Abstract
BACKGROUND: The nasal allergen challenge (NAC) is a tool for evaluating upper airway allergic responses. In the CRITICAL study, NAC with cockroach allergen was used to confirm clinical reactivity in sensitized individuals from urban environments before enrollment onto a subcutaneous immunotherapy trial. OBJECTIVE: Immunologic and transcriptomic predictors of NAC responsiveness were identified. METHODS: NAC was performed in 103 participants. Clinical responses were assessed by the Total Nasal Symptom Score (TNSS) and sneeze score (TSNEEZ), which scale positively with symptom severity. Baseline immunologic markers-including skin prick test wheal size, cockroach-specific IgE, IgG, and IgG(4), and T-cell responses were evaluated. Nasal lavage samples were analyzed for gene expression modules. Clinical trial registration: ClinicalTrials.gov NCT03541187. RESULTS: Larger skin prick test wheal sizes were significantly associated with positive NAC outcomes (2.2 mm larger than negative NAC) and lower reactive doses (hazard ratio = 1.10). Cockroach (i6 extract)-specific IgE levels were inversely correlated with TNSS, while levels of IgE, IgG, and IgG(4) specific to the extract used for therapy showed no association. Higher IL-10 T-cell responses were observed in those without reaction, while Bla g 5 and Bla g 9 dominance correlated negatively with TNSS and positively with TSNEEZ, respectively. Transcriptomic analysis revealed that higher expression of eosinophil- and neutrophil-associated modules and lower expression of type 1 interferon, macrophage, and epithelial barrier modules were linked to positive NAC responses. CONCLUSION: NAC responsiveness to cockroach extract is influenced by skin test reactivity, T- and B-cell regulation, and nasal gene expression. These findings highlight the role of both adaptive and innate immunity in allergic airway responses and suggest potential biomarkers for clinical reactivity.