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Mar.09.2022

COVID-19 in Children

Synopsis

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

Terminology

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

Diagnosis

Clinical Presentation

History

  • Exposure to someone with laboratory-confirmed or probable SARS-CoV-2 infection may be elicited
    • Highest risk exposure includes close contact, defined as being within 6 feet for at least 15 minutes or more within a 24-hour period; direct physical contact (eg, hugging, kissing); sharing food or drink or eating/drinking utensils; or direct exposure to respiratory droplets from coughing or sneezing r16
    • Incubation period is the same as in adult patients; that is, about half of pediatric patients develop first symptom by 4 to 5 days after exposure (range, 2-14 daysr13) r16
  • Presenting patterns among infected children vary
    • Asymptomatic infection may occur in up to half of children r17r18
    • In children who develop symptoms, fever, cough, and sore throat are the most common presenting symptoms
    • Common presenting clinical syndromes include acute respiratory infection, asthma exacerbation, influenzalike illness, isolated fever, gastroenteritis, and vomiting r19
    • Several nonspecific symptoms may occur at once or over the course of illness. Manifestations also may be limited to predominantly 1 system (eg, only upper respiratory symptoms, only gastrointestinal symptoms)
    • Patients with underlying medical conditions may present with concomitant worsening of underlying disease (eg, diabetic ketoacidosis, acute chest syndrome)
  • Course of illness
    • Most children experience mild illness with full recovery within 1 to 2 weeks after onset of symptoms r20
    • Rarely, rapid progression to severe illness with hypoxia, respiratory distress, or shock is observed within first few days of illness r2
    • In some children, a sudden worsening of manifestations (eg, dyspnea, cyanosis) may occur after about a week of minor symptoms r2r3
  • Most common symptoms include: r21
    • Fever
      • May be low-, moderate-, or high-grade
      • Typical duration of fever is 1 to 2 days, but fever may last up to a week during acute infection in a minority of children r2
    • Cough
  • Additional common symptoms may include:
    • General
      • Fatigue, myalgia, poor appetite, and poor feeding
    • Ears, nose, and throat
      • Sore throat
      • Nasal congestion and rhinorrhea
      • New loss of taste or smell (difficult to elicit in young children)
    • Gastrointestinal
      • Abdominal pain, vomiting, and diarrhea
    • Respiratory
      • Shortness of breath and difficulty breathing
    • Neurologic
      • Headache is particularly common
      • Mental status changes and seizures suggest significant underlying neurologic complications
    • Dermatologic
      • Polymorphous rashes
    • Ocular
      • Symptoms consistent with conjunctivitis, usually with watery discharge

Physical examination

  • Vital signs are typically within reference range except patient may have fever (common)
  • Tachycardia, tachypnea, and diminished oxygen saturation may be present with increasingly severe disease
  • Respiratory distress (grunting, flaring, accessory muscle use) and lower airway findings (crackles) may be evident with significant pulmonary involvement
  • Signs of dehydration (eg, dry mucous membranes, delayed capillary refill) may be present with volume depletion
  • Conjunctivitis with conjunctival hyperemia and chemosis may be present in a minority of patients r22
  • Dermatologic lesions may be present in a minority of patients. The most common findings include maculopapular, urticarial, and vesicular lesions as well as chilblainlike acral lesions and transient livedo reticularis r23

Causes and Risk Factors

Causes

  • Infection with SARS-CoV-2 causes COVID-19 disease
  • Incidence
    • True incidence in children is not definitively known r13
  • Transmissibility
    • Primary modes of transmission include contact, large respiratory droplet, and occasionally small respiratory droplet via airborne spread
      • Airborne transmission may occur with prolonged exposure in closed spaces with poor ventilation and high concentration of aerosolized particles (eg, forced expiration during exercise or singing) r16
      • Transmission through contact with contaminated surfaces is considered to be infrequent r16
      • Although vertical transmission is feasible, it is considered rare. Most neonates are thought to acquire infection primarily in the postnatal period when exposed to respiratory droplets from caregivers r10
      • Virus is detectable in stool specimens; however, replication competent virus has not been isolated from stool samples r16
    • Period of infectivity
      • Infected patients are contagious about 1 to 2 days before onset of symptoms. Patients are most contagious at symptom onset, then contagiousness declines gradually over the course of several days r24
      • Most transmission generally occurs from about 1 to 2 days before to 2 to 3 days after symptom onset r24
      • Patients with mild to moderate COVID-19 remain infectious no longer than 10 days after symptom onset r13
      • Patients who are immunocompromised and have severe COVID-19 remain infectious no longer than 20 days after symptom onset r13

Risk factors and/or associations

Age
  • Preterm neonates (less than 37 weeks of gestation) and neonates with significant underlying comorbidity may be at higher risk for severe infection than full-term and otherwise healthy neonates r10
  • Children younger than 2 yearsr6 and adolescents older than 12 yearsr25 experience highest rates of hospitalization
Ethnicity/race
  • Hispanic/Latinx and Black children in the United States experience the highest hospitalization rates r13
Other risk factors/associations
  • Risk factors for severe disease
    • Data are limited. Preliminary data suggest that risk factors may include:
      • Age
        • Infants younger than 1 year r26r27
        • Older teenagers r6
      • Significant medical comorbidity r27r28r29r30
        • Obesity (BMI of 85th percentile or greater)
        • Immunosuppressive disease or receipt of immunosuppressive therapy
        • Medical complexity (including genetic, neurodevelopmental, and metabolic conditions)
        • Medical-related technologic dependence unrelated to COVID-19 (eg, tracheostomy, positive pressure ventilation, gastrostomy)
        • Sickle cell disease
        • Significant cardiopulmonary disease (eg, congenital heart disease, acquired heart disease, chronic lung disease, asthma or any other chronic respiratory disease that requires daily medication for control)
        • Diabetes
        • Chronic kidney disease
        • Chronic liver disease
        • Pregnancy
  • Limited data from retrospective chart review in a small series suggest factors associated with pediatric ICU admission requirement and risk for organ dysfunction, as follows: r31
    • Significant associations with admission to pediatric ICU include:
      • Age older than 12 years
      • Higher initial C-reactive protein level (median, 54 mg/L in pediatric ICU group versus 9 mg/L in adult ICU group)
    • Significant risk factors for organ dysfunction include:
      • Higher C-reactive protein level (median, 110 mg/L in organ dysfunction group versus 14 mg/L in non–organ dysfunction group)
      • Leukocytosis (median WBC count, 15,700 cells/μL in organ dysfunction group versus 7800 cells/μL in non–organ dysfunction group)
      • Thrombocytopenia (median, 149,000 cells/μL in organ dysfunction group versus 268,000 cells/μL in non–organ dysfunction group)

Diagnostic Procedures

Primary diagnostic tools

  • Suspect COVID-19 diagnosis based on clinical presentation with manifestations consistent with possible COVID-19 or SARS-CoV-2
    • While workup is in progress, implement early and maintain strict transmission-based precautions for any patient with concern for SARS-CoV-2 infection:
      • Minimum health care facility transmission–based precautions include using contact and droplet precautions, as well as airborne precautions during aerosol-generating procedures r32
      • Standard precautions include use of gown, gloves, and N95 respirator with eye protection (goggles or face shield) or air purifying respirator that provides eye protection
  • Confirm diagnosis of infection by detecting viral nucleic acid (nucleic acid amplification test) or protein (antigen test) on respiratory specimen r13
  • Guidelines for SARS-CoV-2 testing
    • Infectious Diseases Society of America recommends nucleic acid amplification testing for the following: r33
      • All symptomatic individuals suspected of having COVID-19
      • Asymptomatic individuals with known or suspected contact with a person with COVID-19
      • Asymptomatic individuals whose test results will impact isolation, quarantine, and personal protective equipment usage decisions; dictate eligibility for surgery; or affect administration of immunosuppressive therapy
    • CDC recommends that school-aged children be prioritized for testing in the following scenarios: r13
      • Signs or symptoms of COVID-19 and 1 of the following:
        • Close contact (within 6 feet for 15 minutes or more within a 24-hour period) with someone who has laboratory-confirmed or probable SARS-CoV-2 infection
        • Increased likelihood for exposure (eg, living in or visiting a community with substantial transmission)
      • Known exposure to someone with laboratory-confirmed or suspected SARS-CoV-2 infection r24
        • CDC's best practice recommendation is to obtain a test at day 5 after exposure, when feasible
        • Quarantine measures for individuals without full vaccine-imparted immunity (ie, unvaccinated patients and patients not yet boosted after more than 6 months has elapsed from last dose of primary mRNA series or more than 2 months after Johnson and Johnson vaccine)
          • 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
        • Measures for 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
          • If symptoms develop, begin immediate quarantine until negative test confirms symptoms are not attributable to COVID-19
  • Additional laboratory evaluation and imaging may be necessary as indicated by clinical presentation
    • Additional laboratory tests
      • Patients for whom there is concern for severe disease or for disease complications (eg, MIS-C [multisystem inflammatory syndrome in children], myocarditis): additional tests are needed
      • Clinically unwell patients and those with more than moderate COVID-19 illness: obtain basic set of ancillary laboratory tests: r4
        • CBC with differential
        • Inflammatory markers (eg, erythrocyte sedimentation rate and levels of C-reactive protein, procalcitonin, lactate dehydrogenase, and ferritin)
        • Liver function tests
        • Renal panel (BUN, creatinine) with glucose level
        • Electrolyte levels (including calcium, magnesium, and phosphate)
      • Patients for whom there is clinical concern for alternative diagnosis (eg, sepsis) and those who have complications and severe COVID-19:
        • If clinically unwell and sepsis or bacterial infection is of concern: appropriate blood cultures and other specimens r4
        • If myocardial involvement is of clinical concern: levels of troponin and N-terminal pro–B-type natriuretic peptide r4
        • If there is clinically indicated need for coagulation screening (prothrombin time, partial thromboplastin time, INR, D-dimer, fibrinogen), blood gas levels, and lactate level r4
    • Chest imaging
      • Not usually necessary in most children who have lower respiratory tract infection from COVID-19 r34
      • Chest radiograph results often do not change clinical management or outcomes, and imaging poses risk to infection control measures r34
      • Indications for chest radiograph are based on medical necessity and are similar to general clinical indications for chest radiograph in children (eg, concern for community-acquired pneumonia or worsening of respiratory status)
      • Point of care chest ultrasonography is an acceptable alternative to chest radiograph for investigating pneumonia, when indicated and available r4
    • ECG and echocardiogram
      • Obtain if cardiac concerns are present clinically
  • In children infected with SARS-CoV-2, maintain a broad differential to evaluate for additional conditions, which may present concomitantly r13
    • These additional conditions include diabetic ketoacidosis, intussusception, community-acquired pneumonia, streptococcal pharyngitis, and influenza
    • Proceed with standard evaluation for potential co-occurring conditions while maintaining appropriate infection control measures

Laboratory

  • SARS-CoV-2 testing on respiratory specimens
    • Specimen sources
      • For upper respiratory specimens, nasopharyngeal swabs are preferred. Other sources include throat swab and saliva specimens r4
      • Occasionally, lower respiratory tract specimens may be used (eg, from bronchoalveolar lavage, sputum, endotracheal aspirates) r4
    • Nucleic acid amplification testing
      • Reverse transcription polymerase chain reaction for SARS-CoV-2 RNA
        • This is the platform most commonly used to detect viral RNA
        • Test characteristics to detect SARS-CoV-2 from nasopharyngeal swabs
          • Pooled sensitivity is about 83% r35
          • Pooled specificity is about 99% r35
        • Test does not differentiate between viable and nonviable virus
          • Otherwise healthy recovered patients may shed detectable SARS-CoV-2 RNA (in small concentrations) in upper respiratory specimens up to 3 months after onset of illness r13
          • Replication-competent virus is not reliably recovered and infectiousness is unlikely after 10 days from symptom onset in otherwise healthy patients
        • Nucleic acid amplification testing that generates presumptive results are not appropriate for use as confirmatory testing r36
    • Antigen testing
      • Alternative rapid testing modality primarily used outside health care settings r33
      • Antigen testing is useful to diagnose acute SARS-CoV-2 infection in symptomatic patients
      • Test characteristics
        • Specificity is high for most assays (over 99%) r37
        • Sensitivity is highly variable depending on several factors including specific antigen platform used
          • Sensitivity is highest when viral loads are higher (eg, first week of illness) and higher among symptomatic patients r37
          • Sensitivity of antigen testing typically is about 30% to 40% lower than it is in nucleic acid amplification testing r33
      • Disadvantage compared with nucleic acid amplification testing is risk of false negative in an infected individual with a low viral load early in illness. Serial testing can help diminish false negatives in such cases r33
      • Advantage compared with nucleic acid amplification testing is lower likelihood of detecting residual non–replication-competent viral RNA remaining from a remote infection in recovered patient r33
      • Confirmatory nucleic acid amplification testing may be necessary in the following scenarios: r33
        • Positive antigen test result when pretest probability of virus is low (eg, asymptomatic, low prevalence setting)
        • Negative antigen test when pretest probability is high (eg, symptomatic, close contact with person who tested positive)
      • CDC provides algorithms for antigen testing strategy in congregate and community settings r36
      • Test does not differentiate between viable and nonviable virus r37
  • SARS-CoV-2 serology
    • Seroconversion takes up to 2 weeks from symptom onset in most patients; therefore, antibody testing is more likely to be useful for detecting previous SARS-CoV-2 infection 15 days or more into the course of illness r38r39
    • Serology has the most clinical utility in children during workup for MIS-C to document previous viral exposure
    • When indicated, measure anti–SARS-CoV-2 IgG or total antibody. Fractionating to identify IgM component is not helpful because IgM typically develops somewhat simultaneous to IgG production in response to SARS-CoV-2 infection r39
    • Sensitivity of tests that measure IgG is estimated at 97% and specificity at 98% in appropriately timed, collected, and processed specimens; however, degree of cross-reactivity with other coronaviruses is largely unknown r39r40
    • Patients with severe illness may experience a delay in seroconversion but overall antibody response appears to be more robust than in patients with less severe illness course r39
    • Duration that antibodies are detectable is uncertain r33
  • Routine blood work is not diagnostic, but patterns of typical abnormalities are noted, particularly among patients with severe disease
    • WBC count
      • Leukocyte count within reference range is noted in about 70% of pediatric patients with COVID-19 r41
      • Mild abnormalities in WBC count may be noted, including increased or decreased leukocyte and lymphocyte counts
    • Inflammatory markers
      • Mildly elevated markers of inflammation (eg, erythrocyte sedimentation rate, C-reactive protein, ferritin, l-lactate dehydrogenase, D-dimer, interleukin-6) are common, including slight elevation of procalcitonin
      • Marked elevation of procalcitonin suggests possible concomitant bacterial infection r23
      • Marked elevation in markers of inflammation suggests possibility of severe disease and MIS-C r23
      • Mean C-reactive protein in patients requiring admission is estimated at approximately 9 mg/L r31
    • Liver function tests
      • Mild elevation is common

Imaging

  • Chest imaging
    • Findings on chest imaging in patients with COVID-19 are, in general, nonspecific, overlapping with those of other infections r34
    • Chest radiograph
      • Unilateral or bilateral patchy findings are common
      • Roughly one-third of chest radiographs are normal, one-third demonstrate focal consolidations, and the remainder exhibit ground-glass opacities r42r43
      • Lower and peripheral zones are often affected r39
      • Pleural effusion is an infrequent finding r2
    • Lung ultrasonogram
      • May be useful in facilities with experience using this modality for diagnosis, monitoring, and follow-up r39
      • Possible findings include multiple B lines, irregular thickened pleural line with scattered discontinuities, and subpleural and alveolar consolidation with resolution and improvement in aeration during recovery (ie, reappearance of bilateral A lines) r39
    • Chest CT
      • Not routine but may be required for a subset of hospitalized, symptomatic patients with specific indications for chest CT r34
      • Low-dose CT imaging protocol is preferred for pediatric patients to reduce radiation exposure r44
      • Findings are often milder and more focal as compared with adults
      • Most common abnormal findings include ground-glass opacities and consolidation with unilateral lower lobe predominance. Other reported findings include halo sign, pulmonary nodules, bronchial wall thickening, and crazy paving pattern r44
      • Bilateral lobar consolidation may be noted in children with severe disease r39
      • Peripheral distribution of findings is commonly reported r44
      • Effusion is infrequent
      • In 1 series, normal findings were noted in up to 27% of CT scans in children with COVID-19 r44

Differential Diagnosis

Most common

  • Upper respiratory tract infection in children d1
  • Community-acquired pneumonia in children d2
  • Bronchiolitis d3
  • Pharyngitis d4
  • Influenza d5
  • Respiratory syncytial virus d6
  • Mycoplasma d7
  • Legionnaires' disease (Legionella pneumophila) d8
  • Mycobacterium tuberculosisd9
  • Chlamydia pneumoniaed10
  • Blastomycosis d11
  • Histoplasmosis
  • Differential Diagnosis: COVID-19 in ChildrenNumerous pathogens responsible for pneumonia-type presentation may be considered in the differential diagnosis including viral, bacterial, and fungal pathogens as well as legionella and tuberculosis. Coinfection with more than a single pathogen may occur in up to 6% of patients with acute SARS-CoV-2 infection.Data from Miao H et al: Update on recommendations for the diagnosis and treatment of SARS-CoV-2 infection in children. Eur J Clin Microbiol Infect Dis. 39(12):2211-23, 2020; Perlman et al: Coronaviruses, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In: Bennett JE et al, eds: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020:2072-80.e5; Hoang A et al: COVID-19 in 7780 pediatric patients: a systematic review. EClinicalMedicine. 24:100433, 2020; and Iroh Tam PY: Approach to common bacterial infections: community-acquired pneumonia. Pediatr Clin North Am. 60(2):437-53, 2013.
    Disease conditionDescriptionDifferentiated by
    Viral pneumoniaNumerous viral pathogens may result in an identical presentation including influenza, respiratory syncytial virus, adenovirus, parainfluenza, rhinovirus, human metapneumovirus, and human bocavirus.

    Chest radiograph findings in patients with these pathogens may be quite similar to findings in those with acute COVID-19.
    Positive SARS-CoV-2 test result does not completely exclude the possibility of coinfection with 1 or more additional viral pathogens.

    Using clinical suspicion (eg, based on age, epidemiologic factors) to direct use of specific tests for additional viral pathogens can aid identification of additional and alternate viral pathogens. Multiplex nucleic acid amplification test panels (testing for multiple common pathogens in a single specimen) are available. Rapid antigen testing is available for some common pathogens (eg, respiratory syncytial virus, influenza).
    Atypical pneumonia Pneumonia caused by atypical organisms (eg, Mycoplasma pneumonia, Chlamydia pneumoniae) may have a similar presentation with fever, cough, tachypnea, difficulty breathing, and possibly hypoxia.

    Chest radiograph findings may be quite similar to those noted in patients with acute COVID-19.
    Positive SARS-CoV-2 testing does not completely exclude the possibility of coinfection with atypical organism.

    Improvement with empiric treatment for presumed atypical pneumonia may be consistent with the diagnosis.

    Diagnosis is confirmed by clinical presentation and clinical course in most cases.

    Demonstration of pathogen by nucleic acid amplification test is possible with polymerase chain reaction testing of respiratory specimens. Multiplex nucleic acid amplification test panels (testing for multiple common pathogens in a single specimen) are available.
    Bacterial pneumonia Similar presentation with fever, cough, tachypnea, difficulty breathing, and possibly hypoxia.

    Chest radiographic findings may be quite similar to those noted in patients with acute COVID-19.

    Pathogen responsible for disease is highly dependent on child's age, presence of underlying comorbidities (eg, sickle cell, immunosuppression), and potential exposures (eg, travel, community exposures).
    Positive SARS-CoV-2 test result does not completely exclude the possibility of bacterial coinfection.

    Improvement with empiric treatment for presumed bacterial pneumonia may be consistent with the diagnosis.

    Diagnosis is confirmed by clinical presentation and clinical course in most cases.

Treatment

Goals

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

Disposition

Admission criteria

Admission decisions consider a combination of clinical presentation, supportive care requirement, underlying medical comorbidity, and caregiver's ability to provide home care

Admission is recommended for children with moderate COVID-19 symptoms (eg, clinical or radiographic evidence of lower airway disease) for supportive care and observation r4

Admit all children with severe COVID-19 for expedient management, preferably at a regional center with critical care and extracorporeal membrane oxygenation capability r4

Febrile neonates (most younger than 28 days) require admission for further diagnosis, management, and monitoring r45

Consider admitting children with mild disease and significant underlying comorbidity for management and close monitoring for clinical deterioration r23

Criteria for ICU admission
  • General ICU admission criteria apply: septic shock, cardiogenic shock, acute respiratory distress syndrome, need for advanced airway or ventilatory support, or multiple organ failure r4
  • Admit children with progressing severe disease and critical COVID-19 illness to pediatric ICU for expedient management, preferably at a regional center with extracorporeal membrane oxygenation capability r4

Recommendations for specialist referral

  • COVID-19 is a nationally notifiable disease; manage in consultation with public health authorities
    • Reporting of cases to the CDC is supported by routine case notification through the National Notifiable Diseases Surveillance System and resources provided through the CDC COVID-19 Response Team r46
  • Consult infectious disease specialist to coordinate diagnosis and management with public health authorities
  • Manage complications and severe or critical disease in consultation with appropriate specialty service (eg, pediatric pulmonologist, pediatric intensive care specialist)

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,r51r52r36WHOr53) 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 trialsr57 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 guidelinesr62 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 Societyr47
  • 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 Societyr28
    • 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 conflictingr72
    • 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

Drug therapy

  • Corticosteroids r6
    • Dexamethasone
      • Dexamethasone Oral solution; Children and Adolescents: The NIH guidelines recommend 0.15 mg/kg/dose (maximum dose of 6 mg) PO once daily for up to 10 days for pediatric patients requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO. Not routinely recommended for pediatric patients requiring only low oxygen support. Use in pediatric patients who are profoundly immunocompromised should be considered on a case-by-case basis.
  • Antiviral RNA-polymerase inhibitors
    • Remdesivir
      • Avoid in patients with ALT level more than 5 times the upper reference limit and when estimated GFR is less than 30 mL/minute/1.73 m² r23
      • Can consider shorter treatment duration in mild to moderate disease
        • Remdesivir Solution for injection; Neonates weighing 3.5 kg or more†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 2 days is suggested by the FDA in the Emergency Use Authorization (EUA).
        • Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 2 days is suggested by the FDA in the Emergency Use Authorization (EUA).
        • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 2 days is suggested by the FDA in the Emergency Use Authorization (EUA).
        • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more: 200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days. According to the NIH, up to 5 days of therapy may be considered for patients with new/increasing need for oxygen but who cannot be admitted to the hospital because resources are limited.
      • For admitted patients with COVID-19
        • Remdesivir Solution for injection; Neonates weighing 3.5 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
        • Remdesivir Solution for injection; Infants and Children 1 to 11 years weighing at least 3.5 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
        • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing less than 40 kg NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)†: 5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement.
        • Remdesivir Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
  • SARS-CoV-2 protease inhibitor antivirals
    • Nirmatrelvir-ritonavir r64
      • Do not use in severe hepatic impairment (Child-Pugh Class C).
      • Use with caution in preexisting liver disease.
      • Nirmatrelvir Oral tablet, Ritonavir Oral tablet; Children and Adolescents 12 years and older weighing 40 kg or more: 300 mg nirmatrelvir (two 150 mg tabs) and 100 mg ritonavir (one 100 mg tab) taken together by mouth twice daily for 5 days. Start as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset.
      • Reduce dose to 150 mg nirmatrelvir and 100 mg ritonavir PO twice daily when eGFR is at least 30 but less than 60 mL/minute.
        • Do not use when eGFR is less than 30 mL/minute.
  • Antiviral monoclonal antibodies for SARS-CoV-2
    • Bebtelovimab
      • Bebtelovimab Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more: 175 mg as a single intravenous injection. Administer as soon as possible after positive test for SARS-CoV-2 and within 7 days of symptom onset.
    • Sotrovimab r76
      • Sotrovimab Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more: 500 mg as a single IV infusion. Give as soon as possible after the positive test for SARS-CoV-2 and within 7 days of symptom onset.
  • Janus kinase (JAK) inhibitor
    • Baricitinib r77
      • Baricitinib Oral tablet; Children 2 to less than 9 years: 2 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
      • Baricitinib Oral tablet; Children and Adolescents 9 years of age and older: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines state there are insufficient data to recommend either for or against use in pediatric patients.
      • Reduce dose from 2 mg PO daily to 1 mg PO daily, and 4 mg PO daily to 2 mg PO daily, when eGFR is at least 30 but less than 60 mL/minute.
      • Reduce dose from 4 mg PO daily to 1 mg PO daily when eGFR is at least 15 but less than 30 mL/minute. Do not use in children aged 2 to less than 9 years when eGFR is less than 30 mL/minute.
      • Do not use when eGFR is less than 15 mL/minute.
      • Interrupt therapy if absolute lymphocyte count or absolute neutrophil count decreases to less than 200 cells/µL or 500 cells/µL respectively.
      • Interrupt therapy if AST or ALT increases and drug-induced liver injury is suspected.
  • Interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody
    • Tocilizumab r78
      • Tocilizumab Solution for injection; Children and Adolescents 2 years and older weighing 30 kg or more: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend for or against use in hospitalized children with COVID-19 or multisystem inflammatory syndrome.
      • Tocilizumab Solution for injection; Children and Adolescents 2 years and older weighing less than 30 kg: 12 mg/kg IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. According to the NIH COVID-19 treatment guidelines, data are insufficient to recommend for or against use in hospitalized children with COVID-19 or multisystem inflammatory syndrome.
      • Do not use with elevated ALT or AST above 10 times the upper limit of the reference range

Nondrug and supportive care

  • Measures intended to avoid secondary spread of virus from infected and potentially infected individuals
    • Quarantine in instances of possible infection after close contact exposure to SARS-CoV-2
      • 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 r13
      • CDC's recommended best practice is to obtain test for SARS-CoV-2 at day 5 after exposure for all individuals exposed, when feasible r24
      • Patients without full vaccine imparted immunity (ie, unvaccinated patients and patients not yet boosted after more than 6 months of time has elapsed from last dose of primary mRNA series or more than 2 months after Johnson and Johnson vaccine) r24
        • Quarantine for 5 days then strict mask use for an additional 5 days
        • If quarantine is absolutely not feasible, well-fitting mask use at all times when around others for 10 days after exposure is imperative
        • If symptoms develop, begin isolation measures and obtain immediate testing
      • Measures for individuals who are fully vaccinated and have received booster within appropriate time frame r24
        • No quarantine is necessary
        • Recommend mask wearing for 10 days after exposure
        • If symptoms develop, begin immediate quarantine until negative test confirms symptoms are not attributable to COVID-19
    • Use health care facility–based infection prevention and control measures for patient with suspected or confirmed SARS-CoV-2 infection r79
      • Precaution measures
        • Minimum required are standard, contact, droplet precautions, and airborne precautions during aerosol-generating procedures
        • Standard precautions include use of gown, gloves, and N95 respirator with eye protection (goggles or face shield) or air purifying respirator that provides eye protection
      • Patient placement
        • Preferred is single patient room with dedicated bathroom; close door when safe to do so
        • Limit patient transport outside of room
        • Best option is to dedicate a specific unit and individual health care providers to care for patients
      • Personal protective equipment
        • Adhere to standard precautions; use N95 or higher level respirator, gown, gloves, and eye protection
      • Aerosol generating procedures
        • Avoid procedures with potential to generate aerosols when alternatives exist (eg, medications delivered by metered dose inhaler in lieu of nebulized medications)
        • Cautiously perform procedures that have potential to generate aerosol in an airborne infection isolation room, when possible
      • Visitation
        • In general, it is preferred to limit in-person visitation; adhere to local, state, and federal regulations
      • Environmental infection controls
        • Use dedicated medical equipment (eg, stethoscope)
        • Maintain routine cleaning and disinfection procedures as per hospital protocol
        • Leave cell phones, laptops, and other devices outside room r4
    • COVID-19 isolation measures and transmission-based precautions for those infected with virus (with or without symptoms): r79
      • Most patients who are positive for COVID-19: use symptom-based strategy rather than test-based strategy (recommended). Exceptions include patients with severe immunocompromise and those with severe COVID-19 infection
      • Use the most severe degree of illness (mild to moderate, severe to critical) during clinical course of illness to determine isolation protocol/duration of transmission-based precautions
      • Patients with asymptomatic or symptomatic mild and moderate COVID-19 infection without severe immunocompromise
        • Isolate for 5 days and, if asymptomatic or if symptoms are resolving (without fever for 24 hours), follow that by 5 days of mask wearing when around others r24
      • Patients with severe to critical COVID-19 infection and patients who have moderate to severe immunocompromise:
        • Consult with infectious disease and infection control experts to determine criteria for discontinuing isolation measures and transmission-based precautions
        • Minimum symptom-based requirements for discontinuing isolation and precautions include all of the following:
          • At least 10 days and up to 20 days have passed since onset of first symptom
          • At least 24 hours have passed since last fever (without use of antipyretics)
          • Symptoms have improved
        • May require isolation and precautions for at least 20 days from onset of symptoms (or positive diagnostic test if asymptomatic)
          • Some immunocompromised patients remain infectious for 20 days or more after start of initial symptoms; rarely, replication-competent virus is recovered from severely immunocompromised patients months after initial positive SARS-CoV-2 test result
          • A minority of patients with severe and critical illness are infectious 15 days after onset of symptoms; replication-competent virus has not been detectable in patients with severe or critical illness after 20 days from onset of symptoms
        • Consider using test-based strategy of SARS-CoV-2 nucleic acid testing before discontinuing isolation and transmission-based precautions
          • Before discontinuing isolation measures, test-based strategy requires both of the following:
            • 2 consecutive negative reverse transcription polymerase chain reaction test results to detect SARS-CoV-2 RNA spaced 24 hours or more apart
            • Improvement in symptoms
    • Approach to empiric COVID-19 isolation and transmission-based precaution measures for patients with suspected COVID-19 (ie, rule out SARS-CoV-2 infection) admitted to health care facility r79
      • Empiric isolation and transmission-based precautions may be discontinued with negative results from at least 1 negative nucleic acid amplification test to detect SARS-CoV-2 RNA
      • A second negative test for SARS-CoV-2 RNA may be required if a high level of clinical concern exists for infection despite 1 negative test before clearing from isolation and other transmission-based precautions

Comorbidities

  • Children with immunodeficiency or immunocompromise
    • Consider managing in consultation with infectious disease specialist. COVID-19 treatment-specific therapies and pharmacotherapeutics may be indicated
    • On a case-by-case basis, consider using glucocorticoids to treat patients who have severe COVID-19 based on the theoretical risk of infection worsening in patients with significant immunocompromise r6
    • Consider risk and benefit of pharmacologic immune suppression in consultation with appropriate prescribing specialist to determine if temporary reduction in pharmacologic immunosuppression is warranted r23
      • Some experts recommend reducing T-cell immunosuppression, when applicable, in infected children r47
    • Isolation measures can be modified to 20 days (instead of 10 days for immunocompetent patients) after symptom onset and after resolution of fever and improvement of other symptoms r13
      • A test-based strategy requiring 2 negative tests for SARS-CoV-2 RNA before discontinuing isolation measures can be considered in consultation with infectious disease experts
    • A third dose of vaccine, after the 2-dose primary mRNA COVID-19 vaccine series, is recommended for patients aged 5 years and older with moderate to severe immunocompromise r15
  • Children at high risk for severe COVID-19
    • Consider management in consultation with an infectious disease specialist; COVID-19 treatment-specific therapies and pharmacotherapeutics may be indicated
  • Children with asthma
    • Avoid aerosol-generating procedures when possible. Consider administering respiratory medications via metered dose inhaler with spacer and/or dry powder inhaler (ie, Turbuhaler or Diskus) rather than nebulization r4
  • Children with croup
    • Consider early use of steroids in effort to prevent return visits to health care facility and reduce risk for admission r4
    • Avoid aerosol-generating procedures when possible; consider using epinephrine via metered dose inhaler with spacer or subcutaneous/intramuscular dosing instead of nebulized epinephrine when indicated for severe croup r4

Special populations

  • Neonates
    • Rate of infection in neonates does not appear to be affected by mode of delivery, method of feeding, or contact with mother with suspected or confirmed SARS-CoV-2 infection r10
    • Obtain nucleic acid amplification test result for SARS-CoV-2 in neonates born to mothers with suspected or confirmed COVID-19 at about 24 hours of life; repeat testing is recommended if initial test is negative at 48 hours of life r10
      • A single test between 24 and 48 hours of life is acceptable in asymptomatic infants who may be discharged to home before 48 hours of life r10
    • Maintain high suspicion for alternate and/or concomitant diagnosis responsible for symptoms (eg, temperature instability, cough, difficulty breathing) that may be suggestive of COVID-19 in neonates r10
    • Isolate mothers with suspected or confirmed SARS-CoV-2 infection and their neonates from healthy mothers and neonates r10
      • Rooming both neonate and mother together is recommended in most instances; CDC stresses importance of maternal autonomy in the decision making process
      • Avoid isolating neonates in neonatal ICU unless clinical condition warrants neonatal ICU care
    • Encourage measures to minimize risk of transmission, including general infection prevention and control measures (eg, hand hygiene, wearing a mask) by caregivers while breastfeeding and caring for neonate r10

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 and Prognosis

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 sequelaer71 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 patientsr58 require hospital admission; median length of hospitalization is from 2 to 3 daysr25
  • 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 and Prevention

Screening

At-risk populations

  • Intent of screening is to identify people infected with COVID-19 who are asymptomatic and do not have known, suspected, or reported exposure to SARS-CoV-2 r102
  • Examples of screening include testing of the following groups:
    • Unvaccinated students, faculty, and staff in school setting
    • Unvaccinated individuals before and after travel
    • Unvaccinated employees in a workplace setting
    • Home testing for an individual without symptoms associated with COVID-19 and no known exposure to someone with COVID-19
  • Unvaccinated children and adults are the primary at-risk populations

Screening tests

  • Viral nucleic acid amplification (eg, reverse transcription polymerase chain reaction) performed on upper respiratory specimen
  • Antigen test performed on upper respiratory specimen

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 toolkitr109 and COVID-19 vaccine for children resourcesr110
          • 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
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