Hypersensitivity reactions to multiple biologicals in a pediatric patient with severe persistent asthma

Abstract

Asthma is a common chronic pediatric disease that negatively impacts the quality of patients’ lives. While most cases can be effectively managed with a regimen of inhaled corticosteroids, severe cases require prolonged or frequent courses of oral corticosteroids or the addition of biologic therapies and allergen immunotherapy. Biologics are well tolerated with few side effects; however, reactions as severe as anaphylaxis have been reported. We present a pediatric patient with severe persistent asthma who developed hypersensitivity reactions to three different biologic agents.

Pediatric asthma affects 6 million children in the United States, negatively impacting the quality of patients’ lives.¹ Nearly half of the patients miss days of school each year.² The cost of asthma is estimated as $56 billion in the United States.³ Severe cases have a prevalence of 5% and require prolonged or frequent courses of oral corticosteroids or the addition of biologic therapies and allergen immunotherapy.^4,5 We present a patient with severe persistent asthma who developed hypersensitivity reactions to three biologic agents. At this time, there is only one case report of an adult patient having a severe reaction to three different humanized monoclonal antibodies⁶; this is the first report in a pediatric patient.

CASE PRESENTATION

A 16-year-old girl was diagnosed with severe persistent asthma at age 2. She had allergic rhinitis, obstructive sleep apnea, attention deficit hyperactivity disorder, hereditary thrombophilia, vocal cord dysfunction, and Asperger’s syndrome. She denied chronic urticaria. She had a history of four hospitalizations annually despite treatment with budesonide/formoterol 160/4.5 mcg 2 puffs twice a day, fluticasone/vilanterol 200/25 mcg daily, fluticasone propionate 220 mcg 2 puffs daily, cetirizine 10 mg daily, tiotropium bromide daily, montelukast 10 mg daily, and intranasal fluticasone. She was compliant with the treatment and had proper inhaler device technique. She required oral prednisone for 1 to 2 weeks to control her symptoms; therefore, omalizumab was recommended and started before she visited our clinic. Three and a half hours after the first dose, she developed hives, diffuse erythema, itching, and subjective dyspnea requiring home administration of epinephrine and a visit to the emergency room. Spirometry showed a severe obstructive pattern, the absolute serum eosinophil count was 0.57 10⁹/L, and the fractional exhaled nitric oxide was elevated at 51 ppb. Bronchoscopy, bronchial brush sample, tryptase level, and computed tomography of the chest were normal. A chloride sweat test was normal twice. Whole genome sequencing revealed a variant of unknown significance at p.Q151K in the cystic fibrosis transmembrane conductance regulator protein. Allergy testing was positive for dogs, cats, dust mites, molds, trees, grasses, and weeds.

In the setting of severe persistent eosinophilic asthma, she received mepolizumab subcutaneously after a negative prick test. Three hours later, she had diffuse itchiness and was treated with diphenhydramine. Two and a half hours later, she developed chest tightness and her exam revealed stridor with no wheezing, hives, runny nose, or watery eyes. Her symptoms were felt to be related to vocal cord dysfunction and she received a normal saline nebulizer treatment with resolution within 20 minutes. She was discharged from the office 6 hours after receiving mepolizumab. Eight hours after receiving mepolizumab, she developed hives and was treated in the emergency room with oral diphenhydramine and oral steroids. She continued to have poorly controlled asthma requiring oral steroids, seven emergency room visits, and four hospitalizations per year.

An outside pediatric pulmonologist recommended dupilumab, which is a fully human antibody with low likelihood of causing an adverse reaction, different from the two other biologics which are humanized antibodies (99% vs 90% human component).⁷ Four and a half hours after she received dupilumab in the hospital, she developed hypotension and hives and was treated with intravenous isotonic saline, diphenhydramine and hydrocortisone, and two doses of intramuscular epinephrine, with partial improvement of the systolic blood pressure to the high 80s. She was started on an epinephrine drip because of persistent hypotension, was weaned off the drip on the third day, and was discharged 5 days later.

DISCUSSION

Our patient had severe persistent asthma despite the use of several controller asthma therapies. She did not receive allergen immunotherapy due to the risk of severe asthma exacerbation in poorly controlled asthma; therefore, treatment with biologics was attempted. Based on the time between administration of the drug and the development of symptoms, hypersensitivity reactions can be classified as immediate, with symptoms presenting up to 1 hour after receiving the medication, and nonimmediate or late, with symptoms presenting after 1 hour.^8,9 Immediate hypersensitivity reactions can be immunoglobulin E (IgE) or non-IgE mediated. Some non-IgE–mediated reactions to drugs may be due to mast cell degranulation mediated by the mas-related G protein-couple receptor-X2 (MRGPRX2).¹⁰ Serum tryptase should be collected between 30 and 90 minutes after the episode. In our patient this was not obtained; therefore, comparison with baseline level was not possible.

Reactions as severe as anaphylaxis have been reported in 0.1% to 0.3% of patients, depending on the biologic used, and are more common in females.^7,11 Our patient developed anaphylaxis to omalizumab, urticaria to mepolizumab, and severe protracted anaphylaxis to dupilumab. Skin testing is recommended to assess for IgE antibodies since a positive test is associated with a risk of hypersensitivity reaction on drug reexposure. Desensitization, if the patient is to receive the medication again, has been successful with omalizumab, rituximab, and other monoclonal antibodies.¹² Our patient was offered further evaluation with skin testing for the biologic and additives in these medications but declined.

This report raises the question of whether longer observation or in-hospital observation may be required for some of these patients who have a severe allergic response to one or more biologics.