Philip T. Diaz

Increased Susceptibility to Pulmonary Emphysema among HIV-Seropositive Smokers

Several reports (1-3) have suggested that before recognized AIDS-related respiratory complications develop, some HIV-seropositive persons may develop an accelerated form of lung injury that has physiologic features or findings on computed tomography of the chest that are consistent with pulmonary emphysema. Emphysema, defined as enlargement of the terminal air spaces and destruction of the alveolar walls (4), is uniquely characterized by disappearance of lung tissue (4). Insight into the cellular mechanisms critical to pathogenesis of this condition in humans has been limited by the lengthy course over which the disease develops and by the fact that only a minority of smokers develops significant disease (5). The possibility that HIV-seropositive persons may have a greater risk for developing accelerated lung destruction may have broad biological relevance regarding emphysema pathogenesis. With this in mind, we sought to extend previous anecdotal studies and attempted to prospectively characterize a group of HIV-infected persons exhibiting evidence of emphysema-like destructive lung disease. Methods The study sample consisted of 114 consecutive HIV-seropositive persons who underwent high-resolution computed tomography of the chest (1994 through 1997). This group was a sample of a larger cohort of 321 HIV-seropositive persons who had undergone a detailed assessment of respiratory symptoms and pulmonary function. Most participants were from Columbus, Ohio, and were recruited through advertisements, by word of mouth, and by the Ohio State University Medical Center AIDS-Clinical Trials Unit. Less than 10% of the participants were receiving protease inhibitors at the time of this study. Persons with a history of Pneumocystis carinii pneumonia and other pulmonary complications of AIDS were excluded. Controls consisted of 44 HIV - seronegative volunteers matched for age, sex, and smoking history; they were recruited from the general population by advertisements. All participants completed a modified American Thoracic Society Questionnaire (6) for symptoms, smoking history, drug use, history of pneumonia, and medications. Nonsmokers were identified as having a history of cumulative cigarette smoking of 1 pack-year or less. Pulmonary function studies were performed according to American Thoracic Society standards. The study was approved by the Ohio State University human subjects review board. Informed consent was obtained from all participants. Computed tomography was performed with a GE 9800 CT scanner (GE Medical Systems, Milwaukee, Wisconsin) or a Picker PQ 2000 CT scanner (Picker International, Solon, Ohio) with 1.5-mm collimation at 10-mm intervals through the chest. Scans were obtained at total lung capacity in the supine position. Images were reconstructed by using the high spatial frequency algorithm and were photographed at a lung window width of 1500 Hounsfield units (brightness level, 700 Hounsfield units). Emphysema was considered present if the scans showed evidence of bullae, thin-walled cystic spaces, or abnormal decreases in attenuation, accompanied by vascular disruption. Emphysema severity was estimated by assigning an emphysema score (0 to 10) for each lobe according to the percentage of the lobe that was affected. The lingula was considered a separate lobe. The total score represented the sum for all lobes. Scans were interpreted by two experienced chest radiologists, who were blinded to the patients HIV status and physiologic data. Participants were considered to have clear evidence of at least early emphysema if 1) the computed tomography emphysema score was 6 or higher [for example, 25% of two lobes involved with emphysema] or 2) pulmonary function tests demonstrated a total lung capacity greater than 120% of the predicted value, a diffusing capacity less than 60% of predicted, and computed tomographic evidence of emphysema in more than two lobes. Bronchoalveolar lavage and differential cell counts were performed according to standard techniques (7) on consenting participants. This included 46 HIV-seropositive smokers and 14 control smokers. A sample containing more than 1 000 000 cells was analyzed by a fluorescence-activated cell sorter for T-lymphocyte subtyping. An experienced microbiologist, who was blinded to HIV status, examined all lavage samples for the presence of fungi, acid-fast bacilli, P. carinii, and bacteria. Statistical analyses were performed by using the SAS JMP package (8). Analysis of variance was used to compare groups, and post hoc analysis was performed by using the Dunnett procedure (8). The Pearson chi-square test was used for equality of proportions; exact P values were calculated for small samples (9). Results With the exception of a lower CD4 count and diffusing capacity in the HIV-seropositive group, the two study groups had similar baseline characteristics (Table). Of note, 25% of the HIV-seropositive group had a history of oral thrush; however, other HIV-related opportunistic infections were rarely reported (<2%). The percentage of HIV-seropositive persons who reported any use of intravenous drugs was low (approximately 10%), and no significant differences in the use of intravenous drugs, crack cocaine, or marijuana were found between the HIV-seropositive group and the control group. Table. Clinical and Demographic Characteristics of the Study Groups Clinical variables did not significantly differ between the HIV-seropositive group of this study and the 321 persons in the overall HIV cohort (Table). For example, the median age of the overall cohort was 33 years (range, 20 to 66 years), the median CD4 count was 348 cells/mm3 (range, 0 to 1188 cells/mm3), and the median diffusing capacity was 83.7% of predicted (range, 38.8% to 153%). Sixty-three percent of the overall cohort smoked cigarettes. Emphysema was identified in 17 of 114 HIV-seropositive participants compared with 1 of 44 HIV-seronegative controls (P=0.025). Only one HIV-seronegative participant had a computed tomography emphysema score as high as 6, whereas 14 HIV-seropositive participants had scores between 6 and 23. The mean (SE) emphysema score for the HIV-seropositive group with emphysema was 10.5 1.7, the mean total lung capacity was 110% 6.9% of predicted, and the diffusing capacity was 60.1% 11.3% of predicted. Of note, persons with emphysema had only mild airflow obstruction (ratio of FEV1 to FVC, 69.2% 9.4%), which may relate to a higher than expected number of persons (approximately 30%) demonstrating subpleural or peripheral lesions (10). The Figure shows examples of precocious emphysema in HIV-seropositive persons, with accompanying emphysema scores. Figure. High-resolution computed tomographic scans of the chest.A. arrows B. Because a relatively high proportion of cigarette smokers appeared to be susceptible to early destructive changes, we specifically studied the role of smoking history. Thirty-seven percent (14 of 38) of HIV-seropositive smokers with a smoking history of 12 pack-years or more met criteria for emphysema, compared with 0% (0 of 14) HIV-seronegative controls (P=0.011). Furthermore, 46% (11 of 24) of HIV-seropositive participants with a smoking history of 25 pack-years or more met criteria for emphysema, compared with 0% (0 of 10) in the HIV-seronegative controls (P=0.013). Next, using current pack-year of cigarette smoking as a covariate, we compared lung-cell populations among three groups of smokers: HIV-seronegative smokers (n=14), HIV-seropositive smokers without emphysema (n=34), and HIV-seropositive smokers with emphysema (n=12). The numbers of alveolar macrophages and neutrophils in the lavage fluid were similar among the three groups. Although the two HIV-seropositive groups were found to have threefold more lymphocytes than the uninfected controls, no significant difference in lymphocyte numbers were noted between HIV-seropositive persons with and those without emphysema. However, when lymphocyte subtypes were examined, HIV-seropositive persons with emphysema were found to have the highest percentage of lavage lymphocytes bearing the cytotoxic phenotype; the mean (SE) value in this group was 58% 4.6%, compared with 46.6% 2.3% in HIV-seropositive smokers without emphysema (P<0.05) and 32.2% 4.6% in HIV-seronegative smokers (P<0.01). Of note, no pathogens were observed in microbiological stains of lavage fluid from study participants. Discussion This prospective study demonstrates the development of an accelerated form of pulmonary emphysema in a stable HIV-seropositive outpatient sample. Furthermore, the results suggest that the lesion is related to a heightened susceptibility to cigarette smoke. We hypothesize that HIV infection or secondary inflammatory abnormalities directly accelerate the process of smoking-induced parenchymal lung destruction. The cellular mechanisms predisposing HIV-seropositive smokers to emphysema are unclear. However, immunologic aspects of HIV disease may be relevant to understanding emphysema pathogenesis in the general population. Of particular interest are the many bronchoalveolar lavage and lung pathology studies that have demonstrated increased numbers of cytotoxic lymphocytes in the lungs of HIV-seropositive persons (11-13). Although prevailing theories for emphysema have focused on smoking-induced production of proteolytic enzymes by neutrophils and macrophages (4, 5), recent morphometric analyses of lung biopsy sections from non-HIV-infected smokers have demonstrated a high correlation between lung lymphocytes and the presence of emphysema (14, 15). Furthermore, experimental evidence suggests that viral activation of cytotoxic lymphocytes may contribute to parenchymal lung destruction (16). Another potential mechanism recently hypothesized is that latent viral infections may be an important cofactor in the development of chronic obstructive pulmonary disease (17). Adenoviral proteins, latently expressed in host epithelial cells, a

Cardiac disease in chronic obstructive pulmonary disease.

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.

A Multicenter Pilot Study of a Bronchial Valve for the Treatment of Severe Emphysema

Background: Chronic obstructive pulmonary disease (COPD) affects millions of people and has limited treatment options. Surgical treatments for severe COPD with emphysema are effective for highly selected patients. A minimally invasive method for treating emphysema could decrease morbidity and increase acceptance by patients. Objective: To study the safety and effectiveness of the IBV® Valve for the treatment of severe emphysema. Methods: A multicenter study treated 91 patients with severe obstruction, hyperinflation and upper lobe (UL)-predominant emphysema with 609 bronchial valves placed bilaterally into ULs. Results: Valves were placed in desired airways with 99.7% technical success and no migration or erosion. There were no procedure-related deaths and 30-day morbidity and mortality were 5.5 and 1.1%, respectively. Pneumothorax was the most frequent serious device-related complication and primarily occurred when all segments of a lobe, especially the left UL, were occluded. Highly significant health-related quality of life (HRQL) improvement (–8.2 ± 16.2, mean ± SD change at 6 months) was observed. HRQL improvement was associated with a decreased volume (mean –294 ± 427 ml, p = 0.007) in the treated lobes without visible atelectasis. FEV1, exercise tests, and total lung volume were not changed but there was a proportional shift, a redirection of inspired volume to the untreated lobes. Combined with perfusion scan changes, this suggests that there is improved ventilation and perfusion matching in non-UL lung parenchyma. Conclusion: Bronchial valve treatment of emphysema has multiple mechanisms of action and acceptable safety, and significantly improves quality of life for the majority of patients.

Emphysema-like Pulmonary Disease Associated with Human Immunodeficiency Virus Infection

OBJECTIVE To describe a possible association between prolonged infection with human immunodeficiency virus (HIV) and a pathophysiologic process suggestive of pulmonary emphysema. DESIGN Case series. SETTING The Ohio State University Hospital, Columbus, Ohio. MEASUREMENTS AND MAIN RESULTS We describe four HIV-seropositive individuals ranging in age from 32 to 55 years who presented with dyspnea. Radiographic examination of the chest showed no infiltrates. All patients were presumed to have had prolonged HIV infection (mean CD4 count, 99.8 +/- 43 cells/mm3), but none had a previous history of pneumonia or opportunistic infections. Comprehensive examination of bronchoalveolar lavage fluid showed no pathogens or other complications of HIV infection. All patients had markedly abnormal pulmonary function tests that were suggestive of emphysema with air-trapping, hyperinflation, and a markedly decreased diffusing capacity. However, only minimal evidence of airflow obstruction was noted. Three patients subsequently had high-resolution computed tomographic scans of the chest that revealed emphysema-like bullous changes. Known causes of emphysema were not present in these patients. CONCLUSIONS Our findings support an association between prolonged HIV infection and an emphysema-like process. This syndrome may occur in the absence of previous pulmonary infections or apparent pulmonary complications and is characterized by unusual pulmonary function test abnormalities.

Cigarette Smoking in the HIV-Infected Population

As mortality due to AIDS-related causes has decreased with the use of antiretroviral therapy, there has been a rise in deaths related to non-AIDS-defining illnesses. Given the exceedingly high prevalence of cigarette smoking among individuals living with HIV infection, tobacco has been implicated as a major contributor to this paradigm shift. Evidence suggests that smoking-related illnesses, such as cardiovascular disease, respiratory illnesses, and certain malignancies, contribute substantially to morbidity and mortality among HIV-infected persons. In this review, we summarize the adverse health consequences of smoking relevant to HIV-infected individuals and discuss smoking cessation in this unique population, including a discussion of barriers to quitting and a review of studies that have examined smoking cessation interventions.

HIV infection is associated with reduced pulmonary diffusing capacity

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.

HIV-Associated Lung Infections and Complications in the Era of Combination Antiretroviral Therapy

The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study.

Correlation of HIV-1 detection and histology in AIDS-associated emphysema.

HIV-seropositive individuals are at an increased risk for an accelerated form of emphysema. The purpose of this study was to determine the distribution of HIV-1 RNA in lung tissues and correlate this with the histologic findings and expression of matrix metalloproteases (MMPs). Reverse transcriptase (RT) in situ PCR analysis was performed on 11 AIDS lung autopsy specimens which showed varying degrees of emphysematous changes. In each lung, HIV-1 RNA was detected. In areas of histologically normal lung, very rare HIV-1-infected cells were evident. In contrast, many HIV-1-infected cells were noted in areas of emphysema. HIV-1 gag RNA was evident primarily in macrophages; infected pneumocytes were also seen. Similarly, MMP mRNA and protein, primarily MMP-9, localized to the areas of emphysema. Colabeling experiments documented that MMP expression was found primarily in cells that were HIV-1 negative and adjacent to HIV-1-infected macrophages. These results suggest that AIDS-related emphysema may be due, in part, to direct infection by HIV-1 of, primarily, alveolar macrophages, and concomitant up-regulation of MMP expression in the neighboring, noninfected cells.

Feasibility of distractive auditory stimuli on upper extremity training in persons with chronic obstructive pulmonary disease.

OBJECTIVE To determine the feasibility of distractive auditory stimuli (DAS) used during an upper extremity training (UET) program on perceived dyspnea, functional performance, and health-related quality of life. In addition, to determine the appropriate music tempo used during the UET. DESIGN Experimental, randomized, 3-group design with testing at baseline and 4 weeks. SETTING Outpatient. PATIENTS Thirty patients (13 male and 17 female) with moderate to severe chronic obstructive pulmonary disease (FEV1 41.27% +/- 18% predicted). INTERVENTION Moderate DAS group (n = 10) and slow DAS group (n = 10) subjects were instructed to perform UET for up to 15 minutes 3 to 5 times a week using DAS (walkman, audiocassettes). The control group (n = 10) received the same instructions, but no DAS. MEASURES AND RESULTS Primary outcome measures were perceived dyspnea, functional performance using the 6-minute peg and ring board (6MRPB) count and health-related quality of life. In addition, all subjects recorded the time of UET performance using self-report (daily logs). A significant increase was seen in 6MRPB count (P = .002) between groups. Moderate DAS subjects increased 6MPRB count 46 +/- 21 rings and slow DAS subjects increased 46 +/- 20 rings from baseline to 4 weeks whereas control subjects increased only 5 +/- 4 rings. No significant differences were noted for the remaining variables. CONCLUSION Subjects who used DAS (music) while performing UET improved functional performance whereas controls failed to continue improvement. The DAS is a feasible adjunct to UET that may have the potential to augment the effectiveness of pulmonary rehabilitation training.

Tobacco Use and Cessation Among Women: Research and Treatment-Related Issues

The prevalence of tobacco use in women has increased over the past century. This has resulted in dramatic increases in smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. There is growing literature suggesting that women may be more susceptible than men to the effects of tobacco and to the development of COPD. Women may also have specific barriers that interfere with smoking cessation. This article addresses possible differences in lung function decline and nicotine metabolism in women compared to men. Differences in COPD between the sexes are discussed. Finally, barriers to smoking cessation in women are presented.