Special Considerations in Children
Last Updated: June 11, 2020
Data on disease severity and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children are limited. Overall, several large epidemiologic studies suggest that acute disease manifestations are substantially less severe in children than in adults, although there are reports of children with COVID-19 requiring intensive care unit (ICU)-level care.1-11 Recently, SARS-CoV-2 has been associated with a potentially severe inflammatory syndrome in children (multisystem inflammatory syndrome in children [MIS-C], which is discussed below). Preliminary data from the Centers for Disease Control and Prevention (CDC) also show that hospitalization rates and ICU admission rates for children are lower than for adults. Severe cases of COVID-19 in children were associated with younger age and underlying conditions, although a significant number of the pediatric cases did not have complete data available at the time of the preliminary report. Without widespread testing, including for mild symptoms, the true incidence of severe disease in children is unclear. Data on perinatal vertical transmission to neonates are limited to small case series with conflicting results; some studies have demonstrated lack of transmission, whereas others have not been able to definitively rule out this possibility.12-14 Specific guidance on the diagnosis and management of COVID-19 in neonates born to mothers with known or suspected SARS-CoV-2 infection is provided by the CDC.
Insufficient data are available to clearly establish risk factors for severe COVID-19 disease in children. Based on adult data and extrapolation from other pediatric respiratory viruses, severely immunocompromised children and those with underlying cardiopulmonary disease may be at higher risk for severe disease. Children with risk factors recognized in adults, including obesity, diabetes, and hypertension, may also be at risk, although there are no published data supporting this association and insufficient data to guide therapy. Guidance endorsed by the Pediatric Infectious Diseases Society has recently been published, which provides additional specific risk categorization when considering therapy.15 As data emerge on risk factors for severe disease, it may be possible to provide more directed guidance for specific populations at high risk for COVID-19 and to tailor treatment recommendations accordingly.
Currently, there are no Food and Drug Administration (FDA)-approved agents for the treatment of COVID-19. Based on preliminary clinical trial data, the investigational antiviral agent remdesivir is recommended for the treatment of COVID-19 in hospitalized patients with severe disease (see Remdesivir for detailed information). Of note, remdesivir has not been evaluated in clinical trials that include children with COVID-19. Remdesivir is available for children through an FDA Emergency Use Authorization or through a compassionate use program.
For other agents outlined in these guidelines, there are insufficient data to recommend for or against the use of specific antivirals or immunomodulatory agents for the treatment of COVID-19 in pediatric patients. General considerations such as underlying conditions, disease severity, and potential for drug toxicity or drug interactions may inform management decisions on a case-by-case basis. Enrollment of children in clinical trials should be prioritized when trials are available. A number of additional drugs are being investigated for the treatment of COVID-19 in adults; clinicians can refer to the Antiviral Therapy and Immune Based Therapy sections of these guidelines to review special considerations for use of these drugs in children and refer to Table 2 and Table 3b for dosing recommendations in children.
Multisystem Inflammatory Syndrome in Children
Emerging reports from Europe and the United States have suggested that COVID-19 may be associated with MIS-C (also referred to as pediatric multisystem inflammatory syndrome–temporally associated with SARS-CoV-2 [PMIS-TS]). The syndrome was first described in the United Kingdom, where previously healthy children with severe inflammation and Kawasaki disease-like features were identified to have current or recent infection with SARS-CoV-2.16,17 Additional cases of MIS-C have been reported in other European countries, including Italy and France.18,19 Emerging data suggest that MIS-C may be associated with pediatric patients who are slightly older than children typically seen with Kawasaki disease, and some cases of MIS-C in young adults have been reported.
In the United States, from April 16 through May 4, 2020, the New York City Department of Health and Mental Hygiene received reports of 15 hospitalized children with clinical presentation consistent with MIS-C. Subsequently, the New York State Department of Health has been investigating several hundred cases and a few deaths in children with similar presentations, many of whom tested positive for SARS-CoV-2 infection by reverse transcriptase polymerase chain reaction (PCR) or serology.20 Several other states are now reporting cases consistent with MIS-C.
The current case definition for MIS-C can be found on the CDC website. This case definition, which may evolve as more data become available, includes:
- Fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multiorgan involvement, and
- No alternate diagnosis, and
- Recent or current SARS-CoV-2 infection or exposure to COVID-19.
From the available data, patients with MIS-C present with persistent fever, evidence of systemic inflammation, and a variety of signs and symptoms of multiorgan system involvement, including cardiac, gastrointestinal, renal, hematologic, dermatologic, and neurologic involvement.
Some patients who meet criteria for MIS-C also meet criteria for complete or incomplete Kawasaki disease. An observational study compared data from Italian children with Kawasaki-like illness that was diagnosed before and after the onset of the SARS-CoV-2 epidemic. The data suggest that the SARS-CoV-2-associated cases occurred in children who were older than the children with Kawasaki-like illness diagnosed prior to the COVID-19 epidemic. In addition, the rates of cardiac involvement, associated shock, macrophage activation syndrome, and need for adjunctive steroid treatment were higher for the SARS-CoV-2-associated cases.18 Many patients with MIS-C have abnormal markers of cardiac injury or dysfunction, including troponin and brain natriuretic protein. Echocardiographic findings include impaired left ventricular function, as well as coronary artery dilations, and rarely, coronary artery aneurysms. At presentation, few patients are SARS-CoV-2 PCR positive (nasopharyngeal or nasal swab or stool sample), but most have detectable antibodies to SARS-CoV-2. Emerging observations suggest that there may be a wider range of severity of symptoms than initially recognized. Epidemiologic and clinical data suggest that MIS-C may represent a post-infectious inflammatory phenomenon rather than a direct viral process. The role of asymptomatic infection and the pattern of timing between SARS-CoV-2 infection and MIS-C are not well understood, and currently a causal relationship is not established.
Currently, there is limited information available about risk factors, pathogenesis, clinical course, and treatment for MIS-C. Supportive care remains the mainstay of therapy. There are currently insufficient data for the COVID-19 Treatment Guidelines Panel to recommend either for or against any therapeutic strategy for the management of MIS-C. Although no definitive data are available, many centers consider the use of intravenous immune globulin, steroids, and other immunomodulators (including interleukin-1 and interleukin-6 inhibitors) for therapy, and antiplatelet and anticoagulant therapy. The role of antiviral medications that specifically target SARS-CoV-2 is not clear at this time. MIS-C management decisions should involve a multidisciplinary team of pediatric specialists in intensive care, infectious diseases, cardiology, hematology, and rheumatology.
- 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32193831.
- Cui Y, Tian M, Huang D, et al. A 55-day-old female infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage. J Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179908.
- Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32112072.
- Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus disease 2019 (COVID-19) with high viral load. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32112082.
- Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2,143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32179660.
- Centers for Disease Control and Prevention. Coronavirus Disease 2019 in Children—United States, February 12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm. Accessed June 5, 2020.
- Cui X, Zhang T, Zheng J, et al. Children with coronavirus disease 2019 (covid-19): a review of demographic, clinical, laboratory and imaging features in 2,597 pediatric patients. J Med Virol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32418216.
- Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32181795.
- Tagarro A, Epalza C, Santos M, et al. Screening and severity of coronavirus disease 2019 (COVID-19) in children in Madrid, Spain. JAMA Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32267485.
- DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in children and young adults in the Washington, DC metropolitan region. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405091.
- Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease 2019 (COVID-19) at a Tertiary Care Medical Center in New York City. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
- Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395(10226):809-815. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32151335.
- Fan C, Lei D, Fang C, et al. Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry? Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32182347.
- Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32215598.
- Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32318706.
- Royal College of Paediatrics and Child Health. Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. 2020. Available at: https://www.rcpch.ac.uk/sites/default/files/2020-05/COVID-19-Paediatric-multisystem-%20inflammatory%20syndrome-20200501.pdf. Accessed May 28, 2020.
- Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386565.
- Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32410760.
- Toubiana J, Poirault C, Corsia A, et al. Outbreak of Kawasaki disease in children during COVID-19 pandemic: a prospective observational study in Paris, France. medRxiv. 2020:[Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.05.10.20097394v1.
- New York State. Childhood inflamatory disease related to COVID-19. 2020; https://coronavirus.health.ny.gov/childhood-inflammatory-disease-related-covid-19. Accessed June 1, 2020.