01. Dr Salvi COPD UPDATE 17072022.ppgrtx

COPD UPDATE having latest update in the field of COPD

1. Founder Director, Chest Research Foundation 2002 – 2019 Member, Board of Directors, GOLD (Global Initiative for COPD) (2017 onwards) Vice-President, Indian Chest Society, 2018-19, 2019-20 International Advisory Board Member, Lancet Respiratory Medicine (2015 - 2021) Chair, Chronic Respiratory Diseases Section, Global Burden of Disease, India (2015 onwards) Member, Steering Committee on Air Pollution and Health, Ministry of Health and Family Welfare, Govt. of India Ranked No. 1 Respiratory Scientist in India and No. 79 in the world out of 60,442 Respiratory Scientists by the Stanford University Ranking for 2021. Dr Sundeep Salvi MD, DTCD, DNB (Resp Med), PhD(UK), FCCP (USA), FICS, Hon FRCP (Lon) Director Pulmocare Research and Education (PURE) Foundation, Pune Distinguished Professor of Research, Faculty of Health Sciences, Symbiosis International University

2. Dr Sundeep Salvi MD, DNB, PhD(UK), FCCP(USA), FICS, Hon. FRCP(Lon) [email protected] [email protected] What is New in COPD and Asthma Pulmocare Research and Education (PURE) Foundation Viman Nagar Pune, INDIA Best of Chest, 2022, Kolkata

3. No. of Google Scholar Citations: 1623 25-45% of COPD is Non-Smoking Global Leadership One of the most cited papers on COPD in the world 2010

4. 2022; 10(5): 497-411 70% of COPD in India is Non-Smoking 55% of COPD globally is due to non-smoking causes

5. 2022

6. 2001 GOLD Strategy Report Vestbo , Lange. Am J Respir Crit care Med 2002; 166: 329 GOLD Stage 0

7. COPD Gene Study 43% of smokers with a normal spirometry had emphysema, gas trapping or airway thickening on HRCT 23% had mMRC Grade I-II (22% of GOLD Stage I had mMRC Grade I-II)  QoL  Six-minute walk distance  Exacerbation rate Regan EA et al, JAMA Int Med 2015; 175: 1539-1549 USA SPIROMICS Study ≈ 50% of smokers with Normal Spirometry - CAT Score ≥ 10 - Exacerbation Freq SIMILAR TO - GOLD Stages I, II HRCT showed - Airway wall thickening - ed airway Mucin conc. Woodruff PG et al, New Engl J Med 2016; 374: 1811-1821 USA CANCOLD Study N = 3779, ≈60% smokers, mean age of 56 years with Normal Spirometry - 14% had exacerbations - 24% needed respiratory medications (Inhaled steroids,, bronchodilators, oral steroids) - Poor QoL - Missed social activities - Missed work for income - Missed housework Tan WC et al, Thorax 2014; 69: 709-717 Canada

8. SPIROMETRY INTERPRETATION FEV1/FVC FVC% FVC% Reduced NORMAL (>80%) FEV1/FVC Normal (>70%) Normal s/o RLD <70% = OAD FVC% Normal OAD Mild or Moderate Reduced OAD + RLD or Severe Obstruction (>80%) True RLD ? Normal PRISM (Preserved Ratio Impaired Spirometry)  40%  20% in general population

9. Wijnant SRA et al, Eur Respir J 2020; 55: 1901217 5487 1603 Followed over 4.5 years PRISM = FEV1/FVC >0.7 and FEV1<80% 1/3 rd of PRISM go on to develop frank COPD 1/3 rd of PRISM die early from CVD 1/3 rd of PRISM have RLD What happens to PRISM?

10. Risks of Mortality and Airflow Limitation in Japanese with Preserved Ratio Impaired Spirometry Washio Y et al, AJRCCM 2022 May; Ahead for print N = 3032 Community-based Japanese people followed over a period of 5.3 years with annual Spirometry How many subjects who had PRISM developed airflow obstruction? Risk of all cause mortality among those with PRISM was 2.1-fold (1.3 – 3.4) versus 1.04-fold (0.56 – 1.9) for GOLD Stage I , and 1.8-fold (1.2 – 2.8) for those with GOLD stage II-IV

11. Pre Diabetes Pre Hypertension Pre Eclampsia Pre Cancer Pre COPD Symptoms Risk Factors Spirometry Post bronchodilator FEV1/FVC < 0.7 Spirometry Post bronchodilator FEV1/FVC > 0.7 FEV1 < 80% pred (Preserved Ratio Impaired Spirometry) FEV1 > 80% pred COPD PRISM NORMAL Pre COPD

12. COPD Gene Study 43% of smokers with a normal spirometry had emphysema, gas trapping or airway thickening on HRCT 23% had mMRC Grade I-II (22% of GOLD Stage I had mMRC Grade I-II)  QoL  Six-minute walk distance  Exacerbation rate Regan EA et al, JAMA Int Med 2015; 175: 1539-1549 USA SPIROMICS Study ≈ 50% of smokers with Normal Spirometry - CAT Score ≥ 10 - Exacerbation Freq SIMILAR TO - GOLD Stages I, II HRCT showed - Airway wall thickening - ed airway Mucin conc. Woodruff PG et al, New Engl J Med 2016; 374: 1811-1821 USA CANCOLD Study N = 3779, ≈60% smokers, mean age of 56 years with Normal Spirometry - 14% had exacerbations - 24% needed respiratory medications (Inhaled steroids,, bronchodilators, oral steroids) - Poor QoL - Missed social activities - Missed work for income - Missed housework Tan WC et al, Thorax 2014; 69: 709-717 Canada RETHINC ( Re -defining th erapy in early C OPD Trial. NCT 02867761) Aug 2017 onwards

13. In GOLD I COPD patients, a DLCO < 60% predicted is associated with increased risk of death and worse clinical presentation JP de Torres et al, CHEST 2021; 160: 872-878 DLCO < 60% vs ≥ 60% Mortality: 23% vs 9% HR: 3.37 (1.35 – 1.89) GOLD -I N = 360 DLCO Alive / Dead 109 ± 50 months ≈ 9 years DLCO > 60% N = 313 (87%) DLCO < 60% N = 47 (13%) Clinical and Prognostic Impact of Low Diffusing Capacity for Carbon Monoxide Values in Patients With Global Initiative for Obstructive Lung Disease I COPD

14. Chapter 2: Diagnosis and Initial Assessment A DLCO test should be performed in every patient of COPD with symptoms disproportionate to the degree of airflow obstruction

15. Zhang L et al, 2022; 17: 1365 38 studies N = 16,345 Mean Prevalence: 39.2% (34.0 – 44.4%)  ing severity of COPD Females > Males

16. Healthy COPD, No Exacerbations Exacerbation Exacerbation Exacerbation ↑ ing age Decline in Lung Function with Age Greater decline in lung function – rapid progression of the disease Increases symptoms and worsens quality of life Increases mortality (AECOPD hospitalization – 5 year survival is 50%) Increases economic costs

17. Bafadehl et al, 2019 The respiratory health community have neglected translating the term exacerbation, an event that substantially affects morbidity and mortality in patients with COPD. We propose tha t the term AECOPD be replaced with COPD Crisis Ex – Expression Acerbus – Harsh or Bitter Doctor - How many AECOPDs have you had so far in the last year? Patient - Less than 2% of patients understand the terminology AECOPD UK

18. Mwasuku et al, 2021; 21: 299 Acute Exacerbations of COPD are not taken seriously by the patients and health care providers despite the huge negative impact it has on the lives of COPD patients Respiratory Nurses in the UK working with patients with COPD Association of Respiratory Nurses International Primary Care Group N = 113 Only 4.4% of Nurses thought patients with COPD fully understood the term ‘exacerbation’ Recommended Terms: Flare-Up Lung Attack Crisis UK

19. Holverda S et al, 2020; 8: e25 2-year mortality for AE-COPD hospitalization is higher than that of a heart attack A National Survey was done among patients in Netherlands. They were offered several terms for AECOPD, and they expressed a preference for LUNG ATTACK Connors et al, AJRCCM 1996 Survival AECOPD 1 yr 33% 2 yr 49% Netherlands HEART ATTACK BRAIN ATTACK

20. T he disease was characterized by persistent dyspnea punctuated by acute episodes of worsening, frequently associated with newly developed and/or worsening cough and sputum (labeled as “ acute catarrh ” ) that could lead to “ suffocation. ” Laennec, 1820 Anthonisen , 1987 “Increasing respiratory symptoms, particularly dyspnea, cough and sputum production, and increased sputum purulence” “An acute worsening of respiratory symptoms that results in additional therapy” Mild:  symptoms,  SABA/SAMA Moderate: Antibiotics, Oral steroids Severe: Hospitalization GOLD, 2022

21. Celli B et al, AJRCCM 2021; 204: 1251 Symptoms Function Surrogate markers of underlying process Consensus

22. LABA + LAMA ICS + LABA ICS + LABA + LAMA Deaths Hazard ratio ICS + LABA + LAMA 2.3% 0.72 (0.53 –0.99) ICS + LABA 2.6% 0.89 (0.67-1.16) LABA + LAMA 3.1% Reference  Moderate exacerbations  Severe exacerbations  Rate of hospitalization ICS + LABA + LAMA Lipson et al, NEJM 2018; 378: 1671 Lipson et al, AJRCCM 2020; 201: 1508-1516 N = 10,355 ICS+LABA+LAMA vs ICS+LABA vs LABA+LAMA IMPACT Trial es mortality by 28%

23. Freq of E-COPD No. of deaths Hazard Ratio Old data Hazard Ratio New data Bude 320 + LABA + LAMA 1.08 28 0.54 (0.3 – 0.8) 0.51 (0.33 – 0.8) Bude 160 + LABA + LAMA 1.07 39 0.79 (0.5 – 1.2) 0.72 (0.4 – 1.16) ICS + LABA 1.24 34 0.78 (0.5 –1.3) LABA + LAMA 1.42 49 Ref E-COPD Mortality ETHOS Trial Rabe et al, NEJM 2020; 383: 35=48 N = 8509 Martinez, AJRCCM 2021; 203: 553-564 (Additional data collected) Use of triple drug therapy reduces COPD mortality by 49% But only in the 320 (400) mcg BD Budesonide arm P < 0.05

24. Single Inhaler Triple Therapy (SITT) or Multi-inhaler Triple Therapy (MITT) for COPD Alcázar -Navarrete et al, CHEST 2022 June; Ahead of Print SPAIN Health records from Spanish National Healthcare System SITT = 1011; MIIT = 3614 Risk of Death Persistence with treatment SITT MITT Risk of exacerbations MITT SITT

25. Celli B et al, 2021; 203: 689-698 N = 33,051 from 9 studies Active treatment (N = 21,941) Vs Placebo (N = 11,110) Pharmacotherapy reduced the rate of decline in lung function by 5 mL/ yr (0.8 – 9.1 ml/ yr ) ICS 7.3 ml/ yr (4.1 – 10.5) LABA/LAMA 4.9 ml/ yr (0.9 – 10.6)

26. Hospitalization due to community-acquired pneumonia in patients with chronic obstructive pulmonary disease: incidence, epidemiology & outcomes. Bordon J et al, 2019; Ahead of Print Louisville, Kentucky USA 18,246 patients of COPD 3,419 Pneumonias during 2 years Annual Incidence of Pneumonia: No COPD 509 / 100,000 COPD 9,369 / 100,000 Incidence of Community Acquired Pneumonia is 18-fold greater among patients with COPD

27. Bacterial load and defective monocyte-derived macrophage bacterial phagocytosis in biomass smoke-related COPD Ghosh B et al, ERJ 2019; 53: 1702273 Stable COPD subjects

28. Agarwal A et al, 2019; 20: 171 Potential for Novel Drugs in the Future

29. Streptococcus Moraxella Ramsheh M et al, Lancet Microbe 2021; N = 546, 5 countries

30. Before 2020: Influenza Vaccine Pneumococcal Vaccine 2021 GOLD Strategy Report: Influenza Vaccine Pneumococcal Vaccine Pertussis Vaccine (DPT) Booster VACCINATION in COPD 2022 GOLD Strategy Report: Influenza Vaccine Pneumococcal Vaccine Pertussis Vaccine (DPT) Booster Zoster Vaccine > 50 yrs COVID Vaccine – all ages

31. COPD Cost Pyramid: Value for Money London Respiratory Network and London School of Economics Cost per Quality-of-Life Adjusted Life Years gained (British Thoracic Society Reports, 2012)

32. Association Between Initiation of Pulmonary Rehabilitation After Hospitalization for COPD and 1-Year Survival Among Medicare Beneficiaries Lindenauer et al, JAMA 2021; 323: 1813-1823 Do COPD patients discharged after hospitalization for E-COPD benefit from Pulmonary Rehabilitation if initiated within 3 months after discharge? Retrospective Observational Analysis of 1,97,376 Mortality at the end of 1 year PR started < 90 days vs those >90-365 days 2721 (1.5%) vs 3161 (1.6%) <90 days Younger (74 vs 77) Lived closer (5.8 vs 9.8 miles) Whites > Blacks Lesser comorbidity (3.5 vs 4.2)  mortality by 37%

33. Survival Curves (Cox Regression) Adjusted for age, FEV1 and MRC Dyspnea Score Physical Capacity Can Do Physical Activity Do Do Retrospective Study of 849 COPD subjects Vaes AW et al, CHEST 2022 June; Ahead of print "Can Do, Do Do " Quadrants and 6-Year All-Cause Mortality in Patients With COPD Netherlands Men Women 4125 steps 404 m 6MWD 4005 steps 394 m 6MWD ed risk of death by 64% ed risk of death by 70%

34. Monica Barne and Sundeep Salvi, Lung India 2022; 39: 377-378 P ulmonary R ehabilit a tion for B etter He al th Outcomes PRABAL Misconceptions, misrepresentations or negative connotations surrounding PR have been reported by people with CRDs. Pulmonary Rehabilitation Is it only related to Pulmonary? Rehabilitation: Lost home or livelihood Drug / Alcohol Rehabilitation

35. Smokers >20 pack years Age: 50-74 yrs Low dose CT (LDCT) NELSON Trial Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial de Koning NEJM 2020; 382: 503 ed incidence  24% (6% - 39%) Men: 13,195 Women: 2594 The USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. ed mortality (USPSTF, JAMA 2021; 325: 962-970) US Preventive Services Task Force

36. Prevalence (%) Prevalence of Spirometry-defined Airflow Obstruction / Asthma Delhi Kottayam - Mysuru Delhi children had significantly more Spirometry-defined asthma than children from Kottayam-Mysuru (Salvi et al, Lung India 2021; 38: 408-415)

37. [OR: 1.8 (1.5 – 2.1)] 50% to 210% increased Odds The odds was significantly greater among Delhi children Association between Obesity / Overweight and Spirometry-defined Asthma (Salvi et al, Lung India 2021; 38: 408-415)

38. Morrison CB et al 2022; 119(16): e2119680119 No. of shed cells No. of infected cells IL-13+ IL-13+ IL-13+ IL-13+ Why are asthmatics protected from developing SARS-Cov2 lung complications?

39. Under-use of ICS causes deaths in a dose-related manner Less than 4 units of ICS increased asthma deaths Use of more than 6 canisters of ICS per year reduced mortality by 50% N=30,569 with 562 deaths, 77 due to asthma NEJM 2000; 343: 332-336

40. 2022 August; 39(4): 331 Use of ICS in Asthma is only 6% in India Every patient of asthma, be it mild intermittent, mild persistent, moderate or severe, MUST be treated with ICS Use of ICS must be encouraged for every asthmatic patient in India

41. Faith Centre, Viman Nagar, Pune Dr Sundeep Salvi Mobile: [phone] [email protected]

42. Chapter 3: Evidence supporting prevention and maintenance therapy Pharmacological treatment can reduce COPD symptoms, reduce the frequency and severity of exacerbations and improve health status and exercise tolerance. Data suggests beneficial effects on lung function decline and mortality. Pharmacotherapy of COPD:  Symptoms, quality of life  Exacerbations Pharmacotherapy of COPD: ? Rate of decline in lung function ? Mortality <2021 GOLD 2022 Strategy Report

43. Results Literature Review FGDs with chest Experts In-depth interviews with COPD, Asthma and At Risk Patients 129 Items Demographics Symptoms Risk Factors Co-Morbid ITEM REDUCTION 43 23 8 PEFR + 31 COPD prevalence in the study population (n = 4258) Mean Age : 49 ± 13 PEFR Cut-offs: Male <250; Female <200 Age_>40years Gender (Male > Female) Cough in the absence of a cold Shortness of breath Feeling of chest tightness Wheeze or a whistling noise coming from the chest during breathing Longstanding history of asthma Current + Ex-Smoker OSCAR Questionnairre Final set of 8 questions + PEFR { cut-off value of ≥ 8 (maximum 14)} SENSITIVITY: 51.6% SPECIFICITY: 97.5% POSITIVE PREDICTED VALUE: 52.4% NEGATIVE PREDICTED VALUE: 97.4% OVERALL ACCURACY: 95.2% Best Research Paper at NAPCON 2021 ERS Sliver Travel Award

44. Disease Severity and Proportionate Cost Direct and Indirect Costs of COPD per Patient in India The Economic Cost of COPD in India is an estimated 100,000 Crore Rupees/year 42% 40% 28% 30% 31% 37% 12% 12% 17% 7% 8% 8% Severe 59% Very-severe 16% Moderate 23% Mild 2% ERS Silver Travel Award 2022

45. Moderate–to–Severe COPD exacerbation Death from any cause Budesonide 160 mcg Triple Glyco + Formo Budesonide 320 mcg Triple Bude + Formo Glyco + Formo Bude 160 mcg T Bude + Formo Bude 320 mcg T Rabe et al, 2020; 383: 35-48 ETHOS Trial N = 8500, moderate-to-severe COPD Pneumonia: Bude 320 T - 4.6% ; Bude 160 T - 4.0% ; Bude-Form - 5.0% ; Glyco -Form - 2.9 %)