COVID-19 in Children

Key Points

• COVID-19 is a systemic infection primarily affecting the respiratory system, caused by a recently recognized coronavirus, SARS-CoV-2
• Children tend to experience less severe illness and fewer complications than adults. Fewer children than adults with infection require hospitalization; however, a similar proportion of children and adults who do need hospital admission require ICU level of care
• Asymptomatic infection may occur in up to half of children
• Fever, cough, and upper respiratory symptoms are very common in children who develop symptoms but wide variation in presentation is possible, including asthma exacerbation, influenzalike illness, or gastroenteritis
• The following groups may be at increased risk for severe disease: infants younger than 1 year, adolescents, Black/Hispanic/Native American children, unvaccinated children, and children with medical comorbidity (eg, moderate or severe immunosuppression; obesity; significant cardiac, neurologic, respiratory, or lung disease) ^r1
• Suspect diagnosis of COVID-19 based on clinical presentation with manifestations consistent with possible COVID-19 or contact with SARS-CoV-2; maintain awareness that many patients do not have known exposure due to high transmissibility of Omicron subvariants
• Confirm diagnosis by detecting viral nucleic acid (nucleic acid amplification test) or protein (antigen test) on respiratory specimen
• Maintain a broad differential to evaluate for additional conditions in children infected with SARS-CoV-2
  • Other conditions (eg, diabetic ketoacidosis, intussusception, community-acquired pneumonia, streptococcal pharyngitis, influenza) may present concomitantly in children who test positive for SARS-CoV-2; coinfection with more than a single pathogen may occur
• Supportive care is the mainstay of management for the overwhelming majority of pediatric patients, and most children can be managed safely at home
• Use of COVID-19–specific therapies is indicated in certain patients
  • Remdesivir and dexamethasone are the primary pharmacotherapeutics in certain hospitalized children
  • Nirmatrelvir-ritonavir or remdesivir are used for certain nonhospitalized patients with COVID-19 at high risk of progression to severe disease
• Most children experience mild illness with full recovery; a small percentage have complications (eg, MIS-C) or symptoms beyond 4 weeks
• Vaccination is safe and highly effective at preventing serious COVID-19 illness among pediatric patients
• Measures to protect pediatric population and the community from SARS-CoV-2 infection include vaccination, isolation of those with COVID-19 even without symptoms, staying home when sick, mask wearing, testing including repeat or serial tests when indicated, improving ventilation, and general hygiene measures

Urgent Action

• Promptly institute appropriate isolation measures when any patient presents to health care facility after possible exposure to SARS-CoV-2 or with manifestations concerning for possible COVID-19
• Patients with respiratory distress and/or hypoxia require urgent management with appropriate respiratory support and oxygen administration ^r2
• Patients with shock require resuscitation and urgent diagnosis and management of underlying cause of shock. Rapidly administer fluids to patients with hypovolemic shock, administer empiric antibiotics to patients with concern for septic shock, and provide vasopressor support for patients with cardiogenic shock ^r2

Pitfalls

• Be aware that some children have sudden worsening of manifestations (eg, dyspnea, cyanosis) after about 1 week of mild to moderate symptoms; these worsening manifestations require heightened respiratory support (eg, oxygen, noninvasive or invasive ventilatory support) ^r3r4
• Patient findings consistent with coinfection (eg, exudative pharyngitis, otitis media, vesicular pharyngitis) and other pathogens (eg, concomitant influenza, Mycoplasma pneumoniae, streptococcal pharyngitis, respiratory syncytial virus) do not exclude COVID-19 diagnosis ^r5
  • Proceed with SARS-CoV-2 testing in patients when clinical suspicion exists for COVID-19 regardless of clinical evidence of focal infection or positive testing for other infectious pathogens
• Vaccine coverage is less than optimal among children and adolescents in the United States ^r6
  • Encourage and support community vaccination measures because vaccination is a critical measure to diminish risk of severe disease and decrease pandemic-related adverse indirect effects (eg, higher rates of psychiatric morbidities, loss of education, loss of caregivers, increased child neglect) in pediatric age groups
• Knowledge of COVID-19 illness behavior in children is incomplete and evolving, and coronaviruses are known to mutate and recombine often. These unknowns present ongoing challenges to understanding clinical disease progression and treatment strategies
  • Be aware that CDC, NIH, and professional society guideline recommendations are evolving and subject to frequent modifications

Clinical Clarification

• COVID-19 (coronavirus disease 2019) is a systemic infection primarily affecting the respiratory system, caused by a recently recognized coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) ^d1
• Children tend to experience less severe illness and fewer complications than adults. Fewer children than adults with infection require hospitalization; however, of those who are admitted, a similar proportion of both groups require ICU-level care ^r1
  • Most children who develop severe and critical illness have significant underlying comorbidity; however, approximately 30% of hospitalized children aged 5 to 11 years and 63% of hospitalized children aged 0 to 4 years had no underlying medical conditions in studies from the United States ^r7r8
• Infants younger than 6 months are at higher risk of hospitalization than infants and children aged 6 months to 11 years; infants may present with isolated gastrointestinal symptoms or feeding difficulties ^r8r9
  • Infection in neonates is uncommon; most neonatal infections are asymptomatic ^r8
• Knowledge of disease processes in both children and adults is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to understanding and to clinical management
  • CDC website maintains information about geographic distribution of variants in the United States; current dominant variant is Omicron (several Omicron subvariants), which has increased transmissibility and immune evasion ^r10

Classification

• Illness severity criteria based on NIH COVID-19 treatment guidelines ^r1
  • Asymptomatic or presymptomatic
    • Positive test (antigen or nucleic acid amplification test) with absence of signs or symptoms
  • Mild illness
    • Symptomatic without shortness of breath, dyspnea, or abnormal chest imaging
  • Moderate illness
    • Evidence of lower airway disease by clinical assessment or imaging, and SpO₂ of 94% or greater on room air at sea level
  • Severe illness is defined by presence of any of the following:
    • SpO₂ of less than 94% on room air at sea level
    • PaO₂/FiO₂ of less than 300 mm Hg
    • Greater than 50% lung infiltrates
    • Significant tachypnea
  • Critical illness
    • Respiratory failure (eg, new or increased noninvasive or invasive mechanical ventilation requirement), septic shock, or multiple organ failure
• WHO guidelines similarly classify disease severity into nonsevere, severe, and critical illness, with slight variations (threshold for severe: SpO₂ 90% versus 94% for NIH) and additional pediatric-specific criteria ^r11r12
  • Nonsevere disease: no criteria of severe or critical disease
  • Severe disease: child with any of the following:
    • Severe pneumonia
    • SpO₂ of less than 90% on room air at sea level
    • Pediatric danger signs
      • Very severe chest indrawing (retractions)
      • Grunting
      • Central cyanosis
      • Inability to breastfeed or drink
      • Lethargy or reduced level of consciousness
      • Convulsions
  • Critical disease: child with acute respiratory distress syndrome, sepsis, septic shock, or other conditions that normally require intensive care (eg, mechanical ventilation, vasopressor therapy)

Clinical Presentation

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

• Provide symptomatic and supportive care
• Prevent and manage complications where possible

Disposition

Treatment Options

Standard treatment includes infection control and supportive care for all patients and medications for certain children

• Evidence for treatment in children is sparse; recommendations are primarily based on data in adults, expert opinion, and evidence from non-COVID illnesses
  • The older the child and the more severe the illness, the more applicable adult COVID-19 treatment guidelines become ^r1d1
  • Children most likely to benefit from medications are nonhospitalized patients with mild to moderate COVID-19 who are at highest risk for severe COVID-19 and hospitalized patients with severe disease ^r1
  • Enroll children in clinical trials^r64 and multicenter pragmatic trials whenever possible ^r1
• Resources available with treatment recommendations include:
  • NIH COVID-19 treatment guidelines and WHO clinical management guidelines include pediatric-specific information ^r1r12
  • Infectious Diseases Society of America and WHO guidelines for therapeutics for patients with COVID-19 primarily address management of adults but contain information relevant to pediatric populations ^r11r65
  • American Academy of Pediatrics guidance ^r66

Infection controlmeasures include isolation, source control, and transmission precautions

• For children managed at home: ^r67
  • Keep child at home, except to seek medical care
  • Isolation is required for everyone with positive COVID-19 test result, even in absence of symptoms
  • Try to keep child isolated to single area of house, including use of separate bathroom if available
  • Patient with COVID-19 aged 2 years or older should wear face mask when in contact with others
  • Caregivers should wear face mask, preferably high-quality (eg, N95 or equivalent), when in contact with child with COVID-19
  • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to patient where possible
  • Caregivers should:
    • Wash hands for at least 20 seconds after all contact; alcohol-based hand sanitizer is acceptable if soap and water are not available
    • Clean and disinfect regularly
    • Improve ventilation where possible
    • Not share personal items (eg, towels, dishes, utensils) before proper cleaning
• For hospitalized children: ^r40
  • Place patients in single room, preferably with dedicated bathroom, or cohort patients with same respiratory pathogens (with consideration of other communicable diseases)
  • Children aged 2 years and older should wear face mask for source control when in contact with others
  • Health care workers should use gown, gloves, eye protection (eg, goggles, face shield), and N95 respirator or equivalent when caring for patients with suspected or diagnosed COVID-19 infection
  • Instruct visitors on infection control and provide them with appropriate personal protective equipment
  • Follow transmission-based precautions until meeting criteria for discontinuation
• Duration of isolation ^r40r68
  • Asymptomatic, no immunocompromise
    • Isolate for at least 5 days (with day 0 as day test was performed)
    • If symptoms develop, start isolation over with day 0 as first day of symptoms
  • Mild symptoms, no immunocompromise
    • Isolate for at least 5 days (with day 0 as first day of symptoms), until symptoms are improved and at least 24 hours have passed since last fever without use of antipyretics
  • Moderate symptoms (eg, shortness of breath), no immunocompromise
    • Isolate for at least 10 days (with day 0 as first day of symptoms) until symptoms are improved and at least 24 hours have passed since last fever without use of antipyretics
  • Severe to critical illness (eg, hospitalized), no immunocompromise
    • Isolate for at least 10 days (with day 0 as first day of symptoms) and at least 24 hours have passed since last fever without use of antipyretics and symptoms have improved
      • Test-based strategy may be used to inform duration of isolation: negative results from 2 consecutive respiratory specimens collected 24 hours apart, tested using antigen or nucleic acid amplification test
        • Nucleic acid amplification test may be used but is frequently positive for days to weeks and does not necessarily correlate with being infectious ^r52
  • Immunocompromised patients
    • Moderately to severely immunocompromised individuals may shed replication-competent virus for an extended period; therefore, test-based strategy is recommended
    • Consult with infectious diseases specialist when available
    • Isolate for at least 20 days (with day 0 as first day of symptoms or as day testing was performed) if entirely asymptomatic, plus:
      • At least 24 hours have passed since last fever without use of antipyretics, and
      • Symptoms have improved, and
      • Results are negative from at least 2 consecutive respiratory specimens collected 24 hours apart, tested using antigen or nucleic acid amplification test
        • Nucleic acid amplification test may be used but is frequently positive for days to weeks and does not necessarily correlate with being infectious ^r52
  • Regardless of when isolation ends, avoid contact with persons at high risk and wear a high-quality mask around others until at least day 10 or until 2 sequential rapid antigen tests 48 hours apart are negative
    • Anyone who cannot wear a mask (eg, age under 2 years, significant disability) should isolate at least 10 days
  • Loss of taste and smell may persist for weeks or months and do not affect duration of isolation

Supportive care is the mainstay of management for overwhelming majority of pediatric patients; most children can be managed safely in the home environment ^r69

• For children managed at home: ^r12r67
  • Encourage fluids and nutrition as tolerated by mouth
  • Antipyretics and OTC pain relievers (eg, ibuprofen, acetaminophen) may be given as needed for fever, aches, and other symptoms
  • Caregiver education
    • Educate about emergency signs for worsening COVID-19 manifestations: ^r12
      • Difficulty breathing, fast or shallow breathing, or grunting in infants
      • Blue lips or face
      • Chest pain or pressure
      • New confusion
      • Inability to awaken or not interacting when awake
      • Inability to drink, keep down any liquids, or breastfeed
    • Provide recommended isolation measures to minimize secondary spread of COVID-19 ^r67
    • Advise on when clearance by health care provider is needed to resume sports and physical activity (eg, moderate to severe COVID-19, symptoms of myocarditis following recovery) ^r70
  • Consider providing pulse oximeter for home monitoring of those at high risk for severe disease ^r12
  • Resources for parents are available from various organizations (eg, American Academy of Pediatrics,^r71CDC^r67) to help guide home care for children with COVID-19
• For hospitalized children:
  • Treat dehydration and provide hydration support in standard fashion
    • Use parenteral hydration via IV or enteral hydration via nasogastric tube if patient is unable to tolerate fluids by mouth ^r5
      • Advantage of enteral route is ability to provide added nutritional support when needed
      • Parenteral hydration is preferred for patients with poor or declining clinical status
    • Goal is euvolemic state; aggressive fluid management may impair alveolar oxygen exchange
  • Provide advanced nutritional support if needed ^r28
  • Monitor oxygenation by pulse oximetry or other methods as needed, with awareness that pulse oximetry may be artificially low in darker skin tones ^r1
  • Start oxygen when indicated for persistent SpO₂ less than 90% to 92% ^r72
    • Optimal oxygen saturation is unknown ^r1r12
      • NIH guidelines recommend target of 92% to 97% for most children and WHO recommends greater than 90%
      • NIH guidelines suggest SpO₂ less than 92% (but not less than 88%) if needed to minimize exposure to high fraction of inspired oxygen in children with severe pediatric acute respiratory distress syndrome
  • Provide airway and respiratory support when clinically indicated
    • Conventional oxygenation may use a variety of delivery methods (eg, nasal cannula at 5 L/minute, face mask with reservoir bag at 10-15 L/minute)
    • Perform time-limited (eg, 30- to 90-minute) trial of noninvasive ventilatory support such as high-flow nasal canula (eg, 2 L/kg/minute), CPAP, or BPAP before advancing to invasive mechanical ventilation, when clinical status allows ^r1r56
      • There is insufficient evidence in children to recommend high-flow oxygen over noninvasive ventilation or vice versa
      • For increased work of breathing, BPAP is preferred over CPAP to unload respiratory muscles, except for children who cannot achieve adequate seal with noninvasive ventilation interface or who have significant patient-ventilator asynchrony
      • If indications for endotracheal intubation are already present, high-flow nasal cannula or noninvasive positive pressure ventilation should not be used to delay needed mechanical ventilation
    • There is insufficient evidence regarding awake prone positioning for children with persistent hypoxemia who require high-flow oxygen or noninvasive ventilation and do not require endotracheal intubation; however, do not attempt prone positioning as a rescue to avoid needed intubation
• For critical illness: ^d14
  • In general, evidence to guide critical treatment in pediatric populations is limited but uses information from adult trials and expert opinion ^r1
  • General management of critically ill children is also based on guidance for non-COVID critical illness, such as:
    • Surviving Sepsis Campaign septic shock guideline^r73
    • Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children^r74
    • Pediatric Acute Lung Injury Consensus Conference^r75 recommendations

Medications to treat COVID-19 and coinfections and to prevent complications are indicated in certain children

• Because most children have mild to moderate disease, the risk-benefit ratio for medications in children is different from adults
  • NIH guidelines divide children into low, intermediate, and high risk for progression to severe disease on basis of age, vaccination status, and medical conditions ^r1
    • Patients considered high risk include all moderately to severely immunocompromised patients and unvaccinated patients with any of the following conditions, which have a strong or consistent association with progression to severe disease:
      • Dependence on respiratory support (eg, tracheostomy, noninvasive ventilation)
      • Impaired airway clearance
      • Severe disability with impaired self-care or activities of daily living
      • Severe cardiac disease
      • Severe pulmonary disease (eg, requiring 2 or more daily inhaled medications or any daily systemic medications)
      • Multiple moderate or severe chronic diseases
      • Obesity
    • Children considered intermediate risk include vaccinated patients with conditions strongly associated with progression or those of any vaccination status with any of the following conditions, which have a moderate or inconsistent association with progression to severe disease:
      • Age younger than 1 year
      • Prematurity in children aged 2 years or younger
      • Sickle cell disease
      • Poorly-controlled diabetes
      • Nonsevere cardiac, neurologic, or metabolic disease
    • Children considered low risk include those with no comorbidities or those with any of the following conditions, which have a weak or unknown association with progression to severe disease:
      • Mild asthma
      • Overweight
      • Well-controlled diabetes
    • Many other medical conditions may be associated with risk for severe COVID-19, but evidence in children is more limited or inconsistent ^r46
  • Clinicians should individualize treatment decisions taking into account all factors (eg, ethnicity, number of risk factors)
• For nonhospitalized children: ^r1
  • NIH guidelines recommend use of ritonavir-boosted nirmatrelvir (first choice) or remdesivir (alternate) for children aged 12 years and older at high risk for progression to severe disease
    • There is insufficient evidence to recommend for or against use of remdesivir in children at high risk who are younger than age 12 years, and ritonavir-boosted nirmatrelvir is not authorized for use in children younger than 12 years
  • There is insufficient evidence to recommend for or against use of any antiviral treatment in children at intermediate risk for progression
  • These recommendations also apply to children who are hospitalized for reasons other than COVID-19
    • It is unknown whether children receiving respiratory support for asthma, croup, or bronchiolitis who have concurrent COVID-19 infection would benefit from remdesivir
  • Children at low risk for progression to severe disease are recommended to receive supportive care and infection control measures only
• For children hospitalized for COVID-19: ^r1
  • For children who do not require oxygen:
    • Remdesivir is recommended for those aged 12 to 17 years at high risk for progression to severe disease
    • Remdesivir may be considered on individual basis for those younger than 12 years at high risk for severe disease but there is insufficient evidence to recommend for or against use of remdesivir in this population
  • For children who require conventional oxygen:
    • Remdesivir is recommended for children aged 28 days or older, with the addition of dexamethasone for those with increasing oxygen needs, particularly adolescents
  • For children who require high-flow oxygen or noninvasive ventilation:
    • Dexamethasone alone or dexamethasone with remdesivir is recommended
    • If these children do not improve rapidly (eg, within 24 hours) after dexamethasone is started, baricitinib or tocilizumab may be considered (aged 2 years and older)
      • Tofacitinib may be considered if baricitinib is unavailable
  • For children who require mechanical ventilation or extracorporeal membrane oxygenation:
    • Dexamethasone is recommended
    • If these children do not improve rapidly (eg, within 24 hours) after dexamethasone is started, baricitinib or tocilizumab may be considered (aged 2 years and older)
      • Tofacitinib may be considered if baricitinib is unavailable
  • All children aged 12 years and older who are hospitalized for COVID-19 should receive prophylactic anticoagulation unless contraindicated
  • Administer specific antivirals (eg, oseltamivir for influenza) and appropriate antibiotics (eg, empiric antibiotics for sepsis before confirmation of infectious agent) in accordance with disease severity, acquisition site (community or hospital), epidemiologic risk factors, and local antimicrobial susceptibility patterns ^r1r12
    • Note the co-occurrence of bacterial infection at presentation appears to be low; guidelines recommend against routine empiric antibiotics and recommend daily reassessment for discontinuation in those on antibiotics for suspected bacterial infections
• Details on pharmacotherapeutic options ^r76r77
  • Antiviral agents
    • Nirmatrelvir-ritonavir ^r77
      • Protease inhibitor combination that prevents viral replication with antiviral activity against coronaviruses
      • Authorized by FDA for emergency use in adults and children aged 12 years and older and weighing 40 kg or more who are at high risk for progression to severe disease
      • First choice pharmacotherapeutic indicated for treatment of patients aged 12 years and older with mild to moderate COVID-19 who do not require hospitalization for COVID-19 but are at high risk of progression to severe disease
      • Initiate oral dosing as soon as possible and within 5 days of symptom onset
      • Ritonavir-boosted nirmatrelvir has significant and complex drug interactions; carefully review medication profile (including OTC and herbal supplements) before initiation
        • Liverpool COVID-19 drug interaction website,^r78ritonavir-boosted nirmatrelvir fact sheet^r77, and NIH guidelines^r1 can help identify potential drug interactions
      • Viral rebound and/or recurrence of symptoms and antigen test positivity has been reported following a 5-day course of ritonavir-boosted nirmatrelvir; there is no evidence that additional treatment is needed, but patients should continue to isolate until they meet criteria for discontinuation ^r1
    • Remdesivir ^r76
      • Nucleotide analogue prodrug that inhibits viral RNA polymerases
      • Most beneficial when started early in course of illness (fewer than 7 days after first symptom) in patients meeting criteria for treatment ^r1
      • FDA-approved to treat COVID-19 in adult and pediatric patients aged 28 days and older and weighing 3 kg or more ^r76
      • NIH-recommended for the following pediatric patients: ^r1
        • For nonhospitalized children aged 12 years and older at high risk of severe disease, remdesivir is second choice treatment after nirmatrelvir-ritonavir
        • For hospitalized children aged 12 years and older at high risk of severe disease who have no oxygen requirement
        • For hospitalized children who are on conventional oxygen
        • For hospitalized children who require high-flow oxygen or noninvasive ventilation, recommended as an option with dexamethasone
      • Also consider for the following pediatric patients, although insufficient evidence exists to recommend for or against treatment in these circumstances: ^r1
        • For nonhospitalized children younger than 12 years at high risk of severe disease
        • For hospitalized children younger than 12 years at high risk of severe disease who have no oxygen requirement
  • Immunomodulatory agents
    • Dexamethasone
      • Efficacy and safety data in children are limited; treatment in context of enrollment in a clinical trial is ideal ^r79
      • Recommended for hospitalized pediatric patients under the following circumstances: ^r1
        • For children (particularly adolescents) who require conventional oxygen and have increasing oxygen requirements, as an option along with remdesivir
        • For children requiring high-flow oxygen or noninvasive ventilation (with or without concurrent remdesivir)
        • For children requiring mechanical ventilation or extracorporeal membrane oxygenation
      • Routine use for pediatric patients requiring conventional oxygen is not recommended ^r1
      • Alternative glucocorticoids (eg, prednisone, methylprednisolone, hydrocortisone) may be substituted if dexamethasone is not available ^r1
    • Baricitinib
      • Janus kinase inhibitor that has FDA approval for treating COVID-19 in adults and emergency use authorization for children aged 2 years and older requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation ^r1r76r77
      • Given paucity of data in pediatric population, NIH suggests considering baricitinib (or tocilizumab) in the following circumstances: ^r1
        • For children aged 12 to 17 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (moderate recommendation)
        • For children aged 2 to 11 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (weak recommendation)
      • Infectious Diseases Society of America guidelines endorsed by Pediatric Infectious Diseases Society note that there is very limited data in pediatric populations, including use for other conditions (eg, rheumatoid arthritis) as baricitinib is not approved in children ^r65
    • Tocilizumab ^r77
      • Interleukin-6 receptor antagonist with limited use in pediatric population for COVID-19 ^r80
        • Because tocilizumab is FDA-approved for use in children with other indications (eg, juvenile idiopathic arthritis, cytokine release syndrome), pediatric subspecialists such as rheumatologists or infectious disease specialists may have experience with the drug
      • Authorized by FDA for emergency use in combination with systemic glucocorticoids in children aged 2 years and older who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation ^r77
      • NIH recommendations for tocilizumab, based primarily on extrapolation from adults, are the same as for baricitinib: ^r1
        • For children aged 12 to 17 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (moderate recommendation)
        • For children aged 2 to 11 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (weak recommendation)
    • Tofacitinib
      • Janus kinase inhibitor that has been used off-label in treatment of COVID-19; pediatric use is extrapolated from use in adults
      • Due to FDA approval for use in children aged 2 years and older for juvenile idiopathic arthritis, tofacitinib has an established safety profile in pediatric patients; therefore, NIH guidelines recommend use of tofacitinib as alternative if baricitinib is not available for same indications: ^r1
        • For children aged 12 to 17 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (moderate recommendation)
        • For children aged 2 to 11 years requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation who do not have rapid improvement (eg, within 24 hours) after dexamethasone is started (weak recommendation)
  • Thrombosis prevention and treatment
    • For children aged 12 years and older hospitalized with COVID-19, thromboprophylaxis is recommended unless contraindicated; there is insufficient evidence to recommend for or against prophylactic anticoagulation for children younger than 12 years ^r1
      • Otherwise, children with COVID-19 with indications for prophylactic or therapeutic anticoagulation (eg, institutional protocol, diagnosed thrombosis, receipt of extracorporeal membrane oxygenation or continuous renal replacement therapy) should be managed the same as children without COVID-19 with these indications
      • Low molecular weight heparin (preferred) and unfractionated heparin (alternative) are recommended over oral agents for hospitalized patients
      • Early ambulation and lower-extremity compression garments and devices are low risk and easily implemented precautionary measures
    • Children on anticoagulation or antiplatelet treatment for another indication should continue therapy if diagnosed with COVID-19 (unless significant bleeding or other contraindications develop) ^r1
    • Data regarding risk of thrombotic events in children with acute COVID-19 and effectiveness of thromboprophylaxis are limited ^r1
      • Higher risk patients for venous thromboembolism may include, but are not limited to, pediatric patients with:
        • Elevated D-dimer results
        • Risk factors for severe COVID-19 illness
        • General risk factors for thromboembolic events (eg, obesity, family history, chronic inflammatory conditions)
    • Certain antiplatelet and anticoagulation therapy is recommended for patients with MIS-C; details are available in NIH^r1 and American College of Rheumatology^r53 guidelines ^d15
  • Antibody products
    • Anti–SARS-CoV-2 monoclonal antibody products
      • Neutralizing IgG monoclonal antibodies that bind spike protein of SARS-CoV-2 and prevent attachment of virus to human ACE2 receptors
      • Many products had been used for treatment or prevention under emergency use authorization in adults and in some children, but none are currently authorized due to lack of efficacy against circulating Omicron subvariants
    • Convalescent plasma
      • Plasma from donors with high titers of anti–SARS-CoV-2 antibodies has been granted emergency use authorization for treatment of persons with significant immunosuppression ^r77
      • Evidence in adult population is mixed; evidence in pediatric population is very limited and other options are available (eg, ritonavir-boosted nirmatrelvir, remdesivir)
      • NIH guidelines suggest considering use on case-by-case basis for hospitalized immunocompromised children who meet emergency use authorization criteria for high-titer convalescent plasma use ^r1
        • Given currently circulating Omicron subvariants, NIH guidelines recommend against use of any convalescent plasma collected before emergence of Omicron variants

Many therapies are under investigation for treatment of COVID-19 in pediatric population; consider use of the following only within a clinical trial: ^r1

• Sarilumab
• Anakinra
• Fluvoxamine
• GM-CSF inhibitors (granulocyte-macrophage colony-stimulating factor)
• Inhaled corticosteroids
• Canakinumab
• Bruton tyrosine kinase inhibitors (eg, acalabrutinib, ibrutinib, zanubrutinib)
• Janus kinase inhibitors other than baricitinib and tofacitinib (eg, ruxolitinib)
• Siltuximab

Avoid potential harmful therapies not supported by evidence for treatment of acute COVID-19 in pediatric patients, such as the following: ^r1r5

• Molnupiravir
• Colchicine
• ACE inhibitors and angiotensin receptor blockers (used specifically for COVID-19; continue use if patient is taking for another indication)
• HIV antivirals (eg, lopinavir, ritonavir)
• Chloroquine and hydroxychloroquine
• Azithromycin, without suspicion of bacterial infection
• Ivermectin
• Interferons

Monitoring

• Patients managed at home ^c127
  • Instruct caregiver to monitor for manifestations associated with worsening illness and clinical deterioration, including difficulty breathing, chest pain, syncope, palpitations, mental status changes, and dehydration ^r28
• Hospitalized patients ^c128
  • Clinically monitor for early warning indicators of worsening disease (eg, increased work of breathing, worsening tachypnea, decreased level of consciousness, decreased perfusion or other signs of impending shock) ^r84
  • Monitoring of laboratory markers in hospitalized patients is not rigorously standardized
    • Limited data suggest that serial monitoring of C-reactive protein, procalcitonin, and lactate dehydrogenase may be most informative to track illness trajectory ^r85
• Patients taking remdesivir
  • Baseline liver function testing, prothrombin time, and estimated GFR, with repeat tests as clinically indicated, are recommended ^r1c129
• Return to sports and physical activity recommendations for children who test positive for SARS-CoV-2 ^r70
  • Exercise is not recommended while in isolation
  • Educate all patients and caregivers to report to physician any chest pain, shortness of breath out of proportion for upper respiratory tract infection, new-onset palpitations, or syncope when returning to exercise
  • American Academy of Pediatrics provides detailed return-to-play algorithm based on severity of symptoms
    • Asymptomatic and mild disease
      • Prior to resuming activity or within 2 to 4 weeks of positive test (whichever is sooner), child may be cleared by phone, telehealth, or electronic communication if symptom-free (no chest pain, new-onset palpitations, syncope, shortness of breath) and isolation is complete
      • For any concerning symptoms, examine child in office; consider ECG for any potential cardiac symptoms (eg, syncope, dyspnea on exertion, chest pain)
      • Refer to cardiologist for abnormal ECG or concerning examination findings
    • Moderate illness (defined as 4 or more days of fever, 1 or more week of myalgia or lethargy, hospitalized but not admitted to ICU, no evidence of MIS-C)
      • Physical examination, screening ECG, and American Heart Association 14-element screening evaluation is recommended ^r86c130
      • Child may return to return to activity if physical examination, ECG, and American Heart Association screen are all normal and isolation is complete
      • Refer to cardiologist if American Heart Association screening evaluation is positive, examination is abnormal, or ECG is abnormal
    • Severe illness (defined as ICU admission, intubation, or MIS-C)
      • Restrict from exercise for minimum of 3 to 6 months and require cardiology clearance before allowing child to return to training or competition
• American Academy of Pediatrics recommendations for follow-up after SARS-CoV-2 infection ^r87
  • At least 1 follow-up is recommended for all patients with infection. Type (eg, telehealth, in-office) and timing of visit depend on severity of illness, presence of underlying comorbidities, presence of complications, and completion of isolation period
  • At visit, monitor residual symptoms, assess for development of new symptoms, guide return to activities (eg, physical activity, school, employment), review routine and COVID-19 immunizations, and provide general anticipatory guidance
  • Telephone or virtual visit is appropriate for children with resolved symptoms after asymptomatic or mild disease (less than 4 days of fever higher than 38 °C and less than 1 week of myalgia, chills, or lethargy)
  • In-person visit is recommend for children with moderate disease (more than 4 days of fever higher than 38 °C; more than 1 week of myalgia, chills, or lethargy; and non-ICU hospital stay) or severe disease (ICU stay and/or intubation)

Complications

• Acute complications
  • Coinfection with other viruses and bacteria
    • Coinfection appears to be rare overall but limited data suggest coinfection may occur in some children (6% to 18%) ^r1r55r60
    • Systematic review data suggest that among children with coinfection, almost 60% have concomitant Mycoplasma pneumoniae, 11% influenza A or B, and about 10% respiratory syncytial virus. Other common viral and bacterial infections occurred in the remainder ^{r60c131c132c133}
  • Neurologic complications
    • Up to 20% of hospitalized children may develop neurologic manifestations; these manifestations are transient in most (over 88%) ^r88
    • Neurologic complications are more frequent in children with underlying neurologic disorders ^r19
    • Acute disseminated encephalomyelitis, acute transverse myelitis, Guillain-Barré syndrome, cerebral edema, demyelination, and stroke are among the possible life-threatening complications ^{r89c134c135c136c137c138c139}
  • Cardiovascular involvement
    • Myocarditis, pericarditis, heart failure, and arrhythmias are described ^{r90c140c141c142c143}
    • Underlying mechanisms for cardiotoxicity may be multifactorial caused, at least in part, by direct entry of virus into myocardial cells, hypoxia resulting in hypoxemic myocardial cell damage, and immune-mediated injury secondary to excessive systemic release of cytokines generated by presence of virus ^r91
    • Myocarditis associated with acute COVID-19 is estimated at 1% to 2% of hospitalized COVID-19 patients (primarily adults); overall risk for myocarditis among children younger than 16 years with COVID-19 diagnosis is estimated at less than 0.13% (adjusted risk ratio greater than 30) ^r92r93
    • Subclinical myocarditis was documented by cardiac MRI in a minority of patients recovering from mild or asymptomatic infection in a small group of young athletes; additional studies are needed to determine clinical significance of this finding ^r94
    • Asymptomatic children and children with mild illness may have evidence of cardiac inflammation consistent with myocarditis; therefore, following return to sports and physical activity protocol is necessary ^r70
  • Thrombotic events
    • Appear to develop at much lower frequency than encountered in adult patients
    • Limited data from retrospective cohort study suggest that serious complications (eg, deep venous thrombosis, stroke, pulmonary embolism) may develop in up to 2% of symptomatic hospitalized children and adolescents with COVID-19 ^r95
      • Most children hospitalized with COVID-19 who developed thrombotic complications were 12 years and older and many developed these complications despite thromboprophylaxis
      • Risk factors for development of thrombosis include age 12 years and older, comorbid malignancy, presence of central venous catheter, and MIS-C diagnosis
    • Developing a thrombotic event is a marker for increased mortality risk ^r96
  • Ocular symptoms
    • Anterior uveitis, retinitis, and optic neuritis are among serious but rare ocular complications encountered ^r27
  • Intussusception
    • Several reports of intussusception among infants with SARS-CoV-2 infection have been reported; however, a clear association pointing to intussusception as part of clinical spectrum of COVID-19 in infants rather than being a mere coincidental finding has yet to be determined ^r97
  • Additional complications in children with severe and critical disease may include:
    • Respiratory failure
    • Shock
    • Acute renal failure
    • Coagulopathy
    • Multisystem organ failure
• Postinfectious complication
  • MIS-C ^c144d15
    • Rare inflammatory condition that may develop about 2 to 6 weeks after acute COVID-19 infection ^r98
      • Reported to occur in approximately 0.1% of children with COVID-19 diagnosis ^r60
    • Inflammation may affect any organ but typically involves gastrointestinal system, skin, heart, brain, lungs, kidneys, and eyes
    • Elevated inflammatory markers and abnormal ECG or echocardiogram are common
    • Most MIS-C develops in previously healthy patients ^r60r98
      • Obesity and asthma are the most commonly associated comorbid conditions
    • Presenting manifestations vary in terms of severity and pattern; some children manifest a more mild illness whereas others present in shock or with a Kawasaki-like illness
    • Establish diagnosis based on CDC or WHO clinical criteria ^r99r100
    • Treatment involves initial resuscitation, immunomodulatory therapy (eg, IV immunoglobulin and corticosteroids), and antithrombotic therapy (eg, low-dose aspirin with or without anticoagulation) ^r1r53
• Persistent symptoms and long-term sequelae after acute COVID-19
  • Research is ongoing in children; types and incidences of postacute symptoms (ie, persistent symptoms lasting more than 1-3 months after onset of COVID-19) and long-term sequelae^r101 are still being determined ^r87
    • Long COVID is variously defined as having symptoms 4 or more weeks, 4 to 8 weeks, and 12 weeks after COVID-19 diagnosis, which complicates research; symptoms may be persistent from time of acute infection or new symptoms may develop after asymptomatic or mild acute illness ^r102c145
    • Recently published definition for long COVID in children: ^r103
      • Presence of 1 or more persistent physical symptoms that impair daily function, which may fluctuate and relapse, and that last at least 12 or more weeks after confirmed initial SARS-CoV-2 infection, with no alternative diagnosis
      • Although this definition is intended to standardize research, it corresponds to clinical definitions used for adults
    • Some studies have reported up to 66% of children have symptoms 4 or more weeks from diagnosis; however, studies with a control group suggest 1% to 4% of children may have long COVID-19, depending on age and definition ^r102r104
    • Limited evidence suggests that symptoms of long COVID-19 have resolved by 5 months in a majority of children ^r102r104
  • Long COVID symptoms in children may include respiratory, cardiovascular, neurologic, psychologic, and other symptoms ^r87c146
    • Many symptoms have been reported in children with and without evidence of COVID-19 infection and may be attributable to the pandemic itself (eg, loss of loved ones, changes in schooling, societal disruption, fear of illness and death for self and family, limitations of sports and social activities) ^r102r104
    • Most commonly reported symptoms that were significantly different from a control group without COVID-19 include: ^r104
      • Fatigue
      • Loss of smell and/or taste
      • Respiratory difficulties
      • Dizziness
      • Muscle weakness
      • Chest pain
  • Some evidence indicates an increase in incidence of new-onset type 1 diabetes following COVID-19, an increased frequency of diabetic ketoacidosis at time of type 1 diabetes diagnosis, and an increased risk of diabetic ketoacidosis in children with existing diagnosis of type 1 diabetes who have COVID-19 ^r105r106
• Indirect complications of coronavirus pandemic are numerous and include, but are not limited to, higher rates of psychiatric morbidities, loss of education, unhealthy lifestyle changes, loss of caregivers, and increased child neglect ^r107
  • Global estimate of 10.5 million children have lost a parent or caregiver through May 1, 2022 ^r108r109
    • In the United States, an estimated 228,600 children lost 1 or both parents or primary caregiver grandparent through October 2022, with Black, Hispanic, and Native American children disproportionately affected ^r108r110
  • American Academy of Pediatrics advocates for policies to keep students safe and physically present in school ^r111
    • Measures to mitigate risk of COVID-19 spread in schools include:
      • Encouraging vaccination
      • Testing when exposed or symptomatic
      • Isolating when sick
      • Wearing masks
      • Optimizing ventilation and disinfection measures

Prognosis

• In general, an excellent prognosis is expected for most children diagnosed with COVID-19 ^r20r60
  • Full recovery in most occurs by 2 weeks after onset of illness, but it may take up to 6 weeks in a minority of children ^r20r28
• Overall, children experience less severe illness and fewer acute complications (eg, shock, acute respiratory distress syndrome) than adults, and fewer children require hospital admission ^r72r112
  • ICU requirements in United States
    • About 20% to 30% of children admitted to hospital require ICU level of care, an ICU admission rate similar to that of adults ^r112
    • About half of children who require ICU level of care:
      • Have significant underlying comorbidity ^r107
      • Are aged 12 to 17 years (among children aged 0-17 years) ^r42
  • Hospitalization requirements in United States
    • Highest rates of hospitalization occur among children younger than 4 years and aged 12 to 17 years ^r42r113
    • An estimated 2% of pediatric patients^r112 require hospital admission; median length of hospitalization is from 2 to 3 days^r42
• Severe infection
  • Most children who develop severe infection have underlying comorbid medical conditions (eg, obesity, chronic cardiopulmonary disease, diabetes) ^r112
  • Most severe cases involve severe respiratory disease (71%) and a minority involve severe cardiac (less than 3%) or cardiopulmonary disease (about 9%) ^r89
• Cardiac morbidity
  • Children with severe COVID-19 and reduced left ventricular systolic function
    • Cardiac dysfunction normalizes in approximately 91% of children within 30 days ^r89
  • Children with MIS-C and coronary artery aneurysm
    • Coronary arteries normalize in approximately 79% of children within 30 days ^r89
• Mortality
  • Overall mortality is estimated to be less than 0.04% in children diagnosed with COVID-19 ^r60r112
  • Mortality is estimated to be approximately 1.6% among children with severe COVID-19 or MIS-C ^r89
  • Mortality in pediatric patients with COVID-19 appears to be highest among the following groups:
    • Patients aged 10 to 20 years, especially young adults aged 18 to 20 years ^r114
    • Patients who are Hispanic, Black, and American Indian/Alaska Native ^r114
    • Patients with significant comorbid underlying medical conditions (eg, chronic lung disease, obesity, neurologic and developmental disorders) ^r1

Screening

Prevention

• Primary prevention methods
  • Pharmacologic interventions
    • Vaccination ^r116r117d1
      • Represents a key intervention in prevention of disease in all age groups
      • FDA has approved or granted emergency authorized use of several vaccines in children, and CDC recommends all children aged 6 months and older receive COVID-19 vaccination ^r116r118
      • Safety and efficacy data among children are reassuring and favorable
        • Although a modest degree of vaccine effectiveness against infection is also reported, data suggest that vaccination is highly effective in preventing serious COVID-19 illness including severe disease, hospitalization, and death ^r42r116
          • Hospitalization rates were about 10 times higher among unvaccinated adolescents during period of Delta SARS-CoV-2 variant predominance ^r113
          • Among pediatric patients requiring hospitalization, ICU admission requirement remained stable during period of Delta SARS-CoV-2 variant predominance ^r113
        • High degree of protection against emergency department visits, hospitalizations, and critical illness remains even against Omicron subvariants ^r119
        • Data suggest that monovalent booster dose broadens and strengthens protection against Omicron and other SARS-CoV-2 variants ^r119
          • Data are limited regarding clinical effectiveness of bivalent booster in children, as this was authorized August 31, 2022 for individuals aged 12 years and older, October 12, 2022 for children aged 5 to 11 years, and December 8, 2022 for children aged 6 months through 5 years
          • Duration of immunity following booster doses is not yet known
        • Reported adverse effects are mild and self-limited; most common adverse effect is sore arm ^r116
        • Myocarditis has been reported following vaccination
          • Risk of myocarditis from COVID-19 (or MIS-C) is dramatically higher than that from vaccine ^r93
          • Risk of vaccine-associated myocarditis may be decreased by lengthening interval between first and second doses to 8 weeks ^r116
          • Risk appears highest in males aged 12 to 39 years and seems to be higher after Moderna vaccination than Pfizer ^r116
      • Vaccine uptake data in United States ^r6
        • Data show that uptake of vaccine is significantly lower for younger children than for adolescents and that booster uptake is significantly lower than primary series
          • Estimated uptake data in United States as of May 10, 2023 by age group
            • Younger than 2 years: 4.7% completed primary series, 0.6% had booster dose
            • 2 to 4 years: 6.1% completed primary series, 0.6% had booster dose
            • 5 to 11 years: 32.9% completed primary series, 4.8% had booster dose
            • 12 to 17 years: 61.8% completed primary series, 7.8% had booster dose
      • Vaccination after MIS-C ^r116
        • Experts consider benefits of COVID-19 vaccination outweigh theoretical risk of MIS-like illness or myocarditis for most unvaccinated people, once clinical recovery has been achieved (including return to baseline cardiac function) and at least 90 days have passed since diagnosis of MIS-C
        • Continuing vaccination may also outweigh risks in some patients who developed MIS-C after vaccination was initiated if all of the following criteria are met:
          • MIS-C occurred 90 days or more after most recent dose of vaccine
          • Clinical recovery has been achieved (including return to baseline cardiac function)
          • At least 90 days have passed since diagnosis of MIS-C
        • If MIS-C occurred within 90 days of vaccination, consider:
          • Deferring additional doses
          • Consulting infectious disease specialist, rheumatologist, and/or cardiologist
          • Consulting with Clinical Immunization Safety Assessment COVIDvax project
      • Vaccine-related resources for caregivers and families
        • American Academy of Pediatrics: COVID-19 vaccine campaign toolkit^r120 and information on COVID-19 for parents^r71 in English and Spanish
        • CDC: COVID-19 vaccination resources ^r121
    • Preexposure or postexposure prophylaxis with monoclonal antibodies
      • Previously, tixagevimab-cilgavimab was used for preexposure prophylaxis and bamlanivimab-etesevimab or casirivimab-imdevimab were used as postexposure prophylaxis for some individuals; however, they have diminished efficacy against the Omicron variant and subvariants, and there are currently no options for prophylaxis using monoclonal antibodies ^r1
  • Nonpharmacologic interventions for prevention of infection ^r14r67
    • Proper use of face masks (eg, covering nose and mouth in individuals aged 2 years and older, particularly when physical distancing is not possible or ventilation is poor)
    • Testing (eg, polymerase chain reaction, antigen) is recommended for everyone with symptoms that may be from COVID-19, for those with exposure, and for screening (eg, before gatherings, for certain workplaces, some travel destinations) ^r52
    • Following a known exposure, individuals should wear mask for 10 days, monitor for symptoms, and get tested
      • Testing should be performed immediately if symptoms develop
      • Testing is recommended on day 6 (where day 0 is day of last exposure to someone with COVID-19) regardless of symptoms; if negative, continue to mask until day 10
        • For household members, day 0 ("last exposure") starts when patient has completed isolation
    • Physical distancing
    • Improve ventilation
    • Diligent hand and cough hygiene
      • Recommend supervised use of hand sanitizers for young children. Keep hand sanitizers containing alcohol out of their reach; ingesting a small amount can cause significant toxicity
      • Avoid touching face and mucous membranes
    • Disinfect frequently touched surfaces
    • Hospital protocols include: ^r40
      • Personal protective equipment for providers: N95 masks, eye shields, gowns, and gloves
      • Engineering measures: negative pressure and air filtering
      • Source control for patients with symptoms, exposure, or diagnosis (eg, masks for patients during transport or when contacting others)