Overlap in Immunologic Pathways Between Asthma and Primary Immunodeficiency Disorders

Background Asthma is traditionally conceptualized as a T helper 2 (Th2)-mediated inflammatory airway disease. However, increasing evidence suggests that primary immune dysregulation may underlie or phenotypically mimic asthma in a subset of patients. Overlap between atopy and primary immunodeficiency disorders (PIDs) complicates diagnosis, delays appropriate evaluation, and may lead to suboptimal therapy when immune defects are unrecognized. Objective To review the clinical phenotypes and immunologic mechanisms linking asthma with primary immunodeficiency disorders and to identify clinical and immunologic features that should prompt immune evaluation in patients with severe, refractory, or atypical asthma. Methods A narrative literature review was conducted using PubMed and Scopus databases, covering publications from 2020 to 2025. Studies describing asthma-like airway manifestations, immune pathways, and treatment responses in PIDs were identified. Disorders were categorized by underlying immunologic defect and associated clinical features. Results Several PIDs, including common variable immunodeficiency, selective IgA deficiency, hyper-IgE syndromes, and STAT3- or DOCK8-related disorders, are associated with asthma-like airway inflammation and recurrent wheezing. Shared immunologic mechanisms include Th2 polarization with elevated IL-4, IL-5, and IL-13 signaling; impaired regulatory T cell function; defective mucosal antibody production; and chronic airway epithelial inflammation. These abnormalities may coexist with immune deficiency rather than classic allergic sensitization alone. Clinically, recurrent or severe sinopulmonary infections, poor or incomplete response to inhaled or systemic corticosteroids, early-onset bronchiectasis, and multisystem involvement serve as key clues distinguishing immune dysregulation from isolated atopic asthma. Conclusion Asthma and primary immune dysregulation represent a spectrum of aberrant immune responses rather than discrete clinical entities. Recognition of immune deficiency patterns in patients with difficult-to-control or atypical asthma can facilitate earlier immunologic evaluation, guide decisions regarding immunoglobulin replacement, and inform selection of targeted biologic therapies. Increased awareness of these overlaps is essential for optimizing outcomes in patients with complex airway disease.