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Rahul G Sangani,1 Vishal Deepak,1 Javeria Anwar,1 Zalak Patel,2 Andrew J Ghio3 1Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, West Virginia University, Morgantown, WV, USA; 2Department of Radiology, West Virginia University, Morgantown, WV, USA; 3US EPA, Chapel Hill, NC, USACorrespondence: Rahul G Sangani, Section of Pulmonary, Critical Care, and Sleep Medicine, West Virginia University School of Medicine, 1 Medical Center Dr, PO BOX 9166, Morgantown, WV, 26506, USA, Tel +1 304 293-4661 option &num;2, Fax +1 304-293-3724, Email rgsangani@hsc.wvu.eduBackground: Cigarette smoking (CS)-related monocytosis contributes to the development of chronic lung injuries via complex mechanisms. We aim to determine correlations between measures of CS and monocytes, their capacities to predict chronic lung diseases, and their associations with mortality.Methods: A single-center retrospective study of patients undergoing surgical resection for suspected lung nodules/masses was performed. CS was quantified as cigarettes smoked per day (CPD), duration of smoking, composite pack years (CPY), current smoking status, and smoking cessation years. A multivariate logistic regression analysis was performed.Results: Of 382 eligible patients, 88% were ever smokers. In this group, 45% were current smokers with mean CPD of 27.2± 40.0. CPY and duration of smoking showed positive linear correlations with percentage monocyte count. Physiologically, CPY was associated with progressive obstruction, hyperinflation, and reduced diffusion capacity (DLCO). Across the quartiles of smoking, there was an accumulation of radiologic and histologic abnormalities. Anthracosis and emphysema were associated with CPD, while lung cancer, respiratory bronchiolitis (RB), emphysema, and honeycombing were statistically related to duration of smoking. Analysis using consecutive CPY showed associations with lung cancer (≥ 10 and < 30), fibrosis (≥ 20 and < 40), RB (≥ 50), anthracosis and emphysema (≥ 10 and onwards). Percentage monocytes correlated with organizing pneumonia (OP), fibrosis, and emphysema. The greater CPY increased mortality across the groups. Significant predictors of mortality included percentage monocyte, anemia, GERD, and reduced DLCO.Conclusion: Indices of CS and greater monocyte numbers were associated with endpoints of chronic lung disease suggesting a participation in pathogenesis. Application of these easily available metrics may support a chronology of CS-induced chronic lung injuries. While a relative lesser amount of smoking can be associated with lung cancer and fibrosis, greater CPY increases the risk for emphysema. Monocytosis predicted lung fibrosis and mortality. Duration of smoking may serve as a better marker of monocytosis and associated chronic lung diseases.Keywords: smoking, monocyte, pulmonary fibrosis, lung cancer, mortality, emphysema

Andrew J Ghio,1 Elizabeth N Pavlisko,2 Victor L Roggli,2 Nevins W Todd,3 Rahul G Sangani4 1Human Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, 27514, USA; 2Department of Pathology, Duke University, Durham, NC, USA; 3Department of Medicine, University of Maryland, Baltimore, MD, 21201, USA; 4Department of Medicine, West Virginia University, Morgantown, WV, USACorrespondence: Andrew J GhioHuman Studies Facility, US Environmental Protection Agency, 104 Mason Farm Road, Chapel Hill, NC, USAEmail ghio.andy@epa.govAbstract: It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans’ cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).Keywords: iron, ferritins, pulmonary disease, chronic obstructive, pulmonary emphysema, chronic bronchitis, hypertension, pulmonary, pulmonary fibrosis

Rahul Sangani,1 Andrew Ghio,2 Stacey Culp,3 Zalak Patel,4 Sunil Sharma1 1Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, West Virginia University, Morgantown, WV, USA; 2Human Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, USA; 3Department of Biostatistics, West Virginia University, Morgantown, WV, USA; 4Department of Radiology, West Virginia University, Morgantown, WV, USACorrespondence: Andrew GhioHuman Studies Facility, US Environmental Protection Agency, Chapel Hill, NC, USATel +1 919 966-0670Fax +1 919 966-6271Email ghio.andy@epa.govBackground: Disease heterogeneity in idiopathic pulmonary fibrosis (IPF) often complicates the systematic study of disease, management of patients and clinical investigations.Objective: To describe combined pulmonary fibrosis emphysema (CPFE) phenotype in a rural Appalachian IPF cohort with the highest smoking rates in the United States.Methods: CPFE patients (n = 60) in a developed IPF cohort (n = 153) were characterized. Groups (CPFE vs IPF without emphysema) were categorized based on the predominant HRCT patterns of UIP (n = 109). Demographics, clinical variables, and treatment details were recorded. Kaplan–Meier survival and multivariate logistic regression analysis were performed.Results: The prevalence of CPFE in our IPF cohort was 45% (n = 49). The CPFE group was younger (73.9 vs 78.2), had a more extensive smoking history (93.9% vs 53.3%) with greater mean smoking pack years (49.09 vs 15.39) and had lower percentage predicted DLCO on presentation (38.35 vs 51.09) compared to IPF without emphysema group. Both groups shared equivalent higher burden of comorbidities, including pulmonary hypertension (PH) (46.9% vs 33.3%). One-fifth of patients were prescribed antifibrotics and only a subset (5%) of patients underwent lung transplantation. There was a non-significant trend towards reduced survival in CPFE (p = 0.076). Smoking status and DLCO predicted CPFE in our cohort. Body mass index (BMI), PH, and pirfenidone use were significant predictors of mortality.Conclusion: CPFE was highly prevalent in our rural IPF cohort. In contrast to previous studies, CPFE group was older and had higher female (approx. 30%) occurrence. A greater exposure to cigarette smoke and reduced DLCO at diagnosis predicted CPFE. Lower BMI and PH predicted higher mortality whereas use of pirfenidone improved survival in our cohort. This study highlights a complex interaction of cigarette smoking, advanced fibrosis of UIP, PH and potential utility of antifibrotic agents in CPFE phenotype. Substantial burden of comorbidities, older age, and the limited utilization of advanced therapeutics in the cohort emphasize the challenges faced by rural Appalachian patients.Keywords: combined pulmonary fibrosis emphysema; CPFE, cigarette smoking, pulmonary hypertension; PH, pirfenidone, body mass index; BMI, rural population

Rahul G Sangani,1 Andrew J Ghio,2 John E Parker11Department of Pulmonary and Critical Care Medicine, West Virginia University, Morgantown, WV, USA; 2Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USABledsoe et al presents an interesting study examining the disparities between radiologic and pathologic diagnoses of asbestosis in cases referred for consultation in pulmonary malignancy.1 The authors conclude that the clinical diagnosis of asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers. These findings highlight the confounding role of cigarette smoking in the diagnosis of asbestosis when it is based on non-pathologic criteria.View original paper by Bledsoe et al.

Rahul G Sangani, Andrew J GhioEnvironmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, USAAbstract: The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 µg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues.Keywords: particulate matter, smoking, oxidants, oxidative stress, air pollution