Emphysema and soluble CD14 are associated with pulmonary nodules in HIV-infected patients: implications for lung cancer screening.
ABSTRACT: Lung cancer screening may benefit HIV-infected (HIV) smokers because of an elevated risk of lung cancer, but may have unique harms because of HIV-specific risk factors for false-positive screens. This study seeks to understand whether inflammatory biomarkers and markers of chronic lung disease are associated with noncalcified nodules at least 4?mm (NCN) in HIV compared with uninfected patients.This is a cohort study of Examinations of HIV-Associated Lung Emphysema (EXHALE), including 158 HIV and 133 HIV-uninfected participants.Participants underwent a laboratory assessment [including measurement of D-dimer, interleukin 6, and soluble CD14 (sCD14)], chest computed tomography (CT), and pulmonary function testing. We created multivariable logistic regression models to determine predictors of NCN in the participants stratified by HIV status, with attention to semiqualitative scoring of radiographic emphysema, markers of pulmonary function, and inflammatory biomarkers.Of the 291 participants, 69 had NCN on chest CT. As previously reported, there was no difference in prevalence of these nodules by HIV status. Emphysema and elevated sCD14 demonstrated an association with NCN in HIV participants independent of smoking status, CD4 cell count, HIV viral load, and pulmonary function.Emphysema and sCD14, a marker of immune activation, was associated with a higher prevalence of NCN on chest CT in HIV participants. Patients with chronic immune activation and emphysema may be at higher risk for both false-positive findings and incident lung cancer, thus screening in this group requires further study to understand the balance of benefits and harms.
Project description:To investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities.We assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of the participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated.Of the 2633 participants, 86 (3%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71% male, mean 36 pack-years, P<0.001) and had significantly decreased FEV1/FVC% (P=0.002), and diffusion capacity of carbon monoxide (DLCO) (P=0.002). There was a significant association between pure paraseptal emphysema and interstitial lung abnormalities (P<0.001).The prevalence of pure paraseptal emphysema was 3% in the FHS population, predominantly affects the upper lung zone, and contributes to decreased pulmonary function. Cigarette smoking, aging, and male gender were the factors associated with the presence of paraseptal emphysema. Significant association between paraseptal emphysema and interstitial lung abnormalities was observed.
Project description:The aim of this study was to investigate the association between image characteristics on preoperative chest CT and severe pleural adhesion during surgery in lung cancer patients. We included consecutive 124 patients who underwent lung cancer surgeries. Preoperative chest CT was retrospectively reviewed to assess pleural thickening or calcification, pulmonary calcified nodules, active pulmonary inflammation, extent of emphysema, interstitial pneumonitis, and bronchiectasis in the operated thorax. The extent of pleural thickening or calcification was visually estimated and categorized into two groups: localized and diffuse. We measured total size of pulmonary calcified nodules. The extent of emphysema, interstitial pneumonitis, and bronchiectasis was also evaluated with a visual scoring system. The occurrence of severe pleural adhesion during lung cancer surgery was retrospectively investigated from the electrical medical records. We performed logistic regression analysis to determine the association of image characteristic on chest CT with severe pleural adhesion. Localized pleural thickening was found in 8 patients (6.5%), localized pleural calcification in 8 (6.5%), pulmonary calcified nodules in 28 (22.6%), and active pulmonary inflammation in 22 (17.7%). There was no patient with diffuse pleural thickening or calcification in this study. Trivial, mild, and moderate emphysema was found in 31 (25.0%), 21 (16.9%), and 12 (9.7%) patients, respectively. Severe pleural adhesion was found in 31 (25.0%) patients. The association of localized pleural thickening or calcification on CT with severe pleural adhesion was not found (P = 0.405 and 0.107, respectively). Size of pulmonary calcified nodules and extent of emphysema were significant variables in a univariate analysis (P = 0.045 and 0.005, respectively). In a multivariate analysis, moderate emphysema was significantly associated with severe pleural adhesion (odds ratio of 11.202, P = 0.001). In conclusion, severe pleural adhesion might be found during lung cancer surgery, provided that preoperative chest CT shows substantial pulmonary calcified nodules or emphysema.
Project description:The prevalence of emphysema is higher among HIV-infected (HIV+) individuals compared to HIV-uninfected persons. While greater tobacco use contributes, HIV-related effects on immunity likely confer additional risk. Low peripheral blood CD4+ to CD8+ T-lymphocyte (CD4/CD8) ratio may reflect chronic inflammation in HIV and may be a marker of chronic lung disease in this population. Therefore, we sought to determine whether the CD4/CD8 ratio was associated with chronic obstructive pulmonary disease (COPD), particularly the emphysema subtype, in a cohort of HIV+ subjects.We performed a cross-sectional analysis of 190 HIV+ subjects enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE) study. Subjects underwent baseline laboratory assessments, pulmonary function testing and chest computed tomography (CT) analyzed for emphysema severity and distribution. We determined the association between CD4/CD8 ratio and emphysema, and the association between CD4/CD8 ratio and pulmonary function markers of COPD.Mild or greater emphysema (>10% lung involvement) was present in 31% of subjects. Low CD4/CD8 ratio was associated with >10% emphysema in multivariable models, adjusting for risk factors including smoking, current and nadir CD4 count and HIV RNA level. Those with CD4/CD8 ratio <0.4 had 6.3 (1.1-39) times the odds of >10% emphysema compared to those with a ratio >1.0 in fully adjusted models. A low CD4/CD8 ratio was also associated with reduced diffusion capacity (DLCO).A low CD4/CD8 ratio was associated with emphysema and low DLCO in HIV+ subjects, independent of other risk factors and clinical markers of HIV. The CD4/CD8 ratio may be a useful, clinically available, marker for risk of emphysema in HIV+ subjects in the antiretroviral therapy (ART) era.
Project description:The aim of this study was to evaluate the risk of pneumothorax and need for chest tube insertion in CT-guided lung biopsies and identify predictors focusing on pulmonary emphysema determined with quantitative computed tomography. To that end, we retrospectively analysed the incidence of pneumothorax and chest tube insertion in 371 CT-guided lung biopsies with respect to the quantitative emphysema score determined with the density mask technique. Other possible impact factors considered were lesion diameter, length of biopsy pathway within the lung parenchyma, lung lobe, needle size, puncture technique, patient positioning and interventionalist's level of experience. Quantitative emphysema scores of the lung were significantly higher in patients who developed instant pneumothorax (27%, p?<?0.0001), overall pneumothorax (38%, p?=?0.001) and had chest tube insertion (9%, p?=?0.006) compared to those who did not when analysed with the Mann-Whitney U-test. In logistic regression analysis with inclusion of the other possible impact factors, the quantitative emphysema score remained a statistically significant predictor for all three output parameters. This was confirmed with least absolute shrinkage and selection operator (Lasso) regression analysis. In conclusion, quantitatively determined pulmonary emphysema is a positive predictor of the pneumothorax rate in CT-guided lung biopsy and likelihood of chest tube insertion.
Project description:The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (IL-6), altered coagulation (D-dimer), and immune activation (soluble CD14) are associated with emphysema.We performed a cross-sectional analysis of 114 participants with HIV infection and 89 participants without HIV infection in the Examinations of HIV-Associated Lung Emphysema (EXHALE) study. Participants underwent chest CT imaging with blinded semiquantitative interpretation of emphysema severity, distribution, and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as > 10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among participants with HIV infection.Participants with HIV infection had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for > 10% emphysema in analyses adjusted for cigarette smoking pack-years (OR, 2.24; 95% CI, 1.12-4.48). In multivariable analyses restricted to participants with HIV infection, nadir CD4 < 200 cells/?L (OR, 2.98; 95% CI, 1.14-7.81), and high soluble CD14 level (upper 25th percentile) (OR, 2.55; 95% CI, 1.04-6.22) were associated with increased risk of > 10% emphysema. IL-6 and D-dimer were not associated with emphysema in HIV.HIV is an independent risk factor for radiographic emphysema. Emphysema severity was significantly greater among participants with HIV infection. Among those with HIV, nadir CD4 < 200 cells/?L and elevated soluble CD14 level were associated with emphysema, highlighting potential mechanisms linking HIV with emphysema.
Project description:INTRODUCTION:The disease spectrum for HIV-infected individuals has shifted toward comorbid non-AIDS conditions including chronic lung disease, but quantitative image analysis of lung disease has not been performed. OBJECTIVES:To quantify the prevalence of structural changes of the lung indicating emphysema or fibrosis on radiographic examination. METHODS:A cross-sectional analysis of 510 HIV-infected participants in the multicenter Lung-HIV study was performed. Data collected included demographics, biological markers of HIV, pulmonary function testing, and chest computed tomographic examinations. Emphysema and fibrosis-like changes were quantified on computed tomographic images based on threshold approaches. RESULTS:In our cohort, 69% was on antiretroviral therapy, 13% had a current CD4 cell count less than 200 cells per microliter, 39% had an HIV viral load greater than 500 copies per milliliter, and 25% had at least a trace level of emphysema (defined as >2.5% of voxels <-950HU). Trace emphysema was significantly correlated with age, smoking, and pulmonary function. Neither current CD4 cell count nor HIV viral load was significantly correlated with emphysema. Fibrosis-like changes were detected in 29% of the participants and were significantly correlated with HIV viral load (Pearson correlation coefficient = 0.210; P < 0.05); current CD4 cell count was not associated with fibrosis. In multivariable analyses including age, race, and smoking status, HIV viral load remained significantly correlated with fibrosis-like changes (coefficient = 0.107; P = 0.03). CONCLUSIONS:A higher HIV viral load was significantly associated with fibrosis-like changes, possibly indicating early interstitial lung disease, but emphysematous changes were not related to current CD4 cell count or HIV viral load.
Project description:BACKGROUND:Epidemiological evidence suggests that HIV-infected individuals are at increased risk of lung cancer, but no data exist because large computed tomography (CT) screening trials routinely exclude HIV-infected participants. METHODS:From 2006 to 2013, we conducted the world's first lung cancer screening trial of 224 HIV-infected current/former smokers to assess the CT detection rates of lung cancer. We also used 130 HIV-infected patients with known lung cancer to determine radiographic markers of lung cancer risk using multivariate analysis. RESULTS:Median age was 48 years with 34 pack-years smoked. During 678 person-years, one lung cancer was found on incident screening. Besides this lung cancer case, 18 deaths (8%) occurred, but none were cancer related. There were no interim diagnoses of lung or extrapulmonary cancers. None of the pulmonary nodules detected in 48 participants at baseline were diagnosed as cancer by study end. The heterogeneity of emphysema across the entire lung as measured by CT densitometry was significantly higher in HIV-infected subjects with lung cancer compared with the heterogeneity of emphysema in those without HIV (p ? 0.01). On multivariate regression analysis, increased age, higher smoking pack-years, low CD4 nadir, and increased heterogeneity of emphysema on quantitative CT imaging were all significantly associated with lung cancer. CONCLUSIONS:Despite a high rate of active smoking among HIV-infected participants, only one lung cancer was detected in 678 patient-years. This was probably because of the young age of participants suggesting that CT screening of high-risk populations should strongly consider advanced age as a critical inclusion criterion. Future screening trials in urban American must also incorporate robust measures to ensure HIV patient compliance, adherence, and smoking cessation.
Project description:To investigate the prevalence and natural course of pulmonary cysts in a population-based cohort and to describe the CT image characteristics in association with participant demographics and pulmonary functions.Chest CT scans of 2633 participants (mean age 59.2 years; 50% female) of the Framingham Heart Study (FHS) were visually evaluated for the presence of pulmonary cysts and their image characteristics. These findings were correlated with participant demographics and results of pulmonary function tests as well as the presence of emphysema independently detected on CT. The interval change was investigated by comparison with previous CT scans (median interval 6.1 years).Pulmonary cysts were seen in 7.6% (95% CI 6.6% to 8.7%; 200/2633). They were not observed in participants younger than 40 years old, and the prevalence increased with age. Multiple cysts (at least five) were seen in 0.9% of all participants. Participants with pulmonary cysts showed significantly lower body mass index (BMI) (p<0.001). Pulmonary cysts were most likely to appear solitary in the peripheral area of the lower lobes and remain unchanged or slightly increase in size over time. Pulmonary cysts showed no significant influence on pulmonary functions (p=0.07-0.6) except for diffusing capacity of the lung for carbon monoxide (DLCO) (p=0.03) and no association with cigarette smoking (p=0.1-0.9) or emphysema (p=0.7).Pulmonary cysts identified on chest CT may be a part of the aging changes of the lungs, occurring in asymptomatic individuals older than 40 years, and are associated with decreased BMI and DLCO. Multiple pulmonary cysts may need to be evaluated for the possibility of cystic lung diseases.
Project description: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).
Project description:Quantitative computed tomography (CT) measures of emphysema have been shown to be associated with increased mortality in humans, but genetic variants affecting the quantitative parameters of chest CT that measure degree of emphysema have not yet been examined. In this study, using available chest CT data from a total of 344 emphysema patients, we assessed the correlations between five chronic obstructive pulmonary disease (COPD) susceptibility variants in the cholinergic receptor nicotinic (CHRN) genes and the degree of emphysema and chest CT manifestations. We verified that most of the parameters were significantly correlated with the degree of emphysema. Compared to rs76071148AA and TT genotype carriers, the rs76071148AT genotype carriers exhibited a decreased probability of having severe emphysema (odds ratio [OR] =0.63, 95% confidence interval [CI] =0.40-0.99), whereas the variant rs8040868C allele was negatively correlated with the emphysema index (P=0.002). Interestingly, further stratification analysis grouped by spirometry-diagnosed COPD status revealed that the variant rs8040868C (CT + CC) genotypes exerted a protective effect against severe emphysema with borderline significance (OR =0.41, 95% CI =0.16-1.05) and affected the mean lung density, emphysema index, ratio of airway wall thickness to airway dimensions (AWT/AD), and AWT grade in spirometry-diagnosed non-COPD subjects. The rs76071148 variant was also significantly associated with AWT/AD and AWT grade in those individuals. In summary, we determined that rs8040868 and rs76071148 are promising indicators of the degree of emphysema and chest CT manifestations, especially in spirometry-diagnosed non-COPD subjects.