Abstract
Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died.
Keywords: bamlanivimab and etesevimab, casirivimab and imdevimab, COVID-19, monoclonal antibodies, pediatric, SARS-CoV-2
Over 15 million US children have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19) [1]. While most children with COVID-19 are asymptomatic or have a mild illness, some develop severe disease. Pediatric risk factors for hospitalization and death include age <1 year, obesity, diabetes, sickle cell disease, immunocompromising conditions, congenital or acquired heart disease, and chronic respiratory, kidney, and neurodevelopmental disorders [2]. COVID-19 vaccination, authorized in the United States for children ≥6 months old, remains the most effective approach for the prevention of severe disease. However, vaccine immune responses may be inadequate in some children, while others may acquire infection before the completion of vaccination. Children ≥12 years of age and weighing ≥40 kg who have mild to moderate COVID-19 and comorbidities associated with severe disease are eligible for virus-neutralizing monoclonal antibodies (mAbs) under Emergency Use Authorizations (EUAs) issued by the US Food and Drug Administration (FDA).
Four products, bamlanivimab, bamlanivimab and etesevimab, casirivimab and imdevimab, and sotrovimab, were previously authorized but are inactive against more recent SARS-CoV-2 variants [3]. In February 2022, the FDA authorized bebtelovimab, which had in vitro activity against Omicron subvariants circulating at the time [3].
Evidence for use of mAbs to prevent severe COVID-19 in children and adolescents has largely been extrapolated from randomized controlled trials in adults [4–7]. Few studies have evaluated the outcomes of children following mAb therapy. In this retrospective cohort study, we assessed patients treated with mAbs at seven US pediatric centers.
METHODS
Study Population
We included patients aged ≤21 years receiving mAbs for active COVID-19 at seven pediatric academic hospitals from 12/1/20 to 7/31/21. We set no lower age limit because some patients aged <12 years were treated via Single-Patient Expanded Access (“compassionate use”). Each center applied institutional eligibility criteria based on age and comorbidities (Supplementary Table 1). The mAbs in use during this period were bamlanivimab, bamlanivimab and etesivimab, and casirivimab and imdevimab.
Data Collection
We performed chart reviews to obtain data on demographic characteristics, comorbidities, and Social Vulnerability Index (SVI) (a score assigned to each census tract, ranging from 0 [low vulnerability] to 1 [high vulnerability], reflecting social factors [e.g., poverty, lack of access to transportation, crowded housing] that affect a community’s ability to cope with natural or human-caused disasters [8]). We did not include COVID-19 vaccination history as vaccines were not authorized for patients aged 12–15 years until May 2021.
We collected details from all clinical documentation in the patient’s medical record on safety outcomes, including treatment-emergent adverse events (TEAEs) during and within 7 days of mAb therapy, and clinical outcomes, including COVID-19-related emergency department (ED) visits or hospitalizations at the index hospital within 30 days and non-ED outpatient visits at the index hospital within 3 months. A TEAE was defined as any unfavorable medical occurrence, including abnormal physical exam or laboratory finding, symptom, or disease, whether related to mAb therapy or not, with a start date on or after the mAb administration date [9].
Centers submitted deidentified data using a REDCap (Research Electronic Data Capture, Vanderbilt, TN) database hosted by Boston Children’s Hospital. This study was determined to be exempt from federal human subjects regulations by the Boston Children’s Hospital Institutional Review Board.
Statistical Analyses
We used descriptive statistics for analysis, using frequencies and percentages for categorical variables and medians and interquartile ranges for continuous variables. Analyses were performed using Stata BE 17.0 (StataCorp, College Station, TX).
RESULTS
The cohort included 142 patients: 54 patients from Massachusetts, 36 from Michigan, 17 from Connecticut, 15 from New York, 6 from Washington, 9 from Texas, and 5 from Alabama. Their median age was 16.0 years (IQR 14.7–18.0). Three (2%) patients were <12 years old and treated via Single-Patient Expanded Access. Seventy-three patients (51%) were female. Thirty-three (24%) identified as Black, 33 (24%) as Latinx, and 70 (51%) as White (Table 1). The median SVI was 0.36 (IQR 0.17–0.77), suggesting that at least half of the cohort lived in moderate- to high-vulnerability census tracts. Underlying comorbidities included obesity (body mass index ≥35 kg/m2 if ≥18 years of age; ≥95th percentile for age and gender if <18 years of age) in 56 patients (39%), immunocompromising conditions in 45 (32%), neurodevelopmental disorders in 12 (8%), respiratory diseases other than asthma in 8 (6%), heart disease in 4 (3%), and asthma in 7 (5%).
Table 1.
Demographic and Clinical Characteristic
| Patient Characteristic | Number (%) Unless Otherwise Indicated |
|---|---|
| Age, years (IQR, range) | 16 (IQR 15–18, range 2–21) |
| Gender | |
| Female | 73 (51) |
| Male | 68 (48) |
| Transgender female to male | 1 (1) |
| Racea | |
| Asian | 6 (4) |
| Black | 33 (24) |
| Native Hawaiian/Other Pacific Islander | 3 (2) |
| White | 70 (51) |
| Mixed | 1 (1) |
| Other | 24 (18) |
| Hispanic or Latinob | 33 (24) |
| Social Vulnerability Index, median (IQR) | 0.36 (0.16–0.77) |
| Primary underlying chronic condition | |
| Obesityc | 56 (39) |
| Immunocompromise | 45 (32) |
| Oncologic condition | 8 (6) |
| Rheumatologic condition | 8 (6) |
| Hematopoietic stem cell transplant | 6 (4) |
| Primary immunodeficiency | 8 (6) |
| Gastrointestinal condition | 4 (3) |
| Hematologic condition | 4 (3) |
| Kidney transplant | 3 (2) |
| Heart transplant | 2 (1) |
| Liver/intestinal transplant | 2 (1) |
| Neurodevelopmental disorder | 12 (8) |
| Respiratory diseased | 8 (6) |
| Congenital or acquired heart disease | 4 (3) |
| Asthma | 7 (5) |
| Sickle cell disease | 6 (4) |
| Type 1 diabetes | 2 (1) |
| Other | 2 (1) |
| Days from symptom onset to initial positive COVID-19 polymerase chain reaction (PCR), median (IQR, range)e | 1 (IQR 0–3, range 0–8) |
| Days from initial positive COVID-19 PCR to monoclonal antibody therapy, median (IQR, range) | 3 (IQR 1–4, range 2–10) |
aOf 137 patients with available data on race.
bUnknown for four patients (3%).
cBody mass index ≥35 kg/m2 if ≥18 years of age; ≥95th percentile for age and gender if <18 years of age.
dExcluding asthma as solitary condition.
eFor 131 patients with available data whose symptoms started before their initial positive COVID-19 PCR.
The mAb products used included bamlanivimab in 52 patients (37%), bamlanivimab and etesevimab in 53 (37%), and casirivimab and imdevimab (REGEN-COV) in 37 (26%). Of 138 patients with available data, the infusion site was the ED for 40 (29%), non-ED outpatient settings for 74 (54%), and inpatient settings for 24 (17%). The median number of days from symptom onset to the initial positive COVID-19 polymerase chain reaction (PCR) test was zero (IQR 0-1), and from PCR positivity to mAb therapy was one (IQR 1–3).
Adverse events occurred in nine patients (6%) during mAb therapy and four (3%) in the subsequent week (Table 2); six with bamlanivimab-etesevimab, two with casirivimab-imdevimab, and five with bamlanivimab.
Table 2.
Treatment-Emergent Adverse Events
| Age, Years | Primary Underlying Condition | Event |
|---|---|---|
| During monoclonal antibody infusion visit | ||
| 13 | Neurodevelopmental disorder | Reddish/purplish discoloration of face |
| 18 | Sickle cell disease | Chest pain |
| 2 | Immunocompromise—primary immunodeficiency | Anaphylaxis, with manifestations including hives, facial swelling, tachycardia, tachypnea, periorbital cyanosis |
| 14 | Obesity | Chest tightness |
| 12 | Obesity | Eyes burning, itching, and swelling, during and again shortly after infusion |
| 11 | Immunocompromise—rheumatologic condition | Facial flushing, tingling, and sore throat about 20 min after infusion |
| 19 | Neurodevelopmental disorder | Sensation of “heavy” breathing 50 min into infusion. After a dose of cetirizine and repositioning, sensation improved and attributed by patient to congestion due to COVID-19; tolerated rest of infusion. |
| 19 | Immunocompromise—heart transplant | Acute, transient, intermittent sharp anterior chest pain |
| 20 | Immunocompromise—rheumatologic condition | Intermittent mild tachycardia, improved after normal saline bolus |
| Within 1 week of monoclonal antibody therapy | ||
| 20 | Asthma | Wheezing, shortness of breath, and flushing 2 h after monoclonal antibody infusion |
| 15 | Asthma | Severe leg pain with negative evaluation for deep venous thrombosis and improvement over 48 h |
| 20 | Obesity | Shoulder pain and chest pain for 2 days after infusion |
| 20 | Immunocompromise—hematologic condition | Admitted to medical–surgical intensive care unit for intracranial hemorrhage in setting of severe immune thrombocytopenic purpura flare |
Four (3%) patients had COVID-19-related ED visits within 30 days of mAb receipt, three of whom were hospitalized. A total of eight patients (6%) were admitted to the index hospital for COVID-19 within 30 days: four were immunocompromised, while the remaining four had a neurodevelopmental disorder, obesity, sickle cell disease, and respiratory disease, respectively. The median stay was 3 days (IQR 2.0–9.5). No patient received supplemental oxygen or noninvasive or invasive ventilation. No patient was admitted to the intensive care unit, and none died. One patient received systemic corticosteroids, and none received remdesivir. Two patients received immunomodulatory therapy for suspected multisystem inflammatory syndrome in children, each roughly a month after COVID-19 diagnosis. The first presented with fever, dyspnea, and pancytopenia with high inflammatory markers and received intravenous immune globulin (IVIG). The other presented with polyarthritis and received IVIG followed by tocilizumab although graft-versus-host disease was later thought to be the more likely diagnosis.
Of 139 patients with available 3-month follow-up data, 7 (5%) had non-ED outpatient visits for COVID-19-related issues within 3 months of mAb administration (Supplementary Table 2).
DISCUSSION
We have compiled one of the largest pediatric cohorts to date to receive mAbs for the treatment of COVID-19. While our study is primarily descriptive and not designed to evaluate the efficacy of mAb therapy, we found that our cohort’s 30-day rates of COVID-19-related ED visits (3%) and hospitalizations (6%) were higher than in phase II/III mAb trials (0.9–2%) [4, 7, 10]. The differences in hospitalization rates may possibly reflect lower admission thresholds in children, particularly for young or immunocompromised patients for whom admission criteria are protocolized. Additionally, the higher hospitalization rate may be related to the medical complexity of our cohort, all of whom had an underlying chronic condition, about a third of which were immunocompromising conditions. A case–control study by Rainwater-Lovett et al. of 598 patients aged ≥12 years with COVID-19 at a single US medical center demonstrated similar rates of ED visits (1.9%) among the 270 (45%) patients who received bamlanivimab [11]. On the other hand, Webb et al. demonstrated a higher admission rate (12.6%), using a 14-day follow-up period, in their adult case–control study of 7404 patients, 594 of whom received mAb treatment [12]. None of our patients died or received supplemental oxygen, invasive or noninvasive ventilation, or remdesivir, and the majority received no interventions post-mAb treatment.
Infusion-related adverse events were also more frequent in our cohort (6%) than in the aforementioned studies (0–2.3%) [4, 7, 10–12], but total TEAEs (9%) were much less frequent (19–52%). Most of the later TEAEs (Table 2) could be attributed as plausibly to COVID-19 as to mAb therapy.
Limitations of our study include its retrospective design, using data generated primarily for clinical purposes, thereby precluding the assessment of other potential confounders. Second, missing data due to inconsistent documentation, heterogeneity in clinical practices across institutions, and confounding due to healthcare-seeking behavior could have influenced our findings. Third, the lack of the control group limited the robust evaluation of clinical efficacy and safety. Fourth, our findings cannot be generalized to current circulating SARS-CoV-2 variants and the currently authorized mAb, bebtelovimab. Finally, although the study included patients from centers across the United States, the findings may not be generalizable to other countries. Our study’s major strengths include the analysis of a large sample of diverse pediatric cases across several states and the inclusion of children with a variety of chronic illnesses, including a large number with immunocompromising conditions.
Unfortunately, the ongoing pandemic and continued SARS-CoV-2 evolution have led to variants against which most mAb products are not efficacious. All products used in our study cohort are no longer authorized for use, and bebtelovimab, the only mAb available presently, is anticipated to be inactive against the emerging Omicron subvariants BQ.1 and BQ.1.1.
Our study offers evidence that in a cohort of high-risk pediatric patients, administration of mAbs was feasible, and therapy was generally well tolerated. Particularly for patients with contraindications to antivirals or for whom a three-day outpatient remdesivir course is too logistically challenging, mAbs remain an important pediatric therapeutic option.
Supplementary Material
Financial Support. CRO receives support from the National Institutes of Health (NIH) grant number K23AI159518. LG receives support from the Thrasher Research Fund. MMN served as the principal site investigator and her institution received funding from Gilead Sciences, Inc., for a Gilead-sponsored pediatric remdesivir study; participation ended in September 2021.
Potential conflicts of interest. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of NIH.
Contributor Information
Gilad Sherman, Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School.
Gabriella S Lamb, Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School.
Tanvi S Sharma, Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School.
Elizabeth C Lloyd, Department of Pediatrics, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan, USA.
Jerod Nagel, Department of Pharmacy, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan, USA.
Nada N Dandam, Department of Pharmacy, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan, USA.
Carlos R Oliveira, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Hassan S Sheikha, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Brenda I Anosike, Department of Pediatrics, Children’s Hospital at Montefiore, New York, New York, USA.
Philip Lee, Department of Pediatrics, Children’s Hospital at Montefiore, New York, New York, USA.
Surabhi B Vora, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington, USA.
Karisma Patel, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Paul K Sue, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Beenish Rubbab, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
April M Yarbrough, Department of Pharmacy, Children’s of Alabama, Birmingham, Alabama, USA.
Lakshmi Ganapathi, Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School.
Mari M Nakamura, Division of Infectious Diseases, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School; Antimicrobial Stewardship Program, Boston Children’s Hospital, Boston, MA, USA.
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