Croup

Cite this article as:
Laura Riddick. Croup, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32637

It’s 0200 hours in the Emergency Department and you hear a seal …

As children have returned to school we have seen more croup through the ED so it’s time to refresh your memories!

What is it?

Viral laryngotracheobronchitis. It is essentially inflammation around the main large breathing structures and caused usually by parainfluenza 1 + 3. Other respiratory viruses including SARS-CoV-2 and RSV may also be involved. This inflammation causes a tell-tale cough and noisy breathing due to the obstruction to flow. There may be signs of increased work of breathing too such as sub-costal recession or a tracheal tug. They are generally quite well and are running around the waiting room!

Who gets it?

A lot of children – roughly 2-3% of all children per year! These kids are usually between six months and four years of age, and occurs at the beginning of autumn, though this spring we are seeing a lot of cases. Children with croup may present with a preceding coryza-like illness and a low-grade fever. This then develops into a barking “seal-like” cough and, for some reason, always seems worse at night. Boys are more commonly affected than girls, and some children seem to get it yearly.

How do we treat it?

This depends on your assessment of the child. Croup is a self-limiting viral illness and treatment tends to look to short term reduction in the inflammation to improve the work of breathing. Historically clinicians have used Westley scoring system to score croup and assess their severity before giving medication.

Westley Croup scxore
Westley Croup Score

In children who look unwell, it is important to not upset them by avoiding unnecessary interventions such as excessive handling or performing an ENT exam.

Steroids

If the child is able to take the medication, dexamethasone or prednisolone should be given to all cases of croup where any stridor or increased effort in breathing is present.

Dexamethasone appears to be more efficacious than prednisolone. It has an onset of action within 1 hour (30 minutes – 4 hours) and has a half-life of up to 36-72 hours (Schimmer 2005). There has been debate overdosing with doses of 0.15mg/kg, 0.3mg/kg and 0.6mg/kg of dexamethasone. Ultimately, 0.15mg/kg not inferior to 0.6mg/kg. At the time of writing both NICE and the BNFc recommend 0.15mg/kg as the initial dose of dexamethasone. If there are concerns about re-occurrence patients are occasionally sent home with an additional dose to be taken 12 hours later.

Prednisolone tends to be favoured in the primary care setting, at a dose of 1mg/kg with two additional daily doses. There appears to be no significant clinical difference between the two different steroids in terms of the need for additional treatment or length of stay. Dexamethasone was associated with a reduction in re-attendances, which may be due to the shorter half-life of Prednisolone (Gates 2018, Schimmer 2005)

Nebulised budesonide (2mg stat dose) is reserved for children who cannot take the dose. This may be because it was spat ou tor because they are working too hard to breathe. A Cochrane review in 2018 shows that budesonide is not superior to dexamethasone, with Westley Croup scores better in the dexamethasone group at 6 and 12 hours compared to budesonide. A combination of treatment does not appear to lead to additional benefit (Gates 2018)

Adrenaline/epinephrine

In severe cases, when the child has features of severe work of breathing, including significant recession, hypoxia or tiring, nebulised adrenaline has been used (0.4-0.5ml/kg, maximum 5ml of 1:1000). Adrenaline provides short term relief from respiratory distress and can be a bridge to getting steroids on board. The effects are short-acting and wear off after a couple of hours. It can be repeated every 30 minutes, although if you need repeat doses, anaesthetics and senior colleagues should be involved in this patients’ care.

How do we not treat it?

In the olden days parents tried treating croup at home with steam inhalation (not effective). In hospitals, humidified oxygen has also been tried though this has not been proven to be effective either (Moore 2007). Heliox (oxygen and helium combined) has also been looked at as it may improve airflow. The evidence is limited and safety and efficacy remain questionable (More, 2018). There is no evidence that salbutamol works in croup.

They sound better, what’s next?

If they are well and the stridor has resolved, patients can be discharged home with safety-netting advice. The effects of dexamethasone should last as croup itself is usually limited to 2-3 days of symptoms. Parents need to be aware that some symptoms of respiratory distress can return, usually the following night.

Patients may require a prolonged period of observation if:

  • stridor is still present at rest, or there is increased work of breathing
  • the child is very young (<3 months)
  • an adrenaline nebuliser had to be given
  • there is a past history of severe croup
  • there is a history of upper airway problems (i.e. laryngomalacia or subglottic stenosis)
  • concerns about the child returning (i.e. long-distance, social concerns)

When is it not croup?

  • Epiglottitis – a rare condition thanks to the HiB vaccine. A child would present with sudden onset, fever, drooling and looks unwell holding the head back and neck extended. This is a medical emergency and keeping the patient calm is paramount.
  • Tracheitis– thankfully also rare. It presents with the child acutely unwell after a prolonged course similar to Croup.
  • Anaphylaxis/allergy – this may be accompanied with angioedema, rash and wheeze, and requires swift treatment with IM adrenaline
  • Quinsy/retropharyngeal abscess
  • Foreign body – Usually the history would help suggest this, with a sudden onset history in a well-child.

COVID and croup

Most children admitted into hospital are now swabbed for COVID. This can provide a challenge – balancing upsetting the child (and making the upper airway obstruction worse) and performing an invasive swab. It is sensible not to swab the child whilst there is still concern about acute stridor and work of breathing..

There have been some case studies to suggest a small cohort of patients with croup who were SARS-CoV-2 positive are less responsive to the usual treatment (Venn 2020). These cases may need prolonged admission due to lack of response and the need for additional supportive therapy.

Selected references

  1. Al-Mutairi B, Kirk V. Bacterial tracheitis in children: Approach to diagnosis and treatment. Paediatr Child Health. 2004;9(1):25-30. doi:10.1093/pch/9.1.25
  2. Garbutt JM, Conlon B, Sterkel R, et al. The comparative effectiveness of prednisolone and dexamethasone for children with croup: a community-based randomized trial.  Clin Pediatr (Phila). 2013;52(11):1014–1021.
  3. Gates  A, Gates  M, Vandermeer  B, Johnson  C, Hartling  L, Johnson  DW, Klassen  TP. Glucocorticoids for croup in children. Cochrane Database of Systematic Reviews 2018, Issue 8. Art. No.: CD001955. DOI: 10.1002/14651858.CD001955.pub4. Accessed 28 April 2021
  4. Moore M, Little P. Humidified air inhalation for treating croup: a systematic review and meta-analysis.  Fam Pract. 2007;24(4):295–301
  5. Moraa I, Sturman N, McGuire TM, van Driel ML. Heliox for croup in children. Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No.: CD006822. DOI: 10.1002/14651858.CD006822.pub5
  6. Schimmer B P, Parker K L. Adrenocorticotropic hormone: adrenocortical steroids and their synthetic analogs: inhibitors of the synthesis and actions of adrenocortical hormones. Goodman and Gilman’s the pharmacological basis of therapeutics, 9th edition. New York: McGraw‐Hill, 20051459–1485
  7. Smith DK, McDermott AJ, Sullivan JF. Croup: Diagnosis and Management. Am Fam Physician. 2018 May 1;97(9):575-580. PMID: 29763253.
  8. Sparrow A, Geelhoed G. Prednisolone versus dexamethasone in croup: a randomised equivalence trial. Arch Dis Child. 2006;91(7):580-583. doi:10.1136/adc.2005.089516
  9. Venn AMR, Schmidt JM, Mullan PC. A case series of pediatric croup with COVID-19 [published online ahead of print, 2020 Sep 15]. Am J Emerg Med. 2020;S0735-6757(20)30829-9. doi:10.1016/j.ajem.2020.09.034
  10. https://www.rch.org.au/clinicalguide/guideline_index/Croup_Laryngotracheobronchitis/
  11. https://cks.nice.org.uk/topics/croup/

Sepsis 2020

Cite this article as:
Emma Lim. Sepsis 2020, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32392

Where do we start?

Fever and suspected sepsis is our bread and butter. This post will take you through a whirlwind 2020 sepsis update. We’ll cover what sepsis is, how to recognize deterioration and the recent management updates in light of the new 2020 International Surviving Sepsis Campaign Guidelines1.

For me, it is all about “What keeps me up at night?” and there are two things I worry about. The first is missing cases of suspected sepsis.  Think back to all those hot, miserable children you sent home over your career and the heart sink you feel when someone says, “Remember that child you sent home yesterday?”.  My second worry is making bad choices; making mistakes about how much fluid to give or which antibiotics to choose or when to start inotropes.

What is sepsis?

Let’s start at the beginning. How do you get sepsis? A bacterial or viral infection causes a systemic, inflammatory response syndrome (SIRS). We are used to seeing children who have a fever and a fast heart rate or respiratory rate and a raised white cell count, for example with bronchiolitis. A certain proportion of those children will go on to get sepsis but not a lot.

Spotting sepsis in the paediatric ED is like a game of Where’s Wally: there are a whole lot of hot febrile children with accompanying hot cross parents. Fever is common but sepsis is rare – at a quick glance they all look like Wally, but, of course, there is actually only one real one and it takes a bit of time and patience to find him. It is the same with all those children with fever: around 55% have self-limiting viral infections, only 7-13% have serious bacterial infection (SBI)2-4 and only 1% have sepsis. The picture’s different in PICU; 10% of PICU admissions are for sepsis. The 2015 SPROUT study5 looked at 569 children in PICU with sepsis (8.2% point prevalence). 40% were caused by respiratory infections and 19% percent by bloodstream infections. A quarter (25%) of them died.

That quote “7-13% of febrile children have a serious bacterial infection” seems high. There are predefined criteria (such as pneumonia, urinary tract infection, meningitis, osteomyelitis, septic arthritis), but in a reductionist sense, sepsis is any infection that makes a child so unwell that they are admitted to hospital for more than 72 hours and need IV antibiotics. But, the need for admission is very subjective and dependent on the experience of the doctor and the parents’ level of concern.  The goal posts are constantly shifting.  Ten years ago, we would admit children with osteoarticular infections for 6 weeks of IV antibiotics. Now they can be in and out within 72 hours (with most of their course given orally). That doesn’t mean the infections have got less severe, it’s just that our treatments have changed.  And is a urinary tract infection over a year of age really a serious infection?  Most will get treated with a short course of oral antibiotics, as will children with pneumonia.  Because that’s a whole other controversy; reporting focal consolidation on a X ray is art not science and has been shown to be famously unreliable in double blind studies.  So if we remove children who have simple pneumonia, urinary tract infections in older children,  skin and soft tissue infections that do not have positive cultures, the number of true SBI is quite a lot less than the quoted 1 in 10.

Unbelievably, there is no good definition of ‘sepsis’ in paediatrics6, so we tend to use the adult Sepsis 3 definition7 which states:

“Sepsis is life threatening organ dysfunction caused by a dysregulated host immune response to infection including renal, respiratory, hepatic dysfunction or metabolic acidosis”. A small proportion of children or young people with sepsis will go into septic shock, where shock is defined as hypotension, or impaired perfusion requiring inotropes with a higher risk of death than sepsis.”

This doesn’t really help us spot sepsis early enough to prevent these children going into shock.  So far, there is no reliable way of pinpointing who these children are. However, there is some exciting news. 2020 has brought us new international evidence-based guidelines for the management of septic shock and sepsis associated organ dysfunction in children; the Surviving Sepsis Campaign.

This has been a huge piece of work by an incredible transatlantic consortium, including Mark Peters (for the horse’s mouth listen to our latest RCPCH Paediatric Sepsis Podcasts). I am going to take you through some of these recommendations, but I think everybody should read it themselves.  The consortium took 3 years and reviewed over 500 papers, but you only have to read this one paper, so go on, make your life easy!  

Spotting sepsis

Recommendation number one. In children who present acutely well, “we suggest implementing systematic screening for timely recognition.”

Take note of the word suggest. This means there is some, but not definitive, evidence. We all recognise systematic screening for sepsis is a huge problem for paediatricians. Most children with a fever have a self-limiting viral infection, and many of these children will have fever, tachycardia and tachypnoea. But most do not have sepsis.  However, if we use the UK-based NICE high-risk ‘Red Flag’ criteria, these children are all flagged as potentially having sepsis. They over-trigger, shown by a 2020 paper by Ruud Nijman which showed that 41% of all febrile children in PED present with warning signs of sepsis3. If you look at this paper in some detail, 50% of children aged 1-2 years triggered the NICE red high-risk category for tachycardia alone. This mirrors data from a local audit from the Great North Children’s Hospital Emergency Department, conducted between April and June of 2017. Of 868 patients, 5% had serious bacterial infections, but 50% triggered NICE high-risk criteria. Sam Romaine from Alderhey Children’s Hospital, and part of Enitan Carrol’s group, looked at 12,241 patients and again, 55% triggered NICE high risk criteria8. For a full critical review of Ruud’s paper, take a look at our Searching for Sepsis post.

The NICE high risk criteria have a very high sensitivity but limited specificity, which means although they ‘over-trigger’, if a child doesn’t have any red flags then they are potentially ‘good to go’, helping inform safe discharge.

Is there a better score?

For a long time, adults have used the Q-SOFA score, a quick sepsis related organ failure assessment. Typically, this adult score has performed poorly in children. Enitan Carroll’s group have looked at a modified Q-SOFA score called the LQ-SOFA score (L for Liverpool), modified to predict critical care admission rather than sepsis. Critical care admission is a more common outcome than sepsis, particularly relevant because this helps us understand which children are at risk of deterioration. The modified score, is made up of four simple, straightforward criteria, including capillary refill, AVPU (that’s Alert, Verbal, only to Pain or Unresponsive), heart rate and respiratory rate, purposefully not including blood pressure, making this quick and easy to use as a screening tool. But what did they find? Carroll’s group compared five different scores that could help us predict sepsis or deterioration: lactate, CRP, adult Q-SOFA, NICE and LQ-SOFA. Lactate performed the least well, CRP and Q-SOFA a little bit better, NICE high-risk criteria better again, but best of all was the LQ-SOFA score. 

This work suggests that there are more sensitive tools out there, but these need to be combined with some way of de-escalating children who trigger because most of these children have a SIRS response from a self-limiting viral infection and not sepsis. De-escalation is usually done by ‘a senior review,’ with the intention of differentiating the hot and bothered child who has a viral infection from early sepsis.

Listen to parents

There are many examples of systematic screening protocols, the best being electronic scores. But they are not perfect.  Most importantly, the good ones listen to parents. Parental concern or health professional concern is particularly important for children with complex medical conditions: neurodisability, recurrent chest infections, those with indwelling lines or fed by gastrostomy. These children often don’t have typical signs and symptoms that health care professionals associate with infections or sepsis, often presenting with nothing more than their parents saying that they’re not well or not quite themselves. These children can be hypothermic (due to hypothalamic dysfunction) and run ‘cold’ so when they get an infection, their temperature may goes up to ‘normal’ (37 degrees), not triggering at all. The presenting signs can be very, very subtle like not tolerating their feed, or vomiting, or they may just be miserable and unhappy. This is why any escalation tool or score must in some way include parental concern. The NICE sepsis guidelines from 2017 tells us to pay particular attention to ‘concerns expressed by parents, families or carers’, for example, changes from usual behaviour.’  We must not underestimate the expertise of parents and we should incorporate them into the team of people caring for their children.

Doctors can be wary of parental concern but if we look at a systematic review of family-initiated escalation of care for the deteriorating patients in hospital, we can see that this wariness is unfounded.  Gill et al 20169 looked at a systematic review of ten articles (all descriptive studies) over ten years evaluating response systems for patients and families; five described a triaged response; five reported systems for families to directly activate the rapid response team. There were a total of 426 family-initiated calls, range 0.17 to 11 per month, with no deaths reported. All calls were deemed to be appropriate and three calls resulted in intensive care unit admissions.”

I believe there is evidence that parents only escalate when they need to.  As one of our parents of a child with a complex medical condition said;

Please listen to us when we say something is not right, we can see subtle changes in children, in our children, in their health and behaviour. That may not be apparent to the casual observer or even health professionals like yourselves and children like them cannot speak for themselves. Therefore, as parents, we have to ensure that we advocate for them in the strongest possible terms. We do not think we are better than the team, nor are we full of our own importance. But we are simply trying to give a voice to our children as they don’t have one of their own.”

What do you do next?

The Surviving Sepsis campaign developed a management algorithm for children, and while it is useful, there’s a lot of information, for many different teams in a small space. Firstly, when you look closely, the lower half (in black) is actually all about management in a Paediatric Intensive Care (PICU) setting -treatment of refractory shock and advanced haemodynamic monitoring. For paediatric emergency physicians, there is a lot that has to happen first! Let’s break it down.

The first thing that the international guidelines asks us to do is get intravenous or intraosseous access. Please only have three tries at getting intravenous access and if this isn’t successful, go straight to intraosseous access. It’s a great safe route and can be much easier to get than intravenous especially in children with complex medical conditions whom may be difficult to cannulate. Although it may feel like using an IO in an awake child will be traumatic , flushing with 0.5mg/kg of 2% lignocaine before you infuse fluids, antibiotics and other drugs, will reduce the pain.

Test, tests, tests

Recommendation number two. Get a blood culture.

This should always be your next priority, as long as it does not delay treatment. Let’s just think for a moment about blood cultures. Blood cultures are old technology. They were developed in the 1950s and have not really changed since. Traditionally, blood cultures are read at 48 hours but often don’t give any definitive answer. The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS)10 was a prospective, multi-centre, cohort study of 2844 children under 18  with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 hospitals across Europe and incredibly in 50% of patients the causative organism remained unidentified! Alasdair Munroe explains more in his blood culture post.

What we really want is a point of care test, a test that takes less than 60 minutes, that can quickly differentiate between viral and bacterial infections at the child’s bedside11. Andreola et al12 (and more recent studies by Ruud Nijman again) looked at febrile children and infants in Emergency Departments and this is what they found:

White cell counts, we know, are not helpful. A raised white cell count has poor sensitivity and specificity, so while CRP is better and PCT better still there is room for improvement.  All these tests have problems with sensitivity which means there is still going to be a worrying number of falsely negative tests.  We know this, for example, in children with diseases that progress quickly like meningococcaemia or sepsis who can have normal inflammatory markers early on.

However, new tests are on the horizon. The PERFORM/IRIS group published a diagnostic test using a two-transcript host RNA signature that can discriminate between bacterial and viral infections in febrile children (Herberg, JAMA 2016), using gene arrays to demonstrate up or down regulation of protein expression. Sensitivity in the validation group was 100% and specificity 96.4%13.  

But we don’t just want to know if a child has a bacterial or viral infection, we really want a clinical predictor of severity that could tell us which children are going to get very ill.  We have a few tests, but they’re not very specific. We often look at blood gases, looking for a metabolic acidosis. But that is very broad. What about a lactate >2mmol/l? The international guidelines did not recommend the use of lactate as the evidence is lacking, although it can give an idea of the trend and whether a child is getting better or worse and is generally considered to be best practice and is already standard in adult sepsis. But this is in direct contrast to a study by Elliot Long and team published earlier this year14 looking at predictors of organ dysfunction in over 6000 children presenting to the ED with fever. A lactate of 4 or higher was one of the best performing ED predictor of new organ dysfunction, the need for inotropic support and the need for mechanical ventilation. Take a look at Deirdre Philbin’s DFTB review of the study.

More new tests are coming.  For example, interleukin 6 and 10 may be able to predict which children with febrile neutropenia have serious infections and mid regional pro-adrenoedullin (MR pro-ADM) may be a promising biomarker to predict sepsis and septic shock15. So, watch this space!

Antibiotics

Recommendation number three. Start broad-spectrum antibiotics.

Moving on from tests to treatment, we now want to look at recommendation number three, when to start broad-spectrum antibiotics. There is a change in timing here.

In children with septic shock, antimicrobial therapy should be started as soon as possible and within one hour of recognition of sepsis.”  But, in children with suspected sepsis (i.e. organ dysfunction, but not shock), most of the children we see, guidelines suggest starting antimicrobial treatment as soon as possible after evaluation – you have 3 hours not 1 hour16.

This is important, because it gives you a chance to do tests and decide whether the child in front of you has sepsis or just a SIRS response due to a viral infection. This has bigger implications than just saving hospital beds, because we know timely initial empirical antibiotics will save lives, but unnecessary antibiotic use for all children with fevers increases antibiotic side effects, antibiotic resistance and cost.

Antibiotic choice

There are other recommendations around antibiotics. Importantly, the new consensus recommends a broad-spectrum antibiotic therapy with one single drug in normal children, such as  cefotaxime or ceftriaxone or, if they are allergic, meropenem.

As a quick aside, let’s think about penicillin allergy.

It’s important to get a history and to understand what a ‘real’ penicillin allergy is. We see a lot of children who present with a vague story of having been given a couple of doses of penicillin many years ago, who developed a rash and have been labelled as ‘penicillin allergic’.  But doing that in the heat of the moment can be tricky.

Zagursky believes “Avoidance of cephalosporins, when they are the drug of choice in a penicillin-allergic individual, results in significant morbidity that outweighs the low risk of anaphylaxis. We conclude that there is ample evidence to allow the safe use of cephalosporins in patients with isolated confirmed penicillin or amoxicillin allergy”17

Studies have found the risk of crossover between penicillin/cephalosporin reactions is <1%, so using cephalosporins as a first line is safe.  If the child also has cephalosporin sensitivity, they may need a carbapenem like meropenem.  Later, please think about referring these children to your local allergy service for penicillin or cephalosporin de-labelling, which entails having an antibiotic challenge under controlled, safe circumstances.

Moving on… antibiotics in immunocompromised children

The guidelines suggest using empiric multi-drug therapy in children with immunocompromise and those at high risk for multi-drug resistant pathogens. In this case, you might choose piperacillin-tazobactam and, if shock is present, amikacin. You can add teicoplanin if you suspect a line infection, with rigors when flushing the line, or a line site infection, with redness around their exit site, or signs of any soft tissue cellulitis.

The recommendations also cover antimicrobial stewardship. Once the pathogen and sensitivities are available, the guidelines recommend narrowing antimicrobial therapy coverage. This means narrowing down the antibiotic to something specific to the clinical presentation, site of infection, or risk factors.  Ask yourself these questions:

  • Is the child is showing clinical improvement?
  • Can they have their antibiotics at home? (via a paediatric out-patient antibiotic service)
  • Can they switch to oral antibiotics?
  • Can they stop their antibiotics?  If you don’t find any bugs, and the child is well, then the guidelines recommend stopping antimicrobial therapy.

Remember to phone a friend

Infectious disease teams or microbiologists; you never need to make decisions alone. The guidelines recommended daily assessment with clinical laboratory assessment for de-escalation of antimicrobial therapy. Assessment includes a review of the ongoing indication for antibiotics after the first 48 hours and should be guided by results from microbiology, signs of clinical improvement and evidence of reducing inflammatory markers, such as a halving of CRP, or if the child’s fever has settled for more than 24 hours.

Fluids

Moving on from antibiotics to fluids. The Surviving Sepsis Campaign has another paediatric management algorithm for fluid and vasoactive drugs. It’s also quite busy, incorporating the results of the FEAST study18.  It’s split into two, a green side and a blue side. The green side is for children who live in healthcare systems without intensive care, while the blue side is healthcare systems with paediatric intensive care. The change boils down to being more cautious with fluids.  The guidelines recommend 10-20 ml/kg boluses. I suggest giving 10 ml/kg and then reassessing for signs of fluid overload with hepatomegaly and listening for basal crackles suggesting pulmonary oedema, repeating a second or third bolus as needed.  I use 10 ml/kg because it’s the same in sepsis, in neonates and in trauma.

If the child needs more volume, give them more volume; you can repeat 10ml/kg boluses up to 40 ml/kg or more as needed just use smaller aliquots.  Remember there may still be children who need big volumes of fluid early on, and we have PICU readily available and the technology to support children’s circulation and ventilation and ‘dry them out’ later.  There isn’t enough evidence to fluid restrict children with sepsis in the ‘resource rich’ world just yet but trials are ongoing. The Squeeze Canadian Critical Care Group19 has started a study, so watch this space for results.

Which fluids should you choose?

Please use crystalloids not colloids. And although historically we have used 0.9% saline, it is better to choose balanced or buffered solutions such as Ringer’s lactate or Plasmalyte. Too much saline can cause hyperchloremic acidosis.   

Inotropes

There has been a real sea change in our approach with inotropes. As we’re being more cautious with fluid resuscitation, we need to start giving inotropes earlier. After giving 40 to 60 ml/kg have your inotrope lined up ready to go.  There is good evidence that the drug of choice should be adrenaline20.  You can give adrenaline via a peripheral intravenous cannula or an intra osseous cannula safely if you don’t have central access. There have also been studies in adults that showed that peripheral adrenaline is also safe, especially when given for less than four hours or in a diluted dose.

Safety netting

Most of the febrile children we see will be discharged; safe discharge is a big priority because that’s what the majority of hot bothered children need: good advice and home care.  Winters (2017)21 looked at 33,000 children who were discharged from Emergency Departments with abnormal vital signs. 27,000 (80%) of them were discharged with normal vital signs, with only one case of potentially preventable permanent disability (a child who presented with tummy pains and came back with torsion of the testes, unlucky). 5,500 children (16%) were discharged with abnormal vital signs; there were no permanent disability or deaths from this group. So, you can send children home with fevers safely. But, the proviso to this is they need good safety netting on discharge, including both verbal and written information. This is one of the NICE recommendations. Our discharge safety netting leaflet22, which (gives some straightforward, practical information about giving anti-pyretic medication like paracetamol and ibuprofen), works like a ‘parent’s PEWS’ chart. It allows parents to see if their child is OK to stay at home or if they’re at some risk and should contact the GP, go to a walk in centre or call 111-advice line if they haven’t got better in 48 hours.  If the child is on the ‘high risk’ side, we want to see them back in the Paediatric Emergency Department.

In summary…

So, in summary, please screen for sepsis, we should all be doing it. I don’t know the best systems to help you but, ideally, you should have electronic observations, protocols and local guidelines.  Be aware that in the ED the incidence of sepsis is rare and that recent surviving sepsis campaign guidance suggests you can safely observe while you make a decision on treatment. Give antibiotics within 60 minutes in septic shock, but in sepsis with no shock you have three hours. If you are treating use fluid cautiously, with 10-20 ml/kg boluses and frequent reassessments.  Start adrenaline early if appropriate, and this can be given safely, peripherally.  Finally, safety netting is essential.

Thank you very much for reading this right through to the end! If you want to hear more, please have a listen to our Paediatric Sepsis podcast, hosted by the RCPCH.

Selected references

  1. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Weiss SL et al. Pediatr Crit Care Med. 2020 Feb;21(2):e52-e106. doi: 10.1097/PCC.0000000000002198.PMID: 32032273
  2. Craig JC et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594 10.1136/bmj.c1594
  3. Nijman RG et al. Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study. BMJ. 2013;346:f1706 10.1136/bmj.f1706
  4. van de Maat J et al. Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study. Lancet Infect Dis. 2019;19:382–91. 10.1016/S1473-3099(18)30672-8
  5. Weiss SL et al. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med. 2015 May 15;191(10):1147-57. doi: 10.1164/rccm.201412-2323OC. Erratum in: Am J Respir Crit Care Med. 2016 Jan 15;193(2):223-4. PMID: 25734408; PMCID: PMC4451622.
  6. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis.Pediatr Crit Care Med. 2005 Jan;6(1):2-8. doi: 10.1097/01.PCC.0000149131.72248.E6. PMID: 15636651 Review
  7. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Shankar-Hari M et al. Sepsis Definitions Task Force. JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289. PMID: 26903336
  8. Romaine ST et al. Accuracy of a Modified qSOFA Score for Predicting Critical Care Admission in Febrile Children. Pediatrics. 2020 Oct;146(4):e20200782. doi: 10.1542/peds.2020-0782. PMID: 32978294; PMCID: PMC7786830.
  9. Gill FJ et al. The Impact of Implementation of Family-Initiated Escalation of Care for the Deteriorating Patient in Hospital: A Systematic Review. Worldviews Evid Based Nurs. 2016 Aug;13(4):303-13. doi: 10.1111/wvn.12168. Epub 2016 Jun 3. PMID: 27258792.
  10. Martinón-Torres F et al. EUCLIDS Consortium. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study. Lancet Child Adolesc Health. 2018 Jun;2(6):404-414. doi: 10.1016/S2352-4642(18)30113-5. Epub 2018 Apr 28. PMID: 30169282.
  11. Herberg JA et al. IRIS Consortium. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  12. Andreola, B et al. Procalcitonin and C-Reactive Protein as Diagnostic Markers of Severe Bacterial Infections in Febrile Infants and Children in the Emergency Department, The Pediatric Infectious Disease Journal: August 2007 – Volume 26 – Issue 8 – p 672-677. doi: 10.1097/INF.0b013e31806215e3
  13. Herberg JA et al. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  14. Long E, Solan T, Stephens DJ, et al. Febrile children in the Emergency Department: Frequency and predictors of poor outcome. Acta Paediatr. 2020; 00: 1– 10 
  15. Xia T, Xu X, Zhao N, Luo Z, Tang Y. Comparison of the diagnostic power of cytokine patterns and procalcitonin for predicting infection among paediatric haematology/oncology patients. Clin Microbiol Infect. 2016 Dec;22(12):996-1001. doi: 10.1016/j.cmi.2016.09.013. Epub 2016 Sep 22. PMID: 27665705.
  16. Elke G et al. SepNet Critical Care Trials Group. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis – a secondary analysis of a large randomised controlled trial. Crit Care. 2018 Mar 21;22(1):79. doi: 10.1186/s13054-018-2001-5. PMID: 29562917; PMCID: PMC5863464.
  17. Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018 Jan-Feb;6(1):72-81.e1. doi: 10.1016/j.jaip.2017.08.027. Epub 2017 Oct 7. PMID: 29017833.
  18. Maitland K et al. FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. doi: 10.1056/NEJMoa1101549. Epub 2011 May 26. PMID: 21615299.
  19. Parker, M.J., Thabane, L., Fox-Robichaud, A. et al. A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial. Trials 17, 556 (2016). https://doi.org/10.1186/s13063-016-1689-2
  20. Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med. 2016 Nov;17(11):e502-e512. doi: 10.1097/PCC.0000000000000954. PMID: 27673385.
  21. Winter J, Waxman MJ, Waterman G, Ata A, Frisch A, Collins KP, King C. Pediatric Patients Discharged from the Emergency Department with Abnormal Vital Signs. West J Emerg Med. 2017 Aug;18(5):878-883. doi: 10.5811/westjem.2017.5.33000. Epub 2017 Jul 19. PMID: 28874940; PMCID: PMC5576624.
  22. Lim E, Mistry RD, Battersby A, Dockerty K, Koshy A, Chopra MN, Carey MC, Latour JM. “How to Recognize if Your Child Is Seriously Ill” During COVID-19 Lockdown: An Evaluation of Parents’ Confidence and Health-Seeking Behaviors. Front Pediatr. 2020 Nov 17;8:580323. doi: 10.3389/fped.2020.580323. PMID: 33313025; PMCID: PMC7707121.

Febrile Infection-Related Epilepsy Syndrome (FIRES)

Cite this article as:
Jessica Archibald and Catherine Murphy. Febrile Infection-Related Epilepsy Syndrome (FIRES), Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32716

An 8-year-old presents to the emergency department following a first seizure episode. They had a witnessed generalised tonic-clonic seizure that morning lasting approximately 60 seconds and remain post-ictal. They have a history of being non-specifically unwell yesterday with subjective fever, lethargy and a mild headache. They have no significant past medical history and no family history of seizures. The examination is unremarkable. Whilst in the emergency department they have a further two self-terminating generalised tonic-clonic seizures.

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a rare epileptic encephalopathy that results in prolonged refractory status epilepticus in previously well patients.

Presenting Features

FIRES typically presents in children between the age of 3 to 15 years, with intractable status epilepticus, 2 to 10 days post a febrile illness. The preceding illness is most commonly an upper respiratory tract infection or gastroenteritis. Fevers may have resolved prior to the onset of the acute phase of the condition.

The acute phase of the illness is characterised by frequent seizures, rapidly progressing to status epilepticus. Although the seizures are initially focal in nature, they may evolve into secondary generalised seizures. The acute phase can be prolonged, lasting from weeks to months. An association with rash, liver derangement and arrhythmia has been noted in the literature. There is no latency period.

The chronic phase is denoted by refractory epilepsy, resulting in seizures that may cluster every 2 to 4 weeks. This is often associated with severe neurological impairment and cognitive decline.

FIRES had previously been thought to only occur in children, and New-Onset Refractory Status Epilepticus (NORSE) only in adults, however this theory has been disproven. Although FIRES is more prevalent in children, it has been known to also occur in adults. As such, FIRES is now considered a subtype of NORSE, characterised by a preceding febrile illness. It has previously been known as Acute Encephalitis with Refractory, Bepetitive Partial Seizures (AERRPS) and Devastating Epilepsy in School-age Children (DESC).

Aetiology

The aetiology of FIRES in unknown and as such the pathophysiology remains unclear.

One theory is that FIRES is a form of severe infectious encephalitis, but as yet no infectious agent has been identified, and the refractory nature of the seizures is atypical of encephalitis. Another hypothesis suggests FIRES is the result of an immune response, however, there is not enough evidence to support this theory.

A case identifying anti-GABA A receptor antibodies in the CSF of a patient who presented with severe refractory status epilepticus associated with a fever led to speculation that the condition may be autoimmune-mediated. Again this has not been proven and the case may have been an exception rather than a rule.

Other theories include genetic associations and potential links with metabolic disease, but as yet a cause has not been identified.

Diagnosis and Differentials

The diagnosis of FIRES is essentially clinical, as FIRES is a cryptogenic illness. The work up is initially general, and focused on the exclusion of other treatable causes, such as infectious or autoimmune encephalitis.

A detailed history will identify the preceding febrile illness, and would be focussed on the identification of risk factors for other causes for the presentation, including exposure to animals, drugs and toxins, recent foreign travel and immunosuppression.

Blood sampling will be used to identify an infectious cause for the presentation, through full blood count, blood cultures and a screen for atypical infective agents. Lumbar puncture should be performed for CSF sampling in order to investigate bacterial, viral, fungal or autoimmune causes. CSF may show a mildly elevated white cell count in those with FIRES.

EEGs may show a generalised slowing, in keeping with an encephalopathic picture, but do little in the way of distinguishing between other causes of seizures. However, they are useful in guiding treatment and identifying non-convulsive seizures.

Initial MRI imaging is often normal, however, follow up imaging has been associated with devastating changes. Early MRI, in the first weeks of the acute illness, has shown swelling of the mesial temporal structures and increased T2 weighted signal. Follow up MRI, greater than 6 months after onset, may be associated with bilateral mesial temporal atrophy and increased T2 weighted signal. It should be noted that MRI may be normal in 50% of cases.

Differentials to consider are Dravet Syndrome, which presents with a febrile illness associated with status epilepticus, though this tends to present within the first year of life. Also Alper’s Disease, which presents with refractory seizures in previously well children, and is often associated with liver disease.

The patient is loaded with levetiracetam (40mg/kg) as per hospital guidelines, and admitted under paediatrics locally. A CT head is unremarkable and bloods show mild LFT derangement with normal inflammatory markers. They are treated empirically with intravenous cefotaxime and aciclovir. Later that afternoon they develop a fever of 38.3.

The GCS fluctuates between 11 to 13 with no full recovery to baseline until later that evening. Following two focal seizures the next afternoon, they are transferred to the local tertiary centre for further investigation and management.

Initial Management

Initial management involves treating the seizure, and more often status epilepticus. Local hospitals have their own guideline for managing status epilepticus but the first line is typically benzodiazepines (lorazepam, diazepam, midazolam, clonazepam). Second-line treatment is standard anti-convulsants (levetiracetam, phenytoin, phenobarbitone, sodium valproate), however, FIRES does not typically respond to these medications even in high doses.


The seizure pattern in FIRES is often resistant to multiple anti-epileptics. Alternative treatment options have to be sought although there is limited evidence as to the optimal treatment.

Long-term Management

There is limited data on the treatment of FIRES, however, they all conclude the seizures are very difficult to manage and often require polytherapy. Some of the alternative treatment options include drug-induced burst-suppression comas, immunotherapy, a ketogenic diet, vagus nerve stimulation, therapeutic hypothermia and intravenous magnesium sulfate. The most commonly used and researched options are discussed below.

Burst suppression coma

Burst suppression coma induction is viewed as standard care for refractory status epilepticus. If first and second-line treatments fail the next option involves high doses of anti-convulsants along with anaesthetic agents, for example, an infusion of midazolam, barbiturates or propofol. Unfortunately when the anti-convulsants are weaned the seizures tend to reoccur. Prolonged burst suppression coma has been associated with a significantly worse cognitive outcome and poorer prognosis.

Immunotherapy

Immunotherapy has been trialled due to the suspected role of inflammation in the pathogenesis of FIRES. High dose steroids, intravenous immunoglobulin and plasmapheresis have all been used. There is limited evidence to suggest a beneficial role in the management of refractory epilepsy. A large-scale Japanese study described 2 out of 12 patients responding to steroids, although there is not enough evidence to support this as a treatment option. Treatment with immunotherapy is often associated with significant side effects

Anakinra is a recombinant and modified human interleukin-1 receptor antagonist protein. Recent evidence has shown it to be an effective and promising treatment option in patients with FIRES, though relapse has been reported after withdrawal. It has been shown to decrease the duration of mechanical ventilation and hospital length of stay, and possibly seizure reduction. Future studies are required to understand the optimum dosing regime and safety of anakinra.

Ketogenic diet

A ketogenic diet is a high fat, adequate protein and low carbohydrate diet aimed at imitating the body’s fasting state. The body, therefore, metabolises fat for energy. The early introduction of the ketogenic diet has shown to be beneficial in the management of FIRES in uncontrolled trials. It has been suggested that the ketogenic diet may have an anti-inflammatory, as well as an anti-convulsant effect. Some reports suggest it may also have a positive effect on long term cognition. Currently, it is one of the only management options shown to be effective. Future controlled studies are needed to prove this efficacy.

Vagus nerve stimulation

Vagus nerve stimulation (VNS) involves the implantation of an electrode that produces intermittent electrical stimulation into the left cervical vagus nerve. Case reports have found benefit from VNS in the cessation of seizures in patients with refractory status epilepticus and NORSE. There is limited evidence of its use in FIRES.

Long term effects

The prognosis of FIRES is poor. The outcome varies with the length of the acute phase with mortality rates up to 30%. Of those patients who survive there is 66-100% chance that they will have long term cognitive impairment due to damage of the frontal and temporal lobe functions. Survivors with a normal cognitive function will present with a spectrum of learning disabilities, behavioural disorders, memory issues and sensory changes. There is a high risk of recurrent status epilepticus. Unfortunately, only a small proportion of survivors will have no neurologic sequelae.

The patient required a lengthy PICU admission where they were managed with a burst suppression coma, ketogenic diet, high dose steroids and intravenous immunoglobulin.

They were later diagnosed with Febrile-Infection Related Epilepsy Syndrome after extensive investigations, including a normal brain MRI and a lumbar puncture which showed a mildly elevated white cell count but was otherwise unremarkable.

They are currently seizure free on a combination of oral phenobarbitone, perampanel and levetiracetam but have some cognitive sequelae.

References

  1. Fox K, Wells ME, Tennison M, Vaughn B. Febrile Infection-Related Epilepsy Syndrome (FIRES): A literature Review and Case Study. Neurodiagn J. 2017;57(3):224-233. doi: 10.1080/21646821.2017.1355181. PMID: 28898171
  2. Lee H, Chi C. Febrile infection-related epilepsy syndrome (FIRES): therapeutic complications, long-term neurological and Neuro imaging follow-up. Seizure. 2018;56:53-59.
  3. Serino D, Santarone M, Caputo D, Fusco L. Febrile infection-related epilepsy syndrome (FIRES): prevalence, impact and management strategies. Neuropsychiatric Disease and Treatment. 2019;Volume 15:1897-1903.
  4. NORSE (New Onset Refractory Status Epilepticus) and FIRES (Febrile Infection-Related Epilepsy Syndrome) – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/new-onset-refractory-status-epilepticus-norse
  5. Orphanet: Febrile infection related epilepsy syndrome [Internet]. Orpha.net. 2021 [cited 20 January 2021]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163703
  6. Caputo D, Iorio R, Vigevano F, Fusco L. Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABA A R antibodies. European Journal of Paediatric Neurology. 2018;22(1):182-185.
  7. Diagnostic Evaluation — NORSE INSTITUTE [Internet]. NORSE INSTITUTE. 2021 [cited 20 January 2021]. Available from: http://www.norseinstitute.org/definitions
  8. Dravet Syndrome – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum
  9. Alpers Disease – NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2021 [cited 20 January 2021]. Available from: https://rarediseases.org/rare-diseases/alpers-disease
  10. Wheless. J. Treatment of refractory convulsive status epilepticus in children: other therapies. Seminars in Paediatric Neurology (2010) 17 (3) 190-194.
  11. Kramur U et al. Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment and outcome. Epilepsia (2011) 52: 1956-65.
  12. Gaspard et al. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia (2018). 59 (4) 745-752.
  13. Sakuma et al. 2010. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 121:251–256.
  14. Hon et al. Febrile Infection-Related Epilepsy Syndrome (FIRES): An overview of treatment and recent patents. Recent Patents on Inflammation & Allergy Drug Discovery (2018). 12 (2): 128-135
  15. Maniscalco et al. The off-label use of anakinra in pediatric systemic autoinflammatory diseases. The Advance Musculoskeletal Disease (2020)
  16. Shukla N et al. Anakinra (IL-1 blockade) use in children with suspected FIRES: a single institution experience. Neurol 2018; 90: 346
  17. Lai et al. Anakinra usage in febrile infection related epilepsy syndrome: an international cohort. Annals of Clinical and Translational Neurology (2020). 7(12): 2467 – 2474
  18. Dibue-Adjei et al. 2019. Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review. Brain Stimuatlion. 12 (4) 1101-1110.
  19. Kurukumbi et al. 2019. Vagus nerve stimulation (VNS) in super refractory new onset refractory status epilepticus (NORSE). Case Reports in Neu

Don’t Forget about Malaria…

Cite this article as:
Emma Hulme and Chris McKenna. Don’t Forget about Malaria…, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32891

Sunday (April 25th) is a day to refocus our lens of the past 14 months living and working through the global COVID-19 pandemic and be reminded of the ongoing global battle countless countries are continuing to fight against Malaria. Today is World Malaria Day, a day to celebrate the victories, reflect on the challenges, stand in unity with our global colleagues and remember those many children and individuals who are still losing their lives to a preventable disease. 

Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. It is preventable and curable.

My first experience of how dangerous malaria could be was in Kenya in 2003. I was a febrile third-year medical student, sitting in the back of a pick-up truck following a seemingly endless dirt track to the nearest Health Centre with my unconscious friend who had just had a seizure.  Whilst we both had a rocky few days, we both made full recoveries and are counted amongst the privileged few to survive without ongoing sequelae. Malaria had managed to get through the defensive mosquito nets and antimalarials, but we had access to a vehicle for rapid transport, access to money for treatment, and some knowledge as medical students to ensure we got to the right place, at the right time, and got the right treatment. Many are not so fortunate.

Fast forward five years to Uganda in 2008. I would never get used to the cries of mothers who had carried their children unimaginable distances to our rural hospital only for it to be too late and then to watch the sight of them carrying their lifeless bodies home to be buried. It all just seemed so futile – if only they had a bed net or could have gone to a clinic sooner. Sadly, as in many preventable diseases, the most deprived communities are affected disproportionately and children under five years old carry the biggest death toll.

This year we have been bombarded with daily infection rates and death tolls as increasingly large figures appear on our screens. Clinicians and the public alike were shocked and horrified by these growing numbers. Have we become “statistic-fatigued”? Do the numbers no longer hold their impact? For those of us not living in a malaria-endemic area, the personal experiences are few and far between. These malaria statistics hold the stories of many but the identity of none. Let’s look afresh at these huge numbers and allow ourselves to be shocked and horrified, figures that have remained unacceptable for years, decades, and millennia.

The current yearly figures from WHO report 229 million cases of Malaria worldwide with a death toll of 409 000 the majority (67%) of these being children under 5 years old. That means a child is dying from Malaria every 2 minutes. This is not OK!

Data taken from Targetmalaria.org

 

A concerted global effort over the past few years has saved hundreds of thousands of lives with preventative malaria programmes. The World Health Organisation (WHO) estimates in excess of 1 billion malaria cases and 7 million deaths have been prevented since 2000. The number of countries being declared malaria-free is also increasing. This helps reduce huge systems and economic burdens on a country. The WHO’s E-2025 report is announcing that 26 countries and territories are within reach of zero malaria cases by 2025. This is really encouraging yet there is still a long way to go for many countries, particularly in Africa.  

Every Win Counts

Rural Bo District – Sierra Leone, 2011, Sitting in the shell of a clinic that had been built and subsequently abandoned by an NGO after the civil war, we see over one hundred children, sixty of these testing positive for malaria. A simple treatment, but with no health providers for two hours, one exceedingly difficult to access. 


Fast forward nine years, and I’m sitting in a similar rural setting in Bonthe District, but there is finally a referral process to ensure these children and their mothers can get to the referral hospitals in the major population centres for appropriate management and treatment. 

One of the most effective weapons in continuing this fight is the younger generation, those that grew up in a time where Malaria is no longer an unconquerable giant, but something that can be overcome.  The ‘Zero Malaria’ and ‘Drawing the Line’ campaigns empowered young people to keep taking ground. ‘’Malaria we will not let you steal from us anymore… We are the generation that can end Malaria!’’

Young people across Africa have seen the impact of malaria on their lives and futures and are motivated to take action. Even if malaria doesn’t kill, it prevents young people from going to school, realising their full potential, and building their futures. Recent surveys have shown that young people are keen to volunteer in distributing mosquito nets, sharing information about malaria, as well as engaging with their community and national policymakers to prioritise malaria. 

Malaria experiences from our colleagues at Mbarara University EMIG

As a medical student who has been trained in Uganda – a country where malaria is a major public health problem that is associated with slow socio-economic development and poverty, and the most frequently reported disease at both public and private health facilities. One always hears ‘Common things occur commonly and rare things occur rarely”. Malaria goes beyond being common in our communities; “You can’t just convince a senior house officer or attending that you have learnt something from their ward if you don’t know how malaria manifests in their speciality– for example malaria in pregnancy or severe malaria in paeds. We are expected to be “singing” (having them at our fingertips) the signs and symptoms, investigations, laboratory findings, the treatment plans, and the complications of malaria, like nothing else.

“It goes beyond experiencing malaria as clinicians—some of our colleagues had to become caretakers during their younger years to care for their parents suffering from malaria, which can leave some of them with traumatizing experiences. CoArtem and Panadol are like some food in the home. They should always be there” – Fourth Year Medical student MUST-EMIG.

“Complications of malaria are one of the popular things that we are commonly tested on about on ward rounds” – Fourth-year medical student and founder of MUST-EMIG

So back to 2021, COVID-19, and the challenges ahead…

There are real fears that the challenge of COVID-19 has been a huge threat to the progress made in eliminating Malaria. Many places have faced an increased burden on already fragile health systems. There have been disruptions to the distribution of materials including mosquito nets and antimalarials, as well as reports of increasing reluctance to seek medical care for patients with a fever due to the fear of the stigma of COVID-19. The WHO’s estimates that malaria interventions have been reduced by between 15 and 25 per cent during the pandemic. Furthermore, in 2020, the COVID-19 pandemic likely caused 40-50,000 excess deaths from malaria that otherwise could have been prevented. 

Behind the scenes underreporting also exists and the reality of the global refugee crisis and countless internally displaced persons (IDP) means many are facing ‘syndemics’ of COVID-19 and malaria, combined with any other crisis du jour in a variety of environments. 

So what has been happening with malaria elsewhere? 

Unsurprisingly, the number of malaria cases identified in 2020 in those with recent travel history to an endemic area have fallen. Malaria tests performed (on adults and children) at the Manchester Foundation Trust have fallen by 68% compared to 2019, with 92% fewer positive cases. As travel corridors start to re-open, those working in malaria-free countries will need to start thinking ‘could this be malaria?’ once again. While this fall in testing numbers is not surprising, it doesn’t mean that you shouldn’t include malaria on your list of differentials when warranted.  There is a great refresher on the website and here’s a memory jog for those of us who haven’t thought about malaria for a while.

Think Malaria

  • Fever or anaemia in a child who has recently returned from a malaria-endemic area
    • Ordering appropriate investigations (ideally timed with fever spikes)
    • Familiarise yourself with local protocols
    • Microscopy (thick and thin smears) remains the gold standard. Rapid Diagnostic tests are valuable, particularly in resource-limited settings, but are less sensitive
  • Involve infectious disease services early if required!
  • Severe malaria includes the clinical suspicion with confirmed parasitological and at least one of the following: 
  • High parasite density (≥5%)
  • Impaired consciousness
  • Seizures
  • Circulatory collapse/shock
  • Pulmonary oedema or acute respiratory distress syndrome (ARDS)
  • Acidosis
  • Acute kidney injury
  • Abnormal bleeding or disseminated intravascular coagulation (DIC)
  • Jaundice (must be accompanied by at least one other sign)
  • Severe anemia (Hb <7 g/dL)

OR

  • The inability to take any oral antimalarials even after administration of an antiemetic.
  • A child with malaria can have a bacterial co-infection, be sure to address that if suspected!
  •  It is vital to differentiate uncomplicated vs complicated (severe) malaria early.
  • Oral outpatient management for uncomplicated malaria is reasonable, but urgent inpatient management for severe malaria is required. 

A call to action

Moving forwards there is a call to urgent action to ensure that all the progress that has been made is sustained and built upon. Global and national leaders need to continue to prioritise funding and facilitate research and development into new interventions as well as the delivery of effective prevention and treatments to the most vulnerable areas. There needs to be ongoing recognition and support for those health care workers delivering care in such challenging circumstances to ensure access to Malaria prevention, testing and treatment for all. 

Ultimately, there is hope. The end is in sight and malaria eradication is possible. We had a great start with the Global Malaria Eradication Programme started in the 1950s, but the reality of the times prevented further success. Let’s not forget every child and family behind the statistics. Be outraged by the numbers but also encouraged by the wins. Keep talking about malaria. Encourage and support our global colleagues. Listen to their experiences, learn from them, and keep standing united together to eradicate Malaria.

What can you do today?

Share the post. Encourage our global colleagues today – we stand with you #endmalaria #zeromalaria #drawtheline #zeromalariastartswithme #worldmalariaday. Remember Malaria! Listen to your patients, take a travel history, ensure you make referrals appropriately. Engage the ID team early if you are unsure! 

Selected references

Dyer O. African malaria deaths set to dwarf covid-19 fatalities as pandemic hits control efforts, WHO warns. BMJ 2020; doi:10.1136/bmj.m4711

Mendenhall, E., 2020. The COVID-19 syndemic is not global: context matters. The Lancet, 396(10264), p.1731.

RBM Partnership to End Malaria. (2021). World Malaria Day 2021 Key Messages.

Singer, M., Bulled, N., Ostrach, B., & Mendenhall, E. (2017). Syndemics and the biosocial conception of health. The Lancet, 389(10072), 941–950. doi:10.1016/s0140-6736(17)30003-x 

World Health Organization. (2020). World malaria report. Geneva, Switzerland: World Health Organization.

https://targetmalaria.org/ Accessed 13/4/2021

https://endmalaria.org/ Accessed 13/4/21

https://www.theglobalfund.org/en/ Accessed 13/4/21

Haematology Laboratory Manchester University Foundation Trust (personal communication)

Dr Emma Hulme

MBChB, MPH, MRCGP, DTM&H, DCH, DRCOG, DFRSH

Emma works as a GP in a city practice and in the Emergency Department at the Royal Manchester Children’s Hospital. Before training in General Practice she worked in a number of countries overseas in maternal and child health roles and currently leads the Global DFTB Bubble. The rest of her time is spent chasing after her 3 little people and trying to find a quiet corner for 5 minutes peace!

Christopher McKenna, MPH

Chris is a former critical care paramedic turned final year medical student at the University of Queensland – Ochsner Clinical School in New Orleans, Louisiana. Originally from NJ, he has spent time working on pre-hospital system development in Somaliland and Sierra Leone, as well as time with various NGO/IGO in the Philippines. He is eager to return to Australia for his internship in 2022 with the ultimate goal of pursuing a career in PEM/EM. When not at the hospital, he can be found dreaming about travelling post-COVID, avoiding falling into the Gulf of Mexico/Mississippi River in the search of the perfect burger, or at pub trivia with his partner at a local brewery.

Searching for sepsis

Cite this article as:
Anna Peters. Searching for sepsis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.31160

The child with “fever” is one of the most common paediatric presentations to the emergency department. Most of these children are managed conservatively with parental reassurance and discharged home with a safety net identifying red flags. However, failing to identify those with “sepsis” has devastating consequences. How often do we get it wrong or worry about getting it wrong? We’d all love an evidence-based clear cut path for flagging and managing febrile children at risk of sepsis. Currently the approach in the UK is predicated on the NICE SEPSIS (NG 51) screening system which has anecdotally performed poorly with concerns it is poorly specific (i.e lots of false positives). Nijman and colleagues aimed to objectively assess the impact of the NICE Sepsis screening approach in children.

Nijman RG, Jorgensen R, Levin M, Herberg J and Maconochie IK. Management of Children With Fever at Risk for Paediatric Sepsis: A Prospective Study in Paediatric Emergency Care. Frontiers in Pediatric Care 2020; 8:548154. doi: 10.3389/fped.2020.548154

The lead authors looked at the various warning signs of serious infections in febrile children presenting to PED. Their aim was to then determine these children’s risk of having sepsis and to evaluate their subsequent management.

Who did they study?

Over 5000 children (5156 to be exact) aged 1 month to 16 years old presenting with fever over a period of 9 months from June 2014–March 2015 in a single PED at St Mary’s Hospital, UK were analysed.  Febrile children with no warning signs of sepsis were then excluded from the final cohort. The second largest group excluded from the final cohort was children with a complex medical history (n=119).  The decision to exclude this particular cohort is important given that ‘complex medical patients’ are more likely to have sepsis. The authors make the valid point that this group has features very different from the intended cohort, such as having different management plans in the context of fever. After these exclusions, plus a few further exclusions (lack of consent, lack of complete data or excluded because the child didn’t have any warning signs) the final cohort was of 1551 children. 

What did they do?

They first looked at the numbers of febrile children with tachycardia and tachypnea by using APLS and NICE (the National Institute of Healthcare Excellence) thresholds.  Subsequently, they looked at the numbers of febrile children fulfilling sepsis criteria by using well-known sepsis screening tools (NICE traffic light guidelines, SIRS, qSOFA, Sepsis Trust UK trigger criteria).

All the data for this study (vital signs, clinical signs and symptoms, tests, working diagnosis, need for hospital admission, timeliness of interventions) were collected electronically, having been recorded prospectively for all febrile children.

What did they look for? 

As a primary outcome the study determined:

  1. The incidence of febrile children who present with warning signs of sepsis 
  2. How often these children fulfilled paediatric sepsis criteria 
  3. How frequent invasive bacterial infections (IBIs) occurred in this population 
  4. How frequent PICU admissions occurred in this population.

Secondary outcomes included the compliance of clinicians with the paediatric sepsis 6 care bundle (PS6), what clinical interventions were and were not used from this care bundle and the timeliness of the interventions that were undertaken

What did they find? 

Almost a third of children aged 1 month to 16 years who presented to the PED had fever (28% to be exact).

41% of these febrile children had one or more warning signs (our study population).

The incidence of IBI was 0.39%. Of these children, only 0.3% required PICU admission.

This meant that using the sepsis guideline recommendations, 256 children would need to be treated to catch one IBI. Another way of saying this is the number needed to treat was 256. NNT for any serious outcome was 141.

How did the sepsis guidelines fare?

The thresholds for tachycardia and tachypnoea yielded a high false positive rate.

Adding sepsis criteria to predict the presence of a serious bacterial infection (SBI), IBI or PICU admission was also unreliable, with a lot of false positives.

Lactate levels were not significantly associated with the decision to give IV fluid bolus or presence of SBI, IBI or PICU admission. There WAS, however, a significant association between lactate levels and hospital admission.

Looking at the Paediatric Sepsis 6 Interventions, although many children triggered, two-thirds (65%) of the children with PS6 warning signs had none of PS6 interventions. And when it came to the ‘golden hour? Only a third (36%) of children with IBI or PICU admission received all PS6 interventions in the ‘golden hour with only 39 children (2%) receiving a fluid bolus

What does this all mean?

It is important to note that this study was only conducted in one single PED and in a time period that was before the NICE sepsis guidelines were formally implemented into practice.  The data was collected for this study via an electronic interface. While large amounts of data can be collected rapidly there can sometimes be gaps, either due to extraction issues or brevity on the behalf of clinicians that don’t give a comprehensive picture. Data were also only taken from initial triage and not from any clinical deterioration in the ED.  Given that acuity changes over time, especially in children with fever, this may have missed subsequent clinical change although is a pragmatic approach given the way that sepsis screening tools are applied in nearly all Emergency Departments. 

Numbers needed to treat were exceptionally high. Despite the allure of a protocol-based screening and management pathway,  the benefits of catching true sepsis early must be weighed against the possible unwanted effects of overtreating or overdiagnosing mostly well children in a potentially resource-stretched PED. The study really does highlight the difficulties we face when screening for a septic child in a generally well cohort, the ‘needle in a haystack’.

Essentially, what this study shows us is that serious infections are rare and most children who are categorised as ‘at risk of sepsis’ can in fact be managed conservatively with little intervention other than observation. It is clear that our current guidelines have very poor specificity; and while they tell us to investigate and treat lots of children, a lot of the time we as clinicians choose to rely on our clinical judgement and essentially ‘do nothing’. Observation and good clear red flagging must not be underestimated.  Instead of continuing to research more and better early predictors of sepsis, such as point of care biomarkers, perhaps we should be looking at this from another angle. The focus of the lens can also be flipped; we also need more research on how it can be safe NOT to do anything too. 

We’ll end with some thoughts from the authors

The Infections in Children in the Emergency Department (ICED) study is a single centre, prospective observational study. The study describes unique and carefully curated clinical data of febrile children with warning signs of sepsis, from a period prior to the implementation of the NICE sepsis guidelines. 

Our results confirm what many paediatricians dealing with acutely unwell febrile children already suspected: that many febrile children have warning signs of sepsis, but that the large majority have non-life threatening infections. 

Our findings will hopefully contribute to ongoing discussions about the use of sepsis screening tools in paediatric emergency medicine. Our study makes it clear that current tools lead to a high number of false positive cases, and their usefulness in routine clinical care in paediatric emergency medicine should be questioned. Escalation to senior decision makers of all children with warning signs of sepsis should be aspired, but is seldomly feasible in clinical practice and with unproven impact on reducing missed cases and optimising clinical care for the total cohort of febrile children. 

Although all children with serious infections would have been detected by the various sepsis tools, it is now evident that we need better tools to more selectively identify children at the highest risk of sepsis. Future studies should explore the utility of machine learning as well as the potential of combining clinical signs and symptoms with point of care biomarkers.

Ruud Nijman

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.