Histological proof of pulmonary herpesvirus presence in patients with COVID-19- or influenza-related ARDS

BACKGROUND: Herpes simplex virus type 1 (HSV-1) and cytomegalovirus (CMV) are frequently detected in respiratory samples from patients with acute respiratory distress syndrome (ARDS), yet whether PCR positivity reflects histologically confirmed pulmonary infection and contributes to lung injury remains unclear. We aimed to characterize the histopathological features of pulmonary HSV-1 and CMV using PCR and immunohistochemistry on lung tissue specimens of critically ill patients with influenza- or COVID-19-related ARDS obtained at autopsy. In addition, we sought to correlate pulmonary herpesvirus loads in antemortem bronchoalveolar lavage fluid (BALF) samples with postmortem histological findings. METHODS: In this retrospective autopsy cohort, we included patients with COVID-19- or influenza-related ARDS who died in the intensive care unit and underwent autopsy between 2009 and 2021. Lung tissue blocks were systematically screened for HSV-1 and CMV using PCR and immunohistochemistry. Performance of HSV-1 PCR on BALF for diagnosing proven HSV-1 infection was evaluated with receiver operating characteristic analysis. RESULTS: We included 22 patients with COVID-19- and 20 with influenza-related ARDS. Proven HSV-1-associated necrotizing tracheobronchitis was identified in 6/42 patients (14%). Proven CMV infection was identified in only one patient, displaying focal presence of a few CMV-infected cells. An optimal cutoff of 4.11 log₁₀ copies/mL for HSV-1 in BALF yielded 100% sensitivity and 69% specificity for diagnosis of proven HSV-1 infection. CONCLUSIONS: Pulmonary HSV-1 was associated with tracheobronchitis in a subset of patients in a viral load dependent manner. Pulmonary CMV presence appeared histologically insignificant and likely represents a bystander phenomenon of critical illness.