Category Archives: Respiratory disease

Pneumonias due to opportunistic infections

These are commonly becoming recognized in the immunocompromised patient.

Pneumocystis carinii

This is by far the commonest opportunistic infection, accounting for 80% of the cases of pneumonia in patients with acquired immunodeficiency syndrome (AIDS) particularly when the CD4 lymphocyte count is ::5200/mm3 It is also seen in patients receiving immunosuppressive therapy. In the developing world, however, Pneumocystis carinii pneumonia (PCP) is not infrequently found in malnourished children.
It is likely that infection with the organism occurs by inhalation, perhaps in childhood, and the organism may remain latent for many years, being reactivated when immunosuppression occurs. Clinically the pneumonia is associated with a high fever, breathlessness and dry cough. In patients with AIDS, the clinical features are described.
The typical radiographic appearance of PCP is of a diffuse bilateral alveolar and interstitial shadowing beginning in the perihilar regions and spreading out in a butterfly pattern. A variety of typical chest X-ray appearances are now well recognized including a localized infiltrate, nodule, cavity or a pneumothorax. In patients receiving aerosolized pentamidine for prophylaxis, infiltrate may be localized to the upper zones. Investigation includes induction of sputum with hypertonic saline or fibreoptic bronchoscopy with bronchoalveolar lavage; the diagnosis can be made in 90% of cases by staining using indirect immunofluorescence with monoclonal antibodies. Shadowing on the chest X-ray in AIDS patients, though most commonly due to P. carinii can result from:
• Cytomegalovirus
• M. avium intracellulare
• M. tuberculosis
• L. pneumophila
• Cryptococcus
• Pyogenic bacteria
• Kaposi’s sarcoma
• Lymphoid interstitial pneumonia
• Non-specific interstitial pneumonitis
TREATMENT is with oral trimethoprim-sulphamethoxazole 120 mg kg:” daily in divided doses or i.v. pentamidine 4 mg kg:” daily.
The mortality partly depends on the underlying condition; with treatment it is approximately 25%.

Actinomyces israeli

The clinical picture is that of severe pneumonia, lung abscess or empyema.

JVocardia asteroides

This produces a similar picture to Actinomyces, though of greater severity. The chest X-ray often shows irregular opacities in one or both lungs, particularly in the midzones. Cytomegalovirus Bronchitis and pneumonia may occur but these are usually a more minor part of the generalized systemic illness.

Aspergillus fumigatus

This fungus gives rise to a widespread invasion of lung tissue in patients who are immunocompromised. It is a serious pneumonia that is usually rapidly fatal. Mycobacterium avium intracellulare (MAl) This bacterium causes lung disease in patients with AI DS primarily as part of disseminated disease when CD4 lymphocyte counts are ::s 100/mm3 with the pulmonary complications being of less significance than the extrapulmonary involvement. Therapeutic regimens include combinations of ciprofloxacin, c1ofazimine, rifampicin and ethambutol. Clarithromycin and azithromycin may prove to be particularly efficacious.

Cryptococcus

Infection with this fungus is usually disseminated but pulmonary involvement includes intrathoracic lymph node enlargement and effusions.

Kaposi’s sarcoma

Intrathoracic involvement usually follows cutaneous manifestations and includes nodules or infiltrates in the lungs with lymph node enlargement and endobronchial lesions. Haemorrhage can accompany any of these lesions.

Lymphatic interstitial pneumonia

Infiltration with lymphocytes, plasma cells and immunoblasts characterizes this disease which is more common in children than in adults. It is thought to be a viral pneumonia and causes diffuse reticulonodular infiltrates on the chest X-ray. Corticosteroid therapy appears to be of benefit.

Rare causes of pneumonia

Pneumonia may be seen in the course of infection by Bordetella pertussis, typhoid and paratyphoid bacillus, brucellosis, leptospirosis and a number of viral infections including measles, chickenpox and glandular fever. It is not usually a major feature. Details of these infections are described.

Aspiration pneumonia

The acute aspiration of gastric contents into the lungs can produce an extremely severe and sometimes fatal illness due to the intense destructiveness of gastric acid-the Mendelson syndrome. It can complicate anaesthesia, particularly during pregnancy.
In the absence of a tracheo-oesophageal fistula, aspiration only occurs during periods of impaired consciousness (e.g. during sleep), in reflux oesophagitis or oesophageal stricture, or in bulbar palsy. Because of the bronchial anatomy, the most usual site for spillage is the posterior segment of the right lower lobe. The persistent pneumonia is often due to anaerobes and it may progress to lung abscess or even bronchiectasis. It is vital to identify any underlying problem, since appropriate corrective measures can lead to resolution of the pulmonary problems.

Cryptogenic organizing pneumonia (COP)

This condition is an organizing pneumonia of unknown aetiology although probably not infective. It is characterized by the presence of buds of connective tissue in alveolar ducts and respiratory bronchioles and the absence of any detectable microorganism. Clinical features are a short history of cough and breathlessness with fever, sometimes pleuritic chest pain and a raised ESR, normal white blood count and patchy or confluent shadows bilaterally on the chest X-ray. Finger clubbing is prominent. Lung function tests show a restrictive defect. Diagnosis is important because the disease responds rapidly to corticosteroid treatment.

Diffuse pneumonia (bronchopneumonia)

Diffuse pneumonia is very common. It is differentiated from severe bronchitis by signs of bronchial breathing or patchy shadows on the chest X-ray. Widespread diffuse pneumonia is a common terminal event, largely resulting from an inability of patients dying from other conditions (e.g. cancer) to cough up retained secretions, allowing infection to develop throughout the lungs. Treatment in this situation is rarely appropriate.

General management of pneumonia

This is shown in the algorithm given. Sputum should always be sent for culture. In mild cases treatment should be started immediately with oral cefaclor and erythromycin. More severe cases need to be admitted to hospital and a chest X-ray performed. Other investigations required are:
• Sputum-Gram stain and culture
• White blood-cell count is raised above 15 x 109/litre (with a high neutrophil count) in more than 50% of patients with pneumococcal pneumonia but only in 10% of cases of Legionella or Mycoplasma pneumonia
• Blood culture Treatment should be started immediately (without waiting for the result of these investigations). In more than 20% of cases, more than one organism is involved.  Further investigations may be necessary for the diagnosis of certain types of pneumonia:
• Mycoplasma antibodies (IgM and IgG)-in acute and convalescent samples. Cold agglutinins present in 50%.
• Legionella and Chlamydia antibodies-immunofluorescent tests.
• Pneumococcal antigen-counterimmunoelectrophoresis (eIE) of sputum, urine and serum (three to four times more sensitive than sputum or blood cultures). A high percentage of organisms causing pneumonia (e.g. Mycoplasma pneumoniae, H. influenzae and L. pneumophila) will not respond to penicillin or ampicillin/amoxycillin. These drugs should no longer be prescribed and should be replaced by a combination of bactericidal antibiotics that cover the commonest organisms. Treatment is commenced with cefuroxime 750 mg to 1.5 g i.v. 6-hourly together with erythromycin 500 mg i.v. 6-hourly. The purpose of this programme is to treat pneumonia with sufficient doses of appropriate antibiotics at the earliest stage. The treatment can always be modified and reduced in the light of clinical progress and subsequent bacteriological and serological findings. The chances of identifying a causative organism are greatly decreased in individuals who have received antibiotics in the week prior to their admission to hospital.

The overall mortality for pneumonia is currently 5% but for pneumonia due to Staph. aureus it is in excess of 25%. Patients who die from pneumonia usually have not received the appropriate antibiotics in sufficient doses before or during the early stages of hospital admission. Severe community-acquired pneumonia has a high mortality particularly in those over 65 years. The presence of a respiratory rate :2:30 min “, a diastolic blood pressure ::560 mmHg and a blood urea >7 mmol litre ” indicates a poorer prognosis and the need for intensive care. In spite of treatment in the intensive care unit approximately 50% of such patients will die.

General measures

These include care of the mouth and skin. Fluids should be encouraged, to avoid dehydration. The patient is normally nursed sitting up or in the most comfortable position. Cough should normally be encouraged, but if it is unproductive and distressing, suppressants such as codeine linctus can be given. Physiotherapy is needed to help and encourage the patient to cough. Pleuritic pain may require analgesia, but powerful analgesia (e.g. opiates) should be used with care because they cause respiratory depression.
In severe hypoxia, oxygen therapy should be given;
however, since the hypoxia is often due to a physiological shunt, it may make little difference to the hypoxaemia.

Severe hospital-acquired pneumonias

These should be treated in the same way as severe community- acquired pneumonias once appropriate samples for culture and sensitivities have been taken. Gram-negative bacteria are common and treatment should include i.v. ciprofloxacin or ceftazidime. Immunosuppressed patients may require very high-dose broad-spectrum antibiotics as well as antifungal and antiviral agents.

Complications of pneumonia

Lung abscess

This term is used to describe severe localized suppuration in the lung associated with cavity formation on the chest X-ray, often with the presence of a fluid level, and not due to tuberculosis.
Causes of lung abscesses are many, but the commonest is aspiration, particularly amongst alcohol abusers following aspiration pneumonia. Lung abscesses also frequently follow the inhalation of a foreign body into a bronchus and occasionally occur when the bronchus is obstructed by a bronchial carcinoma.
Abscesses may develop during the course of specific pneumonias, particularly when the infecting agent is Staph. pyogenes or K. pneumoniae. Septic emboli, usually staphylococci, result in multiple lung abscesses. Infarcted areas of lung may occasionally cavitate and rarely become infected. Amoebic abscesses may occasionally develop in the right lower lobe following transdiaphragmatic spread from an amoebic liver abscess. The clinical features are those of persisting and worsening pneumonia associated with the production of large quantities of sputum, which is often foul-smelling owing to the growth of anaerobic organisms. There is usually a swinging fever. Chronic or subacute lung abscesses follow an inadequately treated pneumonia. Fever, malaise and weight loss occur. The chest signs may be few but clubbing often develops. The patient is often anaemic with a high ESR.

Empyema

Empyema means the presence of pus within the pleural cavity. This usually arises after the rupture of a lung abscess into the pleural space or from bacterial spread from a severe pneumonia. Typically an empyema cavity becomes infected with anaerobic organisms and the patient is severely ill with a high fever and a neutrophil granulocytosis.

Investigation

Bacteriological investigation of lung abscess and empyema is best conducted on specimens obtained by transtracheal aspiration, bronchoscopy or percutaneous transthoracic aspiration.

Treatment

Although anaerobic organisms are found in up to 70% of lung abscesses and empyemas, there is usually a mixed flora, often with aerobes, particularly Strep. millen. Anaerobic cocci, black-pigmented bacteroids and fusobacteria are the commonest anaerobes found.
Antibiotics should be given to cover both aerobic and anaerobic organisms; prolonged courses are often necessary. Treatment should be cefuroxime 1 g i.v. 6-hourly, erythromycin 500 mg i.v. 8-hourly and metronidazole 500 mg i.v. 8-hourly for 5 days, followed by oral cefaclor and metronidazole for a prolonged period depending on bacterial sensitivities. Abscesses occasionally require surgery.
Empyemas should be treated by prompt tube drainage or rib resection and drainage of the empyema cavity followed by appropriate antibiotic treatment for up to 6 weeks.

Mycoplasma pneumonia

This is a common cause of pneumonia. It often occurs in patients in their teens and twenties, frequently amongst those living in boarding institutions. Generalized features such as headaches and malaise often precede the chest symptoms by 1-5 days. Cough may not be obvious initially and physical signs in the chest may be scanty. On chest X-ray, usually only one of the lower lobes is involved but sometimes there may be dramatic shadowing in both lower lobes. There is frequently no correlation between the X-ray appearances and the clinical state of the patient.

Algorithm for the management

Algorithm for the
management

The white blood cell count is not raised. Cold agglutinins occur in half of the cases. The diagnosis is confirmed by a rising antibody titre. Treatment is with erythromycin 500 mg four times daily for 7-10 days. Tetracycline is effective.
Although most patients recover in 10-14 days. the disease can be protracted. with cough and X-ray appearance lasting for weeks and relapses occurring. Lung abscesses and pleural effusions are rare.
Extrapulmonary complications can occur at any time during the illness and occasionally dominate the clinical picture. Most are rare but they include:
• Myocarditis and pericarditis
• Rashes and erythema multiforme
• Haemolytic anaemia and thrombocytopenia
• Myalgia and arthralgia
• Meningo-encephalitis and other neurological abnormalities
• Gastrointestinal symptoms (e.g. vomiting. diarrhoea)

Viral pneumonia

Viral pneumonia is uncommon in adults. bacteria being the usual cause of the pneumonia per se. Influenza A virus or adenovirus infection can occasionally produce pneumonia.

Other pneumonias

Haemophilus iniluenzae H. inJluenzae is frequently identified in the yellow-green sputum produced during exacerbation of chronic bron chitis. It is therefore not surprising that this organism may be the cause of pneumonia in people suffering from chronic bronchitis and emphysema. The pneumonia can be diffuse or confined to one lobe. There are no special features to separate it from other bacterial causes of pneumonia. It responds well to treatment with oral cefaclor 250 mg 8-hourly.

Chlamydia psittaci

Typically the individual has been working with infected birds, especially parrots, but a history of contact is not always elicited. The incubation period is 1-2 weeks and the disease may pursue a very low-grade course over several months. Symptoms include malaise, high fever, cough and muscular pains. The liver and spleen are occasionally enlarged and scanty ‘rose spots’ may be seen on the abdomen. The chest X-ray shows segmental or a diffuse pneumonia. Occasionally the illness presents with a high, swinging fever and dramatic prostration with photophobia and neck stiffness that can be confused with meningitis. The diagnosis is confirmed by the demonstration of a rising titre of complement-fixing antibody. Erythromycin or tetracycline are the antibiotics of choice.

Chlamydia pneumoniae

Chlamydia pneumoniae has only recently been recognized as a respiratory pathogen in man. Outbreaks have been reported in institutions and within families suggesting person-to-person spread without any avian or animal reservoir. Serological tests on patients admitted to hospital with community-acquired pneumonia suggest that 5- 10% may be the result of C. pneumoniae infection. Since this infection has only recently been recognized it may account for a substantial number of previous pneumonias in which no organism had been isolated. In general, disease is mild with 50% of C. pneumoniae infections presenting as pneumonia, 28% as acute bronchitis, 10% with a ‘flu-like illness and 12% with upper respiratory illnesses. Type-specific micro immunofluorescence tests are required to distinguish C. pneumoniae from C. psittaci and C. trachoma tis. Treatment is with erythromycin or tetracycline.

Staphylococcus aureus

Staph. aureus normally only causes a pneumonia after a preceding influenza! viral illness. The infection starts in the bronchi, leading to patchy areas of consolidation in one or more lobes, which break down to form abscesses. These may appear as cysts on the chest X-ray. Pneumothorax, effusion and empyemas are frequent. Septicaemia develops with metastatic abscesses in other organs. Fulminating staphylococcal pneumonia occurring in influenza epidemics can lead to death in hours. All patients with this type of pneumonia are very ill; intravenous antibiotics must be administered promptly, but are not always effective.
Areas of pneumonia (septic infarcts) are also seen in staphylococcal septicaemia. This is frequently seen in intravenous drug abusers and also in patients with central catheters being used for parenteral nutrition. The infected puncture site is the source of the Staphylococcus. Pulmonary symptoms are often few but breathlessness and cough occur and the chest X-ray reveals areas of consolidation. Abscess formation is frequent.

Diagnosis and treatment Coxiella bumetii (Q-fever)

The patient develops systemic symptoms of fever, malaise and headache, often associated with multiple lesions on the chest X-ray. The illness may run a chronic course and is occasionally associated with endocarditis. Diagnosis is made by an increase in the titre of complement-fixing antibody, and erythromycin or tetracycline is the usual treatment.

Legionella pneumophila

Three epidemiological patterns of this disease are recognized:
1 Outbreaks amongst previously fit individuals staying in hotels, institutions or hospitals where the shower facilities or cooling systems have been contaminated with the organism
2 Sporadic cases occurring in many parts of the world where the source of the infection is unknown 3 Outbreaks occurring in immunocompromised patients and in middle-aged and elderly male smokers Legionella grows well in water up to 40°C in temperature, and the infection is almost certainly spread by the aerosol route. Adequate chlorination and temperature control of the water supply are important factors in the prevention of the disease.
The incubation period is 2-10 days. Males are affected twice as commonly as females. The infection may be mild, but the characteristic picture is of malaise, myalgia, headache and a fever with rigors and a pyrexia of up to 40°C. Half of the patients have gastrointestinal symptoms, with nausea, vomiting, diarrhoea and abdominal pain. Patients may be acutely ill, with mental confusion and other neurological signs. Haematuria occurs and occasionally renal failure.
The patient is tachypnoeic with initially a dry cough that later may become productive and purulent. The chest X-ray usually shows unilateral lobar and then multilobar shadowing, sometimes with a small pleural effusion.

 Cavitation is rare.

A strong presumptive diagnosis of L. pneumophila infection is possible in the majority of patients if they have three of the four following features:
1 A prodromal virus-like illness
2 A dry cough, confusion or diarrhoea
3 Lymphopenia without marked leucocytosis
4 Hyponatraemia
Hypoalbuminaemia and abnormal levels of liver enzymes are common in this disease. The diagnosis is confirmed by a change in antibody titre, but the quickest way is by the direct immunofluorescent staining of the organism in the pleural fluid, sputum or bronchial washings. A Gram stain does not detect the organism. Culture is possible but takes up to 3 weeks.
The organism is sensitive to erythromycin, which is the antibiotic of choice. Rifampicin is also being used. Mortality can be up to 30% in elderly patients but most patients recover spontaneously.
Prevention is important with chlorination and sealing of water supplies.

Gram-negative bacteria

These are the cause of many hospital-acquired pneumonias but they are occasionally responsible for cases in the community.
Klebsiella pneumoniae. Pneumonia due to Klebsiella usually occurs in the elderly with a history of heart or lung disease, diabetes, alcohol excess or malignancy. The onset is often sudden, with severe systemic upset. The sputum is purulent, gelatinous or blood-stained. The upper lobes are more commonly affected and the consolidation
is often extensive. There is often swelling of the infected lobe so that on the lateral chest X-ray there is bulging of the fissures. The organism can be found in the sputum or in the blood. Treatment is dependent on the sensitivity of the organism, but a cephalosporin or chloramphenicol is usually required. The mortality is high, partly owing to the presence of an underlying condition. Pseudomonas aeruginosa. Pneumonia due to this organism is of considerable significance in patients with cystic fibrosis, since it correlates with a worsening clinical condition  and mortality. It is also seen in patients with neutropenia following cytotoxic chemotherapy. The isolation of P. aeruginosa must be interpreted with care because the organism grows well on bacterial culture medium and may simply represent contamination from the upper airways. Pseudomonal and other Gram-negative infections respond well to treatment with the 4-quinolone antibiotic ciprofloxacin (100-200 mg i.v. over 30-60 min twice  daily) or ceftazidime (2 g bolus i.v. 8-hourly). The combination of tobramycin 3-5 mg kg-l i.v. or i.m. daily in 8-hourly doses together with carbenicillin 5 g i.v. 4-6-hourly is now less commonly used. These antibiotics can however be inhaled direct into the lung via nebulizers and are still used in patients with CF.
Modifications may have to be made in the light of sensitivity testing. Tobramycin is nephrotoxic and also produces vestibular damage, so that blood levels should be monitored. Azlocillin and ticarcillin are also available. Moraxella catarrhalis. This organism, previously known as Branhamella catarrhalis, has been found to be associated with exacerbations of chronic bronchitis and occasionally with fatal pneumonia. Some strains produce a f3-lactamase capable of destroying amoxycillin. The exact role of this organism in bronchopulmonary infection remains to be determined.

Anaerobic bacteria

Infections with these organisms usually occur in those with an underlying condition, e.g. diabetes, and are often associated with aspiration. Bacteroides is the commonest organism and is sensitrve to metronidazole. The prognosis depends largely on the precipitating cause.

Diseases of the lung parenchyma

PNEUMONIAS

Pneumonia may be defined as an inflammation of the substance of the lungs. It is usually caused by bacteria. Clinically it presents as an acute illness characterized in the majority of cases by the presence of cough, purulent sputum and fever together with physical signs or radiological changes compatible with consolidation of the lung. The advent of antibiotics might have been expected to decrease dramatically the mortality from pneumonia. However, mortality statistics obtained from death certificates show the reverse. This is because the dramatic decrease in deaths from pneumonia in children under 10 years has been counterbalanced by an increase in deaths from pneumonia in individuals over the age of 70 years.

CLASSIFICATION

Pneumonia can be classified both anatomically and on the basis of the aetiology.

Site

Pneumonias are either localized, e.g. affecting the whole of one lobe, or diffuse, when they primarily affect the lobules of the lung, often in association with the bronchi and bronchioles, a condition referred to as ‘bronchopneumonia’.

The aetiology of pneumonia in the UK.

The aetiology of pneumonia in the UK.

Aetiology

An aetiological factor can be discovered in approximately 75% of patients. The term ‘atypical pneumonias’ was used to describe pneumonia caused by agents such as Mycoplasma, influenza A virus, Chlamydia and Coxiella burnetii. These types of pneumonia alone account for almost one-fifth of the cases of pneumonia and the term ‘atypical’ should be dropped. Pneumonias may also result from:
• Chemical causes, e.g. aspiration of vomit
• Radiotherapy
• Allergic mechanisms
Mycobacterium tuberculosis is an important cause of pneumonia; it is considered separately, since both its mode of presentation and its treatment are very different from the infective agents.

Precipitating factors

• Strep. pneumoniae-often follows influenza or parainfluenza viral infection
• Hospitalized ‘ill’ patients-often infected with Gramnegative organisms
• Cigarette smoking
• Alcohol excess
• Bronchiectasis (e.g. in cystic fibrosis)
• Bronchial obstruction (e.g. carcinoma) -occasionally associated with infection with ‘non-pathogenic’ organisms
• Immunosuppression (e.g. AIDS or treatment with cytotoxic agents) -organisms include P. carinii, Mycobacterium avium intracellulare, cytomegalovirus
• Intravenous drug abuse-frequently associated with Staph. aureus infection
• Inhalation from oesophageal obstruction -often associated with infection with anaerobes

CLINICAL PRESENTATION

The clinical presentation varies according to the immune state of the patient and the infecting agent. In the commonest type of pneumonia-caused by Strep. pneumoniae- there is often a preceding history of a viral infection. The patient rapidly becomes more ill with a high temperature (up to 39.5°C) , pleuritic pain and a dry cough. A day or two later, rusry-coloured sputum is produced and at about the same time the patient may develop labial herpes simplex. The patient breathes rapidly and shallowly, the affected side of the chest moves less, and signs of consolidation may be present together with a pleural rub.

Chest X-rays to show (a) lobar pneumonia and (b) diffuse pneumonia.

Chest X-rays to show (a) lobar pneumonia and (b)
diffuse pneumonia.

INVESTIGATION

Chest X-ray confirms the area of consolidation but radiological changes lag behind the clinical course so that X-ray changes may be minimal at the start of the illness. Conversely, consolidation may remain on the chest X-ray for several weeks after the patient is clinically cured. The chest X-ray should always return to normal by 6 weeks, except in patients with severe airflow limitation. Persistent changes on the chest X-ray after this time suggest a bronchial abnormality, usually a carcinoma, with persisting secondary pneumonia. Chest Xrays should rarely be repeated more frequently than at weekly intervals during the acute illness and then at 6 weeks after discharge from hospital. In Strep. pneumoniae pneumonia, there is often a white blood cell count that is greater than 15 x 109jlitre (90% polymorphonuclear leucocytosis) and an erythrocyte sedimentation rate (ESR) greater than 100 mm hour-I. The individual features of different pneumonias are given below. The overall investigation and management is shown and discussed.

MANAGEMENT

Asthma is an extremely common disease producing considerable morbidity. The aim of treatment must be:
• To abolish symptoms
• To restore normal or best possible long-term airway function
• To reduce the risk of severe attacks
• To enable normal growth to occur in children
• To minimize absence from school/work This involves:
• Patient and family participation
• Avoidance of identified causes where possible
• Use of lowest effective dose of convenient medications
minimizing short-term and long-term side-effects Many asthmatics belong to self-help groups whose aim is to further their understanding of the disease and to foster self-confidence and fitness.

Control of extrinsic factors

Measures must be taken to avoid causative allergens such as the house-dust mite, pets, moulds and foods (see allergic rhinitis), particularly in childhood. voidance of the house-dust mite is now possible with effective and comfortable covers for bedding and changes to living accommodation. Active and passive smoking should be avoided as should f3-blockers both in tablet and eyedrop form.
Individuals intolerant to aspirin may benefit, though are rarely cured, by avoiding salicylates. Other agents, e.g. preservatives and colouring materials such as tartrazine, should be avoided if shown to be a causative factor. Fifty per cent of individuals sensitized to occupational agents may be cured if they are kept permanently away from exposure. The remaining 50% continue to have symptoms as severe as when exposed to materials at work. This is particularly so if they had been symptomatic for a long time before the diagnosis was made.

This underlines two points:
The importance of the rapid identification of extrinsic causes of asthma and their removal wherever possible (e.g. the family pet) 2 Once extrinsic asthma is initiated, it may become self-perpetuating.

Drug treatment

The mainstay of asthma therapy is the use of therapeutic agents delivered as aerosols or powders directly into the lungs (Practical box 12.4). The advantages of this method of administration are obvious. Drugs are delivered direct to the lung and the first-pass metabolism in the liver is avoided; both these factors mean that much lower doses are necessary and unwanted effects are slight. Both national and international guidelines have been published on the step-wise treatment of asthma (Information box 12.1) based on three important factors:
1 Asthma self-management with regular asthma monitoring using mini peak flow meters and individual treatment plans discussed with each patient.
2 The appreciation that asthma is an inflammatory disease and that anti-inflammatory therapy should be started even in mild cases
3 A diminution in the role ofbronchodilators, e.g. salbutamol since they are not anti-inflammatory and regular treatment with these drugs on their own may be associated with worsening of asthma and even asthma deaths
f32-ADRENOCEPTOR AGONISTS. The newer bronchodilator preparations contain f3-adrenoceptor agonists that, unlike isoprenaline, are selective for the f32-adrenoceptors of the respiratory tract and do not stimulate the f31-adrenoceptors of the myocardium. These drugs are potent bronchodilators in that they cause relaxation of bronchial smooth muscle. Such treatment is very effective in relieving symptoms but does little for the underlying inflammatory nature of the disease. Inhalants such as salbutarnol (IOO p.g) or terbutaline (250 p.g) should be prescribed as two puffs as required.

Inhaled therapy.

Inhaled therapy.

Salmeterol (50-100 p.g), a highly selective and potent f32-adrenoceptor agonist, is effective by inhalation for up to 12 hours, reducing the need for administration to twice daily. Only the mildest asthmatics with intermittent attacks should rely upon this treatment alone. Some patients use nebulizers at home for self-administration of salbutamol or terbutaline. Such treatment is very effective owing to the high dose delivered, but patients must not rely on repeated home administration of nebulized f32- adrenoceptor agonists for worsening asthma, and must be encouraged to seek medical advice urgently if their condition does not improve. Tablets of f32-adrenoceptor agonists are less effective than when the drug is inhaled. To help those who cannot coordinate activation of the aerosol and inhalation, new devices that are breathactivated have been developed.

The step-wise management of asthma.

The step-wise management of asthma.

ANTICHOLINERGIC BRONCHODILATORS. Muscarinic receptors are found in the respiratory tract; large airways contain mainly M3 receptors whereas the peripheral lung tissue contains M3 and Ml receptors. Non-selective muscarinic antagonists such as atropine were used for relief of bronchoconstriction. Currently ipratropium bromide 20-40 p.g three or four times daily or oxitropium bromide (200 p.g twice daily) by aerosol inhalation are used and may be additive to f3radrenoceptor stimulants. ANTI-INFLAMMATORY DRUGS. The exact mode of action of sodium cromoglycate and nedocromil sodium remains unknown but this class of drugs appears to prevent activation of inflammatory cells, possibly by blocking a specific chloride channel which in turn prevents calcium influx. These drugs are particularly effective in patients with milder asthma. Sodium cromoglycate is taken regularly either in the form of a Spincap containing 20 mg or in aerosol form from a metered-dose inhaler delivering 5 mg per puff. The dose should be two puffs four times daily from an inhaler, or one Spincap three or four times daily. Nedocromil sodium is taken as an aerosol at a dose of 4 mg (2 puffs) two to four times daily.
INHALED CORTICOSTEROIDS. All patients who have regular persisting symptoms in spite of treatment with asrequired f32-adrenoceptor agonists, sodium cromoglycate ANTIBIOTICS. There is no evidence that antibiotics are helpful in the management of patients who suffer from properly diagnosed asthma. However, wheezing frequently occurs in exacerbations of chronic bronchitis and emphysema associated with infected sputum. Yellow or green sputum containing eosinophils and bronchial epithelial cells may be coughed up in acute exacerbations of asthma. This is not due to bacterial infection and antibiotics are not required. Management of severe asthma (Emergency box 12.2) Although this condition is often called ‘status asthmaticus’, it is better considered as severe asthma that has not been controlled by the patient’s use of medication. Patients with severe asthma have:
• Inability to complete a sentence in one breath.
• Tachycardia 2: 110 beats per minute.
• Pulsus paradoxus (>10 mmHg). In very severe asthma no paradoxus is detected.
• Wheezing. Chest may be silent in severe asthma owing to insufficient airflow.
PEFR should be measured in all patients presenting with severe asthma, and if below 30% predicted or approximately 150 litre min ” (in adults), the patient should be taken to hospital and started on 40-60% oxygen. Treatment is commenced with 5 mg of nebulized salbutamol or 10 mg terbutaline with oxygen as the driving gas. A chest X-ray is taken to exclude a pneumothorax. If no improvement occurs with nebulized therapy, 250 JoLg of salbutamol or terbutaline should be administered by i.v. infusion over 10 min. Intravenous aminophylline is now not used for severe asthma because of its narrow therapeutic index. Hydrocortisone 200 mg i.v. should be administered 4-hourly for 24 hours and 60 mg of prednisolone should be given orally daily. Patients who do not respond to this regimen may require ventilation.

Treatment of severe asthma.

Treatment of severe asthma.

Patients should be kept in hospital for at least 5 days, since the majority of sudden deaths occur 2-5 days after admission. Oral corticosteroids can be reduced from 60 mg to 30 mg once improvement occurs. Further reduction should be gradual on an outpatient basis until an appropriate maintenance dose or substitution by inhaled corticosteroid aerosols can be achieved.
If the PEFR is greater than 150 litre min-I, patients may improve dramatically on nebulized therapy and may not require hospital admission. Their regular treatment should be increased, probably to include treatment for 2 weeks with 30 mg of prednisolone followed by a gradual reduction in the oral dose and substitution by an inhaled corticosteroid preparation.

PROGNOSIS

Although asthma often improves in children as they reach their teens, it is now realized that the disease frequently returns in the second, third and fourth decades. Overall, in adults, there is a tendency for asthma to improve with age.

CLINICAL FEATURES

Patients suffering from asthma exhibit virtually identical symptoms to those suffering from airflow limitation caused by chronic bronchitis and emphysema. Wheezing attacks and episodic shortness of breath are almost universal. Symptoms are usually worst during the night. Cough is a frequent symptom that sometimes predominates and is often misdiagnosed as being due to bronchitis. Nocturnal cough can be a presenting feature. There is a tremendous variation in the frequency and duration of the attacks. Some patients may have only one or two attacks a year that last for a few hours, whilst others may have attacks lasting for weeks. Some patients can have chronic symptoms. Attacks may be precipitated by all the factors illustrated; the signs of asthma are listed.

Pathogenesis of asthma. ECP, eosinophil cationic

Pathogenesis of asthma. ECP, eosinophil cationic

INVESTIGATION

There is no single satisfactory diagnostic test for all asthmatic patients.

Lung function tests

The diagnosis of asthma is based on the demonstration of a greater than 15% improvement in FEYl or PEFR following the inhalation of a bronchodilator. However, this is often not present if the asthma is in remission or in very severe chronic disease, when little reversibility can be demonstrated.

Peak flow charts

Measurements of PEFR on waking, in the middle of the day, and before bed are particularly useful in demonstrating the variable airflow limitation that characterizes the disease. An example is shown. This technique is also of help in the longer-term assessment of the patient’s disease and its response to treatment. Peak flows need to be measured over several days and preferably over a weekend or short holiday if the effect of work exposure is also being studied.

Exercise tests

These have been widely used in the diagnosis of asthma in children. Ideally, the child should run for 6 min on a treadmill at a work-load sufficient to increase the heart rate above 160 beats per minute. A negative test does not rule out asthma.
Histamine or methacholine bronchial provocation tests
This test indicates the presence of airway hyperreactivity, a feature found in all asthmatics, and can be particularly useful in investigating those patients whose main symptom is cough. The test should not be performed on individuals who have poor lung function (FEV\ <1.5Iitres).

Trial of corticosteroids

Prednisolone 30 mg orally should be given daily for 2 weeks to all patients who present with severe airflow limitation. A substantial improvement (> 15%) confirms the presence of an asthmatic element and that the administration of steroids will prove beneficial to the patient. The dose is slowly reduced over several weeks and is replaced by inhaled corticosteroids in those who will benefit. Blood and sputum tests Patients with asthma may have an increase in the number of eosinophils in peripheral blood (>0.4 x 1Q9/litre). This is rarely helpful in the diagnosis. The presence of large numbers of eosinophils, particularly when present in clumps in sputum, is helpful in the differential diagnosis of asthma from chronic bronchitis and emphysema.

Chest X-ray

There are no diagnostic features of asthma on the chest X-ray. A chest X-ray may be helpful in excluding a pneumothorax, which can occur as a complication, or in detecting the pulmonary shadows associated with allergic bronchopulmonary aspergillosis.
Skin tests Skin-prick tests should be performed in all cases of asthma to help identify extrinsic causes. Experimentally, the inhalation of an allergen that gives rise to a large weal on skin testing will almost always produce an attack of asthma in patients with the disease, but whether this occurs in everyday life depends on the concentrations encountered in the atmosphere.

Allergen provocation tests

These are seldom, if ever, required in the clinical investigation of patients. An exception is the investigation of food allergy causing asthma. This diagnosis is difficult; blind oral challenges with the food disguised in opaque gelatine capsules are necessary to confirm or refute a causative link

PATHOGENESIS AND PRECIPITATING FACTORS

Occupational sensitizers

Over 200 materials encountered at the work-place are known to give rise to occupational asthma. The important causes are recognized occupational diseases in the UK and patients in insurable employment are therefore eligible for statutory compensation provided they apply within 10 years of leaving the occupation in which the asthma developed. The development of asthma following exposure to some of these materials is linked to the development of specific IgE antibody in serum in some cases, whilst in others the cause has yet to be determined.
The proportion of employees developing occupational asthma depends primarily upon the level of exposure. Proper enclosure of industrial processes or appropriate ventilation can greatly reduce the risk. Atopic individuals develop occupational asthma more rapidly when exposed to agents causing the development of specific IgE anti body. Non-atopic individuals can also develop asthma when exposed to such agents, but usually after a longer period.

Occupational asthma in the UK.

Occupational asthma in the UK.

Non-specific factors

The characteristic feature of bronchial hyperreactivity in asthmatics means that as well as reacting to specific antigens their airways will also respond to a wide variety of non-specific stimuli.
COLD AIR AND EXERCISE. Most asthmatics experience an attack of wheezing after prolonged and continuous exercise. Typically, the attack does not occur during the exercise period but at its conclusion. The inhalation of cold, dry air will also precipitate an attack. In both cases the wheezing is thought to be precipitated by the cooling and drying of the epithelial lining of the bronchi. Exercise and cold air provocation tests can be performed.
ATMOSPHERIC POLLUTION AND IRRITANT DUSTS, VAPOURS AND FUMES. Many patients with asthma experience worsening of symptoms on contact with cigarette smoke, car exhaust fumes, strong perfumes or high concentrations of dust in the atmosphere. Further minor epidemics of the disease have occurred during periods of heavy atmospheric pollution in industrial areas, caused by the presence of high concentrations of sulphur dioxide, ozone and nitrogen dioxide in the air.
EMOTION. It is well known that emotional factors may influence asthma, but there is no evidence that patients with the disease are any more psychologically disturbed than their non-asthmatic peers.
DR UGS. Non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, have an important role in the development and precipitation of attacks in approximately 5% of patients with asthma. This effect is almost universal in those individuals who have both nasal polyps and asthma. The precise mechanism involved is unknown but it is thought that treatment with these drugs leads to an imbalance in the metabolism of arachidonic acid. NSAIDs inhibit arachidonic acid metabolism via the cyclooxygenase pathway, preventing the synthesis of  rostaglandins. It is suggested that under these circumstances arachidonic acid is preferentially metabolized via the lipoxygenase pathway, resulting in the production of leukotrienes, previously known as the slow-reacting substances for anaphylaxis.
The airways of the lung have a direct parasympathetic innervation that tends to produce bronchoconstriction. There is no direct sympathetic innervation of the smooth muscle of the bronchi, and antagonism of parasympathetically induced bronchoconstriction is critically dependent  upon circulating adrenaline acting through t32-receptors on the surface of smooth muscle cells. Inhibition of this effect by t3-adrenoreceptor-blocking drugs such as propranolol leads to bronchoconstriction and airflow limitation, but only in asthmatic subjects. The so-called selective t3,-adrenoceptor-blocking drugs such as atenolol may still induce attacks of asthma; their use in asthmatic patients for hypertension or angina should be questioned and calcium antagonists such as nifedipine should be used if appropriate.

Arachidonic acid metabolism and the effect of drugs.

Arachidonic acid metabolism and the effect of
drugs.

Allergen-induced asthma

The experimental inhalation of allergen by atopic asthmatic individuals leads to the development of four types of reaction, as illustrated.
The commonest reaction is immediate asthma, in which airflow limitation begins within minutes of contact with the allergen, reaches its maximum in 15-20 min and subsides by 1 hour. Many asthmatics subsequently develop a more prolonged and sustained attack of airflow limitation that responds poorly to inhalation of bronchodilator drugs such as salbutamol-the late-phase reaction.
The combination of an immediate reaction followed by a late reaction is known as a dual asthmatic response. The inhalation of some materials, particularly occupational sensitizers such as the isocyanates, usually causes the development of an isolated late reaction with no preceding immediate response.
The development of the late-phase reaction is associated with an increase in the underlying level of airway hyperreactivity such that individuals may show continuing  episodes of asthma on subsequent days- recurrent asthmatic reactions.

The pathogenes is of asthma is complex and not fully understood. It involves a number of cells, mediators, nerves and vascular leakage that can be activated by several different mechanisms, of which exposure to allergens is the most important.
MAST CELLS (see p. 133). These are increased in both the epithelium and surface secretions of asthmatics and can generate and release powerful smooth muscle and vasoactive mediators, such as histamine, prostaglandin D2 (PG D2) and leukotriene C. (LTC.), which cause the immediate asthmatic reaction. Since potent J32-adrenoceptor agonists such as salbutamol have little effect on airway inflammation or hyperreactivity but inhibit mast cell mediator release, many other factors are now considered important in the pathogenesis of late and recurrent asthmatic reactions leading to more severe asthma.
EPITHELIUM. Epithelial cells are shed during exacerbations of asthma (they can readily be identified in sputum), causing increased permeability to inhaled allergens, exposure of afferent nerve endings, loss of the putative epithelial-derived relaxant factor, possibly nitric oxide, and neutral endopeptidase capable of breaking down sensory neuropeptides, and generation of chemoattractant factors such as 15-hydroxyeicosatetraenoic acid (l5-HETE). Epithelial cells can also produce cytokines, particularly granulocyte macrophage colony stimulating factor (GM-CSF), tumour necrosis factor-a (TNF-a) and interleukin 8 (IL-8), all capable of initiating and enhancing inflammation.

Different types of asthmatic

Different types of asthmatic

BASEMENT MEMBRANE. Recently biopsy studies have shown that the sub-basement membrane region, the lamina reticularis, is widened even in the mildest asthmatics owing to increased deposition of collagen types III and V and fibronectin, indicating that inflammation occurs at  the earliest stages of the disease.
NERVES. Damage or loss of epithelial cells exposes Cfibre afferent nerve endings that can release the sensory neuropeptides substance P, neurokinin A and calcitonin gene-related peptide, contributing towards bronchoconstriction, microvascular leakage and mucus secretion.
MACROPHAGES AND LYMPHOCYTES. These cells are abundant in the mucous membranes of the airways and the alveoli. Macrophages may play a particularly important role in the initial uptake and presentation of allergens to lymphocytes. They can release prostaglandins,  thromboxanes, leukotriene B. (LTB.) and platelet activating factor (PAF). T-helper lymphocytes (CD4) showevidence of activation and the release of their cytokines may play an important part in the migration and activation of mast cells (IL-3) and eosinophils (IL-S). In addition production of IL-4 leads to the switching of antibody production by B lymphocytes to IgE. The activity of both macrophages and lymphocytes is influenced by corticosteroids but not t32-adrenoceptor agonists.
EOSINOPHILS. These cells are found in large numbers in the bronchial secretions of asthmatics. When activated, they release LTC., PAF and basic proteins such as major basic protein (MBP) and eosinophil cationic protein (ECP) that are toxic to epithelial cells. Both the number and activation of eosinophils is rapidly decreased by corticosteroids.
MEDIATORS. The exact role of the many potent smooth muscle and vasoactive mediators, including LTC., LTD., thromboxanes and the sensory neuropeptides, as well as the chemoattractants LTB. and PAF, remains unknown and awaits the introduction of effective and specific antagonists. Studies with potent selective HI antagonists have shown that histamine plays only a small role in the pathogenesis of the persisting airflow limitation of asthma.

Asthma

Asthma is a common chronic inflammatory condition of the lung airways whose cause is incompletely understood. Symptoms are cough, wheeze, chest tightness and shortness of breath, often worse at night. It has three characteristics:
1 Airflow limitation which is usually reversible spontaneously or with treatment. In chronic asthma inflammation may lead to irreversible airflow limitation.
2 Airway hyperresponsiveness to a wide range of stimuli.
3 Inflammation of the bronchi with eosinophils, T lymphocytes and mast cells with associated plasma exudation, oedema, smooth muscle hypertrophy, mucus plugging and epithelial changes.
The underlying pathology in preschool children may be different in that they may not exhibit appreciable bronchial hyperreactivity. There is no evidence that chronic inflammation is the basis for the episodic asthma associated with viral infections.

PREVALENCE

In many countries, the prevalence of asthma is increasing, particularly in the second decade of life where this disease affects 10-15% of the population. There is also a geographical variation, with asthma being common in, for example, New Zealand, but being much rarer in Far Eastern countries such as China and Malaysia. Long-term follow- up in developing countries suggests that the disease may become more frequent as individuals become more ‘Westernized’. Studies of occupational asthma suggest that a high percentage of the work-force, perhaps up to 20%, may become asthmatic if exposed to potent sensitizers.

CLASSIFICATION

Asthma can be divided into:
• Extrinsic-implying a definite external cause
• Intrinsic or cryptogenic-when no causative agent can be identified
EXTRINSIC ASTHMA occurs in atopic individuals who show positive skin-prick reactions to common inhaled allergens. Positive skin tests to inhalant allergens are shown in 90% of children with asthma, whereas only 50% of adults show this phenomenon. Eczema is often seen in childhood.
INTRINSIC ASTHMA often starts in middle age. Nevertheless, many show positive skin tests and on close questioning give a history of respiratory symptoms compatible with childhood asthma.
This classification is of little value in clinical practice. Non-atopic individuals may develop asthma in middle age from extrinsic causes such as sensitization to occupational agents or aspirin intolerance, or because they were given J3-adrenoreceptor-blocking agents for concurrent  hypertension or angina. Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.

AETIOLOGY AND PATHOGENESIS

There are two major factors involved in the development of asthma and many other stimuli that can precipitate attacks.

Atopy and allergy

The term ‘atopy’ was used by clinicians at the beginning of the century to describe a group of disorders, including asthma and hay fever, that appeared:
• To run in families
• To have characteristic wealing skin reactions to common allergens in the environment
• To have circulating antibody in their serum that could be transferred to the skin of non-sensitized individuals The term is now best used to describe those individuals who readily develop antibodies of IgE class against common materials present in the environment. Such antibodies are present in 30-40% of the population, and there is a link between serum IgE levels and both the prevalence of asthma and airway responsiveness to histamine or methacholine. Genetic and environmental factors affect serum IgE levels. Whilst the precise location of the genes controlling IgE production remains to be determined, early childhood exposure to allergens and maternal smoking have an important influence on IgE production.  The allergens involved are similar to those in rhinitis, though the particle size of pollens (>20 /Lm) means that they are much more likely to cause conjunctivitis, rhinitis and pharyngitis than asthma. Allergens from the faecal particles of the house-dust mite are the most important extrinsic cause of asthma worldwide. The fungal spores from A. fumigatus give rise to a complex series of lung disease, including asthma.

Causes of asthma. RSV, respiratory syncytial virus.

Causes of asthma. RSV, respiratory syncytial virus.

Increased responsiveness of the airways of the lung (airway hyperreactivity)
Bronchial reactivity can be demonstrated by asking the patient to inhale gradually increasing concentrations either of histamine or methacholine (bronchial provocation tests). This induces a transient episode of airflow limitation in susceptible individuals (approximately 20% of the population); the dose of the agonist (provocation dose) necessary to produce a 20% fall in FEV, is known as the PD2oFEV,. Patients with clinical symptoms of asthma respond to very low doses of methacholine, i.e. they have a low PD20FEV, «11 /Lmol). In general, the greater the degree of hyperreactivity, the more persistent the symptoms and the greater the need for treatment. Some patients also react to methacholine but at higher doses and include those with:
• Attacks of asthma only on extreme exertion
• Wheezing or prolonged periods of coughing following a viral infection
• Cough variant asthma
• Problems with asthma only during the pollen season
• Allergic rhinitis, but not complaining of any lower respiratory symptoms until specifically questioned
• Some subjects with no respiratory symptoms Although the degree of hyperreactivity can itself be influenced by allergic mechanisms, its pathogenesis and mode of inheritance remain to be elucidated.

TREATMENT

Postural drainage

Postural drainage is of vital importance and patients must be trained by physiotherapists to tip themselves into appropriate positions at least three times daily for 10- 20 min. Most patients find that lying over the side of the bed with head and thorax down is the most effective position.

Antibiotics

Experience from the treatment of cystic fibrosis suggests that bronchopulmonary infections should be eradicated if progression of the disease is to be halted. In mild cases, intermittent chemotherapy with cefaclor 500 mg three times daily or ciprofloxacin 500 mg twice daily may be the only therapy needed. Flucloxacillin 500 mg 6-hourly is the best treatment if Staph. aureus is isolated.

hloramphenicol

is a useful drug in persistent infection. If the sputum remains yellow or green despite regular physiotherapy and intermittent chemotherapy, or if lung function deteriorates despite treatment with bronchodilators, it is likely that there is infection with Ps. aeruginosa. Treatment requires parenteral or aerosol chemotherapy at regular 3-monthly intervals. Ceftazidime 2 g intravenously 8-hourly or by inhalation (I g twice daily) has been shown to be effective. Ciprofloxacin 500 mg twice daily orally is equally effective. These drugs are replacing older drug regimens involving tobramycin or gentamicin together with tircarcillin or azlocillin. High sputum levels  of some antibiotics can be achieved by inhalation. A treatment regimen of carbenicillin 1 g and gentamicin 80 mg given by a compressor-driven nebulizer twice daily was found to be of benefit in young adult patients with chronic Pseudomonas infection but many physicians prefer intravenous therapy with ceftazidirne.
Bronchodilators Bronchodilators are useful in patients with demonstrable airflow limitation.

Surgery

Unfortunately, bronchiectasis is rarely sufficiently localized for surgery to be of any value.

COMPLICATIONS

The incidence of complications has fallen with antibiotic therapy. Pneumonia, pneumothorax, empyema and metastatic cerebral abscess can occur. Severe, life-threatening haemoptysis can also occur, particularly in patients with cystic fibrosis.
MASSIVE HAEMOPTYSIS ongmates from the high pressure systemic bronchial arteries and has a mortality of 25%. Other causes include pulmonary tuberculosis, aspergilloma, lung abscess and infection, and primary and secondary malignant tumours.
Bed rest and antibiotic treatment is essential together with blood transfusion if required. Urgent fibreoptic bronchoscopy is necessary to detect the source of bleeding. If the haemoptysis does not settle rapidly the affected area must be surgically resected. Bronchial artery embolization is the treatment of choice in those not fit for surgery.

Cystic fibrosis

Cystic fibrosis (CF) is due to an alteration in the viscosity and tenacity of mucus production at epithelial surfaces. The classical form of the syndrome includes bronchopulmonary infection and pancreatic insufficiency, with a high sweat sodium and chloride concentration. It is an autosomally recessive inherited disorder with a carrier frequency in Caucasians of 1 in 22. There is a gene mutation on the long arm of chromosome 7 (7q 21.3 -+ 7q 22.1). A specific deletion in the coding region (the codon for phenylalanine at position 508 in the amino acid sequence [dFsos]) has been found resulting in a defect in a transmembrane regulator protein  now called the cystic fibrosis transmembrane conductance regulator (CFTR) which probably represents a critical chloride channel. The mutation alters the secondary and tertiary structure of the protein leading to a failure of opening of the chloride channel in response to elevated cyclic AMP in epithelial cells. This results in a decreased excretion of chloride into the airway lumen and a threefold increase in the reabsorption of sodium into the epithelial cells. With less excretion of salt there is less excretion of water and increased viscosity and tenacity of airway secretions. A possible reason for the high salt content of sweat is that there is a CFTR-independent mechanism of chlo ride secretion in the sweat gland with an impaired reabsorption of sodium chlo ride in the distal end of the duct.
The frequency of dFsos mutation in CF is 70% in the USA and UK, <50% in southern Europe and 30% in Ashkenazic families. The identification of this transmembrane regulator protein will allow more accurate detection of carriers of the mutant gene.

CLINICAL FEATURES

Although the lungs of babies born with CF are structurally normal at birth, respiratory symptoms are usually the presenting feature. CF is now the commonest cause of recurrent bronchopulmonary infection in childhood, and is an important cause in early adult life. Finger clubbing is almost universal, haemoptysis is frequent and breathlessness occurs in the later stages as airflow limitation develops. Older children may also develop nasal polyps.
Puberty and skeletal maturity are delayed in most patients with the disease. Males are almost always infertile owing to failure of development of the vas deferens and epididymis. Females are able to conceive, but often develop secondary amenorrhoea as the disease progresses. About 85% of patients have symptomatic steatorrhoea owing to pancreatic dysfunction. Children may be born with meconium ileus due to the viscoid consistency of meconium in CF and later in life develop the meconium ileus equivalent (MIE) syndrome, an important cause of small intestinal obstruction unique to CF.
Cholesterol gallstones appear to occur with increased frequency and cirrhosis develops in about 5% of older patients.

Cystic fibrosis-abnormalities and recent therapeutic advances (see text).Cystic fibrosis-abnormalities and recent therapeutic advances (see text).

Cystic fibrosis-abnormalities and recent
therapeutic advances (see text).

DIAGNOSIS

The diagnosis of CF in older children and adults may be difficult. It depends on the clinical history together with:
• A family history of the disease.
• A high sweat sodium concentration over 60 mmol litre -]. (Meticulous technique by laboratories performing regular sweat analysis is essential, but the test is still difficult to interpret in adults.)
• Absent vas deferens and epididymis.
• Decreased immunoreactive trypsin.

TREATMENT

Antibiotic treatment for the respiratory disease is described under bronchiectasis on p. 665 and treatment of pancreatic insufficiency is described. The understanding of the basic abnormality in CF has led to dramatic changes in treatment-potential treatments to improve hydration of secretions include blocking of Na” reabsorption with amiloride or stimulating Cl- secretion with a triphosphate nucleotide (adenosine or uridine triphospates. ATP and UTP) which stimulate nucleotide receptors by a pathway independent of cAMP. Viscosity of secretions is contributed to by macromolecules such as DNA from dead inflammatory cells. Human DNase capable of degrading DNA has been cloned, sequenced and expressed by recombinant techniques. Inhalation of this material has been shown to improve FEV] by 20%. Similarly, inhaled or oral corticosteroids and antiproteases such as inhaled (X] -antitrypsin help to reduce inflammation and improve lung function. So far tested only in experimental animals is the delivery to the epithelium of the normal CFTR gene using as a vector a replication-deficient adenovirus containing normal human CFTR complementary DNA which is trophic for epithelial cells. Successful trials in CF patients would herald a new era of treatment.

Lung transplantation

Indications for this treatment are patients under 60 years with a life expectancy of less than 18 months, no underlying cancer and no serious systemic disease. The main diseases treated by transplantation are:
• Pulmonary fibrosis
• Primary pulmonary hypertension
• Cystic fibrosis
• Bronchiectasis
• Emphysema-particularly O’I-antitrypsin deficiency
• Eisenmenger’s syndrome
Since donor material is limited, single lung transplantation is preferred to double lung or heart-lung transplantation and can be successfully undertaken in pulmonary fibrosis, pulmonary hypertension and emphysema. Bilateral lung transplantation is required in infective conditions to prevent spill-over of bacteria from the diseased lung to a single lung transplant. Eisenmenger’s syndrome requires heart-lung transplant.

COMPLICATIONS AND TREATMENT

1 Early; post-transplant pulmonary oedema needs diuretics and respiratory support by ventilation
2 Infections, particularly within first 3 months:
(a) Bacterial pneumonia-antibiotics
(b) Cytomegalovirus – ganciclovir
(c) Herpes simplex-acyclovir
(d) P. carinii-prophylactic co-trimoxazole
3 Immunosuppression is with cyclosporin, azathioprine and prednisolone
4 Rejection:
(a) Early-first few weeks: high-dose i.v. corticosteroids
(b) Late-3 months: in obliterative bronchiolitis highdose i.v. corticosteroids are sometimes effective Prognosis is improving rapidly with 2-year survival of 75% and 5-year survival of almost 50%.

Chronic cough

Pathological coughing results from two mechanisms:
1 Stimulation of sensory nerves in the epithelium by secretions, foreign bodies, cigarette smoke and tumours
2 Sensitization of the cough reflex in which there is an abnormal increase in the sensitivity of the cough receptors demonstrable by inhalation of the tussive agents capsaicin or low chlo ride solutions Sensitization of the cough reflex presents clinically as a persistent tickling sensation in the throat with paroxysms of coughing induced by changes in air temperature, aerosol sprays, perfumes and cigarette smoke. It is found in association with viral infections, oesophageal reflux, postnasal drip, cough variant asthma, idiopathic cough, and in 15% of patients taking angiotensin converting enzyme (ACE) inhibitors. The association with the latter implicates neuroactive peptides-prostaglandins E2 and F2a and bradykinin. In the absence of chest X-ray abnormalities, investigations should include:
• ENT examination and sinus CT for postnasal drip
• Lung function tests and histamine bronchial provocation testing for cough variant asthma
• Ambulatory oesophageal pH monitoring for oesophageal reflux
• T .scan of thorax for interstitial lung disease
• VIQ scans for recurrent pulmonary embolism
• Fibreoptic bronchoscopy for inhaled foreign body or tumour
• ECG, echocardiography and exercise testing for cardiac causes
• Hyperventilation testing and psychiatric appraisal
Appropriate treatment for any of the conditions discovered can relieve symptoms. In the absence of any pathology management of cough is difficult. Morphine treatment will depress the sensitized cough reflex but its unwanted effects limit its use long term. Nebulized bupivocaine is of value. Demulcent preparations and cough sweets provide temporary relief only.

Nocturnal hypoxia

It has been shown that patients with chronic bronchitis and emphysema who show severe arterial hypoxaemia also suffer from profound nocturnal hypoxaemia with a Pa02 as low as 2.5 kPa (19 mmHg), particularly during the rapid eye movement (REM) phase of sleep. Because patients with chronic bronchitis and emphysema are already hypoxic, the fall in Pao, produces a much larger fall in oxygen saturation (owing to the steepness of the oxyhaemoglobin dissociation curve) and desaturation of up to 50% occurs. The mechanism is alveolar hypoventilation due to:
• Inhibition of intercostal and accessory muscles in REM sleep
• Shallow breathing in REM sleep, which reduces ventilation, particularly in severe chronic bronchitis and emphysema
• An increase in upper airway resistance due to a reduction in muscle tone
These nocturnal hypoxaemic episodes are associated with a further rise in pulmonary arterial pressure, and the  majority of deaths in patients with chronic bronchitis and emphysema occur during the night, possibly due to cardiac arrhythmias. These patients additionally show severe secondary polycythaemia, partly as a result of the severe nocturnal hypoxaemia.
Each episode of desaturation is usually terminated by arousal from sleep, so that normal sleep is reduced and the patient suffers from daytime sleepiness. Patients with arterial hypoxaemia should never be given sleeping tablets, which will further depress respiratory drive. Treatment is with nocturnal administration of oxygen and ventilatory support.

VENTILATORY SUPPORT. Positive pressure ventilation can be administered non-invasively through a tightly fitting nasal mask with bilevel positive airway pressureinspiratory to provide inspiratory assistance and expiratory to prevent alveolar closure, each adjusted independently. The use of these devices to maintain adequate ventilation during sleep and allow respiratory muscles to rest at night, though effective in chronic chest wall (e.g. kyphoscoliosis) or neuromuscular disease (e.g. previous poliomyelitis) has not led to improvement in respiratory function, respiratory muscle strength, exercise tolerance or breathlessness in patients with chronic bronchitis and emphysema.

Obstructive sleep apnoea

This condition occurs most often in overweight middleaged men and affects 1-2% of the population. It can occur in children particularly with enlarged tonsils. The major symptoms and their frequency are: • Loud snoring (95%)
• Daytime sleepiness (90%)
• Unrefreshed sleep (40%)
• Restless sleep (40%)
• Morning headache (30%)
• Nocturnal choking (30%)
• Reduced libido (20%)
• Morning drunkenness (5%)
• Ankle swelling (50/0)
Apnoeas occur when the airway at the back of the throat is sucked closed when breathing in during sleep. When awake this tendency is overcome by the action of opening muscles of the upper airway-the genioglossus and palatal muscles, which become hypotonic during sleep. Partial narrowing results in snoring, occlusion in apnoea and critical narrowing in hypopnoeas. Patients are woken by the struggle to breathe against the blocked throat. The awakenings are so brief that the patient remains unaware of them but is woken thousands of times per night leading to daytime sleepiness and impaired performance. Important contributory factors are obesity, a small pharyngeal opening and chronic airflow limitation.
Correctable factors occur in about one-third of cases and include:
• Encroachment on pharynx: obesity, acromegaly, enlarged tonsils
• Nasal obstruction: nasal deformities, rhinitis, polyps, adenoids
• Respiratory depressant drugs: alcohol, sedatives, strong analgesics
The diagnosis can usually be made by non-invasive ear or finger oximetry, best performed at home, accompanied by observation of the pattern of the snore-silence-snore cycle by the patient’s family. Arterial oxygen saturation falls significantly in a cyclical manner. However, falsenegative or equivocal results may occur in 50% necessitating full polysomnographic studies. These involve:
• Electroencephalography to record patterns of sleep and arousal
• Recording of thoracoabdominal movements to assess breathing
• Oronasal flow
• Oximetry
The diagnosis of sleep apnoea/hypopnoea is made if there are more than 15 apnoeas or hypopnoeas in any 1 hour of sleep. Management consists of correction of treatable factors (see above) with, if necessary, continuous nasal positive airway pressure delivered by a nasal mask during sleep. Such systems raise the pressure in the pharynx by about I kPa, keeping the walls apart.

Section through head,

Section through head,

Bronchiectasis

Bronchiectasis may be defined simply as dilatation of the bronchi.
Bronchial walls become inflamed, thickened and irreversibly damaged. The mucociliary transport mechanism is impaired and frequent bacterial infections ensue. Clinically, the disease is characterized by cough productive of large amounts of sputum.

AETIOLOGY

Bronchial obstruction followed by infection plays a major role. In the past bronchiectasis frequently followed pneumonia in childhood. Bronchiectasis is still a rare complication of whooping cough and measles in the Western world. Localized bronchiectasis also rarely results from tuberculous enlargement of lymph nodes at the hilum of the lung, particularly around the origin of the middle-lobe bronchus. Bronchial obstruction in children from other causes (e.g. inhaled peanuts) can give rise to gross suppurative lung disease and residual bronchiectasis. Progressive bronchiectasis has been described in nonsmoking patients of both sexes, with no other underlying cause. This syndrome is known as chronic bronchial sepsis.
Cystic fibrosis  also leads to bronchiectasis, as over 75% of children with cystic fibrosis now survive to adult life. Occasionally cystic fibrosis may present with bronchiectasis in adults. Bronchiectasis can also be associated with other congenital abnormalities, e.g. Kartagener’s syndrome, which is characterized by sinusitis and transposinon of viscera with bronchiectasis, associated with ‘imrnotile cilia’. Immunoglobulin deficiencies particularly 19A or IgG4 can lead to recurrent infections and bronchiectasis.

CLINICAL FEATURES

Patients with mild bronchiectasis only produce yellow or green sputum after an infection, often viral. Localized areas of the lung may be particularly affected, when sputum production will depend on position. As the condition worsens, the patient suffers from persistent halitosis, recurrent febrile episodes with malaise, and episodes of pneumonia. Clubbing occurs, and coarse crackles can be heard over the infected areas, usually the bases of the lungs. When the condition is severe there is continuous production of foul-smelling, thick, khaki-coloured sputum. Haemoptysis, either as blood-stained sputum or as a massive haemorrhage, can occur. Breathlessness may result from airflow limitation.

INVESTIGATION

THE CHEST X-RAY may be quite normal or may show dilated bronchi with thickened bronchial walls and sometimes multiple cysts containing fluid.
HIGH-RESOLUTION CT SCANNING can show bronchial wall thickening and is the investigation of choice.
BRONCHOGRAMS. This investigation is uncomfortable for the patient and is only required if the diagnosis is in doubt or where there is reason to believe that the disease may be localized and therefore amenable to surgical treatment. The left lower lobe and lingula are the commonest sites for localized disease.
SPUTUM EXAMINATION with culture and sensitivity of the organisms is essential for adequate treatment. The major pathogens are Staph. aureus, Pseudomonas aeruginosa, H. infIuenzae and anaerobes. Other pathogens include Strep. pneumoniae and Klebsiella pneumoniae.  Aspergillus fumigatus can be isolated from 10% of sputum specimens in cystic fibrosis, but the role of this organism is uncertain.

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CT scan showing bronchiectasis in the right middle lobe.

CT scan showing bronchiectasis in the right middle lobe.

COMPLICATIONS

Respiratory failure

The latter stages of chronic bronchitis and emphysema are characterized by the development of respiratory failure. For practical purposes this is said to occur when there is either a Pa02 of less than 8 kPa (60 mmHg) or a Pac02 of more than 7 kPa (55 mmHg).
The persistence of chronic alveolar hypoxia and hypercapnia leads to constriction of the pulmonary arterioles and subsequent pulmonary arterial hypertension.

Corpulmonale

Patients may develop cor pulmonale, which is defined as heart disease secondary to disease of the lung. It is characterized by pulmonary hypertension, right ventricular hypertrophy, and eventually right heart failure. On examination, the patient is centrally cyanosed (owing to the lung disease) and, when heart failure develops, breathlessness and ankle oedema occur. Initially a prominent parasternal heave may be felt due to right ‘ ventricular hypertrophy and a loud pulmonary second sound may be heard. In very severe pulmonary hypertension there is incompetence of the pulmonary valve. With right heart failure, tricuspid incompetence may develop with a greatly elevated jugular venous pressure OVp), ascites and upper abdominal discomfort due to swelling of the liver.

DIAGNOSIS

This is usually clinical. There is a history of breathlessness and sputum production in a lifetime smoker. It is unwise to make a diagnosis of chronic bronchitis and emphysema in the absence of cigarette smoking unless there is a family history of lung disease suggestive of a deficiency of ai-antitrypsin.
In clinical practice, emphysema is often incorrectly diagnosed on signs of overinflation of the lungs (e.g. loss of liver dullness on percussion), since this may occur with other diseases such as asthma. Furthermore, centri-acinar emphysema may be present without signs of overinflation. Some elderly men develop a barrel-shaped chest due to osteoporosis of the spine and a consequent decrease in height. This should not be attributed to emphysema.
In a number of patients the airflow limitation is reversible and the distinction between asthma and chronic bronchitis and emphysema can be difficult.

INVESTIGATION

LUNG FUNCTION TESTS show evidence of airflow limitation. The ratio of the FEVI to the FVC is reduced and the PEFR is low. Lung volumes may be normal or increased, and the gas transfer coefficient of carbon monoxide is low when significant emphysema is present
ON CHEST X-RAY the diagnosis of chronic bronchitis and emphysema is not always possible as the chest Xray can be normal, even when the disease is advanced. The classic features are the presence of bullae, severe overinflation of the lungs with low, flattened diaphragms, and a large retrosternal air space on the lateral film. There may also be a deficiency of blood vessels in the peripheral half of the lung fields compared with relatively easily visible proximal vessels.
THE HAEMOGLOBIN LEVELAND PCV maybe elevated.
BLOOD GASES are often normal. In the advanced case there is evidence of hypoxaemia and hypercapnia.
SPUTUM EXAMINATION is unnecessary in the ordinary case as Strep. pneumoniae or H. influenzae are the only common organisms to produce acute exacerbations. Occasionally Moraxella catarrhalis may be the causative bacterium.
ELECTROCARDIOGRAM. In cor pulmonale the P wave is taller (P pulmonale) and there may be right bundle branch block (RSR’ complex) and the changes of right ventricular hypertrophy.
ai-ANTITRYPSIN. Measurement of serum ai-antitrypsin levels (normal range 20-48 rnmol litre “).

TREATMENT

The single most important aspect in the management of chronic bronchitis and emphysema is to persuade the patient to stop smoking. Even at a late stage of the disease this may slow down the rate of deterioration and prolong the time before disability and death occur. Accompanying heart failure should be treated

Drug therapy

Drug therapy is used both for the short-term management of exacerbations and for the long-term relief of symptoms. In some cases the therapy is similar to that used in asthma

Influence of smoking

Influence of smoking

BRONCHODILATORS. Many patients feel less breathless following the inhalation of a f3-adrenoceptor agonist such as salbutamol (200 f.Lg4-6-hourly). More prolonged and greater bronchodilatation results from the use of the anticholinergic agents ipratropiurn bromide 40 f.Lgfour times daily or oxitropium bromide 200 f.Lgtwice daily. Objective evidence of improvement in the peak flow or FEVI may be small, but with severe disability it may be of considerable help. Long-acting preparations of theophylline are of little benefit.
CORTICOSTEROIDS. In symptomatic patients with chronic bronchitis and emphysema, a trial of corticosteroids is always indicated, since a proportion of patients have a large, unsuspected, reversible element to their disease and airway function may improve considerably. Prednisolone 30 mg daily should be given for 2 weeks, with measurements of lung function before and after the treatment period. If there is objective evidence of a substantial degree of improvement in airflow limitation (>15%), prednisolone should be gradually reduced and replaced by inhaled corticosteroids (beclomethasone 100- 500 f.Lgthree times daily). The long-term value of regular inhaled corticosteroids in all patients with chronic bronchitis and emphysema awaits evaluation.
ANTI BlOTI CS. Prompt antibiotic treatment shortens exacerbations and should always be given in acute episodes as they may prevent subsequent further lung damage. Patients can be given a supply of antibiotics to keep at home to start as soon as their sputum turns yellow or green. Arnoxycillin-resistant H. influenzae has become an increasing problem, occurring in 10-20% of isolates from sputum. Resistance to cefaclor 250 mg 8-hourly is significantly less frequent and it has become the antibiotic of choice.
Long-term treatment with antibiotics remains controversial. They were once thought to be of no value, but eradication of infection and keeping the lower respiratory tract free of bacteria may help to prevent deterioration in lung function.
DIURETIC THERAPY. This is necessary for all oedematose patients.
al-ANTITRYPSIN REPLACEMENT. Weekly or monthly infusions of a,-antitrypsin has been recommended for patients with levels of this compound below 11 mol litre-‘ (310 mg litre “) and abnormal lung function. Whether this modifies the long-term progression of the disease has still to be determined.

Algorithm for the treatment

Algorithm for the treatment

MUCOLYTICS AND VACCINES. There is little evidence that mucolytics are of any benefit, though it is vital that patients are encouraged to cough up sputum, initially with the help of a physiotherapist. Symptomatic treatment with steam inhalations may help to liquefy the sputum so that it can be more easily coughed up. Influenza vaccines should be given yearly to patients with disabling chronic bronchitis and emphysema.