Abstract / Summary
Abstract Background Pulmonary reactivation of herpes simplex virus (HSV) and cytomegalovirus (CMV) is frequently observed in mechanically ventilated patients. However, whether this reflects underlying host immune dysfunction, directly contributes to alveolar inflammation, and/or predicts clinical outcomes such as delayed extubation or mortality remains unclear. Methods In this single-centre prospective observational cohort study (March 2020 - July 2024), we enrolled HSV- and CMV-seropositive adults undergoing mechanical ventilation for acute respiratory failure with a clinical indication for bronchoalveolar lavage (BAL). Alveolar and systemic host-response profiles were compared between high HSV-load (≥ 10⁴ copies/mL) and negative/low HSV-load (< 10⁴ copies/mL) samples using protein biomarker profiling in BAL fluid and plasma (Luminex) and assessment of BAL immune-cell composition (CyTOF). Clinical outcomes, including successful extubation and mortality, were assessed using competing-risk, multistate, time-dependent Cox, and Bayesian joint models. Result Among 299 HSV-seropositive patients, 102 (34%) developed high pulmonary HSV-load (≥ 10⁴ copies/mL). High HSV-load was associated with higher concentrations of selected alveolar inflammatory mediators, while major BAL immune-cell lineages were largely preserved; increased inducible nitric oxide synthase expression in neutrophils was the most prominent cellular signal. High HSV-load was generally detected late during mechanical ventilation. In the principal time-dependent analysis, high HSV-load was not significantly associated with successful extubation (HR 0.80, 95% CI 0.56–1.14) or mortality (HR1.39, 95% CI 0.96–2.01). Landmark analyses at day 7 showed similar results, whereas at day 14 high HSV-load was associated with a lower probability of successful extubation (HR 0.58, 95% CI 0.34–0.98). In a complementary joint model evaluating HSV-load continuously over time, each 1-log 10 increase in HSV-load was associated with higher mortality (HR 1.39, 95% CrI 1.08–2.30), but not with successful extubation (HR 1.06, 95% CrI 0.79–1.34). Among 258 CMV-seropositive patients, only 15 (6%) developed high CMV-load, limiting CMV-specific inference. Conclusion Across complementary analytical approaches, high pulmonary HSV-load was not consistently associated with successful extubation or mortality, although effect estimates generally pointed towards less favourable outcomes. High pulmonary HSV-load was, however, consistently associated with a localized alveolar inflammatory response. Taken together, these findings identify high pulmonary HSV-load as a biologically distinct inflammatory phenotype, while its causal significance for clinical outcomes remains unresolved. Whether targeting HSV improves clinical outcomes would require randomized evaluation. Clinical trial number Not applicable.