Presentation is loading. Please wait.

Presentation is loading. Please wait.

Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם.

Similar presentations


Presentation on theme: "Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם."— Presentation transcript:

1 Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם

2 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

3 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

4 Relative Mortality, Leading Causes of Death in the US, Proportion of 1980 Rate U.S. Centers for Disease Control (CDC)

5 1 Heart disease595,444 2 Cancer573,855 3 Chronic lower respiratory disease (COPD) 137,789 4 Cerebrovascular disease (stroke)129,180 5 Accidents118,043 6 Alzheimer’s Disease83,308 7 Diabetes68,905 8 Nephritis, nephrotic syndrome, nephrosis50,472 9 Influenza & pneumonia50, Suicide37, Septicemia34, Chronic liver disease & cirrhosis31, Essential hypertension & hypertensive renal disease26, Parkinson’s disease21,963 Pneumonitis due to solids & liquids17,001 Leading Causes of Death in the US, 2010 U.S. CDC, 2012

6 COPD  Clinical presentation  Pathophysiology  Management strategy  Treatment

7 אבחנה של COPD  Airflow obstruction that is irreversible  FEV 1 / FVC < 70%

8 Chronic Obstructive Pulmonary Disease (COPD)  גורמי סיכון: –עישון - אקטיבי ופסיבי –זיהום אוויר –חשיפות תעסוקתיות לאבק/עשן –גורמים גנטיים (חסר ב alpha-1-antitrypsin).

9 COPD ועישון  עישון הוא הגורם העיקרי – אם אין עישון – יש לחשוב על אבחנה אחרת!  בכלל האוכלוסיה – ככל שאדם עישן יותר "שנות קופסא" – FEV1 יורד.  גם הסיכון למחלה תלוי ב”מינון” (שנות קופסה).

10 רמזים מרכזיים לאבחנה של COPD  מאפיינים מרכזיים: –גיל > 50 –קוצר נשימה (דיספניאה) – פרוגרסיבי / קבוע. –שיעול פרודוקטיבי כרוני. –חשיפה לגורמי סיכון – בעיקר עישון

11 COPD: Traditional Classification  Emphysema Phenotype The Pink Puffer  Chronic Bronchitis Phenotype The Blue Bloater  Irreversible airflow obstruction

12 COPD— Emphysema Phenotype The Pink Puffer

13 COPD – Emphysema Phenotype “An anatomical alteration of the lung characterized by an abnormal enlargement of the air spaces distal to the nonrespiratory bronchioles, accompanied by destructive changes of the alveolar walls."

14 Emphysema Pathology Bullous Emphysema Centriacinar Emphysema

15 Emphysema Pathology Normal lung Emphysematous lung

16 COPD – Emphysema Phenotype Clinical Features  סמפטומים: –Dyspneaקוצר נשימה פרוגרסיבי. –שיעול לא בולט. –מיעוט (יחסי) בזיהומים ריאתיים.  בדיקה גופנית: –רזים, חולשת שרירים (asthenia). –חזה חביתי, טכיפניאה. –ללא כיחלון בולט ("ורודים"). –ירידה דיפוזית בקולות הנשימה, אקספיריום מוארך. –סרעפות נמוכות. –קולות לב מרוחקים.  אק"ג: ציר ימני, קומפלקסים קטנים.

17  תמונה חסימתית אקספירטורית: –FEV 1 מופחת, FEV 1 / FVC מופחת. –למרבית החולים אין שיפור משמעותי עם מרחיבי סימפונות.  היפראינפלציה ולכידת אוויר: –TLC, RV ו-TLC / RV מוגברים.  ירידה ביכולת הדיפוזיה של חמצן: – D L COמופחת. –היפוקסמיה קלה עם Pco 2 תקין. COPD – Emphysema Phenotype תפקודי ריאה

18 Effect of Emphysema on Diffusion Capacity

19 Emphysema- CXR היפראינפלציה, חדירות יתר סרעפות שטוחות מרווח רטרוסטרנלי גדול

20 Emphysema- HRCT NormalEmphysema

21 COPD—Chronic Bronchitis Phenotype The Blue Bloater

22 COPD – Chronic Bronchitis Phenotype " A clinical disorder characterized by excessive mucus secretion... chronic or recurrent productive cough... on most days for a minimum of three months in the year for not less than two successive years."

23  סמפטומים: –שיעול יצרני כרוני, שפע ליחה "מוגלתית" –זיהומים ריאתיים והתלקחויות תכופות. –קוצר נשימה (מתגבר בהתלקחויות).  בדיקה גופנית: –עודף משקל. –נטיה לכיחלון. –אקספיריום מוארך עם צפצופים. –סימנים של אי-ספיקת לב ימנית (Cor Pulmonale). COPD - Chronic Bronchitis Phenotype Clinical Features

24  תמונה חסימתית אקספירטורית: –FEV 1 מופחת, FEV 1 / FVC מופחת –ללא שיפור משמעותי עם מרחיבי סימפונות  נפחי הריאה ויכולת דיפוזיה ( D L CO ) – תקינים COPD - Chronic Bronchitis Phenotype תפקודי ריאה

25 Chronic Bronchitis with Cor Pulmonale—CXR Chronic Bronchitis with Cor Pulmonale—CXR ללא ממצאים משמעותיים בריאות עצמן לב מוגדל כלי דם ריאתיים מודגשים

26 Cor Pulmonale Phenotype in COPD

27 COPD - Cor Pulmonale Phenotype  שכיחות יותר של: היפוקסמיה קשה היפרקפניאה חמצת נשימתית כרונית.

28 Normal ChronicBronchitis Emphysema

29 COPD  Clinical presentation  Pathophysiology  Management strategy  Treatment

30 Airway Obstruction Pathophysiology Destruction of peribronchial supporting tissue Plugging, inflammation & narrowing of airways

31 Findings in Human BAL Studies  Smokers’ BAL contain 4-5 times more neutrophils than non-smokers  Neutrophils in BAL fluid are the main source of elastase  Cigarette smoke and neutrophils suppress anti- elastase activity  Conclusion: Quantity and activity of elastase is increased in smokers

32 alpha-1-antitrypsin Elastase Anti-Elastase COPD - Pathophysiology HYPOTHESIS

33 Barnes, Nat Rev 2008

34 COPD  Clinical presentation  Pathophysiology  Management strategy  Treatment

35  Relieve symptoms  Improve exercise tolerance  Improve health status AND AND  Prevent disease progression  Prevent & treat exacerbations  Reduce mortality REDUCE SYMPTOMS REDUCE RISK COPD Management Philosophy

36 COPD Management  To determine disease severity & guide therapy, assess: – Symptoms – Severity of airflow limitation – Risk of exacerbation – Presence of comorbidities Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

37 COPD Management  To determine disease severity & guide therapy, assess: – Symptoms: clinical assessment, mMRC or CAT – Severity of airflow limitation – Risk of exacerbation – Presence of comorbidities Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

38 COPD Assessment Tool—CAT Score > 10 considered symptomatic Symptom Assessment

39 COPD Management  To determine disease severity & guide therapy, assess: – Symptoms (clinical assessment, mMRC or CAT) – Severity of airflow limitation (GOLD I-IV) – Risk of exacerbation – Presence of comorbidities Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

40 Grading COPD Severity STAGE CHARACTERISTICS (Post Bronchodilator FEV1) FEV 1 / FVC < 70% I MildFEV 1 ≥ 80% predicted II Moderate50% ≤ FEV 1 ≤ 80% predicted III Severe30% ≤ FEV 1 ≤ 50% predicted IV Very Severe FEV 1 ≤ 30% predicted

41 COPD Management  To determine disease severity & guide therapy, assess: – Symptoms (clinical assessment, mMRC or CAT) – Severity of airflow limitation (GOLD I-IV) – Risk of exacerbation (frequency/year) – Presence of comorbidities Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

42 Definition of COPD Exacerbation  Symptoms worsening beyond daily variations – Cough / sputum / dyspnea  Leads to change in medications  Cause: – Viral infection – Bacterial infection – Pollutants  Diagnosis based on clinical presentation

43 Exacerbations—Critical Events in the Natural History of COPD  Poor quality of life  Accelerated loss of lung function  Exacerbations  increased risk future exacerbations  Increased risk of hospitalization  All-cause 3-year mortality after hospitalization up to 49% (GOLD 2011)

44  Prospective study, cohort 304 males, exacerbations requiring hospitalization, 5-year follow-up Soler-Catalu ῆ a, Thorax 2005 Frequency of COPD Exacerbation & Survival Probability of survival Time (months)

45 Hurst et al, ECLIPSE, NEJM 2010

46 Frequent Exacerbator Phenotype Hurst et al, ECLIPSE, NEJM 2010 Pats with no exacerbation Pats with ≥2 exacerbations Year 1 Year 2 Year 3

47 Treatment of COPD Exacerbations Treat early aggressively to minimize duration, prevent recurrence  Short-acting inhaled bronchodilators (Ventalin, +/- Aerovent, as needed)  Systemic corticosteroids  Antibiotics  Noninvasive ventilation 7 days

48 COPD: Antibiotic treatment  Pathogens: – Streptococcus pneumonia – Haemophilus influenza – Moraxella catarrhalis  Antibiotics: – Cefuroxime, beta-lactam, macrolides, doxycycline

49 Impact of COPD Exacerbations  Treat early aggressively to minimize duration, prevent recurrence

50 COPD Management  To determine disease severity & guide therapy, assess: – Symptoms (clinical assessment, mMRC or CAT) – Severity of airflow limitation (GOLD I-IV) – Risk of exacerbation (frequency / year) – Presence of comorbidities Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

51 Systemic Manifestations & Comorbidities  Cardiovascular disease – Pulmonary hypertension – Ischemic heart disease – Congestive heart failure – Stroke  Lung cancer  Diabetes, metabolic syn  Osteoporosis  Skeletal muscle dysfunction  Depression

52 COPD—Independent Risk Factor for Cardiovascular Morbidity Percent with Condition

53 Higher Rates of Hospitalization Due To Comorbidities Reproduced with permission of Chest, from “Comorbidity and Mortality in COPD Related Hospitalizations in the United States, 1979 to 2001,” Holguin F et al, Vol 128, pp , Copyright © 2005.

54 Higher Mortality Rates Due to Cormorbidities IHD = ischemic heart disease CHF = congestive heart failure RF = respiratory failure PVD = pulmonary vascular disease TM = thoracic malignancy Holguin et al Chest 2005

55 Comorbidity in COPD Traditional View  Airflow obstruction & emphysema affect gas exchange  systemic implications Current Debate  Is airways compromise the central disease process? OR OR  Is it one manifestation of a “systemic” inflammatory state with multiple organ compromise?

56 COPD  Clinical presentation  Pathophysiology  Management strategy  Treatment

57 Ri sk of Exacerbation ≥2 1 0 Frequency of Exacerbations COPD Risk Assessment CD A B Increasing Symptoms (mMRC or CAT score) mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 GOLD IV GOLD III GOLD II GOLD I Severity of Obstruction Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011

58 COPD Treatment Smoking Cessation Short-Term ↓ cough, sputum ↑ lung function Long-Term ↑ survival ↑ QOL ↓ lung function ↓cormorbidities

59 COPD Risk and Smoking Cessation Fletcher CM, Peto R. BMJ. 1977;1: FEV 1 (% of value at age 25) Smoked regularly and susceptible to effects of smoke Never smoked or not susceptible to smoke Stopped smoking at 45 (mild COPD) Stopped smoking at 65 (severe COPD) Disability Death Age (years)

60 COPD Treatment Influenza, Pneumococcal Immunization Short-TermLong-Term ↓ exacerbation frequency

61 Short-TermLong-Term Bronchodilators: Long-acting Beta 2 Agonist or Anti Cholinergic ↓ airflow obstruction ↓ hyperinflation ↑ exercise endurance ↑ tremors, dry mouth ↑ Quality of life ↓ exacerbations Combination: Inhaled Corticosteroid & Long-acting Beta 2 Agonist ↓ airflow obstruction ↓ hyperinflation ↓ dyspnea ↑ exercise tolerance ↑ Quality of life ↑ possibly survival ↓ exacerbations ↑ risk of pneumonia COPD Treatment

62 Symptom- and Risk-Based Treatment Paradigm FEW SYMPTOMS, HIGH RISK OF EXACERBATIONS 1: Combination inhaled corticosteroid/long- acting beta 2 agonist or long-acting anticholinergic 2: Combination 2 long-acting bronchodilators or combination inhaled corticosteroid / long- acting anticholinergic MANY SYMPTOMS, HIGH RISK OF EXACERBATIONS 1: Combination inhaled corticosteroid/long- acting beta 2 agonist or long-acting anticholinergic 2: Combination inhaled corticosteroid/long- acting beta 2 agonist, long-acting anticholinergic 3: May add phosphodiesterase-4 inhibitor or short-acting bronchodilator and theophylline or carbocysteine FEW SYMPTOMS, LOW RISK OF EXACERBATIONS 1: Short-acting bronchodilator 2: Combination of short-acting bronchodilators / introduce long-acting bronchodilator MORE SYMPTOMS, LOW RISK OF EXACERBATIONS 1: Long-acting bronchodilators recommended 2: Combination of long-acting bronchodilators in patients with severe breathlessness I NCREASING A IRWAYS O BSTRUCTION I NCREASING E XACERBATIONS I NCREASING S YMPTOMS Global Initiative for COPD (GOLD) 2011

63 COPD Treatment Short-TermLong-Term Oxygen Therapy↑ exercise endurance↑ survival

64 Oxygen Therapy Improves Survival "The more hours, the better!" Lancet :

65 Indications for Oxygen Therapy  PaO 2 <55 mm Hg or SaO 2 ≤88%  Milder hypoxemia - – In the presence of cor pulmonale or hematocrit >55%  Normoxemic at rest but desaturation during exercise or sleep

66 Oxygen Therapy  Aim: PaO mm Hg or SatO 2 >88%  Nasal masks 1-2L/min  Venturi masks 24%, 28%, 35%  Monitor SatO 2, PaCO 2 and pH  If hypoxemia persists or CO 2 retention worsens: optimize bronchodilators, consider using assisted noninvasive ventilation

67 Noninvasive Ventilation  If hypoxemia persists or CO 2 retention worsens: – Optimize bronchodilators and consider using assisted noninvasive ventilation

68

69 COPD Treatment Short-TermLong-Term Pulmonary Rehabilitation ↓ dynamic hyperinflation ↓ functional dyspnea ↑ exercise endurance ↑ QOL ↑ possibly survival

70 Pulmonary Rehabilitation  Goals: Reduce symptoms, improve quality of life, and increase participation in daily activities  Program includes: – Exercise training (tolerance and muscle strength) – Nutrition counseling – Education

71 Pulmonary Rehabilitation  Components: – Exercise training (bicycle ergometry/treadmill & upper limb exercises) – Education – Nutrition counseling – Smoking cessation  8-12 week duration  Beneficial in a wide range of disability

72  Improves exercise capacity  Improves recovery from exacerbation  Improves QOL  Reduces perceived intensity of breathlessness  Reduces hospitalizations, days in hospital  Reduces anxiety & depression  Benefits beyond immediate training period  May improve survival Benefits of Pulmonary Rehabilitation in COPD

73  Acute reversibility of airways obstruction in response to bronchodilator is a poor predictor of benefit to FEV 1 after 1 year  SF BUILD THIS SLIDE UP

74 Exercise Tolerance & Survival in COPD  365 patients, 2 centers,  Smoking history >10 years  FEV 1 /FVC < 0.70  171 deaths (47%, 43±24 mo), respiratory failure (majority), cardiovascular disease (9%), lung cancer (18%), other causes (23%)  Nonsurvivors older, more severe airflow limitation, lower mean exercise capacity  6MWD best predictor of all- cause mortality Cote & Celli et al, Chest 2007

75  Exercise tolerance predicts survival in COPD Cote & Celli et al, Chest 2007 Exercise Capacity & Survival in COPD F/U (months) Survival probability >350 m <350 m

76 COPD Phenotypes  Emphysema-hyperinflation Dyspnea, exercise intolerance, hyperinflation  Chronic bronchitis Cough & sputum 3 mos/yr, 2 yr  Frequent exacerbator ≥ 2 exacerbations / year  Cor pulmonale  COPD w bronchiectasis HRCT diagnosis, airways colonization?  Mixed asthma-COPD Increased reversibility of obstruction  COPD-eosinophilia  Comorbidities & systemic inflammation ↑ biomarkers (C-reactive protein, serum alymoid A, IL-6, IL-8, tumor necrosis factor α, leukocytes)  α1 antitrypson

77 Phenotype-Specific COPD Treatment TreatmentPhenotypeBenefit RoflumilastFrequent exacerbator (≥ 2 / yr) ↓ exacerbations ↑ quality of life ↑ lung function AzithromycinFrequent exacerbator (≥ 2 / yr) ↓ exacerbations ↑ QOL Chronic antibioticCOPD with bronchiectasis ↓ exacerbations ↓ eradicate colonizing microorganisms ↓ chronic inflammation Inhaled corticosteroids COPD-eosinophilia and Mixed asthma-COPD ↑ lung function

78 COPD Treatment TreatmentPhenotypeBenefit Lung Volume Reduction Surgery / Bronchoscopy Predominantly upper lobe emphysema ↑ exercise capacity Lung Transplantation With failure of medical treatment, select patients ↓ exacerbations ↑ quality of life ↑ lung function

79 COPD – Conclusions  COPD: underdiagnosed; high & rising mortality  Dyspnea, chronic cough, +/- sputum, risk factors  consider COPD  Diagnosis by spirometry: FEV 1 / FVC < 70%  Treatment of stable COPD: consider symptoms, severity of obstruction, frequency of exacerbations  Manage exacerbations: bronchodilators, corticosteroids, +/- antibiotics

80  High rates of comorbidities  Rehabilitation: a standard of care to break the cycle of dyspnea, fear, anxiety, increasing inactivity  A heterogeneous disease: the future is phenotype-specific treatment COPD – Conclusions

81 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

82 Other Airways Obstruction

83 Differential Diagnosis: COPD and Asthma COPD  Onset in mid-life  Symptoms slowly progressive  Long smoking history  Dyspnea during exercise  Largely irreversible airflow limitation ASTHMA  Onset early in life (often childhood)  Symptoms vary from day to day  Symptoms at night/early morning  Allergy, rhinitis, and/or eczema also present  Family history of asthma  Largely reversible airflow limitation

84 COPD – Differential Diagnosis History AsthmaEmphysema Chronic Bronchitis +/-++Smoking Common (usually nocturnal) May be absent Main complaint Productive Cough Episodic Main complaint May be absent Dyspnea ++- Exacerbations Common--Allergy

85 COPD - Differential Diagnosis Physical Examination AsthmaEmphysema Chronic Bronchitis Rare++/- Barrel Chest +++ Prolonged Expiration In severe exacerbation Typical In severe exacerbation Decreased Breathing Sounds -/+/++Rare+/- Wheezing In severe exacerbation +/-++ Cyanosis - In advanced disease - Weight Loss

86 COPD - Differential Diagnosis PFT Asthma Emphysem a Chronic Bronchitis Pulmonary Function Component  Normal/  FEV 1   /No change FEV 1 after Bronchodilator Normal/  Residual Volume (RV) Normal  Total Lung Capacity (TLC) Normal  Diffusion Capacity (D L CO )

87 COPD - Differential Diagnosis Complications AsthmaEmphysema Chronic Bronchitis During exacerbation Common Hypoxemia Rare In advanced disease CommonErythrocytosis In severe exacerbation End-stage disease CommonHypercarbia Rare In advanced disease CommonCor-pulmonale

88 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

89 Bronchiectasis - Definition  מצב בו דלקות וזיהומים גורמים נזק לדרכי האוויר, כך שאלו הופכים למעוותים  ריר מצטבר בדרכי האוויר וקיים קושי לסלקו בשל פגיעה במנגנוני סילוק ההפרשות של דרכי האוויר  התוצאה – זיהומים חוזרים וקשים

90 Bronchiectasis - Pathology

91 Bronchiectasis - Etiology  Recurrent bronchial infections –Airway obstruction (localized) caused by foreign body, benign tumor –Post-infectious (measles, pertussis, S. aureus, TB)  Immune deficiency- hypoglobulinemia, leukocyte dysfunction  Cystic fibrosis  Ciliary dyskinesia (Kartagener's syndrome)  Allergic bronchopulmonary aspergillosis

92 Bronchiectasis - Clinical Features  Chronic productive cough  Coarse crackles, clubbing  Hemoptysis  Obstructive lung disease  Respiratory failure

93 Bronchiectasis - Diagnosis  Chest x-ray  Bronchography  High-resolution CT

94 Bronchiectasis Chest x-ray

95 Bronchiectasis Bronchography

96 Bronchiectasis High-resolution CT

97 Bronchiectasis - Treatment  Antibiotics (p. aeruginosa, s. aureus)  Vaccinations  Physiotherapy  Bronchodilators  Surgery for localized disease

98 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

99 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

100 Bronchiolitis Obliterans - Definition  תהליך הצטלקות כרוני של דרכי האוויר הקטנות של הריאה.  בעקבות כך - הרס פרוגרסיבי של דרכי אוויר אלו המביאה להתפתחות מחלת ריאות חסימתית.  מדובר בהתהליך בלתי הפיך בעיקרו.

101 Bronchiolitis Obliterans - Etiology  Inhalation of toxic fumes (smoke)  Connective tissue disease (RA)  Post BMT, lung & heart-lung transplant  Drugs (eg., gold, penicillamine)  Consequent to respiratory infections (adenovirus, mycoplasma)  Cryptogenic

102 Cryptogenic Bronchiolitis Obliterans Clinical Features  Onset: months to years  Dyspnea and cough with minimal sputum production  Normal breathing sounds, occasionally rhonchi  CXR= normal or hyperinflation,  CT= mosaic attenuation, ground-glass pattern

103 Bronchiolitis Obliterans Inspiratory & Expiratory HRCT מוזאיקה (אוויר כלוא)זכוכית חול

104 Obstructive Pulmonary Disease  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis  Cystic fibrosis  Bronchiolitis obliterans  Alpha-1-antitrypsin deficiency

105 Alpha-1-Antitrypsin Deficiency  5% מחולי אמפיזמה  רמות האנזים בחולים קטנות מ-35%  הגנוטיפ התקין מכונה PiMM והפגום PiZZ  הביטויים הקליניים: –אמפיזמה –שחמת והפטומה.  טיפול – תחליף האנזים (Zymera)


Download ppt "Chronic Obstructive Pulmonary Disease (COPD) פרופ' רפאל ברויאר מכון הריאה ביה"ח האוניברסיטאי הדסה עין-כרם."

Similar presentations


Ads by Google