Key Points

• COVID-19 is a systemic infection primarily affecting the respiratory system, caused by a recently recognized coronavirus, SARS-CoV-2
• Children tend to experience less severe illness and fewer complications than adults. Fewer children than adults with infection require hospitalization; however, a similar proportion of children and adults who do need hospital admission require ICU level of care
• Asymptomatic infection may occur in up to half of children
• 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
• 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
• 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 certain hospitalized children
  • Nirmatrelvir-ritonavir, remdesivir, and bebtelovimab are used for certain nonhospitalized patients with COVID-19 at high risk of progression to severe disease
  • Tixagevimab-cilgavimab may be used for preexposure prophylaxis in certain high-risk patients
• 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; a small percentage have complications (eg, MIS-C) or symptoms beyond 4 weeks
• Vaccination is safe and highly effective at preventing serious COVID-19 illness among pediatric patients
• 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)

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 children and adolescents in the United States ^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 modifications

Clinical Clarification

• COVID-19 (coronavirus disease 2019) is a systemic infection primarily affecting the respiratory system, caused by a recently recognized coronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)
• 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; however, approximately 30% of hospitalized children aged 5 to 11 years and 63% of hospitalized children aged 0 to 4 years had no underlying medical conditions in studies from the United States ^r7r8
• Infants younger than 6 months are at higher risk of hospitalization than infants and children aged 6 months to 11 years; infants may present with isolated gastrointestinal symptoms or feeding difficulties ^r8r9
  • Infection in neonates is uncommon; most neonatal infections are asymptomatic ^r8
• Knowledge of disease processes in both children and adults is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to understanding and to clinical management
  • CDC website maintains information about geographic distribution of variants in the United States; therapeutics for treatment and prevention are altered by prevailing variants ^r10

Classification

• Illness severity criteria (definitions vary depending on source) ^r6r11
  • 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 SpO₂ of 94% or greater on room air at sea level ^r13
  • Severe illness is defined by presence of any of the following:
    • 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: ^r11
      • 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) ^r11
  • Critical illness
    • Respiratory failure (eg, new or increased noninvasive or invasive mechanical ventilation requirement), septic shock, or multiple organ failure ^r13

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 ^r64
• 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 ^r65

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 ^r32
    • Educate about when clearance by a health care provider is needed to resume sports and physical activity (eg, moderate to severe COVID-19, symptoms of myocarditis following recovery) ^r66
  • Antipyretics and OTC pain relievers
    • Ibuprofen or acetaminophen is recommended for symptomatic care ^r4r67
  • Encourage fluids and nutrition as tolerated by mouth
  • Resources for parents are readily available from various medical organizations (eg, American Academy of Pediatrics,^r68CDC^r32, WHO^r69) 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 when needed
      • Parenteral hydration is preferred for patients with poor or declining clinical status
    • Goal is euvolemic state; aggressive fluid management may impair alveolar oxygen exchange
  • Provide advanced nutritional support if needed ^r22
  • Start oxygen when indicated for persistent oxygen saturation less than 92% ^r70
    • Target oxygen saturation is 92% to 96% (WHO recommends greater than 90%) ^r6r11
  • 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 ^r55
    • 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 ^r11

Follow evidence-based recommendations for septic shock and sepsis-related organ dysfunction as outlined in the Surviving Sepsis Campaign guidelines ^r71

Follow evidence-based recommendations for pediatric acute respiratory distress syndrome as outlined in Pediatric Acute Lung Injury Consensus Conference recommendations ^r72

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^r73 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 ^r74
• Updated resources available to aid in most current treatment recommendations and guidance include:
  • NIH COVID-19 treatment guidelines ^r6
  • American Academy of Pediatrics guidance ^r38r75
  • Infectious Diseases Society of America guidance for treatment and management of patients with COVID-19^r76 and for pediatric population^r74r74r76
  • WHO guidelines for treatment^r78, prevention^r77, and clinical care^r11r11r77r78

COVID-19 treatment-specific therapies and pharmacotherapeutic options:

• Antivirals
  • Nirmatrelvir-ritonavir ^r6
    • Protease inhibitor combination 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 do not require hospitalization for COVID-19 but are at high risk of progression to severe disease
    • Initiate oral dosing as soon as possible and within 5 days of symptom onset
    • Ritonavir-boosted nirmatrelvir has significant and complex drug interactions; carefully review medication profile (including OTC and herbal supplements) before initiation
      • Liverpool COVID-19 drug interaction website,^r79ritonavir-boosted nirmatrelvir fact sheet,^r80 and NIH guidelines^r6 can help identify potential drug interactions
    • Reports of symptom rebound after completing 5 days of therapy are being investigated ^r81
      • Patients who test positive after previously being negative or who have recurrent symptoms should isolate again per guidelines; additional treatment with ritonavir-boosted nirmatrelvir is not recommended at this time
  • 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 ^r6
    • FDA-approved to treat COVID-19 in adult and pediatric patients aged 28 days and older and weighing 3 kg or more ^r6
    • NIH-recommended second choice treatment (first choice, nirmatrelvir-ritonavir) for nonhospitalized children aged 12 years and older weighing 40 kg or more with mild to moderate COVID-19 at high risk of progression ^r6
    • 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^r65
• Immunomodulatory agents
  • Dexamethasone
    • Efficacy and safety data in children are limited; treatment in context of enrollment in a clinical trial is ideal ^r82
    • 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
    • Routine use for pediatric patients requiring low levels of oxygen is not recommended ^r6
    • Use has not been studied in patients with severe immunocompromise; given the theoretical potential for harm, consider using to treat severe COVID-19 in patients with significant immunocompromise only on a case-by-case basis ^r6
    • Alternative glucocorticoids (eg, prednisone, methylprednisolone, hydrocortisone) may be substituted if dexamethasone is not available ^r6
  • Baricitinib
    • Immunomodulator (Janus kinase inhibitor) with EUA 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 ^r6r83
    • 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
    • Infectious Diseases Society of America guidelines endorsed by Pediatric Infectious Diseases Society suggest use of baricitinib along with remdesivir in hospitalized patients with severe COVID-19 who cannot receive dexamethasone (which is standard of care); this is based on very limited data in pediatric populations ^r76
  • Tocilizumab
    • Immunomodulator (interleukin-6 inhibitor) with limited use in pediatric population for COVID-19;^r40r84 efficacy data from adult trials are conflicting^r83
    • EUA 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 ^r85
    • NIH does not recommend for or against use for hospitalized children with COVID-19; if used, should be in combination with dexamethasone ^r6
• 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 with EUA (emergency use authorization) in children have included bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, and bebtelovimab (EUA for treatment); and tixagevimab-cilgavimab (EUA for preexposure prophylaxis) ^r38r86
      • However, currently circulating Omicron subvariants have rendered etesevimab, casirivimab-imdevimab, and sotrovimab ineffective, and EUAs have been revised or revoked for these products
      • Bebtelovimab retains efficacy against currently circulating Omicron subvariants and may be considered for non-hospitalized children with mild to moderate COVID-19 at high risk for severe disease ^r6r86
    • Recommended to consider (in consultation with infectious disease specialist) on a case-by-case basis for children who fulfill EUA criteria for high risk of progression to severe disease or hospitalization ^r38
      • May be used for children hospitalized for other indications who coincidentally develop symptomatic infection during hospitalization ^r41
      • Detailed description of risk factors for severe COVID-19 disease (eg, obesity, medical complexity with respiratory technology dependence, specific severe immunocompromising conditions) are available ^r41
    • Treatment in the context of enrollment in clinical trial is ideal ^r82
    • Start treatment, when indicated, as soon as possible after positive SARS-CoV-2 positive test result and within 10 days of symptom onset ^r38
    • 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^r41
    • Vaccination for SARS-CoV-2 after use of monoclonal antibody therapy does not need to be delayed (beyond routine guidance to defer vaccination during acute COVID-19 until criteria are met to discontinue isolation) ^r43
  • Convalescent plasma
    • Given currently circulating Omicron subvariants, NIH guidelines recommend against use of any convalescent plasma collected before the emergence of Omicron variants and notes there is insufficient evidence to recommend either for or against the use of high-titer convalescent plasma that was collected after the emergence of Omicron
    • NIH recommends against use in all hospitalized immunocompetent patients and in mechanically ventilated pediatric patients ^r6
    • 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 ^r19r87
    • NIH recommends considering (in consultation with infectious disease specialist) on a case-by-case basis for hospitalized immunocompromised children who meet EUA criteria for high-titer convalescent plasma use ^r6r83
    • If 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 ^r88
    • Vaccination for SARS-CoV-2 after use of convalescent plasma does not need to be delayed (beyond routine guidance to defer vaccination during acute COVID-19 until criteria are met to discontinue isolation) ^r43
• Thrombosis prevention and treatment
  • For hospitalized children with COVID-19 (not MIS-C), thromboprophylaxis should be the same as for hospitalized children without COVID-19 ^r6
    • Follow institutional guidelines to help direct care decisions regarding use of antiplatelet medications and anticoagulation ^r4
  • Children with COVID-10 who have diagnosed thrombosis or who are receiving extracorporeal membrane oxygenation or continuous renal replacement therapy should be managed the same as children without COVID-19 with these indications ^r6
  • Children on anticoagulation or antiplatelet treatment for another indication should continue therapy if diagnosed with COVID-19 ^r6
  • Data regarding risk of thrombotic events in children with acute COVID-19 and effectiveness of thromboprophylaxis are limited ^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 at highest risk for thrombosis ^r89
    • 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)
    • Individualized approach to thromboprophylaxis with consideration of thrombotic and hemorrhagic risk factors in children with acute COVID-19 is recommended ^r4
  • Certain antiplatelet and anticoagulation therapy is recommended for patients with MIS-C; details are available in NIH^r6 and American College of Rheumatology^r48 guidelines ^d13

Certain therapies are under investigation for treatment of COVID-19; consider use only within a clinical trial: ^r6

• Sarilumab
• Tofacitinib
• Anakinra
• Fluvoxamine
• GM-CSF inhibitors (granulocyte-macrophage colony-stimulating factor)
• Inhaled corticosteroids
• Canakinumab
• Bruton's 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: ^r4r6

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

Monitoring

• Patients managed at home ^c130
  • 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 ^r22
• Hospitalized patients ^c131
  • 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) ^r95
  • Monitoring of laboratory markers in hospitalized patients is not rigorously standardized
    • Limited data suggest that serial monitoring of C-reactive protein, procalcitonin, and lactate dehydrogenase may be most informative to track illness trajectory ^r96
• Patients taking remdesivir
  • Monitoring of liver function test results at least every other day is recommended by some experts while taking remdesivir ^r95c132
• Return to sports and physical activity recommendations for children who test positive for SARS-CoV-2 ^r66
  • 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 recommended to clear patients ^r97c133
    • If child has already advanced back to physical activity or sports on their own and they do not have any abnormal signs or symptoms, no further workup is necessary
    • Asymptomatic and mild disease
      • Child may be cleared by phone or telehealth 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 ^r75
  • At least 1 follow-up is recommended for all patients with infection. Type (eg, telehealth, in-office) and timing of visit depend on severity of illness, presence of underlying comorbidities, presence of complications, and completion of isolation period
  • At visit, monitor residual symptoms, assess for development of new symptoms, guide return to activities (eg, physical activity, school, employment), review routine and COVID-19 immunizations, and provide general anticipatory guidance
  • Telephone or virtual visit is appropriate for children with resolved symptoms after asymptomatic or mild disease (less than 4 days of fever higher than 38 °C and less than 1 week of myalgia, chills, or lethargy)
  • In-person visit is recommend for children with moderate disease (more than 4 days of fever higher than 38 °C; more than 1 week of myalgia, chills, or lethargy; and non-ICU hospital stay) or severe disease (ICU stay and/or intubation)

Complications

• Acute complications
  • Coinfection with other viruses and bacteria
    • Limited data suggest coinfection may occur in some children (6% to 18%) ^r50r60
    • 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 ^{r60c134c135c136}
  • Neurologic complications
    • Up to 20% of hospitalized children may develop neurologic manifestations; these manifestations are transient in most (over 88%) ^r98
    • Neurologic complications are more frequent in children with underlying neurologic disorders ^r18
    • Acute disseminated encephalomyelitis, acute transverse myelitis, Guillain-Barré, cerebral edema, demyelination, and stroke are among the possible life-threatening complications ^{r99c137c138c139c140c141c142}
  • Cardiovascular involvement
    • Myocarditis, pericarditis, heart failure, and arrhythmias are described ^{r100c143c144c145c146}
    • 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 ^r101
    • 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) ^r102
    • 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 ^r103
    • 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 ^r66
  • 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 ^r104
      • 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 ^r105
  • Ocular symptoms
    • Anterior uveitis, retinitis, and optic neuritis are among the serious but rare ocular complications encountered ^r21
  • 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 ^r13r106
  • 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 ^c147d13
    • Rare inflammatory condition that may develop about 2 to 6 weeks after acute COVID-19 infection ^r107
      • Reported to occur in approximately 0.1% of children with COVID-19 diagnosis ^r60
    • Inflammation may affect any organ but typically involves gastrointestinal system, skin, heart, brain, lungs, kidneys, and eyes
    • Elevated inflammatory markers and abnormal ECG or echocardiogram are common
    • Most MIS-C develops in previously healthy patients ^r60r107
      • 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 ^r108r109
    • Treatment involves initial resuscitation, immunomodulatory therapy (eg, IV immunoglobulin and corticosteroids), and antithrombotic therapy (eg, low-dose aspirin with or without anticoagulation) ^r6r48
• 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^r88 are still being determined ^r74
    • Long COVID is variously defined as having symptoms 4 or more weeks, 4 to 8 weeks, and 12 weeks after COVID-19 diagnosis; symptoms may be persistent from the time of acute infection or new symptoms may develop after an asymptomatic or mild acute illness ^r110c148
    • Although some studies have reported up to 66% of children have symptoms 4 or more weeks from diagnosis, studies with a control group suggest 1% to 4% of children may have long COVID-19, depending on age and definition ^r110r111
    • Limited evidence suggests that symptoms of long COVID-19 have resolved in 1 to 5 months in a majority of children ^r110r111
  • Long COVID symptoms in children may include respiratory, cardiovascular, neurologic, psychologic, and other symptoms ^r75c149
    • Many symptoms have been reported in children with and without evidence of COVID-19 infection and may be attributable to the pandemic itself (eg, loss of loved ones, changes in schooling, societal disruption, fear of illness and death for self and family, limitations of sports and social activities) ^r110r111
    • Most commonly reported symptoms that were significantly different from a control group without COVID-19 include fatigue, loss of smell and/or taste, respiratory difficulties, dizziness, muscle weakness, and chest pain ^r111
  • Some evidence indicates an increase in the incidence of new-onset type 1 diabetes following COVID-19, an increased frequency of diabetic ketoacidosis at the 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 ^r112r113
• Indirect complications of coronavirus pandemic are numerous and include, but are not limited to, higher rates of psychiatric morbidities, loss of education, unhealthy lifestyle changes, loss of caregivers, and increased child neglect ^r114
  • Global estimate of 5.2 million children have lost a parent or caregiver through October 31, 2021 ^r115
    • In the United States, an estimated 140,000 children lost a parent or caregiver grandparent through June 2021, with Black, Hispanic, and Native American children disproportionately affected; an additional 400,000 people in the United States have died of COVID-19 since then, undoubtedly adding to the total ^r116
  • American Academy of Pediatrics strongly advocates that the overarching goal is to keep students safe and physically present in school ^r117
    • Measures to mitigate risk of COVID-19 spread in schools include encouraging vaccination, testing when exposed or symptomatic, isolating when sick, wearing masks, and optimizing ventilation and disinfection measures
    • Vaccination of eligible individuals (eg, teachers, custodians, food service workers) helps to protect younger children who are not yet eligible for vaccination ^r34
  • CDC COVID-19 prevention strategies outline methods to mitigate risk of COVID-19 spread in schools ^r118r119

Prognosis

• In general, an excellent prognosis is expected for most children diagnosed with COVID-19 ^r19r60
  • 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 ^r19r22
• Overall, children experience less severe illness and fewer acute complications (eg, shock, acute respiratory distress syndrome) than adults, and fewer children require hospital admission ^r70r74
  • 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 ^r74
    • About half of children who require ICU level of care:
      • Have significant underlying comorbidity ^r114
      • Are aged 12 to 17 years (among children aged 0-17 years) ^r34
  • Hospitalization requirements in the United States
    • Highest rates of hospitalization occur among children younger than 4 years and aged from 12 to 17 years ^r34r120
    • An estimated 2% of pediatric patients^r74 require hospital admission; median length of hospitalization is from 2 to 3 days^r34
• Severe infection
  • Most children who develop severe infection have underlying comorbid medical conditions (eg, obesity, chronic cardiopulmonary disease, diabetes) ^r74
  • Most severe cases involve severe respiratory disease (71%) and a minority involve severe cardiac (less than 3%) or cardiopulmonary disease (about 9%) ^r99
• Cardiac morbidity
  • Children with severe COVID-19 and reduced left ventricular systolic function
    • Cardiac dysfunction normalizes in approximately 91% of children within 30 days ^r99
  • Children with MIS-C and coronary artery aneurysm
    • Coronary arteries normalize in approximately 79% of children within 30 days ^r99
• Mortality
  • Overall mortality is estimated to be less than 0.04% in children diagnosed with COVID-19 ^r60r74
  • Mortality is estimated to be approximately 1.6% among children with severe COVID-19 or MIS-C ^r99
  • 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 ^r121
    • Patients who are Hispanic, Black, and American Indian/Alaska Native ^r121
    • 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 ^r43r123d12
      • Represents a key intervention in prevention of disease in all age groups
      • FDA has authorized use of mRNA vaccines, either Pfizer or Moderna, in children 6 months and older, as of June 17, 2022. CDC recommendations are in place for use of Pfizer-BioNTech vaccine in children aged 5 years and older; revised CDC recommendations based on broadened FDA Emergence Use Authorization are pending ^r124
      • CDC recommends vaccination of children 5 years and older with Pfizer-BioNTech vaccine ^r43r125r126
        • For most children aged 5 to 17 years, primary series is 2 doses of Pfizer separated by 3 to 8 weeks ^r43
        • For moderately to severely immunocompromised children, a third primary dose of Pfizer is recommended 4 weeks after second dose ^r43
      • Safety and efficacy data among children are reassuring and favorable ^r127r128
        • Vaccine efficacy against severe disease, hospitalization, and death continues to be strong even against Omicron variant, similar to adults ^r127
        • Reported side effects are mild and self-limited; most common side effect is sore arm ^r128
        • Myocarditis has been reported following vaccination, particularly in male patients aged 12 to 39 years ^r43
          • Risk of myocarditis from COVID-19 (or MIS-C) is dramatically higher than that from the vaccine
          • Risk of vaccine-associated myocarditis may be decreased by lengthening the interval between first and second doses to 8 weeks
      • Booster doses after completion of primary series
        • A booster dose of Pfizer vaccine is FDA-approved and CDC-recommended for patients aged 5 years and older ^r43r129
          • All children aged 5 years and older are recommended to have a booster dose 5 months or more after the primary series
          • Moderately to severely immunocompromised children aged 12 years and older should have a second booster 4 months or more after the first booster
        • Data suggest that a booster dose broadens and strengthens protection against Omicron and other SARS-CoV-2 variants ^r127
          • Booster dose decreases risk of severe disease, hospitalization, and death from COVID-19 in adults; data on children and adolescents are more limited due to later timing of implementation of boosters
          • During predominance of Omicron variant, COVID-19 booster dose among adolescents aged 16 and 17 years (the first group for whom booster doses were recommended) improved protection against the need for emergency department or urgent care visits from 45% (after 2 doses) to 81% (after booster) ^r127
          • Similarly, vaccine effectiveness against symptomatic infection among adolescents aged 12 to 15 years, which waned over the course of 5 months since second primary dose, increased to 71% after booster ^r130
          • Duration of immunity following booster doses is not yet known
      • 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 ^r34r43
          • Hospitalization rates were about 10 times higher among unvaccinated adolescents during period of Delta SARS-CoV-2 variant predominance ^r120
          • Among pediatric patients requiring hospitalization, ICU admission requirement remained stable during period of Delta SARS-CoV-2 variant predominance ^r120
          • High degree of protection against emergency department visits, hospitalizations, and critical illness remains during Omicron variant predominance ^r127
        • Estimated uptake data in the United States as of May 23, 2022 ^r5
          • About 36% of children aged 5 to 11 years have received atleast 1 dose of COVID-19 vaccine, and 29% are fully vaccinated
            • FDA granted EUA for Pfizer vaccine for 5- to 11-year age group on October 29, 2021, and CDC approved its use on November 2, 2021
          • About 69% of adolescents aged 12 to 17 years have received atleast 1 dose of COVID-19 vaccine, and 59% of adolescents in this age group are fully vaccinated
            • FDA granted EUA 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 EUA 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 ^r43
        • 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
        • CDC guidance notes that benefits for vaccination most likely outweigh risks when MIS-C occurred before patient received any dose of COVID-19 vaccine, particularly when the following criteria are met:
          • High COVID-19 community level, or increased risk of exposure to SARS-CoV-2
          • Clinical recovery (including return to normal myocardial function)
          • 90 days or more have elapsed since MIS-C diagnosis
        • Continuing vaccination may also outweigh the risks in some patients who developed MIS after vaccination was initiated
          • If the above 3 criteria are met and MIS occurred 90 days or more after the most recent dose of vaccine
          • If MIS occurred within 90 days of vaccination, consider deferring additional doses until more evidence is obtained or consult with Clinical Immunization Safety Assessment COVIDvax project^r131
      • Vaccine-related resources for caregivers and families
        • American Academy of Pediatrics: COVID-19 vaccine campaign toolkit^r132 and information on COVID-19 for parents^r68 in English and Spanish
        • Department of Health and Human Services information about COVID-19 ^r133
        • CDC: COVID-19 vaccination resources ^r134
    • Preexposure prophylaxis with monoclonal antibodies ^r6r38
      • 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 EUA 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-cilgavimab
        • Efficacy of tixagevimab-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 ^r38
        • Use is not authorized by FDA in unvaccinated individuals for whom COVID-19 vaccination is recommended
    • Postexposure prophylaxis with monoclonal antibodies
      • Previously, bamlanivimab-etesevimab or casirivimab-imdevimab were used as postexposure prophylaxis for some individuals; however, they have diminished efficacy against the Omicron variant and subvariants, and there are currently no options for postexposure prophylaxis ^r6
  • Nonpharmacologic interventions for prevention of infection ^r15
    • Proper use of face masks (eg, covering nose and mouth in individuals aged 2 years and older, particularly when physical distancing is not possible)
    • Testing and quarantine
      • Testing (eg, polymerase chain reaction, nucleic acid amplification, antigen) is recommended for everyone with symptoms that may be COVID-19, for those with exposure, before gatherings, and as screening for certain workplaces, schools, and travel destinations ^r122
      • Quarantine in instances of possible infection after close contact exposure to SARS-CoV-2 ^r32
        • Close contact exposure is defined as being within 6 feet for 15 minutes or more over a 24-hour period to someone with COVID-19
        • Quarantine measures after exposure for individuals without full vaccine-imparted immunity (ie, unvaccinated patients and patients not yet boosted after more than 5 months has elapsed from last dose of primary mRNA series or more than 2 months after Johnson and Johnson vaccine) ^r32
          • Quarantine for 5 days then strict mask use for an additional 5 days
          • If quarantine is absolutely not feasible, it is imperative to use well-fitting mask at all times when around others for 10 days after exposure
          • Testing at least 5 days after last exposure if no symptoms or immediately if symptoms develop
        • Measures for exposed individuals who are fully vaccinated and have received booster within appropriate time frame
          • No quarantine is necessary
          • Recommend mask wearing for 10 days after exposure
          • Testing at least 5 days after last exposure if no symptoms or immediately if symptoms develop
            • If symptoms develop, begin immediate quarantine until negative test result confirms symptoms are not attributable to COVID-19
    • Physical distancing
    • Improve ventilation
    • Diligent hand and cough hygiene
      • Recommend supervised use of hand sanitizers for young children. Keep hand sanitizers containing alcohol out of their reach; ingesting a small amount can cause significant toxicity
      • Avoid touching face and mucous membranes
    • Disinfect frequently touched surfaces
    • Hospital protocols include: ^r45
      • 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