Introduction 

Chronic obstructive pulmonary disease (COPD) is a common cause of illness in the community associated mainly with cigarette smoking.  It is a progressive disease with considerable morbidity and mortality.  Management of many patients remains suboptimal because of under-diagnosis and inappropriate treatment.  Early detection and appropriate intervention can minimize the progression of COPD and a comprehensive management plan benefits all patients, including those with severe disease. 

Several COPD management guidelines already exist, for example those by the American Thoracic Society, European Thoracic Society and British Thoracic Society, but they do not take into account local conditions such as our health care system and socio-cultural factors.  The Malaysian Thoracic Society initiated efforts to produce COPD management guidelines in 1997 and the following document is aimed at improving overall management of COPD in Malaysia. 

This report is not intended to be construed or to serve as a standard of medical care.  Standards of medical care are determined on the basis of all clinical data available for an individual case and are subject to change as knowledge and technology advance and patterns evolve.  The ultimate judgment regarding a particular clinical procedure and treatment must be made by the doctor in the light of the clinical data presented by the patient and the diagnostic and treatment options available.

Definitions

Chronic obstructive pulmonary disease is a condition characterized by persistent airflow obstruction, which is slowly progressive.  It may be partially reversible and there may be features of airway hyper-reactivity.  Traditionally, it comprises chronic bronchitis and emphysema. 

Chronic bronchitis is defined by the presence of increased bronchial secretions with chronic cough and expectoration on most days for at least 3 months a year in two consecutive years. 

Emphysema is defined anatomically by permanent destructive enlargement of airspaces distal to the terminal bronchioles without obvious fibrosis. 

Majority of patients show features of both conditions. 

Epidemiology

According to the Ministry of Health annual reports from 1990 – 1995, respiratory diseases rank as the most common cause of medical consultations and the fourth leading cause of hospital admission.  There is insufficient morbidity and mortality statistics for Malaysia but the incidence is probably rising.  Data from the United States shows an increased prevalence of 41.5% since 1982.  Mortality rate has risen by nearly 32.9% between 1979 and 1991.  COPD is more common in men than in women, and it increases steeply with age.  Exacerbations and respiratory failure in COPD may result in prolonged hospital stay and costly treatment.  Undeniably, it leads to severe disability and reduced quality of life resulting in loss of productivity with substantial economic impact. 

Risk factors

Recognized risk factors are: 

·         Cigarette smoking.  It is the single most important cause of COPD.  The greater the consumption the higher is the risk. Smoking cessation at any age can reduce the rate of decline of lung function. 

·         Passive smoking

·         Air pollution especially SO₂ and particulates

·         Poverty and low socioeconomic status

·         Viral infection leading to airway hyper-responsiveness

·         Occupational exposure e.g. cadmium and silica

·         Genetic factors e.g.  Alpha1 - antitrypsin deficiency

Prognosis

Factors associated with reduced survival are: 

·         FEV₁ less than 1 L

·         PO₂ less than 60 mm Hg

·         PCO₂ greater than 46 mm Hg

·         ECG or clinical evidence of cor pulmonale

·         FVC less than 2.5 L

·         Continued smoking 

Pathology

·         Chronic bronchitis 

o    Hyperplasia of the secretory cells and mucous gland enlargement are the histological hallmarks of chronic bronchitis, and these are the tissue correlates of increased sputum production.  These changes are due to repeated irritation by pollutants and infections. Airway wall inflammation, stenosis and distortion due to fibrosis may also be present.  The small bronchi and bronchioles are the main sites of the increased resistance to airflow. 

·         Emphysema 

o    Two main forms of emphysema are described.  Centriacinar emphysema is characterized by focal destruction restricted to respiratory bronchioles and the central portion of an acinus, surrounded by relatively normal lung.  Panacinar emphysema involves destruction of all the air spaces supplied by the terminal bronchiole.  The current view is that emphysema occurs as a result of an imbalance between proteases and anti-proteases resulting in a relative increase in proteases and resultant destruction of lung tissue.  

Clinical consequences

COPD is often diagnosed late due to the paucity of symptoms in the early stages of the disease. At presentation patients are usually more than 40 years old and have functional evidence of moderate or severe airflow limitation.  Chronic productive cough is often present.  Dyspnea develops gradually as the years go by resulting in decreased effort tolerance.  In moderate disease, patients may have prolonged expiration or wheezing.  Later hyperinflation occurs with the characteristic increase in the anteroposterior diameter of the chest.  In advanced disease features of respiratory failure and cor pulmonale appear.  

Assessment

Spirometry is essential to diagnose and assess the severity of COPD.  Airflow limitation can be demonstrated by a ratio of FEV1 to FVC of less than 70%.  The FEV1 as a percentage of predicted values is more useful in the later stages of the disease.  Mild COPD is characterized by a FEV1 of more than 70% of the predicted value and severe COPD a FEV1 of less than 50%. 

Reversibility of airflow obstruction can be demonstrated either by a bronchodilator challenge or a trial of corticosteroids for two weeks with spirometry before and after.  A positive spirometric response to bronchodilators or corticosteroids is considered to be present when the FEV1 increases by 200ml and 15% of the baseline value. 

Chest radiography may show features of hyperinflation, bullae, vascular attenuation, large pulmonary arteries and cardiomegaly.  It also helps to exclude other causes of the symptoms. 

More complex investigations are not normally indicated except in difficult cases. 

Arterial blood gases are recommended for those patients with severe COPD and those in acute exacerbations. 

Aims of COPD management

The aims of management of COPD are to: 

·         improve symptoms and quality of life

·         reduce the progressive decline in lung function

·         prevent and treat complications

·         prolong survival

·         reduce the number of exacerbations and need for hospital admissions

Management strategies include: 

·         patient education

·         drug therapy

·         non-pharmacological treatment.  

• Nutrition

Patient education

The patient should be educated about: 

·         The nature of the disease and its cause(s).  Smoking cessation should be emphasized as an essential first step in preventing further damage to the lung. Even patients with advanced airflow obstruction show improved survival rates following smoking cessation.  Strategies to help patients quit their smoking habit include positive reinforcement, group support and nicotine replacement therapy.

·         Its prognosis.  The patient should be informed that although the disease is usually progressive and largely irreversible, symptoms can be improved and further deterioration may be preventable. 

·         Proper use of medications with emphasis on the use of inhaled medications.

·         Non-pharmacological treatment: its modalities, indications and complications.

·         when to seek medical advice

Drug therapy

A major component of the management of COPD is pharmacological therapy.  The inhaled route where applicable, is strongly recommended for delivery of drugs to the lungs.  The recognized advantages of inhaled therapy include direct delivery to the site of action, rapid onset of action, small doses needed to achieve a therapeutic response, and fewer systemic side effects.  A spacer device should be used for patients who are unable to coordinate inhalation with the activation of a metered-dose aerosol.  Alternatively, dry powder inhalers or breath-actuated inhalers should be used. 

Bronchodilators

Bronchodilator drugs are the mainstay of pharmacological therapy.  These drugs relax bronchial smooth muscles and relieve bronchospasm and improve symptoms. 

The three main groups of bronchodilators for use in COPD are:  

·         anticholinergics

·         beta2 agonists

·         methylxanthines 

 

Anticholinergics 

Onset of bronchodilation is relatively slower compared to beta2 agonist.  Significant bronchodilatation occurs within 30 minutes of inhalation and the maximum effect occurs 1.5 to 2 hours after inhalation.  The duration of clinically significant bronchodilation is as long as 4 to 6 hours. Because quaternary anticholinergic agents are poorly absorbed into the circulation, they are virtually free of systemic side effects.  Ipratropium bromide has been shown to be either equivalent to or more potent than beta2 agonist as a bronchodilator in COPD. Unlike beta2 agonists, the efficacy of anticholinergics is maintained despite years of regular, continuous therapy because tachyphylaxis does not develop despite its prolonged usage.  The recommended dose of 2 puffs (or 40 mcg) of ipratropium bromide three to four times a day may be increased for patients with severe airflow limitation.  Ipratropium bromide should be taken regularly rather than on a when-needed basis because of its relatively slow onset of action. 

Example: ipratropium bromide (Atrovent)  

Beta2 agonists 

Beta2 agonists produce bronchodilation more rapidly than anticholinergic agents, acting within 15 minutes of administration with effects lasting 4 to 5 hours.  They are useful as on-demand medications at times of acute Dyspnea.  The main side-effects are tremor and palpitation.  Since the number of beta2 receptors decreases with age, the dose of a beta2 agonist may have to be increased in older patients in order to achieve maximal bronchodilatation at the cost of increased side effects. 

Examples: inhaled beta2 agonists: 

·         salbutamol (Ventolin)

·         terbutaline (Bricanyl)

·         salmeterol (Serevent)  - long acting

·         formoterol (Foradil)  - long acting

At times of acute exacerbation and for patients with chronic severe airflow obstruction, these drugs should be administered using nebulizers.  Alternatively, large volume spacers can be used to deliver larger doses of the drugs from metered dose inhalers.  A combination of ipratropium bromide and a beta2 agonist provides the combined rapid onset of action of the beta2 agonist and the prolonged duration of action of ipratropium.  

Example:

·         salbutamol combined with ipratropium bromide (Combivent MDI)

Methylxanthines 

These drugs have comparable or less bronchodilator effect than anticholinergic agents or beta2 agonists. They are available in oral and parenteral preparations.  They have a narrow therapeutic window and interactions with other drugs are common.  Cimetidine, mexiletine, quinolones, allopurinol, macrolides, nifedipine, tetracycline, aluminum hydroxide, magnesium hydroxide and thiobendazole are known to increase the level of theophylline whereas phenytoin, rifampicin, phenobarbitone, carbamazepine, aminoglutethimide and isoproterenol may reduce it.  Hepatic insufficiency, heart failure, cor pulmonale and viral pneumonia may also increase the blood theophylline level whilst cigarette smoking causes the opposite.  Sustained release preparations taken at bedtime are useful for relieving nocturnal symptoms. Some patients derive subjective benefit from theophylline which cannot be achieved with other bronchodilators.  Theophylline has been shown to prevent respiratory muscle fatigue and to increase contractility of the fatigued diaphragm in the laboratory, but the clinical importance of these observations is not clear. Other non-bronchodilatory effects of theophylline include improved mucociliary transport and increased hypoxic respiratory drive. Blood levels of theophylline should be monitored when indicated such as when toxicity is suspected or when there is lack of response.    Long acting preparations are preferred.  Side effects of methylxanthines include gastric irritation, nausea, diarrhea, headache, tremor, irritability, sleep disturbance, convulsion and cardiac arrhythmia. 

Examples:

·         Oral sustained release preparations:

o    Neulin SR

o    Theodur

o    Euphylline

o    Theo-24

·         intravenous preparation:

o    aminophylline 

Corticosteroids 

These are anti-inflammatory drugs.  Although corticosteroids are of undoubted benefit in asthma, their role in COPD has yet to be established. Corticosteroids can be administered orally, by inhalation or intravenously. Corticosteroids may be beneficial during acute exacerbations. 

During an exacerbation-free period, a trial of prednisolone, 30-40 mg/day for 2 weeks, may be used to test reversibility of the airflow obstruction.  About 10% of patients with stable COPD will show an improvement in FEV1.  Once maximum improvement with oral prednisolone has been attained, high dose inhaled steroid therapy (e.g. at least 800 mcg/day of beclomethasone dipropionate or budesonide) is commenced and prednisolone is tapered off.  However, not all responders to prednisolone show a similar response to inhaled corticosteroids. If high dose inhaled steroids for example, 2000 mcg a day of beclomethasone or budesonide are not effective, prednisolone may be continued at the lowest effective dose.  

Two local side-effects of inhaled corticosteroids, oral candidiasis and hoarseness, can be minimized by using large-volume spacers and by rinsing the mouth. 

Examples of inhaled corticosteroids :

·         beclomethasone dipropionate (Becotide, Becloforte, Beclomet, Respocort, Aldecin)

·         budesonide (Pulmicort)

·         fluticasone (Flovent)

Antibiotics 

The airways of patients with COPD are colonized with Streptococcus pneumonia, Hemophilus influenzae and Moraxella catarrhalis which are also frequently isolated from sputum during exacerbations. Infections, frequently viral in etiology, are one of the most common precipitating factors of acute exacerbations of COPD.  The sputum is usually purulent during an acute exacerbation but the chest radiograph seldom shows an infiltrate.  Evidence of infection includes fever, leucocytosis, increased sputum volume and new lung infiltrates on chest radiograph.  Sputum culture helps to determine appropriate antibiotic therapy but pathogens are difficult to identify during acute exacerbations.  Therefore, treatment is often empirical with broad spectrum antibiotics such as tetracycline/doxycycline, ampicillin/amoxycillin, erythromycin, co-trimoxazole and cefaclor. Second line antibiotics including second generation cephalosporins, ampicillin/sulbactam, amoxycillin/clavulanic acid, newer macrolides, and quinolones should be used if there is concern about beta-lactamase producing organisms or when there is failure to respond to first line antibiotics.  

Others  

The usefulness of mucolytic agents is unproven.  Objective evidence of benefit is lacking and widespread use of these agents cannot be recommended routinely based on the present evidence.  Excessive mucus secretion is probably best controlled by avoiding inhaled irritants from cigarette smoke and exposure to environmental pollutants.  Cough suppressants are undesirable for long-term therapy.