMS-TS is a unique entity, potentially arising from a maladaptive acquired immune response to SARS-CoV-2 infection. 

Cheung EW, Zachariah P, Gorelik M, et al. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City. JAMA. Published online June 08, 2020. doi:10.1001/jama.2020.10374

This is a case series of 17 children, admitted to a hospital in New York city, between April 18th and May 5th 2020 with features of Multisystem Inflammatory Syndrome Related to COVID-19.

Patients included in this series were i. less than 21 years old, ii. presented with a clinical syndrome characterized by prolonged fever, systemic inflammation, shock, end-organ dysfunction, or symptoms reminiscent of Kawasaki Disease or Toxic Shock Syndrome and iii. had evidence of recent (SARS-CoV-2) infection. The baseline characteristics of these children were; median age 8 years (1.8-16), 8 were male (47%); 12 were classified white (70.1%), 4 black (23.5%), 1 Asian (5.9%).

Presentation: All had fever, with median duration of 5 days. 14/17 had GI symptoms. Mucocutaneous findings were common (12 rash, 11 conjunctivitis, 9 lip redness/swelling). 3 were hypoxic at presentation, and 13 had shock. 8 met criteria for KD and 5 for incomplete KD.

Investigations: 8 patients tested positive for SARS-CoV-2 by RT-PCR and 9 by serology.

Xrays: 14 had abnormal chest radiograph findings, most commonly bilateral, interstitial opacities.

Bloods: mean values for a wide variety of investigations shown in paper in table 2. Mainly group were lymphopenic with raised ferritin, d dimers, clotting times, and troponin.

Cardiac: ECG of 16 patients showed nonspecific ST/T-wave abnormalities in 10 and attenuated QRS voltage in 1. Dysrhythmias were noted in 3. Admission echos showed normal to mildly decreased left ventricular function in 11,  or moderate or more ventricular dysfunction in 6.  All patients had normal coronary arteries by measurement, though coronary arteries were described as prominent or echogenic in 7. However one patient (aged 4 years) developed a medium-sized aneurysm (z score, 5.2) of the left anterior descending coronary artery. This patient presented with fever, diarrhea, and shock, with no additional features of KD.

Treatment: 15/17 patients were admitted to PICU; vasoactive support was required in 10. Treatment was varied, 14 received steroids (either methylprednisone or hydrocortisone, prednisolone numbers of each not given). 13/17 received IVIG including 3 patients who did not receive steroids and 8 who met criteria for KD. One patient received tocilizumab.

Outcome: All patients discharged home with no fatalities.

Comparison with other PIMS TS cohorts:

Reports of hyperinflammatory syndrome in children during the Sars CoV2 outbreak has been reported in France, Italy, UK and US. (see https://dontforgetthebubbles.com/pims-ts/)

This cohort used the CDC definition, which is broadly similar to RCPCH and WHO, though in the US paediatrics < 21 years of age.

Like the other cohorts, the age range is older than typically seen in Kawasaki Disease. Fever and GI symptoms are very common. Mucocutaneous signs were also common. Children presented very unwell, with many needing PICU care (88% in this study). Treatment used included IVIG and steroids.

Unlike other cohorts where black ethnicity was pronounced, 70% of this cohort was classified as white. It would be useful to know the demographic breakdown of the local paediatric population who attend this hospital.

Belot, A., D. Antona, S. Renolleau, et al. SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020.” Euro Surveill 25(22). June 4th 2020, https://doi.org/10.2807/1560-7917.ES.2020.25.22.2001010

The first epidemiological surveillance study of SARS-CoV-2-related paediatric inflammatory multisystem syndrome (also known as PIMS-TS).  Carried out in France (population: 67 million) this was a nationwide study through the French public health agency.  156 cases were reported between 1st March and 17th May 2020 through both prospective and retrospective case identification.

Case definition required one or more of the following symptoms: seritis (serositis), characteristics of macrophage activation syndrome (MAS), myocarditis and/or Kawasaki-like disease (KLD).  Cases were divided according to associated Covid status into confirmed, probable or possible CoV and non-CoV.  Comparison was undertaken between non-CoV PIMS and CoV PIMS.

Of note, this definition differs marginally from the UK RCPCH definition of PIMS-TS which is a child with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopaenia) and evidence of single or multi-organ dysfunction.

Age distribution showed a median of 8 years and an interquartile range of 5–11 years.  Peak incidence was week of 18th to 27th April, which was 4-5 weeks behind the peak of the Covid-19 epidemic in France. 

95 of the 156 reported cases were confirmed or probable Covid, supporting a causal link between Covid-19 infection and PIMS.

CoV-PIMS cases (n=108) compared with non-CoV PIMS cases (n=48) had a higher median age (8 vs 3) and showed higher rates of myocarditis (70% vs 10%), macrophage-activation syndrome (23% vs 2%), seritis (22% vs 10%) and ITU admission (67% vs 8%). Rates of Kawasaki-like disease (KLD) were higher in the non-CoV group (81% vs 61%0) supporting the idea that these are ‘classic’ Kawasaki Disease presentations. In the CoV-PIMS groups 73% required vasopressors, 43% were ventilated and one child died.

This is the first epidemiological surveillance study of PIMS-TS indicating rates across a population. It supports a causal link with Covid following 4-5 weeks behind the clinical illness.

Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, Auriau J, Grimaud M, Oualha M, Beghetti M, Wacker J. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation. 2020 May 17. doi: 10.1161/CIRCULATIONAHA.120.048360

A multi-centred retrospective case series studied the early outcomes for children admitted to intensive care for cardiogenic shock, left ventricular dysfunction and severe inflammatory state. The study involved 14 centres in France and Switzerland. The inclusion criteria were admission between 22nd March and 30th April 2020 with fever (>38.5°C), cardiogenic shock or left ventricular dysfunction (left ventricular ejection fraction<50% in the presence of an inflammatory state (CRP> 100 mg/mL).

In summary, left ventricular systolic dysfunction was present in all patients who experienced a low systolic blood pressure. The authors contrast this to Kawasaki disease, in which diastolic dysfunction predominates and only a third of patients experience left ventricular systolic dysfunction.

The authors suggest the rapid resolution of systolic dysfunction in conjunction with a mild to moderate troponin rise implies the mechanism of cardiac impairment associated with SARS-CoV2 in the paediatric population differs to that seen in the adult population. Due to the high BNP levels present in the case series a mechanism of myocardial oedema or stunning is suggested. Very high levels of Interleukin-6 were also seen and may be related to vasoplegia. It was hypothesised these significantly raised results could be caused by stretched cardiomyocytes and cardiac fibroblasts in conjunction with macrophage activation. However, further research would be required to determine the immune mechanisms involved and potentially guide treatment choices.

35 patients were included with a median age of 10 years (IQR 2-16 years), 18 were male. 31 patients were confirmed SARS-CoV2 positive by either a nasopharyngeal RT-PCR, faecal RT-PCR, tracheal swab, or serology using Chemiluminescent Microplate Immunoassay-CMIA technique. 2 other patients were SARS-CoV2 negative, however, had CT chest appearances consistent with SARS-CoV2 changes.

10 of the patients had an identified co-morbidity: 3 (8.5%) had asthma, 1 (3%) had lupus and 6 (17%) were overweight with a BMI greater than 25. There was no data regarding ethnic origin included.

Clinical features: 35 (100%) had fever, 35 (100%) Asthenia, GI symptoms 29 (83%), rhinorrhoea 15 (43%), respiratory distress 23 (65%), adenopathy 21 (60%), rash 20 (57%), meningism 11 (31%), chest pain 6 (71%), cardiogenic shock 28 (80%), ventricular arrhythmia 1 (3%). A large proportion of the patients had shock with low systemic blood pressure with limited information.

Radiology: 2 patients had CT chest appearances “typical” for those with SARS-CoV2.

Bloods: CRP 241 mg/mL (IQR150-311) mg/mL, Troponin I 347 (IQR 186-1267) ng/L (normal <26ng/L), Creatinine Kinase 174 U/L (IQR 110-510), NT-proBNP 41484 pg/mL (IQR 35811-52475) (normal <300 pg/mL), BNP 5743 pg/mL (IQR 2648-11909) normal <100 pg/mL), D-Dimer 5284 ng/ml (IQR 4069-9095), Procalcitonin 36 ng/ml (IQR 8-99), WCC 16 X 10^3/L (IQR 12-23), Neutrophil count 13 X 10^3/L (IQR 8-19), Interleukin 6 135 pg/mL (IQR 87-175) (normal <8.5 pg/mL) 

Treatments: All patients required intensive care management with 10 (28%) needing V-A ECMO for an average of 4.5 days (range 3-6), 28 (80%) needing inotropic medication, 22 (62%) invasive ventilation and 11 (32%) non-invasive ventilation.

25 (71%) were given intravenous immune globulin with 1 (3%) patient given repeated IVIG due to persistent fever 48 hours after the first dose. 12 (34%) received intravenous steroids, dose unclear, due to grading them high-risk with symptoms similar to an incomplete form of Kawasaki disease and 3 patients received interleukin 1 receptor antagonist (anakinra) due to a persistent severe inflammatory state. 23 patients received therapeutic heparin.

Outcomes: No patients died. All 10 patients requiring V-A ECMO were weaned off successfully. The average hospital stay was 8 days (IQR 8-14) with ICU duration of 7 days (3.7-10 days). At the time of publication 7 (20%) patients remained as an inpatient or had residual left ventricular dysfunction.

Complete recovery of left ventricular function, [left ventricular ejection fraction > 60% at day 7] was seen in 25 patients (71%) by an average of 2 days after admission. 5 (14%) had residual mild to moderate left ventricular systolic dysfunction with a left ventricular ejection fraction greater than 45%. This was measured on the last follow up, an average of 12 days after admission.

Other investigations were undertaken to assess cardiac function.

ECG: 1 patient (3%) had ST elevation on ECG.

Echocardiography results: 10 (29%) of patients had an ejection fraction below 30% on admission whilst 25 (71%) had an ejection fraction between 30 and 50%. Global hypokinesis was seen in 31 (89%) with an additional 3 (9%) patients had segmental wall hypokinesis. 1 (3%) patient had Takotsubo syndrome presentation with akinesis of the apical segment Pericardial effusions were diagnosed in 3 (9%) patients.

Coronary artery dilatation, defined as Z-score >2 adjusted for body temperature, was present in 6 patients (17%): 5 patients (14%) had dilatation of the left main stem and 1 (3%) had dilatation of the right coronary artery. Right ventricular function was normal, and no thrombi were seen. No coronary aneurysms have been seen, however, ongoing follow up is planned.

Data was not presented regarding SARS-CoV2 antibodies, however, within the discussion it was noted that those who were serologically positive for SARS-CoV2 already had IgG antibodies suggesting the patients included within the study had contact with the virus “more than 3 weeks before admission”.   

Toubiana Julie, Poirault Clément, Corsia Alice, Bajolle Fanny, Fourgeaud Jacques, Angoulvant François et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study BMJ 2020; 369 :m2094

This cohort study looks at a cluster of patients diagnosed with Kawasakis disease at a hospital in Paris between April 27th and May 11th. During this time they admitted 21 children with a diagnosis of Kawasakis or incomplete Kawasakis, with a median age of 7.9yr and 12/21 female.

Clinical features: All children presented with persistent fever and with initial GI symptoms (vomiting and diarrhoea) with over half fulfilling complete KD criteria (11/21, 52%). The majority were irritable (12/21, 57%) and myocarditis was common (16/21, 76%). Coronary artery dilation was seen in 5/21 (24%) but no aneurysms seen. 8/18 who had chest imaging had lung changes.

Bloods: Inflammatory markers were significantly raised, with a median CRP of 253, PCT 22.5 and IL-6 170. Interestingly mean platelet count was 499 (but up to 838). Median troponin 282 and D dimer 4025 (up to 19330). Ferritin not reported.

COVID-19 status: 8/21 tested positive on swab and 19/21 had positive serology

Treatment: All were given IVIg, following which 5/21 still had fever 36hrs afterwards. They were given a second dose of IVIg and steroids. 15/21 required inotropic support and 11/21 required intubation/ventilation.

Outcomes: Median length of stay was 8 days (rage 5 – 17). There were no deaths.

Three subsequent studies have confirmed very similar presentations of this hyperinflammatory syndrome (PIMS-TS) in children, with initial abdominal pain, fever, diarrhoea and vomiting, progressing to a picture similar to Kawasakis disease but with a significant number developing shock and significant cardiac involvement.

Riphagen, Shelley et al., Hyperinflammatory shock in children during COVID-19 pandemic, The Lancet, May 7th 2020, https://doi.org/10.1016/S0140-6736(20)31094-1

This is the first case series to describe a cluster of children presenting with hyperinflammatory shock during the COVID-19 pandemic.
Eight children aged 4 to 14 years were identified by a paediatric retrieval service based in London in mid-April 2020. Interestingly, of the 8 children, 7 had weights >75th centile. Notably 6 were of Afro-Caribbean descent and 2 were Asian, with no Caucasian children in this cohort. 5/8 were boys. 4 children had exposure to family members with COVID-19.

The clinical presentation was similar to Kawasaki disease, with unrelenting fever, rash, conjunctivitis, peripheral oedema, and extremity pain, in addition to gastrointestinal symptoms. All children developed warm, vasoplegic shock and required inotropic support. Seven children required mechanical ventilation.

Small pleural, pericardial and ascitic effusions, also consistent with a diffuse inflammatory process were also observed. Vascular involvement was demonstrated with echo-bright coronary arteries seen in all children, with a giant coronary aneurysm in one patient. One child died from a large cerebrovascular infarct. Myocardial enzymes were significantly elevated.

A range of investigations were done in all children, and despite this no causative pathogen was identified. Adenovirus and enterovirus were isolated in one child. Four children had known exposures to SARS-CoV-2 in family members, but only two tested positive for SARS-CoV-2 (1 was positive only postmortem). 

In addition to other supportive therapies, all children received IVIG and broad-spectrum antibiotics (ceftriaxone, clindamycin). Six children have been given aspirin.

This clinical presentation may represent a new phenomenon associated with SARS-CoV-2 infection in children and has remarkable similarities to Kawasaki Disease. Following publication of this case series, Evelina London Children’s Hospital has managed >20 similar cases in children. Ten of these children were SARS-CoV-2 antibody positive (unclear which antibody or which test was used).

These findings have garnered particular interest due to the fact that children have otherwise been relatively spared from severe disease due to COVID-19, and here both the temporal association and high proportion of children with seemingly positive serology suggests a possible association with this hyperinflammatory syndrome. Anecdotally, clusters have also been noted in the USA (particularly NYC) and some centres in Spain and Italy. Reports are conspicuously absent from Asia, most notable as Kawasakis disease is more common amongst this population normally. Even more striking is the gross overrepresention of children with an Afro-Carribean background, which given current investigations into the increased incidence of severe adult disease in these communities seems even more pertinent.

As so little is currently known about “garden variety” Kawasakis, it will make defining this disease and its associated with COVID-19 that bit more difficult, but studies are currently ongoing to assess the nature and mechanism of this disease (https://www.diamonds2020.eu/). For now, this cohort doesn’t change the management of childhood COVID-19, nor does it change the management of hyperinflammatory shock or Kawasakis – although the RCPCH have produced excellent guidance for suggested investigations and processes to include these patients in ongoing research.

Paediatric COVID data

First authorLast authorJournalArticle titleDate of PublicationCountryRegion(n) childrenStudy typePaper linkReview
Parri, NBuonsenso, DNEJMChildren with Covid-19 in Pediatric Emergency Departments in Italy01 May 2020ItalyEurope100Clinicalhttps://www.nejm.org/doi/full/10.1056/NEJMc2007617

This report is of confirmed COVID-19 infections in children under 18 years of age who presented to a research collaboration of 17 paediatric emergency departments in Italy between March 3rd and March 27th. The median age was 3.3 years and 57/100 were male. Children under 1 year were overrepresented (40%) followed by children >10yrs (24%).

Helpfully they categorise their patients according to criteria from Dong et. al (see review in Epidemiology top 10): Asymptomatic 21%, Mild 58%, Moderate 19%, Severe 1% and Critical 1%. Only 12% of patients appeared ill on assessment. Interestingly only 4% of patients had Oxygen saturations <94%. Only 38% of children needed admission for severity of illness. There were no deaths. The supplementary appendix includes a huge amount of detailed analysis of the cases, which are summarised below

Clinical features: Fever 54%, Cough 44%, Feeding difficulty 23%, Sore throat 4%, Rhinorrhoea 22%, Diarrhoea 9%, vomiting 10%.

Bloods: Largely unremarkable (although reports of lymphopenia unclear – state 14 patients lymphopenic but that this is 28%? – perhaps only 50 children had bloods, but this is not reported). Procalcitonin <0.5ng/L in 29/23 patients.

Radiology: Chest x-rays performed for 35 children, of which 14/35 had interstitial abnormalities, 6/35 consolidation and 1/35 pleural effusion: remaining 15/35 normal.

Comorbidities: There were 27/100 children with comorbidities – although it appears most had mild illness (did not require respiratory support). This included 6 with cystic fibrosis, 4 neurological, 4 haematological, 4 with a syndrome, 3 with prematurity, 2 with cardiac conditions, 2 immunological, 2 oncological and 1 metabolic disease.

Of the few patients who required respiratory support (9/100) a significant number had comorbidities (6/9), although the rage was broad. This included 2 children with “epileptic encephalopathy”, one of whom also had CHARGE syndrome, a child with autism, a child with a VSD, a child with propionic acidemia, and a child with thrombocytopenia and frequent respiratory infections.

One of the strengths of this study is comparisons across other studies of clinical features of COVID-19 in children. In comparison to Dong et al, CDC data and Lu et al, most features are broadly comparable. Some notable differences are a significantly larger number of infants in the Italian data (40% <1yr compared to 18% in Lu, 12% in Dong and 15.5% in CDC) and a slightly higher number of asymptomatic children (21% compared to 16% Lu, 13% Dong and 1.3% CDC). This most likely represents differences in which population cohorts presented for testing among the different studies – comparisons between cohorts is always difficult currently due to broad differences in the demoninators used. Notably there is no apparent difference in severity according to age in this Italian data, whereas CDC noted increased hospitalisation in children <1yr and Don’t et al noted higher rates of severe or critical illness in infants <1yr.

Broadly speaking this study confirms findings from China and the USA regarding significantly milder illness in children than adults with COVID-19, including many asymptomatic children. Note is made of overrepresentation of children with comorbidities in this cohort (similar to CDC data), although most of these still had mild illness - it is unclear if these children become more unwell, or are more likely to present to be tested.

Tsao, HFearon, DPediatrics Immune Thrombocytopenia (ITP) in a SARS-CoV-2 Positive Paediatric Patient. Pediatrics01 May 2020USANorth America1Clinicalhttps://pediatrics.aappublications.org/content/early/2020/05/19/peds.2020-1419/tab-e-letters?versioned=true

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2. A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications. A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Melé, MLaunes, CjinfLow Impact of SARS-CoV-2 infection among Paediatric Acute Respiratory Disease Hospitalisations21.10.20202SpainEurope110Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30655-1/fulltext

Observational study of children admitted to a Barcelona hospital with acute lower respiratory disease (ALRD) during the first pandemic peak (mid-March to mid-May), comparing those who were SARS-CoV-2 (+) to those who were SARS-CoV-2(-).

Key points

• 125 children with ALRD admitted, 110 consented to be in study

• Only 7 (6%) were SARS-CoV-2 (+)

• SARS-CoV-2 (+) children’s median age was 16.9y: the median for the SARS-CoV-2(-) children was 3.7y

• Co-morbidities: in 2 of the SARS-CoV-2 (+) (1 leukaemia, 1 obesity): in SARS-CoV-2(-) 44% had pre-existing respiratory issues and 13% neurological

• No significant differences were found in the clinical presentation of the 2 groups

• SARS-CoV-2 (+) group had significantly lower WBCs and platelets

• The SARS-CoV-2 (+) child with leukaemia had graft-versus-host and a co-infection with Influenza B and unfortunately died

The children were tested for SARS-CoV-2 when presenting at the hospital. In the 9-week period of the study, 960 children with fever &/or respiratory symptoms were seen and tested and only 56 (6%) were SARS-CoV-2 (+). The authors have then looked at detail at those children requiring admission with ALRD.

Bolanos-Almeida, CSegura, OPIDJ Clinical and epidemiological analysis of COVID-19 children cases in colombia PEDIACOVID20/10/20Colombia South America 5062Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_and_Epidemiologic_Analysis_of_COVID_19.95988.aspx
Dannan, HRamsi, MBMJClinical course of COVID-19 among immunocompromised children a clinical case series15 Oct 2020United Arab EmiratesMiddle East5Clinical - Clinical Featureshttps://casereports.bmj.com/content/bmjcr/13/10/e237804.full.pdf

A case series of five immunocompromised children 2 boys 3 girls, aged 3-12 years from the United Arab Emirates who developed Covid-19 during 2020. They either had mild symptoms or were asymptomatic. They all had a benign course of their illness. None needed a change in their treatment regime nor had a relapse of their underlying condition. The children had prolonged duration of virus shedding post Covid 19 infection. The authors conclude “immunocompromised paediatric patients may not be at a higher risk of developing severe Covid-19.”

Hizal, MCeyhan, M Pediatr PulmonolDiagnostic Value of Lung Ultrasonography in Children with COVID-1921 Oct 2020TurkeyEurope and Asia40Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.25127

This prospective multi-centre study was performed between April and May 2020 at four tertiary paediatric hospitals in Turkey. 40 children up to 18 years of age with confirmed COVID-19, both symptomatic and asymptomatic, had lung ultrasound performed compared to their other chest imaging (x-ray and/or CT) performed at the discretion of their treating clinician.

To minimise bias, bedside point of care lung ultrasounds were performed by a paediatric respiratory physician (‘pulmonologist’) blinded to the child’s symptoms and imaging findings. The ultrasound recordings were independently reviewed by a pulmonologist and radiologist, and when their findings were discrepant, they agreed in consultation on the findings. Chest x-rays and CTs were requested by the child’s treating physicians who were blinded to the lung ultrasound findings and were reported by an ‘experienced’ radiologist blinded to the lung ultrasound findings and clinical presentation. Lung ultrasound findings considered normal included: multiple horizontal A-lines and normal sliding. The presence of three or more B-lines (comet-tail artefacts, representing interstitial syndrome), or confluent B-lines was considered abnormal.

Of the 40 children, median age was 10.5 years with an age range of 0.4 to 17.8 years. Five (12.5%) were under 2 years and 12 (30%) were under 5 years.

All 40 children had both chest x-ray and lung ultrasound performed. Four children (10%) had abnormal chest x-rays with consolidation, lung opacity and pleural effusion.

Twenty-eight (70%) of the children had a chest CT, 12 (43%) of which were abnormal. Bilateral ground glass opacification and consolidation were the most frequent abnormalities seen on CT, mostly in the posterior and lower lung zones.

Lung ultrasound took between 4 and 10 minutes to perform. Eleven (27.5%) of the ultrasounds were abnormal.

Of the 12 children with abnormal CT scans, lung ultrasound was also abnormal for 10 (83.3%). Of the 10 children with abnormal ultrasound and CT, 7 (70%) had normal chest x-rays. Of the two children with abnormal CT but normal ultrasound, the lesions seen on CT were under 1cm in size.

Of the 16 children with normal CTs, ultrasound was also normal in 15 (93.8%).

All 12 children who did not have a CT had normal ultrasounds.

The two most unwell children had abnormal findings on CT, chest x-ray and ultrasound imaging.

Using CT as a standard for ‘disease positive’, ultrasound was found to have the following sensitivity, specificity, positive predictive value and negative predictive values:

CT positive CT negative

Lung US positive 10 1 PPV = 10/11 = 90.9%

Lung US negative 2 15 NPV = 15/17 = 88.2%

Sensitivity

= 10/12 = 83.3% Specificity

= 15/16 = 93.8%

The authors conducted further statistical analysis, including area under the ROC curve and confidence intervals. Confidence intervals were universally wide. The authors compared sensitivity and area under the curve for chest x-ray and lung ultrasound; these were statistically different (McNemar's test: p-value 0.016 and 0.001 respectively). Compared to CT, chest x-rays were falsely negative in 75%, while lung ultrasound was falsely negative in 16.7%.

The authors concluded that although bedside point of care lung ultrasound is not as sensitive as CT, it is still useful in the diagnostic work-up of COVID-19 in children with the undisputable advantage of reducing radiation exposure, minimising nosocomial spread of COVID-19 to other patients and staff by minimising movement around the hospital, and by using easily to disinfect portable ultrasound probe and mobile phone, which can be wrapped in cling film to further minimise contamination.

This study does have several limitations, particularly in that it was a small study, with no control group. The sensitivities, specificities, PPV and NPV have wide confidence intervals (detailed in the paper). A selection bias is also very possible as sicker children are more likely to have been more extensively investigated: some asymptomatic or only minimally symptomatic children did not have CT imaging (although the authors rightly point out that it would have been unethical to have performed CT chests on children in whom their primary clinician didn’t feel it was indicated). And, although portable probes and mobile phones are beneficial from an infection control perspective, the authors say that the image quality may have been compromised.

So what’s the study bottom line? This paper adds to the evidence that although not as sensitive as CT, lung ultrasound is a viable imaging modality in the investigation of COVID-19 in children, with fewer false negatives than x-ray and the benefit of not exposing children to ionizing radiation.

Freeman, MCWheeler, SEJ Pediatric Infect Dis SocImmunocompromised Seroprevalence and Course of Illness of SARS-CoV-2 in One Pediatric Quaternary Care Center01 Oct 2020USANorth America485Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa123/5922694

Study of seroprevalence in 485 immunocompromised children at a paediatric quaternary centre in Pittsburgh, USA, between March and July 2020 (median age 11.9 years, range 0.79-18.9). Testing was done on residual serum taken for other reasons, and the authors point out that this limits the capacity to compare infection rates from their results to the entire paediatric population or to make comparisons between groups. 5 patients (1%) had SARS-CoV2-IgG antibodies (control population from same institution, 0.6%). 27.2% reported prior febrile or respiratory symptoms. 15.7% had a nasopharyngeal swab. 2 patients had rheumatological conditions, 2 solid organ transplant, and 1 solid organ malignancy. None required respiratory support, intensive care, or died. Only 2 patients had a positive NPS and one of these was seronegative (though the time interval between symptoms and blood test may have allowed waning of antibody levels in this case). In this study, all paediatric patients with exposure to SARS-CoV-2 based on the presence of IgG antibodies had relatively minor illness in contrast to reports in immunocompromised adults who seem more likely to be admitted and to have poorer outcomes than children.

Denina, MGarazzino, SPediatr Infect Dis JSequelae of COVID-19 in Hospitalized Children: A 4-Months Follow-Up29 Sep 2020ItalyEurope25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Sequelae_of_COVID_19_in_Hospitalized_Children__A.96024.aspx

This paper is a short report of a study that followed up children hospitalized with COVID-19 in a children’s hospital in Turin, Italy over a 4 month period, and assessed them for sequelae of infection.

Patient cohort: 25 of the 28 patients admitted with COVID-19 between 1 March and 1 June enrolled in the study, 13 male and 12 female. The age range was 0.4 to 15 years, with a median age of 7.75 years. All patients had a SARS-CoV-2 positive nasal swab on admission; 28% were described as having mild disease, 56% moderate disease and 16% severe disease. 52% of the patients had an abnormal lung ultrasound on admission showing a diffuse interstitial pattern, with 38% of these also having multiple area of subpleural consolidation. None were diagnosed with related multi-system inflammatory syndrome.

Follow-up: Patients were followed up 2 weeks post-discharge by telephone, with a subsequent medical examination together with bloods, lung ultrasound and nasal swab on average 35 days (IQR 19-46 days) after discharge. The authors report further follow up by telephone, and in person in some cases, up to 4 months post-discharge.

Imaging: 5 children continued to have abnormal lung ultrasound scans at first follow up, with 2 having persisting consolidation. Of these 2, one had resolved on repeat scan a month later. The other patient had cystic fibrosis and the ongoing lung abnormalities were felt to be related to this underlying condition.

Blood analysis: Most blood markers had normalised at first follow up, with the exception of 5 patients who continued to have some raised inflammatory markers (fibrinogen, ferritin, ESR, D-dimer). These were reported to have normalised on 2nd follow up at 6 weeks post-discharge.

SARS Co-V-2 detection: All nasal swabs were negative for SARS-CoV-2 at first follow up. 20 patients (out of 24 tested) were IgG positive on follow up, 4 were negative (despite positive nasal swabs on admission).

Summary: The findings of this study are positive and reassuring, with the authors reporting complete recovery of all patients and no sequelae of infection 4 months after discharge. This paper is a short report and the authors focus on presenting their laboratory and imaging findings. There is no information about what questions were asked at follow up and what the medical examination involved, so we have a somewhat limited picture of overall health outcomes. This study covered a broad age spectrum, however the cohort was small. Data supportive of these findings from a larger number of children is needed to add weight to the evidence that the prognosis of COVID-19 in children, even those needing hospitalisation, is good.

Bixler, DKoumans, ECDC MMWRSARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 202018 Sep 2020United StatesNorth America121Clinical - Clinical Featureshttps://www.cdc.gov/mmwr/volumes/69/wr/mm6937e4.htm

This Morbidity and Mortality Report from the CDC describes the deaths in children and young adults (<21 years of age) associated with SARS-CoV-2 in the United States (US).

Overall, 121 SARS-CoV-2-associated deaths have been reported in the US to July 31st 2020. When stratified by age: 10% occurred in children <1 year, 20% in children 1-9 years and 70% in children and young people 10-20 years of age. Of the 121 deaths, 63% occurred in males, and the most common ethnicity was Hispanic (45%) followed by non-Hispanic Black (29%). The definition of a “SARS-CoV-2” associated death was left to the jurisdictions reporting the deaths, so it is unclear precisely how this is defined; a not-trivial issue given half of deaths in the UK of children who had tested positive for SARS-CoV-2 were deemed not attributable to the virus (being infected was incidental).

Comorbidities were present in 75% of children who died. The most frequently reported medical conditions included asthma (28%), obesity (27%), neurological and developmental conditions (22%) and cardiovascular conditions (18%).

This report is consistent with previously published data showing higher mortality in individuals of Hispanic or Black ethnicity and in those with comorbidities.

Biko, DMRapp, JBPaediatr RadiolImaging of children with COVID-19: experience from a tertiary children’s hospital in the United States18 Sep 2020USANorth America313Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04830-x

This study looked at 313 SARS-CoV-2 positive children from Children's Hospital Philadelphia and affiliated hospitals with specific attention to radiological imaging performed. Only 55 had any imaging performed, with 51 children having chest X-ray and US, MRI or CT was performed for 23. children Of the 55 children with imaging, 10 met criteria for MIS-C (PIMS-TS).

Of the chest x-ray findings, one third showed abnormalities. The most common finding was related to pneumonia with interstitial opacities or alveolar opacities (total 32 cases). The interstitial opacities were mostly diffuse 10/16. Alveolar opacities were seen in 27% (14/51) of children with xrays. Children with MIS-C were more likely to have interstitial opacities (8/16) and/or pleural effusions (4/5) on chest x-ray.

Of the ten ultrasounds performed, aside from one showing acute appendicitis and another with non-obstructing renal calculi; there were no acute abnormalities.

Treatment data was also collected for the 55 patients who had imaging. Almost all (89%) required hospital admission (range 1->76days), broad spectrum antibiotics were given to 12 (22%).

Overall, most children with SARS-CoV-2 did not require hospital admission or further imaging during their care.

Vann, AMullan, CAm J Emerg MedA case series of pediatric croup with COVID-1915 Sep 2020North AmericaNorth America3Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490245/pdf/main.pdf

This series of three cases from Children's Hospital of the King's Daughters and New York Presbyterian Hospital were found through a retrospective review of children with positive SARS-COV-2 nasopharyngeal RT-PCR swab who also required nebulised non racemic epinephrine (NRE, also known as 1:1000 nebulised adrenaline) in ED. It is important to note that at the time frame searched from 1st March to July 31st 2020, the practice at these hospitals was not to perform SARS-CoV-2 testing for children if they were deemed to have a viral illness and were able to be discharged.

The three cases identified were an 11mo African American boy, 2 year old caucasian female and a 9yo female. All cases were negative for other common viral causes of croup at the time. The presentations appeared to be more prolonged and less responsive to nebulised treatment than usual croup cases with all requiring hospital admission, receiving 3 or more doses of nebulised epinephrine and all receiving >1 dose of dexamethasone due to prolonged time to resolution of stridor at rest. The 11mo boy had 1 day history of symptoms no known sick contacts and the 2 yo girl had two family members with URTI symptoms) (unknown SARS-CoV-2 status and presented with 2 days of symptoms. However the 9yo girl had a mother with positive SARS-COV-2 test 3 days prior to developing symptoms but had been advised not to present to ED until developing respiratory distress- so was seen in ED 7 days from time of symptoms onset. She was the most severe case and was initially managed in an adult ED with racemic epinephrine, codeine and lorazepam iwith initial improvement but represented 12 hours later with return of stridor at rest. She was subsequently transferred to the paediatric hospital, admitted to ICU, failed a trial of BiPap but had improvement after a second trial of Heliox with IV midazolam for anxiolytics. She required 22 hours of helix and dexmedetomidine infusion. She received 6 hours dexamethasone, had an initial dose of Ceftriaxone and given 5 days of IV Remdesivir. She required 4 days of PICU admission with intermittent helix and benzodiazepines for air hunger and respiratory distress and was able to be discharged the subsequent day. She had recovery by one week after discharge. Following these findings, the hospitals have subsequently started testing for SARS-CoV-2 in all children presenting with croup. Whilst more data is required to further understand the presentation of children with SRS-CoV-2 and croup, these cases suggest children with SARS-CoV-2 who do require nebuliser epinephrine tend towards more severe courses of illness.

Chong, CThoon, KClin Infect DisSaliva is not a useful diagnostic specimen in children with Coronavirus Disease 201914 Sep 2020SingaporeAsia18Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1376/5905581

This important pre-print letter from Singapore describes 18 children, 12 asymptomatic, mean age 6.6years, 10 of whom were boys. 53 paired samples of saliva and nasopharyngeal swabs were taken between 22 June and 22 July 2020 during the children’s admission, mean 3.1 paired samples per child.

The detection rate of COVID-18 was significantly lower in saliva than in nasopharyngeal samples with the best sensitivity of only 52.9% in the saliva samples taken between days 4-7.

The authors conclude that “saliva is not a useful specimen for diagnosing COVID-19 in children”

Nino, GLinguraru, GMPediatr PulmonolPEDIATRIC LUNG IMAGING FEATURES OF COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS14 Sep 2020Systematic review and metanalysisSystematic review and metanalysis1026Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.25070

Nino et al conducted a systematic review of the literature using PubMed from 1st December 2019 to 11th July 2020 to describe lung imaging features of COVID-19 in children. They included studies that were peer-reviewed and including children aged 0-18 years with confirmed SARS-CoV-2 on reverse transcription PCR with chest imaging. If a study described both adult and paediatric cases, it was only included if paediatric cases were reported separately. Single case reports and literature reviews were excluded. 3278 articles were found and after various exclusions, the authors were left with 29 studies. They found chest x-ray descriptions were not consistently reported, with no studies describing ultrasound findings, and so when they extracted data for meta-analysis they chose to only analyse CT findings. The 29 studies had a pooled sample size of 1026 children with a mean age of 6.57 years (range 1.5 – 14.5 years).

Their findings boil down to:

• Just over a third of children had normal CT chests (35.7%l; 95% CI: 27.5%-44%). The authors compared this to a recent meta-analysis of lung CT changes in adults, stating that children are 3 x more likely to have a normal CT.

• Just under a third had bilateral lung involvement (27.7%; 95% CI: 19.9%-35.6%).

• The most common finding was ground glass opacities, reported in a little over a third of cases (37.2%; 95% CI: 29.3%-45%), somewhere in the region of half as common as in adults with COVID-19.

• The second most common finding was consolidation or pneumonic infiltrates in approximately one fifth of cases (22.3%; 95% CI: 17.8%-26.9%).

• All other lung CT findings reported in adults with COVID-19 were very uncommon (e.g. halo sign, interstitial changes, interlobular septal thickening, bronchovascular bundle thickening, crazy paving pattern, lymphadenopathy, pleural effusion or pleural thickening).

• Findings typically found in other paediatric respiratory infections, such as hyperinflation, were not seen.

The authors describe several limitations, the biggest being that only CT findings were described, despite the fact x-ray is more frequently used in children. They were also unable to correlate imaging findings with disease severity due to the lack of clinical data in the papers studied. Although the data analysed was from multi-national datasets, the majority were from China, particularly near Wuhan, and so were less international than on first appearances. The authors also explain that radiologists from different parts of the world use different terminology, giving the example “shadow” being often used to describe lung opacities, without specifying whether these were ground glass opacities, pneumonic infiltrates or something else. Perhaps more topically, there were no studies including lung imaging findings in Pediatric Inflammatory Syndrome.

What can we take away from this paper? There are two messages:

• lung CT findings in children with COVID-19 are less frequent and less severe than in adults

• typical changes seen in other paediatric viral respiratory infections do not seem to be present in children with COVID-19

This information may not be particularly useful in clinical practice, except in severely unwell children with COVID-19. Given the risks associated with ionising radiation, plus the not infrequent need for sedation, CT is not commonly used in children with COVID-19, except in extreme cases.

Han, MSChang, SHJAMA PaediatrClinical Characteristics and Viral RNA Detection in Children With Coronavirus Disease 2019 in the Republic of Korea28 Aug 2020KoreaAsia91Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2770150

This Korean case series examined children aged 0-18 years with COVID-19 who presented across 22 facilities (20 hospitals) from February 18-March 31st 2020. It focuses on clinical features and duration of SARS-CoV-2 RT-PCR detection. A total of 91 were identified by SARS-CoV-2RNA RT-PCR on nasopharyngeal/oropharyngeal or sputum swabs due to testing for one of the following reasons: symptomatic, close contact with a confirmed case, testing as apart of outbreak or screening on return from overseas.

Demographics included 53 (58%) male cases, with the median age being 11 years (range 27 days - 18 years). The majority (85, 93%) were previously well. Of the 6 with underlying medical conditions, 3 had asthma and epilepsy respectively.  Exposure was from a household contact in 57 (63%) of cases, with 15 (17%) imported, 11 (12%) cluster-associated, 4 from another contact and 4 remaining an unknown source.

Cases were mostly mild (46, 51%) or asymptomatic 20 (22%). There were 20 moderate, 2 severe cases and 3 unclassified. No children required mechanical ventilation. Fever ≥  38 as seen in 27 (30%) of patents, 54 (60%) had cough or coryza , 8 had loss of smell or taste, 5 had anosmia and 16 (18%) had gastrointestinal symptoms including diarrhoea and abdominal pain. Only one patient had gastrointestinal symptoms without fever or respiratory symptoms. Two thirds of children had symptoms prior to diagnosis (median time 3 days). The duration of symptoms for cases lasted a median of 11 days (range 1-36 days).

The children were tested for SARS-CoV-2 repeatedly to determine cessation of virus RNA detection, however intervals were not standardised, with a median of 3 days (range 1-15 days). Children who were asymptomatic had virus RNA detectable for an average of 14.1 days, and those with URTI or LRTI symptoms, at 18.7 and 19.9 days respectively (difference between these groups was not significant). Twelve children were given treatment with lopinavir-ritonavir and two with hydroxychloroquine. There was no difference in detection between the groups treated with the antiviral lopinavir-ritonavir or not.

This study confirms what many previous studies have demonstrated, which is that children with SARS-CoV-2 can remain PCR positive for prolonged periods. This study adds that this is also the case for children who do not develop symptoms. What is unclear is for how long this represents live virus with replicative potential. Culturable virus has not been detected beyond day 8 of symptoms. The authors of this study did not provide ct values which would enable some estimate of the presence of culturable virus (low ct values usually represent viral fragments).

Oterino Serrano, CBret-Zurita , MEur J RadiolPediatric chest x-ray in covid-19 infection26 Aug 2020spain Europe44Clinical - Clinical Featureshttps://www.ejradiology.com/action/showPdf?pii=S0720-048X%2820%2930425-3

Introduction: This is a radiological case series of the chest x-rays of 44 paediatric patients with confirmed SarsCoV2 infection from a tertiary paediatric hospital in Spain.

Patients <16 years from, 13th March to April 6th 2020, with positive PCR who had a clinical need for a chest x-ray were included. The indication for x-rays were not reported, so the precise nature of this cohort is unclear. All patients were admitted to hospital, so these findings likely represent the most unwell children with COVID-19. Two paediatric radiologists retrospectively and independently reviewed the chest x-ray films to determine the abnormality, distribution and evolution, if repeat x-ray was available.

Patient demographics : Of 44 patients, 29 were male (65.9 %). Median age was 79.8 months (2 weeks – 16 years). 23 (52.3%) had an underlying condition; cardiomyopathies (13.6 %), nephropathies (9%), history of prematurity (6.8 %), liver and renal transplantation (4.5 %), and neoplasm (4.5 %).

Radiological findings : 38 (86%) x-rays had peri-bronchial thickening, mainly perihilar (81%). Ground glass opacities (GCO) occurred in 40%. Consolidation was seen in 8, and a pleural effusion in 4. Four children had a normal chest x-ray. Most children recovered quickly and were discharged. Persistence or worsening of symptoms was observed in 15.9 % of the patients (7/44), they had new consolidation or worsening of features on their repeat x-ray. Unfavourable outcomes were more frequent when initial X-ray had bilateral involvement, diffuse affectation and combination of peri-bronchial cuffing and GGOs.

Conclusion: Most children with symptomatic COVID 19 requiring admission to hospital had some chest x-ray abnormalities, mainly perihilar thinking and ground glass opacities. In general the chest X-rays of children with Covid 19 are non-specific, and not sensitive to the disease.

Yonker, LFasano, AjpedsPediatric SARS-CoV-2: Clinical Presentation, Infectivity and Immune Responses19 Aug 2020USANorth America192Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31023-4/fulltext

This is an observational cohort study from Massachusetts General Hospital, Boston, USA

192 "children" (ages were 0-22 years) were enrolled when they presented with possible Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) at urgent care clinics (with symptoms or because of contact with a case) or were hospitalised with confirmed/ suspected SARS-CoV-2 or Multisystem Inflammatory Syndrome in Children (MIS-C). Dates of enrolment are not given.

Samples were collected after consent/assent: Nasopharyngeal swabs (83 samples), oropharyngeal swabs (105) and blood (100). Viral load was determined from respiratory and plasma samples, and ACE2 expression in the upper airways from the swabs.

Results

125(65%) children were SARS-CoV-2 negative, 49(26%) had acute SARS-CoV-2 infection and 18(9%) had MIS-C. MIS-C children were more likely to be younger and male.

.80% of the SARS-CoV-2(+) children had a known household contact but so did 44% of the SARS-CoV-2(-) and 45%of the MIS-C children. SARS-CoV-2(+) and (-) children presented similarly with non-specific symptoms, and anosmia occurred in 20% of the SARS-CoV-2 (+) group. MIS-C children most commonly had fever, followed by nausea and vomiting, and rash. There was no significant prevalence of any co-morbidities in any of the groups

Viral load in the respiratory samples of the SARS-CoV-2(+) was comparable to adults despite mild or absent symptom even in the youngest children. A comparison is made between children within 2 days of symptom onset and hospitalised adults after 7 days of symptoms, which is unhelpful as these time points are clearly not comparable (viral load rapidly decreases after onset of symptoms).

SARS-CoV-2 antibody response data is presented and is said to show a generalised enhancement of humoral immune responses as a marker of severe MIS-C

ACE2 gene expression of the upper airway was quantified by NP/OP swabs from both infected and non-infected children. ACE2 levels were higher in those with infection of SARS-CoV-2 and those with MIS-C (difference 10-4 – 10-5 log, p=0.004), and there was an increase of ACE2 expression with age, although with high variability. There was no association between ACE2 expression and viral load.

In summary, this study confirms a number of already known elements regarding children with COVID-19 or MIS-C, including that viral loads appear comparable to adults and that many symptoms are non-specific. This study confirms increasing ACE2 expression with age, which may in part explain reduced susceptibility to acquiring infection. Of interest is lack of correlation between viral load and ACE2 expression. Despite strong claims about transmission by the authors, the study does not address this question or add new information on this point.

Carter, MShankar-HariNat MedPeripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection18 Aug 2020United KingdomEurope25Clinical - Clinical Featureshttps://www.nature.com/articles/s41591-020-1054-6.pdf

This study examines the peripheral leukocyte phenotype of children with multi-system inflammatory syndrome in children (MIS-C).

A total of 25 children with a median age of 12.5 (range 7.7-14.4) were included. Clinical features of MIS-C were most commonly gastrointestinal symptoms (72%), polymorphous non-blanching rash (48%), and bilateral non-purulent conjunctivitis (40%). Only 2 (8%) children met criteria for Kawasaki Disease. Of note, 7 (30%) had coronary artery aneurysms. Treatments during admission included high-dose corticosteroids (80%), intravenous immunoglobulin (92%) and biologic agents (56%). Majority (84%) required admission to the paediatric intensive care, however only 2 (8%) of children required mechanical ventilation. Only 1 child (4%) was positive for SARS-CoV-2 PCR, however 17 (68%) were SARS-CoV-2 IgG antibody positive.

Leukocyte phenotyping was done during the acute (n=23), resolution (n=14), and convalescent (n=10) phase of illness. In the acute phase of illness, elevated levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T an B cell subset lymphopaenia were observed. In addition, there were decreased levels of HLA-DR and CD86 expression on antigen-presenting cells. Interestingly, the differential expression of these markers and elevated cytokines resolved as the child recovered.

This important study demonstrates that MIS-C is a distinct immunopathogenic illness. Future studies including larger cohorts of children will be critical in rational development of future therapies for this condition.

Swann, OSemple, MBMJClinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study17 Aug 2020UKEurope651Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/370/bmj.m3249.full.pdf

This large prospective observational study from 260 hospitals in the UK examines the clinical characteristics of children (<19yo) hospitalised with laboratory confirmed SARS-CoV-2 infection between 17th January and 3rd July 2020; as part of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK cohort. The main outcome measures were admission to critical care, in-hospital mortality and MIS-C.

Results;A total of 651 children admitted to 138 hospitals were included; median age was 4.6 (IQR 0.3-13.7); 35% were <12 months of age. Of patients with recorded ethnicity 57% were white, 12% south asian and 10% black. 56% were male and 42% had identified co-morbidities. 

Symptoms;The most common symptoms were fever (70%), cough (35%) nausea / vomiting (32%) and dyspnoea (30%). Three distinct clusters of symptoms were identified: - a discreet respiratory illness - cough, fever, dyspnoea, coryza and wheeze - a mucocutaneous enteric illness - headache, myalgia, sore throat, vomiting, abdominal pain, diarrhoea, fatigue, rash, lymphadenopathy and conjunctivitis - a rarer neurological ilness - seizures and confusion

Critical care and mortality;Critical care admission occurred in 18% (116/632); 8% received inotropic support; 9% received non-invasive and invasive ventilation respectively. Children of black ethnicity had higher odds of critical care admission (OR 2.82). Infants <1mo (OR 3.21, 95% CI 1.36-7.66) and children 10-14 yo (OR 3.23, 95% CI 1.55-6.99) were also more likely to be admitted to critical care. Co-morbidities including prematurity, respiratory and cardiac co-morbidities and obesity were more common in those with critical care admission compared with those receiving ward care.Six (1%) of patients died in hospital, all had serious comorbidities; 89% of children had been discharged alive and 10% remained in hospital at the time of reporting.

MIS-C;Based on the preliminary WHO case definition, 11% (52/456) of admitted children fulfilled diagnostic criteria for MIS-C. Children with MIS-C were older than those without (median 10.7 yo vs 1.6 yo) and were more likely to be of non-white ethnicity (64% vs 42%); obesity was also more common amongst those with MIS-C (10% vs 2%). Children with MIS-C were more likely to require critical care admission (73% vs 15%), receive inotropes (51%), invasive (27%) and non-invasive (35%) ventilation. There were no deaths due to MIS-C.

Of children with MIS-C differences were noted between those who were SARS-CoV-2 PCR positive (acute phase of infection - 56%) and those who were antibody positive (post-acute phase of infection - 44%). Antibody positive MIS-C patients were more likely to be of non-white ethnicity (90% vs 45%), less likely to be obese (0% vs 19%), and more likely to have conjunctivitis (71% vs 16%) and abdominal pain (95% vs 44%) compared to those who were PCR positive. Dyspnoea was more common in PCR positive patients (52% vs 14%). Cardiac complications were also more common in the antibody positive group (75% vs 35%).

Conclusion;The findings of this large prospective study are consistent with previous studies indicating that children represent a small proportion of hospitalised cases of COVID-19 (0.9% here), that outcomes in children are generally favourable and that death due to COVID-19 in children is rare. Similar to previous studies, fever and cough were the most common symptoms, although gastrointestinal symptoms (35%) were more common in this cohort; the identification of a mucocutaneous-enteric symptom cluster with overlap with WHO MIS-C criteria is a novel finding here. Children of black ethnicity were over-represented in overall cases, as well as amongst children admitted to critical care units, consistent with adult data from the UK. Similarly, obesity was associated with increased risk of critical care admission. 

The association of MIS-C with older age and non-white ethnicity are consistent with previous studies. In addition to current WHO criteria, fatigue, headache, myalgia, sore throat and low platelet count were all associated with MIS-C.  The demographic and clinical differences identified between MIS-C patients who were antibody positive compared with those who were PCR positive suggest a spectrum of clinical presentation that varies according to phase of infection and immune response.

Liu, XChen, JJ Infect DisClinical and epidemiological features of 46 children under 1 year old with coronavirus disease 2019 (COVID-19) in Wuhan, China: a descriptive study 06 Aug 2020ChinaAsia46Clinical - Clinical Featureshttps://watermark.silverchair.com/jiaa472.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArgwggK0BgkqhkiG9w0BBwagggKlMIICoQIBADCCApoGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMRenTM0H7AWkHfH5OAgEQgIICa-S2TrctCjayBEO6MxumGRv8cRCshq5YspREyle7HGSz423KjAOkoj9JVSjYnFYK-4AQk_PsUNKgNEiFcKtzxQmmPcFQb4_qXmXXRN7VEKAErKU6bCp94py_9BedSlJbOqx2wvSTyzCA3lx5EpyXjnzmnkGejTdhXYkihOkNa25518np1FWNH7Q3yt3fdkYKfpw-iC8JoXgTZeJUTVn3gwt2t62nwQFHoHNkpQN4lkSFOLRJgvs_n1BJODja2d5JhsOn8kwMg0iQNMzsqNjtaeRa9DjqjejOXaabpQIBrBHGf6HmCENuAy3DkuJTHMSPhMzvScKHa3aTV6n6ue80OZIFX__w-ak7J6YVTNidfBkPIWXL0dX3jVSJlz43rmZLjNi6ybjK5MJA3nBqcN0_ooufj4DNH649asuiXPGEYzuhWfKaIcszBlAIDDIofvOdkMo5B5f1FKWwO-dugrZaOeuO94nPclWiKD5_B_qZX45eBO_a00oSKZYejJho2I6-z19l7qtekqRqIb9ETv4zrSqcguK2sP7wctnmntr3DirqK6Pdp3xs7UCoS_TOvmZgV2o8K8KEMZWHykkK-Zt_Aw5bJNT6_T8-WqNd9saE5ic49bnVRsItNtTaiOqmTjWaOzwvdObd69sTvy6acaya1fL2N5e0fveNorCnz-5AJZtgg0cXZH9mh1Y72xmTPA8EaGRhPoIZ8tNbSfWs21pVDfFoGJNRUhMM1HpJ6V62jpoQ1mDPS-_QD3KqpStGg4QOgyv60xYT3iPz0MND03xLjlqIbbqH-dXQ7w6vuBS_PTgaW7Wa_pduFkGIY_c

This restrospective case series study analyses the clinical features of 46 infants less than 1 years old who were confirmed to have COVID-19 at Wuhan Children’s Hospital (China) between the period 26th January 2020 to 15th March 2020. It was not described how these patients were identified for the study. 25 patients (54.35%) were male and 21 (45.65%) were female. The median age was 5 months (IQR 2-7 months). The authors classed 2 patients (4.35%) as having severe or critical disease, 40 patients (86.96%) as moderate disease, 2 patients (4.35%) as mild disease, and 2 patients (4.35%) as asymptomatic. Sadly one patient (2.17%) died (age 10 months), and the remaining 45 (97.83%) were discharged home.

Cough (n=27; 58.7%) and fever (n=16; 34.78%) were the predominant features, with a minority of other patients experiencing vomiting (n=5; 10.87%); Nasal congestion and rhinorrhoea (n=3; 6.52%); dyspnoea (n=1; 2.17%); tachypnoea (n=1; 2.17%); diarrhoea (n=1; 2.17%); and sneezing (n=1; 2.17%).

With regards to complications, the following were found: liver dysfunction (n=20; 45.45%); cardiac injury (n=38; 86.36%); acute gastroenteritis (n=3; 6.52%); multiple organ dysfunction syndrome (n=1; 2.17%); required mechanical ventilation (n=2; 4.35%).

Common laboratory findings included: Lymphocytosis (n=13; 28.26%); raised ALT (n=11; 25.00%); raised AST (n=20; 45.45%); raised lactate dehydrogenase (n=23; 52.27%); raised creatine kinase (n=10; 22.72%); raised creatine kinase MB (n=38; 86.36%); raised CRP (n=8; 19.05%); raised CD3+ T cell (n=10; 28.57%); raised CD4+ T cell (n=14; 40.00%); raised CD19+ B cell (n=16 patients; 47.51%); raised IL-10 (n=15; 44.12%).

Caro-Dominguez, Pvan Rijn, RPediatr RadiolThoracic imaging of coronavirus disease 2019 (COVID-19) in children: a series of 91 cases04 Aug 2020Spain, Italy, France, Iran, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico International91Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00247-020-04747-5

This international multicentre retrospective study of 91 children with confirmed SARS-CoV-2 describes the radiological findings of their chest imaging. Data was included from Spain, Italy, France, USA, Switzerland, Germany, Sweden, Hong Kong, Netherlands, UK and Mexico. Chest x-rays were reviewed independently by 3 senior paediatric radiologists. Chest CT images were evaluated by a different group of 3 senior paediatric radiologists. Impressions were shared and consensus reached for each image.

Of the 91 children, 11% had severe symptoms requiring PICU and 30 (33%) had coexisting medical conditions including 16 immunocompromised children, 7 children with congenital heart disease and 7 with long-term respiratory conditions. Six (7%) children were asymptomatic.

81 (89%) of the children in the study had chest x-rays. Of these, 10% were entirely normal despite the children being SARS-CoV-2 positive. None of the children with a normal x-ray required PICU admission. The most common abnormal x-ray findings were increased central peribronchovascular markings, bronchial wall thickening (47, 58%) and consolidation (28, 35%). Ground glass opacities and interstitial changes were less common in 16 (19%) and 13 (16%) children respectively. Pleural effusion (6, 7%), pneumothorax (2, 2%) and atelectasis (2, 2%) were uncommon.

24 (26%) of the children had a chest CT, mostly adolescents. The most frequent indication for CT was as a screening tool where the wait time for PCR testing was long. 22 (92%) of the CT scans were abnormal. The two most common CT changes were lower lobe ground glass opacification (21, 88%) and consolidation (14, 58%). The patterns seen on CT mirrored those described in adult studies: peripheral ground glass opacities in early stages, with ground glass with consolidation with or without interlobular septal thickening in more severe cases.

Only 3 children had lung ultrasound. One is described in the article as showing the characteristic B lines in the posterior and lateral left lung and pleural thickening. One asymptomatic child had an MRI for another reason which showed characteristic changes of COVID-19. Following this scan she was tested for COVID-19 on the recommendation of the radiologists.

paper contains numerous examples of x-rays, CTs and lung ultrasound images. The authors make several conclusions, which can be summarised in six points: In contract to adult studies, “bilateral, peripheral and subpleural ground glass opacities and/or consolidation” is not the typical chest x-ray finding of COVID-19 in children.Instead, chest x-rays of children with COVID-19 are nonspecific, frequently demonstrating peribronchovascular markings and airspace consolidation, seen in many other lower airway inflammatory disorders, viral infections and pneumonia. They therefore cannot be used to differentiate between COVID-19 and other childhood lung infections and should not be used as a screening tool for diagnosis of COVID-19 If radiographic imaging is required in symptomatic children, chest x-ray should remain the first imaging modality of choice, to assess for infection or pneumonia.Paediatric COVID-19 CT patterns are predominantly lower lobe ground glass opacity, as in adults, plus a more centrilobular or peribronchovascular pattern, not seen in adults, although it is not clear if this is directly due to COVID-19 or coinfection with other respiratory infectious agents. These findings are nonspecific and resemble other lower respiratory tract infections.CT should be reserved for complex cases or when there is clinical concern to assess for possible complications.In general, paediatric lung ultrasound image quality is superior to that in adults due to a thinner thoracic wall, however the role of lung ultrasound in children with suspected COVID-19 is unclear. The authors suggest lung ultrasound should be evaluated as a potential radiographic tool in paediatric COVID-19.

Heald-Sargent, TKociolek, LKJAMA PaediatrAge-Related Differences in Nasopharyngeal SevereAcute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) Levels in Patients With Mild toModerate Coronavirus Disease 2019 (COVID-19)30 Jul 2020AmericaNorth America97Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2768952

This research letter looked at 145 patients aged 1 month to 65 years old who were symptomatic and had positive SARS-CoV-2 RT-PCR on nasopharyngeal swab at a paediatric hospital in Chicago between March 23 and April 27th, 2020. Included were 46 children aged <5 years, 51 aged 5-17 years of age and 48 adults. Cycle threshold values of RT-PCR were measured and compared across the three age groups. A significant difference was found with children under 5 having lower cycle threshold values than children aged 5-17 and adults. The older children and adults had no significant difference found in cycle threshold.

These findings are at odds with most other studies of viral loads in children, which have shown little clinically relevant difference to levels found in adults (or if anything slightly lower levels). The reason is unclear, but this study confirms what was already known, that children carry viruses in their nasopharynx which is potentially transmissible (previous studies have found culturable virus in children). To what extents this correlates with how infectious children may be remains unknown.

Pavel, A.BYassky, EEJACISARS‐CoV‐2 receptorACE2 protein expression in serum is significantly associated with age29 Jul 2020USANorth AmericaClinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/all.14522

This is a peer review letter to the editor of Allergy, where ACE2 protein expression was measured in children and adults with and without atopic dermatitis using a previous cohort and their samples.

Angiotensin converting enzyme 2 (ACE2) is an integral component of the renin angiotensin system SARS COV2 cell entry is facilitated by ACE2. It is proposed that lower prevalence and maturity of ACE2 in children is one of the reasons for less illness, and less illness severity in children .

Methods: This study used samples from a previous published cohort of 19 healthy infants and toddlers and compared to 17 healthy adults and compared to 29 infants/toddlers and 55 adults with moderate to severe atopic dermatitis. Those with atopic dermatitis are not known to have increased susceptibility to SARS COV2. This cohort was generally healthy with no history of cardiovascular disease. None of paediatric control or AD groups had asthma. None of the control adults, but 17 of the AD adults had asthma.

They also investigated Cathepsin L/CTSL1 in both infant/adult and healthy/AD cohorts. CTSL1 is a protease which cleaves and primes SARS-Cov-1 spike protein, and is hypotheseized to play a similar role in SARS-CoV2.

Results: Adults had more ACE 2 expression than infants/toddlers. AD did not influence ACE2 expression. Males expressed ACE2 more than females. In a sensitivity analysis there was a trend towards increased expression of ACE2 in African American adults, and both African American and Asian toddlers.

CTSL1 was significantly greater in adults than infants/toddlers and was positively associated with ACE2 expression.

Conclusion: These results reflect what is already known, that ACE2 expression is higher in adults than infant/toddler and in men rather than women. It also suggests, and reflects what is seen clinically, that atopy does not increase risk of morbidity or mortality for Covid -19

Moraleda, CTagarro, AClinical infectious DiseasesMulti-Inflammatory Syndrome in Children related to SARS-CoV-2 in Spain25 Jul 2020SpainEurope252Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa1042

Clusters of children with a multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) have been reported in Europe and the USA. The authors describe the epidemiological and clinical features in a case series of children with MIS-C in Spain from March 1st to June 1st, 2020. MIS-C is a potentially severe condition that presents in children with recent SARS-CoV-2 infection. Children younger than 18 years with infection due to SARS-CoV-2 and attended at 49 hospitals were included in this registry. Inclusion criteria included positivity in real-time polymerase chain reaction (RT-PCR) positive, IgM or IgG in lateral-flow rapid test, ELISA or immuno-chemiluminescence serology, or severe disease suggestive of MIS-C and recent household contact with a confirmed patient with COVID-19.

Results; In the study period, 312 patients attended 49 hospitals, and 252 participants were hospitalized. Of them, 181 (72%) were admitted due to causes directly or likely related to SARSCoV-2. The remaining 71 (28%) were admitted due to causes not related with SARS-CoV-2, but were screened and found to be infected with SARS-CoV-2. A total of 31/252 (12%) children were diagnosed as MIS-C and/or Kawasaki disease by their physicians.

 

The peak of MIS-C cases were one month after the peak of admissions for other COVID-19 related reasons and decreased afterward.

Median age and interquartile range were 7.6 [4.5; 11.5] years. A total of 30 (97%) children had microbiological or serological evidence of SARS-CoV-2 infection, and the remaining patient, an 11- year old boy with incomplete Kawasaki disease and pericardial effusion, had epidemiological household contact with a COVID-19 adult patient, his father.

The World Health Organization recently released diagnostic criteria for this condition. All the described patients fulfilled the WHO case definition for MIS-C, except for 1/31 patients (3%). Rash or bilateral non-purulent conjunctivitis, or muco-cutaneous inflammation signs were found in 21/31 (67%) patients; hypotension or shock in 15/31 (48%), features of myocardial dysfunction 25/31 (80%) consisting of pericarditis, valvulitis, arrhythmias or coronary abnormalities in 19/31 (61%); 6 (19%) additional children had only an elevation of a biochemical marker of heart dysfunction (NT-proBNP); evidence of coagulopathy (specifically, elevated D-dimers) was found in 29/30 (97%), and acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain), in 27/31 (87%). No other apparent microbial cause of inflammation as sepsis or staphylococcal or streptococcal shock syndrome was found.

One child already on oral steroids for interstitial lung disease did not fit the WHO criteria for raised inflammatory markers but was included as all other criteria were met.

Thirteen children (45%) fulfilled the criteria of complete or incomplete Kawasaki disease.  Twenty (65%) patients needed admission to the Paediatric Intensive Care Unit, and 6/31 (19%) invasive mechanical ventilation. Cardiac complications consisted of myocardial dysfunction (15/31; 48%), pericardial effusion (6/31; 19%); valvular dysfunction (9/31; 29%), arrhythmias (7/31; 23%) and coronary abnormalities (3/31; 10%, among them 1 aneurysm). Four patients (13%) had renal failure.

Two (6%) patients received Remdesivir and 7/31 (23%) Lopinavir/Ritonavir. A total of 21/31 (68%) children received corticosteroids: 19 of these received methylprednisolone (13 patients received doses of 1 to 2.5 mg/kg/day; 2 patients boluses of 8 and 30 mg/kg/day for 3 days; 4 had dosing unavailable), 20/31 (65%) patients received 2 gr/kg of intravenous immunoglobulin (IVIG) and 13/31 (42%) patients received both IVIG and corticosteroids. All but three patients received broad spectrum antibiotics.

One patient with acute leukaemia and bone marrow transplant died, and one 6-month-old patient (with Downs Syndrome) developed anterior-descendant coronary aneurysm (z-score +9). The rest recovered without sequelae.

Limitations of this study include that some cases without microbiological, serological or epidemiological links may not have been included in this registry. 

The authors conclude SARS-CoV-2 could be a relevant trigger for a delayed cytokine storm and an inflammatory condition, with potentially severe consequences. Coinfections as hMPV may be present and might play a role in triggering the immune response. It is possible that some particular patients with special features such as chronic immunosuppressive treatment influencing inflammatory markers - may have MISC but not fulfil all WHO criteria.

Conclusion The authors concluded MIS-C is a potentially severe condition that presents in some children after SARS-CoV-2 infection. Physicians should be aware of this severe condition in children during COVID-19 epidemics. More studies are necessary to clarify the physiopathology of this syndrome and its treatment. 

Comment Even when removing the child without serological evidence of COVID-19 and the child which did not meet WHO criteria in this study, 29/252 or 11.5% of hospitalised patients developed MIS-C which is significant One death was reported in a patient with leukaemia and one complication in a patient with Downs syndrome but the rest of the patients (27/29, 93%) recovered without sequelae.

Prata-Barbosa, ACunha, AJ Pediatr (Rio J)Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study19 Jul 2020BrazilSouth America79Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0021755720301923

Date, patient identification and location. Between 1st March 2020 and 31st of May 2020, 79 patients aged 1 month to 19 years consecutively admitted to 19 pediatric intensive care units in Brazil with confirmed COVID-19 (RT-PCR in 72/79 and IgM and/or IgG antibodies in the other 7/79) and were included. 10 of these patients including 5 that only had positive antibodies had multisystem inflammatory syndrome (MIS-C) .

Age: median age 4 years( range 1 to 10.3 years)

Gender:43/79( 54%) male.

Ethnicity: 58% were white,25% mixed race, 15% black and 1% Asian.

Comorbidities:32/79( 41%) had previous comorbidities with neuromuscular disease predominant (28%) and chronic respiratory disease 19% , congenital heart disease 16%, diabetes 6% , undernutrition 6% and obesity 3%.

Clinical features : most common symptom was fever 59/79 (76%), followed by cough 40/79(51% ), tachypnoea 39/79 (50% )low oxygen saturation 23/79 (29%) , runny nose 17/79 (22%), diarrhoea 16/79(21%), vomiting 16/79(21%) and red throat 3/79(4%).

In MIS-C (n=10) : presentation included Kawasaki like disease 6/10 (60%), acute cardiac dysfunction 2/10(20%), toxic shock syndrome 1/10(10%), Macrophage activation syndrome 1/10(10%).

.Radiology: 42/68 (62%) had abnormal chest radiographs with 25/42(60%) having diffuse interstitial infiltrate. Chest CT with ground glass opacities in 19/38 (50%).

Bloods: Lymphopenia in 21/59(36%) of non MIS-C group and 5/10(50%) of MIS-C group.

Inflammatory markers including ESR,CRP,LDH,D-dimer, procalcitonin and ferritin were tested in varying number of cases but mainly in MIS-C group and were elevated in most tested patients.

Outcome: 32/79(41%) needed only oxygen therapy. Invasive mechanical ventilation was needed in 14(18%) for median of 7.5 days . Comorbidities were independently associated with the need for invasive mechanical ventilation (OR 5.5). Antibiotics , Oseltamivir and corticosteroids were used in 76%, 43%, and 23% respectively . The median intensive care length of stay was 5 days . There were 2 deaths (3% ) both in none MIS-C group. Age less than 1 year was not associated with a worse prognosis and patients with MIS-C had more severe symptoms, high inflammatory biomarkers but only comorbidities and chronic disease were independent predictors of severity.

Comment and Justification: this is the first study on COVID-19 in Pediatric CIU patients in Brazil which currently has one of the highest rates of infection .It has shown that the characteristics of the disease in Brazil are similar to other countries except age less than 1 year was not associated with a worse prognosis.

Kainth, MLorry, GRPediatricsEarly Experience of COVID-19 in a US Children's Hospital17 Jul 2020USANorth America65Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/07/15/peds.2020-003186

is the first comprehensive report from a major US paediatric centre. It describes all admitted cases of COVID-19 in children and young people (CYP) aged 0-22 years, from 23 Jan to 23 April 2020. It comes from the Cohen Children’s Medical Centre, just outside New York City, which serves a relatively deprived urban population. All had SARS-CoV-2 PCR positive antigen tests.

results are broadly similar to earlier reports from China and Europe, but with some interesting detail. Of the 65 admissions, the median age was 10.3 years, but there was a bimodal distribution, with 29% being infants of < 3 months, and 48% older than 12 years. Those with an underlying medical condition were over-represented (55%).

disease severity was considered mild in 60%, moderate in 26% and severe in 14%. Mean duration of hospital stay was 3.2 days. 23 (35%) went to intensive care. The older CYP did worse than the infants: 44% of 16 previously healthy CYP required any sort of respiratory support (1 ventilated), compared to 26% of 19 infants (none ventilated).

with either immunocompromise (e.g. cancer treatment) or chronic illness (e.g. chronic lung or neuromuscular disease) were identified separately. Although over-represented in the admissions, most did well: 21% of the 14 immunocompromised required oxygen or any respiratory support (3 ventilated), as did 44% of the 16 chronically ill (5 ventilated). There was one death, a toddler with advanced neuromuscular disease. Only one developed multisystem inflammatory syndrome (MIS-C).

esity was a significant risk for admission (but not for severity): 58% of the previously healthy children were obese, more than expected for the population.

expected, the most common presenting symptoms and signs were fever (86%), upper respiratory signs (34%), lower respiratory signs (60%), anorexia (40%), myalgia (34%), abdominal pain (17%) and headache (17%). Two had seizures. Anosmia was rare (1). Interestingly, only 4/10 with known asthma presented with wheezing.,

estigation findings were similar to earlier reports. Increased CRP and white cell counts were seen, showing strong associations with disease severity. Chest X-ray abnormalities were more common than might be expected from clinical status: 21 of 43 X-rayed had abnormal findings.

iviral ‘treatment’ of some sort was given to 40%, including hydroxychloroquine, remdesevir, anakinra and corticosteroids. Outcomes so far were good: 83% discharged well, 5% discharged with ‘sequelae’, 11% still inpatients.

this is further evidence, this time from an American population, that Covid-19 is less dangerous in children than adults, and that the prognosis is good in the vast majority. This is in spite of this population’s high prevalence of underlying serious conditions, obesity, and relative deprivation.

Derespina, KRMedar, SSJ PediatrClinical Manifestations and Outcomes of Critically Ill Children and Adolescents with COVID-19 in New York City.16 Jul 2020USANorth America70Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S002234762030888X

This multicenter retrospective observational study from New York City, USA, considers admissions of patients up to 21 years of age to 9 paediatric intensive care units (PICU) in New York City between 14 March 2020 and 2 May 2020. The authors consider 70 patients who are critically ill with COVID-19 positive nasopharyngeal swabs, and present their clinical manifestations, factors associated with PICU admission, and length of hospital stay. The data collection occurred prior to the definition of the multisystem inflammatory syndrome in children, therefore this presentation is not represented in this study.

he median age of patients included is 15 (IQR 9, 19). 61.4% are male. 74.3% had at least one comorbidity. 72.9% presented with fever, and 71.4% presented with cough. Bi-lateral infiltrates were the most common chest X-ray finding (50%). CRP, procalcitonin, lactate, pro-BNP and IL-6 were elevated. ARDS was associated with significantly longer duration of admission. Back/Latino race was associated with higher probability of discharge home by day 28.

NOTE – Some duplication of data :31 out of the 70 patients who are described in this paper have been discussed in other published reports.

Gaborieau, LMadhi, FJ Clin Med 9(7)Epidemiology and Clinical Presentation of Children Hospitalized with SARS-CoV-2 Infection in Suburbs of Paris14 Jul 2020FranceEurope192Clinical - Clinical Featureshttps://www.mdpi.com/2077-0383/9/7/2227

This paper presents the demographic characteristics, presenting symptoms, co-morbidities, and clinical progression of 192 children hospitalized with either confirmed nasopharyngeal PCR for SARS-CoV-2 (157) or strongly suspected but negative PCR (35) in the Ile-de-France département, in and around Paris, during their period of lockdown, from 23/03/20 to 10/05/20. The male:female ratio was 1.3:1. Those aged <1 made up 49% of the group, and those under ≤1 month, 17.7%. 29.2% had an underlying medical condition. Twenty four (12.5%) required PIC, 19 required ventilatory support (12 by mechanical ventilation) and 3 died.

Wardell, HDixit, AJ Pediatr Infect DisSARS-CoV-2 Infection in Febrile Neonates09 Jul 2020USANorth America4Clinical - Clinical Featureshttps://academic.oup.com/jpids/article/doi/10.1093/jpids/piaa084/5869489

Case reports of 4 term male neonates presenting with fever and testing positive for SARS-CoV-2, in Boston, USA, between 17/04-06/05/20. All infections were likely to have been acquired postnatally from close household contacts. Two had co-infection (1 E. coli UTI, 1 human metapneumovirus). All made a full recovery after a brief illness but 1 was still shedding virus when last tested (20 days). One had evidence of myocardial dysfunction which was postulated to be consistent with a pulmonary immunovascular coagulopathy model. This neonate did not have any co-infection and was treated with remdesivir; claimed to be the first reported use of this drug in a neonate. The only neonate with lymphopenia was that co-infected with hMPV. Authors advise continuing to screen febrile neonates for other infections even when there has been close contact with a proven case of SARS-CoV-2 and the neonate itself is positive.

Yudan, DWenbin,GFront PediatrClinical Characteristics of Children With COVID-19: A Meta-Analysis03 Jul 2020ChinaAsia396Clinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00431/full

This is a meta-analysis of papers published between 1 January and 1 April 2020 undertaken by Chinese authors. The authors undertook a literature search and identified 121 papers worldwide, only 33 studies met the inclusion criteria and more than half these were case reports. Interestingly all the included papers were from China.

396 children in total were identified with an age range 0-17 years (mean 5.5 years), just over 60% were >5 years old, 58% were male. 6.1% of all the included children had underlying diseases. In terms of the transmission route, 86.4% of the children with COVID-19 had close contact with family members with COVID-19 and 10% tested positive for other pathogens, such as influenza virus types A and B and Mycoplasma pneumoniae.

Fever (51.2%) and cough (37.0%) were the most frequent symptom, 17.4% of the children had asymptomatic infections. Furthermore, 66.7% had pneumonia, and 19% had radiologic features of pneumonia but were asymptomatic. Five developed severe or critical illness and required intensive care. The authors report that as of April 1, 2020, two child deaths were recorded in China (a 10-month-old child and a 14-year-old boy) but do not say if these two children were part of the study cohort.

The most frequent abnormal laboratory findings were leukopenia/lymphopenia (28.9%) and increased creatine kinase (20.%). Ground glass opacities were observed on CT scans in 53.9% of the children diagnosed with pneumonia.

The nineteen case reports included 25 patients. Their mean age was 4.6 years 48% were male, and 36% were older than 5 years. 76% of these were in a family cluster. No cases had underlying diseases or other pathogenic infections. Common clinical manifestations included fever (60%), nasal congestion/rhinorrhoea (28%), cough (24%), and digestive tract symptoms (24%). In addition, 11 (47.8%) of the 25 patients had pneumonia, four (16%) were asymptomatic but with imaging features of pneumonia, and one (4%) was critically ill. No deaths were reported. Five (25%) children had GGO on their CT scan. The most prevalent abnormal laboratory finding was increased creatine kinase (58.3%), followed by increased procalcitonin (55.6%), increased LDH (44.4%), and increased white blood cells/lymphocytes (36.8%)

In their discussion the authors conclude “Children are at a lower risk of developing COVID-19 and likely have a milder disease compared with adults. However, the evidence presented in this study is not satisfactory. Further investigations are urgently needed, and our data will be continuously updated.”

Denina,MGarrazino,SPEDIATRICSLung Ultrasound in Children With COVID-1901 Jul 2020ItalyEurope8Clinical - Clinical Features https://pediatrics.aappublications.org/content/early/2020/06/12/peds.2020-1157

Between March 18th and 26th 2020 8 children (age range 3 months to 10 years), 5 of whom were boys were admitted to Regina Margherita Children’s Hospital, Turin with Covid 19 respiratory tract infections. All 8 children had linear array chest ultrasound during routine medical examination. Although the number of patients analysed was small, the high concordance between radiologic and LUS findings suggested that ultrasound may be a reasonable method to detect lung abnormalities in children with COVID-19. The advantage of LUS was that the investigation could be done at the bedside, thus preventing transport of a potential infectious patient through a hospital

Wu, QXing, QPediatricsCo-infection and Other Clinical Characteristics of COVID-19 in Children 01 Jul 2020ChinaAsia74Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/05/04/peds.2020-0961

This retrospective study from 2 hospitals in China examines the clinical and epidemiological characteristics of 74 children with confirmed SARS CoV-2 infection. Consistent with other studies, the majority of children experienced a mild course of illness with only one severe case requiring non-invasive ventilation. All recovered.

Cough was present in 32%, fever in 27% and 40% were asymptomatic at the time of testing. Lymphopenia was present in only 5% of cases. Abnormal CT imaging was observed in 50%, but only 12% showed typical changes of COVID-19.

Of those tested for other respiratory pathogens 19 of 34 had co-infection. Mycoplasma pneumoniae (16) and RSV (3) were the most common pathogens. It is not clear how these pathogens were identified. The significance of Mycoplasma in particular is not entirely clear as asymptomatic upper respiratory tract carriage in children is well recognised; similarly in interpreting serology, false

positives can be problematic.

For cases where exposure history was available 65/68 were household contacts of a confirmed adult case. There was no evidence of transmission from children to others.

This data is consistent with larger paediatrics studies demonstrating a milder course of COVID-19 in children compared with adults. Notably co-infection was not uncommon, illustrating that the presence of another respiratory pathogen should not preclude SARS-CoV-2 testing in children.

Abdel-Mannan, OHacohen, YJAMA NeurolNeurologic and Radiographic Findings Associated With COVID-19 Infection in Children01 Jul 2020UKEurope55Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamaneurology/fullarticle/2767979

This is a retrospective case-series from the United Kingdom of children with neurological symptoms, identified from a larger cohort (n = 55) of SARS-CoV-2 positive children. Of the 55 children, 27 had features of paediatric multisystem inflammatory syndrome (PIMS-TS) and of these, 4 had neurological symptoms.

Clinical Features: The four children had a median age of 12 years (range 8-15 years) and interestingly, two children were of South Asian ethnicity and two of Afro-Caribbean ethnicity. Of the neurological symptoms reported, encephalopathy (4/4), headache (3/4) and brainstem signs such as dysarthria or dysphagia (2/4) were most common. Peripheral nervous system involvement was present in all patients and included proximal muscle weakness (4/4) and decreased reflexes (2/2). Neurological symptoms occurred alongside a range of systemic symptoms but were part of the initial presentation in 2 children.

Investigations: The four children had a range of investigations, including a lumbar puncture (2/4), EEG (3/4), EMG (3/4), MRI (4/4). The CSF was acellular and SARS-CoV2 negative, mild excess of slow activity was seen on EEG, and EMG showed mild myopathic and neuropathic changes. Interestingly, MRI findings were consistent in all four children, and included signal changes in the splenium of the corpus callosum. Three of the four children also had T2 hyperintense lesions associated with restricted diffusion.

Treatments: Therapeutics given varied. Three children received treatment for PIMS-TS more broadly, including methylprednisolone (2/4), dexamethasone (2/4), IVIG (2/4), anakinra (2/4), and rituximab (1/4).

Outcome: At the time of follow-up (median 18 days, range 11-13 days), 2 patients remain in hospital and have residual lower limb weakness and require a wheelchair to mobilise, and 2 patients have been discharged ambulating without support.

Overall, this paper provides a thorough description of neurological features associated with SARS-CoV-2 infection in the setting of multisystem inflammation.

Li, JDai, XJ Med Internet ResIdentification of Symptoms Prognostic of COVID-19 Severity: Multivariate Data Analysis of a Case Series in Henan Province30 Jun 2020ChinaAsia12Clinical - Clinical Featureshttps://www.jmir.org/2020/6/e19636/pdf
Acker, KHan, JClin Pediatr (Phila)Infectious Diseases Diagnoses of Children Admitted With Symptoms of Coronavirus Disease 2019 During an Outbreak in New York City27 Jun 2020North America North America42Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820944399?journalCode=cpja

This is a retrospective review of children with symptoms consistent with COVID-19 who were admitted at a single institution in New York City from March 12th to March 26th. Forty-two children were identified and had symptoms including fever (31), cough (21), increased work of breathing (17) and rhinorrhoea/congestion (16).

Of the 42 children, 5 (12%) had SARS-CoV-2 on nasopharyngeal swab, 15 (36%) had rhinovirus/enterovirus, 4 (10%) had human metapneumovirus 4, and 4 (10%) had bacterial infections. Overall, majority of children (25; 60%) had an infectious agent identified and were SARS-CoV-2 negative. Of the 5 children with SARS-CoV-2, two were neonates discharged within 72 hours with negative bacterial cultures, one was a 7 year old with MRSA bacteraemia and SARS-CoV-2 bacteraemia, one was a 14 year old with leukaemia who presented with fever, and the final patient had acute respiratory distress and required intubation, but was also positive for rhinovirus/enterovirus.

This small study demonstrates that even in the height of the outbreak in New York City, SARS-CoV-2 was responsible for a minority of admissions in children with respiratory symptoms. This highlights the importance of including SARS-CoV-2 in the list of differential diagnoses but ensuring appropriate investigations for viral and bacterial coinfections.

Götzinger, FTebruegge, MLancetCOVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study25 Jun 2020Europe (Austria, Belgium, Bulgaria, Croatia, Denmark, Estonia, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, and the UK)Europe582Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30177-2/fulltext

This European multi centre cohort study recruited from participating centres from  the Paediatric Tuberculosis Network European Trials Groups, to look at 582 cases of paediatric (<18 years old) SARS-CoV-2 infection in 21 countries with 77 healthcare centres. Centres from five additional countries reported no SARS-CoV-2 cases at the time of the study. The breakdown of centres included 454 (78%) tertiary, 54 (9%) secondary and 74 (13%) primary healthcare providers.

Cases were collected retrospectively from known cases prior to 1st April and prospectively between 1-24th April. Diagnosis was made on RT-PCR of SARS-CoV-2 alone. The age group of the population was young, with a median age of 5 (IQR 0.5-12) and 230 (40%) under 2 years of age. Just over half were male (n=311, 53%).

Index case data from history was included, with parents being the suspected index case for 324 patients (56%) and siblings accounting for 24 cases (4%). However a large number of cases (n=234, 40%) were either from someone outside of the immediate family or of unknown transmission.

The most common symptoms patients presented in were fever (n=379, 65%) and respiratory symptoms (n=313, 54% URTI and n=143, 25% LRTI). 128 (2%) had gastrointestinal (GI) symptoms and 40 (7%) had GI symptoms without respiratory symptoms. Asymptomatic patients accounted for 16% of all cases (92). There was confirmed viral co-infection in 5% (n=29) of patients. The study did not capture laboratory values. Chest x-ray was performed in 34% (n=198) of patients. Almost half of the x-rays showed findings consistent with pneumonia and ten (5%) of ARDS.

Of the patients in the study, a quarter (145) had pre-existing medical conditions. Twenty nine patients had pre-existing respiratory conditions (asthma accounting for 16) and malignancy was known in 27 patients. The study collected data on antiviral treatments administered however numbers were small and depended on local practice.

Across the cohort 363 patients (62%) required hospital admission, 48 (8%) required ICU admission. Factors increasing risk of ICU admission (n=48) were found to be age <1 month (n=7/48, 14.6%) the presence of any pre-existing medical condition (n=25/48 52%) and presence of lower respiratory tract infection signs at time of presentation (n=35/48, 73%). Mechanical ventilation was required by 25 patients (4%) and echo was used for 1 patient. Data on treatments given included antivirals: hydroxychloroquine (n=40, 7%), remdesivir (n=17, 3%), lopinavir-ritonavir (n=6, 1%) and oseltamivir (n=3, 1%). Other immunomodulators used were corticosteroids in 22 (4%), IvIG in 7 (1%), tocilizumab (n=4, 1%), anakinra (n=3, 1%) and siltuximab (n=1).

There were 4 deaths (0.69%), all of which were in children >10 years of age. Of the four deaths, one was an out of hospital cardiac arrest.

and two had pre-existing medical conditions; one patient had a stem cell transplant 15 months prior and another patient was managed palliatively due to their pre-existing illness. By time of end study 553 patients had made a full recovery and 25 patients had ongoing symptoms.

Overall, this is one of the first multi-national European studies of SARS-CoV-2 in children. Common symptoms included respiratory and fever but gastrointestinal symptoms were present in over one fifth of cases. Although eight percent of children required ICU admission, the case fatality rate was low at 0.69%. Children at greater risk of intensive care admission had pre-existing medical conditions, were less than 1 month old, or presented with lower respiratory tract symptoms. Asymptomatic infection occurred in 16% of cases. Given that at the time of the study, there were varying practices for screening criteria, it is likely that the true proportion of asymptomatic patients is higher (and true case fatality rate lower).

Zheng, G. Guo, Y.Pediatric PulmonologyClinical Characteristics of Acute Respiratory Syndrome with SARS-CoV-2 Infection in Children in South China.24 Jun 2020China Asia52Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24921
Rossoff, JMuller, WJPediatric blood and cancerBenign course of SARS‐CoV‐2 infection in a series of pediatric oncology patients23 Jun 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/pbc.28504
Gonzales Cortes, Rde Carlos-Vicente, JCIntensive Care Med A multicenter national survey of children with SARS-CoV-2 infection admitted to Spanish Pediatric Intensive Care Units22 Jun 2020SpainEurope50Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00134-020-06146-8

The Spanish Paediatric Intensive Care Society have published their findings of 50 children admitted to 47 PICUs in Spain between 1st March 2020 and 1st May 2020 with SARS-CoV-2. More than 90% of PICUs in Spain were represented in this national database. During the study period there were no deaths from SARS-CoV-2 in children admitted to PICU in the participating PICUs.

The authors divided the children into two groups: those requiring ventilation and those not requiring ventilation, to assess for different characteristics between these groups. Fourteen (28%) of the children were ventilated. Twenty-seven (54%) of the 50 children in the study had suspected PIMS-TS; these children were less likely to require mechanical ventilation (4 of the 27 required ventilation) than those without PIMS-TS. Statistical significance between the two groups was found for age (median age of 2.8 years in the ventilated group, compared to 8.6 years in the non-ventilated group); co-morbidities (12, 24%, of the 50 children had comorbidities; 8 of these were ventilated); and clinical presentation with respiratory difficulties or an ARDS-type picture.

Overall, of the 50 children, 23 (46%) had haemodynamic instability, 20 (40%) had respiratory difficulties and 1 (2%) had neurological symptoms. Shock was present in half of the children (25, 50%), renal failure in 8 (15%) and cardiac dysfunction in 17 (34%).Across the 50 children, white cell count (median 9.26, IQR 5.64-14.46), lymphocytes (median 1.02, IQR 0.42-2.59) and CRP (median 13.9, IQR 4.9-27) were not statistically different between ventilated and non-ventilated children.

These are the preliminary findings from this national registry of children with SARS-CoV-2 admitted to PICU in Spain. Further results and analysis will provide more information regarding critically unwell children with COVID-19.

Rosenzweig, JKaicker, SPediatric Blood and CancerSARS‐CoV‐2 infection in two pediatric patients with immune cytopenias: A single institution experience during the pandemic21 Jun 2020USANorth America2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/pbc.28503
Hildenwall HHerleniusActa PaediatricaPaediatric COVID‐19 admissions in a region with open schools during the two first months of the pandemic21 Jun 2020SwedenEurope63Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303651/
Colmenero ITorello ABritish Journal of DermatologySARS‐CoV‐2 endothelial infection causes COVID‐19 chilblains: histopathological, immunohistochemical and ultraestructural study of 7 paediatric cases 20 Jun 2020SpainEurope7Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19327

Anecdotally, chilblains seem to be associated with Covid-19 in children and young adults. This case series from Madrid describes 7 children (age 11-17) presenting with chilblains on their toes during the pandemic. None had underlying conditions likely to cause chilblains, and in Spain, cold weather wasn’t responsible. The chilblains looked typical, caused only minor pain and itching, and all resolved spontaneously. All had skin biopsies, which showed a variety of inflammatory and vasculitic changes on histology, typical of chilblains: they also looked specifically for SARS-CoV-2 particles in the endothelium of the dermal vessels using immunohistochemistry and electron microscopy and found the virus in all of them.

What is remarkable is that all the children were systemically well, had either mild or no respiratory symptoms; and of the 6 that had nasal and pharyngeal swabs, all were negative for SARS-CoV-2 PCR. Only 4/7 had Covid-19 positive household contacts.The implication is that children can harbour demonstrably invasive coronavirus with minimal symptoms and negative swabs. This has epidemiological as well as clinical significance.

In conclusion, the presence of SARS-CoV-2 in the endothelium of dermal vessels in skin biopsies of children and adolescents with acute chilblains confirms that these lesions are a manifestation of COVID-19. Their clinical and histopathological features are similar to those of chilblains of other aetiologies, and virus-induced vascular damage could explain their pathophysiology. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a role in the pathogenesis of severe forms of the disease. More studies are needed to understand the reasons why previously healthy children, adolescents and young adults present

Heinz, NMartinez, MPaediatr TransplantA Case of an Infant with SARS-CoV-2 hepatitis early afterLiver Transplantation19 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/petr.13778
Xiong, XIp, PJ Pediatr.A Comparison Between Chinese Children Infected with COVID-19 and with SARS18 Jun 2020ChinaAsia244Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301144/

In this study, 244 children with SARS-CoV-2 infection from Wuhan, China are compared to 44 children diagnosed with SARS (SARS-CoV-1) in in Hong Kong in 2003. The clinical details of this series of patients from Wuhan, previously described elsewhere, are compared with those of those of children with SARS-CoV-1. Overall children with SARS-CoV-2 were younger than those with SARS-CoV-1 (median age 82 montsh vs 160 months). Compared with SARS-CoV-1 patients, children with SARS CoV-2 were less likely to have symptoms (20.9% asymptomatic vs 0% of SARS-CoV-1), including fever (40.2% vs 97.7%), myalgia (37.6% vs 0.8%), and chills (32.6% vs 3.7%).

Fewer children with SARS-CoV-2 required supplemental oxygen (4.7% vs 18.6%) and few in either cohort required mechanical ventilation (1.6% vs 2.3%). A single death occurred in a patient with SARS-CoV-2 (a 10 mo with intussusspection) and no cases of PIMS-TS / MIS-C were identified amongst the 244 SARS-CoV-2 infected children from Wuhan.

The most striking difference is the milder clinical illness and relative lack of symptoms in children with SARs-CoV-2 compared with those with SARS-CoV-1. The lack of asymptomatic infections in SARS-CoV-1 is also notable, similar to findings in adults. Whilst the role of asymptomatic patients in the spread of SARS-CoV-2 is unresolved, the milder clinical illness in the majority of patients along with the demonstrated earlier peak in viral shedding relative to symptom onset and resultant role of pre-symptomatic transmission are likely major reasons for the continuing widespread transmission of SARS-CoV-2, where the outbreak of SARS-CoV-1 in 2003 was more readily contained.

Del Barba, P.Barera, G.Pediatr PulmonolCOVID-19 cardiac involvement in a 38-day old infant18 Jun 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/ppul.24895

First (single) case report of an infant with biochemical and echocardiographic evidence of mild cardiac involvement due to SARS-CoV-2 infection. The 38 day old male infant presented to hospital on 27/03/20. Neither the centre nor the country is identified but is likely to be in Italy. Pregnancy had been unremarkable. No delivery details given. Baby was formula fed. Both mother and father were +ve for SARS-CoV-2. He presented with a fever of 37.6oC and rhinitis but no respiratory distress and did not require oxygen therapy. Nasal and nasopharygeal swabs were +ve for SARS-CoV-2. Haemoglobin, lymphocyte count, CRP, ESR, electrolytes, liver transaminases, INR and PTT were normal. Abnormal results: LDH “mildly increased”, platelet count 525,000/μl, procalcitonin 3.28ng/ml, troponin T 8.2ng/dl, creatine kinase-MB 9.8μg/L, D-dimer 13.3 μg/ml, pro-brain natriuretic hormone 208pg/ml, fibrinogen 1.28g/L. CXR showed increased bronchovascular markings but no parenchymal changes (CT not done). A resting heart rate of 140bpm and a transient peak rate of 200bpm were the only cardiac signs (serial ECGs and 24hr recording). First echocardiogram showed no abnormalities but cardiac MR scan showed a “minimal amount” of pericardial effusion with no myocardial edema. Follow up echo 3 days after the first confirmed a 2mm effusion. A panel of other viruses linked to pulmonary and/or cardiac problems in infants was negative. He required no treatment and was discharged after 14 days. Swabs were -ve 21 and 22 days after presentation.

Meethal, LBKociolek, LKj.pedsSARS-CoV-2 Infection in Infants Less than 90 Days Old17 Jun 2020USANorth America18Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30750-2/fulltext
Ekbatani, M. S.Mamishi, S. British Journal of Biomedical Science Atypical and novel presentations of Coronavirus Disease 2019: a case series of three children.16 Jun 2020Iran Asia3Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/09674845.2020.1785102?scroll=top&needAccess=true
Li, YLi, Jpaediatric pulmunologyImmune-related factors associated with Pneumonia in 127 children with Coronavirus Disease in 2019 in Wuhan.16 Jun 2020chinaAsia127Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24907
Stewart, DStojanovic, JLancet. Child & adolescent healthRenal dysfunction in hospitalised children with COVID-1915 Jun 2020UKEurope52Clinical - Clinical Featureshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30178-4.pdf
Ranabothu, SVeerapandiyan, AActa Paediatr.Spectrum of COVID‐19 in Children15 Jun 2020USANorth America1353Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15412
Lanyon, NPeters, MArch Dis ChildhCritical paediatric COVID-19: varied presentations but good outcomes15 Jun 2020United KingdomEurope11Clinical - Clinical Featureshttps://adc.bmj.com/content/early/2020/06/28/archdischild-2020-319602

In this letter from Great Ormond Street Hospital for Children, London, 24 children, who tested positive for Covid-19, were admitted to the intensive care unit between 26th March 2020 and 31st May 2020. Thirteen of these had PIMS-TS. This letter describes the clinical features of the remaining 11.

These 11 had a median age of 5 years (range 0.4-11), 9 were boys, 9 had pre-existing medical conditions, and 4 came from the BAME community. The primary presenting feature was cough 6, apnoea 3, fever 10, gastrointestinal 6 and seizures 3 In all 11 inflammatory markers were raised, median ferritin 898 (range 254-1991), CRP 158 (27-449), LDH 1594 (802-4264) D-Dimer 158 (27-449). 4 children fulfilled the criteria for paediatric acute respiratory distress syndrome, the remaining 7 were admitted to PICU for other reason than respiratory failure. A variety of different forms of respiratory support were provided, invasive mechanical ventilation 9, prone position 4, inhaled pulmonary vasodilators 4, HFOV 2 and ECMO none. 5 children received remdesivir and 6 prophylactic anticoagulation.

All 11 children survived to hospital discharge. The authors conclude “While children can present to PICU with a pattern of illness similar to adult COVID-19 disease this is rare and three quarters of them had risk factors for respiratory infection. A larger number were found to be SARS-COV-2 coincidentally.”

Kanthimathinathan, KJyothish, DHospital PediatricsCOVID-19 - a UK Children's Hospital Experience15 Jun 2020UKEurope45Clinical - Clinical Featureshttps://hosppeds.aappublications.org/content/hosppeds/early/2020/06/06/hpeds.2020-000208.full.pdf
Pan, YZhang, LJIDEpidemiological and Clinical Characteristics of 26 Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Carriers15 Jun 2020ChinaAsia26Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/12/1940/5823633
Lee,HLytrivi,IPediatr TransplantVarying Presentations of COVID-19 in Young Heart Transplant Recipients:a Case Series15 Jun 2020United States of AmericaNorth America4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/petr.13780?af=R

This is a peer reviewed prepublication case report on the experience of Covid-19 among a population of young heart transplant patients from a tertiary centre, Columbia University Irving Medical Centre, New York.

Period Covered: first 3 months of the New York Covid pandemicHospital/Region Covered: the tertiary transplantation programme is one of the largest in the USA covering “hundreds” of patients.

Identification of Patients: 4 patients under the care of the hospital for heart transplantation are included. Case 1 was admitted after referral from secondary care with Covid symptoms and an oxygen requirement.. Cases 2 and 4 presented from home and case 3 was diagnosed during a planned admission for heart biopsy.

Age/Gender: there is a wide age range: case 1 (F)15 years, case 2 (F)25 years, case3 (M)13 months, case 4(F) 29 months.

Comorbidities and immunosuppression: The authors highlight the questions of whether the comorbidities (including immunosuppression) associated with heart transplantation lead to worse outcomes with Covid infection? Also whether immunosuppression has a protective or aggravating effect on outcome and how regimes should be managed?

Two patients (1 and2)also had renal transplants. Case 2 had connective tissue disease (elevated IL-2).

All patients were on various combinations of immunosuppressants (1,2 and 3 on steroids).In only one case (1) was this withheld during infection because of neutropenia.Clinical Features: 3 patients (1,2,3) had symptoms of acute Covid-19 and were nasal/nasopharyngeal positive. Case 1 required supplemental oxygen but no other treatment for 3 days and was then discharged.Cases 2 and 3 did not require admission. Cough: 3/3. Fever: 3/3.Sore throat: 1/3. Abdominal pain: 1/3. All remained well on follow up.

Patient 4 is likely to have had Covid-19 4 weeks prior to admission (symptoms and family history). She presented with a probable post Covid anaemia and hepatitis. She had a rash (acral papular) She was negative on nasal and hepatic Covid assay. Her liver biopsy was consistent with viral hepatitis. Her Covid serology was positive and other viral hepatitis serology negative. She received a blood transfusion

Reported Imaging: CXR:1/4. Normal. Cardiac echo:2/4. No deterioration.

Laboratory: Case1: WCC low 1460/ul, neutropenia (800/ul). ?secondary to immunosuppression or Covid. Elevated inflammatory markers: CRP, ferritin. D-dimer, pro- BNP elevated.

Case 2: no report. Case 3: normal FBC, CRP and LFTs.

Case 4: Hb 6.2 g/dl. Peak ALT elevated 1807 U/L. Peak AST 1070 U/L.

Comment: The centre maintains surveillance (telehealth) of most of it’s patients. Despite possible risk factors of comorbidities and immunosuppression only 4 cases presented. In the acute cases the illness was either mild (2,3) or moderate (1). This is the first report from a paediatric transplant centre and it will be necessary to examine the experience in other centres worldwide.

Case 4 developed hepatitis, anaemia and a rash 4 weeks after probable Covid infection. It is possible that this was Covid related. Viral hepatitis has been reported in a child post liver transplant with acute Covid infection.

Colonna, C.Gelmetti, C.Pediatric dermatologyChilblains in children in the time of Covid‐19: new evidence with serology assay13 Jun 2020ItalyEurope8Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14269
Kesici,SBayracki,BESCFulminant COVID 19 related Myocarditis in an infant12 Jun 2020TurkeyAsia1Clinical - Clinical Featureshttps://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa515/5856627

Clinical Features: 2 year old previously healthy male in contact with Covid19, hospitalized with nausea, vomiting and lethargy. On Day 2 of admission deteriorated with Respiratory distress, filiform pulse and blood pressure was not measurable. There was hepatomegaly. Child was intubated in PICU, while preparing for ECMO went into cardiac arrest. 30 minutes of CPR was performed. During ECMO biopsy of myocardium was taken.

Radiology: Initial CXR – bilateral interstitial infiltrates. Day 2: CXR Cardiomegaly with pleural effusion. ECHO: Severe heart failure

Bloods: Initial bloods negative for inflammatory markers but Troponin was elevated 30 times normal on Day 2.

PCR for viruses were negative including RT PCR for Sars_COV_2 Myocardial Biopsy showed local inflammation, Positive for RT_PCR for COVID 19

Conclusion: Single case report showing the effect of COVID 19 causing heart failure secondary to myocarditis without Kawasaki like syndrome

Zeng, QLYu, ZJTransbound Emerg DisClinical course and treatment efficacy of COVID-19 near Hubei Province, China: a multicentre, retrospective study12 Jun 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/tbed.13674
Jafari, RJavanbakht, MTravel Med Infect DisA 6 months old infant with fever, dyspnea and poor feeding, diagnosed with COVID-1911 Jun 2020IranMiddle East1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1477893920302799
Maltezou, HTsolia, MPediatr Infect Dis JChildren and Adolescents With SARS-CoV-2 Infection Epidemiology, Clinical Course and Viral Loads10 Jun 2020GreeceEurope203Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Children_and_Adolescents_With_SARS_CoV_2.96009.aspx

This study from Greece documents the clinical course and epidemiology of children with laboratory confirmed SARS-CoV-2 infection. Cases were identified from national public health notification data; all children <19yo diagnosed between 26th February and 30th June were included. Schools were closed in Greece from March 11th and gradually re-opened from May 11th onwards. Details including other household cases of SARS-CoV-2 were obtained by parental phone interview.

A total of 203 children with SARS-CoV-2 were included; median age 11yo (range 6 days to 18.4 years); 13% had an underlying condition. Infection was classified as asymptomatic in 111 (54.7%) of children. Children 6-12 years were more likely to have asymptomatic infection (68%); infants were less frequently asymptomatic (22%). Amongst 92 (45.3%) children with symptomatic infection, fever (46%), coryza (28%), cough (26%) and headache (19%) were the most common symptoms; diarrhoea, loss of taste / smell and weakness were reported in 10% of patients respectively. Viral load was not different between asymptomatic and symptomatic cases.

Of hospitalised children (n=24, 11.8%) half were younger than 12 months (median age was 12.2 months); 22% had an underlying condition. Five children required supplemental oxygen, one of whom was admitted to ICU, requiring mechanical ventilation (on a background of spinal muscular atrophy type II). All children recovered. There were no cases of PIMS-TS / MIS-C.

A household contact was implicated as the primary source of infection in 132 cases (65%). An adult was the first household case in the families of 66.8% of confirmed paediatric cases; in 27.2% of cases the child was the only family member infected. Of the remaining cases (n=11, 5.9%), child to adult transmission was evident in 1 case (from a 16 yo girl to her mother); direction of transmission was unclear in the remainder. Despite two thirds of total paediatric cases occurring outside of the national lockdown period, only 4 cases (2%) were determined to have been infected at school.

The findings here are consistent with previous paediatric studies, with COVID-19 following a mild course in the majority and infants comprising a high proportion of paediatric admission. The proportion of asymptomatic cases (54.7%) is higher than some previous reports, although the methodology doesn't clearly exclude the possibility that some pre-symptomatic children were classified as asymptomatic. Importantly, the predominant direction of transmission demonstrated in this study, from adults to children, is consistent with previous epidemiological studies. This finding, consistent across 5 months of surveillance, including periods with schools opened, adds to the body of evidence that transmission between children, and from children to adults, are not the major drivers of SARS-CoV-2 spread.

Marhaeni, WR. S. Mapianto,Indian J PediatrThalassemic Child Presenting with Anosmia due to COVID-19.09 Jun 2020Indonesia Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281692/pdf/12098_2020_Article_3370.pdf
González-Dambrauskas, SKarsies, TPediatricsPediatric Critical Care and COVID1909 Jun 2020InternationalInternational17Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/06/05/peds.2020-1766.full.pdf

In preprint, González-Dambrauskas et al describe 17 children with COVID-19 admitted to international PICUs in Chile, Colombia, Italy, Spain and USA, in April 2020. These are interim results from the CAKE (Critical Coronavirus And Kids Epidemiologic) Study, recruiting between April and December 2020 from almost 60 PICUS in 20 countries. As well as describing the clinical details of each child in detail, this paper also describes four children with myocarditis associated with covid-19.

The 17 children predominantly presented with cough and fever (53% had cough, 76% had fever). Comorbidities were common in 71% of children, including underlying respiratory, cardiac, renal, liver or neurological disorders. Six children (35%) had gastrointestinal (GI) symptoms at presentation.

Of the four children with myocarditis, all were based in Europe, none had previous cardiac disease, and all presented with fever and GI symptoms. One also had a rash and conjunctivitis. These children all developed myocarditis early in their clinical picture, with average duration of symptoms prior to presentation of 3.5 days. All four children received IVIG. Three of these children also required inotropic support; one child also developed ARDS and acute kidney in addition to myocarditis, requiring non-invasive ventilation but not renal replacement therapy. None of the four children with myocarditis required mechanical ventilation. All four children survived to discharge home, with a mean hospital length of stay of 13.5 days.

Cen YLiu Y HClin Infect Dis.Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019 - a multi-centre observational study.08 Jun 2020ChinaAsia5Clinical - Clinical Features https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30341-4/fulltext
MAK, PQKwan, MPediatr.Infect.Dis.J.Anosmia and Ageusia : not an uncommon presentation of COVID-19 infection in children and adolescents.08 Jun 2020USANorth America3Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/.
Trogen, BShust, GPed. Infectious Disease J.COVID-19-Associated Myocarditis in an Adolescent08 Jun 2020USANorth America1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/COVID_19_Associated_Myocarditis_in_an_Adolescent.96126.aspx

This case report details the admission to PICU of a 17-year-old obese male (BMI 30kg/m2) with spondylolysis and a distant history of asthma (not requiring medication for > 5 yrs) who presented to a hospital in New York City during the third week of April with septic shock, after a week’s history of fever, GI symptoms and neck pain.

Clinical features: 7 day history of fever and neck pain and a 6 day history of diarrhoea and vomiting (non-bloody, non-bilious). No neck stiffness, headache, photophobia or respiratory symptoms. At presentation he was febrile, tachycardic and hypotensive (79/66 mmHg) with diffuse abdominal pain. His cardiovascular status remained labile after initial fluid resuscitation and he was admitted to PICU.

Initial bloods: Lymphocytes 0.9 x 103/L, CRP 167 mg/L, ferritin 1275 ng/mL, D-dimer 1218 ng/mL, initial Troponin I level 2.97 ng/mL rising to 6.17 ng/mL 2 hrs later, brain natriuretic peptide 2124 pg/mL, sodium 128 mmol/L, creatinine 1.25 mg/dL, creatine kinase 761 U/L, LDH 346 U/L, INR 1.5, IL-6 28 pg/mL

Microbiology: Nasopharyngeal swab RT-PCR SARS-CoV-2 positive. Other respiratory and GI pathogen PCRs negative, including enterovirus, adenovirus, CMV, EBV, HHV-6, parvovirus B19.

Radiology: Abdominal USS essentially normal. CXR: low lung volumes, normal cardiothymic silhouette and mild, hazy ground glass opacities at the lower lobes bilaterally.

ECG: T-wave inversion particularly in inferior leads.

Cardiac imaging: Initial transthoracic echocardiogram: LV ejection fraction mildly depressed with no obvious intracardiac clots or pericardial effusion. Cardiac MRI: normal sized LV & RV, LVEF 40%, RVEF 39%, area of mid-wall late gadolinium enhancement at inferior LV-RV junction corresponding to area of increased T2 signal as well as an area of hypokinesia, consistent with myocarditis.

Treatment in PICU: Blood pressure normalised on day 1, but remained febrile and tachycardic until day 4. Required 2 days of oxygen via NC. Received anticoagulation, paracetamol/ibuprofen and 48 hrs of piperacillin/tazobactam until blood cultures reported negative. No other anti-inflammatories or IVIg given. Initially started on hydroxychloroquine which was stopped on day 3 when serial ECG demonstrated prolonged QTc interval not present initially. Serial Troponin I and BNP levels normalised by discharge.

Outcome: Discharged on day 5 with 2 week course of anticoagulation (apixaban). Echocardiogram at follow-up one week after discharge demonstrated normal ejection fraction (59%) with qualitatively improved function. However, tissue Doppler imaging signals of the mitral valve annulus were still abnormally diminished with low global longitudinal strain rate, consistent with residual myocardial dysfunction. Repeat ECG showed persistent T-wave inversion in lead III.

The authors conclude with a discussion of the possible mechanisms of cardiac injury secondary to COVID-19, including viral entry via the ACE2 receptor causing direct damage to myocardiocytes, immune-mediated injury secondary to cytokine release or T-cell dysregulation, microvascular damage, endothelial shedding/dysfunction, hypoxia-mediated injury and abnormal coagulation, including DIC, increasing the risk of thrombosis and ischaemic events.

Du, WQ. LiJ Infect Public HealthPersistence of SARS-CoV-2 virus RNA in feces: A case series of children07 Jun 2020ChinaAsia10Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304913
Chen, YXiao, XJ Infect Public HealthRe-evaluation of retested nucleic acid-positive cases in recovered COVID-19 patients: Report from a designated transfer hospital in Chongqing, China07 Jun 2020ChinaAsia4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275981/
Foster, CCampbell, JJ Pediatric Infect Dis Soc.Coronavirus Disease 2019 in Children Cared for at Texas Children’s Hospital: Initial Clinical Characteristics and Outcomes06 Jun 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa072/5854294
Xing, CXu, ZWorld J Clin Cases Serial computed tomographic findings and specific clinical features of pediatric COVID-19 pneumonia: A case report06 Jun 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281042/
Li, C. Wu, B Medicine A 3-month-old child with COVID-19: A case report.05 Jun 2020China Asia1Clinical - Clinical Featureshttps://journals.lww.com/md-journal/fulltext/2020/06050/a_3_month_old_child_with_covid_19__a_case_report.92.aspx
Sun, D., XLiu, Z., SWorld Journal of Pediatrics SARS-CoV-2 infection in infants under 1 year of age in Wuhan City, China05 Jun 2020ChinaAsia36Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs12519-020-00368-y
Gorkem,SCetin,BDiagn Interv RadiolCOVID-19 pneumonia in a Turkish child presenting with abdominal complaints and reversed halo sign on thorax CT05 Jun 2020TurkeyEurope1Clinical - Clinical Featureshttps://www.dirjournal.org/en/covid-19-pneumonia-in-a-turkish-child-presenting-with-abdominal-complaints-and-reversed-halo-sign-on-thorax-ct-167964

This is a case report of a 15 year old girl with Covid-19 from Turkey in an Epublished letter ahead of print with an early description of the “reversed halo sign”(RHS) on chest CT scan in. RHS is described as a central ground glass opacity (due to septal alveolar inflammation) surrounded by denser granulomatous airspace consolidation in the shape of a crescent or ring. It was identified in adult Covid -19 patients in early studies from Wuhan.

The patient presented with abdominal pain (epigastric tenderness). She had no respiratory symptoms and was apyrexial. Covid-19 was identified on nasopharyngeal swab. WCC 4.01x109, lymphocytes 1.92x109, CRP 1.6 mg/l rising to 10 mg/l after five days. Oxygen saturation remained above 95% in air.

Initial abdominal CT identified bilateral patchy alveolar infiltrates in the lower lobes and so an unenhanced low-dose thorax CT was performed. This identified multi focal RHS lesions within bilateral upper, middle and lower lobes. There were multiple multisegmental peripherally located alveolar infiltrations and scattered ground glass opacities.

The patient received hydroxy chloroquine. Interestingly, she did not develop any respiratory symptoms, making an uneventful recovery and was discharged after 8 days.RHS is a distinctive sign on chest CT. As well as occurring in pneumonia (including community acquired pneumonia) it can also be associated with fungal infections, immunosuppression, pneumocystis, TB, sarcoidosis, pulmonary neoplasms and pulmonary infarction. Therefore it can pose diagnostic challenges and management is guided by the clinical history. Although RHS is recognised in the adult Covid-19 literature this is a first report in a paediatric patient.

Mohammadi, A Mirza‑Aghazadeh‑Attari, MJpn J RadiolClinical and radiological characteristics of pediatric patients with COVID-19: focus on imaging findings04 Jun 2020IranMiddle East27Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293432/
Kerber, AYoussef, MIntnl J of DermatologyChilblains-like dermatologic manifestation of COVID-19 diagnosed by serology via multidisciplinary virtual care04 Jun 2020USANorth America1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/ijd.14974
Lin, EShah, AJAMA SurgeryIncidence of COVID-19 in Pediatric Surgical Patients Among 3 US Children’s Hospitals04 Jun 2020USANorth America12Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamasurgery/fullarticle/2766924
Zachariah, PSalman, LJAMA PediatricsEpidemiology, Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York03 Jun 2020USANorth America50Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766920
Wu, HXiang, YJAMA Netw OpenClinical and Immune Features of Hospitalized Pediatric Patients With Coronavirus Disease 2019 (COVID-19) in Wuhan, China03 Jun 2020ChinaAsia157Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamanetworkopen/fullarticle/2766670

In this retrospective case series from Wuhan, China, the clinical and immunological characteristics of children admitted to hospital with confirmed SARS-CoV-2 infection are examined. Details are provided for the 148 children with mild or moderate disease.

The median age was 84 months (IQR 18-123). Fever (40.5%) and cough (44.6%) and vomiting or diarrhoea (21.6%) were the most common symptoms. SARS-CoV-2 PCR became negative at a median of 7 days (IQR 4-11 days).

Lymphopenia was present in only 4.5% of patients; CD 4 lymphopenia in 1.9%. Elevation in CRP (32.4%) and procalcitonin (47.3% elevated; median 0.05 (IQR 0.04-0.08)) was observed in fewer than half of patients. Liver transaminases and LDH were significantly higher in moderate versus mild cases but the vast majority of levels fell within normal range.

Levels of inflammatory cytokines including IL2, IL6, TNG-a and IFN.y were largely normal; the authors note that one patient with severe disease had elevated IL-6 (3869 pg/mL). IL-10 was increased in 14%.No deaths occurred amongst mild and moderate cases and all 148 patients were discharged.

In this large case series of children with mild or moderated SARS-CoV-2 infection, laboratory measures of inflammation were largely normal. Specifically the significant elevations in IL-6, D-dimer, and ferritin characteristic of severe COVID-19 in adults and also PIMS-TS / MIS-C in children were absent in these milder cases. The authors postulate that the relative preservation of CD4 T-cells and the higher levels of IL-10 compared with adults with severe COVID-19 may indicate these as important components of a protective immune response.

As yet our understanding of the drivers of variation in individual immune response to SARS-CoV-2 remains incomplete.

Parri,NLazzerini,MEur J Pediatr Characteristic of Covid-19 infection in paediatric patients: early findings from two Italian Pediatric Research Networks 03 Jun 2020Delayed access or provision of care in Italy resulting from fear of COVID-19Europe130Clinical - Clinical Features https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269687/pdf/431_2020_Article_3683.pdf

This study is published as a short communication describing the clinical presentations and outcomes in children with identified Covid-19 in 61 centres in Italy between 3rd and 26 March 2020.Study Design: A retrospective study coordinated by the CONFIDENCE and COVID-19 Italian Paediatric Study Network’s involving 53(86.9%) hospitals and 8(13.1%) outpatient centres in 10 mainly northern regions. All children (0-18 years) diagnosed positive on screening and testing for Covid-19 by nasal/nasopharyngeal RT-PCR assay were entered into the study. Clinical, laboratory and imaging data was collected on standardised forms.

Study Population: 130 children and adolescents recruited (112 hospital;18 outpatient). <2 years 41 (31.5%), 2-9 years 35 (26.9%)’10-17 years 45 (34.6%). Male 73 (56.2%). Female 57(43.8%) p=0.47.Comorbidities 34 (26.2%) most frequent cardiovascular, respiratory and neuromuscular. No information on ethnicity. One patients data unobtainable.

Disease Severity: The majority of subjects were categorised as being asymptomatic or having mild disease 98/130 (75.4%). 11 (8.5%) were moderate severity, 11 severe and 9 (6.9%).critical. 75 (57.7%)were hospitalised with 15.(11,5%)needing respiratory support (5 needing oxygen, 2 non invasive ventilation and 2 mechanical ventilation). 9 cases were admitted to ICU with 6 being less than 6 months. 3 of the latter were less than 2 months and did not require respiratory support. Children less than 6 months had an increased risk of critical disease than older children: 6/35 (17.1%) vs 3/86 (3.5%) p=0.34. OR 5.6 CI 1.3 to 29.1.

Symptoms: Common symptoms were fever 67(51.5%), dry cough 38(29.2%) and productive cough 16(12.3%). Other symptoms were rhinorrhoea25(19.2%), respiratory distress 17(13%), vomiting 15(11.5%);diarrhoea 10(7.6%); sore throat 9(6.9%). Thoracic pains (3%), somnolence, febrile convulsions (1.5%) and lower limb pains (1.5%) were reported as novel symptoms.

Oxygen saturation at presentation: 91-92% 1(0.8%). <90 1(0.8)

Radiology: 41 (31.5%) of children had CXRs. These were normal in 15 (36.6%). The commonest abnormalities were ground-glass opacities in 17 (41.5%). Focal consolidation was seen in 4 (9.8%). Laboratory: 71 children were reported to have had laboratory tests. The authors report leukopenia (WCC %<5.5x109) and lymphopenia (<1.2x109) in 7/19 patients and 3/19 patients, respectively. They report elevation in aspartate transaminase >50U/l in 11/60 (18.3%) and alanine tranasaminase >45U/l in 8/68 (11.8%).

Outcomes: There were no deaths and all children were reported to have recovered. Comment: The study obtained data on all but one child found Covid-19 positive in this largely hospital based population. The authors acknowledge that there is a bias toward more ill patients with their population than community studies and this may explain the 57.7% admission rate. Also this is reflected in the amount of comorbidity. However, the majority of patients were either asymptomatic or had mild disease and small numbers required respiratory support or ITU. The authors identify the increased likelihood of critical disease in those less than 6 months and their being the majority of ICU cases. They also comment on new presenting symptoms (thoracic pain, somnolence, febrile convulsions and lower limb pains).

Pandey UDien Bard JMedRxIVPediatric COVID-19 in Southern California: clinical features and viral genetic diversity02 Jun 2020CaliforniaNorth America35Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.05.28.20104539v2.full.pdf

A study of 35 children age range 18 days to 18.5 years (median12.5), 57% of whom were boys, seen over an 8 week period in Southern California. Patients were identified by nasopharyngeal swabs submitted to Los Angeles Children’s Hospital between 11 March 2020 and 11 May 2020. 37% were hospitalised with a median inpatient stay of 4 days. Symptoms were diverse with fever and cough being the most common, 1/3 were symptomless. Whole genome sequencing was undertaken on Covid-19 samples. There was an association between disease severity and viral load. Children < 5 years age had a higher viral load and all were symptomatic. There was limited variation in the viral genome though a calculated evolutionary rate was like other RNA viruses. No correlation was identified between disease severity and genetic variation.

Frauenfelder, CBamford APediatricsInfant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir01 Jun 2020United KingdomEurope1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/06/16/peds.2020-1701
Escalera-Antezana, JP Rodríguez-Morales, AJLe Infezioni in MedicinaRisk factors for mortality in patients with Coronavirus Disease 2019 (COVID-19) in Bolivia: An analysis of the first 107 confirmed cases01 Jun 2020BoliviaInternational9Clinical - Clinical Featureshttps://www.infezmed.it/media/journal/Vol_28_2_2020_15.pdf
Manzoni, P Polastri, RoThe Pediatric Infectious Disease Journal: Uncommon Presentation of Coronavirus Disease 2019 Infection in a Child 01 Jun 2020italyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/Uncommon_Presentation_of_Coronavirus_Disease_2019.96134.aspx
Jones, B. A. ." . Slater, B. J. Journal of Pediatric Surgery Case ReportsNon-operative management of acute appendicitis in a pediatric patient with concomitant COVID-19 infection31 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261356/
Alsofayan, YAssiri, AJ Infect Public HealthClinical characteristics of COVID-19 in Saudi Arabia: A national retrospective study31 May 2020Saudi ArabiaMiddle East74Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S1876034120304925
Valente, PBuzzonetti, LJournal of AAPOSOcular manifestations and viral shedding in tears of pediatric patients with coronavirus disease 2019: a preliminary report30 May 2020ItalyEurope27Clinical - Clinical Featureshttps://jaapos.org/article/S1091-8531(20)30115-4/fulltext?rss=yes

27 paediatric patients were identified between 16/03/2020 – 15/04/2020, from Bambino Gesù Children’s Hospital, Rome, Italy. It was not clear how patients were identified/recruited. The mean age was 84 months (range=8 days to 210 months). 74% were male (n=20); 26% were female (n=7).

Clinical features present: - Cough and/or dyspneoa = 15 patients (56%); - Vomiting and/or diarrhoea = 8 patients (30%); - Ocular manifestations consistent with viral conjunctivitis = 4 patients (15%);

In the abstract it states that "At admission, all patients showed ocular manifestations", however there is no other reference to further information in the paper.Radiology/bloods: N/a

Other investigations: Nasopharyngeal swab to COVID-19 tested positive in all 27 patients. Of the 4 patients with apparent viral conjunctivitis, 1 patient resulted positive for SARS-CoV-2 on RT-PCR from conjunctival swab. Of the other patients (n=23), two more patients had positive findings for SARS-CoV-2 in their conjunctival swab without developing clinical signs of conjunctivitis.Outcomes: 27 (100%) discharges. Other salient features: Some preliminary evidence to suggest that SARS-CoV-2 shedding is low in eye secretions/tears.

Olisova, OYShnakhova, LMDermatol TherCutaneous manifestations in COVID‐19: a skin rash in a child30 May 2020RussiaEastern Europe and Northern Asia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13712
Cai, JHe, GJ Med VirolClinical features and the treatment of children with COVID-19: a case series from Wenzhou, China30 May 2020ChinaAsia3Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1002/jmv.26092
Kakuya, FKinebuchi, TJapanese Journal of Infectious DiseasesThe first pediatric patients with coronavirus disease 2019 (COVID-19) in Japan; The risk of co-infection with other respiratory viruses29 May 2020JapanAsia3Clinical - Clinical Featureshttps://www.jstage.jst.go.jp/article/yoken/advpub/0/advpub_JJID.2020.181/_pdf
Zhao, WZhang, FClin PediatrCharacteristics of Children With Reactivation of SARS-CoV-2 Infection After Hospital Discharge28 May 2020ChinaAsia14Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820928057

In this study from Beijing, China, serial nasopharyngeal swabs were performed on children discharged between January 21st and April 18th 2020 following hospital admission with confirmed SARS-CoV-2 infection. Criteria for hospital discharge included clinical improvement and 2 negative RT-PCR tests for SARS-CoV-2 on consecutive nasopharyngeal swabs. Follow up swabs were performed fortnightly following discharge; the authors report on children with subsequent positive RT-PCR on follow up.

In total 14 children were followed, 7 of whom had a subsequent positive SARS-CoV-2 PCR result, none of whom had significant symptoms at the time (one with a temperature of 37.5). There were no significant clinical or laboratory differences between the group with subsequent positive tests compared with those who remained negative.

The authors refer to those who have subsequent positive SARS-CoV-2 PCR as having "reactivation" of infection. This is a misnomer as the persistent shedding of viral RNA has been well recognised in adult studies. This includes a large cohort of over 200 patients from Korea with positive tests following negative PCR results, similar to the children in this study. Importantly no onward transmission from these "re-positive" cases was found amongst 790 contacts in the Korean cohort, suggesting the viral RNA detected in patients with prolonged shedding is not viable. Indeed in a recent in vitro study including 90 SARS-CoV-2 PCR positive samples, only samples taken within 8 days of symptoms onset were capable of infecting cells. This is in keeping with contact tracing data suggesting peak transmissibility occurs before and immediately after symptom onset with limited transmission beyond 5 days of symptom onset.

The likely explanation of the "reactivation" described here is prolonged shedding of non-viable viral RNA with an interim "false negative" samples prior to hospital discharge. Given the available data, it is unlikely that these "re-positive" discharged patients represent an infection risk to others

Oualha, MRenolleau, SArchives de PédiatrieSevere and fatal forms of COVID-19 in children28 May 2020FranceEurope27Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0929693X20301172

The 27 children described here constitute the biggest series to date of children sick enough to need high dependency care during active COVID infection. The criteria for admission were oxygen requirement > 1L/min or underlying disease.

The cohort of 27 were admitted within days of onset of first symptoms and 24 were positive for COVID-19 by PCR of nasal swabs. This is consistent with active virus, rather than PIMS-TS, the Kawasaki like post-COVID syndrome.

24 had respiratory disease, mostly with radiological or CT findings consistent with COVID. 6 had cardiovascular disease and 4 renal problems.

9 required invasive ventilation with median duration 5 days. 10 received non-invasive ventilation and 23 were treated with oxygen. 4 received catecholamines, one ECMO and one renal replacement therapy. The median length of hospital stay was 6 days.

Mean laboratory findings in the group were of elevated CRP, procalcitonin, fibrinogen and D-dimers, consistent with an inflammatory and prothrombotic state. Neutrophil and lymphocyte counts were normal. T cell subsets and cytokine levels were not measured. 70% had underlying conditions, but the spectrum was different from adult experience, with neurological and respiratory problems or sickle cell disease being most common.Three of the five who died had previously been in good health. A teenage girl whose clinical course was suggestive of the cytokine storm seen in adults died within hours of admission. A teenage boy and a 6 year old girl co-infected with other pathogens both died after long PICU stays.

This description confirms that severe illness is rare in children with COVID and shows that even those admitted for HDU care had a shorter illness and better prognosis than that seen in adults. Nonetheless, occasional children do suffer a prolonged illness with multi-organ dysfunction.

Garcia-Salido, ASerrano-Gonzalez, APediatr Crit Care MedChildren in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital27 May 2020SpainEurope7Clinical - Clinical Featureshttps://journals.lww.com/pccmjournal/Abstract/9000/Children_in_Critical_Care_Due_to_Severe_Acute.98028.aspx
Kumar, KJayanthi, CRIJOPresence of viral RNA of SARS-CoV-2 in conjunctival swab specimens of COVID-19 patients25 May 2020IndiaAsia4Clinical - Clinical Featureshttp://www.ijo.in/temp/IndianJOphthalmol6861015-4225372_114413.pdf
Gefen, AMSethna, CPediatric NephrologyPediatric COVID-19-associated rhabdomyolysis: a case report23 May 2020USANorth America1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00467-020-04617-0
Torrelo AColmenero IPaediatric DermatologyErythema multiforme-like lesions in children and COVID-1923 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14246
Armann, J.Berner, R.Dtsch Arztebl IntHospital Admission in Children and Adolescents With COVID-1922 May 2020GermanyEurope128Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271745/
Docherty, ASemple, MBMJFeatures of 20133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study22 May 2020United KingdomEurope310Clinical - Clinical Featureshttps://www.bmj.com/content/bmj/369/bmj.m1985.full.pdf
de Ceano-Vivas, MCalvo CArch Dis ChildSARS-CoV-2 infection in ambulatory and hospitalised Spanish children22 May 2020SpainEurope58Clinical - Clinical Featureshttps://adc.bmj.com/content/archdischild/early/2020/05/22/archdischild-2020-319366.full.pdf

Study design: A retrospective case series of all children seen at a tertiary centre, who were found to have positive PCR for SARS-CoV-2. Testing for SARS-CoV-2 was only conducted in those children who had respiratory symptoms and “criteria for hospitalisation” or who had “underlying chronic pathology”. Children with mild symptoms were not tested even if there was a confirmed case in the household. Comparisons were made between the characteristics of those admitted to hospital and those treated as outpatients. The study was conducted between March 11th and April 9th 2020 at Hospital La Paz, Madrid, Spain.

Inclusion criteria: All children who underwent PCR for SARS-CoV-2 in nasopharyngeal smear, N=349. Of whom 58 (16.6%) had a positive PCR and were the cases analysed.

Key findings: Of the 58 cases: Male 37 (63.8%), Median age 35.5 months (range 3.3-146), Underlying conditions 23 (39.7%), Temperature >39.7degC 41 (70.7%), Cough 42 (72.4%), Rhinorrhoea 33 (56.9%), Breathing difficulty 10 (17.2%), Vomiting 9 (15.5%), Headache 8 (13.8%), Loss of taste 1 (1.7%), Anosmia 1 (1.7%).

Radiology: 40 (69%) had a CXR of which 35 (87.5%) were abnormal: Perihilar infiltrates, ground glass pattern, lobar or multilobar consolidation.

Bloods: 43 (74.1%) had a blood test, median WCC 9145/mm3, median lymphocyte count 2390/mm3.Outcomes: 33 were hospitalised and 25 were treated as outpatients. Of the inpatients, 14 (42.4%) received oxygen therapy for a median of 3 days. 5 were admitted to the PICU (15% of those hospitalised): 3 with severe COVID-19, 1 with a hypertensive crisis and 1 with diabetic ketoacidosis. 31 (53.4%) were treated with hydroxychloroquine, 3 patients were treated with remdesivir. 2 patients with an inflammatory syndrome were also treated with tocilizumab. There was 1 death of a 5/12 old infant with dilated cardiomyopathy and Hurler’s syndrome. The comparisons between the inpatient and outpatient group provide almost no additional useful information.

Comment: As the authors concede, the retrospective nature of the study is a significant weakness. Patients were selected for testing on the basis of symptoms and/or underlying conditions and many other children who could have been infected were never tested. The study is useful in describing the range of symptoms, treatment and outcome in the large selected group of children who tested positive for SARS-CoV-2. It does not, however, add anything new to what is already known about the condition in children.

Scheier, EBalla, UEur Rev Med Pharmacol Sci Lung ultrasound cannot be used to screen for Covid-19 in children21 May 2020IsraelMiddle East1Clinical - Clinical FeaturesCOVID-19 Associated Pediatric Multi-System Inflammatory Syndrome
Li, BYu, CIndian PediatricsRadiographic and Clinical Features of Children With Coronavirus Disease (COVID-19) Pneumonia21 May 2020ChinaAsia22Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1816-8.pdf
Leung, CLeung, CPediatric PulmonologyClinical characteristics of COVID‐19 in children: Are they similar to those of SARS?21 May 2020China Asia43Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/ppul.24855
Zachariah, PGreen, DClin Infect DisSymptomatic Infants have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease than Older Children20 May 2020USANorth America57Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa608/5841161

This research letter details the viral loads of children with confirmed SARS-CoV-2 infection from Columbia University Irving Medical Centre in New York. All children admitted and discharged between March 14th to April 24th 2020 were included, timing of test relative to onset of symptoms, clinical severity along with viral load were compared between infants <1yo and children >1yo.Of 57 patients with positive SARSCoV-2 PCR, 20 (35%) were under 1yo. Compared with older children, viral load was higher amongst infants <1yo (mean cycle threshold 21.05 vs 27.25, p<0.01 - where lower cycle threshold=greater viral load). Infants were tested earlier on average (2 vs 3.8 days from symptom onset) and fewer had severe disease compared with older children (5% vs 32.4%).

In this small hospital-based study symptomatic infants appear were found to have higher viral loads and milder disease compared with older children. This is in contrast to data from some adult studies where a higher viral load correlated with more severe illness.

Amongst several possible explanations for this observation are that: - infants were more likely to be tested early in illness when viral load peaks - declining thereafter - thresholds for hospital presentation may differ between infants and older children - test performance and sample quality may differ between infants and older children - there may possibly be differences in host biology according to age

Although some data suggest that higher SARS-CoV-2 viral load is associated with the presence of viable virus / in vitro infectivity, the exact implications of the findings here in terms of risk of transmission from infants compared with older children is unclear. Further studies examining SARS-CoV-2 viral load dynamics and correlation with clinical course in children are required to better understand potential variation between different age groups.

Venturini, EGalli, LJ PaediatrSevere neutropenia in infants with severe acute respiratory syndrome caused by the novel coronavirus 2019 infection 19 May 2020ItalyEurope2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236669

This case report from the Meyer Children University Hospital, Florence, published as a letter describes two infants with SARS-CoV-2 with transient severe neutropenia (<0.5 x109/l) Clinical Features: The two female infants, aged 23 days and 39 days were admitted with mild respiratory symptoms and low grade fever. Nasopharyngeal swans were positive for Covid-19. There was no clinical deterioration in their condition during admission.

Radiology: not described

Treatment: not described.

Haematology: leukocytes and neutrophils normal on admission. At 5 days neutrophil counts fell to 0.244 x 109/lnand 0.482 x 109/l. Subsequently both improved.

Apart from age and gender there is no other demographic information nor any on treatments.Although neutropenia is described in 6% of cases of Covid-19, severe neutropenia has not been described. In the report cases it was not associated with any change in clinical state. The authors suggest consideration of performing FBCs 5 to 7 days into the illness to identify neutropenia.It requires further studies to see if these findings are replicated and whether they are clinically significant. The severity of the neutropenia could be age dependent reflecting bone marrow maturity as one patient was in the neonatal range and the other just beyond it.

Xiong XTam, PGutComparative study of the clinical characteristics and epidemiological trend of 244 COVID-19 infected children with or without GI symptoms19 May 2020china Asia244Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/05/19/gutjnl-2020-321486.info
Dallan, CSahyoun, CLancetSeptic shock presentation in adolescents with COVID -1919 May 2020SwitzerlandEurope3Clinical - Clinical Featureshttps://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30164-4/fulltext
Giacomet, VZuccotti, GPIDJAcute inflammation and elevated cardiac markers in a two-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with cardiac symptoms 19 May 2020ItalyEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/ACUTE_INFLAMMATION_AND_ELEVATED_CARDIAC_MARKERS_IN.96157.aspx
Dugue, RMishra, NNeurologyNeurologic manifestations in an infant with COVID-1919 May 2020USANorth America1Clinical - Clinical Featureshttps://n.neurology.org/content/neurology/early/2020/05/18/WNL.0000000000009653.full.pdf
Shaw, RYuki, KJ Pediatr Surg Case Rep.Intubation precautions in a pediatric patient with severe COVID-1918 May 2020USANorth America1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S2213576620301299
Guarneri, CNunnari, GThe Lancet, Infection diseasesSilent COVID-19: what your skin can reveal18 May 2020Italy (assumed) Europe3Clinical - Clinical Featureshttps://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30402-3/fulltext#coronavirus-linkback-header
Yoo, SKim, D Pediatrics InternationalReactivation of SARS-CoV-2 after Recovery18 May 2020KoreaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ped.14312
Li, YWu, BBMC PediatricsChest CT imaging characteristics of COVID-19 pneumonia in preschool children: a retrospective study18 May 2020ChinaAsia8Clinical - Clinical Featureshttps://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-020-02140-7
Turbin, RNimchimsky, EOrbitOrbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-1918 May 2020USANorth America2Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/01676830.2020.1768560
Wang, Y.Li, L.The Journal of Infectious DiseasesClinical Outcomes in 55 Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Who Were Asymptomatic at Hospital Admission in Shenzhen, China17 May 2020ChinaAsia15Clinical - Clinical Featureshttps://academic.oup.com/jid/article/221/11/1770/5807958
Voinsky, IGurwitz,DJ Infect.COVID-19 Associated Pediatric Multi-System Inflammatory Syndrome. J Paediatric Infect Dis Soc16 May 2020IsraelMiddle East933Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30303-0/fulltext

In this case report from Detroit, USA, the authors describe a 6yo girl with confirmed SARS-CoV-2 and PIMS-TS / MIS-C requiring ECMO.

Following initial presentation with fever, sore throat and rash, the patient developed refractory hypotension and incomplete features of Kawasaki disease (conjunctivitis, rash, swollen peripheries). Inflammatory markers were elevated (CRP 450 mg/L, ESR 54mm/hr, ferritin 699.5 ng/mL) as were troponin (114ng/L), D-dimer (4.21 mg/L), and fibrinogen (834 mg/dL). Echocardiography showed decreased LV function and bloods demonstrated acute kidney injury (creatinine 1.09mg/dL). SARS-CoV-2 RT PCR was positive from a nasopharyngeal swab; earlier in the illness a group A streptococcal rapid test was positive (NP swab).

Despite inotropic support, the patient's condition deteriorated requiring VA ECMO. IVIG, aspirin and antibiotics (vancomycin, ceftriaxone and clindamycin) were given with gradual clinical and biochemical improvement. The authors also allude to incomplete KD like illness in two other patients at their centre with COVID-19 - both with less severe presentations and recovery following IVIG.

This case adds to a growing number of reports of PIMS-TS / MIS-C in children, highlighting the potential for rapid deterioration in this rare condition and the possible role of IVIG in cases with features of Kawasaki Disease.

Duramaz, BTurel, ODermatol TherAppearance of Skin Rash in Pediatric Patients with COVID-19: Three Case Presentations15 May 2020TurkeyWestern Asia, Southeastern Europe20Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/full/10.1111/dth.13594
Diotallevi, FOffidani, AJ Med VirolSkin Involvement in SARS-CoV-2 Infection: Case Series15 May 2020ItalyEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1002/jmv.26012
He, GCai, JIndian PediatricsSerial Computed Tomography Findings in a Child with Coronavirus Disease (COVID-19) Pneumonia15 May 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s13312-020-1824-8.pdf
Mastrolonardo, MFoti, CDermatologic TherapyThe management of the outbreak of acral skin manifestationsin asymptomatic children during COVID-19 era14 May 2020ItalyEurope38Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13617
Craver, RFinger, LFetal Pediatr PatholFatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c)13 May 2020USANorth America1Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/15513815.2020.1761491
Cordoro, KMMcCalmont, THPediatric DermatologyClustered Cases of Acral Perniosis: Clinical Features, Histopathology and Relationship to COVID‐1912 May 2020USNorth America6Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1111/pde.14227
DeBiasi, RWessel, DJ Pediatr.Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region12 May 2020United StatesNorth America177Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30581-3/fulltext

This is retrospective cohort study, describing 177 children and young adults with confirmed SARS-CoV-2 infection treated between March 15 and April 30 2020 at Children’s National Hospital, Washington DC US. Children and young adults were detected through symptomatic presentation at emergency departments, ambulatory clinics, inpatient units, or by referral for admission from external facilities. Of 177 patients, 44 (25%) were hospitalised, with 9 (5%) classified as critically ill. The aim of the study was to identify if any specific epidemiological or clinical features associated with hospitalisation, or critical care.

Of note this hospital served as a regional centre for providing critical care for young adults aged 21 – 35 years, therefore not all patients would be termed “paediatric patients”. Overall patient age range was from 0.1 - 34.2 years, with a median of 9.6years. Of the total group 12/177 were > 20 years of age, and 37/177 were between age of 15 – 20years.

Results: Age; There was no significant difference in age between the hospitalised and non-hospitalised patients, however in the hospitalised cohort, the critically unwell group were significantly older than the non-critically unwell hospitalised group (17.3 years versus 3.6 years; P =.04) Sex; There was equal representation in total cohort showed (n = 177 52% male, 48% female), as well as the hospitalised cohort (n=44 50% male, 50% female). However males made up 67% of the critically ill cohort (n =9, 67% male, 33% female); but this was not statistically significant (p=0.26)Race/ethnicity: data not provided, authors describe plans to do so in follow up analysis Underlying conditions; 39% of positive patients had an underlying condition (classified as asthma, diabetes, neurological, obesity, cardiac, haematological, oncological). Though asthma was the most common underlying condition (35/177 20%), it was not more common in hospitalised patients (7/44 16%), nor of those admitted, those who were critically unwell (2/9, 22%). Though the numbers where small, specific underlying conditions such as neurological, cardiac, haematological, or oncological underlying conditions were more common in the hospitalised cohort than the non hospitalised cohort. But were not more common in the hospitalised critically ill compared with the hospitalised non critically ill. The authors noted there was no underlying condition present in 96/177 (55%) of overall SARS-CoV-2 infected patients overall, 16/44 (37%) of hospitalized patients and in 2/9 (22%) of critically ill patients.Symptoms; 76% of infected patients presented with respiratory symptoms (rhinorrhea, congestion, sore throat, cough or shortness of breath) with or without fever. Fever was present in 116/177 (66%) but was not more common in the infected hospitalized cohort (34/44, 77%) compared with the non-hospitalized cohort (82/133, 62%; p=0.46). 

Shortness of breath was more common in the hospitalized cohort (11/44, 26%) compared with non-hospitalized (16/133, 12%; p=0.04). Patients in the critically ill cohort were not more likely to have fever or any other specific symptom compared with the non-critically ill cohort.

Critical Care: 9 patients required critical care; which represented 5% (9/177) of total cohort and 20% (9/44) of admitted patients. 4 required intubation (3 ARDS, 2 multiple organ failure); 3 required BiPAP, 1 RAM cannula and 1 High flow nasal cannula. One patient had features consistent with the recently emerged Kawasaki disease-like presentation with hyper-inflammatory state, hypotension and profound myocardial depression; a 4 year male with no underlying conditions.

Summary: A very clear description of 177 patients with Sars CoV 2, in one large centre in Washington DC. 25% of patients needed hospitalisation and 5 % needed critical care. Older teenagers and adults who required admission, were then overrepresented in requiring critical care. Though underlying conditions were more common in hospitalised patients, they were not significantly more common in the hospitalised patients who required critical care. Shortness of breath was the only symptom that was more common in hospitalised patients than non-hospitalised patients. No specific symptom was more apparent in patients needing critical care. One critically ill patient had features of recently described hyperinflammatory state.

Bai, KLi, CPIDJClinical analysis of 25 Novel Coronavirus Infections in Children 12 May 2020China Asia25Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Clinical_Analysis_of_25_Novel_Coronavirus.96172.aspx
Brambilla, IMarseglia, GLThe Pediatric Infectious Disease JournalCOVID-19 in the Pediatric Population Admitted to a Tertiary Referral Hospitap in Northern Italy: Preliminary Clinical Data12 May 2020ItalyEurope17Clinical - Clinical Featureshttps://journals.lww.com/pidj/Citation/9000/COVID_19_in_the_Pediatric_Population_Admitted_to_a.96177.aspx
Brambilla, I.Ciprandi, G.Obesity: A research journalSpecial Issues for COVID‐19 in Children and Adolescents12 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22878
Meslin, PZemouri, NThe Pediatric Infectious Disease JournalCoronavirus Disease 2019 in Newborns and Very Young Infants a Series of Six Patients in France12 May 2020FranceEurope6Clinical - Clinical Featureshttps://journals.lww.com/pidj/Fulltext/2020/07000/Coronavirus_Disease_2019_in_Newborns_and_Very.33.aspx
Cai, XLi, WFront. PediatrClinical Characteristics of 5 COVID-19 Cases With Non-respiratory Symptoms as the First Manifestation in Children12 May 2020ChinaAsiaClinical - Clinical Featureshttps://www.frontiersin.org/articles/10.3389/fped.2020.00258/full
Shekerdemian, LSBurns, JPJAMA PediatricsCharacteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units11 May 2020USA & CanadaNorth America48Clinical - Clinical Featureshttps://jamanetwork.com/journals/jamapediatrics/fullarticle/2766037

This is a cross-sectional study of children admitted to 46 PICUs in North America. 48 children were admitted during the collection period (March 14 to April 3 2020). All had confirmed COVID-19 infection on PCR from a nasal swab.

Most patients presented with respiratory symptoms, but there were other presentations – three with DKA, and one with vaso-occlusive crisis (sickle cell). 86% of these patients had at least one comorbidity. 69% were severely or critically ill on admission, and 25% needed vasoactive drugs. 81% of patients needed respiratory support that exceeded their baseline.

61% had a range of therapies, including Hydroxychloroquine, Azithromycin, Remdisivir, and Tocilizumab. These were used as single agents or in combination with other therapies.

The overall mortality rate was 4.2% (both patients who died had pre-existing comorbidities and developed multisystem organ failure). 32% were still hospitalised at the time of publication (including one patient still receiving ECMO). 65% had been discharged.

This study reinforces what is known about the decreased burden of disease from COVID-19 in children compared with adults. Critically ill children had a less severe course of illness and better hospital outcomes than in adults. Children commonly had medically complex comorbidities. Overall the mortality is much lower in children (4.2%) than has been reported in adults (50-62%).

Chao, JMedar, SJ. Pediatr.Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City 11 May 2020USNorth America46Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)30580-1/pdf
Wehl, G..Rauchenzauner, MKlin PadiatrCo-infection of SARS CoV-2 and influenza A in a Pediatric Patient in Germany.11 May 2020GermanyEurope1Clinical - Clinical Featureshttps://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1163-7385
Oberweis, MGarcia, IPediatr. Infect. Dis. J.Pediatric Life-Threatening Coronavirus Disease 2019 With Myocarditis11 May 2020LuxembourgEurope1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Pediatric_Life_Threatening_Coronavirus_Disease.96160.aspx

In this case report from Luxembourg, the authors describe an 8yo boy of African ethinicity with COVID-19 complicated by myocarditis. Presenting features included fever, cough, fatigue and cervical adenopathy associated with painful erythematous swelling of the skin. Following admission, the patient developed renal failure and refractory hypotension necessitating ICU admission. CRP (151mg/L), ferritin (2869ng/mL), D-dimer and IL-6 were all elevated. Echocardiography demonstrated myocarditis with biventricular dysfunction and troponin was elevated. SARS-CoV-2 infection was confirmed on RT-PCR of nasopharyngeal swab and stool; serology (IgA and IgG) was also positive.

IVIG and tocilizumab (anti-IL-6 monoclonal antibody) were given along with supportive care including enoxaparin and inotropes. The patient made a full recovery with resolution of changes on repeat cardiac imaging and was discharged home on day 10.

This case, likely submitted prior to the description of PIMS-TS / MIS-C, fits with the definition for these syndromes. The myocarditis, refractory hypotension, overlap with features of Kawasaki Disease, laboratory findings suggestive of cytokine storm as well as the patient's African ethnicity are all in keeping with recent reports from UK, Europe and the US. The authors postulate that the "cardiac injury could be due to disproportionate host immune response to SARS-CoV2" and describe a rapid clinical response following administration of tocilizumab.

With emerging reports of PIMS-TS / MIS-C, our understanding of the pathophysiology of this condition will increase. At this stage the role of immunomodulatory agents remain uncertain in PIMS-TS / MIS-C; discussion with paediatric ID clinicians on a case by case basis is recommended.

Zhang, NZheng, XTransl PediatrAnalysis and suggestions for the preview and triage screening of children with suspected COVID-19 outside the epidemic area of Hubei Province10 May 2020ChinaAsia36Clinical - Clinical Features http://dx.doi.org/10.21037/tp.2020.03.08
Andina, D.Torello, A.Paediatric DermatologyChilblains in children in the setting of COVID-19 pandemic09 May 2020SpainEurope22Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14215
Locatelli, ASena, PJ Eur Acad Dermatol VenereolHistologic features of long lasting chilblain‐like lesions in a pediatric COVID‐19 patient09 May 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.16617

This retrospective single case report describes clinical and pathological signs of chilblain-like lesions whilst the patient was asymptomatic. He did not have any signs of autoimmune conditions including on histological examination. The lesions persisted for several weeks whilst he remained positive for SARS-CoV-2 on nasopharyngeal swab. The authors highlight young people with this sign could be carriers of the virus.

A 16-year-old male patient attended Papa Giovanni XXIII Hospital, Italy. His nasopharyngeal swab was positive for SARS-CoV-2. His mother was admitted to hospital for SARS-CoV-2 management following his presentation.

Clinical features: Diarrhoea and dysgeusia were experienced 3 days prior to the onset of skin lesions described as “multiple asymptomatic erythematous oedematous partially eroded macules and plaques on dorsal aspects of the fingers”. A lesion was also noted on second toe.

Radiology: None discussed.

Bloods: "Routine bloods autoimmunity, cryoglobulins, viral serologies all negative or within normal limits"

Treatments: None

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: Histopathological examination demonstrated oedema of the papillary dermis, superficial and deep lymphocytic infiltrate in the perivascular and strong peri-eccrine pattern. Images are provided.

Diercks, GRKwolek, CJInternational Journal of Pediatric OtorhinolaryngologyAsymptomatic COVID-19 infection in a child with nasal foreign body08 May 2020USANorth America1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205643/pdf/main.pdf
Fu, BFu, XMed Clin (Barc)Clinical characteristics of 11 asymptomatic patients with COVID-1908 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205640/pdf/main.pdf
Ma, Y.Zhang, Z.Microbes and InfectionCharacteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China07 May 2020ChinaAsia10Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204664/pdf/main.pdf
Zhang, YSun, BCell Mol ImmunolProtective humoral immunity in SARS-CoV-2 infected pediatric patients07 May 2020China Asia6Clinical - Clinical Featureshttps://www.nature.com/articles/s41423-020-0438-3

This is a study looking at the immune responses of 6 children with Sars-CoV-2 infection and comparing it to controls, in hospitals in China, in “areas other than Wuhan”. The clinical characteristics of the children were described previously (Cai et al Clin. Infect. Dis. 2020). All six children had positive respiratory samples RT PCR positive for Sars-Cov-2. All had a mild respiratory illness, needing no supportive treatment.

It is somewhat difficult to interpret exactly what immunological tests were done on which child from the study report. However, flow cytometry analysis analysing T and B cells was performed on 4 of the positive patients and was compared to five uninfected controls, admitted to the same hospital for non Sars-CoV-2 related reasons. There was no significant difference in lymphocyte count, or percentage of CD3+, CD4+, and CD8+ T cells between positive or control groups. The percentage of IgG+ in total B cells was higher, though not significantly, between groups but the percentage of IgG+ memory B cells was significantly higher in infected group.

The authors used Nucleocapsid protein and receptor binding domain of spike protein (spike-RBD) of SARS-COV-2 as antigen. All 6 infected children were tested for antigen specific antibodies, with 5 of 6 children producing antigen specific antibodies between 2 – 17 days post infection (it is unclear whether these were serial samples, or opportunistic sampling, therefore exact time of production of antigen specific antibodies is unclear). The team report that most of the IgM antibody for spike RBD Sars-CoV-2 was undetectable shortly after disease onset, suggesting class switching occurred within one week of virus exposure.

The team went on to select select serum from one patient with high concentration of spike RBD protein, and demonstrated in vitro it could block the receptor binding between spikeprotein and ACE2 protein, which is considered a vital pathway for Sars-CoV-2 to infect.

Authors conclude that the efficient humoral immune response might explain why the majority of children infected with SARS-CoV-2 had milder symptoms and recovered more easily than adults.

Papa, AVarrassi, GPain TherImages in Practice: Painful Cutaneous Vasculitis in a SARS-Cov-2 IgG-Positive Child06 May 2020ItalyEurope1Clinical - Clinical Featureshttps://link.springer.com/content/pdf/10.1007/s40122-020-00174-4.pdf
Ma, H.Shao, J.BMC MedicineA single-center, retrospective study of COVID-19 features in children: a descriptive investigation06 May 2020ChinaAsia158Clinical - Clinical Featureshttps://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-020-01596-9
Zhang, BZhang SJ InfectionChildren hospitalized for coronavirus disease 2019 (COVID-19): A multicenter retrospective descriptive study06 May 2020ChinaAsia46Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204760/pdf/main.pdf
Wang, YSun, DPediatr Infect Dis JThe Risk of Children Hospitalized With Severe COVID-19 in Wuhan06 May 2020ChinaAsia43Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32384397
Colonna, C. Gelmetti, C.Paediatric DermatologyChilblains-like lesions in children following suspected Covid-19 infection06 May 2020ItalyEurope4Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14210
Li, J.Song, S.Q.The Brazilian Journal of INFECTIOUS DISEASEAn infant with a mild SARS-CoV-2 infection detected only by anal swabs: a case report06 May 2020ChinaAsia1Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S141386702030043X
Xiong, X.Tam, P.Med archivesAre COVID-19 infected children with gastrointestinal symptoms different from those without symptoms? A comparative study of the clinical characteristics and epidemiological trend of 244 pediatric cases from Wuhan05 May 2020ChinaAsia244Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.04.29.20084244v1
Lu, YDu, HPed Infectious Disease JSymptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan05 May 2020ChinaAsia110Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/Symptomatic_Infection_is_Associated_with_Prolonged.96181.aspx

This retrospective study analysed demographic, clinical, laboratory, radiological and therapeutic data from the electronic medical records of 110 children hospitalised with “mild/ordinary” COVID-19 (classified as per the National Health Commission of People’s Republic of China National Recommendations for Diagnosis and Treatment of COVID-19, 7th edition) at Wuhan Children’s Hospital in Hubei, China between 30th January and 10th March 2020. Inclusion criteria: throat or nasopharyngeal swabs RT-PCR SARS-CoV-2 positive and patient discharged from hospital after recovery (an initial cohort of 127 children was reduced to 110 after exclusion of 2 critical cases and 15 children in whom the onset of disease could not be accurately determined).

Study design: Timings of onset of illness, most recent exposure (presumably to SARS-CoV-2-confirmed or symptomatic contacts, although this isn’t specified), diagnosis and discharge from hospital were recorded. Patients were discharged only once they had two consecutive RT-PCR SARS-CoV-2 negative swab results (separated by at least 24 hours). The authors calculated the duration of viral shedding for (a) symptomatic patients (81/110, 74%) as time from onset of illness to discharge and for (b) asymptomatic patients (29/110, 26%) as time from date of most recent exposure OR abnormal chest radiological imaging (reason for imaging not specified in these asymptomatic patients) to discharge. This definition of duration of viral shedding, with starting point presumably in most cases a retrospective parent-reported start of symptoms or exposure to an infectious contact, and end point two negative swabs leading to discharge from hospital, makes interpreting the duration figures problematic. Viral shedding in urine and faeces was not measured.

Clinical features: Median age of the 110 children was 6 years (IQR 2-9); 59/110 male (54%), 51/110 female (46%). Symptoms included: cough and dyspnoea 57/110 (52%), fever 56/110 (51%), GI (including diarrhoea, vomiting, poor feeding, anorexia, abdominal pain) 26/110 (24%), rhinorrhoea 10/110 (9%).Radiology: 64/103 (62%) had unspecified chest imaging reported as demonstrating pneumonia (55/75 symptomatic (73%) and 9/28 asymptomatic (32%)).

Bloods: Leucocytes < 4.0 x 109/L in 6/110 (5%) (all 6 were symptomatic). Leucocytes > 10.5 x 109/L in 12/110 (11%) (9 symptomatic & 3 asymptomatic). Lymphocyte ranges not specified. Haemoglobin < 110 g/L in 13/110 (12%) (all 13 symptomatic). Fibrinogen < 2.0 g/L in 34/90 (38%) (20 symptomatic & 14 asymptomatic). Hs-CRP > 3.0 mg/L in 21/110 (19%) (18 symptomatic & 3 asymptomatic). Procalcitonin > 0.05 ng/mL in 52/110 (47%) (43 symptomatic & 9 asymptomatic). AST > 50.0 U/L in 19/110 (17%) (all 19 symptomatic).

Treatment: None of the patients required oxygen therapy. All of them received antiviral therapy, mostly commonly nebulised interferon-. According to the data table 22/110 received Chinese medicine therapy, although no details are given and it’s not clear if this was pre-hospitalisation. Median duration of hospital stay was 10 days (IQR 8-13).

Conclusions: The median duration of viral shedding using the definitions above was 15 days overall (IQR 11-20 days, range 5-37 days): 17 days (IQR 12-23) in symptomatic patients and 11 days (IQR 9-13) in asymptomatic patients. Symptomatic infection, fever, pneumonia and lymphocyte counts < 2.0 x 109/L were reported to be associated with prolonged duration of shedding.

Garcia-Lara, G.Ruiz-Villaverde, R.Dermatologic TherapyChilblain-like lesions in pediatrics dermatological outpatients during the COVID-19 outbreak 05 May 2020SpainEurope27Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/dth.13516
Merza, MAbdulah, D.Diabetes Metab SyndrCOVID-19 outbreak in Iraqi Kurdistan: The first report characterizing epidemiological, clinical, laboratory, and radiological findings of the disease05 May 2020Iraqi KurdistanMiddle East4Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199697/
Hong-Rui, C.Wan-Xin, C.The Pediatric Infectious Disease Journal:A CASE OF CHILDHOOD COVID-19 INFECTION WITH PLEURAL EFFUSION COMPLICATED BY POSSIBLE SECONDARY MYCOPLASMA PNEUMONIAE INFECTION05 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_CASE_OF_CHILDHOOD_COVID_19_INFECTION_WITH.96183.aspx
Peng, HXu, HJ Clin VirologyCoronavirus disease 2019 in children: Characteristics, antimicrobial treatment, and outcomes04 May 2020China Asia75Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204737/table/tbl0010/
Rahmanzade, RHashemian, SA A PractRespiratory Distress in Postanesthesia Care Unit: First Presentation of Coronavirus Disease 2019 in a 17-Year-Old Girl: A Case Report04 May 2020IranAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227797/pdf/acc-14-e01227.pdf
Morey-Olive, MGarcia-Patos, VAnales de pediatriaCutaneous manifestations in the current pandemic of coronavirus infection disease (COVID 2019)04 May 2020SpainEurope2Clinical - Clinical Featureshttps://www.analesdepediatria.org/en-cutaneous-manifestations-in-current-pandemic-avance-S2341287920300673
Nirenberg, M.Herrera, MDMRJ Am Podiatr Med Assoc.Foot Manifestations in a COVID-19 Positive Patient, A case study04 May 2020SpainEuropeClinical - Clinical Featureshttps://www.japmaonline.org/doi/pdf/10.7547/20-088
Zheng, ZLiu, JJ Cent South Univ (Med Sci)Chest CT findings and clinical features of coronavirus disease 2019 in children03 May 2020ChinaAsia9Clinical - Clinical Featureshttp://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202003236.pdf
Sun, JWang, YJ Infect Dev CtriesDifferent outcome of COVID-19 in members of a family03 May 2020ChinaAsia1Clinical - Clinical Featureshttps://jidc.org/index.php/journal/article/download/12792/2248
Steinberger, SLittle, B PAm J RoentgenolCT Features of Coronavirus Disease (COVID-19) in 30 Pediatric Patients 01 May 2020ChinaAsia30Clinical - Clinical Featureshttps://www.ajronline.org/doi/10.2214/AJR.20.23145
Qiu, LLuo, XPediatr Infect DisA Typical Case of Critically Ill Infant of Coronavirus Disease 2019 With Persistent Reduction of T Lymphocytes01 May 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/9000/A_Typical_Case_of_Critically_Ill_Infant_of.96189.aspx
Tsao, HFearon, DPediatricsThrombocytopenia (ITP) in a SARS-CoV-2 Positive Pediatric Patient01 May 2020USANorth America1Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/pediatrics/early/2020/05/19/peds.2020-1419.full.pdf

A retrospective single case report was reported by Warren Alpert Medical School of Brown University, Rhode Island, USA, highlighting an association between SARS-CoV-2 and immune thrombocytopenia (ITP) in children. The patient was co-positive with rhinovirus and enterovirus, previously described in children managed for SARS-CoV-2.

A 10-year-old female patient was admitted for management of ITP after presenting with a petechial rash. 3 weeks prior she experienced 2 days of symptoms: cough and fever, following exposure to the SARS-CoV-2 virus. She did not have a family history of haematological or autoimmune conditions, any medical problems or medications.

A ‘respiratory panel’ was positive for rhinovirus and enterovirus and negative for coronavirus types 229E, HKU1, NL63, OC43. A Reverse transcriptase-polymerase chain reaction testing was positive for SARS-CoV-2.

Clinical features: Initial illness (3 weeks prior to ED presentation): fever, non-productive cough

Presentation to ED: petechial rash spreading from the legs to chest and neck, oral wet purpura, ecchymoses in the popliteal regions and shins.

Radiology: N/A

Bloods: At presentation: WCC 3.9 X 10^9/L (56% neutrophils, 38% lymphocytes) [Leukopenia without neutropenia or lymphopenia], haemoglobin 13.4 g/dL [normal], platelets 5 X 10^9/L [thrombocytopenia]. ANA borderline positive titers (1:40) in a speckled pattern which was considered not significant.

At 2 week follow up: WCC 6.1 X10^9/L [normal], Platelets 320 X 10^9/L [normal], ALT 56 IU/L [mildly raised], AST 28 IU/L [mildly raised].

Treatments: Intravenous immunoglobulin, paracetamol, and antihistamine to manage ITP.

Outcomes: Discharge from hospital after 1 day. Rash and oral lesions improved after 48 hours. Side effects were noted due to IVIG including headache, vomiting, abdominal pain.

At 2 week follow up platelet count was maintained, white cell count normalised and a mild transaminitis was noted.

Zhu, XCiu, LVirusResCo-infection with respiratory pathogens among COVID-2019 cases30 Apr 2020China Asia11Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0168170220303531
Yu, X.Fu, C.Transboundary and Emerging diseasesEpidemiological and clinical characteristics of 333 confirmed cases with coronavirus disease 2019 in Shanghai, China29 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/10.1111/tbed.13604
Casas, CGarcia-Doval, IBr J DermatologyClassification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases29 Apr 2020spainEurope0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19163

This article from a team in Spain aimed to classify cutaneous manifestations of COVID-19 and relate them to other clinical findings.

From 3rd of April 2020 to 16th of April 2020 they collected 429 cases but excluded 54 leaving a sample of 375 patients. A standardised questionnaire was used, photographs were taken and the questionnaires and photographs were independently reviewed by 4 dermatologists.

Data was collected by Spanish dermatologists from across the country most of whom had been redeployed from their usual dermatology posts.

Patients with an eruption of recent onset (previous 2 weeks) and no clear explanation, plus suspected or confirmed COVID-19 were included.They describe 5 cutaneous manifestations.

Acral areas of Erythema-oedema with some vesicles or pustules: 19% of cases. These were more likely in children.

Other vesicular eruptions: 9%. May also affect the limbs and have a haemorrhagic content, and become larger or diffuse.

3 Urticarial lesions: 19%. Mostly distributed in the trunk or disperse. A few cases were palmar.

Other maculopapular: 47%. Some showed perifollicular distribution and varying degrees of scaling, Some had been described as similar to pityriasis rosea.Livedo or necrosis: 6% Strengths of this study are the large number of patients recruited and that four dermatologists independently reviewed the images. It adds to the understanding of skin manifestations of COVID-19, which may give additional information when trying to make a clinical diagnosis of COVID-19 if other symptoms are non-specific, also the cutaneous manifestations may persist for some time once other symptoms have resolved.

A weakness is the authors did not specify the age of the patients involved so the usefulness for paediatric patients is limited. Also, in some areas, diagnosis of COVID-19 infection could only be made clinically, based on symptoms as the ability to test patients was limited during the height of the pandemic.

Chacon-Aguilar, R.Perez-Moneo, B.An Padiatric (Engl Ed)COVID-19: Fever syndrome and neurological symptoms in a neonate27 Apr 2020SpainEurope1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183976/
Nathan, NCorvol, HLancetAtypical presentation of COVID-19 in young infants27 Apr 2020FranceEurope5Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30980-6/fulltext

This correspondence in the Lancet describes the clinical features of 5 infants with COVID-19 who were admitted to a Paris hospital during the first week after imposed population quarantine in France (from 17th March 2020). At this time at Trousseau Hospital, children needing admission with fever or respiratory symptoms (or both) were admitted to a dedicated SARS-CoV-2 infection unit: during this week 14 infants under the age of 3 months were admitted and of these 5 out of 14 were confirmed SARS-CoV-2 positive on nasopharyngeal swabs.

Age/gender of infants: All 5 of these previously healthy infants with COVID-19 were boys; ages ranged from 1.6 to 2.7 months (median 2.1). All of their parents had mild signs of viral infection (including fever, cough, rhinitis), which could have been indicative of undiagnosed COVID-19.Clinical features at presentation: 5/5 fever (range 37.4 to 38.5 C), 4/5 neurological signs (drowsiness/hypotonia/abnormal “moaning” cry), 4/5 mottled skin, 4/5 runny nose, 4/5 cough, 0/5 dyspnoea, 5/5 normal SpO2, 0/5 digestive symptoms.

Investigations: FBC, CRP & procalcitonin largely unremarkable, with the exception of lymphopaenia in 2/5. Lumbar punctures in 4/5 babies with abnormal neurology reported normal (including negative for RT-PCR SARS-CoV-2). Chest X-rays performed in 4/5 essentially normal.

Outcomes: All 5 showed rapid clinical improvement and received no drugs other than paracetamol. Inpatient stays ranged from 1 to 3 days and duration of fever ranged from 1 to 5 days (max 39C). The infants were followed up for 2 weeks post-discharge with a daily phone call from a paediatrician using a standardised questionnaire.

Conclusion: This encouraging report of a small cohort of SARS-CoV-2 positive infants under the age of 3 months presenting Atypical presentation of COVID-19 in young infantswith fever showed initially concerning signs on admisson, but rapid recovery and minimal intervention needed for all 5 infants.

Piccolo, VBassi, AJournal of the European Academy of Dermatology and VenereologyChillblain-like lesions during COVID-19 pandemic: a preliminary study on 63 patients24 Apr 2020ItalyEurope63Clinical - Clinical Featureshttps://doi.org/10.1111/jdv.16526

This is a report of chilblain like lesions observed during the COVID-19 pandemic, collected through a survey issued to Italian dermatologists and Paediatricians. This is a preliminary report as data collection still ongoing.

Importantly – very few patients in this cohort were tested for COVID-19 (11/63) and only 2 of these patients were positive. It is therefore difficult to extrapolate these findings to paediatric COVID-19 specifically, but is worth being aware of.

63 patients have been reported on with a median age of 14 years (IQR 12 – 16yrs) with feet alone being bar far the most commonly affected area (85/7%) followed by feet and hands together (7%). In uploaded pictures from 54 patients, erythematous-oedematous lesions were most common (31/54) followed by blistering lesions (23/54) and pain and itch were common, although a quarter of lesions were “asymptomatic”. Median time of onset of rash to diagnosis was 10 days. The lesions were generally stable and no other cutaneous signs observed. GI symptoms were the most common co-existing (11.1%) with surprisingly low levels of respiratory symptoms (7.9%).

This is basically a description of a common skin manifestation which coincided with COVID-19, and looked like it could be infectious in origin. Few patients tested, and even fewer positive. An interesting series worth bearing in mind given increasing reports of skin manifestation of COVID-19.

Racalcati, SFantini, FJ Eur Acad Dermatol VenereolAcral cutaneous lesions in the time of COVID-1924 Apr 2020ItalyEurope11Clinical - Clinical Featureshttps://doi.org/10.1111/JDV.16533

This pre-print Letter to the Editor reports on a series of unusual dermatological manifestations presenting to the Dermatologic Unit in Alessandro Manzoni Hospital, Italy in March and April 2020. The authors observed 14 cases, of which 11 were children with a mean age of 14.4 years and a range of 13-18 years. Of the 14 cases, 6 (43%) were male. 3 pairs of cases were siblings.

None of the cases had systemic symptoms (other than mild itch in 3 cases), there was no association with cold exposure, co-morbidities or drug intake, and there was no family history of COVID-19 related symptoms. 3 cases reported cough and fever 3 weeks prior to the onset of the lesions.

The authors believe that these dermatological findings are related to COVID-19 due to the rapid outbreak and clustering of these unusual skin lesions occurring at the same time as the COVID-19 outbreak. In support of this they report multiple similar cases being described from other areas affected by the pandemic. They hypothesise that the skin lesions may represent late manifestations of COVID-19 infection in young, healthy subjects, possibly due to an immunologic response targeting the cutaneous vessels. They accept that this hypothesis cannot be tested until a reliable serological test for antibody response to COVID-19 has been developed.

Clinical features: Acral eruption of erythemato-violaceous papules and macules, with possible bullous evolution or digital swelling. Lesions were found on the feet in 8 cases, hands in 4 cases, and on both sites in 2 cases. 2 children developed erythemato-papular targetoid lesions on the hands and elbows after a few days.

Histology: Lesions on fingers showed diffuse dense lymphoid infiltrate of the superficial and deep dermis, with a prevalent perivascular pattern and signs of endothelial activation. Targetoid lesions on elbows showed mild superficial perivascular dermatitis.

Bloods: Normal FBC, CRP, LDH and D-dimer. Serology was negative for EBV, CMV, Coxsackie and Parvovirus B19.

Outcomes: In all cases the lesions resolved without treatment after 2-4 weeks. It is worth noting that this study is limited both by the small number of cases, but more particularly by the lack of evidence linking these skin lesions with a proven COVID-19 infection.Piccolo et al (Clinical)

Landa, NAguirre, TInternational Journal of DermatologyChillblain-like lesions on feet and hands during the COVID-19 pandemic24 Apr 2020SpainEurope2Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/ijd.14937
Wu, PNie, SGraefes Arch Clin Exp OphthalmolA child confirmed COVID-19 with only symptoms of conjunctivitis and eyelid dermatitis24 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://link.springer.com/article/10.1007/s00417-020-04708-6
Zhang, BZhang SJ InfectPositive rectal swabs in young patients recovered from coronavirus disease 2019 (COVID-19)23 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30233-4/fulltext

In this case series from Dongguan, China, three normally fit & well children aged 14y, 13y and 10m were followed up after positive throat swab for SARS-CoV-2. All three had a subsequent negative throat swab within approximately 7 days, and fully recovered, however 7-9 days later all three had rectal swabs which were positive. These findings raise the question of whether apparently well COVID-19 patients continue to carry and possibly shed the virus. If this was found to be the case in larger and more comprehensive studies, there may be an argument for introduction of strategies to increase avoidance of transmission via the faecal-oral route.

Huang, LZhou, JClin ImagInitial CT imaging characters of an imported family cluster of COVID-1923 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175903/#!po=31.2500
Kan, MJGreenhow, TLJ Ped Inf Dis SocFever without a source in a young infant due to SARS-CoV-222 Apr 2020United States North America1Clinical - Clinical Featureshttps://doi.org/10.1093/jpids/piaa044
Carrabba, GLocatelli, MLancetNeurosurgery in an infant with COVID-1922 Apr 2020Italy Europe1Clinical - Clinical Featureshttps://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30927-2/fulltext
Genovese, GMarzano, AVPediatr DermatolVaricella-like exanthem associated with COVID-19 in an 8-year-old girl: A diagnostic clue?21 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/pde.14201

This single case report describes an 8 year old girl presenting on a hospital in Milan, Lombardy region, Italy, on 21 March 2020 with a painless, non-pruritic papulovesicular rash on the trunk developing 3 days after onset of a mild cough. The rash was predominantly papular with some vesicles with crusting, similar in appearance to chickenpox. Limbs, face, genitalia and mucous membranes were spared. She developed a mild fever 5 days after the onset of the rash, and tested positive for SARS-CoV-2. She had bloods including FBC, renal function, liver function and CRP, all of which were normal with the exception of a mild thrombocytopenia with platelets of 105 x 109/L, which subsequently normalised. The rash lasted 7 days, by which time systemic symptoms had resolved. The young girl had a history of varicella infection a year previously.

The authors quote other case reports of cutaneous manifestations associated with COVID-19: petechial rash, widespread urticaria and varicella-like rash predominantly involving the trunk. Although unable to confirm that the rash was definitely associated with COVID-19, they feel it is likely given the child’s previous history of varicella infection and lack of pruritis to suggest the lesions were insect bites. They suggest papulovesicular eruptions be included in the spectrum of exanthems possibly associated with COVID-19.

Li, HXu, QJ Infect The Profile of Peripheral Blood Lymphocyte Subsets and Serum Cytokines in Children With 2019 Novel Coronavirus Pneumonia20 Apr 2020China Asia40Clinical - Clinical Featureshttps://www.sciencedirect.com/science/article/pii/S0163445320302073?via%3Dihub

This was a retrospective observational study, studying lymphocyte subsets and serum cytokines of 40 children admitted with 2019-nCoV pneumonia to Wuhan Children’s Hospital between 24 January and 22 February 2020. These were compared against the lymphocyte subsets and serum cytokines of 16 children admitted with RSV pneumonia to the same hospital between 10 December 2019 and 22 February 2020. Study authors report they could not compare 2019-nCoV pneumonia to healthy controls, as the city was in lockdown.

It is not described how these patients were selected from all patients admitted with 2019-nCoV pneumonia, and RSV pneumonia, and what proportion the included patients were of the total admitted patients with these conditions.

There were 40 children with 2019-nCoV pneumonia, diagnosed by real time PCR. The mean age was 5.07 years (4.71 SD). 23 were male, with 17 females. All 40 children had a CT performed, 16 had unilateral changes, 26 had bilateral changes, and 1 had no changes. Severity was classed as needing ICU admission, only 1 out of 40 was classed as “severe”.

There were 16 children with RSV pneumonia included with mean age of 1.36 years (0.85 SD). 10 were male, 6 were female. All had CT chest, with 3 unilateral changes, 12 bilateral changes, and 1 with no changes. 2 out of 16 required were classified as severe and needed ICU admission.

Lymphocyte subsets were drawn within first 3 days of admission. Those treated with glucocorticoids (3 2019-nCoV and 4 with RSV pneumonia) had them taken before steroids were administered. They compared mean and % between patient groups. Mean CD3+ CD8+ are higher in 2019-nCoV patients; mean 933N/µL(SD 421) than RSV patients mean 675 N/µL (SD 426) (p = 0.044), CD3+ CD8+ % were also significantly higher in 2019-nCoV pneumonia patients. IL10 levels were significantly lower in children with 2019-nCoV pneumonia, though exact figures were not given. The child with severe 2019-nCoV had serial lymphocyte subsets. The authors concluded that immune responses could play a significant role in the disease and influence the severity of response.

The limitations of the study discussed were the small numbers, the very few patients with severe illness and the lack of a normal control. The authors did not comment on the significant age differences between the groups, and how these patients were selected.

Richardson, SDavidson, KJAMA networkPresenting Characteristics, Comorbidities and Outcomes among 5700 patients hospitalized with COVID-19 in the New York City area20 Apr 2020USANorth America34Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2765184

This is a paper from New York, USA, looking at the presenting characteristics, comorbidities, and outcomes of 5700 patients who were hospitalized with Covid-19. These were patients who were admitted to one of 12 Northwell Health acute care hospitals between 01/03/2020 and 04/04/2020. Clinical outcomes were monitored until 04/04/2020. All patients who were sufficiently medically ill to require hospital admission with confirmed severe acute respiratory syndrome coronavirus 2 infection by positive result on PCR testing of an NPA were included. The median age of patients was 63 years (IQR 52-75), 39.7% were female.

At presentations, 30.7% of patients had a temperature of over 380C. 20% had oxygen saturations of less than 90%. 43.1% of patients were considered tachycardic with a heart rate of over 100.

The majority of patients white cell count and differentials were within normal range. The mean white blood cell count was 7 (IQR 5.2-9.5). Neutrophil count 5.3 (IQR 3.7-7.7), however some patients were mildly lymphopenic, median 0.88 (IQR 0.6-1.2). Most patients had a low CRP, the mean result was 16 (IQR 6.4-26.9). Most patients had a raised ferritin, the mean result was 798 (IQR 411-1515), with 15-400 being considered normal range. Of note lactate dehydrogenase was tested in 70% of the patients and was significantly raised in most patients, the mean being 404 (IQR 300-551) with the normal considered to be 50-242.

A venous lactate was recorded in 44% of patients and all results were normal- <2. The most common comorbidities were hypertension (56.6%), obesity (41.7%) and diabetes (33.8%).

At the study end point 2634 patients had been discharged or had died during hospitalisation. Of these 14.2% were treated in ICU, 12.2% of them received mechanical ventilation, and 21% of these patients died. At the end point of the study of those patients who had received mechanical ventilation 3.3% were discharged alive, 24.5% died, 72.2% were still in hospital. There were no deaths in the under 18 age group (34 patients).

Of the patients who died, those with diabetes were more likely to have received mechanical ventilation or care in the ICU compared to those who did not have diabetes. Interestingly of those who died, those with hypertension were less likely to have received invasive mechanical ventilation than those without hypertension.

As most patients were still in the hospital at the endo point of the study (53.8%) this biases rates toward including patients who died early in their hospital course. The researchers point out that as these patients complete their hospital course, reported mortality rates will decline.

This study was slightly limited by the fact that the data was collected from the electronic heath record database and not the medical notes, from which a greater level of detail may have been established, however it was using this method that allowed for such a large number of patients to have been included and reviewed over a relatively short space of time. It is also limited by the fact that the study population only included patients from within the New York metropolitan area which may underrepresent some ethnic minorities.

Li, HXu, JJournal of Medical VirologyPositive result of SARS-CoV-2 in faeces and sputum from discharged patient with COVID-19 in Yiwu, China20 Apr 2020ChinaAsia0Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25905
Du, AZhang, ZInfectionClinical characteristics of COVID-19 in children compared with adults in Shandong Province, China16 Apr 2020ChinaAsia14Clinical - Clinical Featureshttps://link.springer.com/article/10.1007%2Fs15010-020-01427-2
Xing, YXing, QJ InfecDynamics of faecal SARS-CoV-2 in infected children during the convalescent phase16 Apr 2020ChinaAsia3Clinical - Clinical Featureshttps://www.journalofinfection.com/article/S0163-4453(20)30177-8/fulltext
Jiang, SYu, XClin Chem Lab MedCoinfection of SARS-CoV-2 and multiple respiratory pathogens in children16 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://www.degruyter.com/view/journals/cclm/ahead-of-print/article-10.1515-cclm-2020-0434/article-10.1515-cclm-2020-0434.xml
See, K CIbrahim Hinternational journal of infectious diseasesCOVID-19: Four paediatric cases in Malaysia15 Apr 2020malaysia Asia4Clinical - Clinical Featureshttps://www.ijidonline.com/article/S1201-9712(20)30181-8/fulltext
Shi, BXu, HClin PediatrSevere pneumonia due to SARS-CoV-2 and respiratory syncytial virus infection: a case report15 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.sagepub.com/doi/full/10.1177/0009922820920016?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&#articleCitationDownloadContainer
Chen, JHuang, AGenes Dis.The clinical and immunological features of pediatric COVID-19 patients in China14 Apr 2020ChinaAsia12Clinical - Clinical Featureshttps://reader.elsevier.com/reader/sd/pii/S2352304220300507?token=631DD2FAEE11F02D80D1CC96D2AB2621AA7960348DA5FFDD2FAB802D188A0726E724273D5014403A376291F4BD637C50

This early study from Chongqing, China describes the features of 12 children diagnosed with COVID-19. All had a mild course of illness. CT imaging was abnormal in 10 of 12 with patchy ground glass opacity the most common finding. Lymphopenia was present in 2 children.

The authors also compare the "immune profile" (including lymphocyte counts, immunoglobulins, complement, CRP and IL6 levels) of the 12 children with a group of 20 adults patients. Aside from a lower CRP in children (mean 11.5 vs 23.3mg/L) and expected age-related differences in absolute lymphocyte numbers, there were no significant differences between the groups.

liu, J.Lu, B.JMVDetection of SARS‐CoV‐2 by RT‐PCR in anal from patients who have recovered from coronavirus disease 201914 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25875
Shen, LLan, JJournal of InfectionClinical and laboratory-derived parameters of 199 hospitalized patients with coronavirus disease 2019 in Xiangyang, Hubei Province, China10 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.038
Wang, H.Lu, XiaoxiaPediatric Infectious Disease JournalRehospiatlization of a recovered coronavirus disease 19 (COVID-19) child with positive nucleic acid detection09 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://journals.lww.com/pidj/Abstract/onlinefirst/Rehospitalization_of_a_Recovered_Coronavirus.96214.aspx
Lazerrini, MTrobia, GLancet Child and Adolescent HealthDelayed access of provision of care in Italy resulting from fear of COVID-1909 Apr 2020ItalyEurope12Clinical - Clinical Featureshttps://doi.org/10.1016/S2352-4642(20)30108-5

This is a report of case studies during the COVID-19 pandemic in Italy of children whose presentations were thought to have been delayed due to parental fears of coming to the hospital. They report from 5 hospitals between March 1st and March 27th 2020, where paediatric presentations were reduced between 73–88%.

During this period, in the week of March 23rd to 27th 12 children are identified whose parents reported avoiding accessing hospital due to concerns over SARS-CoV-2 infection . 6 of these were admitted to PICU and there were 4 deaths. The cases include 2 children with DKA, 2 with acute leukaemia, 2 children with cerebral palsy and complex needs, 1 with pneumonia and febrile convulsions, 1 with pyelonephritis, 1 with pyloric stenosis, 1 with a Wilm’s tumour, 1 with vomiting and hypoglycaemia and 1 with a congenital syndrome on dialysis.

This case series highlights the concerns of many paediatricians that more deaths will be seen in children from collateral damage born from the COVID-19 response, than will die of COVID-19. Delayed presentations is a major concern around the world currently, and whilst these cases certainly raise concerns, evidence is needed to ascertain the true presence and extent of this problem.

Zhu, CZhu, LPediatric PulmonologyClinical characteristics of a case series of children with coronavirus disease 201908 Apr 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24767

This is a case series of ten paediatrics patients aged 1 – 17 years with confirmed Covid 19. These cases were retrospectively selected from 3 hospitals in Jiangsu, a coastal province approx 700 km east of Wuhan. Cases were collect from 24th January 2020 to 22nd February 2020. All cases were confirmed by RT-PCR anal or throat swabs. 70% of children presented with symptoms, and 30% were asymptomatic, but were screened due to contact with confirmed family member.

The most common symptoms on presentation were fever (40%), cough, (20%) and headache (20%). There was no report of whether children had underlying conditions. All children had a CT chest completed. Half of the cohort had CT changes. There were 2 cases of bilateral pneumonia, and 3 cases of unilateral pneumonia, 2 of which were in asymptomatic patients. Bloods were unremarkable, one child aged 1 year had Lymphocytosis, all others had normal lymphocyte counts. CRP was not raised in any child. Only one patient in the cohort required oxygen, and there were no ICU admissions. Five children were treated with antiviral medication including lopinavir/ritonavir (n=4) interferon α‐2b (n = 4), and oseltamivir (n = 1).

Of note, 5 children were still in hospital at the end of the case series.

Yuan, JLiu, LClinical Infectious DiseasesPCR assays turned positive in 25 discharged COVID-19 patients08 Apr 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa398
Shen, QZhou, ZPediatric PulmonologyNovel coronavirus infection in children outside of Wuhan, China07 Apr 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24762

This retrospective study examines the clinical characteristics of children admitted to Public Health centre of Changsha, Hunan, China. There were 9 children admitted during the study period 08/01/2019 and 19/02/2020 who tested positive for COVID-19. All had a confirmed contact case with COVID-19. Median age was 8 years, with a minimum age 1 year and oldest was 12 years. Children were predominantly female (6/9, 66%). There was no information provided about co-morbidities.Clinical features: 2/9 were asymptomatic, 1/9 had cough, 4/9 had fever, 1/9 had sore throat and 2/9 had diarrhoea.

Radiology: 2 patients had chest CT that were described as ground glass opacities. No further information was provided about the indications.

Bloods: 1/9 had lymphocytosis in whom other infectious causes were excluded. 1/9 had raised CRP, 4/9 raised ESR, 1/9 raised LDH, 2/9 had raised AST with 0/9 ALT abnormalities. All abnormalities were mild.

Treatments: All (9/9) children were treated10/2.5 mg/kg lopinavir/ritonavir twice daily, orally. 5/9 children received 10 mg/kg azithromycin once a day. One child received meprednisone and immune globulin therapy for febrile convulsion. No additional information regarding treatments were provided.All children required oxygen therapy. None required intensive care or mechanical ventilation.Outcomes: At the end of data collection 3/9 remained under hospital care and were positive for COVID-19. The remainder (6/9) were discharged from hospital. The time spent in hospital varied between 11 and 22 days (median 13.5 IQR 10.75-14 days).

Other salient features: 6/9 children were RT-PCR negative at discharge. The time between initial contact and a negative test varied between 9 and 20 days (median 13.5 IQR 10.75-14 days).

All averages were calculated by the reviewer from the data provided within the article.

Lei, PJiao, JJournal of X-ray Science and TechnologyClinical and computed tomographic (CT) images characteristics in the patients with COVID-19 infection: what should radiologists need to know?07 Apr 2020ChinaAsia1Clinical - Clinical Featureshttps://content.iospress.com/articles/journal-of-x-ray-science-and-technology/xst200670
Han, YFang, YJournal of Medical VirologyA comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults06 Apr 2020ChinaAsia7Clinical - Clinical Featureshttps://doi.org/10.1002/jmv.25835

This retrospective study compares the clinical characteristics of 25 adults and 7 children with acute respiratory disease confirmed as COVID-19. Cases were retrospectively identified from patients admitted to Xian Eighth Hospital in Shaanxi, China, between 31st January and 16th February 2020. The mean age of the children was 1.3 years with a range of 2 months to 13 years, and 4 (57%) were male. None had any co-morbidities.

Clinical features: 5/7 (71%) children had cough, 3/7 (43%) had shortness of breath, 5/7 (71%) had fever, 1/7 (14%) had sore throat and 4/7 (57%) had diarrhoea and/or vomiting.

Radiology: 5/7 (71%) children had “positive findings suggestive of pneumonia” reported on CXR and/or CT. Examples of these findings were ground glass opacities and segmental consolidation in bilateral lung fields, particularly peripherally.

Bloods: No children had a low lymphocyte count (<0.8). Raised lymphocyte counts were not mentioned but raised WCC was reported in 2/7 (29%) children. 2/7 (29%) had a raised CRP (>10). 4/7 (57%) had a raised AST (>50) or ALT (>37). 5/7 (71%) had increased Brain Natriuretic Peptide (>125). 4/7 (57%) had a raised CK Isoenzyme (>30).

Outcomes: All 7 cases in children were classified as mild and recovered within 1-2 weeks. None of the children were admitted to intensive care and none died.Comparison of clinical characteristics in adults and children: Children were more likely than adults to have diarrhoea and/or vomiting (57% vs. 8%, p=0.012). Adults more frequently had a reduced WCC, compared to a raised WCC in children, and raised CK isoenzyme was less common in adults.

Graselli, GPasenti, AJAMABaseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy06 Apr 2020ItalyEurope4Clinical - Clinical Featureshttps://jamanetwork.com/journals/jama/fullarticle/2764365

This is a retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the regional ICU coordinator of the Lombardy ICU Network, and treated at one of the ICUs of the 72 hospitals in the network. Patients were recruited between 20/02/2020 and 18/03/2020 with follow-up on 25/03/2020. Data was collected via telephone. Of the nearly 1600 patients referred for ICU admission, only 4 were between 0 and 20 years of age, with a median age of 16 and interquartile range of 14 to 19 years of age. Three of the four patients (75%) were male and three of the four had comorbidities (specific details not given).

Two required mechanical ventilation. It’s important to note that the patients in this study were those admitted to ICU and not patients on medical wards, in the ED or in the community so the high percentage of ventilated patients in this study is not a reflection of the other patients in the region with SARS-CoV-2. These two patients had relatively low oxygen requirements with an FiO2 of 30% and 50%; relatively low PEEPs of 5 and 14 mmHg; and favourable PaO2/FiO2 ratios of 195 and 323, placing these two patients in the mild to moderate ARDS severity scores (for more information on PaO2/FiO2 ratios have a look at the LITFL explanation at https://litfl. com/pao2-fio2-ratio/). None of the four patients in the 0-20 year old category received ECMO. Information on disposition was only available for two of the four patients. None of these patients died. Two remained on ICU on 25/03/2020 at time of follow-up.What can we take from this study? As the study recruited patients admitted to ICU, the numbers of adolescent patients in this case series is low at only four, with an age range of 16 to 19. The data was collected retrospectively via telephone making it difficult to draw robust conclusions. However, we can see that compared to the older groups of patients in the study, ventilation requirements were lower. Three of the four adolescent patients had comorbidities, which might suggest that children and adolescents without comorbidities in the Lombardy region were less severely unwell and did not require ICU admission.

Lai, WLiu, JPediatr RadiolComputed tomography of the lungs in novel corona virus (COVID-19) infection06 Apr 2020ChinaAsia2Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04664-7
Canarutto, DBarera, GPediatric PulmonologyCOVID-19 infection in a paucisymptomatic infant: raising the index of suspicion in epidemic settings06 Apr 2020ItalyEurope1Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24754

This early single case report from Milan, Italy describes an infant with mild a mild case of COVID-19 who recovered without need for intervention. His father, the implied household index, had an upper airway infection with conjunctivitis without confirmatory testing.

Patient: 32 day old boy, presented to hospital symptomatic

Clinical Features: Cough, fever, rhinitis

Radiology: CXR normal

Bloods: reactive lymphocytes on film, monocytosis (1400/L) and neutrpenia (900/uL), CRP normal

Outcomes: Resolution of fever by day 3 of hospitalisation, full recovery without need for supportive therapy. Breast feeding maintained.

Lin, LShan, HGutGastrointestinal symptoms of 95 cases with SARS-CoV-2 infection02 Apr 2020ChinaAsia5Clinical - Clinical Featureshttps://gut.bmj.com/content/early/2020/04/02/gutjnl-2020-321013
Xing, YXing, QJournal of Microbiology, Immunology and Infection.Prolonged viral shedding in feces of pediatric patients with coronavirus disease 201928 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://dx.doi.org/10.1016%2Fj.jmii.2020.03.021
Yin XLi HRadiology of Infectious Diseases A mild type of childhood COVID-19 - a case report27 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jrid.2020.03.004
Qui, HLancet: Infectious DiseasesClinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study25 Mar 2020ChinaAsia36Clinical - Clinical Featureshttps://doi.org/10.1016/S1473-3099(20)30198-5

Qui and colleagues retrospectively identified 36 children with an EMR diagnosis of COVID-19, during the period Jan 17 through March 1st, at three hospitals in Zhejiang, China, a province 900km to the east of Wuhan. Diagnosis was made by COVID-19 RT PCR for all patients presenting with fever, cough and radiographic presentation, or if there was a history of exposure to an infected individual.

For the mild cohort, 28% of patients were asymptomatic, with moderate cases more likely to have fever of 38oC or higher (47%), cough (24%), vomiting or diarrhoea (10%) or headache (10%). More than half (53%) of patients had ground-glass opacities on CT scan, meeting the case definition for Moderate illness. Key laboratory values of note include lymphopaenia, leukocytopaenia and increased procalcitonin as all associated with moderate illness. No patients in this cohort were hypoxaemic as a result of their pneumonia.

The authors also draw comparisons between adults and children with COVID-19 (less severe illness, less likely to have abnormal investigations), as well as comparing the clinical features and severity of COVID-19 with SARS (milder symptoms and severity) and H1N1 influenza (fewer symptoms, more frequent pneumonia) in children. Wisely, Qui & colleagues note the high rate of findings that are not clinically obvious, and the high proportion of asymptomatic cases make for very challenging case identification in the absence of clear epidemiologic information. “This finding suggests a dangerous situation if community-acquired infections occur.”

Su, LGai, ZEmerging Microbes and InfectionsThe different clinical characteristics of corona virus disease cases between children and their families in China - the character of children with COVID-1925 Mar 2020Asia9Clinical - Clinical Featureshttps://www.tandfonline.com/doi/full/10.1080/22221751.2020.1744483

This study from the Jinan Infectious Disease Hospital retrospectively reviewed cases of nucleic acid-positive SARS-CoV-2 patients between 24th January to 24th February 2020 (detected using the (ORF1ab/N) nucleic acid detection kit by Bio-germ, Shanghai, China). Nine children and members of their family totalling 14 adults were included. Note that two family members missed enrollment as they were at another hospital. Of the 9 children, 6 were female (66%). The age group ranged from 11 months to 9 years and 9 months old (mean age 4.5 years). For eight of the nine children, there was history of their parents having travelled frequently, being in contact with someone from Wuhan or having worked or visited Wuhan. Of note, five of the discharged children were readmitted to hospital because their stool showed positive results in SARS-CoV-2 PCR.

Clinical Features (children): 3 of the 9 children had fever (33%) and one had cough (11.2%). Imaging (children): On chest x-ray and CT, two children had findings consistent with bronchitis (22.2%), one had bronchial pneumonia (11.1%) and a further one had pulmonary consolidation and ground glass opacity. From the two example images included,, findings appear to be bilateral but this was not specified in the body of the text. Bloods (children): 8 of 9 children (88.9%) had normal or decreased white blood cell counts. Six children (66.7%) had increased CK-MB. ALT, AST. All children had a normal CRP, PCT, ESR and IL-6. Clinical Features (adults): Of the 14 adults, 8 (57.1%) had fever, five had cough (35.7%), three had chest tightness or pain (21.4%), a further three had fatigue (21.4%) and one reported a sore throat (7.1%). Imaging (adults): Ten (71.4%) had abnormal imaging mainly pulmonary consolidation, with 7 (50%) having nodular shadow and 7 (50%) having ground glass opacities. Bloods (adults): Four (28.6%) had reduced whice cell count with seven (50%) having lymphocytopaenia.

Zheng, FJin, RCurrent Medical ScienceClinical characteristics of children with coronavirus disease 2019 in Hubei, China24 Mar 2020ChinaAsia25Clinical - Clinical Featureshttps://doi.org/10.1007/s11596-020-2172-6

This is a retrospective case series of 25 children <14 years of age hospitalised with COVID-19 from 10 hospitals across the Hubei province between February 1st and February 10th 2020. It is unclear how the cases were ascertained. 14/25 were male (54%) and the median age was 3yrs (IQR 2-9yrs). Most patients were <3 years (40%). 2 patients had a background of repaired congenital heart disease (both infants), although we have no more detail than this. Both of these children went on to develop critical illness.Clinical features: 13/25 (52%) had fever, 11/25 (44%) had cough, 3/25 (12%) had diarrhoea, and 2/25 (8%) had nasal congestion, vomiting, breathlessness or abdominal pain.

Bloods: Inflammatory markers were not particularly raised, with a median CRP of 14.5mg/L (IQR 0.93 - 25). 10/25 (40%) patients had lymphopenia.

Radiology: CT chest was normal in 8/24 (32%) with unilateral involvement in 5/24 (20%) and bilateral in 12/24 (48%). Changes typically showed patchy shadows. Younger children appeared more likely to have bilateral lung findings than older children.

Co-infection: Other organisms identified included Mycoplasma pneumoniae (3/25, 12%), Influenza B (2/25, 8%) and one of the 2 critically ill children had Enterobacter aerogenes.

Lou, XTian, YJournal of Paediatrics and Child HealthThree children who recovered from novel coronavirus 2019 pneumonia22 Mar 2020ChinaAsia3Clinical - Clinical Featureshttps://doi.org/10.1111/jpc.14871

This is a case series of 3 children diagnosed with COVID-19 and admitted in the Zhengzhou University Children’s hospital in Henan Province, China (dates not provided). They were 2 sisters aged 6 and 8yrs, and a 6m old infant. The children were all infected by a family member, although the family of the 6m infant had no link to Wuhan.

Clinical features: All 3 had a fever, 2 had nasal congestion and rhinitis alongside fatigue, diarrhoea, and headache. The 6yr old girl had a cough.

Radiology: All 3 patients had CT scans with bilateral infiltrates

Bloods: Not reported

Outcomes: No children required intensive care/intubation or had any severe complications. All have been discharged. The 2 sisters were treated with nebulized interferon.

Liu HLan WJournal of InfectionClinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children21 Mar 2020ChinaAsia4Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.007

This study is a review of CT imaging findings in children and pregnant women in a hospital in the Hubei Province. Four children with confirmed COVID-19 infection were included in the study. The bottom line is that pulmonary CT changes in children were mild, with either focal ground glass opacification or focal consolidation. Although CT has been reported as a useful screening tool in adults with suspected COVID-19 infection, the CT changes of the four children were non-specific; the authors conclude that exposure history and clinical symptoms are more helpful for screening in swab-negative children than CT. 41 pregnant women with either laboratory-confirmed or clinically-diagnosed COVID-19 infection were included in the study. All pregnant women had mild courses of their COVID-19 illnesses. Six of the 16 laboratory-confirmed pregnant women and 10 of the 25 clinically diagnosed pregnant women delivered during the study period. There were no cases of vertically transmitted COVID-19 in the neonates born to these pregnant women.

Case 1: 5 year old female with fever, cough and fatigue. No lymphadenopathy. Bloods: low WCC with raised lymphocytes and decreased neutrophil ratio. Normal CRP. CT: normal. Follow-up CT 9 days later remained normal.

Case 2: 11 month old male with fever and cough. No lymphadenopathy Bloods: normal WCC with raised lymphocyte count and decreased neutrophil ratio. Normal CRP. CT chest: single consolidation without peripheral predominance (unlike reported findings in adults).

Case 3: 9 year old female with fever but no cough. No lymphadenopathy. Bloods: normal WCC, low lymphocytes and normal neutrophil ratio. Normal CRP. CT chest: single ground glass opacity without peripheral predominance (unlike reported findings in adults).

Case 4: 2 month old male with cough but no fever. No lymphadenopathy. This infant was coinfected with RSV. Bloods: normal WCC with normal lymphocytes and normal neutrophil ratio. CRP raised (does not say how high). CT chest: multiple focal consolidations and pleural effusion. This infant’s CT findings were more severe than the other three children, thought to be due to coinfection with RSV.

Lu, XWong, GWKNEJMSARS-CoV-2 infection in children18 Mar 2020ChinaAsia171Clinical - Clinical Featureshttps://www.nejm.org/doi/full/10.1056/NEJMc2005073

This retrospective study examines the clinical characteristics of children with confirmed COVID-19 diagnosed at Wuhan Children’s hospital. There were 1391 children tested between Jan 28th and Feb 26th 2020 due to known contact with a case of COVID-19, of these 171 were confirmed to have SARSCoV-2. Median age was 6.7yrs, and there was a relatively even spread amongst age groups. Children were predominantly male (104/171, 60.8%).

Clinical features: 83/171 had cough, 79/171 had pharyngeal inflammation (sore throat), 71/171 had fever. 15/171 had diarrhoea and 13/171 had rhinorrhoea. 49/171 were tachypnoeic on admission and 72/171 were tachycardia. Only 4/171 had Oxygen saturations <92% during hospitalisation. 0/31 infants <1yr were asymptomatic in this cohort, with rates of asymptomatic infection increasing with age. There were higher rates of pneumonia in infants (25/6), but the definition of this is unclear. We also have no information regarding co-infection with other viruses or bacteria.

Radiology: Not delineated into CXR or CT, but descriptions sound like CT findings. The most common was bilateral ground glass opacity (56/171) followed by unilateral patchy shadowing (32/171) and bilateral patchy shadowing (21/171). There were several children with radiographic pneumonia who were asymptomatic.

Bloods: The supplementary appendix contains lab results. Only 6/171 patients had lymphopaenia, the vast majority were in normal range (Med 2.9×109/L, IQR 2.2 – 4.4). CRP was elevated (>10mg/L) in 33/171 (Med 4, IQR 1.3 – 8) of which 27/33 had pneumonia.

Outcomes: 3 patients required ITU admission and intubation. All 3 had comorbidities, including hydronephrosis, leukaemia and intussusception. The child with intussusception suffered multiorgan failure and died after 4 weeks. The cause of death is not clear from the report. As of writing 149 patients had been discharged with 21 stable in the general wards.

Cui, YZha, YJournal of Infectious DiseasesA 55-day-old female infant infected with 2019 novel coronavirus disease: presenting with pneumonia, liver injury, and heart damage17 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa113/5807961

This is a case report of a 55 day old with SARS-CoV-2 who was admitted to hospital in China on February 2, 2020. She was treated with inhaled intereron-alpha-1b, amoxicillin, reduced glutathione, ursodeoxycholic acid, and traditional Chinese medicine lotus qingwen. The child was initially well, although her respiratory status worsened on day 2-6, and she required supplemental oxygen via nasal cannulae. Anal swabs on day 11 and 13 were positive on day 11-13 despite negative pharyngeal swabs.Note is made in the title of this study that the infant sustained liver injury and heart damage. This is on the basis of marginally elevated liver tranaminases and cardiac troponin measurements, for which it is unclear why the tests were performed. There is no indication of any clinical compromise demonstrated. It should be noted that a significant proportion of the child’s care (including investigations) would not be considered standard practice in UK/US/Aus paediatric medicine.

Zhang, CZhou, XMedRxIVClinical characteristics of 34 children with coronavirus disease-2019 in the West of China: a multiple-center case series16 Mar 2020ChinaAsia34Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.12.20034686v1

A pre-print, the information should be treated with caution until it has undergone peer review.This is a further retrospective case study looking at 34 children with confirmed COVID-19 between Jan 1st and Feb 25th 2020 in 4 hospitals in Western China. They were aged 1 month to 12 years.

Clinical features: The most common symptom was fever (26/34) followed by cough (20/34), followed by vomiting (4/34) and diarrhoea (4/34). A significant number had co-infections (16/34) including Mycoplasma pneumoniae (9/34), influenza A or B (12/34) and 2/34 were mononucleosis. One child had a nephroblastoma and one had asthma. The median incubation period was 10 days (IQR 7.75 – 25.25) and median 3 days (IQ 2 – 4) from admission to fever resolution

Bloods: Lymphocytosis was most common (17/34). CRP was not significantly elevated (median 7.56ml/L, IQR 1.21 – 15.13), but was >5 for 20/34, and procalcitonin was not significantly elevated either (0.6, 0.03 – 0.07)

Radiography: On chest CT 14/34 had patchy shadows bilaterally, 14/34 unilaterally, and 6 had normal CT chest.

Ji, LJian, RWorld Journal of PediatricsClinical features of pediatric patients with COVID-19: a report of two family cluster cases16 Mar 2020ChinaAsia2Clinical - Clinical Featureshttps://dx.doi.org/10.1007/s12519-020-00356-2

This is a review of two confirmed paediatric cases of COVID-19 (both from oropharyngeal swabs) from two family clusters with recent travel to Wuhan. One child presented with fever and the other with diarrhoea.

Case one: 15-year-old boy presenting with a one-day history of fever. Clinical features: Temperature 37.9oC, pharyngeal congestion. Normal lung auscultation. Laboratory findings: mildly elevated white cell count at 11.82 x109/L, predominantly neutrophils (67.3%) and 25.7% lymphocytes. His CRP was mildly elevated at 35 mg/L. Radiological findings: normal unenhanced CT chest. Outcome: Symptomatic treatment. Symptoms disappeared after two days. Family information: both parents also tested positive for SARSCoV2.

Case two: 9-year-old boy presented with mild diarrhoea but no cough and no fever. Normal examination. Laboratory findings: normal white cell count and normal CRP. Radiological findings: normal unenhanced CT chest. Outcome. Treated with oral probiotic and symptoms disappeared after 2 days. Family information: Family members had negative COVID-19 swabs but were symptomatic. His mother presented with fever and cough with bilateral peripheral ground glass opacifications on CT chest. The child’s father and two-year old sister had normal CT chests but had mild symptoms consistent with COVID-19: his father had a cough for four days and his twoyear-old sister had a transient two-day low-grade fever.

Xu, YGong, SNature MedicineCharacteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding13 Mar 2020ChinaAsia10Clinical - Clinical Featureshttps://doi.org/10.1038/s41591-020-0817-4

This study presents the results of widespread screening for COVID-19 in Guangzhou in China. 745 children were screened of which 10 were positive for COVID-19. Their ages ranged from 2 months to 15 years.

Clinical features: 6/10 had a fever over 38oC. 5/10 had a cough. 4/10 had a sore throat. 2/10 had rhinorrhoea and 2/10 had diarrhoea.

Radiography: 7/10 had coarse lung markings on CXR with no pneumonia, and 3/10 were normal. CT scans revealed ground glass or patchy opacities in 5/10.Bloods: Basically normal in all cases

They made note that rectal swabs were frequently positive and that these swabs were positive for a longer duration than nasal swabs. The authors suggest on this basis that faecal-oral transmission may be possible, however this is very uncertain and will require further research to elucidate.

Xing, YXing, QmedRxivProlonged presence of SARS-CoV-2 in feces of pediatric patients during the convalescent phase13 March 2020ChinaAsia3Clinical - Clinical Featureshttps://www.medrxiv.org/content/10.1101/2020.03.11.20033159v1

A pre-print, the information should be treated again with caution until it has undergone peer review.

This study of 3 paediatric patients with COVID-19 from Qingdao, China (aged 1.5, 5 and 6 years) all had fevers and none were severe. All children had elevated lymphocytes (>4.4 x 109/L) and 2 of 3 had abnormalities on chest CT (consolidation in one and ground glass changes in the other). The primary point made in the paper is that whilst respiratory swabs were negative within 2 weeks after children became afebrile, stool remained positive for over 4 weeks.

Liu, WLiu, YNEJMDetection of COVID-19 in children in early January 2020 in Wuhan, China12 Mar 2020ChinaAsia6Clinical - Clinical Featureshttps://doi.org/10.1056/NEJMc2003717

This letter to the editor describes a case series from Tongji hospital in Wuhan, China, taken from a cohort of 366 hospitalized children between January 7th and 15th 2020. 6 children were PCR Positive for COVID-19. Of the 6 patients, age range 1-7 years. All had fever >39oC, cough and 4/6 had vomiting. All had lymphocytopenia, with 4/6 leukopenia and 3/6 with neutropenia. One child required an ICU admission, receiving pooled donor IVIG. The median recovery time was 7.5 days. Authors surmise COVID-19 occurs in children with some moderate-severe episodes of illness.

Li, WLi, SPediatric RadiologyChest computed tomography in children with COVID-19 respiratory infection11 Mar 2020ChinaAsia5Clinical - Clinical Featureshttps://doi.org/10.1007/s00247-020-04656-7

This study describes five children with confirmed COVID-19 who had CT chest scans in a large tertiary level hospital in China. Three of the five children had patchy ground-glass opacities on their CT scans but these changes were less severe than those seen in infected adults. The treatment is not detailed in the paper, so presented as published in this summary.

Case 1: 17 month old asymptomatic male. Bloods: CRP 9.4, WCC 9.2. Radiology: CT chest performed on day 4 showed patchy ground glass opacities. Repeat CT on day 9 after treatment had normalised (antiviral, anti-infective, immunoglobulin, interferon and Lianhua qingwen granules). No CXR.

Case 2: 10 month old asymptomatic female. Bloods: CRP 0.9, WCC 14.8. Radiology: Day 2 scan: normal. Not repeated. No CXR.

Case 3: 3 year old male with coryza, productive cough, sore throat and fever after 3 days. Bloods: CRP 0.7, WCC 15.0. Radiology: Day 9 CT showed patchy ground-glass opacities. Repeat CT on day 16 had normalised after treatment (antiviral, anti-infective, immunoglobulin). No CXR.

Case 4: 4 year old asymptomatic male. Bloods: CRP 0.2, WCC 6.6. Radiology: Day 2 CT chest showed patchy ground-glass opacities. Repeat CT on day 7 had normalised after treatment (montelukast, immunoglobulin). No CXR.

Case 5: 6 year old asymptomatic male. Bloods: CRP 0.6, WCC 5.3. Radiology:

Day 3 CT was normal. No CXR.

Xu, R.Hu, XQuantit Imag Med and SurgCT imaging of one extended family cluster of corona virus disease 2019 (COVID-19) including adolescent patients and "silent infection" 10 Mar 2020China Asia1Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136726/
Bahar, BDelaney, MJ Peds Kinetics of viral clearance and antibody production across age groups in children with severe acute respiratory syndrome coronavirus 2 infection09 Mar 2020United StatesNorth America641Clinical - Clinical Featureshttps://www.jpeds.com/article/S0022-3476(20)31114-8/fulltext

This is a retrospective study of SARS-CoV-2 viral clearance and antibody production in children. Children with who were tested with a nasopharyngeal SARS-CoV-2 RT-PCR test from March to June 2020 at Children’s National Hospital Washington, US were included.

Overall, there were 641 positive RT-PCR tests in 592 patients (median of 1 test per patient, max 6 tests) and 5777 negative tests (median of 1 test per patient, max 15 tests). 68 patients had more than 1 RT-PCR test. Of the 238 serological tests done, 69 were positive in a total of 58 patients (median of 1 test per patient).

The median duration of RT-PCR positivity was 19.5 days. Of note, children aged 6-15 years had a longer duration of RT-PCR positivity compared with older children (16-22 years) (median 32 vs 18 days). The median time to achieve positive serology was 18 days, however, to reach sufficient levels of neutralising antibodies was 36 days. IgG class antibodies against the S1 and S2 glycoproteins were detected in blood samples of children prior to viral clearance.

This study provides further insight into the kinetics viral clearance and the antibody response in children infected with SARS-CoV-2. The prolonged period of RT-PCR positivity is consistent with other studies in children and adults. Importantly, it is unknown whether this period of PCR positivity correlates with ongoing shedding of viable virus particles capable of transmission. Unfortunately, this study did not include details of symptoms associated with the laboratory results.

Xia, WHu, DPediatric PulmonologyClinical and CT features in pediatric patients with COVID-19 infection: different points from adults05 Mar 2020ChinaAsia20Clinical - Clinical Featureshttps://doi.org/10.1002/ppul.24718

A case series of 20 paediatric patients with COVID-19 infection identified with COVID-19 NAT on pharyngeal swabs from Wuhan Children’s Hospital. It reviews the clinical information and co-infections.

Clinical features: two thirds had a clear contact history. Incubation 24hrs28 days of life. 13/20 had a cough, 12/20 had a fever. Bloods: 11/20 had (N) CRP, i.e. less than 3mg/L and 80% had PCT >0.05.

Radiology: On CT: Subpleural findings were seen in all 20 patients. 50% had bilateral findings, with a further 6/20 with unilateral findings. Consolidation with a halo in 50% of cases, considered as atypical signs in paediatric patien. Chloral hydrate was the primary sedative for CTs These were predominantly mild cases in the paediatric patients, with CXR adding little diagnostically. An early chest CT exam seemed to be necessary. 9/20 had coinfection, most commonly with mycoplasma (4/9) – although the ‘flu B,’flu A or RSV accounted for almost all of the remainder

Despite this, the physical chest symptoms were mild, with retraction in one case, and another case with cyanosis.

The average length of stay 12.9 days. Some patients were managed on the basis of their CT alone. These are similar to those seen in adults.

Lan, L.Xu, H. Korean J Radiol Early CT Findings of Coronavirus Disease 2019 (COVID-19) in Asymptomatic Children: A Single-Center Experience.04 Mar 2020China Asia4Clinical - Clinical Featureshttps://kjronline.org/Synapse/Data/PDFData/0068KJR/kjr-21-919.pdf
Zhu, YFeng, SJournal of Infection Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)03 Mar 2020ChinaAsia1Clinical - Clinical Featureshttps://doi.org/10.1016/j.jinf.2020.03.033
Dong YJiang ZPediatrics Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China01 Mar 2020ChinaAsia2143Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/03/16/peds.2020-0702/tab-figures-data?versioned=true

This landmark paper is a retrospective epidemiological study of 2143 pediatric patients with suspected or confirmed COVID-19 (Jan 16 – Feb 8 2020) from in and around Hubei province in China. Confirmed cases were diagnosed by PCR of NPA or blood or genetic sequencing from the respiratory tract or blood highly homologous with SARS-CoV-2. To be a suspected case you needed to be high risk (based on community exposure) with any 2 of: fever, respiratory symptoms or diarrhoea/vomiting; normal or lower white cell count +/- raised CRP; abnormal CXR. If you were medium/low risk for community exposure, you could still be a suspected case if you met any 2 of the above criteria and had other respiratory viruses excluded. Patients were classed according to severity.

There were 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases. The median age was 7 years. There were 94 (4.4%) asymptomatic, 1091 (50.9%) mild and 831 (38.8%) moderate, accounting for 94.1% of all cases. Of note, the youngest patients (under 1yr) had the highest proportion of severe and critical illness (10.6%). However, this group also had the highest proportion of “suspected” disease (293/379) – of which we do not know how many had an infection with RSV, HPMV or Flu. This was peak bronchiolitis season. There was one death in a 14yr old boy, for which there are no clinical details available. The highest proportion of asymptomatic cases was in the 6-10yr olds (31.9%), for whom there was no recorded critical illness. Critical illness was uncommon in general (0.6% of all cases). The median time from illness onset to diagnosis was 2 days. Chest imaging was emphasized in delineating the severity (CXR and CT). There are also some interesting epidemiology graphs which essentially map to the well-described adult prevalence of disease and demonstrate Hubei as the epicentre.This large cohort study provides reassuring data about the severity of illness of COVID-19 in children. There is an indication that younger infants may be most likely to be affected most severely, however, this cohort is highly likely to contain children with normal, severe, winter viral infections such as bronchiolitis. Critical illness was extremely rare.

Kai-qian, KThoon, KCClinical Infectious DiseasesA well infant with coronavirus disease 2019 with high viral load28 Feb 2020SingaporeAsia1Clinical - Clinical Featureshttps://doi.org/10.1093/cid/ciaa201

This was a case report of a single 6-month-old with a positive nasopharyngeal swab until D16 of admission to hospital. There had been household transmission. There was a positive NPA with rt-PCR on D1 of admission although the child was asymptomatic – daily swabs remained positive until D17. The child was febrile once during the course of admission although they remained asymptomatic. Blood and stool tests were positive on D2.

They had essentially normal investigations except for a neutropenia.

Cai, JZeng, MClinical Infectious DIseasesA case series of children with 2019 novel coronavirus infection: clinical and epidemiological features28 Feb 2020ChinaAsia10Clinical - Clinical Featureshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa198/5766430

This retrospective study examines 10 children diagnosed with confirmed COVID-19 between 19th Jan and 3rd February 2020 at the Children’s hospital in Shanghai. The age range is from 3 months to 11 years. None had comorbidities. There were no severe cases.

Clinical features: The assumed incubation period (time from exposure to index case to developing symptoms) was between 2 – 10 days, but median (and mode) 7 days. With regard to symptoms, 7/10 had fever >38oC, 6/10 had a cough, 4/10 had a sore throat, 3/10 had nasal congestion, 2/10 had rhinorrhea and 2/10 were sneezing.

Radiology: The chest x-ray was normal in 6/10. The rest had unilateral opacities.

Bloods: Lymphocyte counts were normal in 9/10, raised in one case. CRP ranged from 0.5mg/L to 35mg/L but was <10 for 7/10. Procalcitonin was normal (<0.25) in all children. 2 patients had a mild elevation of ALT (100U/L) or AST (142U/L and 51U/L) Detection of SARS-CoV-2: Virus was found in NP/throat swabs in all patients, and the duration of shedding ranged from 6-22 days (Median 12 days). Stool shedding was prolonged, over 30 days in one patient. No urine was positive, and no serum positive.

Chen, CWang, FLancet pre-print serverCoronavirus disease-19 among children outside Wuhan, China25 Feb 2020ChinaAsia31Clinical - Clinical Featureshttp://dx.doi.org/10.2139/ssrn.3546071

A pre-print, the information should be treated with caution until it has undergone peer review. This is a prospective case series of 31 paediatric cases of COVID-19 diagnosed at the Shenzen Third Peoples hospital between Jan 16th and Feb 19th 2020. This made up 7.9% of all cases diagnosed in Shenzen. They were all confirmed by PCR. None had been exposed to the seafood market in WUhan. The patients received nebulised interferon and, IV ribavirin or oral lopinovir/ritonavir. The median age was 6.75, with most patients (41.9%) aged 5-9. Followed by 0-4yrs (32.2%) and 10-14yrs (19.4%). 41.9% were male.Clinical features: 12/31 Children were asymptomatic. Fever was observed in 14/31, Cough in 13/41, Sore throat in 2/31, Rhinorrhoea in 22/31 and diarrhoea in 2/31. Median duration of fever was 2 days, with a range of 1–9 days. Bloods: Lymphopaenia was not observed. Lymphocytosis occurred in 17/31 patients. CRP was elevated in 4/31 patients. Radiology: On admission 64.5% of CT were normal, with 25% having unilateral pneumonia and 9.7% having bilateral. During hospitalization one child developed a unilateral pneumonia whose radiography was initially normal. Outcome: 23 children had been discharged at the time of writing, and the remainder were well and afebrile.

Xu, XWLi, LJBMJClinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: a retrospective case series19 Feb 2020ChinaAsia2Clinical - Clinical Featureshttps://www.ncbi.nlm.nih.gov/pubmed/32075786

This study looks at a group of 62 patients with COVID-19 in a province outside of Wuhan (Hubei). 2 of these were children, aged 10 and 11. There is a lot of clinical data in the paper but it is not broken down by age, so we cannot make any inference on behalf of the paediatric patients.

Wei, MLiu, YJAMANovel coronavirus infection in hospitalized infants under 1 year of age in China14 Feb 2020ChinaAsia9Clinical - Clinical Featureshttps://doi.org/10.1001/jama.2020.2131

This is a case series of, from Dec 8 2019 to Feb 6 2020, from China of 9 infants – all of whom had been hospitalised.

Clinical presentation: 4/9 fever, 2/9 mild URTI symptoms, 1/9 were asymptomatic. All had family members that were COVID-19 positive. There were no severe complications or ICU admissions.

Parri, NMasi, SPediatrics COVID-19 in 17 Italian Pediatric Emergency Departments09 Jan 2020ItalyEurope170Clinical - Clinical Featureshttps://pediatrics.aappublications.org/content/early/2020/09/21/peds.2020-1235

This is a retrospective review of 170 children with confirmed SARS-CoV-2 who presented to Italian emergency departments between March and May 2020. Children in this cohort had a median age of 45 months and 38 (22%) had a comorbidity. Interestingly, under half (70; 41%) had a family member with confirmed SARS-CoV-2, while 21 (12%) had travelled to areas with documented community transmission. Seven (4%) children were infected from an unknown source.

Similar to other cohort studies, the most common symptoms at presentation were fever (48%), cough (43%), decreased feeding (35%) and rhinorrhoea (20%). Of the 13 children (8%) who required respiratory support, 6 had a pre-existing comorbidity. 17% of children who were SARS-CoV-2 positive were asymptomatic.

A chest X-ray was done in 62 children (36%) and showed unilateral patchy infiltrate with ground-glass changes in 20 (32%) and pneumonia in 14 (32%). Chest CT was done in 3 children and 2 had interstitial abnormalities. Point-of-care lung ultrasound was used in 13 (8%) children as an alternative to other imaging modalities, and as an adjunct in 2 children. Of these, 11 (84%) had sonographic features of interstitial disease and 5 showed an additional consolidation.

Three children in this series met criteria for MIS-C. All were febrile with elevated inflammatory markers and received intravenous immunoglobulin and steroids.

This retrospective cohort study is comparable to other similar studies describing cohorts in China, Europe and the United States. Of note, this series included a larger proportion of children <1 year of age and who had only mild symptoms or were completely asymptomatic, likely explained due to differences in testing criteria between countries. The utility of point-of-care ultrasound was demonstrated for diagnosing more severe disease without exposing children to radiation.

Nepogodiev, DBSJFavourable perioperative outcomes for children with SARS‐CoV‐219 Oct 2020United KingdomInternational88Clinical - Comorbiditieshttps://bjssjournals.onlinelibrary.wiley.com/doi/10.1002/bjs.12038

To better understand the surgical risks for children with confirmed SARS-CoV-2, CovidSurg, a multicentre, observational, international cohort study summarised observations of paediatric SARSCoV-2 surgical patients whose diagnosis had been made from 7 days before to 30 days after surgery and in whom surgery was carried out between 1st January and April 30, 2020. On the ground surgical interventions for children were commonly being delayed or cancelled during the foregone Covid-19 pandemic wave due to concerns for risk of nosocomial SARS-CoV-2 infections, concern for perioperative complications and constrained resources for routine surgery. The authors concerns expanded to include health complications when children’s surgical treatments were delayed or cancelled.

Fifty-two hospitals in 21 countries participated. Assessed were 5,388 patients, of whom 88 were children were under 16 years of age, 56 (63.6%). Diagnosis of SARS-CoV-2 was preoperative was in 48(56%) of the children.The majority (89%) of the children required emergency surgery. The distribution of the disease conditions included benign conditions (81%), trauma (11%) and cancer (8%). There was one death (1/88) in the 30 day post-operative period, low compared to confirmed SARSCoV-2 adult post-operative mortality of 23.8% referred to in this research letter. Pulmonary complications (pneumonia/acute respiratory syndrome or unexpected post-operative ventilation problem) occurred in 12 of the 88 (13.6%) children, also considered low compared to adult pulmonary complications of 51.2% in confirmed SARS-CoV-2 post-operative adults reported in the research letter.

This research letter informs but it probably only begins asking the question whether less restrictive surgical rationing policies should be considered for children. The authors’ call for further studies toward answering the question raised is supported. Due to the likelihood of the influence of age and other likely confounders in the adult perioperative SARS-CoV-2 confirmed patients referred to by the authors in the research letter, observation of matched cohorts of perioperative paediatric surgical patients with confirmed SARS-CoV-2 and those without may be a further worthwhile scenario to explore

Kabesch Msingle authorPed Allergy ImmunologyShielding against SARS‐Cov‐2 infection is not justified in children with severe asthma05 Aug 2020EuropeEurope0Clinical - Comorbiditieshttps://doi.org/10.1111/pai.13327

In the UK, severe asthma was one of the diagnoses which mandated ‘shielding’, i.e. remaining at home at all times, during the lockdown, for children and adults. Some doubted whether this was necessary. This brief report suggests that the doubters were right. Using a database which was originally designed to monitor the use of biologic treatments in severe asthma, the author surveyed 37 major asthma centres in 25 European countries. None of the centres were aware of any symptomatic COVID-19 case from March-July 2020 in any of the roughly 1000 children included.

So was this because shielding prevented it? No, because they compared the 4 countries with strict shielding policies (including the UK) with the others where precautions for asthmatics were the same as everyone else. There was no difference.They conclude that shielding is unnecessary, even in the most severe asthmatics.

Wilkes, MRapaport RJ of PediatricsSevere COVID-19 in Children and Young Adults.23 Jun 2020USANorth America10Clinical - Comorbiditieshttps://www.jpeds.com/article/S0022-3476(20)30764-2/pdf
Kulkarni, RKJadhav, TIndian Journal of PaediatricsFatal Covid-19 in a Malnourished Child with Megaloblastic Anemia17 Jun 2020IndiaAsia1Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297666/
Yuksel, MAriKan, CEur J Gastroenterol HepatolImmune monitoring of a child with autoimmune hepatitis and type 1 diabetes during COVID-19 infection16 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://journals.lww.com/eurojgh/Abstract/9000/Immune_monitoring_of_a_child_with_autoimmune.97545.aspx
Akcabelen, Y. M.Yarali, N.Pediatr Blood Cancer: e28443.COVID‐19 in a child with severe aplastic anemia15 Jun 2020TurkeyMiddle East1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28443?af=R
Cesaro, S.Petris, MGPaediatr Blood CancerScreening for SARS-CoV-2 infection in pediatric oncology patients during the epidemic peak in Italy15 Jun 2020ItalyEurope282Clinical - Comorbiditieshttps://doi.org/10.1002/pbc.28466

Observational study of nasopharyngeal presence of SARS-CoV-2 in a cohort of 282 paediatric oncology patient presenting for scheduled care at 14 specialist centres in Italy between 20/02/20 and 19/04/20. Median age for oncology cases (n=247) was 7 years (range 0-17.9) and for stem cell transplant (SCT) patients (n=35) was 9.6 years (range 0.3-17.6). 10/334 swabs from the oncology group were +ve and 0/56 from the SCT group. Only 2/10 NPS +ve patients had any symptoms (both "mild fever").

Chemotherapy was paused for all NPS +ve patients until 2 clear swabs were obtained 24 hours apart. No adverse outcomes were recorded up to the study end but follow up was only reported up to 30/04/20. This study demonstrates that paediatric oncology patients can remain asymtomatic whilst carrying SARS-CoV-2 in the nasopharynx, and recover spontaneously, without any apparent increased rate of adverse outcomes. Researchers raise the question of whether routine chemotherapy needs to be paused for asymptomatic NP carriage of SARS-CoV-2 but present no evidence for the safety of this course of action.

Flores, VLenica A, CAnn Hematol.SARS-CoV-2 infection in children with febrile neutropenia12 Jun 2020MexicoSouth America3Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289627/

This letter to Annals of Hematology offers a brief description of three children with ALL who presented with febrile illness and were found to be SARS-CoV2 PCR positive. The letter is of note as sadly one of the children died during this illness following cardiac arrest; the authors offer the paper to highlight the occurrence of SARS CoV2 in febrile neutropenic patients; however it prompts further analysis of those cases of severe infection in the context of immunosuppression.

The patients were identified at a centre in Mexico however the time period is not known. The three patients were aged 4yrs, 8yrs and 9yrs. All had ALL, two receiving consolidation chemotherapy and one on immunosuppression with mycophenolate and prednisolone. The latter patient had undergone HSCT for ALL, the time since HSCT was not provided, however this patient was admitted from the community suggesting she wasn’t in the immediate post-transplant period. All patients developed neutropenia either at time of fever or quickly following it and similarly evolved to have ‘respiratory symptoms’. All had negative blood cultures however results of other virology is not provided. Over-all pre-covid health status is not provided within the letter and this might be helpful in understanding the severity of symptoms in the patient who died.

The child who died was 8 years old and presented with febrile neutropenia, they were on mycophenolate and prednisolone following HSCT for ALL. The child quickly developed respiratory distress and required invasive mechanical ventilation; a heamodynamic deterioration led to cardiac arrest and resuscitation measures failed.

The distinguishing features of this child was her immunosuppression and history of HSCT, she was also more profoundly lymphopenic and thrombocytopenic. All other laboratory values were variable between all three patients. Further information on her overall cardiorespiratory status pre-SARS-CoV-2 would be helpful to understand her vulnerabilities and to guide management of children presenting with similar comorbidities in the future.

Gine, CLopez, MJ Laparoendosc Adv Surg Tech A .Thoracoscopic Bullectomy for Persistent Air Leak in a 14-Year-Old Child With COVID-19 Bilateral Pulmonary Disease11 Jun 2020SpainEurope1Clinical - Comorbiditieshttps://www.liebertpub.com/doi/abs/10.1089/lap.2020.0289
Anurathapan, U.Hongeng, S.Bone Marrow Transplantation; www.nature.com/bmt/Hematopoietic stem cell transplantation from an infected SARS-CoV2 donor sibling11 Jun 2020ThailandAsia2Clinical - Comorbiditieshttps://www.nature.com/articles/s41409-020-0969-3
Du, HGao, YAllergyClinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status10 Jun 2020ChinaAsia183Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1111/all.14452
Sabatino, JDi Salvo, GJ Clin MedCOVID-19 and Congenital Heart Disease: Results from a Nationwide Survey08 Jun 2020ItalyEurope4Clinical - Comorbiditieshttps://www.mdpi.com/2077-0383/9/6/1774
Alloway, B. C.Hardy, G.Radiology Case reports Suspected case of COVID-19-associated pancreatitis in a child.06 Jun 2020USANorth America1Clinical - Comorbiditieshttps://reader.elsevier.com/reader/sd/pii/S1930043320302569?token=2F2186726A3F368F41FAC9F6CCCAB2CE9CB00D44308E9ADA898D0795CFDBF9CC12EE79807C3C0390C107B51CF81D49EA
Wahlster, LSankaran, VG Pediatr Blood CancerCOVID-19 presenting with autoimmune hemolytic anemia in the setting of underlying immune dysregulation.03 Jun 2020USANorth America1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28382?af=R
Tennuri, UMiyatani, HClinics (Sao Paulo)Low Incidence of COVID-19 in Children and Adolescent Post-Liver Transplant at a Latin American Reference Center03 Jun 2020BrazilSouth America6Clinical - Comorbiditieshttps://www.scielo.br/pdf/clin/v75/1807-5932-clin-75-e1986.pdf
Mirzaree, SMMVossough, ARadiologyFocal Cerebral Arteriopathy in a COVID-19 Pediatric Patient 02 Jun 2020IranMiddle East1Clinical - Comorbiditieshttps://pubs.rsna.org/doi/pdf/10.1148/radiol.2020202197
Harman KGupta ALancetEthnicity and COVID-19 in children with comorbidities28 May 2020UKEurope12Clinical - Comorbidities https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(20)30167-X/fulltext

Between 25 February 2020 and 28 April 2020, 12h children aged 0 to 16 years with confirmed COVID-19 who required admission to hospital were prospectively identified at Kings College Hospital London. 5 of these had known comorbidities (identified here as Group A) and 7 had no known comorbidities (Group B).

Age: Median age of Group A was 7.1yrs (range 0.2-15.3 with 2 <1 yr) and Group B was 4.8yrs (range 0-15.4).

Gender: 40% (n=2) in Group A and 71% (n=5) in Group B are male gender.

Ethnicity: 80% (n=4) in Group A and 71% (n=5) in Group B were from a black, Asian and minority ethnic (BAME) group.

Comorbidities: In Group A pre-existing comorbidities included cerebral palsy, prematurity, Wilsons disease, and dilated cardiomyopathy.

Clinical features: Most common symptoms on admission in group A and B respectively were fever (60%, n 3/5 and 86% n 6/7) and tachypnoea (60% n 3/5 and 71% n5/7). Liver dysfunction was observed in 4/5 patients in Group A but 2 had underlying liver conditions including one with Wilsons disease who has since had a liver transplant.

Radiology: In Group A radiological evidence of new infiltrates was seen in 50% (n2/4) of patients in Group A who had an x-ray because of clinical indication.

Bloods: In Group A 3 /5 patients had lymphopenia and thrombocytopenia, 3 /4 had raised CRP, 4/5 had liver dysfunction but 2 of these had underlying liver disease, 1/5 had renal dysfunction. None had symptoms that would be compatible with multisystem inflammatory syndrome. No blood data given for Group B.

Outcome: Median length of stay in hospital for Group A was 20 days (range 7-84 days) with 1child with liver transplant still an inpatient on 20th May 2020. For Group B the median stay was 3 days ( range 1-8 days); 1 admitted to hospital for safeguarding concerns and another was a neonate with vertical transmission of Covid-19.

Other salient feature: During this period 2288 adults were admitted to Kings College Hospital so children only formed 0.5% of total admissions. in Group A all children received antibiotics, 1 remdesivir and 1 hydroxychloroquine.

This case study presents data on 12 children with COVID-19 (5 of whom had comorbidities) admitted to Kings College Hospital London during 25th Feb-28th April 2020.

It is noteworthy that 75% of the total children admitted with Covid-19 and 80% of 5 children who had comorbidities were from a black, Asian, and minority (BAME) communities. Even keeping in mind that in Inner London 39% of the population is BAME, this data suggests that ethnicity in children may be an independent risk factor for severe disease. Conclusion is that Children from BAME communities particularly if they have comorbidities, may be at greater risk of severe disease from COVID-19. This is particularly significant given the ongoing investigation into the increased rates of severe COVID-19 infection in adults from BAME backgrounds.

This is a relatively new observation in children and although the numbers are very small, justifies considering this paper to be important.

Ferrari, ABalduzzi, APediatr Blood CancerChildren with cancer in the time of COVID-19: An 8-week report from the six pediatric onco-hematology centers in Lombardia, Italy26 May 2020ItalyEurope286Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28410

This Letter to the Editor describes the findings of 6 paediatric haematology and oncology centres in Lombardy during the 8 weeks after the COVID-19 pandemic began in Italy. Between 20th February 2020 and 15th April 2020 286 patients were tested for COVID-19 when accessing services at these centres: 74 were symptomatic, 25 had close contact with a diagnosed case and 187 were tested for screening purposes. Of these, 21 cases tested positive for COVID-19, with a median age of 6 years (range 1-17 years) and 48% were male.

Of the 21 cases 10 had leukaemia, 5 had soft tissue or bone sarcoma, 2 had lymphoma, two had hepatoblastoma, 1 had a CNS tumour and 1 had colon carcinoma. 15 patients were currently receiving treatment while 6 had completed treatment and were receiving follow up.

Clinical features: 1 patient (who had existing neurological respiratory impairment) developed aspiration pneumonia requiring respiratory support, and 1 developed atypical bilateral pneumonia with mild symptoms.

Outcomes: There were no deaths related to COVID-19 infection. Cancer treatment was modified in 10 cases (delaying chemotherapy, reducing drug doses and postponing surgery).

The authors observe that despite the overwhelming rate of COVID-19 in the general population in the region at the time, relatively few paediatric cancer patients were symptomatic, or tested positive for the virus, and that severe illness was rare. They suggest that these results may indicate that paediatric anti-cancer treatments could continue without major adjustments, especially as alterations may reduce their efficacy.

Of note, these centres experienced a reduction in newly diagnosed cancer cases to 55% of the expected rate, which may reflect delayed access to healthcare services.

Issitt, RWSebire, NJmedRxivCoronavirus (COVID-19) infection in children at a specialist centre: outcome and implications of underlying high-risk comorbidities in a paediatric population25 May 2020UKEurope166Clinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.05.20.20107904v1

A retrospective cohort study published by Great Ormond Street Hospital (GOSH), London, UK suggested children who are defined as vulnerable in the COVID-19 pandemic era do not appear to be at significantly increased risk of being admitted to hospital with COVID-19. In addition, the vulnerable group have similar outcomes to those who are COVID-19 negative. However, the authors do identify children undergoing chemotherapy or radiotherapy are ‘over-represented’ in the vulnerable group. Data was collected from the institution’s electronic health record system. The inclusion criteria were any patient admitted between 01/03/2020 and 15/05/2020 who was admitted with features suggestive of COVID-19 based on the attending clinician’s interpretation, of undefined grade, including fever, cough and “systemic symptoms”. Children were defined as COVID-19 positive by a positive PCR test for nucleic acid in respiratory or blood specimens performed at the referring or presenting hospital or a documented positive familial test. Patients were classified as vulnerable if they fulfilled the high risk shielded list from NHS digital or the institutions local policy that was not provided. Due to the nature of the specialist paediatric services the population of children were highly selected.

166 children fulfilled the criteria; 65 (38.7%) were COVID positive and 101 (60.8%) were negative. The average age for COVID positive group was 9 years [IQR 0.9-14] with 38 (58.5%) males. This compared to the COVID-19 negative group with an average age of 1 year [0.1-5.75], 58 (55.4%) male. The COVID-19 positive patients were significantly older (p<0.001). Differences in ethnicity frequency was statistically significant for Asian ethnicity: 12 (8.5%) COVID-19 positive compared to 6 (5.9%) in the COVID-19 negative group (p=0.02).

The number of vulnerable children who were COVID-19 positive totalled 31 (47.7%) compared to 73 who were COVID-19 negative (72.3%), demonstrating a lower number of vulnerable children were positive for COVID-19, (p=0.002).

Clinical features: Breakdown of symptoms were not provided

Radiology: N/A

Bloods (For those COVID-19 positive):

ALT 41.5 U/L [IQR 29-74], Albumin 32 g/L [IQR 27-36], AntiDNAse 310U/mL [80.8-402], AntiStreptolysin O 285 IU/mL [134-384], AST 70 U/L [43-100], CRP 28 mg/L [10-74], CK 63.5 U/L [35-214], Creatinine 23 umol/L [14-46], D-dimer 1876 ug/L [1043-3618], Ferritin 788 ug/L [445-1863], Fibrinogen 3.65 g/L [2.4-4.8], Interleukin-6 50 pg/ml [50-152], Interleukin-10 50pg/mL, LDH 848 U/L [654-1136], BNP 3550 pg/ml [626-6992], Lymphocytes 1.44 X10^9/L [0.64-2.49], Neutrophils 3.90X10^9/L [1.46-8.6], WBC 8X10^9/L [3.38-13.2], Troponin I 54 ng/L [13-157], Prothrombin time 12 seconds [11.3-13], bilirubin 6 umol/L [3-10], Triglycerides 2.48 mmol/L [1.65-3.56].

The results highlight the difference in results between the COVID positive and negative groups but do not define further differences between vulnerable and non-vulnerable groups. These include a statistically higher average CRP (p=0.002, fibrinogen (p<0.001), albumin (p0.02) neutrophil (p<0.001) and white blood cell count (p<0.001) and a lower LDH (p=0.002),

Treatments: Patient were treated following national or speciality specific guidance. No further information was provided.

Outcomes: Mortality for those who were COVID-19 was 1 (1.5%) who was in the vulnerable group. Additional comments described the primary focus of treatment was aspiration pneumonia. This compared to 4 (4%) in the non-COVID-9 group, all of whom were in the vulnerable group. The difference in mortality rates was not statistically significant.

There was no difference in the proportion of vulnerable patients based on their COVID-19 status: 61% of vulnerable patients who were COVID-19 positive compared to 64.3% who were negative, (p = 0.84). Overall, comparing all patients, a significantly lower proportion of COVID-19 positive patients required mechanical ventilation (27.7%) than COVID-19 negative patients (57.4%), (p<0.001). The individual number of patients were not provided.

The average ICU length of stay for those with COVID-19 was 4 days [2.4-10.6]. For those in the vulnerable subgroup the average was 11 days [3.7-15.1]. The significance of the difference between the vulnerable and non-vulnerable group was not described. However, vulnerable non-COVID-19 patients had a 6 [2.8-12.2] day stay in ICU. The difference between vulnerable COVID-19 positive and negative groups demonstrated no significance (p=0.3).

The average total hospital stay for vulnerable patients with COVID-19 was 16.2 days [3.8-20.8]. This compared to vulnerable COVID-19 negative patient were in hospital for 12.3 days [5.2-19.8]. The difference in duration was not significant (p=0.94).

Other salient features: Breaking down conditions that comprises vulnerable children there was a significant increased number of children with cancer undergoing active chemotherapy or radiotherapy who were admitted to hospital with symptoms and COVID-19 positive status compared to with symptoms but COVID-19 negative [7 VS 3 (p=0.01)]. There was no statistical differences between the COVID-19 positive and negative categories with on the national transplant, transplant medication, haematological cancer, respiratory and rare genetic, metabolic and autoimmune conditions lists or local severe respiratory conditions, rare diseases immunosuppressive therapies and other potential factors lists.

Barsoum, ZSN Comprehensive Clinical MedicinePediatric Asthma & Coronavirus (COVID-19)-Clinical Presentation in an Asthmatic Child—Case Report19 May 2020Northern IrelandEurope1Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s42399-020-00310-3.pdf
Hains, DKrammer, FJAMAAsymptomatic Seroconversion of Immunoglobulins to SARS-CoV-2 in a Pediatric Dialysis Unit14 May 2020USANorth America3Clinical - Comorbiditieshttps://jamanetwork.com/journals/jama/fullarticle/2766215
Boulad, FBouvier, NJAMA Oncol.COVID-19 in Children With Cancer in New York City13 May 2020USNorth America20Clinical - Comorbiditieshttps://jamanetwork.com/journals/jamaoncology/fullarticle/2766112

This research letter reports the results of SARS-CoV-2 screening of patients and caregivers from one of the largest paediatric cancer centres in the US (Memorial Sloan Kettering Cancer Center, New York) in a region with very high levels of community SARS-CoV-2 transmission.

From March 10th to April 12th 2020, inpatients and outpatients with either symptoms of or exposure to SARS-CoV-2 infection underwent RT-PCR testing. Asymptomatic patients were also tested prior to admission, deep sedation and or myelosuppressive chemotherapy, as were caregivers of children being admitted.

Overall 11% (20/178) of paediatric patients returned a positive SARS-CoV-2 result; including 29.3% in the symptomatic / exposed group and 2.5% in the asymptomatic group. In contrast 14.7% (10/76) of asymptomatic caregivers were positive. Despite close contact, 5 of the 10 children of caregivers with SARS-CoV-2 were uninfected.Only 1 of the 20 paediatric patients required hospitalisation for COVID-19 symptoms, without need for critical care.

This data provides reassurance that children with cancer may not be more vulnerable to complications of SARS-CoV-2 infection compared to other children. The lack of specific clinical detail in this report limits the ability to draw more definitive conclusions regarding risk.

The lower rate of asymptomatic carriage in children relative to their caregivers provides further evidence that children, including paediatric cancer patients, may be less susceptible to SARS-CoV-2 infection compared with adults.Clearly infection control strategies must consider the risk of nosocomial spread from infected caregivers as well as paediatric patients, particularly in areas with high levels of community transmission.

Marlais, MTullus KLancet Child Adolesc HealthThe severity of COVID-19 in children on immunosuppressive medication13 May 2020Multi-countryMulti-region18Clinical - Comorbiditieshttps://www.thelancet.com/pdfs/journals/lanchi/PIIS2352-4642(20)30145-0.pdf
Bush, R.Upadhyay, K.Am J TransplantMild COVID-19 in a Pediatric Renal Transplant Recipient13 May 2020USANorth America1Clinical - Comorbiditieshttps://pubmed.ncbi.nlm.nih.gov/32406181/
Zhao, YGao, GPediatr Infect Dis JFIRST CASE OF CORONAVIRUS DISEASE 2019 IN CHILDHOOD LEUKEMIA IN CHINA12 May 2020ChinaAsia1Clinical - Comorbiditieshttps://journals.lww.com/pidj/Abstract/9000/FIRST_CASE_OF_CORONAVIRUS_DISEASE_2019_IN.96166.aspx
Angelletti, AForno, RClin TransplantRisk of COVID-19 in young kidney transplant recipients. Results from a single-center observational study12 May 2020ItalyEurope64Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ctr.13889

Giannina Gaslini Children’s Hospital, Italy undertook this prospective observational study of patients, who received a kidney transplant between January 2010 and March 2020, with stable graft function and were taking chronic immunosuppressant therapy. They were interviewed weekly between 24th February and 12th April 2020 for 7 weeks, using a 12-point structure questionnaire contained in the appendix, to evaluate the health status of themselves and their cohabitants. The data for adults and children were combined presenting a median age of 20 (2-30) years. The demographics were reported as a combined total; 93 were male.

2 patients, an adult (information not included) and 1 girl aged 13, had co-habitants who were positive for SARS-CoV-2. The 13-year-old had a kidney transplant aged 9 years old. At the time of study, she was taking a combination of steroid, calcineurin inhibitor (CNI and mycophenolate mofetil (MMF) and had investigations including a white cell count and haemoglobin within normal limits.

She tested negative for SARS-CoV-2 using a nasopharyngeal swab (test not declared) and did not develop any symptoms in the subsequent 21 days, declared as the incubation period. Anti-SARS-CoV-2 antibodies were also negative at an undefined time point.

Clinical features: No patients developed any clinical symptoms.

Radiology: None discussed.

Bloods: None discussed for patients who were positive for SARS-CoV-2.

Treatments: None.

Outcomes: None.

Other salient features: The authors recommend avoiding altering the immunosuppressive therapy in young transplant recipients who do not have symptoms of SARS-CoV-2 including those who are exposed to positive close contact. Despite observing a relatively large population of kidney transplant recipients, a small number, 2 (1 child) were exposed to SARS-CoV-2, upon which has the conclusions are based.

Koczulla, RAKneidinger, NAmerican Journal of TransplantationSARS-CoV-2 infection in two patients following recent lung transplantation12 May 2020GermanyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.15998
Blanchon, SRochat, IPediatr PulmonolCOVID-19: A Message of Hope From a Young Girl With Severe Cystic Fibrosis11 May 2020SwitzerlandEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24812
Brenner, EUngaro RGastroenterologyCorticosteroids but not TNF Antagonists are Associated with Adverse COVID-19 Outcomes in Pateitns with Inflammatory Bowel Disease: Results from an International Registry. 08 May 2020USANorth America30Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0016508520306557

This is a pre-proof article and therefore has not yet undergone final editing and review.This is an article from America (Carolina) aiming to characterise the clinical course of COVID-19 on patients with inflammatory bowel disease (IBD) and evaluate the association between demographics, clinical characteristics and immunosuppressant treatments of COVID-19 outcomes.

The authors created a surveillance database and healthcare providers were encouraged to voluntarily report all cases of Polymerase Chain Reaction (PCR)-confirmed COVID-19 patients with IBD. A website was developed to enable international contributions. Contributors were asked to report cases a minimum of 7 days from symptom onset and after sufficient time had passed to observe disease course through to resolution of acute illness or death.

525 patients from 33 countries were reported. 7% had severe COVID-19, 31% were hospitalised, 3% of patients died. The median age of patient was 41 years (from 5 to 90). The majority of patients had Crohns Disease (59.4%) and IBD disease activity was classed as remission in 58.9% of cases. The most common class of treatment was TNF antagonist therapy (43.4% of patients).

63.5% of patients had no comorbidities other than IBD. Most patients who died had other co-morbidities. Only 3 paediatric patients (10% of paediatric cases) required hospitalization. After controlling for all other covariates use of systemic corticosteroids and ASA/sulfasalazine use were strongly associated with more serious outcomes after infection with COVID-19 but there was no significant association seen between TNF antagonist use and adverse outcomes.

The authors observed an age-standardized mortality ration of approximately 1.5-1.9 as compared to the general populations of China, Italy and the U.S.

They state it is reassuring that the most commonly used treatment- TNF antagonists- appears not to lead to increased adverse outcome for patients infected with COVID-19.

This study has strength in that it includes data from many countries although how comparable that data can be between countries is debatable. The authors did not look at dosing regimens or what was done in terms of continuing or postponing treatment which may well have varied from one country to another. There may also be some bias towards patients who were unwell enough to present to hospital, there may have been other patients who were infected but not unwell enough to require hospital treatment/testing for COVID-19 who would not have been included in this study population.

de Rojas, TPerez-Martinez, APediatric Blood and CancerCOVID-19 Infection in children and adolescents with cancer in Madrid08 May 2020Italy Europe15Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28397
Andre, NGandemer, VPediatr Blood CancerCOVID-19 in pediatric oncology from French pediatric oncology and hematology centers: High risk of severe forms?08 May 2020FranceEurope33Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/full/10.1002/pbc.28392
Morand, AFabre AArchives de PediatrieChild with liver transplant recovers from COVID-19 infection. A case report. 06 May 2020franceEurope1Clinical - Comorbidities https://www.sciencedirect.com/science/article/pii/S0929693X2030110X

This a case report form France of a 2-and-a-half-year-old girl who recovered from COVID-19 infection, 5 months after a liver transplant; she had co-infection with Epstein-Barr virus (EBV).

The child had received a living donor transplant (father) as she had developed portal hypertension post Kasai portoentemrostoy performed at 53 days of age for biliary atresia.

She had been discharged home 20 days post procedure on tacrolimus immunosuppression therapy and had no immunization against EBV before transplantation.

On day 96 post transplant she was found to have primary EBV infection linked to the transplant- her father was EBV positive- but was asymptomatic of this.

The first developed rhinitis which developed into a fever, cough and tachypnoea. In the few days before this her mother had been hospitalized with pneumonia and found to be COVID-19 positive on nasopharyngeal swab. On day three of the illness the child was referred to hospital where she was found to be positive for COVID-19 on NPA.

On admission she was tachypnoeic with no other signs of respiratory distress, her CRP was low (3). A chest CT showed focal alveolar condensation of the ligula and a stable mediastinal enlargement. Her liver function tests had deteriorated (GGT and AST). An US of the liver showed aggravation of the transplanted biliary tract stenosis and an elevated EBV blood viral load. She was managed symptomatically, and she did not receive any COVID-19 specific treatment.

She recovered from COVID-19 infection despite the high level of immunosuppression caused by her tacrolimus treatment. NPA test samples became negative on day 11. The authors report they reduced the dose of tacrolimus but do not state at which point in the illness nor for how long. They do not state how long it took for her LFTs to return to previous levels nor if there were any consequences of the raised EBV viral load.

The authors suggest liver transplantation is not associated with COVID-19 symptom severity development even when there is high level immunosuppression on tacrolimus. Moreover COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.

It is difficult to draw conclusions based on one case study. Particularly as other studies have shown the severity of COVID-19 is increased when present with other co-morbidities. This particular patient, due to the nature of her original liver insult and the fact that she is a young patient, did not have other co-morbidities, this is often not the case for other patients who have required a liver transplantation.

Michelena, XMarsal, S.Med archivesIncidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs05 May 2020SpainEuropeClinical - Comorbiditieshttps://www.medrxiv.org/content/10.1101/2020.04.30.20086090v1.full.pdf
Sieni, EFavre, CBritish Journal of HaematologyFavourable outcome of Coronavirus‐19 in a 1‐year‐old girl with acute myeloid leukaemia and severe treatment‐induced immunosuppression05 May 2020ItalyEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.16781

This retrospective single case report discusses the progression and treatment of a child with high risk acute myeloid leukaemia having undertaken the third chemotherapy cycle of the induction phase following AIEOP LAM 2013 protocol.

13-month-old female patient attended routine clinic at Myers Hospital, Florence, Italy following completion of the chemotherapy. Routine investigations revealed a low white cell count, haemoglobin and platelet count which necessitated admission for transfusions. The need for admission was the initial reason for testing for SARS-CoV-2. RT-PCR was performed for nasal and pharyngeal swabs. Faecal PCR testing was also positive.

Clinical features: Fever starting on day 3 (the combination of fever and low WCC suggested neutropenic sepsis), vomiting and diarrhoea with negative stool culture.

Radiology: CXR on day 3 showed bilateral reticular markings. A repeat prior to discharge demonstrated “no significant modification from baseline”.

Bloods: Day 0 showed low WCC (80/mmc), haemoglobin (7.9g/dL) and platelet (5000/mmc) count. The elevated CRP was highest at day 5 (7.2mg/dL) and normalised by day 10 (<0.5mg/dL). Additional laboratory investigations included LDH which was highest by day 13 (401 IU/L) and ferratin maximally raised on day 9 (3000 mg/mL). Immunoglobulins were low throughout the illness. On day 3 the results were: IgG 258 mg/dL, IgA 18.7 mg/dL, IgM 7 mg/dL. IL-1β, IL-6, IL-10, TNFα and cardiac enzymes were normal.

Blood microbiology was negative.

Additional laboratory investigations, including cytokines (IL-1β, IL-6, IL-10 and TNFα) and cardiac enzymes, were normal; lactate dehydrogenase slightly increased (up to 401 IU/L at day 13), whereas ferritin values showed moderate elevation from day 9

Treatments: Treatment for neutropenic sepsis with piperacillin-tazobactam and fluconazole was commenced on day 3 due to fever. Hydroxychloroquine day 3-11. On day 4 lopinavir/ritonavir stopping day 12

Outcomes: Was treated on a hospital ward without supplemental oxygen until discharge.

Other features of interest: There was a undetectable viral plasma load by day 16, however nasal swab for SARS-CoV-2 remained positive beyond discharge at day 26. There is no data to suggest a negative test to publication date.

It is unclear if the low WCC, anaemia and thrombocytopenia requiring transfusion was due to the chemotherapy, underlying acute myeloid leukaemia or COVID-19 infection, however, on discharge these values had normalised and were maintained by day 26.

Summary: This case describes a high-risk young patient with acute myeloid leukaemia undergoing chemotherapy presenting with febrile neutropenia. Whilst the symptoms were initially vague, subsequent investigations suggested the underlying cause was SARS-CoV-2. Early anti-viral treatments were commenced. Given the patient’s immunosuppression the authors discuss fears regarding seroconversion, viral dissemination and inflammatory responses which did not occur.

Melgosa, MPerez-Beltran, VPed NephrolSARS-CoV-2 infection in Spanish children with chronic kidney pathologies01 May 2020Spain Europe16Clinical - Comorbiditieshttps://link.springer.com/content/pdf/10.1007/s00467-020-04597-1.pdf
Odièvre, MCorvol, HAm J HematologyDramatic improvement after Tocilizumab of a severe COVID-19 in a child with sickle cell disease and acute chest syndrome01 May 2020FranceEurope1Clinical - Comorbiditieshttps://onlinelibrary.wiley.com/doi/10.1002/ajh.25855

The authors of this case study are based at two hospitals in Paris; in this correspondence they describe the treatment of a 16 year old girl with homozygous sickle cell disease (SCD) admitted to ICU with acute chest syndrome (ACS) and pulmonary emboli complicating COVID-19 pneumonia, in particular the use of Tocilizumab, a humanised anti-IL-6 monoclonal antibody (usual indications include use as immunosuppressant therapy in rheumatoid arthritis and giant cell arteritis in adults and juvenile idiopathic arthritis in children).

Course of SCD prior to admission: The patient had a history of recurrent vaso-occlusive crises and abnormal transcranial dopplers between the ages of 5 and 11 years old, necessitating treatment with exchange transfusions. At 11 years of age she was commenced on daily hydroxyurea with resolution of vaso-occlusive events. She had no history of ACS or pulmonary hypertension; respiratory function and chest radiography were previously normal.

Presentation with COVID-19-19: She presented with isolated fever, with nasophyaryngeal swabs subsequently confirmed as RT-PCR SARS-CoV-2 positive. 7 days later she developed acute chest pain associated with respiratory distress (SpO2 85%).

Radiology: CT pulmonary angiogram (CTPA) showed bilateral pulmonary emboli and bilateral consolidation with right-sided halo sign.

Treatment in ICU: Included non-invasive ventilation, anticoagulation and red cell exchange transfusion followed by simple transfusion (lowest Hb 64 g/L). Based on recent experience in adult SCD patients with COVID-19 disease she also received a single infusion of Tocilizumab (8 mg/kg). The authors report rapid clinical improvement after Tocilizumab with repeat CTPA 5 days later showing complete resolution of pulmonary emboli and consolidation on the right and decrease on the left. She was discharged from hospital 11 days after admission to continue oral anticoagulation for 6 weeks.

Conclusions: Inflammatory cytokines such as IL-6 and TNF- are elevated in COVID-19. COVID-19 pneumonia can cause ACS in SCD patients; there have been several recent reports of successful treatment using Tocilizumab.

Inci Yildirim, ATurkmen Karaagac, AIndian PediatricsCOVID-19 in a Young Girl with Restrictive Cardiomyopathy and Chronic Lung Disease30 Apr 2020TurkeyWestern Asia, Southeastern Europe1Clinical - Comorbiditieshttps://www.indianpediatrics.net/june2020/577.pdf
Russell M.Reardon LThe Journal of Heart and Lung TransplantationCOVID-19 in a paediatric heart transplant recipient: Emergence of donor-specific antibodies 29 Apr 2020UKEurope1Clinical - Comorbidities https://www.jhltonline.org/article/S1053-2498(20)31532-1/fulltext

This is a case report of a 3 year old child who had received a heart transplant at 11 months of age for congenital dilated cardiomyopathy.

Her post-transplant course had been unremarkable except for persistent Ebstein Barr Virus (EBV) viremia. She was on tacrolimus monotherapy.

Her initial symptoms were productive cough with rhinorrhea and nasal congestion, she was not tested for COVID-19 at this point as she had no Centres for Disease Control risk factors for infection and testing was not widely available.

A week later a follow-up telehealth visit was performed and there was improvement in symptoms.Surveillance blood tests demonstrated the following de novo Class II donor specific antibodies: DQ4, DR8 and DQA1*04.

One week later the patient was scheduled for routine admission for intravenous immunoglobulin administration, because of the history of cough had a nasal swab sent for reverse transcriptase polymerase chain reaction testing for COVID-19. Other than an intermittent wet cough she was well, and her observations were within normal limits. She received the immunoglobulin infusion overnight. The next morning the nasal swab was reported as positive for COVID-19 infection.

The patient remained well without symptoms of respiratory distress. Repeat COVID-19 nasal polymerase chain reaction testing was planned for 2 weeks with IVIG administration repeated every month for 2 more months. The authors report that although the patient tolerated IVIG administration with concurrent COVID-19 infection without any notable reaction they would be hesitant to attempt more aggressive forms of desensitisation with active infection until more clinical knowledge of COVID-19 is available.

Climent, F. J.Pérez-Martínez, ARev Esp Cardiol (Engl Ed). Fatal outcome of COVID-19 disease in a 5-month infant with comorbidities27 Apr 2020SpainEurope12Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183979/pdf/main.pdf
Schwierzeck, VKampmeier, SClin Infect DisFirst reported nosocomial outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric dialysis unit27 Apr 2020GermanyEurope13Clinical - Comorbiditieshttps://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa491/5825509

This paper presents the results of an outbreak investigation following a member of staff on a paediatric dialysis unit developing confirmed COVID-19. Detailed contact tracing was carried out and found that 48 cases in total were involved - this included 13 patients, 28 healthcare workers and seven 'accompanying persons'. Of note, of the 3 traced who children tested positive for SARS-CoV-2, only one had symptoms; given these children's high-risk status, their asymptomatic presentations are noteable. The paper discusses hygiene measures put in place to avoid further spread.

Chen, YHuang, KDiabetes CareClinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication24 Apr 2020ChinaAsia3Clinical - Comorbiditieshttps://care.diabetesjournals.org/content/early/2020/05/13/dc20-0660
Poli, PBadolato, RJ. Cyst FibrosAsymptomatic case of COVID-19 in an infant with cystic fibrosis14 Apr 2020ItalyEurope1Clinical - Comorbiditieshttps://www.cysticfibrosisjournal.com/article/S1569-1993(20)30096-5/fulltext#%20

This is the first case report of confirmed SARS-CoV-2 infection in a child with cystic fibrosis. The 1 month-old, from Italy, was diagnosed with CF on newborn screening. SARS-CoV-2 infection was confirmed on nasopharyngeal swab PCR as part of contact tracing following exposure to COVID-19 through his grandfather.

The infant remained asymptomatic throughout follow up and did not require hospital admission.This is one of a limited number of reports of SARS-CoV-2 infection in people with CF. A better understanding of the course of illness in this group will likely emerge with data from ongoing collaborative studies.

Hrusak, OSchrappe, MEur J CancerFlash survey on SARS-CoV-2 infections in pediatric patients on anti-cancer treatment07 Apr 2020International (first author from Czechia)International9Clinical - Comorbiditieshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141482/

This is the report of a data from an international survey of paediatric haematology and oncology clinicians to assess the frequency and severity of SARS-CoV-2 infection amongst children with cancer. The survey, conducted from 16th-17th March 2020, had over 35 respondents from 25 countries. Of an estimated 10,000 patients at risk and over 200 tested, 9 children were positive for SARS-CoV-2. Clinical details are provided for 8 cases, 6 of whom had solid tumours and 2 with acute lymphoblastic leukaemia. 7 had mild or asymptomatic disease, 1 patient required low flow oxygen. Fever was the presenting symptom in 6 patients and one patient also had diarrhoea. All 7 patients with outcome data available made a full recovery.

The interpretation of these data is clearly limited by the study design as well as the relatively early stage of the pandemic during which the survey was conducted. Notwithstanding these limitations, the absence of severe COVID-19 cases in this report provides some early reassurance. More detailed clinical studies are needed to draw firm conclusions about the risk of severe disease in children receiving chemotherapy.

Balduzzi, ABiondi, ALancet pre-print serverLessons after the early management of the COVID-19 outbreak in a pediatric transplant and hemato-oncology center embedded within a COVID-19 dedicated hospital in Lombardia, Italy02 Apr 2020ItalyEurope5Clinical - Comorbiditieshttps://dx.doi.org/10.2139/ssrn.3559560

This report from a paediatric haematology unit in Lombardia, Italy, includes the Italian experience of COVID-19 in children with malignancy so far. At their particular unit, they have had no children with malignancy test positive for COVID-19 (they admit this is dependent on testing criteria, requiring hospitalisation at their institute). They are aware of 5 cases of paediatric cancer patients who have had COVID-19 and have all suffered a mild course, with 3 managed at home and 2 in hospital.

This small case series provides further reassurance for at risk paediatric populations.

Lagana, SMLefkowitch, JHArchives of Pathology & Laboratory MedicineCOVID-19 associated hepatitis complicating recent living donor liver transplantation02 Apr 2020USANorth America1Clinical - Comorbiditieshttps://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2020-0186-SA

This retrospective single case report examines the histopathological features of liver associated COVID-19 in a child admitted to Columbia University Medical Centre, USA. The female child, 6 months old, was admitted for a liver transplant for treatment of biliary atresia. COVID-19 was diagnosed in the donor on post-operative day 2 and confirmed in the patient day 4 post-operatively. The type of test used was not described.

Clinical features: Increased work of breathing requiring CPAP, fever and diarrhoea were developed on post-operative day 4.

Radiology: CXR on post-operative day 4 was described as “no significant changes compared to prior exam with only patchy areas of atelectasis in irregularly aerated lungs”. CXR on day 6 demonstrated “patchy lung opacities bilaterally, mildly increased in the right upper lobe and left lung base”. Bloods: Deranged LFTs exacerbated from baseline on post-operative day 1: AST (maximum 908U/L from 163U/L), ALT (maximum 980U/L from 215U/L), GGT (maximum 473U/L from 174U/L), ALP (maximum 578U/L from 388U/L).

Treatments: Treated with hydroxychloroquine from day 4 post-operative. She required CPAP for an undefined time period. Undefined immunosuppressant treatment was provided for acute transplant rejection, however liver enzymes worsened when commenced.

Outcomes: Remains on a hospital ward without supplemental oxygen.

A liver biopsy was performed on post-operative day 7 demonstrating portal tract expansion through a mixed inflammatory infiltrate which consisted of lymphocytes, rare plasma cells, and interspersed eosinophils, lymphocytic cholangitis, reactive changes in the interlobular bile ducts and mild portal venulitis. These were interpreted as acute cellular rejection.

Other findings of moderate acute hepatitis including an “azonal pattern of clusters of apoptotic hepatocytes” and singly dispersed apoptotic hepatocytes. Other features of interest include large fragments of cytoplasmic debris described as “crumbling” hepatocytes, few mitotic figures, regions of Kupffer cell prominence with sinusoidal and central vein endotheliitis. The authors commented that the extent of hepatocyte apoptosis and large clusters were unusual and not a usual feature of acute cellular rejection (ACR). Central endotheliitis may also be a feature of COVID-19 hepatitis, with the presence of more Kupffer cells and less plasma cells than ACR.

Summary: COVID-19 hepatitis likely presents as a moderate acute hepatitis with prominent clusters of “crumbling” apoptotic hepatocytes. Other features may be lymphohistiocytic inflammation of sinusoidal and central vein endothelium, with the presence of more Kupffer and less plasma cells when compared to ACR.

Turner, DRussel, RJournal of Pediatric Gastroenterology and NutritionCOVID-19 and paediatric inflammatory bowel diseases31 Mar 2020InternationalInternational8Clinical - Comorbiditieshttps://doi.org/10.1097/MPG.0000000000002729

This article outlines the experience from Asia and Europe so far of children with inflammatory bowel disease given the COVID-19 pandemic. This is of particular interest because many of these children receive immunosuppression as part of their treatment, and so could be considered high risk for complications of the disease.

It appears to have been routine practice to suspend treatment for IBD during the outbreak of COVID-19, which resulted in a large number of relapses. No children with IBD contracted COVID-19 in China in the period covered by the survey.

In South Korea treatment for IBD was not suspended. They also have had no cases of COVID-19 in children with IBD.

In the PORTO IBD group of ESPGHAN (covering Europe, some centres in Canada and Israel) treatment was not suspended in 31/32 centres. 7 children with IBD, who were on immunosuppression, had COVID-19. They all suffered a mild illness with no flare of their IBD. There is an additional child case from an international IBD database identified who also experiences mild symptoms (no hospitalisation required).

This survey provides further reassurance that treatment with immunosuppression does not appear to significantly increase the risk of severe disease from COVID-19 in children.

D'Antiga, LLiver transplantationCoronaviruses and immunosuppressed patients: the facts during the third epidemic20 Mar 2020ItalyEurope3Clinical - Comorbiditieshttps://doi.org/10.1002/lt.25756

This letter is from a liver transplant centre in Lombardy, Italy, reporting their experience of patients (including children) with immunosuppression and COVID-19. They have had 3 children post liver transplant test positive for SARS-CoV-2, and none have developed clinical pulmonary disease. They believe due to the widespread nature of infection that many other of their patients may also be infected, but not developed clinically apparent disease.

This provides the first official reports of vulnerable paediatric populations with COVID-19, which so far does not appear to be any more severe than the rest of the population in that age bracket. Further data is awaited.

Weisberg, SFarber, DNat ImmunolDistinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum.5 Nov 2020USANorth America47Clinical - PIMS-TShttps://doi.org/10.1038/s41590-020-00826-9

This study, published online on 5th November 2020, investigates the SARS-CoV-2 antibody response and its protective capacity in 32 adult and 47 paediatric patients seen at New York-Presbyterian/Columbia University Irving Medical Center hospital and the Morgan Stanley Children’s Hospital of New York during the height of the COVID-19 pandemic in New York City from March to June 2020. Children with SARS-CoV-2 infection are often asymptomatic and rarely have severe respiratory symptoms, but may very rarely present with multisystem inflammatory syndrome in children (MIS-C), typically 2-4 weeks after infection with SARS-CoV-2. Adults are more likely to experience respiratory symptoms of varying severity, which can progress to acute respiratory distress syndrome (ARDS) with high mortality (particularly in older adults and those with comorbidities such as diabetes). The authors aimed to investigate the immune response after SARS-Co-2 infection in adults and children with a range of clinical presentations, by analysing antibodies specific for the major SARS-CoV-2 antigens, including the S protein (which binds the cellular receptor for viral entry) and the N protein (necessary for viral replication). They also analysed the neutralising activity of these antibodies in blocking viral infection, which correlates with their protective capacity (only a small fraction of antibodies raised against viral antigens will have neutralising activity).

Study population: There were 4 patient cohorts in the study (2 adult and 2 paediatric, one each of mild and severe disease in each age group) totalling 79 individuals, defined as having been SARS-CoV-2-infected based on symptoms, positive PCR and/or serology:

1. 19/79 (24%) adult convalescent plasma donors (CPDs): recovered from mild COVID-19 respiratory disease without hospitalisation and recruited from the community via web tool as part of convalescent plasma trial (telephone screening to determine eligibility as plasma donors), median age 45 yrs (range 28-69), 10/19 (53%) male, ethnicity: 53% white, 32% Asian, 11% Pacific Islander, 5% Hispanic/Latin American, 5% other/unknown. Median time from onset of symptoms consistent with COVID-19 to sampling during outpatient donation of blood: 24 days (IQR 19-37).

2. 13/79 (16%) adults hospitalised with severe COVID-19 ARDS (COVID-ARDS): median age 62 yrs (range 19-84), male 11/13 (85%), ethnicity: 31% Hispanic/Latin American, 23% Black/African American, 15% white, 38% other/unknown. Co-morbidities: diabetes 4/13 (31%), hypertension 4/13 (31%), current/former smoker 3/13 (23%), COPD 2/13 (15%), chronic neurological disease/dementia 1/13 (8%). Median time from onset of respiratory/COVID-19 symptoms to sampling (after diagnosis of ARDS requiring intubation and admission to ICU): 16 days (IQR 14-21). 30-day in-hospital mortality 6/13 (46%), 4 patients remained hospitalised.

3. 16/79 (20%) children hospitalised with MIS-C (paediatric MIS-C): median age 11 yrs (range 4-17), male 7/16 (44%), ethnicity: 44% Black/African American, 44% white, 25% Hispanic/Latin American, 6% other/unknown. Asthma 4/16 (25%) (no other co-morbidities). Median time after onset of symptoms of MIS-C to sampling on admission to PICU: 6 days (IQR 4-7). 30-day in-hospital mortality 0%, 1/16 (6%) developed respiratory failure/ARDS.

4. 31/79 (39%) children infected with SARS-CoV-2 who didn’t develop MIS-C (paediatric non-MIS-C): median age 11 yrs (range 3-18), male 17/31 (55%), ethnicity: 48% white, 42% Hispanic/Latin American, 13% Black/Latin American, 23% other/unknown. Co-morbidities: asthma 1/31 (3%), chronic kidney disease 1, hypertension 1. Clinical presentation: surgical 9/31 (29%), COVID-19 symptoms 7/31 (23%), psychiatric 4/31 (13%), trauma 3/31 (10%), fever (non-COVID) 2/31 (6%), other 6/31 (19%). Asymptomatic 15/31 (48%). Median time from symptom onset or from confirmed COVID-19 exposure (reportable data for 16 individuals) to sampling during clinical care (including routine screening for admission and procedures): 29 days (IQR 17-44). 30-day in-hospital mortality 0%, 1/31 (3%) developed respiratory failure/ARDS. These samples were obtained from the Columbia University Biobank after screening for appropriate age and exclusion of confounders such as immune deficiency, malignancy and genetic abnormality.

SARS-CoV-2 specific antibodies for each cohort: Blood samples were collected from all 4 cohorts during the same 60 day time window. Levels of antibodies to SARS-CoV-2 S (spike) and N (nucleocapsid) proteins were measured in patient plasma samples (and in a negative control pre-pandemic plasma) using serial dilutions in an indirect ELISA assay to detect anti-S IgG, anti-S IgM, anti-S IgA and anti-N IgG. Detailed results and graphs are reported in the article, together with statistical comparisons between cohorts. Anti-S antibodies were present as IgM (primary response), IgG (prominent in serum) and IgA (prominent in secretions) classes in adult CPDs and COVID-ARDS, with significantly higher concentration in COVID-ARDS patients for all classes. By contrast, anti-S antibody titres and isotype predominance in both paediatric cohorts (MISC-C and non-MIS-C) were similar to each other and to the adult CPDs, showing predominant anti-S IgG, low titres of anti-S IgM (similar to the negative control) and variable titres of anti-S IgA antibodies. The specificity of anti-S IgG for SARS-CoV-2 S protein compared to other coronavirus strains was assessed using a cell-based ELISA: plasma IgG from subject samples (but not pre-pandemic control plasma) bound SARS-CoV-2 protein and the common circulating D614G S protein variant, but did not significantly bind S protein from SARS-CoV-1 or MERS coronaviruses. Anti-N IgG titres were significantly lower in both paediatric cohorts compared to the two adult cohorts. The low titres of anti-N IgG in children were similar in MIS-C and non-MIS-C cohorts. The higher titres of anti-N IgG in adults were similar in CPDs and COVID-ARDS cohorts, suggesting that production of anti-N antibody is age- but not symptom-dependent.

Effect of age on antibodies in each cohort: No significant correlation between age and anti-S IgG in adults or paediatric MIS-C cohort; modest but significant negative correlation between age and anti-S IgG in paediatric non-MIS-C cohort (younger children having higher anti-S titres than teens). Significant correlation between age and anti-N IgG in adult CPDs (younger adults having lower