The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now led to the infection of over 13.5 million children in the United States.1 The morbidity and mortality from COVID-19 is higher in pediatric patients with comorbid conditions including obesity and immunodeficiency.2 Therapeutic options to treat mild to moderate infections in adult and adolescent outpatients at increased risk for progression to severe COVID-19 include antivirals and monoclonal antibodies. Safety and efficacy data are minimal in children and adolescents who have received monoclonal antibodies for COVID-19, and there is less experience with their use in pediatric patients. Here, we present serious adverse reactions associated with the monoclonal antibody bebtelovimab in 2 adolescents.

Case 1 is a 16-year-old male who had congenital posterior urethral valves, which led to end-stage kidney disease resulting in a renal transplant in August 2021. His current immunosuppressive regimen included mycophenolate and tacrolimus. He was fully vaccinated and received a booster against COVID-19 1 year and again 5 months before presentation, respectively. He tested positive for SARS-CoV-2 on a home antigen test 4 days before coming to the infusion center. His symptoms included sore throat, cough, rhinorrhea, and fatigue. His creatinine was 1.14 mg/dL. He was eligible to receive bebtelovimab owing to his age >12 years, weight >40 kg, and immunocompromised status.

Bebtelovimab 175 mg was administered over 1 minute per manufacturer’s instructions through a peripheral IV and flushed slowly through the IV according to standard practice in our unit. Within 2 minutes, the patient began complaining of difficulty breathing. On examination, he was flushed in appearance with notable agitation and respiratory distress. He had marked facial swelling. No urticaria were noted, but the skin over his face and trunk was flushed. No wheezing was heard on chest auscultation. Oxygen, intramuscular epinephrine, and intravenous diphenhydramine were administered. The patient’s respiratory symptoms resolved within 5 minutes; facial swelling improved. He was admitted overnight to observe for possible rebound symptoms of anaphylaxis. He was discharged home the following morning after an uneventful night.

Case 2 is a 15-year-old female with moderate persistent asthma managed with inhaled steroids and albuterol. She was fully vaccinated against COVID-19 vaccination and received a booster dose 1 year and again 5 months before presentation, respectively. She tested positive for SARS-CoV-2 4 days before coming to the infusion center on day 6 of her illness. She had a sporadic cough but no other symptoms. She was eligible for bebtelovimab owing to her age >12 years, weight >40 kg, and her chronic respiratory condition of asthma.

Informed by the previous experience with case 1, and with the current patient’s atopic tendencies, the care team opted to administer intravenous diphenhydramine before administering bebtelovimab 175 mg IV over 1 minute. The medication was flushed slowly through the IV tubing over 1 minute. Two minutes following administration, the patient reported abdominal discomfort and difficulty breathing. She developed diffuse flushing. On examination, she was dyspneic. There was no swelling of her lips or tongue and no urticarial lesions. Lungs were clear to auscultation. Oxygen was administered via facemask. She was given a dose of intramuscular epinephrine, followed by intravenous diphenhydramine, and her symptoms improved within minutes. She was discharged from the infusion center 3 hours later with a prescription for an epinephrine injector in the event of rebound symptoms.

DISCUSSION Preventing the Progression of Mild or Moderate COVID-19

There are several options for management of outpatients with mild or moderate COVID-19, which aim to prevent disease progression resulting in hospitalization or death. These therapeutic options are specifically aimed toward adolescents and adults who are at risk for hospitalization or death from COVID-19 and are not intended for general use. Choosing an optimal therapy should be informed by multiple considerations, including an individual patient’s risk factors for severe COVID-19, potential drug-drug interactions, and availability of treatments in a specific geographic area. Our patients’ risk factors for progression to severe COVID-19 were immunosuppression from solid organ transplantation and moderate persistent asthma. Both conditions are associated with “moderate risk of severe COVID-19.”3 Current recommendations from the National Institutes of Health favor the use of Paxlovid (Pfizer, NYC, NY) or Remdesivir (Gilead Sciences, Foster City, CA) in the setting of mild to moderate COVID in adults; if these options are not available or clinically cannot be used, bebtelovimab (Eli Lilly Company, Indianapolis, IN) can be considered.4 However, the paucity of pediatric-specific data has been a limitation in the development of similar recommendations from the American Academy of Pediatrics.5

Potential Therapies in Children

Paxlovid is an attractive first choice as oral treatment in adolescent outpatients at high risk for progression to severe disease, in the absence of potential significant drug-drug interactions. Paxlovid, effective against all variants of SARS-CoV-2, is a combination of 2 protease inhibitors, nirmatrelvir, and ritonavir. Nirmatrelvir is the component with activity against SARS-CoV-2; ritonavir interferes with its degradation and allows higher levels of nirmatrelvir for a longer time. If started within 5 days of onset of symptoms, Paxlovid has shown 89% effectiveness in reducing hospitalizations and death compared with placebo in an unvaccinated population of adult patients at high risk for progression to severe disease.6 While oral medications for home treatment are extremely attractive, the complexities of using Paxlovid are considerable and relate primarily to the large number of potential drug interactions encountered by the infected individuals most likely to benefit from use of the drug. An excellent resource available to guide clinicians is the US Food and Drug Administration Paxlovid Patient Eligibility Screening Checklist, which offers a comprehensive list of drugs and their potential for serious drug interactions with Paxlovid.7 The guidance of a pharmacist is much appreciated in the decision-making process. For example, to administer Paxlovid safely to the patient who had received a renal transplant requires careful management of his tacrolimus dosing, owing to the potential for either (1) toxicity from supratherapeutic drug levels or (2) graft rejection in the setting of subtherapeutic drug levels. For the patient with asthma, no adjustments in dosage would be required, although she was not eligible to receive Paxlovid as she presented on day 6 of illness.

Remdesivir is the next choice for treatment. Remdesivir, an antiviral agent, targets the highly conserved viral RNA-dependent RNA polymerase and is active against all variants of SARS-CoV-2. It is currently approved for use in all pediatric patients >28 days and >3 kg and should be administered within 7 days of the onset of symptoms. Remdesivir requires 3 successive days of intravenous infusions of the drug; it has been shown to result in an 87% lower risk of hospitalization or death than placebo in an unvaccinated population of adult patients at high risk for progression to severe disease.8 Although the safety profile is very acceptable, in our institution a 3-day requirement for the infusion center presents logistic problems for administration over the weekend. Both of our patients would have been eligible for this treatment and presumed to benefit, although neither received remdesivir owing to these logistical constraints.

The last choice is monoclonal antibody. Treatment of COVID-19 adult outpatients at high risk for progression to severe disease with some monoclonal antibodies has reduced the risk of hospitalization and death by up to 85%.9 The administration of monoclonal antibodies requires an intravenous infusion of a one-time dose within 7 days of onset of symptoms. The major impediment to use has been loss of activity against new variants that have appeared and circulated. The single monoclonal antibody retaining activity against currently circulating subvariants of Omicron is bebtelovimab. However, its newness precludes the availability of published or unpublished data on effectiveness in high-risk populations. Before the circulation of the omicron variant, an unpublished trial among low-risk outpatients showed a reduction in time to sustained symptom resolution from 8 to 6 days compared with placebo.10,11 Consequent to their characterization as proteins monoclonal antibodies are known to confer elevated risk for immunogenicity or hypersensitivity reactions.12 However, only 0.3% of patients were reported to have had infusion reactions in the information concerning bebtelovimab,10 which is comparable to rates of infusion reactions for other types of anti-SARS-CoV-2 monoclonal antibodies.3 The unexpected intensity and frequency of both of our patients developing immediate, severe infusion reactions (anaphylaxis) following administration of bebtelovimab prompted us to bring this to attention.

Our Experience With Anti-SARS-CoV-2 Monoclonal Antibodies

Since 2021 and before the availability of bebtelovimab, we treated 27 adolescents with monoclonal antibody infusions against SARS-CoV-2, including bamlanivimab, casirivimab+imdevimab, bamlanivimab+etesevimab, tixagevimab+cilgavimab, and sotrovimab. Of those patients, 3 had symptoms consistent with a mild infusion reaction, including skin flushing or shortness of breath. Since the availability of bebtelovimab, both patients receiving this drug developed severe reactions consistent with anaphylaxis, and 1 required hospitalization overnight. As there are limited data available for health-care providers concerning the risks versus benefits of monoclonal antibody infusions, we present these cases so that outpatient prescribers may better inform their decision-making for the care of patients with COVID-19.

CONCLUSION

Pediatric outcomes of those who receive monoclonal antibody therapies against COVID-19 are rarely described. Here, we report severe infusion reactions for 2 patients receiving bebtelovimab, one of whom required escalation in care, and describe the treatment options to prevent progression of disease in patients with mild or moderate COVID-19. Prescribers of anti-COVID-19 monoclonal antibody therapies should be aware of the potential for severe infusion reactions or anaphylaxis from these medications.

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