THE IMPLICATIONS OF SMOKING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CANCER

45 Original papers TI S PHE MPLICATIONS OF MOKING IN ATIENTS WITH CO P DHRONIC BSTRUCTIVE ULMONARY ISEASE AND LCUNG ANCER Andreea-Nicoleta Mălăescu , Antonio-Andrei Cotea , Andreea Tîrnoveanu , 1,2,6 1,6 4,6 Lucia-Maria Lotrean , Marius Eremia , Ancua-Alina Constantin , Florin-Dumitru Mihălan , 5,6 6 1,2 1,2,6 Andreea-Roxana Florescu1,3,6 1. National Institute of Pneumophtisiology "Marius Nasta", Bucharest; 2. "Carol Davila" University of Medicine and Pharmacy, Bucharest; 3. “Victor Babeș” University of Medicine and Pharmacy, Timișoara; 4. Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania; 5. "Iuliu Haieganu" University of Medicine and Pharmacy of Cluj-Napoca; 6. AerPur Romania, Bucharest, Romania. Abstract Chronic smoking remains one of the most significant public health concerns worldwide, serving as a major risk factor for respiratory and cardiovascular diseases, as well as various types of cancer. This study explores the impact of smoking on chronic obstructive pulmonary disease (COPD) and lung cancer, focusing on aspects such as prevalence, symptom severity, and epidemiological correlations between these conditions. This study was conducted on a cohort of 164 patients monitored at the National Institute of Pneumophthisiology "Marius Nasta" in Bucharest, identifying a significant association between smoking and pulmonary disease severity. The findings suggest that COPD may contribute to an increased risk of lung cancer, possibly due to shared pathogenic mechanisms such as chronic inflammation, oxidative stress, and tissue hypoxia. Considering the profound impact of these diseases on patients' quality of life and mortality, the study highlights the urgent need for effective preventive strategies, including smoking cessation programs, lung cancer screening, and a multidisciplinary approach to COPD management. Keywords: Tobacco smoking, chronic obstructive pulmonary disease, COPD, lung cancer Rezumat Tabagismul rămâne una dintre cele mai importante probleme de sănătate publică la nivel mondial, servind ca un factor de risc major pentru bolile respiratorii și cardiovasculare, precum și pentru diferite tipuri de cancer. Acest studiu explorează impactul fumatului asupra bolii pulmonare obstructive cronice (BPOC) și cancerului pulmonar, concentrându-se pe aspecte precum prevalena, severitatea simptomelor și corelaiile epidemiologice dintre aceste afeciuni. Internal Medicine 20 4 vol. X I No. 4 - www.srmi.ro2X /inmed-20 4-030610.2478 2 46 Original Papers Introduction Smoking is considered a chronic, relapsing condition, with nicotine being its primary etiological factor , one of the main [1] components of tobacco. Nicotine is responsible for the persistent, voluntary exposure to the risks of smoking due to the high level of dependence it induces. Additionally, the harmful effects of smoking arise from inhaling other substances found in tobacco, including carcinogens, toxic chemicals, and carbon monoxide . Some [2] adverse health effects associated with smoking include malignant diseases in various locations, chronic conditions such as chronic obstructive pulmonary disease, cardiovascular diseases, stroke, type II diabetes, and disorders affecting the reproductive system, immune system, eyes, and periodontal health . A general [3] classification of smoking status identifies daily smokers, characterized by the use of tobacco products every day for at least three months; occasional smokers, who use tobacco but not daily; former smokers, individuals who have abstained from tobacco for at least six months; and, lastly, nonsmokers, defined as those who have smoked fewer than 100 cigarettes over their lifetime . [1] The study of the implications of chronic smoking on overall health remains a priority topic of global interest, given the impact smoking has on the pathogenesis of respiratory, cardiovascular, and various malignant diseases. Extensive research on the epidemiology of smoking supports this claim by documenting the significantly high prevalence of morbidity and mortality among tobacco users. Acest studiu a fost realizat pe o cohortă de 164 de pacieni monitorizai la Institutul Naional de Pneumoftiziologie „Marius Nasta” din București, identificând o asociere semnificativă între fumat și severitatea bolii pulmonare. Descoperirile sugerează că BPOC poate contribui la un risc crescut de cancer pulmonar, posibil din cauza mecanismelor patogene comune, cum ar fi inflamaia cronică, stresul oxidativ și hipoxia tisulară. Având în vedere impactul profund al acestor boli asupra calităii vieii și mortalităii pacienilor, studiul evideniază nevoia urgentă de strategii preventive eficiente, inclusiv programe de renunare la fumat, screening pentru cancerul pulmonar și o abordare multidisciplinară a managementului BPOC. Cuvinte cheie: fumatul de tutun, boală pulmonară obstructivă cronică, BPOC, cancer pulmonar. 47 Original papers Globally, out of a population of 8.1 billion people, 1.3 billion are smokers, resulting in a smoking prevalence of 18% worldwide in the past year. Romania ranks 18th in Europe, with a smoking prevalence of 27.9%. Up to half of tobacco users die from a smoking-related condition . Smoking ranked second in 2021 [4] among the leading risk factors influencing the global burden of disease, following elevated blood pressure . Extensive studies have [5] illustrated the involvement of smoking in the leading causes of preventable death. One indicator of smoking's influence on a population is lung cancer, with 70-90% of lung cancer deaths occurring among smokers. Other smoking-related conditions that impact mortality include COPD in both sexes, laryngeal and esophageal cancer in women, and aortic aneurysm in men . Furthermore, the main [6] diseases discussed in this study, COPD and lung cancer, are among the top causes of death, ranking 4th and 9th globally in 2021 . [5] Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease is a long-term lung condition primarily characterized by dyspnea and cough, with or without sputum production, resulting from the progressive obstruction of the airways due to bronchitis, bronchiolitis, and/or emphysema. It is diagnosed through spirometry, where a post-bronchodilator Tiffeneau index of less than 0.7 confirms the condition. The leading environmental factor contributing to COPD development is smoking; however, other contributing factors include environmental pollution, abnormal lung development, and genetic factors, such as the SERPINA1 gene mutation, which causes -1 antitrypsin deficiency .α [7] Tobacco inhalation disrupts pulmonary homeostasis, leading to both structural and functional alterations. Chronic smoking induces oxidative stress, airway inflammation, cellular senescence, and cell death, all of which play a role in the pathophysiology of COPD . [8] Reactive oxygen species (ROS) play physiological roles in microbial defense, mitochondrial respiration, and intercellular signaling. Oxidative stress occurs when free radical exposure exceeds the antioxidant defense system's capacity, damaging proteins, lipids, and deoxyribonucleic acid (DNA) . This imbalance between oxidants [9] and antioxidants promotes inflammation by upregulating the expression of inflammationrelated genes, increasing mucus secretion, and inactivating antiproteases . The lungs [8] are especially prone to oxidative stress due to their high oxygen concentration, rich blood supply, and constant exposure to external toxins. Remarkably, cigarette smoke contains more than 10¹⁵ free radicals in a single inhalation . [9] When irritants, such as those found in cigarette smoke, enter the airways, they recruit and activate cells such as neutrophils, eosinophils, macrophages, lymphocytes, and epithelial cells, releasing chemotactic factors that initiate or intensify inflammation. It has been shown that inflammation in the small airways of COPD can progress for many years before symptoms appear. Although inflammation affects all areas of the airways, airflow obstruction is primarily caused by damage to the small airways. Therefore, the symptoms are preceded by bronchiolitis with small airway obstruction, peripheral distribution of goblet cells, peribronchiolar fibrosis, and thickening of the bronchial smooth muscle tissue, with emphysema possibly also developing. Additionally, the number of submucosal glands increases, and ciliated epithelial cells are replaced by goblet cells, leading to mucus hypersecretion. The involvement of the Internal Medicine 20 4 vol. X I No. 4 - www.srmi.ro2X 48 Original Papers inflammatory response in the pathogenesis of COPD has therapeutic implications for the use of inhaled corticosteroids, which have also been shown to reduce mortality . Beyond [10] localized inflammation in the lungs and airways, systemic involvement of the inflammatory response has also been documented, with elevated levels of C-reactive protein (CRP), fibrinogen, and leukocytes. This inflammation persists subtly even after smoking cessation . [11] Lung Cancer The most common location for cancer associated with tobacco use is the lungs . [13] The risk of lung cancer is 10 to 30 times higher among smokers, while smoking cessation significantly reduces this risk over time . Although nicotine is the well-known [14] substance in cigarette smoke, it is primarily involved in addiction, and there are predominantly studies that have denied its involvement in the pathogenesis of lung cancer. There are over 5,000 components in cigarette smoke, 73 of which are considered carcinogenic . These include polycyclic [12] aromatic hydrocarbons, tobacco-specific nitrosamines, aromatic amines, benzene, formaldehyde, and acetaldehyde, all of which have direct effects on DNA integrity. In addition to these carcinogenic substances, an important role in the etiology of lung cancer is played by the inflammatory changes in the lungs associated with the activation of nuclear factor kappa B (NF-kB) and the promotion of pulmonary growth and development . Tobacco exposure leads to [13] an increased number of somatic mutations, with the average being several thousand mutations in a bronchial cell . [15] Lung cancer originates in basal epithelial cells and includes non-small cell lung cancer (NSCLC), which accounts for 85% of cases, and small cell lung cancer (SCLC), both of which are closely linked to smoking. The main types of NSCLC are adenocarcinoma in 40% of cases, large cell carcinoma in 10% of cases, and squamous cell carcinoma in the remaining 30% of patients . [16] The Triad of Mortality (Smoking – COPD – Lung Cancer) Aside from the shared etiology of tobacco use, COPD is recognized as an independent risk factor for lung cancer, particularly for squamous cell carcinoma. This finding most likely arises from the common mechanisms in their pathogenesis, which involve the accelerated functional and morphological degradation of the lungs in smokers, genetic predisposition, oxidative stress with direct effects on DNA degradation, or indirect effects through the initiation or maintenance of inflammation, epigenetic changes, and growth factors . [16] 49 Original papers Chronic obstructive pulmonary disease is a direct risk factor for lung cancer, primarily through its involvement in inflammation. In the pathological process leading from COPD to cancer, the exaggerated expression of NFkB leads to the suppression of the protein 53 kilodaltons (p53) gene, while the phosphoinositide 3-kinase (PI3K) pathway drives cell proliferation and suppresses apoptosis. Additionally, the aberrant expression of growth factors involved in tissue remodeling plays a role . Besides the [16] chronic inflammation in COPD, another mechanism involved in carcinogenesis is initiated by hypoxia generated by pulmonary hyperinflation and bronchial obstruction, which activates a transcription factor known as hypoxia-inducible factor 1-alpha (HIF- ).α This factor affects more than 200 genes and can inhibit apoptosis . [17] Lung cancer mortality is among the highest due to late diagnosis and limited treatment efficacy. This situation could be improved through imaging screening of COPD patients for lung cancer using computed tomography . [18] Additionally, secondary prophylaxis with targeted therapies could be used in the future to reduce the risk of lung cancer development. One such initiative would be reducing oxidative stress through the administration of vitamin E, C, or NAC (N-acetylcysteine), although further studies are needed to document their effectiveness . [16] Although the exact mechanisms through which COPD influences the development of lung cancer are not yet fully understood, it is certain that these two pathologies are frequently associated. Further analysis is needed to determine whether COPD is an individual risk factor for lung cancer or if the two pathologies are complications of the same disease, namely chronic smoking . [19] Methods The epidemiological study presented is a descriptive, cross-sectional analysis designed to assess the association between chronic smoking and the presence of comorbidities, specifically lung cancer and chronic obstructive pulmonary disease. The study included 164 patients under medical supervision at the National Institute of Pneumophthisiology "Marius Nasta", Bucharest. Patient selection was based on medical records, and the study groups were defined according to the following inclusion criteria: lGroup 1: Patients diagnosed with lung cancer without a COPD diagnosis. lGroup 2: Patients diagnosed with COPD without an oncological diagnosis. lGroup 3: Patients diagnosed with both COPD and lung cancer. The diagnosis of COPD in patient records was initially suspected due to symptoms of chronic bronchitis and was later confirmed through spirometry. Lung cancer was diagnosed based on medical documentation, including discharge summaries from pulmonology or oncology departments or other medical units where the diagnosis was established. The study Objectives include: 1. Analyze demographic and clinical characteristics of patients with COPD and/or lung cancer, including sex, age, and place of residence. 2. Identify key risk factors for both diseases, with a focus on smoking and occupational exposure to respiratory hazards. 3. Assess the role of COPD as an independent risk factor for lung cancer. 4. Investigate the association between tobacco use and the prevalence of COPD and lung cancer. 5. Evaluate COPD severity in relation to Internal Medicine 20 4 vol. X I No. 4 - www.srmi.ro2X 50 Original Papers smoking history, particularly the impact of cumulative tobacco exposure (packyear index) on disease progression. 6. Identify the most common symptoms associated with COPD and lung cancer. 7. Examine the role of chronic inflammation as a potential shared mechanism in the pathogenesis of both conditions. 8. Analyze relevant biological parameters linked to COPD and lung cancer. 9. Assess the prevalence of common comorbidities, such as bronchiectasis, ischemic heart disease, hypertension, and diabetes mellitus, which may also have smoking as a risk factor. 10.Support the development of screening and prevention programs and promote a multidisciplinary approach to the diagnosis and management of COPD and lung cancer. Exclusion criteria were established to ensure the validity and accuracy of the study results. Patients were excluded if they had: lIncomplete smoking history data; lInterstitial lung diseases that could affect lung function and influence cancer risk; lActive or sequelae pulmonary tuberculosis, to prevent interference between tuberculosis-related lung lesions and COPD/lung cancer; lOther obstructive pulmonary diseases (e.g., bronchial asthma), to maintain a clear distinction between COPD and similar conditions; lSevere cardiovascular diseases (acute myocardial infarction, advanced heart failure, significant arrhythmias) that could impact clinical severity; lOther types of cancer; lDeclined to provide informed consent. The data collected for the study were extracted from patient records and included demographic factors (age, sex, place of residence, occupational exposure), smoking history (smoking status — ever-smoker, never-smoker), pack-years index, and clinical characteristics (COPD severity based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, histological type of lung cancer, symptoms, weight, BMI – body mass index, and blood test results). A never-smoker is an individual who has never smoked or, at most, has experimented with smoking occasionally but never on a daily basis and has not consumed more than 100 cigarettes in total. In our study, the term eversmoker includes both current smokers — individuals who had been smoking for at least six months at the time of questioning — and former smokers, defined as those who had completely quit smoking for at least six months. These data were entered into an Excel database and subjected to statistical analysis to generate a descriptive overview 51 Original papers Internal Medicine 20 4 vol. X I No. 4 - www.srmi.ro2X Table 1. Socio-demographical and clinical characteristics 52 Original Papers of the patient cohorts. Statistical analysis was performed using IBM SPSS version 26.0. We conducted frequencies tests, independent ttest, chi-square test and correlation analyses. The results were presented as mean ± standard deviation (SD) and we considered a p-value lower than 0.05 and R values lower than 0.01 to be statistically significant. The study was approved by the Ethics Committee of the National Institute of Pneumophthisiology "Marius Nasta". Results The study included 164 patients, categorized into three groups: patients with COPD, patients with lung cancer, and patients diagnosed with both conditions. The average age of all patients was 65.68 years, with no significant differences in mean age among the selected groups (Table 1). Chronic Smoking When comparing ever-smokers and neversmokers, we observed a significantly higher proportion of males among ever-smokers (72.9%), whereas females predominated among never-smokers (77.4%). Although ever-smokers had a lower average BMI (27.53 Kg/m vs. 30.73 Kg/m ), this difference was 22 not statistically significant. Similarly, there were no notable differences in blood pressure, heart rate, or oxygen saturation in ambient air. Although place of residence theoretically influences exposure to inhaled respiratory toxins, this factor may have been influenced by the institute's urban location, where data collection took place. Lung cancer characteristics were also analyzed based on smoking status. Among ever-smokers, lung cancer was more frequently located centrally (62.5%), whereas in never-smokers, central and peripheral tumor locations were equally distributed. In never-smokers, the right hemithorax was the predominant site (69.56%), while in ever-smokers, there was no significant difference in tumor location relative to the midline of the thorax. Chronic Obstructive Pulmonary Disease The socio-demographic analysis revealed a significant gender difference in COPD prevalence, with a higher occurrence among men (74%) compared to women (33%). The prevalence of chronic smoking among COPD patients was also assessed. Of the 107 patients with COPD, 93 were ever-smokers (86.92%), while 14 were never-smokers (13.08%) (Figure 1). The severity of COPD, assessed using GOLD stages based on forced expiratory volume in 1 second (FEV1) values, did not show statistically significant differences between ever-smokers and never-smokers (p = 0.328). 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