1. Chronic obstructive bronchitis and emphysema
chronic obstructive airway disease
(COAD, COLD)
( chronic obstructive pulmonary disease )
COPD

2. COPD
emphysema bronchitis
„pink puffer” „blue bloater”

3. Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998
Proportion of 1965 Rate
3.0
Coronary
Heart
Disease
Stroke
Other CVD
COPD
All Other
Causes
2.5
2.0
1.5
1.0
0.5
–59%
–64%
–35%
+163%
–7%

4. Evidence-based medicine
(The Global Burden of Disease study) (Science 1996; 274: )

5. Epidemiology
4-7% of adult population ( 600 million patients worldwide)
Prevalence expected to rise 3x in 10 years.
By 2020, it becomes the 3rd most frequent cause of death ( 4,7 million cases of death – WHO, 1999)

6. COPD morbidity in Hungary

7. Definition
COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarly caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
ATS/ERS Task Force, 2004

8. CIBA Guest Symposium: Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions (1959)
1./ Obstructive emphysema: abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls and without obvious fibrosis.
2./ Chronic bronchitis: the presence of chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes (heart failure, tbc, bronchiectasis, tumor, lung abscess) of chronic cough have been excluded. 1

9. Differential diagnosis of airway obstruction
Chronic bronchitis
Emphysema
COPD
Airflow obstruction
Adapted from Snider GL. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease
Am J Respir Crit Care Med. 1995; 152: S77–S121
Asthma
Adapted from Snider 1995

10. Etiology: host factors

12. Etiology: acquired risk

13. Effect of smoking on annual decline in lung function Fletcher C, Peto R: BMJ 1977:i: 1645

15. T lymphocytes in COPD * p<0.05 with healthy nonsmokers
§ p<0.05 with stable CB
Zhu J et al. AJRCCM 2001; 164: 15

16. Cells orchestrating the inflammation in COPD

17. Oxidativ stress
epithel, macroph.

19. Pathology
Large airways: goblet cell metaplasia, increased mucus production
Medium and small airways ( 7-9. generation): inflammation similar to asthma in certain patients
Small airways ( generation) : bronchial wall inflammation, degeneration, fibrosis
Alveoli: elastin loss and alveolar surface loss

21. Loss of alveolar attachments in smokers
Saetta M, Ghezzo H, Kim WDM, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis 1985; 132:
Normal
Smoker
Saetta et al. ARRD 1985

22. Airway muscle thickness Increase in COPD
Non-smoker
COPD
© M Saetta
Saetta. 1998

23. Small airways in COPD
Barnes, NEJM,2004

24. Causes of Airflow Limitation
Irreversible
Fibrosis and narrowing of the airways
Loss of elastic recoil due to alveolar destruction
Destruction of alveolar support that maintains patency of small airways

25. Causes of Airflow Limitation
Reversible
Accumulation of inflammatory cells, mucus, and plasma exudate in bronchi
Smooth muscle contraction in peripheral and central airways
Dynamic hyperinflation during exercise

26. Airflow limitation Driving pressure (parenchyma) =
Resistance (small airways)

27. Structure - function relationships in COPD
EMPHYSEMA
SMALL AIRWAYS ABNORMALITIES
Alveolar wall destruction
Air space enlargement Capillary network reduction
Alveolar attachments loss
Small airways narrowing
Airway wall thickening
Adapted from Barberà JA, Ramírez J, Roca J, et al. Lung structure and gas exchange in mild chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141: . . . .
High VA/Q areas
Low VA/Q areas
Barberà et al. ARRD 1990

28. COPD
asthma
neutrophils
no AHR*
no bronchodilation
no corticosteroid
effect
eosinophils
AHR*
good bronchodilator effect
good corticosteroid
effect
10 –
40 %
“ Wheezy bronchitis ”
reversibility threshold: 12 –15% (>200ml) FEV1- increase
*AHR= airway hyperreactivity

29. Characteristics of phenotypes
bronchitis emphysema
Dynamic lung volumes decreased decreased
( FEV1 , FEV1/FVC)
Static lung volumes
TLC normal or mild increase increased
RV moderate increase increasd
Diffusion capacity normal or mild decreased
decrease
Blood gas hypoxaemia, hypercapnia hypoxaemia in end-stage
exercise hypoxaemia: no change, improves hypoxaemia
or deteriorates deteriorates
Cor pulmonale frequently seldom

30. Classification ( GOLD 2006 )
FEV1 (ref%* ) symptoms
cough, sputum
mild  80 % morning sputum,
( FEV1/FVC  70% ) minimal breathing dyscomfort
moderate % dyspnea on moderate exertion with or without wheezing,
discolored sputum,
severe – 50 % acute worsening with infection, with
significant erosion of QoL
very severe < 30% n cough, wheezing,
breathlessness on minimal exertion
signs of RHF,
significantly impaired QoL

31. Pharm.spir.
Beta-2 agonist
Parasympatho-
lytics
Xantin derivate

32. Systemic consequences/comorbidities in COPD
Expiratory flow limitation
Air trapping
Exacerbation
Hyperinflation
Dyspnea
Reduced exercise
tolerance
Életminőség
Inactivity
In patients with COPD, there is a cycle of airflow limitation, dyspnea, and reduced exercise endurance.
The physiological impairment in COPD is characterized by airflow limitation, air trapping, and hyperinflation.
These physiologic abnormalities lead to dyspnea (or breathlessness).
Dyspnea in itself is unpleasant, and it also severely limits the amount of activity a patient can undertake. Often patients will avoid situations that demand physical activity.
Avoiding exercise leads to deconditioning and worsening of the disease and, ultimately, the patient’s health-related quality of life suffers.
COPD is often associated with acute exacerbations of symptoms.
Exacerbations are periodic worsenings of disease that are often triggered by respiratory tract infections.
As COPD worsens, patients are more likely to experience exacerbations, which become more severe.
Exacerbations may have a long-term impact on the disease and can contribute to premature mortality.
Deconditioning
Systemic consequences
e.g. Muscle atrophy/wasting, CHD depression, osteoporosis, anaemia

33. Airway inflammation and systemic consequences in COPD (theory)
Tüdő
Inzulin resistance,
II. type diabetes
Muscle wasting/atrophy
TNFa
IL-6 ?
Local
inflammation
Osteoporosis
Cardiovascular
events
CRP
Liver

35. GOLD Workshop Report Four components of COPD Management
Asses and monitor disease
Reduce risk factors
Manage stabil COPD
Education
PharmacologicGyógyszeres
Non-pharmacologic
Manage exacerbations

37. Treatment of COPD (GOLD 2003) inhalative corticosteroids
Surgical treatment ?
longterm oxigen treatment
(chronic respiratoryy failure)
inhalative corticosteroids
(  3 exacerbation in the previous 3 years)
One or more long acting bronchodilators,
rehabilitation
Short acting anticholinergic and/or 2-agonist as needed
Avoidance of risk factors, influenza vaccination
FEV1  80% %  FEV1 < 80% %  FEV1 < 50% FEV1 < 30% or
without or with symptoms chronic respiratory or
right heart failure
airway obstruction (FEV1/FVC < 70%)
I. mild II. moderate III. severe IV. very severe

38. Respiratory insufficiency in COPD
acute exacerbation
pink puffer blue bloater
partial global
(hypoxaemic/transfer failure) (pump-, ventilatory failure)

39. Non-invasive mechanical ventilation in respiratory insufficiency

40. wheezing, chest tightness, increased cough and sputum purulence
Main symptomps in acute exacerbation of COPD
increased dyspnea
wheezing, chest tightness, increased cough and sputum purulence
+/-
reduced exercise tolerance, fever , change in chest x-ray, leukocytosis
malice, disturbed sleep, daytime sleepiness, depression, confusion (CO2 retention)

41. AE COPD  hospitalisation  re-admission  death
Several studies have analysed the impact of COPD exacerbations leading to hospitalisation. Being hospitalised for a COPD exacerbation has been shown to be a key risk factor for re-hospitalisation and premature death, with mortality rates between 23% and 43% within one year after the event.
1Eriksen, Ugeskr Laeger 2003
2Groenewegen, Chest 2003
3Almagro, Chest 2002
4Connors, Am J Respir Crit Care Med 1996

42. Exacerbations of COPD
Viral infections (Rhino,Infl, Parainfl,Adeno, RSV)
Bacterial infections (H.i.,S.p.,M.c.,P.a.,S.a., Enterobact.), atypical( M.p., C.p.)
Inhalation of environmental irritants (NO2,
SO2, PM10, ozone)
deviation from diet
Predisposing factors (smoking, severe comorbidity, bacterial colonisation in the stable phase) 42

43. New strains of bacteria and AE COPD
Sethi, NEJM 2002
Timeline and molecular typing for a patient with chronic obstructive pulmonary disease. The horizontal line is a timeline, with each number indicating a clinic visit. The arrows indicate exacerbations. Isolates of Haemophilus influenzae were assigned types based on banding patterns on gel electrophoresis. The gel on the right shows whole bacterial cell lysates of isolates recovered at visits 5 through 9. A, B, and C indicate the molecular types based on banding patterns. Molecular mass standards are noted on the left of the gel in kilodaltons.
H.influenzae with
new antigen
structure
Immune and
inflammatory response AE

44. Role of antibiotics - „fall and rise „ hypothesis
Miravitlles M, ERJ 2002
The "fall and rise" hypothesis of bacterial exacerbations of COPD. Some patients with COPD show bacterial colonisation of the lower airways. This
colonisation is usually due to potentially pathogenic microorganisms (PPMs) in low concentrations. Under specific circumstances, these PPMs may proliferate and produce an increased inflammatory reaction in the host. When this proliferation exceeds a certain clinical threshold (– - –), symptoms of acute exacerbation (AE)appear. Under antibiotic (AB) therapy (–––: AB1; : AB2; – – –: AB3), the concentration of PPMs decreases, and, when the threshold is crossed again, the clinical symptoms disappear (cure (C)). When the intensity and speed of the bactericidal activity of the AB is increased, recovery occurs more rapidly and the time to the next exacerbation (double-headed horizontal arrow) is prolonged. AB activity produces a "fall" in bacterial concentrations, which, if not completely eradicated after the pressure of the antimicrobial agent is removed, "rise" again. Some modifying factors may change the threshold of clinical symptoms (double-headed vertical arrow).

48. Are antibiotics needed? (Procalcitonin Guided Therapy)
Standard group
Procalcitonin group
Christ Crain, Lancet 2004
P=0.03
P<0.0001
P=0.003
P=0.003
P<0.0001
45/45
9/9
100
38/42
27/31 80
2/3 60
16/31
Antibiotic prescriptions (%) 40
11/29
PCT (ng/ml)
< 0,1 bacterial infection very unlikely no antibiotics recommended, 0,1 – 0,25 bacterial infektion unlikely antibiotics only, if infection seems clinially probable 0,25 – 0,5 bacterial infektion probable antibiotcs recommended > 0,5 bacterial infektion probable, antibiotcs strongly recommended 20
4/28
2/15
0/10
CAP
AECOPD
Bronchitis
Asthma
Others
PCT (ng/ml) - < 0,1 not recommanded
- > 0,5 strongly recommanded

49. Antibacterial treatment of AECOPD
pathogens treatment
1./ acute tracheobronchitis atipical agent ? macrolide ?
2./ Chronic bronchitis H. influenzae aminopenicillin/cv
without comorbidity M. catarrhalis cefalo. II, III
( FEV1 > 50% ) res. S. pneumoniae ? makrolide II.
3./ Chronic bronchitis with „ „
comorbidity ( FEV1 < 50% ) res. Pneumococcus ! respiratory kinolon
4./ Chronic bronchial infection „ respiratory kinolon
Gram-neg enterobact Ps. eruginosa
= ciprofloxacin 11

50. COPD Exacerbation - Steroids
COPD, no steroids
30 pack-years
FEV1 < 1,5 l
Group A: Placebo
Group B: Methylprednisolone 4x125 mg i.v.
tappering until day 14
Niewoehner DE. N Engl J Med 1999; 340: 50

51. Antibiotic Consumption in 26 Countries
Goossens.HA. Lancet 2005; 365:579-87 51

52. Penicillin resistent S.pneumoniae
EARSS, 2006