Category Archives: Respiratory disease

Disorders of the diaphragm

Diaphragmatic fatigue

The diaphragm can become fatigued if the force of contraction during inspiration exceeds 40% of the force it can develop in a maximal static effort. When this occurs acutely in patients with exacerbations of chronic airflow limitation or CF or in quadriplegics, positive-pressure ventilation is required followed by attempts to increase the strength and endurance of the diaphragm by breathing against a resistance for 30 min a day.
UNILATERAL DIAPHRAGMATIC PARALYSIS is common and symptomless. The affected diaphragm is usually elevated and moves paradoxically on inspiration. A sniff causes the paralysed diaphragm to rise, the unaffected diaphragm to descend. Causes include:
• Surgery
• Carcinoma of the bronchus with involvement of the phrenic nerve
• Neurological, including poliomyelitis, herpes zoster
• Trauma to cervical spine, birth injury, subclavian vein puncture
• Infection: tuberculosis, syphilis, pneumonia
BILATERAL DIAPHRAGMATIC WEAKNESS or paralysis causes breathlessness in the supine position and is a cause of sleep apnoea leading to daytime headaches and somnolence. Tidal volume is decreased and respiratory rate increased. Vital capacity is substantially reduced when lying down, and sniffing causes a paradoxical inward movement of the abdominal wall best seen in the supine position. Causes include viral infections, multiple sclerosis, motor neurone disease, poliomyelitis, Guillain-Barre syndrome, quadriplegia after trauma and rare muscle diseases. Treatment is either diaphragmatic pacing or nighttime assisted ventilation.

Subdivisions of the mediastinum and mass lesions.

Subdivisions of the
mediastinum and mass lesions.

(T scan of a dermoid cyst in the mediastinum.

(T scan of a dermoid cyst in the mediastinum.

COMPLETE EVENTRATION OF THE DIAPHRAGM

invariably left-sided) is a congenital condition in which muscle is replaced by fibrous tissue. It presents as marked elevation of the left hemidiaphragm, sometimes associated with gastrointestinal symptoms. Partial eventration, usually on the right, causes a hump (often anteriorly) on the diaphragmatic shadow on X-ray.
HERNIAS occur through the diaphragm, the commonest being through the oesophageal hiatus, but occasionally anteriorly, through the foramen of Morgani, posterolaterally through the foramen of Bochdalek or at any site following  traumatic tears.

Mediastinal lesions

The mediastinum is defined as the region between the pleural sacs. It is additionally divided. Tumours affecting the mediastinum are rare. Masses are detected very accurately on CT scan.

Retrosternal or intrathoracic thyroid

The commonest mediastinal tumour is a retrostemal or intrathoracic thyroid, which is nearly always an extension of the thyroid present in the neck. Enlargement of the thyroid by a colloid goitre or malignant disease and, rarely, in thyrotoxicosis causes displacement of the trachea and oesophagus to the opposite side. Symptoms of compression develop insidiously before producing the cardinal feature of dyspnoea. Very occasionally an intrathoracic thyroid may be the cause of dysphagia and, rarely, of hoarseness of the voice and vocal cord paralysis from stretching of the recurrent laryngeal nerve. The treatment is surgical removal.

Thymic tumours

The thymus is large in childhood and occupies thesuperior and anterior mediastinum. It involutes with age  but may be enlarged both by cysts, which are rarely symptomatic, or turnours, which may cause the symptoms of myasthenia gravis or may lead to compression of the trachea or, rarely, the oesophagus. Surgery is the treatment of choice. Approximately half of the patients resenting with a thymic turnour have myasthenia gravis.

Pleuro-pericardial cysts

These cysts, which may be up to 10 ern in diameter, are filled with dear fluid and are usually situated anteriorly in the cardiophrenic angle on the right in 70% of cases. Infection only rarely occurs; malignant change does not occur. The diagnosis is usually made by needle aspiration. No treatment is required, but these patients should be followed up as an increase in cyst size suggests an alternative pathology; surgical excision is then advisable.

Further reading

Davies RJ & Oilier S (1989) Allergy: the Facts. Oxford: Oxford University Press.
Miller AC & Harvey JE (1993) Guidelines for the management of spontaneous pneumothorax. British Medical Journal 307, 114-116.
Weinberger SE (1993) Medical Progress: Recent advances in pulmonary medicine. New England Journal of Medicine328, 1389-1397 and 1462-1470.

Disorders of the chest wall and pleura

Trauma

Trauma to the thoracic wall can be due to penetrating wounds and can lead to pneumothoraces or haemothoraces.

RIB FRACTURES

Rib fractures can be caused by trauma or coughing (particularly in the elderly), and can occur in patients with osteoporosis. Pathological rib fractures may be due to metastatic spread from carcinoma of the bronchus, breast, kidney, prostate and thyroid. Ribs can also become involved by a mesothelioma. Fractures may not be readily visible on a PA chest X-ray, and lateral X-rays and oblique views may be necessary.
Pain may prevent adequate chest expansion and coughing and this can lead to pneumonia. Treatment is with adequate analgesia using oral agents or by local infiltration or an intercostal nerve block. More than one fracture in one rib can lead to a flail segment with paradoxical movement, i.e. part of the chest wall moves inwards during inspiration. This can produce inefficient ventilation and may require intermittent positive- pressure ventilation.

RUPTURE OF THE TRACHEA OR A MAJOR BRONCHUS

Rupture of the trachea or even a major bronchus can occur during deceleration injuries, leading to pneumothorax, surgical emphysema, pneumomediastinum and haemoptysis. Surgical emphysema is caused by air leaking into the subcutaneous connective tissue; this can also occur after the insertion of an intercostal drainage tube. A pneumomediastinum occurs when air leaks from the lung inside the parietal pleura and extends along the bronchial walls.

RUPTURE OF THE OESOPHAGUS

Rupture of the oesophagus from external injury, endoscopic procedures, bougienage or necrotic carcinoma may lead to the serious complication of mediastinitis. This requires vigorous antibacterial chemotherapy.

LUNG CONTUSION

This causes widespread fluffy shadows on the chest X-ray due to intrapulmonary haemorrhage. This may give rise to adult respiratory distress syndrome or shock lung.

Kyphoscoliosis

Kyphoscoliosis may be congenital, idiopathic, due to disease of the vertebrae such as tuberculosis or osteomalacia, or due to neuromuscular disease such as Friedreich’s ataxia or poliomyelitis. The respiratory effects of severe kyphoscoliosis are often more pronounced than might be expected and respiratory failure and death often occur in the fourth or fifth decade. The abnormality should be corrected at an early stage if possible. Bilevel positive airway pressure ventilation delivered through a tightly fitting nasal mask is the treatment of choice for respiratory failure.

Ankylosing spondylitis

Limitation of chest wall movement is often well compensated by diaphragmatic movement and the respiratory effects of this disease are relatively mild. It is associated with upper lobe fibrosis of unknown aetiology. Pectus excavatum and carinatum Pectus excavatum causes few problems other than embarrassment due to the deep vertical furrow in the chest, which can be corrected surgically. The heart is seen to lie  well to the left on the chest X-ray. Pectus carinatum (pigeon chest) is often the result of rickets. No treatment is required.

Dry pleurisy

‘Dry pleurisy’ is the term used to describe pleurisy when there is inflammation but no appreciable effusion. The localized inflammation produces sharp localized pain, made worse on deep inspiration, coughing and occasionally on twisting and bending movements. Common causes are pneumonia, pulmonary infarct and carcinoma. Rarer causes are rheumatoid arthritis and systemic lupus erythematosus.
EPIDEMIC MYALGIA (BORNHOLM DISEASE) is due to infection by Coxsackie B virus. This illness is common in young adults in the late summer and autumn and is characterized by an upper respiratory tract illness followed by pleuritic pain in the chest and upper abdomen with tender muscles. The chest X-ray remains normal and the illness clears within I week.

Pleural effusion

A pleural effusion is an excessive accumulation of fluid in the pleural space. It can be detected on X-ray when 300 ml or more of fluid is present and clinically when 500 ml or more is present. The chest X-ray appearances range from the obliteration of the costophrenic angle to dense homogeneous shadows occupying part or all of the hemithorax. Fluid below the lung (a subpulmonary effusion) can simulate a raised hemidiaphragm. Fluid in the fissures may resemble an intrapulmonary mass.

The physical signs

DIAGNOSIS

This is by pleural aspiration. The fluid that accumulates may be a transudate or an exudate. TRANSUDATES. Effusions that are transudates can be bilateral. The protein content is less than 30 g litre-I and the lactic dehydrogenase is less than 200 IU litre -I. Causes include:
• Heart failure
• Hypoproteinaemia (e.g. nephrotic syndrome)
• Constrictive pericarditis
• Hypothyroidism
• Ovarian tumours producing right-sided pleural
effusion – Meigs’ syndrome
EXUDATES. The protein content of exudates is greater than 30 g litre-I and the lactic dehydrogenase is greater than 200 IU litre-I. Causes include:

Untitled

Pleural biopsy may be necessary to diagnose the cause of the effusion. Treatment is of the underlying condition.

MALIGNANT PLEURAL EFFUSIONS

Malignant pleural effusions that reaccumulate and are symptomatic can be aspirated to dryness followed by the instillation of a sclerosing agent such as tetracycline or bleomycin. Effusions should be drained slowly since rapid shift of the mediastinum causes severe pain and occasionally shock. This treatment produces only temporary relief.

Chylothorax

This is due to the accumulation of lymph in the pleural space, usually resulting from leakage from the thoracic duct due to trauma or to infiltration by carcinoma.

Empyema

This is the presence of pus in the pleural space and can be a complication of pneumonia.

Pneumothorax

‘Pneumothorax’ means air in the pleural space. It may occur due to trauma to the chest or may be spontaneous. Pneumothorax may be localized if the visceral pleura has previously undergone adhesion to the parietal pleura, or generalized if the whole hemithorax contains air. Normally the pressure in the pleural space is negative but this is lost once a communication is made with atmospheric pressure; the elastic recoil pressure of the lung then causesit to partially deflate. If the communication between the airways and the pleural space remains (an open pneumothorax), a bronchopleural fistula is created. Once the communication between the lung and the pleural space is obliterated, air will be reabsorbed at a rate of 1.25% of the total radiographic volume of the hemithorax per day. Thus, a 50% collapse of the lung will take 40 days to reabsorb completely once the pneumothorax is closed. It has been postulated that a valvular mechanism may develop through which air can be sucked during inspiration but not expelled during expiration. The intrapleural pressure remains positive throughout breathing, the lung deflates further, the mediastinum shifts, and venous return to the heart decreases, with increasing respiratory and cardiac embarrassment. This tension pneumothorax is very rare unless the patient is on positive ventilation.

Spontaneous pneumothorax

This usually occurs in young males, the male-to-female ratio being 6 : 1. It is caused by the rupture of a pleural bleb, usually apical, and is thought to be due to congenital defects in the connective tissue of the alveolar walls. Both lungs are affected with equal frequency. Often these patients are tall and thin.
In patients over 40 years of age, the usual cause is underlying chronic bronchitis and emphysema. Rarer causes include bronchial asthma, carcinoma, a lung abscess breaking down and leading to bronchopleural fistula, and severe pulmonary fibrosis with cyst formation. The sudden onset of unilateral pleuritic pain or increasing breathlessness are the usual presenting features. If the pneumothorax enlarges, the patient becomes more breathless and may develop pallor and tachycardia.  here may be few physical signs if the pneumothorax is small. The characteristic features and management. The main aim is to get the patient back to active life as soon as possible.

Pneumothorax: an algorithm for management.

Pneumothorax: an algorithm for management.

Simple aspiration.

Simple aspiration.

Tumours of the respiratory tract

Bronchial carcinoma accounts for 95% of all primary tumours of the lung. Alveolar cell carcinoma accounts for 2% of lung tumours and other less malignant or benign tumours account for the remaining 3%.

BENIGN TUMOURS

Pulmonary hamartoma

This is the most common benign tumour of the lung and is usually seen as a very well-defined round lesion 1-2 em in diameter in the periphery of the lung. Growth is extremely slow, but the tumour may reach several centimetres in diameter. Rarely it arises from a major bronchus and causes obstruction.

Bronchial carcinoid

This rare tumour resembles intestinal carcinoid tumour and is locally invasive, eventually spreading to mediastinal lymph nodes and finally to distant organs. It is a highly vascular tumour that projects into the lumen of a major bronchus causing recurrent haemoptysis. It grows slowly and eventually blocks the bronchus, leading to lobar collapse. Rarely, it gives rise to the carcinoid syndrome.

Cylindroma, chondroma and lipoma

These are extremely rare tumours that may grow in the bronchus or trachea, causing obstruction.

TRACHEAL TUMOURS

Primary tumours of the trachea are very rare-the relative incidence compared to laryngeal and bronchial tumours is 1 : 75 and 1 : 180 respectively. The majority are malignant. Benign tumours are extremely rare but include squamous papilloma, leiomyoma, haemangiomas and tumours of neurogenic origin.

DIAGNOSIS AND TREATMENT

These tumours are diagnosed in the same way as bronchial carcinoma. Tracheal tumours cause severe and rapidly progressive dyspnoea and stridor. Flow-volume curves show typical and dramatic reductions in inspiratory flow (extrathoracic tracheal tumours).
Laser treatment provides rapid and effective destruction of tumour with temporary relief of symptoms. Radiotherapy is often given and occasionally surgery may be possible. The prognosis is very poor.

MALIGNANT TUMOURS

Bronchial carcinoma

This is the most common malignant tumoUl: in the Western World and is now the third most common cause of death in the UK after heart disease and pneumonia. Mortality rates worldwide are highest in Scotland, closely followed by England and Wales. In the UK, 35000 people die each year from bronchial carcinoma, with a male-tofemale ratio of 3.5 : 1. Although the rising mortality from this disease has levelled off in men, it continues to rise in women, accounting for 1 in 8 of all deaths from malignant disease in women, second only to carcinoma of the breast.
The strength of the association between cigarette smoking and bronchial carcinoma overshadows any other aetiological factors  but there is a higher incidence of bronchial carcinoma in urban compared with rural areas, even when allowance is made for cigarette smoking. Passive smoking (the inhalation of other people’s smoke by non-smokers) increases the risk of bronchial carcinoma by a factor of 1.5. Occupational factors include exposure to asbestos, and an association is also claimed for workers in contact with arsenic, chromium, iron oxide, petroleum products and oils, coal tar,
products of coal combustion, and radiation. Tumours associated with occupational factors are mostly adenocarcinomas and appear to be less related to cigarette smoking.

CElL TYPES

Bronchial carcinoma is divided into small-cell carcinoma and non-small-cell carcinoma, a division based on the characteristics of the disease and its response to treatment. Studies of mean doubling times of carcinomas indicate that development from the initial malignant change to presentation takes many years; for adenocarcinoma it takes approximately 15 years, for squamous carcinoma 8 years and for small-cell carcinoma 3 years.

Non-small-cell carcinoma

QUAMOUS OR EPIDERMOID CARCINOMA is the commonest carcinoma in this group, accounting for approximately 40% of all carcinomas. It occasionally cavitates, and widespread metastases occur relatively late.
LARGE-CELL CARCINOMA represents a less welldifferentiated tumour that metastasizes early. It accounts for 25% of all tumours.
ADENOCARCINOMA arises peripherally from mucous glands in the small bronchi and often produces a subpleural mass. Invasion of the pleura and the mediastinal lymph nodes is common, as are metastases to the brain and bones. Adenocarcinoma accounts for approximately 10% of all bronchial carcinomas and frequently arises in or around scar tissue. It is the commonest bronchial carcinoma associated with asbestos and is proportionally more common in non-smokers, in women, in the elderly, and in the Far East.
ALVEOLAR CELL CARCINOMA (BRONCHIOLAR CARCINOMA)accounts for only 1-2% of lung tumours and occurs either as a peripheral solitary nodule or as diffuse nodular lesions of multicentric origin. Occasionally this tumour is associated with expectoration of very large volumes of mucoid sputum.

Death rates from lung cancer (age standardized) per 100000 according to tobacco consumption in male British doctors.

Death rates from lung cancer (age standardized)
per 100000 according to tobacco consumption in male British doctors.

Small-cell carcinoma

This tumour, often called oat-cell carcinoma, accounts for 20-30% of all lung cancers. It arises from endocrine cells (Kulchitsky cells). These cells are members of the APUD system, which explains why many polypeptide hormones are secreted by these tumours. Some of these polypeptides act in an autocrine fashion, i.e. they feed back on the cells and cause cell growth. Small-cell carcinoma is now considered to be a systemic disease. Although the tumour is rapidly growing and highly malignant, it is the only one of the bronchial carcinomas that responds to chemotherapy.

CLINICAL FEATURES

The frequencies of the common symptoms of lung cancer on presentation. Chest pain and discomfort are often described as fullness and pressure in the chest. Sometimes the pain may be pleuritic owing to invasion of the pleura or ribs.
Commonly there are no abnormal physical signs. Enlarged supraclavicular lymph nodes are frequently found with small-cell carcinoma. There may be signs of a pleural effusion or of lobar collapse. Signs of an unresolved pneumonia or of associated underlying disease (e.g, diffuse pulmonary fibrosis in asbestosis) may be present.

Direct spread

The tumour may directly involve the pleura and ribs. Carcinoma in the apex of the lung can erode the ribs and involve the lower part of the brachial plexus (C8, Tl and T2), causing severe pain in the shoulder and down the inner surface of the arm (Pancoast’s tumour). The sympathetic ganglion may also be involved, producing Horner’s syndrome. Further extension may involve the recurrent laryngeal nerve as it passes down the aortic arch, causing unilateral vocal cord paresis with hoarseness and a bovine cough, and rarely the tumour may cause spinal cord compression.
Bronchial carcinoma can also directly invade the phrenic nerve, causing paralysis of the diaphragm. It can involve the oesophagus, producing progressive dysphagia, and the pericardium, producing pericardial effusion and  malignant dysrhythmias. It can also involve the superior vena cava, producing superior vena caval obstruction . leading to early morning headache, facial congestion and oedema involving the upper limbs; the jugular veins are distended, as are the veins on the chest that form a collateral circulation with veins arising from the abdomen.

The frequency of the common presenting symptoms of bronchial carcinoma.

The frequency of the common presenting
symptoms of bronchial carcinoma.

Metastatic complications

Bony metastases are common, giving rise to severe pain and pathological fractures. There is frequent involvement of the liver. Secondary deposits in the brain present as a change in personality, epilepsy or a focal neurological lesion. Carcinoma of the bronchus is a cause of secondary deposits in the adrenal gland.
Non-metastatic extrapulrnonary manifestations Although approximately 10% of small-cell tumours are thought to produce ectopic hormones at some stage, clinically important extra pulmonary manifestations are relatively rare apart from finger clubbing.  Hypertrophic pulmonary osteoarthropathy (HPOA) occurs in approximately 3% of all bronchial carcinomas, particularly squamous-cell carcinomas and adenocarcinomas. Symptoms include joint stiffness and severe pain in the wrists and ankles, sometimes associated with gynaecomastia. X-rays show the characteristic proliferative periostitis at the distal ends of long bones, which have an onion-skin appearance. HPOA is invariably associated with clubbing of the fingers. It may regress after resection of the lung tumour or as a result of vagotomy at thoracotomy.

INVESTIGATION

Chest X-ray

This is the most valuable screening test for bronchial carcinoma. It is a relatively insensitive test, however, since the tumour mass needs to be between 1 and 2 em in size to be recognized reliably. CT scanning can identify small tumour masses (see Fig. 12.12), but is at present too timeconsuming  and expensive to replace the chest X-ray. About 70% of all bronchial carcinomas arise centrally, the rest peripherally (particularly adenocarcinomas). At the time of clinical presentation the chest X-ray will demonstrate over 90% of carcinomas. A small proportion  arise within the main bronchus or trachea or else present with metastatic or non-metastatic complications but with no detectable mass on the chest X-ray.

Non-metastatic extrapulmonary

Non-metastatic extrapulmonary

Bronchial carcinoma can appear as round shadows on a chest X-ray (see p. 644). Characteristically the edge of the tumour has a fluffy or spiked appearance, though  sometimes it may be entirely smooth with cavitation, particularly when the tumour is epidermoid in type. Carcinoma  can also cause collapse of the lung.
Carcinoma causing partial obstruction of a bronchus interrupts the mucociliary escalator, and bacteria are retained within the affected lobe. This gives rise to the so-called secondary pneumonia that is commonly seen on  a chest X-ray of a patient presenting with bronchial carcinoma.
The hilar lymph nodes on the side of the tumour are frequently involved in carcinoma of the lung. A large pleural effusion may also be present. Carcinoma can spread through the lymphatic channels of the lung to give rise to lymphangitis carcinomatosa ; this is usually unilateral and associated with striking dyspnoea. The chest X-ray shows streaky shadowing throughout the lung. This appearance may be seen in both lungs, particularly when it is due to metastatic spread, usually from turn ours below the diaphragm (the stomach and colon) and from the breast Computed tomography CT is particularly useful for identifying pathological changes in the mediastinum (e.g. enlarged lymph nodes, local spread of the tumour) and for identifying secondary spread of carcinoma to the opposite lung by detecting masses too small to be seen on the chest X-ray. Lymph nodes larger than 1.5 cm are considered pathological, although whether they are due to metastatictumour, reactive hyperplasia or previous lung disease (e.g. tuberculosis) can only be determined by biopsy. A normal CT scan prior to surgery excludes the need for mediastinoscopy and node biopsy. CT scanning should be extended to include the liver, adrenal glands and the brain to identify distant metastases if present.

Magnetic resonance imaging

This may have some advantages over CT in mediastinal lesions when they are near to major vessels . Fibreoptic bronchoscopy. This technique is used to obtain cytological specimens from peripheral lesions as well as to obtain biopsy evidence of any tumours seen. If the carcinoma involves the first 2 cm of either main bronchus, the tumour is inoperable. Widening and loss of the sharp angle of the carina indicates the presence of enlarged mediastinal lymph nodes, either malignant or reactive. They can be biopsied by passage of a needle through the bronchial wall. Vocal cord paresis on the left indicates involvement of the recurrent laryngeal nerve and inoperability. Transthoracic fine-needle aspiration biopsy This involves the direct aspiration through the chest wall of peripheral lung lesions under appropriate X-ray or CT screening. Specimens can be obtained from 75% of peripheral lesions that could not be biopsied transbronchially.  Pneumothorax occurs in 25% of patients,
occasionally requiring drainage. Mild haemoptysis occurs in 5%. Implantation metastases do not occur.

TREATMENT

Unlike some other cancers, there has been no improvement in survival from carcinoma of the bronchus apart from small cell cancer (see below). Only 20% of patients are alive 1 year after diagnosis and only 6-8% after 5 years (cf. 50% for breast or cervix).
Surgery The only treatment of any value for non-small-cell cancer of the lung is surgery. Only 20% of all cases are suitable for resection and only 25-30% survive for 5 years. The mortality of thoracotomy in patients over 65 years with metastatic disease exceeds the expected 5-year survival rate and should therefore be avoided.
PREOPERATIVE ASSESSMENT. Radionuclide scanning for detection of metastatic disease in liver and bone is rarely positive in the absence of symptoms or abnormal enzyme tests (serum alkaline phosphatase) and is therefore unnecessary. A normal chest CT scan indicates no mediastinal spread of the tumour and favours curative resection.
Because of their common aetiology, chronic bronchitis and emphysema are frequently present. An FEV I of less than 1.5 litres is not compatible with an active life following pneumonectomy, although the surgery itself can be successfully accomplished. This also applies when the gastransfer test is reduced by 50%.

Radiation therapy for cure

High-dose radiotherapy (6500 rad; 65 Gy) can produce results that are as good as those of surgery in patients who are fit and who have slowly growing squamous carcinoma. It is the treatment of choice if the tumour is inoperable for reasons such as poor lung function. Radiation pneumonitis (defined as an acute infiltrate precisely confined to the radiation area and occurring within 3 months of radiotherapy) develops in 10-15%. Radiation fibrosis, a fibrotic change occurring within 1 year or so of radiotherapy and not precisely confined to the radiation area, occurs to some degree in all cases. These complications are usually of little importance. Symptomatic radiation treatment Bone pain, haemoptysis and the superior vena cava syndrome respond favourably to irradiation in the short term.

Chemotherapy

This is not effective for the treatment of non-small-cell cancer of the lung. In small-cell cancer, single or combination chemotherapy has resulted in a fivefold increase in median survival from 2 to 10 months. A small number of patients enjoy several years of remission. Good results  have been achieved with the combination of mitomycin, ifosfamide and cisplatin. The unwanted effects are greater than with single-agent chemotherapy with etoposide alone, which should be reserved for elderly patients and those with additional medical or physical disabilities.
Laser therapy, endobronchial irradiation and tracheobronchial stents This is used in the palliation of inoperable lung cancer. The techniques are complementary and considerable skill is required both in deciding which single or combination of therapies is required and in their execution. Tracheobronchial narrowing from intraluminal tumour or extrinsic compression causes disabling breathlessness, intractable cough and complications which may lead to death including infection, haemoptysis and respiratory failure. A neodymium-Yag (Nd-Yag) laser passed through a fibreoptic brochoscope can be used to vaporize inoperable fungating intraluminal carcinoma involving short segments of trachea or main bronchus. Benign tumours, strictures and vascular lesions can also be effectively treated with immediate relief of symptoms. Endobronchial irradiation (brachytherapy) is useful for the treatment of both intraluminal tumour and malignant extrinsic compression. A radioactive source is afterloaded into a catheter placed adjacent to the carcinoma under fibreoptic bronchoscope control. Radiation dose falls rapidly with distance from the source minimizing damage to adjacent normal tissue. Reduction in endoscopically assessed tumour size occurs in 70-95% of cases. Tracheobronchial stents made of silicone or as expandable metal springs are now available for insertion into strictures caused by tumour or from external compression or when there is weakening and collapse of the tracheobronchial wall.

Terminal care 

Patients dying of cancer of the lung need attention to their overall well-being. They must not be ignored simply because they cannot be cured. A lot can be done to make the patient’s remaining life symptom-free and as active as possible.
Daily treatment with prednisolone (up to 15 mg daily) may improve appetite. Morphine or diamorphine must be given regularly for pain, either in the form of a sustained- release morphine sulphate tablet twice daily or else as regular elixirs or injections. Many patients benefit from  a continuous subcutaneous injection of opiates given by a pump. Candidiasis and other infections in the mouth are common and must be looked for and treated. Patients taking opiates are frequently constipated, so regular laxatives should be prescribed. Short courses of palliative radiotherapy for bone pain, severe cough or haemoptysis are helpful.
Both the patient and the relatives require counselling, a task that should be shared between nurses, social workers, hospital chaplains and doctors.

SCREENING FOR LUNG CANCER

Screening programmes (yearly chest X-ray, 4-monthly sputum cytology) have been tried in high-risk groups but the success rate is minimal, underlining the need for prevention.
Secondary tumours Metastases in the lung are very common and usually present as round shadows 1.5-3 cm in diameter. They may
be detected on chest X-ray in patients already diagnosed as having carcinoma. The primary is usually in the
• Kidney
• Prostate
• Breast
• Bone
• Gastrointestinal tract
• Cervix or ovary
They nearly always develop in the parenchyma and are often relatively asymptomatic even when the chest X-ray shows extensive pulmonary metastases. It is rare for metastases to develop in the bronchi, when they may present with haemoptysis.
Carcinoma, particularly of the stomach, pancreas and breast, can involve mediastinal glands and spread along the lymphatics of both lungs (lymphangitis carcinornatosa), which can lead to progressive and severe breathlessness. On the chest X-ray, bilaterallymphadenopathy is seen together with streaky basal shadowing fanning out over both lung fields.
Occasionally a pulmonary metastasis may be detected as a solitary round shadow on chest X-ray in an asymptomatic patient. The commonest primary tumour to do this is a renal carcinoma. The differential diagnosis includes:
• Primary bronchial carcinoma
• Tuberculoma
• Benign tumour of the lung
• Hydatid cyst
Single pulmonary metastases can be removed surgically but, as CT scans usually show the presence of small metastases undetected on chest X-ray, surgery is seldom performed.

Lung cysts

These may be congenital, bronchogenic cysts or may result from a sequestrated pulmonary segment. Hydatid disease causes fluid-filled cysts. Thin-walled cysts are due to lung abscesses, which are particularly found in staphylococcal pneumonia, tuberculous cavities, septic pulmonary infarction, primary bronchogenic carcinoma, cavitating metastatic neoplasm, or paragonimiasis caused by the lung fluke Paragonimus westermani.

Occupational lung disease

Exposure to dusts, gases, vapours and fumes at work can lead to the development of the following types of lung disease:
• Acute bronchitis and even pulmonary oedema from irritants such as sulphur dioxide, chlorine, ammonia or the oxides of nitrogen
• Pulmonary fibrosis due to mineral dust
• Occupational asthma
• Extrinsic allergic bronchiolar alveolitis
• Bronchial carcinoma due to industrial agents (e.g. asbestos, polycyclic hydrocarbons, radon in mines)
The degree of fibrosis that follows inhalation of mineral dust varies. While iron (siderosis), barium (baritosis) and tin (stannosis) lead to dramatic dense nodular shadowing on the chest X-ray, their effect on lung function and symptoms is minimal. Exposure to silica or asbestos, on the other hand, leads to extensive fibrosis and disability. Coal dust has an intermediate fibrogenic effect and accounts for 90% of all compensated industrial lung diseases. Lung fibrosis from exposure to asbestos has become an increasing problem. The term pneumoconiosis means the accumulation of dust in the lungs and the reaction of the tissue to its presence. The term is not wide enough to encompass all occupational lung disease and is now generally used in relation to coal dust and its effects on the lung.

Coal-worker’s pneumoconiosis

Improved conditions and contraction of the coal industry have led to a considerable reduction in the number of cases of pneumoconiosis to about 2 per 1000 wage earners. The disease is caused by dust particles approximately 2-5 f.Lm in diameter that are retained in the small airways and alveoli of the lung. The incidence of the disease is related to total dust exposure, which is highest at the coal face, particularly if ventilation and dust suppression are poor. Two very different syndromes result from the inhalation of coal.

Simple pneumoconiosis

This simply reflects the deposition of coal dust in the lung. It produces a fine micro nodular shadow on the chest X-ray and is by far the commonest type of pneumoconiosis. It is graded on the chest X-ray appearance according to standard categories set by the International Labour Office (see below). Considerable dispute remains about the effects of simple pneumoconiosis on respiratory function and symptoms, many arguing that the development of the latter is largely due to chronic bronchitis and emphysema, commonly related to cigarette smoking. Categories of simple pneumoconiosis are as follows: 1 Small round opacities are definitely present but are few in number.
2 Small round opacities are numerous but normal lung markings are still visible.
3 Small round opacities are very numerous and normal lung markings are partly or totally obscured. The importance of simple pneumoconiosis is that it may lead to the development of progressive massive fibrosis (PM F) (see below). This virtually never occurs on a background of category 1 simple pneumoconiosis but occurs in 30% of those with category 3. Usually category 2 simple pneumoconiosis, which carries a 7% risk of developing PMF, must be present before benefit may be awarded for disability.

Progressive massive fibrosis

The lesions in this disease are round fibrotic masses several centimetres in diameter, almost invariably in the upper lobes and sometimes having necrotic central cavities. The pathogenesis of PMF is still not understood, though it seems clear that some fibrogenic promoting factor is present in individuals developing the disease. This was thought to be M. tuberculosis, but is now thought to be immune complexes, analogous to the development of large fibrotic nodules in coal miners with rheumatoid arthritis (Caplan’s syndrome). The development of both rheumatoid factor and antinuclear factor in the serum of patients with PMF is common, as it is in those suffering from asbestosis and silicosis. Pathologically there is apical destruction and disruption of the lung, resulting in emphysema and airway damage. Lung function tests show a mixed restrictive and obstructive ventilatory defect with loss of lung volume, irreversible airflow limitation and reduced gas transfer.
The patient with PMF suffers considerable effort dyspnoea, usually with a cough. The sputum can be black. The disease can progress (or even develop) after exposure to coal dust has ceased. Eventually respiratory failure may intervene.

Silicosis

This disease is uncommon though it may still be encountered in workers in foundries where sand used in moulds has to be removed from the metal casts (fettling), in sand blasting, and amongst stone-masons, pottery and ceramic workers.
Silicosis is caused by the inhalation of silica (silicon dioxide). This dust is highly fibrogenic. For example, a coal miner can remain healthy with 30 g of coal dust in his lungs but would be dead if he had inhaled 3 g of silica. Silica seems particularly toxic to alveolar macrophages and readily initiates the fibrogenic mechanism. The chest X-ray appearances and clinical features of the disease are similar to those of PMF. The chest Xray appearance is distinctive: thin streaks of calcification are seen around the hilar lymph nodes (‘eggshell’ calcification).

Asbestosis

Asbestos is a mixture of silicates of iron, magnesium, nickel, cadmium and aluminium, and has the unique property of occurring naturally as a fibre. It possesses remarkably resistant properties to heat, acid and alkali, hence its widespread use. Asbestos is mined in southern Africa, Canada and the former USSR. World production is 4 million tons, of which 90% is chrysotile, 6% crocidolite and 4% amosite in type.
Chrysotile or white asbestos is the softest asbestos fibre. Each fibre is often as long as 2 em but only a few micrometres thick. It is less fibrogenic than crocidolite. Crocidolite (blue asbestos) is particularly resistant to chemical destruction. It exists in straight fibres up to 50/-tm in length and 1-2/-tm in width. It is now known that this type of asbestos is by far the most important in the development of all types of asbestosis and particularly of mesothelioma. This may be due to the fact that it is readily trapped in the lung. Its long, thin shape means that it can be inhaled, but subsequent rotation against the long axis of the smaller airways, particularly in turbulent  airflow during expiration, causes the fibres to impact. Crocidolite is also particularly resistant to macrophage and neutrophil enzymic destruction. Exposure to asbestos occurred particularly in naval shipbuilding yards and in power stations but its ubiquitous use meant that light exposure was common. Up to 50% of urban dwellers had evidence of asbestos bodies (asbestos fibre covered in protein secretions) in their lungs at post mortem. New regulations in the UK prevent the use of crocidolite and severely restrict the use of chrysotile, and enforce careful dust control measures. These changes should eventually abolish the problem.
There is an important synergistic relationship between asbestosis and cigarette smoking and the development of bronchial carcinoma, usually adenocarcinoma; the risk is increased fivefold. There is also an increased risk in nonsmokers and it is also present in workers exposed to  asbestos who do not have clinically recognized asbestosis but who do have pleural plaques or thickening. Workers will continue to be exposed to blue asbestos in the course of demolition or in the replacement of insulation, and it should be remembered that there is a considerable time lag between exposure and development of the disease, particularly mesothelioma (20-40 years). The diseases caused by asbestos are summarized. Bilateral-diffuse pleural thickening, asbestosis, mesothelioma and asbestos-related carcinoma of the bronchus are all eligible for industrial injuries benefit in the UK, but account for only one-quarter of the number of cases of compensation compared to coal-worker’s pneumoconiosis. Asbestosis is the disease most frequently compensated (900 cases per year). This progressive disease is characterized by breathlessness and is accompanied by finger clubbing and bilateral basal endinspiratory crackles. Fibrosis not detectable on chest Xray may be revealed on CT scan. No treatment is known to alter the progress of the disease, though corticosteroids are often prescribed. The number of cases of mesothelioma presenting for compensation has increased fivefold in the last decade to over 400 cases per year. Often open lung biopsy is needed to obtain sufficient tissue for diagnosis. No treatment influences the universally fatal outcome. Although pleural effusions are the commonest presentation of mesothelioma, occasionally they may have a benign origin and may regress spontaneously.

Byssinosis

This disease occurs worldwide but is declining rapidly in areas where the numbers of people employed in cotton mills are falling. In the UK the disease is confined to areas of Lancashire and Northern Ireland. The symptoms start on the first day back at work after a break (Monday sickness) with improvement as the week progresses. Tightness in the chest, cough and breathlessness occur within the first hour in dusty areas of the mill, particularly in the blowing and carding rooms where raw cotton is cleaned and the fibres are straightened. The exact nature of the disease and its aetiology remain disputed. Two important features are that pure cotton does not cause the disease, and that cotton dust has some effect on airflow limitation in all those exposed. Individuals with asthma are particularly badly affected by exposure to cotton dust. The most likely aetiology is endotoxins from bacteria present in the raw cotton causing constriction of the airways of the lung. There are no changes on the chest X-ray and there is considerable dispute as to whether the progressive airflow limitation seen in some patients with the disease is due to the cotton dust or to other effects such as cigarette smoking or coexistent asthma.

The effects of asbestos on the lung.

The effects of asbestos on the lung.

Berylliosis

Beryllium-copper alloy has a high tensile strength and is resistant to metal fatigue, high temperature and corrosion. It is used in the aerospace industry, in atomic reactors and in many electrical devices. Although beryllium is inhaled into the lungs, it causes a systemic poisoning that gives rise to a clinical picture similar to sarcoidosis. The major chronic problem is that of progressive dyspnoea with pulmonary fibrosis. However, strict control of levels in the working atmosphere have made the disease a rarity.

INVESTIGATION

POLYMORPHONUCLEAR LEUCOCYTE COUNT is raised in acute cases.
PRECIPITATING ANTIBODIES are present in the serum. One-quarter of pigeon fanciers have precipitating antibody against pigeon protein and droppings in their serum but only a small proportion have lung disease. Precipitating antibodies are evidence of exposure, not disease.
LUNG FUNCTION TESTS show a restrictive ventilatory defect with a decrease in gas transfer.
BRONCHOALVEOLAR LAv AGE shows increased cells (lymphocytes and granulocytes).
DIFFERENTIAL DIAGNOSIS
Although an extrinsic allergic bronchiolar alveolitis due to inhalation of the spores of Micropolyspora faeni is common among farmers, it is probably more common for these individuals to suffer from asthma related to inhalation of antigens from a variety of mites that infest stored grain and other vegetable material. The common ones are Lepidoglyphus domesticus, L. destructor and Acarus siro. Symptoms of asthma resulting from inhalation of these allergens are often mistaken for farmer’s lung. Pigeon fancier’s lung is quite common, but alveolitis from budgerigars is very rare.

MANAGEMENT

Prevention is the aim. This can be achieved by change in work practice, with the use of silage for animal fodder and the drier storage of hay and grain. It is difficult to control pigeon fancier’s lung, since individuals remain addicted to their hobby.
Prednisolone, initially in large doses of 30-60 mg daily, is necessary to cause regression of the early stages of the disease. Established fibrosis will not resolve and in some patients the disease may progress inexorably to respiratory failure in spite of intensive therapy. Farmer’s lung is a recognized occupational disease in the UK and sufferers are entitled to compensation depending on their degree of disability.

Humidifier fever

Humidifier fever may present with the typical features of extrinsic allergic bronchiolar alveolitis without any radio graphic changes. This disease has occurred in outbreaks in factories in the UK, particularly in printing works. In North America it is more commonly found in office  locks with contaminated air-conditioning systems. The cause remains unknown but probably involves several bacteria or even amoebae. Humidifier fever can be prevented by sterilization of the recirculating water used in the very large humidifying plants in industry.

Drug-induced lung disease

Drugs may produce a wide variety of disorders of the respiratory tract. Pulmonary infiltrates with fibrosis may result from the use of a number of cytotoxic drugs used in the treatment of cancer. The commonest cause of these reactions is bleomycin. The pulmonary damage is doserelated, occurring when the total dosage is greater than 450 mg, but will regress in some cases if the drug is stopped. The most sensitive test is a decrease in gas transfer and therefore gas transfer should be measured repeatedly during treatment with the drug. The use of corticosteroids may help resolution.
Some of the most important drugs affecting the respiratory tract are shown in Table 12.12, together with the types of reaction they produce. The list is not exhaustive; for example, over 20 different drugs are known to produce a systemic lupus erythematosus-like syndrome, sometimes complicated by pulmonary infiltrates and fibrosis. Paraquat ingestion can cause severe pulmonary oedema and death, and fibrosis develops in many of those who survive.

RADIATION DAMAGE

Irradiation of the lung during radiotherapy can cause a radiation pneumonitis. Patients complain of breathlessness and a dry cough. Radiation pneumonia results in a restrictive lung defect. Corticosteroids should be given in the acute stage.

Drug-induced respiratory disease.

Drug-induced respiratory disease.

Simple and prolonged pulmonary eosinophilia

Simple pulmonary eosinophilia is a relatively mild illness with a slight fever and cough and usually lasting for less than 2 weeks. It is probably due to a transient allergic reaction in the alveolus. Many allergens have been implicated, including Ascaris lumbricoides, Ankylostoma braziliense and Trichuris trichiura as well as drugs such as paminosalicylic acid, aspirin, penicillin, nitrofurantoin and sulphonamides. Often, no allergen is identified. No treatment is required and the disease is self-limiting. Occasionally, however, the disease becomes more prolonged, with a high fever lasting for over a month. There is usually an eosinophilia in the blood and this condition is called prolonged pulmonary eosinophilia. Similar allergens are thought to be involved, with the addition of Strongyloides stercoralis. In both conditions the chest Xray shows either localized or diffuse opacities. Corticosteroid therapy is indicated, with resolution of the disease over the ensuing weeks.

Asthmatic bronchopulmonary eosinophilia

This is characterized by the presence of asthma, transient fleeting shadows on the chest X-ray, and blood or sputum eosinophilia. By far the commonest cause worldwide is allergy to A. fumigatus (see below), although Candida albicans may be an allergen in a small number of patients. In many, the appropriate allergen has still to be identified. Diseases caused by Aspergillus fumigatus. The various types of lung disease caused by A. fumigatus are illustrated.
The spores of A. fumigatus (5 J-Lm in diameter) are readily inhaled and are present in the atmosphere throughout the year, though they are at their highest concentration in the late autumn. They can be grown from the sputum in up to 15% of patients with chronic lung disease in whom they do not produce disease. They are an important cause of extrinsic asthma in atopic individuals.

Allergic bronchopulmonary aspergillosis

In allergic bronchopulmonary aspergillosis Aspergillus actually grows in the walls of the bronchi and eventually produces proximal bronchiectasis. There are episodes of eosinophilic pneumonia throughout the year, particularly in late autumn and winter. The episodes present with a wheeze, cough, fever and malaise. They are associated with expectoration of firm sputum plugs containing the fungal mycelium, which results in the clearing of the pulmonary infiltrates on the chest X-ray. Occasionally the large mucus plugs obliterate the bronchial lumen, causing collapse of the lung.
Repeated episodes of eosinophilic pneumonia left untreated can result in progressive pulmonary fibrosis that is often seen in the upper zones and can give rise to a similar chest X-ray appearance to that produced by tuberculosis.
The peripheral blood eosinophil count is usually raised, and total levels of IgE are extremely high (both that specific to Aspergillus and non-specific). Skin-prick testing with protein allergens from A. fumigatus gives rise to positive immediate skin tests. Sputum may show eosinophils and mycelia, and precipitating antibodies are usually found in the serum.
Lung function tests show a decrease in lung volumes and gas transfer in more chronic cases but in all cases evidence of reversible airflow limitation can be demonstrated. Treatment for this allergic pneumonia is with prednisolone 30 mg daily, which readily causes clearing of the pulmonary infiltrates. Frequent episodes of the disease can be prevented by long-term treatment with prednisolone, but doses as high as 10-15 mg daily are usually required. Moderately severe asthma itself requires continuous treatment with oral corticosteroids. Inhaled corticosteroids do not influence the occurrence of pulmonary infiltrates but are useful for the asthmatic element of the disease.

Diseasescaused by Aspergillus fumigatus

Diseasescaused by Aspergillus fumigatus

Aspergilloma and invasive aspergillosis

This is a totally separate disease from allergic bronchopulmonary aspergillosis. It simply represents the growth within previously damaged lung tissue of A. fumigatus, which forms a ball of mycelium within lung cavities. The typical appearance on the chest X-ray is of a round lesion with an air ‘halo’ above it. The continuing antigenic stimulation gives rise to large quantities of precipitating antibody in the serum. The aspergilloma itself causes little trouble, though occasionally massive haemoptysis may occur, requiring resection of the damaged area of lung containing the aspergilloma. Although treatment with antifungal agents, such as amphotericin (250 J.Lgkg” i.v.), has been tested in both allergic bronchopulmonary aspergillosis and aspergilloma, this has had little success, though it remains the only treatment for invasive aspergillosis, when it is often combined with flucytosine (200 mg kg” i.v. daily in four doses).

Tropical pulmonary eosinophilia

This condition presents with cough and wheeze together with fever, lassitude and weight loss. The typical appearance of the chest X-ray is of bilateral hazy mottling that is frequently uniformly distributed in both lung fields. The individual shadows may be as large as 5 mm or may become more confluent, giving the appearance of pneumonia. It is found in many tropical countries, but particularly in the Asian subcontinent, due to an allergic reaction to microfilaria, probably from Wuchereria hancrofti.
The disease is characterized by a very high eosinophil count in peripheral blood. The filarial complement fixation test is positive in almost every case. The treatment of choice is diethylcarbamazine at a dose of 5 mg kg:” body weight for 10-14 days; this usually produces a good response.

The hypereosinophilic syndrome

This disease is characterized by eosinophilic infiltration in various organs, sometimes associated with an eosinophilic arteritis. The heart muscle is particularly involved, but pulmonary involvement in the form of pleural effusion or interstitial lung disease occurs in about 40% of cases. Typical features are fever, weight loss, recurrent abdominal pain, persistent non-productive cough and congestive cardiac failure. Corticosteroid treatment may be of value
in some cases.

Polyarteritis nodosa

This is a rare disease characterized by foci of necrotizing arteritis that sooner or later affect many organs in the body. The lungs are rarely involved, except in the variant of polyarteritis nodosa known as the Churg-Strauss syndrome.
The upper respiratory tract may be involved, with nasal obstruction and rhinorrhoea. The chest X-ray may show consolidation that is ill-defined and transgresses anatomical boundaries. These shadows may disappear and reappear over periods of 2-12 weeks, and some may represent intra-alveolar haemorrhage or pulmonary infarcts. pANCA is usually negative in the serum. The overall 5- year survival for polyarteritis nodosa is 80% with corti costeroids and immunosuppressive therapy.
Microscopic polyarteritis involves the kidneys and the lungs, resulting in recurrent haemoptysis. pANCA is usually positive in the serum.

Allergic granulomatosis

The pathology of this condition is dominated by an eosinophilic infiltration and it occurs in patients usually in their fourth decade who have a previous history of rhinitis and asthma. It may simply represent an unusual progression of allergic disease in a subset of predisposed individuals. It is characterized by a high blood eosinophil count, vasculitis of small arteries and veins, and extravascular granulomas. The lungs, peripheral nerves and skin are most often affected and renal failure is much less common than in generalized polyarteritis nodosa. Transient patchy pneumonia-like shadows may occur as in polyarteritis nodosa, but sometimes these can be massive and bilateral. Skin lesions include tender subcutaneous nodules as well as petechial or purpuric lesions. The disease responds well to corticosteroids. pANCA can be positive.

GOODPASTURE’S SYNDROME AND IDIOPATHIC PULMONARY HAEMOSIDEROSIS

Goodpasture’s syndrome

The disease often starts with an upper respiratory tract infection followed by cough and intermittent haemoptysis, tiredness and eventually anaemia, though massive bleeding may occur. The chest X-ray shows transient blotchy shadows due to intrapulmonary haemorrhage. These features usually precede the development of an acute glomerulonephritis by several weeks or months. The course of the disease is variable; some spontaneously improve while others proceed to renal failure. The disease usually occurs in individuals over 16 years of age. It is thought to be due to a type II cytotoxic hypersensitivity reaction, the hypothesis being that there may be a shared antigen between a virus and the basement membrane of both kidney and lung. Anti-GBM antibodies are found in the serum and pANCA may be positive. An association with influenza A2 virus has been reported. Treatment is with corticosteroids, but plasmapheresis to remove the antibodies has led to dramatic improvement in some cases.

Idiopathic pulmonary

haemosiderosis

This is a similar disease to Goodpasture’s syndrome, but the kidneys are less frequently involved. Most cases occur in children under 7 years of age. Characteristically, haemosiderin-containing macrophages are found in the sputum. The child develops a chronic cough and anaemia and the chest X-ray shows diffuse shadows due to intrapulmonary bleeding, and eventually miliary nodulation. There is an association with a sensitivity to cows’ milk, and an appropriate diet is usually tried. The prognosis in general is poor and treatment with corticosteroids or azathioprine is usually given.

PULMONARY FIBROSIS AND HONEYCOMB LUNG

Pulmonary fibrosis is the end result of many diseases of the respiratory tract. It may be:
LOCALIZED, e.g. following unresolved pneumonia.
BILATERAL, e.g. in tuberculosis.
WIDESPREAD, e.g. in cryptogenic fibrosing alveolitis, due to drugs (busulphan, bleomycin and cyclophosphamide) or in industrial lung disease. Sometimes with widespread fibrosis a typical radiological appearance is seen that is known as honeycomb lung. This refers to the presence, often diffusely in both lungs, of cysts between 0.5 and 2 ern in diameter that are thickwalled and do not fill with opaque material on bronchography. The cystic air spaces probably represent dilated and thickened terminal and respiratory bronchioles.

The main causes of honeycomb lung.

The main causes of honeycomb lung.

Cryptogenic fibrosing alveolitis «(FA)

This relatively rare disorder of unknown aetiology causes diffuse fibrosis throughout the lung fields, usually in late middle age. The cardinal features are progressive breathlessness and cyanosis, which eventually lead to respiratory failure, pulmonary hypertension and cor pulmonale. Gross clubbing occurs in two-thirds of cases and bilateral fine end-inspiratory crackles are heard on auscultation. Rarely, an acute form known as the Hamman-Rich syndrome occurs. The chest X-ray appearance initially is of ground-glass appearance, progressing to obvious small nodular shadows with streaky fibrosis and finally a honeycomb lung.
A number of autoimmune diseases are seen in association with this, condition. For example, chronic active hepatitis occurs in 5-10% of cases. Similar lung changes are also seen in rheumatoid arthritis, systemic sclerosis and Sjogren’s syndrome, often associated with Raynaud’s phenomenon. CFA has also been reported in association with coeliac disease, ulcerative colitis and renal tubular acidosis.

PATHOGENESIS

Histologically there are two main features:
1 Cellular infiltration and thickening and fibrosis of the alveolar walls
2 Increased cells within the alveolar space (mainly shed type II pneumocytes and macrophages) The pathogenesis of damage and fibrosis is complex and several factors are involved.

INVESTIGATION

CT SCAN shows characteristic changes.
RESPIRATORY FUNCTION TESTS show a restrictive ventilatory defect-the lung volumes are reduced, the FEV I and FVC ratio is normal to high (with both values being reduced) and gas transfer is reduced. Peak flow rates may be normal.
BLOOD GASES show an arterial hypoxaemia with normal PaC02′
THE ESR is high.
BRONCHOALVEOLAR LAVAGE shows increased numbers of cells (particularly neutrophils).
ANTINUCLEAR FACTOR is positive in one-third of patients.
RHEUMATOID FACTOR is positive in 50% of patients.
IN YOUNGER PATIENTS histological confirmation may be necessary, requiring a transbronchiallung biopsy or even an open lung biopsy to obtain a larger specimen.

DIFFERENTIAL DIAGNOSIS

The diagnosis of CFA can be made in an elderly person presenting with the above signs and laboratory test results. In younger people the differential diagnosis includes extrinsic allergic alveolitis, bronchiectasis, chronic left heart failure, sarcoidosis, industrial lung disease and lymphangitis carcinoma to sa.

PROGNOSIS AND TREATMENT

The median survival time for patients with CFA is approximately 5 years although mortality is very high with the acute form. Treatment with prednisolone (30 mg daily) is usually prescribed for disabling disease, though its benefit has still to be proved by appropriate controlled trials. Azathioprine or cyclophosphamide may also be used. Supportive treatment includes oxygen therapy. Extrinsic allergic alveolitis In this disease there is a widespread diffuse inflammatory reaction in both the small airways of the lung and alveoli. It is due to the inhalation of a number of different antigens, as illustrated in Table 12.11. By far the commonest of these diseases worldwide is farmer’s lung, which affects up to 1 in 10 of the farming community in poor, wet areas around the world. In Western countries the incidence is almost certainly declining as more mechanized farming procedures are introduced.

PATHOGENESIS

Histologically there is an initial infiltration of the small airways and alveolar walls with neutrophils followed by lymphocytes and macrophages, leading to the development of non-caseating granulomas. These comprise multinucleated giant cells, occasionally containing the inhaled antigenic material. The major allergic response to the inhaled antigens is through cellular immunity, though there is evidence in some cases of an additional immediate hypersensitivity reaction involving specific IgE antibody and the deposition of immune complexes. All these mechanisms can attract and activate alveolar macrophages, so that continued antigenic exposure results in the development of pulmonary fibrosis.

Pathogenesis of pulmonary fibrosis.

Pathogenesis of pulmonary fibrosis.

CT scan showing cryptogenic fibrosing alveolitis.

CT scan showing cryptogenic fibrosing alveolitis.

CLINICAL FEATURES

The typical history is that of the onset of fever, malaise, cough and shortness of breath several hours after exposure to the causative antigen. For example, a farmer forking hay in the morning may only notice symptoms during the late afternoon and evening that resolve by the following morning. On examination the patient may have a fever, tachypnoea and coarse end-inspiratory crackles and wheezes throughout the chest. Cyanosis may be severe even at rest. Continuing exposure leads to a chronic illness characterized by severe weight loss, effort dyspnoea and cough, and the features of fibrosing alveolitis. The chest X-ray shows fluffy nodular shadowing with the subsequent development of streaky shadows, particularly in the upper zones, and, in very advanced cases, honeycomb lung.

Extrinsic allergic bronchiolar alveolitis

Extrinsic allergic bronchiolar alveolitis

Histiocytosis X

CLINICAL FEATURES

There are three variants of this disease, all characterized by the presence of granulomas consisting predominantly of characteristic histiocytes intermingled with eosinophilic and neutrophilic granulocytes, giant cells and lymphocytes. Electron microscopic studies have shown that the histiocytes contain granules characteristic of Langerhan cells. Fibrosis may occur early, with the development of multiple small cysts producing a honeycomb appearance.

Eosinophilic granuloma

This is the commonest variant in adults. It presents with increasing effort dyspnoea and cough. The chest X-ray shows diffuse bilateral mottling with translucencies with thick walls, and gas transfer is decreased. Recurrent pneumothorax occurs. The granulomas can also be found in bones.

Letterer-Siwe disease

This is usually a fatal disease of infancy that occurs under the age of 3 years. It is a widespread disease with skin lesions, lymphadenopathy, hepatosplenomegaly and bone lesions.

Hand-Schiiller-Christian disease

This usually begins under the age of 5 years. It is characterized by defects in bone, exophthalmos and diabetes insipidus. Pulmonary lesions show diffuse nodular shadows with hilar lymphadenopathy simulating sarcoidosis.

PROGNOSIS

Both Hand-Schuller-Christian disease and eosinophilic granuloma may recover spontaneously; survival for 20 years has been reported for both conditions.

TREATMENT

Treatment is with corticosteroids and cyclophosphamide, though there is no evidence as yet that this treatment substantially alters the outcome.

Wegener’s granulomatosis

This disease. of unknown aetiology is characterized by lesions involving the upper respiratory tract, the lungs and the kidneys. Often the disease starts with severe rhinorrhoea with subsequent nasal mucosal ulceration followed by cough, haemoptysis and pleuritic pain. Occasionally there may be involvement of the skin and nervous system. A chest X-ray usually shows single or multiple nodular masses or pneumonic infiltrates with cavitation. The most remarkable radiographic feature is the migratory pattern, with large lesions clearing in one area and new lesions appearing in another.
The typical histological changes are usually best seen in the kidneys, where there is a necrotizing glomerulonephritis. This disease responds well to treatment with cyclophosphamide 150-200 mg daily. A variant of Wegener’s granulomatosis called ‘mid-line granuloma’ particularly affects the nose and paranasal sinuses and is particularly mutilating; it has a poor prognosis. Anti-neutrophil cytoplasmic antibodies (ANCA) ANCA is found in the acute phase of vasculitides associated with neutrophil infiltration of the vessel wall and may be found in a wide range of diseases. cANCA is more specific for Wegener’s granulomatosis (greater than 90%) but only in the active stage. cANCA positivity is found in only one-third of inactive or treated cases. pANCA is closely associated with a number of vasculitic syndromes, Churg-Strauss syndrome and microscopic polyarteritis; 10-15% of cases of progressive glomerulonephritis with anti-glomerular basement membrane (GBM) antibodies are pANCA positive and these are the most likely to suffer pulmonary haemorrhage.

RESPIRATORY MANIFESTATIONS OF SYSTEMIC CONNECTIVE TISSUE DISEASE

Rheumatoid disease

The features of respiratory involvement in rheumatoid disease are illustrated.

Pleural adhesions, thickening and effusion are the commonest lesions. The effusion is often unilateral and tends to be chronic. It has a low glucose content but this can occur in any chronic pleural effusion. Rheumatoid diffuse fibrosing alveolitis can be considered as a variant of the cryptogenic form of the disease (see p. 694). The clinical features and gross appearance are the same but the disease is often more chronic. Rheumatoid nodules showing the typical histological appearances are rare in the lung. On the chest X-ray these appear as single or multiple nodules ranging in size from a few millimetres to a few centimetres. The nodules frequently cavitate. They usually produce no symptoms but can give rise to a pneumothorax or pleural effusion. Obliterative disease of the small bronchioles is rare. It is characterized by progressive breathlessness and irreversible airflow limitation. Corticosteroids may prevent progression.
Involvement of the cricoarytenoid joints gives rise to dyspnoea, stridor, hoarseness and occasionally severe obstruction necessitating tracheostomy. Caplan’s syndrome is due to a combination of dust inhalation and the disturbed immunity of rheumatoid arthritis. It occurs particularly in coal-worker’s pneumoconiosis but it can occur in individuals exposed to other dusts, such as silica and asbestos. Typically the lesions appear as rounded nodules 0.5-5 cm in diameter, though sometimes they become incorporated into large areas of fibrosis that are indistinguishable radiologically from progressive massive fibrsis. There may be little evidence of simple pneumoconiosis prior to the development of the nodule.
These lesions may precede the development of the arthritis. Rheumatoid factor is always present in the serum.

The respiratory manifestations of rheumatoid disease

The respiratory manifestations of rheumatoid
disease

Systemic lupus erythematosus

The commonest respiratory manifestation of this disease, occurring in up to two-thirds of cases, is the development of pleurisy, with or without an effusion. Effusions are usually small and bilateral. Basal pneumonitis is often present, perhaps as a result of poor movement of the diaphragm, or restriction of chest movements due to pleural pain. Pneumonia also occurs, either due to infection or to the disease process itself. Unlike rheumatoid arthritis, diffuse pulmonary fibrosis is rare.

Systemic sclerosis

Autopsy studies have indicated that there is almost always some evidence of diffuse fibrosis of alveolar walls and obliteration of capillaries and the alveolar space. Severe changes result in nodular then streaky shadowing on the chest X-ray, followed by cystic changes, ending up with a honeycomb lung. Function tests indicate a restrictive lesion and poor gas transfer.
Pneumonia may occur due to inhalation from the dilated oesophagus. Breathlessness may be worsened by restriction of chest wall movement due to thickening and contraction of the skin and trunk.

PULMONARY INFILTRATION WITH EOSINOPHILIA {PIE}

The common types and characteristics of these diseases are shown in Table 12.9. They range from very mild, simple, pulmonary eosinophilias to the often fatal polyarteritis nodosa.

Common types and characteristics

Common types and characteristics

Other mycobacteria

M. kansasii occurs in water and milk, though not in soil.
Disease caused by this mycobacterium has mainly been described in Europe and the USA. It rarely causes a relatively benign type of human pulmonary disease, usually in middle-aged males. Men working in dusty jobs (e.g. miners) apear to be especially at risk, as are those who have underlying chronic bronchitis and emphysema. M.avium intracellulare is an important cause of pulmonary infection in AIDS patients

GRANULOMATOUS LUNG DISEASE

A granuloma is a mass or nodule composed of chronically inflamed tissue formed by the response of the mononuclear phagocyte system (macrophage/histiocyte) to a slowly soluble antigen or irritant. If the foreign substance is inert (e.g. an inhaled dust), the phagocytes turn over slowly; if the substance is toxic or reproducing, the cells turn over raster, producing a granuloma. A granuloma is characterized by epithelioid multinucleate giant cells, as seen in tuberculosis. Granulomas may be caused by:
• Tuberculosis
• Fungal and helminthic infections
• Hypersensitivity reactions
• Neoplasms
They are also found in disorders with no known cause, such as sarcoidosis.

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disorder, commonly affecting young adults and usually presenting with bilateral hilar lymphadenopathy, pulmonary infiltration and skin or eye lesions. The diagnosis is confirmed on the histological evidence of widespread, non-caseating, epithelioid granulomas in more than one organ. Poisoning with beryllium can rarely produce a clinical and histological picture identical to sarcoidosis, though contact with this element is now strictly controlled.

EPIDEMIOLOGY AND AETIOLOGY

Sarcoidosis is a common disease that is often detected by mass X-ray studies. There is great geographical variation. The prevalence in the UK is approximately 19 in 100000 of the population. It is common in the USA but is uncommon in Japan. The course of the disease is much more severe in American Blacks than in Whites. There is no relation with any histocompatibility antigen, but cases of sarcoidosis are seen within families, possibly suggesting an environmental factor. Other aetiological factors suggested are an atypical mycobacterium or fungus, the Epstein-Barr virus and occupational, genetic, social or other environmental factors (a higher incidence occurs in rural rather than in urban populations); none have been substantiated.

IMMUNOPATHOLOGY

TYPICAL SARCOID GRANULOMAS consist of focal accumulations of epithelioid cells, macrophages and lymphocytes, mainly T cells.
DEPRESSED CELL-MEDIATED REACTIVITY to tuberculin and other antigens such as Candida albicans is present.
OVERALL LYMPHOPENIA-circulating T lymphocytes are low but B cells are slightly increased.
BRONCHOALVEOLAR LAVAGE shows a great increase in the number of cells; lymphocytes (particularly CD4 helper cells) are greatly increased.
ALVEOLAR MACROPHAGEs-the number is increased but they represent a reduced percentage of the total number of cells.
TRANSBRONCHIAL BIOPSIES show infiltration of the alveolar walls and interstitial spaces with mononuclear cells, mainly T cells, prior to granuloma formation. It seems likely that the decrease in circulating T lymphocytes and changes in delayed hypersensitivity responses are the result of sequestration of lymphocytes within the lung. There is no evidence to suggest that patients with sarcoidosis suffer from an overall defect in cellular immunity, since the frequency of fungal, viral and bacterial infections is not increased and there is no substantiated evidence of a greater risk of developing malignant neoplasms.

CLINICAL FEATURES

The peak incidence is in the third and fourth decades, with a female preponderance. Sarcoidosis can affect many different organs of the body. The commonest presentation is with respiratory symptoms or abnormalities found on chest X-rays (50%). Fatigue or weight loss occurs in 5%, peripheral lymphadenopathy in 5% and a fever in 4%. A chest X-ray may be negative in up to 20% of non-respiratory cases, though lesions may be detected later.
BILATERAL HILAR LYMPHADENOPATHY is a characteristic feature of sarcoidosis. It is often symptomless and simply detected on a routine chest X-ray. Occasionally, the bilateral hilar lymphadenopathy is associated with a dull ache in the chest, malaise and a mild fever. Although the chest X-ray may not show any evidence of infiltration in the lung fields, evidence from CT scanning, transbronchial biopsies and bronchoalveolar lavage indicate that the lung parenchyma is nearly always involved.

CT scan in sarcoidosis.

CT scan in sarcoidosis.

The differential diagnosis of the bilateral hilar lymphadenopathy
includes:
LYMPHOMA-though it is rare for this only to affect the hilar lymph nodes.
PULMONARY TUBERCULOSIS-though it is rare for the hilar lymph nodes to be symmetrically enlarged.
CARCINOMA OF THE BRONCHUS with malignant spread to the contralateral hilar lymph nodes-again it is rare for this to give rise to a typical symmetrical picture.
In the early stages it may be difficult to distinguish enlarged lymph nodes on the chest X-ray from the pulmonary arteries, and lymph node enlargement is not always symmetrical. It is for these reasons that, in the absence of additional erythema nodosum, histological confirmation of the disease process is advisable.

Pulmonary infiltration

This type of sarcoidosis may be progressive and may lead to increasing effort dyspnoea and eventually cor pulmonale and death. The chest X-ray shows a mottling in the mid-zones proceeding to generalized fine nodular shadows. Eventually, widespread pulmonary line shadows develop, reflecting the underlying fibrosis. A honeycomb appearance can occasionally occur. Pulmonary function tests show a typical restrictive lung defect. It is possible to have a normal chest X-ray with abnormal lung function tests; conversely, lung infiltration may be present on the X-ray with lung function tests in the normal range.

Extrapulmonary manifestations

Skin and ocular sarcoidosis are the commonest extrapulmonary presentations.
SKIN SARCOIDOSIS. This is seen in 10% of cases; apart from erythema nodosum, a chilblain-like lesion known as lupus pernio is seen, as are nodules. Sarcoidosis is the commonest cause of erythema nodosum. The association of bilateral symmetrical hilar lymphadenopathy with erythema nodosum only occurs in sarcoidosis.
ANTERIOR UVEITIS. This is common and may present with misting of vision, pain and a red eye, but posterior uveitis may simply present as progressive loss of vision. Although ocular sarcoidosis accounts for about 5% of uveitis presenting to ophthalmologists, evidence of asymptomatic uveitis may be found in up to 25% of patients with sarcoidosis. Conjunctivitis may occur and retinal lesions have been recognized recently. Keratoconjunctivitis sicca and lacrimal gland enlargement may also occur. Uveoparotid fever is a syndrome of bilateral uveitis and parotid gland enlargement together with occasional development of facial nerve palsy and is sometimes seen with sarcoidosis.
METABOLIC MANIFESTATIONS. It is rare for sarcoidosis to present with problems of calcium metabolism, though hypercalcaemia is found in 10% of established cases. Hypercalcaemia and hypercalciuria can lead to the development of renal calculi and nephrocalcinosis. The cause of the hypercalcaemia has been shown to be high circulating 1,25-dihydroxy vitamin D3, with the l ohydroxylation occurring in sarcoid macrophages in the lung in addition to that taking place in the kidney.
THE CENTRAL NERVOUS SYSTEM. Involvement of the CNS is rare (2%) but can lead to severe neurological disease.
BONE AND JOINT INVOLVEMENT. Arthralgia without erythema nodosum is seen in 5% of cases. Bone cysts are found, particularly in the digits, with associated swelling. In the absence of swelling, routine X-rays of the hands are unnecessary.
HEPATOSPLENOMEGALY. Sarcoidosis is a cause of hepatosplenomegaly, though it is rarely of any clinical consequence.
CARDIAC INVOLVEMENT. Cardiac involvement is rare (3%). Ventricular dysrhythmias, conduction defects and cardiomyopathy with congestive cardiac failure may be seen.

INVESTIGATION

CHEST X-RAY

FULL BLOOD COUNT. Mild normochromic, normocytic anaemia with raised ESR.
SERUM BIOCHEMISTRy-raised serum calcium and hypergammaglobulinaemia.
TRANSBRONCHIAL BIOPSY is the most useful investigation. Positive results are seen in 90% of cases of pulmonary
sarcoidosis with or without X-ray evidence of lung involvement. The test provides positive histological evidence of a granuloma in approximately one-half of patients with clinically extrapulmonary sarcoidosis in whom the chest X-ray is normal.
THE KVEIM TEST, which involved an intradermal injection of sarcoid tissue, was regularly used for confirmation of the diagnosis. It should not now be used because of the risk of transmission of infection. It is less sensitive and less specific than transbronchial biopsy which has superseded it.
TUBERCULIN TEST is negative in 80% of patients with sarcoidosis; it is of no diagnostic value.
SERUM LEVEL OF ACE is two standard deviations above the normal mean value in over 75% of patients with untreated sarcoid. Raised (but lower) levels are also seen in patients with lymphoma, pulmonary tuberculosis, asbestosis and silicosis, rendering the test of no diagnostic value. However, it is a simple test and is of use in assessing the activity of the disease and therefore as a guide to treatment with corticosteroids. Reduction of serum ACE during treatment with corticosteroids has not, however, yet been proved to reflect resolution of th e disease.
LUNG FUNCTION TESTS show a restrictive lung defect with pulmonary infiltration. There is a decrease in TLC, a decrease in both FEV! and FVC and a decrease in gas transfer.

TREATMENT

Both the need to treat and the value of corticosteroid therapy are contested in many aspects of this disease. Hilar lymphadenopathy on its own with no evidence of chest X-ray involvement of the lungs or decrease in lung function tests does not require treatment. Persisting infiltration on the chest X-ray or abnormal lung function tests are unlikely to improve without corticosteroid treatment. If the disease is not improving spontaneously 6 months after diagnosis, treatment should be started with prednisolone 30 mg for 6 weeks, reducing to alternate day treatment with prednisolone 15 mg for 6-12 months. Although there are no controlled trials that have proved the efficacy of such treatment, it is difficult to withhold corticosteroids when there is continuing deterioration of the disease.
Topical or systemic prednisolone should be given for patients suffering from involvement of the eyes or the presence of persistent hypercalcaemia. The erythema nodosum of sarcoidosis will respond rapidly to a short course of prednisolone 5-15 mg for 2 weeks. Myocardial sarcoi dosis and neurological manifestations are also treated with prednisolone, and uveoparotid fever responds rapidly to steroids.

PROGNOSIS

Sarcoidosis is a much more severe disease in certain racial groups, particularly American Blacks, where death rates of up to 10% have been recorded. It is probable that the disease is fatal in less than 1 in 20 individuals in the UK, most often as a result of respiratory failure and cor pulmonale but, rarely, from myocardial sarcoidosis and renal damage. The chest X-ray provides a guide to prognosis. The disease remits by 2 years in over two-thirds of patients with hilar lymphadenopathy alone, in approximately one-half with hilar lymphadenopathy plus chest X-ray evidence of pulmonary infiltration, but in only one-third of patients with X-ray evidence of infiltration without any demonstrable lymphadenopathy.

TUBERCULOSIS

Tuberculosis is on the increase particularly where immunosuppressive drugs have altered the host defence mechanisms, or in AIDS. In developing countries, it still remains a problem partly because of inadequately supervised treatment.

EPIDEMIOLOGY

For the last 20 years tuberculosis was thought to be under control, but it is now the world’s leading cause of death from a single infectious disease due to:
• Inadequate programmes for disease control
• Multiple drug resistance
• Co-infection with HIV
• Rapid rise in the world’s population of young adultsthe age group with the highest mortality from tuberculosis
Although the risk of contracting tuberculosis is between 20 and 50 times greater in the developing countries compared to the Western World even there the disease is on the increase. In the last 5 years there has been a 12% increase in the USA, a 33% increase in Switzerland and a 25% increase in Italy.
In the UK, there has been no decline in the number of cases with 7000 new cases per year. In the UK the incidence of tuberculosis in immigrants from the Asian subcontinent and West Indies is 40 and four times as common, respectively, as in the native White population. This has led to great variation in the frequency of the disease in different areas of the UK. It is a notifiable disease.

PATHOLOGY

The first infection with M. tuberculosis is known as primary tuberculosis. It is usually subpleural, often in the mid to upper zones. Within an hour of reaching the lung, tubercle bacilli reach the draining lymph nodes at the hilum of the lung and a few escape into the bloodstream. The initial reaction comprises exudation and infiltration with neutrophil granulocytes. These are rapidly replaced by macro phages that ingest the bacilli. These interact with T lymphocytes with the development of cellular immunity that can be demonstrated 3-8 weeks after the initial infection by the development of a positive reaction in the skin to an intradermal injection of protein from tubercle bacilli (tuberculin).
At this stage the classical pathology of tuberculosis can be seen. Granulomatous lesions consist of a central area of necrotic material of a cheesy nature, called caseation, surrounded by epithelioid cells and Langhans’ giant cells with multiple nuclei, both cells being derived from the macrophage. Lymphocytes are present and there is a varying degree of fibrosis. Subsequently the caseated areas heal completely and many become calcified. It is now known that at least 20% of these calcified primary lesions contain tubercle bacilli, initially lying dormant but capable of being activated by depression of the host defence system. Reactivation leads to typical post-primary pulmonary tuberculosis with cavitation, usually in the apex or upper zone of the lung. ‘Post-primary tuberculosis’ refers to all forms of tuberculosis that occur after the first few weeks of the primary infection when immunity to the mycobacterium has developed.

CLINICAL FEATURES AND INVESTIGATION

Primary tuberculosis is symptomless in the great majority of individuals. Occasionally there may be a vague illness, sometimes associated with cough and wheeze. A small transient pleural effusion or erythema no do sum may occasionally occur, both representing allergic manifestations of the infective process. Enlargement of lymph nodes compressing the bronchi can give rise to collapse of segments or lobes of the lung. Apart from cough and a monophonic wheeze, the individual remains remarkably well and the collapse disappears as the primary complex heals. Occasionally, persistent collapse can give rise to subsequent bronchiectasis, often in the middle lobe (Brock’s syndrome).
The manifestations of primary and post-primary tuberculosis, together with the times when they usually occur. Extrapulmonary manifestations are summarized. Miliary tuberculosis can occur within 3 years of the primary infection, or can occur much later as a manifestation of reactivation or, rarely, reinfection with tubercle bacillus. Reactivation in the lung, or indeed in any extrapulmonary location, can occur as immunity wanes, usually with age and chronic ill-health and all manifestations.

Miliary tuberculosis

This disease is the result of acute diffuse dissemination of tubercle bacilli via the bloodstream. It can be a difficult diagnosis to make, especially in older people, where it is particularly covert. This form of disseminated tuberculosis is universally fatal without treatment. It may present in an entirely non-specific manner with the gradual onset of vague ill-health, loss of weight and then fever. Occasionally the disease presents as tuberculosis meningitis. Usually there are no abnormal physical signs in the early stages, although eventually the spleen and liver become enlarged. Choroidal tubercles are seen in the eyes. These lesions are about one-quarter of the diameter of the optic disc and are yellowish and slightly shiny and raised in nature, later becoming white in the centre. There may be one or many in each eye. The chest X-ray may be entirely normal in miliary tuberculosis as the tubercles are not visible until the miliary shadows are 1 or 2 mm in diameter; they have a hard outline. The lesions can increase in size up to 5-10 mm. Sarcoidosis and staphylococcal or Mycoplasma pneumonia can mimic the chest X-ray appearance of miliary tuberculosis.
The Mantoux test is positive but is occasionally negative in people with very severe disease. Transbronchial biopsies are frequently positive before any abnormality is  visible on the chest X-ray. CT scanning may reveal lung parenchymal abnormalities at an earlier stage. Biopsy and culture of liver and bone marrow may be necessary in patients presenting with a pyrexia of unknown origin (PUQ). In the past, a trial of antituberculous therapy was often used in individuals with a PUQ. The fever should settle within 2 weeks of starting chemotherapy if it is due to tuberculosis. This approach is still occasionally used in susceptible individuals when a diagnosis cannot be confirmed.

The manifestations of primary and post-primary tuberculosis.

The manifestations of
primary and post-primary
tuberculosis.

Pulmonary tuberculosis

Typically there is gradual onset of symptoms over weeks or months. Tiredness, malaise, anorexia and loss of weight together with a fever and cough remain the outstanding features of pulmonary tuberculosis. Drenching night sweats are now rather uncommon and are more usually due to anxiety. Sputum in tuberculosis may be mucoid, purulent or blood-stained. Many patients suffer a dull ache in the chest and it is not uncommon for patients to complain of recurrent colds. A pleural effusion or pneumonia can be the presenting feature of tuberculosis. Physical examination is of little value. Finger clubbing is only present if the disease is advanced and associated with considerable production of purulent sputum. There are often no physical signs in the chest even in the presence of extensive radiological changes, though occasionally persistent crackles may be heard. Physical signs of an associated effusion, pneumonia or fibrosis may be present.
An abnormal chest X-ray is often found with no symptoms, but the reverse is extremely rare-pulmonary tuberculosis is unlikely in the absence of any radiographic abnormality. The chest X-ray (Fig. 12.36) typically shows patchy or nodular shadows in the upper zones, loss of volume, and fibrosis with or without cavitation. Calcification may be present. The X-ray appearances alone may strongly suggest tuberculosis, but every effort must be made to obtain microbiological evidence. A single X-ray does not give an indication of the activity of the disease. Very similar chest X-ray appearances occur in histoplasmosis and other fungal infections of the lung,
including cryptococcosis, coccidioidomycosis and aspergillosis. Lymph node tuberculosis manifestation The patient presents with a tender lump, usually supraclavicular or in the anterior triangle of the neck. This form of tuberculosis.

Tuberculosis in patients with AIDS

Intrathoracic lymphadenopathy and diffuse or miliary infiltrates is common in patients with AIDS, and cavitation less common than in patients without AIDS. Disseminated tuberculosis is particularly frequent, occurring in over one-third of cases.

DIAGNOSIS

CHEST X-RAY

STAINING. The sputum is stained with Ziehl-Nielsen (ZN) stain for acid and alcohol-fast bacilli (AAFB). CULTURE. The sputum is cultured on Dover’s or Lowenstein- Jensen medium for 4-8 weeks. Cultures to determine the sensitivity of the bacillus to antibiotics talce a further 3-4 weeks.
FIBREOPTIC BRONCHOSCOPY with washings from the affected lobes is useful if no sputum is available. This has replaced techniques such as gastric washings. BIOPSIES of the pleura, lymph nodes and solid lesions within the lung (tuberculomas) may be required to malce the diagnosis.
The slow growth of M. tuberculosis in culture has hindered the ability to malce a rapid definitive diagnosis. Newer techniques are being developed which should play an increasing role in rapid diagnosis. Radiolabelled DNA probes specific for various mycobacterial species can identify organisms in culture. The sensitivity of these methods has been enhanced by amplifying target DNA using the polymerase chain reaction. This allows direct testing of sputum and other fluids providing a laboratory diagnosis within 48 hours; it is still being evaluated.

Chest X·ray showing tuberculosis of left upper lobe with cavitation.

Chest X·ray showing tuberculosis of left upper lobe with cavitation.

PREVENTION

BeG vaccination

Vaccination with BeG (Bacille Calmette-Guerin) has been given to schoolchildren in the UK since 1954. BeG is a bovine strain of M. tuberculosis that lost its virulence after growth in the laboratory for many years. Early trials showed that it decreases the risk of developing tuberculosis by about 70%. With the continuing decrease in the incidence of tuberculosis it is becoming less cost-effective to administer this vaccine, and the procedure is being stopped in certain areas of the UK. However, in other areas with a high immigrant population, the vaccine is being administered 6 weeks after birth rather than at the traditional age of 13 years. This is to prevent the disease from developing in young children, where it can progress extremely rapidly and in whom any delay in diagnosis can be fatal. BeG is only given to individuals who are tuberculin-negative; those with positive tests are further screened by a chest X-ray. BeG should be given at a dose of 0.1 ml intradermally to children and adults, but at a dose of 0.05 ml to infants. The practice of BCG vaccination in the UK, thereby producing cellular immunity and a positive tuberculin test, is an important reason why the Mantoux test is of little value in clinical practice for subsequent diagnosis of active disease.

Contact tracing

Tuberculosis is spread from person to person and effective tracing of close contacts has helped to limit spread of the disease as well as to identify diseased individuals at an early stage. Screening procedures involve screening all close family members or other individuals who share the same kitchen and bathroom facilities. Occasionally, close contacts at work or school may also be screened. Contacts who are ill should be thoroughly investigated for tuberculosis. If they are well, a chest X-ray is talcen and a tuberculin test is performed. In adults, even if the tuberculin test is positive, provided the chest X-ray is negative nothing more need be done. In patients with HIV infection, who have not had BCG, chemoprophylaxis with isoniazid is often given. In children, a positive tuberculin test is usually taken as evidence of infection, and treatment is instituted. If the tuberculin test is negative in children and young adults «35 years) it is repeated at 6 weeks, and if it remains negative then BeG is administered. If it has become positive (without BeG), this is again taken as an indication of active disease and the individual is treated. Children under the age of 1 year who have a family member with tuberculosis are given chemoprophylaxis with a daily dose of isoniazid 5-10 mg kg:” for 6 months together with immunization with a strain of BeG that is resistant to isoniazid.
In general, much greater emphasis is placed on contact tracing and investigation of those under the age of 35 years and in some immigrant groups (Irish and Asian) in whom the disease is more virulent and prevalent.

Tuberculin testing.

Tuberculin testing.

TREATMENT

Bed rest does not affect the outcome of the disease. Some patients will require hospitalization for a brief period; these include ill patients, those in whom the diagnosis is uncertain and, most importantly, those individuals from whom it is essential to gain cooperation. The most important factor in the successful treatment of tuberculosis lies in the continual self-administration of drugs for 6 months; lack of patient compliance is a major reason why 5% of patients do not respond to treatment. In vitro resistance to one or more of the antituberculous drugs occurs in less than 1% of patients in the UK. Long stay in hospital is now only required for persistently uncooperative patients, many of whom are homeless and abuse alcohol.

Six-month regimen

This is now standard practice for patients with pulmonary and lymph node disease: daily administration of rifampicin 600 mg and isoniazid 300 mg. (For those whose body weight is below 55 kg, rifampicin is reduced to 450 mg daily.) These are given as combination tablets and are taken 30 min before breakfast, since the absorption of rifampicin is influenced by food. This is supplemented for the first 2 months by pyrazinamide at a dose of 1.5 g (body weight <55 kg) or 2.0 g daily. Studies have indicated that pyrazinamide is of particular value in treating mycobacteria present within macrophages and for this reason it may have a very valuable effect on preventing subsequent relapse.

Longer regimens

Treatment of bone tuberculosis should be continued for a total of 9 months and of tuberculous meningitis for 12 months. The drugs used are the same as for pulmonary tuberculosis with pyrazinamide prescribed for the first 2 months only.

Drug-resistant organisms

The development of resistance after initial drug sensitivity (secondary drug resistance) occurs in patients who do not comply with the treatment regimens. Primary drug resistance is seen in immigrants and those exposed to others infected with resistant organisms. Multidrug resistance occurring particularly in patients with HIV infection is a major therapeutic problem with a high mortality. Nosocomial transmission of multidrug-resistant tuberculosis to health care workers and to other patients is recognized and poses a major public health problem. The drug treatment of suspected drug resistance in HIV -positive and HIV-negative patients is:
• With multiple drug resistance use at least three drugs to which the organism is sensitive.
• With resistance to one of the four main drugs, use the other three.
Therapy should be continued for up to 2 years and in HIV-positive patients for at least 12 months after negative cultures.

Unwanted effects of drug treatment

RIFAMPICIN. This drug induces liver enzymes, which may be transiently elevated in many patients. The drug should only be stopped if the serum bilirubin becomes elevated, which is extremely rare. Thrombocytopenia has been reported. Rifampicin stains body secretions pink and the patients should be warned of the change in colour of their urine, tears and sweat. Induction of liver enzymes means that concomitant drug treatment may be made less effective (see Chapter 14) and oral contraception should not be used.
ISONIAZID. This gives rise to very few unwanted effects. At high doses it may produce a peripheral neuropathy but this is extremely rare when the normal dose of 200- 300 mg is given daily. Nevertheless, it is customary to prescribe pyridoxine 10 mg daily to prevent this effect Occasionally, isoniazid gives rise to allergic reactions in the form of a skin rash and fever, with hepatitis occuring in less than 1% of cases. The latter, however, may be fatal if the drug is continued.

PYRAZINAMIDE. The main unwanted effect of this drug is severe hepatic toxicity, though recent experience suggests that this is much rarer than initially thought using present dosage schedules. Gout due to hyperuricaemia may occur.
ETHAMBUTOL. This drug can cause a dose-related retrobulbar neuritis that presents with colour blindness for green, reduction in visual acuity and a central scotoma. It usually reverses provided that the drug is stopped when symptoms develop; patients should therefore be warned of its effects. Because of this problem ethambutol is rarely used unless resistance of M. tuberculosis is present to one or more of the other drugs. All patients should be seen by an ophthalmologist prior to treatment.
STREPTOMYCIN. The main unwanted effect of streptomycin is irreversible damage to the vestibular nerve. It is more likely to occur in the elderly and in those with renal impairment. Allergic reactions to streptomycin are more common than to rifampicin, isoniazid and pyrazinamide. This drug is only used if patients are very ill and not responding adequately to therapy.

Follow-up

Patients should be seen regularly for the duration of chemotherapy and once more after 3 months, since relapse, though very unlikely, usually occurs within this period of time.

Chemoprophylaxis

Patients who have any chest X-ray changes compatible with previous tuberculosis and who are about to undergo long-term treatment that has an immunosuppressive effect, such as renal dialysis or treatment with corticosteroids, should receive chemoprophylaxis with isoniazid 200-300 mg daily.