JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Prevention
CD8+ T cells and Risk for Bacterial Pneumonia and All-Cause Mortality Among HIV-Infected Women
Gohil, Shruti K. MD, MPH*; Heo, Moonseong PhD†; Schoenbaum, Ellie E. MD†; Celentano, David ScD‡; Pirofski, Liise-anne MD§,‖
*Department of Medicine, Division of Infectious Diseases and
†Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
‡Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Departments of §Medicine
‖Division of Infectious Diseases, Microbiology and Immunology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.
Correspondence to: Liise-anne Pirofski, MD, Division of Infectious Diseases, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer Building, Room 610, Bronx, NY 10461 (e-mail: firstname.lastname@example.org).
S.K. Gohil obtained the data, directed and interpreted the analysis, and wrote the manuscript; M. Heo completed the statistical analyses and edited the manuscript; E.E. Schoenbaum was an HERS coinvestigator, who guided the statistical analysis approach and its interpretation, and edited the manuscript; D. Celentano was a coinvestigator of the HERS and edited the manuscript; and L. Pirofski was the principal investigator, who directed and interpreted the analysis, and edited the manuscript.
Supported by the National Institutes of Health (Grants R01AI45459 and R01AI44374 to L.P.) and National Institute of Allergy and Infectious Disease institutional Geographic Medicine and Emerging Infections training grant (5T32 AI070117 to S.K.G.).
Presented at the Infectious Disease Society of America Annual Conference, October 2010, Vancouver, British Columbia, Canada.
The authors have no conflicts of interests to disclose.
Received August 12, 2011
Accepted January 17, 2012
Background: Bacterial pneumonia risk is disproportionately high among those infected with HIV. This risk is present across all CD4+ T-cell levels (TCLs), suggesting that additional factors govern susceptibility. This study examines CD8+ TCLs and risk for HIV-associated bacterial pneumonia and all-cause mortality.
Methods: Demographic, clinical, and laboratory data were obtained for 885 HIV-infected women enrolled in the HIV Epidemiologic Research Study (HERS). Bacterial pneumonia cases were identified using clinical, microbiological, and radiographic criteria. CD8+ TCLs were assessed at 6-month intervals. Statistical methods included Cox proportional hazards regression modeling and covariate-adjusted survival estimates.
Results: Relative to a referent CD8+ TCL of 401–800 cells per cubic millimeter, risk for bacterial pneumonia was significantly higher when CD8+ TCLs were <400 (hazard ratio 1.65, P = 0.017, 95% confidence interval 1.10 to 2.49), after adjusting for age, CD4+ TCL, viral load, and antiretroviral use. There was also a significantly higher risk of death when CD8+ TCLs were ≤400 cells per cubic millimeter (hazard ratio 1.45, P = 0.04, 95% confidence interval 1.02 to 2.06). Covariate-adjusted survival estimates revealed shorter time to pneumonia and death in this CD8+ TCL category, and the overall associations of the categorized CD8+ TCL with bacterial pneumonia and all-cause mortality were each statistically significant (P = 0.017 and P < 0.0001, respectively).
Conclusions: CD8+ TCL ≤400 cells per cubic millimeter was associated with increased risk for pneumonia and all-cause mortality in HIV-infected women in the HERS cohort, suggesting that CD8+ TCL could serve as an adjunctive biomarker of pneumonia risk and mortality in HIV-infected individuals.
Patients infected with HIV are 25 times more likely to develop bacterial pneumonia and 100 times more likely to develop invasive disease with Streptococcus pneumoniae, the leading cause of bacterial pneumonia worldwide.1,2 Although this risk is associated with reduced CD4+ T-cell levels (TCLs), almost half of all HIV-associated bacterial pneumonias occur at CD4+ TCLs >200 cells per cubic millimeter.2,3 Hence, additional host factors must contribute to susceptibility. Among candidate immunologic factors, CD8+ T cells are of particular interest in the pathogenesis of HIV, bacterial pneumonia, and lung disease. HIV controllers have elevated levels of functional HIV-specific CD8+ T cells.4,5 Murine data suggest a beneficial immunoregulatory role for CD8+ T cells in innate and acquired immunity to pneumococcal and other pneumonias.6–10 CD8+ T cells have also been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD) and smoking-related lung injury.11–13 However, to our knowledge, the importance of CD8+ TCL in resistance to HIV-associated pneumonia has not been examined previously.
High rates of bacterial pneumonia, higher hospitalization rates, and recurrent bacterial pneumonias have been reported in HIV-infected women before and after the highly active antiretroviral therapy era.14–16 Additionally, despite having higher baseline CD4+ TCLs, HIV-infected women have a higher risk for bacterial pneumonia than HIV-infected men.17 In this study, we examine the relationship between CD8+ TCL, bacterial pneumonia, and all-cause mortality in HIV-infected women.
We studied HIV-infected participants in the HIV Epidemiologic Research Study (HERS), a multicenter prospective study that enrolled 885 HIV-infected and 425 HIV-uninfected women aged 16–55 years from April 1993 to January 1995, concluding in April 2000.18 Enrollment criteria are detailed elsewhere.16,18 Briefly, women with clinical AIDS were excluded, but women with CD4+ TCLs <200 cells per cubic millimeter were included if they had no prior clinical AIDS-defining illness. Participants underwent semiannual research visits with standardized interviews to obtain information on sociodemographic status, substance use, medical history, intercurrent hospitalizations, and antiretroviral (ARV) use. All patients underwent blood collection for immunologic analysis, including CD3+, CD4+, and CD8+ T-lymphocyte subset quantification. Viral load (VL) was measured prospectively starting in 1997 using version 3.0 ultrasensitive branched-DNA signal amplification assay (Bayer Diagnostics, Pittsburgh, PA); for samples collected before that point, VL was measured retrospectively.19 Medical records were obtained for all hospitalizations and reviewed per standardized protocol. Episodes meeting predetermined criteria for bacterial pneumonia as defined by Kohli et al16 were included in this analysis. A national death index search was used to assess mortality; death certificates and medical records were reviewed for all deaths identified.
Definition of Bacterial Pneumonia
Pneumonia cases were identified as per the definitions of bacterial pneumonia previously reported by Kohli et al.16 “Definitive” cases were defined by presence of a new or progressive infiltrate on chest radiograph and a positive sputum, blood, or pleural fluid culture with no identifiable primary source other than lung, and clinical findings suggestive of bacterial pneumonia, including response to antibacterial therapy, positive sputum Gram stain, cough, shortness of breath, or respirations >20 breaths per minute. “Probable” cases included a new or progressive infiltrate on chest radiograph with no diagnosis of Pneumocystis jiroveci pneumonia (PJP), and either a clinical response to antibacterials or positive sputum Gram stain and temperature >37.8°C. Gram stains were deemed positive if granulocytes and organisms were reported ≥2+, negative if there were no organisms, and inadequate if there were <2+ granulocytes. Probable cases also required clinical criteria, including cough, shortness of breath, or respiratory rate >20 breaths per minute. “Presumed” cases were defined as those with a physician discharge diagnosis of bacterial pneumonia, infiltrate on admission chest radiograph, and no criteria consistent with PJP. We included all HIV-infected pneumonia cases (HIV+PNA+) identified by Kohli et al, except 7 cases for whom records were not identifiable by our group. For all pneumonia cases, diagnostic chest radiographs used for infiltrate determination were dated within 48 hours of admission. We excluded participants whose radiographs demonstrated bilateral interstitial infiltrates or whose test results were positive for PJP, mycobacteria, endocarditis, or malignancy. HIV-infected, pneumonia-negative (HIV+PNA−) participants were defined as those who never developed pneumonia throughout the duration of the HERS.
Based on the aforementioned criteria, 200 cases of bacterial pneumonia were identified among HIV-infected HERS participants from 1993 to 2000. CD8+ TCLs obtained at 6-month intervals were assessed for all participants. Baseline characteristics were compared between participant groups using Student t test or Wilcoxon rank-sum test for continuous variables and chi-square tests for categorical variables. For HIV+PNA+ participants, CD8+ TCLs were assessed until the time closest to but antedating the pneumonia event or death, depending on the outcome. The mean (SD) time interval between the last CD8+ TCL and the time of pneumonia was 136 (110) days ranging from 5 to 836 days. Both the mean and median (110 days) time intervals were within 6 months of the pneumonia event. For those with recurrent pneumonia, CD8+ TCLs until the first event were used. For HIV+PNA− participants, CD8+ TCLs until the last time available were assessed. Risk for bacterial pneumonia (primary end point) and all-cause mortality (secondary end point) for HIV+ subjects was determined as a function of CD8+ TCLs by Cox proportional hazards regression modeling, from which covariate-adjusted survival curves were estimated. Time-dependent covariates included time of enrollment, CD4+ TCL, log10VL, and ARV duration. Baseline age at enrollment and smoking status were included as time-independent covariates. Smoking status was considered positive if participants reported any or ever cigarette use and negative if reported never having smoked. Twelve participants whose pneumonia event antedated the first HERS visit were excluded from the analyses. To quantify within-subject variations in CD8+ TCL, we computed variance, SD, and range of biannually measured CD8+ TCLs for those subjects who had more than 1 CD8+ TCL available. We applied t tests weighted (after removal of 1 outlier) by the square root of number of observations minus 1 to compare within-subject variations between cohorts. Analyses were performed using SAS software, version 9.1 (SAS Institute, Cary, NC).
Baseline characteristics for each cohort are displayed in Table 1. There were 200 bacterial pneumonias among 885 HIV-infected subjects. Mean age was 36.3 years among HIV-infected patients who developed pneumonia (HIV+PNA+), older than HIV-infected patients who did not (HIV+PNA−), P = 0.024. Compared with HIV+PNA− participants, HIV+PNA+ participants were more likely to have ever smoked (P < 0.0004), be of African American ethnicity (P = 0.019), and report fewer years spent in school (P = 0.052). There were no differences in ARV duration, reported alcohol use, or injection drug use between the HIV+PNA+ and HIV+PNA− participants. Additional data and subgroup analyses of bacterial pneumonia risk were reported previously.16 CD4+ TCL was significantly lower (366 cells/mm3) and log10VL significantly higher (3.5) in HIV+PNA+ than in HIV+PNA− participants (P < 0.0001 for each parameter). Mean baseline CD8+ TCLs were significantly higher among HIV-infected than HIV-uninfected participants (941 vs 684 cells/mm3, respectively, P < 0.001). There was no significant difference in baseline CD8+ TCL between HIV+PNA+ and HIV+PNA− participants.
There was significantly more variation in absolute CD8+ TCLs (P = 0.0016), SD (P = 0.0064), and range of CD8+ TCLs (P = 0.0134) in the HIV+PNA+ cohort compared with the HIV+PNA− cohort when weighted t tests were applied (Fig. 1A). Thus, there was more within-subject and within-cohort variation in CD8+ TCL among HIV+PNA+ than among HIV+PNA− participants. We also observed an increase in mean CD8+ TCL around visit 10 in the HIV+PNA+ cohort. The percentage of HIV+PNA+ participants on potent ARVs increased from 36% before visit 10 to 100% after that visit. Potent ARV use also increased before and after visit 10 from 30% to 100% for HIV+PNA− participants. To account for possible effects of ARV use on CD8+ TCL, we determined log10VL as a function of time; this did not show significant variation between the PNA+ and PNA− cohorts (Fig. 1B).
The overall incidences of pneumonia and mortality were 12.9 and 15.9 per 100 person-years, respectively, among HIV-infected participants with CD8+ TCL ≤400 cells per cubic millimeter (Table 2). At the time closest to but antedating the pneumonia event within 6 months, the mean CD4+ TCL was 267 cells per cubic millimeter, log10VL was 3.75, with 13.5% of subjects reported having started potent ARVs. To determine a threshold of CD8+ TCL at which bacterial pneumonia rates were highest, we examined CD8+ TCL in the HIV+PNA+ cohort by multiple increments across all visits. The most common CD8+ TCL was between 401 and 800 cells per cubic millimeter (Fig. 2A). The distribution of HIV+PNA+ participants by CD8+ TCL category using values within 6 months antedating the pneumonia event was similar to that seen in all participants (Fig. 2B). The percentage of HIV+PNA+ participants among the total number of participants in each CD8 category, using the CD8+ TCL antedating the pneumonia event for cases and the baseline level for all participants, is shown in Figure 2C. The lowest percentage of participants had CD8+ TCLs between 401 and 800 cells per cubic millimeter and the highest percentage had CD8+ TCLs either ≤400 or between 1201 and 1600 cells per cubic millimeter.
Cox proportional hazards models for pneumonia and all-cause mortality among HIV+PNA+ participants are shown in Table 3. The overall associations of the 5 CD8+ TCL categories with bacterial pneumonia and all-cause mortality were statistically significant (P = 0.017 and P < 0.0001, respectively), even after adjustment for CD4+ TCL, VL, age, and ARV duration. We defined our referent category as CD8+ TCL of 401–800 cells per cubic millimeter as it was the most common CD8+ TCL range among all groups. Relative to this referent, risk for pneumonia was highest when CD8+ TCL was ≤400 cells per cubic millimeter [hazard ratio (HR) 1.65, P = 0.017, 95% confidence interval 1.10 to 2.49]. The highest all-cause mortality was also observed when CD8+ TCLs were ≤400 compared with the referent range of 401–800 cells per cubic millimeter (HR 1.45, P = 0.04, 95% confidence interval 1.02 to 2.06). Both of these results reflect adjustment for CD4+ TCL, log10VL, age, and ARV duration, and remained statistically significant when further adjusted for smoking (HR 1.61, P = 0.024; HR 1.49, P = 0.035, for pneumonia and mortality, respectively). Upon further adjustment for African American ethnicity, pneumonia and mortality risk also remained significant and borderline significant, respectively (HR 1.58, P = 0.03; HR 1.44, P = 0.054, respectively). Hence, our data indicate that compared with a referent of 401–800 cells per cubic millimeter, a CD8+ TCL <400 was associated with a higher risk for pneumonia and all-cause mortality, adjusting for CD4+ TCL, VL, age, ARV duration, smoking, and African American ethnicity. The results were similar when the model was repeated using the ≤400 cells per cubic millimeter category as the referent. CD8+ TCL categories of 801–1200, 1201–1600, and >1600 cells per cubic millimeter were not significantly different from the referent in either the pneumonia or the mortality model. Although the Cox proportional hazards model included CD4+ TCL as a time-varying variable and thereby adjusted for the nadir CD4+ TCL, we computed nadir CD4+ TCL for each subject and replaced the time-varying CD4+ TCL by the time-independent nadir CD4+ TCL in the Cox model. Nadir CD4+ TCL was significantly associated with pneumonia but not significantly associated with all-cause mortality. The overall results concerning CD8+ TCL categories remained unchanged in the nadir CD4+ TCL model.
Covariate-adjusted survival estimates based on the fitted Cox models for time to pneumonia and death are shown in Figure 3 for participants aged 50 years, CD4+ TCL of 200 cells per cubic millimeter, log10VL of 4, and ARV duration of 500 days. These parameters were chosen to reflect a high-risk group for both pneumonia and mortality. Among HIV+PNA+ participants, 65% of those with CD8+ TCLs 401–800 cells per cubic millimeter were estimated to be pneumonia-free 5 years from study entry, compared with 50% of those with CD8+ TCLs ≤400 cells per cubic millimeter. Analysis of time to death revealed that 16% more participants were estimated to be alive at 5 years in the 401–800 than in the ≤400 cells per cubic millimeter CD8+ TCL category. Similar, though less dramatic, differences were observed for nonsmokers. The covariate survival estimate model was computed several times, with changes in age, CD4+ TCL, log10VL, smoking status, and race. Neither time to pneumonia nor mortality differences were observed between the cohorts when age was decreased to 35 years, CD4+ TCL was increased to 400 cells per cubic millimeter, log10VL was decreased to 1.7, or when including only non–African American participants.
A sensitivity analysis conducted by Kohli et al16 established that their results were similar when either all definitive, probable, and presumed cases or only definitive and probable cases were included. However, when we repeated our analyses separately for definitive versus probable and possible pneumonia, none of the CD8+ TCL categories were significant compared with the referent CD8+ TCL category 400–800 cells per cubic millimeter, whereas CD4+ TCL counts were significant in both analyses.
A total of 69 participants had more than 1 pneumonia event. CD8+ TCLs of participants in this subgroup were similar to those in Figure 2 (data not shown). Cox proportional hazards model for those with recurrent pneumonia revealed no significant difference by CD8+ TCL category, perhaps owing to a smaller sample size. However, 49% of those with recurrent pneumonia had CD8+ TCLs >800 cells per cubic millimeter within 6 months of their first pneumonia event. Mean CD8+ TCL was 1420 cells per cubic millimeter for 8 participants with >5 pneumonia events and <200 cells per cubic millimeter for 2 such participants.
CD8+ TCLs increase early in HIV infection and remain persistently elevated during the early chronic phase of HIV disease.20,21 The mean baseline CD8+ TCL of HIV-infected participants in our study was similar to that reported by other groups.22,23 Baseline CD8+ TCLs were not significantly different between HIV+PNA+ and HIV+PNA− participants in our study, but there was a statistically significant association between CD8+ TCL antedating the pneumonia event and bacterial pneumonia whereby a CD8+ TCL ≤400 cells per cubic millimeter was associated with a 1.7 times higher risk of pneumonia and 1.5 times higher risk for death compared with a referent CD8+ TCL of 401–800 cells per cubic millimeter. These findings remained statistically significant after adjusting for CD4+ TCL, VL, age, ARV use, smoking, and ethnicity.
The possibility that low total CD8+ TCL could increase the risk for an HIV-associated complication like pneumonia is not surprising given that HIV controllers have an expanded and more functional CD8+ T-cell compartment and a reduction in CD8+ TCL has been linked to HIV disease progression.4,5,23,24 The possible impact of CD8+ TCL loss and the risk for pneumonia is further underscored by preclinical models demonstrating the importance of CD8+ T cells in host defense against pulmonary pathogens. For example, in mice, CD8+ T cells can compensate for CD4+ T cells in resistance to pulmonary mycobacterial and fungal pathogens, including HIV-associated pathogens such as Pneumocystis jiroveci and Cryptococcus neoformans.9,25–27 Of relevance to the risk for bacterial pneumonia, CD8+ T cells were required for protection against S. pneumoniae in immunized and naive mice 6,7 and recruited to the lungs in surviving mice.28 Similar results have been reported for Klebsiella pneumoniae.29 Our findings suggest that the possibility that CD8+ T cells contribute to resistance to HIV-associated bacterial pneumonia deserves further study.
Our data reveal a peak in the percentage of pneumonias (19%) in the CD8+ TCL category of 1201–1600 cells per cubic millimeter, although risk for pneumonia and all-cause mortality in CD8+ TCL categories >800 cells per cubic millimeter was not statistically different from the referent group (401–800 cells/mm3) in the Cox proportional hazards analysis. Nonetheless, among 69 participants with recurrent pneumonias, almost half (34 participants or 49%) had CD8+ TCL >800 cells per cubic millimeter, with the mean level among those with >5 episodes being 1420 cells per cubic millimeter. This is intriguing in light of the damage–response framework,30 which highlights that host damage can occur in the setting of either an insufficient or a vigorous immune response. Given ample evidence for CD8+ T-cell–mediated inflammation, we wonder whether higher CD8+ TCLs could be associated with increased disease risk by inducing excessive inflammation. Along these lines, high CD8+ TCLs were inversely correlated with forced expiration volume in 1 second and implicated as mediators of smoking-associated lung injury and COPD,31,32 and among HIV-infected smokers, CD8+ TCLs were significantly higher in bronchoalveolar lavage from those with than without COPD.33 In mice with PJP, CD4 depletion led to death due to respiratory compromise with CD8+ T-cell–mediated lung injury,34 and HIV-infected patients with Pneumocystis after starting ARVs had high quantities of rapidly proliferating CD8+ T cells in their bronchoalveolar lavage fluid.35 Several studies have implicated CD8+ T cells in lung inflammation in Pneumocystis colonization and progressive pulmonary decline in patients with HIV.34,36 Hence, our data raise the possibility that, as per the damage–response framework,30 either low or high CD8+ TCLs could contribute to susceptibility to HIV-associated bacterial pneumonia.
HIV+PNA+ participants had significantly more variability in their CD8+ TCLs than HIV+PNA− participants. At present, the significance of this finding is unclear. Further studies are required to evaluate the activation status and antigen specificity of CD8+ T cells in patients with pneumonia as these parameters were not evaluated in the HERS cohort. Nonetheless, our data show that CD8+ TCLs are not uniform and that greater fluctuation could be associated with risk for HIV-associated pneumonia. The rise in mean CD8+ TCL that was observed at later times in both the HIV+PNA+ and HIV+PNA− cohorts could reflect an effect of ARV introduction, as the percentage of those having started ARV increased from approximately 36% to nearly 100% with time.
At present, our data are most relevant for HIV-infected individuals with CD4+ TCL in lower ranges who are not on ARVs, such as those in resource-limited settings. As measurement of CD8+ TCL is performed on the same sample as CD4+ TCL and both measurements are commonly obtained even in resource-limited settings,37,38 our results suggest that CD8+ TCL could serve as an adjunctive biomarker for HIV-associated pneumonia risk, in addition to other known risk factors. Our findings may also be important in non–HIV-associated and/or nonbacterial pneumonia, as CD8+ T cells can contribute to the pathogenesis of influenza.39 In light of growing recognition that influenza morbidity and mortality are driven by secondary bacterial pneumonia,40,41 it is logical to hypothesize that CD8+ T-cell involvement in host defense against influenza could alter the inflammatory milieu and predispose the host to bacterial pneumonia. This area requires further investigation.
Our study has several limitations. First, most of the pneumonias did not meet definitive criteria for bacterial pneumonia, with the caveat that the definitive category required culture-proven bacterial pneumonia, which is very difficult to obtain. Although a sensitivity analysis conducted by Kohli et al16 found similar results when all definitive, probable, and presumed cases were included, and when limited to definitive and probable cases, this was not the case in our study. The most likely explanation for this is that the effect of CD4+ TCL on pneumonia and all-cause mortality is substantially greater than that of CD8+ TCL; however, our study was not designed to address this question. Based on our findings, future studies should endeavor to examine CD8+ TCLs among patients with predefined CD4+ TCLs and pneumonia definitions. Second, HERS included only women; hence, studies are needed in men. Third, we were not able to account for certain comorbid illnesses that could have confounded our findings, such as viral infections and history of lung disease (eg, COPD). Fourth, although our data suggest that CD8+ TCLs ≤400 cells per cubic millimeter may be a useful adjunct to CD4+ TCLs for identifying patients at risk for bacterial pneumonias and death, the HERS spanned a period during which potent ARVs first became available. Thus, most participants in the pneumonia cohort were not on potent ARV therapy. Although ARV therapy is now widely available in the United States and other resourced countries, there are many HIV-infected individuals living in areas where ARVs are not readily or consistently available. Our findings are most relevant to the latter and for patients who do not adhere to their ARV regimens. Finally, the scope of our study and conclusions are limited by our inability to assess CD8+ T-cell activation status, effector, or memory CD8+ T cells, as such data were not collected in the HERS.
In summary, we evaluated CD8+ TCL and pneumonia risk in a large prospective cohort of HIV-infected women and identified an association between CD8+ TCLs ≤400 cells per cubic millimeter and risk for bacterial pneumonia and all-cause mortality relative to a referent range of 401–800 cells per cubic millimeter. These findings suggest that CD8+ TCLs ≤400 cells per cubic millimeter may be a useful adjunct to CD4+ TCLs for identifying patients at risk for pneumonias and death, particularly in individuals with low CD4+ TCLs and/or who are not on ARVs. Furthermore, our finding that CD8+ TCLs were more variable in HIV-infected participants who developed pneumonia and tended to be higher in those who had highly recurrent pneumonia suggests that the role of CD8+ T cells in the pathogenesis of pneumonia is complex and requires further study.
The authors acknowledge the HERS committee members and the Centers for Disease Control and Prevention and, particularly, Lytt Gardner, who provided the HERS data sets and statistical and editorial guidance. They also acknowledge the Center for AIDS Research at Albert Einstein College of Medicine for providing statistical support (AI051519).
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