Topographic diversity of the respiratory tract mycobiome and alteration in HIV and lung disease.

RATIONALE: Microbiome studies typically focus on bacteria, but fungal species are common in many body sites and can have profound effects on the host. Wide gaps exist in the understanding of the fungal microbiome (mycobiome) and its relationship to lung disease. OBJECTIVES: To characterize the mycobiome at different respiratory tract levels in persons with and without HIV infection and in HIV-infected individuals with chronic obstructive pulmonary disease (COPD). METHODS: Oral washes (OW), induced sputa (IS), and bronchoalveolar lavages (BAL) were collected from 56 participants. We performed 18S and internal transcribed spacer sequencing and used the neutral model to identify fungal species that are likely residents of the lung. We used ubiquity-ubiquity plots, random forest, logistic regression, and metastats to compare fungal communities by HIV status and presence of COPD. MEASUREMENTS AND MAIN RESULTS: Mycobiomes of OW, IS, and BAL shared common organisms, but each also had distinct members. Candida was dominant in OW and IS, but BAL had 39 fungal species that were disproportionately more abundant than in the OW. Fungal communities in BAL differed significantly by HIV status and by COPD, with Pneumocystis jirovecii significantly overrepresented in both groups. Other fungal species were also identified as differing in HIV and COPD. CONCLUSIONS: This study systematically examined the respiratory tract mycobiome in a relatively large group. By identifying Pneumocystis and other fungal species as overrepresented in the lung in HIV and in COPD, it is the first to determine alterations in fungal communities associated with lung dysfunction and/or HIV, highlighting the clinical relevance of these findings. Clinical trial registered with www.clinicaltrials.gov (NCT00870857).

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.

Pneumocystis jirovecii colonization is associated with enhanced Th1 inflammatory gene expression in lungs of humans with chronic obstructive pulmonary disease.

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.

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.

Acute physiologic effects of secondhand smoke exposure in children.

INTRODUCTION: We investigated the hypothesis that exhaled carbon monoxide (eCO), heart rate (HR), and blood pressure (BP) would increase acutely in exposed but not in unexposed children. METHODS: In a nonrandomized controlled design, parent-child dyads were assigned to groups based on exposure: child subjects, 7-18 years of age, exposed to smoking daily in the home (exposed) or with no household exposure (unexposed control). HR, BP, and eCO were measured before and after exposure to a parent smoking 1 cigarette (exposed) or a time-lapse equivalent (control). The primary analysis compared mean acute changes in physiological measures following intervention or control procedure. RESULTS: Forty-one dyads were enrolled. At baseline, no differences in child gender, race, ethnicity, HR, BP, lipids, or fasting glucose were noted between exposure groups. Following experimental or control procedures, the median change in eCO was similar between groups (-0.1 ppm exposed vs. 0.0 ppm unexposed, p = .27). Acute hemodynamic changes were also similar between exposed and unexposed children, respectively: (HR change 4.2 vs. 2.6 beats per minute, p = .62; systolic blood pressure change 0.08 vs. 0.41 mm Hg, p = .91; diastolic blood pressure 0.08 vs. 2.27 mm Hg, p = .37). DISCUSSION: This is the first study to report on acute physiologic changes of secondhand smoke exposure in children in a naturalistic setting. A single acute dose of passive smoke exposure in children did not alter the physiologic variables of HR or BP. Further in-home study using continuous monitoring is needed. Demonstration of acute effects may serve as clinical feedback to motivate parents to quit smoking.

Discovery of the gene signature for acute lung injury in patients with sepsis.

The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) was described 30 yr ago, yet making a definitive diagnosis remains difficult. The identification of biomarkers obtained from peripheral blood could provide additional noninvasive means for diagnosis. To identify gene expression profiles that may be used to classify patients with ALI, 13 patients with ALI + sepsis and 20 patients with sepsis alone were recruited from the Medical Intensive Care Unit of the University of Pittsburgh Medical Center, and microarrays were performed on peripheral blood samples. Several classification algorithms were used to develop a gene signature for ALI from gene expression profiles. This signature was validated in an independently obtained set of patients with ALI + sepsis (n = 8) and sepsis alone (n = 1). An eight-gene expression profile was found to be associated with ALI. Internal validation found that the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 100% accuracy, corresponding to a sensitivity of 100%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 100%. In the independently obtained external validation set, the gene signature was able to distinguish patients with ALI + sepsis from patients with sepsis alone with 88.9% accuracy. The use of classification models to develop a gene signature from gene expression profiles provides a novel and accurate approach for classifying patients with ALI.

Airway obstruction is increased in pneumocystis-colonized human immunodeficiency virus-infected outpatients.

We investigated the relationship of Pneumocystis colonization, matrix metalloprotease levels in sputum, and airway obstruction in a cohort of human immunodeficiency virus (HIV)-infected outpatients. Pneumocystis-colonized subjects had worse obstruction of airways and higher levels of matrix metalloprotease-12 in sputa, suggesting that Pneumocystis colonization may be important in HIV-associated chronic obstructive pulmonary disease.

Emphysema is associated with thoracic vertebral bone attenuation on chest CT scan in HIV-infected individuals.

BACKGROUND: Age-related chronic diseases are prevalent in HIV-infected persons in the antiretroviral therapy (ART) era. Bone mineral density (BMD) loss and emphysema have separately been shown to occur at a younger age and with lesser risk exposure in HIV-infected compared to HIV-uninfected individuals. In non-HIV infected smokers, emphysema has been shown to independently predict low BMD. We hypothesized that emphysema would independently associate with thoracic vertebral bone attenuation, a surrogate for bone mineral density, in HIV-infected individuals. METHODS: Clinical, pulmonary function, and radiographic data were analyzed for 164 individuals from the University of Pittsburgh's HIV Lung Research Center cohort. Chest CT scans were used to quantify emphysema and compute Hounsfield Unit (HU) attenuation of the 4th, 7th, and 10th thoracic vertebrae. The association between mean HU attenuation values across the three vertebrae and radiographic emphysema, age, sex, body mass index (BMI), steroid use, viral load, CD4 count, and forced expiratory volume in the first second (FEV1) was assessed by univariate and multivariate analyses. RESULTS: In univariate analysis, mean HU attenuation decreased with increasing age (p<0.001), pack years (p = 0.047), and percent emphysema (p<0.001). In a multivariable model, including pack years, age, sex, ART and steroid use, greater emphysema was independently associated with this surrogate marker of BMD in HIV-infected individuals (p = 0.034). CONCLUSIONS: The association of emphysema with thoracic bone attenuation in HIV-infected individuals is consistent with previous reports in non-HIV infected smokers. These findings suggest that emphysema should be considered a potential marker of osteoporosis risk in HIV-infected individuals.

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.

Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort.

OBJECTIVE: To determine associations between circulating markers of immune activation, immune cell senescence, and inflammation with HIV-associated abnormalities of pulmonary function. DESIGN: HIV infection is an independent risk factor for abnormal pulmonary function. Immune activation, immune senescence, and chronic inflammation are characteristics of chronic HIV infection that have been associated with other HIV-associated comorbidities and may be related to pulmonary disease in this population. METHODS: Participants from an HIV-infected cohort (n = 147) completed pulmonary function testing (PFT). Markers of T-cell activation and senescence were determined by flow cytometry, and plasma levels of interleukin-6, interleukin-8, and C-reactive protein (CRP) were measured, as was telomere length of peripheral blood mononuclear cells (PBMC). Regression models adjusting for clinical risk factors were constructed to examine relationships between biomarkers and PFT outcomes. RESULTS: Activated CD25(+) T cells and activated/senescent CD69(+)/CD57(+)/CD28(null) CD4(+) T cells, interleukin-6, and CRP were associated with PFT abnormalities. Shortening of PBMC telomere length correlated with airflow obstruction and diffusing impairment. Paradoxically, circulating senescent CD57(+)/CD28(null) CD8(+) T cells were associated with better PFT outcomes. CONCLUSION: Circulating T cells expressing markers of activation and inflammatory cytokine levels are independently correlated with PFT abnormalities in HIV-infected persons. Overall telomere shortening was also associated with pulmonary dysfunction. The paradoxical association of senescent CD8(+) T cells and better PFT outcomes could suggest an unrecognized beneficial compensatory function of such cells or a redistribution of these cells from the circulation to local compartments. Further studies are needed to differentiate and characterize functional subsets of local pulmonary and circulating T-cell populations in HIV-associated pulmonary dysfunction.

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.

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.

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.

HIV and chronic obstructive pulmonary disease: is it worse and why?

Smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are of particular concern in the HIV-infected population. Smoking rates are high in this population, and long-term exposure to cigarette smoke in the setting of HIV infection may increase the number of complications seen. Before the era of combination antiretroviral therapy, HIV-infected persons were noted to have an accelerated form of COPD, with significant emphysematous disease seen in individuals less than 40 years old. Unlike many of the AIDS-defining opportunistic infections, HIV-associated COPD may be more common in the current era of HIV because it is frequently reported in patients without a history of AIDS-related pulmonary complications and because many aging HIV-infected individuals have had a longer exposure to smoking and HIV. In this review, we document the epidemiology of HIV-associated COPD before and after the institution of combination antiretroviral therapy, review data suggesting that COPD is accelerated in those with HIV, and discuss possible mechanisms of HIV-associated COPD, including an increased susceptibility to chronic, latent infections; an aberrant inflammatory response; altered oxidant-antioxidant balance; increased apoptosis associated with HIV; and the effects of antiretroviral therapy.

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 in 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.

Serologic responses to pneumocystis proteins in HIV 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 3 sequential serum samples up to 18 months before and 3 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 before 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 [odds ratio (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 before 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. CONCLUSIONS: 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 per microliter.