Cigarette Smoking, and Blood Monocyte Count Correlate with Chronic Lung Injuries and Mortality

Abstract

Background: 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 (DL_CO). 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 DL_CO.

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: emphysema; lung cancer; monocyte; mortality; pulmonary fibrosis; smoking.

Figure 1

Flow chart demonstrating selection of study subjects.

Figure 2

Cigarette smoking increased monocytes in the peripheral blood. Different indices of smoking in the study cohort are provided according to quartiles of pack years (A). One-way ANOVA and Tukey’s honest significant difference (HSD) calculator was used to identify significant difference between the groups. Mean values of composite pack years increased across the groups with significant difference existed between all groups. Quit years decreased significantly for groups Q1-Q2, Q1-Q3, and Q1-Q4. Mean number of cigarettes smoked per day increased significantly between groups Q1-Q2, Q1-Q3, Q1-Q4, Q2-Q4, and Q3-Q4. Lastly, mean duration of smoking (years) increased significantly between groups Q1-Q2, Q1-Q3, Q1-Q4, Q2-Q3, and Q2-Q4. Mean absolute monocyte count (x10²/µL) increased significantly across the groups: NS- Q2, NS- Q3, NS-Q4, Q1-Q2, Q2-Q3, and Q1- Q4 (B). Similar significance was maintained across groups for percentage monocyte count: NS- Q1, NS-Q2, NS-Q3, NS-Q4, and Q1-Q4. The correlation between percentage monocytes and composite pack years was significant (C). *Statistically significant (p<0.05).

Figure 3

Increasing prevalence of radiologic and histologic findings with increasing intensity of smoking. The proportion of patients with radiologic evidence of any emphysema, centrilobular (CL) emphysema, paraseptal (PS) emphysema, ILD pattern, and mixed centrilobular-ground glass opacity (CL-GGO) and subpleural reticular (SPR)-interstitial lung abnormality (ILA) pattern increased across the groups, p<0.05 (A). Histological findings of emphysema, fibrosis, desquamative interstitial pneumonia (DIP) and anthracosis varied significantly, p<0.05 (B).

Figure 4

Radiographic findings in a 67-year-old-male active smoker patient with 100 CPY smoking history. Axial presurgical CT chest images showed advanced centrilobular (yellow arrowhead), paraseptal (yellow arrow) and bullous emphysema (asterisk) (A). (B) represented bibasilar subpleural reticular changes with traction bronchiolectasis (solid red arrow) and traction bronchiectasis (dotted yellow arrow).

Figure 5

Histopathologic findings in a 67-year-old-male active smoker patient with 100 CPY smoking history who underwent right lower lobectomy for suspicious nodule. Photomicrographs of lung specimen showed (a) invasive squamous cell carcinoma with keratin pearls (black arrows) [50X], (b) interstitial fibrosis (black arrow) and anthracotic pigment deposition (green arrow) [100X], (c) respiratory bronchiolitis with macrophages contain finely granular brown pigments (black arrow) [100X], and (d) interstitial fibrosis (black arrow), accumulation of macrophages in the airspace (green arrow) and associated architectural distortion [50X].

Figure 6

Pathology of resected lung nodule/mass in never smokers and quartiles of smoking pack years. While adenocarcinoma trended towards significance, rates of squamous cell cancer increased, and frequencies of atypical adenomatous hyperplasia, neuro-endocrine cancer and benign pathology decreased between the groups. *Statistically significant (p<0.05).

Figure 7

Box plots for the various PFT measures in never smokers (NS) and quartiles of CPY (A–C). All measures showed a relationship with smoking except for TLC (p<0.05). Percentage predicted FEV₁ and FVC as well as ratio FEV₁/FVC declined with smoking (A). For FEV₁, there were significant differences between NS and all quartiles, Q1-Q3, and Q1-Q4. For FVC, significant differences were demonstrated between NS-Q3 and NS-Q4 whereas for the FEV₁/FVC ratio, comparisons between NS and all quartiles were significant. Percentage predicted RV and TV/TLC increased across all groups (B). For predicted RV, significant differences were demonstrated for NS-Q3 and NS-Q4. For predicted RV/TLC, significance was evident in comparisons between NS-Q2, NS-Q3, and NS-Q4. Percentage predicted DL_CO decreased in quartiles of CPY (C). Significant differences were observed between NS-Q1, NS-Q2, NS-Q3, NS-Q4, and Q1-Q4. There was a linear negative correlation between either CPY or percentage monocyte count and PFT measures of ratio FEV₁/FVC (r=−0.28, p<0.0001, and r=−0.19, p=0.0001, respectively) and percentage predicted DL_CO (r=−0.31, p<0.0001, and r=−0.13, p=0.01, respectively) (D).

Figure 8

Relationship between indices of smoking, blood monocyte count and groups of radiologic abnormalities. For mean years since quitting smoking, there were significant differences between no disease and emphysema only, no disease and ILA+emphysema, and no disease and ILD+emphysema (A). For mean composite pack years of smoking, significant comparisons included no disease and emphysema only, no disease and ILA+emphysema, no disease and ILD+emphysema, ILA and emphysema, ILA and ILA+emphysema, and ILA and ILD+emphysema (A). There were significant increases in both absolute monocyte (x10²/µL) and percentage monocyte count associated with radiologic injuries, p<0.05 (B). Significant differences in absolute monocyte count were observed between no disease and emphysema, no disease and ILA+emphysema, no disease and ILD+emphysema, ILA and emphysema, ILA and ILA+emphysema, ILA and ILD+emphysema, and emphysema and ILD+emphysema. With percentage monocyte count significance was evident in comparisons between no disease and emphysema, no disease and ILA+emphysema, no disease and ILD+emphysema, ILA and ILA+emphysema, ILA and ILD+emphysema, emphysema and ILA+emphysema, emphysema and ILD+emphysema. *Statistically significant (p<0.05).

Figure 9

Significant predictors for histologic lung injuries. Based on a logistic regression model consisting of current smoking status, successive CPY, percentage monocyte count, and percentage predicted DL_CO<70, the odds ratio of significant predictors of histologic lung injuries were displayed. Lung cancer was associated with CPY≥10 or ≥20. Anthracosis showed association with all CPY smoked and percentage monocyte count. While organizing pneumonia (OP) was only associated with percentage monocyte count, fibrosis was associated with moderate smoking exposure and percentage monocyte count. Respiratory bronchiolitis showed correlations with current smoking, CPY≥50, and percentage predicted DL_CO<70. Lastly, all variables of the models predicted emphysema: current smoking, CPY (≥10 and onwards), percentage monocyte count, and percentage predicted DL_CO<70.