Andrew Tagg. The child with a limp, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.23509
This post is based on the talk Andrew Tagg was invited to give at BadEMFest20 in Capetown. Unfortunately, world events made that a little challenging.
Humans evolved from Homo erectus to Homo sapiens around 500,000 years ago. Fossils dug up from by the Leakeys in Olduvai Gorge, Tanzania, revealed how we moved from shuffling knucklewalkers to the upright hominids we recognize today. Walking on two legs allowed us the freedom to use our hands – to communicate, to use tools, and to keep ourselves safe.
How do we walk?
The normal human gait is comprised of three distinct phases:
- The contact phase – from heel strike to flat foot
- The stance phase – from flat foot to heel off the ground
- The swing phase – the propulsion phase as weight transfers from the toes
The swing phase normally comprises 40% of the gait cycle.
Like Sherlock Holmes or his progenitor, Joseph Bell, if you watch your patient walk you can get a lot of clues as to the potential underlying pathology before you even exchange a word with them or their parents.
Antalgic gait
This hobbling gait has a normal contact phase and normal propulsion with a decreased stance phase. In essence, the patient is trying to decrease the amount of time spent bearing weight through the hip joint itself.
Trendelenburg gait
In this gait disturbance, the hip muscles are too weak and so the unaffected side drops towards the floor. It suggests a biomechanical issue such as ass avascular necrosis, or a slipped capital femoral epiphysis.
Circumduction gait
The patient swings their leg out and around to clear the floor. This is often due to a leg-length discrepancy in the delayed diagnosis of developmental dysplasia of the hip (DDH).
Equinus gait
Toe walking, though normal up to the age of three may suggest that the child is unwilling or uncomfortable engaging their gastrocnemius muscles in walking. This can occur in many conditions.
The rate of presentation to the emergency department with an atraumatic limp is approximately 1.4 per 1000 in children under the age of 14. It occurs more often in boys than in girls (1.7:1) and the median age is 4.4 years. When we consider the potential causes the list is massive. In this post, we are going to concentrate on both the more common conditions and those diagnoses that we really shouldn’t miss. Whilst any part of the limb might be the cause (from the toes to the hip) this post is going to focus on causes centred around the hip joint. They account for about 60% of cases of limp. That doesn’t mean you shouldn’t look in their shoes for pebbles or look at their toes though!
Let’s break it down to some age-specific diagnoses and those that can occur at any age
Late presentation of developmental dysplasia of the hip (DDH)
It is just possible that routine screening with Ortolani’s and Barlows test might have missed a case of hip dysplasia. The limb resultant limb shortening can be hard to detect if it is bilateral but this is one time to get out the tape measure and look for a leg length discrepancy as you measure from anterior superior iliac spine (ASIS) to medial malleolus.
If you don’t have a tape measure to hand then look for a positive Galeazzi sign, suggesting a shorter hip segment on the affected side.
Original by Walt Shumway
Transient synovitis
This diagnosis accounts for the majority of cases of atraumatic limp and may follow an upper respiratory tract infection though the evidence for causation is poor. It is most common in young boys, aged 4 to 8 years of age and is self-limiting in nature. It’s a diagnosis of exclusion rather than anything else made easier by the well-appearing, afebrile child. It should respond to simple NSAIDs though is recurrent in 20% of cases.
Dr. Sathya Subramaniam, Pediatric EM Fellow – Kings County/SUNY Downstate and The POCUS Atlas
According to Viera and Levy, bedside sonography has a sensitivity of 90% and specificity of 100% to detect an effusion. Unfortunately, it doesn’t help with determining the cause.
Occult trauma
It’s beyond the scope of this post to talk about NAI and long bone injuries in children (especially as Nikki Abela did such a great job at DFTB18) so instead, it’s worth thinking about toddlers’ fractures. These occur due to torsional force on the tibia, accompanied by a fall, and may only be picked up as tenderness over the distal third of the tibia. That first set of x-rays performed in the emergency room may not show any obvious pathology with signs only becoming obvious after a couple of weeks. This is one of those occasions where ultrasound may be much more helpful though if clinical suspicion remains it should be treated with immobilization and close follow-up. Repeat imaging may then show the beginnings of some callus formation or a radionuclide bone scan may be needed. If they are not toddling and waddling it is not going to be a toddler’s fracture.
Case courtesy of Dr. Jeremy Jones, Radiopaedia.org. From the case rID: 9317
Neuromuscular
Although unlikely to present as an isolated limp, cerebrovascular events may present as hemiparesis; It’s beyond the scope of this post to go into them in more detail. Watch this space.
Perthes disease
This is idiopathic avascular necrosis of the growing femoral head and typically presents in boys at the younger end of the scale (4 to 8 years old). Because of this, these children are often shorter than their peers and there is a possible association with hyperactivity. The classical findings on a plain AP x-ray of the pelvis include sclerosis leading to destruction and the eventual collapse and flattening of the femoral head. As this is a biomechanical problem, they might present with a slow onset antalgic gait with pain on internal rotation and ABduction. Around 20% of cases are bilateral.
Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org. From the case rID: 7980
Both MRI and bone scan are equally sensitive if the plain films are equivocal. Treatment may be surgical or conservative depending on the degree of bone destruction and the age of the child. Left unchecked neovascularization occurs with the destruction of the femoral head.
Though first described in 1897, it was not until 1910 that it was found to be unrelated to tuberculosis. Arthur Legg, Jacques Calvé and Georg Perthes are guilty of its eponymous name.
Transient synovitis
I think we’ve said enough about transient synovitis already.
Neuromuscular
As well as a stroke a limp might be the initial feature of an ascending paralysis in Guillain-Barré. We’ll talk about that and ADEM another time.
Slipped Capital Femoral Epiphysis
A slipped capital femoral epiphysis or slipped upper femoral epiphysis is more common on older, overweight boys, over the age of 10 years of age. There is often a structural weakness of the physis itself so it is more common in cases of endocrine dysregulation (such as hypothyroidism) and metabolic conditions (such as renal osteodystrophy). The proximal epiphysis displaces anteriorly and laterally relative the metaphysis. Involvement of the medial obturator nerve may mean that they present as knee pain rather than hip pain. Early fixation and we mean in less than 24 hours in unstable cases, can ward off the threat of life-long pain and deformity. Plain AP films may not be enough in the case of subtle slippage. So if you are suspicious then you should go ahead and order a lateral film as well. A lot of other hip pathology is made easier to spot in a frog-leg lateral. Don’t do this if you are suspicious of a SCFE, you might make things much, much worse.
Look for Klein’s line. A line along the superior aspect of the femoral neck should intercept with the epiphysis. Imagine it as an ice cream slipping off the cone on a hot summer day.
Adapted from case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org. From the case rID: 2715
Case courtesy of Dr. Hani Salam, Radiopaedia.org. From the case rID: 9298
Some things need to be in our differential no matter the age of the child.
Septic arthritis
The hip is the most commonly infected joint with the haemategenous spread of organisms grown dependent on the local flora. Young children (under the age of 2), those who are immunosuppressed or asplenic are at higher risk. In Australia, for instance, the commonest organisms grown are Staphylococcus aureus and Group B Streptococcus (especially now that Haemophilus influenzae b infections have been almost wiped out by immunization). In the youngest, patients consider the weirder organisms like Kingella kingae and Salmonella (in patients with sickle cell disease).
The juvenile physis does not prevent the spread from a remote source from entering the epiphysis and so haematogenous spread (rather than direct local invasion) is often the culprit. The hip is classically held in a position of external rotation, ABduction and, flexion, perhaps in an effort to maximize the joint space and minimize the pain.
It would be great if there was a way we could differentiate the serious diagnosis of septic arthritis from something less serious, such as transient synovitis. Step forward Meninder Kocher et al. and their seminal paper.
Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and transient synovitis of the hip in children: an evidence-based clinical prediction algorithm. JBJS. 1999 Dec 1;81(12):1662-70.
They looked at 17 years of data for patients that presented to a single tertiary hospital with an acutely irritable hip. This amounted to 282 cases in all of which only 168 had their hip joint aspirated. Of this 168, only 26 had true septic arthritis as confirmed by a positive culture of joint aspirate or 50,000 WCC in the aspirate with a positive culture, 9 had a positive joint culture and negative blood cultures and 3 had only positive blood cultures. By performing a multivariate analysis they then looked for key indicators that differentiated cases of septic arthritis from the more benign irritable hip. Four key factors cropped up. They were a history of fever, inability to bear weight, a WBC greater than 12 x 109/l and an ESR ≥ 40mm/hr. If you had none of these then the probability of having septic arthritis is 0.1%. But if you have all four it jumps to 99.8%.
Of course, this is all the primary literature that most people read but when Kocher tried to validate the study having all four markers gave the chance of having septic arthritis as 93% and when Luhmann et al. tried to externally validate the criteria it dropped to 59%. Caird et al. must have realized that not many of us use ESR any more and so appended the more common C-reactive protein (CRP). Having all 5 gave a 97.5% positive predictive value though there were only 14 cases of transient synovitis, and 5 of septic arthritis.
Osteomyelitis
An indolent course and a non-specific physical examination make this a difficult diagnosis to pick up at first glance. Around 1.5-2% of all children presenting with an atraumatic limp will have osteomyelitis. Plain films may be unremarkable early in the course of the illness and only show periosteal changes after a week to 10 days. An MRI scan is more sensitive and if the diagnosis is still a challenge then radionuclide scanning might pinpoint the infection. The hip is one of the more common joints affected (25%) followed by the tibia/fibula (25%) then the humerus (13%). Osteomyelitis and septic arthritis can coexist as infection from the bone spreads to the joint capsule.
One case series suggests that 40% of cases are due to transient synovitis, chronic muscle sprain or trauma accounted for 16% and no diagnosis was made in 30%. All those diagnoses we have to learn for exams are much less common (Perthes’ disease 2%, osteomyelitis 1.5%, toddlers’ fractures 1%, and SCFE 1%). What has not been mentioned, as the incidence is incredibly low is the thing that many parents worry about – cancer.
Malignancy
Whilst parents may not have heard of a slipped capital femoral epiphysis or Kocher’s criteria but they have heard of cancer and so we need to address it. Primary benign tumours (unicameral bone cysts, for example, as well as malignant ones can present as bony hip pain. Hip pain can also be a presenting feature in haematological malignancies such as acute lymphoblastic leukaemia. The most common malignant bone tumours in infants are osteogenic sarcoma and Ewing’s sarcoma. Both of these are most common in the second decade of life.
Persistent pain, coupled with constitutional symptoms such as night sweats, weight loss and night pain are highly suspicious and should prompt imaging and blood tests.
Selected references
Please, Just STOP LIMPING from Tim Horeczko and the PEM Playbook
Septic arthritis from PEM Morsels
Adamson J, Waterfield T. Fifteen-minute consultation: The limping child. Archives of Disease in Childhood-Education and Practice. 2019 Jun 29:edpract-2018.
Caird MS, Flynn JM, Leung YL, Millman JE, Joann GD, Dormans JP. Factors distinguishing septic arthritis from transient synovitis of the hip in children: a prospective study. JBJS. 2006 Jun 1;88(6):1251-7.
Fischer SU, Beattie TF. The limping child: epidemiology, assessment and outcome. The Journal of bone and joint surgery. British volume. 1999 Nov;81(6):1029-34.
Flynn JM, Widmann RF. The limping child: evaluation and diagnosis. JAAOS-Journal of the American Academy of Orthopaedic Surgeons. 2001 Mar 1;9(2):89-98.
Herman MJ, Martinek M. The limping child. Pediatrics in review. 2015 May;36(5):184-95.
Hill D, Whiteside J. Limp in children: Differentiating benign from dire causes. Journal of Family Practice. 2011 Apr 1;60(4):193.
Hussain M, Gholipour B, Owen N. A pictorial review of the radiological presentations of the child presenting with an acute limp in the emergency department. Clinical Radiology. 2019 Oct 1;74:e14.
Leet AI, Skaggs DL. Evaluation of the acutely limping child. American Family Physician. 2000 Feb 15;61(4):1011-8.
Lewis D, Logan P. Sonographic diagnosis of toddler’s fracture in the emergency department. Journal of Clinical Ultrasound. 2006 May;34(4):190-4.
Long B, Koyfman A, Gottlieb M. Evaluation and Management of Septic Arthritis and its Mimics in the Emergency Department. Western Journal of Emergency Medicine. 2019 Mar;20(2):331.
McCarville MB. The child with bone pain: malignancies and mimickers. Cancer Imaging. 2009;9(Special issue A):S115.
Mooney III JF, Murphy RF. Septic arthritis of the pediatric hip: update on diagnosis and treatment. Current opinion in pediatrics. 2019 Feb 1;31(1):79-85.
Perry DC, Bruce C. Evaluating the child who presents with an acute limp. BMJ. 2010 Aug 20;341:c4250.
Ryan DD. Differentiating Transient Synovitis of the Hip from More Urgent Conditions. Pediatric annals. 2016 Jun 15;45(6):e209-13.
Sawyer JR, Kapoor M. The limping child: a systematic approach to diagnosis. American family physician. 2009 Feb 1;79(3):215.
Singhal R, Perry DC, Khan FN, Cohen D, Stevenson HL, James LA, Sampath JS, Bruce CE. The use of CRP within a clinical prediction algorithm for the differentiation of septic arthritis and transient synovitis in children. The Journal of bone and joint surgery. British volume. 2011 Nov;93(11):1556-61.
Vieira RL, Levy JA. Bedside ultrasonography to identify hip effusions in pediatric patients. Ann Emerg Med. 2010;55(3) :284-9
Wainwright, AM; Catterall, A (2010). “Chapter 27: Legg–Calvé–Perthes disease: Its name”. In Benson, M; Fixsen, J; MacNicol, M; Parsch, K (eds.). Children’s orthopaedics and fractures (3rd ed.). London: Springer. p. 465
Acute COVID management in children – evidence summary
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
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:
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:
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:
ALS in hospital recommendations:
Pre-hospital and Rapid Response Teams recommendations:
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:
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:
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
Copy
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:
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:
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):
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
2 (semi-elective) – a delay in procedure (>30 days) could be detrimental
3 (elective) – can be delayed >30d
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:
Pertaining care of the newborn:
Advised against:
Can be considered:
Care of the unwell newborn
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
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:
The main recommendations are summarised here:
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:
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:
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.