Examine this patient's chest.
· Productive cough.
· Increasing dyspnoea.
· Weight loss.
* History of smoking.
· History of alpha-antitrypsin deficiency.
· Begin with examination of the sputum pot.
· Observe the patient from the end of the bed - for obvious breathlessness, pursed lip breathing and symmetrical chest
movements - and count respiratory rate.
· Look for nail changes such as tar staining.
· Feel the palms for warmth and the pulse for rapid bounding pulse (signs of carbon dioxide retention).
· Look at the lips and tongue for central cyanosis.
· Comment on the active contractions of the accessory muscles of respiration such as sternocleidomastoids, scaleni and trapezii.
· Palpate for tracheal deviation and measure the distance between the cricoid cartilage and suprasternal notch (less than three
fingers' breadth in emphysema).
· Comment on the raised JVP.
Comment on the barrel-shaped chest.
· Apex beat.
· Chest expansion.
· Vocal fremitus.
Look for hyper-resonance and obliteration of cardiac and liver dullness.
· Breath sounds (diminished breath sounds).
· Vocal resonance.
· Forced expiratory time: normal individuals can empty their chest from full inspiration in 4 seconds or less. The end-point of FET
is detected by auscultating
over the trachea in the suprasternal notch. Prolongation of the FET to more than 6 seconds indicates airflow obstruction.
· Loud pulmonary second heart sound.
Palpable liver due to hepatic displacement comment on upper border of liver by percussion).
p class=MsoNormal style='text-align:left;mso-pagination:none;mso-layout-grid-align:
none;text-autospace:none;direction:ltr;unicode-bidi:embed'>This patient has features of chronic
obstructive airway disease (COAD) (lesion) due to cigarette smoking (aetiology) and is very cyanosed at rest (functional status).
What do you understand by the term 'chronic bronchitis'?
Chronic bronchitis is cough with mucoid expectoration for at least 3 months in a year for 2 successive years.
What is the definition of emphysema?
Emphysema is the abnormal permanent enlargement of the airway distal to the terminal respiratory bronchioles with destruction of
their walls. Clinical, radiological and lung function tests give an imprecise picture in an individual case but a com-bination of all these
features gives a reasonable picture.
What do you understand by the term 'COAD'?
The term COAD encompasses chronic obstructive bronchitis (with obstruction of small airways) and emphysema (with destruction of
lung parenchyma, loss of lung elasticity, and closure of small airways). Most patients also have mucus plugging (N Engl J Med 2000:
What is the mechanism of airflow limitation in COAD?
It is a variable mixture of loss of alveolar attachments, inflammatory obstruction of the airway and luminal obstruction with mucus.
What is the role of inflammatory mechanisms in COAD?
Macrophages and epithelial cells in airways are activated by cigarette smoke and other irritants and release neutrophil chemotactic
factors including interleukin-8 and leukotriene B4. Neutrophils and macrophages then release proteases that break down connective
tissue in the lung parenchyma, resulting in emphysema, and also stimulate hypersecretion of bronchial mucus. The chronic
inflammatory process in COPD differs markedly from that seen in bronchial asthma, with different inflam-matory cells, mediators,
inflammatory effects and responses to treatment (Thorax 1998: 53:129 36; Chest 2000; 117 (suppl): 10S-14S).
.................. r- ..................................................... j ............
In C©AD the protease-antiprotease balance is tipped in favour of proteolysis because of either an increase in proteases (including
neutrophil elastase, proteinase
3, cathepsins, matrix metalloproteases 1, 2, 9 and 12) or a deficiency of anti-proteases (including tz~-anUtrypsin, elafin, secretory
leukoprotease inhibitor and tissue inhibitors of matrix metalloproteases).
What is the role of high-resolution CT in the diagnosis of
emphysema ? It is the most sensitive (but expensive) technique for the diagnosis of emphysema. It is useful in evaluating
symptomatic patients with almost normal pulmonary function except for a low carbon monoxide diffusing capacity - a combination of
findings that occurs in emphysema, interstitial lung disease and pulmonary vascular disease (Radiology 1992; 182:817-21 ).
How would you differentiate emphysema from chronic bronchitis?
Emphysema Chronic bronchitis
Pink puffer Blue bloater
Cyanosis Absent Prominent
Dyspnoea ++ +
Hyperinflation ++ +
Cor pulmonale - Common
Respiratory drive High Low
If the patient was between the ages of 30 and 45 years, what would you consider to be the underlying cause of the
emphysema? Smoking, alpha-antitrypsin (AAT) deficiency.
How would you treat an acute exacerbation?
· Nebulized bronchodilators (terbutaline, ipratropium bromide).
· Intravenous antibiotics (BMJ 1994; 308:871 2), initially amoxicillin and, if there is no clinical response, then a
second-generation cephalosporin, quinoline or co-amoxiclav.
· Oxygen (24%).
· Intravenous hydrocortisone and oral steroids. (Note. Steroid therapy is useful only in acute exacerbations and, unlike in asthma,
it does not influence the course of chronic bronchitis.)
What is the role of inhaled steroids in COPD?
Inhaled steroids are recommended for symptomatic patients with moderate to severe COAD and for patients with frequent
exacerbations but not for patients with mild COAD (N Engl J Med 2000; 343: 1960-1). Budenoside, fluticasone and triamcinolone
were studied in long-term clinical trials (N Engl J Med 1999; 340: 1948-53; Lancet 1999; 353: 1819-23; BMJ 2000: 320: 1297-303)
and all were similar except that triamcinolone has deleterious effects on bone density (N Engl J Med 2000; 343: 1902-9).
What are the organisms commonly associated with exacerbations of COAD?
Haemophilus infiuenzae and Streptococcus pneumoniae are the commonest organisms identified in the sputum during
exacerbations of COAD, accounting for 43% and 25% respectively of positive cultures in one study. Moraxella (previously
Branhamella) catarrhalis is also frequently isolated from sputum during exacer-bations. Less commonly, Chlamydia pneumoniae or
Pseudomonas aeruginosa have been associated with some exacerbations.
What clinical features would suggest that this patient is suitable for long-term domiciliary oxygen therapy?
° COAD: forced expiratory volume in I second (FEV1) less than 1.5 litres; forced vital capacity (FVC) less than 2 litres; stable
chronic respiratory failure (Pao2 <7.3 kPa, that is, 55 mmHg) in patients who have (1) had peripheral oedema or (2) not
necessarily had hypercapnia or oedema (N Engl J Med 1995; 333:710-14); carboxyhaemoglobin of less than 3% (i.e. patients
who have stopped smoking).
· Terminally ill patients of whatever cause with severe hypoxia (Pao2 <7.3 kPa).
How can the sensation of breathlessness be reduced?
By the use of either promethazine or dihydrocodeine.
How would you treat acute respiratory failure?
If Pao2 is less than 8 kPa, administer 24% oxygen. There is no need for oxygen when Pao2 is greater than 8 kPa. Monitor blood
gases after 30 minutes. If Pa02 is rising (by I kPa), monitor blood gases hourly. If Pao2 continues to rise, administer doxapram. If, in
spite of this, the patient continues to deteriorate, artificial ventilation may be called for.
What do you know about non-invasive ventilation?
Non-invasive ventilation is an alternative approach to endotracheal intubation to treat hypercapnic ventilatory failure which occurs in
COAD. It thus reduces the complications of endotracheal intubation such as infection and injury to the trachea. Non-invasive
ventilation is pressure-support ventilation delivered with a face mask and a piece of white foam placed in the face mask to reduce
the amount of internal dead space. In a recent randomized trial, non-invasive ventilation was shown to reduce the need for
endotracheal intubation, length of hospital stay and in-hospital mortality rate in selected patients with acute exacerbations of COAD
(N Engl J Med 1995; 333: 817-22).
What do you know about the molecular genetics of COAD?
· It was first described in Sweden. The patient is deficient in alpha-antitrypsin, with activity approximately 15% that of the normal
value; concentrations of 40% or more are required for health. The patient is homozygous for the protease inhibitor (Pi) ZZ gene.
Other genetic combinations and their percentage normal activity are PiMS (80%), PiMZ (60%), PiSS (60%), PiSZ (40%). Six
per cent of the population is heterozygous for S(PiMS) and 4% for Z(PiMZ), making an overall frequency of 1 in 10 for the
carriage of the defective gene. Liver transplantation results in conversion to the genotype of the donor.
· In the lung, alpha1-antitrypsin inhibits the excessive actions of neutrophil and macro-phage elastase, which cigarette smoke
promotes. When the lung is heavily exposed to cigarette smoke, the protective effect of alpha 1-antitrypsin may be
over-whelmed by the amount of elastase released or hy a direct oxidative action of cigarette smoke on the alpha 1 -antitrypsin
molecule. The emphysema is panacinar and is seen in the lower lobes of the lungs. Smoking increases the severity and
decreases the age of onset of emphysema. Liver disease is a much less common complication. Human alpha 1 -antltrypsm
prepared from pooled plasma from normal donors is recommended for patients over 18 years with serum levels below 11 gmol/l and
abnormal lung function.
· The siblings of an index case should be screened for this disorder. Their identifi-cation should be followed by counselling to
avoid smoking and occupations with atmospheric pollution. Children of homozygotes will inherit at least one Z gene and hence
will be heterozygotes. They should avoid pairing with another heterozygote if they wish to avoid the risk of producing an
Tumour necrosis factor-alpha (TNF-alpha )
COAD is 10 times more common in Taiwanese with a polymorphism in the promoter region of the gene for TNF-alpha resulting in
increased production of TNF-alpha (Am J Respir Crit Care Med 1997; 156:136-9). However, the same polymorphism in the UK
population is not associated with increased risk of COAD (Eur Respir J 2000; 15: 2814).
Microsomal epoxide hydrolase
A polymorphism variant of microsomal epoxide hydrolase, an enzyme involved in the metabolism of epoxides that may be generated
in tobacco smoke, has been associated with a quintupling of the risk of COAD (Lancet 1997; 350: 663).
What is the role of surgery in COAD?
· Bullectomy may improve gas exchange and airflow, and reduce dyspnoea in selected patients with bu]lae larger than one third
of the hemithorax and accom-panying lung compression.
· Lung-volume reduction surgery (N Engl J Med 2000; 343: 239-45) results in functional improvements including increased
FEV1, reduced total lung capacity, improved function of respiratory muscles, improved exercise capacity and improved quality
of life (J Thorac Cardiovasc Surg 1999; 112: 1319-29; Am J Respir Crit Care Med 1999; 160: 2018-27). These benefits persist
for at least a year but the long-term benefits are not known and are currently being investigated by the National Emphysema
Treatment Trial Group (Chest 1999; 116: 1750-61).
· Single lung transplantation: this has been successful for at least 34 years in patients with COAD. The criteria for selecting
patients for transplantation have not been established. It does not improve survival but improves quality of life (J Thorac
Cardiovasc Surg 1991; 101: 623-32).
What are the general indications for lung transplantation?
The general indication is end-stage lung disease without alternative forms of therapy. Patients should be below 60 years of age and
should have a life expectancy of less than 12 or 18 months; they should not have an underlying cancer or other serious systemic
illness. The most common lung diseases are pulmonary fibrosis, emphysema (particularly alpha 1 -antitrypsin deficiency),
bronchiectasis, cystic fibrosis and primary pulmonary hypertension.
What is the role of nutrition in COAD?
Undernutrition is associated with reduced respiratory muscle function and an increased mortality rate. A high dietary intake of n-3
fatty acids may protect cigarette smokers against COAD.
Mention some newer treatments for COAD.
· Antagonists of inflammatory mediators: 5-1ipoxygenase inhibitors, leukotriene B4 antagonists, interleukin-8 antagonists, tumour
necrosis factor inhibitors and antioxidants.
· Protease inhibitors: neutrophil elastase inhibitors, cathepsin inhibitors, non-selective matrix metalloprotease inhibitors, elafin,
secretory leukoprotease inhibitor, alpha 1-antitrypsin.
· New anti-inflammatory agents: phosphodiesterase-4 inhibitors, nuclear factor-kappaB inhibitors, adhesion molecule inhibitors
and p38 mitogen-activated protein kinase inhibitors (N Engl J Med 2000; 343:19601 ).
Peter Howard, contemporary chest physician, Sheffield; his chief interest is long-term domiciliary oxygen therapy.
Peter Barnes, contemporary physician and professor, National Heart and Lung Institute London