REVIEW URRENT C OPINION
What role do viruses play in nosocomial pneumonia? Charles-Edouard Luyt, Nicolas Bre´chot, and Jean Chastre
Purpose of the review Viruses are an increasingly recognized cause of community-acquired pneumonia (CAP), but their exact role in nosocomial pneumonia is still debated. This review focuses on the role of viruses as a cause of nosocomial pneumonia. Recent findings Respiratory viruses may be responsible for healthcare-associated pneumonia, because affected patients and those with CAP have the same risk factors for viral disease. In mechanically ventilated patients, viruses belonging to the Herpesviridae family, namely herpes simplex virus (HSV) and cytomegalovirus, can be reactivated and cause bronchopneumonitis or ventilator-associated pneumonia, respectively. Recent results confirmed the high rate of HSV reactivation in the distal airways of mechanically ventilated patients, and that patients with high virus loads (>105 copies/ml of bronchoalveolar lavage fluid) have poorer outcomes than those with low or no virus load. However, the responsibility of mimivirus, initially described as a possible cause of pneumonia, was not confirmed for nosocomial pneumonia. Summary Respiratory viruses are mainly responsible for CAP, but they may also cause healthcare-associated pneumonia. HSV bronchopneumonitis and cytomegalovirus pneumonia are not rare diseases, and patients with Herpesviridae lung infections have worse prognoses than those without. Whether or not those Herpesviridae infections are responsible for true morbidity or morbidity remains to be determined. Keywords cytomegalovirus, herpes simplex virus, ventilator-associated pneumonia, viral pneumonia
INTRODUCTION In recent years, viruses have been identified as an increasingly frequent cause of community-acquired pneumonia (CAP) [1], not only because of emerging or pandemic respiratory viruses [2], but also because of the development of technologies permitting sample processing in a rapid turn-around time. Viruses recovered from the lower respiratory tract of patients who developed nosocomial pneumonia [hospital-acquired, healthcare-associated pneumonia (HCAP) or ventilator-associated pneumonia (VAP)] have also been described, but controversies about their pathogenicity and their roles in pneumonia persist. This review examines the roles of viruses as causes of nosocomial pneumonia. Because only data on patients with VAP are available, we focused this review on only nonimmunocompromised VAP patients. www.co-infectiousdiseases.com
VIRUSES RECOVERED FROM THE LOWER RESPIRATORY TRACT Mainly respiratory viruses (i.e. influenza, rhinovirus, respiratory syncytial virus, human metapneumovirus, and adenovirus) are responsible for causing CAP [1], and mostly latent viruses, particularly Herpesviridae, are recovered from the lower Service de Re´animation Me´dicale, Institut de Cardiologie, Groupe Hospitalier Pitie´ –Salpeˆtrie`re, Assistance Publique–Hoˆpitaux de Paris, and Universite´ Paris 6–Pierre et Marie Curie, Paris, France Correspondence to Charles-Edouard Luyt, Service de Re´animation Me´dicale, Institut de Cardiologie, Groupe Hospitalier Pitie´ –Salpeˆtrie`re, 47-83, boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France. Tel: +33 1 42 16 38 16; fax: +33 1 42 16 38 17; e-mail: charles-edouard.luyt@ psl.aphp.fr Curr Opin Infect Dis 2014, 27:194–199 DOI:10.1097/QCO.0000000000000049 Volume 27 Number 2 April 2014
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What role do viruses play in nosocomial pneumonia? Luyt et al.
KEY POINTS Viruses are commonly recovered from patients suffering from nosocomial pneumonia: respiratory viruses may be recovered from patients suffering from healthcareassociated pneumonia, and Herpesviridae from patients with prolonged mechanical ventilation. Viruses belonging to the Herpesviridae family (HSV and CMV) are frequently recovered from the distal airways of mechanically ventilated patients, and associated with morbidity and mortality. The true pathogenicity of Herpesviridae (innocent bystanders or true pathogens) is, however, still not known.
respiratory tract of patients who develop nosocomial pneumonia. Stimuli causing Herpesviridae reactivation are not specific, and may include immunosuppression, stress, hormonal change, traumatic lesions, and other acute illnesses. During their stays, ICU patients are known to experience immunoparalysis: an initial proinflammatoryresponse phase is followed by an anti-inflammatory response that attempts to balance the former, thereby leading to immunoparalysis, which is responsible for nosocomial infections and latentvirus reactivation [3,4 ]. Among Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) are both reactivated in ICU patients. Mimivirus, an emergent virus, has also been described as a possible cause for nosocomial pneumonia. &
RESPIRATORY VIRUSES Respiratory viruses are mainly responsible for CAP [1], but do not seem to cause VAP. In a cohort of 39 VAP patients, no respiratory viruses were detected [5]. However, these viruses may be the cause of HCAP. In a recent retrospective study, 134 HCAP and 64 CAP patients were tested for respiratory viruses: 34% of the HCAP patients had at least one respiratory virus recovered either in the lower respiratory tract or the nasopharyngeal swab [6 ], with the most frequent being rhinovirus, parainfluenza virus, human metapneumovirus and influenza. Intriguingly, patients with viral HCAP or bacterial VAP had the same mortality rate [6 ]. &&
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ROLE OF HERPES SIMPLEX VIRUS IN NOSOCOMIAL PNEUMONIA Reactivated HSV-1 can be isolated from the saliva of 1–5% of the general population, whereas about half
of ICU patients have viral reactivation. Bruynseels et al. [7] reported that 22% of nonselected ICU patients had HSV reactivation in the throat, whereas Luyt et al. [8] found that, among 201 nonimmunocompromised patients mechanically ventilated for at least 5 days, 109 (54%) had HSV detected in the throat. In that study, reactivation was asymptomatic in 56% of the patients, but associated with herpetic labial ulceration or gingivostomatitis in 48 (44%) of 109 patients with oropharyngeal viral reactivation. HSV could be detected in the distal airways of 5–64% of ICU patients, with these differences depending on the population and the diagnostic method used [7–23,24 ,25,26 ] (Table 1). However, HSV detection in the lower airways does not mean viral pulmonary parenchymal disease; HSV detection might reflect airway contamination by saliva, tracheobronchial reactivation without parenchymal involvement or true HSV bronchopneumonitis [8,27]. HSV bronchopneumonitis was initially described in immunocompromised patients [28,29], but other data showed that it can occur in nonimmunosuppressed patients with acute respiratory distress syndrome (ARDS) [13], after surgery [9,14,30,31] or in burn victims [10,32]. Among 201 patients suspected of having developed VAP, 42 (21%) had developed true HSV bronchopneumonitis, defined as clinical deterioration motivating the sampling of distal airways by fiber optic-guided bronchoalveolar lavage (BAL), presence of HSV in BAL fluid (PCR and viral culture, or either of the two), and specific nuclear inclusions (characteristic cytopathic effect) in BAL-collected cells [8]. Although the pathophysiology of HSV bronchopneumonitis has not been fully elucidated, it is probably initiated by oropharyngeal reactivation, followed by downward contamination of the tracheobronchial tree. This hypothesis is supported by several reported findings. On the basis of their autopsy study, Nash [33], and Nash and Foley [34] concluded that the anatomic distribution of the lesions suggested a downward infection. Moreover, Bruynseels et al. [7] found that, in 72% of patients with HSV detected in their distal airways, the virus was also isolated in the oropharyngeal cavity on the same day or the days preceding detection in the distal airways. Luyt et al. [8] described similar results: in all patients with HSV detected in their throat and distal airways, the virus was also isolated from the oropharynx on the same day or the days preceding detection in the distal airways. However, HSV was sometimes detected only in the tracheobronchial tree [7,8], so another pathophysiologic mechanism (lung reactivation or infection from blood) cannot be excluded [18]. Notably, oropharyngeal HSV reactivation may occur early in critically ill patients
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Respiratory infections
(as early as day 5 after ICU admission) [7,8], with later onset of HSV bronchopneumonitis, after an average of 14 days on mechanical ventilation [8]. The clinical symptoms of HSV bronchopneumonitis are nonspecific and often mimic bacterial pneumonia with fever, hypoxemia and purulent pulmonary secretions. However, because HSV orallabial lesions (HSV lip vesicles, lip wound or gingivostomatitis) are frequently associated with HSV bronchopneumonitis, the appearance of such lesions in mechanical ventilation patients should alert clinicians to look for HSV bronchopneumonitis [8,21]. Notably, multivariate analysis retained HSV detection in the oropharynx and the presence of labial lesions as being significantly associated with HSV bronchopneumonitis [8]. Radiologic abnormalities of HSV bronchopneumonitis are nonspecific, including localized or diffuse infiltrates, localized consolidations or ARDS [8,13]. Atelectasis and pleural effusions may also be observed, but the link between those findings and HSV bronchopneumonitis has never been formally established [35]. In a more recent computed tomography (CT) scan study on two immunocompetent
patients, ground-glass attenuations, air-space consolidations and interlobular thickening were seen [36]. Histologic examination is the key for the diagnosis. In the respiratory tract, HSV detection may be due to oropharyngeal contamination or tracheal shedding, without pulmonary parenchymal disease. Other than virus detection in sterile fluids, HSV infection can be confirmed by the presence of a characteristic cytopathic effect: multinucleated giant cells with specific nuclear inclusions. For pneumonia, lung biopsy is the gold standard, but it is not realistic in ICU patients [37,38] because of its complexity and risks. The search for a specific cytopathic effect on cells collected during BAL could be an alternative [8], but this technique is difficult to implement in routine because it requires trained pathologists. Using the HSV load in BAL fluid could be another option. This approach is based on the association of HSV bronchopneumonitis with a high virus load [8]. Luyt et al. [8] showed that an HSV load exceeding 8 104 copies/106 cells had 81% [95% confidence interval (CI) 69–90%] sensitivity and 83% (95% CI 71–91%) specificity for the diagnosis of HSV bronchopneumonitis.
Table 1. Studies that evaluated the frequency of HSV detection in the lower respiratory tract of ICU patients Patient population ARDS
HSV-detection frequencya 14/46 (30.4%)
VAP
37/308 (12.0%)
Immunocompromised and nonimmunocompromised Immunocompromised Postsurgical
42b
Manifestations of HSV involvement
Diagnostic method
Reference
Tracheobronchitis
Viral culture, cytopathic effect
[13]
Pulmonary infiltrates
Viral culture, cytopathic effect
[10]
Tracheobronchitis
Viral culture
[11]
53/1199 (4.4%)
Pneumonia
Viral culture
[12]
36b
Pneumonia
Viral culture
[9]
Postsurgical
3/54 (5.6%)
Postsurgical
8/142 (5.6%)
Pneumonia
Viral culture
[14]
Fever, lymphopenia
Viral culture
[15]
Postsurgical
11/104 (10.6%)
None
Viral culture
[16]
All ICU
58/361 (16.1%)
None
Viral culture
[7]
All on MV ARDS
106/393 (27%) 22/53 (42/41.5%)
VAP suspected
129/201 (64.2%)
VAP suspected þ
PCR
[17]
PCR
[18]
Bronchopneumonitis
PCR, viral culture, cytopathic effect
[8]
NR
PCR
[19]
82/260 (31.5%)
NR
PCR
[20]
b
53b
HSVþ
None None
NR
PCR
[21]
All on MV
65/105 (61.9%)
48
None
PCR
[22]
VAP suspected
62/191 (32.5%)
NR
PCR
[23]
VAP suspected
76/237 (32.1%)
NR
PCR
[24 ]
VAP suspected
26/77 (33.8%)
NR
PCR
[25]
VAP suspected
26/93 (28%)
None
Viral culture, PCR, serology
[26 ]
HSV
&
&
ARDS, acute respiratory distress syndrome; HSV, herpes simplex virus; MV, mechanical ventilation; NA, not available; NR, not reported; VAP, ventilatorassociated pneumonia. a Frequency of viral detection in tracheal aspirate or bronchoalveolar lavage fluid. b Studied retrospectively.
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What role do viruses play in nosocomial pneumonia? Luyt et al.
Published evidence supports the real pathogenicity of HSV in nonimmunocompromised patients. In 1982, Tuxen et al. [13] had found that 30% of ARDS patients with a lung biopsy had histologically confirmed herpetic disease. Those patients had longer mechanical ventilation durations and hospital stays, and a higher mortality rate than those without herpetic lung disease [13]. In the study by Luyt et al. [8], the 42 patients who developed HSV bronchopneumonitis had longer mechanical ventilation durations than the 149 who did not, but their mortality rates were the same. Two other studies described similar results: the first found that the prognosis was worse for patients with high HSV loads (>105 copies/ml) in BAL fluid than those with less than 105 copies/ml [20]; and the other showed that patients with high HSV loads (>105 copies/ml) more frequently developed ARDS, stayed longer in the ICU than those with low virus loads and had higher mortality [24 ]. However, the true pathogenicity of HSV in the lower airways remains controversial. Is it a real parenchymal disease with its own morbidity and mortality, or is it merely a marker of the severity of the underlying disease? Only a randomized trial evaluating a specific antiviral treatment could answer that question. Very few data are available on acyclovir efficacy in this setting. Most studies concern series or clinical cases [11,39]. Luyt et al. [8] evaluated 42 nonimmunocompromised patients with HSV bronchopneumonitis, 19 of whom were treated with acyclovir and 23 received no treatment. In this population, acyclovir had no impact on mechanical ventilation, length of ICU stay or mortality. But that study was not randomized and was not designed to test the benefit of acyclovir. The only randomized, placebo-controlled trial was conducted on ARDS patients: the authors showed that none of the 17 patients receiving acyclovir had HSV reactivation in their distal airways, whereas 15/21(71.4%) placebo-treated patients had reactivated HSV in their distal airways. However, their respective mechanical ventilation durations (mean SD 20 19 vs. 14 11 days) and ICU mortality rates (47 vs. 43%) were comparable [40]. &
ROLE OF CYTOMEGALOVIRUS IN NOSOCOMIAL PNEUMONIA Little is known about CMV pneumonia in nonimmunocompromised ICU patients. Published findings are summarized in Table 2. Notably, the frequency of CMV detection in the lungs (range 6–30%) depended on the population studied [23,26 ,41–45]: for the studies including all ICU patients, it was low (15%) [41,43]. Also, Scheithauer et al. [23] found that CMV was detected in the BAL fluids of 17.8% of their patients suspected of having developed VAP. Cytomegalovirus can be detected in the blood after a median ICU stay of 12 days, with the highest viremia being detected after a median stay of 26 days [46]. CMV pneumonia develops after an average of 3 weeks on mechanical ventilation [41–45]. Although pulmonary involvement was diagnosed by lung biopsy, this technique is cumbersome and difficult to implement in routine practice. At present, other than the histologic examination on an open-chest lung biopsy, no specific test exists to diagnose CMV VAP. In one study, patients were considered to have developed CMV pneumonia based on clinical suspicion (VAP clinical signs or ARDS) and CMV detection in the distal airways or a specific cytopathic effect in BAL-collected cells [44]. A disadvantage of that strategy is the risk of falsepositives. Indeed, as for HSV bronchopneumonitis, CMV detection in BAL fluid does not necessarily mean viral VAP. The isolation of CMV in BAL fluid may reflect virus reactivation without true pneumonia. For the latter, cytology of BAL-collected cells to look for a specific cytopathic effect is a key component to making the diagnosis. However, the cytopathic effect depends on the virus: intranuclear inclusions are HSV-specific, whereas intracytoplasmic inclusions are CMV-specific [27]. Moreover, BAL-fluid cytology is probably less sensitive for CMV pneumonia than HSV bronchopneumonitis, as suggested by the BAL-collected cells of only 1 of 11 patients exhibiting a cytopathic effect [27]. Virus load should replace cytology in the near future, but data are still lacking [27]. Nonetheless, the search for CMV in BAL fluid may be recommended for unexplained ARDS or pneumonia without microbiologic documentation. Again, BAL fluid must be sent to the laboratory and requires an experienced pathologist to look for the specific cytopathic effect. Moreover, the outcomes of patients with CMV pneumonia are not well known. CMV reactivation detected in the blood seems to be associated with poor prognosis [44,46,47]. High-level circulating CMV (>1000 copies/ml) was associated with increased mortality or prolonged ICU stays [46]. A more recent study evaluated the prognosis of patients with CMV infection, including CMV VAP, the latter being defined as combination of clinical signs of pneumonia and CMV detection in BAL fluid [44]. Although the authors did not specifically evaluate the prognosis of patients with CMV VAP, as defined above, they found that mortality of patients with CMV infection tended to be higher
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Respiratory infections Table 2. Studies that evaluated the frequency of CMV detection in the lower respiratory tract of ICU patients Patient population
CMV-detection frequencya
Manifestations of CMV involvement
ARF or VAP
25/86 (29.1%)
Postoperative, SAPS II >40
7/56 (12.5%)
Diagnostic methods
Reference
Diffuse interstitial pneumonia
Histology (autopsy for 60, lung biopsy for 26)
[41]
NR
Viral culture, PCR
[42]
Unexplained ARDS
30/100 (30%)
Pneumonia, fibrosis
Histology (lung biopsy)
[43]
Patients on MV
11/242 (4.5%)
Pneumonia
Viral culture
[44]
VAP suspected
34/191 (17.8%)
NR
PCR
[23]
Patients with severe sepsis
25/86 (29.1%)
NR
Viral culture, PCR
[45]
VAP suspected
22/93 (23.7%)
NR
Viral culture, PCR, serology
[26 ] &
ARDS, acute respiratory distress syndrome; ARF, acute respiratory failure; CMV, cytomegalovirus; MV mechanical ventilation; NR, not reported; SAPS, Simplified Acute Physiology Score; VAP, ventilator-associated pneumonia. a Frequency of viral detection in tracheal aspirate or bronchoalveolar lavage fluid.
than that of patients without CMV infection [44]. A recent but small study including 22 patients found the same results and shared the same conclusions [26 ]. But again, as for HSV bronchopneumonitis, it is impossible to know whether CMV detection in the distal airways is simply an attestation of the severity of the underlying disease or a real disease with its own morbidity/mortality. Only a clinical trial evaluating the benefit of a specific antiviral treatment in such a population could answer that question. No reported randomized controlled trial has evaluated the use of antiviral therapy in critically ill patients. When CMV pneumonia was suspected in patients with unexplained ARDS and confirmed by lung biopsy, some patients who received ganciclovir were cured [43]. Those authors concluded that specific anti-CMV treatment could be useful, but the results warrant confirmation in a randomized trial. Because of ganciclovir toxicity and the absence of solid evidence of the potential benefits of this treatment, we still cannot recommend its use in critically ill patients [27].
mimivirus. At present, no definite conclusion can be drawn on the potential role of mimivirus in nosocomial pneumonia.
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MIMIVIRUS In 2005, Acanthamoeba polyphaga mimivirus (mimivirus) was described as a potential causative pathogen of pneumonia. After a first case report of a technician (accidental contamination) [48], Berger et al. [49] reported that mimivirus was a possible cause in 6/120 nosocomial pneumonia episodes. However, other studies yielded conflicting results. In a retrospective study using two real-time PCR assays, Dare et al. [50] screened 496 respiratory specimens from nine pneumonia patient populations for mimivirus; it was not detected in any sample. More recently, Vanspauwen et al. [51 ] tested the BAL samples of 260 patients suspected of having developed VAP; none was positive for &
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CONCLUSION To date, no evidence supports that respiratory viruses are responsible for VAP. However, it seems that those viruses might have been responsible in some HCAP cases, probably because HCAP and CAP patients have the same risk factors for viral disease. Herpes simplex virus detection in the respiratory tract is frequent in ICU patients, and high HSV load is associated with worse prognosis. Sometimes, HSV bronchopneumonitis can occur. However, the exact outcomes of HSV reactivation and/or HSV bronchopneumonitis are not fully elucidated: is HSV an innocent bystander or a real pathogen with its own morbidity/mortality? Cytomegalovirus pneumonia is difficult to diagnose. As for HSV, the exact significance of CMV detection in the distal airways is not completely known. Although patients with CMV reactivation detected in the blood seem to have a more pejorative prognosis than those without, the outcome of CMV VAP remains to be determined more precisely. Acknowledgements The authors thank Janet Jacobson for editorial assistance during the writing of this manuscript. Conflicts of interest C.-E.L. has received fees from ThermoFischer Brahms for lectures on procalcitonin. N.B. has no conflicts of interest to disclose. J.C. has received fees from Pfizer, Bayer, Trius, Astellas, Janssen, Cubist and Sanofi for consultancies, and lecture fees from Pfizer. Volume 27 Number 2 April 2014
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What role do viruses play in nosocomial pneumonia? Luyt et al.
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Heininger A, Haeberle H, Fischer I, et al. Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis. Crit Care 2011; 15:R77. 46. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. J Am Med Assoc 2008; 300:413– 422. 47. Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care 2009; 13:R68. 48. Raoult D, Renesto P, Brouqui P. Laboratory infection of a technician by mimivirus. Ann Intern Med 2006; 144:702–703. 49. Berger P, Papazian L, Drancourt M, et al. Ameba-associated microorganisms and diagnosis of nosocomial pneumonia. Emerg Infect Dis 2006; 12:248–255. 50. Dare RK, Chittaganpitch M, Erdman DD. Screening pneumonia patients for mimivirus. Emerg Infect Dis 2008; 14:465–467. 51. Vanspauwen MJ, Schnabel RM, Bruggeman CA, et al. Mimivirus is not & a frequent cause of ventilator-associated pneumonia in critically ill patients. J Med Virol 2013; 85:1836–1841. A large epidemiological study investigating the potential role of mimivirus in ventilator-associated pneumonia. The authors found that among 214 patients suspected of having developed VAP, none had mimivirus recovered in their lung sample, questioning the importance of mimivirus as a cause of pneumonia in ICU patients. &
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What role do viruses play in nosocomial pneumonia? Charles-Edouard Luyt, Nicolas Bre´chot, and Jean Chastre
Purpose of the review Viruses are an increasingly recognized cause of community-acquired pneumonia (CAP), but their exact role in nosocomial pneumonia is still debated. This review focuses on the role of viruses as a cause of nosocomial pneumonia. Recent findings Respiratory viruses may be responsible for healthcare-associated pneumonia, because affected patients and those with CAP have the same risk factors for viral disease. In mechanically ventilated patients, viruses belonging to the Herpesviridae family, namely herpes simplex virus (HSV) and cytomegalovirus, can be reactivated and cause bronchopneumonitis or ventilator-associated pneumonia, respectively. Recent results confirmed the high rate of HSV reactivation in the distal airways of mechanically ventilated patients, and that patients with high virus loads (>105 copies/ml of bronchoalveolar lavage fluid) have poorer outcomes than those with low or no virus load. However, the responsibility of mimivirus, initially described as a possible cause of pneumonia, was not confirmed for nosocomial pneumonia. Summary Respiratory viruses are mainly responsible for CAP, but they may also cause healthcare-associated pneumonia. HSV bronchopneumonitis and cytomegalovirus pneumonia are not rare diseases, and patients with Herpesviridae lung infections have worse prognoses than those without. Whether or not those Herpesviridae infections are responsible for true morbidity or morbidity remains to be determined. Keywords cytomegalovirus, herpes simplex virus, ventilator-associated pneumonia, viral pneumonia
INTRODUCTION In recent years, viruses have been identified as an increasingly frequent cause of community-acquired pneumonia (CAP) [1], not only because of emerging or pandemic respiratory viruses [2], but also because of the development of technologies permitting sample processing in a rapid turn-around time. Viruses recovered from the lower respiratory tract of patients who developed nosocomial pneumonia [hospital-acquired, healthcare-associated pneumonia (HCAP) or ventilator-associated pneumonia (VAP)] have also been described, but controversies about their pathogenicity and their roles in pneumonia persist. This review examines the roles of viruses as causes of nosocomial pneumonia. Because only data on patients with VAP are available, we focused this review on only nonimmunocompromised VAP patients. www.co-infectiousdiseases.com
VIRUSES RECOVERED FROM THE LOWER RESPIRATORY TRACT Mainly respiratory viruses (i.e. influenza, rhinovirus, respiratory syncytial virus, human metapneumovirus, and adenovirus) are responsible for causing CAP [1], and mostly latent viruses, particularly Herpesviridae, are recovered from the lower Service de Re´animation Me´dicale, Institut de Cardiologie, Groupe Hospitalier Pitie´ –Salpeˆtrie`re, Assistance Publique–Hoˆpitaux de Paris, and Universite´ Paris 6–Pierre et Marie Curie, Paris, France Correspondence to Charles-Edouard Luyt, Service de Re´animation Me´dicale, Institut de Cardiologie, Groupe Hospitalier Pitie´ –Salpeˆtrie`re, 47-83, boulevard de l’Hoˆpital, 75651 Paris Cedex 13, France. Tel: +33 1 42 16 38 16; fax: +33 1 42 16 38 17; e-mail: charles-edouard.luyt@ psl.aphp.fr Curr Opin Infect Dis 2014, 27:194–199 DOI:10.1097/QCO.0000000000000049 Volume 27 Number 2 April 2014
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What role do viruses play in nosocomial pneumonia? Luyt et al.
KEY POINTS Viruses are commonly recovered from patients suffering from nosocomial pneumonia: respiratory viruses may be recovered from patients suffering from healthcareassociated pneumonia, and Herpesviridae from patients with prolonged mechanical ventilation. Viruses belonging to the Herpesviridae family (HSV and CMV) are frequently recovered from the distal airways of mechanically ventilated patients, and associated with morbidity and mortality. The true pathogenicity of Herpesviridae (innocent bystanders or true pathogens) is, however, still not known.
respiratory tract of patients who develop nosocomial pneumonia. Stimuli causing Herpesviridae reactivation are not specific, and may include immunosuppression, stress, hormonal change, traumatic lesions, and other acute illnesses. During their stays, ICU patients are known to experience immunoparalysis: an initial proinflammatoryresponse phase is followed by an anti-inflammatory response that attempts to balance the former, thereby leading to immunoparalysis, which is responsible for nosocomial infections and latentvirus reactivation [3,4 ]. Among Herpesviridae, herpes simplex virus (HSV) and cytomegalovirus (CMV) are both reactivated in ICU patients. Mimivirus, an emergent virus, has also been described as a possible cause for nosocomial pneumonia. &
RESPIRATORY VIRUSES Respiratory viruses are mainly responsible for CAP [1], but do not seem to cause VAP. In a cohort of 39 VAP patients, no respiratory viruses were detected [5]. However, these viruses may be the cause of HCAP. In a recent retrospective study, 134 HCAP and 64 CAP patients were tested for respiratory viruses: 34% of the HCAP patients had at least one respiratory virus recovered either in the lower respiratory tract or the nasopharyngeal swab [6 ], with the most frequent being rhinovirus, parainfluenza virus, human metapneumovirus and influenza. Intriguingly, patients with viral HCAP or bacterial VAP had the same mortality rate [6 ]. &&
&&
ROLE OF HERPES SIMPLEX VIRUS IN NOSOCOMIAL PNEUMONIA Reactivated HSV-1 can be isolated from the saliva of 1–5% of the general population, whereas about half
of ICU patients have viral reactivation. Bruynseels et al. [7] reported that 22% of nonselected ICU patients had HSV reactivation in the throat, whereas Luyt et al. [8] found that, among 201 nonimmunocompromised patients mechanically ventilated for at least 5 days, 109 (54%) had HSV detected in the throat. In that study, reactivation was asymptomatic in 56% of the patients, but associated with herpetic labial ulceration or gingivostomatitis in 48 (44%) of 109 patients with oropharyngeal viral reactivation. HSV could be detected in the distal airways of 5–64% of ICU patients, with these differences depending on the population and the diagnostic method used [7–23,24 ,25,26 ] (Table 1). However, HSV detection in the lower airways does not mean viral pulmonary parenchymal disease; HSV detection might reflect airway contamination by saliva, tracheobronchial reactivation without parenchymal involvement or true HSV bronchopneumonitis [8,27]. HSV bronchopneumonitis was initially described in immunocompromised patients [28,29], but other data showed that it can occur in nonimmunosuppressed patients with acute respiratory distress syndrome (ARDS) [13], after surgery [9,14,30,31] or in burn victims [10,32]. Among 201 patients suspected of having developed VAP, 42 (21%) had developed true HSV bronchopneumonitis, defined as clinical deterioration motivating the sampling of distal airways by fiber optic-guided bronchoalveolar lavage (BAL), presence of HSV in BAL fluid (PCR and viral culture, or either of the two), and specific nuclear inclusions (characteristic cytopathic effect) in BAL-collected cells [8]. Although the pathophysiology of HSV bronchopneumonitis has not been fully elucidated, it is probably initiated by oropharyngeal reactivation, followed by downward contamination of the tracheobronchial tree. This hypothesis is supported by several reported findings. On the basis of their autopsy study, Nash [33], and Nash and Foley [34] concluded that the anatomic distribution of the lesions suggested a downward infection. Moreover, Bruynseels et al. [7] found that, in 72% of patients with HSV detected in their distal airways, the virus was also isolated in the oropharyngeal cavity on the same day or the days preceding detection in the distal airways. Luyt et al. [8] described similar results: in all patients with HSV detected in their throat and distal airways, the virus was also isolated from the oropharynx on the same day or the days preceding detection in the distal airways. However, HSV was sometimes detected only in the tracheobronchial tree [7,8], so another pathophysiologic mechanism (lung reactivation or infection from blood) cannot be excluded [18]. Notably, oropharyngeal HSV reactivation may occur early in critically ill patients
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Respiratory infections
(as early as day 5 after ICU admission) [7,8], with later onset of HSV bronchopneumonitis, after an average of 14 days on mechanical ventilation [8]. The clinical symptoms of HSV bronchopneumonitis are nonspecific and often mimic bacterial pneumonia with fever, hypoxemia and purulent pulmonary secretions. However, because HSV orallabial lesions (HSV lip vesicles, lip wound or gingivostomatitis) are frequently associated with HSV bronchopneumonitis, the appearance of such lesions in mechanical ventilation patients should alert clinicians to look for HSV bronchopneumonitis [8,21]. Notably, multivariate analysis retained HSV detection in the oropharynx and the presence of labial lesions as being significantly associated with HSV bronchopneumonitis [8]. Radiologic abnormalities of HSV bronchopneumonitis are nonspecific, including localized or diffuse infiltrates, localized consolidations or ARDS [8,13]. Atelectasis and pleural effusions may also be observed, but the link between those findings and HSV bronchopneumonitis has never been formally established [35]. In a more recent computed tomography (CT) scan study on two immunocompetent
patients, ground-glass attenuations, air-space consolidations and interlobular thickening were seen [36]. Histologic examination is the key for the diagnosis. In the respiratory tract, HSV detection may be due to oropharyngeal contamination or tracheal shedding, without pulmonary parenchymal disease. Other than virus detection in sterile fluids, HSV infection can be confirmed by the presence of a characteristic cytopathic effect: multinucleated giant cells with specific nuclear inclusions. For pneumonia, lung biopsy is the gold standard, but it is not realistic in ICU patients [37,38] because of its complexity and risks. The search for a specific cytopathic effect on cells collected during BAL could be an alternative [8], but this technique is difficult to implement in routine because it requires trained pathologists. Using the HSV load in BAL fluid could be another option. This approach is based on the association of HSV bronchopneumonitis with a high virus load [8]. Luyt et al. [8] showed that an HSV load exceeding 8 104 copies/106 cells had 81% [95% confidence interval (CI) 69–90%] sensitivity and 83% (95% CI 71–91%) specificity for the diagnosis of HSV bronchopneumonitis.
Table 1. Studies that evaluated the frequency of HSV detection in the lower respiratory tract of ICU patients Patient population ARDS
HSV-detection frequencya 14/46 (30.4%)
VAP
37/308 (12.0%)
Immunocompromised and nonimmunocompromised Immunocompromised Postsurgical
42b
Manifestations of HSV involvement
Diagnostic method
Reference
Tracheobronchitis
Viral culture, cytopathic effect
[13]
Pulmonary infiltrates
Viral culture, cytopathic effect
[10]
Tracheobronchitis
Viral culture
[11]
53/1199 (4.4%)
Pneumonia
Viral culture
[12]
36b
Pneumonia
Viral culture
[9]
Postsurgical
3/54 (5.6%)
Postsurgical
8/142 (5.6%)
Pneumonia
Viral culture
[14]
Fever, lymphopenia
Viral culture
[15]
Postsurgical
11/104 (10.6%)
None
Viral culture
[16]
All ICU
58/361 (16.1%)
None
Viral culture
[7]
All on MV ARDS
106/393 (27%) 22/53 (42/41.5%)
VAP suspected
129/201 (64.2%)
VAP suspected þ
PCR
[17]
PCR
[18]
Bronchopneumonitis
PCR, viral culture, cytopathic effect
[8]
NR
PCR
[19]
82/260 (31.5%)
NR
PCR
[20]
b
53b
HSVþ
None None
NR
PCR
[21]
All on MV
65/105 (61.9%)
48
None
PCR
[22]
VAP suspected
62/191 (32.5%)
NR
PCR
[23]
VAP suspected
76/237 (32.1%)
NR
PCR
[24 ]
VAP suspected
26/77 (33.8%)
NR
PCR
[25]
VAP suspected
26/93 (28%)
None
Viral culture, PCR, serology
[26 ]
HSV
&
&
ARDS, acute respiratory distress syndrome; HSV, herpes simplex virus; MV, mechanical ventilation; NA, not available; NR, not reported; VAP, ventilatorassociated pneumonia. a Frequency of viral detection in tracheal aspirate or bronchoalveolar lavage fluid. b Studied retrospectively.
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What role do viruses play in nosocomial pneumonia? Luyt et al.
Published evidence supports the real pathogenicity of HSV in nonimmunocompromised patients. In 1982, Tuxen et al. [13] had found that 30% of ARDS patients with a lung biopsy had histologically confirmed herpetic disease. Those patients had longer mechanical ventilation durations and hospital stays, and a higher mortality rate than those without herpetic lung disease [13]. In the study by Luyt et al. [8], the 42 patients who developed HSV bronchopneumonitis had longer mechanical ventilation durations than the 149 who did not, but their mortality rates were the same. Two other studies described similar results: the first found that the prognosis was worse for patients with high HSV loads (>105 copies/ml) in BAL fluid than those with less than 105 copies/ml [20]; and the other showed that patients with high HSV loads (>105 copies/ml) more frequently developed ARDS, stayed longer in the ICU than those with low virus loads and had higher mortality [24 ]. However, the true pathogenicity of HSV in the lower airways remains controversial. Is it a real parenchymal disease with its own morbidity and mortality, or is it merely a marker of the severity of the underlying disease? Only a randomized trial evaluating a specific antiviral treatment could answer that question. Very few data are available on acyclovir efficacy in this setting. Most studies concern series or clinical cases [11,39]. Luyt et al. [8] evaluated 42 nonimmunocompromised patients with HSV bronchopneumonitis, 19 of whom were treated with acyclovir and 23 received no treatment. In this population, acyclovir had no impact on mechanical ventilation, length of ICU stay or mortality. But that study was not randomized and was not designed to test the benefit of acyclovir. The only randomized, placebo-controlled trial was conducted on ARDS patients: the authors showed that none of the 17 patients receiving acyclovir had HSV reactivation in their distal airways, whereas 15/21(71.4%) placebo-treated patients had reactivated HSV in their distal airways. However, their respective mechanical ventilation durations (mean SD 20 19 vs. 14 11 days) and ICU mortality rates (47 vs. 43%) were comparable [40]. &
ROLE OF CYTOMEGALOVIRUS IN NOSOCOMIAL PNEUMONIA Little is known about CMV pneumonia in nonimmunocompromised ICU patients. Published findings are summarized in Table 2. Notably, the frequency of CMV detection in the lungs (range 6–30%) depended on the population studied [23,26 ,41–45]: for the studies including all ICU patients, it was low (15%) [41,43]. Also, Scheithauer et al. [23] found that CMV was detected in the BAL fluids of 17.8% of their patients suspected of having developed VAP. Cytomegalovirus can be detected in the blood after a median ICU stay of 12 days, with the highest viremia being detected after a median stay of 26 days [46]. CMV pneumonia develops after an average of 3 weeks on mechanical ventilation [41–45]. Although pulmonary involvement was diagnosed by lung biopsy, this technique is cumbersome and difficult to implement in routine practice. At present, other than the histologic examination on an open-chest lung biopsy, no specific test exists to diagnose CMV VAP. In one study, patients were considered to have developed CMV pneumonia based on clinical suspicion (VAP clinical signs or ARDS) and CMV detection in the distal airways or a specific cytopathic effect in BAL-collected cells [44]. A disadvantage of that strategy is the risk of falsepositives. Indeed, as for HSV bronchopneumonitis, CMV detection in BAL fluid does not necessarily mean viral VAP. The isolation of CMV in BAL fluid may reflect virus reactivation without true pneumonia. For the latter, cytology of BAL-collected cells to look for a specific cytopathic effect is a key component to making the diagnosis. However, the cytopathic effect depends on the virus: intranuclear inclusions are HSV-specific, whereas intracytoplasmic inclusions are CMV-specific [27]. Moreover, BAL-fluid cytology is probably less sensitive for CMV pneumonia than HSV bronchopneumonitis, as suggested by the BAL-collected cells of only 1 of 11 patients exhibiting a cytopathic effect [27]. Virus load should replace cytology in the near future, but data are still lacking [27]. Nonetheless, the search for CMV in BAL fluid may be recommended for unexplained ARDS or pneumonia without microbiologic documentation. Again, BAL fluid must be sent to the laboratory and requires an experienced pathologist to look for the specific cytopathic effect. Moreover, the outcomes of patients with CMV pneumonia are not well known. CMV reactivation detected in the blood seems to be associated with poor prognosis [44,46,47]. High-level circulating CMV (>1000 copies/ml) was associated with increased mortality or prolonged ICU stays [46]. A more recent study evaluated the prognosis of patients with CMV infection, including CMV VAP, the latter being defined as combination of clinical signs of pneumonia and CMV detection in BAL fluid [44]. Although the authors did not specifically evaluate the prognosis of patients with CMV VAP, as defined above, they found that mortality of patients with CMV infection tended to be higher
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Respiratory infections Table 2. Studies that evaluated the frequency of CMV detection in the lower respiratory tract of ICU patients Patient population
CMV-detection frequencya
Manifestations of CMV involvement
ARF or VAP
25/86 (29.1%)
Postoperative, SAPS II >40
7/56 (12.5%)
Diagnostic methods
Reference
Diffuse interstitial pneumonia
Histology (autopsy for 60, lung biopsy for 26)
[41]
NR
Viral culture, PCR
[42]
Unexplained ARDS
30/100 (30%)
Pneumonia, fibrosis
Histology (lung biopsy)
[43]
Patients on MV
11/242 (4.5%)
Pneumonia
Viral culture
[44]
VAP suspected
34/191 (17.8%)
NR
PCR
[23]
Patients with severe sepsis
25/86 (29.1%)
NR
Viral culture, PCR
[45]
VAP suspected
22/93 (23.7%)
NR
Viral culture, PCR, serology
[26 ] &
ARDS, acute respiratory distress syndrome; ARF, acute respiratory failure; CMV, cytomegalovirus; MV mechanical ventilation; NR, not reported; SAPS, Simplified Acute Physiology Score; VAP, ventilator-associated pneumonia. a Frequency of viral detection in tracheal aspirate or bronchoalveolar lavage fluid.
than that of patients without CMV infection [44]. A recent but small study including 22 patients found the same results and shared the same conclusions [26 ]. But again, as for HSV bronchopneumonitis, it is impossible to know whether CMV detection in the distal airways is simply an attestation of the severity of the underlying disease or a real disease with its own morbidity/mortality. Only a clinical trial evaluating the benefit of a specific antiviral treatment in such a population could answer that question. No reported randomized controlled trial has evaluated the use of antiviral therapy in critically ill patients. When CMV pneumonia was suspected in patients with unexplained ARDS and confirmed by lung biopsy, some patients who received ganciclovir were cured [43]. Those authors concluded that specific anti-CMV treatment could be useful, but the results warrant confirmation in a randomized trial. Because of ganciclovir toxicity and the absence of solid evidence of the potential benefits of this treatment, we still cannot recommend its use in critically ill patients [27].
mimivirus. At present, no definite conclusion can be drawn on the potential role of mimivirus in nosocomial pneumonia.
&
MIMIVIRUS In 2005, Acanthamoeba polyphaga mimivirus (mimivirus) was described as a potential causative pathogen of pneumonia. After a first case report of a technician (accidental contamination) [48], Berger et al. [49] reported that mimivirus was a possible cause in 6/120 nosocomial pneumonia episodes. However, other studies yielded conflicting results. In a retrospective study using two real-time PCR assays, Dare et al. [50] screened 496 respiratory specimens from nine pneumonia patient populations for mimivirus; it was not detected in any sample. More recently, Vanspauwen et al. [51 ] tested the BAL samples of 260 patients suspected of having developed VAP; none was positive for &
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CONCLUSION To date, no evidence supports that respiratory viruses are responsible for VAP. However, it seems that those viruses might have been responsible in some HCAP cases, probably because HCAP and CAP patients have the same risk factors for viral disease. Herpes simplex virus detection in the respiratory tract is frequent in ICU patients, and high HSV load is associated with worse prognosis. Sometimes, HSV bronchopneumonitis can occur. However, the exact outcomes of HSV reactivation and/or HSV bronchopneumonitis are not fully elucidated: is HSV an innocent bystander or a real pathogen with its own morbidity/mortality? Cytomegalovirus pneumonia is difficult to diagnose. As for HSV, the exact significance of CMV detection in the distal airways is not completely known. Although patients with CMV reactivation detected in the blood seem to have a more pejorative prognosis than those without, the outcome of CMV VAP remains to be determined more precisely. Acknowledgements The authors thank Janet Jacobson for editorial assistance during the writing of this manuscript. Conflicts of interest C.-E.L. has received fees from ThermoFischer Brahms for lectures on procalcitonin. N.B. has no conflicts of interest to disclose. J.C. has received fees from Pfizer, Bayer, Trius, Astellas, Janssen, Cubist and Sanofi for consultancies, and lecture fees from Pfizer. Volume 27 Number 2 April 2014
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What role do viruses play in nosocomial pneumonia? Luyt et al.
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J Med Virol 2013; 85:1836–1841. A large epidemiological study investigating the potential role of mimivirus in ventilator-associated pneumonia. The authors found that among 214 patients suspected of having developed VAP, none had mimivirus recovered in their lung sample, questioning the importance of mimivirus as a cause of pneumonia in ICU patients. &
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