Pulmonary manifestations in smoking-related diseases : clinical studies with emphasis on chronic obstructive pulmonary disease and rheumatoid arthritis

Smoking is a risk factor for a number of diseases including chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). Cigarette smoke initiates an inflammatory response which leads to structural changes in the airways and in the lung parenchyma. The present work was undertaken in order to shed light on pulmonary manifestations of two common smoking-related diseases, COPD and RA. A retrospective review on bronchoalveolar lavage (BAL) constituents, encompassing 132 smokers with normal lung function and 44 ex-smokers, was performed. Two hundred and ninetyfive neversmokers served as reference group. The median (5-95 percentile) cell concentration in smokers were 382.1 (189.7-864.3) X 106 /L which was higher compared to the neversmokers. The majority of cells were alveolar macrophages (median 96.7%; range 73.2-99.6%, lymphocytes (2%; range 0.2-26%) and neutrophils (0.6%; range 0-6%). Cell concentration was positively correlated to cumulative smoking history. One hundred and five patients with newly-diagnosed RA, (70% ACPA+), underwent high resolution computer tomography (HRCT) examination and a sub group of 23 patients also performed bronchoscopy and BAL. A group of 43 non-diseased smokers and never smokers were examined as control. Parenchymal lung abnormality on HRCT was found in 63% of ACPA+ compared to 37% ACPARA patients, 30% control regardless of smoking status. The level of ACPA was higher in BAL fluid than sera in ACPA+ RA patients. Forty smokers with normal lung function, (mean 35 pack-years), 40 healthy never-smokers, and 40 COPD-patients of GOLD, I-II, (38 PY), performed HRCT. In addition BAL was performed. Percentage of pixels between -750-900 HU (%HDS) was calculated. Lung density was increased in smokers (44.0% ± 5.8%) compared to never smokers (38.3 ± 5.8%), p<0.001. Cell concentration in BAL was positively correlated to lung density in smokers (r=0.50, p<0.001). Females had denser lungs than males. Regional air trapping was assessed on expiatory HRCT on 40 never-smokers, 40 smokers and 40 COPD-patients. Emphysema, micronoduli, bronchial wall thickening was determined on inspiratory HRCT. Air trapping index (AI) was quantified as the ratio of mean lung attenuation at expiration and inspiration. Regional air trapping was present in 63% of smokers and 45% of never smokers. Smokers with visible regional air trapping had an AI of 0.81, while smokers without visible air trapping had an AI of 0.91. A negative correlation between AI and neutrophils in BAL was observed. Smokers with regional air trapping had better lung function and less emphysema compared to smokers without. We demonstrate inflammatory and structural changes in the lungs in smokers by means of HRCT and BAL. These changes are apparent even before clinical symptoms occur. The studies highlight the heterogeneity in smoking-related diseases which may be of importance in terms of disease progression and patient phenotypes. LIST OF SCIENTIFIC PAPERS I Karimi R, Tornling G, Grunewald J, Eklund A, Sköld CM. Cell recovery in bronchoalveolar lavage fluid in smokers is dependent on cumulative smoking history. PLoS One 2012; 7(3):e34232. Epub 2012 Mar 29. II Reynisdottir G, Karimi R, Joshua V, Olsen H, Hensvold AH, Harju A, Engström M, Grunewald J, Nyrén S, Eklund A, Klareskog L, Sköld CM, Catrina AI. Structural lung changes and local anti-citrulline immunity are early features of anti citrullinated-proteins antibodies positive rheumatoid arthritis. Arthritis and Rheumatology 2014; 66, 31–39. III Karimi R, Tornling G, Forsslund H, Mikko M, Wheelock ÅM, Nyrén S, Sköld CM. Lung density on high resolution computer tomography (HRCT) reflects degree of inflammation in smokers. Respir Research 2014, 15: 23. IV Karimi R, Tornling G, Forsslund H, Mikko M, Wheelock ÅM, Nyren S, Sköld CM. Determination of air trapping in smokers by high resolution computer tomography (HRCT). In manuscript. CONTENTS