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 email@example.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.
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 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.
|First author||Last author||Journal||Date of Publication||Paper link|
|S Balasubramanian||A V Ramanan||INDIAN PEDIATRICS||7 May 2020||https://indianpediatrics.net/CONVID29.03.2020/SA-00159.pdf|
|Ye, Y||Guyatt, G H||CMAJ||4 May 2020||https://www.cmaj.ca/content/cmaj/early/2020/05/04/cmaj.200648.full.pdf|
|Al Giwa||Probst, M A||EB medicine||3 May 2020||https://www.ebmedicine.net/topics/infectious-disease/COVID-19|
|Health Policy Team||RCPCH||RCPCH website||1 May 2020||https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf|
|van den Berg, J||Terheggen, U||ESPNIC online||28 Apr 2020||https://espnic-online.org/Media/Files/ESPNIC-ESPR-COVID19-Transport-Consensus-recommendations-040420202|
|Lynch, J||Sultan, S||IDSA guidelines website||27 Apr 2020||https://www.idsociety.org/practice-guideline/covid-19-guideline-infection-prevention/|
|Joseph, T||Moslehi, M A||International pulmonologist’s consensus group on COVID||26 Apr 2020||https://www.unah.edu.hn/dmsdocument/9674-consenso-internacional-de-neumologos-sobre-covid-19-version-ingles|
|Marini, J J||Gattinoni, L||JAMA||24 Apr 2020||https://jamanetwork.com/journals/jama/fullarticle/2765302|
|Shen, K-L||Wang, X-F||World Journal of Pediatrics||24 Apr 2020||https://link.springer.com/article/10.1007/s12519-020-00362-4|
|Cstagnoli, R||Licari, A||JAMA Pediatrics||22 Apr 2020||https://jamanetwork.com/journals/jamapediatrics/fullarticle/2765169|
|K Chiotis||MM Nakamura||J Pediatric Infect Dis Soc||22 Apr 2020||https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piaa045/5823622|
|Yuki, K||Koutsogiannaki, S||Clin Immunol||20 Apr 2020||https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169933/|
|Chiotos, K.||Nakamura, M||J Pediatric Infect Dis Soc||18 Apr 2020||https://academic.oup.com/jpids/article-pdf/doi/10.1093/jpids/piaa045/33112599/piaa045.pdf|
|APLS Australia||Retrieved from the APLS Australia website||14 Apr 2020||https://apls.org.au/sites/default/files/uploadedfiles/APLS%20Australia%20Statement%20on%20Paediatric%20Resuscitation%20during%20the%20COVID-19%20pandemic%20v1.0.pdf|
|Matava, CT||Fiadjoe, JE||Anesthesia & Analgesia||13 Apr 2020||https://journals.lww.com/anesthesia-analgesia/Abstract/publishahead/Pediatric_Airway_Management_in_COVID_19_patients__.95683.aspx|
|Matthai, J||Sobhan, P||Indian Pediatr.||12 Apr 2020||https://indianpediatrics.net/CONVID29.03.2020/SA-00162.pdf|
|Matthai||Sobhan||Ind Pediatrics||12 Apr 2020||https://www.ncbi.nlm.nih.gov/pubmed/32279064|
|Mimouni, F||Mendlovic, J||Journal of Perinatology||10 Apr 2020||https://www.nature.com/articles/s41372-020-0665-6|
|Morray, B. H.||Sathanandam, S. K.||J Invasive Cardiol||9 Apr 2020||https://www.invasivecardiology.com/sites/invasivecardiology.com/files/articles/images/Morray%202020%20Apr%209%20AOP%20wm.pdf|
|Morray||Sathanandam||J Invasive Cardiol||9 Apr 2020||https://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|
|Balasubramanian||Ramanan||Ind Pediatrics||9 Apr 2020||https://www.ncbi.nlm.nih.gov/pubmed/32273490|
|Edelson, D||Topjian, A||Circulation||9 Apr 2020||https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.120.047463|
|Thampi, S||Ong, J||Paediatr Anaesth||8 Apr 2020||https://onlinelibrary.wiley.com/doi/epdf/10.1111/pan.13863|
|Phua, J||Du, B||Lancet Resp Med||6 Apr 2020||https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30161-2.pdf|
|Ashokka, B||Choolani, M||American Journal of Obstetrics and Gynecology||3 Apr 2020||https://www.ajog.org/article/S0002-9378(20)30430-0/fulltext|
|Ashokka||Choolani||Am J Obs & Gyn||3 Apr 2020||https://www.ajog.org/action/showPdf?pii=S0002-9378%2820%2930430-0|
|Wilson, K||Rello, J||American Thoracic Society||3 Apr 2020||https://www.thoracic.org/professionals/clinical-resources/disease-related-resources/covid-19-guidance.pdf|
|Misra, D. P||Zimba, O.||Clin Rheumatol 2020||31 Mar 2020||https://link.springer.com/article/10.1007/s10067-020-05073-9|
|DP Misra||O Zimba||Clin Rheum||31 Mar 2020||https://link.springer.com/article/10.1007%2Fs10067-020-05073-9#author-information|
|Hasan, A||Fergie, J||Cureus||31 Mar 2020||https://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, K||Perkins, GD||International Liaison Committee on Resuscitation (ILCOR)||30 Mar 2020||https://costr.ilcor.org/document/covid-19-infection-risk-to-rescuers-from-patients-in-cardiac-arrest|
|Chandrasekharan, P||Lakshminrusimha, S||American Journal of Perinatology||30 Mar 2020||https://www.thieme-connect.com/products/ejournals/pdf/10.1055/s-0040-1709688.pdf|
|Cook, T M||Higgs, A||Anaesthesia||27 Mar 2020||https://onlinelibrary.wiley.com/doi/full/10.1111/anae.15054|
|Ford, N||Doherty, M||JIAS||26 Mar 2020||https://onlinelibrary.wiley.com/doi/epdf/10.1002/jia2.25489|
|Mimouni||Mendlovic||J Perinatology||25 Mar 2020||https://www.nature.com/articles/s41372-020-0665-6.pdf|
|Al Giwa, LLB||Duca, A||Emerg Med Pract||24 Mar 2020||https://www.ebmedicine.net/topics/infectious-disease/COVID-19|
|Kneyber, M||Rimsensberger, P||European Society for Paediatric and Neonatal Intensive Care||23 Mar 2020||https://scp.com.co/wp-content/uploads/2020/04/2020-ESPNIC-PEMVECC-COVID-19-practice-recommendations.pdf.pdf|
|Molloy, E||Bearer, CF||Pediatric Research||23 Mar 2020||https://www.nature.com/articles/s41390-020-0881-y_reference.pdf|
|Wang, Y||Zhu, L-Q||World Journal of Pediatrics||12 Mar 2020||https://link.springer.com/content/pdf/10.1007/s12519-020-00353-5.pdf|
|Shen, K-L||Yang, K-L||World Journal of Pediatrics||5 Feb 2020||https://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:
- 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:
- Addition of viral filters on all airway devices (BVM, SGA, ETT) where available
- Preferentially allocating the most experienced clinician to manage the airway
- 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
- 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.
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
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
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
- 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
- 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
Immune modulation (contributed by Dr Alberto Pinzon)
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.
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.
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:
- 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
- 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.
- 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.
- 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.