Lorrie Lucht

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.

Airway Obstruction Is Increased in Pneumocystis-Colonized Human Immunodeficiency Virus-Infected Outpatients

ABSTRACT 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.

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/&mgr;l and higher log HIV-RNA levels. Forced expiratory volume in 1 s (FEV1) percentage predicted, FEV1/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-&ggr; 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.

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 (DLCO) % 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 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±sd 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. Diffusing capacity impairment in HIV infection is multifactorial, and causes may vary between smokers and never smokers http://ow.ly/qag5I

HIV infection is associated with diffusing capacity impairment in women

Abstract: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 Womens 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 infection, and that either DLCO impairment or airflow obstruction may cause respiratory symptoms in this population.

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+/CD28null 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+/CD28null 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.

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.

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.