REVIEW URRENT C OPINION

Profiles of chronic obstructive lung disease: characteristics of stable chronic obstructive lung disease in different parts of Asia Arvind B. Bhome a and Bill Brashier b

Purpose of review This review discusses the recent Asian chronic obstructive lung disease (COPD) studies that characterize stable COPD, to understand its peculiarities. Recent findings Asian research has improved our understanding of COPD. Household air pollution (HAP) is as important as smoking. Smoking in Asia is varied, and noncigarette smoking exposure remains under-investigated. Prevalence studies are often questionnaire based. Spirometry-based prevalence needs study. Burden of obstructive lung disease studies are getting published. Female COPD in Asia is predominantly HAP induced. The patients are underweight, milder ’Global Initiative for Obstructive Lung Disease- class’ and have compromised health-related quality of life often with depression and anxiety, but other comorbidities do occur and are getting defined. Nonsmokers‘ COPD is often associated with small airway thickening, less emphysema, but considerable morbidity. Asian COPD may have an eosinophilic component, but its significance is unknown. There is genetic predisposition among some Asians to COPD, and among some patients to lung cancer. The emerging pandemic of lifestyle diseases demands that metabolic and cardiovascular comorbidities in COPD need investigation. Summary COPD in Asia is increasing and burdensome. It is affecting both sexes; is caused by HAP as much as smoking; causes poor quality of life and intense psychological burden; and is associated with unique patho-physiology, which will require research and action. Keywords chronic obstructive lung disease characteristics, chronic obstructive lung disease in Asia, nonsmokers’ chronic obstructive lung disease, phenotypes of chronic obstructive lung disease

INTRODUCTION That chronic obstructive lung disease (COPD) is a major killer in Asia is no longer the news [1 ,2]. But the picture of COPD in Asia is still emerging. The purpose of this review is to characterize stable COPD in Asia at the current state of our knowledge. &

CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA: MORE HETEROGENEOUS THAN ELSEWHERE? The WHO Global Infobase on COPD mortality shows that Asia is in the highest category of more than 43.9/100 000 age-standardized mortality range (China 124.6, India 90.4, Vietnam 80.2, Pakistan 68.2, Bangladesh 63.9, Indonesia 55.5, Malaysia 50.0 and Sri Lanka 60.8). Some countries of the

Association of South Southeast Asian Nations (ASEAN) (Thailand 37.2 and Philippines 25.3) are better, whereas Singapore (13.7), Korea (16.7) and Japan (4.2) certainly match the West and fare better than the Americas (USA 25.2 and Canada 16.9) (Fig. 1) [1 ]. This means there are 556 000 and 1 354 000 deaths per year in India and China, respectively, that is, more than 20% and about &

a

Indian Coalition for the study of Obstructive Lung Diseases and bChest Research Foundation, Kalyaninagar, Pune, India Correspondence to Dr Arvind B. Bhome, 401 Yashod Apartments, CTS No.70B/1B, Erandawane, Pune 411004, India. Tel: +91 9371026216, 91 0 20 25667718, 91 0 20 24338988; e-mail: [email protected] com, [email protected] Curr Opin Pulm Med 2014, 20:165–172 DOI:10.1097/MCP.0000000000000033

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KEY POINTS  COPD in Asia is burdensome and threatens to nullify growth and prosperity of Asia.  COPD in Asia is more heterogeneous than elsewhere in the world; because of the contribution of HAP, unique causative agents, unique smoking habits, poverty and the use of solid liquid fuels for cooking, heating and lighting.  The patho-physiology of smokers’ and nonsmokers’ COPD is unique and needs better characterization for best care at affordable cost.  Asians have unique susceptibility to COPD and to comorbidities, may respond differently to drugs, and need alternative approaches to smoking cessation, pollution control and comprehensive care strategies.

50% of world deaths (2 748 000 annually) [2]. The differences within Asia are not ‘gross domestic product- dependent’ alone. The Global Burden of Disease Study 2010 provides unique insight into this aspect. Globally, the childhood nutritional and communicable diseases are decreasing, although life-style diseases are increasing. COPD contributes two of every three

cases of pulmonary morbidity. Disability adjusted life years (DALYs) due to COPD are ranked third, fifth and ninth in China, India and ASEAN, respectively, as compared with ninth globally. In East Asia, Japan and South Korea, the DALYs due to COPD are decreasing but those due to cancer are increasing [3 ]. The ‘comparative risk association’ analysis as part of the same Global Burden of Disease 2010 study looked at 67 risk factors. Particulate matter less than 2.5 microns (PM2.5), household air pollution (HAP) and ozone are proven contributors to COPD DALYs. PM2.5 levels in Asia often exceed 5–30 mg/m3, which are levels proven to be diseasecausing elsewhere. Thus, HAP ranks first, third and fifth in South Asia, ASEAN and China, respectively, but fourth globally. PM2.5 ranks fourth, sixth and ninth in China, South Asia, Japan and Korea, respectively, but ninth globally. Tobacco smoke is ranked at second place in Asia as well as globally [4 ]. HAP is caused by solid fuels, liquid fuels (kerosene) and heating or lighting fuels (Wick lamps – carbon black). The studies on HAP differ in sample size, design and methodology, and some recent extensive systematic reviews and meta-analysis exist [5 ] (Fig. 2). HAP and kerosene contribute greatly to COPD in Asia [6,7]. &&

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Estimated age standardized death rate (per 100 000), chronic obstructive pulmonary disease, both sexes, 2004 Canada 16.9

EU Scandinavia < 16.3

USA 25.2

China 124.6

India 90.4

Singapore 13.7 Japan 4.2, Korea 16.7

Vietnam 80.2

Mortality (per 100 000) < 10.6 10.6 < 16.3 16.3 < 25.2

Indonesia 55.5

25.2 < 38.1 38.1 < 43.9 ≥ 43.9

6 4. 12

Source: Mathers, C.D., C. Benard, K.M. Iburg, M. Inoue, D. Ma Fat, K Shibuya, C. Stein, N. Tomijima and H. Xu, Global burden of Diseases: data sources, methods and results., 2008 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organisation concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2013. All rights reserved

0. 6 10 16.6 .3 25 .2 38 43.1 .9

Not available

Distribution of country rate

FIGURE 1. Diversity in age standardized death rates from COPD in Asia both sexes. COPD, chronic obstructive lung disease. Reproduced with permission from [1 ]. &

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Profiles of chronic obstructive lung disease in Asia Bhome and Brashier

Forest plot showing risk of COPD in population exposed to solid fuels

Forest plot showing risk of chronic bronchitis in population exposed to solid fuels Studies

OR (95% CI) Weight %

Studies separated by diagnosis criteria COPD: lung function Kiraz et al. 2003 Døssing et al. 1994 Orozco et al. 2006 Dennis et al. 1996 Liu et al. 2007 Liu et al. 2007 Ekici et al. 2005 Caballero et al. 2008 Orozco-Levi et al. 1996 Liu et al. 2007 Liu et al. 2007 Regalado et al. 2006 Orozco-Levi et al. 2006 Zhong et al. 2007 Subtotal (I2 = 91.8%; p

Turkey Saudi Arabia Spain Columbia China China Turkey Columbia Spain China China Mexico Spain China

28.90 (8.71–95.90) 17.40 (10.55–28.70) 4.50 (1.43–14.20) 3.90 (1.67–9.10) 3.10 (1 .63–5.90) 2.80 (0.84–9.30) 2.50 (1.56–4.00) 2.40 (1 .99–2.90) 1.80 (0.54–6.00) 1.70 (1 .20–2.40) 1.60 (0.80–3.20) 1.50 (0.52–4.30) 1.50 (0.49–4.60) 1.40 (1.31–1.50)

Biomass Wood Wood and charcoal Wood Biomass Coal Biomass Wood Wood Biomass Coal Biomass Charcoal Biomass

4.34 6.21 4.47 5.31 5.86 4.33 6.27 6.73 4.33 6.52 5.73 4.73 4.55 6.81

2.96 (2.01–4.37) 76.18

< 0.001)

COPO: doctor diagnosed Sezer et al. Chapman et al. Xu et al. Xu et al. Subtotal (I2 =

2004 2005 2007 2007

Turkey China China China

Biomass Coal Coal Firewood/straw

96.9%; p < 0.001) Overall (I2 = 97.3%; p < 0.001)

6.60 (2.16–20.20) 520 (4.74–5.70) 1.30 (0.77–2.20) 0.70 (0.45–1.10)

4.55 6.80 6.15 6.31

229 (0.70–7.52)

23.82

2 3 4 5 8 10 20 30

Nepal

7.87 (4.67–13.26)

5.70

Dutt et al.

1996

India

4.17 (0.46–38.02)

0.69

Perez-Padilla et al.

1996

Mexico

3.90 (2.00–7.60)

4.48

Uzun et al.

2003

Turkey

3.36 (1.80–6.26)

4.83

Akhtar et al.

2007

Pakistan

3.32 (1.12–9.88)

2.33

Golshan et al.

2002

Iran

2.91 (1.92–4.40)

6.79

Akhtar et al.

2007

Pakistan

2.51 (1.64––3.83)

6.69

Ekici et al.

2005

Turkey

2.50 (1.56–4.00)

6.20

Albalak et al.

1999

Bolivia

2.50 (1.25–5.00)

4.29

Akhtar et al.

2007

Pakistan

2.38 (1.88–3.01)

8.67

QUreshi

1994

India

2.10 (1.50–2.94)

7.61

Akhtar et al.

2007

Pakistan

2.01 (1.67–2.42)

9.12

Cetinkaya et al.

2000

Turkey

1.96 (1.36–2.82)

7.32

Kiraz et al.

2003

Turkey

1.90 (1.20–3.01)

6.30

Menezes et al.

1994

Brazil

1.49 (0.92–2.41)

6.10

Menezes et al.

1994

Brazil

1.30 (0.74–2.27)

5.38

Behera and Jindal

1991

India

1.18 (0.83–1.67)

7.49

2.32 (1.92–2.80) 100.00

1

Log of odds ratio

Weight %

1984

Overall (I2 = 68.9%; p < 0.001)

2.80 (1.85–4.23) 100.00

1

OR (95% CI)

Pandey

2

3 4 5 7 10

20 30 40

Log of odds ratio

FIGURE 2. Meta-analysis of 23 studies of HAP in COPD. Ten studies reported COPD based on both physician diagnosis and spirometry, 11 reported chronic bronchitis based on respiratory questionnaire data and two reported both COPD and CB. The pooled effect estimate for lung function diagnosed COPD (OR 2.96) was greater than those diagnosed by a doctor (OR 2.29), with a combined pooled effect estimate of 2.80 for COPD (left panel). The pooled effect estimate for CB was 2.32 (right panel). COPD, chronic obstructive lung disease; OR, odds ratio; HAP, household air pollution. Modified with permission from Kurmi OP, Semple S, Simkhada P, et al. COPD and chronic bronchitis risk of indoor air pollution from solid fuel: a systematic review and meta-analysis. Thorax 2010; 65:221–228.

CURRENT GAPS IN KNOWLEDGE OF CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA Many prevalence studies of COPD from Asia are poor in methodology. Recently, McKay et al. [8] attempted to estimate the COPD prevalence in India, and could not identify a single study with spirometric definition of COPD. Large population surveys from the Middle East and North Africa region [the BREATHE study, a ten country study with the Arabic acronym BREATHE – Algeria, Egypt, Jordan, Lebanon, Morocco, Saudi Arabia, Syria, Tunisia, Turkey, United Arab Emirates and Pakistan] [9], based on symptoms questionnaires but not spirometry, indicate low prevalence. The same applies to the ‘Indian study on epidemiology of asthma, respiratory symptoms and chronic bronchitis in adults’ (INSEARCH; 11 Indian cities), with a prevalence of 3.49% [10]. Luckily, the Burden of Obstructive Lung Disease (BOLD) protocol has generated uniformity in study designs, providing realistic data using postbronchodilator FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity ratio) of less than 70%, from an increasing number of Asian countries joining continuously; a recent addition was Kashmir, North India, with 19% prevalence [11]. Many populationbased studies, however, indicate rampant underdiagnosis [12–14]. The causes may be lack of

spirometry equipment, skills or knowledge, not probing the variety of smoking choices available during surveys, and nonsmokers’ COPD.

SMOKING AND CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA A recent Global Adult Tobacco Survey (GATS) indicated smoking rates vary from 64% in Indonesia to 22% in Nepal (men), and 10% in the Philippines to 1% in Bangladesh (women). India has 111.2 million smokers (99.9 men and 11.3 women) consuming 105 billion cigarettes and 553 billion bidis annually. The GATS China report indicates that 53% of men and 2.4% of women are smokers (86% daily), with the COPD age group (>45 years) smoking heavily [15]. Many Asians smoke tobacco through filterless local cigarettes (bidis), water pipes (hookahs/shisha) and kerkets (Fig. 3). The bidi is common in India, with tobacco rolled in Tendu leaves (Diospyros elanoxylon). The bidi produces three times more carbon monoxide and five times more tar compared with a cigarette. To keep it lit, one has to take deep inspirations. Burnt tobacco and Tendu leaves generate more particulates and toxins that deposit more distally in the small airways and lung parenchyma. The Global Youth Tobacco Study-India (2005 – 10–13 year-old youths) showed 8.3% were

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Havana cigar, handcrafted pipe, ancient chutta and cigarette

Portable hukkah/shisha Sitting hukkah/shisha - Water pipe Relative sizes bidi unfiltered, bidi filtered-herbal, cigarette

FIGURE 3. Smoking choices for Asians.

smokers (2.3% bidis), of which 12.5% were frequent smokers and 50% nicotine dependent [16]. Tendu leaves emit naphthoquinones, coumarins and volatile organic compounds. Bidis generate hydrogen cyanide, phenols and polyaromatic hydrocarbons. Water-pipe smoking (hookah/shisha) allows a larger smoke volume inhalation (50–100), higher nicotine dose (10), contains carcinogens, carbon monoxide and aldehydes, and is associated with COPD, cancer and periodontitis [11,17–21]. A retrospective study showed that water-pipe smoking predisposes to ischaemic heart disease (IHD) and COPD similar to cigarette smoking [22]. A meta-analysis of six studies showed that compared with nonsmokers, water-pipe smokers had poorer lung function similar to cigarette smokers, with nicotine craving being equally high [23].

female COPD patients did prove that the biomass exposed patients have less emphysema and more air-trapping with less symptoms such as cough, but more desaturation and may have bronchial hyperresponsiveness (BHR) [25]. The Asian Network of Obstructive Lung Disease (ANOLD) study showed that COPD patients exposed to biomass and dusty jobs had more frequent symptoms, more severe airflow limitation and poorer quality of life than those not exposed [26]. The patho-physiology of nonsmokers’ COPD is still evolving, with probably same level of oxidative stress as smokers’ COPD. Also, new toll-like receptor and apoptosis-based pathways are being investigated for the mechanism of HAP-induced COPD [27 ]. This will help us to better understand nonsmokers’ COPD. &

NONSMOKERS’ CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA

THE CLINICAL PROFILE OF CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA: VARIATION WITHIN ASIA

HAP-induced COPD has been gathering attention lately. A meta-analysis of 23 studies on HAP-induced COPD and chronic bronchitis showed good correlation of pulmonary function tests and physician diagnosis, with questionnaire method coming third [5 ] (Fig. 2). Presumably, Asian COPD in women is HAP induced. This nonsmokers’ COPD is similar to smokers’ COPD in clinical features, spirometry, inflammation and systemic manifestations. It is more likely to have small airway obstruction than emphysema [5 ,24 ]. A computed tomography (CT) functional imaging study of biomass exposed and nonexposed

The BREATHE study showed that 47.5% of COPD patients were frequent exacerbators, 5.5% were severely dyspnoeic, 28.4% reported lost workdays, 47.9% found routine exhausting, 37.5% dreaded socializing, 31.7% avoided family gatherings, and 42.3–53.2% reported psychological distress with COPD Assessment Test scores of 16.2  9.1– 20.9  10.2 suggesting poor health-related quality of life (hrQOL) [28]. The ANOLD study (922 COPD patients and seven cities– pulmonology clinics) showed that smokers’ COPD was largely of ‘Global Initiative for Obstructive Lung Disease (GOLD) class II’ disease severity, 40% had cough, 48–49% had

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phlegm, 21–22% were classified as chronic bronchitis, 71–72% had wheeze; and dyspnoea on the Medical Research Council scale was I to II for many (> 50%), grade IV for 6% and grade 0 for 15%. The median Saint George’s Respiratory Questionnaire score was 36.2 with variation among countries. Philippines had worse hrQOL and dyspnoea than Japan, maybe because of different healthcare systems. The best hrQOL was in China and the worst in the Philippines, although the Japanese hrQOL being worse than the Chinese needs further analysis [26].

THE CLINICAL PROFILE OF CHRONIC OBSTRUCTIVE LUNG DISEASE IN ASIA VERSUS THE WEST An Indian study measured hrQOL and dyspnoea – both by two methods each – and found good correlation with severity of disease, but not with age, comorbidities, illiteracy and smoking quantity, raising questions whether Indian patients do have poorer hrQOL than Western ones for the same GOLD category [29]. Whether hrQOL indicates COPD care or socio-cultural issues is also not clear. All Asian COPD studies report lower BMI for the same GOLD class as the West, suggesting poor prognosis with higher mortality, but dietary and anthropometric differences need to be ruled out.

SPUTUM CYTOLOGY PHENOTYPES The high eosinophil count in induced sputum even in smokers’ COPD seen in Asia may resemble asthma. A Chinese study showed that eosinophils in induced sputum cannot differentiate between asthma and COPD even though COPD is primarily noneosinophilic (< 3% eosinophils) [30]. The reason is unknown and may indicate a reversible component. As most studies of COPD exclude individuals with reversible airflow obstruction and diagnosed asthma, HAP and endotoxins in poorly ventilated homes may also cause recruitment of eosinophils. Previously, a Japanese study of 33 COPD patients showed increased eosinophilic cationic protein – suggesting eosinophilic inflammation as in asthma, although HAP may not have a role in Japan. Conversely, recent COPD data from Nepal (high HAP) showed patients with sputum neutrophilia as opposed to eosinophilia in induced sputum [31]. Currently, it would be premature to suggest any evidence of geographic variation in inflammation, although eosinophils may have an important role in the pathogenesis of Asian COPD indicating steroid responsiveness and/or BHR as suggested by a Chinese study in the past (54.5% of 33 COPD patients showing BHR). This BHR in COPD may not be related to noneosinophilic

factors, and the correlation between presence of eosinophils and BHR or airflow has not been proven yet.

FUNCTIONAL IMAGING PHENOTYPES COPD phenotype definition by CT functional imaging has been studied by many researchers worldwide. Most studies describe emphysema with three primary high resolution CT phenotypes in COPD, A type (airway dominant and emphysema absent), E type (emphysema dominant) and M type (mixed). The A phenotype mostly includes nonsmokers with higher BMI, eosinophils in sputum, wheeze and response to steroids. The E type usually has fixed airway obstruction, refractory to steroids and no cough with sputum. The M phenotype usually has the lowest spirometry, higher airway inflammation and is more bronchodilator and inhaled corticosteroids responsive than A and E. This approach employs emphysema severity indices based on low attenuation area percentages. Previously, researchers have shown that emphysematous phenotypes E and M fare worse than A phenotype in terms of BMI, dyspnoea, spirometry parameters, lower inspiratory capacity/ total lung capacity (IC/TLC) ratio and higher residual volume (RV)/TLC ratio [higher dynamic hyperinflation (DHI)], and the E phenotype is the worst among them in terms of dyspnoea, spirometry, DHI and IC/TLC ratio. Additionally, the luminal area and wall area percentages as CT parameters of bronchial wall thickening have been shown to correlate with FEV1%, with luminal area and wall area percentages of sixth-generation bronchus correlating better with FEV1% than third, as COPD affects smaller airways predominantly. The Hokkaido study had earlier described phenotypes of COPD based on emphysema severity and showed the poor correlation between FEV1% or GOLD class and emphysema, but good correlation of emphysema severity with low BMI and poorer hrQOL. Nishimura et al. [32 ] from the same group recently demonstrated that CT and diffusion factor in lung for carbon monoxide (DLCO)-based emphysema severity can differentiate rapid annual FEV1 decliners from slow decliners and sustainers (nondecliners). This was never possible with FEV1%-based GOLD classification. A study from Taiwan last year, correlated CT with 6-min walking distance and lung function, and showed that walking ability of COPD patients negatively correlated with emphysema severity but positively with inspiratory capacity and FEV1% predicted. This could mean that COPD causes DHI and ventilation perfusion defects, which together decrease effort tolerance. The emphysema severity can

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reduce the anaerobic threshold and maximal oxygen utilization during exercise in COPD patients. The presence of emphysema reduces the IC/TLC ratio and increases the RV/TLC ratio, which are physiological markers of DHI. However, emphysema may not be able to predict the mortality of COPD in Asia [33]. Fan et al. [34] have recently combined CT and MRI imaging to calculate not only the emphysema index but also perfusion defects in the lungs and correlated the same with spirometry, TLC and DLCO, to show that perfusion defects and poorer lung function occur with E and M phenotypes but not with A. Kurashima et al. [35 ] focused attention on Di (inner diameter) and Ai (luminal area) from third, fifth and sixth-generation bronchi to show that asthma airways are narrower than COPD, and fifth-generation Di and Ai correlated best with mid-expiratory flow rates of 50 and 25%, whereas wall area percentage was increased in COPD but not in asthma. There are no data on functional imaging of indoor-air pollution and dusty occupation phenotypes of COPD, specifically, even though Camp et al. [24 ] and Kurmi et al. [5 ] have shown that these phenotypes have more small airway thickening than emphysema.

of 1100 patients, there was increased anxiety, depression and poor hrQOL [42]. In rural China, 7597 patients showed that age, dyspnoea and lung function were related to anxiety (r ¼ 0.972) and depression (r ¼ 0.989) [43]. A prospective geriatric study from Singapore recently showed that high levels of interleukin-6 and C-reactive protein induced depression and enhanced risk of bronchospasm independent of smoking status, BMI and other inflammatory diseases [44]. These comorbidities cause a vicious cycle of immobilization, lost autonomy, low self-esteem, emotional lability, exacerbation and systemic inflammation.

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COMORBIDITY PATTERN OF ASIAN CHRONIC OBSTRUCTIVE LUNG DISEASE The profile of stable Asian COPD differs in this aspect as well, both from the West and within Asia.

Lung cancer and chronic obstructive lung disease: shared cause, shared prevalence? Lung cancer and COPD have a shared cause of smoke exposure, and hence their association is often investigated. Previous COPD, emphysema and chronic bronchitis were associated with a cancer diagnosis (odds ratio of 1.29, 1.55 and 1.22, respectively), and asthma with decreased odds in a retrospective study [45]. A review of lung cancer patients from Fudan showed that 21.6% had spirometric discharge diagnosis of COPD [46]. Such association forms the basis of genotyping studies as well, and CHRNA3 was associated with COPD and lung cancer in China and Korea [47 ,48 ], whereas a study from Hong Kong did not find increased risk of lung cancer in nonsmoking females when compared with smokers (male/female) [49]. &

&

Metabolic syndrome COPD affects multiple systems. A Korean National Health and Nutrition Study showed prevalence of metabolic syndrome in men with only abdominal obesity [36].

Anxiety and depression in chronic obstructive lung disease Sekhar et al. [37] showed that 56% of COPD individuals had at least two comorbidities, 50% had depression, 44% anaemia, 32% hypertension, 15% diabetes and 7% IHD. Han et al. [38] demonstrated that alexithymia is quite common in COPD. In Taiwan, depression increased 1.88-fold in COPD [39]. Sharma et al. [40] evaluated the mental health of 391 Indian patients and found a higher psychiatric comorbidity of 44.8% (anxiety 20.6%, depression 13.2% and obsessive disorder 4.6%). A study from Guangzhou of 7995 patients showed that self-reported physician diagnosis of COPD and symptom perception are the main determinants of depression but not FEV1 [41]. In a Xuzhou study 170

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Miscellaneous comorbidities Other comorbidities described in some studies were gastroesophageal reflux disease [50,51], psoriasis [52] and osteoporosis [53], but this does not mean a cause–effect relationship.

CONCLUSION With so much heterogeneity in Asian COPD, phenotype definition holds the key to maximize therapeutic benefits. The multiple ongoing cohort studies may enable us to characterize COPD leading to personalized treatment and rehabilitation, and reduce the burden of DALYs by reducing smoking, ambient and household pollution, thus helping Asians achieve healthy prosperity. Acknowledgements B.A.B. represents India at the Asian Network for Obstructive Lung Diseases (ANOLD) and is principal investigator for the proposed ICOLD study in India and convener of Indian Coalition for Obstructive Lung Volume 20  Number 2  March 2014

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Disease: a multiinstitutional pan-national initiative involving Chest Research Foundation, Pune; National Institute of Epidemiology, Chennai; Indian Institute of Genomics and Integrative Biology, New Delhi; Sher-e-Kashmir Institute of Medical Sciences, Srinagar, Kashmir; North Eastern Indira Gandhi Institute of Health and Medical Sciences, Shillong, Meghalaya. He gratefully acknowledges the support of these organizations. B.B. is director of academics and molecular and basic research at Chest Research Foundation, Pune and is Principal Coordinator for the ICOLD study network. He joins the principal author in acknowledging the support of the above organizations. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mathers CD, Bernard C, Iburg KM, et al. Updated projections of global & mortality and burden of disease, 2002-2030: Data sources, methods and results. Evidence and Information for Policy Working Paper, World Health Organization, October 2005. WHO Global Infobase updated on 20th January 2011. Available online: https://apps.who.int/infobase/Index.aspx. [Accessed 10 November 2013]. An important overview of the global mortality estimates and projections for the next couple of decades. 2. Bhome AB. COPD in India: iceberg or volcano? J Thorac Dis 2012; 4:298– 309. 3. Murray CJL, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for && 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2197– 2223. This is a must read for anyone who wants to understand the disease burden dynamics of 291 causes of disease and injuries expressed as DALYs in, 20 age groups, both sexes, 187 countries from 1990–2005 to 2010 in a global burden series capturing premature mortality, prevalence and severity of ill-health. The article is in a series of articles that has shaped global health policy over the last two decades and is a unique global collaboration spanning across all continents and most countries. 4. Lim SS, Vos T, Abraham D, et al. A comparative risk assessment of burden of && disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2224–2260. && This is in the same league as [3 ] It quantifies disease burden – deaths and DALYs – in terms of 67 risk factors and their clusters causing those diseases of global significance. This exercise has been done comparing how these risks have changed with the changing disease profiles from 1990 to 2010. A must read for the clarity of understanding the global health issues and formulating the policy for prevention and mitigation. 5. Kurmi OP, Lam KBH, Ayres JG. Indoor air pollution and the lung in low- and && medium-income countries. Eur Respir J 2012; 40:239–254. This article is in a series on air pollution and lung disease of special importance, as it provides a comprehensive review of literature on indoor pollution and discusses issues relevant to understand the scattered literature on the subject with multiple variables. Although not Asia specific, it contains a very useful discussion on many Asian studies. A must read for anyone interested in nonsmokers’ COPD. 6. Lam NL, Smith KR, Gauthier A. Kerosene: a review of household uses and their hazards in low and middle income countries. J Toxicol Environ Health B Crit Rev 2012; 15:396–432. 7. Lam N, Chen Y, Weyant C, et al. Household light makes global heat: high black carbon emissions from kerosene wick lamps. Environ Sci Technol 2012; 46:13531–13538. 8. McKay AJ, Mahesh PA, Fordham JZ, Majeed A. Prevalence of COPD in India: a systematic review. Prim Care Respir J 2012; 21:313–321.

9. Tageldin MA, Nafti S, Khan JA, et al., BREATHE Study group. Distribution of COPD-related symptoms in the Middle East and North Africa: results of the BREATHE study. Respir Med 2012; 106 (Suppl. 2):S25–S32. 10. Jindal SK, Aggarwal AN, Gupta D, et al. Indian study on epidemiology of asthma, respiratory symptoms and chronic bronchitis in adults (INSEARCH). Int J Tuberc Lung Dis 2012; 16:1270–1277. 11. Koul PA. Chronic obstructive pulmonary disease: Indian guidelines and the road ahead. Lung India 2013; 30:175–177. 12. Brashier B, Londhe J, Madas S, et al. Prevalence of self-reported respiratory symptoms, asthma and chronic bronchitis in slum area of a rapidly developing Indian city. Open Journal of Respiratory Diseases 2012; 2:73–81. 13. Yang G, Wang y, Zeng Y, et al. Rapid health transition in China, 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2013; 381:1987–2015. 14. Kiyohara K, Kojimahara N, Sato Y, Yamaguchi N. Changes in COPD mortality rate after amendments to the Preventive Vaccination Law in Japan. Eur J Public Health 2013; 23:133–139. 15. Global Adult Tobacco Study 2013. http://www.who.int/tobacco/surveillance/gats/en/ and http://www.who.int/tobacco/global_report/2013/en/index.html. [Accessed 30 November 2013] 16. Global Youth Tobacco Survey 2005. http://www.who.int/fctc/reporting/Annexoneindia.pdf. [Accessed 30 November 2013] 17. Jawad M, Jawad S, Mehdi A, et al. A qualitative analysis among regular waterpipe tobacco smokers in London universities. Int J Tuberc Lung Dis 2013; 17:1364–1369. 18. Boskabady MH, Farhang L, Mahmodinia M, et al. Comparison of pulmonary function and respiratory symptoms in water pipe and cigarette smokers. Respirology 2012; 17:950–956. 19. Jawad M, Abass J, Hariri A, et al. Water-pipe smoking: prevalence and attitudes among medical students in London. Int J Tuberc Lung Dis 2013; 17:137–140. 20. Abughosh S, Wu I-H, Peters RJ, et al. Ethnicity and water-pipe smoking among US students. Int J Tuberc Lung Dis 2012; 16:1551–1557. 21. Khabour OF, Alzoubi KH, Eissenberg T, et al. Water-pipe tobacco and cigarette smoking among university students in Jordan. Int J Tuberc Lung Dis 2012; 16:986–992. 22. Mahmud T, Bokhari SN, Aasim M. Comparison of frequency of undiagnosed chronic obstructive pulmonary disease in current or former tobacco smokers having ischaemic heart disease. Indian J Chest Dis Allied Sci 2012; 54:111– 116. 23. Auf RA, Radwan GN, Loffredo C, et al. Assessment of tobacco dependence in waterpipe smokers in Egypt. Int J Tuberc Lung Dis 2012; 16:132– 137. 24. Camp PG, Ramirez-Venegas A, Sansores RH. COPD phenotypes in biomass && smoke- versus tobacco smoke-exposed Mexican females. Eur Respir J 2013; doi: 10. 1183/09031936.00206112 [Epub ahead of print] This study tested nonsmoker biomass exposed COPD female patients and controlled matched ex-smoker COPD female patients never exposed to biomass fuel with CT functional imaging software and proved that biomass exposed COPD patients had very little emphysema (0.7 versus 2.3, P ¼ 0.001) and more airway wall thickening with air trapping (2.6 versus 1.5, P ¼ 0.02) as compared with smoking-induced COPD patients, and also had lower symptom scores, hrQOL and more desaturation at rest and exercise (P < 0.05). 25. Gonza´lez-Garcı´a M, Torres-Duque CA, Bustos A, et al. Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to woodsmoke. Int J Chron Obstruct Pulmon Dis 2012; 7:367–373. 26. Oh YM, Bhome AB, Boonasawat W, et al. Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities. Int J Chron Obstruct Pulmon Dis 2013; 8:31–39. 27. Sussan TE, Ingole V, Kim JH, et al. Source of biomass cooking fuel determines & pulmonary response to household air pollution. Am J Respir Cell Mol Biol 2013. [Epub ahead of print] This animal exposure experiment by Indian and US researchers mimicked human exposure to wood smoke and cow-dung cakes by replicating the same in mice to first establish the effect of acute exposure resulting in robust proinflammatory cytokine production, neutrophilic inflammation, airway resistance and hyper-responsiveness, all of which were higher in cow-dung exposed mice in comparison to wood smoke exposed. As opposed to this, subchronic exposure resulted in more changes in wood smoke exposed mice than cow-dung exposed mice; and were characterized by eosinophilic inflammation, PM-specific antibody responses and alveolar destruction. Mechanisms that underlie this were studied by using mice deficient in 5 receptors [toll-like receptors (TLR)-2,3,4,5 and IL-1R], of which three receptors were found to demonstrate inflammatory responses via My88 on exposure to wood smoke or cowdung, viz. IL-1R, TLR-4 and TLR-2. The authors conclude that subchronic exposure to PM collected from households burning biomass fuel elicits a persistent pulmonary inflammation largely through activation of TLR and IL-1R pathways, which could increase the risk for chronic respiratory diseases. 28. Uzaslan E, Mahboub B, Beji M, et al., BREATHE Study Group. The burden of chronic obstructive pulmonary disease in the Middle East and North Africa: results of the BREATHE study. Respir Med 2012; 106 (Suppl 2): S45–S59. 29. Shavro SA, Ezhilarasu P, Augustine J, et al. Correlation of health related quality of life with other disease indices in Indian chronic obstructive disease patients. Int J Chron Obstrct Pulmon Dis 2012; 7:291–296.

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Obstructive, occupational and environmental diseases 30. Cao Y, Gong W, Zhang H, et al. A comparison of serum and sputum inflammatory mediator profiles in patients with asthma and COPD. J Int Med Res 2012; 40:2231–2242. 31. Neopane A, Sharma L, Dulal S, et al. Value of sputum differential count in chronic obstructive airway disease. J Nepal Health Res Counc 2013; 11:26– 29. 32. Nishimura M, Makita H, Nagai K, et al. Annual change in pulmonary function && and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185:44–52. This recent study from the Hokkaido study shows the annual decline in FEV1-based classification into rapid, slow and nondecliners can be correlated with emphysema severity rather than FEV1%. DLCO also varied with emphysema severity and correlated well with CT changes. Rapid decliners were independently associated with CT-based or DLCO-based emphysema severity. 33. Chen LF, Wang CH, Chou PC, et al. Association between emphysema score, six-minute walk and cardiopulmonary exercise tests in COPD. Open Respiratory Medicine Journal 2012; 6:104–110. 34. Fan L, Xia Y, Guan Y, et al. Characteristic features of pulmonary function test, CT volume analysis and MR perfusion imaging in COPD patients with different HRCT phenotypes. Clin Respir J 2013. [Epub ahead of print] 35. Kurashima K, Hoshi T, Takayanagi N, et al. Airway dimensions and pulmonary & function in chronic obstructive pulmonary disease and bronchial asthma. Respirology 2012; 17:79–86. Patients with COPD have wall thickness without narrowing from third to sixth generations of bronchi. Asthma patients have narrow airways, with fifth generation corresponding with FEV1 the most. Mixed asthma with emphysema patients had sixth-generation airways correlated best with pulmonary function. 36. Park BH, Park MS, Chang J, et al. Chronic obstructive pulmonary disease and metabolic syndrome: a nationwide survey in Korea. Int J Tuberc Lung Dis 2012; 16:694–700. 37. Sekhar TVDS, Bokam B, Muppalla LL, et al. Comorbid conditions in patients with physician diagnosed COPD: data from a tertiary centre in South India. Int J Med Sci Public Health 2013; 2:738–742. 38. Han D, Zhang Y, Li B, et al. Alexithymia in Chinese chronic obstructive pulmonary disease (COPD) patients: the prevalence and related factors of alexithymia. Psychiatry Res 2012; 198:274–278. 39. Tsai TY, Livneh H, Lu MC, et al. Increased risk and related factors of depression among patients with COPD: a population-based cohort study. BMC Public Health 2013; 13:976. 40. Sharma BB, Singh S, Sharma VK, et al. Psychiatric morbidity in chronic respiratory disorders in an Indian service using GMHAT/PC. Gen Hosp Psychiatry 2013; 35:39–44. 41. Loerboks A, Jiang CQ, Thomas GN, et al. COPD and depressive symptoms: findings from the Guangzhou Biobank Cohort Study. Ann Behav Med 2012; 44:408–415. 42. Lou P, Zhu Y, Chen P, et al. Prevalence and correlations with depression, anxiety, and other features in outpatients with chronic obstructive pulmonary disease in China: a cross-sectional case control study. BMC Pulmonary Medicine 2012; 12:53. 43. Zhang L, Lou P, Zhu Y, et al. Impact of risk factors, activities and psychological disorders on the health of patients with chronic obstructive pulmonary disease in China: a cross-sectional study. BMC Public Health 2013; 13:627.

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44. Lu Y, Feng L, Feng L, et al. Systemic inflammation depression and obstructive lung function: a population-based study. Respir Res 2013; 14:53. 45. Wang H, Yang L, Zou L, et al. Association between chronic obstructive pulmonary disease and lung cancer: a case-control study in Southern Chinese and a meta-analysis. PLoS One 2012; 7:e46144. doi:10.1371/journal. pone.0046144. 46. Zhang J, Zhou JB, Lin XF, et al. Prevalence of undiagnosed and undertreated chronic obstructive pulmonary disease in lung cancer population. Respirology 2013; 18:297–302. 47. Yang L, Qiu F, Lu X, et al. Functional polymorphisms of CHRNA3 predict risks & of chronic obstructive pulmonary disease and lung cancer in Chinese. PLoS One 2012; 7:e46071. doi:10.1371/journal.pone.0046071. The authors wanted to test two single nucleotide polymorphisms (SNPs) (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor a-3 (CHRNA3) gene in the Chinese population, to explore whether there exist common predictor risks for COPD and lung cancer as both diseases have a shared cause. The said SNPs were genotyped in 1511 COPD patients, 1559 lung cancer patients and 1677 controls in South and East China. They found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR ¼ 1.32) and lung cancer (OR ¼ 1.57), respectively. The rs6495309CC genotype contributed to more rapid decline of annual FEV1 in both COPD cases and controls (P ¼ 0.05), and it was associated with advanced stages of COPD (P ¼ 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer ( hazard ratio ¼ 1.41). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G > A. The data show a statistical association and suggest biological plausibility that the rs6495309T > C polymorphism contributed to the increased risks and poor prognosis of both COPD and lung cancer. 48. Kim WJ, Oh YM, Kim TH, et al. CHRNA3 variant for lung cancer is associated & with chronic obstructive pulmonary disease in Korea. Respiration 2013; 86:117–122. The authors wanted to explore the genetic predisposition of Korean people to COPD and to lung function decline and development of emphysema. They studied two SNPs (rs660652 and rs12910984) in 219 Korean Cohort Study on Obstructive Lung Disease COPD individuals and 305 controls. All patients were subjected to volumetric CT scans to quantify the emphysema severity. They found significant association between rs12910984 and COPD. There was no association with FEV1 or emphysema severity and genotypes among COPD patients, but there was significant association with DLCO. 49. Leung CC, Lam TH, Yew WW, et al. Obstructive lung disease does not increase lung cancer mortality among female never-smokers in Hong Kong. Int J Tuberc Lung Dis 2012; 16:546–552. 50. Huang KW, Luo JC, Leu HB, et al. Chronic obstructive pulmonary disease: an independent risk factor for peptic ulcer bleeding: a nationwide populationbased study. Aliment Pharmacol Ther 2012; 35:796–802. 51. Kamble NL, Khan NA, Kumar N, et al. Study of gastro-oesophageal reflux disease in patients with mild-to-moderate chronic obstructive pulmonary disease in India. Respirology 2013; 18:463–467. 52. Chiang YY, Lin HW. Association between psoriasis and chronic obstructive pulmonary disease: a population-based study in Taiwan. Eur Acad Dermatol Venereol 2012; 26:59–65. 53. Rittayamai N, Chuaychoo B, Sriwijitkamol A. Prevalence of osteoporosis and osteopenia in Thai COPD patients. Med Assoc Thai 2012; 95:1021–1027.

Volume 20  Number 2  March 2014

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Profiles of chronic obstructive lung disease: characteristics of stable chronic obstructive lung disease in different parts of Asia.

This review discusses the recent Asian chronic obstructive lung disease (COPD) studies that characterize stable COPD, to understand its peculiarities...
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