Some studies suggested a high incidence of human herpesvirus (HHV) reactivation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To evaluate the prevalence of HHV reactivations in a population with various severity degrees of coronavirus disease 2019 (COVID-19), we analyzed 102 individuals and compared them with 51 SARS-CoV-2-negative subjects admitted in the same period (January–July 2022) for acute respiratory failure. Positivity was found in 76% of subjects for at least one HHV, and in 46% for ≥2 HHV. These proportions were more prevalent in SARS-CoV-2-positive than in negative patients (83% vs. 61%; 56% vs. 27%, respectively). The most common HHV was HHV-7 both in the whole population (51%) and in SARS-CoV-2-positive and -negative subjects (57% and 39%, respectively); human cytomegalovirus, herpes simplex virus-1, Epstein–Barr virus, and HHV-6 were more represented in SARS-CoV-2-positive individuals. No single or combined HHV reactivation was associated with the 60-day mortality rate. However, cytomegalovirus reactivation was an independent predictor of COVID-19 severity and longer hospitalizations, while the occurrence of ≥3 any HHV reactivations was independently associated with the aforementioned outcomes and ventilatory support need. Taken together, our data suggest that in patients with moderate-to-severe COVID-19, the diagnosis of HHV coinfections can add useful prognostic information.

Herpes simplex virus 1 (HSV-1) is a rare cause of acute hepatitis, especially in patients with chronic immunosuppression. We performed whole-genome HSV-1 sequencing with a metagenomics approach on peripheral blood samples from an Italian case of fatal acute liver failure with high circulating HSV-1 (1,129,900,000 copies/mL), followed by phylogenetic analysis. After multiple sequence alignment, a final dataset of 182 whole-genome sequences was selected. The sequenced HSV-1 strain belonged to a phylogenetic clade isolated in Florida in 2002 (OQ724868.1). A characterization of single nucleotide polymorphisms and indels was performed to determine their effects on the viral genome: only one variant, classified as an indel, was detected with a high impact effect (c.905_906insGTTTT) in the UL49A gene, which is known to encode a membrane protein regulating virion morphogenesis, replication and assembly. In addition, this study also detected variants in other genes involved in crucial steps of the HSV-1 life cycle, like alpha-regulation (US7), capsid transport (UL36) and viral polymerase function (UL30). In conclusion, the results of this variant analysis confirmed that in HSV-1 hepatitis, some viral regions may be hotspots for adaptive mutations with a substantial impact on viral replication or immune evasion.