COVID-19: Management in children

INTRODUCTION — Starting in late 2019, a novel coronavirus rapidly spread throughout the world, resulting in a global pandemic. The virus was designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the illness it caused coronavirus disease 2019 (COVID-19). The clinical spectrum of COVID-19 ranges from asymptomatic infection to mild respiratory tract symptoms to severe pneumonia with acute respiratory distress syndrome and multiorgan dysfunction.

Understanding of COVID-19 is evolving. The World Health Organization, the United States Centers for Disease Control and Prevention, the American Academy of Pediatrics, and other expert groups provide ongoing guidance for evaluation, management, and prevention. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

This topic will discuss the management of COVID-19 in children. The epidemiology and clinical features of COVID-19 that are specific to children, multisystem inflammatory syndrome in children, and COVID-19 in pregnancy are discussed separately:

●(See "COVID-19: Clinical manifestations and diagnosis in children".)

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

●(See "COVID-19: Overview of pregnancy issues".)

●(See "COVID-19: Antepartum care of pregnant patients with symptomatic infection".)

●(See "COVID-19: Intrapartum and postpartum issues".)

In addition, please refer to our COVID-19 homepage to view the complete list of UpToDate COVID-19 topics.

ASSESSMENT OF SEVERITY — We use the definitions of severity provided in the multicenter interim guidance on the use of antivirals for children with COVID-19 (table 1) [1]:

●Mild or moderate disease – No new or increased supplemental oxygen requirement

●Severe disease – New requirement for supplemental oxygen or increased requirement from baseline without new or increased need for ventilatory support (noninvasive or invasive)

●Critical disease – New or increased need for noninvasive or invasive mechanical ventilation, sepsis, multiorgan failure, or rapidly worsening clinical trajectory

GENERAL MANAGEMENT CONSIDERATIONS

Management of chronic medications

●NSAIDs – Nonsteroidal anti-inflammatory drugs (NSAIDs) that are used chronically for other conditions may be continued unless there are other reasons for discontinuation (eg, gastrointestinal bleeding, renal injury) [2-4]. Despite initial concerns about the safety of NSAIDs in patients with COVID-19 [5,6], in a meta-analysis of 11 observational studies (>683,000 participants), exposure to NSAIDs was not associated with increased risk of SARS-CoV-2 infection, severe/critical COVID-19 disease, or all-cause mortality [7].

●Asthma medications – Considerations related to the safety of glucocorticoid and nebulized medications for children with asthma are discussed separately. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic'.)

●ACE inhibitors and angiotensin receptor blockers – Children receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents if there is no other reason for discontinuation (eg, hypotension, acute kidney injury) [8]. This approach is supported by multiple guideline panels [9-13].

Although there has been speculation that patients with COVID-19 who are receiving ACE inhibitors or ARBs may be at increased risk for adverse outcomes, the hypothesis is not supported by findings from observational studies. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

●Immunosuppressive therapy – For children receiving immunosuppressive therapy, we discuss the benefits and risks of reducing immunosuppressive therapy with the prescribing specialist (eg, oncologist, transplant clinician, rheumatologist, gastroenterologist). Although the relationship between immune compromise and severe COVID-19 disease has not been well established in children [14,15], management of viral infections in immunocompromised hosts typically includes reduction of baseline immunosuppression, if reduction is possible [16,17]. Information about adjusting immunosuppressive therapy for specific conditions is presented separately. (See "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression'.)

Management of multisystem inflammatory syndrome in children — The management of multisystem inflammatory syndrome in children is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Management'.)

Management of possible coinfection with influenza — Recommendations for antiviral therapy for influenza infection in children are unchanged during the COVID-19 pandemic [2]. If indicated, antiviral therapy for influenza can be initiated while awaiting laboratory results. If initiated, antiviral therapy can be discontinued when influenza has been excluded through molecular testing. Antiviral therapy and laboratory testing for influenza are discussed separately. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy' and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Diagnosis'.)

INDICATIONS FOR HOSPITALIZATION — Indications for hospitalization in children with COVID-19 include:

●Severe or critical lower respiratory tract disease (table 1)

●Nonsevere disease with underlying conditions that increase the risk of severe disease (eg, immune compromise)

●Fever in infant younger than 30 days

MANAGEMENT OF HOSPITALIZED CHILDREN

Supportive care for all patients — We provide supportive care for all pediatric patients with COVID-19 as recommended by various national committees [1,2,18]. Supportive care is the mainstay of therapy for patients with severe or critical COVID-19 [19]. Most children with COVID-19 improve with supportive care, even those with severe disease [1]. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Society guideline links'.)

Routine supportive care measures include:

●Provision of respiratory support, including supplemental oxygen and ventilatory support (noninvasive or invasive); respiratory status may change suddenly after approximately one week of symptoms [20]. (See "Initial assessment and stabilization of children with respiratory or circulatory compromise" and "Technique of emergency endotracheal intubation in children".)

●Provision of fluid and electrolyte support. (See "Fluid and electrolyte therapy in newborns" and "Clinical assessment of hypovolemia (dehydration) in children" and "Treatment of hypovolemia (dehydration) in children in resource-abundant settings".)

●Provision of empiric antibiotics as indicated for community-acquired or health care-associated pneumonia; continuation of empiric antibiotics should be determined by cultures and other microbial tests and clinical condition. Bacterial coinfections at the time of presentation appear to be infrequent [21,22]. (See "Pneumonia in children: Inpatient treatment".)

●Monitoring for cytokine release syndrome by monitoring blood pressure for hypotension, oxygen saturation for worsening hypoxemia, and biomarkers.

•We obtain baseline C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase (LDH), and interleukin-6 (IL-6).

•We monitor CRP, D-dimer, ferritin, and LDH two or three times per week or if there is concern for worsening disease.

●Provision of thromboprophylaxis – Interventions to reduce the risk of venous thromboembolism (VTE) may be warranted for children hospitalized with COVID-19 [23,24].

We encourage nonpharmacologic strategies for VTE prophylaxis (eg, intermittent pneumatic compression devices [size permitting] and early mobilization).

For hospitalized children without multisystem inflammatory syndrome in children (MIS-C), we make decisions about pharmacologic VTE prophylaxis on a case-by-case basis, considering other VTE risk factors (table 2) and the child's risk of bleeding. The pharmacologic approach to VTE prophylaxis in hospitalized children is discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis'.)

The risk of thrombotic complications in children with COVID-19 has not been well defined. In two multicenter cohort studies (one from the United States, the other from Spain, each including >400 patients), between 1 and 2 percent of children hospitalized with SARS-CoV-2 (excluding children with MIS-C) had thrombotic complications (eg, deep vein thrombosis of the upper or lower extremity, pulmonary embolism, intracardiac thrombosis, cerebral sinovenous thrombosis) [25,26]. Most of the patients with thrombotic complications were ≥12 years of age; many had risk factors for thrombosis, and some received thromboprophylaxis before developing thrombosis. Underlying risk factors for thrombosis included cancer, obesity, critical illness, and central venous catheter. The usefulness of D-dimer >5 times the upper limit of normal as a predictor of thrombosis was inconsistent.

The risk of VTE in children with MIS-C and VTE prophylaxis for children with MIS-C are discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Antithrombotic therapy'.)

SARS-CoV-2 antiviral therapy for select patients — Given the lack of data from controlled trials supporting the efficacy of antiviral agents for the treatment of COVID-19 in children [27], we agree with recommendations from the multicenter interim guidance on the use of antiviral agents for children with COVID-19 and other experts that antiviral therapy should be considered on a case-by-case basis and preferably occur in the context of a clinical trial, if a clinical trial is available [1,28]. Information about ongoing clinical trials is available from ClinicalTrials.gov.

Antiviral therapy for COVID-19 should be reserved for children with documented SARS-CoV-2 infection if testing is available [1].

●Potential indications – Decisions to use antiviral therapy should be individualized according to disease severity, clinical trajectory, existing evidence of effectiveness, and underlying conditions that may increase the risk for progression. Studies of the effectiveness and safety of antiviral therapy have predominantly been performed in adults with severe lower respiratory tract disease [29-31]; these studies are discussed in detail separately. (See "COVID-19: Management in hospitalized adults", section on 'Specific treatments'.)

Despite the unproven benefits, we suggest antiviral therapy for children with documented severe or critical COVID-19. Antiviral therapy also may be warranted for children with mild or moderate disease and an underlying condition that increases or may increase the risk of severe disease (eg, medical complexity, congenital heart disease, among others). (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Risk factors for severe disease'.)

●Choice of agent/regimen

•Remdesivir – Remdesivir is a prodrug of a nucleotide analog that inhibits ribonucleic acid (RNA)-dependent RNA polymerase and has activity against coronaviruses [32-35].

When a decision is made to use antiviral therapy in a child who cannot be enrolled in a clinical trial, we suggest remdesivir rather than other antiviral agents, in agreement with the multicenter panel [1]. Although data regarding the benefits of remdesivir for children with COVID-19 are limited, it is preferred to other antiviral agents because data from randomized and observational studies in adult patients suggest that it may reduce time to recovery (particularly in patients who are not critically ill); it appears to be well tolerated [1,36-45]. Studies of remdesivir in adult patients with COVID-19 are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Remdesivir'.)

When the supply of remdesivir is limited, it should be prioritized for patients who do not require ventilation (invasive or noninvasive); the benefits for those who require ventilation are uncertain [2,46]. (See 'Assessment of severity' above.)

The optimal role of remdesivir in patients with COVID-19 remains uncertain, and some experts suggest not using it in hospitalized patients [47,48]. In the United States, remdesivir has been approved by the US Food and Drug Administration (FDA) for the treatment of both hospitalized and nonhospitalized COVID-19 in adults and children ≥28 days of age who weigh ≥3 kg [49,50].

Remdesivir is dosed according to weight as follows [50]:

-≥3 to <40 kg – 5 mg/kg intravenous (IV) loading dose on day 1, followed by 2.5 mg/kg IV every 24 hours

-≥40 kg – 200 mg IV loading dose on day 1, followed by 100 mg IV every 24 hours

The usual duration of therapy is up to 5 days for children with severe disease; for children with critical disease who are not improving after 5 days, the duration may be extended to up to 10 days [1,51].

Reported adverse effects of remdesivir include nausea, vomiting, and transaminase elevations. In a review of compassionate use of remdesivir in 77 children hospitalized with severe SARS-CoV-2 infection, 33 percent had adverse events and 16 percent had serious adverse events, most of which were related to COVID-19 or underlying conditions (eg, hypoxia, acute respiratory failure, recurrence of acute lymphocytic leukemia) [52]. The only adverse events to occur in more than one patient were elevation of serum aminotransferases (in nine) and anemia (in two). Cases of bradycardia attributable to remdesivir have also been reported [53-56].

Licensure of remdesivir in hospitalized children <12 years of age was supported by trials in adult patients and a single-arm, open-label study in 53 children ≥28 days with confirmed mild, moderate, or severe SARS-CoV-2 infection (41 were <12 years of age), in which remdesivir was associated with improvement in clinical status [49,50,57]. Study participants were unvaccinated.

•Baricitinib – Baricitinib is approved by the FDA for the treatment of adult patients who are hospitalized with COVID-19 and require oxygen or ventilatory support or extracorporeal membrane oxygenation [58]. For children age ≥2 to 18 years, it has an emergency use authorization (EUA) [59]. However, there is limited information about the benefits and risks of baricitinib in children with COVID-19 [2]. It should ideally be used in the context of a clinical trial.

Baricitinib is a Janus kinase inhibitor used for the treatment of rheumatoid arthritis. In addition to its immunomodulatory effects, it is thought to have antiviral effects through interference with viral entry. Baricitinib may provide a mortality benefit for select patients, including those already receiving glucocorticoids. In studies in patients ≥18 years of age, baricitinib appeared to reduce mortality and the combination of baricitinib and remdesivir appeared to modestly improve the time to recovery without increased rates of infection, VTE, or other adverse events [59-62]. Studies of baricitinib in adult patients are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Baricitinib and JAK inhibitors'.)

•Hydroxychloroquine and chloroquine – We recommend not using hydroxychloroquine or chloroquine for the treatment of COVID-19 in children. It has not been proven effective and is associated with severe adverse reactions [63-67]. Hydroxychloroquine is not licensed for this indication, and its EUA for the treatment of COVID-19 in the United States has been revoked [68,69].

•Lopinavir-ritonavir – We do not recommend routine use of lopinavir-ritonavir given the absence of efficacy and unfavorable pharmacodynamics [18,30,31,70,71]. (See "COVID-19: Management in hospitalized adults", section on 'Others'.)

Individualized adjunctive therapy

Glucocorticoids — We make decisions about the use of glucocorticoids for immune-mediated complications of COVID-19 on a case-by-case basis according to disease severity [72]. Although glucocorticoids have been associated with decreased mortality in adult patients [73-75], trials in children are ongoing and the benefits and risks are uncertain. Pending results of these trials, administration of glucocorticoids ideally should occur in the context of a clinical trial. Information about ongoing clinical trials is available from ClinicalTrials.gov.

For select children with severe or critical COVID-19 who cannot participate in a clinical trial (ie, those who require mechanical ventilation or those who require supplemental oxygen and have risk factors for disease progression), low-dose glucocorticoids may be warranted at the time of admission [72,76]; the duration of therapy is up to 10 days or until discharge, whichever is shorter. In an observational study in adults, extending glucocorticoid therapy beyond discharge was not associated with decreased rates of readmission or death [77].

Low-dose glucocorticoid regimens include one of the following (dexamethasone is preferred if available) [2,76,78]:

●Dexamethasone 0.15 mg/kg orally, IV, or nasogastrically (NG) once daily (maximum dose 6 mg)

●Prednisolone 1 mg/kg orally or NG once daily (maximum dose 40 mg)

●Methylprednisolone 0.8 mg/kg IV once daily (maximum dose 32 mg)

●Hydrocortisone

•For neonates (<1 month of age) – 0.5 mg/kg IV every 12 hours for 7 days followed by 0.5 mg/kg IV once daily for 3 days

•For children ≥1 month – 1.3 mg/kg IV every 8 hours (maximum dose 50 mg; maximum total daily dose 150 mg)

The use of glucocorticoids is supported by randomized trials comparing glucocorticoids with placebo or usual care, predominantly in adult patients with severe or critical COVID-19. In a meta-analysis of seven randomized trials, in a total of 1703 critically ill patients [79-82], glucocorticoids reduced 28-day all-cause mortality (33 versus 41 percent, odds ratio 0.66, 95% CI 0.53-0.82) without increased serious adverse events [73]. The results were similar with dexamethasone or hydrocortisone. Another meta-analysis of randomized trials comparing glucocorticoids with standard care irrespective of disease severity concluded that glucocorticoids probably reduce all-cause mortality at a median of 28 days (24.5 versus 27.5 percent; risk ratio 0.89, 95% CI 0.80-1.00) and may increase ventilator-free days [83]. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'.)

Although the WHO strongly recommends systemic glucocorticoids for patients with severe or critical COVID-19, they acknowledge that the applicability of the recommendation for children is uncertain because children were underrepresented in the clinical trials supporting benefit [76]. (See 'Society guideline links' below.)

Glucocorticoids plus tocilizumab — Tocilizumab is a monoclonal antibody that reduces inflammation by blocking the IL-6 receptor. It is used in the management of several rheumatologic conditions in children and adults (eg, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome).

Tocilizumab is approved for the treatment of COVID-19 in hospitalized adult patients who are receiving systemic glucocorticoids and require supplemental oxygenation, mechanical ventilation (noninvasive or invasive), or extracorporeal membrane oxygenation [84]. It has EUA for treatment of such hospitalized children ≥2 years of age [85]. However, there is limited information about the benefits and risks of tocilizumab in children with COVID-19 [2,70,86]. It should ideally be used in the context of a clinical trial.

Tocilizumab is dosed according to patient weight [85]:

●<30 kg – 12 mg/kg IV in a single 60-minute infusion

●≥30 kg – 8 mg/kg IV in a single 60-minute infusion (maximum 800 mg per infusion)

Tocilizumab may be repeated once ≥8 hours after the initial infusion if clinical signs or symptoms worsen or do not improve after the first dose.

Tocilizumab should be avoided in individuals with hypersensitivity to tocilizumab, uncontrolled serious infections other than COVID-19, absolute neutrophil count <1000 cells/microL, platelet counts <50,000/microL, alanine aminotransferase >5 times the upper limit of normal, or elevated risk for gastrointestinal perforation [2,85]. Tocilizumab should be used with caution in immunocompromised individuals as very few were included in randomized trials. Administration of live vaccines (eg, measles, mumps, rubella, varicella) should be deferred for at least two weeks after the final infusion of tocilizumab [87]; some experts would wait at least four weeks before administration of live vaccines.

Tocilizumab may reduce progression to mechanical ventilation, duration of hospitality, and mortality in adults with COVID-19, but the findings are inconsistent. Studies describing the use of tocilizumab in adult patients with COVID-19 are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)'.)

In adult patients with COVID-19, the most commonly reported adverse reactions were constipation, diarrhea, nausea, anxiety, insomnia, hypertension, and superinfection [85,88].

Other adjunctive therapies — We make decisions about the use of other adjunctive therapies for immune-mediated complications of COVID-19 on a case-by-case basis according to disease severity and in consultation with specialty services as indicated (eg, rheumatology, infectious diseases) [72]. The immune response to SARS-CoV-2 is variable and may include marked systemic inflammation and/or immune suppression [89].

We do not routinely use other immune modulators (interferon alfa-2b, interferon-beta 1b, convalescent plasma from recovered COVID-19 patients) in the treatment of children hospitalized with COVID-19, except in the context of a clinical trial [72]. The benefits and risks are uncertain [2,72,75,90-98]. The use of immune-modifying therapies in children with multisystem inflammatory syndrome and the use of immune-modifying therapies in adults are discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Immunomodulatory therapy' and "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

Information about ongoing clinical trials is available from ClinicalTrials.gov.

Although there are no available data on the use of vitamin A for the treatment of COVID-19, vitamin A has long been used as an adjunctive therapy in the treatment of measles, and its use has been associated with decreased morbidity and mortality from measles-associated pneumonia [99]. Vitamin A deficiency may be associated with impairment of humoral and cell-mediated immunity, and even mild vitamin A deficiency may lead to increased morbidity from measles and other viral respiratory infections [99]. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Vitamin A'.)

OUTPATIENT MANAGEMENT — Children with documented or suspected COVID-19 and mild symptoms (eg, fever, cough, pharyngitis, other respiratory symptoms) generally can be managed at home unless they have a chronic condition that increases their risk of severe disease.

Outpatient management of children with SARS-CoV-2 infection is focused on prompt provision of outpatient therapy for select patients at high risk of progression to severe disease, provision of symptomatic and supportive care, monitoring for clinical deterioration, and prevention of transmission to others (isolation).

The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) provide additional guidance on what to do when someone is sick [100,101]. (See 'Prevention of transmission' below.)

Outpatient therapy for select children

Potential indications — We consider outpatient therapy for children with mild-to-moderate COVID-19 disease who are at high risk for progression to severe disease on a case-by-case basis. Robust evidence associating specific underlying conditions with progression to severe illness in children is limited [1,102].

Potential indications for outpatient therapy in children include [103,104]:

●One or more of multiple underlying conditions (eg, congenital heart disease/cardiovascular disease; genetic, neurologic, or metabolic condition)

●Lack of vaccination against COVID-19

●Expected inadequate response to COVID-19 vaccine (eg, due to immunosuppressive disease or immunosuppressive therapies)

●Medical-related technologic dependence not related to COVID-19 (eg, tracheostomy positive pressure ventilation)

●Having obesity (body mass index ≥95^th percentile for age and sex [males: (calculator 1), females: (calculator 2)])

Available outpatient therapies for children and adolescents with SARS-CoV-2 infection must be initiated within five to seven days of symptom onset, which requires that decisions about treatment be made soon as soon as possible after a positive test.

Choice of therapy — When outpatient antiviral therapy is warranted for children with COVID-19, we suggest nirmatrelvir-ritonavir or intravenous (IV) remdesivir (depending on age, weight, and other factors) rather than other therapies (table 3). Molnupiravir is an alternative for patients ≥18 years of age if nirmatrelvir-ritonavir and remdesivir are unavailable or clinically inappropriate. Although there is limited information about the effectiveness of these interventions in children and adolescents, in randomized trials in nonhospitalized adults, they substantially reduced the risk of hospitalization. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)

Administration of these agents is discussed below. (See 'Antiviral therapies' below.)

We choose among the suggested therapies on a case-by-case basis, considering the (table 3) [2,18]:

●SARS-CoV-2 variant/subvariant (if known) or the prevalence of circulating SARS-CoV-2 subvariants, which affects susceptibility (table 4).

Given the high frequency of circulation of the Omicron (B.1.1.529) variant and the Omicron BA.2 subvariant throughout the United States, bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, and bebtelovimab are no longer authorized for use in the United States (including territories and jurisdictions) [105-108].

In the United States, the regional prevalence of circulating variants is available from the CDC [109].

●Local availability of therapies; limited supplies may warrant prioritization for those at highest risk of severe disease (table 5) [2,110] (ie, unvaccinated children and children expected to have an inadequate vaccine response).

●Duration of symptoms; all of the available outpatient therapies should be initiated as soon as possible after positive SARS-CoV-2 test and within a specified time from symptom onset:

•Five days for nirmatrelvir-ritonavir and molnupiravir

•Seven days for remdesivir

●Feasibility of administering parenteral medications (eg, remdesivir)

●Feasibility of administering oral medications (eg, nirmatrelvir-ritonavir tablets cannot be chewed, broken, or crushed)

●Child's age; the therapies are approved or authorized for particular age groups:

•Age ≥28 days and weight ≥3 kg – Remdesivir (US Food and Drug Administration [FDA] approved)

•Age ≥12 years and weight ≥ 40 kg – Nirmatrelvir-ritonavir (EUA)

•Age ≥18 years – Molnupiravir (EUA)

●Comorbidities and potential for drug-drug interactions (particularly with nirmatrelvir-ritonavir)

Antiviral therapies

●Nirmatrelvir-ritonavir — Nirmatrelvir-ritonavir is an oral protease inhibitor that prevents viral replication. It is expected to retain activity against Omicron (including subvariants), but data are limited [2,111].

The FDA issued an EUA for nirmatrelvir-ritonavir for the treatment of mild-to-moderate COVID-19 disease in adults and children who are ≥12 years of age and weigh ≥40 kg who are at high risk for progression to severe disease (table 6) [112]. In randomized trials in adult outpatients, nirmatrelvir-ritonavir reduced the risk of hospitalization or death [113-116]. Data in children are limited [117]. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy'.)

•Timing and dose – Nirmatrelvir-ritonavir should be initiated as soon as possible following COVID-19 diagnosis and within five days of symptom onset. The dose varies according to estimated glomerular filtration rate (eGFR) [112]:

-eGFR ≥60 mL/min (normal kidney function) – Nirmatrelvir 300 mg (two 150 mg tablets) and ritonavir 100 mg taken together orally twice daily for five days

-eGFR 30 to 59 mL/min (moderately reduced kidney function) – Nirmatrelvir 150 mg and ritonavir 100 mg taken together orally twice daily for five days

When prescribing nirmatrelvir-ritonavir, specify the dose for each active ingredient to avoid dosing errors and facilitate provision of the correct packaging configuration [118].

•Contraindications and precautions – Nirmatrelvir-ritonavir is not recommended for patients with eGFR <30 mL/min or for patients with severe hepatic impairment (Child-Pugh class C) (table 7).

Nirmatrelvir-ritonavir is a CYP3A inhibitor, and coadministration is contraindicated with drugs that are highly dependent upon CYP3A for clearance and in which an elevated level may be dangerous [112]. Coadministration is also contraindicated with potent CYP3A inducers, which may reduce levels of nirmatrelvir and/or ritonavir and result in loss of efficacy or resistance.

Specific interactions of nirmatrelvir-ritonavir with other medications may be determined using the Lexicomp drug interactions tool (Lexi-Interact) included in UpToDate. The FDA provides a patient eligibility screening checklist and guidance for managing drug interactions with nirmatrelvir-ritonavir [119,120]; the Infectious Diseases Society of America also provides guidance for the management of drug interactions with nirmatrelvir-ritonavir [121].

The decision to use nirmatrelvir-ritonavir in patients with uncontrolled/untreated human immunodeficiency virus (HIV) should factor in the potential risk of causing HIV protease inhibitor resistance [112].

There have been reports of recurrent symptoms and/or a positive SARS-CoV-2 test ("rebound" COVID-19) two to eight days after completion of treatment with nirmatrelvir-ritonavir [122]. In such cases, the CDC recommends that the isolation period be restarted. Limited evidence suggests that recurrent disease is mild, and evidence that another course of antiviral therapy is beneficial is lacking. In addition, recurrent symptoms also occur in patients who are not treated with nirmatrelvir-ritonavir or other medications [123-125]. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Isolation at home' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on '"Rebound" COVID-19 after nirmatrelvir-ritonavir treatment'.)

●Remdesivir — IV remdesivir is commercially available and another option for nonhospitalized children with a positive test for SARS-CoV-2 who have symptomatic mild-to-moderate COVID-19 and are at risk for progression to severe disease [2,70]. It is approved for children ≥28 days who weigh ≥3 kg [49]. In a randomized trial in nonhospitalized adults with at least one risk factor for disease progression, remdesivir reduced the risk of hospitalization [126]. Data in children are limited [117].

Remdesivir should be initiated as soon as possible and within seven days of symptom onset. It is dosed according to weight as follows [50]:

•≥3 to <40 kg – 5 mg/kg IV day 1, followed by 2.5 mg/kg IV on days 2 and 3

•≥40 kg – 200 mg IV on day 1, followed by 100 mg IV on days 2 and 3

Given the three-day regimen, remdesivir may be most feasible for children and adolescents residing in skilled nursing facilities.

●Molnupiravir — Molnupiravir is a nucleoside analogue that inhibits SARS-CoV-2 replication. It is available through EUA for the treatment of mild-to-moderate COVID-19 in nonpregnant individuals ≥18 years of age who are at high risk for progression to severe disease and for whom other authorized treatments are not accessible or clinically appropriate [127]. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

Outpatient monoclonal antibody therapy — Outpatient monoclonal antibody therapy is no longer available for the treatment of COVID-19. The FDA paused authorization for bebtelovimab in November 2022 because it is not expected to neutralize Omicron subvariants BQ.1, BQ.1.1, and XBB, which are the predominant subvariants circulating in the United States [108].

Symptomatic and supportive care — Symptomatic care for COVID-19 in the outpatient setting is similar to that for other upper respiratory or gastrointestinal clinical syndromes:

●Fever (see "Fever in infants and children: Pathophysiology and management", section on 'Management of fever')

●Pain or discomfort – Either NSAIDs or acetaminophen may be used as needed for symptomatic treatment of pain or discomfort

●Upper respiratory tract infection (see "The common cold in children: Management and prevention", section on 'Symptomatic therapy')

●Pharyngitis (see "Acute pharyngitis in children and adolescents: Symptomatic treatment", section on 'Symptomatic treatment')

●Acute gastroenteritis (see "Acute viral gastroenteritis in children in resource-abundant countries: Management and prevention", section on 'Management')

●Adequate vitamin D intake — Adequate intake of vitamin D is necessary for bone health. Vitamin D supplementation may be necessary to meet the recommended intake (table 8), particularly for children with limited exposure to sunlight (eg, those remaining inside while self-isolating). However, the role of vitamin D in the treatment and prevention of COVID-19 is uncertain, and doses exceeding the upper level intake are not recommended [2,128-131]. (See "Vitamin D and extraskeletal health", section on 'COVID-19' and "Overview of vitamin D".)

Monitoring for deterioration — Caregivers of children who are managed at home should be counseled about symptoms of clinical deterioration, which may occur suddenly after approximately one week of symptoms and should prompt urgent re-evaluation, ideally at a medical center with expertise in caring for children with COVID-19 [20].

Manifestations of clinical deterioration include [100,101,132,133]:

●Severe respiratory distress, difficulty breathing (for infants: grunting, central cyanosis, inability to breastfeed)

●Chest pain or pressure

●Blue lips or face

●Findings associated with shock (eg, cold, clammy, mottled skin; new confusion; difficulty arousing; substantially reduced urine output)

●Inability to drink or keep down any liquids

Isolation at home — Isolation at home is discussed in detail separately. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the home setting' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

AVOIDANCE OF UNPROVEN INTERVENTIONS — Neither azithromycin nor hydroxychloroquine/chloroquine have been proven effective in improving symptoms or preventing progression in patients with COVID-19. We recommend not using them in the management of SARS-CoV-2 in children [2,18,103,134-136].

Investigational agents, including fluvoxamine and ivermectin, should be used only in the context of a clinical trial; evidence of benefit is lacking [2,18,70,137-139]. Misuse of forms of these agents not intended for humans (eg, veterinary ivermectin) may lead to severe toxicity, including death [140-142]. Although preliminary studies of fluvoxamine in adult patients suggest benefits in reducing hospitalization, death, and/or disease progression, additional data are needed before it can be recommended for children outside of a clinical trial. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

FOLLOW-UP — The type (eg, telehealth versus in-person visit with primary care provider or specialist), timing, and content of follow-up for children and adolescents recovering from acute SARS-CoV-2 infection is individualized according to underlying comorbidities, severity of illness, persistence of symptoms, and complications. We follow the guidance provided by the American Academy of Pediatrics (AAP) [143].

●Children without multisystem inflammatory syndrome in children (MIS-C) – Children with >4 days of symptoms (eg, fever, chills, myalgia, lethargy) and children who required hospitalization may require phone or video follow-up during isolation to ensure continued recovery [143]. After the isolation period is over and before return to physical activity, they should have an in-person visit. Children with asymptomatic or mild disease (<4 days of symptoms) and resolution of symptoms can have follow-up by video, phone, or in person (after the isolation period is over) before return to physical activity.

The follow-up visit should address [143]:

•Ongoing and newly developed symptoms, including cardiorespiratory symptoms, loss of smell or taste (may manifest in feeding changes in young children), neurodevelopmental symptoms (eg, motor, cognitive, language impairment; inattention; memory problems), fatigue, headache, and mental health sequelae [143]. In addition, children with a history of SARS-CoV-2 infection should be screened for diabetes symptoms (eg, increased thirst, increased hunger, frequent urination, weight loss, fatigue, abdominal pain, nausea, vomiting); SARS-CoV-2 infection has been associated with increased incidence of diabetes mellitus in some [144-150], but not all [151], studies.

Children with ongoing symptoms and worrisome signs should be evaluated as clinically indicated (eg, for myocarditis or MIS-C, intracranial pathology in children with headache and worrisome features (table 9)).

Otherwise, we minimize diagnostic testing and provide supportive care focused on improving function (eg, by setting achievable goals) for the first 12 weeks of recovery [143,152]. Although persistent symptoms may be related to SARS-CoV-2 infection, they also may be related to the conditions of the pandemic (eg, social isolation, death of a family member, trauma of hospitalization, decreased physical activity) [153-156]. In longitudinal follow-up of a matched cohort of children and adolescents with SARS-CoV-2 infection, most symptoms that were reported at the time of diagnosis resolved within 6 to 12 months [157]. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Post-COVID-19 condition ("long COVID")'.)

Additional testing or referral to a multidisciplinary post-COVID-19 clinic may be warranted for children whose symptoms persist for >12 weeks [143].

•Return to activities of daily living (eg, school, work, recreational activities)

•Behavioral and mental health surveillance [48,158].

•Guidance for return to activity (eg, school, sports, employment), including provision of support as indicated (eg, gradual return to school).

-Before returning to physical activity (eg, organized sports training, practice, or competition; physical education class within school; recreational sports), children should be evaluated by their clinician for cardiac symptoms (eg, chest pain, palpitations, syncope, shortness of breath out of proportion to respiratory tract illness) because of the possibility cardiac complications of SARS-CoV-2 [159]. Return to play following COVID-19 is discussed separately. (See "COVID-19: Return to sport or strenuous activity following infection".)

•COVID-19 immunization (if eligible) and catch-up of routine immunizations (if necessary). (See "COVID-19: Vaccines" and "Standard immunizations for children and adolescents: Overview", section on 'Catch-up schedule'.)

•Reinforcement of strategies to prevent infection. (See 'Prevention of transmission' below.)

•Education about symptoms that should prompt re-evaluation. (See 'Symptomatic and supportive care' above.)

•Healthy habits – Adequate nighttime sleep, maintaining a consistent daily schedule, adequate hydration and nutrition, and avoidance of alcohol and drugs.

Testing for SARS-CoV-2 after recovery is not recommended unless the child or adolescent is newly symptomatic or has been exposed to someone recently diagnosed with SARS-CoV-2 infection. A negative SARS-CoV-2 test is not necessary to discontinue isolation but may be used to determine when masking can be discontinued [160]. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Isolation at home' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

●Children with MIS-C – Follow-up of children with MIS-C is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Follow-up'.)

PREVENTION

Prevention of transmission

●Preventing transmission from infected mother to newborn – Prevention of transmission from infected mother to newborn after delivery is discussed separately. (See "COVID-19: Intrapartum and postpartum issues", section on 'Postpartum care of infected patients'.)

●Preventing transmission from children with documented or suspected COVID-19 – Infection prevention for persons with SARS-CoV-2 infection in health care and home settings is discussed separately. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

●Preventing transmission from asymptomatic children with potential exposure – The management of asymptomatic children with potential exposure to COVID-19, including wearing masks and monitoring for symptoms, is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Post-exposure management'.)

●Preventing transmission from asymptomatic frontline workers to household members – Specific guidance for prevention of transmission from asymptomatic frontline/essential workers with potential unrecognized exposure to SARS-CoV-2 to household members is lacking. In addition to COVID-19 vaccination, adherence to prevention strategies during work (eg, use of personal protective equipment, handwashing) is recommended. The Centers for Disease Control and Prevention (CDC) provides additional recommendations to prevent transmission of COVID-19 outside of work and personal prevention strategies [160,161]. The CDC recommends that individuals who live in areas with a high COVID-19 community level wear a mask indoors in public [162-164]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

In addition, health care and other frontline workers may choose to implement additional measures after work (eg, changing out of work clothes and shoes and/or showering before contact with household members), although it is uncertain whether these practices lower the risk of transmission. Physical distancing, use of face masks, and/or improving ventilation in the home also may be warranted, particularly if household members are at increased risk for severe infection [160,165,166]. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Risk factors for severe disease'.)

●Preventing transmission to asymptomatic children without known exposure

•Routine health care – Routine well-child care is necessary for preventive health care and screening (eg, newborn screening immunizations, anticipatory guidance, developmental surveillance). We agree with the American Academy of Pediatrics (AAP) that routine care should continue during the COVID-19 pandemic [167,168].

Strategies that can be used to separate children who are well from children who are ill or possibly ill include [167,169-171]:

-Scheduling home visits

-Use of telemedicine

-Scheduling well-visits in the morning and sick visits in the afternoon

-Seeing children for sick visits in a different part of the clinic, designated examination rooms, or at a different office site (or practice)

The AAP provides information and resources about telemedicine [170], including information about state-by-state payer policies.

•Gathering with other children – When gathering with children from other households, caregivers should consider whether family members or close contacts are at increased risk for severe COVID-19 disease (eg, immunocompromised or with certain underlying conditions) and the COVID-19 vaccination status of individual family members [172].

Steps caregivers can take to protect their children include [161]:

-Getting eligible children vaccinated against COVID-19 (see "COVID-19: Vaccines", section on 'Children')

-Gathering outside when possible

-Keeping children ≥6 feet from people from other households when they are indoors in public

-Avoiding poorly ventilated spaces and crowds

-Having children ≥2 years of age wear a face mask in public spaces in areas where the COVID-19 community level is high (see 'Use of face masks' below)

Use of face masks — The CDC recommends that individuals ≥2 years of age wear a high-quality, well-fitting, and comfortable face mask if they have symptoms, have tested positive for SARS-CoV-2, or have been exposed to someone with COVID-19 [163] (See "COVID-19: Epidemiology, virology, and prevention", section on 'Wearing masks in the community'.)

In addition, although local regulations should be followed, the recommends that individuals ≥2 years of age wear a high-quality, well-fitting, and comfortable face mask when they are in indoor public settings in areas where the COVID-19 community level is high [163,164,173]. Masks that are most protective, fit well, and will be worn consistently are preferred; the preferred mask type may vary from person to person [174]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)

When the COVID-19 community level is medium or low and local regulations do not require masks in indoor public settings, the CDC and AAP suggest that decisions about wearing masks in indoor settings should be individualized according to the child and family's circumstances (eg, whether household and other contacts are vaccinated, immunocompromised, at high risk of severe disease) [164,166].

The AAP provides additional information about face masks for children, including tips for increasing proper wearing and use and guidance for indoor and outdoor mask use in unvaccinated children. Recommendations from the CDC and AAP regarding face masks for children and adolescents in the school setting are provided below. (See 'In-person school and child care' below.)

The WHO provides the following age-based guidance for use of well-fitting masks in areas with community or cluster transmission when interacting with individuals outside the immediate household (independent of vaccination status) [175]:

●Age 5 years and younger; children with conditions that make it difficult to wear a mask or interfere with wearing a mask (eg, cognitive or respiratory impairment, developmental disorder); children who are doing physical activities that may affect breathing (eg, running, jumping) – Masks are not required

●Age 6 to 11 years – Mask use is recommended in:

•Indoor settings if the ventilation is poor, not properly maintained, or cannot be assessed

•Indoor settings if the ventilation is adequate but physical distancing of ≥1 meter cannot be maintained

●Age 12 and older – Mask use is recommended:

•In crowded, enclosed, or poorly ventilated spaces

•Following a recent exposure to COVID-19 when sharing a space with others

•When sharing a space with someone who has COVID-19 or has symptoms of COVID-19

•In individuals at high risk of severe complications from COVID-19

Additional details are available in the living guideline [175]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Wearing masks in the community'.)

Safe use of hand sanitizer — Although washing hands with soap and water is preferred whenever possible, alcohol-based hand sanitizer is safe for use in children when the sanitizer is used according to the information on the Drug Facts label; there is no cause for concern if children eat or lick their hands after the hand sanitizer has fully dried [176].

Counseling regarding safe use of alcohol-based hand sanitizer includes [176-178]:

●Use hand sanitizer in a well-ventilated area; inhalation of alcohol vapors may be associated with adverse effects (eg, dizziness, nausea, headache) [177]

●Avoid homemade hand sanitizer, which may be ineffective or cause skin burns

●Keep hand sanitizers out of the reach and sight of children

●Supervise the use of hand sanitizer in children younger than six years to avoid ingestion and/or eye exposure from touching the eyes or splashing

•Systemic toxicity – Even a small amount of liquid hand sanitizer can cause alcohol poisoning in children (including hypoglycemia) [179]. (See "Ethanol intoxication in children: Epidemiology, estimation of toxicity, and toxic effects" and "Ethanol intoxication in children: Clinical features, evaluation, and management".)

Hand sanitizers made with isopropyl alcohol (isopropanol) may be more toxic than those that contain ethanol (ethyl alcohol) [180]. Hand sanitizers that contain methanol (methyl alcohol) or methylated spirits should be avoided; ingestion of methanol can be life threatening [180-182]. The US Food and Drug Administration (FDA) has noted an increase in hand sanitizer products that are labeled to contain ethanol but have tested positive for contamination with methanol or 1-propanol. The FDA provides a list of these products and other products that contain potentially harmful ingredients on its website. In addition, the FDA has placed all alcohol-based hand sanitizers from Mexico on import alert because of frequent contamination with toxic ingredients, including methanol and 1-propanol [183]. (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis" and "Methanol and ethylene glycol poisoning: Management".)

•Eye injury – Eye exposure may result in severe injury [178,184-186]. In the event of eye exposure, rinse the eyes immediately with gently running water (eg, from a sink tap, water bottle, emergency shower) for at least 15 to 20 minutes. Patients who develop symptoms after rinsing (eg, redness, pain, irritation, visual impairment, photophobia) should seek urgent eye examination [178].

Pre-exposure prophylaxis

SARS-CoV-2 immunization — SARS-CoV-2 immunization is the optimal method of pre-exposure prophylaxis for eligible individuals (table 10 and figure 1). The Centers for Disease Control and Prevention provide multiple resources for pediatric health care professionals.

SARS-CoV-2 immunization is discussed separately. (See "COVID-19: Vaccines" and "COVID-19: Allergic reactions to SARS-CoV-2 vaccines".)

Pre-exposure prophylaxis with monoclonal antibodies — In the United States, the Food and Drug Administration revoked emergency use authorization for copackaged tixagevimab-cilgavimab for pre-exposure prophylaxis because it is unlikely to be active against the most prevalent Omicron subvariants (table 4) [187]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)

Postexposure prophylaxis

Monoclonal antibodies — No monoclonal antibodies are approved or authorized for postexposure prophylaxis in the United States. In late January 2022, the FDA paused the emergency use authorization (EUA) for combination bamlanivimab-etesevimab and combination casirivimab-imdevimab due to the widespread high frequency of circulation of the Omicron variant, which is highly unlikely to be susceptible to bamlanivimab-etesevimab or casirivimab-imdevimab (table 4) [105,188,189].

Other agents — We avoid postexposure prophylaxis with hydroxychloroquine. In a meta-analysis of three randomized trials [190-192], rates of symptomatic infection (approximately 9 percent), hospitalization (<1 percent), and death (<1 percent) were similar in hydroxychloroquine and placebo groups [18].

Other agents for prevention of SARS-CoV-2 are being evaluated in clinical trials, but none has been proven effective in children. Postexposure prophylaxis is discussed in greater detail separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'No role for post-exposure prophylaxis'.)

SPECIAL POPULATIONS

Children with special health care needs — The American Academy of Pediatrics provides information about caring for children and youth with special health care needs during the COVID-19 pandemic [193].

Closure of school may be particularly challenging for children and youth with special health care needs, who were receiving services at school (eg, speech therapy, behavior, mental health services) and/or have barriers to remote learning (eg, lack of access to a laptop/tablet or the internet, language barrier) [194]. In the United States, pediatric health care providers can review the child's Individualized Education Program to help the caregiver determine what services the child should be receiving (including compensatory services). A fact sheet from the Department of Education provides additional information. (See "Definitions of specific learning disorder and laws pertaining to learning disorders in the United States", section on 'Individuals with Disabilities Education Act'.)

Consensus priorities for safer in-person school for children with medical complexity include [195]:

●Encouraging all school personnel in close proximity with children with complex health needs to be vaccinated against COVID-19 and to wear a mask (even if they are vaccinated)

●Assigning and maintaining individual seats for the children with medical complexity during transportation to and from school

●Ensuring that each child has their own medical equipment or single-use disposable equipment at school

●Discussing COVID-19 mitigation strategies in Individualized Education Plan meetings; the strategies should be based upon the child's daily routines and should include contingency plans

●Providing families the opportunity to switch from in-person to virtual or homebound school based on COVID-19 spread or illness

●Identifying circumstances during which the child should remain home

●Ensuring a respiratory protection plan is in place for school staff performing high-risk care (eg, nebulized treatments, tracheostomy suctioning)

●Educating school staff and families about the increased risks of COVID-19 for children with complex health needs

●Providing at-school COVID-19 testing for staff and students

●Having at least one medical staff member available to address acute COVID-19 symptoms or questions

Children with attention deficit hyperactivity disorder — The European attention deficit hyperactivity disorder (ADHD) guidelines group provides guidance for management of ADHD during the COVID-19 pandemic and guidance for starting stimulants or atomoxetine in children who did not have an in-person cardiovascular assessment before the pandemic [196,197].

The AAP provides suggestions to support students with special needs, including ADHD, and their families.

Children with rheumatic disease — The American College of Rheumatology has issued guidance regarding ongoing management of rheumatic disease in children during the COVID-19 pandemic according to their clinical status (eg, without exposure or infection, with close/household exposure, with asymptomatic infection, with symptomatic infection) [198].

Children involved with the child welfare system — The AAP provides guidance for children and families involved with the child welfare system during the COVID-19 pandemic [199].

ADDRESSING OR MITIGATING INDIRECT EFFECTS OF THE PANDEMIC

Disruption of immunization — Although the United States Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) consider routine vaccination an essential preventive care service that should not be delayed because of the COVID-19 pandemic, routine immunization of children and adolescents has decreased [200]. Disruption of immunization services increases the risk of outbreaks of vaccine-preventable illnesses [201]. Children who have recovered from acute COVID-19 infection can receive routine childhood immunizations as soon as they have completed isolation. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

Adherence to recommendations for infants born to women who are hepatitis B surface antigen (HBsAg) positive or whose HBsAg status is unknown is particularly important for prevention of mother-to-child transmission of hepatitis B virus, especially if the delivery occurs at an unplanned facility or is attended by staff who are not knowledgeable about managing infants born to mothers who are HBsAg positive [202]. (See "Standard immunizations for children and adolescents: Overview", section on 'Benefits of vaccines' and "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Routine infant immunization'.)

Resources and guidance related to continuation of immunization during the pandemic are available from multiple professional groups, including the American Academy of Pediatrics (AAP), the National Network of Immunization Coalitions, and the CDC.

Physical health effects

●Physical activity and food security – The COVID-19 pandemic and measures to limit the spread of SARS-CoV-2 has been associated with decreased physical activity and increased screen time in children and adolescents, as well as food insecurity [203-214]:

These effects can be mitigated through caregiver role-modeling of healthy behaviors, involving children in family activities, and promotion of self-discipline and self-sufficiency skills [215-218]. Guidance for physical activity and diet in children and adolescents is provided separately. (See "Physical activity and strength training in children and adolescents: An overview", section on 'Physical activity' and "Dietary recommendations for toddlers and preschool and school-age children".)

The American Academy of Pediatrics (AAP) provides the following resources related to physical activity and healthy nutrition:

•AAP guidance on supporting healthy nutrition and physical activity during the COVID-19 pandemic

•AAP guidance on return to sports and physical activity

•AAP guidance on obesity management and treatment during COVID-19

•AAP and Food Research and Action Center toolkit to address food insecurity

●Injury – The COVID-19 pandemic has been associated with increased risk of injury, including firearm injury and intentional or unintentional ingestion [219-226].

Mental health effects

Mental health effects and associated factors – In observational studies of school-age children and adolescents, the COVID-19 pandemic has been associated with: increased symptoms of and/or hospitalization for depression, nonsuicidal self-injury, suicidality, anxiety, disordered eating, and insomnia; increased exposure to domestic and family violence; and increased use of alcohol or other drugs [227-240]. In a meta-analysis of 29 studies including >80,000 children ≤18 years of age, 25 percent had clinically elevated depression symptoms and 20 percent had clinically elevated anxiety symptoms, approximately twice prepandemic estimates [230]. During the pandemic, the rates of emergency department visits for suicidality and positive primary care screening tests for symptoms of depression and suicide risk increased among adolescents and young adults [229,241].

Poor mental health and suicidal behaviors are associated with exposure to adverse childhood experiences (ACEs), which has increased during the COVID-19 pandemic. The cross-sectional Adolescent Behaviors and Experiences Survey evaluated the association between specific ACEs (eg, emotional abuse, physical abuse, sexual violence, physical teen dating violence, electronic bullying, parent or caregiver job loss, food insecurity) and mental health/suicidal behaviors in 4390 high school students <18 years of age during the COVID-19 pandemic [242]. Approximately 75 percent of students reported exposure to ≥1 ACE. Poor mental health and suicidal behaviors were associated with exposure to increasing numbers of ACEs and with exposure to particular ACEs (eg, emotional abuse, sexual violence, physical teen dating violence).

School closures have been associated with increased risk of violence and vulnerability and decreased opportunities for referral to child protective services [243-246]. Vulnerable children and adolescents (eg, those who are homeless or in foster care; have a history of maltreatment; are lesbian, gay, bisexual, gender diverse, queer, questioning) are at particular risk for violence and adverse mental health effects [247].

●Monitoring for and mitigation of mental health effects – Given the potential for mental health effects of COVID-19 and the COVID-19 pandemic, children and adolescents with COVID-19 require monitoring for possible mental health problems [48,248]. Symptoms of mental health problems include mood changes, irritability, and feelings of sadness or hopelessness [48,242].

Clinicians can look for signs of caregiver stress, irritability, depression, and/or harsh responses to child behaviors during each clinical encounter [244]. They should ask about caregiver stress levels, methods to manage stress, social supports, resource stability, and substance use. If privacy can be assured during office or telemedicine visits, clinicians should also ask about exposure to abuse, household violence, and mental health [48,247].

Clinicians can offer coping strategies (eg, deep breathing, calling a friend or family member), resources, and/or referrals to mental health providers to families who may benefit from these interventions.

●Resources related to child care, emotional and behavioral health needs, prevention of violence, and mitigating long-term effects of ACEs include:

•American Academy of Pediatrics guidance on supporting the emotional and behavioral health needs during the COVID-19 pandemic [158]

•Child Care Aware of America

•Global Partnership to End Violence Against Children

•The National Child Traumatic Stress Network

•The WHO: Addressing violence against children, women and older people during the COVID-19 pandemic: Key actions

•Children: The hidden pandemic 2021: A joint report of COVID-19 associated orphanhood and a strategy for action

•The AAP clinical report on trauma-informed care

Loss of a parent or caregiver — Between March 2020 and May 2022, an estimated ≥7.5 million children lost a parent and ≥10.5 million children lost a parent or primary or secondary caregiver to COVID-19 [249]. Loss of a caregiver is an ACE and may affect long-term health and well-being [250]. Adverse effects may be mitigated through programs that promote safe, stable, nurturing relationships [251].

Resources for grieving children are available from [252]:

●The American Academy of Pediatrics and the Children's Hospital of Philadelphia

●The Child Mind Institute

●The National Child Traumatic Stress Network

Preparing children and adolescents for the loss of a loved one is discussed separately. (See "Preparing children and adolescents for the loss of a parent or guardian".)

IN-PERSON SCHOOL AND CHILD CARE — The emergence and predominance of the highly transmissible variants (eg, Omicron [B.1.1.529]) warrant adherence to multiple mitigation measures to prevent school-related transmission, particularly among unvaccinated students and staff members [253-257]. In an observational study, after Massachusetts rescinded its statewide school masking requirement in February 2022, school districts that discontinued universal masking had a higher incidence of COVID-19 among students and staff than those that did not [257]. Additional measures may be necessary to prevent transmission between teachers/staff and from teachers/staff to household contacts [258-261].

A number of professional organizations provide guidance regarding in-person school and child care attendance, including the:

●ABC Science Collaborative, developed by the Duke School of Medicine and the Duke Clinical Research Institute

●American Academy of Pediatrics (AAP) [262], which provides specific guidance on:

•Safe transportation in motor vehicles [263]

•Child care [264]

●The Centers for Disease Control and Prevention (CDC) operational guidance for K-12 schools and early care and education programs to support safe in-person learning [265]

●The eSchool+ Initiative, a cross-disciplinary collaboration from Johns Hopkins University

●National Academies of Sciences, Engineering, and Medicine [266]

●Washington University Pediatric and Adolescent Ambulatory Research Consortium [267]

●World Health Organization (WHO) [268]

•Considerations for school-related public health measures in context of COVID-19

•Checklist to support schools re-opening and preparation for COVID-19 resurgences or similar public health crises

•Questions and answers

Key recommendations include [262,265,266,268-271]:

●Promotion of vaccination for eligible staff and students [272]

●Inclusion of multiple perspectives (eg, public health and infectious disease experts, educators, parents/caregivers, teachers, community leaders) and permits regional variation.

●Having training and safeguards in place (eg, protocols and necessary supplies and personnel for hand hygiene, face masks, cleaning, disinfection, ventilation, symptom screening, testing). Multilayered mitigation strategies are particularly important with widespread circulation of highly transmissible variants (eg, Delta [B.1.617.2], Omicron [B.1.1.529]) [273].

In the school or child care setting, the CDC recommends that masks be worn indoors by all individuals ≥2 years of age, including those who are up to date with their COVID-19 vaccinations, in areas where the COVID-19 community level is high [164].

●Establishing a protocol for monitoring and responding to changes in transmission in the school or community as well as children with COVID-19 symptoms or exposure [265,267,269].

●Providing realistic and practical mitigation strategies with flexibility to accommodate different types of students (eg, young children, those with developmental disabilities), classroom/school environments (eg, size, ventilation), and other factors.

●Consideration of the benefits and risks for all concerned parties (students, staff, parents/caregivers, community); the magnitude of benefits and risks may differ for students and teachers/staff. In addition to education, schools provide services to children with special health care needs, meals, opportunities to develop social/emotional skills, and physical activity. In a 2018 national survey, approximately 50 percent of adult teachers and adults living with school-aged children had conditions that are considered definite or possible risk factors for severe COVID-19 [274].

●Special considerations for vulnerable populations (eg, those with developmental challenges, those who are medically fragile or live in poverty) [275].

The eSchool+ Initiative provides a tracker that categorizes school reopening plans according to consideration of 12 categories (eg, core academics, SARS-CoV-2 protection, food and nutrition, caregiver choice, teacher and staff choice, children of poverty and disadvantage).

SPORTS AND EXTRACURRICULAR ACTIVITIES — Centers for Disease Control and Prevention (CDC) guidance recommends that individuals who live in areas with high COVID-19 community levels wear a mask indoors in public [162-164]. In areas with moderate or low COVID-19 community levels, children and adolescents should follow local regulations.

Decisions about participation in sports and extracurricular activities for children and adolescents should be made on a case-by-case basis and in accordance with local regulations and guidance [159,269,276]. Factors to consider include local disease activity, COVID-19 vaccination status, and other mitigation measures (eg, mask wearing, ventilation) and whether the activities increase the risk of transmission among students or staff (eg, by resulting in or requiring deep breathing [eg, intense exercise, shouting, singing]). Observational studies suggest that the risk of transmission is lower with outdoor than indoor sports activity [277]. Although indoor sports (eg, wrestling, gymnastics, ice hockey), close contact team sports, and intense exercise have been associated with increased transmission [260,278-282], there are reports of successful implementation of stringent mitigation protocols [283]. Social gatherings associated with team sports also may increase the risk of transmission [276].

Return to play or strenuous activity following infection is discussed separately (algorithm 1). (See "COVID-19: Return to sport or strenuous activity following infection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topics (see "Patient education: COVID-19 and children (The Basics)" and "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Assessment of severity – Children with COVID-19 and severe or critical lower respiratory tract disease generally require hospital admission. (See 'Assessment of severity' above.)

•Severe disease is defined by a new requirement for supplemental oxygen or increased requirement from baseline without new or increased need for ventilatory support (noninvasive or invasive).

•Critical disease is defined by new or increased need for noninvasive or invasive mechanical ventilation, sepsis, multiorgan failure, or rapidly worsening clinical trajectory.

●Supportive care – Supportive care (eg, respiratory support, fluid and electrolyte support, monitoring for cytokine release syndrome) is the mainstay of therapy for children with severe or critical COVID-19. (See 'Supportive care for all patients' above.)

●Management of hospitalized children – We agree with recommendations from the multicenter interim guidance on the use of antiviral agents for children with COVID-19 and other experts that antiviral therapy should be considered on a case-by-case basis and preferably occur in the context of a clinical trial, if a clinical trial is available. (See 'SARS-CoV-2 antiviral therapy for select patients' above.)

•Decisions regarding antiviral therapy should be individualized according to disease severity, clinical trajectory, and underlying conditions that may increase the risk for progression.

•When a decision is made to use antiviral therapy in a hospitalized child who cannot be enrolled in a clinical trial, we suggest remdesivir rather than other antiviral agents (Grade 2C). Randomized trials in adults suggest a potential benefit.

•We recommend not using hydroxychloroquine or chloroquine (Grade 1B). Their emergency use authorization has been revoked, their clinical benefit is unproven, and they have potential toxicity.

For hospitalized children who cannot be enrolled in a clinical trial, we make decisions about the use of adjunctive therapies for immune-mediated complications (eg, glucocorticoids, interleukin-6 inhibitors) of COVID-19 on a case-by-case basis. (See 'Individualized adjunctive therapy' above.)

●Outpatient management – Children with documented or suspected COVID-19 and mild symptoms (eg, fever, cough, pharyngitis, other respiratory symptoms) generally should be managed at home unless they have a chronic condition that increases their risk of severe disease. Decisions regarding outpatient antiviral therapy are made on a case-by-case basis (table 3). Additional management is focused on prevention of transmission to others (ie, isolation), monitoring for clinical deterioration (eg, difficulty breathing, cyanosis, symptoms of shock), and supportive care. (See 'Outpatient therapy for select children' above and 'Symptomatic and supportive care' above.)

Symptomatic care for COVID-19 in the outpatient setting is similar to that for other upper respiratory or gastrointestinal clinical syndromes. It is discussed separately. (See "The common cold in children: Management and prevention", section on 'Symptomatic therapy' and "Acute pharyngitis in children and adolescents: Symptomatic treatment", section on 'Symptomatic treatment' and "Fever in infants and children: Pathophysiology and management", section on 'Management of fever' and "Acute viral gastroenteritis in children in resource-abundant countries: Management and prevention", section on 'Management'.)

Prevention of transmission focuses on isolation, hygiene, and masking. The Centers for Disease Control and Prevention and World Health Organization provide guidance about preventing transmission of COVID-19 in the home and outpatient setting. (See 'Prevention of transmission' above.)

●Pre-exposure prophylaxis – SARS-CoV-2 immunization is the only method of pre-exposure prophylaxis for eligible individuals. Pre-exposure prophylaxis with copackaged tixagevimab-cilgavimab is no longer authorized because it is unlikely to be active against circulating variants. (See 'Pre-exposure prophylaxis' above.)

●Management of indirect effects – Management of COVID-19 in children also encompasses management of indirect effects, particularly adverse physical and mental health effects of prolonged home confinement (eg, decreased physical activity, poorer quality diet, social isolation, increased risk of violence). (See 'Addressing or mitigating indirect effects of the pandemic' above.)