2 Effects of Smoking on Asthma SK Jindal” Abstract Tobacco smoking has several adverse associations with asthma. The odds ratios for prevalence of asthma are high for both active smoking and ETS exposures. In-utero exposure of foetus from maternal smoking, as well as its tertiary exposure from maternal passive-smoking are also known to be responsible for development of asthma in childhood. Smoking adversely affects the health and treatment-outcomes of asthma. There are increased requirements of drugs for smoker and ETS exposed asthmatics. Smoking is also an important factor in the development of airway remodelling, fixed airway obstruction and an ‘exaggerated lung function decline. Mescine Postgraduate Intute of Mec ‘Chancigarht60012 TT rtbaste simaking isthe most common cause of chron alway diseases sch os chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). On the other hand, asthma is an airway disorder which commonly starts in childhood Smoking is not directly responsible as a cause of asthma in most of these patients. There however is enough of evidence which point towards the adverse effects of smoking on 5) i.e, passive smoking are known to influence asthma in one or the other way (Table 1). asthma," Both active smoking and exposure to environmental tobacco smoke (E 1, Smoking as a risk factor ‘The absence of a demonstrable relationship of smoking with asthma in some earlier studies can be possibly explained because of its irritant effects on the airways triggering acute episodes, for which an asthmatic would tend to avoid smoking. While epidemiological relationship of smokingwith asthma in children is known, for about two decades, the recent studies from India done on large populations hi example, the Indian study on Epidemiology of Asthma, Respiratory symptoms and chronic bronchitis (INSEARCH) demonstrated odds ratios of 1.82 for cigarette and 2.87 for bidi smoking in a sample population of 169575 adults of over 15 years of age (Table 2).° The other study which used data on self-reported asthma from the India’s third National Family Health Survey (NFHS) reported odds ratios of 1.72 and 1.35 for women and men respectively (Table 2).* In a study which used the data of Korean Youth Risk Behaviour Survey on association of asthma symptoms with smoking and drinking, 21.7% of 3432 adolescent asthmatics were current strongly supported the smoking association of asthma in adults.!25* For ‘Table 1 : Different associations of atopy and asthma with smoking exposure jgher odds ratios Airway inflammation, remodeling and lung, + Allergic sensitisation function decline + Asthma + Daggerated lung function decine 2. Poorer asthma contol + Fixed airway obstruction 5. Treatment effects + Increased Emergency Room visits + Increased hosptalisations + Relative resistance to inhaled corticosteroids : + Increased theophylline clearance sequent acute episodes + Increased need for maintenance pharmacotherapy 3. Development of asthma due to In-utero smoking exposure + Maternal smoking (Passive) + Maternal passive smoking from others Clewtiary smoking ‘+ 7 Requinement for add-on therapy with ics and monoclonal ent antibodies + Differential treatment responsesSUPPLEMENT To JOURNAL OF THE ASSOCIATION OF PHSICIANS OF INDIA“ MARCH201 VOL. 33 Table 2: Odds Ratio (OR) of smoking with asthma reported inrecent studi Aative Smoking ETS Exposure (OR 5% CI" OR 5% CI" Tindal Sketal, Cigarcte 182 (1542.15 Both childhood ami and adulthood Biais 287 2.58- 136 (116 thers 2. AgrawalS, Men ani" Women 172(134- 221) 3. Kim 0,2012" Smoking of > 20 days: (OR=177 (126-249) 4. Mitchell etal, Cigaretes/ 2012" aayou, 17 135 Ca nee Intervals smokers compared to 10.9% in the asymptomatic group.” ‘The epidemiological relationship of ETS-exposure with asthma in children, though variable from different countries, is significantly high in most of the recent studies." The ISAAC Phase Three programme examined the influence of parental smoking in children of 6-7 years and 13-14 years age-groups employing a study-questionnaire.* Both maternal and paternal smoking were associated with an increased risk of asthma in children of both age groups though the odds ratios were higher for maternal smoke exposure. ‘There was also a clear dose relationship of number of asthma symptoms with number of cigarettes smoked.’ ETS exposure was also shown to increase the risk of respiratory symptoms in 1718 never-smoker Chinese school-children.? There was also a dose re: tionship of number of cigarettes with impairment of lung function assessed by spirometry performed al baseline and at 18 month follow-up.’ Similarly, prevalence of wheeze and asthma was shown among ETS exposed Japanese children of 6 to 15 years of age. There was an increased prevalence of wheeze and asthma in children of 6 to 10 years of age who were exposed to heavy passive smoking of 7 or more pack years in the households.” These results are quite consistent with the findings of earlier studies which had pointed to the smoking exposure as an important risk factor of prevalence of asthma." Maternal smoking was shown to have strong and significant association as was concluded in a meta-analysis of longitudinal studies on incidence of asthma and wheezing; this relationship was particularly significant for the first 5-7 years of life than for the incidence in the school years." Effects on asthma-control Smoking exposure is known to adversely impact the control of asthma in both children and adults There is aggravation of respiratory symptoms, acute respiratory infections and bronchial hyper-responsiveness amongst nonsmoker individuals exposed to smoking of parents, sibs and friends." ETS exposure from parents is also related to the severity of asthma and emergency department visits of asthmatic children.””"* In our own study on 200 never-smoker patients of asthma of 15 to 50 years of age, the control was poor and morbidity greater amongst patients exposed to ETS at home and/or at work.” ‘The poor asthma control amongst ETS exposed individuals is further supported by the findings of a recent study which demonstrated a significant reduction in episodes of poor asthma control after a decrease in ETS exposure in childre: There were fewer hospitalisation and emergency department visits after the caregivers were provided with no-smoking cessation counselling or ETS-exposure education.” Ina similar study, smoking of caregivers was strongly associated with child exposure to ETS amongst inner-city asthmatic children in Chicago. Measures for smoking cessation amongst the caregivers are therefore important for adequate control of asthma. In another study among 3761 children of below 12 years of age, household ETS exposure ‘was shown to predict asthma attacks for girls (OR: 3.11, 95% C.L, = 1.24 1.76) Development of asthma: In-utero exposure Maternal smoking during pregnancy constitutes an important source of ETS-exposure for the foetus in-utero, The foetus may also be exposed to paternal smoking from the father or other family ‘members in the company of the pregnant mother, sometimes referred to as “tertiary smoking” The in-utero smoking exposure is shown to be associated with lung immaturity, poor lung function and development of asthma in early childhood. There was higher incidence of asthma in children of mothers who smoked. There is strong evidence in favour of foetal programming and very early life events such as ETS exposure and use of chemical domestic products in the development of asthma. The intrauterine insult from several such exposures could be blamed for early sensitisation and at least for some of the phenotypes of asthma. Similar association of foctal exposure to maternalactive and passive smoking has been shown with occurrence of wheeze, childhood asthma and atopic illnesses in Hong Kong Chinese children” The maternal smoking and childhood asthma relationship was examined in babies born in Japan in 2001 during two specified weeks.* The -year cumulative incidence among 36888 subjects increased to 14.4% from 11.7% with a risk ratio of 1.24 for maternal smoking.®* The authors have therefore concluded strongly on the necessity to stop or discourage maternal smoking especially during pregnancy. ‘The interaction between maternal smoking during. pregnancy and prematurity was examined in an Urban cohort of 1448 children in Boston; maternal smoke exposure and prematurity together had odds ratio of 3.8 (95% C.L. 1.8 ~ 8.0) for recurrent wheezing.” In this study, the in-utero maternal smoking alone was not shown to increase the risk of wheezing. Both maternal asthma and cigarette smoking were shown to increase the risk of preterm birth and other adverse perinatal outcomes in a retrospective analysis of 172305 singleton pregnancies in South Australia.” Besides development of asthma, maternal smoking while in utero has been shown to be associated with poor control of asthma." A case analysis of 2 multicentre case control studies on 2481 Latino and black subjects with asthma was done to study the clinical effect and relative contribution of passive smoking. An odds ratio of 1.5 (95 CI 1.1 - 2.0) of in-utero exposure was seen with poor asthma control among children of 8 to 17 years of age, implying the later effects of in-utero exposure. There were also other secondary outcomes such as the occurrence of early-onset asthma, daytime symptoms and asthma-related Limitation of activities with in utero smoking in this study." Development of fixed airway obstruction and lung, function decline Persistent inflammation in asthma causes structural changes in the airways responsible for thickness of bronchial walls, reduction of the airway lumen, decline in lung function and fixed airway obstruction. Smoking modifies the inflammatory responses of asthmatic patients in causing squamous cell metaplasia and increased, expression of inflammatory cytokines.” The morphological and functional changes which occur due to remodelling result in severer forms of asthma and relative non-responsiveness to anti-asthma therapy. Continued smoking exposure, airway hyper- responsiveness and eosinophilic inflammatory are important factors which lead to the development of chronic airway obstruction due to airway remodelling.” Such patients behave like those of chronic obstructive pulmonary disease. This is in consistence with the Dutch hypothesis, first postulated in 1961 that COPD developed due to exaggerated airways damage from smoking exposure of patients with underlying atopic diagnosis, The effect of smoking studied in 793 asthma patients aged 14 to 44 years clearly demonstrated, an early lung function decline compared with nonsmokers." There was also a dose-response relationship of spirometric measures with smoking. Another population based study (Tasmanian Longitudinal Health Study) on a cohort born in 1961 reports the development of fixed airway obstruction in middle age contributed by active smoking and current clinical asthma.** The authors of the study concluded that the association of fixed airway obstruction was equivalent to a 33 pack-year history of smoking for late onset current clinical asthma compared to 24 pack-year history for late onset clinical asthma There are also experimental data in mice to suggest that airway remodelling may occur even from in-utero exposure to maternal smoking. Off- springs of mice exposed to cigarette smoke during pregnancy had increased airway smooth muscle layer, collagen deposition and other changes seen, in airway remodelling.” Interestingly, a recent review cites the dangerous relationship of asthma with substance abuse (cocaine, marijuana, cigarette, heroin and alcohol) in causing lung function decline, increase in number of life-threatening asthma attacks and high asthma mortality.” Smoking, allergic sensitisation and airway inflammation There are a few reports on smoking relationship with different forms of atopy and asthma. Both active smoking and ETS exposure are shown to be associated with increased odds of developing aspirin-exacerbated respiratory disease.™ There were odds ratios of 1.54, 3.46 and 5.09 for active smoking, childhood ETS exposure and both childhood and adulthood ETS exposure. Foetal exposure to maternal active and passive smoking were also shown to relate to other atopic illnesses such as allergic rhinitis and eczema."” The effect of ETS exposure on the development of allergic sensitisation in children was compared in children aged 2-3 years born with and without a maternal history of allergic disease.” Using a propensity score method to control forSUPPLEMENT To JOURNAL OF THE ASSOCIATION OF PHSICIANS OF INDIA“ MARCH201 VOL. 35 confounding variables, early life ETS exposure was found to be strongly associated with allergic sensitisation in children without maternal history while it reduced the sensitisation in those with positive maternal history.” Increased concentrations of prostaglandin E(2) and cysteinylleukotrienes in sputum supernatants of smoker asthma patients point towards the up- regulation of these mediators by smoking and causing worsening of airway inflammation.” Smoking effect on airway inflammation has been also shown in preschool asthmatic children exposed to maternal tobacco smoking.‘ ETS exposed children with multiple trigger wheeze had increased nitric oxide." Smoking may also affect the association of asthma with gene expression. Ina study on ADAM33 gene polymorphism in Japanese women, a significant interaction was reported between some of the single nucleotide polymorphisms (SNPs) and smoking. However, there is limited information on the subject. No association of ETS exposure and, the studied polymorphism was seen in another study from Mexico. 6. Effe There is relatively less information on the effects of smoking on pharmacotherapy of asthma. Smoking modifies the dosages and effects of drugs, especially of those administered through inhalational route. Further, the response to therapy is poor in the presence of airway remodeling. Smoking is one of the most modifiable risk factor for adverse outcomes of asthma such as increased severity, asthma related quality of life, generic mental health status and longitudinal risk of hospitalisation. Smoking cessation as well as control of ETS-exposure should therefore constitute important and essential components of asthma therapy“ Asthmatic subjects who smoke were shown to develop resistance to inhaled corticosteroid therapy with one year trial of budesonide. Even in mild asthma, the efficacy of short term, ICS was shown to be significantly impaired in a placebo controlled study on 38 steroid naive patients. The mechanism of development of ICS resistance in smokers is not exactly known, of the mechanisms which have been put forwards include the alterations in airway inflammatory cells, changes in glucocorticosteroid receptors and reduced histone deacetylase activity.” Cigarette smoking may also necessitate changes in the requirement of bronchodilator drugs. It increases the clearance of theophylline, therefore reducing s on asthma-therapy and o' the bronchodilatory e! theophylline.” ‘Smoking may also increase the cholinergic tone in asthma, the additional use of anticholinergic agents such as inhaled ipratropium bromide was found to add to the bronchodilatory effect.°° Inhaled tiotropium has also been shown to reduce the reliever inhaler use and improve lung function in patients with clinical features of both asthma and COPD." There are however, no studies on the use of the antimuscarinic drugs in asthma alone. fect in patients on oral Smoker asthmatics may also benefit from additional use of leukotriene receptor antagonists as was shown in the Smoking Modalities Outcomes of Glucocorticoid Therapy in Asthma (SMOG) trial.” The role of monoclonal anti IgE antibody therapy with omalizumab in smoker asthmatics is not established, but requires further investig IgE in the patients.’ Interestingly in a recent study, asthma patients with a smoking history of > 11 pack-years tended to show greater benefit with montelukast while those with smoking of < 11 pack-years benefitted more with fluticasone.”* In conclusion, smoking exposure is known to influence the development of allergic sensitisation, and asthma as an important risk-factor. It also impacts the various asthma outcomes and treatment modalities. Smoking cessation as well as adoption of measures to avoid ETS-exposure are essential steps for the comprehensive and effective management of asthma. A probabilistic model of biological ageing of the lungs convincingly demonstrates that the combination of smoking with asthma (or COPD) is more harmful than asthma (or COPD) alone.* tion in view of the elevated total serum References 1. FlodinU Jonsson P, Zeger Axelson O.An epidemiologic study of bronchial asthma and smoking Epidemiology 1995; 65035. 2. Srouz\, Pin Oryszezyn MP, Le Moual N, Kauffman F Relationships fof actve emoking to arthma and acthma severtyintheEGEA study. Epidemiologiea study on the genetisand environment ofasthma Er fespir) 2000; 154707, 3. Spears M, Cameron E, Chaudhuri R Thomson NC. Challenges of ing asthma In people who smoke. Expert Rev Clin Immune! 4 Jindal SK, Gupta D. The relationship between tobacco smoke ang bronchial asthma Indian JMed Res 2004 120°443-453 5. Jindal SK, AggarwalAN,Gupta D, Agarwal R, Kumar R, Kaur T, Chaudhry K, Shah B Indian study on epidemiology of asthma, respiratory symptoms and evnie bronehitisin adults INSEARCH} Ine Tubere Lung Dis 2012;161270-77 6. Agrawal. fect of ndoor ae polltin rom blamass and sli fuel combustion on prevalence of setreporte asthma among adult ‘men and women in india: findings from a nationwide large-scale «cross-sectional survey. Asthma 2012; 48385-65,36 10. 1s. 20 2 24 2. 26. Kim 0, Kim 3H. Association of asthma symatoms with cigarette smoking and alcohol consumption in Korean adolescents. Nurs Health Se 2012;24 In pres Mitchell EA Beasley KeiU. Montfort, Odhiambo JTheassecation| between tobacco and the risk of asthma, thinoconjuctvts and eczema in children and adolescents analyses from phase Three of ‘the SAAC programme. Tovar 2012; 57981-49. He QQ. Wong TW, Ou, Jang 20. YU, Ou H, Gao, Wong AH, Lu Wi, Mu JG. Environmental tobacco smoke exposure and Chinese schoo! childrens expiratory healtha prospective cohor study. Am ‘JPrevMed2011;4:887-53, ‘Tanaka K Miyake Arakawa M Sasaki, OnyaY. Prevalence ofasthma and wheeze inrelation to passive smoking in Japanese children. Ann Fidel 2007; 171008-10 Chhabra 5K, Gupta CK, Chhabra ® Rajpal S. Risk factors for development of bronchial asthma in children in Del. Ann Allergy Asthena Immune! 1999; 83:385-390 Martinez ED, Clive M, Burrows B. Increased nedence of asthma in ‘children of smoking meters, Pediatr 1992:8621-6 Ehulich RL DUTeitD, Jordaan &Zwarenstein M Potter, elmink A, ta Ask factors for childhood asthma ang wheezing Importance of matemalandhousehold smoking Am /Respi Crit Care Med 1996, sks, Strachan DP, CookDDG, Heath elects of pase smoking, 6, Parental smoking and childhood asthma: longitudinal and case-control studies Thorax 1998'53204-12. Spitzer Wo,LavrenceV, Dales HG, Archer MC Clark? etalLinks between passive smoking and disease: abestevidence synthesis ‘report ofthe Working Group on Passive Smoking, Cin Invest Med O'Connell Logan 8. Parental smoking in childhood asthma. Ann ‘Alergy 1974;32.1025 Murray AB, Morrison Passive smoking anltheseasonalitference of severity of asthma in children Chest 1988; 94701-08, Evans D, Levison M4, Feldman CH, eta. The impact of passive smoking on emergency room visit of urban chien with asthma, ‘Ar Rev Respir Dis 1987; 1355587-72, Jindal SK, Gupta D, Singh A. Indices of morbidity and control of asthma n adult patients exposed environmental tobacco smoke (hes 1994, 106.746. Banner AS, The war against cigarette smoking, The final bates (Chest 1994; 106:562-53. Gerald, Gerald, Gibson Patek Zhang, MeClureLA Changes In environmental tobacco smoke exposure and asthma morbialty among utban school eileen. Chest 2009; 135:911-16. Kumar B, Curtis LM, KhianS, Moy ,Shalowite MU, Sharp, Ourazo- ‘Arvizu RA, Snannon 1), Welss KB. A community-based study of tobacco smoke exposure amonginne-city children withastrmain (Chicago. J Alergy Cin immuno! 2008; 12:754-58, Strong C,ChangL. Family secieeconomicstatushousehold tobacco smoke, and asthma attack among children below 12 years of age Gender diferences. Child HealthCare 2013; August 1 (Epub ahead of print Gortmake SL Walker DK, Jacobs F Ruch-RossH.Parentalsmoking| and rk of childhood asthma, Am Pubic Health 1962,72574-9, Weitzman M, Gortmaker 5, Walker DK, Sobol A. Maternal smoking and childhood asthma, Pedatice 1990; 85:505-1 De Luca G, Olver F Melott 6, Aiello 6, Lubrano L, Boner AL Fetal and early postatallferoots of asthma. Mater Fetal Neonatal Med 2010; 23(Suppl 3) 80.83. 2. 2 2, 20. a1 2. 2. Pa 2s. 6 7. 38 40 4 a. Lee SL, Lam TH, Leung TH, Wong WH, Schooling M, Leung GM Lau YL Foetal exposure to maternal passive smoking is associated with ctildhoed asthma, allergi rhinitis, and eczema, Scientific World Journa} 2012:542985, Kanoh M, Kant, Hara M, Harada S, Gon ¥,KanamaruH, hia Longitudinal studyof parental smoking hablts and development of| asthma in early childhood. Prey Med 2012; 5494-8, Robison RG, Kumar R, Arguelles LM, Hong X, Wang G, Apollon 5, Bonzagni A, Ort X, Pearson C, Pongracic JA, Wang X. Maternal smoking during pregnancy, prematurity and fecurent wheezing in early childhood. PedhatPulmono! 2012; 47666-73 Fodyl NA Stark MY, Schell, Grzeshowiak LE, Clifton VL Perinatal cutcome following maternal asthma and cigaretesmoking during pregnancy. ur Respir 52013; July 30 (Eau ahead of print (hss; Teheurekjian H RothLA Nguyen, Sen5,GalanterM Davis | Farr, Gland FD, Kumar Avil PC Brigine-Buenaventura E, CChapelaR Ford JG, ea. fect af seconé-hand smoke on asthma control among black and Latina children. J Allergy Clinimmuno! 2012; 129:1478-83, ‘StLaurent Bergeron C Page, Couture LavioletteM Boulet LP. Infuence of smoking on airway inflammation and remedeling in asthma, Clin Exp Alergy 2008; 381582 Janson € The importance of airvayemedling in thenatural course ‘of asthma. Clnespir2010;4 (Suppl. 1:28, armsenL, Gotti V, Makowska Rasmussen L, Backer V. Asthma patients wt smoke have sign of eronc airflow limitation before ge 45 JAsthma 2010; 4736266 Perret JL Dharmage SC, Matheson MC. Johns DP GurrinLC Burgess JAMarrone J Markos) Morison 5, Feather L Thomas PS, McDonal CF Giles G6, Hopper J, Wood-BakerR, Abramson MU, Walters EH The interplay between the etecs of Metime a:thma, smoking ang atopy on fixed aifow obstruction in midcle-age. Am) Respirrit are Med 2013; 187 42-48. Biaceuiere My, Timens W, Melgert BN, Geerings M, Postma DS, Hykera MN. Matemal smoking during pregnancy induces airway remodeling in mice offspring, EurRespi)2008, 33.1133-40, Caponnetto P,Auditore R, Russ C, Ala A, Campagna, Demma S,PolosaR "Dangerous eatonship' asthma and substance abuse “Adele Dis 2013;32:158-67. (Chang JE, Ding Martin-azaro White A, Stevenson DD. Smoking, environmental tabacco smoke, and asprin-exacerbated respiratory disease. Ann Alergy Asthma Immunol 2012; 10814-18, Havstad SL Johnson CC, Zoatl EM, Ezell JM, Woodcroft K, Ownby DR Weglenka G Tobacco smoke exposure and allergic sensitization inchidrerca propensity scoreanalysis Respirology 2012; 171068-72 Kontogiann’ K, Bakakos P, Kostas K, Milas G,Papaportyiou A, Papin 5, Kovlours NG, Loukide:S. Levels of prostaglanalnE(2) and Cysteiny-eukotrenes in sputum supermatant of patients with asthma: the effect af snaking Chin Exp Allergy 2013; 43:616-28 Kalliola 5, Peltonen AS, Malmberg LP, Sarna 5, Hamalainen M, Monenen L Makela Maternal smoking affect ing funetion ane away fanmaton nyoung children wth multple rigger wheeze. “Allergy Cin Immunol 2013, 131.730. ‘Miyake Tanaka K, Arakawa M, ADAM polymorphisms, smoking and asthmain Japanese women: the Kyushu Okinawamatemal ang child health study nt Tere Lung Dis 2012; 1674-8, ‘Munoz 8, Magana 1), Romero Toledo | uare2PererE, Loper Maya | Leyva-Garia N, LopezCampos C, Davila-Sorja Vi, Albores A The relationship among I-13, STP1 and CYPIAT polymorphisms and environmental tobacco smoke In a population of children vith asthma in Northern Mexica. Enviton Toxic! Pharmacol 2012; 332262,SUPPLEMENT To JOURNAL OF THE ASSOCIATION OF PHSICIANS OF INDIA“ MARCH201 VOL. 7 “44, Elsner MD barren C.The influence of cigarette smoking on adult asthma outcomes. Nicotine Tob Res 2007; 953-56, 45. Boulet LP FitzGerald JM Mevor RA, Zimmerman 5, Chapman KR Infuence of current or former smoking on asthma management and contol. an Respir 2008; 152758. ‘46. Livingston, Thomson NC, Chalmers GW, Impact of smoking on asthma therapy: acta review of cinial evidence, Orugs 2005; 55:1521-35, 447. Thomson NC, Spears M. The influence of smoking onthe treatment response in patients with asthma, Curr Opin Alergy Clin Immun 448. Pedersen 8, Dah , Karsrom , Peterson CG, VengeP. Eosinophil and neutrophil activity in asthma in a one-year tral with inhaled budesonide Theimpact of smoking. Am JRespir Cit CareMed 1996, 153:1518-28, 4 so. Chalmers GW, Macleod KJ, Little SA, Thomson Ll, MeSharry CCP, Thomson NC. Influence of cigarette smoking on inhaled coticosterid treatment in mild asthma, Thorax 2002;57:226-0, [AnmadZ, Singh Sk. Relative and adaltional bronchodilator response ‘ofsabutamo and ipratropium nsmokerand nonsmoker asthmatics sAsthma 2010; 47340. Magnussen H, Bugnas 8, van Noord Schmidt 2 Gerken Kesten. Inyprovements with iottopiur in COPD patients with concomitant asthma Resp fed 2008; 10255056 Lazarus SC, Chinehlh¥M Rollngs UJ, etal Smoking affects response to inhaled corticosteroids or leuketrene receptor antagonist in asthma. Am Respir Cit Care Med 2007; 175:785-790. Price D, Popov TA, BjermerL Lu 5, Petrov R,andormael, Mehta A Stus0, Palos? Philp G.Efectof montelukast for reatmentof asthmain igarette smokers. JAllegy Cin immuno! 2013; 13176371 CChiappa 5, Winn J Vinuela A, Tpney H, Spector D.A probabilistic ‘mae! of biological ageing ofthe lungs for analyzing the effect of smoking, asthma and COPD, Respir es 2013; 1660.