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1.  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.
doi:10.4172/2155-6113.1000365
PMCID: PMC4318265  PMID: 25664201
HIV; COPD; Emphysema; Diffusion impairment; Drug use; Pulmonary function; Cocaine
2.  Heart–Lung Interaction via Infection 
Annals of the American Thoracic Society  2014;11(Suppl 1):S52-S56.
Lung and cardiovascular disease are increasingly recognized to occur in the same patient populations. Infections, either through stimulation of inflammation or through direct infection, can lead to end-organ damage and have been postulated as a potential link between lung and cardiovascular diseases. Mechanisms by which infections may link lung and cardiac diseases include effects of systemic infections, microbial translocation of pathogens from the gastrointestinal tract or other sites, damaging effects of metabolic products, or influences of smoking on the microbiome. Other mechanisms, such as alterations in the local microbiome, environmental exposures, or immune regulation by microbial communities, may be important. These relationships are likely quite complex, with multiple routes between infection and disease possible. A better understanding of the links of infection to lung and heart disease can improve our understanding of the pathogenesis of these disorders and uncover novel therapeutic approaches.
doi:10.1513/AnnalsATS.201306-157MG
PMCID: PMC3972975  PMID: 24437407
microbial translocation; metabolomics; pulmonary function; cardiovascular; HIV
3.  Contributors to diffusion impairment in HIV-infected persons 
The European respiratory journal  2013;43(1):195-203.
Abnormal diffusing capacity is common in HIV-infected individuals including never smokers. Etiologies for diffusing capacity impairment in HIV are not understood, particularly in those without a history of cigarette smoking.
A cross-sectional analysis of 158 HIV-infected individuals without acute respiratory symptoms or infection to determine associations between a DLCO % predicted and participant demographics, pulmonary spirometric measures (FEV1 and FEV1/FVC), radiographic emphysema (fraction of lung voxels <-950 Hounsfield units), pulmonary vascular/cardiovascular disease (echocardiographic tricuspid regurgitant jet velocity [TRV], N-terminal pro-brain natriuretic peptide), and airway inflammation (induced sputum cell counts), stratified by history of smoking.
Mean DLCO was 65.9% predicted, and 55 (34.8%) participants had a significantly reduced DLCO (<60 % predicted). Lower DLCO % 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 (standard deviation) DLCO was 72.7% (13.4%) predicted, and DLCO 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 DLCO 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.
doi:10.1183/09031936.00157712
PMCID: PMC4023348  PMID: 23429919
HIV; Pulmonary function; Diffusing capacity; AIDS
4.  Chest Computed Tomography Findings in HIV-Infected Individuals in the Era of Antiretroviral Therapy 
PLoS ONE  2014;9(11):e112237.
Background
Chest radiographic abnormalities were common in HIV-infected individuals in the pre-combination antiretroviral therapy era, but findings may differ now due to a changing spectrum of pulmonary complications.
Methods
Cross-sectional study of radiographic abnormalities in an HIV-infected outpatient population during the antiretroviral therapy era. Demographics, chest computed tomography, and pulmonary function tests were obtained in HIV-infected volunteers without acute respiratory illness from the University of Pittsburgh HIV/AIDS clinic. Overall prevalence of radiographic abnormalities and potential risk factors for having any abnormality, nodules, or emphysema were evaluated using univariate and multivariable analyses.
Results
A majority of the 121 participants (55.4%) had a radiographic abnormality with the most common being emphysema (26.4%), nodules (17.4%), and bronchiectasis (10.7%). In multivariate models, age (odds ratio [OR] per year  = 1.07, 95% confidence interval [CI] 1.04–1.14, p<0.001), pneumonia history (OR  = 3.60, 95% CI  = 1.27–10.20, p = 0.016), and having ever smoked (OR  = 3.66, p = 0.013, 95% CI  = 1.31–10.12) were significant predictors of having any radiographic abnormality. Use of antiretroviral therapy, CD4 cell count, and HIV viral load were not associated with presence of abnormalities. Individuals with radiographic emphysema were more likely to have airway obstruction on pulmonary function tests. Only 85.8% participants with nodules had follow-up imaging resulting in 52.4% having stable nodules, 23.8% resolution of their nodules, 4.8% development of a new nodule, and 4.8% primary lung cancer.
Conclusions
Radiographic abnormalities remain common in HIV-infected individuals with emphysema, nodules, and bronchiectasis being the most common. Age, smoking, and pneumonia were associated with radiographic abnormalities, but HIV-associated factors did not seem to predict risk.
doi:10.1371/journal.pone.0112237
PMCID: PMC4237318  PMID: 25409510
5.  HIV infection is associated with diffusing capacity impairment in women 
Journal of acquired immune deficiency syndromes (1999)  2013;64(3):10.1097/QAI.0b013e3182a9213a.
Respiratory dysfunction is common in HIV, 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 (DLCO) 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 DLCO impairment and airflow obstruction. Providers should be aware that DLCO impairment is common in HIV and that either DLCO impairment or airflow obstruction may cause respiratory symptoms in this population.
doi:10.1097/QAI.0b013e3182a9213a
PMCID: PMC3857225  PMID: 23979000
HIV; Pulmonary function; Pulmonary diffusing capacity; AIDS; Hepatitis C, chronic
6.  HIV Infection is associated with reduced pulmonary diffusing capacity 
Journal of acquired immune deficiency syndromes (1999)  2013;64(3):10.1097/QAI.0b013e3182a9215a.
Rationale:
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 to HIV-uninfected individuals.
Methods:
Cross-sectional analysis of 300 HIV-infected and 289 HIV-uninfected men enrolled from 2009-2011 in two clinical centers of the Lung HIV Study. Participants completed pre- and post-bronchodilator spirometry, diffusing capacity (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 to 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 compared to those with CD4 cell counts ≥200 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 to HIV-uninfected patients.
Conclusions:
HIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.
doi:10.1097/QAI.0b013e3182a9215a
PMCID: PMC3845879  PMID: 23979001
Pulmonary function; FEV1; DLCO; gas exchange; COPD; HIV/AIDS
7.  The human mycobiome in health and disease 
Genome Medicine  2013;5(7):63.
The mycobiome, referring primarily to the fungal biota in an environment, is an important component of the human microbiome. Despite its importance, it has remained understudied. New culture-independent approaches to determine microbial diversity, such as next-generation sequencing methods, are greatly broadening our view of fungal importance. An integrative analysis of current studies shows that different body sites harbor specific fungal populations, and that diverse mycobiome patterns are associated with various diseases. By interfacing with other biomes, as well as with the host, the mycobiome probably contributes to the progression of fungus-associated diseases and plays an important role in health and disease.
doi:10.1186/gm467
PMCID: PMC3978422  PMID: 23899327
8.  Pneumocystis jirovecii colonization is associated with enhanced Th1 inflammatory gene expression in lungs of humans with chronic obstructive pulmonary disease 
Microbiology and immunology  2014;58(3):202-211.
Chronic obstructive pulmonary disease (COPD) is a complex disease, the pathogenesis of which remains incompletely understood. Colonization with Pneumocystis jirovecii may play a role in COPD pathogenesis; however, the mechanisms by which such colonization contributes to COPD are unknown. The objective of this study was to determine lung gene expression profiles associated with Pneumocystis colonization in patients with COPD to identify potential key pathways involved in disease pathogenesis. Using COPD lung tissue samples made available through the Lung Tissue Research Consortium (LTRC), Pneumocystis colonization status was determined by nested PCR. Microarray gene expression profiles were performed for each sample and the profiles of colonized and non-colonized samples compared. Overall, 18 participants (8.5%) were Pneumocystis-colonized. Pneumocystis colonization was associated with fold increase in expression of four closely related genes: INF-γ and the three chemokine ligands CXCL9, CXCL10, and CXCL11. These ligands are chemoattractants for the common cognate receptor CXCR3, which is predominantly expressed on activated Th1 T-lymphocytes. Although these ligand–receptor pairs have previously been implicated in COPD pathogenesis, few initiators of ligand expression and subsequent lymphocyte trafficking have been identified: our findings implicate Pneumocystis as a potential trigger. The finding of upregulation of these inflammatory genes in the setting of Pneumocystis colonization sheds light on infectious-immune relationships in COPD.
doi:10.1111/1348-0421.12135
PMCID: PMC4106795  PMID: 24438206
chronic obstructive; microarray; Pneumocystis jirovecii; Pulmonary disease; Th1 cells
9.  STAT4-dependent and independent T helper type-2 responses correlate with protective immunity against lung infection with Pneumocystis murina‡ 
Although it is clear that the loss of CD4+ T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific T helper mechanisms mediating protection are not well understood. Th1, Th2 and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in P. murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and Balb/c mice 14 days post-challenge, but only Balb/c Stat4-/- mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4-/-, but not Balb/c Stat4-/-, mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched antibodies were increased in BL/6 Stat4-/- mice, but not Balb/c Stat4-/- mice. Supporting our experimental observations, plasma from HIV infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5 and IL-13 compared to HIV infected individuals who were not colonized. Collectively, our data suggests that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.
doi:10.4049/jimmunol.1300431
PMCID: PMC3679253  PMID: 23650614
10.  Future Directions -- Lung Aging, Inflammation, and HIV 
Clinics in chest medicine  2013;34(2):325-331.
SYNOPSIS
Chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) are unusually prevalent among persons infected with HIV. In many cases these disease states are identified at younger ages than would be expected in the general population. Recent epidemiologic, basic science, and cross-sectional clinical data have implicated immune dysfunction and cellular senescence as potential drivers of advanced presentations of age-related diseases in HIV-infected persons. This article describes how HIV-associated COPD and PH may fit into a paradigm of immunosenescence and outlines the hypothesized associations among chronic HIV infection, immune dysfunction and senescence, and cardiopulmonary outcomes.
doi:10.1016/j.ccm.2013.01.010
PMCID: PMC3659341  PMID: 23702180
HIV; chronic obstructive pulmonary disease; pulmonary hypertension; immune activation; immune senescence; inflammation
11.  HIV-associated Obstructive Lung Diseases 
Clinics in chest medicine  2013;34(2):273-282.
In the era of effective antiretroviral therapy (ART), epidemiologic studies have found that HIV-infected persons have a higher prevalence and incidence of chronic obstructive pulmonary disease than HIV-uninfected persons. Recently, pulmonary function studies in HIV-infected persons have shown a high prevalence of airway obstruction, bronchodilator reversibility, and impaired diffusing capacity. In comparison to 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 chapter will review the evidence linking HIV infection to obstructive lung disease and discuss management issues related to the treatment of obstructive lung disease in HIV-infected patients.
doi:10.1016/j.ccm.2013.02.002
PMCID: PMC3690924  PMID: 23702176
Chronic obstructive pulmonary disease; emphysema; asthma; HIV; AIDS; smoking-related lung disease
12.  Widespread Colonization of the Lung by Tropheryma whipplei in HIV Infection 
Rationale: Lung infections caused by opportunistic or virulent pathogens are a principal cause of morbidity and mortality in HIV infection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in individuals infected with HIV.
Objectives: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota.
Methods: We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage (BAL) and mouths of 82 HIV-positive and 77 HIV-negative subjects.
Measurements and Main Results: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple’s disease, were significantly more frequent in BAL of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects, but only 1 HIV-negative individual (13.4 versus 1.3%; P = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on eight BAL samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lung-derived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple’s disease.
Conclusions: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.
doi:10.1164/rccm.201211-2145OC
PMCID: PMC3734615  PMID: 23392441
human; microbiome; metagenome; 16S ribosomal RNA; bronchoalveolar lavage
13.  Comparison of the Respiratory Microbiome in Healthy Nonsmokers and Smokers 
Rationale: Results from 16S rDNA-encoding gene sequence–based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome.
Objectives: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort.
Methods: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome.
Measurements and Main Results: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not.
Conclusions: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.
doi:10.1164/rccm.201210-1913OC
PMCID: PMC3734620  PMID: 23491408
lung; microbiome; smoking; bronchoscopy; metagenome
14.  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.
doi:10.1186/1471-2466-14-75
PMCID: PMC4021087  PMID: 24884738
AIDS; HIV; Pulmonary disease; Chronic obstructive; Respiratory tract diseases; Sleep apnea syndromes
15.  Pathogenesis of HIV and the Lung 
Current HIV/AIDS reports  2013;10(1):42-50.
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.
doi:10.1007/s11904-012-0140-x
PMCID: PMC3567220  PMID: 23079728
HIV; AIDS; Lung Neoplasms; Lung Diseases; Obstructive; Pulmonary Emphysema; Asthma; Pulmonary Hypertension; Pneumonia; Pneumocystis; Pneumonia; Bacterial
16.  Physiologic Changes in a Nonhuman Primate Model of HIV-Associated Pulmonary Arterial Hypertension 
Pulmonary arterial hypertension (PAH) is increased in HIV, but its pathogenesis is not fully understood. Nonhuman primates infected with simian immunodeficiency virus (SIV) or SIV-HIV chimeric virus (SHIV) exhibit histologic changes characteristic of human PAH, but whether hemodynamic changes accompany this pathology is unknown. Repeated measurements of pulmonary artery pressures would permit longitudinal assessments of disease development and provide insights into pathogenesis. We tested the hypothesis that SIV-infected and SHIV-infected macaques develop physiologic manifestations of PAH. We performed right heart catheterizations, echocardiography, and computed tomography (CT) scans in macaques infected with either SIV (ΔB670) or SHIV (89.6P), and compared right heart and pulmonary artery pressures, as well as pulmonary vascular changes on CT scans, with those in uninfected control animals. Right atrial, right ventricular systolic, and pulmonary artery pressures (PAPs) were significantly elevated in 100% of macaques infected with either SIV or SHIV compared with control animals, with no difference in pulmonary capillary wedge pressure. PAPs increased as early as 3 months after SIV infection. Radiographic evidence of pulmonary vascular pruning was also found. Both SIV-infected and SHIV-infected macaques exhibited histologic changes in pulmonary arteries, predominantly consisting of intimal and medial hyperplasia. This report is the first to demonstrate SHIV-infected and SIV-infected macaques develop pulmonary hypertension at a high frequency, with physiologic changes occurring as early as 3 months after infection. These studies establish an important nonhuman primate model of HIV-associated PAH that will be useful in studies of disease pathogenesis and the efficacy of interventions.
doi:10.1165/rcmb.2011-0434OC
PMCID: PMC3604086  PMID: 23239493
pulmonary hypertension; HIV; SIV; SHIV; macaque model
17.  Serum (1→3)-β-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 co-morbidities. HIV-infected individuals are also susceptible to fungal infection and colonization, but whether fungal translocation occurs and influences HIV progression or co-morbidities is unknown.
Methods
Serum (1→3)-β-D-glucan 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 (≥40pg/ml) and low (<40pg/ml) levels of (1→3)-β-D-glucan with HIV-associated variables, inflammation markers, and pulmonary function and pulmonary hypertension measures were determined.
Results
Forty-eight percent had detectable (1→3)-β-D-glucan, and 16.7% had high levels. Individuals with high (1→3)-β-D-glucan were more likely to have CD4 counts below 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 ART (68.2% vs. 90.0%, p=0.006). Plasma IL-8 (p=0.033), TNF-α (p=0.029), and CD8+CD38+ (p=0.046) andCD8+HLA-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 (1→3)-β-D-glucan.
Conclusions
We found evidence of peripheral fungal cell wall polysaccharides in an HIV-infected cohort. We also demonstrated an association between high serum (1→3)-β-D-glucan, HIV-associated immunosuppression, inflammation, and cardiopulmonary co-morbidity. These results implicate a new class of pathogen in HIV-associated microbial translocation and suggest a role in HIV progression and co-morbidities.
doi:10.1097/QAI.0b013e318271799b
PMCID: PMC3494803  PMID: 22972021
HIV; COPD; (1→3)-β-D-glucan; pulmonary hypertension; emphysema; inflammation
19.  Colonization by Pneumocystis jirovecii and Its Role in Disease 
Clinical Microbiology Reviews  2012;25(2):297-317.
Summary: Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research.
doi:10.1128/CMR.00013-12
PMCID: PMC3346301  PMID: 22491773
20.  Cardiopulmonary function in individuals with HIV infection in the antiretroviral therapy era 
AIDS (London, England)  2012;26(6):731-740.
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/sec (SD 0.32). Eighteen participants (15.5%) had PASP of at least 40 mmHg, and 9 (7.8%) had TRV of at least 3.0 m/sec. Elevated TRV was significantly associated with CD4 cell counts below 200 cells/μl and higher log HIV RNA levels. Forced expiratory volume in one second (FEV1) percent predicted, FEV1/forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLco) percent 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 increased 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.
Conclusions
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 COPD coexist in HIV and may arise secondary to common inflammatory mechanisms.
doi:10.1097/QAD.0b013e32835099ae
PMCID: PMC3606053  PMID: 22210636
HIV; pulmonary hypertension; emphysema; COPD; inflammation
21.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
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.
doi:10.1371/journal.pone.0058812
PMCID: PMC3595204  PMID: 23554932
22.  Asthma Diagnosis and Airway Bronchodilator Response in HIV-infected Individuals 
Background
Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected persons, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART).
Objective
To determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.
Methods
A cross-sectional analysis of 223 HIV-infected individuals 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 (≥200ml and ≥12% increase in FEV1 or FVC) in 20 participants (9.0%). Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (p=0.04), body mass index >29.6kg/m2 (vs.<29.6kg/m2) (p=0.03), history of bacterial or Pneumocystis pneumonia (p=0.01), and with not currently taking ART (p=0.04), and in univariate analysis with parental history of asthma (n=180; p=0.004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (p=0.02) or BDR (p=0.02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (p=0.02) and RANTES (p=0.02), while BDR was associated with high plasma macrophage inflammatory protein (MIP)-1α (p=0.002), and sputum MIP-1β levels (p=0.001).
Conclusion
Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, the absence of ART, and elevated HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.
doi:10.1016/j.jaci.2011.11.015
PMCID: PMC3294124  PMID: 22177327
HIV; asthma; airway obstruction; allergy
23.  Distribution of Pneumocystis jirovecii in lungs from colonized COPD patients 
Pneumocystis jirovecii has been detected in lung tissue from patients with chronic obstructive pulmonary disease (COPD) and is associated with disease severity. The regional distribution of the organism in lungs is unknown, but differences in distribution of Pneumocystis could affect estimates of colonization prevalence. We examined the distribution of Pneumocystis in the lungs of 19 non-HIV-infected patients with COPD who were undergoing lung transplantation. DNA was extracted from explanted lungs. We found Pneumocystis colonization in lung tissue of 42.1% of patients with advanced COPD; however, there was significant regional variation in colonization between lung segments of individual patients. Colonization was detected more commonly in the lower and middle lobes than the upper lobes. These findings suggest that single samples from an individual may underestimate the prevalence of Pneumocystis colonization and future studies may obtain a higher yield of Pneumocystis colonization detection when sampling the lower lobes.
doi:10.1016/j.diagmicrobio.2011.05.008
PMCID: PMC3159032  PMID: 21851870
chronic obstructive pulmonary disease; Pneumocystis jirovecii; lung
24.  Pneumocystis infection and the pathogenesis of chronic obstructive pulmonary disease 
Immunologic research  2011;50(2-3):175-180.
With increases in the immunocompromised patient population and aging of the HIV+ population, the risk of serious fungal infections and their complications will continue to rise. In these populations, infection with the fungal opportunistic pathogen Pneumocystis jirovecii remains a leading cause of morbidity and mortality. Infection with Pneumocystis (Pc) has been shown to be associated with the development of chronic obstructive pulmonary disease (COPD) in human subjects with and without HIV infection and in non-human primate models of HIV infection. In human studies and in a primate model of HIV/Pc co-infection, we have shown that antibody response to the Pc protein, kexin (KEX1), correlates with protection from colonization, Pc pneumonia, and COPD. These findings support the hypothesis that immunity to KEX1 may be critical to controlling Pc colonization and preventing or slowing development of COPD.
doi:10.1007/s12026-011-8218-x
PMCID: PMC3151531  PMID: 21717077
Pneumocystis; HIV; SIV; Pulmonary disease; COPD
25.  Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia 
Background
Immune responses to Pneumocystis jirovecii are not well understood in HIV infection, but antibody responses to proteins may be useful as a marker of Pneumocystis risk or presence of Pneumocystis pneumonia (PcP).
Design
Retrospective analysis of a prospective cohort
Methods
Enzyme-linked immunosorbent assays of antibodies to recombinant Pneumocystis proteins of major surface glycoprotein fragments (MsgC1, C3, C8, and C9) and of antibody titers to recombinant kexin protein (KEX1) were performed on three sequential serum samples up to 18 months prior to and three samples after first AIDS-defining illness from Multicenter AIDS Cohort Study participants and compared between those who had PcP or a non-PcP AIDS-defining illness.
Results
Fifty-four participants had PcP and 47 had a non-PcP AIDS-defining illness. IgG levels to MsgC fragments were similar between groups prior to first AIDS-defining illness, but the PcP group had higher levels of IgG to MsgC9 (median units/ml 50.2 vs. 22.2, p=0.047) post-illness. Participants with PcP were more likely to have an increase in MsgC3 (OR 3.9, p=0.02), MsgC8 (OR 5.5, p=0.001), and MsgC9 (OR 4.0, p=0.007). The PcP group was more likely to have low KEX1 IgG prior to development of PcP (OR 3.6, p=0.048) independent of CD4 cell count and to have an increase in high IgG titers to KEX1 after PcP.
Conclusion
HIV-infected individuals develop immune responses to both Msg and kexin proteins after PcP. Low KEX1 IgG titers may be a novel marker of future PcP risk before CD4 cell count has declined below 200 cells/μl.
doi:10.1097/QAI.0b013e3182167516
PMCID: PMC3150634  PMID: 21372726
HIV; Acquired Immunodeficiency Syndrome; Pneumocystis; serology

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