Key Points

• COVID-19 is a respiratory tract infection with a newly 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
  • Most children who develop severe and critical illness have significant underlying comorbidity
• Asymptomatic infection may occur in up to half of children
• In children who develop symptoms, fever, cough, and sore throat are the most common presenting symptoms
• Common presenting clinical syndromes in children include acute respiratory infection, asthma exacerbation, influenzalike illness, isolated fever, gastroenteritis, and vomiting
• Preliminary data suggest the following groups may be at increased risk for increasingly severe disease: infants younger than 1 year, older adolescents, and children with significant medical comorbidity (eg, medical complexity, severe immunosuppression, obesity, cardiopulmonary disease, chronic kidney disease, sickle cell disease, diabetes)
• Suspect diagnosis of COVID-19 based on clinical presentation with manifestations consistent with possible COVID-19 or contact with SARS-CoV-2
• 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 in up to 6% of patients with acute SARS-CoV-2 infection
• 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 not routine
  • Remdesivir and dexamethasone are the primary pharmacotherapeutics in limited use for children meeting specific indications for use
  • Nirmatrelvir-ritonavir may be recommended for treatment of some nonhospitalized patients aged 12 years and older with mild to moderate COVID-19 at high risk of progression to severe disease
• Administer other antivirals (eg, oseltamivir for influenza) and appropriate antibiotics (eg, empiric antibiotics for sepsis) in accordance with severity of disease, site of acquisition (community or hospital), epidemiologic risk factors, and local antimicrobial susceptibility patterns
• Measures intended to avoid secondary spread of SARS-CoV-2 include isolation of infected individuals and quarantine after possible exposure for patients with incomplete vaccination and booster series
• Most children experience mild illness with full recovery within 1 to 2 weeks after onset of symptoms
• Critical measures to protect pediatric population from SARS-CoV-2 infection and severe COVID-19 include community vaccination and other primary prevention strategies (eg, physical distancing, mask wearing when physical distancing is not possible, hand hygiene). Vaccination appears to be highly effective at preventing serious COVID-19 illness among pediatric patients

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 ^r1
• 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 ^r1

Pitfalls

• Be aware that some children have a 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, ventilatory support [noninvasive or invasive]) ^r2r3
• 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 or reduce risk for positive SARS-CoV-2 test result ^r4
  • 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 adolescents in the United States. Just over one-half of eligible adolescents are estimated to have completed vaccination series as of January 5, 2022 ^r5
  • 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, unhealthy lifestyle changes, 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 and sporadic modifications

Clinical Clarification

• COVID-19 (coronavirus disease 2019) is a respiratory tract infection with a newly recognized coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)
• 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 ^r6
  • Most children who develop severe and critical illness have significant underlying comorbidity ^r7r8r9
• Infection in neonates is uncommon and when neonates do become infected, most are asymptomatic or experience mild course of illness before full recovery ^r10
• 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 ^r11

Classification

• Illness severity criteria (definitions vary depending on source)
  • Asymptomatic
    • Absence of signs or symptoms and normal chest radiograph (if obtained) ^r12
  • Mild illness
    • Symptomatic without shortness of breath, dyspnea, or abnormal chest imaging ^r13
  • Moderate illness
    • Evidence of lower airway disease by clinical assessment or imaging and lack of hypoxia with SpO₂ of 94% or greater on room air at sea level ^r13
  • Severe illness
    • Children with significant hypoxia or hypoxemia without new or increased noninvasive or invasive ventilatory support requirement as evidenced by either of the following:
      • SpO₂ of less than 94% on room air at sea level or, for patients with chronic hypoxemia, a decrease from baseline of greater than 3% ^r13
      • PaO₂/FiO₂ of less than 300 mm Hg ^r13
    • Greater than 50% lung infiltrates ^r13
    • Significant tachypnea as defined by the following respiratory rates: ^r14
      • Older than 5 years: 30 or more breaths per minute
      • Age 1 to 5 years: 40 or more breaths per minute
      • Age 2 to 11 months: 50 or more breaths per minute
      • Younger than 2 months: 60 or more breaths per minute
    • Signs of severe respiratory distress (eg, deep retractions, grunting) ^r14
  • Critical illness
    • Respiratory failure (eg, new or increased noninvasive or invasive mechanical ventilation requirement), septic shock, or multiple organ failure ^r13
• Significant immunocompromise and potential for severe immunosuppression
  • Determine degree of immunocompromise using underlying disease severity and duration, clinical stability, complications, and any potentially immunosuppressing treatment. May require consultation with an expert in immunocompromise ^r13
  • Some conditions and treatments considered to pose risk for significant immunocompromise or severe immunosuppression include: ^r15
    • Active solid tumor treatment and hematologic malignancies
    • Solid organ transplant and immunosuppressive therapy
    • Chimeric antigen receptor–T cell or hematopoietic stem cell transplant (patient within 2 years of transplantation or currently taking immunosuppression therapy)
    • Moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome, combined primary immunodeficiency disorders)
    • Untreated or advanced HIV (eg, CD4 T lymphocyte count less than 200 cells/mm³, history of an AIDS-defining illness without immune reconstitution, clinical manifestations of symptomatic HIV)
    • Active treatment with any of the following:
      • High-dose corticosteroids (ie, 20 mg or more prednisone or equivalent per day when administered for 14 days or longer)
      • Alkylating agents
      • Antimetabolites
      • Transplant-related immunosuppressive drugs
      • Cancer chemotherapeutic agents classified as severely immunosuppressive
      • Tumor necrosis factor blockers
      • Other biologic agents that are immunosuppressive or immunomodulatory

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

Implement early and maintain strict transmission-based precautions for any patient with possible SARS-CoV-2 infection

• Minimum health care facility transmission-based precautions include contact, respiratory droplet, and airborne precautions during aerosol-generating procedures ^r32
• Use of gown, gloves, and N95 respirator with eye protection (goggles or face shield) or air purifying respirator that provides eye protection is standard

Supportive care is the mainstay of management for the overwhelming majority of pediatric patients; most children can be managed safely in the home environment ^r47

General supportive measures may include:

• Basic supportive care measures
  • Caregiver education
    • Provide anticipatory guidance for home care and resources about emergency warning signs for worsening COVID-19 manifestations
    • Provide recommended isolation measures to minimize secondary spread of COVID-19 ^r13
    • Educate about avoidance of sports and physical activity until cleared by physician ^r48
  • Antipyretics and OTC pain relievers
    • Ibuprofen or acetaminophen is recommended for symptomatic care ^r4r49
  • Encourage fluids and nutrition as tolerated by mouth
  • Resources for parents are readily available from various medical organizations (eg, American Academy of Pediatrics,^r50CDC,^r51r52r36WHO^r53) to help guide home care for children with COVID-19
• Advanced supportive care measures
  • 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 ^r4
      • Advantage of enteral route is ability to provide added nutritional support
      • 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 ^r23
  • Start oxygen when indicated for persistent oxygen saturation less than 92% ^r54
    • Target oxygen saturation is 92% to 96% ^r6
  • Provide airway and respiratory support when clinically indicated
    • Perform a 30- to 90-minute trial of noninvasive ventilatory support (CPAP, BPAP, high-flow nasal canula) before advancing to invasive mechanical ventilation, when clinical status allows ^r39
    • Optimize first-pass intubation success by having most experienced provider perform procedure ^r4

Administer specific antivirals (eg, oseltamivir for influenza) and appropriate antibiotics (eg, empiric antibiotics for sepsis) in accordance with disease severity, acquisition site (community or hospital), epidemiologic risk factors, and local antimicrobial susceptibility patterns ^r14

Follow evidence-based recommendations for septic shock and sepsis-related organ dysfunction as outlined in the Surviving Sepsis Campaign guidelines ^r55

Follow evidence-based recommendations for pediatric acute respiratory distress syndrome as outlined in Pediatric Acute Lung Injury Consensus Conference recommendations ^r56

General guidance regarding use of COVID-19–specific treatments in children:

• The older the child and the more severe the illness: consider using recommended adult COVID-19 treatment guidelines ^r6d12
• Enroll children in clinical trials^r57 and multicenter pragmatic trials whenever possible ^r6
• Most COVID-19 treatment trials to date have not included pediatric patients; therefore, pharmacotherapeutic treatments largely are based on expert opinion or reflect data obtained from adult series ^r58
• Frequently updated resources available to aid in most current treatment recommendations and guidance include:
  • NIH COVID-19 Treatment Guidelines ^r6
  • American Academy of Pediatrics COVID-19 Interim Guidance ^r59
  • Infectious Diseases Society of America Pediatric COVID-19 Clinical Guidance ^r58
  • Infectious Diseases Society of America Therapeutics and Interventions resources and Guidelines on the Treatment and Management of Patients With COVID-19 ^r60r61
  • WHO COVID-19 Clinical Management: Living Guidance ^r14

COVID-19 treatment-specific therapies and pharmacotherapeutic options:

• No drugs are specifically approved by FDA for treatment of COVID-19 in children younger than 12 years ^r13
• Nirmatrelvir-ritonavir ^r62
  • Protease inhibitor that prevents viral replication with antiviral activity against coronaviruses
  • First choice pharmacotherapeutic indicated for treatment of patients aged 12 years and older and weighing 40 kg or more with mild to moderate COVID-19 who are at high risk of progression to severe disease and do not require hospitalization for COVID-19
  • 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,^r63ritonavir-boosted nirmatrelvir fact sheet,^r64 and NIH guidelines^r62 can help identify potential drug interactions
• Remdesivir
  • Nucleotide analogue prodrug that inhibits viral RNA polymerases
  • Most beneficial when started early in the course of illness (fewer than 7 days after first symptom) in patients meeting criteria for treatment ^r65
  • FDA approved to treat COVID-19 in hospitalized adult and pediatric patients aged 12 years and older and weighing 40 kg or more ^r6
  • Available through FDA emergency use authorization or expanded access (ie, compassionate use) programs for hospitalized children younger than 12 years weighing from 3.5 kg to less than 40 kg ^r66
  • Studies are ongoing to evaluate safety and efficacy in children ^r13
  • FDA recommended third choice treatment (first choice, nirmatrelvir-ritonavir; second choice, sotrovimab) for high-risk nonhospitalized children aged 12 years and older weighing 40 kg or more with mild to moderate COVID-19 ^r65
  • Recommended for the following hospitalized pediatric patients with COVID-19: ^r6
    • Children 12 years or older with risk factors for severe disease and an emergent or increasing supplemental oxygen requirement
    • Children 16 years or older with an emergent or increasing supplemental oxygen requirement regardless of risk factors for severe disease
  • Consider using (in consultation with infectious disease specialist) for the following hospitalized pediatric patients with COVID-19 (recommended) ^r6
    • Children of any age with emergent or increasing supplemental oxygen requirement
  • Additional multicenter interim guidance recommendations for use of antivirals for children with severe or critical disease, as established by a panel of pediatric infectious disease physicians and pharmacists, are outlined in a report in the Journal of the Pediatric Infectious Diseases Society^r47
• Dexamethasone
  • Efficacy and safety data in children are limited; treatment in context of enrollment in a clinical trial is ideal ^r67
  • Recommended for select hospitalized pediatric patients with severe or critical COVID-19 who require any of the following: ^r6
    • High-flow oxygen
    • Noninvasive ventilation or invasive mechanical ventilation
    • Extracorporeal membrane oxygenation
  • Use has not been studied in patients with severe immunocompromise; given the theoretical potential for harm, consider—on a case-by-case basis—using to treat severe COVID-19 in patients with significant immunocompromise ^r6
  • Alternative glucocorticoids (eg, prednisone, methylprednisolone, hydrocortisone) may be substituted if dexamethasone is not available ^r6
• 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 ACE-2 receptors
  • Products with emergency use authorizations for treatment in children with mild to moderate COVID-19 at high risk for severe disease have included bamlanivimab plus etesevimab (children weighing more than 1 kg), casirivimab plus imdevimab (children 12 and older and 40 kg or greater), sotrovimab (children 12 years and older and 40 kg or greater), and bebtelovimab (children 12 and older and 40 kg or greater) ^r27r68
    • Sotrovimab and bebtelovimab are thought to be the only monoclonal antibody formulations with efficacy against Omicron variant; the FDA's emergency use authorizations for the others have been emended to specify variant susceptibility, effectively suspending their use in the United States ^r65r68
  • Recommended to consider (in consultation with infectious disease specialist) on a case-by-case basis for children who fulfill emergency use authorization criteria for high risk of progression to severe disease or hospitalization ^r27
    • May be used for children hospitalized for other indications who coincidentally develop symptomatic infection during hospitalization ^r28
    • Detailed description of risk factors for severe COVID-19 disease (eg, obesity, medical complexity with respiratory technology dependence, specific severe immunocompromising conditions) are available ^r28
  • Treatment in the context of enrollment in clinical trial is ideal ^r67
  • Start treatment, when indicated, as soon as possible after positive SARS-CoV-2 positive test result and within 10 days of symptom onset ^r27
  • Additional multicenter interim guidance recommendations for use of monoclonal antibody products in children with mild to moderate COVID-19 at high risk for severe disease, as established by a panel of pediatric infectious disease physicians, pediatric critical care physicians, pediatric hematologists, and pharmacists, are outlined in a report in the Journal of the Pediatric Infectious Diseases Society^r28
  • Defer vaccination for SARS-CoV-2 90 days or more after use of monoclonal antibody therapy ^r69
• Convalescent plasma
  • Essentially, there are no safety and efficacy data available for children and little clinically meaningful efficacy data available for adults. Cochrane review suggests no reduction in mortality and little to no impact on clinical improvement measures ^r20r70
  • Given paucity of available evidence, NIH does not recommend for or against use in children in the outpatient or hospital setting who do not require mechanical ventilation ^r6
  • NIH recommends against use in mechanically ventilated pediatric patients ^r6
  • When used, ideal timing for administration is early in course of illness, particularly in patients lacking a significant positive treatment response to remdesivir and glucocorticoids and in those with impaired humoral immunity ^r71
  • Recommend considering (in consultation with infectious disease specialist) on a case-by-case basis for hospitalized children who fulfill emergency use authorization for high-titer convalescent plasma use ^r6r72
  • Defer vaccination for SARS-CoV-2 90 days or more after use of convalescent plasma ^r69
• Baricitinib
  • Immunomodulator (Janus kinase inhibitor) with emergency use authorization in place for use in combination with remdesivir in hospitalized adults and in children aged 2 years and older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation ^r6r72
  • Given extreme lack of data in pediatric population, NIH does not recommend for or against use in combination with remdesivir when corticosteroids cannot be used ^r6
• Tocilizumab
  • Immunomodulator (interleukin-6 inhibitor) with limited use in pediatric population for COVID-19;^r73r29 efficacy data from adult trials are conflicting^r72
  • Emergency use authorization is available for use in combination with systemic glucocorticoids in children aged 2 years and older requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation ^r74
  • NIH does not recommend for or against use in combination with dexamethasone for hospitalized children with COVID-19 ^r6

Avoid potential harmful therapies not supported by evidence for treatment of acute COVID-19 in pediatric patients (outside of clinical trials), such as the following: ^r4

• Interleukin-1 receptor antagonists (eg, anakinra)
• Colchicine
• ACE inhibitors and angiotensin receptor blockers
• Lopinavir and ritonavir (HIV antivirals)
• Chloroquine and hydroxychloroquine
• Azithromycin, without suspicion of bacterial infection
• Ivermectin
• Nebulized interferon beta-1a

Thromboprophylaxis

• Data regarding risk of thrombotic events in children with acute COVID-19 and effectiveness of thromboprophylaxis are limited ^r4
• Individualized approach to thromboprophylaxis with consideration of thrombotic and hemorrhagic risk factors in children with acute COVID-19 is recommended ^r4
• Early ambulation and lower extremity compression garments and devices are low risk and easily implemented precautionary measures
• Some experts recommend prophylactic low molecular weight heparin for hospitalized children with COVID-19 or MIS-C at highest risk for thrombosis ^r75
  • 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, and general risk factors for thromboembolic events (eg, obesity, family history, chronic inflammatory conditions)
• Follow institutional guidelines to help direct care decisions regarding use of antiplatelet medications and anticoagulation ^r4

Monitoring

• Patients managed at home
  • 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 ^r23
• Hospitalized patients
  • 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) ^r80
  • Monitoring of laboratory markers in hospitalized patients is not rigorously standardized
    • Limited data suggest that serial monitoring of C-reactive protein, procalcitonin, and l-lactate dehydrogenase may be most informative to track illness trajectory ^r81
• Patients taking remdesivir
  • Monitoring of liver function test results at least every other day is recommended by some experts while taking remdesivir ^r80
• Return to sports and physical education recommendations for children who test positive for SARS-CoV-2 ^r48
  • American Academy of Pediatrics provides a detailed return to play algorithm based on severity of symptoms
    • Child may return to sports after they complete appropriate isolation measures, minimum symptom-free period has elapsed, they are able to perform normal activities of daily living, and they display no concerning symptoms and signs
    • American Heart Association 14-element screening evaluation is required before clearance for all patients ^r82
    • Asymptomatic and mild disease
      • Child may be cleared by phone or telemedicine visit if symptom-free (no chest pain, palpitations, syncope, shortness of breath) and American Heart Association screening evaluation is negative
      • Examine child in office and consider ECG if American Heart Association screening evaluation is positive before clearance
    • Moderate illness (defined as 4 or more days of fever, 1 or more week of myalgia or lethargy, not admitted to ICU, no evidence of MIS-C)
      • Physical examination and screening ECG is recommended for all patients before clearing for exercise
      • Cardiologist must clear child for return to play 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 a minimum of 3 to 6 months and require cardiology clearance before allowing child to return to training or competition
• Progression strategy for return to physical activity after clearance depends on age
  • Children younger than 12 years after mild illness:
    • Allow to progress back into activity according to their own tolerance
  • Children aged 12 years and older after mild illness:
    • Graduated return to play protocol over the course of at least a week (recommended)
  • Extended progression is recommended for children with more than mild illness
• American Academy of Pediatrics recommendations for follow-up after SARS-CoV-2 infection ^r83
  • At least 1 follow-up is recommended for all patients with infection. Type (telehealth, in-person visit) 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
    • Limited data suggest coinfection may occur in some children (up to 6%) ^r43
    • 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 ^r43
  • Neurologic complications
    • Up to 20% of hospitalized children may develop neurologic manifestations; these manifestations are transient in most (over 88%) ^r84
    • Neurologic complications are more frequent in children with underlying neurologic disorders ^r19
    • Acute disseminated encephalomyelitis, acute transverse myelitis, Guillain-Barré, cerebral edema, demyelination, and stroke are among the possible life-threatening complications ^r85
  • Cardiovascular involvement
    • Myocarditis, pericarditis, heart failure, and arrhythmias are described ^r86
    • 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 the presence of virus ^r87
    • Data regarding risk of myocarditis associated with acute COVID-19 are emerging. Overall risk for myocarditis among children younger than 16 years with a COVID-19 diagnosis is estimated at less than 0.13% (adjusted risk ratio greater than 30) ^r88
    • 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 ^r89
    • 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 ^r48
  • 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 ^r90
      • 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 ^r91
  • Ocular symptoms
    • Anterior uveitis, retinitis, and optic neuritis are among the serious but rare ocular complications encountered ^r22
  • 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 the clinical spectrum of COVID-19 in infants rather than being a mere coincidental finding has yet to be determined ^r13r92
  • 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 ^d13
    • Rare inflammatory condition that may develop about 2 to 6 weeks after acute COVID-19 infection ^r93
      • Reported to occur in approximately 0.1% of children with COVID-19 diagnosis ^r43
    • 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 ^r43r93
      • 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 ^r94r95
    • Treatment involves initial resuscitation, when indicated, followed by immunomodulatory therapy (ie, IV immunoglobulin with or without concomitant corticosteroids) and antithrombotic therapy (ie, low-dose aspirin with or without anticoagulation) ^r96
• 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^r71 are largely unknown ^r58
• 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, and increased child neglect ^r8
  • American Academy of Pediatrics strongly advocates that the overarching goal is to keep students safe and physically present in school ^r97
    • Measures to mitigate risk of COVID-19 spread in schools include encouraging vaccination, physical distancing, and wearing masks and optimizing ventilation and disinfection measures
    • Vaccination of eligible individuals (eg, teachers, custodians, lunch aids) helps to protect younger children who are not yet eligible for vaccination ^r25
  • CDC COVID-19 prevention strategies outline methods to mitigate risk of COVID-19 spread in schools ^r98r99

Prognosis

• In general, an excellent prognosis is expected for most children diagnosed with COVID-19 ^r20r43
  • 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 ^r20r23
• Overall, children experience less severe illness and fewer acute complications (eg, shock, acute respiratory distress syndrome) than adults, and fewer children require hospital admission ^r54r58
  • ICU requirements in the 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 ^r58
    • About half of children who require ICU level of care:
      • Have significant underlying comorbidity ^r8
      • Are aged 12 to 17 years (among children aged 0-17 years) ^r25
  • Hospitalization requirements in the United States
    • Highest rates of hospitalization occur among children younger than 4 years and aged from 12 to 17 years ^r25r100
    • An estimated 2% of pediatric patients^r58 require hospital admission; median length of hospitalization is from 2 to 3 days^r25
• Severe infection
  • Most children who develop severe infection have underlying comorbid medical conditions (eg, obesity, chronic cardiopulmonary disease, diabetes) ^r58
  • Most severe cases involve severe respiratory disease (71%) and a minority involve severe cardiac (less than 3%) or cardiopulmonary disease (about 9%) ^r85
• Cardiac morbidity
  • Children with severe COVID-19 and reduced left ventricular systolic function
    • Cardiac dysfunction normalizes in approximately 91% of children within 30 days ^r85
  • Children with MIS-C and coronary artery aneurysm
    • Coronary arteries normalize in approximately 79% of children within 30 days ^r85
• Mortality
  • Overall mortality is estimated to be less than 0.04% in children diagnosed with COVID-19 ^r43r58
  • Mortality is estimated to be approximately 1.6% among children with severe COVID-19 or MIS-C ^r85
  • 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 ^r101
    • Patients who are Hispanic, Black, and American Indian/Alaska Native ^r101
    • Patients with significant comorbid underlying medical conditions (eg, chronic lung disease, obesity, neurologic and developmental disorders) ^r6

Screening

Prevention

• Primary prevention methods:
  • Pharmacologic interventions
    • Vaccination ^d12
      • Represents a key intervention in prevention of disease in all age groups
      • FDA has approved vaccination of children 5 years and older with Pfizer-BioNTech product ^{r58r103r104r105}
      • Safety and efficacy data among children aged 5 to 11 years are reassuring and favorable ^r52
        • Vaccine efficacy is reported to be about 91% (similar efficacy as reported in adult trials)
        • Reported side effects are mild and self-limited; most common side effect is sore arm
      • Third dose of mRNA vaccine
        • Recommended 28 days after second dose in primary series for moderately and severely immunocompromised patients 5 years and older who were previously vaccinated with the 2-dose mRNA vaccine series ^r51
      • Booster dose after completion of primary series ^r106
        • Booster dose of Pfizer vaccine is FDA approved and CDC recommended for patients aged 12 years and older ^r69r107
        • Recommended interval between final dose of primary series and mRNA booster dose include the following: ^r51
          • 5 months after receiving Pfizer-BioNTech primary series
          • 5 months after receiving Moderna vaccine primary series
          • 2 months after receiving Johnson and Johnson vaccine
        • Data suggest that a booster dose broadens and strengthens protection against Omicron and other SARS-CoV-2 variants ^r51
          • 2-dose mRNA vaccine (eg, Pfizer, Moderna) series is about 35% effective for Omicron variant; COVID-19 booster dose improves vaccine effectiveness for Omicron variant to about 75% ^r24
          • Booster dose decreases risk of severe disease, hospitalization, and death from COVID-19 ^r24
        • Moderately or severely immunocompromised patients who have received a third primary series dose of mRNA vaccine require booster dose at least 5 months (Pfizer and Moderna) after the third primary series dose ^r69
      • Vaccine primary series efficacy and uptake data
        • Although a modest degree of vaccine effectiveness against infection is reported, data suggest that vaccine is highly effective in preventing serious COVID-19 illness including severe disease, hospitalization, and death ^r25r69
          • Hospitalization rates were about 10 times higher among unvaccinated adolescents during period of Delta SARS-CoV-2 variant predominance ^r100
          • Among pediatric patients requiring hospitalization, ICU admission requirement remained stable during period of Delta SARS-CoV-2 variant predominance ^r100
        • Estimated uptake data as of January 5, 2022 ^r5
          • 25% of children aged 5 to 11 years have received at least 1 dose of COVID-19 vaccine
            • FDA granted emergency use authorization for Pfizer vaccine for 5- to 11-year age group on October 29, 2021, and CDC approved its use on November 2, 2021
          • 63% of adolescents aged 12 to 17 years have received at least 1 dose of COVID-19 vaccine, and 53% of adolescents in this age group are fully vaccinated
            • FDA granted emergency use authorization for Pfizer vaccine for 12- to 15-year age group on May 11, 2021, and CDC approved its use on May 12, 2021
            • FDA granted emergency use authorization for Pfizer vaccine for patients aged 16 years and older on December 11, 2020, and CDC approved its use on December 12, 2020
      • Vaccination after MIS-C
        • Data are lacking regarding safety and efficacy after MIS-C; weigh theoretical risk of dysregulated immune response after vaccination with risk of COVID-19 infection ^r69
        • CDC guidance notes that benefits for vaccination most likely outweigh risks, particularly when the following criteria are met: ^r69
          • High to substantial SARS-CoV-2 transmission in community
          • Clinical recovery (including return to normal myocardial function)
          • 90 days or more have elapsed since MIS-C diagnosis
          • MIS-C occurred before patient received any dose of COVID-19 vaccine
      • Numerous vaccine-related resources are available for medical caregivers and families; some such resources include:
        • US Department of Health and Human Services: COVID-19 vaccines for children ^r108
        • American Academy of Pediatrics: COVID-19 vaccine campaign toolkit^r109 and COVID-19 vaccine for children resources^r110
        • CDC: COVID-19 vaccination resources ^r111r112
        • Infectious Diseases Society of America: COVID-19 vaccines and immunity resources ^r113
    • Preexposure prophylaxis with monoclonal antibodies ^r27r114
      • Consider using preexposure anti-SARS-CoV-2 monoclonal antibody administration on a case-by-case basis in consultation with infectious disease specialist for patients at high risk for severe disease aged 12 years and older and weighing 40 kg or more
        • Consider for patients who meet emergency use authorization criteria who have NOT been recently exposed to an individual with SARS-CoV-2 infection AND either of the following:
          • Moderate or severe immunocompromise with potentially inadequate immune response to COVID-19 vaccination
          • Unable to be fully vaccinated owing to severe documented adverse reaction to COVID-19 vaccine or vaccine components
      • Available option is tixagevimab plus cilgavimab
        • Efficacy of tixagevimab plus cilgavimab monoclonal antibody formulation may be significantly limited for Omicron variant
        • May be given to eligible high-risk patients at least 2 weeks after their last COVID-19 vaccine dose; duration of protection is anticipated to continue for up to 6 months ^r27
        • Use is NOT authorized by FDA in unvaccinated individuals for whom COVID-19 vaccination is recommended
    • Postexposure prophylaxis with monoclonal antibodies
      • Consider using postexposure anti-SARS-CoV-2 monoclonal antibody administration on a case-by-case basis in consultation with infectious disease specialist for children at high risk for severe disease with high risk of exposure (eg, household) who meet emergency use authorization criteria ^r27r114
      • Fully vaccinated patients are not eligible for postexposure prophylaxis unless they are not expected to mount an adequate immune response to vaccination ^r28
        • Patients are considered to be fully vaccinated 2 weeks or more after last dose in 2 dose series (eg, Pfizer, Moderna) or 2 weeks or more after receipt of single dose vaccine (eg, Johnson and Johnson) for the purpose of postexposure prophylaxis considerations ^r68
      • Available options include bamlanivimab plus etesevimab and casirivimab plus imdevimab
      • Efficacy of these monoclonal antibody formulations may be significantly limited for Omicron variant ^r65
      • Start treatment as soon as possible to eligible patients, when indicated; optimal time frame is within 96 hours after confirmed SARS-CoV-2 exposure; may be useful up to a maximum of 7 days after confirmed exposure ^r27
  • Nonpharmacologic interventions ^r16
    • Physical distancing
    • Proper use of face masks (covering nose and mouth in individuals 2 years and older, particularly when physical distancing is not possible)
    • 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
    • Improve ventilation
    • Use quarantine and self-isolation measures as needed
    • Hospital protocols include:
      • Personal protective equipment for providers: N95 masks, eye shields, gowns, and gloves
      • Engineering measures: negative pressure and air filtering
      • Masks for patients if transport is required