Impact of acyclovir use on survival of patients with ventilator-associated pneumonia and high load herpes simplex virus replication

Abstract

Background: Herpes simplex virus (HSV) replication can be detected in the respiratory secretions of a high proportion of ventilated intensive care unit (ICU) patients. However, the clinical significance remains poorly defined. We investigated whether patients with ventilator-associated pneumonia not responding to antibiotics and in whom high levels of HSV could be detected in respiratory secretions benefit from acyclovir treatment.

Methods: Respiratory secretions (bronchoalveolar lavage fluid or tracheal aspirates) were tested for HSV replication by quantitative real-time PCR. ICU survival times, clinical parameters, and radiographic findings were retrospectively compared between untreated and acyclovir treated patients with high (> 10⁵ HSV copies/mL) and low (10³-10⁵ HSV copies/mL) viral load.

Results: Fifty-seven low and 69 high viral load patients were identified. Fewer patients with high viral load responded to antibiotic treatment (12% compared to 40% of low load patients, p = 0.001). Acyclovir improved median ICU survival (8 vs 22 days, p = 0.014) and was associated with a significantly reduced hazard ratio for ICU death (HR = 0.31, 95% CI 0.11-0.92, p = 0.035) in high load patients only. Moreover, circulatory and pulmonary oxygenation function of high load patients improved significantly over the course of acyclovir treatment: mean norepinephrine doses decreased from 0.05 to 0.02 μg/kg body weight/min between days 0 and 6 of treatment (p = 0.049), and median PaO₂/FiO₂ ratio increased from 187 to 241 between day 3 and day 7 of treatment (p = 0.02). Chest radiographic findings also improved significantly (p < 0.001).

Conclusions: In patients with ventilator-associated pneumonia, antibiotic treatment failure, and high levels of HSV replication, acyclovir treatment was associated with a significantly longer time to death in the ICU and improved circulatory and pulmonary function. This suggests a causative role for HSV in this highly selected group of patients.

Keywords: Acyclovir; Bronchoalveolar lavage fluid; Real-time polymerase chain reaction; Simplexvirus; Ventilator-associated pneumonia.

Fig. 1

Enrollment of patients with ventilator-associated pneumonia according to low or high viral load between 2013 and 2018: intensive care unit (ICU) patients on ventilator support received a quantitative real-time polymerase chain reaction (PCR) testing of their respiratory material (bronchoalveolar lavage or tracheobronchial aspirates) in context of a ventilator-associated pneumonia. Figure indicates numbers of patients; figures next to outward pointing arrows show excluded patients. Reasons for exclusion are indicated in boxes. HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2; AML, acute myelogenous leukemia; T-ALL, T cell acute lymphoblastic leukemia. *Statistically significant with p < 0.05 by Fisher’s exact test

Fig. 2

a–c Kaplan-Meier analysis of intensive care unit survival after starting antiviral treatment or after HSV detection: day 0 (d0) was defined as the date of first detection of significant HSV-1/2 replication in untreated patients or as the date of acyclovir treatment start for patients receiving. + = censored. The p values were calculated using a log-rank test. a Entire cohort. b Subgroup with low viral load (10³–10⁵ HSV copies/mL). c Subgroup with high viral load (> 10⁵ HSV copies/mL)

Fig. 3

a–c Hazard ratios for ICU death from the adjusted multivariable Cox model: the multivariable Cox model was adjusted for age, sex, and SOFA score at d0. The hazard ratios are labeled on the x-axis. The horizontal bars are 95% confidence intervals (95% CI), and significant (< 0.05) p values are indicated with asterisk. a Entire cohort. b Subgroup with low viral load (10³–10⁵ HSV copies/mL). c Subgroup with high viral load (> 10⁵ HSV copies/mL)

Fig. 4

a–c Development of clinical parameters in high viral load patients after start of antiviral treatment. Day 0 (d0) was defined as the date of first detection of significant HSV-1/2 replication in untreated patients or as the date of acyclovir treatment start for patients receiving. a Circulatory function as measured by norepinephrine doses given for circulatory support. b Respiratory function as measured by PaO₂/FiO₂ ratio. c Pulmonary infiltrates as measured by a semiquantitative score. In a and b, p values are from the Friedman test, while horizontal brackets indicate significant differences (*p < 0.05) between time points by Conover’s post hoc test. In c, the Wilcoxon signed-rank test was used to compare the last available X-ray or CT before d0 to the maximum change within a time span of 3 to 15 days