Respiratory virus-associated infections in HIV-infected adults admitted to the intensive care unit for acute respiratory failure: a 6-year bicenter retrospective study (HIV-VIR study)

Acute respiratory failure (ARF) is the leading cause of admission to the intensive care unit (ICU) in HIV-infected patients [1‐3]. Infectious causes are predominant, although the proportion of opportunistic infections has decreased significantly in the era of combination antiretroviral therapy (ART) [2, 4, 5]. In contrast, the burden of non-HIV-related pulmonary events, such as bacterial pneumonia, acute bronchitis and acute exacerbation of chronic obstructive pulmonary disease (COPD) has been shown increasing [2, 3, 6]. These important changes in the etiologic panel of ARF in HIV-infected patients question the role of respiratory viruses. Indeed, using nucleic acid amplification test such as multiplex polymerase chain reaction (mPCR), these pathogens have been shown highly prevalent (20–56%) in large cohorts of adult patients admitted to the ICU for all-cause ARF [7, 8], community-acquired pneumonia [9, 10], hospital-acquired pneumonia [11], acute exacerbation of COPD [12, 13], and asthma [14], compared to asymptomatic adults [15, 16]. High prevalence has also been described in specific immunocompromised populations, such as cancer and hematology patients [17, 18]. In contrast, little is known about the epidemiology of respiratory viruses in HIV-infected patients [19, 20], especially those admitted to the ICU, and the prevalence of respiratory viruses according to the CD4 T-cell deficiency. Moreover, coinfections with virus and opportunistic pathogens may occur. Overall, respiratory virus-associated infections may affect prognosis.

Therefore, we conducted a comprehensive observational study among adult HIV-infected ICU patients with ARF explored with respiratory mPCR. Our goals were to describe the prevalence of respiratory viruses, coinfections with non-viral pathogens, and hospital outcome.

This retrospective study investigated the epidemiology of respiratory viruses in HIV-infected adults admitted to the ICU for ARF. Real-time mPCR tests identified at least one virus in the respiratory tract of 27% of patients, but with a non-viral copathogen in two-thirds of cases. The prevalence of respiratory virus-associated infection did not vary along with the level of the CD4 T-cell deficiency, except for Rhinovirus which was more prevalent in patients with a CD4 lymphocyte count below 200 cells/µL. In multivariate analysis, respiratory virus-associated infection was not associated with a worse prognosis.

In this study, more than one patient out of four (27%) were infected with at least one respiratory virus. This finding illustrated the high yield of an aggressive diagnostic strategy with a broad panel mPCR on respiratory tract specimens. Our results are original since prior works having described the etiological panel of ARF in HIV-infected ICU patients were conducted before the era of real-time mPCR [2, 4, 22]. Interestingly, the rate of viral documentation that we observed was similar to what had been described (27 to 29%) previously in non-HIV adults admitted to the ICU for an acute respiratory disorder requiring intubation [7, 8].

We identified at least one non-viral copathogen in more than two-thirds of the patients with a viral documentation, in line with a recent report in a population with a high prevalence of tuberculosis [19, 23]. Non-opportunistic acute lung infections, including pneumonia, acute bronchitis and exacerbation of COPD, were the first cause of ARF, consistent with previous reports in Western countries [2, 4]. This finding highlights the burden of chronic respiratory conditions in aging HIV-infected populations [6]. Here, more than 40% of patients were smokers. Synergistic effects of tobacco and HIV [24] in promoting chronic bronchitis and pro-COPD changes in the lung [25] have been demonstrated. Moreover, high rates of viral documentation within airways of COPD patients both at stable state and during exacerbation have been reported [26]. These data may explain the high rate of viral documentation that we observed. In multivariate analysis, smoking was independently associated with respiratory virus-associated infection. This finding is in line with previous works demonstrating that tobacco exposure alters immune responses to Rhinovirus [27], Influenza Virus [28] and Respiratory Syncytial Virus [29]. Interestingly, female gender was associated with an increased risk of respiratory virus-associated infection on multivariate analysis. Prior cohort studies in primary care described an increased risk for development of Influenza-like illnesses in women compared to men [30, 31]. However, to our knowledge, no prior study has specifically explored this point in HIV-infected populations admitted for ARF.

In this study, we also aimed to investigate a putative role of the HIV-related CD4 T-cell deficiency in promoting respiratory virus-associated infection. Previous studies explored this point in children, but with conflicting results. Annamalay et al. described similar rates of viral documentation in HIV-infected and non-infected children admitted for lower respiratory tract infections [32], whereas O’Callaghan-Gordo et al. observed that respiratory virus-associated infections were 6 to 16 times more prevalent among HIV-infected children admitted for pneumonia [33]. As we did not include a comparative non-HIV population, we rather examined whether or not the rate of viral documentation varied along with the level of CD4 T-cell deficiency. Finally, we found no association between the CD4 lymphocyte count and the risk of respiratory virus-associated infection, in line with a previous report focusing on Influenza viruses [34].

Rhinovirus was the predominant virus, accounting for more than 40% of viral documentations. This high prevalence was consistent with that of previous reports in ICU patients with ARF [7], community-acquired pneumonia [35] or acute exacerbation of COPD [13]. Surprisingly, Rhinovirus was much more prevalent in low-CD4 patients. This finding is original, since no prior work has specifically explored this point in adults. In HIV-infected children, Rhinovirus has been shown highly prevalent, during both pneumonia and bronchiolitis, but without data regarding a putative association with the level of CD4 T-cell deficiency [32, 36]. Other data in hematology and cancer adults demonstrated high rates of Rhinovirus documentation within airways during respiratory tract infections [37, 38]. To explain this high prevalence in immunocompromised patients, a mechanism of prolonged viral shedding has been proposed, rather than iterative reinfections as observed in COPD patients [39]. The prolonged Rhinovirus shedding may be attributable to an inefficient immunological control of a single infectious episode [40, 41]. Therefore, in pediatric hematopoietic stem cell transplant recipients with a persistent Rhinovirus shedding (≥ 30 days), Piralla et al. demonstrated significant lower CD4, CD8 and NK lymphocyte counts at the onset of infection, as compared to children with a brief Rhinovirus shedding. Moreover, a decrease in Rhinovirus load was associated with significant increases of the same lymphocyte counts [42]. These data would suggest an important role for the T-cell immunity in the control of Rhinovirus infection, and subsequently, may explain a delayed Rhinovirus clearance in low-CD4 HIV-infected patients, resulting in persistent shedding and increased prevalence.

We observed a high rate of dual infection, either virus–bacteria or virus–opportunistic pathogen. These findings made us consider the prognostic impact of such coinfections. Studies in ICU adult patients with pneumonia suggested that virus–bacteria coinfection was associated with a worse prognosis [43]. In mice, the coinfection of Influenza with Streptococcus pneumoniae [44], Legionella pneumophila [45] or Staphylococcus aureus [46] impaired the anti-Influenza immune response and increased mortality. Whether similar synergistic effects exist in virus–opportunistic pathogen coinfection remain unknown. Only one animal study has explored the couple Pneumocystis jirovecii–Influenza, but in a successive rather than concomitant model [47]. Unfortunately, in our study, the low number of observations prevented us from analyzing the prognosis according to the presence of coinfections.

Our study has several limitations. First, this study included adult patients with ARF that required ICU admission, preventing any conclusion on other populations such as HIV-infected children or HIV-infected adults with ARF that did not require ICU admission. Second, the study was retrospective, so we did not control the microbiological investigations. The preferred sample for mPCR test in non-intubated patients was not the sputum, but the nasopharyngeal swab [48]. Several factors may have discouraged clinicians to use sputum, including the high number of patients unable to produce sputum [49] and the highly viscous nature of this sample that can make nucleic acid extraction difficult [50]. By definition, an mPCR was performed in the respiratory tract of every included patient because it was a criterion for patient screening. But some other microbiological tests were only occasionally performed, i.e., cytomegalovirus PCR. Furthermore, the retrospective design prevented us from obtaining a number of data, which were rarely reported in medical records by physicians, including vaccine history, Pneumocystis jirovecii prophylaxis, symptoms before hospital referral, and duration of symptoms before ICU admission. Third, only patients having undergone an mPCR in the respiratory tract within the 72 h following their ICU admission were screened; this might suggest a confounding of indication. Fourth, the choice to classify patients according to their CD4 lymphocyte count on the ICU admission, instead of the latest known value, might be criticized. However, this choice was guided by the high number of missing values in the latest CD4 lymphocyte count as well as the number of newly diagnosed patients without any prior CD4 lymphocyte count. Fifth, we assumed that a virus identified with PCR in nasopharyngeal or lower respiratory tract samples was always a pathogen of the respiratory tract, whatever the clinical picture and radiological features. This might be criticized since respiratory viruses might be present in asymptomatic adult subjects [15], even if it seems rare, about 2% of asymptomatic adults seen at the emergency department [16]. Sixth, to avoid overinterpreting the data, we decided to consider respiratory viruses as a homogeneous group of pathogens in the analysis stratified by respiratory virus-associated infection. This might be criticized since the pathogenicity differs from one viral species to another.

Viruses are frequently identified in the respiratory tract of HIV-infected patients with ARF that required ICU admission, but with a non-viral copathogen in two-thirds of cases. Rhinovirus is the predominant viral specie; its prevalence is highest in patients with a CD4 lymphocyte count below 200 cells/µL.