HSV-1 reactivation is associated with an increased risk of mortality and pneumonia in critically ill COVID-19 patients

Abstract

Background Data in the literature about HSV reactivation in COVID-19 patients are scarce, and the association between HSV-1 reactivation and mortality remains to be determined. Our objectives were to evaluate the impact of Herpes simplex virus (HSV) reactivation in patients with severe SARS-CoV-2 infections primarily on mortality, and secondarily on hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) and intensive care unit-bloodstream infection (ICU-BSI). Methods We conducted an observational study using prospectively collected data and HSV-1 blood and respiratory samples from all critically ill COVID-19 patients in a large reference center who underwent HSV tests. Using multivariable Cox and cause-specific (cs) models, we investigated the association between HSV reactivation and mortality or healthcare-associated infections. Results Of the 153 COVID-19 patients admitted for ≥ 48 h from Feb-2020 to Feb-2021, 40/153 (26.1%) patients had confirmed HSV-1 reactivation (19/61 (31.1%) with HSV-positive respiratory samples, and 36/146 (24.7%) with HSV-positive blood samples. Day-60 mortality was higher in patients with HSV-1 reactivation (57.5%) versus without (33.6%, p = 0.001). After adjustment for mortality risk factors, HSV-1 reactivation was associated with an increased mortality risk (hazard risk [HR] 2.05; 95% CI 1.16–3.62; p = 0.01). HAP/VAP occurred in 67/153 (43.8%) and ICU-BSI in 42/153 (27.5%) patients. In patients with HSV-1 reactivation, multivariable cause-specific models showed an increased risk of HAP/VAP (csHR 2.38, 95% CI 1.06–5.39, p = 0.037), but not of ICU-BSI. Conclusions HSV-1 reactivation in critically ill COVID-19 patients was associated with an increased risk of day-60 mortality and HAP/VAP.

Reactivation of Herpes Simplex Virus Type 1 (HSV-1) Detected on Bronchoalveolar Lavage Fluid (BALF) Samples in Critically Ill COVID-19 Patients Undergoing Invasive Mechanical Ventilation: Preliminary Results from Two Italian Centers

“…In line with our results, two recent single-center studies reported that in hospitalized patients with severe or critical COVID-19 pneumonia, the frequency of HSV-1 reactivation was 31% on respiratory samples [12], and 30% in the plasma [2]. Differently from our study, an independent association was found between steroid treatment and HSV-1 reactivation [2].…”

“…Our findings may support the hypothesis that, if existent, any unfavorable prognostic impact of HSV-1 reactivation in intubated COVID-19 patients could be mitigated (or cancelled) by proper antiviral treatment. Another possibility is that the association with mortality of HSV-1 reactivation in critically ill COVID-19 patients may be driven by blood reactivation and not by respiratory reactivation [12]. In our study, we detected blood HSV-1-DNA only in three patients with reactivation detected on BALF.…”

Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality

“…In this context, the immunosuppression induced by SARS-CoV-2 direct pathogenic effects, the unregulated host response and the use of drugs to modulate such response (e.g., steroids and immunomodulators) make critically ill patients affected by coronavirus disease 2019 (COVID-19) at high risk for viral reactivation [ 6 – 9 ]. A recent large observational study indicated that the Herpes simplex 1 virus reactivated in around a quarter of COVID-19 patients requiring mechanical ventilation and impacted secondary infections and mortality [ 10 ]. Unfortunately, in this population, very little data are available on CMV reactivation which is one of the most pathogenetic viruses and seems to be closely related to worse outcomes in other intensive care unit (ICU) populations [ 11 , 12 ].…”

Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons

“…Furthermore, it is well described that herpesvirus reactivations are associated with worse outcomes in non-COVID patients, with increased length of stay in ICU, increased length of mechanical ventilation, and increased mortality [23][24][25]. Similarly, HSV-1 and CMV reactivations have been observed in critically-ill COVID-19 ICU patients, and herpesvirus reactivations in these patients has been associated with an increased risk of pneumonia and mortality [11,26]. Thus, it could be that anti-IFN autoantibodies are a predisposing factor for pathogenic herpesvirus reactivations in a subset of COVID-19 patients, and this may have important implications for our understanding of the immunologic phenomena underlying severe COVID-19, risk stratification, and of course possible herpesvirus-directed therapeutic options.…”

“…Notably, concomitant herpesvirus (e.g. herpes simplex virus type 1, HSV-1; cytomegalovirus, CMV; varicella-zoster virus, VZV) reactivations have increasingly been recognized to be associated with more severe disease and worse clinical outcomes in critically-ill COVID-19 patients [11]. However, despite the importance of a functional IFN system in maintaining herpesvirus latency in experimental settings [12][13][14], potential associations between the presence of anti-IFN autoantibodies, herpesvirus reactivations, and clinical outcomes in critically-ill patients have yet to be investigated.…”