Adiposity influences airway wall thickness and the asthma phenotype of HIV-associated obstructive lung disease: a cross-sectional study.

BACKGROUND: Airflow obstruction, which encompasses several phenotypes, is common among HIV-infected individuals. Obesity and adipose-related inflammation are associated with both COPD (fixed airflow obstruction) and asthma (reversible airflow obstruction) in HIV-uninfected persons, but the relationship to airway inflammation and airflow obstruction in HIV-infected persons is unknown. The objective of this study was to determine if adiposity and adipose-associated inflammation are associated with airway obstruction phenotypes in HIV-infected persons. METHODS: We performed a cross-sectional analysis of 121 HIV-infected individuals assessed with pulmonary function testing, chest CT scans for measures of airway wall thickness (wall area percent [WA%]) and adipose tissue volumes (mediastinal and subcutaneous), as well as HIV- and adipose-related inflammatory markers. Participants were defined as COPD phenotype (post-bronchodilator FEV1/FVC < lower limit of normal) or asthma phenotype (doctor-diagnosed asthma or bronchodilator response). Pearson correlation coefficients were calculated between adipose measurements, WA%, and pulmonary function. Multivariable logistic and linear regression models were used to determine associations of airflow obstruction and airway remodeling (WA%) with adipose measurements and participant characteristics. RESULTS: Twenty-three (19 %) participants were classified as the COPD phenotype and 33 (27 %) were classified as the asthma phenotype. Body mass index (BMI) was similar between those with and without COPD, but higher in those with asthma compared to those without (mean [SD] 30.7 kg/m(2) [8.1] vs. 26.5 kg/m(2) [5.3], p = 0.008). WA% correlated with greater BMI (r = 0.55, p < 0.001) and volume of adipose tissue (subcutaneous, r = 0.40; p < 0.001; mediastinal, r = 0.25; p = 0.005). Multivariable regression found the COPD phenotype associated with greater age and pack-years smoking; the asthma phenotype with younger age, female gender, smoking history, and lower adiponectin levels; and greater WA% with greater BMI, younger age, higher soluble CD163, and higher CD4 counts. CONCLUSIONS: Adiposity and adipose-related inflammation are associated with an asthma phenotype, but not a COPD phenotype, of obstructive lung disease in HIV-infected persons. Airway wall thickness is associated with adiposity and inflammation. Adipose-related inflammation may play a role in HIV-associated asthma.

Contributors to diffusion impairment in HIV-infected persons.

Abnormal diffusing capacity is common in HIV-infected individuals, including never smokers. Aetiologies for diffusing capacity impairment in HIV are not understood, particularly in those without a history of cigarette smoking. Our study was a cross-sectional analysis of 158 HIV-infected individuals without acute respiratory symptoms or infection with the aim to determine associations between a diffusing capacity of the lung for carbon monoxide (D(LCO)) % predicted and participant demographics, pulmonary spirometric measures (forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity), radiographic emphysema (fraction of lung voxels < -950 Hounsfield units), pulmonary vascular/cardiovascular disease (echocardiographic tricuspid regurgitant jet velocity, N-terminal pro-brain natriuretic peptide) and airway inflammation (induced sputum cell counts), stratified by history of smoking. The mean D(LCO) was 65.9% predicted, and 55 (34.8%) participants had a significantly reduced D(LCO) (<60% predicted). Lower D(LCO) % predicted in ever-smokers was associated with lower post-bronchodilator FEV1 % predicted (p<0.001) and greater radiographic emphysema (p=0.001). In never-smokers, mean±SD D(LCO) was 72.7±13.4% predicted, and D(LCO) correlated with post-bronchodilator FEV1 (p=0.02), sputum neutrophils (p=0.03) and sputum lymphocytes (p=0.009), but not radiographic emphysema. Airway obstruction, emphysema and inflammation influence D(LCO) in HIV. Never-smokers may have a unique phenotype of diffusing capacity impairment. The interaction of multiple factors may account for the pervasive nature of diffusing capacity impairment in HIV infection.

Pulmonary symptoms and diagnoses are associated with HIV in the MACS and WIHS cohorts.

BACKGROUND: Several lung diseases are increasingly recognized as comorbidities with HIV; however, few data exist related to the spectrum of respiratory symptoms, diagnostic testing, and diagnoses in the current HIV era. The objective of the study is to determine the impact of HIV on prevalence and incidence of respiratory disease in the current era of effective antiretroviral treatment. METHODS: A pulmonary-specific questionnaire was administered yearly for three years to participants in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS). Adjusted prevalence ratios for respiratory symptoms, testing, or diagnoses and adjusted incidence rate ratios for diagnoses in HIV-infected compared to HIV-uninfected participants were determined. Risk factors for outcomes in HIV-infected individuals were modeled. RESULTS: Baseline pulmonary questionnaires were completed by 907 HIV-infected and 989 HIV-uninfected participants in the MACS cohort and by 1405 HIV-infected and 571 HIV-uninfected participants in the WIHS cohort. In MACS, dyspnea, cough, wheezing, sleep apnea, and incident chronic obstructive pulmonary disease (COPD) were more common in HIV-infected participants. In WIHS, wheezing and sleep apnea were more common in HIV-infected participants. Smoking (MACS and WIHS) and greater body mass index (WIHS) were associated with more respiratory symptoms and diagnoses. While sputum studies, bronchoscopies, and chest computed tomography scans were more likely to be performed in HIV-infected participants, pulmonary function tests were no more common in HIV-infected individuals. Respiratory symptoms in HIV-infected individuals were associated with history of pneumonia, cardiovascular disease, or use of HAART. A diagnosis of asthma or COPD was associated with previous pneumonia. CONCLUSIONS: In these two cohorts, HIV is an independent risk factor for several respiratory symptoms and pulmonary diseases including COPD and sleep apnea. Despite a higher prevalence of chronic respiratory symptoms, testing for non-infectious respiratory diseases may be underutilized in the HIV-infected population.

Pathogenesis of HIV and the lung.

Antiretroviral therapy has improved longevity for HIV-infected persons, but long-term HIV infection is now complicated by increased rates of chronic medical conditions including pulmonary disorders. Chronic obstructive pulmonary disease, lung cancer, asthma, and pulmonary hypertension are becoming common comorbidities of HIV infection, and these diseases may develop as a result of HIV-related risk factors, such as antiretroviral drug toxicities, colonization by infectious organisms, HIV viremia, immune activation, or immune dysfunction. It also appears that the ability to control HIV infection does not completely eliminate the risk for infectious complications, such as bacterial pneumonia and tuberculosis. The effect of HIV infection on lung-specific immune responses is being elucidated to help develop better prevention and treatment strategies in HIV-infected persons.

Asthma diagnosis and airway bronchodilator response in HIV-infected patients.

BACKGROUND: Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected subjects, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART). OBJECTIVE: We sought to determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms. METHODS: We performed a cross-sectional analysis of 223 HIV-infected subjects with data on respiratory symptoms and diagnoses, pulmonary function, sputum cell counts, and asthma-related cytokines and chemokines in serum/sputum. RESULTS: Doctor-diagnosed asthma was present in 46 (20.6%), and BDR (≥200 mL and ≥12% increase in FEV(1) or forced vital capacity) was present in 20 (9.0%) participants. Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (P = .04), body mass index of greater than 29.6 kg/m(2) (vs <29.6 kg/m(2), P = .03), history of bacterial or Pneumocystis pneumonia (P = .01), and not currently taking ART (P = .04) and in univariate analysis with parental history of asthma (n = 180, P = .004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (P = .02) or BDR (P = .02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (P = .02) and RANTES (P = .02) levels, whereas BDR was associated with high plasma macrophage inflammatory protein 1α (P = .002) and sputum macrophage inflammatory protein 1ß (P = .001) levels. CONCLUSION: Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, absence of ART, and increased HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.

Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era.

RATIONALE: Before the introduction of combination antiretroviral (ARV) therapy, patients infected with HIV had an increased prevalence of respiratory symptoms and lung function abnormalities. The prevalence and exact phenotype of pulmonary abnormalities in the current era are unknown. In addition, these abnormalities may be underdiagnosed. OBJECTIVES: Our objective was to determine the current burden of respiratory symptoms, pulmonary function abnormalities, and associated risk factors in individuals infected with HIV. METHODS: Cross-sectional analysis of 167 participants infected with HIV who underwent pulmonary function testing. MEASUREMENTS AND MAIN RESULTS: Respiratory symptoms were present in 47.3% of participants and associated with intravenous drug use (odds ratio [OR] 3.64; 95% confidence interval [CI], 1.32-10.046; P = 0.01). Only 15% had previous pulmonary testing. Pulmonary function abnormalities were common with 64.1% of participants having diffusion impairment and 21% having irreversible airway obstruction. Diffusion impairment was independently associated with ever smoking (OR 2.46; 95% CI, 1.16-5.21; P = 0.02) and Pneumocystis pneumonia prophylaxis (OR 2.94; 95% CI, 1.10-7.86; P = 0.01), whereas irreversible airway obstruction was independently associated with pack-years smoked (OR 1.03 per pack-year; 95% CI, 1.01-1.05; P < 0.01), intravenous drug use (OR 2.87; 95% CI, 1.15-7.09; P = 0.02), and the use of ARV therapy (OR 6.22; 95% CI, 1.19-32.43; P = 0.03). CONCLUSIONS: Respiratory symptoms and pulmonary function abnormalities remain common in individuals infected with HIV. Smoking and intravenous drug use are still important risk factors for pulmonary abnormalities, but ARV may be a novel risk factor for irreversible airway obstruction. Obstructive lung disease is likely underdiagnosed in this population.

Decreased Lung Function and All-Cause Mortality in HIV-infected Individuals.

RATIONALE: Human immunodeficiency virus (HIV) infection is associated with pulmonary disease and worse lung function, but the relationship of lung function with survival in HIV is unknown. OBJECTIVES: To determine whether lung function is associated with all-cause mortality in HIV-infected individuals. METHODS: HIV-infected participants from cohorts in three locations underwent pre- and post-bronchodilator spirometry and determination of single-breath diffusing capacity of the lung for carbon monoxide (DlCO) in 2008-2009, computed tomographic (CT) scanning of the chest for quantitative emphysema and airway measures, and echocardiography for estimated left ventricular systolic and diastolic function and tricuspid regurgitant velocity. Bivariate analysis and multivariable Cox proportional hazards models were used to determine whether decreased lung function was independently associated with increased all-cause mortality. Models were adjusted for covariates including age, sex, body mass index, smoking status, self-reported hepatitis C status, HIV viral levels, CD4+ T-cell counts, hemoglobin, antiretroviral therapy, and illicit drug use. RESULTS: Overall, 396 HIV-infected participants underwent pulmonary function testing. Thirty-two participants (8%) died during a median follow-up period of 69 months. A post-bronchodilator FEV1-to-FVC ratio less than 0.7 (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.10-5.58) and a DlCO less than 60% (HR, 2.28; 95% CI, 1.08-4.82) were independently associated with worse mortality. Also, hepatitis C (HR, 2.68; 95% CI, 1.22-5.89) and baseline plasma HIV RNA level (HR per ln RNA copies/ml, 1.50; 95% CI, 1.22-1.86) were associated with mortality in HIV-infected participants. The only CT or echocardiographic measure associated with greater mortality in univariate analysis was greater wall thickness of medium-sized airways (HR for wall area percent, 1.08; 95% CI, 1.00-1.18; P = 0.051), but none of the CT or echocardiogram measures were associated with mortality in multivariable analysis. CONCLUSIONS: Airflow obstruction and impaired diffusing capacity appear to be associated with all-cause mortality in HIV-infected persons over an average of 6 years of follow-up. These data highlight the importance of lung dysfunction in HIV-infected persons and should be confirmed in larger cohorts and with extended follow-up periods. Clinical trial registered with www.clinicaltrials.gov (NCT00869544, NCT01326572).

Novel relationships of markers of monocyte activation and endothelial dysfunction with pulmonary dysfunction in HIV-infected persons.

OBJECTIVE: Chronic obstructive pulmonary disease is a common comorbidity in HIV, with prevalence and severity of disease incompletely explained by risk factors such as smoking and age. Unique HIV-associated factors, including microbial translocation, monocyte activation, and endothelial dysfunction, have been described in other comorbidities, but have not been investigated in relation to pulmonary abnormalities in HIV. This study assessed the relationship of these pathologic processes to pulmonary function in HIV-infected and uninfected individuals and determined if relationships were unique to HIV. DESIGN: Longitudinal observational study. METHODS: Total 274 participants completed pulmonary function testing. Markers of inflammation (IL-6, IL-8, and TNFα), microbial translocation (lipopolysaccharide, sCD14), monocyte activation (sCD163, sCD14, and IL-2 receptor), and endothelial dysfunction (endothelin-1) were measured at baseline. Cross-sectional and longitudinal analyses were performed, adjusting for pertinent covariates. RESULTS: In HIV-infected individuals, higher IL-6 and endothelin-1 associated with worse forced expiratory volume in one second (FEV1) percentage-predicted, and higher sCD163 associated with worse FEV1/forced vital capacity. IL-6, TNFα, lipopolysaccharide, sCD163, IL-2 receptor, and endothelin-1 associated with diffusing impairment. sCD163 and endothelin-1 interacted with HIV status in relationship to pulmonary function. In HIV-infected individuals only, baseline endothelin-1 was associated with lower FEV1, and sCD163 and endothelin-1 were associated with lower diffusing capacity during follow-up. CONCLUSION: Circulating markers of HIV-associated humoral abnormalities are associated with airflow obstruction and diffusing impairment and baseline measures of monocyte activation and endothelial dysfunction associate with lower pulmonary function over time in HIV-infected persons. These findings suggest mechanisms of the disproportionate burden of chronic obstructive pulmonary disease in HIV-infected persons.

Elevated NT-pro-brain natriuretic peptide level is independently associated with all-cause mortality in HIV-infected women in the early and recent HAART eras in the Women's Interagency HIV Study cohort.

BACKGROUND: HIV-infected individuals are at increased risk of right and left heart dysfunction. N-terminal-pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac ventricular strain and systolic dysfunction, may be associated with all-cause mortality in HIV-infected women. The aim of this study was to determine if elevated levels of NT-proBNP is associated with increased mortality in HIV-infected women. DESIGN: Prospective cohort study. METHODS AND RESULTS: We measured NT-proBNP in 936 HIV-infected and 387 age-matched HIV-uninfected women early (10/11/94 to 7/17/97) and 1082 HIV-infected and 448 HIV-uninfected women late (4/1/08 to 10/7/08) in the highly active antiretroviral therapy (HAART) periods in the Women's Interagency HIV Study. An NT-proBNP >75th percentile was more likely in HIV-infected persons, but only statistically significant in the late period (27% vs. 21%, unadjusted p = 0.03). In HIV-infected participants, NT-proBNP>75th percentile was independently associated with worse 5-year survival in the early HAART period (HR 1.8, 95% CI 1.3-2.4, p<0.001) and remained a predictor of mortality in the late HAART period (HR 2.8, 95% CI 1.4-5.5, p = 0.002) independent of other established risk covariates (age, race/ethnicity, body mass index, smoking, hepatitis C serostatus, hypertension, renal function, and hemoglobin). NT-proBNP level was not associated with mortality in HIV-uninfected women. CONCLUSION: NT-proBNP is a novel independent marker of mortality in HIV-infected women both when HAART was first introduced and currently. As NT-proBNP is often associated with both pulmonary hypertension and left ventricular dysfunction, these findings suggest that these conditions may contribute significantly to adverse outcomes in this population, requiring further definition of causes and treatments of elevated NT-proBNP in HIV-infected women.

Infections in "noninfectious" lung diseases.

Many chronic pulmonary diseases, including those that are not primarily infectious in etiology, have some aspects of their pathogenesis that are influenced by infectious organisms. Microorganisms may contribute to chronic lung diseases, either directly (i.e., overt infection) or indirectly, via the amplification of inflammatory pathways that are critical to host defense. As techniques for detecting and characterizing microorganisms have advanced, investigations of both infecting and colonizing organisms have yielded new insights into mechanisms of pulmonary disease. In addition, changes in patterns of infection and microbial resistance have important implications for treatment. Examples of these infectious-pulmonary associations, including Haemophilus influenzae infection and chronic obstructive pulmonary disease, nontuberculous mycobacteria and bronchiectasis, and human immunodeficiency virus and obstructive lung disease, are reviewed.

Pulmonary Function in HIV-Infected Recreational Drug Users in the Era of Anti-Retroviral Therapy.

BACKGROUND: Individuals with HIV infection commonly have pulmonary function abnormalities, including airflow obstruction and diffusion impairment, which may be more prevalent among recreational drug users. To date, the relationship between drug use and pulmonary function abnormalities among those with HIV remains unclear. OBJECTIVE: To determine associations between recreational drug use and airflow obstruction, diffusion impairment, and radiographic emphysema in men and women with HIV. METHODS: Cross-sectional analysis of pulmonary function and self-reported recreational drug use data from a cohort of 121 men and 63 women with HIV. Primary outcomes were the presence (yes/no) of: 1) airflow obstruction, (pre- or post-bronchodilator forced expiratory volume in 1 second/forced vital capacity<0.70); 2) moderate diffusion impairment (diffusing capacity for carbon monoxide <60% predicted); and 3) radiographic emphysema (>1% of lung voxels <-950 Hounsfield units). Exposures of interest were frequency of recreational drug use, recent (since last study visit) drug use, and any lifetime drug use. We used logistic regression to determine associations between recreational drug use and the primary outcomes. RESULTS: HIV-infected men and women reported recent recreational drug use at 56.0% and 31.0% of their study visits, respectively, and 48.8% of men and 39.7% of women reported drug use since their last study visit. Drug use was not associated with airway obstruction or radiographic emphysema in men or women. Recent crack cocaine use was independently associated with moderate diffusion impairment in women (odds ratio 17.6; 95% confidence interval 1.3-249.6, p=0.03). CONCLUSIONS: In this cross-sectional analysis, we found that recreational drug use was common among HIV-infected men and women and recent crack cocaine use was associated with moderate diffusion impairment in women. Given the increasing prevalence of HIV infection, any relationship between drug use and prevalence or severity of chronic pulmonary diseases could have a significant impact on HIV and chronic disease management.

Human immunodeficiency virus-associated obstructive lung diseases.

In the era of effective antiretroviral therapy (ART), epidemiologic studies have found that persons infected with human immunodeficiency virus (HIV) have a higher prevalence and incidence of chronic obstructive pulmonary disease than HIV-uninfected persons. In comparison with HIV-uninfected persons and those with well-controlled HIV disease, HIV-infected persons with poor viral control or lower CD4 cell count have more airflow obstruction, a greater decline in lung function, and possibly more severe diffusing impairment. This article reviews the evidence linking HIV infection to obstructive lung disease, and discusses management issues related to the treatment of obstructive lung disease in HIV-infected patients.

Perivascular adipose tissue of the descending thoracic aorta is associated with systemic lupus erythematosus and vascular calcification in women.

OBJECTIVE: Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Traditional CVD and SLE-disease related risk factors do not fully account for this increased risk. Perivascular adipose tissue (PVAT) is a visceral adipose depot in close proximity to blood vessels possibly influencing CVD. We hypothesized that women with SLE have an increased volume of descending thoracic aortic PVAT (aPVAT) associated with increased vascular calcification. METHODS: Using electron beam computed tomography, we quantified the aPVAT in clinically CVD-free SLE women (n = 135) and age-/race-matched healthy controls (HC, n = 152). Coronary artery calcification (CAC) and aortic calcification (AC) were quantified using Agatston scores and the aPVAT was quantified using standard Hounsfield Units (HU) for adipose tissue. RESULTS: Women with SLE had greater median aPVAT (32.2 cm(3) vs HC aPVAT 28.6 cm(3), p = 0.0071) and greater median AC (26.0 vs HC AC 6.0, p = 0.0013) than the healthy control women. Total aPVAT (per 25 cm(3)) remained significantly associated with SLE after adjusting for CVD risk factors (Odds Ratio 1.74 [95% Confidence Interval: 1.04-2.9], p = 0.034), but was attenuated when adjusting for circulating inflammatory markers (p = 0.34). In a logistic regression analysis, SLE aPVAT (per 25 cm(3)) was associated with AC (6.78 [2.0-23], p = 0.0019), which remained significant after adjusting for circulating inflammatory markers (p = 0.0074), and CAC (2.66 [1.4-5.0], p = 0.0028). CONCLUSIONS: Total aPVAT is greater in clinically CVD-free SLE women than in age-/race-matched controls and is associated with calcification in different vascular beds.

HIV infection is associated with diffusing capacity impairment in women.

Respiratory dysfunction is common with HIV infection, but few studies have directly assessed whether HIV remains an independent risk factor for pulmonary function abnormalities in the antiretroviral therapy era. Additionally, few studies have focused on pulmonary outcomes in HIV+ women. We tested associations between risk factors for respiratory dysfunction and pulmonary outcomes in 63 HIV+ and 36 HIV-uninfected women enrolled in the Women's Interagency HIV Study. Diffusing capacity (DL(CO)) was significantly lower in HIV+ women (65.5% predicted vs. 72.7% predicted, P = 0.01), and self-reported dyspnea in HIV+ participants was associated with both DL(CO) impairment and airflow obstruction. Providers should be aware that DL(CO) impairment is common in HIV infection, and that either DL(CO) impairment or airflow obstruction may cause respiratory symptoms in this population.

The impact of HAART on the respiratory complications of HIV infection: longitudinal trends in the MACS and WIHS cohorts.

OBJECTIVE: To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART). DESIGN: Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women's Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively. METHODS: Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era. RESULTS: Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2-2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3-1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8-2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02-8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3-1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5-2.4; p<0.001). CONCLUSION: HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.

Serum (1→3)-ß-D-glucan levels in HIV-infected individuals are associated with immunosuppression, inflammation, and cardiopulmonary function.

BACKGROUND: Translocation of gastrointestinal bacteria in HIV-infected individuals is associated with systemic inflammation, HIV progression, mortality, and comorbidities. HIV-infected individuals are also susceptible to fungal infection and colonization, but whether fungal translocation occurs and influences HIV progression or comorbidities is unknown. METHODS: Serum (1→3)-ß-D-glucan (BG) was measured by a Limulus Amebocyte Lysate assay (Fungitell) in 132 HIV-infected outpatients. Selected plasma cytokines and markers of peripheral T-cell activation were measured. Pulmonary function testing and Doppler echocardiography were performed. Relationship of high (≥40 pg/mL) and low (<40 pg/mL) levels of BG with HIV-associated variables, inflammation markers, and pulmonary function and pulmonary hypertension measures were determined. RESULTS: Forty-eight percent of patients had detectable BG, and 16.7% had high levels. Individuals with high BG were more likely to have CD4 counts less than 200 cells/µL (31.8% vs. 8.4%, P = 0.002), had higher log10 HIV viral levels (2.85 vs. 2.13 log copies/mL, P = 0.004), and were less likely to use antiretroviral therapy (68.2% vs. 90.0%, P = 0.006). Plasma IL-8 (P = 0.033), TNF-α (P = 0.029), and CD8CD38 (P = 0.046) and CD8HLA-DR (P = 0.029) were also increased with high levels. Abnormalities in diffusing capacity (P = 0.041) and in pulmonary artery pressures (P = 0.006 for pulmonary artery systolic pressure and 0.013 for tricuspid regurgitant velocity) were more common in those with high BG. CONCLUSIONS: We found evidence of peripheral fungal cell wall polysaccharides in an HIV-infected cohort. We also demonstrated an association between high serum BG, HIV-associated immunosuppression, inflammation, and cardiopulmonary comorbidity. These results implicate a new class of pathogen in HIV-associated microbial translocation and suggest a role in HIV progression and comorbidities.

Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era.

OBJECTIVE: To determine relationship of echocardiographic measures of pulmonary hypertension to lung function and inflammatory biomarkers in HIV-infected individuals. DESIGN: Cross-sectional study of 116 HIV-infected outpatients. METHODS: Doppler-echocardiography and pulmonary function testing were performed. Induced sputum and plasma cytokines, sputum cell counts and differentials, markers of peripheral T-cell activation, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Univariate and multivariate analyses determined relationship of echocardiographic variables to pulmonary function, inflammation, and NT-proBNP. RESULTS: Mean estimated pulmonary artery systolic pressure (PASP) was 34.3 mmHg (SD 6.9) and mean tricuspid regurgitant jet velocity (TRV) was 2.5 m/s (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and nine (7.8%) had TRV of at least 3.0 m/s. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/µl and higher log HIV-RNA levels. Forced expiratory volume in 1 s (FEV(1)) percentage predicted, FEV(1)/forced vital capacity, and diffusing capacity for carbon monoxide (DLco) percentage predicted were significantly lower in those with elevated PASP or TRV. Sputum interleukin-8, peripheral interleukin-8, peripheral interferon-γ levels, and CD8(+) T-cell expression of CD69(+) were associated with increasing PASP and TRV. Log NT-proBNP was significantly higher with increasing PASP and TRV. Left ventricular function was not associated with PASP or TRV. CONCLUSION: Echocardiographic manifestations of pulmonary hypertension are common in HIV and are associated with respiratory symptoms, more advanced HIV disease, airway obstruction, abnormal DLco, and systemic and pulmonary inflammation. Pulmonary hypertension and chronic obstructive pulmonary disease coexist in HIV and may arise secondary to common inflammatory mechanisms.