The surge of the SARS-CoV-2 Omicron variant (B.1.1.529) coincided with new treatment options for mild and moderate COVID-19 in high-risk adolescents and adults. The oral antivirals nirmatrelvir/ritonavir and monoclonal antibody sotrovimab1 were given Emergency Use Authorization (EUA) in the US for children ≥12 years of age, although studies leading to their approval did not include pediatric patients.2,3 Furthermore, a 3-day course of remdesivir reduced hospitalizations in high-risk outpatients but the study included only 8 patients <18 years of age.4 Molnupiravir was also only studied in adult patients and not authorized for children.5 In sum, data describing the use of any of these agents in pediatric patients is limited.
Based on US Food and Drug Administration (FDA) EUA criteria, pediatric-specific guidance,6 and national prioritization schema,7 our institution prioritized monoclonal antibodies and early antivirals for individuals who were severely immunocompromised or incompletely vaccinated with risk factors including severe obesity, medical complexity with respiratory technology dependence, or multiple other risk factors. Overall, 95% of SARS-CoV-2 strains were Omicron variant in our region by late December 2021.8 Here, we describe characteristics of patients approved and not approved for therapy, treatment-related process measures and short-term outcomes associated with early COVID-19 therapy in high-risk pediatric patients.
MATERIALS AND METHODS
In early 2021, our tertiary care children’s hospital established a COVID-19 Therapeutics Committee to review requests for early treatment of SARS-CoV-2 infection in high-risk patients. This Committee consisted of experts in Infectious Diseases, Emergency Medicine, and Pharmacy. The Committee added new antiviral therapies and monoclonal antibodies for the treatment of mild and moderate infection as these agents became available. Requests came primarily from pediatric subspecialty providers at our institution; however, community providers also applied for therapy for their patients. We encouraged requests for symptomatic severely immunocompromised patients including transplant and oncology patients, those with primary immunodeficiencies, severe obesity, or significant underlying cardiac or pulmonary conditions or other medical complexities (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/E847, for further definition of high-risk conditions). However, providers could submit an intake for any potentially eligible patient, including those who were asymptomatic. Mild COVID-19 was defined as symptoms of viral illness or upper respiratory tract infection and moderate infection included patients with signs or symptoms of pneumonia without sustained hypoxia. The intake process required submission of information about patient age, weight, underlying condition(s), SARS-CoV-2 test positivity (type of test and date), symptom onset, and vaccination status.
To determine which treatment(s) to offer, we considered each individual’s age and weight, geographic location, vaccination status and ability to respond to vaccination, potential drug interactions, underlying renal and liver function and current infusion center or inpatient bed availability. We prioritized oral therapy (nirmatrelvir/ritonavir) when a patient was not hospitalized and eligible based on timing of infection, age and drug interactions. For those for whom nirmatrelvir/ritonavir was not an option, a monoclonal antibody (sotrovimab) was considered next during periods when it was available. Administration in our outpatient infusion center was preferred; when not possible, the Emergency Department (ED) was used for administration. A 3-day course of remdesivir was favored for eligible patients <12 years of age or <40 kg, patients who were already hospitalized, and patients who were not eligible for other therapies. As with the monoclonal antibody therapy, infusion of remdesivir in the outpatient infusion center was arranged when possible; if necessary, a patient could receive dosing in the ED or as an inpatient. Assessment of baseline renal and hepatic function was recommended before remdesivir administration. See Table, Supplemental Digital Content 2, https://links.lww.com/INF/E848) for treatment prioritization schema.
After IRB approval, medical records for patients for whom early COVID-19 treatment was requested between December 22, 2021, and January 30, 2022, were reviewed for patient demographics, underlying conditions, SARS-CoV-2 vaccination status, days since first symptom or positive test (PCR or rapid antigen), medication adherence, treatment associated adverse events, and ED visits and hospitalizations within 7 days after request intake. A Fisher-Exact test was used to calculate whether there was a significant difference between approved and not approved requests in terms of ethnicity.
RESULTS
COVID-19 treatment requests for 94 patients were reviewed; 66 (70%) received approval for sotrovimab, nirmatrelvir/ritonavir, or remdesivir (Table 1). Molnupiravir was not recommended for any patients. Immunocompromised patients comprised most requests (66%), with malignancy being the most frequent immunocompromising condition. The most common reasons for denial of therapy were fully vaccinated status (46%) and not being considered in the highest risk categories (61%). Supplies of the various agents varied throughout the study time period; nirmatrelvir/ritonavir and sotrovimab were especially limited in the early weeks. Only 1 patient who was deemed eligible did not receive any treatment caused by lack of availability. Self-identified race and ethnicity categorizations were similar between those for whom therapy was approved versus not approved.
TABLE 1. -
Characteristics of Patients for Whom COVID-19 Therapy Was Requested and Approved
| Patient Characteristics |
Therapy Requested (N, %), N = 94 |
Therapy Approved (N, %), N = 66 |
|
Median age in y (range) |
13 (0.6-24) |
12 (0.6-24) |
| <5 |
16 (17) |
12 (18) |
| 5–11 |
20 (21) |
13 (20) |
| 12–17 |
49 (52) |
33 (50) |
| 18+ |
9 (10) |
8 (12) |
|
Gender
|
| Female |
43 (46) |
30 (45) |
|
Ethnicity
|
|
|
| Hispanic |
33 (35) |
24 (36) |
| Non-Hispanic |
61 (65) |
42 (64) |
|
Race
|
| White or Caucasian |
41 (44) |
27 (41) |
| Black or African-American |
5 (5) |
4 (6) |
| Asian |
5 (5) |
2 (3) |
| Hawaiian/Pacific-Islander |
4 (4) |
4 (6) |
| Alaska Native/American-Indian |
3 (3) |
3 (5) |
| Multiple |
7 (7) |
5 (7) |
| Other*
|
23 (24) |
19 (29) |
| Unknown/Refused |
6 (6) |
2 (3) |
|
Underlying condition(s)†
|
| Immunocompromised |
62 (66) |
45 (68) |
| Malignancy |
29 (31) |
23 (35) |
| Solid organ transplant |
9 (10) |
7 (11) |
| Hematopoietic cell transplant |
4 (4) |
3 (5) |
| Primary immunodeficiency |
6 (6) |
5 (8) |
| Rheumatologic condition |
5 (5) |
3 (5) |
| Other immunocompromise |
9 (10) |
4 (6) |
| Obesity |
13 (14) |
12 (18) |
| Chronic lung disease |
17 (18) |
11 (17) |
| Chronic kidney disease |
4 (4) |
2 (3) |
| Congenital heart disease |
6 (6) |
3 (5) |
| Diabetes mellitus |
3 (3) |
1 (2) |
| Sickle cell disease |
1 (1) |
1 (2) |
|
Vaccine status
|
| Ineligible (<5 y of age) |
16 (17) |
12 (18) |
| Unknown |
1 (1) |
1 (2) |
| Eligible (5+ y of age) |
77 (82) |
53 (80) |
| 0 doses |
35 (37) |
28 (42) |
| 1 dose |
6 (6) |
6 (9) |
| 2 doses |
25 (27) |
15 (23) |
| 3 doses |
11 (12) |
4 (6) |
|
Not approved (N = 28)‡
|
| Fully vaccinatedc
|
13 (46) |
N/A |
| Not in highest risk categories |
17 (61) |
|
| Too late in infection§
|
4 (14) |
|
| No treatment available |
1 (4) |
|
| Tixagevimab/cilgavimab recipient |
1 (4) |
|
*The majority of those who chose “Other” race also chose Hispanic ethnicity.
†Patients may have more than 1 indication.
‡Defined as ≥2 doses of SARS-CoV-2 vaccination per Centers for Disease Control guidance.
§Defined as ≥7 d for patients <12 y of age and ≥10 d for patients ≥12 y of age.
Median age of children who received therapy was 16, 14.5 and 8 years for sotrovimab, nirmatrelvir/ritonavir and remdesivir, respectively (see Table, Supplemental Digital Content 3, https://links.lww.com/INF/E849). Median days from start of infection to first dose of therapy was 3 for sotrovimab (range: 0–6) and nirmatrelvir/ritonavir (range: 1–6) and 2 (range: 0–9) for remdesivir. Therapy was not given to 19 patients, despite approval, most often because of family refusal or improving symptoms. Two patients did not receive remdesivir because baseline ALT was too high. Remdesivir treatment occurred most frequently in the inpatient setting (59% of the time), while sotrovimab was administered more often in the outpatient infusion center (55% of the time). Adverse events were rare following all agents; 1 patient had chest pain during infusion of sotrovimab and for 2 days after, leading to an ED visit. Another patient was seen in the ED for an episode of shortness of breath during a course of nirmatrelvir/ritonavir. Both were discharged in good condition. No patients had a rise in alanine aminotransferase or creatinine after remdesivir. Three patients were hospitalized during the 7-day follow-up period for potentially COVID-19 related disease: one who was not approved for treatment, one who was approved for sotrovimab but did not receive it, and one after treatment with remdesivir. See Table, Supplemental Digital Content 3, https://links.lww.com/INF/E849, for further details.
DISCUSSION
We provide one of the first descriptions of early COVID-19 treatment in high-risk pediatric patients infected with the Omicron variant of SARS-CoV-2. We found that these therapies were generally well-tolerated and subsequent COVID-19-related ED visits or hospitalizations were uncommon. Although logistical challenges because of both medication supply and administration were present during the study period, they did not significantly impact our ability to provide therapy to those deemed eligible by our internal criteria.
While most SARS-CoV-2 infected children do well without therapy, treatment of mild or moderate infection should be considered in those at highest risk of progression to severe disease. Recent data demonstrates that hospitalization rates in children 0–4 years increased significantly during times of Omicron-variant predominance; information regarding treatment in pediatric patients has thus become even more important.9 However, despite FDA EUA for sotrovimab and nirmatrelvir/ritonavir, and now bebtelovimab,10 in patients ≥12 years of age and more recent FDA approval of remdesivir for children <12 years, safety and efficacy data for these agents in pediatric patients remain scarce. In this study, we begin to demonstrate the feasibility of allocation and administration of these agents in pediatric patients, especially high-risk outpatients.
Several patients in our study received therapy as inpatients. These were generally patients hospitalized for reasons other than COVID-19 who were found to be positive for SARS-CoV-2 during admission screening or patients for whom outpatient administration of IV therapeutics was not feasible because of limited capacity in our infusion center or ED. Remdesivir most required inpatient admission due to the need for multiple intravenous doses over several days. As availability of nirmatrelvir/ritonavir has increased in the ensuing months since our study, admissions solely for the administration of remdesivir decreased.
Many patients who were approved for therapy did not ultimately receive it. Reasons for this varied by therapy but family refusal was most common in those approved for remdesivir. Other reasons included symptoms improving without therapy and preremdesivir baseline ALT being too high. Only one patient did not receive therapy because of limited infusion center capacity.
Although we saw no indicators of disparities in our approval process, we continue work to explore potential equity issues as documented in the distribution of COVID-19 therapies in adults.11,12 Disparities before the actual referral submission would not be visible in our analysis as we did not include all patients who were potentially eligible for COVID-19 treatment.
Limitations of this study include its observational and retrospective nature, lack of controls, small sample size at a single center, short follow-up period, and the possibility that not all events and outcomes were reported in the medical record. Given this, the efficacy of these treatments could not be assessed. In addition, systematic monitoring of adverse events was not performed. As symptomatic patients with severe underlying conditions were more likely to have therapies requested and approved, assessment of treatment impact on broader populations is difficult. Larger studies examining the safety and efficacy of early treatment of COVID-19 specifically in high-risk pediatric patients are required.
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