Pediatric spontaneous‐reporting patterns for biologics approved or used for asthma: Analysis of the FDA adverse event reporting system

Abstract

Background

Pediatric post‐marketing evidence for biologics used for asthma remains limited and uneven across agents. We characterized pediatric spontaneous‐reporting patterns for biologics approved or used for asthma in the FDA Adverse Event Reporting System.

Methods

We analyzed pediatric reports involving omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab from 2015 through 2025. Reports were summarized by age, sex, reporting year, outcomes, and preferred terms. Serious‐outcome and indication‐linked classifications were performed. Disproportionality was assessed using reporting odds ratios, proportional reporting ratios, chi‐square statistics, and information components. Pediatric signals were compared with adult findings and interpreted according to method agreement, report volume, and sparse‐data restrictions.

Results

We identified 5155 pediatric reports. Dupilumab accounted for 3787 reports (73.5%) and omalizumab for 1152 (22.3%). Serious outcomes were reported in 1273 reports (24.7%), with substantial variation across biologics. Dupilumab showed prominent injection‐site, dermatologic, and ocular reporting, whereas omalizumab showed respiratory, asthma‐related, hypersensitivity‐related, and vital‐sign reporting. Of 43 pediatric signals supported by at least two disproportionality criteria, 31 were also identified in adults. After restricting to terms with at least five reports, 33 signals remained for the main analysis. Narrow anaphylaxis‐related domains occurred in 17 dupilumab, 113 omalizumab, 3 mepolizumab, 3 benralizumab, and no tezepelumab reports. Among dupilumab reports, 83.4% were classified as asthma‐related and 15.2% as mixed indications.

Conclusions

Pediatric FAERS reports showed biologic‐specific reporting patterns. These patterns may reflect potential drug‐related events, underlying disease activity, treatment failure, indication mix, monitoring, and reporting practices. The findings are hypothesis‐generating and do not establish incidence, causality, or asthma‐specific safety profiles.

This figure presents pediatric FAERS reports for five biologics approved or used for asthma care, highlights the principal reporting domains observed across agents, and summarizes clinical and reporting contexts that should be considered when interpreting spontaneous‐reporting patterns.

Key message.

Pediatric spontaneous reports showed biologic‐specific reporting patterns, but these patterns may reflect underlying disease, treatment failure, indication mix, monitoring, and reporting practices and should not be interpreted as incidence estimates, causal associations, or asthma‐specific safety profiles.

1. INTRODUCTION

Asthma is one of the most common chronic diseases in children and a leading cause of missed school days, emergency room visits, and hospitalizations. ¹ , ² Although many pediatric patients achieve adequate control with inhaled corticosteroids and stepwise controller therapy, some continue to experience recurrent exacerbations, persistent symptoms, impaired lung function, or corticosteroid dependence. ³ , ⁴ These children often have complex inflammatory phenotypes, overlapping allergic diseases, variable adherence, and substantial treatment burden. ⁵ For this population, biologic therapy has become an increasingly important component of precision asthma care. ⁶ , ⁷ , ⁸

Biologic therapies have shifted severe asthma management from a primarily symptom‐based approach toward pathway‐directed treatment. ⁹ Omalizumab targets immunoglobulin E and has long been used for allergic asthma. ¹⁰ Mepolizumab and benralizumab target the IL‐5 pathway through IL‐5 or IL‐5 receptor alpha, reducing eosinophilic inflammation. ¹¹ , ¹² , ¹³ Dupilumab inhibits IL‐4 and IL‐13 signaling through blockade of IL‐4 receptor alpha, a central pathway in Type 2 inflammation. ¹⁴ Tezepelumab targets thymic stromal lymphopoietin, an upstream epithelial cytokine involved in multiple inflammatory cascades. ¹⁵

Evaluating post‐marketing safety reports for asthma biologics in children presents several challenges. Randomized controlled trials remain essential for determining efficacy and short‐term safety, but pediatric trials are generally smaller than adult trials and may not be powered to detect uncommon, delayed, or phenotype‐specific adverse events. ¹⁶ Trial eligibility criteria may exclude children with severe comorbidity, unstable disease, recent infection, or complex atopic conditions, thereby limiting generalizability to real‐world practice. ¹⁷ In addition, several biologics are used across multiple Type 2 inflammatory diseases, including asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and allergic or eosinophilic disorders. ¹⁸ , ¹⁹ , ²⁰ This overlapping indication structure complicates post‐marketing interpretation because reports may reflect underlying disease activity, comorbid atopy, treatment failure, product‐use issues, or drug exposure.

Spontaneous reporting systems such as the FDA Adverse Event Reporting System (FAERS) provide a complementary source of post‐marketing pharmacovigilance evidence. ²¹ A pediatric‐focused pharmacovigilance approach is particularly important for asthma biologics. Pediatric indications are often established after initial adult approvals, and pediatric post‐marketing reports may therefore accumulate later and unevenly across agents. However, previous pharmacovigilance studies have evaluated biologics in asthma or allergic diseases, but many have focused on all‐age populations, single agents, or broad adverse event categories. Less is known about how pediatric reporting patterns differ across biologics used for asthma, whether pediatric signals are also observed in adult reports, and how serious outcomes, hypersensitivity‐related terms, and indication context contribute to their interpretation.

Accordingly, we conducted a pediatric FAERS study of omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab. We characterized biologic‐specific reporting patterns, serious‐outcome categories, hypersensitivity‐related reporting domains, pediatric–adult signal concordance, and indication‐linked reporting context. The objective was not to estimate incidence, comparative risk, or causality, but to provide a structured, hypothesis‐generating description of pediatric post‐marketing reports for clinicians and pharmacovigilance researchers.

2. METHODS

2.1. Data source

We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS), a publicly available spontaneous‐reporting database maintained by the US Food and Drug Administration. FAERS quarterly data files from the first quarter of 2015 through the fourth quarter of 2025 were downloaded from the FDA quarterly data extracts on May 10, 2026.

FAERS contains reports submitted by health‐care professionals, consumers, manufacturers, and other reporters. Available fields include patient demographics, reported products, coded preferred terms, reporter characteristics, reporting countries, and serious outcomes. Because FAERS is a spontaneous‐reporting system without exposure denominators, report counts do not represent incidence, prevalence, treated‐patient counts, or exposure‐adjusted risk.

2.2. Study drugs and report selection

The study drugs were omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab. These agents were selected because they are approved or used in asthma care and target major inflammatory pathways relevant to severe asthma and Type 2 inflammation. Products were identified from the FAERS drug files using generic names and corresponding brand‐name variants. Drug names were standardized by converting them to uppercase, removing punctuation and spacing inconsistencies, and mapping recognized generic and brand names to the corresponding biologic. The mapping included XOLAIR, NUCALA, FASENRA, DUPIXENT, and TEZSPIRE for omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab, respectively.

For the primary analysis, the analytic dataset was constructed at the report–biologic pair level. Only report–biologic pairs with at least one primary‐suspect (PS) record for the study biologic were included in the primary cohort. Secondary‐suspect (SS), interacting (I), and concomitant (C) records were retained only for descriptive role summarization and were not used as independent inclusion criteria. Role categories were treated as non‐mutually exclusive because a single report could contain multiple DRUG records for the same biologic with different role codes.

Pediatric reports were defined as reports involving patients younger than 18 years or classified in a pediatric age category. Reports with missing exact age but available pediatric age‐group information were retained. Adult reports used for comparative analyses included patients aged 18 years or older. Because several study biologics have indications beyond asthma, particularly dupilumab, the analysis evaluated biologics relevant to asthma care rather than asthma‐indication‐specific incidence. Indication overlap was considered when interpreting all findings.

2.3. Deduplication and variables

After merging the quarterly files, reports were deduplicated according to standard FAERS conventions. For duplicate versions of the same case, the most recent case version was retained using the FAERS case identifier and latest FDA receipt date. The final analytic unit was the deduplicated FAERS report/case.

Extracted variables included age, age group, sex, reporting year and quarter, biologic, MedDRA preferred terms, reporter type, reporting country, event country, drug role, and serious outcomes. Serious outcomes included death, hospitalization, life‐threatening outcome, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, and other serious outcome designations. A composite serious‐outcome variable was defined as the presence of at least one serious outcome.

Age groups were categorized as younger than 2 years, 2–5 years, 6–11 years, and 12–17 years. Sex was classified as female, male, or unknown. Preferred terms were analyzed at the report level; therefore, a report could contain multiple preferred terms.

2.4. Descriptive analysis

Pediatric report characteristics were summarized overall and by biologic using counts and percentages for categorical variables and medians with interquartile ranges for age. Frequently reported preferred terms were summarized overall and by biologic. Reporting trends were described by calendar year and quarter and were interpreted as changes in report counts rather than incidence rates because FAERS lacks exposure denominators.

2.5. Disproportionality analysis

For each biologic–preferred‐term pair, a two‐by‐two contingency table was constructed within the pediatric cohort of reports involving the five study biologics. The comparator group comprised reports involving the other four study biologics. Thus, disproportionality was assessed within a restricted biologic‐comparator cohort rather than against the wider FAERS database. The resulting estimates describe relative reporting enrichment within this restricted cohort and do not represent incidence, comparative clinical risk, or comparisons with the general FAERS reporting population.

We calculated the reporting odds ratio (ROR) with its 95% confidence interval, proportional reporting ratio (PRR), chi‐square statistic, and information component (IC) with its 95% credibility interval. p values for disproportionality analyses were adjusted using the Benjamini–Hochberg false discovery rate procedure across biologic–preferred‐term comparisons. A positive ROR required a lower 95% confidence limit greater than 1. PRR positivity required PRR ≥2, chi‐square ≥4, and at least 3 pediatric reports. IC positivity required a lower credibility limit greater than 0. A signal supported by at least two disproportionality criteria was defined as a biologic–preferred‐term pair meeting at least two of the prespecified ROR, PRR, and IC criteria based on the same underlying FAERS data. The chi‐square statistic was used as part of the PRR criterion and was not treated as an independent signal criterion. Sparse cells, infinite estimates, and very wide intervals were interpreted cautiously. For the main‐text signal table, signals were additionally restricted to at least 5 pediatric reports and support from at least 2 criteria; method‐limited or sparse findings were retained in the Materials S1.

FAERS drug‐role codes (PS, SS, I, and C) were summarized for each biologic at the report–biologic pair level. Because a single report may contain multiple drug records for the same biologic with different role codes, role categories were treated as non‐mutually exclusive.

2.6. Serious outcomes and hypersensitivity‐related reporting

Two report‐level hypersensitivity domains were defined. The narrow anaphylaxis‐related domain included anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, and anaphylactoid shock. The broader hypersensitivity‐related domain additionally included hypersensitivity, drug hypersensitivity, type I hypersensitivity, angioedema, face edema, lip swelling, pharyngeal edema, laryngeal edema, throat tightness, urticaria, flushing, and pruritus. These domains were based on coded preferred terms and were not clinically adjudicated diagnoses. The broad domain was intended to capture hypersensitivity‐related coding patterns rather than clinically confirmed immediate hypersensitivity reactions; individual terms such as pruritus, flushing, and urticaria are nonspecific and may have alternative explanations.

Injection‐related, serum‐sickness‐related, and cytokine‐release‐related terms were examined as exploratory domains. In addition, because head and neck dermatitis has been described in dupilumab‐treated patients with atopic dermatitis, we performed a targeted search for this exact preferred term and for dermatitis‐related terms containing head, neck, facial, face, or scalp descriptors among pediatric dupilumab reports.

Among pediatric omalizumab reports, co‐occurrence analyses assessed whether vital‐sign‐related or respiratory‐related terms appeared in the same report as a narrow or broad hypersensitivity‐related term. Co‐occurrence indicated reporting context only and did not establish temporal sequence, clinical attribution, anaphylaxis, or causality.

2.7. Indication‐linked classification

Indication terms were linked to individual study biologics using the FAERS drug sequence identifier. Reports were classified as asthma‐related when at least one asthma‐related indication term was recorded, non‐asthma‐related when only prespecified non‐asthma indication terms were recorded, mixed when both asthma‐related and non‐asthma‐related indication terms were present, and missing or unclear when no classifiable indication information was available. Because FAERS indication fields may be incomplete or inconsistently coded, these categories were used descriptively and were not considered confirmation of a clinical diagnosis.

2.8. Pediatric–adult signal comparison

For each pediatric biologic–preferred‐term signal, the corresponding adult result was evaluated using the same comparator structure and signal thresholds. Signals were classified as shared pediatric–adult signals when the same biologic–preferred‐term pair met the prespecified criteria in both age groups; signals meeting consensus criteria only in pediatric reports were classified as pediatric‐specific exploratory signals. Adult comparisons were interpreted with consideration of report volume and sparse‐data limitations.

3. RESULTS

3.1. Cohort characteristics

After report selection and deduplication, 5155 pediatric FAERS report–biologic pairs involving the five study biologics were included. Dupilumab accounted for 3787 reports (73.5%), followed by omalizumab (n = 1152, 22.3%), mepolizumab (n = 107, 2.1%), benralizumab (n = 81, 1.6%), and tezepelumab (n = 28, 0.5%) (Table 1 and Figure 1A). The median age was 12 years (interquartile range, 9–15), and 2850 reports (55.3%) recorded male sex, 2225 (43.2%) recorded female sex, and 80 (1.6%) had unknown sex. Most reports involved children aged 6–11 or 12–17 years (Figure 1B). Detailed age‐ and sex‐specific cross‐tabulations are provided in Table S5. At the report–biologic pair level, all 5155 pairs contained at least one PS record; 2207 pairs also contained SS records, none contained I records, and 5 contained C records. Of these, 2944 pairs were PS‐only.

TABLE 1.

Characteristics and serious outcomes of pediatric FAERS reports involving biologic therapies approved or used for asthma.

Biologic	Overall	Dupilumab	Omalizumab	Mepolizumab	Benralizumab	Tezepelumab
Reports, n	5155	3787	1152	107	81	28
Age, median (IQR), years	12 (9–15)	11 (8–14)	12 (10–15)	13 (10–15)	14 (12–16)	15 (14–16.2)
Female, n (%)	2225 (43.2)	1576 (41.6)	544 (47.2)	51 (47.7)	41 (50.6)	13 (46.4)
Male, n (%)	2850 (55.3)	2164 (57.1)	583 (50.6)	50 (46.7)	38 (46.9)	15 (53.6)
Unknown sex, n (%)	80 (1.6)	47 (1.2)	25 (2.2)	6 (5.6)	2 (2.5)	0 (0)
Serious outcome, n (%)	1273 (24.7)	402 (10.6)	766 (66.5)	47 (43.9)	37 (45.7)	21 (75)
Death, n (%)	16 (0.3)	4 (0.1)	10 (0.9)	1 (0.9)	1 (1.2)	0 (0)
Hospitalization, n (%)	604 (11.7)	207 (5.5)	347 (30.1)	28 (26.2)	15 (18.5)	7 (25)
Life‐threatening, n (%)	56 (1.1)	8 (0.2)	41 (3.6)	1 (0.9)	4 (4.9)	2 (7.1)
Disability	40 (0.8)	18 (0.5)	19 (1.6)	1 (0.9)	1 (1.2)	1 (3.6)
Congenital anomaly	5 (0.1)	0 (0.0)	3 (0.3)	1 (0.9)	1 (1.2)	0 (0.0)
Required intervention	5 (0.1)	2 (0.0)	2 (0.2)	1 (0.9)	0 (0.0)	0 (0.0)
Other serious outcome	789 (15.3)	229 (6.0)	498 (43.2)	25 (23.4)	22 (27.2)	15 (53.6)

Note: Data are shown as n (%) unless otherwise indicated. Age is presented as median (interquartile range). Values represent deduplicated FAERS reports rather than unique treated patients or incidence rates. Serious‐outcome categories were defined using FAERS seriousness indicators and were not mutually exclusive; therefore, category‐specific counts do not sum to the number of reports with any serious outcome. “Other serious outcome” is a FAERS seriousness category and does not represent a single clinically homogeneous endpoint.

Abbreviations: FAERS, FDA adverse event reporting system; IQR, interquartile range.

FIGURE 1.

Characteristics of pediatric FAERS reports involving biologic therapies approved or used for asthma. (A) Number of pediatric reports by biologic. (B) Distribution of pediatric reports by age group and sex. (C) Most frequently coded preferred terms in the pediatric cohort. Bars represent report‐level counts rather than unique treated patients, incidence rates, or causal adverse‐event frequencies. Preferred terms may represent reported clinical events, underlying disease manifestations, indications, treatment effectiveness, or product‐use and reporting context. FAERS, FDA adverse event reporting system.

A serious outcome was designated in 1273 reports (24.7%). The proportions varied across biologics, from 10.6% for dupilumab to 75.0% for tezepelumab; however, the latter estimate was based on only 28 reports. Hospitalization was recorded in 604 reports (11.7%), life‐threatening outcomes in 56 (1.1%), disability in 40 (0.8%), and death in 16 (0.3%). Other serious outcome was the most frequently recorded seriousness category (n = 789, 15.3%). Serious‐outcome categories were not mutually exclusive (Table 1).

The most frequently coded preferred terms overall included asthma, cough, dyspnoea, injection site pain, nasopharyngitis, pruritus, rash, headache, eczema, and wheezing (Figure 1C). The complete ranking of the 30 most frequently coded preferred terms is provided in Table S6. Biologic‐specific rankings of the 10 most frequently coded preferred terms are provided in Table S7.

3.2. Temporal reporting patterns

Pediatric reports increased over time, with a marked rise after 2021 (Figure S1A). Dupilumab contributed substantially to the increase in recent years and became the dominant biologic in pediatric reports (Figure S1B,C). When aligned by years since approval, dupilumab showed a steep increase in later post‐approval years, whereas omalizumab showed a more established and variable reporting pattern (Figure S1D,E). Annual reporting counts by biologic are provided in Table S8. These trends reflect spontaneous report counts and should not be interpreted as incidence rates, utilization rates, or changes in absolute risk.

3.3. Pediatric disproportionality signals

The primary analysis identified 43 pediatric signals supported by at least two disproportionality criteria. After restricting to biologic–preferred‐term pairs with at least five reports, 33 signals supported by at least two disproportionality criteria remained (Table 2 and Figure 2). The distribution of FAERS drug‐role codes at the report–biologic pair level is reported in Table S10, confirming that 100% of the final pediatric cohort (5155/5155 report–biologic pairs) contained at least one primary‐suspect record. Consequently, applying a primary‐suspect restriction yielded identical results to the primary analysis.

TABLE 2.

Main supported pediatric disproportionality signals for biologics approved or used for asthma.

Biologic	Preferred term	Pediatric reports	ROR (95% CI)	PRR	IC (95% CrI)	BH‐adjusted p value	Signal class
Benralizumab	Nausea	7	4.52 (2.09–9.81)	3.99	1.68 (0.65–2.71)	.001	Supported by 3 criteria
Benralizumab	Oropharyngeal pain	6	3.51 (1.54–7.98)	3.11	1.38 (0.27–2.49)	.009	Supported by 3 criteria
Dupilumab	Dry skin	94	3.31 (1.74–6.28)	3.4	0.30 (0.01–0.59)	.001	Supported by 3 criteria
Dupilumab	Injection site pain	351	2.56 (1.91–3.45)	2.44	0.25 (0.09–0.40)	<.001	Supported by 3 criteria
Dupilumab	Injection site swelling	162	3.91 (2.32–6.61)	3.9	0.32 (0.09–0.54)	<.001	Supported by 3 criteria
Dupilumab	Skin exfoliation	69	4.63 (1.94–11.06)	4.99	0.34 (0.00–0.68)	.003	Supported by 3 criteria
Dupilumab	Conjunctivitis	45	2.21 (1.02–4.79)	2.32	0.23 (−0.19–0.65)	.114	Supported by ≥2 criteria
Dupilumab	Dry eye	38	9.36 (1.83–47.89)	13.73	0.40 (−0.05–0.86)	.026	Supported by ≥2 criteria
Dupilumab	Injection site erythema	118	2.36 (1.44–3.86)	2.37	0.24 (−0.02–0.50)	.003	Supported by ≥2 criteria
Dupilumab	Injection site rash	43	2.88 (1.18–7.01)	3.11	0.28 (−0.15–0.71)	.06	Supported by ≥2 criteria
Dupilumab	Ocular hyperaemia	84	3.27 (1.66–6.40)	3.37	0.30 (−0.01–0.60)	.003	Supported by ≥2 criteria
Dupilumab	Rash macular	27	4.00 (1.09–14.61)	4.88	0.33 (−0.20–0.87)	.096	Supported by ≥2 criteria
Dupilumab	Skin fissures	28	6.91 (1.34–35.74)	10.11	0.39 (−0.14–0.92)	.063	Supported by ≥2 criteria
Dupilumab	Sleep disorder	39	2.61 (1.07–6.39)	2.82	0.27 (−0.18–0.72)	.095	Supported by ≥2 criteria
Mepolizumab	Headache	13	2.93 (1.63–5.27)	2.62	1.26 (0.49–2.03)	.002	Supported by 3 criteria
Omalizumab	Application site pain	6	45.40 (2.56–806.45)	Inf	1.82 (0.71–2.93)	.022	Supported by 3 criteria
Omalizumab	Asthmatic crisis	61	90.18 (25.42–319.96)	105.98	2.08 (1.72–2.44)	<.001	Supported by 3 criteria
Omalizumab	Blood pressure decreased	83	625.14 (38.75–10086.32)	Inf	2.13 (1.82–2.44)	<.001	Supported by 3 criteria
Omalizumab	Blood pressure diastolic decreased	7	52.42 (2.99–918.64)	Inf	1.86 (0.83–2.89)	.018	Supported by 3 criteria
Omalizumab	Blood pressure increased	8	59.47 (3.43–1031.11)	Inf	1.89 (0.92–2.86)	.014	Supported by 3 criteria
Omalizumab	Blood pressure systolic increased	14	101.98 (6.08–1710.88)	Inf	2.00 (1.26–2.74)	.005	Supported by 3 criteria
Omalizumab	Body temperature decreased	13	94.86 (5.63–1597.04)	Inf	1.99 (1.22–2.76)	.006	Supported by 3 criteria
Omalizumab	Bronchial obstruction	7	52.42 (2.99–918.64)	Inf	1.86 (0.83–2.89)	.018	Supported by 3 criteria
Omalizumab	Face oedema	6	45.40 (2.56–806.45)	Inf	1.82 (0.71–2.93)	.022	Supported by 3 criteria
Omalizumab	Gastrointestinal disorder	15	36.36 (6.79–194.56)	52.12	1.93 (1.21–2.65)	<.001	Supported by 3 criteria
Omalizumab	Haemoptysis	6	45.40 (2.56–806.45)	Inf	1.82 (0.71–2.93)	.022	Supported by 3 criteria
Omalizumab	Heart rate decreased	27	65.20 (12.59–337.69)	93.82	2.02 (1.49–2.56)	<.001	Supported by 3 criteria
Omalizumab	Hypotension	7	52.42 (2.99–918.64)	Inf	1.86 (0.83–2.89)	.018	Supported by 3 criteria
Omalizumab	Lower respiratory tract infection	25	36.20 (9.86–132.91)	43.44	1.96 (1.40–2.52)	<.001	Supported by 3 criteria
Omalizumab	Respiratory tract inflammation	6	45.40 (2.56–806.45)	Inf	1.82 (0.71–2.93)	.022	Supported by 3 criteria
Omalizumab	Rhinitis	13	31.61 (5.84–171.01)	45.17	1.90 (1.13–2.67)	<.001	Supported by 3 criteria
Omalizumab	Tonsillitis	6	45.40 (2.56–806.45)	Inf	1.82 (0.71–2.93)	.022	Supported by 3 criteria
Omalizumab	Type I hypersensitivity	5	38.38 (2.12–694.60)	Inf	1.77 (0.56–2.97)	.027	Supported by 3 criteria

Note: The table includes biologic–preferred‐term pairs reported in at least five pediatric reports and supported by at least two disproportionality methods. Comparators were pediatric reports involving the other four study biologics. Signals were classified as “supported by 3 criteria” when they met the prespecified ROR, PRR, and IC criteria, and as “supported by ≥2 criteria” when they met at least two of these criteria. These criteria were calculated using the same underlying FAERS data and should not be interpreted as independent replication. Estimates describe relative reporting enrichment and do not represent incidence, causality, or comparative clinical risk. Infinite PRR values arose when no corresponding reports were present in the comparator group.

FIGURE 2.

Main supported pediatric disproportionality signals for biologics approved or used for asthma. The bubble plot presents biologic–preferred‐term pairs reported in at least five pediatric reports and supported by at least two prespecified disproportionality criteria. Bubble size represents the number of pediatric reports, color represents the log2‐transformed reporting odds ratio, and shape indicates the number of criteria met: Circles denote signals supported by three criteria (ROR, PRR, and IC), whereas triangles denote signals supported by at least two criteria. These criteria were calculated using the same underlying FAERS data and therefore represent method agreement rather than independent replication. Estimates describe reporting enrichment within the restricted five‐biologic comparator cohort and do not establish incidence, causality, or comparative clinical risk.

The presence of a disproportionality signal does not imply a drug‐related adverse event: respiratory and vital‐sign terms may reflect underlying disease activity, treatment failure, or post‐administration monitoring and stimulated reporting, whereas injection‐site, dermatologic, and ocular terms are more plausibly linked to direct drug exposure. Dupilumab signals clustered in injection‐site, dermatologic, and ocular domains. Omalizumab signals included respiratory, vital‐sign, and hypersensitivity‐related terms. Mepolizumab showed one supported main‐text signal (headache), while benralizumab showed two (nausea and oropharyngeal pain). No tezepelumab signal met the main‐text threshold. Several omalizumab estimates were large or infinite because corresponding preferred terms were absent among comparator biologics; these indicate marked reporting enrichment within the restricted cohort rather than incidence or comparative clinical risk. Additional sparse or method‐limited exploratory signals are presented in Table S9. These findings were not included among the main supported signals because they were based on small pediatric case counts or limited method agreement.

3.4. Pediatric‐adult signal concordance

Of the 43 pediatric signals supported by at least two disproportionality criteria, 31 also met the same criteria in the corresponding adult analysis, yielding an overall adult concordance of 72.1%. Concordance increased to 87.9% after restricting the analysis to pediatric preferred terms with at least five reports and to 91.2% after restricting the analysis to biologics with at least 100 pediatric reports. Twelve signals were classified as pediatric‐specific in the primary analysis, but most were based on small pediatric counts or were not stable under sensitivity restrictions (Tables S1 and S2). These findings indicate that apparent pediatric specificity was sensitive to report volume and sparse data.

3.5. Anaphylaxis‐ and hypersensitivity‐related reporting

Narrow anaphylaxis‐related reporting domains were observed in 17 dupilumab reports (0.4%), 113 omalizumab reports (9.8%), 3 mepolizumab reports (2.8%), 3 benralizumab reports (3.7%), and no tezepelumab reports (Table 3). Broader hypersensitivity‐related domains were observed in 367 dupilumab reports (9.7%), 316 omalizumab reports (27.4%), 12 mepolizumab reports (11.2%), 13 benralizumab reports (16.0%), and 10 tezepelumab reports (35.7%). The tezepelumab percentage was based on only 28 total reports and should therefore be interpreted cautiously.

TABLE 3.

Anaphylaxis‐ and hypersensitivity‐related reporting domains in the pediatric cohort.

Biologic	Dupilumab	Omalizumab	Mepolizumab	Benralizumab	Tezepelumab
Reports	3787	1152	107	81	28
Narrow anaphylaxis‐related reports, n (%)	17 (0.4%)	113 (9.8%)	3 (2.8%)	3 (3.7%)	0 (0.0%)
Broader hypersensitivity‐related reports, n (%)	367 (9.7%)	316 (27.4%)	12 (11.2%)	13 (16.0%)	10 (35.7%)
Narrow domain with any serious outcome, n	16	111	3	3	0
Narrow domain with hospitalization, n	3	42	1	1	0
Narrow domain with life‐threatening outcome, n	1	18	0	1	0
Narrow domain with death, n	0	0	0	0	0
Broader domain with any serious outcome, n	45	264	8	7	8
Injection‐related reaction reports, n	1	1	0	0	0
Serum sickness‐related reports, n	1	0	0	0	0

Note: Data are report‐level counts or n (%) as indicated. The narrow anaphylaxis‐related domain included anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, and anaphylactoid shock. The broader hypersensitivity‐related domain additionally included hypersensitivity, drug hypersensitivity, type I hypersensitivity, angioedema, face oedema, lip swelling, pharyngeal oedema, laryngeal oedema, throat tightness, urticaria, flushing, and pruritus. Domains were based on coded preferred terms and were not clinically adjudicated diagnoses. A report could contain multiple preferred terms and seriousness categories; therefore, counts were not mutually exclusive. No coded cytokine‐release‐related preferred terms were identified. FAERS reports do not establish incidence, temporal sequence, or causality.

Among reports in the narrow domain, serious outcomes were designated in 16 of 17 dupilumab reports, 111 of 113 omalizumab reports, and all 3 reports for both mepolizumab and benralizumab. No deaths were recorded among narrow‐domain reports. Exact preferred‐term frequencies are provided in Table S3. Among omalizumab reports, narrow anaphylaxis‐related terms co‐occurred with vital‐sign‐related terms in 11 reports and respiratory‐related terms in 35 reports; the corresponding counts for the broader hypersensitivity domain were 58 and 111 reports, respectively (Table S4). Co‐occurrence within the same report does not establish temporal sequence, clinical adjudication, or causality. Targeted searches for the exact preferred term “head and neck dermatitis” among dupilumab reports and for cytokine‐release‐related terms among benralizumab reports identified no corresponding coded terms.

3.6. Indication‐linked classification

Indication‐linked classification showed that 3160 dupilumab reports (83.4%) were asthma‐related, while 576 (15.2%) involved mixed asthma and non‐asthma indications, 8 (0.2%) were non‐asthma‐related, and 43 (1.1%) had missing or unclear indication information (Table 4). Among omalizumab reports, 1084 (94.1%) were asthma‐related, 26 (2.3%) involved mixed indications, 13 (1.1%) were non‐asthma‐related, and 29 (2.5%) were missing or unclear. Asthma‐related classifications accounted for all mepolizumab and tezepelumab reports and 78 of 81 benralizumab reports (96.3%). These classifications were based on coded indication fields and should not be interpreted as clinically adjudicated diagnoses.

TABLE 4.

Indication‐linked classification of pediatric FAERS reports by biologic.

Biologic	Dupilumab	Omalizumab	Mepolizumab	Benralizumab	Tezepelumab
Reports	3787	1152	107	81	28
Asthma‐related, n (%)	3160 (83.4)	1084 (94.1)	107 (100.0)	78 (96.3)	28 (100.0)
Mixed, n (%)	576 (15.2)	26 (2.3)	0 (0.0)	1 (1.2)	0 (0.0)
Non‐asthma‐related, n (%)	8 (0.2)	13 (1.1)	0 (0.0)	1 (1.2)	0 (0.0)
Missing or unclear, n (%)	43 (1.1)	29 (2.5)	0 (0.0)	1 (1.2)	0 (0.0)

Note: Indication terms were linked to the corresponding biologic using the FAERS drug sequence identifier. Asthma‐related reports contained at least one asthma‐related indication term; non‐asthma‐related reports contained only prespecified non‐asthma indication terms; mixed reports contained both asthma‐related and non‐asthma‐related indication terms; and missing or unclear reports had no classifiable indication information. Because FAERS indication fields may be incomplete or inconsistently coded, these descriptive categories do not confirm clinical diagnoses. Values represent reports rather than unique treated patients or incidence rates.

Abbreviation: FAERS, FDA adverse event reporting system.

4. DISCUSSION

In this pediatric FAERS study of biologics approved or used for asthma, we identified distinct biologic‐specific spontaneous‐reporting patterns. Dupilumab reports were characterized mainly by injection‐site, dermatologic, and ocular terms, whereas omalizumab reports showed prominent respiratory, asthma‐related, hypersensitivity‐related, and vital‐sign terms. Most stable pediatric signals supported by at least two disproportionality criteria were also identified in adult reports, while apparent pediatric‐specific signals were sensitive to restrictions based on report volume. These findings provide a structured, hypothesis‐generating description of pediatric reporting patterns rather than estimates of incidence, comparative risk, or causality.

Dupilumab has expanded rapidly across pediatric Type 2 inflammatory diseases, and reports involving dupilumab may include asthma, ²² atopic dermatitis, ²³ eosinophilic esophagitis, ²⁴ allergic comorbidity, ²⁵ or overlapping indications. Thus, the high report count for dupilumab should not be interpreted as evidence of higher risk. It more likely reflects utilization, broader indication footprint, label expansion, patient and clinician awareness, and reporting practices. The dupilumab signal profile was clinically coherent. Injection‐site pain, injection‐site swelling, injection‐site erythema, injection‐site rash, dry skin, skin exfoliation, skin fissures, ocular hyperaemia, conjunctivitis, and dry eye clustered together. ²⁶ , ²⁷ This pattern is consistent with local administration reactions, underlying dermatologic disease activity, and ocular surface events reported with dupilumab, particularly in patients with Type 2 inflammatory disease. No coded preferred term for head and neck dermatitis was identified among pediatric dupilumab reports. Other dermatitis terms were present but do not establish anatomical localization or a specific clinical syndrome. No cytokine‐release‐related term was identified for benralizumab. These absences do not exclude the possibility that such events were captured under nonspecific MedDRA terms or were underreported.

Omalizumab showed a different reporting pattern. ²⁸ Respiratory, asthma‐related, hypersensitivity‐related, and vital‐sign terms were prominent, including asthmatic crisis, bronchial obstruction, type I hypersensitivity, blood pressure decreased, heart rate decreased, and hypotension. These findings may reflect the clinical contexts in which omalizumab is administered and reported. Omalizumab has a long history of use in allergic asthma and is associated with hypersensitivity monitoring. ²⁹ , ³⁰ Several estimates were extremely large or infinite because corresponding preferred terms were concentrated almost entirely within omalizumab reports. These estimates indicate reporting enrichment within this restricted cohort; sparse‐cell inflation is a well‐recognized limitation when comparator cells are near zero, and interpretation should focus on clinical context rather than absolute ROR or PRR magnitude.

Because anaphylaxis is a recognized safety concern, patients may receive enhanced post‐administration observation, increasing the likelihood that blood pressure, heart rate, respiratory, or other clinical changes are documented and reported, particularly when a suspected hypersensitivity event is being evaluated. Stimulated reporting may therefore contribute to the observed disproportionality of some vital sign terms. The respiratory terms may also reflect underlying asthma severity, acute exacerbation, persistent disease activity, treatment failure, or symptoms that prompted medical evaluation. In our report‐level co‐occurrence analysis, hypersensitivity‐related terms appeared in some reports with vital sign or respiratory terms; however, this co‐occurrence does not establish temporal sequence or demonstrate that the reported terms formed part of the same clinical episode. The narrow and broader hypersensitivity‐related domains were based on coded preferred terms and were not clinically adjudicated diagnoses. Accordingly, this analysis neither confirms nor excludes an increased risk of immediate hypersensitivity with omalizumab; it identifies a coded spontaneous reporting pattern that may reflect drug‐related events together with post‐administration monitoring, stimulated reporting, underlying disease severity, and clinical documentation practices.

Asthma‐related PTs require particular caution. Terms such as asthma, asthmatic crisis, drug ineffective, therapeutic response decreased, condition aggravated, and product‐use terms may represent underlying disease activity, treatment failure, indication coding, or product‐use and reporting context rather than adverse drug reactions. In severe pediatric asthma, biologic exposure and disease severity are tightly linked because biologics are preferentially prescribed to children already at high risk of exacerbation, hospitalization, and corticosteroid exposure. ³¹ This creates substantial confounding by indication. Therefore, asthma‐related signals should be framed as reporting patterns related to asthma control or exacerbation context rather than direct adverse drug reactions.

The pediatric‐adult comparison was one of the most clinically informative components of the study. Most stable pediatric signals supported by at least two prespecified disproportionality criteria were also observed in adult reports, particularly dupilumab injection‐site, dermatologic, and ocular signals and omalizumab respiratory or vital‐sign signals. ¹⁰ , ³² This suggests that many pediatric findings reflect broader biologic‐specific reporting profiles rather than uniquely pediatric safety phenomena. Apparent pediatric‐specific signals decreased substantially after sparse‐data restrictions. Thus, the primary message is not that children have numerous unique biologic safety signals, but that pediatric‐specific classifications in spontaneous reporting systems are highly sensitive to small cell counts. Adult findings may therefore provide useful context for pediatric pharmacovigilance, while pediatric‐specific findings should be interpreted conservatively and validated in studies with exposure denominators.

This study has several strengths. It focused specifically on pediatric reports, evaluated multiple biologics approved or used for asthma in a shared analytic framework, used multiple disproportionality methods, classified signals by method agreement, compared pediatric findings with adult reporting patterns, performed sensitivity analyses for sparse data, examined detailed serious‐outcome categories and hypersensitivity‐related reporting domains, and incorporated report‐level co‐occurrence and indication‐linked analyses. Together, these components provide a broader pharmacovigilance overview than a single‐agent or single‐method analysis.

4.1. Limitations

This study also has important limitations. FAERS is a spontaneous reporting database and cannot estimate incidence, prevalence, absolute risk, or comparative risk. Reports may be incomplete, selectively submitted, stimulated by publicity or regulatory attention, and affected by differential reporting across countries, reporters, manufacturers, and time periods. Although reports were deduplicated according to standard FAERS procedures, unrecognized duplication cannot be completely excluded. Exposure denominators are unavailable, and report counts are not equivalent to treated patient counts. Confounding by indication is particularly important in severe asthma because children receiving biologics may already have high baseline risks of exacerbation, infection, hospitalization, and corticosteroid exposure. Preferred terms may reflect symptoms, diagnoses, disease worsening, lack of efficacy, administration issues, or product‐use problems rather than adverse drug reactions. Indication fields may be missing or inconsistently coded, and report‐level co‐occurrence does not establish temporal sequence, clinical diagnosis, or causality. Finally, small pediatric report counts for mepolizumab, benralizumab, and tezepelumab produced unstable estimates with wide confidence intervals. Because included biologics, especially dupilumab, are used across multiple Type 2 inflammatory diseases, the findings should be interpreted as pediatric reporting patterns for asthma‐relevant biologics rather than asthma‐indication‐confirmed safety risks. Finally, because disproportionality was assessed using the other four study biologics as the comparator group rather than the wider FAERS database, alternative comparator selections could produce different disproportionality signals and should therefore be considered when interpreting the findings.

4.2. Clinical implications

These findings may help clinicians place pediatric post‐marketing reports in context rather than infer comparative safety. Dupilumab‐associated reporting should be interpreted with attention to indication mix and underlying Type 2 inflammatory disease, whereas omalizumab‐associated respiratory, hypersensitivity‐related, and vital‐sign terms should be considered in relation to asthma severity, monitored administration, and evaluation of suspected acute reactions. Denominator‐based pediatric studies are needed before these reporting patterns can inform comparative risk estimates.

In conclusion, pediatric FAERS reports involving biologic therapies approved or used for asthma showed distinct biologic‐specific reporting patterns. Dupilumab reports were characterized mainly by injection‐site, dermatologic, and ocular terms, whereas omalizumab reports showed prominent respiratory, asthma‐related, hypersensitivity, and vital‐sign terms. Most stable pediatric signals were shared with adult reports, while apparent pediatric‐specific signals were sensitive to sparse‐data restrictions. These results are hypothesis‐generating and do not establish incidence, causality, comparative risk, or asthma‐specific safety profiles; validation in denominator‐based pediatric studies is needed.

AUTHOR CONTRIBUTIONS

Yue Zhang: Conceptualization; methodology; formal analysis; writing – original draft. Yile Liu: Visualization; software; methodology. Lingli Chen: Investigation; validation; formal analysis. Yating Chen: Investigation; visualization; software. Xiangrong Zheng: Writing – review and editing; conceptualization; supervision.

FUNDING INFORMATION

This work was supported by the Natural Science Foundation of Hunan Province, China (2025JJ90181) and the Degree and Postgraduate Education Reform Project of Central South University (2023JGB116).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

This study used publicly available, de‐identified data from the FDA Adverse Event Reporting System (FAERS) and did not involve direct interaction with human participants. Institutional review board approval and informed consent were not required.

Supporting information

Table S1. Pediatric signals supported by at least two disproportionality criteria with adult comparison.

Table S2. Summary of pediatric‐adult concordance across sensitivity analyses.

Table S3. Exact preferred‐term frequencies within anaphylaxis‐, hypersensitivity‐, respiratory‐, vital‐sign‐, and dermatologic‐related reporting domains.

Table S4. Report‐level co‐occurrence of hypersensitivity‐related, vital‐sign, and respiratory terms among pediatric omalizumab reports.

Table S5. Detailed age and sex cross‐tabulation of the pediatric cohort.

Table S6. Top 30 frequently coded preferred terms in the overall pediatric cohort.

Table S7. Top 10 frequently coded preferred terms by biologic therapy.

Table S8. Annual reporting trends of pediatric asthma biologic reports, 2015–2025.

Table S9. Sparse or method‐limited exploratory disproportionality signals.

Table S10. Drug‐role distribution among pediatric FAERS report–biologic pairs.

Figure S1. Temporal reporting patterns for pediatric FAERS reports involving asthma biologics. (A) Total number of pediatric reports by report year. (B) Annual number of pediatric reports by biologic. (C) Quarterly reporting trends by biologic. (D) Number of reports by years since approval for selected biologics. (E) Percentage of each biologic's pediatric reports by years since approval. Reporting trends reflect spontaneous report counts and should not be interpreted as incidence rates, utilization rates, or changes in absolute risk.

Zhang Y, Liu Y, Chen L, Chen Y, Zheng X. Pediatric spontaneous‐reporting patterns for biologics approved or used for asthma: Analysis of the FDA adverse event reporting system. Pediatr Allergy Immunol. 2026;37:e70495. doi: 10.1111/pai.70495

DATA AVAILABILITY STATEMENT

The raw FAERS data are publicly available from the US Food and Drug Administration FAERS public dashboard and quarterly data files. Processed analysis outputs supporting the findings of this study are provided in the Table S1.