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Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV

Triplette, Matthewa; Justice, Amyb; Attia, Engi, F.a; Tate, Janetb; Brown, Sheldon, T.c; Goetz, Matthew, Bidwelld; Kim, Joon, W.c; Rodriguez-Barradas, Maria, C.e; Hoo, Guy W., Sood; Wongtrakool, Cherryf; Akgün, Kathleenb; Crothers, Kristinaa

doi: 10.1097/QAD.0000000000001701

Objective: Aging people living with HIV (PLWH) face an increased burden of comorbidities, including chronic obstructive pulmonary disease (COPD). The impact of COPD on mortality in HIV remains unclear. We examined associations between markers of COPD and mortality among PLWH and uninfected study participants.

Design: Longitudinal analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study.

Methods: EXHALE includes 196 PLWH and 165 uninfected smoking-matched study participants who underwent pulmonary function testing and computed tomography (CT) to define COPD and were followed. We determined associations between markers of COPD with mortality using multivariable Cox regression models, adjusted for smoking and the Veterans Aging Cohort Study (VACS) Index, a validated predictor of mortality in HIV.

Results: Median follow-up time was 6.9 years; the mortality rate was 2.7/100 person-years among PLWH and 1.7/100 person-years among uninfected study participants (P = 0.11). The VACS Index was associated with mortality in both PLWH and uninfected study participants. In multivariable models, pulmonary function and CT characteristics defining COPD were associated with mortality in PLWH: those with airflow obstruction (forced expiratory volume in 1 s/ forced vital capacity <0.7) had 3.1 times the risk of death [hazard ratio 3.1 (95% confidence interval 1.4–7.1)], compared with those without; those with emphysema (>10% burden) had 2.4 times the risk of death [hazard ratio 2.4 (95% confidence interval 1.1–5.5)] compared with those with ≤ 10% emphysema. In uninfected subjects, pulmonary variables were not significantly associated with mortality, which may reflect fewer deaths limiting power.

Conclusion: Markers of COPD were associated with greater mortality in PWLH, independent of the VACS Index. COPD is likely an important contributor to mortality in contemporary PLWH.

aDepartment of Medicine, University of Washington, Seattle, Washington

bDepartment of Medicine, VA Connecticut Healthcare System, Yale University, West Haven, Connecticut

cDepartment of Medicine, James J. Peters VA Medical Center, Icahn School of Medicine at Mt. Sinai, New York City, New York

dDepartment of Medicine, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, California

eInfectious Diseases Section, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas

fDepartment of Medicine, Atlanta VA Medical Center, Emory University, Atlanta, Georgia, USA.

Correspondence to Matthew Triplette, 1100 Fairview Ave. N., Mailstop D5-360, Seattle, WA, 98109, USA. E-mail:

Received 28 August, 2017

Revised 4 October, 2017

Accepted 4 October, 2017

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In the contemporary antiretroviral therapy era, people living with HIV (PLWH) are surviving to older age [1]; however, these patients face an increased burden of comorbidities [2–4]. The impact of this multimorbidity is profound; PLWH experience excess mortality compared with uninfected persons [5,6], and most of these deaths are attributable to chronic non-AIDS-related disease [7–9]. The prevalence of chronic obstructive pulmonary disease (COPD), and the emphysema subtype, is greater in PLWH as well [10–15]. This is largely because of more smoking in PLWH, but there may be an independent contribution related to HIV infection [16–19].

COPD is associated with increased symptoms, hospitalization and frailty in PLWH [20–23], but an association with mortality has not been determined. Understanding the impact of COPD on mortality in HIV is important in considering the public impact and clinical significance of COPD in this population and to support smoking cessation interventions and early COPD diagnosis. Specific COPD markers may also be useful in prediction models for mortality in HIV. In this study, we sought to determine whether physiologic and radiographic markers of COPD were associated with mortality in a cohort of PLWH and uninfected study participants. Moreover, we sought to determine whether these markers of COPD were independent of the Veterans Aging Cohort Study (VACS) Index (, a validated research and clinical tool that predicts mortality in PLWH but does not include markers of pulmonary dysfunction [24].

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The study utilizes the Examinations of HIV-Associated Lung Emphysema (EXHALE) study, a pulmonary substudy of VACS described in detail elsewhere [25,26]. VACS study participants were enrolled into EXHALE at four Veterans Affairs Medical Centers between 2009 and 2012. PLWH and uninfected study participants were recruited matched on smoking status. Study participants were ineligible if they had chronic pulmonary diseases other than COPD or asthma, and had experienced recent acute respiratory symptoms. Study participants were followed from enrollment through March 2017, with deaths determined from the Veterans Affairs vital status file. Cause of death information, summarized from International Classification of Diseases (ICD)-9 to ICD-10 coding, was available through December 2014. About 366 patients were enrolled and underwent any testing, with five patients excluded because of abnormalities precluding further testing (four with aortic aneurysms and one with a pulmonary mass). In total, 342 study participants were included in pulmonary function testing (PFTs) analyses and 323 included in computed tomography (CT) analyses, based on completion of tests.

Demographic and smoking information was collected from self-completed surveys at enrollment. Laboratory data were obtained via electronic medical record. The VACS Index was calculated at enrollment using electronic medical record data closest to EXHALE enrollment, no longer than 12 months prior. The VACS Index was developed in Veterans and externally validated, and predicts mortality in PLWH and uninfected persons [24,27–29]. The VACS Index incorporates age, CD4+, viral load, hepatitis C serostatus, hemoglobin, estimated glomerular filtration rate, and the fibrosis-4 index for liver fibrosis. The Index assumes normal CD4+ cell count and undetectable viral load for uninfected study participants.

Pulmonary markers were obtained from PFTs and chest CT images. PFTs were performed to American Thoracic Society standards at clinical laboratories. Testing included postbronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and diffusion capacity (DLCO). Percentage-predicted values were calculated based on National Health and Nutrition Examination Survey III data [30–34]. COPD was defined as airflow obstruction (FEV1/FVC <0.7) [35], and alternatively as FEV1/FVC below lower limit of normal (LLN, <5th percentile) [30]. CT scans were performed at baseline using a protocol described previously [25]. These scans were interpreted by a thoracic radiologist blinded to clinical data to determine semiquantitative emphysema scoring, which was dichotomized at the overall median of 10% involvement. Scans also underwent quantitative emphysema analysis using University of Pittsburgh software for lung segmentation followed by density mask technique to quantify percentage of low attenuation areas (LAA) (Hounsfield units ≤−950) consistent with emphysema [36–39].

Baseline characteristics were compared by HIV status using χ2 testing. We used Cox proportional hazards regression to examine variable associations with mortality, stratified by HIV status. Patients were right censored at end of follow-up (March 2017) or death. There was no loss-to-follow-up for the death outcome. Separate bivariate Cox models were created for variables including the pulmonary markers: airflow obstruction (by both methods), FEV1%-predicted, FVC % predicted, DLCO %-predicted, more than 10% emphysema, %LAA. Seven multivariable models for PLWH and uninfected study participants were created for the pulmonary markers adjusted for smoking pack-years and the VACS Index. We created three models including the entire cohort with multiplicative interaction terms between HIV status and airflow obstruction and emphysema more than 10%, respectively. In the models, sex was not included as there were no deaths among the 20 women, and race/ethnicity was not included and was not associated with the variables of interest or outcome. All models had limited power to detect less than moderate associations with mortality: we had 80% power to detect a mortality hazard ratio of 2.2 for categorical variables of interest in the entire cohort and 80% power to detect a mortality hazard ratio of 2.7 (in PLWH) and 3.7 (in uninfected study participants) for categorical variables of interest in stratified models.

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Of 361 study participants, 196 were PLWH and 165 were uninfected (Table 1). Median enrollment age was 54 [interquartile range (IQR) 50–59] and 94% were men. PLWH largely had well controlled disease: 14% had CD4+ cell count less than 200 cells/μl and 17% had viral load more than 400 copies/ml. The median VACS Index was 29 (IQR 18–42) in PLWH compared with 18 (IQR 12–27) in the uninfected (P < 0.001). PLWH had higher pack-years of smoking that did not reach statistical significance (P = 0.06). PLWH had lower DLCO %-predicted (53 vs. 57, P = 0.005), and a higher prevalence of emphysema > 10% (31 vs. 16%, P = 0.003). Median follow-up was 6.9 years and similar by HIV status. The majority (93%) of study participants alive at study end had Veterans Affairs follow-up within the last 12 months. The mortality rate was 2.7/100 person-years among PLWH (33 deaths) and 1.7/100 person-years among uninfected study participants (18 deaths; P = 0.11). Of those with available cause of death data (59%), 23% died from heart disease, 37% from cancer, and 6.7% from respiratory causes. Only 9.5% of PLWH died from HIV/AIDS-related causes. The VACS Index was associated with mortality in both groups, as was older age and other specific VACS Index components. (Supplemental Table 1,

Table 1

Table 1

The pulmonary markers were associated with mortality in unadjusted and adjusted models (Supplemental Figure 1,, Table 2). In adjusted models, airflow obstruction [FEV1/FVC <0.7: hazard ratio 3.1, 95% confidence interval (CI) 1.4–7.1, FEV1/FVC <LLN: hazard ratio 4.3, 95% CI 1.9–9.8], FEV1%-predicted (hazard ratio 1.3, 95% CI 1.0–1.7, 10-unit decrease), DLCO %-predicted (hazard ratio 1.8, 95% CI 1.3–2.5, 10-unit decrease) and emphysema as semiquantitative > 10% (hazard ratio 2.4, 95% CI 1.1–5.5) and %LAA (hazard ratio 1.3, 95% CI 1.1–1.7, 5% increase) were associated with mortality in PLWH, independent of smoking pack-years and the VACS Index. Among the uninfected, there were no significant associations with mortality in adjusted models, though emphysema > 10% had a similar hazard ratio (hazard ratio 2.1, 95% CI 0.62–7.4). In whole cohort models, interaction between HIV status and airflow obstruction was significantly associated with mortality, using either definition of obstruction (P = 0.04 for both). There was no significant interaction between emphysema more than 10% and HIV status.

Table 2

Table 2

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In this study, we examined the association of COPD with mortality in a longitudinal cohort of PLWH and uninfected study participants. We found that markers that define COPD (airflow obstruction), grade severity (FEV1), and emphysema (emphysema >10%, %LAA, and DLCO) were associated with mortality in PLWH, independent of smoking and the VACS Index.

COPD is the third leading cause of death in the United States and is outpacing other leading causes of mortality [40]. The impact of COPD is also underestimated, as concomitant COPD is an unreported contributor to other causes of death, and underdiagnosed [40–43]. In the general population, FEV1 decline, the key measure grading COPD severity, is a well established predictor of death in patients with COPD [44–46]. To our knowledge, the association of markers of COPD with mortality in HIV has not been previously established. Previous studies suggest that COPD is not only more prevalent in PLWH, but also has substantial clinical impact. COPD may be associated with a higher symptom burden in PLWH [22,23,47], and PLWH are more likely to have acute exacerbations and hospitalizations related to COPD [48,49]. Those who are admitted with COPD-related diagnoses may face higher in-hospital mortality [50]. PLWH may also experience an accelerated decline in pulmonary function [51–53]. We have previously shown that emphysema is associated with increased immune activation and inflammation [25,54], and increased functional limitation in PLWH [26].

Our study adds to this literature by establishing that markers of COPD and emphysema are associated with increased mortality among PLWH. Although the majority of cohort deaths were not directly related to respiratory causes, COPD is an important contributor or cofactor in other deaths from chronic disease (such as lung cancer and heart disease) [43]. Given the prevalence and impact of COPD in HIV, these findings support increased attention to smoking cessation in PLHW to reduce COPD incidence and attenuate pulmonary decline. Unfortunately, there are limited studies addressing cessation interventions in PLWH [55,56]. Our findings also highlight the importance of interventions to diagnose and manage COPD in PLWH to prevent decline in health. Finally, markers of COPD may have a role in mortality prediction models in HIV, such as the VACS Index, though this will require further study. Our finding of no significant associations with mortality among uninfected study participants is reflective of limited power, and should not imply that COPD is not associated with mortality in the general population. However, the finding of significant interaction between airflow obstruction and HIV status (whether defined as a fixed ratio or LLN) is intriguing, suggesting a potential differential impact of COPD on mortality in PLWH.

The study has several strengths. First, detailed smoking information on study participants allowed us to understand the contribution of COPD markers independent of smoking. Second, we carefully characterized physiologic and radiographic pulmonary data, including CT images that were analyzed by semi-quantitative and quantitative methods to define emphysema. Finally, we had comprehensive follow-up on enrolled participants, with a median of 6.9 years of follow-up. Our study had certain weaknesses as well. Participants were largely male Veterans, which may limit generalizability. We also did not have comprehensive information on cause of death. Finally, the study power limited our ability to detect associations, particularly in uninfected study participants.

In conclusion, we found that markers of COPD and emphysema were associated with mortality in PLWH. These findings underscore the importance of COPD in aging PLWH, and the need for attention to smoking cessation, COPD diagnosis and COPD management in patients with HIV. We plan further studies aiming to examine these markers in a larger cohort of PLWH, adjust for other comorbidities such as cardiovascular disease that often coexist with COPD, and determine whether pulmonary markers add predictive value to the VACS Index.

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The authors thank the Veterans who participated in EXHALE and the coordinators who made the study possible. This material is the result of work supported with the resources and the use of facilities at the Veterans Affairs Connecticut Healthcare System, New Haven, Connecticut; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; the Atlanta Veterans Affairs Medical Center, Decatur, Georgia; and the James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA.

M.T., A.J., J.T., K.A., and K.C. contributed to the conception and design of the manuscript; A.J., J.T., S.T.B., M.B.G., J.W.K., M.C.R-B., G.W.S.H., and C.W., K.C. contributed to the acquisition of data; M.T., A.J., E.F.A., J.T., and K.C. conducted the data analysis and interpretation of the data; M.T. drafted the article; all authors revised the article for important intellectual content and appoved the final version of the article.

The work was supported by the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) (R01 HL090342 to K.C., and T32 HL007287 supporting M.T. under Drs Robb Glenny and Jared Randall Curtis).

The authors must disclaim that the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.

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Conflicts of interest

There are no conflicts of interest.

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chronic disease; chronic obstructive pulmonary disease; HIV; pulmonary emphysema

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