The role of viruses in nosocomial pneumonia Laurent Chiche, Jean-Marie Forel and Laurent Papazian

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1 The role of viruses in nosocomial pneumonia Laurent Chiche, Jean-Marie Forel and Laurent Papazian Réanimation Médicale, Assistance Publique Hôpitaux de Marseille, URMITE CNRS-UMR 6236, Université de la Méditerranée, Marseille, France Correspondence to Laurent Papazian, Réanimation Médicale, Hôpital Nord, chemin des Bourrely, Marseille, France Tel: ; fax: ; laurent.papazian@ap-hm.fr Current Opinion in Infectious Diseases 2011, 24: Purpose of review The frequency and impact of viruses among intensive care unit (ICU) nonimmunocompromised patients remains controversial. This review analyzes their place as causal pathogens in ventilator-associated pneumonia, as well as their effects on ICU patients outcomes. Recent findings Herpesviruses, namely herpes simplex virus (HSV) and cytomegalovirus (CMV), are the most frequent viruses detected among nonimmunosuppressed ICU patients, as confirmed by recent prospective studies. Patients infected with these viruses show increased morbidity and, especially for CMV, mortality. An increase of bacterial or fungal superinfections was observed in ICU patients with CMV reactivation. A therapeutic trial of acyclovir (HSV antiviral) in ICU patients was negative. Concerning CMV, pathogenicity was suggested by histologic assessment in ICU patients, and recent murine models with a positive effect of prophylaxis with ganciclovir that prevented postseptic CMV reactivation and secondary lung damage. Summary Using efficient and rapid virologic diagnostic tests (antigenemia or PCR), the identification of viruses in ICU patients is frequent. Their role in the occurrence of ventilator-acquired pneumonia and their impact on patient outcome depend on the virus. There is sufficient evidence suggesting CMV pathogenicity to conduct an interventional randomized trial using anti-cmv drugs. Keywords cytomegalovirus, intensive care unit, mechanical ventilation, nosocomial pneumonia, ventilator-associated pneumonia, virus Curr Opin Infect Dis 24: ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Viral diseases have recently been the subject of numerous investigations in critically ill patients admitted to intensive care units (ICUs). The reason for this particular interest is not only related to the increasing attention to the severe respiratory syndrome associated with severe acute respiratory syndrome, avian flu and, more recently, H1N1 pandemic influenza, but, instead, because of the availability of efficient and rapid virologic diagnostic tests. The aim of this review was to consider the arguments about the role of viruses in causing pneumonia in nonimmunocompromised ICU adult patients. Viruses: from immunocompromised patients to critically ill (nonimmunosuppressed or immunocompetent ) patients Two different situations have to be considered: community-acquired and nosocomial viral pneumonias. The viruses responsible for these two kinds of pneumonia are different (Table 1). Community-acquired respiratory viral infections markedly increase morbidity and/or mortality in immunosuppressed patients presenting abnormalities such as in hematopoietic/solid organ transplantation, malignant hematologic disease and AIDS [1]. As a consequence of impaired cell-mediated immunity in these patients, cytomegalovirus (CMV) reactivation is an important cause of severe nosocomial infection, mainly pneumonia [2]. Conversely, among nonimmunosuppressed critically ill patients, pneumonia, the most commonly reported nosocomial infection, is often attributed to bacteria. However, because a large proportion of ventilator-associated pneumonia (VAP) episodes are of unknown origin, it can be supposed that these microbiologically negative episodes might be, at least in part, due to viruses that are not routinely searched for, or even not yet recognized. Indeed, in 1996, Papazian et al. [3] showed, on the basis of the histologic assessment of autopsies and lung biopsies performed in patients who presented with acute respiratory failure and/or symptoms suggestive of VAP, that 25 of 86 nonimmunocompromised patients had histological findings compatible with CMV lung disease. They demonstrated for the first time ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /QCO.0b013e328343b6e4

2 Role of viruses in nosocomial pneumonia Chiche et al. 153 Table 1 Viruses identified in ICU patients Virus Endogenous Exogenous Community HSV, CMV Influenza, parainfluenza, adenovirus, rhinovirus, RSV, coronavirus, metapneumovirus Nosocomial HSV, CMV Mimivirus, CMV (transfusion), H1N1 pandemic influenza? CMV, cytomegalovirus; HSV, herpes simplex virus; RSV, respiratory syncytial virus. that CMV could be responsible for VAP in nonimmunocompromised patients. In a recent study, the molecular assays (multiplex RT-PCR associated with the enzyme hybridization assay) used to detect respiratory viruses presented a higher sensitivity than the conventional virological assays routinely used [4]. Indeed, investigating patients with severe pneumonia (some cases of which were nosocomial), respiratory viruses were detected in bronchoalveolar lavage (BAL) samples from nearly one-third of the patients, and up to two-thirds when only patients without bacterial cause were considered. Virus detection, however, does not necessarily mean viral disease [5], and as the clinical presentation of these viral infections (mainly pneumonia) has absolutely no specific biological or radiological features, causal relationship between detected viruses and outcome is still a matter of debate, with a variable level of evidence among different viruses. Which viruses for intensive care unit nonimmunosuppressed patients? Viral infections can be related to viruses acquired in the community. Some nosocomial viral infections are also diagnosed during the ICU stay. Exogenous community-acquired viruses Except for immunocompromised patients, the role of respiratory viruses as a cause of nosocomial pneumonia is probably limited in nonimmunosuppressed ICU patients. Indeed, Daubin et al. [6] showed that only two out of 39 patients suspected of having developed VAP had a respiratory sample positive for respiratory viruses (one enterovirus and one influenza). Luyt et al. [7] used PCR to test the BAL fluid of 201 nonimmunocompromised patients for several respiratory viruses and found positive samples in only 11 patients. Intensive care units are, however, potential high-risk areas for the transmission of such respiratory viruses and, theoretically, an influenza pandemic might result in a dramatic surge of critically ill patients, and ICU healthcare workers are likely to be at high risk of infection, increasing the risk of infectious spread from patient to other patients and to healthcare workers [8]. Exogenous nosocomial acquired viruses A recent study suggests that mimivirus could be an agent of pneumonia, especially in critically ill mechanically ventilated patients [9]. Vincent et al. [10 ] performed a matchedcohort study in 55 patients with a positive serology for mimivirus matched to 55 seronegative patients. Patients with a positive serology for mimivirus showed longer duration of mechanical ventilation and ICU stay. However, histological signs of mimivirus pneumonia have never been described in humans and the role of mimivirus as a putative pneumonia agent remains a matter of debate. Herpes viruses: the threat from the inside Finally, herpes viruses [herpes simplex virus (HSV) and CMV] are the most frequent viruses detected among nonimmunosuppressed ICU patients. As most adult patients have already encountered these viruses (and are seropositive at admission), reactivation is considered to be the main mechanism of these special nosocomial infections. Actually, the bystander or pathogen debate concerns both HSV [11] and CMV [12], and definitive proof of causality demonstrating CMV and/or HSV as pathogens awaits controlled clinical trials of specific antiviral therapies. According to already available data, it is, however, suggested that both viruses could affect differently ICU patients outcome. Why should herpes simplex virus and cytomegalovirus be considered in a different way in nonimmunosuppressed intensive care unit patients? There are some data suggesting that HSV and CMV do not carry the same pathogenicity. Histological data Open-lung biopsies in 100 patients with acute respiratory distress syndrome (ARDS) showed that 30 had histological findings compatible with CMV lung disease, whereas findings were compatible with HSV pneumonia only in three [13]. In a recent study, Luyt et al. [7] found that, out of 201 patients suspected of having VAP, 42 were diagnosed with HSV bronchopneumonitis. But BAL fluid and bronchial biopsies were positive in only 10 patients, whereas only one specimen was positive in the remaining patients (BAL for 25, and bronchial biopsies for 7). These authors did not exclude the possibility of two different types of HSV lung involvement, one corresponding to proximal lesions of the tracheobronchial tree and the other to more distal lung involvement. Finally, according to histological data [3,13], tracheobronchitis could be considered as the main manifestation of herpetic infection, whereas true herpetic pneumonia

3 154 Respiratory infections is probably marginal in nonimmunosuppressed ICU patients. Clinical (outcome) data In contrast to HSV, virtually all studies have documented that CMV infection is associated with an increased duration of both mechanical ventilation and ICU stay, and sometimes to an increased mortality rate [14 17,18,19,20]. Cook et al. [20] showed an endemic prevalence (22 49%) of occult herpes family viral infection/ reactivation in critically ill surgical patients. In this latter study, HSV patients had the same outcome as patients without viral infections [20], and in contrast, CMV patients exhibited increased length of stay and duration of mechanical ventilation. No impact of HSV on morbidity and mortality was found by Scheithauer et al. [21]. Conversely, in the work of Tuxen et al. [22], De Vos et al. [23], Linssen et al. [24] and Luyt et al. [7], patients with herpetic tracheobronchitis had longer mechanical ventilation and hospital stays, but no impact on mortality in the latter. An increased rate of bacterial or fungal superinfections was observed in ICU patients with CMV reactivation [14,15,18 ]. Luyt et al. [7] reported slightly more VAP episodes in patients with HSV bronchopneumonitis during mechanical ventilation than in patients without HSV bronchopneumonitis, but the difference was not significant. Physiopathologic data Lung is considered as the main site of CMV latency and reactivation [25], but not for HSV. It was reported that HSV was found in the throat in 22% of ICU patients, whereas 41% of the patients expressed it after surgery [26]. In 201 nonimmunocompromised patients ventilated for at least 5 days, HSV was detected in the throat of 109 patients (54%) by Luyt et al. [7]. Reactivation was asymptomatic in 56% of these patients, whereas it was associated with herpetic ulceration of the lip or gingivostomatitis in 48 (44%) out of 109 patients with reactivation. As the presence of HSV in the throat was a risk factor for development of HSV infections in the lower respiratory tract, this suggests that viral reactivation or infection in the oropharynx reaches the lower respiratory tract by aspiration. Bruynseels et al. [26] detected HSV in the lower respiratory tract secretions of 16% of mechanically ventilated patients in whom the virus was detected. Similarly, Ong et al. [27] detected HSV in 27% of their mechanically ventilated patients. Luyt et al. [7] identified HSV, either by PCR or virus culture, in BAL fluid of 64% of 201 nonimmunocompromised ventilated patients. However, HSV detection in the lower respiratory tract does not necessarily means herpetic pulmonary disease. It is still not known whether HSV recovery from lower respiratory tract samples of nonimmunocompromised ventilated patients is related to viral contamination of the lower respiratory tract from mouth or throat, a local tracheobronchial excretion of the virus due to its reactivation without parenchymal involvement, or true HSV bronchopneumonitis. Therapeutic data To date, only one prospective study was related to antiviral use in ARDS patients [28]. It was conducted more than 20 years ago by Tuxen et al. [22] after their preliminary study. Forty-five patients with ARDS underwent double-blind randomization into a treatment group who received prophylactic acyclovir intravenously. In spite of a prevention of HSV reactivation in the acyclovir group, there was neither improvement of the respiratory failure nor in the duration of ventilator support or mortality [28]. No such trial has been conducted for CMV. Finally, a robust clue for the pathogenicity of CMV comes from studies of murine CMV, in which prophylaxis with ganciclovir prevented postseptic murine CMV reactivation and tumor necrosis factor (TNF) release, as well as the adverse clinical outcome of lung fibrosis [29,30 ]. Public enemy number one for intensivists: cytomegalovirus Cytomegalovirus infection is common, with seroprevalence rate increasing steadily from 65% among year-olds to 91% in those at least 80 years of age [31]. Among nonimmunosuppressed ICU patients, clinical trials investigating the incidence of CMV infection did not show initially uniform results [14,15]. These discrepancies may be explained by differences in study design, patient populations, and/or diagnostic methods used. Indeed, there are different diagnostic methods regarding CMV: viral cultures, antigenemia, and PCR assays [32]. Culture-based assays (conventional and shell-vial cultures) carry a low sensitivity and are highly timeconsuming. The antigenemia assay is sensitive and quantitative although it requires sufficient leukocytes in peripheral blood and is more labor-intensive than the PCR assays. Finally, the PCR assays have been considered as the better diagnostic test due to their high sensitivity and rapid turnover time. More recently, prospective studies including a large number of nonimmunosuppressed patients were conducted in medical [18 ] or surgical [19] ICUs and used either antigenemia or plasma PCR to screen for CMV reactivation. In a medical ICU, using a weekly screening, 39 of the 242 patients (16.1%) developed an active CMV infection, as diagnosed by positive antigenemia (85%) and/or positive rapid viral culture in BAL fluid (26%) [18 ]. ICU mortality (54 vs. 37%, P ¼ 0.082) and in-hospital mortality (59 vs. 41%, P ¼ 0.058) were increased in patients with active CMV

4 Role of viruses in nosocomial pneumonia Chiche et al. 155 infection, as compared with those without active CMV infection. Active CMV infection and Simplified Acute Physiology Score II at admission were independently associated with ICU death on multivariate analysis. Moreover, the patients with active CMV infection had a longer duration of mechanical ventilation, longer ICU stay and were significantly more prone to develop bacterial nosocomial infections. Limaye et al. [19] conducted a multicenter study recruiting patients from six ICUs. They used plasma quantitative PCR tested three times per week and showed that CMV viremia was detectable in 33% of patients (>1000 genomes/ml of plasma in 20% of patients). The presence of CMV viremia and especially CMV of high viral load was an independent risk factor for poor outcome (hospitalization or death by day 30). Of importance, the authors performed a landmark analysis and showed that the statistical association of CMV with increased length of stay was not artifactual (simply due to the fact that the longer a patient remained in ICU the greater the chance of detecting CMV), and might be causal. So, using either antigenemia or PCR for repeated screening, CMV infection was suspected in 1 of 6 ICU patients, and up to 1 of 3 patients if we consider only seropositive and/or more severe patients at admission. From the available studies, and for the same reasons explaining discrepancies concerning the prevalence of CMV infection, it remains difficult to identify specific risk factors for developing an active CMV infection. Age is sometimes considered as a risk factor for CMV infection [18 ]. The association between CMV infection and sex was not reported [14,15]. Other risk factors identified included mechanical ventilation at admission, bacterial pneumonia, and corticosteroid use [18 ]. There are conflicting results concerning a possible correlation of severity scores with the risk of acquiring CMV infection [14,15]. The risk of CMV infection was higher in patients with sepsis even when controlled for age and the initial severity of illness [33,34]. von Müller et al. [34] recently reported that up to one-third of patients with septic shock developed an active CMV infection. Multiple hypotheses could explain the propensity of septic patients to develop CMV infection. First, patients with severe sepsis develop a state called immunoparalysis or compensatory antiinflammatory response syndrome [35]. Then, bacterial sepsis by itself can reactivate latent CMV infection through TNF production [36]. And finally, exogenous catecholamine infusion, administered during septic shock, can also stimulate CMV activation [37]. Data obtained in the murine CMV model indicate that a proinflammatory state driven by various stimuli (i.e. sepsis or intra-abdominal bacterial infection) triggers CMV reactivation in the lungs of latently infected mice, which ultimately results in pulmonary fibrosis [38]. TNFa is a cytokine known to directly stimulate immediate early CMV gene expression in vitro [36], and may exert a pivotal role [37]. However, as both severity scores and TNF plasma levels on admission were not different between patients with or without CMV reactivation [39,40], other mechanisms are probably involved in CMV reactivation. Critically ill patients frequently demonstrate profound immunity abnormalities as a result of either their illness or its treatment [41]. During the following compensatory anti-inflammatory response syndrome, the immune function may be impaired [35,41]. Studies on severely immunocompromised patients clearly demonstrated that T- cell immunity is crucial in the control of CMV replication. However, in a recent study, von Müller et al. [40] showed that active CMV infection occurred in patients with septic shock despite detection of CMV-specific IFNgproducing CD4þ T-cell precursors in blood, suggesting that CMV reactivation is not primarily triggered by T-cell immunosuppression. Chilet et al. [39 ] reported similar results among non-septic patients (trauma ICU) and found CMV-specific T-cell immunity (CD4 and CD8þ) was preserved in most critically ill patients experiencing CMV reactivation. In patients with T-cell deficiency due to T-cell-depleted hematopoietic stem cell transplantation [42], and in animal models [43], natural killer (NK) cells may at least partially substitute for the absence of adaptive T-cell immunity. There is also little evidence of the crucial role of NK cells to maintain herpesviruses latency in humans [44]. The fact that critically ill patients seem capable of mounting T- cell responses to CMV [39,40] strongly suggests that the role of NK cells in maintaining CMV latency should be clearly evaluated in the context of ICU patients [45]. Conclusion There is enough evidence today suggesting CMV pathogenicity to conduct an interventional randomized trial using anti-cmv drugs. Efforts should be done to better identify which specific ICU patients have the highest risk for developing active CMV infection. Considering both recent murine data [30 ] and past experience in solid organ transplantation [46], the most effective therapy might be prophylaxis or preemptive treatment. 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