Pulmonary herpes simplex virus and cytomegalovirus in patients with acute respiratory distress syndrome related to COVID-19

Abstract

Purpose: Human herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), frequently reactivate in critically ill patients, including those with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The clinical interpretation of pulmonary herpesvirus reactivation is challenging and there is ongoing debate about its association with mortality and benefit of antiviral medication. We aimed to quantify the incidence and pathogenicity of pulmonary CMV and HSV reactivations in critically ill COVID-19 patients.

Methods: Mechanically ventilated COVID-19 patients seropositive for CMV or HSV were included in this observational cohort study. Diagnostic bronchoscopy with bronchoalveolar lavage was performed routinely and analyzed for alveolar viral loads and inflammatory biomarkers. Utilizing joint modeling, we explored the dynamic association between viral load trajectories over time and mortality. We explored alveolar inflammatory biomarker dynamics between reactivated and non-reactivated patients.

Results: Pulmonary reactivation (> 10⁴ copies/ml) of CMV occurred in 6% of CMV-seropositive patients (9/156), and pulmonary reactivation of HSV in 37% of HSV-seropositive patients (63/172). HSV viral load dynamics prior to or without antiviral treatment were associated with increased 90-day mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.04-1.47). The alveolar concentration of several inflammatory biomarkers increased with HSV reactivation, including interleukin (IL)-6, IL-1β, granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor (TNF).

Conclusion: In mechanically ventilated COVID-19 patients, HSV reactivations are common, while CMV reactivations were rare. HSV viral load dynamics prior to or without antiviral treatment are associated with mortality. Alveolar inflammation is elevated after HSV reactivation.

Keywords: Acute respiratory distress syndrome (ARDS); Antiviral treatment; Cytomegalovirus (CMV); Herpes simplex virus (HSV); Viral reactivation.

Fig. 1

Flowchart of screening and inclusion process. Numbers of patients with numbers of BAL samples are displayed for the study period from March 31th, 2020, until June 4th, 2021. After excluding 11 ineligible patients, the cohort comprised 194 patients. Patients not at risk for reactivation (i.e., seronegative patients) were excluded based on their particular virus serostatus, resulting in distinct cohorts. Specifically, CMV-seronegative patients were excluded, resulting in a CMV cohort of 156 patients (all IgG positive for CMV), while HSV-seronegative patients were similarly excluded, resulting in an HSV cohort of 172 patients (all IgG positive for HSV). *A reactivation was considered ‘clinically relevant’ in case of a viral load of > 10⁴ c/ml in the BAL fluid. BAL bronchoalveolar lavage, CMV cytomegalovirus, HSV herpes simplex virus, IgG immunoglobulin G, PCR polymerase chain reaction

Fig. 2

Aalen–Johansen plot for probability of state membership in the HSV cohort. A This figure illustrates the transition probabilities within a multistate modeling framework [20, 33]. All patients initially start in state 1 and could transition to the end states 3 (extubated) and 4 (deceased), either or not passing through the event state 2 (i.e., having a clinically relevant reactivation for CMV or HSV). B Aalen–Johansen plot illustrating the probability of state membership, with data presented up to day 90 and the last data point provided at 83 days. Left: probability of state membership at baseline; all patients start non-reactivated (blue). Blue = intubated, without clinically relevant HSV reactivation; orange = intubated, with clinically relevant HSV reactivation; green = no clinically relevant HSV-reactivation, extubated; red = no clinically relevant HSV reactivation, deceased. Right: probability of state membership at HSV reactivation; all patients start reactivated (orange). Orange = intubated, with clinically relevant HSV reactivation; green = HSV reactivated (> 10⁴ c/ml), extubated; red = HSV reactivated (> 10⁴ c/ml), deceased. Y-axis: probability of state membership. X-axis: days since intubation. Clinically relevant reactivation refers to a viral load of > 10⁴ c/ml in the BAL fluid. CMV cytomegalovirus, HSV herpes simplex virus, BAL bronchoalveolar lavage

Fig. 3

Alveolar biomarker dynamics for HSV-reactivated and non-reactivated patients, pre- and post-reactivation and pre-and post-treatment initiation. This figure displays the longitudinal profiles of four selected biologically relevant biomarkers that show a significant difference in reactivation biomarker dynamics, compared to the non-reactivated group. HSV reactivation refers to a clinically relevant reactivation (viral load of > 10⁴ c/ml in the BAL fluid). A Sampling time points before and after reactivation, for HSV-reactivated patients (n = 10), and matched controls without HSV reactivation (n = 10). B Sampling time points before and after treatment, for HSV-reactivated patients who received antiviral treatment (n = 11), and matched controls without HSV reactivation who did not receive antiviral treatment (n = 11). Patient selection is shown in Fig. S9. Orange and blue lines indicate the trajectories of alveolar biomarker concentrations for HSV-reactivated versus non-HSV-reactivated patients, respectively. Dotted line indicates the 95% confidence intervals. Linear mixed-effects models were used to provide beta and 95% confidence intervals. G-CSF granulocyte colony stimulating factor, IL interleukin, TNF tumor necrosis factor, CI confidence interval