Chronic Obstructive Pulmonary Disease and its Non-Smoking Risk Factors in India

Abstract

The rising prevalence of the chronic obstructive pulmonary disease (COPD) is generally attributed to smoking, since the role of other risk factors among non-smokers are not well established especially in low and middle income countries like India. This is also reflected by the limited literature available on non-smoking related COPD risk factors like indoor and outdoor air pollution. The present review is an attempt to assess the influence of non-smoking risk factors on COPD and its measures in Indian subcontinent. The most noteworthy factors among non-smokers appear to be the use of biomass fuel for cooking and heating purposes. We observed that the studies undertaken to evaluate the role of such risk factors are inconclusive due to weak methodologies and small sample sizes, may be due to limited financial resources. The present review suggests the need of a nationally representative study to estimate the effect of each of the potential modifiable risk factor (other than smoking) for framing impactful public health policies to prevent and manage COPD at community and population level in India.

Keywords:

• biomass fuel
• COPD
• India
• indoor and outdoor air pollution
• risk factor

Introduction

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by persistent airflow limitation that is usually progressive and is associated with enhanced chronic inflammatory response in the airways to noxious particles or gasses (1). COPD symptoms include dyspenea, chronic cough and sputum production. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of COPD does not include patient-reported, physician-diagnosed chronic bronchitis and emphysema, as they can be present in individuals with normal lung function (1).

COPD is a multifactorial complex disease, considerably influenced by interaction of genetic and environmental risk factors (2). Tobacco smoking has been considered as the leading cause underlying rising prevalence of COPD across the globe (3, 4). Majority of COPD prevalence surveys and clinical trials were based on participants who smoke or have history of tobacco smoking (3, 4). This in turn has over shadowed the importance of other lifestyle and environmental risk factors (5). Recent evidences suggest that non-smoking related COPD is higher than previously believed, particularly in the low and middle income countries (LMICs), accounting for 1/4^th to 1/3^rd of all COPD cases (6).

Globally, a noticeable proportion of COPD cases are known to be non-smokers, ranging from 22.9% in UK (6) to 47% in South Africa (5). In India specifically, 69% of COPD cases were found to be never smokers in a study conducted on 1200 slum dwellers in Pune, Maharashtra (7). In another ­setting, the overall prevalence of COPD was found to be 2.44% (95%CI = 1.43–3.45) among non-smoking women of Tiruvallur district of Tamilnadu in south India (8).

Several risk factors (apart from smoking) have been identified in various studies conducted both globally (5, 6, 9) and in India (10, 11). Large proportion of the women in developing countries, as compared to developed countries, is exposed to biomass fuel that cause non-smoking related COPD. Further, COPD is influenced by occupation based lifestyle factors (like dust, fumes, smoke and other pollutants) commonly present in LMICs, including India (12).

At present, there is not a single nationally representative study that assessed the non-smoking related risk of COPD in India. However, there are studies available for selected geographical locations across India that had evaluated variety of non-smoking related risk factors of COPD (8, 10, 13). Hence, a review to evaluate each non-smoking risk factor of COPD and to identify high risk population groups would help in understanding the magnitude of the problem. This will further help in designing necessary public health policy to prevent and manage COPD among the target population groups. Keeping the above in mind, the present review was aimed to gather all the available evidence for each of the risk factor (other than smoking) reported to be associated with COPD in Indian subcontinent.

Epidemiological burden

COPD is one of the top five causes of mortality with 2.9 million deaths and was ranked 9^th (approximately 7.67 million) in the loss of disability adjusted life years (DALYs) in 2010 (14). According to world health statistics, COPD is expected to be the third leading cause of deaths by 2030 (15) of which almost 90% of COPD deaths occur in LMICs (16). In South Asia, COPD was ranked 5^th in causing both mortality and loss of DALYs in 2010 (14). In 1996, the estimated  burden of COPD in India was over 12 million, based  on several studies sponsored by the Indian  Council of Medical Research (ICMR), involving 35,295 adults of age >35 years. (10). In 2004, the age-standardized death rate due to COPD in India was 102.3 per 100,000 amongst both sexes (17), which would translate to 556,000 COPD cases (18). However, the epidemiological data currently available for India is still thin and underestimate the total burden of COPD.

Salvi and his colleagues have summarized the various challenges in determining true prevalence of COPD in population studies (19). There are great variations in the reported morbidity, which could partly be due to differences in the definition of a ‘case’ (20). COPD is often wrongly described by its prototype chronic bronchitis in most epidemiological studies (21). For instance, Tan and Ng (22) reported 6.3% COPD prevalence in Asia-Pacific region compared to 3.9% World Health Organization (WHO) estimate (19). Thus, it is sometimes difficult to accumulate and compare the findings of prevalence and risk factors of chronic bronchitis along with that of COPD, as done in several Indian studies (23–32). Further, diagnosis of COPD based on GOLD guidelines (1) involves lung function measures, important ones being forced vital capacity (FVC) and forced expiratory volume in 1^st second (FEV₁).

These are assessed by pre and post bronchodilator spirometry which is not easy to perform in poorly resourced population based epidemiological studies (33, 34). Thus, COPD often remains underreported in LMICs (35). Moreover, recently the issues with considering of defining COPD (FEV₁/FVC < 0.7) and grading its severity (FEV₁ < 80% predicted) according to GOLD guidelines (1) have been discussed (36, 37). It has been pointed out that the use of fixed FEV₁/FVC ratio introduces significant age and gender bias that can result in under-diagnosis in young adults and over-diagnosis in elderly adults, especially in East Asians (37).

Similarly, % predicted FEV₁ value is highly dependent on an individual's age and thus the severity of the airway obstruction or lung deterioration could be misclassified, especially in elderly population (37). The use of forced expiratory flow at 25–75% of FVC (FEF_25-75%) or flow when 75% of FVC has been exhaled (FEF_75%) by clinicians for decision making has also been discouraged as discordance has been reported while using these measures compared to standard use of FEV₁/FVC and FEV₁ values as airways obstruction can go undetected in upto 2.9% cases by FEF_25-75% and 12.3% cases by FEF_75% (38).

The mortality data also underestimates COPD as a cause of death because the disease is more likely to be cited as a contributory rather than an underlying cause of death, or may not be cited at all (39). Depending on the severity of the disease, the 5-year mortality rate for patients with COPD varies from 40% to 70%. A recent systematic review suggests the prevalence of chronic bronchitis to lie between 6.5–7.7% in rural India, but accurate general prevalence of COPD / chronic bronchitis across Indian subcontinent still remains unpredicted (40). In addition, the commonly associated co-morbidities related to COPD like cardiovascular disease, lung cancer, osteoporosis and diabetes are increasing the epidemiological burden by several folds (41).

Although the prevalence rates are available in 10 out of 28 Indian states but heterogeneity in study design and quality makes it difficult to assess the national prevalence of COPD. Moreover, because of paucity of data and inconsistency in the study settings, estimating the general prevalence rate of COPD in India remains a challenge where specific population characteristics persist (40). According to small prevalence studies conducted across India (Table 1), the median prevalence rates are 5.5% for males and 3.2% for females. Thus, clearly COPD is more common among males than females that can be contributed to the associated lifestyle factors like smoking and occupational hazards. The male to female ratio varied from 1.32:1 to 2.6:1 with median ratio of 1.6:1.5 (42). However, these studies were confined to limited areas and do not represent the general population of that state or region.

Table 1. Prevalence of COPD in Indian states

	Prevalence (%)
Population	Men	Women	Male:Female ratio	Reference
Delhi	3.36	2.54	1.3	(43)
Delhi	7.0	4.3	1.6	(44)
Patna	2.12	1.33	1.6	(45)
UP	6.67	4.48	1.5	(29)
New Delhi	8.1	4.6	1.8	(28)
Delhi (rural)	4.7	3.5	1.3	(32)
Delhi (urban)	8.0	4.3	1.9
Punjab	2.28	1.63	1.4	(46)
North India (rural)	9.4	4.9	1.9	(27)
North India (urban)	3.7	1.6	2.3
North India (rural)	6.2	3.9	1.6	(47)
North India (urban)	4.2	1.6	2.6
Tamil Nadu	4.08	2.55	1.6	(48)
Madras	1.9	1.2	1.6	(24)
Mysore	11.1	4.5	2.4	(49)
4 sites^1	5.0	3.2	1.6	(10)

¹The 4 sites include Bangalore, Chandigarh, Delhi and Kanpur.

Risk factors

The most common risk factor of COPD worldwide is tobacco smoking (21, 50–54). According to series of studies initiated by ICMR (INSEARCH-I) in India, smokers had 3 times more risk of developing COPD as compared to non-smokers (10). Further, among smokers, bidi smokers were at a higher risk of developing COPD (8.2%) than the cigarette smokers (5.9%) (55). However, numerous other non-modifiable (age, gender and genetic factors) and modifiable factors (indoor and outdoor air pollution, exposure to environmental tobacco smoke and occupational dust and chemicals) have also been identified as potential risk factors of COPD among non-smokers worldwide (5, 6) including India (17). In addition, diet, long standing asthma, recurrent respiratory infection in early childhood and tuberculosis are also known to play a role in development of COPD among non-smokers (6). Briefly, the risk of developing COPD is related to the total burden of inhaled particles that an individual encounters over the life time through above mentioned exposures and to any other factor that effect their lung growth during gestation and childhood such as low birth weight and respiratory infections (1).

Salvi and Barnes (5) efficiently gathered the evidences of non-smoking risk factors of COPD dating back to 1963 which included environmental (56) and ­occupational exposures (57). According to WHO statistics, the causes for COPD have opposite patterns according to the geographic areas (58). In high- and middle-income countries, tobacco smoke is the biggest risk factor (3). In contrast, exposure to indoor air pollution like biomass fuel due to cooking and heating purposes in low-income settings, specifically Asian countries, is causing COPD burden (59) along with outdoor air pollution and poor socio-economic status (6). The summary of studies evaluating the risk factors associated with COPD in Indian population is summarized in Table 2.

Table 2. COPD non-smoking risk factors evaluated in India

Risk factor	Study population	Variable	Effect size	Source
Indoor air pollution /Biomass fuel	900 non-smoking women (>30 years; 66% <50 years) from rural Tamilnadu	COPD Prevalence in biomass fuel users vs clean fuel users.	OR = 1.24 (0.36–6.64)	(8)
		COPD cases were defined as: reversibility test result of <15% improvement in FEV1 compared to prebronchodilator FEV1, or postbronchodilator improvement of FEV1 < 200 mL, and FEV1/FVC < 70% and no history of atopy or pattern of disease suggestive of asthma
	2180 females > 20 years	COPD and Chronic Bronchitis	OR = 3.0 (1.8–4.9)	(152)
	Gujjars females from Kashmir	Chronic Bronchitis in females using solid fuel vs clean fuel	OR = 2.1 (1.5-2.94)	(153)
	560 Gujjars > 15 years of age	Chronic Bronchitis in individuals with >4 and <4 hours spent near fireplace	OR = 3.5 (1.4 – 8.8)
	315 women aged 15–60 years from Pondicherry	Chronic Bronchitis (Lung functions were assessed by measuring FVC, FEV1 PEFR)	OR = 2.8 (0.7 – 11.4)	(81)
	3718 females engaged in household cooking	Chronic Bronchitis (Respiratory Symptoms and deteriorated lung function measured by spirometry)	OR = 1.97 (1.16 – 3.22)	(79)
	28 Chandigarh healthy females using biomass fuel and 28 healthy unexposed females	Chronic Bronchitis (Carboxyhaemoglobin estimated by double wavelength spectrophotometry)	OR = 3.04 (2.15 – 4.31)	(84)
Environmetal Tobacco smoke (ETS) Exposure	35295 adults of >35 years age from Bangalore, Chandigarh, Delhi, Kanpur	ETS exposure among non-smokers where COPD was defined by chronic bronchitis criteria, diagnosed from the presence of cough and expectoration on most of the days for at least 3 months in ≥ 1 or 2 consecutive years	OR = 1.4 (1.2–1.6)	(10)
Outdoor Air Pollution	Delhi (over a four-year period from 2000–2003)	Suspended Particulate Matter	r = 0.474, p < 0.01	(13)
		Respirable Suspended Particulate Matter	r = 0.353, p < 0.05
		Temperature	r = -0.318, p < 0.05
Occupational Hazards in Glass bangle Workers	73 chronic bronchitic workers, 220 asymptomatic workers and 88 unexposed controls in Lucknow	Air way obstruction assessed by pulmonary function	RR = 8.3 in asymptomatic workers	(119)
			RR = 19.3 in bronchitis workers (p < 0.001)
Genetic Markers	200 COPD cases and 370 controls from North India (70.79% subjects aged 55–75 years) diagnosed by GOLD guidelines*	AAT PiZ	OR = 3.82 (p = 0.03)	(146)
	204 COPD cases (mean age 57.83 ± 10.58 years) and 208 controls (mean age 56.35 ± 8.12 years) from North India diagnosed by GOLD guidelines*	GSTM1	OR = 2.58 (1.7–3.8, p  = 0.001)	(154)
		GSTT1	OR = 2.11, (1.3–3.6, p = 0.007)	(145)
	200 COPD cases (mean age 52.10 ± 15.50 years) and 200 controls (mean age 44.26 ± 14.42 years) from North India diagnosed by GOLD guidelines*
Underweight (BMI < 18 kg/m^2)	286 Patients > 35 years of age (53% females) in Kolkata	Airflow obstruction defined as FEV1/FVC < 0.7	95% CI = 0.19–0.65; p = 0.02	(117)

FVC: Forced Vital capacity and FEV₁: Forced Expiratory Volume in 1^st second.

*GOLD Guidelines: FEV₁ <80% predicted and FEV₁/FVC < 0.7.

Indoor air pollution

The principal sources of indoor air pollutants that are related to development of COPD include smoke produced by domestic use of different cooking fuels and environmental tobacco smoke or passive smoke (60, 61). The available evidence shows that comparatively low birth weight babies are born to women exposed to biomass smoke from open fires (62) and environmental tobacco smoke (63). The outcome of low birth weight is an independent risk factor of COPD associated with poor lung growth and lung function during childhood and adulthood (64).

Domestic fuel

Around 50% of the world's population (about 2.4 billion people) uses biomass fuel as the primary energy source and almost 2 million deaths per year are attributable to solid fuel use, with more than 99% of these occurring in developing countries (6, 11, 65, 66). Indoor air pollution from solid fuel use in developing countries was estimated to account for about 1.6 million deaths annually in 2004 and about 500,000 in India in 2010, suggesting a serious impact on health (67, 68). An odds of 2.3 (CI = 1.5–3.5) for COPD has been seen with exposure to biomass smoke in a meta analysis of 36 global studies (69). Further, 400–550,000 prematured deaths and 4–6% of Indian National burden of disease has been attributed to annual use of biomass fuel and indoor air pollution respectively (62).

Indoor exposure to domestic fuel combustion, especially biomass fuel, is reported to be an important cause of chronic bronchitis and COPD in females in studies from India, Nepal, China, South Africa, Turkey, etc. (70–76). It has been argued that the exposure to biomass fuel has larger risk for COPD than tobacco smoking (11). It has also been suggested that the women with domestic exposure to combustion of biomass fuel may develop COPD with clinical characteristics and have impaired quality of life with increased mortality similar in extent to those of the tobacco smokers (77). Women exposed to biomass smoke are even reported to have more local scarring and pigment deposition in the lung parenchyma and fibrosis in the small airway wall (78).

In a large study of 3608 nonsmoking Indian women involved in domestic cooking, 13% participants reported respiratory symptoms (79). Further, increased prevalence of COPD-related respiratory symptoms and deteriorated lung function have been reported among Indian women using biomass fuel for cooking compared to controls (80, 81).

In rural areas of developing countries, biomass fuel burning is often carried out in indoor environment with open fire using poorly functioning stoves with limited ventilation facilities (61). Due to socio-cultural reasons, rural Indian women are exposed to fuels for 30-40 years throughout their life equivalent to ~60,000 hours, starting from a very early age in an enclosed space with poor ventillatory facilities and seasonal variations (80). The common type of cooking devices used are ­kerosene stoves (wick type or pressure type), coal lighted angithi, gas stoves operated with liquid petroleum gas (LPG) and chullas in which biomass fuels are used (80). Biomass fuel usually involves wood, crop residues and animal dung whose burning emits a variety of toxins due to their low combustion efficiency.

It is estimated that biomass fuel is used in over 70% of Indian homes for cooking and heating purposes (59). Further, 90% of rural and 32% of urban households use biomass stoves for cooking purpose (82). In rural India, 62% of households use firewood and 14% cook with dung cakes while 13% use straw, shrubs, grass and agricultural crop residues to fire their stoves. In urban India, 22% use firewood, 8% use kerosene and the rest uses cleaner fuels such as LPG or natural gas (83) for cooking and heating purpose.

Biomass smoke contains a large number of pollutants including ambient particulate matter of less than 10 μm in aerodynamic diameter (PM₁₀), carbon monoxide, nitrogen dioxide, sulfur dioxide, formaldehyde, asbestos fibers, microorganisms, allergens and polycyclic organic matter, including carcinogens (84, 85). WHO safety standards specify that the PM₁₀ concentration is 150 μg/m³ in 24 hours (5). Environment Protection Agency (EPA) safety standards specify that the carbon monoxide concentration should be no more than 10 ppm in 8 hours (5). However, burning of biomass fuel generates a mean concentration of 300–3000 μg /m³ PM₁₀ in 24 hours and concentrations of 30,000 μg/m³ can be reached during cooking periods depending on the type of fuel, ventilation and duration of combustion (86). In homes using biomass fuel, concentration of carbon monoxide can be 2–50 parts per million (ppm) in 24 hours and 10–500 ppm during cooking (63).

Evidence from south Indian states inform that the concentration of respirable particulate matter (RPM) ranges from 500–2000 μg/m³ during cooking with biomass fuel in households, which on 24 hours’ of exposure ranged from 90 ± 21 μg/m³ for those not involved in cooking to 231 ± 109 μg/m³ for those who cooked in Tamil Nadu (87). In Andhra Pradesh, the mean 24 hours’ average concentrations ranged from 73–732 μg/m³ in gas versus 80–573 μg/m³ solid fuel using households, respectively (88).

Even among biomass fuels the severity of pollutants varies. For instance, benzene concentration in indoor kitchen using wood fuel was found to be significantly lower (p < 0.01) in comparison to dung fuel used in variety of Indian kitchen facilities (89, 90). Indoor mean concentrations of PM_2.5 and associated Poly Aromatic Hydrocarbon (PAH) during cooking ranges from 1.19 ± 2.29 to 2.38 ± 0.35 μg/m³ among biomass fuel users and 6.21 ± 1.54 to 12.43 ± 1.15 μg/m³ among plant material users in rural north Indian homes. Similarly, PM₁₀ and total PAH ranges from 3.95 ± 1.21 to 8.81 ± 0.78 μg/m³ and 7.75 ± 1.42 to 15.77 ± 1.05 μg/m³, respectively (91).

The blood carboxy hemoglobin concentrations in non-smoking healthy females from Chandigarh and its adjoining areas in India exposed to different types of cooking fuel were 2-5 times significantly higher than those in non-smoking healthy unexposed females (who had not done any cooking seven days prior to investigation) (84). The observed carboxy hemoglobin values were 7.52% (0.67%) for kerosene, 15.74% (0.83%) for biomass fuel and 17.16% (0.62%) for liquid petroleum gas, compared with 3.52% (0.33%) in the control subjects (84).

The FVC values are reported to be the worst in biomass and mixed fuel users as compared to other groups, for instance, a negative correlation between lung function, cooking duration and exposure index, was reported among rural Indian women (80). The Pondicherry urban slums of India using biofuels experienced more respiratory symptoms (23%) than those using kerosene (13%; p > 0.05) or LPG (8%; p < 0.05). Moreover, the values of lung function were significantly lower in biofuel users compared with both kerosene (p < 0.01) and LPG users (p < 0.001) (81). Further, COPD prevalence was higher in biomass fuel users than the clean fuel users 2.5 vs. 2% (Table 2) and it was two times higher (3%) in women who spend >2 hours/day in kitchen while cooking in Tamil Nadu, India (8).

Interestingly, a cytogenetic analysis (micronucleus and chromosomal aberration) have reported higher frequency of DNA damage in biomass fuel users exposed for > 5 years compared to LPG in Indian women (92). A minimum required biomass exposure index of 60 has been identified which is significantly associated with chronic bronchitis after adjusting for age, passive smoking and occupational exposure. In the district of Mysore in Karnataka state of India, it was observed that one in every 20 non-smoking women having biomass fuel exposure index of ≥110 develops chronic bronchitis (93).

The heavy dependency on the use of biomass fuel in rural parts of India is due its negligible cost, high availability and its involvement in the socio-cultural milieu of people's life from centuries. Thus, taking biomass fuel out of people's life will be a challenge, but we can certainly explore the possibilities to avoid its exposure. Therefore, India needs to develop a policy for separate kitchen on the lines of separate toilets for hygiene, with proper ventilation and promote the use of chimneys for both cooking and heating purposes.

Environmental tobacco smoke exposure

Passive smoke or environmental tobacco smoke exposure among non-smokers, especially in women and children, is very common in Asian countries including India (94). Among over 7000 chemicals identified in second hand tobacco smoke, at least 250 of them are known to be harmful (61). Parental smoking is reported to result in significant decline in FEV₁ among children (94, 95). The additional exposure to second hand smoke has been reported to further increase the prevalence of COPD among biomass fuel users (3.9% in biomass fuel users and 4.8% in addition of regular passive smoking) in rural areas of southern India in Mysore (49).

Outdoor Air Pollution

The evidences from both longitudinal and cross sectional studies support the association of high concentration of outdoor air pollutants with COPD exacerbation and worsening of pre-existing COPD (96–99). Air pollution has been consistently increasing in developing countries attributable to industrialization and traffic congestion, specifically in Asia (100). This has raised the gaseous and particulate matter component concentrations of urban ambient air which is associated with increasing respiratory morbidity (101). Moreover, strong evidence exists for adverse effects of outdoor and traffic-related air pollution on lung development in children (97, 98). The deleterious effects of particulate pollutants, such as ozone and nitrogen-dioxide, on airway are also known, such as, increase in bronchial reactivity (102), airway oxidative stress (103), pulmonary and systemic inflammation (104, 105), amplification of viral infections (106) and reduction in airway cilliary activity (107).

India is listed as heavily polluted along with other South Asian countries in a global air pollution survey conducted by WHO (108), where 13 out of 20 most polluted cities were from India. Studies conducted in capital city, Delhi, showed comparatively higher prevalence of respiratory symptoms in its higher pollution zones (72) and an increase of 24.9% in emergency room visits for COPD due to higher levels of outdoor pollutants (109). Suspended particulate matter (SPM) together with relative humidity were found to explain 33% variability in COPD in Delhi during the assessment of hospital admissions attributed to respiratory morbidity from 2000–2003 (13) and significant correlations were reported for various pollutants (see Table 2). A couple of studies have also been reported from Mumbai, another metropolitan city of India, presenting the high prevalence of COPD (110) and the health expenditure burden attributable to air pollution (111).

The outdoor air pollution in Indian cities is difficult to control, due to their large population size, constantly increasing population density of cities, the rising needs for livelihood of people and high sentiments attached to sociocultural activities. The role of Indian government is extremely important at least in gradually transforming unplanned cities to planned cities keeping public health as major criteria for restructuring the urban landscape. In addition, India needs a policy on migration for restricting the constantly expanding city area by developing facilities compatible to the aspiring rural India.

Occupational Hazards

There is an established relationship between COPD and occupational exposure to toxic gases at workplace (112), grain dust in farms (57) and dust or fumes in factories (113). Occupational agents may act similar to smoking, requiring other promoting factors before an effect is seen (114).

India is the largest producer of pesticides in Asia and is third largest consumer in the world (115), which overall affects the respiratory health of the population. COPD prevalence has been seen higher (p < 0.001) among agricultural workers spraying cholinesterase-inhibition pesticides (18.1%) compared to controls (6.9%) in Eastern India (116). Further, 22% of farm laborers and 31% of cotton/jute workers were found to have deteriorated lung function (FEV₁/FVC < 0.7) in a study conducted in West Bengal (117). High prevalence of chronic bronchitis in different sub-occupational groups of brassware workers (118) and ventillary dysfunction among glass bangle workers (119) have also been reported in India. The long term exposure of metal dust was evaluated among metal polish workers in 25 brass and steel ware polishing industries at Moradabad and unexposed controls in North India, where 6.7% of polishers were found to have chronic bronchitis (120). A total of 58.6% polishers had one or more respiratory symptoms like chronic cough and chronic phlegm compared to only 25.5% of the controls (p < 0.05). In addition, the polishers exhibited significantly greater reductions in lung function over the work shift (120). A higher prevalence of chronic bronchitis has also been seen among railway workers (16.7%) compared to controls (8.9%) in India; as the peak expiratory flow rate <300L/min was observed in 54.6% railway workers compared to only 2.2% in controls (121).

Thus, the exposure to occupational factors has serious ill respiratory effects on the health of workers that requires government policy ensuring the healthy working environment in Indian factories.

Socio-Economic Position

The differences in socio-economic position (SEP) is also reported to be correlated with lung function (122). The factors related to poor SEP plays important role in the development of COPD which includes poor dietary habits involving low consumption of fresh fruits while consuming food items having low anti-oxidants (123), poor housing conditions (124) and relatively more exposure of occupational dust and indoor air pollution from biomass combustion (125). These poor living conditions are also related to intra-uterine growth retardation, childhood respiratory tract infection, exposure to tobacco smoke, biomass smoke and other indoor air pollutants and occupational risks (5).

The research gap in exploring the differences in the prevalence of COPD in various socioeconomic groups needs to be addressed in India as well, where there is a huge problem of inequity.

Other Risk Factors

Male sex and increasing age are well established non-modifiable risk factors of COPD (21, 52, 54, 126). Apart from smoking, this relationship could be attributed to greater exposure to environmental and occupational pollutants among men and the cumulative effect of all risk factors with advancing age. Jain et al. (127) summarized the gender-related differences existing in COPD patients in India that included an early age of onset in females compared to males (mean age of 58.34 ± 9.99 years v/s 61.57 ± 10.37 years, p < 0.001). Females represented more dyspenea at presentation (grade 3 v/s grade 2, p < 0.001) which could be explained by relatively more bronchial obstruction (mean FEV₁ of 43.39 ± 13.28 v/s 48.42 ± 14.52, p < 0.001), more exaceberations and higher prevalence of systemic features (127).

The difference in body mass index (BMI) is also reported to be associated with the development of COPD. For instance, a hospital based study found that 83% of COPD patients were found to have BMI < 18 kg/m² in the city of Luknow in North India (128). However, the loss of body weight can also be a consequence rather than a risk factor of progression of the disease as BMI was found to be negatively correlated with duration of hospital stay (r = –0.0103, p = 0.03) (128). The positive correlation between oxidative stress and BMI in COPD status and predicted % of FEV₁ has also been reported. COPD patients were found to have increased plasma lipid peroxidation ( p = 0.006) and decreased antioxidant glutathione ( p = 0.005), glutathione peroxidase ( p = 0035) and catalase activity ( p = 0.008) in another Indian study and all these markers were found to be correlated with BMI of the patients (129).

History of pulmonary tuberculosis has been reported to be a strong predictor of COPD (130). This infection is associated with airway fibrosis and the immune response to mycobacteria which can result in airway inflammation, a characteristic of COPD (5). Similarly, chronic asthma is reported to cause lung remodeling (131) resulting in irreversible and progressive airflow obstruction and development of COPD that are similar to those resulting from smoking (132). However, treatment of asthma with corticosteroid helps in preventing irreversible airflow obstruction (133). The literature on such conditions is lacking from India but some evidence points towards the relationship between COPD and arsenicosis (chronic arsenic toxicity) resulting from consuming contaminated ground water in West Bengal region on India (134).

In last five years, due to the advent of genome-wide association studies (135–137), the genetics of COPD has moved beyond α-1 antitrypsin gene (138–142). Several genetic variants are reported to be associated with COPD in Indian population namely PIM3 allele of alpha-1-antitrypsin gene (143), GSTT1, GSTM1 and GSTM3 (144, 145), PiZ and Pi S (146), cytokine gene polymorphisms (IL1B, IL1RN, TNF-α, and IL4) (144), CYP2E1 and NAT2 (147), GSTP1 and mEPHX (148), COX2 and p53 (149), CYP1A1, CYP1A2, and CYBA (150), TIMP-1 and α1AT (151). Our group is running “COPD genetics Consortium,” in collaboration with leading hospitals in North and West India, which aims to understand genetic predisposition to COPD in India, funded by Department of Biotechnology, Government of India.

Conclusion

The available data suggest that a number of modifiable risk factors other than smoking are apparently associated with COPD in India, the most important being the use of biomass fuel. However, the lack of strong evidences demands the need of conducting a nationally representative study with appropriate methodology to estimate the effect size of each of the potential risk factor (other than smoking) that can then help in framing health policies to prevent and manage COPD in Indian population. India should develop a consortium of clinicians, epidemiologists and biological anthropologists for planning population based nation-wide study to estimate prevalence and incidence of COPD and identify significant modifiable risk factors associated with it. Such studies should use well established universal definitions and validated diagnostic criteria and procedure for measuring various risk factors. The future study design for this work may consider exposures like rural vs. urban divide, geographic or ecological variation, socio-economic inequality and ethnic diversity in Indian population.

Declaration of Interest Statement

We declare that the authors of the manuscript have no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Funding

We are thankful to Wellcome Trust, UK, for support and Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India for funding “COPD Genetics Consortium” project.