Effect‐modifying impact of age on sex‐based differences during oral immunotherapy

Epidemiological studies have consistently reported significant sex-based disparities in the prevalence of atopic disease.1, 2 In food allergy, the 1:1.8 female-to-male ratio observed in children was shown to be completely reversed after puberty at 1:0.53, and then to normalize after menopause.3 This likely reflects the biological effect of sex hormones on mast cells and cytokine production.4 The reason for male predominance during childhood is unknown but may take root in utero.5 There is a lack of data on how sex-based differences impact therapeutic response.6 Here, we sought to assess sex-based differences in therapeutic response to oral immunotherapy (OIT) in a large cohort of patients aged 7 months to 46 years (see Data S1). When considering the whole cohort, 573 of 909 patients (63.0%) were male, and the only observable difference between sex was age (Table 1). Female patients in the cohort were in average 1 year older than male patients (p = .02). The female-to-male ratio was 1:1.84 before the age of 13 (n = 849), after which it decreased to 1:1.26 (n = 160). When stratifying for age, asthma was found significantly less prevalent in females (OR 0.66, p = .03) before 13. There was no other sex-based difference in baseline characteristics prior to treatment in the subgroups. When assessing treatment tolerance, females under 13 were less likely to experience reactions graded CoFAR 3 and above (OR 0.46, p = .04) than males. In contrast, after 13, females experienced significantly more reactions graded CoFAR 2 and above (OR 2.03, p = .03). For both variables (CoFAR 2 vs 3), the effect of female sex was significantly different before and after the age of 13 (p = .006 and p = .004, respectively). Age was also found to modify the effect of sex on respiratory symptoms (p = .02), anaphylaxis (p = .04), or epinephrine use (p = .02). In multivariate analysis, sex and age were not individually associated with severity of dose-related reactions. However, the interaction term between the two was found to be an independent predictor of dose-related reaction severity, along with baseline asthma, higher food-specific IgE and lower total IgE (Table 2). To the best of our knowledge, this is the first study reporting sex-based differences in OIT. The observed interaction with raises a concern that sex-based differences can be missed unless analyses specifically control for it. Proper assessment of sex-based differences in OIT is critical to ensure equal quality of care for male and female patients. Small cohorts and clinical trials that lack power to assess such interactions should nevertheless stratify sex-based data by age, so that relevant trends can be observed and eventually combined to allow proper analysis. The main limitation of our study is its retrospective design relying on patient chart review. The smaller proportion of patients older than 13 may have limited our ability to detect significant differences in this subgroup. For example, while we were able to show that female sex affects epinephrine use differently before and after the age of 13, we lacked power to conclude whether this difference is driven by a reduced risk in female children, an increased risk in females after puberty, or both. We could not separate the biologic effect of sex from the behavioral effect of gender, which could have influenced patient decisions regarding use of medication, dose observance, co-factor avoidance, and symptom reporting. In conclusion, our data show that sex-based differences exist in OIT but depend on an interaction with patient age. To avoid missing clinically relevant sex-based differences, future studies assessing the effect of sex in OIT should be stratified for age or otherwise account for this interaction. These will help better inform decisions on whether and when to initiate OIT in female patients and could eventually lead to personalized approaches according to sex. CB, LP, AD, KS, RL, FG, and PB evaluated and documented patient data. CE, SL, and PB conceived the study and collected the data. CE, CB, and PB analyzed the data and drafted the manuscript. All authors critically reviewed and approved the final manuscript. This study was supported by the Ste-Justine Foundation. PB was supported by the Fonds de recherches en Santé du Québec (281662). CE was supported by the SFA (Société Française d'Allergologie) and the ANAFORCAL (Association Nationale de Formation Continue en Allergologie). The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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