Background: Emphysema is more prevalent in HIV-infected (HIV+) patients independent of smoking behavior. Nonetheless, health effects of emphysema in this population are poorly understood. We determined whether emphysema is associated with a greater burden of pulmonary symptoms and a lower 6-minute walk distance (6MWD) in HIV+ compared with HIV-uninfected (HIV-) subjects. Methods: We performed a cross-sectional analysis of 170 HIV+ and 153 HIV- subjects in the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. Subjects completed a self-assessment of respiratory symptoms, pulmonary function testing, and 6MWD testing as well as a chest computed tomography to determine emphysema severity. We used regression models to determine the association of emphysema with respiratory symptoms and 6MWD in HIV+ subjects and compared this to HIV- subjects. Results: Models stratified by HIV status demonstrated an association between > 10% radiographic emphysema and chronic cough and/or phlegm and 6MWD in HIV+ subjects. These associations persisted among the subset without airflow obstruction: those with emphysema had 4.2 (95% confidence interval: 1.3 to 14) times the odds of chronic cough and/or phlegm and walked 60 m (95% confidence interval: 26 to 93) less distance than those without emphysema. There was no association between > 10% emphysema and symptoms or 6MWD in HIV- subjects. Conclusions: In our cohort, > 10% radiographic emphysema was associated with chronic cough and/or phlegm and lower 6MWD in HIV+ but not HIV- subjects. These findings were robust even among HIV+ subjects with milder forms of emphysema and those without airflow obstruction, highlighting the clinical impact of emphysema in these patients.

Rationale: Airway hyperresponsiveness (AHR) is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM) cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF) secretion into the environment.

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.

Background Maternal smoking in utero has been associated with adverse health outcomes including lower respiratory tract infections in infants and children, but the mechanisms underlying these associations continue to be investigated. We hypothesized that nicotine plays a significant role in mediating the effects of maternal tobacco smoke on neonatal alveolar macrophage (AM) function, the resident immune cell in the neonatal lung. Methods Primary AMs were isolated at postnatal day 7 from a murine model of in utero nicotine exposure. The murine AM cell line MH-S was used for additional in vitro studies. Results In utero nicotine increased IL-13 and transforming growth factor beta one (TGFβ1) in the neonatal lung. Nicotine-exposed AMs demonstrated increased TGFβ1 and increased markers of alternative activation with diminished phagocytic function. However, AMs from mice deficient in the α7 nicotinic acetylcholine receptor (α7 nAChR) had less TGFβ1, reduced alternative activation and improved phagocytic functioning despite similar in utero nicotine exposure. Conclusion In utero nicotine exposure, mediated in part via the α7 nAChR, may increase the risk of lower respiratory tract infections in neonates by changing the resting state of AM towards alternative activation. These findings have important implications for immune responses in the nicotine-exposed neonatal lung.

There is abundant epidemiological data linking prenatal environmental tobacco smoke with childhood asthma and wheezing, but the underlying molecular and physiological mechanisms that occur in utero to explain this link remain unelucidated. Several studies suggest that nicotine, which traverses the placenta, is a causative agent. Therefore, we studied the effects of nicotine on lung branching morphogenesis using embryonic murine lung explants. We found that the expression of α 7 nicotinic acetylcholine receptors, which mediate many of the biological effects of nicotine, is highest in pseudoglandular stage lungs compared with lungs at later stages. We then studied the effects of nicotine in the explant model and found that nicotine stimulated lung branching in a dose-dependent fashion. α-Bungarotoxin, an antagonist of α 7 nicotinic acetylcholine receptors, blocked the stimulatory effect of nicotine, whereas GTS-21, a specific agonist, stimulated branching, thereby mimicking the effects of nicotine. Explants deficient in α 7 nicotinic acetylcholine receptors did not respond to nicotine. Nicotine also stimulated the growth of the explant. Altogether, these studies suggest that nicotine stimulates lung branching morphogenesis through α 7 nicotinic acetylcholine receptors and may contribute to dysanaptic lung growth, which in turn may predispose the host to airway disease in the postnatal period.

Chronic obstructive pulmonary disease (COPD) is common in people living with HIV (PLWH). We sought to evaluate the appropriateness of COPD diagnosis and management in PLWH, comparing results to HIV-uninfected persons. We conducted a cross-sectional analysis of Veterans enrolled in the Examinations of HIV-Associated Lung Emphysema study, in which all participants underwent spirometry at enrollment and reported respiratory symptoms on self-completed surveys. Primary outcomes were misdiagnosis and under-diagnosis of COPD, and the frequency and appropriateness of inhaler prescriptions. Misdiagnosis was defined as having an International Classification of Diseases (ICD)-9 diagnosis of COPD without spirometric airflow limitation (post-bronchodilator forced expiratory volume in 1-second [FEV1]/Forced vital capacity [FVC] < 0.7). Under-diagnosis was defined as having spirometry-defined COPD without a prior ICD-9 diagnosis. The analytic cohort included 183 PLWH and 152 HIV-uninfected participants. Of 25 PLWH with an ICD-9 diagnosis of COPD, 56% were misdiagnosed. Of 38 PLWH with spirometry-defined COPD, 71% were under-diagnosed. In PLWH under-diagnosed with COPD, 85% reported respiratory symptoms. Among PLWH with an ICD-9 COPD diagnosis as well as in those with spirometry-defined COPD, long-acting inhalers, particularly long-acting bronchodilators (both beta-agonists and muscarinic antagonists) were prescribed infrequently even in symptomatic individuals. Inhaled corticosteroids were the most frequently prescribed long-acting inhaler in PLWH (28%). Results were overall similar amongst the HIV-uninfected. COPD was frequently misdiagnosed and under-diagnosed in PLWH, similar to uninfected-veterans. Among PLWH with COPD and a likely indication for therapy, long-acting inhalers were prescribed infrequently, particularly guideline-concordant, first-line long-acting bronchodilators. Although not a first-line controller therapy for COPD, inhaled corticosteroids were prescribed more often.

Maternal smoking during pregnancy has been associated with adverse effects on respiratory health. Whereas the epidemiologic link is incontrovertible, the mechanisms responsible for this association are still poorly understood. Although cigarette smoke has many toxic constituents, nicotine, the major addictive component in cigarette smoke, may play a more significant role than previously realized. The objectives of this study were to determine whether exposure to nicotine prenatally leads to alterations in pulmonary function and airway geometry in offspring, and whether α7 nicotinic acetylcholine receptors (nAChRs) mediate these effects. In a murine model of in utero nicotine exposure, pulmonary function, airway size and number, methacholine response, and collagen deposition were examined. Exposure periods included Gestation Days 7–21, Gestation Day 14 to Postnatal Day 7, and Postnatal Days 3–15. Prenatal nicotine exposure decreases forced expiratory flows in offspring through α7 nAChR–mediated signals, and the critical period of nicotine exposure was between Prenatal Day 14 and Postnatal Day 7. These physiologic changes were associated with increased airway length and decreased diameter. In addition, adult mice exposed to prenatal nicotine exhibit an increased response to methacholine challenge, even in the absence of allergic sensitization. Collagen expression was increased between adjacent airways and vessels, which was absent in α7 nAChR knockout mice. These observations provide a unified mechanism of how maternal smoking during pregnancy may lead to lifelong alterations in offspring pulmonary function and increased risk of asthma, and suggest potential targets to counteract those effects.

INTRODUCTION: Prior studies comparing abnormalities in pulmonary function between HIV-infected and HIV-uninfected persons in the current era are limited. OBJECTIVES: To determine the pattern and severity of impairment in pulmonary function in HIV-infected compared with HIV-uninfected individuals. METHODS: Cross-sectional analysis of 300 HIV-infected men and 289 HIV-uninfected men enrolled from 2009 to 2011 in 2 clinical centers of the Lung HIV Study. Participants completed pre- and postbronchodilator spirometry, diffusing capacity of the lung for carbon monoxide (DLCO) measurement, and standardized questionnaires. RESULTS: Most participants had normal airflow; 18% of HIV-infected and 16% of HIV-uninfected men had airflow obstruction. The mean percent predicted DLCO was 69% in HIV-infected vs. 76% in HIV-uninfected men (P < 0.001). A moderately to severely reduced DLCO of ≤60% was observed in 30% of HIV-infected compared with 18% of HIV-uninfected men (P < 0.001), despite the fact that 89% of those with HIV were on antiretroviral therapy. A reduced DLCO was significantly associated with HIV and CD4 cell count in linear regression adjusting for smoking and other confounders. The DLCO was lowest in HIV-infected men with CD4 cell counts <200 cells per microliter compared with those with CD4 cell counts ≥200 cells per microliter and to HIV-uninfected men. Respiratory symptoms of cough, phlegm and dyspnea were more prevalent in HIV-infected patients particularly those with abnormal pulmonary function compared with HIV-uninfected patients. CONCLUSIONS: HIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200 cells per microliter. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.

Objectives: The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects. Methods: We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD. Results: Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1-39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO). Conclusions: A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.