---
title: "HSV-1 and CMV Reactivation Linked to Worse Outcomes and Mortality in ICU COVID-19 Patients"
id: "plos-one-9-herpesvirus-reactivation-is-associated-with-mortality-in-critically-ill-icu"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-9-herpesvirus-reactivation-is-associated-with-mortality-in-critically-ill-icu"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0354153"
published_at: "2026-07-17T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# HSV-1 and CMV Reactivation Linked to Worse Outcomes and Mortality in ICU COVID-19 Patients
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-9-herpesvirus-reactivation-is-associated-with-mortality-in-critically-ill-icu
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0354153)
- **Published At:** 2026-07-17T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This retrospective single-center study analyzed 455 consecutive ICU patients with confirmed SARS-CoV-2 infection treated between March 2020 and December 2021. Routine PCR screening for **HSV-1** (in BALF) and **CMV** (in whole blood) was performed per local protocol. - Viral reactivation (HSV-1, CMV, or both) occurred in 164 patients (36%). Isolated HSV-1 and isolated CMV reactivations each occurred in 12% of the cohort; combined reactivation occurred in 13%. - Median time from ICU admission to viral detection was 4 days for both HSV-1 and CMV, and detection rates increased with longer ICU stays. - Detection of **HSV-1** was associated with substantially worse respiratory failure metrics, greater need for invasive mechanical ventilation and vvECMO, longer durations of organ support, and higher rates of renal replacement therapy and sepsis. - ICU survival was lower when **HSV-1** was detected (32% vs 67%; p < 0.001); this association remained significant after multivariable adjustment. **CMV** detection was not independently associated with the same adverse outcome pattern. - Higher **neutrophil-lymphocyte ratio** (NLR) correlated with detection of HSV-1 and CMV and was independently associated with increased ICU mortality. - Patients with viral reactivation had higher peak inflammatory markers (CRP, leucocyte counts), more frequent pulmonary embolism, longer ICU length of stay, and higher 30- and 90-day mortality. - Antiviral treatment practices varied: nearly all patients with isolated HSV-1 received acyclovir (98%), whereas fewer CMV-positive patients received ganciclovir. Institutional thresholds for treatment and dosing were described but initiation often relied on clinical judgment. - Study limitations inherent to the report include its retrospective, single-center design and that reactivation was defined virologically by any positive PCR without viral-load thresholds; details about some analyses or additional confounders were provided in supplementary materials.
## Clinical Analysis & Structured Key Points
SKIP TO MAIN CONTENT Advertisement plos.org Create account Sign in About Browse Publish advanced search 0 Save 0 Citation 12 View 0 Share OPEN ACCESS PEER-REVIEWED RESEARCH ARTICLE Herpesvirus reactivation is associated with mortality in critically ill ICU patients with COVID-19: Insights from a retrospective single-center analysis of 455 cases Stefanie Michel , Cilian Kempf, Nina Pirschtat, Frank Herbstreit, Bettina Budeus, Sebastian Voigt, Jutta Dedy, Thorsten Brenner, Simon Dubler Published: July 17, 2026 https://doi.org/10.1371/journal.pone.0354153 Article Authors Metrics Comments Media Coverage Abstract Background Methods Results Discussion Conclusion Supporting information References Reader Comments Figures Abstract Background Critically ill patients with COVID-19 frequently develop viral reactivation, yet the clinical significance of herpes simplex virus type 1 (HSV-1) and cytomegalovirus (CMV) remains a matter of debate. Methods We conducted a retrospective single-center study of 455 consecutive intensive care unit (ICU) patients with confirmed SARS-CoV-2 infection between March 2020 and December 2021. Patients underwent screening for HSV-1 and CMV in whole blood and respiratory samples. A multivariable model was used to independently investigate risk factors associated with mortality. Results The mean age was 57 years (range: 13–94 years), and 316 (69%) were male. During a median ICU stay of 14 (0–90) days, viral reactivation (either HSV-1 or CMV or both) occurred in 164 (36%) patients. HSV-1 and CMV co-reactivation was detected in 57 (13%) patients, isolated HSV-1 reactivation was observed in 54 (12%) patients and isolated CMV reactivation in 53 (12%) patients. Median time from ICU admission to viral detection was 4 days, with a stepwise increase with longer ICU stay. Detection of HSV-1 was associated with decreased ICU survival (32% versus 67%; p 0.9), as was the mean body mass index of 29 kg/m² (p = 0.8). A difference was observed in the occurrence of pulmonary embolism, which was markedly more frequent in patients with viral reactivation (HSV-1, CMV, or both) than in those without reactivation (24% vs 10%; p 0.9, respectively). Pulmonary embolism was observed more than twice as often in patients with isolated HSV-1 reactivation compared with those without any herpesvirus reactivation (27% vs 10%; p = 0.003). Patients with isolated HSV-1 reactivation required invasive mechanical ventilation more than twice as frequently, and the duration of invasive mechanical ventilation was more than three times longer than in patients without viral reactivation (98% vs 48%; p < 0.001, and 463 vs 112 h; p < 0.001, respectively). The initial Horowitz index (PaO₂/FiO₂ ratio) was lower in patients with than without HSV-1 reactivation (107 vs 135 mmHg; p = 0.031). vvECMO support was required more than three times as often and had to be maintained for more than twice as long compared with patients without HSV-1 reactivation (58% vs 18%; p < 0.001, and 311 vs 114 h; p = 0.009, respectively). Secondary referral patients had a higher rate of isolated HSV-1 reactivation (15% vs 7.7%; p = 0.017), with a subsequently higher incidence of vvECMO therapy (72% vs 20%; p < 0.001) compared with patients admitted directly or transferred internally. Renal replacement therapy was administered more than twice as frequently in patients with than without HSV-1 reactivation (57% vs 25%; p < 0.001) and was maintained for a longer duration (193 h vs 70 h; p = 0.003). Sepsis was described more often in patients with isolated HSV-1 reactivation (79% vs 37%; p < 0.001). ICU length of stay was longer in patients with than without HSV-1 reactivation (19 vs 6 days; p < 0.001). Thirty-day mortality was markedly increased in patients with than without HSV-1 reactivation (60% vs 33%; p < 0.001). Supplementary S2 Table shows the characteristics of patients with isolated HSV-1 reactivation. Among the 54 patients with isolated HSV-1 reactivation, 53 (98%) received antiviral therapy, whereas only one patient did not. Patients with isolated CMV reactivation Among the 164 patients with viral reactivation, 53 (32%) were positive exclusively for CMV. The median age was 56 years (compared with 57 years in patients without any reactivation; p = 0.6), and the majority were male (71%; p = 0.9). T
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