Sex-Dependent Integration of Symptoms and Functional Vulnerability in Interstitial Lung Disease: eurILDreg Study

Background and aims: In interstitial lung diseases (ILD), patient-centred disease burden is only partly explained by physiological impairment, with substantial variation in symptoms, psychological distress, and functional limitation among patients with similar lung function. We examined whether sex modifies longitudinal patient-centred outcomes in ILD and whether differences emerge at the level of outcome structure and domain integration. Methods: In a prospective multicentre eurILDreg cohort, repeated measures of lung function, patient-reported outcome measures (K-BILD, EQ-5D-5L, LCQ), and Clinical Frailty Scale (CFS) were analysed. Longitudinal trajectories and time × sex interactions were evaluated using linear mixed-effects models. Sex-stratified correlation analyses assessed cross-domain outcome structure and symptom-physiology integration. Results: Baseline global PROM total and domain scores as well as functional vulnerability were comparable between women and men, including EQ-5D-5L index (p = 0.337), K-BILD Total (66.4 ± 19.9 vs 68.2 ± 18.6; p = 0.271), LCQ Total (7.2 ± 3.0 vs 7.0 ± 3.0; p = 0.107), and CFS (mean 3.24 in both sexes; SD 1.24 vs 1.38). Despite similar global scores, EQ-5D-5L domain profiles differed. Women reported greater limitations in daily activities (2.04 vs 1.90), higher pain/discomfort (2.27 vs 2.07), while mobility and self-care were similar. In addition, anxiety/depression (AD ≥ 2) showed a borderline higher frequency in women (χ² = 3.71, p = 0.054). Sex differences were evident in cross-domain outcome structure. Coupling between global health perception and ILD-specific psychological domains was stronger in women (EQ-5D × K-BILD Psychological: r = 0.452 vs 0.380; EQ-5D Anxiety/Depression × K-BILD Psychological: r = -0.555 vs -0.486), whereas men showed stronger coupling between psychological and physical cough domains (LCQ Psychological × LCQ Physical: r = 0.635 vs 0.560). Longitudinal trajectories were broadly similar by sex. A borderline sex interaction was observed for K-BILD (time × sex -0.243 points/month; p = 0.053; -0.081 vs -0.324 points/month). CFS increased over time (+0.0172 points/month; p = 0.0084) without sex differences. Conclusions: Sex differences in ILD are not expressed through differences in overall disease severity, functional vulnerability, or average PROM trajectories, but through differences in how patient-centred outcomes are organised and integrated. Clinically, these findings suggest that women may benefit more from interventions targeting psychological distress, pain, and cough-related burden, whereas men may require strategies focused on preserving function and mitigating symptom-driven deterioration. In summary, sex alters how ILD is perceived, processed, and lived. Recognising sex as a modifier is essential for the development of person-centred ILD care.