Prognostic association of BALF mNGS-defined HSV reactivation in immunocompromised patients with severe pneumonia: a multicenter retrospective study

Background Severe pneumonia is common among patients admitted to the intensive care unit (ICU). Herpes simplex virus (HSV) reactivation is frequently detected in patients with severe pneumonia, particularly in immunocompromised individuals. Although metagenomic next-generation sequencing (mNGS) enables rapid and broad-spectrum pathogen detection, the clinical significance of bronchoalveolar lavage fluid (BALF) mNGS-defined HSV reactivation in immunocompromised patients with severe pneumonia remains unclear. Methods This retrospective multicenter cohort study included 350 adults admitted to ICUs at five hospitals with severe pneumonia between November 2021 and November 2025. BALF for mNGS was obtained within 24 hours after ICU admission. HSV-1 reactivation was operationally classified as BALF mNGS HSV-1 DNA positivity using a prespecified viral RPM-r threshold ≥3.0; this definition does not establish HSV pneumonia. The primary endpoint was 28-day mortality measured from ICU admission. A multivariable logistic regression model evaluated the association of HSV with mortality and modification of this association by immune status. Results Among 350 patients, 144 (41.14%) were immunocompromised and 206 (58.86%) were immunocompetent. HSV-1 reactivation was identified in 51/144 (35.42%) and 35/206 (16.99%) patients, respectively (P < 0.001). Among immunocompromised patients, 28-day mortality was 32/51 (62.75%) with HSV reactivation and 34/93 (36.56%) without it (Fisher exact P = 0.003). The corresponding rates in immunocompetent patients were 8/35 (22.86%) and 56/171 (32.75%); no statistically significant association was observed (Fisher exact P = 0.318). The adjusted HSV-by-immune-status interaction was statistically significant (OR = 4.451, 95% CI 1.449–13.668; P = 0.009). From the overall adjusted interaction model, the HSV-associated OR was 2.622 (95% CI 1.275–5.395) in immunocompromised patients and 0.589 (95% CI 0.249–1.394) in immunocompetent patients. In a separate model restricted to immunocompromised patients, the adjusted HSV-associated OR was 2.403 (95% CI 1.155–5.002; P = 0.019). The observed association with CMV co-detection within the HSV-positive subgroup was exploratory. Conclusions Among patients with severe pneumonia, BALF mNGS-defined HSV-1 reactivation was associated with higher 28-day mortality in immunocompromised patients, while no statistically significant association was observed in immunocompetent patients. Immune status modified the observed association on the odds-ratio scale. These findings are observational and do not establish HSV pneumonia, a causal effect of HSV, benefit from earlier mNGS testing, or an indication for antiviral therapy.