Mortality In Never-smokers Research Articles

Association between environmental cadmium exposure and increased mortality in the U.S. National Health and Nutrition Examination Survey (1999-2018).

Cadmium (Cd) is toxic to human health and increases overall mortality. In this study, we investigated the association between Cd exposure and all-cause, cardiovascular (CVD), and cancer mortality in the general population and the mediating effect of smoking on these association. We used data from U.S. National Health and Nutrition Examination Survey for 1999-2018. To evaluate the hazard ratio (HR) for mortality, a multiple Cox regression analysis was conducted by adjusting for age, sex, race/ethnicity, body mass index, smoking, alcohol, hypertension, diabetes, hyperlipidemia, and history of CVD and cancer. A causal mediation analysis was performed to estimate the effects of smoking. Among the 31,637 subjects, 5452 (12.3%) died. Blood Cd concentrations were significantly associated with all-cause (HR 1.473, 95% confidence interval [CI] 1.403-1.546, p < 0.001), CVD (HR 1.445, 95% CI 1.344-1.554, p < 0.001), and cancer (HR 1.496, 95% CI 1.406-1.592, p < 0.001) mortality. Urinary Cd concentrations were also significantly associated with them. Using feature selection via machine learning, the importance of Cd in all-cause and cancer mortality was second only to age. The association between Cd concentrations and all-cause mortality was significant in both ever-smokers and never-smokers. The mediating effect of smoking was estimated at 32%, whereas a large proportion (68%) remained a direct effect of Cd. In a subgroup analysis of subjects with cancer history, blood Cd concentrations were significantly associated with cancer-related deaths in those with a history of breast, gastrointestinal, and skin cancers. High Cd exposure is an important risk factor for all-cause, CVD, and cancer mortality among the general population. Cd exposure increased the risk of death even in never-smokers, and its effects unrelated to smoking were substantial, suggesting the importance of regulating other sources of Cd exposure such as food and water. Using national large-scale data, we found that low-level environmental exposure to cadmium significantly increased the risk of all-cause, cardiovascular, and cancer mortality in the general population even after adjusting for several risk factors. Although smoking is a major source of cadmium exposure, cadmium was nevertheless significantly associated with all-cause mortality in never-smokers, and the mediating effect of smoking on this association was only 32%. Hence, other sources of cadmium exposure such as food and water may be important.

Low-Dose Computed Tomography (LDCT) Lung Cancer Screening in Asian Female Never-Smokers Is as Efficacious in Detecting Lung Cancer as in Asian Male Ever-Smokers: A Systematic Review and Meta-Analysis

IntroductionLung cancer in never-smokers is the major cancer cause of death globally. We compared the efficacy of low-dose computed tomography (LDCT) lung cancer screening among never-smokers versus ever-smokers using systematic review and meta-analysis. MethodsLDCT lung cancer screening studies that simultaneously included both ever-smoker and never-smoker participants published by April 30, 2021, were searched through PubMed and Scopus. Primary outcome measure was relative risk (RR) of lung cancer diagnosed among never-smokers versus ever-smokers. ResultsA total of 14 studies (13 from Asia) were included (141,396 ever-smokers, 109,251 never-smokers, 1961 lung cancer cases diagnosed). RR of lung cancer diagnosed between ever-smokers versus never-smokers overall was 1.21 (95% confidence interval [CI]: 0.89–1.65), 1.37 (95% CI: 1.08–1.75) among males, and 0.88 (95% CI: 0.59–1.31) among females. RR was 1.78 (95% CI: 1.41–2.24) and 1.22 (95% CI: 0.89–1.68) for Asian female never-smokers versus male never-smokers and versus male ever-smokers, respectively, and 0.99 (95% CI: 0.65–1.50) versus high-risk ever-smokers (≥30 pack-years). Proportional meta-analysis revealed significantly more lung cancers diagnosed at first scan (95.4% [95% CI: 84.9–100.0] versus 70.9% [95% CI: 54.6–84.9], p = 0.010) and at stage 1 (88.5% [95% CI: 79.3–95.4] versus 79.7% [95% CI: 71.1–87.4], p = 0.071) among never-smokers versus ever-smokers, respectively. RR of lung cancer death and 5-year all-cause mortality in never-smokers versus ever-smokers was 0.27 (95% CI: 0.1–0.55, p < 0.001) and 0.13 (95% CI: 0.05–0.33, p < 0.001), respectively. ConclusionsThe RR of lung cancer detected by LDCT screening among female never-smokers and male ever-smokers in Asia was statistically similar. Overall and lung cancer specific mortality from the lung cancer diagnosed from LDCT screening was significantly reduced among never-smokers compared to ever-smokers.

Immune Status and Mortality in Smokers, Ex-smokers, and Never-Smokers: The Ludwigshafen Risk and Cardiovascular Health Study.

Elevated leukocyte counts are associated with cardiovascular disease. Smoking induces inflammation and alters levels of leukocyte subtypes. Our aim was to investigate the effect of smoking on circulating immune cells and their association with mortality. Lymphocyte subtypes were identified by flow cytometry of fluorescent-labeled cells. We analyzed the association of leukocytes with mortality using Cox regression and assessed their effect on risk prediction based on principle components (PCs) using area under the receiver operating characteristic curve and net-reclassification in 2173 participants from the Ludwigshafen Risk and Cardiovascular Health Study, a prospective case-control study in patients who underwent coronary angiography. The numbers of T cells, monocytes, and neutrophils were higher and natural killer cells were lower in smokers compared with never-smokers. In never-smokers, lymphocyte counts were inversely associated with mortality while a positive association was observed for neutrophils. The neutrophil-to-lymphocyte ratio (NLR) had the strongest association in never-smokers with a hazard ratio (95% confidence interval) of 1.43 (1.26-1.61). No associations were found in smokers. Adding the first five PCs or the NLR to a risk prediction model based on conventional risk factors did not improve risk prediction in smokers, but significantly increased the area under the curve from 0.777 to 0.801 and 0.791, respectively, in never-smokers. Lymphocyte counts were inversely associated with mortality in never-smokers but not in active smokers. Markers of innate immunity, namely total neutrophils and CD11b+/CD18+ and CD31+/CD40- granulocytes, were directly associated with mortality. Adding markers of immune function like PCs or the NLR to basic risk models improved risk prediction in never-smokers only. Total leukocyte counts were higher in active smokers as compared to never-smokers due to elevated counts of neutrophils and monocytes but declined in ex-smokers with increasing time since quitting. In the never-smokers but not in smokers, lymphocyte counts were inversely associated with mortality while there was a direct association with neutrophils, even after adjustment for conventional cardiovascular risk factors. Adding markers of immune function to basic risk models improved risk prediction in never-smokers only. Our data indicate that smoking status has an important impact on the ability of leukocyte counts to predict long-term cardiovascular outcomes.

Investigation of Leukocyte Telomere Length and Genetic Variants in Chromosome 5p15.33 as Prognostic Markers in Lung Cancer.

Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Editor’s Note on Methodological Criticism and an Updated AnalysisObjectiveTo investigate the shape of the causal relation between body mass index (BMI) and mortality.DesignLinear and non-linear mendelian randomisation analyses.SettingNord-Trøndelag Health (HUNT)...

Prevalence and Effects of Emphysema in Never-Smokers with Rheumatoid Arthritis Interstitial Lung Disease

AimsAutoimmune conditions such as rheumatoid arthritis-related interstitial lung disease (RA-ILD) have been linked to the existence of emphysema in never-smokers. We aimed to quantify emphysema prevalence in RA-ILD never-smokers and investigate whether combined pulmonary fibrosis and emphysema (CPFE) results in a worsened prognosis independent of baseline disease extent. MethodsRA-ILD patients presenting to the Royal Brompton Hospital (n=90) and Asan Medical Center (n=155) had CT's evaluated for a definite usual interstitial pneumonia (UIP) pattern, and visual extents of emphysema and ILD. ResultsEmphysema, identified in 31/116 (27%) RA-ILD never-smokers, was associated with obstructive functional indices and conformed to a CPFE phenotype: disproportionate reduction in gas transfer (DLco), relative preservation of lung volumes. Using multivariate logistic regression, adjusted for patient age, gender and ILD extent, emphysema presence independently associated with a CT-UIP pattern in never-smokers (0.009) and smokers (0.02).On multivariate Cox analysis, following adjustment for patient age, gender, DLco, and a CT-UIP pattern, emphysema presence (representing the CPFE phenotype) independently associated with mortality in never-smokers (p=0.04) and smokers (p<0.05). Conclusion27% of RA-ILD never-smokers demonstrate emphysema on CT. Emphysema presence in never-smokers independently associates with a definite CT-UIP pattern and a worsened outcome following adjustment for baseline disease severity.

Beverage Habits and Mortality in Chinese Adults ,

There is limited research examining beverage habits, one of the most habitual dietary behaviors, with mortality risk. This study examined the association between coffee, black and green tea, sugar-sweetened beverages (soft drinks and juice), and alcohol and all-cause and cause-specific mortality. A prospective data analysis was conducted with the use of the Singapore Chinese Health Study, including 52,584 Chinese men and women (aged 45-74 y) free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. Beverages were examined with all-cause and cause-specific (cancer, CVD, and respiratory disease) mortality risk with the use of Cox proportional hazards regression. The associations between coffee, black tea, and alcohol intake and all-cause mortality were modified by smoking status. Among never-smokers there was an inverse dose-response association between higher amounts of coffee and black tea intake and all-cause, respiratory-related, and CVD mortality (black tea only). The fully adjusted HRs for all-cause mortality for coffee for <1/d, 1/d, and ≥2/d relative to no coffee intake were 0.89, 0.86, and 0.83, respectively (P-trend = 0.0003). For the same black tea categories the HRs were 0.95, 0.90, and 0.72, respectively (P-trend = 0.0005). Among ever-smokers there was no association between coffee or black tea and the outcomes. Relative to no alcohol, light to moderate intake was inversely associated with all-cause mortality (HR: 0.87; 95% CI: 0.79, 0.96) in never-smokers with a similar magnitude of association in ever-smokers. There was no association between heavy alcohol intake and all-cause mortality in never-smokers and a strong positive association in ever-smokers (HR: 1.56; 95% CI: 1.40, 1.74). Green tea and sugar-sweetened beverages were not associated with all-cause or cause-specific mortality. Higher coffee and black tea intake was inversely associated with mortality in never-smokers, light to moderate alcohol intake was inversely associated with mortality regardless of smoking status, heavy alcohol intake was positively associated with mortality in ever-smokers, and there was no association between sugar-sweetened beverages and green tea and mortality.

Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis.

Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival.

Interim Analysis Results of a Phase 2 Trial of Low-Dose Radiation Therapy for Palliation of Diffuse Large B-Cell Lymphoma

Results: A total of 1484 patients were identified (372 current, 1014 former, and 98 never smokers). The 5-year incidence of SPLC was 13%, 7%, and 0% for current, former, and never smokers (p Z 0.03 comparing current and never). In the follow-up period, only one never smoker developed a SPLC at 7 years. On MVA, when restricting the analysis to ever smokers with pack-years (PY) as a continuous variable, the risk of SPLC was significantly increased with tobacco exposure with a HR of 1.08 (95% CI Z 1.02-1.16, p Z 0.031), corresponding to an 8% increased risk per 10 PY. For the entire cohort, there were no differences in LC or DM based on smoking status. When grouped as never smokers (nZ 98), former smokers quit > 5 yrs prior to surgery (n Z 493), former smokers quit 5 yrs prior to surgery (nZ 521), and current smokers (nZ 372), OS was significantly worse for current smokers when compared to all other cohorts (p 5 years), and 0.783 (95% CI Z 0.66-0.929, p Z 0.005) for former smokers ( 5 years). There was a trend toward higher post-operative mortality in never smokers as compared to ever smokers (0% vs 3.3%, p Z 0.069). Conclusions: In this, the largest series of its kind, it was demonstrated that increasing tobacco exposure is associated with a higher risk of SPLC. Never smokers have a low incidence of SPLC. This has implications for post-treatment surveillance in this population as well as for patients undergoing stereotactic body radiation therapy. Finally, current smokers are at increased risk of mortality, while former and never smokers have comparable outcomes. Author Disclosure: J.M. Boyle: None. J.P. Chino: None. D. Tandberg: None. K.A. Higgins: None. C.R. Kelsey: None.

Commentary: Does mortality from smoking have implications for future Mendelian randomization studies?

Commentary: Does mortality from smoking have implications for future Mendelian randomization studies?

Association of Alcohol Intake With Pancreatic Cancer Mortality in Never Smokers

An international panel of experts characterized the evidence linking alcoholic beverage consumption to pancreatic cancer as limited. Primary concerns include inconsistent results from underpowered studies, residual confounding by smoking, and the question of whether the association varies by type of alcoholic beverage. The association of alcohol intake with pancreatic cancer mortality was examined using data from the Cancer Prevention Study II, a prospective study of US adults 30 years and older. Alcohol consumption was self-reported on a 4-page questionnaire in 1982. Based on follow-up through December 31, 2006, there were 6847 pancreatic cancer deaths among 1,030,467 participants. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards regression analysis controlling for age, sex, race/ethnicity, education, marital status, body mass index, family history of pancreatic cancer, and personal history of gallstones, diabetes mellitus, or smoking. The RRs (95% CIs) of pancreatic cancer mortality associated with current intake of less than 1, 1, 2, 3, and 4 or more drinks per day compared with nondrinkers were 1.06 (0.99-1.13), 0.99 (0.90-1.08), 1.06 (0.97-1.17), 1.25 (1.11-1.42), and 1.17 (1.06-1.29), respectively (P< .001 for trend). Consumption of 3 or more drinks per day was associated with pancreatic cancer mortality in never smokers (RR, 1.36; 95% CI, 1.13-1.62) and in ever smokers (RR, 1.16; 95% CI, 1.06-1.27). This association was observed for consumption of liquor (RR, 1.32; 95% CI, 1.10-1.57) but not beer (RR, 1.08; 95% CI, 0.90-1.30) or wine (RR, 1.09; 95% CI, 0.79-1.49). These results strengthen the evidence that alcohol consumption, specifically liquor consumption of 3 or more drinks per day, increases pancreatic cancer mortality independent of smoking.

Cigarette smoking, weight gain, and coronary mortality: results from the Chicago Western Electric Study.

Prospective studies of overweight and coronary heart disease (CHD) have presented inconsistent findings. Previous inconsistencies may be explained by the modifying effect of cigarette smoking on the association between weight gain and coronary mortality. We prospectively studied 1531 men 40 to 59 years of age who were employed at the Hawthorne Works of the Western Electric Company in Chicago, Ill. Information collected at the initial examination in 1958 included recalled weight at age 20, present weight, height, smoking status, and other CHD risk factors. Vital status was known for all men on the 25th anniversary: 257 CHD deaths occurred over 31,644 person-years of experience. Cox regression analysis was used to investigate risk of coronary mortality associated with change in body mass index (deltaBMI) and its modification by smoking status after adjustment for age, major organ system disease, family history of CHD, and BMI at age 20. Adjustment was not performed for blood pressure or serum total cholesterol because these are intervening variables. DeltaBMI was positively associated with risk of coronary mortality in never-smokers but not in current-smokers (P for interaction =.088). For never-smokers with deltaBMI classified as stable, low gain, moderate gain, or high gain, adjusted relative risks of coronary mortality were 1.00, 1.75, 1.75, and 3.07, respectively (P for trend=.010). For current-smokers, the respective adjusted relative risks were 1.00, 0.78, 1.05, and 1.03 (P for trend=.344). These results support the hypothesis that cigarette smoking modifies the association between weight gain and coronary mortality. Future investigations of weight gain and coronary mortality should account for the modifying effect of cigarette smoking.

Spirometric findings and mortality in never-smokers

The relation of ventilatory function to overall mortality has been studied in 662 male and 2048 female never-smokers who during the period 1976–1978 participated in the Copenhagen City Heart Study, a prospective community study of more than 14,000 men and women randomly selected from the general population of the City of Copenhagen. Until the end of 1986, 195 subjects who said they were never-smokers died. Mortality was analyzed using the proportional hazards model of Cox. In addition to measures of ventilatory function, the mortality analysis included age, sex, body-mass index, alcohol consumption, school education, diabetes mellitus, heart disease and bronchial asthma as confounding factors. Forced expiratory volume in 1 second (FEV 1) as a percentage of that predicted, forced vital capacity (FVC) as a percentage of that predicted and the ratio of FEV 1 to FVC were significant risk factors for mortality among both sexes. The relative risk of death associated with a 50% decrease in FEV 1 and FVC as a percentage of a predicted value was 1.65 and 1.81, respectively. This study confirms that lowered ventilatory function is a strong risk factor for mortality among never-smokers of both sexes.

Thinness and mortality

The relationship of thinness to mortality was examined in White adult members of the Kaiser Permanente Medical Care Program who had at least three multiphasic health checkups between 1964 and 1972, with mortality follow-up through 1980. A detailed comparison was performed of the mortality patterns of (decile 1 of Quetelet's index) and weight (deciles 4 and 5) cohort members who were age 40-79 years and free of illness at the beginning of follow-up. Thin male (relative risk 1.6, 95 per cent confidence limits 1.0, 2.6) and female (R.R. 2.1, 95 per cent C.L. 1.1, 3.9) current cigarette smokers were at increased risk of mortality compared with average weight smokers. Unmeasured differences between thin and average weight smokers with respect to quantity of cigarettes smoked may have contributed to the apparent association of thinness with mortality in smokers. Thinness was not associated with increased mortality in never smokers and ex-smokers (R.R. 1.0 in men and women). As association of long-term weight loss with mortality was present in thin and average weight men and in thin women.

Thinness and mortality.

The relationship of thinness to mortality was examined in White adult members of the Kaiser Permanente Medical Care Program who had at least three multiphasic health checkups between 1964 and 1972, with mortality follow-up through 1980. A detailed comparison was performed of the mortality patterns of "thin" (decile 1 of Quetelet's index) and "average" weight (deciles 4 and 5) cohort members who were age 40-79 years and free of illness at the beginning of follow-up. Thin male (relative risk 1.6, 95 per cent confidence limits 1.0, 2.6) and female (R.R. 2.1, 95 per cent C.L. 1.1, 3.9) current cigarette smokers were at increased risk of mortality compared with average weight smokers. Unmeasured differences between thin and average weight smokers with respect to quantity of cigarettes smoked may have contributed to the apparent association of thinness with mortality in smokers. Thinness was not associated with increased mortality in never smokers and ex-smokers (R.R. 1.0 in men and women). As association of long-term weight loss with mortality was present in thin and average weight men and in thin women.