Hidden cognitive dysfunction in severe asthma: prevalence, genetic susceptibility, and independence from clinical remission

Severe asthma is a complex systemic disease frequently accompanied by multiple comorbidities. Cognitive dysfunction has been increasingly recognized as a potential but under-explored comorbidity in this population, with limited data regarding its true prevalence, optimal screening tools, and associated risk factors. This study aimed to evaluate the prevalence of cognitive dysfunction in patients with severe asthma and to identify clinical, metabolic, and genetic factors associated with cognitive impairment. This study included an index cross-sectional evaluation of 145 adults with severe asthma who were receiving biologic therapy, followed by longitudinal assessment of clinical remission. Participants underwent clinical assessment, pulmonary function testing, inflammatory biomarker evaluation, genotyping of selected cytokine gene polymorphisms (IL-4, IL-6, IL-13, and TNF-α), and cognitive screening using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Possible cognitive dysfunction was operationally defined as any degree of impairment detected by either screening instrument, whereas normal cognitive status required normal results on both tests. Patients were subsequently followed for clinical remission assessment; cognitive testing was not repeated. Group comparisons and multivariable logistic regression were performed to identify factors associated with possible cognitive dysfunction. Overall, 58 of 145 patients (40.0%) screened positive for possible cognitive dysfunction. MoCA identified cognitive abnormalities in a greater proportion of patients than MMSE, including abnormalities in patients whose MMSE scores remained within the normal range. Patients with possible cognitive dysfunction were significantly older and more frequently had adult-onset asthma, diabetes mellitus, and hypertension. Asthma control, lung function, exacerbation frequency, corticosteroid exposure, and type 2 inflammatory biomarkers did not differ significantly according to cognitive status. IL-6 polymorphism was significantly associated with cognitive screening status. In multivariable analysis, diabetes mellitus was independently associated with higher odds of possible cognitive dysfunction, whereas childhood-onset asthma was associated with lower odds. Neither clinical remission nor its individual components differed significantly according to cognitive status. Possible cognitive dysfunction was identified by screening in a substantial proportion of patients with severe asthma in this cohort. MoCA detected cognitive abnormalities more frequently than MMSE, particularly milder abnormalities that were not identified by MMSE. Cognitive screening status was associated more closely with age, metabolic comorbidity, and selected inflammatory genetic factors than with conventional measures of asthma control, type 2 inflammation, or clinical remission. These findings support consideration of cognitive screening in patients with severe asthma who have relevant risk factors, while comprehensive neuropsychological assessment remains necessary to confirm cognitive impairment.