Severe varicella-zoster virus pneumonia: a multicenter cohort study

Pneumonia is associated with significant morbidity and mortality worldwide [1]. The importance of viruses as pathogens responsible for community-acquired pneumonia (CAP) has been emphasized by several epidemic outbreaks over the last decade: severe acute respiratory syndrome (SARS), avian influenza A (H5N1) virus, and the 2009 pandemic influenza A (H1N1) [2–5]. It is estimated that about 200 million cases of viral CAP occur annually, accounting for 17 to 39% of CAP [6–10]. In the intensive care unit (ICU) setting, viruses have been reported to account for up to one-third of patients with severe CAP, with a similar mortality to that observed with bacterial pneumonia [11]. The availability of new molecular techniques (such as polymerase chain reaction (PCR)) has greatly increased our ability to detect a wide range of viruses in respiratory secretions [12–15]. Nevertheless, although convincing data are available for agents such as influenza virus or respiratory syncytial virus and their role in severe pneumonia, the role of other recently discovered viruses (bocavirus, coronavirus NL63) remains debated and requires further research [16–19].

Varicella-zoster virus (VZV) is one of eight herpes viruses known to cause human infection and is distributed worldwide. Varicella or chickenpox is defined as the VZV primo-infection. In adults, VZV infection is associated with a greater number of complications, of which pneumonia is the most common and serious. Since its initial description in 1942, VZV-related community-acquired pneumonia (VZV-CAP) has become increasingly recognized as a serious and potentially lethal complication of what was once considered a relatively benign and self-limited viral infection [20]. A study with systematic chest X-ray showed an incidence of 16.3% of VZV-CAP in adult patients [21]. Autopsy findings have demonstrated the role of VZV in fatal cases of pneumonia. Microscopic findings included pulmonary edema, extensive alveolar hemorrhage, and mononuclear cell infiltration with histological evidence of intranuclear inclusion bodies [22, 23].

Data on critically ill adult patients with VZV-CAP are limited to case reports and small case series. The purpose of this study was to describe the clinical, biological, and radiological features and the outcome of severe forms of VZV-CAP (i.e., requiring ICU admission) in a large cohort and to report its implication for ICU management.

This retrospective study was conducted in 29 French adult ICUs (see Additional file 1: Table S1). This study has been approved by the French Intensive Care Society Ethics Committee (n°15-12) and an authorization to use patient data from the French Data Protection Agency (n°1868870). According to French law, a waiver of informed consent was obtained.

We identified 102 patients with severe forms of VZV-CAP who were admitted to 29 French ICUs. Underlying immunosuppression accounted for half of the patients we evaluated, mainly related to impaired cellular immune response (lymphoproliferative disorders, immunosuppressive drugs for solid-organ transplant recipients, and/or steroid exposure). Nevertheless, we identified severe illness from VZV-CAP among 11 (11%) young and healthy patients. More than half of the patients required invasive mechanical ventilation, of which 80% met ARDS criteria. Risk factors for intubation were related to the severity of the respiratory failure, the presence of an early bacterial co-infection, and the onset of other organ failures. In addition to antiviral therapy, high doses of steroids were used in 10 (10%) patients without benefit either on improvement of respiratory parameters or on mortality, and were associated with an increased number of superinfections.

There was a 5 (3–7)-day period of illness prior ICU admission, which is similar to influenza virus infection and other causes of viral pneumonia [5, 28, 29]. All patients but four presented with a typical chickenpox skin rash, suggesting that VZV-CAP is mostly a dreaded complication of primary VZV infection rather than recurrent VZV infection. The four patients without rash were all immunocompromised (solid cancer or hematological malignancy). Atypical cases of recurrent VZV infection with pulmonary involvement have been reported, almost exclusively in immunocompromised patients, and cannot be excluded in our study [30–33]. In addition, exogenous clinical reinfection by VZV has also been demonstrated and is thought to occur more likely in immunocompromised patients [30]. The illness course was characterized by a short period of acute and severe respiratory deterioration, requiring invasive mechanical ventilation in half of the cases, shortly after ICU admission. We identified that risk factors for intubation were related to the presence of a bacterial co-infection, the severity of the respiratory failure, and the onset of other organ failures. Neither comorbidities nor underlying immunosuppression were independent predictors of invasive mechanical ventilation. These results are in agreement with previous studies suggesting that the underlying medical context was no longer significantly associated with the risk for intubation after adjustment for the severity of the acute disease [34–36]. The factors we identified are easy to assess at the bedside and may contribute to recognizing hospital admission patients who may benefit from early ICU admission.

In our study, the overall mortality was 24% and reached 43% in patients who received invasive mechanical ventilation. Viruses have been increasingly recognized as pathogens responsible for both severe community-acquired and healthcare-associated pneumonia [11, 29]. Choi et al. recently demonstrated in a prospective study that, in the ICU setting, the mortality rate of patients with viral pneumonia was similar to that of patients with bacterial pneumonia [11]. Nevertheless, most of our knowledge on severe forms of viral pneumonia is related to the influenza virus. We report that patients with VZV-CAP who required intubation experienced a long period of invasive mechanical ventilation (14 (7–21) days) and a high rate of bacterial co-infections (69%). These findings might be explained by the extent of skin and mucosal vesicular lesions. Indeed, previous clinical and autopsy studies have demonstrated that these lesions are responsible for necrotic and hemorrhagic foci distributed both in the upper airways and in the lower respiratory tract that may promote bacterial co-infection [37, 38]. In our study, 36% of the patients who underwent fiberoptic bronchoscopy had vesicular lesions on bronchial mucosa.

In addition to antiviral therapy, the use of steroids has been reported by observational studies in the treatment of VZV pneumonia [39–41]. The role of steroids in the management of pneumonia remains controversial. On the one hand, steroids might have the potential to decrease intrapulmonary inflammation and thus to reduce some ARDS-related pulmonary lesions. But, on the other hand, steroids might increase immunosuppression, favor persistent viral replication, and promote superinfection. Based on the results of two randomized controlled trials, the benefit-to-risk ratio argues for its use in severe Pneumocystis jirovecii pneumonia in the acquired immunodeficiency syndrome [42, 43]. A recent meta-analysis reported that it may decrease the risk of ARDS as adjunctive therapy in community-acquired pneumonia [44]. On the other hand, no benefit has been demonstrated with the use of steroids in influenza pneumonia [45]. In 1998, Mer and Richards [39] reported on 15 adult patients treated for VZV-CAP, six of whom received steroids in addition to antiviral therapy and supportive care. These six patients experienced clinical improvement, a significantly shorter ICU and hospital length of stay, and no mortality when compared to those who did not receive steroids. However, the study design precluded any robust conclusion. Another study from Saudi Arabia reported improvement in oxygenation parameters in 10 adult patients treated for VZV-CAP with steroids as adjunctive therapy [40]. This was not our experience in the present study. Ten patients received steroids 4.5 (1–15) days after ICU admission. We compared these 10 patients to 60 matched controls who did not receive steroids. There was no difference between the steroid group and the nonsteroid group in ICU and hospital mortality. However, patients treated with steroids had a longer duration of invasive mechanical ventilation, more bacterial superinfection, and an increased ICU and hospital length of stay than control patients not treated with steroids. Thus, our data did not report any benefit associated with the use of steroids as adjunctive therapy in severe VZV-CAP.

Our study has several limitations. First, given the retrospective design over a long period of time, supportive care practices may have changed throughout the study period and influenced the results. However, we report the largest study on the severe forms of VZV-CAP and we believe that it adds valuable data to the current knowledge. Second, we had no biological identification of VZV for all patients included our study. Nevertheless, clinical signs and symptoms of chickenpox are obvious in most cases and laboratory diagnosis is restricted to unusual cases. Thus, we can reasonably assume that the patients included in the present study had VZV-CAP. Third, due to the limited number of death we were unable to identify independent predictors of hospital mortality. However, we report predictors of invasive mechanical ventilation that conceivably may be related to mortality. Fourth, for the diagnosis of VZV-CAP we used a database encoded by physicians at patient ICU discharge and we cannot exclude that some patients with VZV-CAP had been missed.

In conclusion, severe VZV-CAP in adults is an acute respiratory disease that requires invasive mechanical ventilation in more than half of the cases. Although underlying medical conditions or immunosuppression are common, healthy young individuals may be involved. We identified that respiratory disease severity, early bacterial co-infection, and other organ failures on ICU admission were independent risk factors for invasive mechanical ventilation. Early recognition of these factors may help to identify patients that may benefit from close monitoring to ensure that no treatment delay occurs when intubation is required. Adjunctive steroid therapy did not influence mortality and increased the risk of superinfection.