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Abstract：
OBJECTIVE: 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).
CONCLUSIONS: 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.
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).
CONCLUSIONS: 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.
摘要：
目的：人类疱疹病毒，特别是巨细胞病毒（CMV）和单纯疱疹病毒（HSV），经常在危重病人重新激活，包括与2019年冠状病毒疾病相关的急性呼吸窘迫综合征（ARDS）患者（COVID-19）。肺疱疹病毒再激活的临床解释是具有挑战性的，并且关于其与死亡率和抗病毒药物的益处的关系正在进行辩论。我们旨在量化危重COVID-19患者肺部CMV和HSV再激活的发生率和致病性。
方法：将CMV或HSV血清阳性的机械通气COVID-19患者纳入这项观察性队列研究。常规进行支气管肺泡灌洗的诊断性支气管镜检查，并分析肺泡病毒载量和炎症生物标志物。利用关节建模，我们探讨了病毒载量随时间变化的轨迹与死亡率之间的动态关联.我们探索了再激活和未再激活患者之间的肺泡炎症生物标志物动态。
结果：在6％的CMV血清阳性患者（9/156）中发生了CMV的肺再激活（>104拷贝/ml），在37％的HSV血清阳性患者中，HSV的肺再激活（63/172）。HSV病毒载量动力学前或不抗病毒治疗与增加的90天死亡率相关（风险比[HR]1.24，95％置信区间[CI]1.04-1.47）。几种炎症生物标志物的肺泡浓度随着HSV再激活而增加，包括白细胞介素（IL）-6，IL-1β，粒细胞集落刺激因子（G-CSF），和肿瘤坏死因子（TNF）。
结论：在机械通气的COVID-19患者中，HSV再激活很常见,而CMV再激活是罕见的。在抗病毒治疗之前或不抗病毒治疗的HSV病毒载量动态与死亡率相关。HSV再激活后肺泡炎症升高。
方法：将CMV或HSV血清阳性的机械通气COVID-19患者纳入这项观察性队列研究。常规进行支气管肺泡灌洗的诊断性支气管镜检查，并分析肺泡病毒载量和炎症生物标志物。利用关节建模，我们探讨了病毒载量随时间变化的轨迹与死亡率之间的动态关联.我们探索了再激活和未再激活患者之间的肺泡炎症生物标志物动态。
结果：在6％的CMV血清阳性患者（9/156）中发生了CMV的肺再激活（>104拷贝/ml），在37％的HSV血清阳性患者中，HSV的肺再激活（63/172）。HSV病毒载量动力学前或不抗病毒治疗与增加的90天死亡率相关（风险比[HR]1.24，95％置信区间[CI]1.04-1.47）。几种炎症生物标志物的肺泡浓度随着HSV再激活而增加，包括白细胞介素（IL）-6，IL-1β，粒细胞集落刺激因子（G-CSF），和肿瘤坏死因子（TNF）。
结论：在机械通气的COVID-19患者中，HSV再激活很常见,而CMV再激活是罕见的。在抗病毒治疗之前或不抗病毒治疗的HSV病毒载量动态与死亡率相关。HSV再激活后肺泡炎症升高。
