Andrew Yen

Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

BACKGROUND It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis in vivo. We evaluated the impact of host immunity by comparing M. tuberculosis and human gene transcription in sputum between human immunodeficiency virus (HIV)-infected and uninfected patients with tuberculosis. METHODS We collected sputum specimens before treatment from Gambians and Ugandans with pulmonary tuberculosis, revealed by positive results of acid-fast bacillus smears. We quantified expression of 2179 M. tuberculosis genes and 234 human immune genes via quantitative reverse transcription-polymerase chain reaction. We summarized genes from key functional categories with significantly increased or decreased expression. RESULTS A total of 24 of 65 patients with tuberculosis were HIV infected. M. tuberculosis DosR regulon genes were less highly expressed among HIV-infected patients with tuberculosis than among HIV-uninfected patients with tuberculosis (Gambia, P < .0001; Uganda, P = .037). In profiling of human genes from the same sputa, HIV-infected patients had 3.4-fold lower expression of IFNG (P = .005), 4.9-fold higher expression of ARG1 (P = .0006), and 3.4-fold higher expression of IL10 (P = .0002) than in HIV-uninfected patients with tuberculosis. CONCLUSIONS M. tuberculosis in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by NO, carbon monoxide, and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages, with consequent decreased NO expression and/or by poor granuloma formation with consequent decreased hypoxic stress.

Bronchoarterial ratio in never-smokers adults: Implications for bronchial dilation definition.

Bronchiectasis manifests as recurrent respiratory infections and reduced lung function. Airway dilation, which is measured as the ratio of the diameters of the bronchial lumen (B) and adjacent pulmonary artery (A), is a defining radiological feature of bronchiectasis. A challenge to equating the bronchoarterial (BA) ratio to disease severity is that the diameters of airway and vessel in health are not established. We sought to explore the variability of BA ratio in never‐smokers without pulmonary disease and its associations with lung function.

Disease Severity Dependence of the Longitudinal Association Between CT Lung Density and Lung Function in Smokers

BACKGROUND In smokers, the lung parenchyma is characterized by inflammation and emphysema, processes that can result in local gain and loss of lung tissue. CT measures of lung density might reflect lung tissue changes; however, longitudinal data regarding the effects of CT lung tissue on FEV1 in smokers with and without COPD are scarce. METHODS The 15th percentile of CT lung density was obtained from the scans of 3,390 smokers who completed baseline and 5‐year follow‐up of the Genetic Epidemiology of COPD (COPDGene) study visits. The longitudinal relationship between total lung capacity‐adjusted lung density (TLC‐PD15) and FEV1 was assessed by using multivariable mixed models. Separate models were performed in smokers at risk, smokers with preserved ratio and impaired spirometry (PRISm), and smokers with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system. RESULTS The direction of the relationship between lung density and lung function was GOLD stage dependent. In smokers with PRISm, a 1‐g/L decrease in TLC‐PD15 was associated with an increase of 2.8 mL FEV1 (P = .02). In contrast, among smokers with GOLD III to IV COPD, a 1‐g/L decrease in TLC‐PD15 was associated with a decrease of 4.1 mL FEV1 (P = .002). CONCLUSIONS A decline in TLC‐PD15 was associated with an increase or decrease in FEV1 depending on disease severity. The associations are GOLD stage specific, and their presence might influence the interpretation of future studies that use CT lung density as an intermediate study end point for a decline in lung function. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Recurrent Pneumonia, Persistent Cough, and Dyspnea in a 41-Year-Old Man

A 41-year-old man with a history of bronchiectasis, recurrent pneumonia, persistent dys pnea, and cough presented to the hospital for a second opinion. He had an unknown chest radiograph abnormality as a young adult and multiple episodes of pneumonia, including four episodes of pneumonia within the previous 3 years for which he was hospitalized twice. The patient had been followed by a pulmonologist for the previous 3 years. Since his most recent hospitalization for pneumonia, the patient had persistent cough with production of abundant clear secretions. The patient denied fevers, chills, fatigue, hemoptysis, chest pain, night sweats, and weight loss. He denied ever smoking. The patient had no exposure to farming, birds, hot tubs, or chemicals. Family history was signifi cant for paternal death from colon cancer, but no lung disease. Physical examination was signifi cant for left lower posterior rales and right midposterior rhonchi. He had no evidence of heart failure. Genetic screening was negative for cystic fi brosis. Repeated respiratory cultures were negative. A chest CT scan from an outside institution 2 years previously showed nodular and lobular ground-glass lung opacities, variably involving all lobes, with confl uence and consolidation in the basal left upper lobe, lingula, and posterobasal segment of the left lower lobe. Air bronchograms were present in the lingula. There was no evidence of bronchiectasis, despite the reported history. An air cyst was noted in the left upper lobe ( Figs 1A, 1B ). Chest radiography at the time of presentation to our institute showed patchy opacities in both midlung zones and at the left lung base ( Figs 1C, 1D ). A repeat chest CT scan demonstrated the increased extent of previously seen ground glass and consolidation in all lobes, although some lingular consolidation had improved ( Figs 1E, 1F ). Mediastinal lymph nodes were generally increased in size, measuring up to 1.3 cm. Diagnostic bronchoscopy with BAL and transbronchial biopsies were nondiagnostic. Bacterial, Recurrent Pneumonia, Persistent Cough, and Dyspnea in a 41-Year-Old Man

Multifocal Endobronchial Fibromas Presenting as Unilobar Emphysema

Tracheobronchial fibromas are very rare, locally-invasive tumors of the airways. Fewer than 30 cases have been reported within the English-speaking literature. Historically, these neoplasms have been diagnosed as isolated endobronchial masses, with affected patients presenting with wheezing, cough, stridor, hemoptysis, dyspnea, or pneumonia. We report the case of 39-year-old man with multiple, synchronous endobronchial fibromas causing unilobar emphysema. A computed tomographic scan and bronchoscopy with biopsy were performed preoperatively to diagnose these lesions in the orifices of the anterior segment and the lingula within the left upper lobe. The patient underwent successful video-assisted left upper lobectomy, without recurrence at 3 years. This is the first report of a synchronous presentation of multiple pulmonary endobronchial fibromas within the same patient and the first report of endobronchial fibroma presenting as unilobar air trapping. Recognition of the unusual presentation of this uncommon pathology can lead to timely intervention.

Visual Estimate of Coronary Artery Calcium Predicts Cardiovascular Disease in COPD

BACKGROUND: COPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD. METHODS: CAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow‐up were recorded. Accuracy of the CAC scores was measured by using receiver‐operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events. RESULTS: CAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r = 0.84; P < .001). Over 5 years of follow‐up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c‐indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack‐years, FEV1, percent emphysema, and CT scanner type, a Weston score ≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 [95% CI, 1.32 to 3.53]; P = .002), but a Agatston score ≥ 400 was not (hazard ratio, 1.75 [95% CI, 0.99‐3.09]; P = .053). CONCLUSIONS: A simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.