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

In interstitial lung diseases (ILDs), patient-centred disease burden is only partly explained by physiological impairment, with considerable variability in symptoms, psychological distress, and functional limitation among patients with similar lung function. We investigated whether sex modifies longitudinal patient-centred outcomes in ILD and whether differences emerge in outcome structure and cross-domain integration.

In a prospective multicentre eurILDreg cohort, repeated measures of lung function, patient-reported outcome measures (K-BILD, EQ-5D-5L, LCQ), and the Clinical Frailty Scale (CFS) were analysed. Longitudinal trajectories and time × sex interactions were assessed using linear mixed-effects models. Sex-stratified correlation analyses examined cross-domain outcome structure and symptom-physiology integration.

Baseline global PROM scores and 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). Despite similar global scores, EQ-5D-5L domain profiles differed: women reported greater limitations in usual activities (2.04 vs. 1.90) and higher pain/discomfort (2.27 vs. 2.07), while mobility and self-care were similar. Anxiety/depression (AD ≥2) was more frequent in women, reaching borderline significance (χ2 = 3.71, p = 0.054). Sex differences were most 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 largely similar by sex: EQ-5D-5L (p = 0.330) and LCQ (p = 0.105) remained stable. A borderline sex interaction was observed for K-BILD (time × sex -0.243 points/month; p = 0.053). CFS increased modestly over time (+0.0172 points/month; p = 0.0084) without sex differences.

Sex differences in ILD are not primarily reflected in overall disease severity, functional vulnerability, or average PROM trajectories, but in how patient-centred outcomes are organised and interconnected. These findings suggest sex-specific patterns in the experience of ILD, with women showing stronger links between global health perception and psychological burden and men between psychological and physical symptom domains. Recognising sex as a modifier of patient-reported outcomes may help refine interpretation of PROMs and support more personalised, sex-informed ILD care.