DR. dr. Zulkifli Amin, SpPD, K-P, FCCP Tempat/Tanggal Lahir : Singkarak, 10 Oktober 1952 Jabatan : Staf Subag. Pulmonologi FKUI / RSCM

The Bright Future of Obstructive Lung Disease

Introduction Chronic Obstructive Pulmonary Disease, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. Penyakit Paru Obstruktif Kronis (PPOK) merupakan penyakit yang dapat dicegah dan diobati dengan karakteristik berupa keterbatasan aliran udara persisten yang biasanya progresif serta berhubungan dengan inflamasi kronis yang disebabkan oleh gas atau partikel iritan tertentu. Eksersebasi dan komorbid berkontribusi terhadap beratnya penyakit (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

persistent airflow limitation Chronic Obstructive Pulmonary Disease, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. persistent airflow limitation PPOK dan keterbatasan aliran udara yang persisten © 2016 Global Initiative for Chronic Obstructive Lung Disease

Mechanisms Underlying Airflow Limitation in COPD Small airways disease Airway inflammation Airway fibrosis luminal plugs Increased airway resistance Parenchymal destruction Loss of alveolar attachments Decrease of elastic recoil Keterbatasan aliran udara yang persisten disebabkan oleh dua mekanisme mendasar Yaitu : Small airway disease Dan Destruksi parenkim paru (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

chronic inflammatory response Chronic Obstructive Pulmonary Disease, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. chronic inflammatory response PPOK dan Respon inflamasi kronis © 2016 Global Initiative for Chronic Obstructive Lung Disease

Chronic Inflamatory Response Pada tingkat seluler, terdapat berbagai proses biologis yang turut serta dalam pathogenesis PPOK. At the cellular level, many biological processes characterise the development of COPD. Cigarette smokers develop some degree of lung inflammation, but the COPD patient develops a far greater degree of inflammation that progresses rapidly with advanced disease, often accompanied by systemic inflammation and inflammation in the heart, blood vessels and skeletal muscle. Chung KF, Adcock IM. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. European Respiratory Journal 2008 31: 1334-1356 Eur Respir J 2008 31: 1334-1356

Global Burden of Disease Global burden disease study memperkirakan bahwa PPOK yang semula ranking 6 sebagai penyebab kematian pada tahun 1990 Akan menjadi ranking ketiga pada 2020 The Global Burden of Disease Study projected that COPD, which ranked sixth as a cause of death in 1990, will become the third leading cause of death worldwide by 2020 (GOLD 2016) Murray and Lopez NEJM 2013;369:448

Risk Factors for COPD Faktor risiko yang paling umum ditemui adalah rokok tembakau, ganja juga merupakan faktor resiko PPOK Di beberapa negara, faktor resiko dapat juga disebabkan oleh polusi udara lingkungan, polusi akibat paparan pekerjaan ataupun polusi dalam rumah tangga (akibat pembakaran biomassa) (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

Smoking: still a problem Merokok adalah faktor resiko utama dan terpenting Smoking is the most encountered risk factor for COPD Smoking is considered by far the most important risk factor associated with functional decline in COPD.

E cigarettes Vaping Sales in USA in 2013 $ 1 billion Rokok elektrik yang sedang digandrungi Sales in USA in 2013 $ 1 billion

Aging Populations Risk Factors for COPD Genes Infections Socio-economic status Selain factor resiko yang telah disebutkan diatas, terdapat factor resiko lain yaitu Genetik, status social ekonomi, infeksi paru di waktu kecil dan penuaan Genes The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin (GOLD 2016) Socioeconomic Status Poverty is clearly a risk factor for COPD but the components of poverty that contribute to this are unclear. There is strong evidence that the risk of developing COPD is inversely related to socioeconomic status (GOLD 2016) Infections A history of severe childhood respiratory infection has been associated with reduced lung function and increased respiratory symptoms in adulthood (GOLD 2016) Aging Populations © 2016 Global Initiative for Chronic Obstructive Lung Disease

Ito dan kawan kawan, pada tahun 2009 mengemukakan bahwa terdapat hubungan yang kuat antara penuaan dengan inflamasi kronis There is increasing evidence for a close relationship between aging and chronic inflammatory diseases. COPD is a chronic inflammatory disease of the lungs, which progresses very slowly and the majority of patients are therefore elderly There is evidence that accelerating aging of lung in response to oxidative stress is involved in the pathogenesis and progression of COPD, particularly emphysema Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death.  This results from a failure of organs to repair DNA damage by oxidative stress (nonprogrammed aging) and from telomere shortening as a result of repeated cell division (programmed aging). During aging, pulmonary function progressively deteriorates and pulmonary inflammation increases, accompanied by structural changes, which are described as senile emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation, for example, by reducing antiaging molecules, such as histone deacetylases and sirtuins, and this consequently induces accelerated progression of COPD. Recent studies of the signal transduction mechanisms, such as protein acetylation pathways involved in aging, have identified novel antiaging molecules that may provide a new therapeutic approach to COPD. Ito K, Barnes PJ. Chest. 2009 Jan;135(1):173-80

Exacerbations and comorbidities contribute to the overall severity Chronic Obstructive Pulmonary Disease, a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. Exacerbations and comorbidities contribute to the overall severity PPOK dan eksarsebasi akut serta komorbiditas © 2016 Global Initiative for Chronic Obstructive Lung Disease

COPD Exacerbations Exacerbation is defined as an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication Eksarsebasi PPOK adalah kejadian akut yang ditandai dengan perburukan gejala respirasi pasien bila dibandingkan hari hari biasanya (termasuk variasi hariannya) serta membutuhkan perubahan terapi (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

COPD Comorbidities Agusti A and Vestbo AJRCCM 20122;184:507 PPOK seringkali disertai dengan penyakit lain (komorbiditas) yang dapat memberikan dampak signifikan terhadap prognosis (GOLD 2016) Agusti A and Vestbo AJRCCM 20122;184:507

indoor/outdoor pollution SPIROMETRY: Required to establish diagnosis EXPOSURE TO RISK FACTORS SYMPTOMS shortness of breath tobacco chronic cough occupation sputum indoor/outdoor pollution Diagnosis klinis PPOK perlu dipertimbangkan pada pasien dengan gejala sesak napas, batuk kronis atau produksi sputum, dan adanya riwayat paparan terhadap faktor resiko PPOK. Spirometri dibutuhkan untuk membuat diagnosis PPOK, bila terdapat VEP1/KVP<0.70 maka hal tersebut mengkonfirmasi adanya hambatan aliran udara, seperti yang terjadi pada PPOK A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and a history of exposure to risk factors for the disease (GOLD 2016) Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD (GOLD 2016) è SPIROMETRY: Required to establish diagnosis © 2016 Global Initiative for Chronic Obstructive Lung Disease

Symptoms of COPD The characteristic symptoms of COPD are chronic and progressive dyspnea, cough, and sputum production that can be variable from day-to-day. Dyspnea : Progressive, persistent and characteristically worse with exercise. Chronic cough : May be intermittent and may be unproductive. Chronic sputum production : COPD patients commonly cough up sputum. Sesak napas yang progresif (semakin lama semakin memburuk) persistan (menetap) ditandai dengan memburuknya sesak bila beraktivitas Batuk kronis bisa intermiten, bisa saja tidak produktif Didapatkan produksi sputum kronis (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

Assessment of COPD Combine Assessment Assess symptoms Assess degree of airflow limitation Combine Assessment Assess aspek dibawah ini : 1) Assess gejala 2) Assess derajat hambatan aliran udara 3) Assess resiko eksarsebasi 4) Assess komorbiditas (GOLD 2016) Assess Risk of Exacerbations Assess comorbidities

Assessment of COPD Assess symptoms COPD Assessment Test (CAT) : An 8-item measure of health status impairment in COPD (http://catestonline.org) Clinical COPD Questionnaire (CCQ) : Self-administered questionnaire developed to measure clinical control in patients with COPD (http://www.ccq.nl). Nilai gejala : Kuesioner tervalidasi seperti COPD Assessment Test (CAT) atau Clinical COPD Questionnaire (CCQ) direkomendasikan untuk mengassess gejala klinis secara komprehensif. Skala modified British Medical Research Council (mMRC) hanya mengassess sesak napas.(GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

Assessment of COPD Assess degree of airflow limitation Use spirometry for grading severity according to spirometry, using four grades split at 80%, 50% and 30% of predicted value In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 > 80% predicted GOLD 2: Moderate 50% < FEV1 < 80% GOLD 3: Severe 30% < FEV1 < 50% GOLD 4: Very Severe FEV1 < 30% predicted Nilai derajat hambatan aliran udara dengan spirometri © 2016 Global Initiative for Chronic Obstructive Lung Disease

Assessment of COPD Assess Risk of Exacerbations To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV1 < 50 % of predicted value are indicators of high risk. One or more hospitalizations for COPD exacerbation should be considered high risk. Prediktor terbaik untuk menjadi eksarsebator frekuen (eksarsebasi dua atau lebih pertahun) adalah riwayat kejadian perawatan sebelumnya. Resiko eksarsebasi juga meningkat bersamaan dengan hambatan aliran udara yang semakin memburuk. Perawatan karena eksarsebasi PPOK juga berhubungan dengan prognosis yang buruk dan meningkatnya resiko kematian (GOLD 2016) © 2016 Global Initiative for Chronic Obstructive Lung Disease

Assessment of COPD Assess comorbidities Comorbidities should be actively looked for and treated appropriately Most frequent comorbidities are cardiovascular disease, depression and osteoporosis Nilai komorbiditas : Penyakit kardiovaskular, osteoporosis, depresi, ansietas, disfungsi otot skeletal, sindroma metabolik dan kanker paru sering terdapat pada penderita PPOK. Komorbid ini mempengaruhi kematian, perawatan dan perlu secara rutin diobati dengan tepat © 2016 Global Initiative for Chronic Obstructive Lung Disease

Combined Assessment (C) (D) (B) (A) Risk ≥ 2 or > 1 leading (GOLD Classification of Airflow Limitation)) Risk (Exacerbation history) ≥ 2 or > 1 leading to hospital admission 1 (not leading to hospital admission) Symptoms (C) (D) (A) (B) CAT < 10 4 3 2 1 CAT > 10 Kombinasi asesmen PPOK : Pada gambar terdapat kombinasi beberapa asesmen untuk meningkatkan tatalaksana PPOK Breathlessness mMRC 0–1 mMRC > 2 © 2016 GOLD

Spirometric Classification Exacerbations per year Combined Assessment Patient Characteristic Spirometric Classification Exacerbations per year CAT mMRC A Low Risk Less Symptoms GOLD 1-2 ≤ 1 < 10 0-1 B More Symptoms > 10 > 2 C High Risk GOLD 3-4 D © 2016 Global Initiative for Chronic Obstructive Lung Disease

COPD Management Disease Management should now be focusing on 2 key areas Reducing Symptoms Reducing Risk. Reduce Risk Prevent disease progression Prevent and treat exacerbations Reduce Mortality Reduce Symptoms Relieve Symptoms Improve Exercise tolerance Improve Health status Setelah PPOK terdiagnosis, tatalaksana efektif perlu didasari pada assessment perorangan, terhadap gejala penyakit dan resiko di masa yang akan datang : 1) Mengatasi gejala 2) Meningkatkan toleransi aktivitas fisik 3) Meningkatkan status kesehatan dan 1) Mencegah progresivitas penyakit 2) Mencegah dan mengatasi eksersebasi 3) Mengurangi mortalitas © 2016 Global Initiative for Chronic Obstructive Lung Disease

Non Pharmacologic Treatment Smoking cessation Physical Activity Vaccination Rehabilitation Terapi nonfarmakologis © 2016 Global Initiative for Chronic Obstructive Lung Disease

Smoking cessation can slow the rate of lung function decline 100 Never smoked or not susceptible to smoke 80 Smoked regularly and susceptible to its effects 60 FEV1 (% of value at age 25) Stopped at 45 40 Disability Smoking cessation memiliki peran terbaik untuk mempengaruhi perjalanan penyakit alami PPOK Pemberian konseling oleh dokter atau petugas kesehatan lain secara signifikan meningkatkan angka berhenti merokok bila dibandingkan usaha pasien sendiri. Bahkan konseling yang singkat (3 menit) berhasil meningkatkan angka berhenti merokok sebesar 5-10%. Pemberian nicotine replacement therapy dan farmakoterapi dengan vareicline, bupropion atau nortriptyline dapat meningkatkan angka berhenti merokok jangka panjang dan secara signifikan bermakna bila dibandingkan placebo.(GOLD 2016) Pencegahan merokok : Mendukung secara komprehensif terhadap peraturan peraturan larangan merokok, mendukung program program yang konsisten serta jelas dalam memberikan pesan anti rokok. Bekerja dengan instansi pemerintah untuk melegalisasi sekolah tanpa rokok, fasilitas umum tanpa rokok termasuk lingkungan kerja, dukung pasien untuk menjadikan rumah bebas rokok.(GOLD 2016) Smoking cessation can prevent or delay the development of airflow limitation or reduce its progression.1 Smoking cessation at any age or at any stage of the disease will help the prognosis. The importance of anti-smoking measures is universally recognized and all guidelines stress the necessity for smoking cessation as the first and most important step in the management of COPD.2 Patients who stop smoking slow down the rate of progression of the disease and although FEV1 continues to decline, it can return to a normal rate of decline. References 1. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645–8. 2. GOLD. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Updated 2008. Available at http://www.goldcopd.com/ 20 Death Stopped at 65 25 50 75 Age (years) Adapted from Fletcher C, et al. Br Med J. 1977; 1: 1645–1648.

Rehabilitation : Unbeatable, Evidence A Rehabilitasi medik : Pasien pada semua stadium penyakit mendapatkan manfaat dari program latihan dengan peningkatan toleransi aktivitas fisik dan gejala sesak dan lemah badan. Manfaat tersebut dapat dipertahankan bahkan setelah mengikuti satu kali program rehabilitasi paru.

Non-pharmacological management of COPD Pulmonary rehabilitation offered to a broader group of patients GOLD Patients Essential Recommended Depending upon local guidelines A Smoking cessation (may include pharmacological support) Physical activity Flu/Pneumococcal vaccination B–D Pulmonary rehabilitation © 2016 Global Initiative for Chronic Obstructive Lung Disease

A Treatment Options LABA or LAMA SABA and SAMA Theophylline First Recommended choice: SABA Prn Or SAMA Prn Alternative choice: LABA or LAMA SABA and SAMA Other Possible Choices*: Theophylline Less symptoms Low risk A 0 - 1 not leading to hospital admission GOLD 2 GOLD 1 Terapi pada kelompok A MMRC 01 CAT <10 © 2016 Global Initiative for Chronic Obstructive Lung Disease

B Treatment Options LABA or LAMA LABA and LAMA Theophylline More symptoms low risk B First Recommended choice: LABA or LAMA Alternative choice: LABA and LAMA Other Possible Choices*: SABA and/or SAMA Theophylline 0 - 1 not leading to hospital admission GOLD 2 GOLD 1 Terapi pada kelompok B MMRC ≥2 CAT ≥10 © 2016 Global Initiative for Chronic Obstructive Lung Disease

C Treatment Options ICS + LABA or LAMA Or LABA and PDE4-inh First Recommended choice: ICS + LABA or LAMA Alternative choice: LABA and LAMA Or LABA and PDE4-inh LAMA and PDE4-inh Other Possible Choices*: SABA and/or SAMA Theophylline Less symptoms High risk C GOLD 4 ≥1 Or ≥2 leading to hospital admission GOLD 3 Terapi pada kelompok C MMRC 01 CAT <10 © 2016 Global Initiative for Chronic Obstructive Lung Disease

D Treatment Options First Recommended choice: ICS + LABA And/ or LAMA Alternative choice: ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LABA and LAMA or LAMA and PDE4-inh Other Possible Choices*: Carbocysteine SABA and/or SAMA Theophylline More symptoms high risk D GOLD 4 ≥1 Or ≥2 leading to hospital admission GOLD 3 Terapi pada kelompok D MMRC ≥2 CAT ≥10 © 2016 Global Initiative for Chronic Obstructive Lung Disease

Bronchodilators work by Relieve dyspnea by deflating the lungs Allowing improved lung emptying with each breath Improvement in exercise tolerance Reduces the elastic load on the inspiratory muscles. Manfaat bronkodilator Eur Respir Rev 2006; 15: 99, 37–41

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