Non-smoking COPD: A Growing Concern

Chronic obstructive pulmonary disease (COPD) is currently ranked as the fourth leading cause of death worldwide, according to the WHO report for 2021,[1] accounting for 5% of all global deaths. A large majority of those deaths, in the under-70-year age group, happen in low- and middle-income countries (LMICs). In India, COPD is second only to cardiovascular diseases as the most common cause of death and is continuing to show an increasing prevalence compared to other noncommunicable diseases. Even though the link between smoking and COPD was recognized as early as the 1870s, a formal warning regarding their association happened only by 1964 even in the USA, and it took another two decades for the US General Surgeons report to explicitly state that “cigarette smoking is the major cause of chronic obstructive lung disease.” However, identification of other risk factors of COPD other than smoking took much longer. Recognition of smoking as an important and leading cause of COPD could have led to the channeling of all major epidemiological, transitional, and clinical research in COPD in that direction. This could partially explain the dearth of publications and lack of in-depth understanding of the role of other risk factors for COPD in the last century. Nonsmoking COPD (NS-COPD) came into focus by the later part of the 20th century as many researchers realized its importance over the years. Since its first Indian description in 1959,[2] not much research was happening in NS-COPD in India. There was an acute lack of knowledge regarding its risk factors, disease burden, clinical characteristics, pathogenesis, and therapeutic and prognostic implications. Over the past two decades, a significant body of evidence has been accumulating but not enough to answer all the questions regarding NS-COPD. Salvi and Barnes in their article in the Lancet in 2009 reported 25%–45% of COPD to be never-smokers. This meant that the actual prevalence of NS-COPD must be much higher than previously suspected.[3] They identified biomass fuel burning as a major cause of NS-COPD. Other major risk factors identified included a history of pulmonary tuberculosis (TB) and chronic asthma. Socioeconomic status of an individual was also found to be another important risk factor for NS-COPD. Prior to these findings, the recognized risk factors for NS-COPD only included outdoor and indoor air pollution along with occupational exposure and tobacco smoke. Major risk factors for COPD in never-smokers which have fairly good evidence include air pollution, both indoor and outdoor, asthma, several occupational exposures, infections such as TB, HIV, and recurrent childhood infections, impaired lung growth, low socioeconomic status, environmental tobacco smoke, older age, and genetic factors.[4] Prevalence studies on NS-COPD show wide variations depending on the socioeconomic situations in the countries where it was undertaken. Results from the CanCOLD study reported a prevalence of COPD of 6.4% among never-smokers, constituting 27% of all COPD subjects.[5] In the Burden of Obstructive Lung Disease study, 6.6% of COPD among the never-smokers were found to be mild (GOLD stage I), and 5.6% to be moderate to very severe (GOLD stage II+). In this study, never-smokers had less severe COPD than ever smokers.[6] However, 23.3% of the COPD were never-smokers belonging to GOLD stage II+ COPD. A systematic review on prevalence of NS-COPD in India reported that among those exposed to biomass fuel, there was a 10 % pooled prevalence of COPD.[7] Another review on nonsmoking risk factors for COPD identified biomass fuel burning as the most important risk factor for NS-COPD in India.[8] A common opinion expressed in all these studies looking at NS-COPD was an urgent need for a properly conducted nation-wide epidemiological study with adequate representation from all parts of the country, to estimate the prevalence of NS-COPD and to identify the various risk factors as well as to investigate each of the potentially modifiable nonsmoking risk factors, their pathogenesis, specific clinical presentations, and possible management strategies. The award-winning original epidemiological research work appearing in this issue of PULMON, looking at the prevalence of respiratory morbidity among construction workers in a rural area in Kerala, is a commendable effort in this direction. The study could identify a significant association between cement dust exposure among construction workers and an increase in respiratory morbidity. The findings from this study will be a significant addition to the limited body of evidence on NS-COPD in our state. Hope this work inspires the young pulmonologists and researchers in our state and pave the way for further research on various aspects of NS-COPD in the community. Epidemiological studies across the world have identified many of the major occupational groups at risk for COPD. They include, but are not limited to, farmers, industrial workers, miners, and jobs involving exposure to diesel exhaust fumes. Workers in information industry and administrative support formed a significant group followed by those working as gardeners, warehouse workers, and sculptors. It has been estimated that 26%–53% of NS-COPD is due to occupational exposures. The Multi-Ethnic Study of Atherosclerosis Lung Study identified a linear relationship between duration of exposure (>15 years) and severity of airflow obstruction.[9] It was also noted that the severity of COPD was higher among those who had occupational airborne exposure. One Swedish longitudinal cohort study reported an increased risk of mortality from COPD due to occupational exposure.[10] One study estimates population attributable risk percent (PAR%) for COPD due to work-related factors at 15% which means that 15% of the disease incidence in the population can be attributed to the exposure.[11] PAR is a measure of the effect of control measures in a population. Hence, knowing PAR will help policy-makers while deciding on public health interventions. In a Danish cohort, occupational exposure accounted for 48% of the NS-COPD population.[12] A study among Swedish construction workers reported a COPD prevalence of 24% among all workers and 53% among never-smokers while the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults reported a prevalence of 56% among occupational exposure group.[13] A Mortality and Morbidity Weekly Report in 2019, analyzing data from 2013 to 2017, estimated the prevalence of COPD among nonsmoking working adults at 2.2% in the US with the highest prevalence among those working in the information industry (3.3%) and office and administrative workers (3.3%) along with those working in mining (3.1%) industry.[14] Nonsmoking women showed a higher prevalence of COPD than their male counterparts at workplace. Air pollution has been estimated to be the cause for nearly 50% of NS-COPD worldwide. The WHO recommends an annual mean concentration of <5 µg/m3 for particulate matter with aerodynamic diameter <2.5 µg (PM <2.5), <10 µg/m3 for NO2, and <60 µg/m3 for the peak season mean 8-h ozone concentration.[15] A large study looking at the effects of long-term exposure to air pollution among women living near busy roads found that, over a period of 5 years, the prevalence of COPD increased when the PM10 increased by 7 μg/m3 and NO2 concentration increased by 16 μg/m3.[16] Biomass fuel smoke and environmental tobacco smoke constitute the major indoor air pollutants leading to the development of COPD. A biomass exposure index (average hours spent cooking per day × number of years of cooking) of 60 and above has been found to be independently associated with chronic bronchitis after adjusting for other known factors.[17] While burning of biomass fuel can generate a PM10 of 300–3000 mcg/m3 in 24 h, the WHO safety standards prescribe an upper limit of 150 μg/m3. However, the concentration can reach much higher levels depending on various conditions and biomass fuel type.[18] Looking at published literature on the clinical characteristics of NS-COPD, there are significant differences when compared with smoking COPD (S-COPD). In a systematic review of available literature, published in 2023, majority of the patients with NS-COPD presented with mild-to-moderate obstruction conforming to GOLD 1–2+ category.[19] They tend to be older than their S-COPD counterparts with equal prevalence among the sexes in the developed nations and a female preponderance in the LMICs, especially with increasing severity of illness. NS-COPD has fewer respiratory symptoms in comparison to S-COPD. The prevalence of pulmonary comorbidities such as asthma, bronchiectasis, and previous history of pulmonary TB seems higher in NS-COPD. GOLD 2 NS-COPD tends to have a higher prevalence of extrapulmonary comorbidities such as systemic hypertension, heart disease, diabetes mellitus, and stroke when compared to never-smokers without airway obstruction. However, in comparison to S-COPD, there were no major differences. Exacerbations were similar in both groups based on available data. The Korea COPD Subgroup Study reported higher rates of NS-COPD among female gender, obese individuals, and less educated people.[20] It was also high among those with respiratory and allergic comorbidities. The association was also noted with systemic hypertension, gastroesophageal reflux disease, and osteoporosis. Other factors such as rates of exacerbation, symptom, and exercise capacity scores were comparable with that of S-COPD. Radiologically, S-COPD showed more emphysematous lungs while NS-COPD was more associated with post-TB lung sequelae and bronchiectasis. Lung function tests were similar in the two groups, but lung function declined more rapidly in S-COPD over a 5-year period. NS-COPD males and females tend to be of two distinct phenotypes, with males showing a predominant emphysema phenotype and females, an airway phenotype.[21] An observational epidemiological study looking at the gender/race differences revealed the highest prevalence of COPD among black women who never smoked, followed by white women and then white men. Black nonsmoking men had the least odds of developing COPD.[22] Each of the potential risk factors of NS-COPD seems to exert its effect through a different mechanism of action. Translational studies have identified a whole range of possible mechanisms for the pathogenesis of COPD in never-smokers. If inflammation could explain one pathogenesis, oxidative stress could be the reason for another. Other prominently mentioned mechanisms include cytokines and chemokine release, transforming growth factor-β, matrix metalloproteinase 9 (MMP9), MMP10, MMP12, mitogen-activated protein kinase, Integrin αVβ3, MMP1, MMP10, airway remodeling, tracheobronchial stenosis, small airway disease, altered immunity, genetic factors, and accelerated lung aging.[4] Prenatal maternal smoking and biomass smoke exposure and prematurity are implicated in suboptimal lung development in children resulting in subnormal lung function in adulthood. Subnormal lung function in otherwise normal adults is seen to predispose them to the development of COPD in later life in the absence of tobacco smoke or environmental pollution. The risk of COPD among asthmatic is as high as 12-fold. In the CanCOLD study, advanced age and asthma history showed an independent association with NS-COPD of all types of severities. The presence of HIV infection with a low CD4 count seems to increase the risk for COPD. This has been brought out in several studies including systematic reviews and case–control studies.[23,24] Analysis of the China Chronic Disease Risk Factor Surveillance survey revealed an increased risk of COPD with low educational status and income in the NS-COPD group.[25] The Korea National Health and Nutrition Examination Survey IV also reports a higher risk of COPD among the lower income group.[26] Early diagnosis of COPD in the nonsmoking population continues to be a significant challenge for the clinician. Early identification of risk factor has a major influence on the outcome of NS-COPD. The most important intervention in arresting the progression of NS-COPD is the removal of susceptible individuals from the culprit environment. The type of intervention required will be based on the inciting factor. For example, in the case of indoor air pollution, intervention should include education and cultural modification. Education should be imparted to women and children regarding the usage of cleaner cooking fuel, more efficient stove, improving ventilation in the kitchen and home, and encouraging social, cultural, and behavioral changes in cooking.[27] In the absence of specific guidelines, conventional management based on GOLD guidelines is the only recommended treatment for all types of NS-COPD. Identifying cost-effective preventive measures and ensuring its implementation are the cornerstones in the success of reducing the load of NS-COPD in the community. Meanwhile, the promotion of research for the identification of specific pathways of pathogenesis of various risk factors will help in developing targeted therapies in the management of COPD due to specific etiologies. The onus is upon clinicians, researchers, professional bodies, and industry to impress on policy-makers to prioritize the implementation of primary preventive measures at workplaces, ensuring safe air quality levels, and enacting laws for stringent pollution control measures.