Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Background: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results: Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George's Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions: Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa

A Novel Spirometric Measure Identifies Mild COPD Unidentified by Standard Criteria

Rationale: In chronic obstructive pulmonary disease both smaller and larger airways are affected. Forced expiratory volume in one second (FEV1) mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow. Objective: To evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6), and small airway measures and gas trapping in quantitative chest computed tomography (CT), and clinical outcomes in the COPD Gene cohort. Methods: 7,853 current and ex-smokers were evaluated for airflow obstruction using recently defined linear iteratively-derived equations of Hansen et al.1 11 to determine lower limits of normal equations for pre-bronchodilator FEV1/FVC, FEV1/FEV6, FEV3/FEV6 and FEV3/FVC. General linear and ordinal regression models were applied to the relation between pre-bronchodilator spirometry and radiologic and clinical data. Main Results: Of the 10,311 participants included in the COPDGene Phase 1 study, participants with incomplete quantitative CT or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with ratio of FEV1 to forced vital capacity (FEV1/FVC) greater than lower limit of normal, 15.4% had abnormal FEV3/FEV6. Compared to participants with normal FEV3/FEV6 and FEV1/FVC, abnormal FEV3/FEV6 was associated with significantly greater gas trapping, St. George Respiratory Questionnaire score, mMRC dyspnea score, BODE index, and shorter six-minute walking distance (all P < 0.0001), but not CT22 evidence of emphysema. Conclusions: Current and ex-smokers with pre-bronchodilator FEV3/FEV6 1 < lower limit of normal as the sole abnormality identifies a distinct population with evidence of small airway disease in quantitative CT, impaired indices of physical function and quality of life otherwise deemed normal by current spirometric definition

TLR7 promotes smoke-induced experimental lung damage through the activity of mast cell tryptase

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target