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 10 5 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.