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 is extremely common; fever, cough, sore throat, vomiting, and diarrhea are common in children who develop symptoms
• Diagnose COVID-19 in anyone with symptoms or known exposure with a positive nucleic acid amplification test or antigen test result
• Supportive care is the mainstay of management for the overwhelming majority of pediatric patients, and most children can be managed safely at home
• Children who are at increased risk for severe disease include those with certain comorbidities (eg, severe immunocompromise, diabetes, prematurity, obesity, chronic cardiac disease, seizure disorders, chronic pulmonary disease), children aged 12 years and older or younger than 1 year, and Black children ^r1r2
• 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; 4% of previously healthy children have critical disease (mechanical ventilation, ICU admission, or death) and up to 15% may have long-COVID symptoms more than 12 months following acute infection ^r3r4
• Vaccination is safe and highly effective at preventing serious COVID-19 illness among pediatric patients; clinicians should encourage vaccination to improve uptake
• Measures to protect pediatric population and the community from SARS-CoV-2 infection include vaccination, staying home when sick, mask wearing, testing that includes repeat or serial tests when indicated, improving ventilation, and general hygiene measures

Urgent Action

• Promptly institute appropriate infection control 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 ^r5
• Patients with shock require resuscitation and urgent diagnosis and management of underlying cause of shock ^r5

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) ^r6r7
• Clinical findings or positive testing for additional conditions does not exclude COVID-19 diagnosis because of coinfections
• Vaccine coverage is less than optimal among children and adolescents in the United States ^r8
• Coronaviruses mutate frequently and variants differ in transmissibility and behavior; research on COVID-19 and long-term sequelae is ongoing

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 ^r9
• Many children who develop severe and critical illness have underlying comorbidity; however, data from July 2023 to March 2024 in the United States show that 50% of children aged 17 years and younger admitted to hospital, and 40% of children admitted to ICU, had no underlying conditions ^r10
  • Among hospitalized children with no underlying conditions, 18% were admitted to ICU
• Infants younger than 6 months are at higher risk of hospitalization than other children; infants may present with isolated gastrointestinal symptoms or feeding difficulties ^r11r12r13
  • Infection in neonates is uncommon; most neonatal infections are asymptomatic ^r12
• 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 ^r14

Classification

• Illness can be classified into mild, moderate, severe, and critical; children may also have asymptomatic or presymptomatic infection ^r1r9
  • Mild disease is symptomatic but without shortness of breath or abnormal chest imaging
  • Moderate disease indicates lower respiratory infection with SpO₂ of 90% to 94% or greater on room air at sea level
    • The exact oxygen saturation cutoff that differentiates moderate from severe disease is arbitrary; use clinical judgment
    • Indicators of pneumonia in children are cough or difficulty breathing plus tachypnea or retractions
    • Tachypnea depends on age:
      • Younger than 2 months: 60 or more breaths per minute
      • 2 months to 11 months: 50 or more breaths per minute
      • 1 year to 5 years: 40 or more breaths per minute
      • Over 5 years: 30 or more breaths per minute
  • Severe disease is based on any of the following: SpO₂ less than 90% to 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) of less than 300 mm Hg, significant tachypnea, or lung infiltrates greater than 50%
    • Additional signs of severe disease in children include: very severe chest indrawing, grunting, central cyanosis, inability to breastfeed or drink, lethargy, unconsciousness, or convulsions
  • Critical disease is defined by any condition that normally requires intensive care (eg, respiratory failure, sepsis, shock, multiple organ failure)

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 of children is less available than that for treatment of adults; guidance synthesizes evidence for safety and efficacy in children as well as applicability of data obtained from adults
  • The older the child and the more severe the illness, the more applicable adult COVID-19 treatment guidelines become ^r1d1
  • Use risk stratification to identify children who are most likely to benefit from medications ^r2
  • Enroll children in clinical trials^r59 and multicenter pragmatic trials when possible ^r1
• Resources available with treatment recommendations include:
  • Pediatric Infectious Diseases Society guidance ^r2
  • WHO guidelines for clinical management and for therapeutics ^r9r60
  • Infectious Diseases Society of America guidelines ^r60r61
  • NIH COVID-19 treatment guidelines (archived) ^r1r9
  • American Academy of Pediatrics guidance ^r62

Infection controlmeasures include source control and transmission precautions

• For children managed at home: ^r21
  • Keep child at home while symptomatic, except to seek medical care
    • For otherwise healthy children, keep home until fever-free for 24 hours (without use of antipyretics) and symptoms are improving; children aged 2 years and older should use a mask for an additional 5 days and take extra precautions (eg, testing, distancing, improving ventilation) to avoid exposing vulnerable people
    • For children with immunocompromise, follow guidance for health care settings
  • Improve ventilation whenever possible
  • Practice good hygiene
  • Use face masks to protect others
    • Caregivers should wear well-fitted, high-quality masks (eg, N95, KN95) when possible
    • Children aged 2 years or older with COVID-19 can wear face masks
    • Ensure that persons with underlying medical conditions are not exposed to patient when possible
• For hospitalized children: ^r22
  • 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; isolation for health care settings is longer than for the community
    • Discontinuing transmission-based precautions ^r22
      • Mild to moderate illness, no immunocompromise
        • Isolate for at least 10 days (with day 0 as first day of symptoms or day of testing if asymptomatic the entire time) until symptoms are improved and at least 24 hours have passed since last fever without use of antipyretics
      • Severe to critical illness, no immunocompromise
        • Isolate for at least 10 days and up to 20 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
        • In addition to symptoms improving, the following criteria may be used: negative results from 2 consecutive respiratory specimens collected 48 hours apart 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 ^r49
      • Immunocompromised patients
        • Moderately to severely immunocompromised individuals may shed replication-competent virus for an extended period
        • Consult with infectious diseases specialist when available
        • Use test-based strategy: negative results from 2 consecutive respiratory specimens collected 48 hours apart using antigen or nucleic acid amplification test
          • If symptomatic, also ensure at least 24 hours have passed since last fever without use of antipyretics and symptoms have improved
          • Nucleic acid amplification test may be used but is frequently positive for days to weeks and does not necessarily correlate with being infectious ^r49
      • 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 ^r2

• For children managed at home: ^r9
  • 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: ^r9
      • 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 infection control measures to minimize secondary spread of COVID-19 ^r21
    • 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) ^r62
  • Consider providing pulse oximeter for home monitoring of those at high risk for severe disease ^r9
  • Resources for parents are available from various organizations in English and Spanish (eg, American Academy of Pediatrics,^r63CDC^r21) to help guide home care for children with COVID-19
• For hospitalized children:
  • Treat dehydration in standard fashion and provide cautious hydration support ^r9
    • Goal is euvolemic state; aggressive fluid management may impair alveolar oxygen exchange
  • Provide advanced nutritional support if needed ^r31
  • 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% ^r64
    • Optimal oxygen saturation is unknown ^r1r9
      • NIH guidelines recommend target of 92% to 97% for most children and WHO recommends greater than 90%
      • NIH guidelines suggest target 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 guidance incorporates information from adult patients and from other diseases, such as: ^r1
    • Surviving Sepsis Campaign septic shock guideline ^r65
    • Society of Critical Care Medicine guideline on prevention and management of pain, agitation, neuromuscular blockade, and delirium in children ^r66
    • Pediatric Acute Lung Injury Consensus Conference recommendations ^r67

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
  • Pediatric Infectious Diseases Society recommends risk stratification based on certain comorbidities, exacerbating factors, and prior immunity ^r2
    • High risk meets all of the following criteria:
      • Definite or probable risk factor for severe COVID-19
        • Definite risk factors include chronic cardiovascular, neurologic, or pulmonary disease except asthma; diabetes; obesity; prematurity; or severe immunocompromise
        • Probable risk factors include chronic gastrointestinal, liver, or kidney disease; mild to moderate immunocompromise; neurologic disabilities (eg, trisomy 21); or sickle cell disease
      • Exacerbating factors, including 2 or more comorbidities, severe or uncontrolled comorbidity, or age younger than 1 year or 12 years and older
      • No prior immunity, defined as infection within the past 4 months or fully up-to-date immunizations
    • Moderate-risk patients have a risk factor for severe COVID-19 and either of the following criteria:
      • No exacerbating factors
      • Presence of exacerbating factor(s) but immunocompetent with prior immunity
    • Low-risk patients are patients with no definite or probable risk factors for severe COVID-19
  • 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 ^r48

    • NIH COVID-19 treatment guidelines panel's framework for assessing the risk of progression to severe COVID-19 based on patient conditions and COVID-19 vaccination status.

      NIV, noninvasive ventilation.<br><br>* See the current COVID-19 vaccination schedule from the CDC: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html<br>† Recent SARS-CoV-2 infection (ie, within 3–6 months) may confer substantial immunity against closely related variants. A patient's recent infection history should be factored into the risk assessment. <br>‡ The degree of risk conferred by obesity in younger children is less clear than it is in older adolescents. <br>§ This includes patients with a tracheostomy and those who require NIV. <br>¶ The data for this group are particularly limited.

      From NIH: Coronavirus Disease (COVID-19) Treatment Guidelines. Table 3b. Updated February 29, 2024. Accessed November 13, 2024. https://www.ncbi.nlm.nih.gov/books/NBK570371/pdf/Bookshelf_NBK570371.pdf

      Conditions	Risk level by vaccination status	Risk level by vaccination status
      	Not up to date*†	Up to Date*
      Strong or consistent association with progression to severe COVID-19
      Moderately or severely immunocompromised (see Special Considerations in People Who Are Immunocompromised in NIH COVID-19 Treatment Guidelinesr1)	High	High
      • Obesity (BMI ≥ 95th percentile for age), especially severe obesity (BMI ≥ 120% of 95th percentile for age)‡ • Medical complexity with dependence on respiratory technology§ • Severe neurologic, genetic, metabolic, or other disability that results in impaired airway clearance or limitations in self-care or activities of daily living • Severe asthma or other severe chronic lung disease requiring ≥ 2 inhaled or ≥ 1 systemic medications daily • Severe congenital or acquired cardiac disease • Multiple moderate to severe chronic diseases • Pregnancy	High	Intermediate
      Moderate or inconsistent association with progression to severe COVID-19
      • Aged < 1 year • Prematurity in children aged ≤ 2 years • Sickle cell disease • Diabetes mellitus (poorly controlled) • Chronic kidney disease • Nonsevere cardiac, neurologic, or metabolic disease¶	Intermediate	Intermediate
      Weak or unknown association with progression to severe COVID-19
      • Mild asthma • Overweight • Diabetes mellitus (well controlled)	Low	Low

  • Clinicians should individualize treatment decisions taking into account all factors (eg, ethnicity, number of risk factors)
    • Recommendations below summarize NIH guidelines, which offer "strong," "moderate," or "weak" recommendations, and Pediatric Infectious Diseases Society guidelines, which offer "recommend," "suggest," or "consider" for certain actions
• For nonhospitalized children: ^r1r2
  • For children at high risk, use ritonavir-boosted nirmatrelvir (Emergency Use Authorization for ages 12 years and older and 40 kg or more, and FDA-approved for ages 18 and older) or remdesivir (FDA-approved for ages birth to adult and 1.5 kg or more)
    • NIH guidelines recommend ritonavir-boosted nirmatrelvir as first choice and remdesivir as alternate for children aged 12 years and older
    • Pediatric Infectious Diseases Society recommends selecting therapy based on age, availability, contraindications, administration, cost, and patient/caregiver preference
    • Pediatric Infectious Diseases Society also advocates considering convalescent plasma for nonhospitalized immunocompromised children at high risk for progression, with recognition of the uncertainty of risks and benefits
  • For children at intermediate/moderate risk, Pediatric Infectious Diseases Society advises individualized decisions and NIH notes insufficient evidence to recommend for or against use of any antiviral treatment
  • For children at low risk for progression to severe disease, offer supportive care and infection control measures only
  • These recommendations also apply to children who are hospitalized for reasons other than COVID-19 who would otherwise meet criteria for treatment
• For children hospitalized for COVID-19:
  • For children who do not require oxygen: ^r1r2
    • Remdesivir is recommended by NIH for those aged 12 to 17 years at high risk and may be considered on an individual basis for those younger than 12 years at high risk, for whom there is insufficient evidence to recommend for or against use
    • Pediatric Infectious Diseases Society has no recommendation for treatment of patients without an oxygen requirement
  • For children who require conventional oxygen: ^r1r2
    • Use remdesivir for children aged 12 years and older; use is recommended or suggested in children under aged 12 years at moderate or high risk and should be considered in children younger than age 12 years at low risk
    • Consider adding dexamethasone to remdesivir for those with increasing oxygen needs, particularly adolescents
  • For children who require high-flow oxygen or noninvasive ventilation: ^r1r2
    • Use dexamethasone alone or dexamethasone with remdesivir
    • Consider adding baricitinib or tocilizumab, particularly if these children are worsening or do not improve within 24 hours after dexamethasone is started
      • Tofacitinib may be considered if neither baricitinib nor tocilizumab are available, although the drug is not labeled for use in treating COVID-19 in pediatric patients
  • For children who require mechanical ventilation or extracorporeal membrane oxygenation: ^r1r2
    • Use dexamethasone
    • Consider adding baricitinib or tocilizumab, particularly if these children are worsening or do not improve within 24 hours after dexamethasone is started
      • Tofacitinib may be considered if neither baricitinib nor tocilizumab are available, although the drug is not labeled for use in treating COVID-19 in pediatric patients
    • Some panelists from the Pediatric Infectious Diseases Society would consider using remdesivir for these patients
  • Use prophylactic anticoagulation in hospitalized children aged 12 years and older unless contraindicated ^r1
  • 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 ^r1r9
    • 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 ^r68r69
  • Antiviral agents
    • Nirmatrelvir-ritonavir ^r68r69r70
      • Protease inhibitor combination that prevents viral replication with antiviral activity against coronaviruses
      • FDA Emergency Use Authorization for children aged 12 years and older and weighing 40 kg or more who are at high risk for progression to severe disease and full approval for adults
        • Do not use in severe hepatic impairment (Child-Pugh class C)
        • Use with caution in preexisting liver disease
        • Reduce dosage when estimated GFR is at least 30 but less than 60 mL/minute/1.73 m²; do not use when estimated GFR is less than 30 mL/minute/1.73 m²
      • 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 medications including OTC and herbal supplements before initiation
        • Liverpool COVID-19 drug interaction^r71 website and ritonavir-boosted nirmatrelvir fact sheet^r70 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 isolate until they meet criteria for discontinuation ^r1
    • Remdesivir ^r68r72
      • Nucleotide analogue prodrug that inhibits viral RNA polymerases
      • FDA-approved to treat COVID-19 in adult and pediatric patients from birth to age younger than 18 years and weighing 1.5 kg or more ^r68
        • Avoid in patients with ALT level more than 5 times the upper reference limit and when estimated GFR is less than 30 mL/minute/1.73 m² ^r31
      • Most beneficial when started early in course of illness (fewer than 7 days after first symptom) in patients meeting criteria for treatment ^r1
      • Remdesivir for nonhospitalized children may pose a logistical challenge, requiring 3 days of infusion capacity and monitoring and IV access; may be most useful for children who are unable to take nirmatrelvir-boosted ritonavir due to age or drug interactions
  • Immunomodulatory agents
    • Dexamethasone
      • Efficacy and safety data in children are limited; optimal dose and duration are not known for pediatric patients ^r2r73
      • Treatment of COVID-19–associated bronchiolitis, croup, or asthma should follow usual standard of care, including steroids where indicated
      • 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 ^r1r68r69
        • Reduce dosage when estimated GFR is less than 60 mL/minute/1.73 m²; do not use in children aged 2 to less than 9 years when estimated GFR is less than 30 mL/minute/1.73 m² or children aged 9 years and older when estimated GFR is less than 15 mL/minute/1.73 m²
        • Interrupt therapy if AST or ALT increases and drug-induced liver injury is suspected
        • Interrupt therapy if absolute lymphocyte count or absolute neutrophil count decreases to less than 200 cells/µL or 500 cells/µL, respectively
      • Baricitinib should not be used with tocilizumab or tofacitinib
      • Tablets may be used in water for enteral administration
    • Tocilizumab ^r69
      • Interleukin-6 receptor antagonist with limited use in pediatric population for COVID-19 ^r74
        • 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
      • FDA Emergency Use Authorization for 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; FDA approved for adults ^r68r69
        • Do not use with elevated ALT or AST above 10 times the upper limit of reference range
      • Tocilizumab should not be used with baricitinib or tofacitinib
    • Tofacitinib ^r69
      • 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 ^r1
      • Tofacitinib should not be used with baricitinib or tocilizumab
  • 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)
  • 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
      • Products that had been authorized for emergency use for treatment are unavailable due to lack of efficacy against circulating Omicron subvariants
      • The only currently authorized monoclonal antibody, pemivibart, is used for preexposure prophylaxis in certain circumstances
    • 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 ^r69
      • Evidence in adult population is mixed; evidence in pediatric population is very limited and other options are available (eg, ritonavir-boosted nirmatrelvir, remdesivir)
      • 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 ^r1r2
        • 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: ^r1

• Molnupiravir (other than for patients aged 18 years and older) ^r1r2
• 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 ^c93
  • Instruct caregiver to monitor for manifestations associated with worsening illness and clinical deterioration, including difficult or rapid breathing, chest pain, dehydration, lightheadedness, blue lips or face, new confusion, inability to awaken or not interacting when awake, or inability to drink or breastfeed ^r9
• Hospitalized patients ^c94
  • 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) ^r79
  • Monitoring of laboratory markers in hospitalized patients should be based on routine practice for level of care
• Patients taking remdesivir
  • Baseline liver function testing, prothrombin time, and estimated GFR with repeat tests as clinically indicated, are recommended ^r1c95
• Return to sports and physical activity recommendations for children who test positive for SARS-CoV-2
  • Myocarditis is a rare complication of COVID-19 (and many other infections), with increased morbidity and mortality in the presence of high-intensity activity ^r80
    • Estimates of SARS-CoV-2–related myocarditis are 150 cases per 100,000 population (though mostly adults); college-age and young professional athletes who underwent screening (ECG, echocardiogram, and troponin testing) showed 0.7% prevalence of cardiac involvement ^r80r81
    • Educate all patients and caregivers to report chest pain, shortness of breath out of proportion for upper respiratory tract infection, new-onset palpitations, or syncope during illness, and any of these symptoms that occur when returning to exercise
  • Recommend rest while symptomatic and gradual return to prior level of physical activity ^r9r21
    • Guidance from many organizations has not been updated to conform with the latest public health guidance; however, general principles remain the same: ^r81r82r83
      • Use severity of disease to determine timing and additional evaluations needed
        • For asymptomatic or mild infections without fever: no medical evaluation is required; resume physical activity no sooner than 3 days from positive test result, provided symptoms are resolved or improved
        • For moderate infections including fever or cardiopulmonary symptoms during illness (chest pain, palpitations, syncope, dyspnea): clinician evaluation is recommended; resume physical activity no sooner than 5 days from positive test result, provided all symptoms are resolved
          • Consider ECG, echocardiogram, and troponin levels during evaluation; refer to cardiology as needed
          • Patients with infections 3 or more months ago who have already returned to full physical activity without any symptoms do not need further evaluation
        • For severe infections, including anyone hospitalized or diagnosed with MIS: cardiologist consultation is recommended before activity is resumed
      • Evaluate any cardiopulmonary symptoms that emerge or recur when exercise resumes
        • Order ECG, echocardiogram, and troponin levels if not already done
        • Consider cardiologist consultation and cardiac MRI

Complications

• Acute complications
  • Coinfection with other viruses and bacteria
    • Coinfection appears to be rare overall but depends on other circulating pathogens (eg, influenza) ^r1r54
    • Prescribe antibiotics only for clinically confirmed or suspected bacterial infections; routine empiric antibiotics are not recommended ^r1
  • Common complications in children with severe and critical disease may include:
    • Respiratory failure and acute respiratory distress syndrome
    • Shock
    • Acute renal failure
    • Coagulopathy
    • Multisystem organ failure
  • Cardiovascular involvement
    • Myocarditis, pericarditis, heart failure, and arrhythmias are described ^{r84c96c97c98c99}
    • 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 ^r85
    • 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) ^r86r87
    • Athletes are at higher risk of sequelae from myocarditis, as high-intensity activity increases risk of sudden cardiac death in athletes with myocarditis ^r80r81
      • Estimates of prevalence of cardiac inflammation in athletes range from 0.4% to 3%; follow return-to-play guidance for resuming physical activity
  • 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 ^r18
    • Acute disseminated encephalomyelitis, acute transverse myelitis, Guillain-Barré syndrome, cerebral edema, demyelination, and stroke are among the possible life-threatening complications ^{r89c100c101c102c103c104c105}
  • Thrombotic events
    • Appear to develop at much lower frequency than encountered in adult patients
    • Overall incidence of venous thromboembolism in hospitalized pediatric patients is estimated at 1.5% ^r90
      • D-dimer level of 5 times normal value was associated with venous thromboembolism
    • Developing a thrombotic event is a marker for increased mortality risk ^r91
    • Thromboprophylaxis appears safe, with very low rates of major bleeding ^r90
  • Ocular symptoms
    • Anterior uveitis, retinitis, and optic neuritis are among serious but rare ocular complications encountered ^r30
• Postinfectious complications
  • MIS-C ^c106d15
    • Rare inflammatory condition that may develop about 2 to 6 weeks after acute COVID-19 infection ^r92
      • Reported to occur in approximately 0.1% of children with COVID-19 diagnosis early in the pandemic; incidence decreased in 2022 ^r54r93
    • Inflammation may affect any organ but typically involves gastrointestinal system, skin, heart, brain, lungs, kidneys, and eyes
    • Most MIS-C develops in previously healthy patients ^r54r92
      • Obesity and asthma are the most commonly associated comorbid conditions
    • Establish diagnosis based on CDC or WHO clinical criteria ^r9r94
    • Treatment involves initial resuscitation, immunomodulatory therapy (eg, IV immunoglobulin and corticosteroids), and antithrombotic therapy (eg, low-dose aspirin with or without anticoagulation) ^r1r95
  • Long COVID or post–COVID-19 conditions
    • Symptoms attributable to COVID-19 may persist or develop following acute infection; this is called post–COVID-19 conditions, long COVID, or postacute sequelae of COVID-19
      • Definitions were developed to standardize duration and provide more accurate information on incidence; WHO created separate clinical definitions for adults and for children and adolescents
      • WHO definition: post–COVID-19 condition in children and adolescents occurs in individuals with a history of confirmed or probable SARS-CoV-2 infection, when experiencing symptoms lasting at least 2 months that initially occurred within 3 months of acute COVID-19 ^r96
        • Symptoms have an impact on everyday functioning
        • Symptoms may be persistent or new onset after an initial recovery; symptoms may fluctuate or relapse
      • US National Academies of Sciences, Engineering, and Medicine definition of long COVID: an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing-and-remitting, or progressive disease state that affects 1 or more organ systems ^r97
    • Long COVID symptoms in children may include respiratory, cardiovascular, neurologic, psychologic, and other symptoms ^c107
      • Common symptoms include fatigue, altered smell/anosmia, anxiety, brain fog/confusion, dyspnea, and myalgia ^r96r97r98
      • Numerous other symptoms have been reported ^r96r97
    • Long COVID may affect up to 24% of pediatric patients; risk factors include female sex, older age, and more severe disease ^r4
      • A majority of pediatric patients with long COVID experience resolution of symptoms, but almost 15% were still experiencing symptoms at greater than 12 months of follow-up
    • Research is ongoing; long-term sequelae are still being determined ^{r99r100r101r102}
      • Research definition parallels the clinical definition: 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 ^r103
      • Research is complicated because symptoms may be due to comorbidities, hospitalization, other viral illnesses, pandemic-related stresses, and other factors, as well as no longer having a control group of children who have not had COVID-19 due to widespread prevalence ^r98r101
  • 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 ^r104r105
• 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 neglect and violence ^{r106r107r108r109}

Prognosis

• In general, an excellent prognosis is expected for most children diagnosed with COVID-19 ^r25r54
  • Full recovery in most occurs by 2 weeks after onset of illness, but many children have symptoms up to 12 weeks ^r4r25r31
• Overall, children experience less severe illness and fewer acute complications than adults, and fewer children require hospital admission ^r2r64
  • 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 ^r44
      • While underlying conditions are a significant risk factor for critical disease, approximately 40% of pediatric patients requiring intensive care have no underlying conditions ^r3r10
    • 4% of previously healthy children develop critical illness, defined as mechanical ventilation requirement, ICU admission, or death ^r3
  • Hospitalization rates have decreased over time; highest rates of hospitalization among children in the United States are for infants younger than 6 months, who are vaccine ineligible ^r11
  • 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 ^r54
  • 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 ^r110
    • Patients who are Hispanic, Black, and American Indian/Alaska Native ^r110
    • Patients with significant comorbid underlying medical conditions (eg, chronic lung disease, obesity, neurologic and developmental disorders) ^r1

Screening

Prevention

• Primary prevention methods
  • Pharmacologic interventions
    • Immunization ^r112d1
      • Represents a key intervention in prevention of disease in all age groups
      • CDC recommends all children aged 6 months and older stay up to date on COVID-19 vaccines and recommends vaccination of pregnant individuals to protect infants before they are eligible for vaccine ^r112
      • Safety and efficacy data among children are reassuring and favorable ^r113
        • Vaccination is highly effective in preventing emergency department visits, hospitalizations, death, MIS, and long COVID ^{r21r44r94r112r114r115}
        • Most adverse effects are mild and self-limited ^r112
          • The most common adverse effects are injection site pain, fever, fatigue, headache, chills, myalgia, arthralgia, diarrhea, and in young children, irritability, sleepiness, and loss of appetite
          • Myocarditis has been reported rarely following vaccination, especially in males aged 12 to 39 years
            • Risk of myocarditis from COVID-19 (or MIS-C) is dramatically higher than that from vaccine ^r87
            • Risk of vaccine-associated myocarditis may be decreased by lengthening interval between first and second doses to 8 weeks ^r112
      • American Academy of Pediatrics encourages vaccination for all children age 6 months and older and provides resources for caregivers on vaccination ^r63
      • Vaccine update among children is suboptimal
        • Data from the 2023 to 2024 season shows that the estimated percentage of children in the United States who were up to date with COVID-19 vaccination, including boosters, was approximately 18% for ages 12 to 17 years, 13% for ages 5 to 11 years, and 6% for ages 6 months to 4 years ^r8
    • Preexposure or postexposure prophylaxis with monoclonal antibodies
      • Pemivibart may be used for preexposure prophylaxis in children aged 12 years and older, weighing 40 kg or more, who have moderate to severe immunocompromise, and who would not be expected to mount an adequate response to immunization ^r69
        • Emergency Use Authorization is restricted to areas where the proportion of circulating variants with substantially reduced susceptibility to pemivibart is 90% or less
      • Previously, several other monoclonal antibody products were used for preexposure or postexposure prophylaxis for some individuals; however, they have diminished efficacy against the Omicron variant and subvariants and are no longer authorized ^r69
  • Nonpharmacologic interventions for prevention of infection ^r21r23
    • Stay home when sick
    • Improve ventilation whenever possible
    • Ensure good hygiene
      • Supervise use of hand sanitizers for young children and keep hand sanitizers containing alcohol out of their reach, as ingestion can cause toxicity
      • Avoid touching face and mucous membranes
      • Disinfect frequently touched surfaces
    • Use face masks in individuals aged 2 years and older with symptoms and during recovery, particularly around vulnerable individuals
    • Recommend testing (eg, polymerase chain reaction, antigen) for everyone with symptoms of or exposure to COVID-19 ^r49
    • Maintain increased distance from anyone with symptoms
    • In the school setting, wearing a face mask and improving ventilation may reduce spread, and using testing to replace or reduce quarantine may reduce transmission and missed days of school ^r116r117