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ARTICLE IN PRESSG Model Arch Bronconeumol. 2016;xxx(xx):xxx–xxx www.archbronconeumol.org Review Is Chronic Obstructive Pulmonary Disease Caused by Wood Smoke a Different Phenotype or a Different Entity? Carlos A. Torres-Duque,a,∗ María Carmen García-Rodriguez,b Mauricio González-Garcíaa a Fundación Neumológica Colombiana, Universidad de La Sabana, Bogotá, Colombia b Fundación Neumológica Colombiana, Bogotá, Colombia a r t i c l e i n f o Article history: Received 9 November 2015 Accepted 4 April 2016 Available online xxx Keywords: Chronic obstructive pulmonary disease Wood smoke Phenotype Biomass a b s t r a c t Around 40% of the world’s population continue using solid fuel, including wood, for cooking or heating their homes. Chronic exposure to wood smoke is a risk factor for developing chronic obstructive pul- monary disease (COPD). In some regions of the world, this can be a more important cause of COPD than exposure to tobacco smoke from cigarettes. Signiﬁcant differences between COPD associated with wood smoke (W-COPD) and that caused by smoking (S-COPD) have led some authors to suggest that W-COPD should be considered a new COPD phenotype. We present a review of the differences between W-COPD and S-COPD. On the premise that wood smoke and tobacco smoke are not the same and the physiopathological mechanisms they induce may differ, we have analyzed whether W-COPD can be considered as another COPD phenotype or a distinct nosological entity. © 2016 SEPAR. Published by Elsevier Espa˜na, S.L.U. All rights reserved. Enfermedad pulmonar obstructiva crónica por humo de le˜na: ¿un fenotipo diferente o una entidad distinta? Palabras clave: Enfermedad pulmonar obstructiva crónica Humo de le˜na Fenotipo Biomasa r e s u m e n Alrededor del 40% de la población mundial sigue utilizando combustibles sólidos, entre ellos la le˜na, para cocinar o calentar sus hogares. La exposición crónica al humo de le˜na es un factor de riesgo para el desarrollo de enfermedad pulmonar obstructiva crónica (EPOC). En algunas zonas del mundo este factor puede ser más importante que la exposición al humo de tabaco, generalmente inhalado como humo de cigarrillo, como causa de EPOC. Se han descrito diferencias signiﬁcativas entre la EPOC relacionada con humo de le˜na (EPOC-L) y la EPOC causada por humo de tabaco (EPOC-T) que han llevado a plantear por algunos autores que la EPOC- L pueda ser considerada un nuevo fenotipo de la EPOC. Presentamos una revisión de las diferencias entre la EPOC-L y la EPOC-T. Basados en que el humo de la le˜na y el humo del tabaco no son iguales, y que podrían inducir mecanismos ﬁsiopatológicos en algún punto diferentes, hacemos un análisis acerca de si la EPOC-L debe considerarse un fenotipo diferente de la EPOC o una entidad nosológica distinta. © 2016 SEPAR. Publicado por Elsevier Espa˜na, S.L.U. Todos los derechos reservados. Please cite this article as: Torres-Duque CA, García-Rodriguez MC, González- García M. Enfermedad pulmonar obstructiva crónica por humo de le˜na: ¿un fenotipo diferente o una entidad distinta?. Arch Bronconeumol. 2016. http://dx.doi.org/ 10.1016/j.arbres.2016.04.004 ∗ Corresponding author. E-mail address: firstname.lastname@example.org (C.A. Torres-Duque). Introduction A phenotype is a set of observable characteristics in an indi- vidual resulting from the interaction between their genotype and the environment.1,2 These characteristics are not only physical traits but also biochemical and functional characteristics. Genotype refers to an individual’s genetic make-up (combination of genes). The manner in which the information contained in the genes (geno- type) translates to observable characteristics (phenotype) depends on different factors, the most important of which are how dominant the gene is and how it interacts with the environment.1,2 1579-2129/© 2016 SEPAR. Published by Elsevier Espa˜na, S.L.U. All rights reserved. ARBR-1373; No. of Pages 7 ARTICLE IN PRESSG Model 2 C.A. Torres-Duque et al. / Arch Bronconeumol. 2016;xxx(xx):xxx–xxx In the clinical setting, the concept of phenotype has been used to identify groups of patients who share attributes that distin- guish them from others, making up clinical subgroups.3 A good example of this idea of phenotype is chronic obstructive pul- monary disease (COPD), a disease in which the underlying genes are unknown (with the exception of alpha-1 antitrypsin deﬁciency). Since phenotype differentiation has clinical implications, the term “clinical phenotype” has been proposed, which is deﬁned as “a sin- gle or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically mean- ingful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death).”4 The term COPD came into use around 50 years ago5 and ini- tially included 2 entities, chronic bronchitis and emphysema, which shared a common risk factor (smoking) and a common functional change (persistent airﬂow obstruction).6,7 The most pure cases of these 2 entities had sufﬁciently different clinical characteristics to enable them to be separated into the 2 classic COPD pheno- types: chronic bronchitis or “blue bloater” and emphysema or “pink puffer”. However, it was not known then that different phenotypes would eventually determine different therapeutic interventions and outcomes, so little importance was given to the separation of the phenotypes, and use of the generic term COPD expanded. The concept of clinical phenotypes in COPD is now being revisited, thanks to long-term follow-up of patient cohorts and technological advances.3,4,8,9 Although the implications of sepa- ration by phenotypes are still debated, they have been included in some clinical guidelines.10 The most widely accepted pheno- types are: emphysema, chronic bronchitis, frequent exacerbator, and asthma-COPD overlap syndrome.3,4,8–10 The growing wealth of data on the differences between biomass smoke-related COPD, particularly wood smoke, and tobacco smoke-related COPD11,12 has led experts to propose biomass COPD as an additional phenotype.13,14 This proposal is controversial, and warrants a review of the existing information on these differences and the applicability of the term phenotype in the presence of risk factors that could be considered different. In this review, we discuss the differences between wood smoke-related COPD (W-COPD) and tobacco smoke-related COPD (T-COPD). We have used the general term T-COPD, although a more accurate name would be cigarette smoke COPD, as this smoke con- tains an additional number of chemical products apart from those derived from burning tobacco.15,16 Since the role of these chem- icals cannot be clearly separated from the role of tobacco in the pathogenesis of COPD, we will use the generic term T-COPD. For this review, we searched the Medline, LILACS and Cochrane databases, using the terms biomass, biomass fuels, wood, wood smoke, indoor air pollution, respiratory diseases, chronic bronchi- tis and chronic obstructive pulmonary disease, and the connectors AND/OR. Exposure to Wood Smoke as a Risk Factor for Chronic Obstructive Pulmonary Disease Around 40% of the world’s population, particularly in develop- ing countries, still use solid fuel, whether coal or biomass (wood, vegetable remains and dung), to cook or heat their homes.17,18 In some countries, these fuels are the main source of energy for over 70% of the rural population.17,18 In countries where migra- tion from rural areas to cities is high, the population of urban dwellers over the age of 40 years frequently has a signiﬁcant history of exposure to biomass combustibles. One example is Colombia, where 39% of the population over 40 years of age living in the 5 main cities had cooked with wood for more than 10 years before relocating.19 In 2010, indoor air pollution from solid fuels was the 30% P<.001 25% 20% 15% 10% COPD prevalence, % 5% 0% Exposure, years .00 < 10 years 10-19 years 20-29 years ≥ 30 years NK Fig. 1. Prevalence of COPD by years of exposure to wood smoke.40 The prevalence of COPD in individuals exposed to wood smoke increases signiﬁcantly as the duration of exposure lengthens. NK: not known (individuals exposed to wood smoke who did not report years of exposure). third risk factor for death throughout the world (3.5 million deaths a year).20 A growing number of studies support the hypothesis that expo- sure to solid fuels, including wood, is a risk factor for respiratory diseases, including acute respiratory disease in children, COPD, chronic bronchitis, airﬂow obstruction, bronchial hyperreactivity, asthma, tuberculosis and lung cancer.21–39 Our group has docu- mented the association between exposure to wood smoke for over 10 years and asthma in the population >40 years of age.39 Three systematic reviews and meta-analyses conﬁrm that indi- viduals chronically exposed to solid fuels at home have a higher risk of developing COPD.36–38 In the case of wood smoke, the risk of COPD increases signiﬁcantly with the length of exposure (Fig. 1)40 and with simultaneous exposure to tobacco smoke.40,41 Although the risk is consistently greater in women, a populational study (n=5539) showed that, after adjusting for age, smoking, educational level and occupational exposure, men exposed to wood smoke for more than 10 years had a higher risk of COPD (odds ratio [OR] women: 1.84; OR men: 1.53).40 Exposure to wood smoke has also been described as a risk factor for COPD in developed countries.33 Air pollution in the home due to burning solid fuels is thought to be the main worldwide risk factor for COPD,42,43 although the prevalence of biomass-related COPD has not been precisely deﬁned. The PREPOCOL study found a prevalence of 6.7% for W-COPD com- pared to 7.8% for T-COPD.40 Some populational studies, however, found no association between exposure to biomass fuels and COPD.44,45 Most of the cohorts evaluated in these studies lived near sea level, where cooking is usually done outdoors or with better ventilation. In contrast, many of the studies which document this association were performed in areas situated at high or intermediary altitudes, where, due to low temperatures, cooking is done all year round inside poorly ventilated homes as it occurs in winter in regions that have seasons. ARTICLE IN PRESSG Model C.A. Torres-Duque et al. / Arch Bronconeumol. 2016;xxx(xx):xxx–xxx 3 Although exposure to wood smoke has been associated with respiratory diseases other than COPD,24,46–48 this review focuses on the differences between W-COPD and T-COPD. Differences Between Chronic Obstructive Pulmonary Disease due to Wood Smoke and Chronic Obstructive Pulmonary Disease due to Tobacco Smoke Although the risk of COPD has been proven for all types of solid fuels, studies which best characterize COPD due to this type of exposure have focused on COPD caused by inhala- tion of wood smoke.11–14,24,32,34,47,49 Several studies show that W-COPD has both signiﬁcant differences and similarities with T- COPD.13,40,47,49–62 The main differences are described below and summarized in Table 1. Demographic Differences W-COPD is more common in women, who are more often involved in the task of preparing food.11 Women with W-COPD are consistently reported to be shorter in height, with a higher body mass index (BMI) than women with T-COPD.40,47,49–51,54–56 Since most women with W-COPD are of a rural origin, and most of those with T-COPD are from urban conglomerations, differences in height and BMI may be due to ethnic and envi- ronmental reasons that require investigation. Moreover, women with W-COPD are older, suggesting that patients with this type of exposure need more time to develop the disease or are diagnosed later.40,49–51,55,56 Clinical Differences Although several studies have shown that the frequency of respiratory symptoms (cough, expectoration, and dyspnea) and chronic bronchitis is high in subjects exposed to biomass smoke,36,38 studies comparing W-COPD and T-COPD do not consis- tently ﬁnd signiﬁcant differences. Some studies show that W-COPD symptoms are more frequent or have more impact13,49,62 but others do not.51,53,56 With regard to the physical examination, González- García et al.49 found more frequent rhonchus and wheezing in W-COPD. Functional and tomographic ﬁndings, described below, document greater bronchial compromise, backing up studies which show more frequent cough, expectoration, rhonchus and wheezing in W-COPD. Differences in Quality of Life A study of 138 women with COPD showed that, among women with the same degree of obstruction, those with W-COPD had a poorer health status (poorer quality of life and worse dyspnea) than those with T-COPD, with no differences in comorbidities (Fig. 2).62 Furthermore, Camp et al., using the Saint George’s Hospital Ques- tionnaire, found worse symptoms and more compromised activity indices in women with W-COPD.13 Differences in Lung Function Compared with T-COPD, obstruction in W-COPD is milder, both overall and after adjusting for age,13,40,47,49–51,56 and the decline in forced expiratory volume in 1 second (FEV1) is smaller and more homogeneous than in T-COPD.50 Some studies show that car- bon dioxide arterial pressure (PaCO2) is higher (lower ventilation) and oxygen arterial pressure (PaO2) and oxygen arterial saturation (SaO2) are lower in W-COPD than in T-COPD.13,49,50,56 The lower oxygenation rates observed in W-COPD may be explained in part by Table 1 Differences Between W-COPD and T-COPD. Characteristics W-COPD T-COPD Demographic data40,47,49–51,54–56 Sex Predominantly women Predominantly men Age Highest Lowest Height Lowest Highest BMI Highest Lowest Clinical characteristics38,49 Cough and expectoration Very common Common Chronic bronchitis Common Common Rhonchus and wheezing Common Less common Lung function tests13,40,47,49–51,54–56 PaCO2 Higher (some studies) Less high PaO2 and SaO2 Lower Less low Obstruction (FEV1−FEV1/FVC) Mild More severe Reduced FEV1 Lowest Highest Bronchial hyperreactivity Highest Lowest DLCO and DLCO/VA Normal or mildly reduced More reduced Radiography-tomography13,47,49,51,54,59 Emphysema Uncommon and mild Common and more severe Bronchial thickening Common Less common Bronchiectasis Common Uncommon Atelectasis Common Uncommon Histology Emphysema Mild More severe Anthracosis Common Less common Airway ﬁbrosis Common Less common Thickening of arteriole intima Common Less common Outcomes and clinical phenotypes13,51,56,61,62 Pulmonary hypertension More common Less common Quality of life Similar or symptoms and activities more compromised Similar or symptoms and activities less compromised Survival Similar after adjusting for age Less after adjusting for age Similar Exacerbator phenotype Similar Similar Asthma-COPD overlap phenotype More common Less common Emphysema phenotype Uncommon More common BMI: body mass index; DLCO: carbon monoxide diffusing capacity; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; PaCO2: carbon dioxide arte- rial pressure; PaO2: oxygen arterial pressure; SaO2: oxygen saturation; VA: alveolar volume. hypoventilation. It remains to be determined whether this behav- ior is related with a higher BMI in these patients, most of whom are women over 50 years of age. Normal or mildly altered diffusing capacity (DLCO) and DLCO/alveolar volume (DLCO/VA) ratio are consistently observed in W-COPD compared to T-COPD, in which these parameters are sig- niﬁcantly reduced.49,54 This ﬁnding correlates with the lower grade of emphysema found on computed tomography (CT) in patients with W-COPD,13,54,59 and occurs at all levels of COPD severity (Fig. 3A and B).49 Mildly reduced DLCO with normal DLCO/VA in women with W-COPD has been described in cases with signiﬁcantly compromised small airways with little emphysema (pseudophysi- ological emphysema).63 Compromised diffusion correlates better with reduced FEV1 in women with T-COPD than in those with ARTICLE IN PRESSG Model 4 C.A. Torres-Duque et al. / Arch Bronconeumol. 2016;xxx(xx):xxx–xxx 80 60 40 Quality of life, SGRQ 20 SGRQ-TSGRQ-ISGRQ-ASGRQ-S *P<.01 0 N=138 Risk factor WoodTobacco Fig. 2. Quality of life in COPD by wood smoke or tobacco smoke exposure.62 In W-COPD, overall quality of life scores (SGRQ) and all individual domain scores are poorer. SGRQ: Saint George’s Hospital Respiratory Questionnaire. W-COPD, underpinning the greater contribution of emphysema to airﬂow obstruction in T-COPD (Fig. 4).49 Women with W-COPD have greater bronchial hyperreactivity than women with T-COPD (Fig. 5).55 Further research is needed to determine if this correlates with the higher frequency of the asthma-COPD overlap phenotype observed in biomass-related COPD.5 Taking into account the predominant role that inhaled corticosteroids may have in patients with asthma-COPD overlap syndrome,9,10 these medications can be presumed to have a differ- ent impact on W-COPD than on T-COPD. Differences in Exercise Tolerance Some studies which included the 6-minute walking test found no signiﬁcant differences in distances walked between patients 120 100 80 60 FEV1 (% predicted) 40 20 0 40 20 DLCO (% predicted) 8060 100 120 COPD wood COPD tobacco Fig. 4. Correlation between FEV1 (%) and DLCO by exposure.49 Greater correlation is observed between FEV1 and DLCO in T-COPD (P<.001, r=0.599) than in W-COPD (P=.014, r=0.320). DLCO: carbon monoxide diffusing capacity; FEV1: forced expiratory volume in 1 s. with W-COPD and T-COPD.13,56,62 Camp et al.13 reported lower arterial oxygen saturation measured by pulse oximetry (SpO2) at the end of the test in women with W-COPD, but this was not reported in other studies. Tomography and Histological Differences Patients with W-COPD have consistently less emphysema and more airway changes (bronchial thickening and ﬁbrosis, bronchiec- tasis, and atelectasis) than patients with T-COPD on both chest radiographs and histological studies.13,51,52,54,59 These morpholog- ical differences can be related with a less compromised DLCO and probably with the ﬁndings of greater bronchial hyperreactivity55 and more frequent asthma phenotype in W-COPD.51 Differences in Pulmonary Hypertension A recent study found that pulmonary hypertension on echocar- diography was more common in patients with W-COPD than in those with T-COPD.60 In a previous study, our group, on the basis of radiographical evaluations, suggested the same in patients with 100 120 110 100 90 80 70 60 50 40 90 80 70 60 50 40 DLCO (%) DLCO/VA (%) 30 20 Mild Moderate Severe COPD severity Mild Moderate Severe COPD severity COPD wood COPD tobacco A B Fig. 3. (A) DLCO (%) by exposure and degree of obstruction.49 (B) DLCO/VA (%) by exposure and degree of obstruction.49 In T-COPD, DLCO and DLCO/VA are more heavily compromised. DLCO/VA is normal in W-COPD at all levels of severity. DLCO: carbon monoxide diffusing capacity; VA: alveolar volume. ARTICLE IN PRESSG Model C.A. Torres-Duque et al. / Arch Bronconeumol. 2016;xxx(xx):xxx–xxx 5 10 5 4 3 2 1 .5 .4 .3 .2 PC20 (mg/ml) .1 .05 W-COPD T-COPD Fig. 5. Bronchial hyperreactivity evaluated by PC20 by exposure.55 White circles: W-COPD; black circles: T-COPD. PC20 geometric mean: W-COPD versus T-COPD: 0.39 (0.06–5.13) versus 1.24 (0.34–9.39), P=.028. PC20: methacholine concentration causing ≥20% reduction in FEV1. severe COPD,49 and Sandoval et al.61 showed a high rate of PH among individuals exposed to wood smoke compared to those with T-COPD. The origin of PH in W-COPD patients does not appear to be related solely with hypoxic pulmonary vasoconstriction, but also to direct effects caused by the inhaled substances or indirect inﬂammatory-mediated effects.64 Differences in the Incidence of Bronchial Anthracoﬁbrosis The incidence of bronchial anthracoﬁbrosis and its severity in individuals exposed to wood smoke or tobacco smoke has not been evaluated in prospective studies, and no differences are known. However, anthracoﬁbrosis is commonly encountered in the airway of subjects exposed to wood smoke, sometimes accompa- nied by bronchial stenosis.65–67 A signiﬁcant proportion of these patients show documented airway obstruction65 possibly aggra- vated by their central airway stenosis. It is currently impossible to ascertain if bronchial anthracoﬁbrosis is yet another feature of W-COPD that appears more commonly and in a more severe form than in T-COPD, or if it is a speciﬁc entity accompanied by obstruction. Differences in Meaningful Clinical Outcomes After adjusting for age, sex, and disease severity, no differ- ences were found in survival between W-COPD and T-COPD.56,57 Nor were differences identiﬁed in exacerbation rates between the 2 groups,51 but it should be noted that no prospective data are available on this aspect. Differences in the Distribution of Clinical Phenotypes Golpe et al.51 evaluated the frequency of clinical phenotypes deﬁned by the Spanish COPD guidelines10 in patients with COPD caused by biomass or tobacco smoke. Similarly to the ﬁndings discussed above, they found a greater frequency of emphysema phenotype in T-COPD. The asthma-COPD overlap phenotype was more common in biomass COPD, but the difference disappeared after adjusting for sex. No difference was found in the frequencies of chronic bronchitis or exacerbator phenotypes.51 Possible Reasons for Differences Between Chronic Obstructive Pulmonary Disease due to Wood Smoke and Chronic Obstructive Pulmonary Disease due to Tobacco Smoke It is reasonable to expect that the greater airway inﬂamma- tory involvement and the lower rate of emphysema in W-COPD compared to T-COPD have an etiological, pathogenic and physio- pathological basis. However, very little data are available to explain the reasons for these differences. The composition of wood smoke, which contains hundreds of chemical compounds and particulates) is just as complex23,68 as that of cigarette smoke.15,16 Wood combustion is generally incom- plete, generating greater concentrations of certain substances such as CO, benzene, and polycyclic hydrocarbons, such as benzopyrene, compared to cigarette smoke.23 Practically 100% of the particu- lated material in cigarette smoke is less than 2.5 m in size.69 This proportion is nearer 90% in wood smoke68; the remaining 10% of particles are between 2.5 and 10 m in size. The role of this distri- bution of particle size in the greater airway compromise and more common development of anthracoﬁbrosis in W-COPD has not been determined. Silva et al.70 recently reviewed pathogenic mechanisms involved in biomass COPD. As in T-COPD, many of these mech- anisms are related with inﬂammatory activation and oxidative stress, whereas no obvious signiﬁcant differences in the mecha- nisms involved in the generation of respiratory injury in W-COPD were identiﬁed. Although the lower rate or absence of emphy- sema in W-COPD might suggest less proteolytic activity against exposure to biomass smoke, a recent study found no differences in this respect when comparing exposure to biomass smoke and to cigarette smoke.64 Some authors have suggested that differences between W-COPD and T-COPD may be determined in part by dif- ferences in the characteristics of exposure,11 but research is needed to support this view. In summary, the physiopathological mechanisms involved in W-COPD remain unclear, but it seems that inﬂammatory activa- tion in the airway is different, and of a greater magnitude, and that proteolytic activity induces less emphysema. Chronic Obstructive Pulmonary Disease due to Wood Smoke: A New Chronic Obstructive Pulmonary Disease Phenotype or a Different Entity? The evidence consistently supports differences between W- COPD and T-COPD with respect to greater inﬂammatory airway compromise and a much lower or absent degree of emphysema in the former. The etiological factors, wood smoke and cigarette smoke, can be grouped under the heading of noxious particles or gases, but they are also different,23 so it is reasonable to propose that W-COPD be considered a distinct disease, rather than a new COPD phenotype.13,14 Additionally, recognition that exposure to wood smoke may be associated with radiological, functional and histological manifestations that differ from those described under the deﬁnition of COPD, such as pulmonary inﬁltrates, restrictive patterns and particulate deposits in the lung,24,46–48 may be taken as yet another argument for separating it into a different nosological entity. Even if it can be agreed, using the present deﬁnition, to describe obstructive disease caused by exposure to wood smoke as COPD, W-COPD could still not be considered a different clinical phenotype, since its clinical, functional, histological and radiological differ- ences do not lead to differences in meaningful outcomes, such as exacerbations and mortality, as proposed in the deﬁnition of clinical phenotype.4 ARTICLE IN PRESSG Model 6 C.A. Torres-Duque et al. / Arch Bronconeumol. 2016;xxx(xx):xxx–xxx From a nosological point of view, the model of respiratory dis- ease caused by wood smoke leads us to question the deﬁnition of COPD.71 COPD has been deﬁned as a non-speciﬁc functional characteristic (irreversible airﬂow limitation [post-bronchodilator obstruction]) in the presence of an imprecise exposure (noxious particles or gases), in the absence of a single etiological factor or a highly speciﬁc or pathognomonic feature.72 If a single etiological factor or a highly-speciﬁc deﬁning patho- logical trait is present, the identiﬁcation of clinical phenotypes is a valid approach to achieve the goal of designing individualized patient management.3,9 If the etiological factor of a disease is not identiﬁed, or is not unique, as in the case of COPD (noxious parti- cles or gases), and the disease is deﬁned by a non-speciﬁc trait, the different characteristics and outcomes of a group may represent a distinct, separate entity, rather than another phenotype expression. Irrespective of whether W-COPD is considered a new pheno- type or a distinct entity, the most important consideration is how it affects prognosis and treatment. It can be presumed that the physiopathological mechanisms of W-COPD are different, and that a different approach to treatment may needed. In view of the predominating airway compromise, anti-inﬂammatories, such as inhaled corticosteroids, can be expected to play a more important role. Further research is required on the physiopathological mech- anisms and treatment of disease caused by wood smoke. Better understanding of these differences could be applied to the consid- erable number of cases of COPD unrelated with cigarette or wood smoke,73,44 and disorders due to occupational and environmen- tal air pollution which are classiﬁed under COPD could be better characterized. The term COPD has been unquestionably important. On the road toward personalized treatment, beyond the stage in which pheno- typing has a central role, differentiation by etiological or causative agent remains essential.71,74 The idea of COPD as a syndrome which encompasses diverse speciﬁc entities is growing, and it appears to be time to rethink the deﬁnition of COPD.3 Conclusions W-COPD differs from T-COPD. The causative factor (wood smoke) and the characteristics of exposure are also different, and this might mean that the physiopathological mechanisms and/or its severity differ in some respect, explaining the greater inﬂam- matory airway compromise and the lack of emphysema that are features of W-COPD. Therapeutic options would therefore also dif- fer, and a greater role would be given to anti-inﬂammatories, such as inhaled corticosteroids. From this standpoint, W-COPD is bet- ter understood as a distinct disease rather than a COPD phenotype, bringing into question the accuracy of COPD deﬁnitions. 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