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Prof.(Dr.) Pranab Baruwa MBBS,DTCD,MD(TB&Chest Dis.), MNAMS(Resp.Med.) Fellow ICS

Prof.(Dr.) Pranab Baruwa MBBS,DTCD,MD(TB&Chest Dis.), MNAMS(Resp.Med.) Fellow ICS Trained in USA as WHO Fellow. Formerly : Prof. & Head, Dept. of TB & Chest Dis. Gauhati Medical College,. Guwahati. Principal cum Chief Superintendent, Tezpur Medical College, Tezpur.

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Prof.(Dr.) Pranab Baruwa MBBS,DTCD,MD(TB&Chest Dis.), MNAMS(Resp.Med.) Fellow ICS

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  1. Prof.(Dr.) Pranab Baruwa MBBS,DTCD,MD(TB&Chest Dis.), MNAMS(Resp.Med.) Fellow ICS Trained in USA as WHO Fellow. Formerly : Prof. & Head, Dept. of TB & Chest Dis. Gauhati Medical College,. Guwahati. Principal cum Chief Superintendent, Tezpur Medical College, Tezpur. Principal cum Chief Superintendent, Assam Medical College, Dibrugarh. Dean, Faculty of Medicine, Dibrugarh University, Dibrugarh. President,Indian Chest Society 2010-2011 ICS-Dr. S.N. Tripathy Oration. "PHENOTYPES IN COPD. WHAT IS NEW?"

  2. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Pawels RA, Buist AS et al Am J Respir Crit Care Med. 2001. 163: 1256-1276 Celli BR, Mac Nee W. Eur Resp J. 2004.23:932-946 Buist AS, Meburnie MA. et.al. Lancet 2007.370:741-750 COPD is a “preventable and treatable disease state characterized by airflow limitation that is not fully reversible. It is usually progressive and is associated with an abnormal inflammatory response of the lung to noxious particles or gases”. Exacerbations and co morbidities contribute to the overall severity in individual patients. COPD is a leading cause of morbidity and mortality globally. It is on the rise. On average, 10% of adult worldwide have COPD.

  3. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • The Predominant risk factor for COPD is cigarette smoking. • The relationship between smoking and COPD is not absolute. • COPD can occur in lifelong non-smokers. • More than 15% of subjects worldwide who die from COPD are non-smokers. • Less than 30% of subjects with significant smoking history develop COPD. • Several factors influence in the development of COPD- inhaled gases & particles, Genetics, health in early life, Nutrition, Gender, Socio-economic status, BMI etc. Lawlor DA., Ebrahim S.et.al. Thorax 2005,60:851-858. Silverman EK. Med. Clin North Am. 1996,80:501-522. A Lakke PL., Scharling H. et.al. Thorax.2006:61:935-939

  4. Decline in Lung Function PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • In non smokers FEV1 declines at the rate of 20-30 ml/yr in adult. • In most smokers FEV1 declines at the rate of 30-45 ml/yr • In Susceptible/ COPD persons FEV1 declines at the rate of 80-100 ml/yr. David AL & Silverman EK. Respir Res 2001,2:20-26

  5. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • Response to treatment in different COPD Patient is not same. • Clinical presentation, pathological/ radiological findings and even prognosis are different. • Likely to be a group of heterogeneous disorders J A Wedzicha Thorax 2000;55:631-632

  6. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. How to define prognosis? Celli BR., Cote CG et.al. N. Engl. J. Med 2004:350:1005-1012 Puhan MA., Garcia–Aymerich J. et.al. Lancet 2009:374:704-711 Jones RC., Donalson G.C. et.al. Am J Respir Crit Care Med.2009:180:1189-1195 • COPD severity measured by forced expiratory volume in 1 second (FEV1) alone does not recognise pathophysiological abnormalities in this heterogeneous condition. • Several indexes has been developed over the time to explain the prognosis of COPD with limited benefit • BODE index(BMI, FEV1, dyspnoea and exercise capacity) • ADO index (age, dyspnoea, FEV1) • DOSE index (dyspnoea, FEV1, smoking, and exacerbation frequency)

  7. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Respiratory Research 2009:10-41. MeiLan K. Han, Agusti A. et.al. Am J Respir Crit Care Med. Med.2010:182:598-604. • All patients do not respond equally to all drugs. • The need to identify “responders” to a particular therapeutic intervention is crucial. • Thus the concept of a clinical phenotype in COPD has emerged. • Phenotyping in COPD is a relatively young endeavor as compared to many other fields. • A MEDLINE search revealed just over 400 Phenotyping papers published in COPD, compared to more than 5000 in breast cancer.

  8. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Evolving concept of phenotype • The classic 'Blue Bloater' was described as a younger patient with chronic bronchitis, who often presented with congestive right heart failure. • The classic 'Pink Puffer' was an older and skeletal muscle-wasting patient who had unrelenting, disabling dyspnea and clear evidence of emphysema. Dornhorst AC Lancet 1955:1:1185-1187 • Historically, Dornhorst in 1955 for the first time described two clinical phenotypes of COPD- the classic ‘Blue Bloaters’ & ‘Pink Puffers’.

  9. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Evolving concept of phenotype There are several other diseases where management revolves around phenotypes e.g.- • In Breast cancer, presence of Estrogen & Progesterone receptors within the tumour determines response to therapy. • In Asthma- cellular phenotypes of asthma (Eosinophilic,Neutrophilic & pauci granulocytic) were use to direct successful application of Mepolizumab (anti IL-5) therapy • In COPD, Roflumilast was initially tried in a general COPD patients without much benefit. However, a sub population of COPD patients with FEV1 <50% predicted, chronic cough and sputum production demonstrated greatest clinical response. Rakha EA,Ellis IO Pathology:2009:41:40—47 Wenzel SE.N. Engl.J.Med.2009:360:1026—1028 Meilan K Han.Augusti A. et. al. Amer.J. Resp. and Crit.Care Med.2010:182:598—604.

  10. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Rice JP., Saccone NL. et.al. Adv. Genet 2001:42:69-76. Han M.K., Augusti A. et. al. Amer.J. Resp & Crit care Med 2010 :182 598-604. • The classic definition of Phenotype is “the observable structural and functional characteristics of an organism determined by its genotype and modulated by its environment’’. • An international group of experts has defined COPD phenotype as “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to treatment, speed of progression of the disease or death)”

  11. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • Han MK et.al. have suggested that clinical phenotypes in COPD should- • Have predictive value • Be prospectively validated for each of the out comes to which they may relate • Be able to classify patients into distinct subgroups that provide prognostic information thereby help us to determine the most appropriate therapy. Han M.K., Augusti A. et. al. Amer.J. Resp & Crit care Med 2010 :182 598-604.

  12. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • Proportional Venn diagram of OLD in the United States (NHANES III surveys from 1988 to 1994) and United Kingdom (GPRD 1998) for all ages. Soriano JB, Davis KJ. et.al. CHEST 2003; 124:474–481

  13. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • Proportional Venn diagram of OLD in the United States (NHANES III surveys from 1988 to 1994) and United Kingdom (GPRD 1998) for all ages. Soriano JB, Davis KJ et al.CHEST 2003; 124:474–481

  14. ICS-Dr. S.N. Tripathy Oration.

  15. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Various studies have identified several clinical phenotypes in COPD Casanova C ., Cole C. et al Am. J Resp crit care med.2005:171:591-597 Kitagushi Y., Fujimoto k. et al. Resp. Med. 2006 100: 1742-1752 Makita H. Nasuhara Y. et al. Thorax 2007:62:932-937 Marsh SE, Travers J. et al Thorax 2008:63:761-767

  16. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Burgel PR. Paillsseur J.I et al. Eur.Resp.Jour. 2010: 36:531-539. Hurst J.R, Vestbo J. et al. N.Engl. J. Med. 2010: 363: 1128-1138. Jo KW, Ra SW et al. Int. J. Tuber.Lung.Dis. 2010:.14:1481-1488. Garcia Aymerich J., Gomez FP. et al. Thorax 2011:66:430-437.

  17. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Based on a series of factors, majority of the studies have identified distinguished 3-5 Phenotypes in COPD.

  18. ICS-Dr. S.N. Tripathy Oration.

  19. ICS-Dr. S.N. Tripathy Oration.

  20. ICS-Dr. S.N. Tripathy Oration.

  21. ICS-Dr. S.N. Tripathy Oration. • MeiLan K Han et al stated that phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. • Proposed the following variation on COPD definition: “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death).” • This more focused definition allows for classification of patients into distinct prognostic and therapeutic subgroups for both clinical and research purposes.

  22. Characteristics of COPD phenotypes ICS-Dr. S.N. Tripathy Oration. Classified according to HRCT findings • A total of 172 patients with stable COPD (FEV1<80%) were examined by chest HRCT. • Emphysematous changes and bronchial wall thickening (BWT) were evaluated visually. • COPD patients were classified into three phenotypes: absence of emphysema, with little emphysema with or without bronchial wall thickening (A phenotype), emphysema without bronchial wall thickening (E phenotype), and emphysema with bronchial wall thickening phenotype (M phenotype). • Morphological phenotypes of COPD show several clinical characteristics. • Different responsiveness to treatment with bronchodilators and ICS to different Phenotypes. Fusimoto K., Kitaguchi Y. et.al Respirology 2006:11:731-740

  23. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Garcia Aymerich et.al in the Phenotypic Characterization and Course of COPD (PAC-COPD) study recruited 342 patients with COPD at their 1st hospitalization and followed them for 4 years. 3 different COPD Phenotypes were indentified and prospectively validated : Severe respiratory COPD, Moderate respiratory COPD and Systemic COPD. Garcia. Aymerich J., Federico P. et.al Arch. Bronconeumol 2009:45(1)4-11. Garcia Aymerich J., Gomez F.D. et.al Thorax 2010 doi:10:1136/thx.2010:15:44-84.

  24. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Study of COPD Phenotypes by using Principal Component and cluster analysis. Burgel et.al defined 4 different clinical phenotypes, different from GOLD classification. Patients with comparable airflow limitation (FEV1) belonged to different phenotypes, had marked differences in symptoms, co-morbidities and predicted mortality. Burgel P.R., Pailaseur J.L. et.al Eur. Respir J., 2010:36:531-539.

  25. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Proportional classification of COPD Phenotypes • Marsh et.al defined 3 phenotypic subgroups in a study on 96 COPD patients • 18/96 subjects (19%) had classical phenotypes of chronic bronchitis and/or emphysema but no asthma. • 53/96 (55%) COPD patients asthma was the predominant COPD phenotype. • 25/96 (26%) COPD patients had no classical asthma, chronic bronchitis or emphysema. Marsh SE., Travers J. et.al Thorax 2008:63:761-767.

  26. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. • According to Marc Miravitlles et.al. among all phenotypes described, there are 3 principal phenotypes that are associated with distinct clinical, prognostic and different therapeutic response to currently available therapies. • “Overlap” or mixed COPD-asthma phenotype • (2) Exacerbator phenotype and • (3) Emphysema hyperinflation phenotype Miravitlles M. Myriam Calle et.al. Arch Bronconeumol. 2012;48:86-98.

  27. PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Other Phenotypes Other Phenotypes • Other phenotypes have been defined, but these have very little clinical significance. • “Fast decliner”- a patient who suffers a loss of lung function, expressed by FEV1, faster than average. To identify this phenotype a strict follow-up of the lung function for at least 2 years is required, no specific treatment has been identified for this type of patients. • Rapid decline in FEV1 is predictive of morbidity, mortality and hospitalization rates. Celli BR., Thomas NE. et.al. Amer J. Respir Crit Care Med. 2008:178:331-338. Wise RA. Am J. Med. 2006:119:4-11.

  28. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Other Phenotypes • Chronic bronchitis phenotypes, defined as cough and expectoration for at least 3 months of the year for 2 consecutive years. This phenotype is usually associated with airway disease, which can be visualized with high-resolution computed tomography (HRCT). • Chronic bronchitis can accompany any of the three phenotypes. • COPD patients with chronic bronchitis are younger, more commonly men, more likely to be current smoker, more symptomatic and have more frequent comorbidities. Am. Thora. Society. Amer J. Respir Crit Care Med. 1995:152:77-121 Victor Kim, Mailan K. Hans et.al. Chest 2011:140:626-633.

  29. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Other Phenotypes Bronchiectasis phenotypes. • Martinez-Garcia and Collegues in a series on 91 Spanish patients with well characterized, clinically stable-moderate to severe COPD patients have shown 57.6% to have Bronchiectasis on HRCT. They were associated with severe airflow obstruction, isolation of potentially pathogenic micro organism (PPM) from sputum and at least one hospitalization for COPD exacerbations in the previous year. • In the East London COPD study 50% of patients with COPD had Bronchiectasis. • 29% of patients with COPD in primary care in U.K. were reported to have Bronchiectasis. Martínez-García MA , Soler-Cataluña JJ, et al Chest . 2011 ; 140 ( 5 ): 1130 - 1137 . Garcia-aymerich J., Gomez FP. et.al. Thorax 2011:66:432-437 O’Brien C, Guest PJ. et.al. Thorax 2000:55:635-642. Bafadhal M.Umar I. et.al. chest 2011:140:634-642

  30. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Other Phenotypes • A systemic phenotype has also been defined in patients who present obesity, cardiovascular disease, diabetes or systemic inflammation. • One special phenotype is emphysema due to alpha- 1-antitrypsin deficiency, appears early in life, particularly in smokers and has a genetic base. Garcia-aymerich J., Gomez FP. et.al. Thorax 2011:66:432-437 Videl R., Blanco I. et.al. Arch. Bronconeumol 2006:42:645-659

  31. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. MeiLan K. Han., Agusti A. et.al. Am J. Respir Crit Care Med 2010;182:598-604

  32. ICS-Dr. S.N. Tripathy Oration. PHENOTYPES IN COPD Mixed COPD-Asthma Phenotype • Patients present with characteristics of more than one obstructive airway disease. • About 13-20% COPD patients reported to have overlap phenotypes. • Increasing trend in elderly population –up to 50% in those aged over 70 years. • Marsh et.al have reported 55% COPD patients to be mixed COPD- Asthma Phenotype. Hardin M., Silverman E K et.al. Respri, Res. 2011.12:127. Soriano J B., Davis K J. et.al. Chest. 2003:124:474:481. Marsh S.E., Travers J. et.al Thorax 2008:63:761-767.

  33. PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Definition of the Mixed (COPD-Asthma) Phenotype • Recently consensus diagnostic criteria for Overlap (mixed) phenotype has been defined by a group of experts. • To be diagnosed with an Overlap phenotype a patient must fulfil 2 Major criteria or 1 Major and 2 Minor criteria among the following. • A – Major criteria: very positive bronchodilator response (> 400ml and >15% FEV1), sputum eosinophilia or previous diagnosis of asthma. • B – Minor criteria: increased total serum IgE, previous history of atopy or positive bronchodilator test (>200ml and >12% in FEV1) on atleast 2 occasions. Soler-Cataluna J.J., Coslo B. et.al. Consensus document on overlap asthma-COPD. Phenotype. Arch Bronconeumol.2012.

  34. ICS-Dr. S.N. Tripathy Oration. PHENOTYPES IN COPD Definition of the Mixed (COPD-Asthma) Phenotype • The diagnosis of the mixed phenotype will be established by the presence of a combination of the following factors: • History of asthma and/or atopy, • Reversibility in the bronchodilator test, • Notable eosinophilia in respiratory and/or peripheral secretions, • High IgE, • Positive prick test to pneumoallergens and • High concentrations of exhaled NO Papi A, Romagnoli M. et.al. Am J. Respir Crit Care Med. 2000:162:1773-1777.

  35. ICS-Dr. S.N. Tripathy Oration. PHENOTYPES IN COPD Mixed (COPD-Asthma) Phenotype Mixed (COPD-Asthma) Phenotype Differential Treatment Differential Treatment • The clinical justification for the mixed phenotype lies in its demonstrated sensitivity to the anti-inflammatory action of Inhaled Corticosteroids.(ICS) • Treatment with steroid reduces number of sputum eosinophils. • Serum Surfactant Protein –D (SP-D) levels indicate rensponse to ICS. • Greater airflow reversibility, a high concentration of eosinophils in spontaneous or induced sputum or a greater concentration of exhaled NO as markers of the response to ICS in COPD, even in mild to moderate stages. Brightling CE., Monteiro W et.al. Lancet 2000:356:1480-1485, Brightling CE., Mckenna S. et.al. Thorax 2005:60:193-198, Lee J.H., Lee Y.K. et.al. Resp. Med. 2010;104:542-549, Fujinoto K., Kubo K. Chest 1999:115:697-702, Sin D.D., Man SFP et.al. Am J. Respir Crit Care Med. 2008;177:1207-1214.

  36. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Mixed (COPD-Asthma) Phenotype Differential Treatment • Based on the clinical, functional and inflammatory characteristics of COPD patients. i.e. in Mixed phenotypes, (instead of severity of airflow obstruction measured FEV1 alone), a high dose ICS treatment has been recommended. • The Canadian Guideline specify that “if the asthma component in COPD is prominent, earlier introduction of ICS may be justified” • The Japanese Guideline dedicates a chapter to “treatment of COPD complicated by Asthma”. • The Spanish Guideline of COPD direct treatment according to phenotypes. Anderson D., MacNee W. Int. J. COPD.2009:4:321-335 Miravitlles M. Arch. Bronconeumol. 2009.45:27-34. O’Donnel DE., Aaron S. et.al. Can. Respir. J. 2007;14(suppl B) 5-32. Nagi A., Aizawa H. et.al. 2009http/www/s.orjp. Miravitlles M., Calle M., et.al. Arch. Bronconeumol. 2012:48:86-98.

  37. ICS-Dr. S.N. Tripathy Oration. PHENOTYPES IN COPD Exacerbator Phenotype • “Exacerbators” are defined as those COPD patients who present with 2 or more exacerbations per year. • These exacerbations should be separated by at least 4 weeks after the end of treatment of the previous exacerbation or 6 weeks after the onset of the exacerbation in cases that have received no treatment. • Exacerbator phenotype of COPD is independent of disease severity. • Estimation of Serum Amyloid-A (SAA) is a better marker for diagonosis of exacerbations. Soler-cataluna J.J., Rodriguez R.R. COPD 2010:7:276-284. Bozinovski S., Hutchinson A. et.al. Am J. Respir Cirt Care Med. 2008:177:269-278. Shahab L., Jarvis M.J. et.al. Thorax 2006:61:1043-1047. Seemungal T., Harper O.R. et.al. Am J. Respir Cirt Care Med.2001:164:1618-1623. Hurst J.R., Vestbo J. et.al. N. Engl J. Med.2010:363:1128-1138.

  38. ICS-Dr. S.N. Tripathy Oration. • Hurst et al analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. • Results • Exacerbations became more frequent (and more severe) as the severity of COPD increased. • 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations. • The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. • phenotype was also associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. N Engl J Med 2010:363:1128-1138.

  39. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Exacerbator Phenotype • RISK FACTORS ASSOCIATED WITH REPEATED EXACERBATIONS. • Older age • COPD severity • History of previous exacerbations • Inflammation • Bacterial load (stable phase) • Chronic bronchial hypersecretion • Comorbidity/extrapulmonary manifestations Greater baseline dyspnea Low FEV1 Low Pao2 Greater airway inflammation Greater systemic inflammation Cardiovascular Anxiety-depression Myopathy Reflux disease M. Miravitlles., Moiriam C. et.al. Arch. Bronconeumo. 2012:48:86-98

  40. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Exacerbator Phenotype Differential Treatment • Long-acting bronchodilators (LABA), have been shown to reduce the frequency of exacerbations • ICS in patients who present frequent exacerbations, especially when associated with bronchodilators, produces a significant reduction in the number of exacerbations and an improvement in HRQL. • Tiotropium has been shown to reduce exacerbation rates, improve quality of life and increases FEV1. Vogelmeier C., Hederer B. et.al. N. Engl. J. Med 2011:364:1093-1103. Kardos P., Wencker M et.al. Am J. Respir Crit Care Med 2007:175:144-149. Wedzicha JA., Calverley PMA el.al. Am J. Respir Crit Care Med 2008:177:19-26.

  41. PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Exacerbator Phenotype Differential Treatment • Roflumilast is a new oral anti-inflammatory drug that acts by selectively inhibiting phosphodiesterase IV has been approved for preventing exacerbations in patients with severe COPD with FEV1<50% with cough and chronic expectoration and frequent exacerbations. • Roflumilast is indicated for the exacerbator phenotype with chronic bronchitis. • Macrolides may be administered for a prolonged time, as they have anti-inflammatory and immunomodulatory actions in addition to their possible antibacterial action. Calverley PMA., Sanchez-Toril F. et.al. Am J. Respir Crit Care Med 2007:176;154-161. Fabbri LM, Calverley PMA. et.al. Lancet 2009:374:695-703. Sevilla-Sanchez D, Soy-Muner D. et.al. Arch. Bronconeumol.2010:46:244-254.

  42. PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Exacerbator Phenotype Differential Treatment • PULSE (Pulsed moxifloxacin Usage and its Long-term impact on the reduction of Subsequent Exacerbation) study, studied the efficacy of 5 days cycles of 400mg of Moxifloxacin every 8 weeks in patients with stable COPD. • This treatment reduced the risk for exacerbation by 20% in the intention-to-treat (ITT) analysis, 25% in the per-protocol (PP) analysis and 45% in patients who presented purulent or mucopurulent sputum, without a significant increase in bacterial resistances. • Administration of Nebulized Tobramycin in Severe COPD colonized by Pseudomonas aerugenosa reduced No. of severe exacerbation by 42%. Sethr S., Jones PW., et.al. Respir Res 2010:11:10. Dal Negro R., Micheletto C. et.al. Adv. Ther. 2008:25:1019-1030.

  43. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Definition of Emphysema-Hyperinflation Phenotype COPD patients who present dypnoea and intolerance to exercise as the predominating symptoms. They are characterized by presence of functional data of hyperinflation, Emphysema on HRCT study, variability of the Carbon Monoxide (CO) diffusing capacity(DLCO), tendency towards a lower BMI. Miravitlles M. et.al. Arch Bronconeumol 2012:48:86-98. Grydeland TB., Thorsen et.al. Respir Med. 2011;105:343-351. Mair G. Maclay J. et.al. Respir Med 2010:104:1683-1690.

  44. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Diagnosis of Emphysema-Hyperinflation Phenotype • HRCT. • FEV1 is strongly related to COPD severity. • FEV1% Predicted is weakly related to the extent of emphysema. • Reduction in DLCO is more strongly correlated with the severity of emphysema as assessed by HRCT. Hoidal JR., Eur Respir J. 2001 18:741-743, Baldi S. Miniati M. et.al. Am. J. Respir Crit Care Med 2001:164:585-589.

  45. PHENOTYPES IN COPD PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Differential Treatment of Emphysema-Hyperinflation Phenotype • Several studies have demonstrated improvements in forced vital capacity (FVC) after administration of long acting bronchodilator (LABA), with improvement in Inspiratory Capacity and reduction in air trapping with no significant improvements in FEV1. • This improvement in the volume (FVC) without changes in airflow(FEV1) is more frequent as the bronchial obstruction becomes more severe. Newton MF., O’Donnell DE et.al. Chest 2002:121:1042-1050, Tashkin DP, Celli B et.al. Am J. Respir Crit Care Med 2008:177:164-169.

  46. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Differential Treatment of Emphysema-Hyperinflation Phenotype • NETT study also did not demonstrate the superiority of surgical intervention versus conservative treatment, however, in patients with emphysema in the upper lobes and low exercise capacity, a significant reduction in mortality was achieved after lung volume reduction surgery (LVRS). • In addition, the improvement in lung function after surgery was accompanied by a significant reduction in the number of exacerbations and prolonged period of exacerbation-free life. Martinez FJ., Foster G. et.al. Am J. Respir Crit Care Med 2006:173:1326-1334. Washko GR., Fan VS et.al. Am J. Respir Crit Care Med 2008:177:164-169.

  47. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Differential Treatment of Emphysema-Hyperinflation Phenotype • Long-acting bronchodilators (LABA) are the Principal drug for treatment. • They improve symptoms and exercise capacity and, consequently, improve the state of health • Benefits reached at the clinical level do not translate into an improvement of the degree of obstruction (changes in FEV1) with improvements in degree of dyspnea and exercise tolerance. • Tiotropium has been shown to improve quality of life and degree of dyspnoea. Tashkin DP., Cooper CB. Chest 2004:125:249-259. O’Donnell FT., Gerken F. et.al. Eur Respir J. 2004:23:832-840

  48. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Differential Treatment of Emphysema-Hyperinflation Phenotype • Anti-inflammatory treatment with inhaled corticosteroids(ICS), has not been shown to be as effective as in other phenotypes. • Oral anti-inflammatory Roflumilast did not offer good results for reduction of exacerbations. Lee JH., Lee YK et.al. Respir Med 2010:104:542-549. Rennard SI., Calverley PMA. et.al. Respir Res 2011:12-18.

  49. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. Differential Treatment of Emphysema-Hyperinflation Phenotype • Patients with an emphysema-hyperinflation phenotype could benefit more from a double bronchodilator therapy -- Formoterol and Tiotropium, Fluticasone-Salmeterol combination. • They are benefitted more from respiratory rehabilitation due to its beneficial effects on dyspnea and exercise tolerance. Rabe KF., Timmer W. et.al. Chest 2008:134:255-262, Casaburi R, Zuwallack R.N. Eng. J. Med 2009:360:1329-1335.

  50. PHENOTYPES IN COPD ICS-Dr. S.N. Tripathy Oration. SUMMARY • COPD is a leading cause of morbidity and mortality Globally. • It is on the rise. • FEV1 can not be used in isolation for optimal diagnosis, assessment of severity, follow-up and response to therapy. • Significant heterogeneity of clinical presentation, disease progression and response to different medications exists. • Phenotypes should be able to classify COPD patients into subgroups for determining the specific therapy to achieve better clinical results. • Phenotyping in COPD is a relatively young endeavor. • Efforts should be made to bring out International consensus statement on phenotypes based management of CPOD.

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