key: cord-0754364-kv5sl4v8
authors: Zachariah, Philip
title: COVID-19 in Children
date: 2021-11-15
journal: Infect Dis Clin North Am
DOI: 10.1016/j.idc.2021.11.002
sha: 2faac5123e71bac9d878b2634ba976bc04f630dd
doc_id: 754364
cord_uid: kv5sl4v8

Though COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and are often non-respiratory. Adolescents and children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multi-system inflammatory syndrome (MIS-C) with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized for COVID-19. Therapeutic options for severe respiratory disease with hypoxia include Remdesivir and glucocorticoids. Therapies for MIS-C include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.

The historic advent of COVID-19 has not spared children. Since March 2020, close to seven million children have tested positive for SARS-CoV-2 in the US, 1 infected in the household and rarely other communal settings. 2,3 Current evidence is mixed on differential susceptibility of children vs. adults to be infected once exposed, 4 but more conclusive on the effectiveness of standard infection control strategies (masking, social distancing). 5 Hypotheses to why rates of infection and severe disease are lower in pediatrics include age-specific differences in the expression of the binding receptors for SARS-COV-2 (angiotensin-converting enzyme 2, and TMPRSS2) 6, 7 or pre-existing immunity to seasonal coronaviruses. 8 Variability in the immune response once infected compared to adults seems likely. 9 Infected children demonstrate stronger innate immune responses compared to adults with higher expression of genes associated with interferon signaling, and the NLRP3 inflammasome. 7 The striking racial and socio-economic disparities in clinical disease and severe outcomes, well described in adults, have been noted in multiple pediatric studies and non-white children are overrepresented in many case series. [10] [11] [12] [13] 

The clinical spectrum of pediatric COVID-19 is diverse, arguably more than in adults.

The majority of children are asymptomatic or mildly symptomatic. Rates of asymptomatic disease are estimated to be around 30% overall 14 and could be as high as 50% in children. 15 Asymptomatic seroconversion in hospitalized children has been noted. 16 J o u r n a l P r e -p r o o f Among symptomatic patients, distinct syndromes occur at varying time points, with severe disease occurring either early or late in an individual child. Adolescents and medically complex children present early with predominantly respiratory manifestations. 12, 17 Infants often have fever without additional manifestations. 18, 19 A subset of mostly previously healthy children presents 4-6 weeks after an initial mild or inapparent infection with a delayed immune response characterized by higher fever, rising inflammatory markers ,with what is now termed multisystem inflammatory syndrome in children (MIS-C). 20, 21 The community peak of MIS-C has been noted to be 2-5 weeks after the peak of acute COVID-19 in a particular locality. 22 The case definition for MIS-C is broad 23 and includes the presence of fever, laboratory evidence of inflammation, along with evidence of severe multisystem involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological). Two groups feature prominently in MIS-C presentations: i) older children with shock and cardiac dysfunction, gastrointestinal symptoms and highly abnormal laboratory parameters (lymphopenia and elevated markers of cardiac injury) and, ii) younger children with features of Kawasaki disease (KD) with rash and mucocutaneous findings and a higher risk of coronary artery aneurysms. 24

While MIS-C symptoms overlap with KD, cytopenia in the former is an important distinction. 25 This hyperinflammatory response has been variously attributed to a superantigen mediated process, 26 activation of specific T-cell subsets 27 and /or higher antibody levels. 28 Overall rates of hospitalization for pediatric COVID-19 are low (~2%), but among those hospitalized, rates of ICU admission are comparable to adults and higher for MIS-C. 29 Median duration of hospitalization is typically close to a week. 30 Data from the CDC on patients with COVID-10 aged 0-24 years from March to December 2020 showed 2.5% requiring hospitalization and 0.8% requiring admission to an intensive care unit. 31 The rarity of severe J o u r n a l P r e -p r o o f disease in pediatrics continues to be born out with current estimates suggesting that only 0.1%-2 % of all child COVID-19 cases result in hospitalizations and that mortality is extraordinarily rare but can be up to 1% of hospitalizations. 1, 22 The circulation of the more transmissible delta variant has significantly increased COVID-19-associated pediatric hospitalization rates but the proportions of those hospitalized with severe disease has remained similar in the U.S. 32

Respiratory manifestations typically include upper respiratory or influenza-like symptoms, with fever variably present. 33 Pathognomonic symptoms such as anosmia and loss of taste are seen in older children. 12 Infants may present with apnea. 34 A higher fever curve and the presence of multisystem findings suggests overlap with MIS-C where respiratory findings are rarely predominant. 24 Around 30% of patients hospitalized in critical care units show evidence of acute respiratory distress syndrome (ARDS) with higher inflammatory markers, pronounced radiographic findings 35 and pathology which shows type 2 pneumocyte atypia, pulmonary microthrombosis and exudative diffuse alveolar damage. 36 Viral bronchiolitis or asthma exacerbations are not typical presentations and rates of both initially plummeted during early waves of COVID-19. 37, 38 The presence of either of these should raise suspicion for viral co-infections.

The prevalence of gastrointestinal (GI) symptoms as the index presentation for pediatric COVID-19 has varied across case series. 17 However, GI manifestations occur in the majority of cases of MIS-C 24 and persistent antigenemia from a GI source has been linked to pathogenesis. 39 Symptoms range from nausea, vomiting and diarrhea to more severe phenotypes that may mimic J o u r n a l P r e -p r o o f acute appendicitis or intussusception. 12, 40 In severe cases, radiographic findings can resemble that of inflammatory bowel disease. 41

The cardiac manifestations of SARS-Cov2 are predominantly seen in severe cases of MIS-C with accompanying evidence of myocardial inflammation, necrosis and direct viral invasion. 42 In case series of MIS-C, reduced left ventricular ejection fraction is present in over half of the patients, while the overwhelming majority of children with cardiac manifestations had elevated cardiac troponins. 20, 43 In a large case series of 1733 patients, cardiac dysfunction was reported in 484 patients (31.0%), pericardial effusion in 365 (23.4%), myocarditis in 300 (17.3%), and coronary artery dilatation or aneurysms in 258 (16.5%). 43

Neurologic symptoms occur in 20% of children with COVID-19 and more commonly in those with pre-existing neurologic disorders. 44 Infants may present with non-localizing neurologic symptoms (e.g. new seizures, apneic episodes). Adolescents can have severe headaches, sometimes overlapping with pseudotumor cerebri syndrome. 45 Classic post infectious sequelae, e.g. peripheral neuropathy, demyelination, transverse myelitis and Guillain barre syndrome, all can follow recent SARS-CoV-2 infection, sometimes without additional systemic manifestations. 46, 47 Other severe manifestations such as encephalopathy, stroke, demyelination and cerebral edema are rare. 44 Interestingly, neuropathology does not suggest viral infection of the CNS and SARS-CoV-2 is rarely detected in the CSF. 48 J o u r n a l P r e -p r o o f

Transient rash, usually maculopapular in nature, can occur in both acute and late COVID-19. 12,17 SARS-CoV-2 infection can trigger cutaneous vasculitis, causing benign entities like perniosis ("COVID toes") to acral gangrene. Petechiae can occur as part of thrombocytopeniaassociated syndromes like Henoch Schoenlein Purpura. 49 Mucocutaneous manifestations seen in MIS-C are similar to that in KD, including polymorphous rash and involvement of the oral mucosa. 50

Clinical thrombotic events are rare in children in comparison to adults with COVID-19;

they are more common in older children with MIS-C and in those with pre-existing risk factors for thrombosis (e.g. cancer, presence of a central line). These can include deep vein thrombosis, pulmonary embolism and strokes. 51 Diabetic ketoacidosis has been reported as a presentation for children hospitalized with MIS-C, 52 as well as a complication in those children with known diabetes. 53 Acute renal failure is noted in up to a quarter of children hospitalized in the ICU with MIS-C but usually resolves by discharge. 54

The initial approach to a pediatric patient with suspected COVID-19 should aim to: i) confirm the diagnosis, ii) identify competing causes, iii) define the risk of disease progression in an individual child using clinical and/or laboratory risk factors, iv) choose antiviral and immunomodulatory therapy as applicable and, v) provide excellent supportive care.

Testing for SARS-CoV-2 is ideally done using nucleic acid amplification (NAAT) and antigen tests should be interpreted accounting for pre-test probability. Antigen testing has reduced sensitivity, but usually correlates with NAAT when the viral load and infectiousness is highest and thus can be a useful adjunct. The possibility of false negatives should be considered taking into account the local average positivity rate over the past 7-10 days. 55 Though nasopharyngeal swabs specimens are the gold standard, studies show equivalent performance using mid-turbinate, anterior nasal, saliva or a combined anterior nasal/oropharyngeal swabs in symptomatic adults. 56 Prolonged shedding and viral evolution is described particularly in immunocompromised children. 57 SARS-CoV-2 PCR is mostly negative in MIS-C 20 and serology testing should be done to confirm exposure. 58 Increased viral loads have been associated with severity of disease in adults 59 but data in pediatrics is conflicting. 60, 61 Viral loads seem similar between adults and children. 7 The routine use of cycle thresholds from PCRs is not currently part of clinical care and caution must be exercised when comparing across assays, and in light of the potential variability attributable to different sampling practices. 62

Since the absolute risk for hospitalizations due to acute COVID-19 is low in children, a careful assessment for competing causes should be considered in severely ill children. Both common (e.g. bacterial enteritis) 63 Accurate risk prediction scores are not available, though it seems clear that severe COVID-19 correlates with overall derangement of most of these parameters, which are more severe in MIS-C. 68 Elevated CRP is a prognostic marker for critical care admission in pediatric acute COVID-19, 69 while CRP, lymphopenia and BNP elevations are the strongest predictors for ICU admission worse outcomes in MIS-C. 17, 68 Genetic screening for immune system defects, usually as part of research efforts, may be considered particularly for younger children with no associated co-morbidities who present with severe acute COVID-19. Defects in interferon J o u r n a l P r e -p r o o f signaling and the presence of interferon antibodies have been described. 70 Immune phenotyping can also help distinguish between MIS-C and acute COVID-19, with activation of CD8+ cells 27 and specific cytokine elevations observed in MIS-C. 71

The majority of children with acute COVID-19 recover completely with supportive care alone. 1 Comparative data on efficacy for therapeutic agents is mostly derived from studies in adults so any observed relative risk reduction must be interpreted in light of the lower absolute risk and the larger number needed to treat in pediatrics. 72 Ongoing updated guidance is available from the Pediatric Infectious Diseases Society, 73 National Institutes of Health 74 and the Infectious Disease Society of America. 75 Most pediatric patients hospitalized with acute COVID-19 patients have comorbidities. 10, 12 Obesity is an independent risk factor for severe disease in adults and most likely in adolescents. 17, 35, 76 Medical complexity, an amalgam of conditions including neurodevelopmental delay, genetic syndromes, and respiratory technology dependence, is prevalent in most severe COVID-19 case series 30 but individual risk ratios are not available. The role of immunocompromise is nuanced. Unexpectedly lower rates of morbidity and mortality have been reported in immune-compromised patients including those with hematologic malignancies, hematopoietic stem cell transplantation, and solid organ transplantation but these do contribute to disease severity. [77] [78] [79] Adults with primary immune deficiency (e.g. specific antibody deficiency) have had severe outcomes 80 but data is scarce in pediatrics. 81 Children and adolescents with COVID-19 and sickle cell disease often present with typical vasoocclusive J o u r n a l P r e -p r o o f crisis but severe outcomes are rarely described. 82 Asthma has been noted to be prevalent in hospitalized children, 83 76 but whether it is an independent risk factor for COVID-19 is unclear. 84 Diabetes mellitus and chronic renal failure despite initial reports 85 have not conclusively been shown to be independent risk factors for severe disease in children.

Neutralizing antibodies target conserved epitopes on the SARS-CoV-2 spike protein located on the Receptor Binding Domain (RBD). 86 Currently available products include Bamlanivimab/Estevimab, Casirivimab/Imdevimab and Sotrovimab. Administered as a single dose infusion or subcutaneously (Casirivimab/Imdevimab) , these products have been shown to decrease COVID-19 related hospitalizations and mortality in placebo-controlled trials in adults. 87, 88 The magnitude of this reduction is sizeable (~70% relative reduction) when administered within a short window (72 hours) from diagnosis 86 and also correlates with biological endpoints like decreases in viral load. 74 Adverse events seem mostly limited to rare infusion reactions in adults (~1%). The FDA has issued emergency use authorization of these agents in patients 12 years and over, weighing > 40 kg, who are not hospitalized for COVID-19 and are at high risk for disease progression. Risk factors relevant to adolescents mentioned in these EUAs include obesity, immunosuppressive disease, chronic cardiac or pulmonary disease, neuro-developmental delay, technology dependence, sickle cell disease, chronic renal disease, and diabetes. 87 The lower absolute risk, lack of accurate risk factor stratification, and the logistics of administration complicate pediatric use. Most hospitals have chosen a more targeted approach using local data to select subgroups at highest use within the current FDA criteria. 89 A significant drawback with J o u r n a l P r e -p r o o f the use of these products is the evolution of viral variants (e.g. those with L452R or E484K substitutions in the spike protein) with decreased susceptibility and clinicians should monitor the local distribution of variants prior to use. 90 .

Remdesivir, an RNA polymerase inhibitor, was previously studied for pediatric use in Ebola. 91 Data for efficacy in COVID-19 is drawn from an RCT of 1062 adults where remdesivir reduced time to recovery compared to placebo (10 days vs. 15 days; RRR 1.29; 95% CI, 1.12-1.49; P < 0.001), but showed no statistically significant difference in mortality by day 29. The benefit was greatest in patients randomized during the first 10 days after symptom onset and those requiring supplemental oxygen but not higher respiratory support (e.g. mechanical ventilation) at enrollment (RR 1.45; 95% CI, 1.18-1.79). 92 Currently remdesivir is standard of care for adults who require supplemental oxygen in the US, but other studies have demonstrated no impact on mortality and it is not currently recommended by the World Health Organization. 93, 94 Remdesivir can be considered in children with new or worsening oxygen requirement in addition to supportive care alone, though data regarding efficacy and safety in children are lacking. 73 Equivalency has been demonstrated between 5 and 10-day courses in adults. 95 A pediatric-specific pharmacokinetic study is ongoing, but results are not available yet.

Adverse events are rare and include elevated transaminases, transient gastrointestinal symptoms and elevation of prothrombin levels. 96 J o u r n a l P r e -p r o o f

Multiple large RCTs have failed to demonstrate an effect of azithromycin either alone or in combination with hydroxychloroquine to improve outcomes in hospitalized patients or outpatients with COVID-19. 97 Ivermectin and Nitazoxanide are also agents with other pediatric indications that have been proposed for use in COVID-19 but have not yet shown any benefit . 74

Evidence for glucocorticoid use comes from a large trial of 2104 adults who were randomized to receive dexamethasone 6 mg once per day for ten days compared to 4321 patients 

The use of IVIG as first-line therapy for MIS-C evolved from its known efficacy in preventing coronary artery aneurysms in KD, the overlapping presentations of MIS-C with KD, and its potential effectiveness in non-SARS CoV-2 myocarditis. 67 Administration of IVIG is the primary treatment modality for MIS-C and is usually administered at a dose of 2gm/kg similar to use in KD. 67, 103 Second doses of IVIG, while typically used for unresponsive KD, are not usually recommended for MIS-C. 67

Other immunomodulators can be considered in refractory cases or in the rare instance of contra-indications to using steroids. Tocilizumab, an interleukin-6 inhibitor used to treat cytokine storm, has shown decreased mortality when added to steroids, for adults with rapidly increasing respiratory support and evidence of systemic inflammation. 104 In adults, baricitinib, an oral agent that inhibits Janus kinases 1 and 2, seems to have an impact on time to recovery when used along with Remdesivir and can be considered in the rare instances of contraindications to steroid use or as addition to standard of care. 105, 106 Anakinra has not conclusively shown a benefit for adults with COVID-19 pneumonia, 107 but is the most accepted immunomodulatory therapy in MIS-C that is refractory to both IVIG and steroids. 67, 103 Based on previous experience with KD, TNF-α blockade with Infliximab can be considered as a potential therapeutic agent for those with a MIS-C phenotype that most closely resembles refractory KD. 103

Optimum ventilatory strategies for children with COVID-19 have not been defined but trials of noninvasive support followed by lung protective strategies that minimize ARDS are advised. 108 The use of appropriate infection control (e.g. airborne isolation and N-95 use) is necessary when using non-invasive strategies that are aerosol generating. Consensus guidelines advise systemic anti-coagulation with low-dose low molecular weight heparin for children hospitalized for COVID-19-related illness (including MIS-C) in the presence of markedly elevated D-dimer levels or other risk factors for hospital associated venous thromboembolism. 109 The rate of secondary infections in adults have been estimated to be 24% 110 , but is likely lower in children and antibiotic use should be minimized in the absence of known bacterial coinfection.

J o u r n a l P r e -p r o o f

The majority of children recover from COVID-19 without complications. Neonates born to pregnant mothers with COVID-19 have been reported to have small increases in adverse outcomes like respiratory complications but perinatal transmission is rare. 111 Follow-up for children with MIS-C done at 6 months shows limited residual organ-specific sequalae. 112 Reinfections remain rare even in adults. Potential long-term effects, collectively known as Post-Acute Sequelae of SARS-CoV-2 infection (PAS-C), following an initial mild infection is 

COVID-19 Outbreak at an Overnight Summer School Retreat -Wisconsin

COVID-19 Cases and Transmission in 17 K-12 Schools -Wood County

Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Metaanalysis

Low SARS-CoV-2 Transmission in Elementary Schools -Salt Lake County

Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults

Natural mucosal barriers and COVID-19 in children

Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Reduced development of COVID-19 in children reveals molecular checkpoints gating pathogenesis illuminating potential therapeutics

Hospitalization Rates and Characteristics of Children Aged <18 Years Hospitalized with Laboratory-Confirmed COVID-19 -COVID-NET, 14 States

Racial and/or Ethnic and Socioeconomic Disparities of SARS-CoV-2 Infection Among Children

Clinical Features, and Disease Severity in Patients With Coronavirus Disease 2019 (COVID-19) in a Children's Hospital in

Severe COVID-19 in children and young adults in the Washington, DC metropolitan region. The Journal of pediatrics. 2020. 14. Center for Disease Control and Prevention . COVID-19 Pandemic Planning Scenarios

Age-dependent effects in the transmission and control of COVID-19 epidemics

Asymptomatic Seroconversion of Immunoglobulins to SARS-CoV-2 in a Pediatric Dialysis Unit

SARS-CoV-2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth. The Journal of pediatrics

Symptomatic Infants Have Higher Nasopharyngeal SARS-CoV-2 Viral Loads but Less Severe Disease Than Older Children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Febrile Infants Without Respiratory Distress. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Multisystem inflammatory syndrome in U.S. children and adolescents. The New England journal of medicine

Multisystem inflammatory syndrome in children in New York State. The New England journal of medicine

Trends in Geographic and Temporal Distribution of US Children With Multisystem Inflammatory Syndrome During the COVID-19 Pandemic. JAMA pediatrics. 2021. 23. Center for Disease Control and Prevention .a. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children

COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis

Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

Quantitative SARS-CoV-2 Serology in Children With Multisystem Inflammatory Syndrome (MIS-C)

Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study

Characteristics and Outcomes of Children With Coronavirus Disease 2019 (COVID-19) Infection Admitted to US and Canadian Pediatric Intensive Care Units

COVID-19 trends among persons aged 0-24 years -United States

Among Children and Adolescents -COVID-NET, 14 States

Systematic review of reviews of symptoms and signs of COVID-19 in children and adolescents. Archives of disease in childhood

COVID-19 Associated With Life-Threatening Apnea in an Infant Born Preterm: A Case Report

Clinical manifestations and outcomes of critically ill children and adolescents with coronavirus disease

An autopsy study of the spectrum of severe COVID-19 in children: From SARS to different phenotypes of MIS-C

Bronchiolitis in COVID-19 times: a nearly absent disease?

Pediatric asthma exacerbations during the COVID-19 pandemic: Absence of the typical fall seasonal spike in Washington, DC

Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier

Global Reports of Intussusception in Infants With SARS-CoV-2 Infection

Gastrointestinal Symptoms as a Major Presentation Component of a Novel Multisystem Inflammatory Syndrome in Children That Is Related to Coronavirus Disease 2019: A Single Center Experience of 44 Cases

SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome. The Lancet Child & adolescent health

Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

Pseudotumor cerebri syndrome associated with MIS-C: a case report

Neurological issues in children with COVID-19

Arteritis and Large Vessel Occlusive Strokes in Children After COVID-19 Infection

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital

Leucocytoclastic vasculitis secondary to COVID-19 infection in a young child

Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children During the COVID-19 Pandemic

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C. Blood

New onset diabetes with diabetic ketoacidosis in a child with multisystem inflammatory syndrome due to COVID-19

Acute Kidney Injury in Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic: Experience From PICUs Across United Kingdom

Interim Guidance for Antigen Testing for SARS-CoV-2

The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Increased viral variants in children and young adults with impaired humoral immunity and persistent SARS-CoV-2 infection: A consecutive case series

Information for healthcare providers about multisystem inflammatory syndrome in children

SARS-CoV-2 viral load is associated with increased disease severity and mortality

Comparison of Upper Respiratory Viral Load Distributions in Asymptomatic and Symptomatic Children Diagnosed with SARS-CoV-2 Infection in Pediatric Hospital Testing Programs

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

College of American Pathologists (CAP) Microbiology Committee Perspective: Caution Must Be Used in Interpreting the Cycle Threshold (Ct) Value. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Mistaken MIS-C: A Case Series of Bacterial Enteritis Mimicking MIS-C

IFN-gamma receptor 2 deficiency initial mimicry of multisystem inflammatory syndrome in children (MIS-C)

Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2

Discriminating multisystem inflammatory syndrome in children requiring treatment from common febrile conditions in outpatient settings

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2

Factors linked to severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. The Lancet Child & adolescent health

Risk Factors for Severe COVID-19 in Children

Susceptibility to severe COVID-19

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2

Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2

Multicenter interim guidance on use of antivirals for children with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Severe Coronavirus Disease-2019 in Children and Young Adults in the

COVID-19 in children with cancer in New York City

Characterization of COVID-19 disease in pediatric oncology patients: The New York-New Jersey regional experience

The pediatric solid organ transplant experience with COVID-19: an initial multi-center, multi-organ case series

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Consortium UPC-. COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience

Varying presentations and favourable outcomes of COVID-19 infection in children and young adults with sickle cell disease: an additional case series with comparisons to published cases

Clinical Characteristics and Outcomes of Hospitalized and Critically Ill Children and Adolescents with Coronavirus Disease 2019 at a Tertiary Care Medical Center

Asthma among hospitalized patients with COVID-19 and related outcomes

Underlying Medical Conditions Associated With Severe COVID-19 Illness Among Children

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. The New England journal of medicine

Journal of the Pediatric Infectious Diseases Society. 2021. 90. Prevention CfDCa. SARS-CoV-2 Variant Classifications and Definitions

Controlled Trial of Ebola Virus Disease Therapeutics. The New England journal of medicine

Remdesivir for the Treatment of Covid-19 -Final Report. The New England journal of medicine

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results. The New England journal of medicine

A living WHO guideline on drugs for covid-19

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. The New England journal of medicine

Factsheet for Healthcare Providers on Remdesivir for Pediatric Patients

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dexamethasone in Hospitalized Patients with Covid-19. The New England journal of medicine

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Multisystem Inflammatory Syndrome in Children: Survey of Protocols for Early Hospital Evaluation and Management

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children

Multisystem Inflammatory Syndrome in Children -Initial Therapy and Outcomes. The New England journal of medicine

A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process. The Lancet Child & adolescent health

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. The New England journal of medicine

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. The New England journal of medicine

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group

Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial

Invasive and noninvasive ventilation strategies for acute respiratory failure in children with coronavirus disease 2019

Consensus-based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illness

Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis

Association of Maternal SARS-CoV-2 Infection in Pregnancy With Neonatal Outcomes

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study. The Lancet Child & adolescent health

RECOVER: Researching COVID to Enhance Recovery