Pulmonary Herpes Simplex Virus Reactivation in Invasively Mechanically Ventilated Patients With COVID-19 in Intensive Care Unit

Abstract

Patients in intensive care units (ICU) under mechanical ventilation, particularly those with SARS-CoV-2 infection, are highly susceptible to Herpes simplex virus (HSV) reactivation. Given the lack of data on the SARS-CoV-2 Omicron and Delta variants, this study aimed to assess the prevalence of pulmonary HSV reactivation in mechanically ventilated patients with SARS-CoV-2 pneumonia. The impact of HSV replication on SARS-CoV-2 replication, and conversely, was investigated, along with the susceptibility of HSV strains to antiviral therapies. This retrospective study included 381 mechanically ventilated ICU patients in Lyon. Overall, 103 patients (27.0%) experienced HSV reactivation, with a trend toward a higher prevalence among SARS-CoV-2-positive patients (32.8%) compared to SARS-CoV-2-negative (24.1%; p value = 0.058). HSV reactivation was significantly higher with the Delta variant (46.2%) compared to Omicron (27.1%; p value = 0.045); the Delta variant was associated with a 2.38-fold increased risk of HSV reactivation. HSV-positive patients exhibited a 1-log lower SARS-CoV-2 viral load compared to HSV-negative patients, a finding indicative of the natural course of SARS-CoV-2 infection followed by HSV reactivation, rather than viral interference. Unexpectedly, acyclovir resistance mutations appeared in the UL23 gene in at least 13.6% of HSV-1 strains in patients with an HSV load above 10⁵ copies/mL. Complementary phenotypic and genotypic approaches allowed to identify three novel substitutions in UL30: Q217R, D741A, and E756K, classified as polymorphisms. Further optimization is needed in the management of mechanically ventilated ICU patients with pulmonary HSV reactivation, especially regarding antiviral resistance testing.