Therapeutic Management of Nonhospitalized Children With COVID-19
Last Updated: August 8, 2022
This section outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the therapeutic management of nonhospitalized children (i.e., pediatric patients aged <18 years) with mild to moderate COVID-19. These recommendations are also for children who have mild to moderate COVID-19 and are hospitalized for reasons other than COVID-19. For patients aged ≥18 years, see Therapeutic Management of Nonhospitalized Adults With COVID-19. Throughout this section, the term “COVID-19” refers to the acute, primarily respiratory illness due to infection with SARS-CoV-2, which is in contrast to multisystem inflammatory syndrome in children (MIS-C), a postinfectious inflammatory condition.
Treatment Considerations for Children With COVID-19
Currently, no results from pediatric clinical trials that evaluated the treatment of COVID-19 have been published. Data evaluating the use of pharmacologic therapy in children with COVID-19 are limited largely to descriptive reports.1,2 Therefore, more high-quality randomized trials, observational studies, and pharmacokinetic studies are urgently needed. Whenever possible, clinical trials of therapeutics and multicenter observational cohorts should enroll children with COVID-19.
Published guidance documents on the treatment of COVID-19 in children have been mostly extrapolated from recommendations for adults with COVID-19, recommendations for children with other viral infections, and expert opinion.3-5 Applying adult data from COVID-19 trials to children is a unique challenge because most children experience a mild course of illness with COVID-19. Relative to adults, children with COVID-19 have substantially lower mortality and less need for hospitalization. Because of these differences in epidemiology and disease severity, the effect sizes for children are likely to be smaller than those observed in adults; therefore, to produce a beneficial outcome, the number needed to treat is higher. Collectively, these factors influence the risk versus benefit balance for pharmacologic therapies in children.
Other challenges are the uncertainty about which comorbid conditions place children at the highest risk of severe COVID-19 and the uncertainty about the absolute magnitude of the increased risk from those comorbid conditions. For children with COVID-19, the number and severity of their comorbid conditions influence decisions about pharmacologic treatment. For more information on risk factors for children with COVID-19, see Special Considerations in Children.
In the absence of sufficient clinical trial data on the treatment of children with COVID-19, the Panel’s recommendations for the therapeutic management of nonhospitalized children are based largely on adult safety and efficacy data from clinical trials (see Table 3a). No pediatric comparative studies have been published; therefore, all quality of evidence ratings for the Panel’s recommendations in this section are based on expert opinion (i.e., a III rating).
The majority of children with mild to moderate COVID-19 will not progress to more severe illness; therefore, the Panel recommends managing these patients with supportive care alone (AIII). The risks and benefits of therapy should be assessed based on COVID-19 disease severity, age, vaccination status, and the presence of underlying medical conditions that may place the patient at high risk of severe COVID-19. For the Panel’s framework for assessing the risk of progression to severe COVID-19 based on patient conditions and vaccination status, see Table 3b.
Table 3a. Therapeutic Management of Nonhospitalized Children With COVID-19
Table 3b. The Panel’s Framework for Assessing the Risk of Progression to Severe COVID-19 Based on Patient Conditions and COVID-19 Vaccination Status
Rationale for the Panel’s Framework for Assessing the Risk of Progression to Severe COVID-19
Although mortality associated with COVID-19 in children is low overall, severe disease can occur, especially in those with risk factors.6 Risk stratification for severe disease in children remains challenging. Imprecise definitions of comorbid conditions, insufficient granularity for differentiating the severity of comorbidities (e.g., mild vs. severe lung disease, poorly controlled vs. well-controlled diabetes), and small sample sizes limit the conclusions that can be drawn from individual studies and make comparing findings across studies difficult.
Further, asymptomatic SARS-CoV-2 infection detected during admission screening for children who are hospitalized for reasons other than COVID-19 may affect the estimated risk of severe COVID-19, particularly for patient groups that may have protocolized admissions (e.g., children with febrile neutropenia, infants aged <90 days with fever). In addition, published data evaluating these associations in children are limited largely to case series without control groups and observational studies with methodologic limitations.
Despite these challenges, a risk-stratification framework needs to be developed that identifies the patient groups likely to benefit from receiving treatment and prioritizes patients who are most likely to benefit when supplies are limited. Both the Pediatric Infectious Diseases Society and the American Academy of Pediatrics advocate for a risk-stratified approach toward identifying the patients who are at the highest risk of progression to severe COVID-19 among those eligible for therapies under Food and Drug Administration (FDA) Emergency Use Authorizations (EUAs).5,7
The Panel’s approach to risk stratification and prioritization considers COVID-19 vaccination status, immune function, clinical risk factors, the strength of evidence demonstrating an association between each clinical risk factor and severe disease, and expert opinion.6,8-21 See Special Considerations in Children for more information on clinical risk factors. Table 3b provides the Panel’s framework for this risk stratification. The Panel suggests that decisions regarding treatment be individualized, particularly for patients in the intermediate risk category. The number and severity of comorbid conditions and a child’s vaccination status, including the time since vaccination, should be considered.Comorbid conditions associated with severe COVID-19 are separated into the following categories in Table 3b:
- Strong or Consistent Association With Progression to Severe COVID-19: Comorbid conditions for which the published literature most consistently supports an increased risk of severe COVID-19. Patients in this category are moderately or severely immunocompromised, at risk of severe COVID-19, and not expected to develop an adequate immune response to COVID-19 vaccination.
- Moderate or Inconsistent Association With Progression to Severe COVID-19: Comorbid conditions and ages for which the published literature supports an association with severe COVID-19, but the data that support that association may be moderate or inconsistent. In addition, the absolute risk of progression to severe disease or death is likely modest for any of the patients in this category.
- Weak or Unknown Association With Progression to Severe COVID-19: Comorbid conditions for which the data suggesting an association with severe COVID-19 are weak or for which an association is unknown. Patients with no comorbidities are included in this category.
Because COVID-19 vaccines are highly effective in preventing severe disease, individuals who are not immunocompromised and who are vaccinated are likely to have a low absolute risk of severe disease. Therefore, the potential for benefit from antiviral treatment is less clear. Patients with up-to-date vaccination status (i.e., those who have received the recommended booster dose(s), if eligible, or have completed the primary series but are not yet eligible for a booster) are at the lowest risk of progression to severe COVID-19.22 For patients who have had the primary series of vaccinations (i.e., those who are fully vaccinated but not up to date), the level of protection against severe disease may be less than it is for patients who are up to date, but data comparing these groups are limited.22 However, evidence suggests that vaccine protection against severe COVID-19 wanes over time, so clinicians should consider the time since a child’s vaccination when making treatment decisions.23,24
COVID-19-related outcomes are worse among medically underserved populations, although this factor is not strictly a comorbid condition. Some racial and ethnic groups experience disproportionate rates of COVID-19 hospitalization and are less likely to receive specific therapies.25-28 These factors may be relevant when making clinical decisions about treatment.29,30 See Special Considerations in Children for more information.
Rationale for the Panel’s Recommendations for Drug Therapies
Ritonavir-Boosted Nirmatrelvir (Paxlovid)
Ritonavir-boosted nirmatrelvir has received an FDA EUA for the treatment of mild to moderate COVID-19 in nonhospitalized adolescents aged ≥12 years and weighing ≥40 kg who are at high risk of progression to severe COVID-19.31
The EPIC-HR trial enrolled adults aged ≥18 years who were at high risk of severe COVID-19; they were randomized to receive ritonavir-boosted nirmatrelvir or placebo. The primary outcome of COVID-19-related hospitalization or all-cause mortality occurred in 8 of 1,039 patients (0.8%) who received ritonavir-boosted nirmatrelvir and in 66 of 1,046 patients (6.3%) who received placebo, an 89% relative risk reduction.32 No pediatric patients were included in the trial, and no pediatric safety data were made available.
Ritonavir has been used extensively in pediatric patients as a pharmacokinetic booster for the treatment of HIV and hepatitis C, and it has a known and tolerable side effect profile. In the FDA EUA, the dose of ritonavir-boosted nirmatrelvir authorized for adolescents aged ≥12 years and weighing ≥40 kg is expected to result in a drug exposure similar to that observed in adults.31
Given the high efficacy of ritonavir-boosted nirmatrelvir in adults, its overall manageable side effect profile, the pediatric clinical experience with ritonavir, and the convenience of an oral medication, the Panel recommends the use of ritonavir-boosted nirmatrelvir for nonhospitalized adolescents ≥12 years of age and weighing ≥40 kg who have mild to moderate COVID-19 and who are at the highest risk of progression to severe COVID-19 (BIII).
Because of the potential for significant drug-drug interactions with some concomitant medications, ritonavir-boosted nirmatrelvir may not be the safest choice for some patients. See Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications for more information.
Remdesivir is approved by the FDA for use in hospitalized and nonhospitalized pediatric patients aged ≥28 days and weighing ≥3.0 kg.33 Remdesivir is expected to be active against the Omicron variant of concern (VOC), although in vitro and clinical data are currently limited.34
In a study that included nonhospitalized adults with mild to moderate COVID-19 who were at high risk of progression to severe disease, treatment with 3 consecutive days of intravenous (IV) remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death, when compared to placebo.35 Although adolescents aged ≥12 years were eligible for inclusion, the trial included only 8 patients aged <18 years; therefore, no conclusions regarding the efficacy of remdesivir in children can be made from this trial. In addition, clinical experience data from hospitalized children with COVID-19 who received remdesivir through a compassionate use program have been reported.2,36 Given the demonstrated efficacy of remdesivir in the overall study population, its overall favorable side effect profile, and clinical experience with remdesivir in hospitalized children, remdesivir, as an alternative to ritonavir-boosted nirmatrelvir, can be considered for children aged ≥12 years who are at the highest risk of progression to severe COVID-19 (CIII).
For nonhospitalized children aged <12 years who are at the highest risk of progression to severe disease and for children who are at intermediate risk of severe disease, there is insufficient evidence to recommend either for or against the routine use of remdesivir for the treatment of COVID-19. An additional, important consideration is that remdesivir requires an IV infusion for 3 consecutive days, so logistical constraints may preclude the administration of remdesivir in many settings.
Anti-SARS-CoV-2 Monoclonal Antibodies
Although 4 anti-SARS-CoV-2 monoclonal antibody (mAb) products have received FDA EUAs for the treatment of nonhospitalized adolescents aged ≥12 years and weighing ≥40 kg who are at high risk of severe COVID-19, only bebtelovimab is currently available for use, as it is the only anti-SARS-CoV-2 mAb with in vitro activity against the Omicron VOC and its subvariants (BA.1, BA1.1., BA.2, BA.4, BA.5).37
Bebtelovimab was studied in different arms of the Phase 2 BLAZE-4 clinical trial in nonhospitalized patients, which was conducted before the emergence of the Omicron VOC.37 Although in vitro data showed that bebtelovimab demonstrated activity against all known Omicron subvariants, no clinical data determine the efficacy of bebtelovimab for the treatment of COVID-19 caused by the Omicron VOC. Therefore, there is insufficient evidence for the Panel to recommend either for or against the use of bebtelovimab in pediatric patients aged ≥12 years who have mild to moderate COVID-19 and who are at the highest risk of progression to severe COVID-19.
Pharmacologic Therapies Not Recommended for Nonhospitalized Children With COVID-19
The FDA EUA for molnupiravir is limited to people aged ≥18 years, and there are no data on the safety of molnupiravir in children.38 The mechanism of action of molnupiravir has raised concerns about potential mutagenesis in mammalian cells. See Molnupiravir and Therapeutic Management of Nonhospitalized Adults With COVID-19 for additional information.
Corticosteroids are not indicated for the treatment of COVID-19 in nonhospitalized children. However, corticosteroids should be used per usual standards of care in children with asthma and croup triggered by SARS-CoV-2 infection. Children with COVID-19 who are receiving corticosteroids for an underlying condition should continue this therapy as directed by their health care providers.
- Schuster JE, Halasa NB, Nakamura M, et al. A description of COVID-19-directed therapy in children admitted to US intensive care units 2020. J Pediatric Infect Dis Soc. 2022;11(5):191-198. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35022779.
- Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe COVID-19. Pediatrics. 2021;147(5):e202004780. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33883243.
- Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2. J Pediatric Infect Dis Soc. 2020;9(6):701-715. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32318706.
- Dulek DE, Fuhlbrigge RC, Tribble AC, et al. Multidisciplinary guidance regarding the use of immunomodulatory therapies for acute coronavirus disease 2019 in pediatric patients. J Pediatric Infect Dis Soc. 2020;9(6):716-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32808988.
- Wolf J, Abzug MJ, Anosike BI, et al. Updated guidance on use and prioritization of monoclonal antibody therapy for treatment of COVID-19 in adolescents. J Pediatric Infect Dis Soc. 2022;11(5):177-185. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35107571.
- Havers FP, Whitaker M, Self JL, et al. Hospitalization of adolescents aged 12–17 years with laboratory-confirmed COVID-19—COVID-NET, 14 states, March 1, 2020–April 24, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(23):851-857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34111061.
- Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment of coronavirus disease 2019 in children and adolescents. J Pediatric Infect Dis Soc. 2021;10(5):629-634. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33388760.
- Graff K, Smith C, Silveira L, et al. Risk factors for severe COVID-19 in children. Pediatr Infect Dis J. 2021;40(4):e137-e145. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33538539.
- Fernandes DM, Oliveira CR, Guerguis S, et al. Severe acute respiratory syndrome coronavirus 2 clinical syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr. 2021;230:23-31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33197493.
- Gotzinger F, Santiago-Garcia B, Noguera-Julian A, et al. COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020;4(9):653-661. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32593339.
- Kompaniyets L, Agathis NT, Nelson JM, et al. Underlying medical conditions associated with severe COVID-19 illness among children. JAMA Netw Open. 2021;4(6):e2111182. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34097050.
- Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and outcomes of US children and adolescents with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19. JAMA. 2021;325(11):1074-1087. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33625505.
- Mukkada S, Bhakta N, Chantada GL, et al. Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study. Lancet Oncol. 2021;22(10):1416-1426. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34454651.
- CDC COVID-19 Response Team. Coronavirus disease 2019 in children—United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422-426. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32271728.
- Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 at a tertiary care medical center in New York City. J Pediatr. 2020;223:14-19. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
- DeBiasi RL, Song X, Delaney M, et al. Severe coronavirus disease-2019 in children and young adults in the Washington, DC, metropolitan region. J Pediatr. 2020;223:199-203. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405091.
- Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(6):e20200702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179660.
- Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr. 2020;16(3):251-259. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32193831.
- Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a children’s hospital in New York City, New York. JAMA Pediatr. 2020;174(10):e202430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492092.
- Delahoy MJ, Ujamaa D, Whitaker M, et al. Hospitalizations associated with COVID-19 among children and adolescents—COVID-NET, 14 states, March 1, 2020–August 14, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(36):1255-1260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34499627.
- Wanga V, Gerdes ME, Shi DS, et al. Characteristics and clinical outcomes of children and adolescents aged <18 years hospitalized with COVID-19—six hospitals, United States, July–August 2021. MMWR Morb Mortal Wkly Rep. 2021;70(5152):1766-1772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34968374.
- Centers for Disease Control and Prevention. Stay up to date with your COVID-19 vaccines. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html. Accessed July 25, 2022.
- Dorabawila V, Hoefer D, Bauer UE, et al. Risk of infection and hospitalization among vaccinated and unvaccinated children and adolescents in New York after the emergence of the Omicron variant. JAMA. 2022;327(22):2242-2244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35559959.
- Klein NP, Stockwell MS, Demarco M, et al. Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2 mRNA vaccination in preventing COVID-19-associated emergency department and urgent care encounters and hospitalizations among nonimmunocompromised children and adolescents aged 5–17 years—VISION Network, 10 states, April 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(9):352-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35239634.
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- Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. 2022. Available at: https://www.fda.gov/media/155050/download.
- Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med. 2022;386(15):1397-1408. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35172054.
- Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214787Orig1s015lbl.pdf.
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- Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. 2022. Available at: https://www.fda.gov/media/155054/download.