Sex-specific patterns of symptom burden, psychological distress, and work productivity impairment in post-acute sequelae of COVID-19: a 10-month dynamic cohort study

Abstract

Abstract Background A considerable proportion of patients experience post-acute sequelae of COVID-19 (PASC). Increasing evidence suggests sex-related differences, yet systematic longitudinal analyses remain limited. This study aimed to examine sex-specific differences in symptoms, psychological burden, work productivity and physical activity over ten months following acute COVID-19. Methods In this prospective, dynamically enrolled cohort study, patients with ongoing symptoms after confirmed SARS-CoV-2 infection were followed over a 10-month observation period. Patients conducted at the post-COVID outpatient clinic of the department of respiratory medicine and infectious diseases at Hannover Medical School, Germany. The assessment included patient-reported outcome measures, pulmonary function tests, six-minute walk tests, and capillary blood gas analysis. All outcome comparisons between sexes were adjusted for age, BMI, COVID-19 severity, and comorbidities using generalised linear mixed-effects models, with sex-by-time interaction terms tested to assess whether differences changed over follow-up, and p-values corrected for multiple testing across all outcome comparisons using the Holm method. A sensitivity analysis was performed in the subgroup of patients with complete follow-up at all four visits. Results Five hundred ninety patients attended to our clinic and a total of 433 patients were eligible and consecutively enrolled. Males were older (56 years vs. 52 years, p = 0.002), had more cardiovascular comorbidities (16% vs. 5%, p < 0.001), and experienced more severe COVID-19 (28% vs. 8%, p < 0.001). After adjustment for age, BMI, COVID-19 severity, and comorbidities, and Holm correction for multiple testing across all 27 outcome comparisons, females showed higher fatigue (Fatigue Assessment Scale, adjusted β = 3.3, Holm-adjusted p = 0.006), higher anxiety (GAD-2, β = 0.5, p = 0.021), lower quality of life (EQ-5D-3L, β = -0.6, p = 0.004), and greater work productivity impairment, both as a continuous score (WPAI-VAS, β = 1.3, p = 0.031) and as a binary indicator of clinically relevant impairment (OR = 3.0, p = 0.020). Females also had higher percent-predicted (pp) total lung capacity ( p < 0.0001) and lower pCO 2 ( p < 0.0001), whereas males had higher pp diffusion capacity ( p = 0.001). Headache ( p < 0.001) and chest tightness ( p = 0.011) were reported more frequently by females. None of these differences varied significantly over the 10-month follow-up (all sex-by-time interaction p ≥ 0.41), indicating no evidence that these differences changed over time. No significant sex differences remained after adjustment for depression (PHQ-2), lung function parameters, sex/height-adjusted exercise capacity, post-exercise dyspnoea or oxygen saturation, or most acute-COVID-19 symptoms other than headache and chest tightness. Regression models separately for each sex revealed fever (OR = 2.48, 95% CI: 1.11–5.57, p = 0.027) and diarrhoea (OR 2.33, 95%CI: 1.05–5.16, p = 0.038) during acute COVID-19 were associated with higher odds of work productivity impairment (WPAI-VAS ≥ 2) in males. In females, higher BMI (OR = 2.06, 95% CI: 1.13–3.76, p = 0.018) and dyspnoea during acute COVID-19 (OR = 4.38, 95% CI: 1.55–12.40, p = 0.005) were associated with increased odds. Formal interaction analyses showed a significant interaction only for dyspnoea after Holm correction. Conclusions After accounting for baseline imbalance in age, BMI, COVID-19 severity, and comorbidities, and after correcting for multiple testing, sex-specific differences persisted for fatigue, anxiety, quality of life, and work productivity impairment, as well as selected lung function parameters. These differences did not change significantly across the 10-month observation period and did not show a significant sex-by-time interaction. The findings support the need for individualised, sex-specific follow-up focused on fatigue, psychological burden, and work productivity in patients with PASC.