8/24/2010

CHRONIC
OBSTRUCTIVE AIRWAY
DISEASES

Stanton Kessler and Eugen Petcu

Stanton Kessler and Eugen Petcu

Lung: Normal histology

1
8/24/2010

2
8/24/2010

3
8/24/2010

4
 8/24/2010

FVC Forced Vital Capacity This is the volume of air that can forcibly be blown out after full
inspiration, measured in liters.

FEV1 Forced Expiratory Volume in 1 This is the maximum volume of air that can forcibly blow out in
Second the first second during the FVC manoeuvre, measured in liters.
Along with FVC it is considered one of the primary indicators of
lung function.

FEV1/FVC FEV1% This is the ratio of FEV1 to FVC. In healthy adults this should be
approximately 75–80%.
PEF Peak Expiratory Flow This is the maximal flow (or speed) achieved during the
maximally forced expiration initiated at full inspiration, measured
in liters per second.

FEF 25–75% or Forced Expiratory Flow 25–75% This is the average flow (or speed) of air coming out of the lung
25–50% or 25–50% during the middle portion of the expiration (also sometimes
referred to as the MMEF, for maximal mid-expiratory flow).

FIF 25–75% or 25– Forced Inspiratory Flow 25–75% This is similar to FEF 25–75% or 25–50% except the measurement is
50% or 25–50% taken during inspiration.

FET Forced Expiratory Time This measures the length of the expiration in seconds.

TV Tidal volume During the respiratory cycle, a specific volume of air is drawn into
and then expired out of the lungs. This volume is tidal volume.

TLC Total Lung Capacity Maximum volume of air present in the lungs. Effectively the Vital
Capacity plus residual volume.

TLCO Diffusing Capacity The carbon monoxide uptake from a single inspiration in a
standard time (usually 10 sec).
MVV Maximum Voluntary A measure of the maximum amount of air that can be inhaled and
Ventilation exhaled in one minute, measured in liters/minute.

COPD: Characteristics
 Increased resistance to outflow
- Due to airway obstruction

 Significantly reduced FEV1sec due to

- Increased resistance to outflow
- Decreased elasticity and increase
compliance caused by damage of elastic
tissue in the pulmonary interstitium

 Reduced FVC
- Due to decreased elasticity and increased
compliance
 Reduced FEV1sec/FVC
 Increased TLC and RV (esp. emphysema)

5
 8/24/2010

COPD
Chronic bronchitis and emphysema

• Have common etiology
Have common etiology: tobacco smoking (90%)
: tobacco smoking (90%)

– Chronic bronchitis produces more prominent 
obstruction
– Emphysema
Emphysema produces extensive loss in elasticity
produces extensive loss in elasticity

• Lead to same complications

CHRONIC BRONCHITIS

• DEF: persistent productive cough, producing mucoid sputum
p p g p g p

• for at least 3 consecutive months in at least 2 consecutive 
years

• in the absence of specific lung diseases. 

6
 8/24/2010

Etiology - SMOKING

• Irritation from cigarette smoke stimulates mucus gland 
secretion epithelial metaplasia (loss of cilia)
secretion, epithelial metaplasia (loss of cilia) 

• These changes predispose the patients to repeated respiratory 
infection which may aggravate the chronic bronchitis.

Etiology– AIR POLLUTION

• Pollutants in the air that may possibly affect the lungs 
yp y g
include sulphur oxides, nitrogen oxides, and various 
hydrocarbons. 

• At present there is no consensus on a pollutant 
concentration that increases the risk of chronic bronchitis. 

7
 8/24/2010

Classification
Simple chronic bronchitis:
bronchitis: productive cough
without evidence of airflow obstruction

 Chronic asthmatic bronchitis with intermittent

bronchospasm and wheezing

 Chronic obstructive bronchitis (bronchiolitis)

with airflow obstruction associated with damage of
small airways (small airway disease)

Morphology
 Macroscopic
- Hyperaemia
H i andd swelling
lli off b
bronchial
hi l mucosa
- Mucinous or mucopurulent secretions

 Histology
- Hypertrophy of submucosal mucous glands:glands:
Increased Reid index (N=0.4): ratio of the thickness of the
mucous glands to the thickness of the wall between the epithelium
and the underlying cartilage

- Metaplasia of goblet cell in bronchial lining

- Inflammatory infiltration

- Sclerosis

8
 8/24/2010

Chronic Bronchitis

Chronic Obstructive Bronchiolitis

• Also known as small airway disease

• Histology
– Goblet cell metaplasia (excessive mucus 
production → mucus plugs)
production  → mucus plugs)
– Inflammation
– Fibrosis
– Smooth muscle cell hyperplasia

• Lumen narrowing  airway obstruction
Lumen narrowing 

9
 8/24/2010

Small Airway Disease

Clinical Correlates

• Cough, sputum production

• Dyspnea

• Recurrent infections

• Hypoxemia and cyanosis
Hypoxemia and cyanosis (obstructive bronchitis)
(obstructive bronchitis)

• Weight gain (unknown reason) 

10
 8/24/2010

Acute Exacerbation: Acute on Chronic

Bronchiolitis

Emphysema

- Abnormal permanent enlargement of the airspaces

distal to the terminal bronchiole

- Destruction of alveolar wall with loss of elastic recoil

- Absence of obvious fibrosis

NB: airspace enlargement without wall destruction

is called overinflation (bronchial asthma)

11
 8/24/2010

Pathology
• The lungs are expanded and voluminous due to air‐trapping. 
• The diaphragm may be flattened or displaced downwards. 
• The emphysematous areas are paler than the rest of the lung 
and contains little blood. 
• The lungs pit on pressure owing to the lack of elasticity. 

• Microscopically, there is loss of alveolar septa with 
enlargement of air spaces. 

Emphysema

12
 8/24/2010

Emphysema
Normal alveoli

Proteases and Antiproteases in Pathogenesis

of Emphysema

• Metabolism of elastic tissue depends on
– Proteinase (elastase)
P t i ( l t )
– Antiproteinase (α
Antiproteinase (α1‐AT 
AT –– antitrypsin)

• Antitrypsin is coded by Pi
is coded by Pi (proteinase inhibitor) locus on chr. 14
• Terminology
– Normal allele 
N
Normal allele –
l ll l – M
– Normal gene 
Normal gene –– PiMM
– Mutated gene with low 
Mutated gene with low α
α1‐AT activity 
activity –– PiZZ

13
 8/24/2010

Centrilobular emphysema
• It initially involves air spaces in the centre of
lobules

• The respiratory bronchioles are primarily

involved while the alveolar ducts and alveoli
at the periphery of the lobule are
unaffected.

Etiopathogenesis of
Centroacinar Emphysema

Cigarette smoking

Impaction of smoke particles in the wall
of respiratory bronchioli

Chemotaxis and activation of neutrophils
and macrophages

Release of pproteases
oteases (elastase)

Damage of elastic fibres

Dilation of respiratory bronchioli

14
 8/24/2010

Panlobular emphysema
• Emphysema
Emphysema involving all air spaces beyond 
involving all air spaces beyond
the terminal bronchioles in a relatively 
uniform manner. 

• This form is associated with alpha‐1‐anti‐
trypsin deficiency

Etiopathogenesis of
Panacinar Emphysema

PiZZ g
genotype
yp

Low α1-AT level

Uncontrolled protease activity

Damageg of elastic fibres

Dilation of respiratory bronchioli,
alveolar ducts and sacs

15
 8/24/2010

Pathogenesis of Emphysema -
Consequence of: protease- anti-protease imbalance
oxidant- antioxidant imbalance

Morphology
• Macroscopic
– Location
• Centroacinal emphysema: upper lobes
Centroacinal emphysema: upper lobes
• Panacinar emphysema
Panacinar emphysema: entire lungs, more 
: entire lungs, more 
prominent in the lower lobes
– Overinflation, grossly visible air spaces
– Apical blebs and bullae (centroacinar 
emphysema) 
emphysema)
• Histology
– Thinning and destruction of alveolar wall
– Large air spaces (confluent alveoli)
– Reduced number of alveolar capillaries
– No fibrosis

16
 8/24/2010

Centroacinar Emphysema

Centroacinar Emphysema
with Bullae

17
 8/24/2010

Centro--acinar Emphysema
Centro

Pan--acinar Emphysema
Pan

18
 8/24/2010

Obstruction in
Emphysema
1. Loss of elastic recoil

2. During expiration air is trapped in the alveoli 

3. Efforts to exhale (accessory muscles)

4 Increased pressure within alveoli
4. Increased pressure within alveoli

5. Compression of lower airways (bronchioli)

6. Narrowing of bronchiolar lumen and obstruction

Arterial Blood Gases

1
1. Reduced surface area and bronchial obstruction
Reduced surface area and bronchial obstruction

2. Mild hypoxemia at rest, worsening with exercises

3. Activation of breathing

4. No or mild hypocapnia (no fibrosis, preserved diffusion
No or mild hypocapnia (no fibrosis, preserved diffusion) 
) 
respiratory alkalosis

19
 8/24/2010

Clinical Correlates
• Dyspnea (insidious but steadily progressive)

• Hyperventilation

• Pursing lips and use of accessory muscles

Mild hypoxia and hyperventilation  “pink

• Mild hypoxia and hyperventilation 
Mild hypoxia and hyperventilation  pink puffers
puffers”

• Barrel chest and w
Barrel chest and weight loss
eight loss

Complications
• Respiratory failure (late, but severe)
– Non
Non‐‐ventilatory respiratory failure
• End
End‐‐stage: 
stage: respiratory acidosis
respiratory acidosis

• RSHF (cor pulmonale)

• Pneumothorax (bullae rupture)

20
 8/24/2010

Conditions Related to
Emphysema

 Compensatory emphysema (overinflation)

after surgical resection of a lobe or lung
 Senile emphysema (overinflation) due to
age--related loss of lung elastic tissue
age
 Obstructive emphysema (overinflation)
after subtotal obstruction by a tumour or foreign
b d
body
 Mediastinal (interstitial)
(interstitial) emphysema – the
entrance of air into the lung interstitium,
mediastinum and/or subcutaneous tissue

Bronchial Asthma
• A disease characterised by paroxysmal narrowing of the 
bronchial airways which is reversible spontaneously or as a 
bronchial airways, which is reversible spontaneously or as a
result of treatment.

• Clinically: episodic dyspnoea, cough, wheezing

• Types:   Extrinsic asthma
Intrinsic asthma

21
 8/24/2010

Extrinsic Asthma
- Develops
p early
y in life
- Induced by exposure to an extrinsic Ag
house dust, pollens, fungal spores, milk,
eggs, fish, cereals, nuts and, chocolate
- Associated allergic manifestations:
rhinitis, eczema, urticaria
- Positive family history

Mechanism of Extrinsic
Asthma
Type I Hypersensitivity Reaction

1 Underlying abnormality: predominant activation of TH
Underlying abnormality: predominant activation of TH‐‐2
2 Release of IL
Release of IL‐‐4 and IL‐
4 and IL‐5

3 Production of IgE
Production of IgE by plasma cells; activation of mast cells and
by plasma cells; activation of mast cells and
eosionophils
p

4. Ag+IgE+mast cell

5. Mast cell degranulation
Mast cell degranulation

22
 8/24/2010

Mechanism of Extrinsic Asthma

(Cont.)
6. Early phase reaction
1 Mast
1. Mast cell mediators
cell mediators activate sub
activate
activate sub‐
sub‐epithelial vagal 
sub‐epithelial vagal
receptors
2. Broncho‐
Broncho‐constriction, edema and mucus secretion
7. Late‐phase reaction (begins in 4 
Late‐ (begins in 4 –– 8 hours and persists 12 
8 hours and persists 12 –– 24 
hours)
1. Mast cell (and other) mediators induce influx of all 
types of WBCs (esp. eosinophils)
( )
2. Acute inflammatory reaction
• Major basic protein from eosionophils 
from eosionophils  epithelial 
damage and bronchoconstiction

Mediators in Extrinsic
Asthma
Name Action

LTC4 Prolonged Bronchoconstriction

LTD4 Vascular permeability
LTE4 Mucus secretion
Acetylcholine Stimulation of M-receptors  Bronchospasm

Histamine Bronchoconstriction
PGD2 Bronchoconstriction
Vasodilation
PAF Aggregation of platelets  histamine &
serotonin release
IL-1, TNF, IL-6, NO,
eotaxin,
neuropeptides,
bradykinin

23
 8/24/2010

Prognosis
• The overall prognosis for extrinsic asthma is good

• Well‐controlled cases, the attacks usually cease later in 
childhood or adolescence

• Occasionally, a severe paroxysm can result in respiratory 
failure.
failure

Intrinsic Asthma
 Viral infection

 Aspirin

 Low
Low--molecular-
molecular-weight occupational-
occupational-related
substances
- Histamine
Histamine--like substances
- Substances affecting autonomous NS
- Irritant g
gases ((e.g.,
g , NH3,, SO2))
- Plastic fumes

 Physical exercises

 Cold
 Psychological stress

24
 8/24/2010

Mechanisms of Intrinsic
Asthma
• Exact mechanism is unknown

• Hypothetical mechanisms
– Decreased threshold of vagal receptors
Decreased threshold of vagal receptors in 
bronchial mucosa (viral infection)
– Deregulated production of arachidonic acid 
Deregulated production of arachidonic acid 
metabolites
– Direct stimulation of 
Direct stimulation of vagal receptors
vagal receptors (gases, 
fumes, cold air)

Morphology

 Macroscopic
- Over distended lungs (over inflation)
- Occlusion of bronchial tree by mucinous plugs

 Histology of bronchial tree

- Mucus plugs (with eosinophils)
- Goblet cell hyperplasia
- Submucosal gland hypertrophy
- Inflammatory infiltration (esp. eosinophils)
- Smooth muscle cell hypertrophy
- Basement membranes thickening
NB: alveoli are not damaged

25
 8/24/2010

Bronchial Asthma

Eosinophils in Mucus Plug and Bronchial

Mucosa

Mucus Plug

26
 8/24/2010

Mucin Cast in Bronchial Asthma

Genetics of asthma
• ADAM‐
ADAM‐33: matrix metalloproteinase from bronchial smooth 
muscle cells and fibroblasts
muscle cells and fibroblasts
– ADAM‐
ADAM‐33 pleomorphism 
33 pleomorphism   bronchial SMC hyperplasia and 
subendothelial fibrosis

• GSTM1
• IL10, IL4, IL4R, IL13
• ADRB2
• TNF
• NOD1

27
 8/24/2010

Clinical Course
• Attacks 
– Bronchospasm
– Overinflation
– Clinical presentation
• Wheezing
• Severe dyspnea
• Coughing

• Status astmaticus: potentially fatal nonreleting attack (days, 
Status astmaticus: potentially fatal nonreleting attack (days, 
rarely –– weeks)
rarely 
• Intervals between attacks: no manifestations

Laboratory Diagnosis
• Sputum cytology
– Curshmann’s spirals: twisted mucous plugs 
admixed with sloughed epithelium
– Eosinophils
– Charcot
Charcot‐‐Leyden crystals: crystalloids of eosinophil 
proteins

• Elevated eosinophil count in peripheral blood

• Elevated serum IgE

28
 8/24/2010

Curshman Spirals and

Charcot--Leyden Crystals
Charcot

Bronchiectasis
• Definition: b
Definition: bronchiectasis is an irreversible 
ronchiectasis is an irreversible 
dilatation of the bronchi with formation of 
large spaces or cavities

• Etiology
– Destruction of muscles and elastic supporting 
tissue resulting from or associated with
– Chronic necrotizing infection

29
 8/24/2010

Predisposing Lesions
• Bronchial obstruction: infection distal to obstruction with 
Bronchial obstruction: infection distal to obstruction with 
subsequent destruction of bronchial wall
q
– Tumor
– Foreign body
– Mucus plug
• Necrotizing or suppurative pneumonia (TB,  (TB, S. aureus, 
S. aureus, 
H.Influenzae, Psedomonas)
• Purulent rhinosinusitis
Purulent rhinosinusitis: aspiration of bacteria 
: aspiration of bacteria 
p
• Cystic fibrosis
Cystic fibrosis: obstruction by viscid mucus
: obstruction by viscid mucus
• Immunodeficiency (IgA): repeated bacterial infection
• Kartagener syndrome

Morphology
• Bronchial and bronchiolar dilation (up to four times)
Bronchial and bronchiolar dilation (up to four times)
• Lower lobes

• Bronchioli extend to the pleura (in normal 
lung, 2 –– 3 cm peripleural zone is free of 
lung, 2 
visible bronchioli)
visible bronchioli)

30
 8/24/2010

Bronchiectasis

Bronchus

Bronchiectasis with
Suppuration

31
 8/24/2010

Clinical Manifestations
• Cough

• Malodorous purulent sputum
– Sometimes bloody

• Fever

• Dyspnea

Complications and
Causes of Death
• Bronchial obstruction  respiratory failure (ventilatory)

• Progressive necrosis → lung abscess
Progressive necrosis → lung abscess

• Septic embolism (brain abscesses)

• Cor pulmonale (caused by progressive fibrosis)
Cor p lmonale (ca sed b progressi e fibrosis)

• Secondary amyloidosis

32