Prevention and treatment of COVID-19 in pediatric patients
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The number of pediatric COVID-19 cases in the United States has continued to rise.
According to the American Academy of Pediatrics and the Children’s Hospital Association, pediatric cases from Oct. 28 to Nov. 4 numbered 107,350 — 24% of the total weekly reported COVID-19 cases in the U.S. That is more than double the proportion reported around the same time last year.
The increase in cases underscores the importance of prevention and treatment of COVID-19 in children.
Vaccination
On Oct. 29, the FDA authorized the emergency use of the Pfizer-BioNTech vaccine for the prevention of COVID-19 in children aged 5 through 11 years. According to the briefing document provided by Pfizer to the FDA’s Vaccines and Related Biological Products Advisory Committee, the vaccine was evaluated among 1,517 vaccine recipients and 751 placebo recipients aged 5 to younger than 12 years.
Participants received two doses at the recommended interval of 21 days apart and were followed up for at least 2 months after their second dose. The most common adverse events in these children were mild to moderate and occurred within the first 1 to 2 days after dosing. They included injection site pain, fatigue, headache, muscle pain and chills. Most side effects resolved quickly. There were no adverse events leading to withdrawal from the study and no cases of myocarditis or pericarditis through 3 months of follow-up.
The vaccine produced a robust immune response against all variants, including the delta variant, with more than 90% protection against symptomatic COVID-19 and adequate titers to confer protection.
It is extremely important that the Pfizer-BioNTech COVID-19 vaccine formulations be used for their designated patient populations. The pediatric dosing is 10 µg, or one-third of the adolescent and adult dose. The vial with the purple cap is for patients aged 12 years or older, and the vial with the orange cap is for patients aged 5 through 11 years. When the purple cap vial is diluted with 1.8 mL of diluent, it is administered as a dose of 30 µg/0.3 mL. When the orange cap vial is diluted with 1.3 mL of diluent, it is administered as a dose of 10 µg/0.2 mL. Once diluted, these vials are different concentrations and they cannot be interchanged.
Moderna also has tested its vaccine in children and adolescents, reporting levels of protection similar to those seen among adults. However, the FDA has said that it will need more time — perhaps until January — to review the company’s request for an emergency use authorization (EUA) for adolescents aged 12 to 17 years in order to further review the risk for myocarditis in this population.
Because of this, Moderna has said it will postpone filing an EUA request for a 50 µg half-dose of the vaccine for children aged 6 to 11 years.
Remdesivir
Remdesivir was approved by the FDA on Oct. 22, 2020, for the treatment of adults and pediatric patients 12 years or older and weighing at least 40 kg who have COVID-19 and require hospitalization. This was determined as a result of a double-blind, randomized, placebo-controlled trial of remdesivir in adult patients hospitalized with COVID-19 and evidence of lower respiratory tract infection. The data showed that remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19.
However, data are lacking in children, despite an EUA for hospitalized pediatric patients weighing at least 3.5 kg. In Spain, a multicenter cohort study showed that most children receiving remdesivir for COVID-19 experienced successful clinical outcomes. In the aforementioned observational study of eight patients ranging from 4 months to 11.6 years old, patients were dosed with 5 mg/kg of remdesivir on day 1, followed by 2.5 mg/kg on days 2 to 10. Half of the children had underlying medical conditions, and three-quarters required admission to the pediatric ICU. All patients received hydroxychloroquine before receiving remdesivir, and some received azithromycin, lopinavir/ritonavir, corticosteroids and tocilizumab. No patients had elevated liver enzymes over the course of therapy, although liver enzymes may be elevated with remdesivir, and seven of the eight children achieved a successful clinical outcome. The patient who died started remdesivir 11 days after COVID-19 symptoms began. In a case report of a 16-year-old male with obesity, the patient developed sinus bradycardia after a loading dose of remdesivir that improved 2 days after discontinuation. Although rare, this side effect has also been seen in adults, and clinicians should be aware of potential hepatotoxicity and cardiovascular effects with remdesivir in pediatric patients.
Steroids
Steroids have become a mainstay in COVID-19 treatment in adults, but data for children are lacking. In an international observational cohort study of pediatric patients with multisystem inflammatory syndrome following or associated with COVID-19 (MIS-C), patients were treated with IV immune globulin (IVIG) plus glucocorticoids or glucocorticoids alone. In all, 614 children from 32 countries were included in the study, and researchers reviewed outcomes that included a composite of inotropic support or mechanical ventilation by day 2 or later or death and reduction in disease severity on an ordinal scale.
The composite primary outcome occurred in 56 patients receiving IVIG plus glucocorticoids and 17 patients receiving solely glucocorticoids, which was not statistically significant. In addition, disease severity reduction did not differ between the two groups. When the study investigators restricted their analyses to patients who met WHO criteria for MIS-C, they found modest evidence of benefit with glucocorticoids alone over IVIG alone.
Monoclonal antibodies
REGEN-COV is a combination of monoclonal antibodies casirivimab and imdevimab that has been shown to reduce the viral load in patients with COVID-19 and is authorized for emergency use in patients aged 12 years or older and weighing at least 40 kg. The study by Weinreich and colleagues included a cohort of patients aged younger than 18 years who were treated for COVID-19 in the outpatient setting. The primary objective was to evaluate the safety and tolerability of REGN10933+REGN10987, as well as to monitor serum concentrations over time. Results from the phase 3 trial have not yet been shared.
Additional clinical trials are also actively recruiting or preparing to recruit adolescent and pediatric patients for treatment with REGEN-COV. Bamlanivimab and etesevimab constitute another combination of monoclonal antibodies that have been authorized for emergency use by the FDA in pediatric patients aged 12 years or older weighing at least 40 kg. Sotrovimab has also been approved for emergency use in this population. Patients younger than 12 years old have very limited data available to determine appropriate use of monoclonal antibodies.
Conclusion
The NIH last updated its special considerations in children in April 2021. According to the recommendations, remdesivir may be considered in hospitalized children of all ages who have emergent or increasing need for supplemental oxygen. Dexamethasone may be considered for hospitalized children requiring high-flow oxygen, noninvasive ventilation, invasive mechanical ventilation or extracorporeal membrane oxygenation. There is insufficient evidence to recommend monoclonal antibody products for patients who are not hospitalized but have risk factors for severe disease.
The panel recommends consulting a pediatric infectious disease specialist in cases where a monoclonal antibody may seem appropriate because adult studies are currently the most available literature. An evaluation of risks vs. benefits and considerations of limited research must be considered when treating pediatric patients with severe or symptomatic COVID-19. Additional research is still needed to further review vaccinations and treatments for children.
- References:
- American Academy of Pediatrics. Children and COVID-19: State data report. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/. Accessed Nov. 4, 2021.
- Beigel JH, et al. N Engl J Med. 2020;101056/NEJMoa2007764.
- CDC. Pfizer-BioNTech COVID-19 Vaccine: Vaccine dosage chart. Published Nov. 4, 2021. Accessed Nov. 30, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/downloads/Pfizer-Dosage-Chart.pdf.
- Chow EJ, et al. J Pediatric Infect Dis Soc. 2021;doi:10.1093/jpids/piab029.
- Clinicaltrials.gov. Safety, tolerability, and efficacy of anti-spike (S) SARS-CoV-2 monoclonal antibodies for the treatment of ambulatory adult and pediatric patients with COVID-19. Identifier NCT04425629. June 11, 2020.
- FDA approves first treatment for COVID-19. Published Oct. 22, 2020. Accessed Nov. 30, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19.
- FDA authorizes Pfizer-BioNTech COVID-19 vaccine for emergency use in children 5 through 11 years of age. https://www.fda.gov/news-events/press-announcements/fda-authorizes-pfizer-biontech-covid-19-vaccine-emergency-use-children-5-through-11-years-age. Published Oct. 29, 2021. Accessed Nov. 30, 2021.
- Jenco M. Pfizer’s COVID-19 vaccine for kids would require different doses, dilution, storage. American Academy of Pediatrics News. https://publications.aap.org/aapnews/news/15855/Pfizer-s-COVID-19-vaccine-for-kids-would-require. Published Oct. 8, 2021. Accessed Nov. 30, 2021.
- McArdle AJ, et al. N Engl J Med. 2021;10.1056/NEJMoa2102968.
- Méndez-Echevarría A, et al. Eur J Pediatr. 2021;doi:azit10.1007/s00431-020-03876-1.
- Moderna provides update on timing of U.S. emergency use authorization of its COVID-19 vaccine for adolescents. https://investors.modernatx.com/news-releases/news-release-details/moderna-provides-update-timing-us-emergency-use-authorization. Published Nov. 1, 2021. Accessed Nov. 30, 2021.
- NIH. Special considerations in children. Published April 21, 2021. https://www.covid19treatmentguidelines.nih.gov/special-populations/children/.
- Pfizer. BNT162B2 [COMIRNATY (COVID-19 Vaccine, mRNA)]: Vaccines and Related Biological Products Advisory Committee Briefing Document. Published Oct. 22, 2021. Accessed No. 30, 2021. https://www.fda.gov/media/153409/download.
- Walter EB, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2116298.
- Weinreich DM, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2108163.
- For more information:
- Kira Voyer, PharmD, is a PGY1 pharmacy resident at Denver Health Medical Center.
- Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.