Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease
13 Respiratory disease
The lungs, with their combined surface area of greater than 500 m2, are directly open to the external environment. Thus structural, functional or microbiological changes within the lungs can be closely related to epidemiological, environmental, occupational, personal and social factors. Primary respiratory diseases are responsible for a major burden of morbidity and untimely deaths, and the lungs are often affected in multisystem diseases.
Respiratory symptoms are the most common cause of presentation to the family practitioner. Asthma occurs in more than 10% of British children; bronchial carcinoma is the most common fatal malignancy in the developed world; the lung is the major site of opportunistic infection in those immunocompromised by the acquired immunodeficiency syndrome (AIDS) or by anti-allograft and anticancer chemotherapeutic regimens; and the spectre of tuberculosis, particularly the emergence of multiple drug-resistant strains, is back with us.
A number of important research advances have occurred in recent years. The discovery of the genetic mechanism of cystic fibrosis provides a novel opportunity to develop gene therapy strategies to replace the defective gene. The lung is especially favoured for gene therapy since its airway epithelial cells are accessible to nebulised particles and the extensive microvascular pulmonary capillary endothelium is available to intravenously delivered agents. Finally, recent advances in our understanding of the cellular and molecular mechanisms underlying diseases such as asthma and the acute (formerly adult) respiratory distress syndrome (ARDS) are likely to lead to rational, mechanism-based therapy within the foreseeable future.
pages 483 - 486
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=C01370350
For problems or suggestions concerning this service, please contact: email@example.com
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
APPLIED ANATOMY AND PHYSIOLOGY
Figure 13.1 The major bronchial divisions and the fissures, lobes and segments of the lungs. The position of the oblique fissure is such that the left upper lobe is largely anterior to the lower lobe. On the right side the transverse fissure separates the upper from the anteriorly placed middle lobe which is matched by the lingular segment on the left side. The site of the lobe determines whether physical signs are mainly anterior or posterior. Each lobe is composed of two or more bronchopulmonary segments, i.e. the lung tissue supplied by the main branches of each lobar bronchus. BRONCHOPULMONARY SEGMENTS: Right-Upper lobe (1) Anterior (2) Posterior (3) Apical. Middle lobe (1) Lateral (2) Medial. Lower lobe (1) Apical (2) Posterior basal (3) Lateral basal (4) Anterior basal (5) Medial basal. Left-Upper lobe (1) Anterior (2) Apical (3) Posterior (4) Lingular. Lower lobe (1) Apical (2) Posterior basal (3) Lateral basal (4) Anterior basal.
Figure 13.2 The acinus-the basic gas exchange unit of the lung.
The upper respiratory tract includes the nose, nasopharynx and larynx. It is lined by vascular mucous membranes with ciliated epithelium on their surfaces. The lower respiratory tract includes the trachea and bronchi. These form an interconnecting tree of conducting airways eventually joining, via around 64 000 terminal bronchioles, with the alveoli to form the acini. The lower respiratory tract is lined with ciliated epithelium as far as the terminal bronchioles. The larynx and large bronchi are supplied with sensory nerve receptors involved in the cough reflex.
Some knowledge of the patterns of branching of the lobar and segmental bronchi is necessary for interpreting investigations, including chest radiographs and CT scans. Major bronchial and pulmonary divisions are shown in Figure 13.1. (See also bronchoscopic appearances in Fig. 13.8, p. 492.)
The acinus is the gas exchange unit of the lung (see Fig. 13.2) and comprises branching respiratory bronchioles leading to clusters of alveoli. The alveoli are lined mostly with flattened epithelial cells (type I pneumocytes), but there are some, more cuboidal, type II pneumocytes. The latter produce surfactant, a mixture of phospholipids, which acts to reduce surface tension and counteract the tendency of alveoli to collapse. Type II pneumocytes also display a remarkable capacity to divide and reconstitute the type I pneumocytes after lung injury.
The right ventricle pumps blood against the relatively low pulmonary vascular resistance. Blood flows through a rich capillary network, intimately adjacent to alveoli (see Fig. 13.2), facilitating gas exchange. Increased pulmonary vascular resistance-due, for example, to thromboembolism (see p. 562) or to destructive changes caused by chronic obstructive pulmonary disease (COPD, see p. 508)-results in right ventricular hypertrophy, and eventually right heart failure (cor pulmonale) ensues.
GAS EXCHANGE, VENTILATION, BLOOD FLOW AND DIFFUSION
Gas exchange in the lungs is suboptimal unless there is sufficient ventilation, distributed uniformly to different parts of the lungs and matched by uniform distribution of blood flow. Furthermore, abnormal diffusion of oxygen or carbon dioxide across the alveolar-capillary membrane impairs gas exchange.
In clinical practice the important consequences of impaired gas exchange are hypoxaemia and hypercapnia.
Hypercapnia (PaCO2 > 6 kPa) is generally caused by conditions resulting in alveolar hypoventilation or ventilation-perfusion mismatch (see Box 13.1). Hypoventilation may be caused by depression of the respiratory centre in the medulla; in contrast, stimulation of the respiratory centre causes hypocapnia and respiratory alkalosis (see Box 13.2). Ventilation-perfusion mismatch is thought to be largely responsible for the hypercapnia of COPD and severe asthma.
13.1 COMMON CAUSES OF HYPERCAPNIA (RAISED PaCO2)
Central sleep apnoea
Chronic obstructive airways disease (COPD)
13.2 SOME INFLUENCES ON THE RESPIRATORY CENTRE
Upper brain-stem lesions Central neurogenic hyperventilation
Input from receptors Pain; muscles and joints; pulmonary afferents
Increased PaCO2 Via central and peripheral chemoreceptors
Increased arterial [H+] Via peripheral chemoreceptors
Decreased PaO2 (< 8 kPa at rest) Via peripheral chemoreceptors
Sedative drugs Opiates, benzodiazepines
13.3 COMMON CAUSES OF HYPOXAEMIA
Ventilation-perfusion mismatch (poorly ventilated lung)
Alveolar underventilation (raised PaCO2)
Impairment of diffusion (less important at rest)
Right-to-left shunts (circulatory channels bypassing lungs)
Reduced oxygen-carrying capacity of blood (PaO2 may be normal) (anaemia; inactivated haemoglobin)
Corrected by oxygen
Causes of hypoxaemia are shown in Box 13.3. Blood flow wasted on perfusing poorly ventilated lung is probably the most important of these and contributes to the hypoxaemia found, for example, in bronchial obstruction (due to secretions, mucosal oedema, bronchoconstriction or tumours), destruction of elastic tissue (e.g. emphysema), pulmonary collapse, consolidation, fibrosis or oedema, and chest wall deformities. In conditions where the area of alveolar-capillary interface available for gas exchange is reduced (e.g. emphysema), impaired diffusion may contribute to hypoxaemia. This effect may not be significant at rest, but may limit the amount of oxygen which can be taken up during exercise.
Hypoxaemia due to ventilation-perfusion mismatch, hypoventilation or diffusion impairment is reversed by giving oxygen. In right-to-left shunts-as, for example, in congenital heart diseases and pulmonary vascular anomalies-blood does not pass through alveolar capillaries and therefore oxygen does not fully correct the hypoxaemia. Hypoxaemia also occurs if the oxygen-carrying capacity of the blood is reduced-as, for example, in anaemia or carbon monoxide poisoning.
The normal arterial PaO2 is over 12 kPa at the age of 20 and falls to around 11 kPa at 60. Above this age a further fall in PaO2 of up to 1.3 kPa may occur on lying down because of closure of small airways in the dependent regions of the lungs.
Under physiological conditions hypoxaemia and hypercapnia both stimulate ventilation. In some patients with COPD, tolerance to chronic hypercapnia ensues, and in such patients administration of high concentrations of oxygen removes the remaining hypoxaemic stimulus for ventilation, resulting in worsening hypercapnia. Patients with COPD who have chronic hypercapnia should therefore receive, if required, low concentrations of oxygen (e.g. 24-28%), adjusted according to arterial blood gas analysis (see p. 512). Patients with pure asthma do not have chronic hypercapnia and it is therefore safe, and indeed important, to give high concentrations of oxygen during exacerbations of asthma (see p. 520).
Integration link: Oxyhemoglobin dissociation curve
Taken from Physiology 5e
Integration link: Emphysema - pathology
Taken from General & Systematic Pathology 4e
Each day our lungs are directly exposed to more than 7000 litres of air which contain varying amounts of inorganic and organic particles as well as potentially lethal bacteria and viruses. In general terms, physical mechanisms including cough are particularly important in defence of the upper airways, whereas the lower airways are protected by complex mucociliary mechanisms, by the antimicrobial properties of surfactant and the lung-lining fluids, and by resident alveolar macrophages.
Most large particles are removed from inspired air by the nose, which is composed of a 'stack' of fine aerodynamic filters comprising fine hairs and columnar ciliated epithelium which cover the turbinate bones. The larynx acts as a sphincter during cough and expectoration and is an essential mechanism protecting the lower airways during swallowing and vomiting.
Figure 13.3 The mucociliary escalator. Scanning electron micrograph of the respiratory epithelium showing large numbers of cilia (C) overlaid by the mucus 'raft' (M).
13.4 PROTECTIVE AGENTS IN THE LUNG-LINING FLUID
Surfactant proteins-bacterial opsonisation
Immunoglobulins (IgA, IgG, IgM)-bacterial opsonisation, generation of the immune response
Complement-bacterial opsonisation, generation of the inflammatory response
Bactericidal proteins-bacterial killing
Proteinase inhibitors-protection of host tissues during the inflammatory response
Particles with a diameter greater than 0.5µm that survive passage through the nose will be trapped by the lining fluid of the trachea and bronchi and cleared by the 'mucociliary escalator' (see Fig. 13.3). This highly effective small particle clearance mechanism works by a complex interaction between cilia, which are a series of small projections on the surface of respiratory epithelial cells, and mucus, which forms a 'raft' on top of the cilia. Particles are trapped by the mucus which is then swept by the cilia in a cephalic direction. Other important functions of mucus include dilution of noxious substances, lubrication of the airways, and humidification of inspired air. Mucus is mostly secreted by goblet cells within the respiratory epithelium and is composed of the mucus glycoproteins and a variety of other proteins (see Box 13.4) which, although present in low concentrations, play an important role in the defence of the bronchial tree. A number of factors reduce mucociliary clearance by interfering with ciliary function or by causing actual ciliary damage. These include pollutants, cigarette smoke, local and general anaesthetic agents, bacterial products and viral infection. There is also a rare autosomal recessive condition (1 in 30 000 live births) called primary ciliary dyskinesia, which is characterised by repeated sinusitis and respiratory tract infections which progress to persistent lung suppuration and bronchiectasis, thus reinforcing the importance of ciliary clearance in antibacterial lung defences.
Surfactant and other defensive proteins
In addition to its surface active properties which are so important in lung mechanics, surfactant contains a number of proteins, including surfactant protein A, which can opsonise bacteria and other particles, rendering them susceptible to phagocytosis by macrophages. Lung-lining fluids also contain other defensive proteins (see Box 13.4) including immunoglobulins, complement, defensins (powerful antibacterial peptides) and a variety of antiproteinases (including a1-antitrypsin) which play an important role in protecting healthy tissues from damage which would be incurred by the release of proteinases from inflammatory cells during the inflammatory response.
Figure 13.4 Alveolar macrophages. Scanning electron micrograph showing alveolar macrophages (arrow) patrolling the alveolar spaces of the lung.
These multipotent cells normally patrol the interior of the alveoli (see Fig. 13.4), where they display a formidable array of mechanisms by which they recognise and destroy bacteria and other foreign particles. The remarkably versatile resident macrophage can also 'call in reinforcements' by generating mediators which cause an inflammatory response and attract granulocytes and monocytes. It may also generate an immune response by presenting antigens and by releasing specific lymphokines. Finally, the alveolar macrophage exerts important scavenging functions in the clearance of dead bacteria and other cells during the aftermath of infection and inflammation. Nevertheless, it is important to appreciate that the excessive or uncontrolled release of some of these powerful macrophage products may cause disordered inflammation or scarring responses which are likely to be important in the pathogenesis of a variety of inflammatory diseases including asthma, COPD and other inflammatory/scarring conditions of the lung, e.g. fibrosing alveolitis.
ISSUES IN OLDER PEOPLE
The vast reserve capacity of the respiratory system means a significant reduction in function can occur with ageing with only minimal effect on normal breathing, but the ability to combat acute respiratory disease is reduced.
Lung volumes fall gradually with age; the FEV1/VC ratio falls by around 0.2% per year from 70% at the age of 40-45 years. The decline is less rapid in men.
There are reduced ventilatory responses to hypoxia and hypercapnia in old age, so older people may be less tachypnoeic for any given fall in PaO2 or rise in PaCO2.
Reduced numbers of glandular epithelial cells lead to a reduction in protective mucus and thus impaired defences against infection.
Maximum oxygen uptake declines with age due to a combination of changes in the respiratory and cardiovascular systems. This leads to a reduction in cardiorespiratory reserve and exercise capacity.
The chest wall becomes less mobile due to reduced intervertebral disc spaces and ossification of the costal cartilages; respiratory muscle strength and endurance also decline. These changes only become important in the presence of other respiratory disease.
Ageing leads to reduced elastic recoil in the small airways, which causes a tendency for these to collapse during expiration, particularly in dependent areas of the lungs, thus reducing ventilation and increasing ventilation-perfusion mismatch.
INVESTIGATION OF RESPIRATORY DISEASE
It is essential to take a detailed history from the patient, and much can be learned from a careful physical examination (see Box 13.5). Routine haematological and biochemical investigations can provide indices of infection, immunosuppression and evidence of metastasis of lung tumours, but a number of special investigations are often required in the diagnosis and monitoring of lung disease.
The 'plain' chest radiograph
Many diseases, including bronchial carcinoma and pulmonary tuberculosis, cannot be detected at an early stage without a radiograph of the chest. A lateral film provides additional information about the likely nature and situation of a pulmonary, pleural or mediastinal abnormality. Comparison with previous radiographs may help to distinguish between a 'new' or progressive change which is thus potentially serious, and 'old' or static abnormalities which may be of no importance. In some diseases, such as COPD and asthma, there is often no radiographic abnormality. In these diseases functional assessment (see p. 493) is of much more value in detecting abnormality.
Computed tomography (CT)
13.5 SUMMARY OF TYPICAL PHYSICAL SIGNS IN THE MORE COMMON RESPIRATORY DISEASES
Pathological process Movement of chest wall Mediastinal displacement Percussion note Breath sounds Vocal resonance Added sounds
Consolidation (as in lobar pneumonia) Reduced on side affected None Dull High-pitched bronchial Increased; whispering pectoriloquy Fine crepitations1 early; coarse crepitations later
Collapse due to obstruction of a major bronchus Reduced on side affected Towards lesion Dull Diminished or absent Reduced or absent None
Collapse due to peripheral bronchial obstruction Reduced on side affected Towards lesion Dull High-pitched bronchial Increased; whispering pectoriloquy None early; coarse crepitations later
Localised fibrosis and/or bronchiectasis Slightly reduced on side affected Towards lesion Impaired Low-pitched bronchial Increased Coarse crepitations
Cavitation (usually associated with consolidation or fibrosis) Slightly reduced on side affected None, or towards lesion Impaired Bronchial Increased; whispering pectoriloquy Coarse crepitations
Pleural effusion Empyema Reduced or absent (depending on size) on side affected Towards opposite side Stony dull Diminished or absent (occasionally bronchial) Reduced or absent (occasionally increased) Pleural rub in some cases (above effusion)
Pneumothorax Reduced or absent (depending on size) on side affected Towards opposite side Normal or hyper-resonant Diminished or absent (occasionally faint bronchial) Reduced or absent Tinkling crepitations when fluid present
Bronchitis (acute or chronic) Normal or symmetrically diminished None Normal Vesicular with prolonged expiration Normal Rhonchi,2 usually with some coarse crepitations
Bronchial asthma Symmetrically diminished None Normal Vesicular with prolonged expiration Normal or reduced Rhonchi, mainly expiratory and high-pitched
Bronchopneumonia Symmetrically diminished None May be impaired Usually harsh vesicular with prolonged expiration Normal Rhonchi and coarse crepitations
Diffuse pulmonary emphysema Symmetrically diminished None Normal or hyper-resonant Diminished vesicular with prolonged expiration Normal or reduced Expiratory rhonchi
Interstitial lung disease Symmetrically diminished None Normal Harsh vesicular with prolonged expiration Usually increased End-inspiratory crepitations not influenced by coughing
1 Crepitations = crackles.
2 Rhonchi = wheeze.
This has virtually taken over from conventional tomography in centres where it is available. Conventional tomography was valuable in determining the position and size of a pulmonary nodule or mass and whether calcification or cavitation was present. It was also useful in localising lesions for percutaneous needle biopsy and in assessing the mediastinum and thoracic cage. In all of these examples, however, computed tomography is more sensitive and accurate. CT is now routinely used in the pre-operative assessment of patients with lung cancer, particularly for assessing mediastinal spread, and the presence of metastases in the liver or adrenals. Its value in imaging the mediastinum can be greatly enhanced by using an intravenous contrast which outlines the mediastinal vessels. High-resolution CT is particularly useful in diagnosing interstitial fibrosis, and in identifying bronchiectasis (see Fig. 13.5).
The main value of this technique is in the detection of pulmonary thromboemboli. 133Xe gas is inhaled (the ventilation scan) and 99mTc-labelled macroaggregates of albumin, or albumin microspheres, are injected intravenously, the particles becoming transiently trapped in pulmonary microvessels and providing the 'perfusion' scan. Pulmonary emboli can be detected as a 'filling defect' in the perfusion scan (see Fig. 13.6), but patients with asthma, COPD or other forms of obstructive airways disease may also have disordered pulmonary vascular distribution. However, in these patients the ventilation scan shows defects which match the areas of reduced perfusion on the perfusion scan, whereas the perfusion defects in pulmonary embolism are not matched to defects on the ventilation scan. Ventilation-perfusion scanning is also useful in pre-operative assessment of the functional effects of lung cancer and bullae.
Positron emission tomography (PET)
Whole-body PET with 18-fluorodeoxyglucose (FDG) is showing considerable utility in the investigation of pulmonary nodules and in staging mediastinal lymph node involvement and distal metastatic disease in patients with lung cancer. Recent studies have shown that FDG-PET can prevent unnecessary surgery in 20% of patients with non-small-cell lung cancer.
Figure 13.5 Computed tomography of the thorax. This scan shows extensive dilatation of the bronchi (bronchiectasis) with thickened walls (arrows) in both lower lobes.
Figure 13.6 Lung ventilation and perfusion scintigraphy. A Multiple perfusion defects present in left upper zone and right mid-zone of perfusion scan. B Normal ventilation scan. The appearances in A indicate a high probability of recent pulmonary embolism.
Figure 13.7 Normal digital subtraction pulmonary angiogram of the right lung.
This is the definitive method of diagnosing pulmonary emboli, particularly in the acutely ill and shocked patient or when ventilation-perfusion scans are equivocal. Conventional pulmonary angiography is performed by passing contrast medium down a catheter inserted via the femoral vein into the main pulmonary artery. This catheter can also be used to measure pulmonary artery pressure and instil thrombolytic agents such as streptokinase. Digital subtraction angiography (DSA) is a technique whereby images obtained before contrast injection are digitised and subtracted from post-contrast images, thus removing bones and other background structures from the final digital images. This technique is more sensitive and requires much less contrast to obtain high-quality images (see Fig. 13.7). Other techniques for imaging the pulmonary arteries include the use of contrast-enhanced spiral CT-'CT pulmonary angiography'-which is increasingly used in the diagnosis of pulmonary thromboembolism (see p. 562).
The larynx may be inspected indirectly with a mirror or directly with a laryngoscope. Fibreoptic instruments allow a magnified view to be obtained.
The trachea (see Fig. 13.8) and larger bronchi are inspected by a bronchoscope of flexible fibreoptic or rigid type. Rigid bronchoscopy usually requires general anaesthesia. Structural changes, such as distortion or obstruction, can be seen. Abnormal tissue in the bronchial lumen or wall can be biopsied, and bronchial brushings, washings or aspirates can be taken for cytological or bacteriological examination. The range of vision is limited by the calibre of the subsegmental bronchi, but peripheral lesions can sometimes be reached by flexible biopsy forceps directed under fluoroscopic control. Small biopsy specimens of lung tissue taken by forceps passed through the bronchial wall (transbronchial biopsies) may reveal sarcoid granulomata or malignant diseases and may be helpful in diagnosing certain bronchocentric disorders (e.g. extrinsic allergic alveolitis, cryptogenic organising pneumonia), but are generally too small to be of diagnostic value in diffuse interstitial lung disease (see p. 552).
The mediastinoscope is introduced through a small incision at the suprasternal notch to give a view of the upper mediastinum. Biopsy of some mediastinal nodes is possible, which may be of value in obtaining a diagnosis and in determining whether a bronchial carcinoma has spread to the mediastinum and is, therefore, inoperable.
Pleural aspiration and biopsy
Figure 13.8 Bronchoscopic appearances of the lower trachea, carina and the right and left main bronchi.
Pleural aspiration and biopsy using an Abram's needle is a 'blind' procedure but often provides histological evidence of the cause of a pleural effusion. Transthoracic needle biopsy (with radiological guidance) may be useful in obtaining a cytological diagnosis from a peripheral lung lesion. In difficult cases, thoracoscopy may be necessary to obtain diseased tissue; the recent introduction of video-assisted thoracoscopic lung biopsy reduces the need for thoracotomy in cases of interstitial lung disease when lung biopsy is required (see p. 552).
The tuberculin test (see p. 537) may be of value in the diagnosis of tuberculosis. Skin hypersensitivity tests are useful in the investigation of allergic diseases.
IMMUNOLOGICAL AND SEROLOGICAL TESTS
The presence of pneumococcal antigen (revealed by counterimmunoelectrophoresis) in sputum, blood or urine may be of diagnostic importance. Exfoliated cells colonised by influenza A virus (see p. 525) can be detected by fluorescent antibody techniques. In blood, high or rising antibody titres to specific organisms (such as Legionella, Mycoplasma, Chlamydia or viruses) may eventually clinch a diagnosis suspected on clinical grounds. Precipitating antibodies may be found as a reaction to fungi such as Aspergillus (see p. 540) or to antigens involved in allergic alveolitis (see p. 556).
Sputum, pleural fluid, throat swabs, blood and bronchial washings and aspirates can be examined for bacteria, fungi and viruses. In some cases, as when Mycobacterium tuberculosis is isolated, the information is diagnostically conclusive but in other circumstances the findings must be interpreted in conjunction with the results of clinical and radiological examination.
HISTOPATHOLOGICAL AND CYTOLOGICAL EXAMINATION
Histopathological examination of biopsy material (obtained from pleura, lymph node or lung) often allows a 'tissue diagnosis' to be made. This is of particular importance in suspected malignancy or in elucidating the pathological changes in interstitial lung disease (see p. 550). Important causative organisms, such as M. tuberculosis, Pneumocystis carinii or fungi, may be identified in bronchial washings, brushings or transbronchial biopsies.
Cytological examination of exfoliated cells in sputum, pleural fluid or bronchial brushings and washings or of fine-needle aspirates from lymph nodes or pulmonary lesions can support a diagnosis of malignancy but a tissue biopsy is necessary in most cases to confirm the diagnosis. Cellular patterns in bronchial lavage fluid may help to distinguish pulmonary changes due to sarcoidosis (see p. 552) from those caused by fibrosing alveolitis (see p. 555) or allergic alveolitis (see p. 556).
LUNG FUNCTION TESTING
Pulmonary function tests are used to aid diagnosis, assess functional impairment and monitor treatment or progression of disease. Common abbreviations used in pulmonary function testing are shown in Box 13.6. Simple spirometry should be a routine procedure carried out by all doctors when assessing a patient who is breathless.
13.6 ABBREVIATIONS USED IN PULMONARY FUNCTION TESTING
Abbreviation Stands for
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
VC Vital capacity (relaxed)
PEF Peak (maximum) expiratory flow
TLC Total lung capacity
FRC Functional residual capacity
RV Residual volume
TLCO Gas transfer factor for carbon monoxide
KCO Transfer coefficient for carbon monoxide
Spirometry and peak flow
The forced expiratory volume in 1 second (FEV1) and vital capacity (VC) are obtained from maximal forced and relaxed expirations into a spirometer. The results are compared with predicted values based on age, sex, height and ethnic group. The FEV1/VC ratio is also a useful diagnostic aid, with values of less than 70% defining airflow obstruction (see Box 13.7). Acute reversibility testing using inhaled short-acting ß2-adrenoceptor agonists (e.g. salbutamol or terbutaline) should be carried out when airflow obstruction is seen; full reversibility is diagnostic of asthma (see p. 513). Peak expiratory flow (PEF) monitored via a small portable meter can be usefully recorded by patients at home or at work in order to assess asthma control on an objective basis. Peak flow monitoring can be used by patients as a basis for self-management plans. Serial measures show any circadian changes, and responses to occupational exposure or therapy are of value in both the diagnosis and the management of asthma.
The plotting of flow versus volume during both maximal expiratory and inspiratory manoeuvres is of major help in differentiating central airflow obstruction (leading to stridor) from diffuse airflow obstruction as seen in COPD and asthma.
13.7 PATTERNS OF ABNORMAL VENTILATORY CAPACITY
Asthma Emphysema Lung fibrosis
FEV1 Low Low Low
VC Low Low Low
FEV1/VC Low Low Normal
DLCO Normal Low Low
KCO Normal Low Low
TLC High High Low
RV High High Low
Measurement of total lung capacity and residual volume is best performed using a whole body plethysmograph, but can be measured by a helium dilution method. In general, restrictive defects lead to reduced values, and obstructive defects to increased values (see Box 13.7 and Fig. 13.9).
Measurement of diffusing capacity
The diffusing capacity (DLCO) is a measure of the lung's ability to transfer gas from alveoli to blood. The test utilises uptake of carbon monoxide from a single breath of 0.3% mixture in air; this gas is chosen because it combines rapidly with haemoglobin and provides a true estimate of diffusion across the alveolar capillary membrane. The diffusing capacity is reduced in patients with disease principally affecting alveoli such as fibrosing alveolitis or emphysema. The transfer coefficient (KCO) is a measure of diffusing capacity expressed per volume of ventilated lung during the single breath test and is useful to confirm that a low DLCO is due to alveolar disease rather than maldistribution of ventilation. High values of DLCO may be seen in alveolar haemorrhage.
Arterial blood gases and oximetry
Figure 13.9 Normal lung volumes and schematic tidal flow-volume curves. A Volume-time plot during tidal breathing (I), forced inspiration (II) and forced expiration (III). B Schematic tidal flow-volume curve in a normal subject and in a patient with COPD and moderate airflow obstruction.
The measurement of hydrogen ion concentration, PaO2 and PaCO2, and derived bicarbonate concentration of arterial blood is essential in assessing the degree and type of respiratory failure and for measuring overall acid-base status. Use of a pulse oximeter allows a non-invasive continuous method of assessing oxygen saturation in patients who require continuous monitoring in order to assess hypoxaemia and its response to therapy, including supplemental oxygen.
Formal exercise testing with measurement of metabolic gas exchange and respiratory and cardiac responses using cycle ergometry or treadmill exercise is useful in providing a detailed analysis of both pulmonary and cardiac function in the breathless patient. Exercise challenge with measurement of spirometry before and after can also be helpful in demonstrating exercise-induced asthma. Finally, the 6-minute walk test or 'shuttle' test can provide a simple but objective assessment of disability and response to treatment.
pages 486 - 494
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013005
For problems or suggestions concerning this service, please contact: firstname.lastname@example.org
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > MAJOR MANIFESTATIONS OF LUNG DISEASE
MAJOR MANIFESTATIONS OF LUNG DISEASE
Cough is the most frequent symptom of respiratory disease. It is caused by stimulation of sensory nerves in the mucosa of the pharynx, larynx, trachea and bronchi. Sensitisation of the normal cough reflex is also observed following viral infections, oesophageal reflux, post-nasal drip, 'cough variant' asthma and in 10-15% of patients (particularly women) taking angiotensin-converting enzyme (ACE) inhibitors. Rarely, cough may also arise following stimulation of the parietal pleura: for example, during the aspiration of a pleural effusion. The nature and characteristics of cough originating at various levels of the respiratory tract are given in Box 13.8.
Origin Common causes Nature/characteristics
Pharynx Post-nasal drip Usually persistent
Larynx Laryngitis, tumour, whooping cough, croup Harsh, barking, painful, persistent, often associated with stridor
Trachea Tracheitis Painful
Bronchi Bronchitis (acute) and COPD Dry or productive, worse in mornings
Asthma Dry or productive, worse at night
Bronchial carcinoma Persistent (often with haemoptysis)
Lung parenchyma Tuberculosis Productive, often with haemoptysis
Pneumonia Dry initially, productive later
Bronchiectasis Productive, changes in posture induce sputum production
Pulmonary oedema Often at night (may be productive of pink, frothy sputum)
Interstitial fibrosis Dry, irritant and distressing
The explosive quality of a normal cough is lost in patients with severe airflow obstruction, respiratory muscle paralysis or vocal cord palsy. Paralysis of a single vocal cord gives rise to a prolonged, low-pitched, inefficient 'bovine' cough accompanied by hoarseness. Patients with sensitisation of the cough reflex typically have symptoms induced by changes in air temperature or exposure to cigarette smoke or perfumes. Coexistence of stridor indicates partial obstruction of a major airway (e.g. laryngeal oedema, tumour or an inhaled foreign body) and requires urgent investigation and treatment. Sputum production is common in patients with acute or chronic cough and its nature and appearance can provide valuable clues as to the aetiology (see p. 485).
Acute or transient cough most commonly relates to viral-induced lower respiratory tract infection, post-nasal drip resulting from rhinitis or sinusitis, or throat-clearing secondary to laryngitis or pharyngitis. Acute cough occurring in the context of more serious diseases such as pneumonia, aspiration, congestive heart failure or pulmonary embolism is usually easy to diagnose due to the presence of other clinical features.
Patients with chronic cough often represent more of a diagnostic challenge, especially those individuals with a normal examination, chest radiograph and lung function studies. In this context, most cough can be explained by post-nasal drip secondary to nasal or sinus disease; asthma, where cough may be the principal or exclusive clinical manifestation; or gastro-oesophageal reflux. The latter cause may require ambulatory pH monitoring or a prolonged trial of anti-reflux therapy (see p. 775) to diagnose. Bordetella pertussis infection in adults can also result in protracted cough and should always be suspected in those in close contact with children. While less than 1% of patients with a bronchogenic carcinoma have a normal chest radiograph on presentation, fibreoptic bronchoscopy or spiral CT of the airways is advisable in most adults with otherwise unexplained cough of recent onset (especially in smokers) as this may reveal a small intrabronchial tumour or unexpected foreign body (see Fig. 13.10).
Figure 13.10 Bronchoscopic appearances of inhaled foreign body (tooth) with a covering mucous film.
Breathlessness or dyspnoea can be defined as an unpleasant subjective awareness of the sensation of breathing. It is a common symptom of cardiac and respiratory disease, but it may occur as a result of disorders of other systems, e.g. diabetic ketoacidosis or severe anaemia.
Breathless patients with asthma or COPD often also describe a 'tight chest'. Pleural pain (see p. 499) of any cause is associated with limitation of breathing.
13.9 PHYSIOLOGICAL BASIS OF DYSPNOEA
Increased ventilatory drive
? PaCO2-e.g. COPD
? PaO2-e.g. cyanotic congenital heart disease, asthma, COPD
Acidaemia-e.g. diabetic ketoacidosis, lactic acidosis
Reduced ventilatory capacity
? Lung volume, e.g. restrictive lung diseases-pneumonia, pulmonary oedema, interstitial lung diseases
? Resistance to airflow, e.g. asthma, COPD, upper airway or laryngeal obstruction
In broad physiological terms, patients usually perceive discomfort either from an increased ventilatory rate or drive, which can be provoked by a variety of factors, or from any disease which causes sufficient reduction of ventilatory capacity (see Box 13.9). Other factors, however, including the stimulation of intrapulmonary receptors (e.g. J receptors), augment the ventilatory response in many bronchopulmonary disorders.
It follows that dyspnoea often has a multifactorial aetiology, e.g. acute respiratory infections may stimulate the respiratory rate as a consequence of fever, hypoxaemia and, in severe cases, by acidaemia or hypercapnia. They may also reduce ventilatory capacity by increasing bronchial resistance and by restricting ventilation because of pleural pain.
While it is useful to understand the physiological basis of dyspnoea, patients often present either as an emergency with acute breathlessness (with prominent symptoms even at rest) or with chronic dyspnoea on exertion, and it is useful therefore to describe the causes of dyspnoea in this fashion (see Box 13.10).
13.10 SOME CAUSES OF DYSPNOEA
System Acute dyspnoea at rest Chronic exertional dyspnoea
Cardiovascular *Acute pulmonary oedema (see p. 377) Chronic heart failure (see p. 377)
Myocardial ischaemia (angina equivalent) (see p. 378) Myocardial ischaemia (angina equivalent) (see p. 378)
Respiratory *Acute severe asthma *COPD
*Acute exacerbation of COPD *Chronic asthma
*Pneumothorax Bronchial carcinoma
*Pneumonia Interstitial lung disease (sarcoidosis, fibrosing alveolitis,
*Pulmonary embolus extrinsic allergic alveolitis, pneumoconiosis)
Acute respiratory distress syndrome Chronic pulmonary thromboembolism
Inhaled foreign body (especially in the child) Lymphatic carcinomatosis (may cause intolerable dyspnoea)
Lobar collapse Large pleural effusion(s)
Laryngeal oedema (e.g. anaphylaxis)
Others Metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis, uraemia, overdose of salicylates, ethylene glycol poisoning) Severe anaemia
Psychogenic hyperventilation (anxiety or panic-related)
*Denotes a common cause.
AN APPROACH TO THE DIFFERENTIAL DIAGNOSIS IN THE PATIENT WITH CHRONIC EXERTIONAL DYSPNOEA
Chronic obstructive pulmonary disease (COPD)
There is usually a history of exertional dyspnoea, often associated with wheeze, over many months or years, with a steady decline in exercise capacity (e.g. initially breathlessness on hills and stairs, but eventually after walking a few paces on the flat). Chronic cough productive of sputum, usually most troublesome in the mornings, is the rule and there is often a history of recurrent acute exacerbations, usually in the winter months. In late disease orthopnoea, nocturnal breathlessness and ankle swelling may supervene as a result of the development of cor pulmonale.
Central cyanosis at rest or after minimal exertion, wheeze and pursing of the lips during expiration, and intercostal indrawing during inspiration are common examination findings. The antero-posterior diameter of the chest may be increased (barrel chest) and there may be a reduced crico-sternal distance with a 'tracheal tug' on inspiration.
The chest radiograph may show signs of hyperinflation and/or bullae; arterial blood gases may reveal hypoxaemia, hypercapnia and a raised plasma bicarbonate, indicating compensated type II respiratory failure. It is important to note that patients presenting with type II respiratory failure (see p. 506) may not be distressed by breathlessness. There will often be a severe obstructive defect on spirometry, with a low FEV1 and little, if any, improvement after bronchodilator therapy.
It is often difficult to differentiate breathlessness due to heart disease from that caused by lung disease. A history of cough, wheezing and nocturnal breathlessness may occur in cardiac failure as well as in patients with lung disease. A history of angina or hypertension may be useful in implicating a cardiac cause (see Fig. 13.11).
On examination, an increase in heart size as judged by a displaced apex beat, a raised jugular venous pressure (JVP) and cardiac murmurs may implicate cardiac disease (although these signs can occur in severe cor pulmonale). The chest radiograph may show cardiomegaly and an ECG may provide evidence of left ventricular disease. Arterial blood gases may be of value, since in the absence of an intracardiac shunt or obvious pulmonary oedema the PaO2 in cardiac disease is not usually reduced significantly and the PaCO2 is low or normal.
Interstitial or alveolar disease of the lung
A large number of conditions can cause interstitial lung disease (see p. 550), which may be difficult to distinguish from other conditions including infiltrating malignancy and certain opportunistic lung infections (see Box 13.74, p. 551). It is imperative to elicit a detailed history, including lifetime occupation and exposure to birds and other sources of organic agents which may provoke lung disease. The chest radiograph is nearly always abnormal, but early changes may be very subtle. Pulmonary function tests usually show a restrictive defect (reduced vital capacity) and reduced gas transfer. Arterial blood gases may show hypoxaemia, or haemoglobin desaturation may be detected by oximetry, particularly during formal exercise testing, which may be valuable in early disease; the PaCO2 is seldom elevated, even in advanced disease.
Diseases of the chest wall or respiratory muscles
These are usually obvious on history, examination and chest radiography. Other rarer causes of alveolar hypoventilation, e.g. brain-stem defects, primary alveolar hypoventilation and alveolar hypoventilation in gross obesity, may cause disordered breathing and cyanosis, but these conditions are not usually associated with breathlessness. Bilateral diaphragmatic weakness or palsy results in breathlessness that is characteristically worse on lying; this is associated with a drop in the vital capacity. Patients with major chest wall abnormalities, or problems with ventilatory drive or muscle strength tend to develop problems initially during sleep, with nocturnal hypoxaemia and hypercapnia which resolve during the day.
As will be considered below, pulmonary thromboembolism often presents with acute breathlessness with or without chest pain. However, chronic pulmonary thromboembolic disease (see p. 562) should be suspected in patients who present with more gradual onset of breathlessness, in particular those with a previous history of thromboembolic events or those with marked exertional breathlessness but a relatively normal chest radiograph. Leg swelling and an elevated JVP may arouse suspicion but clearly can also occur in cardiac failure.
Breathlessness which is not caused by organic disease of the heart or lungs is also relatively common. It creates a particularly difficult clinical problem when it occurs in patients with pre-existing disease, such as asthma or heart disease. It is possible in most patients to ascertain by careful questioning whether the sensation of breathlessness is different from that caused by exertion in the past, or dyspnoea associated with any pre-existing lung or heart disease.
Figure 13.11 Features that can distinguish cardiac from non-cardiac dyspnoea. N.B. Non-cardiac dyspnoea may coexist with occult or symptomatic heart disease. Psychological factors may amplify cardiac or non-cardiac symptoms or occur in isolation.
Psychogenic breathlessness is usually described as an 'inability to get enough air into the lung' and this leads to extra deep breaths having to be taken. This form of breathlessness rarely disturbs sleep, but may be present after waking for another reason. Symptoms occur predominantly at rest and may even be relieved by exercise. Specialist centres use a number of features to develop a 'points' score in the assessment of this problem, often called anxiety-related hyperventilation-see Box 13.11. Occasionally, formal exercise testing may be required to be confident that patients have breathlessness which does not have an organic cause.
13.11 SOME FACTORS POINTING TO PSYCHOGENIC HYPERVENTILATION
'Inability to take a deep breath'
Frequent sighing/erratic ventilation at rest
Short breath-holding time in the absence of severe respiratory disease
Difficulty in performing/inconsistent spirometry manoeuvres
High score on Nijmegen anxiety questionnaire
Induction of symptoms during submaximal hyperventilation
Resting end-tidal CO2 < 4.5%
Overt 'hysterical' or panic-related hyperventilation is associated with paraesthesia in the hands and feet, cramps and carpopedal spasm due to acute respiratory alkalosis; it can present as a respiratory emergency but rarely creates a diagnostic problem. It must always, however, be included in the differential diagnosis of acute-onset breathlessness (see Box 13.10). It is best treated with oxygen and reassurance delivered in a quiet environment rather than by rebreathing into a bag as formerly suggested.
AN APPROACH TO THE PATIENT WITH ACUTE SEVERE DYSPNOEA
Acute severe breathlessness is one of the most common medical emergencies. The presentation is often dramatic and it is easy for the inexperienced clinician to be disconcerted. Although there are usually a number of possible causes, attention to the history and a rapid but careful examination will usually suggest a diagnosis which can often be confirmed by routine investigations, including chest radiograph, electrocardiogram (ECG) and arterial blood gases. Some specific features aiding in the diagnosis of important causes of acute severe breathlessness are considered in detail in Box 13.12.
13.12 DIFFERENTIAL DIAGNOSIS OF ACUTE SEVERE DYSPNOEA
Condition History Signs Chest radiography Arterial blood gases ECG Other tests
Left ventricular failure Chest pain Orthopnoea Palpitations
*A previous cardiac history Central cyanosis JVP (? or?)
*Sweating Cool extremities
*Dullness and crepitations at bases Cardiomegaly
*Upper zone vessel enlargement
*Overt oedema/pleural effusions ? Pa O2 ? Pa CO2 Sinus tachycardia
*Signs of myocardial infarction Arrhythmia *Echocardiography (? left ventricular function)
Massive pulmonary embolus Recent surgery or other risk factors Chest pain Previous pleurisy
*Dizziness Severe central cyanosis
*Absence of signs in the lung (unless previous pulmonary infarction) Shock (tachycardia, reduced blood pressure) May be subtle changes only Prominent hilar vessels
*Oligaemic lung fields ?Pa O2 ? Pa CO2 Sinus tachycardia S1Q3T3 pattern ? T (V1-V4) Right bundle-branch block *Echocardiography
*CT pulmonary angiography
Acute severe asthma *History of previous episodes, asthma medications, wheeze Tachycardia and pulsus paradoxus Cyanosis (late)
*? peak flow, rhonchi *Hyperinflation only (unless complicated by pneumothorax) ? Pa O2 ? Pa CO2 (until late) Sinus tachycardia (bradycardia with severe hypoxaemia -late)
Acute exacerbation of COPD *Previous episodes (admissions) If in type II respiratory failure, may not be distressed Cyanosis
*Signs of COPD (barrel chest, intercostal indrawing, pursed lips, tracheal tug)
*Signs of CO2 retention (warm periphery, flapping tremor, bounding pulses) *Hyperinflation Signs of emphysema Signs of events precipitating exacerbation ? or ? Pa O2 In type II failure Pa CO2 ?, with ¯ ? [H+] and ¯ ?bicarbonate Nil, or signs of right ventricular failure (in cor pulmonale)
Pneumonia *Prodromal illness
*Pleurisy Fever, confusion
*Consolidation Cyanosis (only if severe) *Pneumonic consolidation ? Pa CO2 ? Pa O2 Tachycardia ? CRP ? White cell count Sputum and blood culture
Metabolic acidosis *Evidence of diabetes/renal disease
*Overdose of aspirin or ethylene glycol Fetor (ketones)
*Hyperventilation without physical signs in heart or lungs
*Dehydration Air hunger (Kussmaul's respiration) Normal *Pa O2 normal ? Pa CO2 ? pH (¯ H+)
Psychogenic (a diagnosis of exclusion) Previous episodes *Not cyanosed
*No heart signs
*No lung signs Carpopedal spasm Normal *Pa O2 normal ? Pa CO2
*pH normal or ¯ ?(H+ ?) End-tidal PaCO2
*Low exercise tolerance test
*Denotes a valuable discriminatory feature.
Figure 13.12 CT showing retrosternal multinodular goitre (small arrow) causing acute severe breathlessness and stridor due to tracheal compression (large arrow).
It is important to ascertain the rate of onset and severity of the breathlessness and whether associated cardiovascular symptoms (chest pain, palpitations, sweating and nausea) or respiratory symptoms (cough, wheeze, haemoptysis, stridor-see Fig. 13.12) are present. A previous history of repeated episodes of left ventricular failure, asthma or exacerbations of COPD is valuable. Recent intake of drugs or a history of other diseases (renal disease, diabetes or anaemia) should be established. In the severely ill patient it may be necessary to obtain a brief history from friends, relatives or ambulance personnel. In children, particularly pre-school toddlers, the possibility of inhalation of a foreign body (see Fig. 13.10, p. 495) or acute epiglottitis should always be considered.
The severity of the condition should be assessed immediately by the level of consciousness, degree of central cyanosis, evidence of anaphylaxis (urticaria or angio-oedema), patency of the upper airway, ability to speak (in single words or sentences), and the cardiovascular status assessed by heart rate and rhythm, blood pressure and degree of peripheral perfusion. Examination should then be targeted on digital clubbing, clinical evidence of anaemia or polycythaemia, and any clinical features of diabetes, renal failure or any other chronic disease. A detailed examination of the respiratory system should include the respiratory rate, clinical evidence of CO2 retention, pattern of breathing, position of the trachea, degree and symmetry of chest expansion, and whether there are areas of hyper-resonance or dullness on percussion. Breath sounds should be compared on each side of the chest and at the bases, and the presence of abnormal sounds noted. The peak expiratory flow should be measured whenever possible. Leg swelling may suggest cardiac failure or venous thrombosis.
Chest pain is a major and frequent manifestation of both cardiac and respiratory disease and is considered in detail on page 372. In general, however, lung disease only gives rise to chest pain when there is pleural or chest wall involvement and hence tends to be predominantly peripheral (see Box 13.13). Central chest pain or tightness is a feature of acute airways obstruction in asthma and COPD or may reflect disorders of the oesophagus (see p. 775) or thoracic aorta (see p. 448). Tracheitis produces severe upper chest pain worse on coughing. Persistent dull central chest pain is also a feature of malignant disease affecting the mediastinum.
13.13 DIFFERENTIAL DIAGNOSIS OF CHEST PAIN
Myocardial ischaemia (angina)
Mitral valve prolapse syndrome
Massive pulmonary embolus
Connective tissue disorders
Intercostal muscle injury
Costochondritis (Tietze's syndrome)
Epidemic myalgia (Bornholm disease)
Prolapsed intervertebral disc
Thoracic outlet syndrome
Coughing up blood, irrespective of the amount, is an alarming symptom and nearly always brings the patient to the doctor. A clear history should be taken to establish that it is true haemoptysis and not haematemesis or epistaxis (nosebleed). Haemoptysis must always be assumed to have a serious cause until appropriate investigations have excluded bronchial carcinoma, thromboembolic disease, tuberculosis etc. (see Box 13.14).
13.14 CAUSES OF HAEMOPTYSIS
Parasites (e.g. hydatid disease, flukes)
Lung vascular disease
Goodpasture's syndrome (see p. 614)
Idiopathic pulmonary haemosiderosis
Acute left ventricular failure
Many episodes of haemoptysis are unexplained, even after full investigation, and are likely to be caused by simple bronchial infection. A history of repeated small haemoptyses, or blood-streaking of sputum, is highly suggestive of bronchial carcinoma. Chronic fever and weight loss may suggest tuberculosis. Pneumococcal pneumonia is often the cause of 'rusty'-coloured sputum but can cause frank haemoptysis, as can all the pneumonic infections which lead to suppuration or abscess formation (see p. 530). Bronchiectasis and intracavitary aspergilloma (see p. 541) can cause catastrophic bronchial haemorrhage and in these patients there may be a history of previous tuberculosis or pneumonia in early life. Pulmonary thromboembolism is a common cause of haemoptysis and should always be considered. Major risk factors include immobilisation, malignant disease of any organ, cardiac failure and pregnancy.
Physical examination may reveal clues as to the underlying diagnosis, e.g. finger clubbing in bronchial carcinoma or bronchiectasis; other signs of malignancy such as cachexia, hepatomegaly, lymphadenopathy etc.; fever or signs of consolidation and pleurisy in pneumonia or pulmonary infarction; leg signs of deep venous thrombosis in a minority of patients with pulmonary infarction; and signs of systemic diseases including rash, purpura, haematuria, splinter haemorrhages, lymphadenopathy or splenomegaly in the uncommon systemic diseases which may be associated with haemoptysis.
In catastrophic acute haemoptysis, the patient should be nursed on the side of the suspected source of bleeding, haemodynamically resuscitated and then bronchoscoped. Ideally this is performed under general anaesthesia using a rigid bronchoscope which allows optimal bronchial suction and can be used to maintain adequate ventilation during anaesthesia. Angiography and bronchial arterial embolisation (see Fig. 13.13), or even emergency pulmonary surgery, can be life-saving in the acute situation.
Figure 13.13 Bronchial artery angiography. An angiography catheter has been passed via the femoral artery and aorta into an abnormally dilated right bronchial artery (arrows). Contrast is seen flowing into the lung. This patient had post-tuberculous bronchiectasis affecting the right upper lobe and presented with massive haemoptysis. Bronchial artery embolisation was successfully carried out.
In the vast majority of cases, however, the haemoptysis itself is not life-threatening and it is possible to follow a logical sequence of investigations which include:
Chest radiograph, which may give clear evidence of a localised lesion including pulmonary infarction, a tumour (malignant or benign), pneumonia or tuberculosis.
Full blood count and other haematological tests including clotting screen.
Bronchoscopy, which will often be necessary to exclude a central bronchial carcinoma (not visible on the chest radiograph) and to provide a tissue diagnosis in other cases of suspected bronchial neoplasia.
Ventilation-perfusion ([Vdot]/[Qdot]) lung scan, which is helpful in establishing a diagnosis of suspected pulmonary thromboembolic disease. CT pulmonary angiography may be necessary in patients with pre-existing lung disease where interpretation of the [Vdot]/[Qdot] scan can be difficult.
CT, which is particularly useful in investigating peripheral lesions seen on the chest radiograph which may not be accessible to bronchoscopy and facilitates accurate percutaneous needle biopsy where indicated.
THE SOLITARY RADIOGRAPHIC PULMONARY LESION
Patients frequently present because they have been found to have an abnormal chest radiograph. A common clinical problem is created by the adult with few or no symptoms, who has been found to have a single peripheral lesion (nodule) detected by chest radiography. There are many causes of the 'peripheral radiograph shadow', some of which are shown in Box 13.15. Primary bronchial carcinoma is the most likely cause in a middle-aged or elderly adult, particularly if a smoker.
13.15 THE SOLITARY PULMONARY NODULE
'Pseudotumour'-fluid collection in a fissure
Aspergilloma (usually surrounded by air 'halo')
The single most important investigation is examination of previous radiographs, if they exist, since if a lesion has been present for more than 2 years and has not changed, it can be assumed to be non-malignant. If there are no previous radiographs or if previous films are normal, CT can be of great value in defining the lesion more precisely, demonstrating the presence of calcification and cavitation within it, and identifying whether other smaller lesions exist in other areas of the lung which may not be apparent on the conventional radiograph. The injection of intravenous contrast medium at the time of the CT provides information regarding the vascularity of the lesion, with malignant tumours tending to show greatest contrast enhancement. CT will also show hilar and mediastinal lymphadenopathy, which is important in the staging of a primary bronchial carcinoma. A positive 18FDG-PET scan (see p. 491) is also suggestive of a malignant lesion.
Bronchoscopy is unlikely to allow direct inspection of a peripheral lesion, but a diagnosis of malignant disease or infection can be achieved by examination of bronchial washings and brushings obtained from the segment of lung in which the lesion is seen on the chest radiograph or CT. Biopsy of the lesion via the bronchoscope may be possible with the aid of radiographic screening. Percutaneous needle biopsy under CT guidance has proved to be the most effective procedure for the diagnosis of solitary pulmonary nodules with few complications (pneumothorax and haemorrhage). On occasion, a definitive diagnosis can only be made by surgical resection.
Whenever bacterial infection is included in the clinical differential diagnosis, an antibiotic should be given during the period in which the investigations are being performed; the patient should then undergo a repeat radiograph to see whether there has been a reduction in size of the opacity. In elderly patients in whom a primary malignant lesion is suspected, but who are considered unfit for any form of curative treatment, observation by repeat radiograph at intervals of a few weeks may be the most appropriate management decision.
This term is used when serous fluid accumulates in the pleural space. The presence of frank pus (empyema) or blood (haemothorax) in the pleural space represents separate conditions; empyema is considered elsewhere (see p. 569). In general, pleural fluid accumulates as a result of either increased hydrostatic pressure or decreased osmotic pressure ('transudative effusion', as seen in cardiac, liver and renal failure), or from increased microvascular permeability due to disease of the pleural surface itself or injury in the adjacent lung ('exudative effusion'). Some causes of pleural effusion are shown in Boxes 13.16 and 13.17.
Pleural effusion may be unilateral or bilateral. Bilateral effusions often occur in cardiac failure, but are also seen in patients with connective tissue diseases and hypoproteinaemia. The likely cause of the majority of pleural effusions can usually be identified if a careful history is taken and a comprehensive clinical examination performed.
Particular attention should be paid to recent history of respiratory infection, the presence of heart, liver or renal disease, smoking history, occupation-for example, exposure to asbestos, contact with tuberculosis, and risk factors for thromboembolism such as recent immobilisation or operation.
13.16 CAUSES OF PLEURAL EFFUSION
Pneumonia ('para-pneumonic effusion')
Subdiaphragmatic disorders (subphrenic abscess, pancreatitis etc.)
Hypoproteinaemia (nephrotic syndrome, liver failure, malnutrition)
Connective tissue diseases (particularly systemic lupus erythematosus and rheumatoid arthritis)
Acute rheumatic fever
Post-myocardial infarction syndrome
Meigs' syndrome (ovarian tumour plus pleural effusion)
Asbestos-related benign pleural effusion
13.17 PLEURAL EFFUSION: MAIN CAUSES AND FEATURES
Cause Appearance of fluid Type of fluid Predominant cells in fluid Other diagnostic features
Tuberculosis Serous, usually amber-coloured Exudate Lymphocytes (occasionally polymorphs) Positive tuberculin test
Isolation of M. tuberculosis from pleural fluid (20%)
Positive pleural biopsy (80%)
Malignant disease Serous, often blood-stained Exudate Serosal cells and lymphocytes Often clumps of malignant cells Positive pleural biopsy (40%)
Evidence of malignant disease elsewhere
Cardiac failure* Serous, straw-coloured Transudate Few serosal cells Other evidence of left ventricular failure
Response to diuretics
Pulmonary infarction* Serous or blood-stained Exudate (rarely transudate) Red blood cells Eosinophils Evidence of pulmonary infarction
Source of embolism
Factors predisposing to venous thrombosis
Rheumatoid disease* Serous Turbid if chronic Exudate Lymphocytes (occasionally polymorphs) Rheumatoid arthritis; rheumatoid factor in serum
Cholesterol in chronic effusion; very low glucose in pleural fluid
Systemic lupus erythematosus (SLE)* Serous Exudate Lymphocytes and serosal cells Other manifestations of SLE
Antinuclear factor or anti-DNA in serum
Acute pancreatitis Serous or blood-stained Exudate No cells predominate High amylase in pleural fluid (greater than in serum)
Obstruction of thoracic duct Milky Chyle None Chylomicrons
*Effusion often bilateral.
Symptoms and signs of pleurisy often precede the development of an effusion, especially in patients with underlying pneumonia, pulmonary infarction or connective tissue disease. Frequently, however, the onset is insidious. Breathlessness is the only symptom related to the effusion and the severity depends on the size and rate of accumulation of the fluid. The physical signs in the chest are those of fluid in the pleural space-namely, reduced chest wall movement on the affected side, stony dullness on percussion, and reduced or absent breath sounds and vocal resonance. Large effusions cause displacement of the trachea and mediastinum to the opposite side.
The chest radiograph shows a dense uniform opacity in the lower and lateral parts of the hemithorax, shading off above and medially into translucent lung (see Fig. 13.14). Occasionally, the fluid is localised below the lower lobe ('subpulmonary effusion'), the appearances simulating an elevated hemidiaphragm. A localised opacity may be seen when the effusion is loculated-for example, in an interlobar fissure.
Figure 13.14 Pleural effusion. Chest radiograph showing the characteristic opacification of a large left-sided effusion.
This investigation is invaluable in differentiating between a loculated pleural effusion and pleural tumour and allows examination of the diaphragm and subdiaphragmatic space. It also helps to localise an effusion prior to aspiration and pleural biopsy.
Pleural aspiration and pleural biopsy
Absolute proof that an effusion is present can be obtained only by the aspiration of fluid. Since the chances of obtaining a diagnosis from pleural biopsy material are much greater than by examination of the pleural liquid alone, pleural biopsy is always indicated whenever a diagnostic aspiration of pleural fluid is performed. Ideally, ultrasound or CT should be used to indicate the most appropriate site for pleural aspiration and biopsy. If these are not readily available, the pleural biopsy needle should be inserted through an intercostal space at the area of maximum dullness on percussion and at the site of maximum radiological opacity as shown by postero-anterior and lateral films. At least 50 ml of fluid should be withdrawn initially, aliquots being placed in separate containers for microbiological examination (including culture for tuberculosis), cytology and biochemical examination. Whenever there is a strong suspicion of tuberculosis, a large volume of pleural liquid should be submitted to the laboratory. Pleural biopsies should be taken after the initial pleural fluid sample has been aspirated for diagnostic purposes and before further drainage is undertaken.
The appearance of the fluid can be straw-coloured, blood-stained, purulent or chylous. Knowledge of the biochemical characteristics of pleural fluid can be very valuable in determining the aetiology of a pleural effusion. The most useful indices to measure are protein, lactate dehydrogenase, glucose and pH (see Fig. 13.15). The predominant cell type (neutrophil, eosinophil, lymphocyte, red blood cell) provides useful information, and fluid should always be examined for malignant cells.
Estimation of the total and differential peripheral blood leucocyte count, a tuberculin test and examination of the sputum for tubercle bacilli should be routine in most situations. A chest radiograph may disclose an underlying pulmonary lesion and indicate its nature. If the lung is obscured by a massive effusion, the radiograph should be repeated after the fluid has been aspirated. Other investigations which may be of help include bronchoscopy, biopsy or aspiration of enlarged regional lymph nodes, thoracoscopy and serological tests for antinuclear and rheumatoid factors.
The main diagnostic features and more important causes of pleural effusion are shown in Box 13.17.
Aspiration of pleural fluid may be necessary to relieve breathlessness. It is inadvisable to remove more than 1 litre on the first occasion because 're-expansion' pulmonary oedema occasionally follows the aspiration of larger amounts. A pneumothorax may be produced even by a careful operator, and a chest radiograph must always be taken after the procedure.
Treatment of the underlying cause-for example, heart failure, pneumonia, pulmonary embolism or subphrenic abscess-will often be followed by resolution of the effusion. However, certain conditions require special measures as detailed below.
Para-pneumonic pleural effusion
Figure 13.15 Pleural effusion. Biochemical characteristics.
Pleural effusions complicating pneumonia require complete and often repeated aspiration to ensure that an empyema has not developed and that one does not develop, and to reduce the extent of pleural thickening.
Tuberculous pleural effusion
Patients with tuberculous effusions should always receive antituberculosis chemotherapy (see p. 538). Aspiration is required initially if the effusion is large and causing breathlessness. The addition of prednisolone 20 mg daily by mouth for 4-6 weeks in patients with large effusions will promote rapid absorption of the fluid, obviate the need for further aspiration and may prevent fibrosis.
Effusions caused by malignant infiltration of the pleural surfaces usually reaccumulate rapidly. To avoid the distress of repeated aspirations, an attempt should be made to drain all fluid via an intercostal tube and then obliterate the pleural space (pleurodesis) by the injection of substances which produce an inflammatory reaction and extensive pleural adhesions. The agents most frequently used are talc and tetracycline.
A variety of respiratory disorders manifest themselves during sleep. For example, nocturnal cough and wheeze are characteristic features of asthma, and the hypoventilation that occurs during normal sleep can exacerbate respiratory failure in patients with restrictive lung disease such as kyphoscoliosis, diaphragmatic palsy, muscle weakness (e.g. muscular dystrophy) or intrinsic lung disease (e.g. COPD, pulmonary fibrosis). In contrast, a small but important group of disorders cause problems only during sleep. Patients with such disorders have normal lungs and day-time respiratory function but have either abnormalities of ventilatory drive (central sleep apnoea) or upper airway obstruction (obstructive sleep apnoea) that are manifested during sleep. Of these, the obstructive sleep apnoea/hypopnoea syndrome is by far the most common and important disorder.
THE SLEEP APNOEA/HYPOPNOEA SYNDROME
It is now recognised that 2-4% of the middle-aged population suffer from recurrent upper airway obstruction during sleep. Due to the ensuing sleep fragmentation they experience day-time sleepiness, especially in monotonous situations, and this results in a threefold increased risk of road traffic accidents and a ninefold increased risk of single-vehicle accidents.
The problem results from recurrent occlusion of the pharynx during sleep, most often starting at the level of the soft palate. On inspiration the pressure in the throat is subatmospheric. During wakefulness upper airway dilating muscles-including the palatoglossus and genioglossus-actively contract during each inspiration to preserve airway patency. During sleep, muscle tone declines and the ability of the upper airway dilating muscles to maintain pharyngeal patency falls. In most people sufficient tone persists to result in uncompromised breathing during sleep. However, in those who for some reason have a narrow throat when awake, upper airway muscle tone is more important and when it falls during sleep the airway narrows. If the narrowing is slight, turbulent flow and vibration occur, resulting in snoring; around 40% of middle-aged men and 20% of middle-aged women snore. If the upper airway narrowing progresses to the point of occlusion or near-occlusion, sleeping subjects increase respiratory effort to try to breathe until the increased effort transiently awakens them, so briefly that they have no recollection, but long enough for the upper airway dilating muscles to open the airway again. Then a series of deep breaths are taken before the subject rapidly returns to sleep, snores and becomes apnoeic once more. This recurrent cycle of apnoea, awakening, apnoea, awakening etc. may repeat itself many hundreds of times per night and result in severe sleep fragmentation. The awakenings are associated with surges in blood pressure which may lead to an increased frequency of hypertension, ischaemic heart disease and stroke.
Predisposing factors to the sleep apnoea/hypopnoea syndrome include being male, which doubles the risk, probably due to a testosterone effect on the upper airway, and obesity, found in about half the patients and having the effect of narrowing the throat by parapharyngeal fat deposits. Nasal obstruction or anomalies of the upper airway can further exacerbate the problem. Acromegaly and hypothyroidism also predispose individuals to this condition by causing submucosal infiltration and narrowing of the upper airway. The condition is often familial, and in these families the maxilla and mandible are back-set, thus narrowing the upper airway. Alcohol and sedatives predispose to snoring and apnoeas by relaxing the upper airway dilating muscles.
Excessive day-time sleepiness is the principal symptom and snoring is virtually universal. The patient usually feels that he or she has been asleep all night but wakes unrefreshed. Bed partners report loud snoring in all body positions and will often have noticed multiple breathing pauses (apnoeas). Difficulty with concentration, impaired cognitive function and work performance, depression, irritability and nocturia are other features.
Provided that the sleepiness does not result from inadequate time in bed or from shift work etc., any person who falls asleep during the day when not in bed, who complains that his or her work is impaired by sleepiness, or who is a habitual snorer with multiple witnessed apnoeas should be referred to a sleep or respiratory specialist. A more quantitative assessment of day-time sleepiness can be obtained by questionnaire (see Box 13.18).
13.18 EPWORTH SLEEPINESS SCALE
How likely are you to doze off or fall asleep in the situations described below? Use the following scale to choose the most appropriate number for each situation:
0 = would never doze
1 = slight chance of dozing
2 = moderate chance of dozing
3 = high chance of dozing
Sitting and reading
Sitting, inactive in a public place (e.g. a theatre or a meeting)
As a passenger in a car for an hour without a break
Lying down to rest in the afternoon when circumstances permit
Sitting and talking to someone
Sitting quietly after a lunch without alcohol
In a car, while stopped for a few minutes in the traffic
Normal subjects average 5.9 (S.D. 2.2) and patients with severe obstructive sleep apnoea average 16.0 (S.D. 4.4)
Figure 13.16 Sleep apnoea/hypopnoea syndrome: overnight oxygen saturation trace. The left panel shows the trace of a 46-year-old patient during a night when he slept without continuous positive airway pressure (CPAP) and had 53 apnoeas plus hypopnoeas/hour, 55 brief awakenings/hour and marked oxygen desaturation. The right panel shows the next night when he slept with a CPAP of 10 cm H2O delivered through a tight-fitting nasal mask which abolished his breathing irregularity and awakenings and improved his oxygenation.
Overnight studies of breathing, oxygenation and sleep quality are diagnostic (see Fig. 13.16) but the level of complexity of investigations will vary depending on the probability of diagnosis, differential diagnosis and resources. The current threshold for diagnosing the sleep apnoea/hypopnoea syndrome is 15 apnoeas/hypopnoeas per hour of sleep, where an apnoea is a 10-second or longer breathing pause and a hypopnoea a 10-second or longer 50% reduction in breathing.
13.19 DIFFERENTIAL DIAGNOSIS OF PERSISTENT SLEEPINESS
Lack of sleep
Inadequate time in bed
Extraneous sleep disruption (e.g. babies/children)
Excessive caffeine intake
Physical illness (e.g. pain)
Sleep apnoea/hypopnoea syndrome
Periodic limb movement disorder (recurrent limb movements during non-REM sleep, frequent nocturnal awakenings)
Sleepiness with relatively normal sleep
Idiopathic hypersomnolence (rare)
Neurological lesions (e.g. hypothalamic or upper brain-stem infarcts or tumours)
A number of other conditions can cause day-time sleepiness but these can usually be excluded by a careful history (see Box 13.19). Narcolepsy is a rare cause of sleepiness, occurring in 0.05% of the population (see p. 1133), and is associated with cataplexy (when muscle tone is lost in fully conscious people in response to emotional triggers and they may flop over-see p. 1133), hypnagogic hallucinations (hallucinations at sleep onset) and sleep paralysis. Idiopathic hypersomnolence occurs in younger individuals and is characterised by long nocturnal sleeps.
In a few patients advice to avoid evening alcohol and lose weight suffices, but most need to use continuous positive airway pressure (CPAP) delivered by a nasal mask every night at home. CPAP keeps the throat open by making the upper airway pressure above atmospheric. The pressure for CPAP is set in the laboratory to the lowest that will prevent apnoeas, hypopnoeas and awakenings. The effect is often dramatic (see Fig. 13.16) and CPAP results in improvements in symptoms, day-time performance, quality of life and survival. Unfortunately, 30-50% of patients are poorly compliant or do not tolerate such therapy. There is no evidence that upper airway surgery has any role in the management of this condition but mandibular advancement devices may be effective in some patients.
Respiratory failure results from a disorder in which lung function is inadequate for the metabolic requirements of the individual. Its classification into type I and type II relates to the absence or presence of hypercapnia (raised PaCO2). A summary of respiratory failure and its characteristic blood gas abnormalities is shown in Box 13.20.
Management of acute type I respiratory failure
The most common causes of acute type I respiratory failure (PaO2 < 8.0 kPa) are listed in Box 13.21.
All patients should be treated with a high-concentration (= 35%) of oxygen delivered by an oronasal mask. Young children may need to be treated in oxygen tents, since few of them tolerate masks. Very ill patients may require immediate ventilatory support, often involving tracheal intubation and mechanical ventilation (see p. 204). Effective management requires prompt diagnosis and treatment of the underlying disorder. Close monitoring is essential and arterial blood gases taken on presentation should be repeated within 20 minutes to establish that treatment has achieved acceptable PaO2 levels. If there is no improvement despite treating the underlying condition, an early decision about mechanical ventilation is necessary. In acute left ventricular failure, in massive pulmonary embolism and when pulmonary infarction or pneumonia is the cause of pleural pain, treatment with opiates is entirely appropriate, but these drugs should never be used in asthma or COPD, except immediately prior to and during assisted mechanical ventilation.
13.20 RESPIRATORY FAILURE
Type I (PaO2 <> 6.6 kPa)
Acute Chronic Acute Chronic
Typical blood gases PaO2?? PaO2? PaO2? PaO2?
PaCO2 ? or ? PaCO2 ? PaCO2¯? PaCO2?
pH ? or ? pH ? pH? pH? or ?
HCO3 ? HCO3 ? HCO3 ? HCO3?
Causes Acute asthma Emphysema Acute severe asthma COPD
Pulmonary embolus Lung fibrosis Acute epiglottitis Primary alveolar hypoventilation
Pulmonary oedema Lymphangitis Inhaled foreign body Kyphoscoliosis
ARDS carcinomatosa Respiratory muscle paralysis Ankylosing spondylitis
Pneumothorax Right-to-left shunts Flail chest injury
Pneumonia Anaemia Sleep apnoea
Therapy Treat underlying disorder Treat underlying disorder Treat underlying disorder Treat underlying disorder
High-concentration O2 Controlled long-term O2 Controlled low-concentration O2 Controlled long-term O2
Mechanical ventilation if necessary Mechanical ventilation (or tracheostomy) if necessary Mechanical ventilatory support if necessary
13.21 COMMON CAUSES OF ACUTE TYPE I RESPIRATORY FAILURE
Acute severe asthma (causes type II failure when life-threatening)-see page 519
Acute exacerbation of COPD (also causes type II failure)-see page 512
Left ventricular failure and other causes of pulmonary oedema-see page 377
Pulmonary embolism-see page 562
Pneumonia-see page 526
Pneumothorax-see page 570
ARDS-see page 198
Management of type II respiratory failure
In acute type II respiratory failure, also known as asphyxia, CO2 retention occurs (PaCO2 > 6.6 kPa) and causes severe acute respiratory acidosis (see Box 13.20). Treatment is aimed at immediate or very rapid reversal of the precipitating event-e.g. dislodgement of a laryngeal foreign body or tracheostomy, fixation of ribs in a flail chest injury, reversal of narcotic poisons, treatment of acute severe asthma etc. In some cases it will be necessary to support ventilation temporarily by means of non-invasive ventilation (see p. 204) or intubation and mechanical ventilation if the condition causing respiratory failure cannot immediately be reversed.
13.22 SOME CAUSES OF 'ACUTE ON CHRONIC' TYPE II RESPIRATORY FAILURE
Retention of secretions
Rib fractures/intercostal muscle tears
Central nervous system depression (narcotic drugs)
The most common cause of chronic type II respiratory failure is COPD. Here CO2 retention may occur on a chronic basis, the potential for acidaemia being corrected by renal conservation of bicarbonate, which results in the plasma pH remaining within the normal range. The status quo is often maintained until there is a further pulmonary insult (see Box 13.22), such as an exacerbation of COPD which precipitates an episode of 'acute on chronic' respiratory failure.
The further acute increase in PaCO2 results in acidaemia and worsening hypercapnia, and may lead to drowsiness and eventually coma. The principal aim of treatment in type II respiratory failure is to achieve a safe PaO2 (PaO2 > 7.0 kPa) without inducing extremes of PaCO2 or pH while identifying and treating the precipitating condition (see Box 13.22). It is important to note that in the patient who already has severe lung disease, only a small insult may be required to tip the balance towards catastrophic respiratory failure. Moreover, in contrast to acute severe asthma, a patient with type II respiratory failure due to COPD may not be overtly distressed despite being critically ill with severe hypoxaemia, hypercapnia and acidaemia.
In the initial assessment it is important to evaluate the patient's conscious level and his or her ability to respond to commands, particularly the ability to cough effectively. This may give a preliminary indication of whether intubation and tracheal suction may be necessary to clear secretions or whether physiotherapy will be helpful. The decision regarding mechanical ventilation can be complex and difficult. Ideally, an early decision should be made, based mainly on whether there is a potentially remediable precipitating condition (see Box 13.22) and whether the patient is likely to regain an acceptable quality of life. It is important to remember that while physical signs of CO2 retention (confusion, flapping tremor, bounding pulses etc.) can be helpful if present, they are often unreliable; there is no substitute for arterial blood gases in the assessment of initial severity and response to treatment.
13.23 ASSESSMENT AND MANAGEMENT OF 'ACUTE ON CHRONIC' TYPE II RESPIRATORY FAILURE
N.B. Patient may not appear distressed despite being critically ill.
Conscious level (response to commands, ability to cough)
CO2 retention (warm periphery, bounding pulses, flapping tremor)
Airways obstruction (wheeze, intercostal indrawing, pursed lips, tracheal 'tug')
Right heart failure (peripheral oedema, raised JVP, hepatomegaly, ascites)
Background functional status and quality of life
Signs of precipitating event (see Box 13.22)
Arterial blood gases (severity of hypoxaemia, hypercapnia and acidaemia)
Maintenance of airway
Treatment of specific precipitating event (see Box 13.22)
Frequent physiotherapy ± pharyngeal suction
Controlled oxygen therapy
Start with 24% controlled-flow mask
Aim for a PaO2 = 7 kPa (a PaO2 < 5 is very dangerous)
If PaCO2 continues to rise or patient cannot achieve a safe PaO2 without severe hypercapnia and acidaemia, respiratory stimulants (e.g. doxapram) or mechanical ventilatory support may be required
Prompt intervention may occasionally be necessary for some precipitating conditions, e.g. intercostal tube drainage of pneumothoraces or injection with local anaesthetic for fractured ribs and torn muscles; such interventions can result in a dramatic improvement of respiratory function (see Box 13.23). Generally, however, treatment is empirical and includes low-concentration controlled oxygen therapy (24-28% oxygen), physiotherapy, bronchodilators, broad-spectrum antibiotics and diuretics (see p. 512). While the dangers of hypercapnia should not be under-estimated, it is important to recognise that severe hypoxaemia must be reversed if the patient is not to suffer potentially fatal arrhythmias or severe cerebral complications. The aim of oxygen therapy is not necessarily to achieve a normal PaO2; even a small increment of increase in the PaO2 will often have a greatly beneficial effect on oxygen delivery to tissues since the arterial values of these patients are often on the very steep part of the oxygen saturation curve. If controlled oxygen treatment causes an increase in the PaCO2 associated with a reduction in pH, invasive or non-invasive ventilatory support (see p. 203) may be required. Doxapram (1.5-4 mg min-1) by slow intravenous infusion should only be used as a respiratory stimulant where non-invasive ventilation is not available or is poorly tolerated, or in those with reduced respiratory drive due to sedatives or anaesthetic agents. Even in these circumstances this agent provides only minor and transient improvements in arterial blood gas parameters.
The delivery of oxygen to tissue mitochondria is controlled by factors exerting influences at various levels, including: inspired oxygen concentration (FiO2); alveolar ventilation; ventilation-perfusion distribution within the lung; haemoglobin and concentrations of agents such as carbon monoxide which may bind to haemoglobin; influences on the oxygen-haemoglobin dissociation curve (see p. 192); cardiac output; and distribution of capillary blood flow within the tissues.
Many of the causes of hypoxaemia (see Box 13.21) are corrected by increasing the FiO2, but right-to-left shunting, either through circulatory channels bypassing the lung or through parts of the lung in which the alveoli are inaccessible to inspired oxygen, is less susceptible to such therapeutic approaches. The increased amount of dissolved oxygen carried by the blood which has perfused alveoli with a high PaO2 can saturate the haemoglobin in small quantities of shunted blood, but persistence of cyanosis when 100% oxygen is breathed indicates that the shunt is larger than 20% of the cardiac output.
The consequences of severe hypoxaemia include: systemic hypotension, pulmonary hypertension, polycythaemia, tachycardia, and undesirable cerebral consequences ranging from confusion to coma.
The objectives of oxygen therapy are:
to overcome the reduced partial pressure and quantity of oxygen in the blood
to increase the quantity of oxygen carried in solution in the plasma, even when the haemoglobin is fully saturated.
100% oxygen is both irritant and toxic if inhaled for more than a few hours. Premature infants develop retrolental fibroplasia and blindness if exposed to excessive concentrations. In adults, pulmonary oxygen toxicity (as manifested by pulmonary oedema) would not be expected to occur unless the patient had been treated with inappropriately high concentrations of oxygen for more than 24 hours.
Oxygen should always be prescribed in writing with clearly specified flow rates or concentrations.
High concentrations for short periods, such as 60% oxygen via a high-flow mask, are particularly useful in acute type I respiratory failure such as commonly occurs in pneumonia or asthma.
Low concentrations, via a 24% or 28% controlled-flow mask, are the most accurate method of delivering controlled oxygen therapy, particularly in type II respiratory failure. However, when a low concentration of oxygen is required continuously for more than a few hours, 1-2 litres per minute delivered via nasal double cannulae allows patients to eat and to undergo physiotherapy etc. while continuing to receive oxygen. When high-flow masks are used, the oxygen should be humidified by passing it over warm water. This is not necessary with low-flow masks or nasal cannulae, as a high proportion of atmospheric air is mixed with oxygen.
Chronic oxygen delivery from cylinders delivered to the home, or more conveniently from an oxygen concentrator, is often given via a low-concentration mask or nasal cannulae. Assessment for long-term oxygen therapy requires that patients should have a PaO2 of less than 7.3 kPa breathing air and an FEV1 of less than 1.5 litres in the steady state (i.e. at least 1 month since the previous exacerbation) (see p. 512). Long-term oxygen delivery has also been achieved by transtracheal microcatheters which have proved to be both oxygen-saving and of cosmetic benefit.
Patients with initially severe respiratory failure (type I or type II) or those who fail to improve despite optimal medical therapy may require mechanical ventilation. The various types of invasive (via an endotracheal tube) or non-invasive (via a face or nasal mask) ventilation are detailed on page 204. In many patients with respiratory failure, intermittent positive pressure ventilation (IPPV) with full sedation is indicated but nasal positive pressure ventilation (NPPV), delivered by a nasal mask, has proved to be of great value in the treatment of acute on chronic and chronic respiratory failure. Patients who benefit most from long-term (usually nocturnal) NPPV are those with skeletal deformity, especially kyphoscoliosis, and neuromuscular disease. However, NPPV can also be of value in some patients with central alveolar hypoventilation. It is now in widespread use in the acute situation in patients with COPD and type II respiratory failure, usually to try to avoid tracheal intubation and IPPV, but also in weaning such patients from mechanical ventilation.
Lung transplantation is now an established treatment for carefully selected patients with advanced cardiopulmonary disease unresponsive to medical treatment. Transplantation of both heart and lungs was the first successful approach for many disorders (see Box 13.24). However, improved surgical techniques and the shortage of donor organs have led to the development of isolated lung transplantation using double or single lungs. More recently, living lobar transplantation has been introduced. Single-lung transplantation is best applied for older patients with emphysema and patients with intrapulmonary restrictive disorders such as lung fibrosis. It is contraindicated in patients with chronic bilateral pulmonary infection, such as cystic fibrosis and bronchiectasis, where bilateral lung transplantation is the favoured option. Combined transplantation of the heart and lungs remains necessary for the treatment of patients with advanced congenital heart disease such as Eisenmenger's syndrome and is preferred by some surgeons for the treatment of primary pulmonary hypertension unresponsive to prostenoid therapy.
13.24 SOME INDICATIONS FOR HEART-LUNG TRANSPLANTATION
Parenchymatous lung disease
Langerhans cell histiocytosis
Pulmonary vascular disease
Primary pulmonary hypertension
Thromboembolic pulmonary hypertension
Eisenmenger's syndrome (see p. 470)
pages 494 - 508
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013041
For problems or suggestions concerning this service, please contact: email@example.com
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > OBSTRUCTIVE PULMONARY DISEASES
OBSTRUCTIVE PULMONARY DISEASES
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Chronic obstructive pulmonary disease is the internationally preferred term encompassing chronic bronchitis and emphysema. By definition COPD is a chronic, slowly progressive disorder characterised by airflow obstruction (FEV1 < 80% predicted and FEV1/VC ratio <70%) which does not change markedly over several months. The impairment of lung function is largely fixed but may be partially reversible by bronchodilator therapy. Historically, the term 'chronic bronchitis' was used to define any patient who coughed up sputum on most days of at least 3 consecutive months for more than 2 successive years (provided other causes of cough had been excluded) and 'emphysema' referred to the pathological process of a permanent destructive enlargement of the airspaces distal to the terminal bronchioles. Although 'pure' forms of these two conditions do exist, there is considerable overlap in the vast majority of patients.
Integration link: COPD
Taken from General & Systematic Pathology 4e
The death rate from COPD currently exceeds 25 000/year (> 20-fold higher than asthma) in England and Wales and this condition accounts for over 10% of all hospital medical admissions in the United Kingdom.
Aetiology and natural history
The single most important cause of COPD is cigarette smoking although in developing countries exposure to smoke from biomass and solid fuel fires is also important. Smoking is thought to have its effect by inducing persistent airway inflammation and causing a direct imbalance in oxidant/antioxidant capacity and proteinase/antiproteinase load in the lungs. Individual susceptibility to smoking is, however, very wide, with only 15% of smokers likely to develop clinically significant COPD. Recent studies have also emphasised the strong familial risks associated with the development of COPD, with the incidence of disease in an individual who smokes and has an affected sibling being 4.7 times that of matched controls. A small additional contribution to the severity of COPD has been reported in patients exposed to dusty or polluted air. An association also exists between low birth weight, bronchial hyper-responsiveness and the development of COPD. Alpha1-antitrypsin deficiency can cause emphysema in non-smokers but this risk is increased dramatically in enzyme-deficient patients who smoke. Stopping smoking slows the average rate of the decline in FEV1 from 50-70 ml/year to 30 ml/year (i.e. equal to non-smokers) (see Fig. 13.17). Interestingly, there is no evidence that acute exacerbations or drug therapy affect the rate of decline of the FEV1.
Figure 13.17 Model of annual decline in FEV1 with accelerated decline in susceptible smokers. When smoking is stopped, subsequent loss is similar to that in healthy non-smokers.
Figure 13.18 The pathology of emphysema. A Normal lung. B Emphysematous lung showing gross loss of the normal surface area available for gas exchange.
Most patients develop airway wall inflammation, hypertrophy of the mucus-secreting glands and an increase in the number of goblet cells in the bronchi and bronchioles with a consequent decrease in ciliated cells. There is, therefore, less efficient transport of the increased mucus in the airways. Airflow limitation reflects both mechanical obstruction in the small airways and loss of pulmonary elastic recoil. Loss of alveolar attachments around such airways makes them more liable to collapse during expiration.
Emphysema is usually centriacinar, involving respiratory bronchioles, alveolar ducts and centrally located alveoli. More rarely, panacinar emphysema (see Fig. 13.18) or paraseptal emphysema develops, with the latter responsible for blebs on the lung surface and/or giant bullae. Pulmonary vascular remodelling caused by persistent hypoxaemia results in pulmonary hypertension and right ventricular hypertrophy and dilatation.
Integration link: Emphysema - pathology
Taken from General & Systematic Pathology 4e
13.25 CLASSIFICATION AND DIAGNOSIS OF COPD
Severity Spirometry Symptoms
Mild FEV1 60-79% predicted Smoker's cough ± exertional breathlessness
Moderate FEV1 40-59% predicted Exertional breathlessness ± wheeze, cough ± sputum
Severe FEV1 < 40% predicted Breathlessness, wheeze and cough prominent, swollen legs
The clinical state is dictated largely by the severity of disease (see Box 13.25). The initial symptoms are usually repeated attacks of productive cough, usually after colds during the winter months, which show a steady increase in severity and duration with successive years until cough is present all the year round. Thereafter, patients suffer recurrent respiratory infections, exertional breathlessness, regular morning cough, wheeze and occasionally chest tightness. Sputum may be scanty, mucoid, tenacious and occasionally streaked with blood during infective exacerbations. Frankly purulent sputum is indicative of bacterial infection, which often occurs in these patients. Breathlessness is aggravated by infection, excessive cigarette smoking and adverse atmospheric conditions.
In patients with mild to moderate disease the respiratory examination may be normal. However, variable numbers of inspiratory and expiratory rhonchi, mainly low- and medium-pitched, are audible in most patients. Crepitations (crackles) which usually, but not always, disappear after coughing may be audible over the lower zones.
Physical signs associated with severe disease are outlined in Box 13.26. These reflect pulmonary hyperinflation, hypoxaemia, the development of cor pulmonale (pulmonary hypertension and right heart failure) and polycythaemia.
Integration link: "Pink puffers" and "blue bloaters"
Taken from General & Systematic Pathology 4e
Pulmonary bullae are thin-walled airspaces created by rupture of alveolar walls. They may be single or multiple, large or small, and tend to be situated subpleurally. Rupture of subpleural bullae may cause pneumothorax (see p. 570), and occasionally bullae increase in size, compress functioning lung tissue and further embarrass pulmonary ventilation. Respiratory failure and cor pulmonale are generally late complications in COPD patients.
Pulmonary function tests
The diagnosis and classification of COPD rest on objective demonstration of airways obstruction by spirometric testing (see Box 13.25). An abnormal FEV1 (< 80% predicted), with an FEV1/VC ratio of < 70% and little variation in serial PEF, strongly suggests COPD. A normal FEV1 excludes the diagnosis. The relationship between FEV1 and PEF is poor in COPD, and PEF in particular may under-estimate the degree of airflow obstruction in these patients.
Reversibility testing to salbutamol and ipratropium bromide is necessary to detect patients with substantial increases in FEV1 who really have asthma, and to establish the post-bronchodilator FEV1 which is the best predictor of long-term prognosis. Significant reversibility is defined as a 15% and at least 200 ml increase in FEV1. Evidence of a similar objective response to a course of oral prednisolone (30 mg daily for 2 weeks) should also be performed in all patients with COPD.
13.26 CLINICAL ABNORMALITIES IN PATIENTS WITH ADVANCED AIRFLOW OBSTRUCTION
Rhonchi, especially on forced expiration
A reduction in the length of the trachea palpable above the sternal notch
Tracheal descent during inspiration (tracheal 'tug')
Contraction of the sternomastoid and scalene muscles on inspiration
Excavation of the suprasternal and supraclavicular fossae during inspiration, together with indrawing of the costal margins and intercostal spaces
Increased antero-posterior diameter of the chest relative to the lateral diameter; loss of cardiac dullness
Loss of weight common (often stimulates unnecessary investigation)
Pursed lip breathing-physiological response to decrease air trapping
Flapping tremor and bounding pulse (due to hypercapnia)
Peripheral oedema which may indicate cor pulmonale
Raised JVP, right ventricular heave, loud pulmonary second sound, tricuspid regurgitation
Lung volumes show an increase in total lung capacity (TLC) and residual volume (RV) due to gas trapping; the carbon monoxide transfer factor and coefficient are markedly reduced in patients with a severe emphysema component. Alveolar underventilation causes a fall in PaO2 and often a permanent increase in PaCO2, especially in severe cases. Measurement of arterial blood gases should be performed in all patients with severe COPD (FEV1 < 40% predicted).
Exercise tests are of little diagnostic value but can provide an objective assessment of exertional dyspnoea.
Figure 13.19 Gross emphysema. High-resolution CT showing emphysema most evident in the right lower lobe.
COPD cannot be diagnosed on a chest radiograph but this investigation is useful in excluding other pathology. In moderate and severe COPD the chest radiograph typically shows hypertranslucent lung fields with disorganisation of the vasculature, low flat diaphragms or 'terracing' of the hemidiaphragms and prominent pulmonary artery shadows at both hila. Bullae may also be observed. CT can be used to quantify the extent and distribution of emphysema (see Fig. 13.19) but its clinical value is currently restricted to the assessment of bullous emphysema and the potential for lung volume reduction surgery or lung transplantation (see p. 508). Patients with a1-antitrypsin deficiency typically display basal disease, compared with the predominantly apical disease seen in smokers with normal a1-antitrypsin levels.
Polycythaemia (see p. 904) may develop but should not be assumed to be secondary without measurement of PaO2. Venesection may be considered if the haematocrit is above 0.55.
The treatment of patients with stable COPD is outlined in Figure 13.20.
Reduction of bronchial irritation
It is of extreme importance that the patient who smokes should stop completely and permanently. Participation in an active smoking cessation programme, together with the use of nicotine replacement therapy, leads to a higher quit rate. In well-motivated patients bupropion (150 mg once daily increasing to 150 mg 12-hourly on day 7) commenced 1-2 weeks prior to stopping smoking is also a valuable adjunct to smoking cessation. Bupropion is contraindicated in those patients with a history of epilepsy or known CNS tumour and should only be used for 7-9 weeks (see Box 13.27).
Figure 13.20 Summary of management of COPD.
Telephone advice for patients wanting to stop smoking is available in the UK on:
NHS Smoking Helpline: 0800 1690169
QUIT: 0800 002200.
13.27 RECOMMENDATIONS FOR USING ANTI-SMOKING INTERVENTIONS*
Smokers who are not motivated to try to stop smoking
Record smoking status at regular intervals
Encourage change in attitude regarding smoking to improve motivation
Motivated light smokers (< 10/day)
Involve in anti-smoking support programme
Motivated heavy smokers (10-15/day)
As above plus nicotine replacement therapy (NRT) (minimum 8 weeks)
Motivated heavy smokers (> 15/day)
As above plus bupropion if NRT and behavioural support unsuccessful and patient remains motivated
Dusty and smoke-laden atmospheres should be avoided; this may involve a change of occupation.
Treatment of respiratory infection
Respiratory infection should be treated promptly because it aggravates breathlessness and may precipitate type II respiratory failure in patients with severe airflow obstruction. Purulent sputum is treated with amoxicillin 250 mg 8-hourly (clarithromycin 250-500 mg 12-hourly if penicillin-sensitive) pending sputum culture results. Co-amoxiclav 375 mg 8-hourly should be used if there is no response or if a ß-lactamase-producing organism is cultured. The usual causative organisms are Streptococcus pneumoniae or Haemophilus influenzae. A 5-10-day course of treatment is usually effective. Well-informed, reliable patients can be given a supply of one of these drugs and start a course of treatment on their own initiative when the need arises.
Continuous suppressive antibiotic treatment is not advised as it is apt to promote the emergence of drug-resistant organisms within the respiratory tract. Influenza immunisation should be offered to all patients each year.
Bronchodilator and anti-inflammatory therapy
COPD-role of regular inhaled corticosteroids
'Several large RCTs have found no evidence for a long-term beneficial effect of inhaled corticosteroid therapy on the annual decline in FEV1 in patients with smoking-related COPD.'
Pauwels RA, Lofdahl CG, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue to smoke. N Engl J Med 1999; 340:1948-1953.
Burge PS, Calvertey PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-1303.
Bronchodilator therapy with regular inhaled anticholinergic agents and short-acting ß2-agonists taken as required provides useful symptomatic relief in the majority of patients. In moderate and severe COPD these agents should be used regularly and in combination, and low-dose inhaled steroids considered in patients with severe COPD and frequent exacerbations requiring hospital admission. These latter agents should not be used routinely (see EBM panel). Theophyllines and long-acting ß2-adrenoceptor agonists are of limited value in COPD but may produce small increases in exercise tolerance and quality of life. There is no role for other anti-inflammatory drugs. It is vital to check inhaler use as many patients with COPD struggle to use metered-dose inhalers (MDIs) effectively; dry powder inhalers or large-volume spacer devices are often preferable. The use of home nebulisers to deliver high doses of bronchodilator drugs is controversial. Treatment is expensive and may have important side-effects; however, a few patients may show significant objective or subjective improvements with such treatment.
Exercise should be encouraged and outpatient-based pulmonary rehabilitation programmes, while not affecting the FEV1, can improve exercise performance and reduce breathlessness. Obesity, poor nutrition, depression and social isolation should be identified and, if possible, improved. Expectorants, cough suppressants and mucolytic agents are of no proven benefit. Sedatives and opiate-based analgesic preparations are contraindicated.
Long-term domiciliary oxygen therapy
13.28 PRESCRIPTION OF LONG-TERM OXYGEN THERAPY (LTOT) IN COPD
Arterial blood gases measured in clinically stable patient on optimal medical therapy on at least two occasions 3 weeks apart
PaO2 < 7.3 kPa irrespective of PaCO2 and FEV1 < 1.5 litres
PaO2 7.3-8 kPa plus pulmonary hypertension, peripheral oedema or nocturnal hypoxaemia
Patient stopped smoking
Use at least 15 hours/day at 2-4 litres/min to achieve PaO2 > 8 kPa without an unacceptable rise in PaCO2
COPD-role of long-term domiciliary oxygen therapy (LTOT)
'Two RCTs have demonstrated that long-term oxygen therapy (used for = 15 hours/day) in patients with COPD and chronic and severe hypoxaemia improves survival, reduces secondary polycythaemia and prevents the progression of pulmonary hypertension. LTOT did not improve survival in patients with moderate hypoxaemia or in those with arterial desaturation occurring only at night.'
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxaemic chronic obstructive lung disease. A clinical trial. Ann Intern Med 1980; 93:391-398.
MRC Working Group. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681-686.
Crockett AJ, Cranston JM, Moss JR, Alpers JH. Domiciliary oxygen for COPD (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.brit-thoracic.org.uk
Long-term low-concentration oxygen therapy (2 litres/min by nasal cannulae) decreases pulmonary hypertension, reduces secondary polycythaemia, improves neuropsychological health and, most importantly, prolongs life in hypoxaemic COPD patients. The most efficient method of providing oxygen in this way is by an oxygen concentrator. Low-concentration oxygen should be administered for 15 hours or more per 24 hours. The criteria for the prescription of long-term oxygen therapy are given in Box 13.28.
Medical assessment and clearance are required in all patients who are dyspnoeic on walking 50 m. In practice, all patients with a resting PaO2 on air of < 9.0 kPa will require supplemental oxygen since at usual in-flight cabin pressures equivalent to an altitude of 5000-8000 feet the PaO2 of such patients will fall below 7 kPa. Hypercarbia or gross hypoxaemia while breathing air (PaO2 < 6.7 kPa) is a relative contraindication to air travel. Additional hazards include expansion of non-functioning emphysematous bullae and abdominal gases and drying of bronchial secretions.
A very small group of patients are suitable for surgical intervention. Young patients, particularly those with a1-antitrypsin deficiency and severe disease, should be considered for lung transplantation (usually single-lung), and surgical removal of expanding or very large bullae may be indicated in some patients. Lung volume reduction surgery, in which the most severely affected areas of emphysematous lung are removed in order to improve pulmonary mechanics, particularly by enhancing diaphragmatic function, is currently under assessment.
Treatment of acute COPD exacerbations
13.29 MANAGEMENT OF ACUTE COPD EXACERBATIONS
In the community
Add or increase bronchodilator therapy
Antibiotics (see p. 511)
Oral corticosteroids if patient already on oral corticosteroids, if previous response to such treatment, if airflow obstruction fails to respond to bronchodilator therapy or if first presentation of disease (prednisolone 30 mg daily for 1 week)
Check arterial blood gases (ABGs), chest radiograph, ECG, full blood count, urea and electrolytes; measure FEV1 + peak flow; send sputum for culture
Oxygen: 24-28% via mask, 2 litres/min by nasal prongs; check ABGs within 60 mins and adjust according to PaO2 (try to keep = 7.5 kPa) and PaCO2/pH
Bronchodilators: nebulised ß2-adrenoceptor agonist (+ ipratropium bromide if severe) 4-6-hourly. If no response consider i.v. aminophylline infusion
Oral corticosteroids: indicated as above
Diuretics: indicated if JVP elevated and oedema present
If pH <> 6, consider ventilatory support (invasive or non-invasive IPPV, see p. 508). If patient continuing to deteriorate despite non-invasive ventilation support, and endotracheal intubation not indicated (e.g. previous poor quality of life, significant comorbidity), doxapram can be considered
Prophylactic subcutaneous low molecular weight heparin
N.B. All patients should be reviewed 4-6 weeks after hospital discharge to assess ability to cope at home, FEV1, inhaler technique and understanding of treatment, and the potential need for LTOT or a home nebuliser.
The assessment and management of type I and type II respiratory failure are detailed on page 505. Acute exacerbations of COPD can present as increased sputum volume and purulence, increased breathlessness and wheeze, chest tightness and sometimes fluid retention. The differential diagnosis includes pneumonia, pneumothorax, left ventricular failure, pulmonary embolism, lung cancer and upper airway obstruction. The management of an acute COPD exacerbation is outlined in Box 13.29. Any patient with severe breathlessness, cyanosis, worsening oedema, impaired conscious level or poor social circumstances should be referred for hospital admission.
COPD EXACERBATIONS-role of non-invasive ventilation
'RCTs have demonstrated that the early use of non-invasive ventilation of patients with an acute exacerbation of COPD associated with mild to moderate respiratory acidosis (arterial pH 7.25-7.35, PaCO2 > 6 kPa) reduces the need for endotracheal intubation, the length of hospital stay and the in-hospital mortality.'
Brochard L, Mancebo J, Wysocki M, et al. Non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333:817-822.
Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet 2000; 355:1931-1935.
The best guide to the progression of COPD is the decline in FEV1 over time (normally 30 ml/year). The prognosis is inversely related to age and directly related to the post-bronchodilator FEV1. Patients with atopy have a significantly better survival but to date no drug treatment (aside from long-term oxygen therapy) has been shown to affect disease outcome. Pulmonary hypertension in COPD implies a poor prognosis. The mean survival of patients admitted with an acute exacerbation of COPD associated with an elevated PaCO2 that reverts to normal on recovery is 3 years.
Asthma is defined as a disorder characterised by chronic airway inflammation and increased airway responsiveness resulting in symptoms of wheeze, cough, chest tightness and dyspnoea. It is characterised functionally by the presence of airflow obstruction which is variable over short periods of time or is reversible with treatment. It is not a uniform disease but rather a dynamic clinical syndrome which has a number of clinical patterns. Many patients with well-controlled asthma are asymptomatic with normal lung function between exacerbations, although even these patients have evidence of chronic airway inflammation and hyper-responsiveness. By contrast, in some patients with chronic asthma the asthma progresses, leading to irreversible obstruction of the airways (see Box 13.30).
13.30 CARDINAL PATHOPHYSIOLOGICAL FEATURES OF ASTHMA
Usually reverses spontaneously or with treatment
Exaggerated bronchoconstriction to a wide range of non-specific stimuli, e.g. exercise, cold air
Eosinophils, lymphocytes, mast cells, neutrophils; associated oedema, smooth muscle hypertrophy and hyperplasia, thickening of basement membrane, mucous plugging and epithelial damage (see Fig. 13.22, p. 515)
Asthma is common and its prevalence is increasing. Studies using objective measurements of lung function, airway responsiveness and symptoms suggest that about 7% of adults and up to 15% of children in the UK have asthma. There is considerable interest in the reasons for the increase in the prevalence of asthma, most probably relating to changes in the indoor environment including early exposure to air allergens and cigarette smoke, fewer childhood infections and changes in diet. There is a wide variability in the geographical prevalence of asthma, with the highest rates observed in New Zealand, Australia and the UK, and the lowest in countries such as China and Malaysia.
Asthma is multifactorial in origin, arising from the interaction of both genetic and environmental factors. Airway inflammation characterising asthma occurs when genetically susceptible individuals are exposed to environmental factors, but the exact processes may vary from patient to patient. The timing, intensity and mode of exposure to aero-allergens are important environmental factors which stimulate the production of IgE.
It has long been known that asthma and atopy run in families. Asthma which begins in childhood generally occurs in atopic individuals who produce significant amounts of IgE on exposure to small amounts of common antigens. This contrasts with those patients who develop asthma in adult life and who are non-atopic, so-called 'intrinsic' or late-onset asthma. First-degree relatives of asthmatic patients have a higher prevalence of asthma when compared to relatives of non-asthmatic patients. Atopic individuals demonstrate positive reactions to antigens delivered in skin prick tests and have a high prevalence of asthma, allergic rhinitis, urticaria and eczema. Several potential gene linkages (e.g. chromosome 11q13) to asthma and atopy have been suggested; however, the genetic contribution to asthma remains poorly defined. It possibly involves polygenic inheritance with several genes contributing to the asthmatic tendency in any one individual, and genetic heterogeneity where different combinations of genes lead to asthma in different individuals.
The importance of environmental factors in the aetiology of asthma has been particularly evident in studies of populations who have migrated from one country to another. The change to a modern, urban, economically developed society seems to be particularly associated with the development of asthma.
Indoor. The indoor environment is a particularly important cause of asthma in children since allergen exposure early in life appears to be important in determining sensitisation. House dust mites abound in carpets, soft furnishings and bedding, and pet-derived allergens are widespread in houses where dogs or cats are kept. Other allergens of relevance are fungal spores and cockroach antigens. Pollutants such as nitrogen dioxide are found in higher concentrations indoors than outside as a result of gas cookers. Sulphur dioxide and particulate pollutants are released from open fires. Passive exposure to cigarette smoke immediately following birth increases the risk of developing asthma.
Outdoor. Experimental and population studies have shown that nitrogen dioxide, ozone, sulphur dioxide and air-borne particulates exacerbate asthma symptoms. The predominant source of nitrogen dioxide comprises motor vehicle emissions and fuel-burning industries. Nitrogen dioxide reacts with sunlight and oxygen in a photochemical reaction to produce ozone. Sulphur dioxide is created by the burning of fossil fuels and emissions from diesel-powered vehicles. Such vehicles also contribute to the development of air-borne particulates. Finally, levels of grass and flower pollens vary considerably according to the atmospheric conditions, as do allergens from rapeseed, soya bean and other crops. Interactions between atmospheric pollutants, aero-allergens and climate will have important effects on asthma, with some studies showing exposure to air pollution increasing airway responsiveness to allergens. Several epidemics of acute asthma have been associated with thunderstorms in patients sensitised to both pollen and fungal antigens.
Work. Many agents encountered in the workplace may induce occupational asthma, e.g. isocyanates, epoxy resins and wood dust.
Beta2-adrenoceptor antagonists (ß-blockers) can induce bronchoconstriction even when administered in the form of eye drops. Hence ß-blockers should be avoided in patients with asthma or COPD. Approximately 10% of asthmatic patients develop bronchoconstriction when given salicylates (e.g. aspirin) or non-steroidal anti-inflammatory agents.
Many viral and bacterial infections of the respiratory system produce a transient increase in airway responsiveness in asthmatic patients. Viruses in particular are an important cause of asthma exacerbations.
Smoking during pregnancy is thought to increase the risk of developing atopic disease in infancy, and passive exposure to smoking has an adverse effect on asthma and other respiratory diseases.
Anxiety and psychosocial factors
Any cause of severe anxiety or stress (see p. 252) can exacerbate asthma, and acute emotion may provoke an acute attack, but there is no evidence that asthmatics are primarily psychologically disturbed.
Figure 13.21 Changes in peak flow following allergen challenge. A similar biphasic response is observed following a variety of different challenges. Occasionally an individual will develop an isolated late response with no early reaction.
Figure 13.22 Pathological changes in asthma. A Pathological changes seen in the bronchus of an asthmatic. B Histological section of bronchus in a patient with asthma, demonstrating pathological changes as illustrated in A. (I = inflammatory cells in bronchial tissues; SM = smooth muscle; BM = basement membrane; EP = epithelium; M = mucus in airway lumen) C Mucus plug expectorated by patient with acute severe asthma.
The inhalation of an allergen in a sensitised atopic asthmatic patient results in a two-phase bronchoconstrictor response (see Fig. 13.21). The inhaled allergen rapidly interacts with mucosal mast cells via an IgE-dependent mechanism, resulting in the release of mediators such as histamine and the cysteinyl leukotrienes which lead to bronchoconstriction. A full spectrum of inflammatory cells, however, are involved in the perpetuation of the chronic inflammatory reaction in the bronchial wall which characterises asthma. It is now known that epithelial and smooth muscle cells are also capable of releasing inflammatory mediators rather than acting solely as passive targets. All of these cells are also involved in the initiation of asthma in non-atopic patients. T lymphocytes are present in increased numbers in asthmatic airways and have an important role in the regulation of the inflammatory response. They are programmed to release inflammatory cytokines amongst which IL-4 and IL-5 are of importance since they both recruit eosinophils to the airway and delay apoptosis of these cells. This pattern of cytokine release, which also includes IL-15, GM-CSF and IL-10, identifies the T cells as being of TH2 subtype. Eosinophils are characteristically present in increased numbers in the airway. These cells release bioactive lipid mediators and oxygen radicals; their granules also contain toxic basic proteins including major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin and eosinophil peroxidase. The number of airway macrophages is also increased in asthma and these cells may be activated by a number of mechanisms including a low affinity IgE receptor. Epithelial shedding (see Fig. 13.22) is commonly observed in airway biopsies from asthmatic patients. This has long been recognised as a feature of fatal asthma. Microvascular leakage is also a feature and may be triggered by many inflammatory mediators. This results in plasma exudation into the lumen of the airways, contributing to mucous plugging, decreased mucociliary clearance, release of kinins and complement fragments and oedema of the airway wall which facilitates epithelial stripping. The increase in airway smooth muscle bulk around the airways appears to be a particularly important contributory factor in airflow obstruction. Likewise, airway inflammation induces an imbalance between cholinergic and peptidergic neuronal control, causing exaggerated bronchoconstrictor responses. As a result of the ongoing airway inflammation, therefore, the asthmatic airway wall is thickened by oedema, cellular infiltration, increased smooth muscle mass and hypertrophy of mucus-secreting glands. With increasing severity and chronicity of the disease, remodelling of the airway occurs, leading to fibrosis of the airway wall, fixed narrowing of the airway and a reduced response to bronchodilator medication. Although in clinical practice patients with asthma are sometimes classified as having 'extrinsic' asthma (occurring in relation to inhalation of environmental antigens) or 'intrinsic' asthma (occurring without any definable relationship to an environmental antigen), the pathological features of the airway inflammation are identical. It is likely that the inflammatory cascade of asthma can be initiated by a variety of different factors in different patients.
Typical symptoms of asthma comprise wheeze, breathlessness, cough and a sensation of chest tightness. These symptoms may occur for the first time at any age, and may be episodic or persistent. Patients with episodic asthma are usually asymptomatic between exacerbations, which occur during viral respiratory tract infections or after exposure to allergens. This pattern of asthma is commonly seen in children or young adults who are atopic. In other patients the clinical pattern is of persistent asthma with chronic wheeze and breathlessness. This may sometimes make it difficult to distinguish from wheeze due to COPD or more unusual causes, e.g. cardiac failure. (Note that acute pulmonary oedema or an inhaled foreign body in a child can cause acute wheeze which can mimic acute severe asthma-see below.) This pattern is more common in older patients with adult-onset asthma who are non-atopic and typifies intrinsic asthma. The variable nature of symptoms is a characteristic feature. Typically, there is a diurnal pattern (see Fig. 13.23), with symptoms and peak expiratory flow measurement being worse in the early morning. Symptoms such as cough and wheeze often disturb sleep and the term 'nocturnal asthma' emphasises this. Cough may be the dominant symptom and the lack of wheeze or breathlessness may lead to a delay in making the diagnosis of so-called 'cough variant asthma'. Symptoms may be specifically provoked by exercise ('exercise-induced asthma'). All of these descriptive clinical terms are useful in emphasising the characteristic features of asthma particular to each patient and highlight the fact that asthma is not a uniform static disease but a broad dynamic syndrome.
Acute severe asthma
This term has replaced status asthmaticus as a description of life-threatening attacks of asthma. Patients are usually extremely distressed, using accessory muscles of respiration, are hyperinflated and tachypnoeic. Respiratory symptoms are accompanied by tachycardia, pulsus paradoxus (loss of pulse pressure on inspiration due to reduced cardiac return as a consequence of severe hyperinflation) and sweating. In very severe asthma central cyanosis occurs and airflow may have become so restrictive that rhonchi are no longer produced. The presence of a silent chest and bradycardia in such patients is an ominous sign.
A diagnosis of asthma is made on the basis of a compatible clinical history plus a demonstration of variable airflow obstruction (see Box 13.31) which may classically be seen as 'morning dipping' of the peak expiratory flow (see Fig. 13.23).
Figure 13.23 'Morning dipping'. Serial recordings of peak expiratory flow (PEF) in patients with COPD and asthma. Note sharp overnight fall (morning dip) and subsequent rise during the day in patients with asthma, which does not occur in patients with COPD.
13.31 MAKING A DIAGNOSIS OF ASTHMA
Compatible clinical history plus either/or:
= 15% improvement in FEV1 or PEF following administration of a bronchodilator (see Fig. 13.24) or
= 15% spontaneous change in PEF during 1 week of home monitoring (see Fig. 13.23)
In more difficult situations where the above tests are negative, an exercise test, a histamine or methacholine bronchial provocation test (see p. 517), an occupational exposure test or a trial of oral corticosteroids (e.g. prednisolone 30 mg daily for 2 weeks) may be required. An elevated sputum or peripheral blood eosinophil count, or an increased serum level of total or allergen-specific IgE (radioallergosorbent test-RAST) may also be helpful. It is particularly important, however, to be aware that wheeze is audible in many conditions other than asthma.
Pulmonary function tests
Figure 13.24 Reversibility test. Forced expiratory manoeuvres before and 20 minutes after inhalation of a ß2-adrenoceptor agonist. Note the increase in FEV1 from 1.0 to 2.5 litres.
Figure 13.25 Exercise-induced asthma. Serial recordings of forced expiratory volume in 1 second (FEV1) in a patient with bronchial asthma before and after 6 minutes of strenuous exercise. Note initial slight rise on completion of exercise, followed by sudden fall and gradual recovery. Adequate warm-up exercise or pre-treatment with a ß2-adrenoceptor agonist, nedocromil sodium or a leukotriene antagonist (e.g. montelukast sodium) often protects against exercise-induced symptoms.
Measurement of the FEV1/VC ratio or PEF provides a fairly reliable indication of the degree of airflow obstruction, and can also be used to determine whether and to what extent it can be relieved by bronchodilator drugs (see Fig. 13.24). These parameters are also used to examine whether asthma is provoked by exercise (see Fig. 13.25), hyperventilation or occupational exposure. Serial recordings of PEF are useful in distinguishing patients with chronic asthma from those with fixed or irreversible airflow obstruction associated with COPD. In asthma there is usually a marked diurnal variation in PEF, the lowest values being recorded in the mornings ('morning dipping') (see Fig. 13.23). Serial PEF recordings are also invaluable in the assessment of a patient's response to corticosteroid therapy and in the long-term monitoring of patients with poorly controlled disease. They are also essential in monitoring response to treatment in acute severe asthma.
Measurement of bronchial reactivity can be of value in diagnosing asthma and in assessing the effects of treatment. This can be achieved by administering increasing concentrations of substances such as histamine and methacholine by inhalation until there is a 20% fall in FEV1 or PEF. This concentration is called the PC20. Patients with asthma show evidence of bronchoconstriction at much lower concentrations than normal subjects.
In an acute attack of asthma the lungs appear hyperinflated. Between episodes the chest radiograph is usually normal. In long-standing chronic cases the appearances may be indistinguishable from hyperinflation caused by emphysema and a lateral view may demonstrate a 'pigeon chest' deformity. Occasionally, when a large bronchus is obstructed by tenacious mucus, there is an opacity caused by lobar or segmental collapse.
A chest radiograph should be performed in all patients with acute severe asthma. This is especially important if there is poor response to treatment and assisted ventilation is being contemplated, since pneumothorax is a rare but potentially fatal complication. The chest radiograph may rarely show mediastinal, pericardial or subcutaneous emphysema in patients with acute severe asthma.
Allergic bronchopulmonary aspergillosis may complicate chronic persisting asthma (see p. 540) and produce areas of segmental/subsegmental collapse and proximal bronchiectasis.
Arterial blood gas analysis
Measurements of arterial blood gas pressures (PaO2 and PaCO2) are indispensable in the management of patients with acute severe asthma.
Successful management of asthma mandates that the patient or parents of a child with asthma understand the nature of the condition and its treatment. Patient education should begin at the time of diagnosis and be revisited in every subsequent consultation between patient, doctor or nurse. Education involves the patient understanding the nature of asthma, the practical skills necessary to manage asthma successfully and the adoption of appropriate actions in response to deteriorating asthma. It is important for patients to appreciate differences between reliever (bronchodilator) and preventer (anti-inflammatory) medications and patients should be fully capable of using their inhaler devices. Use of a peak flow meter provides patients with an objective measure of airway obstruction and allows them to monitor the effect of treatment and the severity of exacerbations. There is clear evidence that the development of a personalised asthma action plan for patients improves outcome and this should be discussed individually with patients.
ASTHMA-role of self-management plans
'Self-management plans advising asthmatic patients how to respond to worsening symptoms or PEF lead to less need for emergency medical care, less time off work and a better quality of life.'
Lahdensno A, Halahtela T, Herals J, et al. Randomised comparison of guided self-management and traditional treatment of asthma over one year. BMJ 1996; 312:748-752.
Ignacio-Garcia J, Gonzalez-Santos P. Asthma self-management education program by home monitoring of peak expiratory flow. Am J Respir Crit Care Med 1995; 151:353-359.
Avoidance of precipitating factors
There are few instances in which a single agent can be identified as a cause of an asthma exacerbation; however, where possible, measures can be taken to prevent or reduce allergen exposure, such as avoiding contact with household pets.
Desensitisation is a highly specialised technique in which repeated injections of an allergen are given in an attempt to produce blocking antibody of IgG type which can prevent the allergen from binding to specific IgE on mast cells. It is most commonly used in well-documented life-threatening anaphylactic reactions to insect stings; there is little evidence of its benefit in asthma and this form of therapy has largely been abandoned in the UK because of the attendant risks.
Management of chronic persistent asthma
Treatment should be stepped up or down as required, with PEF monitoring being key to such decisions. The patient should be allowed to select the best inhaler device for himself or herself, and compliance and inhaler technique must be checked at every opportunity. All metered dose inhalers (MDIs) which remain the most cost-effective inhaler devices will be reformulated over the next few years to replace conventional chlorofluorocarbon (CFC) propellants with hydrofluoroalkanes (HFAs). While these products are equally effective and as safe as current CFC-containing MDIs, the aerosol characteristics are different and this may be noticed by patients. In patients with mild to moderate asthma (on step 1-3 medication-see below and Fig. 13.26) the aim of treatment should be to abolish or minimise all symptoms, permit unrestricted exercise and prevent exacerbations. In patients with more severe disease (on step 4-5 medication) the aim should be to achieve the best possible and most stable PEF, to improve symptoms and exercise capacity, and to reduce the need for bronchodilator drug use as far as possible with the least adverse effects from the drugs used.
Step 1 Occasional use of inhaled short-acting ß2-adrenoceptor agonist bronchodilators
Figure 13.26 Concept of step-up and step-down drug treatment in asthma.
Short-acting bronchodilators, such as salbutamol or terbutaline, are used by inhalation as required for the relief of occasional minor symptoms. If the patient is using ß2-adrenoceptor agonists more than once daily, move to step 2. Beta2-adrenoceptor agonist therapy alone is only recommended if it is used occasionally and when this allows the patient to lead an active normal life free from nocturnal and exercise-induced asthmatic symptoms.
Step 2 Regular inhaled anti-inflammatory agents
Inhaled short-acting ß2-adrenoceptor agonists are used as required and the patient is commenced on a regular inhaled steroid (beclometasone dipropionate, budesonide or fluticasone propionate) up to 800 µg daily (or 400 µg daily for fluticasone propionate). Alternatively, sodium cromoglicate or nedocromil sodium can be used instead of an inhaled corticosteroid, but these drugs are rarely effective outside childhood.
INHALED SHORT-ACTING ß2-ADRENOCEPTOR AGONISTS-regular versus as-needed treatment
'Systematic review of 24 RCTs found that regularly scheduled as opposed to as-needed use of short-acting inhaled ß2-adrenoceptor agonists in people with mild intermittent asthma provides no additional clinical benefit.'
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol [salbutamol] in mild asthma. Asthma Clinical Network. N Engl J Med 1996; 335:841-847.
Walters EH, Walters J. Inhaled short-acting beta2-agonist use in asthma: regular vs as needed treatment (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Step 3 High-dose inhaled corticosteroids, or low-dose inhaled corticosteroids plus a long-acting inhaled ß2-adrenoceptor agonist
Inhaled short-acting ß2-adrenoceptor agonists are used as required plus an inhaled corticosteroid in the dose range 800-2000 µg daily. Alternatively, a long-acting ß2-adrenoceptor agonist (e.g. formoterol (eformoterol) fumarate 6 µg 12-hourly or salmeterol 50 µg 12-hourly) or a sustained-release theophylline may be added. When corticosteroids are inhaled in high dose via a conventional pressurised MDI, the use of a large-volume spacer (holding chamber) is recommended. When dry powder inhalers are used, mouth-rinsing and gargling with spitting out of the rinsing liquid after each treatment should be encouraged. Spacers and mouth-rinsing are recommended to decrease gastrointestinal absorption of swallowed drug, and to lower the risk of developing the local side-effect of oropharyngeal candidiasis. Recent studies have suggested that the addition of a long-acting ß2-adrenoceptor agonist is more effective in improving symptoms, improving lung function and reducing exacerbations than increasing the dose of inhaled corticosteroids.
CHRONIC ASTHMA-role of long-acting ß2-adrenoceptor agonists
'RCTs have found that in patients whose asthma is poorly controlled by inhaled corticosteroids, the addition of a long-acting ß2-adrenoceptor agonist improves symptoms and lung function and reduces exacerbations.'
Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994; 344:219-224.
Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 387:1405-1411.
Further information: www.brit-thoracic.org.uk
Step 4 High-dose inhaled corticosteroids and regular bronchodilators
Inhaled short-acting ß2-adrenoceptor agonists are used as required with an inhaled corticosteroid (800-2000 µg daily) plus a sequential therapeutic trial of one or more of:
inhaled long-acting ß2-adrenoceptor agonist (e.g. salmeterol 50 µg 12-hourly or formoterol fumarate (eformoterol fumarate) 12 µg 12-hourly)
leukotriene receptor antagonist (e.g. montelukast sodium)
inhaled ipratropium bromide or oxitropium bromide
long-acting oral ß2-adrenoceptor agonist (sustained-release salbutamol or terbutaline preparations)
high-dose inhaled ß2-adrenoceptor agonists
sodium cromoglicate or nedocromil sodium.
The role of anti-IgE antibody therapy in patients with severe atopic asthma is under evaluation.
Step 5 Addition of regular oral corticosteroid therapy
Step 4 treatment is given plus regular prednisolone tablets prescribed in the lowest amount necessary to control symptoms as a single daily dose in the mornings.
Using this 'stepwise' approach to asthma management (see Fig. 13.26), the initial treatment for each patient should be chosen individually depending upon severity of disease. In general, it is better to start with a treatment regimen which is likely to achieve disease control rapidly and then 'step down' rather than to start with inadequate treatment and then have to 'step up'. Patient compliance is also likely to be better when symptom control is achieved rapidly. Regular review is important and if there has been good symptomatic control for 3-6 months a step down should be made. This is of particular importance in those taking oral and high-dose inhaled corticosteroids (steps 3-5).
Short-course oral corticosteroid treatments
Short courses of 'rescue' oral corticosteroids are often required to regain control of symptoms. For adults, 30-60 mg of prednisolone can be given initially and the same dose continued in a single daily dose each morning until 2 days after control is re-established. In children, a dose of 1-2 mg/kg body weight can be used. Tapering of the dose to withdraw treatment is not necessary unless given for more than 3 weeks. Indications for 'rescue' courses include:
symptoms and PEF progressively worsening day by day
fall of PEF below 60% of the patient's personal best recording
onset or worsening of sleep disturbance by asthma
persistence of morning symptoms until midday
progressively diminishing response to an inhaled bronchodilator
symptoms severe enough to require treatment with nebulised or injected bronchodilators.
Increase in dose of inhaled corticosteroid
Doubling the dose of inhaled corticosteroids is often advised to control minor exacerbations of asthma not severe enough to warrant treatment with oral prednisolone. This appears to be effective in many cases.
Management of acute severe asthma
The aims of management are to prevent death, to restore pulmonary function to the patient's best as quickly as possible, to maintain optimal pulmonary function and to prevent early relapse. The features of acute severe asthma are shown in Box 13.32.
13.32 IMMEDIATE ASSESSMENT OF ACUTE SEVERE ASTHMA
Features of severity
Pulse rate > 110 per min
Unable to speak in sentences
PEF < 50% of expected
N.B. Apparent distress and respiratory rate may be misleading.
Exhaustion, confusion, reduced conscious level
Arterial blood gases in life-threatening asthma
A normal (5-6 kPa) or high CO2 tension
Severe hypoxaemia (< 8 kPa), especially if being treated with oxygen
A low pH or high [H+]
PEF should be recorded immediately in all patients unless they are too ill to cooperate. PEF measurements are most easily interpreted when expressed as a percentage of the predicted normal value or of the previous best value obtained on optimal treatment. When neither of these is known, decisions have to be made on the absolute value recorded, remembering that normal values vary with age, sex and height. In a previously fit asthmatic patient, recordings of <200 l/min are indicative of severe disease, and values of <100 l/min must be taken as evidence of life-threatening asthma.
Immediate treatment (see Fig. 13.27)
Oxygen. Oxygen should be given at the highest concentration available (usually 60%). High-concentration oxygen therapy does not cause or aggravate carbon dioxide retention in asthma, and the presence of carbon dioxide retention must not be interpreted as a contraindication for the use of high-concentration oxygen treatment. Thereafter, the concentration of oxygen used can be adjusted according to the arterial blood gas measurements. A PaO2 of > 8.5-9 kPa should be maintained if possible.
High doses of inhaled ß2-adrenoceptor agonists. When possible, ß2-adrenoceptor agonists should be nebulised using oxygen. Salbutamol 2.5-5 mg or terbutaline 5-10 mg should be given initially and repeated within 30 minutes if necessary. When treatment is given outside hospital and oxygen is not available, an air compressor can be used to drive the nebuliser. An alternative method of giving high doses of ß2-adrenoceptor agonists in general practice is multiple actuations of an MDI into a large-volume spacer device.
Systemic corticosteroids. Systemic corticosteroids are necessary for the treatment of all cases of acute severe asthma. Oral prednisolone 30-60 mg (or intravenous hydrocortisone 200 mg if the patient is unable to swallow or vomiting) should be given initially.
Figure 13.27 Immediate treatment of patients with acute severe asthma.
ACUTE ASTHMA-use of intravenous aminophylline
'Two SRs of RCTs examining the effect of adding intravenous aminophylline to initial standard therapy with nebulised ß2-adrenoceptor agonists and systemic corticosteroids in acute asthma failed to demonstrate any beneficial effect of aminophylline. The frequency of adverse effects was also higher with aminophylline.'
Parameswaran K, Beida J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Hart SP. Should aminophylline be abandoned in the treatment of acute asthma in adults? QJM 2000; 93:761-765.
Use of intravenous aminophylline is not recommended (see EBM panel).
13.33 CONTINUED MANAGEMENT OF ACUTE SEVERE ASTHMA
If features of severity persist:
Ipratropium bromide 0.5 mg should be added to the nebulised ß2-adrenoceptor agonist
Continue nebulised ß2-adrenoceptor agonist treatment every 15-30 minutes as necessary. Reduce to 4-hourly once clear clinical response
Magnesium sulphate (25 mg/kg i.v., maximum 2 g)
13.34 INDICATIONS FOR ASSISTED VENTILATION IN ACUTE SEVERE ASTHMA
Deterioration of arterial blood gas tensions despite optimal therapy
PaO2 < 8 kPa and falling
PaCO2 > 6 kPa and rising
pH low and falling (H+ high and rising)
Exhaustion, confusion, drowsiness
All patients must be closely supervised and oxygen therapy continued. If features of severity persist, additional measures may be required (see Box 13.33). Systemic corticosteroid treatment with oral prednisolone 30-60 mg daily is recommended for patients responding to treatment, but intravenous hydrocortisone 200 mg 6-hourly should be continued in the seriously ill. Mechanical ventilation is necessary as a life-saving procedure in a few patients. Indications for endotracheal intubation and intermittent positive pressure ventilation are shown in Box 13.34.
Monitoring of treatment
PEF recordings should be made every 15-30 minutes to assess early response and as necessary thereafter. In hospital PEF values should be charted 4-6-hourly before and after inhaled bronchodilator treatments throughout the period of hospital stay.
Repeat measurement of arterial blood gas tensions and pH or H+ within 1-2 hours is necessary in all patients if the first arterial sample showed features of life-threatening disease (see Box 13.33). Continuous monitoring of oxygen saturation by pulse oximetry is valuable in all patients to help assess response. Oximetry may also prevent the need to repeat an arterial puncture in some patients.
The prognosis of individual asthma attacks is generally good. There is occasionally a fatal outcome, especially if treatment is inadequate or delayed. Spontaneous remission is fairly common in episodic asthma, particularly in children, but rare in chronic asthma. Seasonal fluctuations can occur in both types of asthma. Atopic subjects with episodic asthma are usually worse in the summer when they are more heavily exposed to antigens, while chronic asthmatic patients are usually worse in winter months because of the increased frequency of viral infections.
Prior to discharge from hospital, patients should have been taking discharge medication (i.e. changed from nebulised drugs) for 24 hours and have a PEF of 75% predicted or personal best over that period. They should also have their own PEF meter, a written self-management plan, an adequate supply of medication and an appointment to be reviewed by their GP within 7 days.
Aetiology and pathogenesis
Bronchiectasis is the term used to describe abnormal dilatation of the bronchi. It is usually acquired (see Box 13.35) but may result from an underlying congenital defect of immune or ciliary function.
13.35 CAUSES OF BRONCHIECTASIS
Ciliary dysfunction syndromes
Primary ciliary dyskinesia (immotile cilia syndrome)
Primary hypogammaglobulinaemia (see p. 795)
Pneumonia (complicating whooping cough or measles)
Allergic bronchopulmonary aspergillosis (see p. 540)
In the UK the symptoms of bronchiectasis can often be tracked back to a severe bacterial infection in childhood consequent upon whooping cough or measles. World-wide, pulmonary tuberculosis remains the most common cause of bronchiectasis.
Bronchiectasis may be due to bronchial distension resulting from the accumulation of pus beyond a lesion obstructing a major bronchus, such as compression by tuberculous hilar lymph nodes, an inhaled foreign body or a bronchial tumour. Recurrent infection and chronic obstruction by viscid mucus are both factors in causing bronchiectasis in cystic fibrosis (see p. 522). Rarely, it may be the result of congenital dysfunction of the cilia, which is a feature of, for example, Kartagener's syndrome (bronchiectasis, sinusitis and transposition of the viscera), or immunoglobulin deficiency.
The bronchiectatic cavities may be lined by granulation tissue, squamous epithelium or normal ciliated epithelium. There may also be inflammatory changes in the deeper layers of the bronchial wall and hypertrophy of the bronchial arteries. Chronic inflammatory and fibrotic changes are usually found in the surrounding lung tissue.
Bronchiectasis may involve any part of the lungs but the more efficient drainage by gravity of the upper lobes usually produces less serious symptoms and complications than when bronchiectasis involves the lower lobes.
The groups of clinical features that occur in more severe cases are shown in Box 13.36.
Physical signs in the chest may be unilateral or bilateral. If the bronchiectatic airways do not contain secretions and there is no associated lobar collapse, there are no abnormal physical signs. When there are large amounts of sputum in the bronchiectatic spaces numerous coarse crepitations can be heard over the affected areas. When collapse is present the character of the physical signs depends on whether or not the proximal bronchus supplying the collapsed lobe is patent (see Box 13.5, p. 490).
13.36 SYMPTOMS OF BRONCHIECTASIS
Due to accumulation of pus in dilated bronchi
Chronic productive cough usually worse in mornings and often brought on by changes of posture. Sputum often copious and persistently purulent in advanced disease
Due to inflammatory changes in lung and pleura surrounding dilated bronchi
Fever, malaise and increased cough and sputum volume when spread of infection causes pneumonia, which is frequently associated with pleurisy. Recurrent pleurisy in the same site often occurs in bronchiectasis
Can be slight or massive and is often recurrent. Usually associated with purulent sputum or an increase in sputum purulence. Can, however, be the only symptom in so-called 'dry bronchiectasis'
When disease is extensive and sputum persistently purulent a decline in general health occurs with weight loss, anorexia, lassitude, low-grade fever, and failure to thrive in children. In these patients digital clubbing is common
Bacteriological and mycological examination of sputum
This is necessary in all patients but is especially important in bronchiectasis associated with cystic fibrosis and in any patient who has had numerous courses of antibiotics.
Bronchiectasis, unless very gross, is not usually apparent on a chest radiograph. In advanced disease the cystic bronchiectatic spaces may be visible. Abnormalities produced by associated pulmonary infection and/or collapse are evident. A diagnosis of bronchiectasis can only be made with certainty by CT (see Fig. 13.5, p. 491).
Assessment of ciliary function
A screening test can be performed in patients suspected of having a ciliary dysfunction syndrome by assessing the time taken for a small pellet of saccharin placed in the anterior chamber of the nose to reach the pharynx, when the patient can taste it. This time should not exceed 20 minutes and is greatly prolonged in patients with ciliary dysfunction. It is also possible to assess ciliary function by measuring ciliary beat frequency using biopsies taken from the nose. If ciliary function is thought to be impaired, the ciliary ultrastructure should also be determined by electron microscopy.
In addition to optimising treatment with inhaled bronchodilators and corticosteroids to enhance airway patency, the aim of this measure is to keep the dilated bronchi empty of secretions. Efficiently performed, it is of great value both in reducing the amount of cough and sputum and in preventing recurrent episodes of bronchopulmonary infection. In its simplest form, postural drainage consists of adopting a position in which the lobe to be drained is uppermost, thereby allowing secretions in the dilated bronchi to gravitate towards the trachea, from which they can readily be cleared by vigorous coughing. 'Percussion' of the chest wall with cupped hands aids dislodgement of sputum, and a number of mechanical devices are available which cause the chest wall to oscillate, thus achieving the same effect as postural percussion and chest wall compression. The optimum duration and frequency of postural drainage depend on the amount of sputum but 5-10 minutes once or twice daily is a minimum for most patients. Forced expiratory manoeuvres ('huffing and puffing') are of help in augmenting the expectoration of sputum.
The policy governing the use of antibiotics in most patients with bronchiectasis is the same as that in COPD (see p. 511). Some, especially those with cystic fibrosis, present difficult therapeutic problems because of secondary infection with bacteria such as staphylococci and Gram-negative bacilli, in particular Pseudomonas species. In these circumstances antibiotic therapy should be guided by the microbiological results but frequently requires the use of oral ciprofloxacin (250-750 mg twice daily) or ceftazidime by intravenous injection or infusion (100-150 mg/kg daily in three divided doses). The bronchi of some patients with cystic fibrosis also become colonised by Aspergillus fumigatus.
Surgery is only indicated in a small minority of individuals. These are usually young patients in whom the bronchiectasis is unilateral and confined to a single lobe or segment as demonstrated by CT. Unfortunately, many of the patients in whom medical treatment proves unsuccessful are also unsuitable for pulmonary resection because of either extensive bronchiectasis or coexisting chronic lung disease. Resection of areas of bronchiectatic lung has no role in the management of the progressive forms of bronchiectasis-for example, those associated with ciliary dysfunction and cystic fibrosis.
The disease is progressive when associated with ciliary dysfunction and cystic fibrosis, and inevitably causes respiratory failure and right ventricular failure. In other patients the prognosis can be relatively good if postural drainage is performed regularly and antibiotics are used judiciously.
As bronchiectasis commonly starts in childhood following measles, whooping cough or a primary tuberculous infection, it is essential that these conditions receive adequate prophylaxis and treatment. The early recognition and treatment of bronchial obstruction are also particularly important.
Epidemiology and pathogenesis
Figure 13.28 Cystic fibrosis: basic defect in the pulmonary epithelium. A The CF gene codes for a chloride channel (1) in the apical (luminal) membrane of epithelial cells in the conducting airways. This channel is normally controlled by cyclic adenosine monophosphate (cAMP) and indirectly by ß-adrenoceptor stimulation. It is one of several apical ion channels which together control the quantity and solute content of airway-lining fluid. Normal channels appear to inhibit the adjacent epithelial sodium channels (2). B In CF, one of many CF gene defects causes absence or defective function of this chloride channel (3). This leads to reduced chloride secretion and loss of inhibition of sodium channels with excessive sodium resorption (4) and dehydration of the airway lining. The resulting abnormal airway-lining fluid is believed to predispose to infection by mechanisms which are not fully understood.
Cystic fibrosis (CF) is the most common severe autosomal recessive disease in Caucasians, occurring with a carrier rate of 1 in 25 and an incidence of about 1 in 2500 live births (see p. 344). CF is the result of mutations affecting a gene (located on the long arm of chromosome 7) which encodes for a chloride channel known as cystic fibrosis transmembrane conductance regulator (CFTR), which is essential for the regulation of salt and water movement across cell membranes. The most common CFTR mutation in northern European and American populations is d508, but numerous mutations have now been identified in this region. The genetic defect causes an increased sodium chloride content in sweat and increased electrical potential difference across the respiratory epithelium which can be detected in the nose (see Fig. 13.28). This results in much increased viscosity of secretions in the lung and other organs, which causes ciliary dysfunction and chronic bronchial infection. Recurrent exacerbations of bronchial infection predispose to bronchial wall damage, eventually causing bronchiectasis, often predominantly in the upper lobes initially but subsequently in all areas of both lungs, with the end result of death from respiratory failure. There are also disorders in the gut epithelium, and in the pancreas and liver (causing intestinal malabsorption, diabetes and hepatic cirrhosis). Most men with CF are infertile due to failure of development of the vas deferens. Population carrier screening is feasible but unlikely to affect overall patient numbers significantly. However, early diagnosis can be achieved by neonatal screening, and in some cases by amniocentesis.
13.37 COMPLICATIONS OF CYSTIC FIBROSIS
Distal intestinal obstruction syndrome
Increased frequency of gallstones
Diabetes (11% of adults)
Lung function is normal at birth, which leads to the hope that if the basic defect can be corrected by gene therapy many of the sequelae (see Box 13.37) might be avoided. Bronchiectasis, however, usually develops at a young age. Initially, the bacteria associated with CF are those expected in bronchiectasis of other causes (see p. 521), but infection with Staphylococcus aureus tends to be early in CF and the majority have Pseudomonas infection at an early age. Repeated lung infections, inflammation and scarring almost inevitably lead to respiratory failure and death.
The management of established cystic fibrosis is that of severe bronchiectasis (see opposite). All patients with cystic fibrosis who produce sputum should have regular chest physiotherapy, which should be performed more frequently during exacerbations. Lung infections are usually predominantly caused by Pseudomonas species and Staph. aureus. Unfortunately, the bronchi of many CF patients eventually become colonised with pathogens which are resistant to most antibiotics; Pseudomonas aeruginosa and Burkholderia cepacia (previously known as Pseudomonas cepacia) are the main culprits. Infections with Haemophilus influenzae can be treated with a number of antibiotics and Staph. aureus should be treated with flucloxacillin or erythromycin. Patients requiring frequent courses of intravenous antibiotics for the control of Pseudomonas infections can, with benefit, be taught self-administration via an in-dwelling central venous port and cannula, implanted subcutaneously in the chest wall to allow intravenous therapy at home. Nebulised antibiotic therapy, mainly with colistin, is used between exacerbations in an attempt to suppress chronic pseudomonal infection.
CYSTIC FIBROSIS-role of nebulised anti-pseudomonal antibiotics
'Meta-analysis of RCTs demonstrates that nebulised anti-pseudomonal antibiotic therapy improves lung function and decreases the risk of infective exacerbations and hospitalisation in patients with cystic fibrosis and Pseudomonas aeruginosa infection. The long-term benefit and impact of such treatment on quality of life and survival remain to be determined.'
Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340:23-30.
Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.update-software.com/ccweb/cochrane/revabstr/ab001021.htm
Treatment with nebulised recombinant human DNAase (rhDNAase) has been available since 1994. The aim of this therapy is to solubilise DNA derived from disintegrated inflammatory cells, which is a major contributor to the viscosity of bronchial secretions in CF, in which it is present in abundance. This therapy has been shown to improve pulmonary function and increase well-being in a subgroup of patients, and perhaps also to reduce the number of infective exacerbations. There is also some evidence that it can reduce the neutrophil elastase load and, therefore, decelerate bronchial wall tissue damage. It has to be emphasised that this treatment is very expensive and is not of benefit to all patients, which makes clinical selection of patients for such treatment difficult. Aerosol a1-antitrypsin treatment has been used to reduce the neutrophil elastase load, but this form of therapy is even less established than rhDNAase.
A number of patients with cystic fibrosis develop symptoms of bronchospasm, which can be treated effectively with bronchodilators following appropriate reversibility tests. Allergic bronchopulmonary aspergillosis (see p. 540) is also a well-recognised complication of CF. It is also common for 'atypical mycobacteria' to be cultured from the sputum of CF patients, but it is frequently difficult to determine whether these organisms are causing disease, or are benign 'colonisers' of the bronchiectatic airways which do not require specific therapy.
The prognosis of CF has greatly improved in the last decade, mainly because of better control of bronchial sepsis and maintenance of nutrition. The median survival of patients with CF is now predicted to be at least 40 years for children born in the 1990s. Organ transplantation remains last-resort therapy for patients with end-stage disease.
The potential for somatic gene therapy
The discovery of the CF gene and the fact that the lung defect is located in the respiratory epithelium (which is accessible by inhaled therapy) presents an exciting opportunity for gene therapy. The CF gene could be 'packaged' within a liposome or incorporated by genetic engineering into a modified viral vector and delivered to the respiratory epithelium with the aim of correcting the genetic defect. The feasibility of this approach is currently under investigation and initially promising results have been obtained in preliminary studies of the CF gene delivered to the nasal mucosa of CF patients. Studies of the delivery of the gene to the bronchi are in progress.
ISSUES IN OLDER PEOPLE
OBSTRUCTIVE PULMONARY DISEASE
Both COPD and asthma are common in old age and are not mutually exclusive. A bias towards misdiagnosis of COPD rather than asthma is well recognised in elderly men and those of lower socio-economic class.
Older people with poor vision have difficulty reading PEFmeters.
Older people perceive acute bronchoconstriction less well than younger patients, so their description of symptoms is not a reliable indicator of severity, and 'on demand' bronchodilators may not be appropriate as a first step in treatment.
The beneficial effects of stopping smoking on the rate of loss of lung function decline with age but remain valuable up to the age of 80.
Most older people cannot use metered dose inhalers because of difficulty coordinating and triggering the device. Even mild cognitive impairment virtually precludes their use. Spacer devices are much preferred by patients. Frequent demonstration and reinstruction in the use of all devices are required.
Mortality rates for acute asthma are higher in old age, partly because patients under-estimate the severity of bronchoconstriction and develop less tachycardia and pulsus paradoxus for the same degree of bronchoconstriction.
Advanced age in itself is not a barrier to intensive care or mechanical ventilation in an acute episode of asthma or COPD, but a decision about this can be difficult and should be shared with the patient (if possible), relatives and general practitioner.
pages 508 - 524
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013094
For problems or suggestions concerning this service, please contact: firstname.lastname@example.org
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > INFECTIONS OF THE RESPIRATORY SYSTEM
INFECTIONS OF THE RESPIRATORY SYSTEM
Infections of the upper and lower respiratory tract continue to be a major cause of morbidity and mortality throughout the world, with patients at the extremes of age or with pre-existing lung disease or immune suppression being at particular risk. Viruses are the most frequent cause of upper respiratory illnesses, with bacteria being responsible for the majority of community- and hospital-acquired pneumonia in adults. Organisms such as Mycoplasma, Coxiella and Chlamydia are less common causes of severe pneumonia. Pulmonary infection by Mycobacterium tuberculosis, atypical mycobacteria and fungi results in diseases of a more chronic type. These are described separately.
UPPER RESPIRATORY TRACT INFECTIONS
13.38 THE COMMON AND MOST IMPORTANT UPPER RESPIRATORY TRACT INFECTIONS: CLINICAL FEATURES, COMPLICATIONS AND MANAGEMENT
Infection Clinical features Complications Management
Acute coryza (common cold) Rapid onset. Burning and tickling sensation in nose. Sneezing. Sore throat. Blocked nose with watery discharge. Discharge usually green/yellow after 24-48 hrs. Nasal allergy can give rise to similar clinical features Sinusitis. Lower respiratory tract infection (bronchitis/pneumonia). Hearing impairment, otitis media (due to blockage of eustachian tubes) Most do not require treatment. Paracetamol 0.5-1 g 4-6-hourly for relief of systemic symptoms. Nasal decongestant in some cases. Antibiotics not necessary in uncomplicated coryza
Acute laryngitis Often a complication of acute coryza. Dry sore throat. Hoarse voice or loss of voice. Attempts to speak cause pain. Initially, painful and unproductive cough. Stridor in children (croup) because of inflammatory oedema leading to partial obstruction of a small larynx Complications rare. Chronic laryngitis. Downward spread of infection may cause tracheitis, bronchitis or pneumonia Rest voice. Paracetamol 0.5-1 g 4-6-hourly for relief of discomfort and pyrexia. Steam inhalations may be of value. Antibiotics not necessary in simple acute laryngitis
Acute laryngo-tracheobronchitis (croup)* Initial symptoms like common cold. Sudden paroxysms of cough accompanied by stridor and breathlessness. Contraction of accessory muscles and indrawing of intercostal spaces. Cyanosis and asphyxia in small children, if appropriate treatment not given Asphyxia. Death. Superinfection with bacteria, especially Strep. pneumoniae and Staph. aureus. Viscid secretions may occlude bronchi Inhalations of steam and humidified air/high concentrations of oxygen. Endotracheal intubation or tracheostomy to relieve laryngeal obstruction and allow clearing of bronchial secretions. Intravenous antibiotic therapy for seriously ill (co-amoxiclav or erythromycin). Maintain adequate hydration
Acute epiglottitis Fever and sore throat, rapidly leading to stridor because of swelling of epiglottis and surrounding structures (infection with H. influenzae). Stridor and cough in absence of much hoarseness may distinguish acute epiglottitis from other causes of stridor Death from asphyxia which may be precipitated by attempts to examine the throat-avoid using a tongue depressor or any instrument unless facilities for endotracheal intubation or tracheostomy are immediately available Intravenous antibiotic therapy essential. Co-amoxiclav or chloramphenicol. Other measures as for acute laryngotracheobronchitis
Acute bronchitis and tracheitis Often follows acute coryza. Initially irritating unproductive cough accompanied by retrosternal discomfort of tracheitis. Chest tightness, wheeze and breathlessness when bronchi become involved. Tracheitis causes pain on coughing. Sputum is initially scanty or mucoid. After a day or so sputum becomes mucopurulent, more copious and, in tracheitis, often blood-stained. Acute bronchial infection may be associated with a pyrexia of 38-39°C and a neutrophil leucocytosis. Spontaneous recovery occurs over a few days Bronchopneumonia. Exacerbation of chronic bronchitis which often results in type II respiratory failure in patients with severe COPD. Acute exacerbation of bronchial asthma Specific treatment rarely necessary in previously healthy individuals. Cough may be eased by pholcodine 5-10 mg 6-8-hourly. In patients with COPD (see p. 508) and asthma (see p. 513) aggressive treatment of exacerbations may be required. Amoxicillin 250 mg 8-hourly should be given to previously healthy patients who are thought to be developing bronchopneumonia (see also p. 526)
Influenza (a specific acute illness caused by a group of myxoviruses- two common types, A and B) Sudden onset of pyrexia associated with generalised aches and pains, anorexia, nausea and vomiting. Degree of ill health ranges from mild to rapidly fatal. Usually harsh unproductive cough. Most patients do not develop complications and acute symptoms subside within 3-5 days, but may be followed by 'post-influenzal asthenia' which can persist for several weeks. During epidemics the diagnosis is usually easy. Sporadic cases may have to be diagnosed by virus isolation, fluorescent antibody techniques or serological tests for specific antibodies Tracheitis, bronchitis, bronchiolitis and bronchopneumonia. Secondary bacterial invasion by Strep. pneumoniae, H. influenzae and Staph. aureus may occur. Toxic cardiomyopathy may cause sudden death (rare). Encephalitis, demyelinating encephalopathy and peripheral neuropathy are also rare complications Bed rest is advisable until fever has subsided. Paracetamol 0.5-1 g 4-6-hourly can be used to relieve headache and generalised pains. Pholcodine 5-10 mg 6-8-hourly may be given to suppress cough. Specific treatment for pneumonia (see p. 528) may be necessary
*Whooping cough (caused by Bordetella pertussis) is often considered a disease of non-immunised children but it also occurs in sporadic 'epidemics' in middle life when immunisation effectiveness has waned. After a short, febrile tracheobronchitis (which itself is responsive to antibiotics), severe episodic paroxysmal coughing bouts, associated with laryngospasm and often leading to intercostal muscle tears or fractured ribs, may persist for many weeks.
13.39 RESPIRATORY INFECTIONS CAUSED BY VIRUSES
Clinical syndrome Usual cause (other causes in parentheses)
Epidemic influenza Influenza A and B
'Influenza-like' illness Adenoviruses, rhinoviruses (enteroviruses)
Sore throat Adenoviruses (enteroviruses, parainfluenza viruses, influenza A and B in partially immune)
Common cold (coryza) Rhinoviruses (coronaviruses, enteroviruses, adenoviruses, respiratory syncytial virus)
'Feverish' cold Rhinoviruses, enteroviruses (influenza A and B, parainfluenza viruses, respiratory syncytial virus)
Croup Parainfluenza 1, 2, 3 (rhinoviruses, enteroviruses)
Bronchitis Rhinoviruses, adenoviruses (influenza A and B)
Bronchiolitis Respiratory syncytial virus (parainfluenza 3)
Pneumonia Influenza A and B, chickenpox (respiratory syncytial virus, parainfluenza, measles and adenoviruses in children and elderly)
The clinical features, complications and management of the common and most important upper respiratory tract infections are summarised in Box 13.38. The vast majority of these illnesses, of which acute coryza (common cold) is by far the most common, are caused by viruses (see Box 13.39). Immunity is short-lived and virus-specific. Other viral infections include acute laryngitis and acute laryngotracheobronchitis. Bacterial infection is the usual cause of acute tonsillitis, otitis media and epiglottitis.
ACUTE UNCOMPLICATED UPPER RESPIRATORY TRACT INFECTIONS-role of antibiotics
'Two SRs of RCTs have found no evidence that antibiotics have a clinically important effect in patients with acute undifferentiated upper respiratory tract infections. Antibiotics can prevent the non-suppurative complications of ß-haemolytic streptococcal pharyngitis.'
Arrol B, Kenealy T. The use of antibiotics versus placebo in the common cold (Cochrane Review). Cochrane Library, issue 3, 1999. Oxford: Update Software.
Fahey T, Stocks N, Thomas T. Systematic review of the treatment of upper respiratory tract infection. Arch Dis Child 1998; 79:225-230.
INFLUENZA VACCINE-use in elderly people
'One SR of cohort studies and several recent RCTs have found that influenza vaccination reduces the risk of influenza and death in elderly people.'
Gross PA, Hermogenes AW, Sacks HS, et al. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995; 123:518-527.
Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy of influenza vaccination in elderly persons living in the community. N Engl J Med 1994; 31:778-784.
Further information: www.clinicalevidence.org
Most patients with upper respiratory tract infections recover rapidly and specific investigation is indicated only in more severe illness. The possibility of acute epiglottitis, which represents a medical emergency, must be considered at all times (see Box 13.38). Viruses can be isolated from exfoliated cells collected on throat swabs, and may be identified retrospectively by serological tests. Certain viruses can be identified in exfoliated cells by the fluorescent antibody technique, allowing the pathogen to be identified more rapidly. Throat swabs may also be helpful if streptococcal pharyngitis is suspected, and examination of the blood will identify infectious mononucleosis (see p. 16). Radiographic examination may be required if an underlying chronic infection involving the sinuses is suspected.
Pneumonia is defined as an acute respiratory illness associated with recently developed radiological pulmonary shadowing which either is segmental or affects more than one lobe. As the setting in which a pneumonia develops has such major implications for the likely organisms involved and hence dictates the immediate choice of antibiotics, pneumonias are now classified as community-acquired, hospital-acquired, or those occurring in the immunocompromised host or damaged lung (including suppurative and aspirational pneumonia).
This form of pneumonia is responsible for over 1 000 000 admissions per year in the UK. Infection is usually spread by droplet inhalation and, while most patients affected are previously well, cigarette smoke, alcohol and corticosteroid therapy all impair ciliary and immune function. Other risk factors include old age, recent influenza infection, pre-existing lung disease and, for certain forms of pneumonia, contact with sick birds (Chlamydia psittaci) or farm environments (Coxiella burnetii). Knowledge of the patient's recent travel history and local epidemics is also valuable. Appropriate investigation allows a microbiological diagnosis to be made in approximately 60% of patients with pneumonia. 'Lobar pneumonia' is a radiological and pathological term referring to homogeneous consolidation (red hepatisation) of one or more lung lobes, often with associated pleural inflammation; bronchopneumonia refers to more patchy alveolar consolidation associated with bronchial and bronchiolar inflammation often affecting both lower lobes.
Patients present with a short illness of cough, fever and malaise, often associated with pleuritic chest pain which is occasionally referred to the shoulder or anterior abdominal wall. The cough is characteristically short, painful and at first dry, but later becomes productive and may become rust-coloured or even frankly blood-stained. The sudden onset of a high fever can result in rigors or, in children, vomiting or a febrile convulsion. Appetite is usually lost and headache is a frequent accompanying symptom. In patients with severe pneumonia confusion can be an early and dominant problem. Certain features may suggest a particular microbiological diagnosis (see Box 13.40).
13.40 CLINICAL AND RADIOLOGICAL CHARACTERISTICS OF COMMUNITY-ACQUIRED PNEUMONIAS CAUSED BY SPECIFIC ORGANISMS
Organism Frequency* Clinical features Radiological features
Streptococcus pneumoniae 30%(+) Young to middle-aged, rapid onset, high fever, rigors, pleuritic chest pain, herpes simplex labialis, 'rusty' sputum Lobar consolidation, one or more lobes
Chlamydia pneumoniae 10% Young to middle-aged, large-scale epidemics or sporadic, often mild, self-limiting disease Small segmental infiltrates
Associated sinusitis, pharyngitis, laryngitis
White cell count often normal, liver transaminases elevated
Usually diagnosed on serology
Mycoplasma pneumoniae 9% Children and young adults, autumn and 3-4-yearly cycles Patchy or lobar consolidation, hilar lymphadenopathy may be seen
Insidious onset, headaches, systemic features, often few signs in chest
Erythema nodosum, myocarditis, pericarditis, meningoencephalitis, rash, haemolytic anaemia
Legionella pneumoniae 5% Middle to old age, recent travel, local epidemics around point source, e.g. cooling tower Shadowing may spread despite antibiotics and often slow to resolve
Headache, malaise, myalgia, high fever, dry cough, gastrointestinal symptoms
Confusion, hepatitis, hyponatraemia, hypoalbuminaemia
Haemophilus influenzae 3% Often underlying lung disease, purulent sputum Bronchopneumonia
Staphylococcus aureus < 1% Coexistent debilitating illness Lobar or segmental. Abscess formation, residual cysts
Often complicates viral pneumonia
Can arise from, or cause, abscesses in other organs, e.g. osteomyelitis
Chlamydia psittaci < 1% Contact with sick birds Patchy lower lobe consolidation
Malaise, low-grade fever, protracted illness
Coxiella burnetii Farm or abattoir contact Multiple segmental opacities
Chronic course, influenza-like illness, dry cough, conjunctivitis, hepatomegaly, endocarditis
Klebsiella pneumoniae < 1% Systemic disturbance marked, widespread consolidation, often in upper lobes, purulent dark sputum, high mortality Expansion of affected lobes
Actinomyces israelii < 1% Mouth commensal Cervicofacial, abdominal or pulmonary infection, empyema, chest wall sinuses, pus with 'sulphur grains' Abscesses, pleural effusions and bone involvement
Primary viral pneumonias Influenza, parainfluenza and measles can cause pneumonia commonly complicated by bacterial infection Respiratory syncytial virus seen mainly in infancy Varicella (chickenpox) can cause severe pneumonia Chickenpox produces multiple miliary nodular shadows which may calcify
*No microbiological diagnosis established in approximately 40% of patients with community-acquired pneumonia admitted to hospital.
Physical signs include a significant pyrexia, tachycardia, tachypnoea, evidence of hypoxaemia and, not infrequently, hypotension and confusion. Pleurisy often results in diminution of respiratory movement and a pleural rub on the affected side. At a variable time after onset, generally within 2 days, signs of consolidation appear, with impairment of the percussion note and high-pitched bronchial breath sounds. When resolution begins, numerous coarse crepitations are heard, indicating liquefaction of the alveolar exudate. If a para-pneumonic pleural effusion develops, physical signs of fluid in the pleural space are usually found, but bronchial breath sounds can persist and the presence of an empyema (see p. 569) may be suspected only from the recurrence or persistence of pyrexia. Upper abdominal tenderness is sometimes apparent in patients with lower lobe pneumonia or if there is associated hepatitis.
The main objectives of investigating patients with a clinically based diagnosis of pneumonia are:
to obtain a radiological confirmation of the diagnosis
to exclude other conditions that may mimic pneumonia (see Box 13.41)
to obtain a microbiological diagnosis
to assess the severity of the pneumonia
to identify the development of complications.
In lobar pneumonia, the chest radiograph shows a homogeneous opacity localised to the affected lobe or segment; this usually appears within 12-18 hours of the onset of the illness (see Fig. 13.29). Radiological examination is also particularly helpful if a complication such as pleural effusion, intrapulmonary abscess formation or empyema is suspected. Hilar lymphadenopathy is occasionally seen in mycoplasma pneumonia, and lung cavities are more frequently observed in patients with staphylococcal or pneumococcal serotype 3 pneumonia. Follow-up radiological examination is essential as failure of a pneumonia to resolve may indicate underlying bronchial obstruction (e.g. a foreign body or carcinoma).
13.41 DIFFERENTIAL DIAGNOSIS OF PNEUMONIA
Often presents like bacterial pneumonia, but pyrexia usually less, cough not as troublesome, haemoptysis much more common and the source of embolism may be apparent
Acute pulmonary tuberculosis can simulate pneumonia, but patients seldom as acutely ill. Tuberculous pleurisy may also present like a bacterial pleural infection
Pulmonary oedema, especially if unilateral and localised, may be difficult to distinguish from pneumonia on the chest radiograph. Absence of fever and presence of heart disease favour a diagnosis of oedema
Inflammatory conditions below the diaphragm
Conditions such as cholecystitis, perforated peptic ulcer, subphrenic abscess, acute pancreatitis and hepatic amoebiasis may be mistaken for lower lobe pneumonia associated with diaphragmatic pleurisy
Pulmonary eosinophilia, intrathoracic manifestations of connective tissue disorders, acute allergic alveolitis, Wegener's granulomatosis
Every effort should be made to establish a microbiological diagnosis, as such information is invaluable in tailoring antibiotic therapy and in managing any complications. The identification of organisms such as Legionella pneumophila also has important public health implications. Rapid results can sometimes be obtained with 'bedside' complement fixation tests for antigen levels (for example, of H. influenzae and Pneumocystis carinii) in urine and other body fluids. In patients who are severely ill a microbiological diagnosis becomes essential and, if sputum cannot be obtained, an attempt should be made to aspirate secretions or washings from the trachea or lower respiratory tract either by bronchoscopy or by inserting a needle through the cricothyroid membrane. Some patients can be induced to produce sputum by the administration of nebulised hypertonic saline. A summary of the microbiological investigations required in patients with community-acquired pneumonia is provided in Box 13.42; see also Figure 13.30.
Arterial blood gas measurements
These should be measured in all patients admitted to hospital with a diagnosis of pneumonia.
General blood tests
A high neutrophil leucocytosis favours a diagnosis of bacterial (particularly pneumococcal) pneumonia; patients with pneumonia caused by atypical agents tend to have a marginally raised or normal white cell count. A marked leucopenia indicates either a viral aetiology or an overwhelming bacterial infection.
Assessment of disease severity
Figure 13.29 Pneumonia of the right middle lobe. A Postero-anterior (PA) view: consolidation in right middle lobe with characteristic opacification beneath the horizontal fissure and loss of normal contrast between the right heart border and lung. B Lateral view: consolidation confined to the anteriorly situated middle lobe.
It is essential that in every patient with a clinical diagnosis of pneumonia an assessment is made to determine the severity of the disease. The use of simple clinical and laboratory parameters can determine very accurately those at high risk of death (see Box 13.43) and forms an important guide to the level of patient monitoring required. This assessment also has an important bearing on antibiotic choice. As a simple guide, patients with two or more of the four cardinal markers of severity, namely a respiratory rate = 30, a diastolic blood pressure = 60 mmHg, a serum urea = 7 mmol/l or the presence of confusion, have a 36-fold higher risk of dying compared with those patients without such features. Likewise, it is important to appreciate that a higher proportion of patients with mycoplasma pneumonia die compared to those with pneumococcal pneumonia and that in the latter condition coexistent septicaemia increases the mortality rate significantly.
13.42 MICROBIOLOGICAL INVESTIGATIONS IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA
Severe community-acquired pneumonia
The above tests plus consider:
Tracheal aspirate, induced sputum, bronchoalveolar lavage, protected brush specimen or percutaneous needle aspiration. Direct fluorescent antibody stain for Legionella and viruses
Serology-Legionella antigen in urine. Pneumococcal antigen in sputum and blood. Immediate IgM for Mycoplasma
Cold agglutinins-positive in 50% of patients with Mycoplasma
Throat/nasopharyngeal swabs-helpful in children or during influenza epidemic
Pleural fluid-should always be sampled when present in more than trivial amounts, preferably with ultrasound guidance
Sputum-direct smear by Gram (see Fig. 13.30) and Ziehl-Neelsen stains. Culture and antimicrobial sensitivity testing
Blood culture-frequently positive in pneumococcal pneumonia
Serology-acute and convalescent titres to diagnose Mycoplasma, Chlamydia, Legionella and viral infections. Pneumococcal antigen detection in serum
Figure 13.30 Gram stain of sputum showing Gram-positive diplococci characteristic of Strep. pneumoniae (arrows).
With appropriate intervention most patients respond promptly to antibiotic treatment. Delayed recovery suggests either that some complication such as empyema has developed or that the diagnosis is incorrect. Alternatively, the pneumonia may be secondary to a proximal bronchial obstruction or recurrent aspiration which delays recovery.
Oxygen should be administered to all hypoxaemic patients, and high concentrations (=35%) should be used in all patients who do not have hypercapnia associated with advanced COPD. Assisted ventilation should be considered at an early stage in all patients who remain significantly hypoxaemic despite adequate oxygen therapy. Most patients with moderate to severe pneumonia also require intravenous fluids and occasionally inotrope support (see p. 203).
13.43 FEATURES ASSOCIATED WITH A HIGH MORTALITY IN PNEUMONIA
Age 60 years or older
Respiratory rate > 30/min
Diastolic blood pressure 60 mmHg or less
More than one lobe involved on chest radiograph
Presence of underlying disease
Hypoxaemia (PaO2 < 8 kPa)
Leucopenia (white blood cells < 4000 × 109/litre)
Leucocytosis (white blood cells > 20 000 × 109/litre)
Raised serum urea (> 7 mmol/l)
Positive blood culture
13.44 ANTIBIOTIC TREATMENT FOR COMMUNITY-ACQUIRED PNEUMONIA (CAP)
Amoxicillin 500 mg 8-hourly orally
If patient allergic to penicillin
Clarithromycin 500 mg 12-hourly orally or
Erythromycin 500 mg 6-hourly orally
If Staphylococcus is cultured or suspected
Flucloxacillin 1-2 g 6-hourly i.v. plus
Clarithromycin 500 mg 12-hourly i.v.
If Mycoplasma or Legionella is suspected
Clarithromycin 500 mg 12-hourly orally or i.v. or
Erythromycin 500 mg 6-hourly orally or i.v. plus
Rifampicin 600 mg 12-hourly i.v. in severe cases
Clarithromycin 500 mg 12-hourly i.v. or Erythromycin 500 mg 6-hourly i.v. plus
Co-amoxiclav 1.2 g 8-hourly i.v. or Ceftriaxone 1-2 g daily i.v. or Cefuroxime 1.5 g 8-hourly i.v. or Amoxicillin 1 g 6-hourly i.v. plus flucloxacillin 2 g 6-hourly i.v.
Antibiotics should be given as soon as a clinical diagnosis of pneumonia is made. If possible, culture specimens should be sent prior to starting antibiotics but such treatment should not be delayed if, for example, a sputum sample is not readily available. The antibiotic regimens currently recommended in uncomplicated and severe community-acquired pneumonia are detailed in Box 13.44. If Strep. pneumoniae is identified as the causative organism, benzylpenicillin 1-2 g 6-hourly (i.v.) can be used in place of amoxicillin. Oral cephalosporins should not be used in the management of community-acquired pneumonia as they do not penetrate well into sputum or bronchial fluids and do not cover likely organisms. Patients with proven Klebsiella pneumonia should be treated with gentamicin (dose according to patient age, weight, creatinine clearance and intended frequency of use) plus either ceftazidime 1 g 8-hourly (i.v.) or ciprofloxacin 200 mg 12-hourly (i.v. infusion). Chlamydia pneumoniae is a somewhat difficult organism to culture and hence most cases are diagnosed late or retrospectively on serological grounds. In proven or suspected (epidemic) cases, erythromycin or tetracycline is recommended. Psittacosis is treated with tetracycline 500 mg 6-hourly orally or 500 mg 12-hourly i.v., or erythromycin at an equivalent dose. Actinomycosis, which is now regarded as an anaerobic bacterial infection, responds best to benzylpenicillin 2-4 g 6-hourly (i.v.). Chickenpox pneumonia is usually treated with oral aciclovir 200 mg five times daily for 5 days.
In most cases of uncomplicated pneumococcal pneumonia a 7-10-day course of treatment is usually adequate, although treatment is usually required for 14 days or longer in patients with Legionella, staphylococcal or Klebsiella pneumonia.
Treatment of pleural pain
It is important to relieve pleural pain in order to allow the patient to breathe normally and cough efficiently. Mild analgesics such as paracetamol are rarely adequate and most patients require pethidine 50-100 mg or morphine 10-15 mg by intramuscular or intravenous injection. Opiates, however, must be used with extreme caution in patients with poor respiratory function.
Formal physiotherapy is not indicated in patients with community-acquired pneumonia; however, assisted coughing is important in patients who suppress cough because of pleural pain. The administration of analgesic drugs should be coordinated with this form of physiotherapy to optimise patient cooperation.
Assessing progress can be difficult in patients with pneumonia. Although the response to antibiotics may be rapid and dramatic, fever may persist for several days and the chest radiograph often takes several weeks or even months to resolve, especially in the elderly. Failure to respond to therapy may indicate use of the wrong antibiotic, mixed infection, bronchial obstruction, the wrong diagnosis (e.g. pulmonary thromboembolism) or the development of a complication (see Box 13.45).
13.45 COMPLICATIONS OF PNEUMONIA
Empyema-see page 569
Retention of sputum causing lobar collapse
Development of thromboembolic disease
Pneumothorax-particularly with Staph. aureus
Suppurative pneumonia/lung abscess-see below
ARDS, renal failure, multi-organ failure
Ectopic abscess formation (Staph. aureus)
Hepatitis, pericarditis, myocarditis, meningoencephalitis
Pyrexia due to drug hypersensitivity
SUPPURATIVE AND ASPIRATIONAL PNEUMONIA (INCLUDING PULMONARY ABSCESS)
Suppurative pneumonia is the term used to describe a form of pneumonic consolidation in which there is destruction of the lung parenchyma by the inflammatory process. Although microabscess formation is a characteristic histological feature of suppurative pneumonia, it is usual to restrict the term 'pulmonary abscess' to lesions in which there is a fairly large localised collection of pus, or a cavity lined by chronic inflammatory tissue, from which pus has escaped by rupture into a bronchus.
Suppurative pneumonia and pulmonary abscess may be produced by infection of previously healthy lung tissue with Staph. aureus or Klebsiella pneumoniae. These are, in effect, primary bacterial pneumonias associated with pulmonary suppuration. More frequently, suppurative pneumonia and pulmonary abscess develop after the inhalation of septic material during operations on the nose, mouth or throat under general anaesthesia, or of vomitus during anaesthesia or coma. In such circumstances gross oral sepsis may be a predisposing factor. Additional risk factors for aspiration pneumonia include bulbar or vocal cord palsy, achalasia or oesophageal reflux and alcoholism. Intravenous drug users are at particular risk of developing lung abscess, often in association with endocarditis affecting the pulmonary and tricuspid valves. Aspiration into the lungs of acid gastric contents can give rise to a severe haemorrhagic pneumonia often complicated by the acute respiratory distress syndrome (ARDS, see p. 198). The clinical features of a suppurative pneumonia are summarised in Box 13.46.
Bacterial infection of a pulmonary infarct or of a collapsed lobe may also produce a suppurative pneumonia or a lung abscess. The organism(s) isolated from the sputum include Strep. pneumoniae, Staph. aureus, Strep. pyogenes, H. influenzae and, in some cases, anaerobic bacteria. In many cases, however, no pathogens can be isolated, particularly when antibiotics have been given.
13.46 CLINICAL FEATURES OF SUPPURATIVE PNEUMONIA
Acute or insidious
Cough productive of large amounts of sputum which is sometimes fetid and blood-stained
Pleural pain common
Sudden expectoration of copious amounts of foul sputum occurs if abscess ruptures into a bronchus
High remittent pyrexia
Profound systemic upset
Digital clubbing may develop quickly (10-14 days)
Chest examination usually reveals signs of consolidation; signs of cavitation rarely found
Pleural rub common
Rapid deterioration in general health with marked weight loss can occur if disease not adequately treated
Chest radiograph features
There is a homogeneous lobar or segmental opacity consistent with consolidation or collapse. A large, dense opacity, which may later cavitate and show a fluid level, is the characteristic finding when a frank lung abscess is present. Occasionally, a pre-existing emphysematous bulla becomes infected and appears as a cavity containing an air-fluid level.
In many patients oral treatment with amoxicillin 500 mg 6-hourly is effective. If an anaerobic bacterial infection is suspected (e.g. from fetor of the sputum), oral metronidazole 400 mg 8-hourly should be added. Antibacterial therapy should be modified according to the results of microbiological examination of the sputum. Prolonged treatment for 4-6 weeks may be required in some patients with lung abscess. Removal or treatment of any obstructing endobronchial lesion is essential.
In contrast to uncomplicated community-acquired pneumonia, physiotherapy is of great value, especially when large abscess cavities have formed. It may not be possible to drain lower lobe cavities without postural coughing.
In most patients there is a good response to treatment and although residual fibrosis and bronchiectasis are common sequelae, these seldom give rise to serious morbidity. Abscesses that fail to resolve despite optimal medical therapy require surgical intervention.
Hospital-acquired or nosocomial pneumonia refers to a new episode of pneumonia occurring at least 2 days after admission to hospital. The term includes post-operative and certain forms of aspiration pneumonia, and pneumonia or bronchopneumonia developing in patients with chronic lung disease, general debility or those receiving assisted ventilation.
The factors predisposing to the development of pneumonia in a hospitalised patient are listed in Box 13.47. The elderly are particularly at risk and this condition now occurs in 2-5% of all hospital admissions.
13.47 FACTORS PREDISPOSING TO NOSOCOMIAL PNEUMONIA
Reduced host defences against bacteria
Reduced immune defences (e.g. corticosteroid treatment, diabetes, malignancy)
Reduced cough reflex (e.g. post-operative)
Disordered mucociliary clearance (e.g. anaesthetic agents)
Bulbar or vocal cord palsy
Aspiration of nasopharyngeal or gastric secretions
Immobility or reduced conscious level
Vomiting, dysphagia, achalasia or severe reflux
Bacteria introduced into lower respiratory tract
Dental or sinus infection
Intravenous cannula infection
The most important distinction between hospital- and community-acquired pneumonia is the difference in the spectrum of pathogenic organisms, with the majority of hospital-acquired infections caused by Gram-negative bacteria. These include Escherichia, Pseudomonas and Klebsiella species. Infections caused by Staph. aureus (including multidrug-resistant-MRSA-forms) are also common in hospital, and anaerobic organisms are much more likely than in pneumonia acquired in the community. This profile of organisms in part reflects the high rate of colonisation of the nasopharynx of hospital patients with Gram-negative bacteria, together with the poor host defences and general inability of the severely ill or semiconscious patient to clear upper airway and respiratory tract secretions.
The clinical features and investigation of patients with hospital-acquired pneumonia are very similar to community-acquired pneumonia (see pp. 526-528). In the elderly or debilitated patient who develops acute bronchopneumonia (or 'hypostatic pneumonia') symptoms of acute bronchitis are followed after 2 or 3 days by increased cough and sputum purulence associated with a rise in temperature. Breathlessness and central cyanosis may then appear, but pleural pain is uncommon. In the early stages the physical signs are those of acute bronchitis followed by the development of crepitations. There is a neutrophil leucocytosis and the chest radiograph shows mottled opacities in both lung fields, chiefly in the lower zones.
Adequate Gram-negative coverage is usually obtained with:
a third-generation cephalosporin (e.g. cefotaxime) plus an aminoglycoside (e.g. gentamicin)
a monocyclic ß-lactam (e.g. aztreonam) plus flucloxacillin.
Aspiration pneumonia can be treated with co-amoxiclav 1.2 g 8-hourly plus metronidazole 500 mg 8-hourly. The nature and severity of most hospital-acquired pneumonias dictate that these antibiotics are all given intravenously, at least initially.
Physiotherapy is of particular importance in the immobile and elderly, and adequate oxygen therapy, fluid support and monitoring are essential. The mortality from hospital-acquired pneumonia is high (approximately 30%).
PNEUMONIA IN THE IMMUNOCOMPROMISED PATIENT
13.48 COMMON CAUSES OF IMMUNE SUPPRESSION: ASSOCIATED LUNG INFECTION
Cause Lung infection
Neutropenia Cytotoxic drugs Staph. aureus
Agranulocytosis Gram-negative bacteria
Acute leukaemia Candida albicans
T cell defect (± B cell defect) Lymphoma C. albicans
Chronic lymphocytic Mycobacterium tuberculosis
leukaemia (CLL) Pneumocystis carinii
Immunosuppressive drugs Cytomegalovirus
Bone marrow transplants Staph. aureus
Splenectomy H. influenzae
Antibody production CLL Strep. pneumoniae
Myeloma H. influenzae
Pulmonary infection is common in patients receiving immunosuppressive drugs and in those with diseases causing defects of cellular or humoral immune mechanisms. For example, patients with AIDS are susceptible to many types of pneumonia, in particular Pneumocystis carinii (see p. 120). It is important to recognise, however, that the common pathogenic bacteria are responsible for the majority of lung infections in immunocompromised patients (see Box 13.48). Despite this, the Gram-negative bacteria, especially Pseudomonas aeruginosa, are more of a problem than Gram-positive organisms, and unusual organisms or those normally considered to be of low virulence or non-pathogenic may become 'opportunistic' pathogens. Likewise, infection is often due to more than one organism. Pneumocystis carinii and other fungi such as Aspergillus fumigatus (see pp. 540-542), viral infections, cytomegalovirus (see p. 30), herpesviruses, and infections with M. tuberculosis and other types of mycobacteria (see opposite) are all common causes of infection in patients who are immunocompromised.
The patient usually presents with fever, cough, breathlessness and infiltrates on the chest radiograph. Patients may develop non-specific symptoms, and a high index of suspicion is required to determine the site and nature of the infection. In general, the onset of symptoms tends to be less rapid in patients with opportunistic organisms such as Pneumocystis carinii and mycobacterial infections. In Pneumocystis carinii pneumonia symptoms of cough and breathlessness can be present several days or weeks before the onset of systemic symptoms or even a chest radiograph abnormality.
Lung biopsy offers the greatest chance of establishing a diagnosis if examination of sputum or bronchoalveolar lavage fluid has not revealed a pathogen. This, however, is a relatively high-risk and invasive procedure and should be reserved for patients in whom less invasive procedures fail to establish a diagnosis and in whom there has been no response to broad-spectrum antibiotic treatment. Some patients who cannot produce sputum can be induced to do so by the inhalation of nebulised hypertonic saline. Fibreoptic bronchoscopy should be performed early since a diagnosis can often be established by examination of lavage fluid, bronchial brushings or transbronchial biopsies.
Whenever possible, treatment should be based on an established aetiological diagnosis. In practice, however, the cause of the pneumonia is frequently not known when treatment has to be started. Hence, broad-spectrum antibiotic therapy is required (e.g. a third-generation cephalosporin, or a quinolone, plus an antistaphylococcal antibiotic, or an antipseudomonal penicillin plus an aminoglycoside) and this treatment is thereafter tailored according to the results of investigations and the clinical response. The management of P. carinii infection is detailed on page 121.
Tuberculosis (TB) remains the most common infectious disease in the world, with an estimated one-third of the population infected and 2.5 million deaths annually. In the mid-1980s, the falling global incidence reversed in both developed and developing nations (see Box 13.49). In 1999 there were an estimated 8.4 million new cases of tuberculosis world-wide (up 5% from 1997), with 3 million occurring in South-east Asia and 2 million in Africa (where two-thirds are HIV-infected). By 2005, WHO predicts there will be 10.2 million new cases and Africa will have more cases than any other region (up 10% annually). In England and Wales there has been a 21% increase in notifications since 1987. Annual rates of tuberculosis are highest amongst non-white ethnic groups (Indian subcontinent, black African and Chinese) and in urban areas. In 1998, over half of all notified patients were born outside the UK, one-third of cases occurred in young adults and an estimated 3.3% were HIV-coinfected. Apart from HIV, several other factors are recognised to increase the risk of individuals developing tuberculosis (see Box 13.50).
13.49 REASONS FOR THE INCREASING INCIDENCE OF PULMONARY TUBERCULOSIS
Ø HIV (mainly urban)
Ø Immigration from high prevalence areas
Ø Increasing life expectancy of the elderly
Ø Social deprivation (injection drug use, homelessness, poverty)
Ø Drug resistance (MDRTB)
Ø Reduced priority for TB control
o HIV (mainly urban)
o Population increase (75% predicted increase in India over 30 years)
o Lack of access to health care
o Poverty, civil unrest
o Ineffective control programmes
o Drug resistance (MDRTB)
13.50 FACTORS INCREASING THE RISK OF TUBERCULOSIS
1. Age (children > young adults)
2. First-generation immigrants from high prevalence countries
3. Close contacts of patients with smear-positive pulmonary tuberculosis
4. Chest radiograph evidence of self-healed tuberculosis
5. Primary infection < 1 year previously
4) Malignancy (especially lymphoma, leukaemia)
5) Type 1 diabetes mellitus
6) Chronic renal failure
7) Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal bypass, cancer of the pancreas, malabsorption)
13.51 SITE-SPECIFIC MYCOBACTERIAL DISEASE
Pulmonary M. tuberculosis
Lymph node M. tuberculosis
Soft tissue/skin M. leprae
M. ulcerans (prevalent in Africa, northern Australia and South-east Asia) M. marinum
Disseminated (seen in immunodeficiency states) MAC (HIV-associated)
(MAC = Mycobacterium avium complex--M. scrofulaceum, M. intracellulare and M. avium)
Mycobacterium tuberculosis belongs to a complex of organisms with M. bovis (reservoir cattle) and African and Asian variants (reservoir humans); all cause clinical tuberculosis. In addition, other species of environmental mycobacteria (often termed 'atypical') may cause human disease (see Box 13.51). The sites commonly involved are the lungs, lymph nodes, skin and soft tissues. With the advent of HIV, disseminated infection with Mycobacterium avium complex (MAC) has become common when severe immunodeficiency exists (CD4 count < 50 cells/ml-see p. 121). Environmental mycobacteria are low-grade pathogens (with the exception of M. malmoense and M. ulcerans), tending to cause disease in the setting of immunocompromise or scarred lungs. The significance of an isolate depends on the species, site of isolation, number of isolates and whether or not there is a recognised association with the clinical presentation. Where the isolate is from a non-sterile site, multiple positive cultures are usually required to confirm infection.
Pathology and pathogenesis
Infection with M. tuberculosis occurs most frequently through inhalation of infected droplets, with the primary infection occurring in the lung (see Fig. 13.31). Occasionally, the tonsil, intestine or skin may be the site of primary disease. Following inhalation of M. tuberculosis, a small subpleural lesion (the Ghon focus) develops with rapid transport of bacilli to the regional (hilar) lymph nodes and the development of the primary complex. Non-specifically activated macrophages that have ingested the bacilli then aggregate and the lesions enlarge. At 2-4 weeks, two distinct T cell-mediated immune responses start. A delayed-type hypersensitivity reaction destroys non-activated macrophages containing bacilli but also results in tissue necrosis and caseation. Cell-mediated immunity results in macrophages being activated into epithelioid cells with the formation of granulomas seen at the periphery of the caseation. The virulence factors of M. tuberculosis have not been fully elucidated. The organism is versatile, with the ability to multiply rapidly outside cells within cavities, survive inside macrophages preventing fusion between the lysosome and phagosome, and survive in a relatively inactive state with only infrequent bursts of division.
Integration link: TB - histopathology
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
Figure 13.31 Primary pulmonary tuberculosis. (1) Spread from the primary focus to hilar and mediastinal lymph glands to form the 'primary complex', which in most cases heals spontaneously. (2) Direct extension of the primary focus-'progressive pulmonary tuberculosis'. (3) Spread to the pleura-tuberculous pleurisy and pleural effusion. (4) Blood-borne spread: few bacilli-pulmonary, skeletal, renal, genitourinary infection often months or years later; massive spread-miliary tuberculosis and meningitis.
13.52 TIMETABLE OF TUBERCULOSIS
Time from infection Manifestations
3-8 weeks Primary complex, positive tuberculin skin test
3-6 months Meningeal, miliary and pleural disease
Up to 3 years Gastrointestinal, bone and joint, and lymph node disease
Around 8 years Renal tract disease
From 3 years onwards Post-primary disease due to reactivation or reinfection
In 85-90% of cases the primary complex heals spontaneously in 1-2 months and the tuberculin skin test becomes positive. In 10-15%, multiplication of M. tuberculosis is not contained and lymph node enlargement results in either local pressure effects, lymphatic spread to the pleura or pericardium, or rupture into an adjacent bronchus or pulmonary blood vessel. Where dissemination has occurred, disease may progress rapidly to the development of miliary and meningeal tuberculosis. Also, foci of infection may be set up in bone, the lung, the genitourinary and gastrointestinal tracts, or lymph nodes, which may progress to clinical disease (see Box 13.52). However, 85-90% of patients develop latent infection (positive tuberculin test or radiographic evidence of self-healed tuberculosis). Within this group 5-10% reactivate during their life-time, resulting in post-primary disease. This is predominantly pulmonary (75%) and infectious (50% smear-positive). Re-exposure to smear-positive pulmonary tuberculosis may result in post-primary disease and accounts for up to one-third of all cases. The likelihood of infection after exposure (30%), development of progressive primary disease (30%) and reinfection from other infectious cases (50%) are all increased in HIV-infected individuals. Where good immune function is retained in HIV, clinical disease resembles classical post-primary tuberculosis. However, where significant immunodeficiency has occurred, the presentation is more likely to be disseminated or extrapulmonary (see Box 13.53 and opposite).
Integration link: Sequence of TB infection
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
13.53 TUBERCULOSIS IN HIV
Infection after exposure
Progressive primary disease after infection
Reactivation of latent infection
Reinfection with new strain
Reduced smear-positive rates in pulmonary TB
Atypical chest radiograph appearance
Increased disseminated disease
More extrapulmonary infection
Greater risk of adverse drug reactions
Clinical features: pulmonary disease
Primary pulmonary tuberculosis
Integration link: TB - gross pathology
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
Infection usually occurs in childhood and is generally asymptomatic; a few patients develop a self-limiting febrile illness. A history of contact with a person with active pulmonary tuberculosis is often obtained. Clinical disease results either from the development of a hypersensitivity reaction or from the infection pursuing a progressive course (see Box 13.54). Erythema nodosum may be the presenting feature of primary tuberculosis and is associated with a strongly positive tuberculin skin test. Progressive primary disease may appear during the course of the initial illness or after a latent interval of weeks or months. The features depend on the site affected (see below).
13.54 FEATURES OF PRIMARY TUBERCULOSIS
Infection (4-8 weeks)
§ Influenza-like illness
§ Skin test conversion
§ Primary complex
¨ Lymphadenopathy (hilar (often unilateral), paratracheal or mediastinal)
o Collapse (especially right middle lobe)
o Consolidation (especially right middle lobe)
o Obstructive emphysema
o Cavitation (rare)
¨ Pleural effusion
¨ Erythema nodosum
¨ Phlyctenular conjunctivitis
This is a severe infection often diagnosed late. The disease may start suddenly but more frequently there is a period of 2-3 weeks when fever, night sweats, anorexia, weight loss and a dry cough are present. Hepatosplenomegaly may be present (25%) and the presence of headache may indicate coexistent tuberculous meningitis. Auscultation of the chest is frequently normal, although with more advanced disease widespread crackles are evident. Choroidal tubercles occur in 5-10%. The chest radiograph reveals fine 1-2 mm lesions (millet seeds) throughout the lungs, although occasionally the appearances are coarser. Anaemia and leucopenia may be present. An unusual presentation seen usually in the elderly is 'cryptic' miliary tuberculosis (see Box 13.55).
13.55 PRESENTATION OF CRYPTIC TUBERCULOSIS
¨ Age over 60 years
¨ Intermittent low-grade pyrexia of unknown origin
¨ Unexplained weight loss, general debility (hepatosplenomegaly in 25-50%)
¨ Normal chest radiograph
¨ Blood dyscrasias; leukaemoid reaction, pancytopenia
¨ Negative tuberculin skin test
¨ Confirmation by biopsy (granulomata and/or acid-fast bacilli demonstrated) of liver or bone marrow
Post-primary pulmonary tuberculosis
13.56 CLINICAL PRESENTATION OF PULMONARY TUBERCULOSIS
§ Chronic cough, often with haemoptysis
§ Pyrexia of unknown origin
§ Unresolved pneumonia
§ Exudative pleural effusion
§ Asymptomatic (diagnosis on chest radiograph)
§ Weight loss, general debility
§ Spontaneous pneumothorax
13.57 CHRONIC COMPLICATIONS OF PULMONARY TUBERCULOSIS
M Massive haemoptysis
M Cor pulmonale
M Atypical mycobacterial infection
M Lung/pleural calcification
M Obstructive airways disease
M Bronchopleural fistula
M Empyema necessitans
M Anorectal disease
M Poncet's polyarthritis
Figure 13.32 Chest radiograph: major manifestations and differential diagnosis of pulmonary tuberculosis. Less common manifestations include pneumothorax, ARDS (see p. 198), cor pulmonale and localised emphysema.
Disease in adults is usually a result of post-primary disease. A subacute illness characterised by cough, haemoptysis, dyspnoea, anorexia and weight loss associated with fevers and night sweats is typical. Other clinical presentations are listed in Box 13.56. Auscultation of the chest frequently reveals localising signs but may be normal. The earliest radiological change is typically an ill-defined opacity situated in one of the upper lobes. Disease often involves two or more areas of lung and may be bilateral; as disease progresses, consolidation, collapse and cavitation develop to varying degrees (see Fig. 13.32). The presence of a miliary pattern or cavitation indicates active disease although there is a wide differential. In extensive disease, collapse may be marked and result in significant displacement of the trachea and mediastinum. Occasionally, a caseous lymph node may drain into an adjoining bronchus, resulting in tuberculous pneumonia. The complications of pulmonary tuberculosis are shown in Box 13.57.
Clinical features: extrapulmonary disease
The most common extrapulmonary site of disease is the lymph nodes. Cervical and mediastinal glands are affected most frequently, followed by axillary and inguinal; in 5% of patients, more than one region is involved. Disease may represent primary infection, spread from contiguous sites or reactivation of infection. Supraclavicular lymphadenopathy is usually a result of spread from mediastinal disease. The nodes are usually painless and initially mobile but become matted together with time. When caseation and liquefaction occur, the swelling becomes fluctuant and may discharge through the skin with the formation of a 'collar-stud' abscess and sinus formation. Approximately half of patients fail to show any constitutional features such as fevers and night sweats. The tuberculin skin test is usually strongly positive. During or after treatment, paradoxical enlargement, development of new nodes and suppuration may all occur but without evidence of continued infection; rarely, surgical excision is necessary. In non-immigrant children in the UK, most mycobacterial lymphadenitis is caused by environmental (atypical) mycobacteria, especially of the M. avium complex (see Box 13.51).
Tuberculosis can affect any part of the bowel and patients may present with a wide range of symptoms and signs (see Fig. 13.33). Upper gastrointestinal tract involvement is rare and is usually an unexpected histological finding in an endoscopic or laparotomy specimen. Ileocaecal disease accounts for approximately half of abdominal tuberculosis cases. Fever, night sweats, anorexia and weight loss are usually prominent and a right iliac fossa mass may be palpable. Up to 30% of cases present with an acute abdomen. Ultrasound or CT may reveal thickened bowel wall, abdominal lymphadenopathy, mesenteric thickening or ascites. Barium enema and small bowel enema reveal narrowing, shortening and distortion of the bowel with caecal involvement predominating. Diagnosis rests on obtaining histology by either colonoscopy or mini-laparotomy. The main differential diagnosis is Crohn's disease (see p. 808). Tuberculous peritonitis is characterised by abdominal distension, pain and constitutional symptoms. The ascitic fluid is exudative and cellular with a predominance of lymphocytes. Laparoscopy reveals multiple white 'tubercles' over the peritoneal and omental surfaces. Low-grade hepatic dysfunction is common in miliary disease when biopsy reveals granulomata. Occasionally, patients may be frankly icteric with a mixed hepatic/cholestatic picture.
Figure 13.33 Systemic presentations of extrapulmonary tuberculosis.
Disease occurs in two main forms (see Fig. 13.33 and p. 478): pericardial effusion and constrictive pericarditis. Fever and night sweats are rarely prominent and the presentation is usually insidious with breathlessness and abdominal swelling. Pulsus paradoxus, a very raised JVP, hepatosplenomegaly, prominent ascites and the absence of peripheral oedema are common to both types of disease. Pericardial effusion is associated with increased pericardial dullness and a globular enlarged heart on chest radiograph. Constriction is associated with atrial fibrillation (< 20%), an early third heart sound and pericardial calcification in 25%. Diagnosis is on clinical, radiological and echocardiographic grounds. The pericardial effusion is blood-stained in 85% of cases. Coexistent pulmonary disease is very rare, with the exception of pleural effusion. Open pericardial biopsy can be performed in patients with effusion where there is doubt about the diagnosis. The addition of corticosteroids has been shown to be beneficial when added to antituberculosis treatment (see below) for both.
Central nervous system disease
By far the most important form of central nervous system tuberculosis is meningeal disease. This is life-threatening and may be rapidly fatal if not diagnosed early. Clinical features, investigations and management are dealt with on page 1192.
Bone and joint disease
Tuberculosis of the spine usually presents with chronic back pain and typically involves the lower thoracic and lumbar spine (see Fig. 13.33). The infection starts as a discitis and then spreads along the spinal ligaments to involve the adjacent anterior vertebral bodies, causing angulation of the vertebrae with subsequent kyphosis. Paravertebral and psoas abscess formation is common. CT is valuable in gauging the extent of disease, the amount of cord compression, and the site for needle biopsy or open exploration if required. The major differential diagnosis is malignancy, which tends to affect the vertebral body and leave the disc intact. In the absence of spinal instability or cord compression, patients can be treated as outpatients. Tuberculosis can affect any joint, but most frequently involves the hip or knee. Presentation is usually insidious with pain and swelling; fever and night sweats are uncommon. Radiological changes are often non-specific but, as disease progresses, reduction in joint space and erosions appear.
Fever and night sweats are rare with renal tract tuberculosis and patients are often only mildly symptomatic for many years. Haematuria, frequency and dysuria are often present, with sterile pyuria found on urine microscopy and culture. In women, infertility from endometritis, or pelvic pain and swelling from salpingitis or a tubo-ovarian abscess may occur infrequently. In men, genitourinary tuberculosis may present as epididymitis or prostatitis.
Diagnosis (see Box 13.58)
Mycobacterial infection can be confirmed by direct microscopy of samples (Ziehl-Neelsen or auramine staining) and culture. Confirmation of the isolate as M. tuberculosis is obtained through standard culture methods (growth characteristics, pigment production and biochemical tests) or molecular DNA technology (hybridisation probes, polymerase chain reaction amplification). After decontamination, samples should be cultured on solid medium as well as into liquid medium, which provides more rapid growth. Drug susceptibility profiles can be obtained within 1-2 weeks of growth using the BACTEC system. Where MDRTB is suspected, molecular methods allow the detection of rifampicin resistance (a marker for multidrug resistance) in primary specimens as well as cultures. If a cluster of cases suggests a common source, fingerprinting of isolates with restriction-fragment length polymorphism (RFLP) or DNA amplification can help confirm this.
Primary tuberculosis in children is rarely confirmed by culture. In adults, direct microscopy is positive in 60% of pulmonary and 5-25% of extrapulmonary cases (highest for lymph node and lowest for meningeal disease). In 10-20% of patients with pulmonary disease and 40-50% of patients with extrapulmonary disease, culture is also negative and the diagnosis is clinical.
Control and prevention
13.58 DIAGNOSIS OF TUBERCULOSIS
§ Sputum (induced with nebulised hypertonic saline if not expectorating)
§ Gastric washing (mainly used for children)
§ Bronchoalveolar lavage
§ Transbronchial biopsy
¨ Fluid examination (cerebrospinal, ascitic, pleural, pericardial, joint)
¨ Tissue biopsy (from affected site; also bone marrow/liver may be diagnostic in patients with disseminated disease)
Ä Diagnostic test
è Circumstantial (ESR, C-reactive protein, anaemia etc.)
è Tuberculin skin test (low sensitivity/specificity; useful only in primary or deep-seated infection)
Ä Auramine fluorescence
è Nucleic acid amplification
Ä Solid (Löwenstein-Jensen, Middlebrook)
Ä Liquid (e.g. BACTEC)
è Response to empirical antituberculous drugs (usually seen after 5-10 days)
BCG (the Calmette-Guérin bacillus) is an attenuated vaccine derived from M. bovis, which was developed in 1921 (see pp. 1213-1214). Its protective efficacy is up to 80% for 10-15 years and is greatest for preventing disseminated disease in children. In the UK it is recommended for the following tuberculin skin test-negative groups:
Kall children 10-14 years of age
Kcontacts < 2 years old
Kimmigrants from countries where tuberculosis is endemic
Kinfants in high prevalence ethnic groups
Khealth-care workers at risk.
Only those who do not respond to tuberculin are vaccinated. Grade 3-4 tuberculin skin test responders should be referred for clinical and radiological examination. Tuberculin skin testing is usually performed using the Heaf or Mantoux technique (see Box 13.59 and Fig. 13.34). Some countries do not use BCG because they value the diagnostic sensitivity of the tuberculin skin test as a measure of recent primary infection. Occasional complications include a local BCG abscess and disseminated infection in immunocompromised persons.
Chemoprophylaxis is given to prevent infection progressing to clinical disease. It is recommended for children aged less than 16 years with strongly positive Heaf tests, children aged less than 2 years in close contact with smear-positive pulmonary disease, those in whom recent tuberculin conversion has been confirmed, and babies of mothers with pulmonary tuberculosis. It should be considered for HIV-infected close contacts of a patient with smear-positive disease. Rifampicin and isoniazid for 3 months, rifampicin and pyrazinamide for 2 months, or isoniazid for 6 months are all effective.
13.59 SKIN TESTING IN TUBERCULOSIS
Tests using purified protein derivative (PPD) False negatives
Heaf (read at 3-7 days) Severe TB (25% of cases negative)
Multipuncture method Newborn and elderly
Grade 1: 4-6 papules HIV (if CD4 count < 200 cells/ml)
Grade 2: Confluent papules forming ring Recent infection (e.g. measles) or immunisation
Grade 3: Central induration Malnutrition
Grade 4: > 10 mm induration Immunosuppressive drugs
Mantoux (read at 2-4 days) Using 10 tuberculin units: positive when
induration 5-14 mm (equivalent to Heaf grade 2)
and > 15 mm (Heaf grade 3-4)
In the UK an active contact-screening programme operates, beginning with compulsory notification of all tuberculosis cases. The aim of contact tracing is to identify a possible index case with clinical disease, other cases infected by the same index patient (with or without evidence of disease), and close contacts who should receive BCG vaccination. Approximately 10-20% of close contacts of patients with smear-positive pulmonary tuberculosis and 2-5% of those with smear-negative, culture-positive disease have evidence of tuberculosis infection. Close contacts of patients with pulmonary disease are seen in dedicated clinics where their BCG and clinical status is reviewed, Heaf tests are performed (except in those below 16 years of age), and the need for radiography is assessed. Outcomes include chemotherapy (for active disease), chemoprophylaxis (to prevent infection progressing to active disease), BCG immunisation or discharge.
Figure 13.34 Gradings of the Heaf test response.
A Negative. B Grade 1. C Grade 2. D Grade 3. E Grade 4.
13.60 TREATMENT OF TUBERCULOSIS AND DISSEMINATED MAC
Initial Months Continuation Months
New cases HRZE 2 HR 4
New cases: resource-poor settings HRZS or HRZE 2 HT1 or HE 6
Relapses and treatment failures HRZE2 2+ = 2 drugs3 6-10
MDRTB = 5 drugs4 24
Disseminated MAC = 4 drugs5 2-6 2 drugs6 12+
First-line drugs7: Ethambutol (E), isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (S), rifabutin, thiacetazone (T)1
Second-line drugs: Clarithromycin (or azithromycin), ofloxacin (or ciprofloxacin), protionamide (or ethionamide), cycloserine, capreomycin, para-aminosalicylic acid (PAS)
1 Thiacetazone is bacteriostatic and contraindicated in HIV.
2 Additional second-line agents may be indicated until sensitivities are known.
3 Guided by sensitivity results.
4 Dependent on sensitivities.
5 Ciprofloxacin, ethambutol, azithromycin, rifabutin is a recommended regimen.
6 When CD4 count > 100 cells/ml reduction to azithromycin and one other drug is safe.
7 HRZE and S can all be given by intermittent dosing (directly observed therapy).
Short-course therapy with 2 months of four drugs (rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) followed by 4 months of rifampicin and isoniazid is now recommended for all patients with new-onset, uncomplicated pulmonary or extrapulmonary tuberculosis (see Box 13.60). The fourth drug (ethambutol or streptomycin) can be omitted in patients in whom isoniazid resistance is unlikely (previously untreated white patients, presumed HIV-negative individuals and those having no contact with a possible patient with drug-resistant disease). Streptomycin is now rarely used in the UK but it is an important component of short-course treatment regimens in developing nations. Drugs should be given as a single daily dose before breakfast. Patients should be considered for longer treatment (9-12 months) where meningeal disease is present, there is HIV coinfection, or drug intolerance occurs and a second-line agent is substituted. Relapse is rare when the strain is fully sensitive (< 2%) and adherence to drug therapy is complete. In patients with a history of past treatment, four drugs must be used until the sensitivity results are obtained. In the UK drug resistance in newly diagnosed patients is uncommon (overall < 5%) and is more frequently observed in isolates from ethnic minority patients. The treatment of MDRTB is complex and depends on the sensitivity of the isolate. Five or more drugs are used and the patient must be admitted to a negative-pressure isolation room for treatment until deemed non-infectious.
Most patients can be treated at home, although where there is uncertainty about the diagnosis, intolerance of medication, questionable compliance, a background of adverse social conditions or a significant risk of MDRTB (culture positive after 2 months on treatment, contact with known MDRTB), patients should be admitted. Where drug resistance is not expected, patients can be assumed to be non-infectious after 2 weeks of quadruple therapy including rifampicin and isoniazid. Combined drug preparations (including rifampicin and isoniazid with or without pyrazinamide) reduce tablet load and allow relatively simple screening for compliance as the urine can be assessed visually for an orange-red colour. Directly observed therapy (DOT) is recommended where patients are unlikely to comply (alcoholics, injection drug users, the mentally ill and patients failing previous therapy), where there is multidrug resistance (as part of the continuation phase) and where there are language difficulties. In developing nations, DOT dispenses with the need for initial hospitalisation to receive streptomycin, is cost-effective and is less disruptive to patients' lives. Most importantly, it improves adherence. All the first-line agents can be given thrice weekly. Currently, WHO recommends DOT therapy for all patients with tuberculosis at a global level.
In choosing a suitable drug regimen, it is important to bear in mind underlying comorbidity (renal and hepatic dysfunction, eye disease, peripheral neuropathy and HIV as well as the potential for drug interactions (rifampicin is a potent cytochrome inducer). Baseline liver function and subsequent regular monitoring are important for patients with underlying liver disease treated with standard therapy including rifampicin, isoniazid and pyrazinamide, all of which are potentially hepatotoxic. Patients treated with the first-line drug rifampicin should always be warned that their urine, tears and other secretions will develop a bright orange/red coloration. Ethambutol should be used with caution in patients with renal failure, with appropriate dose reduction and monitoring of drug levels.
Corticosteroids are recommended in tuberculous pericarditis as they reduce the need for pericardiectomy in constrictive pericarditis and repeat aspiration or open surgical drainage in pericardial effusion. They are also advised for moderate to severe tuberculous meningitis. In patients with ureteric disease, pleural effusion, primary endobronchial disease or severe disseminated disease, corticosteroids should be considered, although the evidence is less certain. Surgery is still occasionally required (e.g. for massive haemoptysis, loculated empyema, constrictive pericarditis, lymph node suppuration, spinal disease with cord compression), but usually only after a full course of antituberculosis treatment.
PULMONARY TUBERCULOSIS-optimal choice of antituberculous drugs
'Two large RCTs have shown that 6 months of treatment are as effective as longer courses if a four-drug combination (isoniazid, rifampicin, pyrazinamide and ethambutol, or isoniazid, rifampicin, pyrazinamide and streptomycin) is used for 2 months followed by isoniazid and rifampicin for 4 months. One RCT has shown no difference between streptomycin and ethambutol as the fourth drug. One SR shows no difference between daily and thrice-weekly short course regimens.'
Global Tuberculosis Programme. Treatment of tuberculosis. Geneva: World Health Organisation; 1997 (WHO/TB/97.220).
British Thoracic Society. A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis: results during the 36 months after the end of chemotherapy and beyond. Br J Dis Chest 1984; 78:330-336.
Mwandumba HC, Squire SB. Fully intermittent dosing with drugs for tuberculosis (Cochrane Review). Cochrane Library, issue 1, 2001. Oxford: Update Software.
Further information: www.clinicalevidence.org
CHEMOTHERAPY FOR TUBERCULOSIS-optimal duration of therapy
'RCTs have found no evidence of a difference in relapse rates between 6 and 9 months' chemotherapy in people with pulmonary tuberculosis. In contrast, SR of 9 trials comparing 6 months of treatment with shorter-duration regimens demonstrates consistently higher relapse rates (range 1-8%) in the shorter treatment arms. On the basis of such data, WHO recommends 6 months of treatment in all patients with active pulmonary tuberculosis infection.'
Gelband H. Regimens of less than six months for treating tuberculosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53:536-548.
Further information: www.cochrane.co.uk
13.61 MAIN ADVERSE REACTIONS OF FIRST-LINE ANTITUBERCULOUS DRUGS
Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol
Mode of action Cell wall synthesis DNA transcription Unknown Protein synthesis Cell wall synthesis
Major adverse reactions Peripheral neuropathy1 Febrile reactions Hepatitis 8th nerve damage Retrobulbar neuritis3
Hepatitis2 Hepatitis Gastrointestinal disturbance Rash Arthralgia
Gastrointestinal disturbance Hyperuricaemia
Less common adverse reactions Lupoid reactions Interstitial nephritis Rash Nephrotoxicity Peripheral neuropathy
Seizures Thrombocytopenia Photosensitisation Agranulocytosis Rash
Psychoses Haemolytic anaemia Gout
12-5%; reduced to 0.2% with supplementary pyridoxine.
3Reduced visual acuity and colour vision with higher doses; usually reversible.
21.5%; increased with age, slow acetylator status, rifampicin use and alcohol.
Adverse drug reactions occur in 10% of patients but are significantly more common where there is HIV coinfection (see Box 13.61).
In the absence of major complications, short-course therapy using four drugs initially is curative. Occasionally, patients die of overwhelming infection (usually miliary disease or bronchopneumonia) and some patients succumb to the later complications of tuberculosis (e.g. cor pulmonale). A few patients die unexpectedly soon after commencing therapy and it is possible that some of these individuals have subclinical hypoadrenalism that is unmasked by a rifampicin-induced increase in steroid metabolism. In HIV-associated tuberculosis, mortality is increased but mainly as a result of superimposed bacterial infection.
RESPIRATORY DISEASES CAUSED BY FUNGI
Most fungi encountered by humans are harmless saprophytes but some species may, in certain circumstances, infect human tissue or promote damaging allergic reactions.
The term 'mycosis' is applied to disease caused by fungal infection. Predisposing factors include metabolic disorders such as diabetes mellitus, toxic states (for example, chronic alcoholism), diseases in which immunological responses are disturbed such as AIDS, treatment with corticosteroids and immunosuppressive drugs, and radiotherapy. Local factors such as tissue damage by suppuration or necrosis and the elimination of the competitive influence of a normal bacterial flora by antibiotics may also facilitate fungal infection.
The diagnosis of fungal disease of the respiratory system is usually made by mycological examination of sputum-microscopic examination of stained films for fungal hyphae being extremely important-supported by serological tests and in some cases by skin sensitivity tests.
Most cases of bronchopulmonary aspergillosis are caused by Aspergillus fumigatus, but other members of the genus (A. clavatus, A. flavus, A. niger and A. terreus) occasionally cause disease. The conditions associated with Aspergillus species are listed in Box 13.62.
13.62 CLASSIFICATION OF BRONCHOPULMONARY ASPERGILLOSIS
Atopic (allergic) asthma (see p. 514)
Allergic bronchopulmonary aspergillosis (asthmatic pulmonary eosinophilia)
Extrinsic allergic alveolitis (Aspergillus clavatus)
Invasive pulmonary aspergillosis
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)
This is caused by hypersensitivity reactions to A. fumigatus involving the bronchial wall and peripheral parts of the lung. In the vast majority of patients it is associated with bronchial asthma, but it can occur in non-asthmatic patients and is a recognised complication of cystic fibrosis. It is one of the causes of pulmonary eosinophilia (see p. 560), since it is characterised by fleeting radiographic abnormalities associated with peripheral blood eosinophilia.
Fever, breathlessness, cough productive of bronchial casts and worsening of asthmatic symptoms can all be manifestations of ABPA, but frequently the diagnosis is suggested by abnormalities on routine chest radiographs of patients whose asthmatic symptoms are no worse than usual. When repeated episodes of ABPA have caused bronchiectasis, the symptoms and complications of that disease often overshadow those of asthma.
The disease is characterised by recurrent transient radiograph abnormalities of two main types: diffuse pulmonary infiltrates and lobar or segmental pulmonary collapse. Permanent radiographic changes of bronchiectasis ('tram-line', ring and 'gloved-finger' shadows) are seen predominantly in the upper lobes in patients with advanced disease.
The diagnostic features are shown in Box 13.63. Not all are required to make a confident diagnosis.
13.63 DIAGNOSTIC FEATURES OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
Asthma (in the majority of cases)
Peripheral blood eosinophilia > 0.5 × 109/litre
Presence or history of chest radiograph abnormalities
Positive skin test to an extract of A. fumigatus
Serum precipitating antibodies to A. fumigatus
Elevated total serum IgE
Fungal hyphae of A. fumigatus on microscopic examination of sputum
In the absence of safe and effective antifungal agents which can be given long-term, the main aims of therapy are:
suppression of the immunopathological responses to A. fumigatus with low-dose oral corticosteroid therapy (prednisolone 7.5-10 mg daily)
optimal control of associated asthma
prompt, effective management of exacerbations associated with new chest radiograph changes-prednisolone 40-60 mg daily and physiotherapy. If lobar collapse persists for more than 7-10 days, bronchoscopy to remove impacted mucus should be performed to prevent the development of bronchiectasis.
Inhaled air-borne spores of A. fumigatus may lodge and germinate in damaged pulmonary tissue, and an 'aspergilloma' (a ball of Aspergillus fungus) can form in any area of damaged lung in which there is a persistent abnormal space. The most common cause of such pulmonary damage is tuberculosis (see Fig. 13.35), but an aspergilloma can develop in an abscess cavity, a bronchiectatic space or even a cavitated tumour. Most, but not all, are caused by A. fumigatus.
An aspergilloma often produces no specific symptoms but may be responsible for recurrent haemoptysis, which is often severe. The presence of a fungus ball in the lung can also give rise to non-specific systemic features such as lethargy and weight loss.
The development of a fungal ball within a cavity produces a tumour-like opacity on radiograph. An aspergilloma can usually be distinguished from a peripheral bronchial carcinoma by the presence of a crescent of air between the fungal ball and the upper wall of the cavity. Aspergillomata may be multiple.
The diagnosis is usually suspected because of the chest radiograph findings. Serum precipitins to A. fumigatus can be demonstrated in virtually all patients. Sputum contains hyphal fragments on microscopy which are often only scanty, and is usually positive on culture. Less than 50% of patients exhibit skin hypersensitivity to extracts of A. fumigatus.
Figure 13.35 Aspergilloma in left upper lobe cavity. Aspergilloma demonstrated using conventional tomography. Rounded fungal ball (arrows) separated from the wall of the cavity by a 'halo' of air.
Specific antifungal therapy is of no value. Surgical removal of the aspergilloma is indicated in patients who have massive haemoptysis and in whom thoracotomy is not contraindicated because of poor respiratory reserve. Bronchial artery embolisation is an alternative approach to the management of recurrent haemoptysis.
INVASIVE PULMONARY ASPERGILLOSIS
Invasion of previously healthy lung tissue by A. fumigatus is uncommon but can produce a serious and often fatal condition which usually occurs in patients who are immunocompromised by either drugs or disease. The source of the infection can be an aspergilloma but this is by no means always so.
Spread of the disease to the lungs is usually rapid, with the production of consolidation, necrosis and cavitation. There is grave systemic disturbance. The formation of multiple abscesses is associated with the production of copious amounts of purulent sputum which is often blood-stained.
A much more indolent form of invasive pulmonary aspergillosis is now recognised.
Invasive pulmonary aspergillosis should be suspected in any patient thought to have severe suppurative pneumonia (see p. 530) which has not responded to antibiotic therapy. The diagnosis can be established by the demonstration of abundant fungal elements in stained smears of sputum. Serum precipitins can be demonstrated in some, but not all, patients.
ISSUES IN OLDER PEOPLE
In the developed world the vast majority of deaths from pneumonia occur in the elderly.
Older people are at increased risk of and from respiratory infection because of reduced immune responses, reduced respiratory muscle strength and endurance, altered mucus layer, poor nutritional status and the increased prevalence of chronic lung disease.
Influenza has a much higher complication rate, morbidity and mortality in old age. Vaccination significantly reduces morbidity and mortality in old age but uptake is poor.
Other medical conditions may also predispose to infection; for example, swallowing difficulties due to stroke increase the risk of aspiration pneumonia.
Elderly patients are more likely to present with atypical symptoms, especially confusion.
Most cases of tuberculosis in old age represent reactivation of previous, often unrecognised disease and may be precipitated by steroid therapy, diabetes mellitus and the factors above. Cryptic miliary tuberculosis is an occasional alternative presentation. Older people more commonly suffer adverse effects from antituberculous chemotherapy and require close monitoring.
If the diagnosis is established at an early stage, antifungal therapy can be successful. Amphotericin 0.25-1 mg/kg daily by slow intravenous infusion over 6 hours should be given in combination with flucytosine 150-200 mg/kg daily by mouth or by intravenous infusion, in four divided doses. The combination of flucytosine and amphotericin prevents resistance to flucytosine developing and allows a smaller daily dose of amphotericin to be used than would be possible if this drug was used on its own. Liposomal amphotericin is recommended when toxicity precludes the use of conventional amphotericin. Itraconazole has been used successfully in the treatment of invasive aspergillosis.
Histoplasmosis, coccidioidomycosis, blastomycosis and cryptococcosis
See pages 93-95.
pages 524 - 542
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013166
For problems or suggestions concerning this service, please contact: email@example.com
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > TUMOURS OF THE BRONCHUS AND LUNG
TUMOURS OF THE BRONCHUS AND LUNG
Between 1995 and 1996 there were more than 36 000 lung cancer deaths in the UK (see Box 13.64). Bronchial carcinoma is by far the most common (> 90%) lung tumour; by comparison, benign tumours of the lung are rare. Primary carcinomas of other organs, in particular the breast, kidney, uterus, ovary, testes and thyroid, may give rise to metastatic pulmonary deposits, as may an osteogenic or other sarcoma. Bronchial tumours also represent the most common cause of obstruction to a major bronchus (see Box 13.65).
13.64 THE BURDEN OF LUNG CANCER
36 000 deaths/year in the UK
25% of all cancer deaths
8% of all male deaths and 4% of all female deaths
More than threefold increase in deaths since 1950
Most rapidly increasing cause of cancer death in women
Most common cause of cancer death in men
After breast cancer, the second most common cause of cancer death in women in England and Wales
13.65 CAUSES OF LARGE BRONCHUS OBSTRUCTION
Bronchial carcinoma or adenoma (see Box 13.70)
Enlarged tracheobronchial lymph nodes (malignant or tuberculous)
Inhaled foreign bodies (especially right lung and in children)
Bronchial casts or plugs consisting of inspissated mucus or blood clot (especially asthma, haemoptysis, debility)
Collections of mucus or mucopus retained in the bronchi as a result of ineffective expectoration (especially post-operative following abdominal surgery)
Giant left atrium
Congenital bronchial atresia
Fibrous bronchial stricture (e.g. following tuberculosis)
Figure 13.36 Collapse of the right lung: effects on neighbouring structures. A Chest radiograph. B Artist's impression.
The clinical and radiological manifestations of bronchial obstruction (see Figs 13.36 and 13.37) depend on the site of the obstruction, whether the obstruction is complete or partial, the presence or absence of secondary infection, and the extent of pre-existing lung disease. Signs of displacement of the mediastinum or elevation of the diaphragm only occur if a major portion of the lung becomes collapsed. Bacterial infection affecting the distal lung is almost inevitable whenever a major bronchus is significantly obstructed. Hence pneumonia is often the first clinical manifestation of a bronchial carcinoma, even when the degree of obstruction is insufficient to cause collapse.
The cause of bronchial obstruction should be determined at bronchoscopy; this procedure also enables biopsy of abnormal tissue and the removal of foreign bodies, mucus plugs or tenacious secretions.
Figure 13.37 Radiological features of lobar collapse caused by bronchial obstruction. The dotted line in the drawings represents the normal position of the diaphragm. A The radiograph shows an example of left upper lobe collapse which is often the most difficult to identify; this is due to the hazy, ill-defined shadowing on the PA view. B The collapsed left upper lobe is more easily seen on the lateral view (line indicates posterior margin of collapsed left upper lobe). C Radiograph of collapsed left lower lobe (arrow) causing increased density behind heart and loss of normal clarity between lung and both the left hemidiaphragm and descending thoracic aorta.
PRIMARY TUMOURS OF THE LUNG
Cigarette smoking is by far the most important single factor in the causation of lung cancer. It is thought to be directly responsible for at least 90% of lung carcinomas, the risk being directly proportional to the amount smoked and to the tar content of cigarettes. For example, the death rate from the disease in heavy cigarette smokers is 40 times that in non-smokers. The effect of 'passive' smoking is more difficult to quantify but is currently believed to be a factor in 5% of all lung cancer deaths. Exposure to naturally occurring radon has been estimated to cause 5% of lung cancers. The incidence of lung cancer is also slightly higher in urban than in rural dwellers; this may reflect differences in atmospheric pollution (including tobacco smoke) or occupation since a number of industrial products (e.g. asbestos, beryllium, cadmium and chromium) are associated with lung cancer.
The incidence of bronchial carcinoma increased dramatically during the 20th century (see Fig. 13.38) and it is now the most common fatal malignancy in the developed world, with escalating incidences in the less developed world as the prevalence of cigarette smoking increases. The current data for lung cancer in the UK are shown in Box 13.64. It accounts for more than 50% of all male deaths from malignant disease and the incidence of lung cancer deaths is expected to climb over the next 10 years, with an increasing number unrelated to smoking.
Figure 13.38 Mortality trends from lung cancer in England and Wales, 1921-90 by age and year of death. A Males. B Females. Note the decline in mortality from lung cancer in men towards the end of this period, reflecting a change in smoking habit.
Bronchial carcinomas arise from the bronchial epithelium or mucous glands. The common cell types are listed in Box 13.66.
13.66 COMMON CELL TYPES OF BRONCHIAL CARCINOMA
Cell type %
When the tumour arises in a large bronchus, symptoms arise early, but tumours originating in a peripheral bronchus can attain a very large size without producing symptoms. Such a tumour, which is usually of the squamous type, may undergo central necrosis and cavitation, when it may have similar radiographic features to a lung abscess (see Fig. 13.39).
Bronchial carcinoma may involve the pleura either directly or by lymphatic spread and extend into the chest wall, invading the intercostal nerves or the brachial plexus and causing severe pain. The primary tumour, or tumour within lymph node metastases, may spread into the mediastinum and invade or compress the pericardium, oesophagus, superior vena cava, trachea, phrenic or left recurrent laryngeal nerves. Lymphatic spread to supraclavicular and mediastinal lymph nodes is also frequently observed. Blood-borne metastases occur most commonly in liver, bone, brain, adrenals and skin. Even a small primary tumour may cause widespread metastatic deposits and this is a particular characteristic of small-cell-type lung cancers.
Figure 13.39 Large cavitated bronchial carcinoma in left lower lobe.
Lung cancer may present in a number of different ways. Most commonly, symptoms reflect local involvement of the bronchus, but may also arise from spread to the chest wall or mediastinum, from distant blood-borne spread or, less commonly, as a result of a variety of non-metastatic paraneoplastic syndromes (see Box 13.67).
13.67 NON-METASTATIC EXTRAPULMONARY MANIFESTATIONS OF BRONCHIAL CARCINOMA
Inappropriate antidiuretic hormone (ADH) secretion causing hyponatraemia
Ectopic adrenocorticotrophic hormone (ACTH) secretion
Hypercalcaemia due to secretion of parathyroid hormone (PTH)-related peptides
Carcinoid syndrome (see p. 801)
Myasthenia (Eaton-Lambert syndrome, see p. 1185)
Hypertrophic pulmonary osteoarthropathy
Polymyositis and dermatomyositis
Cough is the most common early symptom; sputum is purulent if there is secondary infection. Bronchial obstruction may lead to pneumonia, and a recurrent pneumonia at the same site or one which is slow to respond to treatment, particularly in a cigarette smoker, should immediately suggest the possibility of bronchial carcinoma. A lung abscess may sometimes develop, leading to cough productive of large volumes of purulent sputum. A change in the character of the 'regular' cough of a smoker, particularly if it is associated with other new respiratory symptoms, should always alert the clinician to the possibility of bronchial carcinoma.
Haemoptysis is a common symptom, especially in tumours arising in large bronchi. Occasionally, central tumours invade large vessels, causing massive haemoptysis which may be fatal. Repeated episodes of scanty haemoptysis or blood-streaking of sputum in a smoker are highly suggestive of bronchial carcinoma and should always be investigated.
Breathlessness may reflect occlusion of a large bronchus, resulting in collapse of a lobe or lung or the development of a large pleural effusion. Stridor may occur where spread of the tumour to the subcarinal and paratracheal glands causes compression of the main bronchi or lower end of the trachea or, rarely, where the trachea is the site of the primary tumour.
Pleural pain usually reflects malignant invasion of the pleura, although it can reflect distal infection. Involvement of the intercostal nerves or brachial plexus may cause pain in the chest or upper limb along the appropriate nerve root distribution. Bronchial carcinoma in the apex of the lung ('superior sulcus tumour') may cause Horner's syndrome (ipsilateral partial ptosis, enophthalmos, a small pupil and hypohidrosis of the face) due to involvement of the sympathetic chain at or above the stellate ganglion, and/or Pancoast's syndrome (pain in the shoulder and inner aspect of the arm) caused by involvement of the lower part of the brachial plexus. Mediastinal spread may result in dysphagia.
The patient may also present with symptoms due to blood-borne metastases, such as focal neurological defects, epileptic seizures, personality change, jaundice, bone pain or skin nodules. Lassitude, anorexia and weight loss usually indicate the presence of metastatic spread. Finally, the patient may present with symptoms referable to the presence of a number of non-metastatic extrapulmonary manifestations (see Box 13.67). Hypercalcaemia is usually caused by squamous carcinoma and causes polyuria, nocturia, fatigue, constipation, confusion and occasionally coma. The most frequently encountered endocrine syndromes (inappropriate antidiuretic hormone (ADH) secretion and ectopic adrenocorticotrophic hormone (ACTH) secretion) are usually associated with small-cell lung cancer. Associated neurological syndromes may occur with any type of bronchial carcinoma.
Examination is usually normal unless there is significant bronchial obstruction, or the tumour has spread to the pleura or mediastinum. A tumour obstructing a large bronchus produces the physical signs of collapse (or occasionally obstructive emphysema) and may give rise to pneumonia that is characterised by a relative absence of physical signs and a slow response to treatment. A monophonic or unilateral rhonchus (wheeze) suggests the presence of a fixed bronchial obstruction, and the presence of stridor indicates obstruction at or above the level of the main carina. A hoarse voice associated with an ineffectual or 'bovine' cough usually indicates left recurrent laryngeal nerve palsy. Phrenic nerve paralysis causes unilateral diaphragmatic palsy and hence dullness to percussion and absent breath sounds at a lung base. Involvement of the pleura produces the physical signs of pleurisy or of pleural effusion (see p. 501). Bronchial carcinoma is also the most common cause of the superior vena cava syndrome, which presents initially as bilateral engorgement of the jugular veins and later as oedema affecting the face, neck and arms. Digital clubbing is often seen and may be a component part of a syndrome called hypertrophic pulmonary osteoarthropathy (HPOA), which is characterised by periostitis of the long bones, most commonly the distal tibia, fibula, radius and ulna. This gives rise to pain and tenderness in the affected joints and often pitting oedema over the anterior aspect of the shin. Radiographs of the painful bone show subperiosteal new bone formation. HPOA, while most frequently associated with bronchial carcinoma, can occur with other tumours and has been described in association with cystic fibrosis.
The main aims of investigation are to confirm the diagnosis, establish the histological cell type and define the extent of the disease.
The common radiological features of bronchial carcinoma are illustrated in Figure 13.40. Further investigation to obtain a histological diagnosis and determine operability is nearly always indicated.
Figure 13.40 Common radiological presentations of bronchial carcinoma. (See Box 13.68 for details.)
Bronchoscopy is usually the most useful investigation as it can provide tissue (biopsies and bronchial brush samples) for pathological examination and allow direct assessment of the proximity of central tumours to the main carina (see Fig. 13.41). If abnormal tissue is not visible at bronchoscopy, bronchial washings and directed biopsies can be taken from the lung segment in which the tumour is shown to be located on radiological examination. In patients who are not fit enough for a bronchoscopy, examination of sputum cytology can be a valuable diagnostic aid (see Fig. 13.42). Pleural biopsy is indicated in all patients with pleural effusions. If bronchoscopy fails to obtain a cytological diagnosis, percutaneous needle biopsy under CT guidance is appropriate for peripheral tumours or mediastinoscopy for patients with suspected mediastinal involvement. Not infrequently, thoracoscopy or thoracotomy is required to obtain a definitive histological diagnosis. In patients with metastatic disease the diagnosis can often be confirmed by needle aspiration or biopsy of enlarged lymph nodes, skin lesions, where indicated, liver or bone marrow.
13.68 COMMON RADIOLOGICAL PRESENTATIONS OF BRONCHIAL CARCINOMA
1 Unilateral hilar enlargement
Central tumour. Hilar glandular involvement. Beware-peripheral tumour in apical segment of a lower lobe can look like an enlarged hilar shadow on the PA radiograph
2 Peripheral pulmonary opacity (see p. 500)
Usually irregular but well circumscribed. May have irregular cavitation within it. Can be very large
3 Lung, lobe or segmental collapse
Usually caused by tumour within the bronchus causing occlusion. Lung collapse can be produced by compression of the main bronchus by enlarged lymph glands
4 Pleural effusion
Usually indicates tumour invasion of pleural space; very rarely a manifestation of infection in collapsed lung tissue distal to a bronchial carcinoma
5-7 Broadening of mediastinum, enlarged cardiac shadow, elevation of a hemidiaphragm
Paratracheal lymphadenopathy may cause widening of the upper mediastinum. A malignant pericardial effusion will cause enlargement of the cardiac shadow. If a raised hemidiaphragm is caused by phrenic nerve palsy, screening will show it to move paradoxically upwards when patient sniffs
8 Rib destruction
Direct invasion of the chest wall or blood-borne metastatic spread can cause osteolytic lesions of the ribs
Figure 13.41 Bronchoscopic view of a bronchogenic carcinoma. There is distortion of mucosal folds, partial occlusion of the airway lumen and abnormal tumour tissue.
Figure 13.42 Sputum sample showing a cluster of carcinoma cells. There is keratinisation, showing orangeophilia of the cytoplasm, and non-keratinised forms are also seen. The nuclei are large and 'coal-black' in density. These are the features of squamous cell bronchogenic carcinoma.
After establishing a histological diagnosis, investigations should focus on determining whether the tumour is operable. This requires excluding involvement of central mediastinal structures or spread of tumour to distant sites and ensuring that the patient's respiratory and cardiac function is sufficient to allow surgical treatment (see Box 13.69). The propensity of small-cell lung cancer to metastasise early dictates that very few patients with this tumour type are suitable for surgical intervention and that more detailed pre-operative staging is advisable before resection is contemplated. Head CT, radionuclide bone scanning, liver ultrasound and bone marrow biopsy can be reserved for patients with clinical, haematological or biochemical evidence of tumour spread to such sites.
Cure can only be achieved by surgical resection. Unfortunately, in the majority of cases (approximately 85%) surgery is not possible or appropriate, and such patients can only be offered palliative therapy. Radiotherapy, and in some cases chemotherapy, can relieve distressing symptoms.
As discussed, careful staging is essential prior to surgical resection and equal attention must be given to the patient's respiratory reserve and cardiac status. This, coupled with improvements in surgical and post-operative care, now offers 5-year survival rates of > 75% in stage I disease (N0, tumour confined within visceral pleura) and 55% in stage II disease, which includes resection in patients with ipsilateral peribronchial or hilar node involvement.
13.69 CONTRAINDICATIONS TO SURGICAL RESECTION IN BRONCHIAL CARCINOMA
N.B. In otherwise fit individuals, direct extension of tumour into the chest wall, diaphragm, mediastinal pleura or pericardium or to within 2 cm of the main carina does not exclude surgery. Though surgically resectable, patients with N2 (ipsilateral mediastinal) nodes may require neoadjuvant or adjuvant therapy.
Distant metastasis (M1)
Invasion of central mediastinal structures including heart, great vessels, trachea and oesophagus (T4)
Malignant pleural effusion (T4)
Contralateral mediastinal nodes (N3)
FEV1 < 0.8 litres
Severe or unstable cardiac or other medical condition
While much less effective than surgery, radical radiotherapy can offer long-term survival in certain patients with bronchial carcinoma. It is of greatest value, however, in the palliation of distressing complications such as superior vena caval obstruction, recurrent haemoptysis, and pain caused by chest wall invasion or by skeletal metastatic deposits. Obstruction of the trachea and main bronchi can also be relieved temporarily by radiotherapy. Radiotherapy can be used in conjunction with chemotherapy in the treatment of small-cell carcinoma and is particularly efficient at preventing the development of brain metastasis in patients who have had a complete response to chemotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART), in which a similar total dose is given in smaller but more frequent fractions, offers better survival prospects than conventional schedules.
The treatment of small-cell carcinoma with combinations of cytotoxic drugs, sometimes in combination with radiotherapy, can increase the median survival of patients with this highly malignant type of bronchial carcinoma from 3 months to well over a year. Combination chemotherapy leads to better outcomes than single-agent treatment. In particular, oral etoposide leads to more toxicity and worse survival than standard combination chemotherapy. Current recommendations include i.v. cyclophosphamide, doxorubicin and vincristine or i.v. cisplatin and etoposide. The above regimens are given every 3 weeks for 3-6 cycles. Nausea and vomiting peak for 3 days after each cycle of chemotherapy and are best treated with 5-HT3 receptor antagonists (see p. 220).
The use of combinations of chemotherapeutic drugs requires considerable medical skill and expertise and it is recommended that such treatment should only be given under the supervision of clinicians experienced in such treatment. In general, chemotherapy is far less effective in non-small-cell bronchial cancers. However, recent studies in such patients using platinum-based chemotherapy regimens have shown a 30% response rate associated with a small increase in survival.
SMALL-CELL LUNG CANCER-role of prophylactic cranial irradiation
'Meta-analysis of seven RCTs has found that prophylactic cranial irradiation reduces the risk of developing brain metastases and improves survival in patients with small-cell lung cancer in complete remission.'
Auperin A, Arriagada R, Pignon J-P, et al. Prophylactic cranial irradiation for people with small-cell lung cancer in complete remission. N Engl J Med 1999; 341:476-484.
Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk
Laser treatment via a fibreoptic bronchoscope is essentially palliative, the aim being to destroy tumour tissue occluding major airways to allow re-aeration of collapsed lung. The best results are achieved in tumours of the main bronchi.
General aspects of management
As in other forms of carcinoma, effective communication, pain relief and attention to diet are important (see Ch. 5). Lung tumours can cause clinically significant depression and anxiety, and these may need specific therapy. Hypercalcaemia (see p. 715) is an uncommon but important complication of lung cancer, particularly squamous cell carcinoma. Treatment in the acute situation involves intravenous rehydration, maintenance of a good urine output and administration of bisphosphonates. Thereafter, steroids may be effective and mithramycin may be necessary to maintain a normal blood calcium. Demeclocycline can be useful for controlling inappropriate ADH secretion in patients with small-cell lung cancer. The management of malignant pleural effusions is outlined on page 503.
STAGE IV NON-SMALL-CELL LUNG CANCER-role of palliative chemotherapy
'Four SRs of RCTs have found that chemotherapy significantly prolongs 1-year survival in patients with stage IV non-small-cell lung cancer. The survival benefit is greatest with regimens containing cisplatin. Quality of life issues remain undefined.'
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated individual patient data from 52 randomised clinical trials. BMJ 1995; 311:899-909.
Marino P, Pampallona S, Preatoni A, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: results of a meta-analysis of the literature. Chest 1994; 106:861-865.
Further information: www.meds.com/pdq/nonsmallcell_pro.html
13.70 RARER TYPES OF LUNG TUMOUR
Tumour Status Histology Typical presentation Prognosis
Adenosquamous carcinoma Malignant Tumours with areas of unequivocal squamous and adeno-differentiation Peripheral or central lung mass Stage-dependent
Carcinoid tumour (see p. 801) Low-grade malignant Neuro-endocrine differentiation Bronchial obstruction, cough 95% 5-year survival with resection
Bronchial gland adenoma Benign Salivary gland differentiation Tracheobronchial irritation/obstruction Local resection curative
Bronchial gland carcinoma Low-grade malignant Salivary gland differentiation Tracheobronchial irritation/obstruction Local recurrence occurs
Hamartoma Benign Mesenchymal cells, cartilage Peripheral lung nodule Local resection curative
Bronchoalveolar carcinoma Malignant Tumour cells line alveolar spaces Alveolar shadowing, productive cough Variable, worse if multifocal
The overall prognosis in bronchial carcinoma is very poor, with around 80% of patients dying within a year of diagnosis and less than 6% of patients surviving 5 years after diagnosis. The best prognosis is with well-differentiated squamous cell tumours which have not metastasised and are amenable to surgical treatment. The clinical features and prognosis of other less common benign and malignant tumours of the lung are given in Box 13.70.
SECONDARY TUMOURS OF THE LUNG
Blood-borne metastatic deposits in the lungs may be derived from many primary tumours (see p. 542). The secondary deposits are usually multiple and bilateral. Often there are no respiratory symptoms and the diagnosis is made by radiological examination. Breathlessness may be the only symptom if a considerable amount of lung tissue has been replaced by metastatic tumour. Endobronchial deposits are uncommon but can cause haemoptysis and lobar collapse.
PULMONARY LYMPHATIC CARCINOMATOSIS
Lymphatic infiltration may develop in patients with carcinoma of the breast, stomach, bowel, pancreas or bronchus. This grave condition causes severe and rapidly progressive breathlessness associated with marked hypoxaemia. The diagnosis is often suggested by the chest radiograph, which shows diffuse pulmonary shadowing radiating from the hilar regions, often associated with septal lines.
TUMOURS OF THE MEDIASTINUM
The mediastinum can be divided into four major compartments with reference to the lateral chest radiograph (see Fig. 13.43):
superior mediastinum-above a line drawn between the lower border of the 4th thoracic vertebra and the upper end of the body of the sternum
anterior mediastinum-in front of the heart
middle mediastinum-between the anterior and posterior compartments
posterior mediastinum-behind the heart.
Figure 13.43 The divisions of the mediastinum described in the diagnosis of mediastinal masses. (1) Superior mediastinum. (2) Anterior mediastinum. (3) Middle mediastinum. (4) Posterior mediastinum. Sites of the more common mediastinal tumours are also illustrated.
13.71 SOME CAUSES OF A MEDIASTINAL MASS
Persistent left superior
Germ cell tumour
Hernia through the diaphragmatic foramen of Morgagni
A variety of conditions can present radiologically as a mediastinal mass (see Box 13.71).
Benign tumours and cysts arising within the mediastinum are frequently diagnosed when radiological examination of the chest is undertaken for some other reason. In general, they do not invade vital structures but may cause symptoms by compressing the trachea or occasionally the superior vena cava. A dermoid cyst may very occasionally rupture into a bronchus.
13.72 SYMPTOMS AND SIGNS PRODUCED BY MALIGNANT INVASION OF THE STRUCTURES OF THE MEDIASTINUM
Trachea and main bronchi
Stridor, breathlessness, cough, pulmonary collapse
Dysphagia, oesophageal displacement or obstruction on barium swallow examination
Left recurrent laryngeal nerve
Paralysis of left vocal cord giving rise to hoarseness and 'bovine' cough
Superior vena cava
SVC obstruction results in non-pulsatile distension of neck veins, oedema and cyanosis of head, neck, hands and arms. Dilated anastomotic veins on chest wall
Pericarditis and/or pericardial effusion
Malignant mediastinal tumours are distinguished by their power to invade as well as compress structures such as bronchi and lungs (see Box 13.72). As a result, even a small malignant tumour can produce symptoms, although as a rule the tumour has attained a considerable size before this happens. Included in this category are mediastinal lymph node metastases, lymphomas, leukaemia, malignant thymic tumours and germ-cell tumours. Aortic and innominate aneurysms have destructive features resembling those of malignant mediastinal tumours.
A benign mediastinal tumour generally appears as a sharply circumscribed opacity situated mainly in the mediastinum but often encroaching on one or both lung fields (see Fig. 13.44). A malignant mediastinal tumour seldom has a clearly defined margin and often presents as a general broadening of the mediastinal shadow. CT together with MRI are the investigations of choice for mediastinal tumours.
Figure 13.44 Large mass (intrathoracic goitre-arrows) extending from right upper mediastinum.
Bronchoscopy should be carried out in most patients because bronchial carcinoma is a common cause of mediastinal tumour by secondary lymphatic spread.
If enlarged lymph nodes are suspected in the anterior mediastinum, tissue from these nodes can be removed for histological examination by mediastinoscopy. However, surgical exploration of the chest with removal of part or all of the tumour is often required to obtain a histological diagnosis.
Benign mediastinal tumours should be removed surgically because most produce symptoms sooner or later. Some of them, particularly cysts, may become infected, while others, especially neural tumours, have the potential to undergo malignant transformation. The operative mortality is low provided there is not a relative contraindication to surgical treatment, such as coexisting cardiovascular disease, COPD or extreme age.
The treatment of lymphoma and leukaemia is described on pages 931 and 939 respectively. The management of malignant thymomas is surgical. Lymph node metastases from bronchial carcinoma often respond well, though temporarily, to radiotherapy or, in the case of small-cell carcinoma, to chemotherapy. Complications such as superior vena caval and tracheal obstruction can also be treated with radiotherapy or a combination of radiotherapy and chemotherapy, and the placement of internal stents is now possible for localised obstruction of both these structures.
ISSUES IN OLDER PEOPLE
Ageing is a major risk factor for the development of lung cancer.
Elderly patients tend to present with more advanced disease.
There is evidence that older patients are less likely to be referred for bronchoscopy or CT-guided needle biopsy than younger patients, although these procedures are well tolerated and safe even in very old patients. The only older patients who should not be referred are those with other significant pathology who are not fit for investigation or intervention.
The 5-year survival rates for older patients who undergo surgery for squamous cell carcinoma are little different from those for younger patients.
High-intensity chemotherapy regimens for small-cell carcinoma have high levels of toxicity in old age without significant survival benefits.
pages 542 - 550
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013232
For problems or suggestions concerning this service, please contact: firstname.lastname@example.org
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > INTERSTITIAL AND INFILTRATIVE PULMONARY DISEASES
INTERSTITIAL AND INFILTRATIVE PULMONARY DISEASES
INTERSTITIAL PULMONARY DISEASES
Interstitial lung diseases are a heterogeneous group of conditions caused by diffuse thickening of the alveolar walls with inflammatory cells and exudate (e.g. the acute respiratory distress syndrome-ARDS), granulomas (e.g. sarcoidosis), alveolar haemorrhage (e.g. Goodpasture's syndrome, see p. 614) and/or fibrosis (e.g. fibrosing alveolitis). Some are the result of exposure to known agents (e.g. asbestos), whereas in others, such as sarcoidosis, the cause is unknown. Lung disease may occur in isolation, or as part of a systemic connective tissue disorder-for example, in rheumatoid arthritis and systemic lupus erythematosus. Interstitial lung diseases may present acutely, as in acute drug reactions and ARDS, but more often the natural history is one of slowly progressive loss of alveolar-capillary gas exchange units over months or even years. This relentless progression of increased lung stiffness, disordered matching of ventilation and perfusion, and defects in gas transfer results in worsening exertional dyspnoea which, in many cases, eventually progresses to respiratory failure, pulmonary hypertension and death.
There is a very wide range of causes of interstitial lung disease (see Box 13.73). Some, like sarcoidosis, are quite common whereas others are rare. Despite the different causes and pathological processes involved, many interstitial lung diseases give rise to similar symptoms, physical signs, radiological changes and disturbances of pulmonary function and are therefore worthy of collective consideration. Nevertheless, the various underlying aetiologies present very different implications for prognosis and therapy. Moreover, interstitial lung diseases may be confused with other conditions with similar clinical and radiological features (see Box 13.74). Therefore a general approach to interstitial lung disease will be considered before a more detailed description of some specific disorders.
13.73 SOME CAUSES OF INTERSTITIAL LUNG DISEASE
Cryptogenic fibrosing alveolitis
Exposure to organic dusts, e.g. farmer's lung, bird fancier's lung
Exposure to inorganic dusts, e.g. asbestosis, silicosis
As part of systemic inflammatory disease, e.g. ARDS, fibrosing alveolitis in connective tissue disorders
Some forms of pulmonary eosinophilia
Exposure to irradiation and drugs
Rare disorders, e.g. alveolar proteinosis, Langerhans cell histiocytosis
13.74 CONDITIONS WHICH MIMIC INTERSTITIAL LUNG DISEASES
Parasites, e.g. filariasis
Leukaemia and lymphoma
Diagnosis of interstitial lung disease: a general approach
The first task is to differentiate the disorder from other conditions which can mimic interstitial lung diseases (ILDs) (see Box 13.74), and then to determine which of the many causes of ILD is implicated. Establishing a diagnosis is important for a number of reasons. Firstly, there are prognostic implications; for example, sarcoidosis is frequently self-limiting (see p. 552), whereas cryptogenic fibrosing alveolitis (CFA, see p. 555) is most often fatal. Secondly, establishing a specific diagnosis will avoid inappropriate treatment; for example, the powerful immunosuppressive regimens used for some cases of cryptogenic fibrosing alveolitis would be undesirable if the underlying condition was asbestosis or extrinsic allergic alveolitis (see p. 556). Thirdly, some ILDs can be expected to respond better than others to treatment, e.g. a good symptomatic response to corticosteroids could be predicted in sarcoidosis, whereas the prognosis would need to be much more guarded in cryptogenic fibrosing alveolitis. Finally, a lung biopsy taken when the patient is already established on empirical immunosuppressive therapy is not only associated with a higher morbidity and mortality, but the tissue obtained is more difficult to interpret histologically; it is desirable, therefore, to be confident about the diagnosis before starting any therapy.
Establishing a diagnosis often presents a considerable clinical challenge, necessitating meticulous attention to the history and physical signs together with the judicious and selective use of investigations (see Fig. 13.45).
Figure 13.45 Algorithm for the investigation of patients with interstitial lung disease following initial clinical and chest radiograph examination. (CFA = cryptogenic fibrosing alveolitis; UIP = usual interstitial pneumonia; TBB = transbronchial biopsy; HRCT = high-resolution CT)
The duration of disease may sometimes be difficult to ascertain. In the early stages particularly, gradually progressive shortness of breath on exertion may be the only symptom, and hence the patient may not present clinically until there is quite extensive lung pathology. It is clearly important to elicit a detailed history of exposure to organic dusts, inorganic dusts and drugs, including the degree and duration of such exposure. A 'lifetime' occupational history is essential for this purpose. Contact with birds at home or in the working environment is the cause of the most common form of extrinsic allergic alveolitis, but such enquiry is easily overlooked. A history of rashes, joint pains or renal disease may suggest an underlying connective tissue disorder or vasculitis (see Ch. 20).
In many cases, especially in early disease, there may be few, if any, physical signs. In advanced disease tachypnoea and cyanosis may be obvious at rest, and there may be signs of pulmonary hypertension and right heart failure. Digital clubbing may be prominent, particularly in cryptogenic fibrosing alveolitis or asbestosis. There may be restriction of lung expansion and showers of end-inspiratory crepitations on auscultation over the lower zones posteriorly and laterally. Extrapulmonary signs, including lymphadenopathy or uveitis, may be present in sarcoidosis (see Box 13.75) and arthropathies or rashes may suggest an ILD occurring as a manifestation of a connective tissue disorder (see p. 559).
No single blood test is diagnostic for a particular interstitial lung disease. Some laboratory tests may be useful in indicating systemic disease or providing crude indices of disease activity. The ESR and C-reactive protein may be non-specifically elevated. Serological tests may be of value: antinuclear antibodies, rheumatoid factor etc. in connective tissue diseases, and antiglomerular basement membrane antibodies in Goodpasture's syndrome (see p. 614). Serum levels of angiotensin-converting enzyme (ACE) may be elevated in sarcoidosis, but the test is not specific for this condition.
The chest radiograph may show a fine reticular shadowing, a reticulonodular or even a nodular pattern of infiltration at the bases and periphery (see Fig. 13.46A). In advanced disease there may be cystic areas and honeycombing.
Figure 13.46 Cryptogenic fibrosing alveolitis. A Chest radiograph showing bilateral, predominantly lower zone and peripheral coarse reticulonodular shadowing and small lungs. B The CT shows honeycombing and scarring which is most marked peripherally.
High-resolution CT is extremely valuable in detecting early interstitial lung disease and assessing the extent and type of involvement (see Fig. 13.46B), and is also helpful in identifying hilar and paratracheal lymphadenopathy, particularly in sarcoidosis.
Bronchoalveolar lavage is not often of diagnostic value, but there are some important exceptions (see Fig. 13.45). Increased numbers of lymphocytes in bronchoalveolar lavage fluid occur in sarcoidosis and extrinsic allergic alveolitis, whereas a neutrophilia is suggestive of cryptogenic fibrosing alveolitis or pneumoconiosis. In the rare disease, alveolar proteinosis (see p. 562), copious lipoproteinaceous material is recovered in the lavage fluid and large numbers of iron-laden macrophages are seen in pulmonary haemosiderosis (see Box 13.84, p. 562).
Examination of biopsy material is an important diagnostic procedure in most cases. Bronchial and transbronchial biopsies obtained via the fibreoptic bronchoscope will usually establish the diagnosis in sarcoidosis and in some conditions which mimic ILDs, such as lymphatic carcinomatosis and certain infections. However, this approach provides only a small sample of tissue, and in less specific disorders such as cryptogenic fibrosing alveolitis a larger surgical biopsy sample is often necessary to yield a confident diagnosis. This can be obtained by limited thoracotomy or video-assisted thoracoscopy (VATS).
Sarcoidosis is a multisystem granulomatous disease. It is most common in colder climates (e.g. Scandinavian countries). The lung is affected in over 90% of cases. While the aetiology of sarcoidosis remains uncertain, it is associated with imbalance between subsets of T lymphocytes and other disturbances of cell-mediated immunity, but the relationship between these phenomena and sarcoidosis has not yet been explained. The lesions are histologically similar to tuberculous follicles, apart from the absence of caseation and tubercle bacilli, but there is no convincing evidence that the disease is caused by any of the mycobacteria. Chronic beryllium poisoning produces a disease which mimics sarcoidosis both pathologically and clinically but exposure to beryllium is now extremely uncommon. Histological changes resembling those of sarcoidosis are occasionally seen in individual organs, such as lymph nodes, in conditions such as carcinoma and fungal infections, but these localised 'sarcoid reactions' are not associated with systemic sarcoidosis.
The mediastinal and superficial lymph nodes, lungs, liver, spleen, skin, eyes, parotid glands and phalangeal bones are most frequently affected, but all tissues may be involved (see Figs 13.47 and 13.48). The characteristic histological feature consists of non-caseating epithelioid granulomas which usually resolve spontaneously; fibrosis occurs in up to 20% of cases of pulmonary sarcoidosis and it is impossible at present to identify this group of patients prospectively. The overall mortality rate of sarcoidosis is low (1-5%) and usually relates to the involvement of vital organs, particularly the heart. Calcium metabolism may be disturbed, causing hypercalciuria, hypercalcaemia and, rarely, nephrocalcinosis.
Figure 13.47 The range of possible systemic involvement in sarcoidosis.
13.75 PRESENTATION OF SARCOIDOSIS
Asymptomatic-abnormal routine chest radiograph (c. 30%) or abnormal liver function tests
Respiratory and constitutional symptoms (20-30%)
Erythema nodosum and arthralgia (20-30%)
Ocular symptoms (5-10%)
Skin sarcoid (including lupus pernio) (5%)
Superficial lymphadenopathy (5%)
Other (1%), e.g. hypercalcaemia, diabetes insipidus, cranial nerve palsies, cardiac arrhythmias, nephrocalcinosis
Figure 13.48 Pathological lesions in sarcoidosis. A Nasal cutaneous sarcoid lesions. B Histology of sarcoidosis in the lung, showing non-caseating granulomas (arrows).
Since sarcoid lesions can develop in almost any tissue, the mode of presentation can be quite variable (see Box 13.75). Patients can present with an 'acute' form of sarcoidosis with erythema nodosum, peripheral arthropathy, uveitis, bilateral hilar lymphadenopathy, lethargy and occasionally fever. Alternatively, the disease has a more insidious onset and presents with cough, exertional breathlessness or one of the protean extrapulmonary manifestations. Clubbing and cyanosis are unusual even in advanced pulmonary disease and, in contrast to cryptogenic fibrosing alveolitis, inspiratory crepitations are not a prominent feature.
Skin sensitivity to tuberculin is depressed or absent in most (but not all) patients, and the Mantoux reaction is, therefore, a useful 'screening' test; a strongly positive reaction to one tuberculin unit virtually excludes sarcoidosis. The presence of 'rim enhancement' with central necrosis in the lymph nodes on contrast-enhanced CT suggests tuberculous lymphadenopathy. Although the diagnosis can often be made with a fair measure of confidence from the clinical and radiological features (see Box 13.75), it should, if possible, be confirmed histologically by biopsy of an involved organ (e.g. superficial lymph node or skin lesion). Transbronchial lung biopsy confirms the diagnosis in 80-90% of cases, even in those with a normal chest radiograph and no pulmonary symptoms. Bronchoalveolar lavage usually yields fluid with an increased proportion of lymphocytes.
The plasma level of ACE is often elevated. While not specific for sarcoidosis, this test may be valuable in the assessment of disease activity and response to treatment. Lymphopenia, hypercalciuria and a moderately elevated ESR are also frequently observed. Hypercalcaemia may occur but seldom causes symptoms. The chest radiograph features have been used to stage sarcoidosis (see Box 13.76). A radionuclide scan using 67gallium is usually positive in patients with active disease and shows abnormal uptake in affected organs.
When parenchymal lung disease is significant there may be disordered pulmonary function tests with a reduction in gas transfer and typical restrictive abnormalities (see p. 493) occurring in more advanced disease, particularly if fibrosis has occurred.
In stage III and IV sarcoidosis assessment of disease progression is made by repeated measurement of lung volumes, carbon monoxide transfer factor and serial chest radiographs.
13.76 CHEST RADIOGRAPH CHANGES IN SARCOIDOSIS
Radiograph shows bilateral hilar enlargement, usually symmetrical; paratracheal nodes often enlarged
Spontaneous resolution within 1 year in the majority of cases. Often asymptomatic, but may be associated with erythema nodosum and arthralgia
Radiograph shows a combination of hilar glandular enlargement and pulmonary opacities which are often diffuse
Patients are breathless or have a cough. Spontaneous improvement occurs in the majority
Radiograph shows diffuse pulmonary shadows without evidence of hilar adenopathy
Disease less likely to resolve spontaneously
Can cause progressive ventilatory failure, pulmonary hypertension and cor pulmonale
Stage I and II disease usually resolves spontaneously and treatment is seldom required. Patients with persistent erythema nodosum, pyrexia and arthralgia may benefit from non-steroidal anti-inflammatory drugs. Short-term oral corticosteroid therapy is occasionally required for patients with severe systemic features, anterior uveitis or hypercalcaemia.
Symptomatic stage III pulmonary sarcoidosis and sarcoidosis involving the eyes or other vital organs (especially the heart or brain) usually need to be treated with corticosteroids, which may have to be continued for several years. Sarcoidosis typically responds rapidly to prednisolone 20-40 mg daily (see EBM panel); thereafter the disease is usually suppressed by a maintenance dose of 7.5-10 mg daily, or 20 mg on alternate days. Methotrexate and hydroxychloroquine are effective second-line or steroid-sparing agents.
PULMONARY SARCOIDOSIS-role of systemic steroids
'RCTs indicate that oral steroids improve symptoms, respiratory function and radiographic appearance in patients with stage II and III pulmonary sarcoidosis. However, these effects are small and there are no data beyond 2 years to indicate whether such therapy influences long-term disease progression.'
Gibson GJ, Prescott RJ, Muers MF, et al. The British Thoracic Society Sarcoidosis Study: effects of long term corticosteroid treatment. Thorax 1996; 51:238-247.
Paramothayan NS, Jones PW. Corticosteroids for pulmonary sarcoidosis (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
CRYPTOGENIC FIBROSING ALVEOLITIS
Cryptogenic fibrosing alveolitis (CFA; also referred to as idiopathic pulmonary fibrosis in North America) exemplifies many of the typical features of interstitial lung disease. By definition this form of fibrosing alveolitis is not associated with an overt systemic or connective tissue disorder. The Epstein-Barr virus and exposure to metal and wood dusts have been reported to be associated with the disease. CFA has an incidence of 6-10 per 100 000 per year and is about twice as common among cigarette smokers as in non-smokers. Men are also more commonly affected than women.
CFA is probably not a single disease entity and other forms of idiopathic interstitial lung disease are now recognised both clinically and pathologically (see Box 13.77). Such differentiation is important as many of these conditions have a much better response to corticosteroid therapy and a better prognosis.
13.77 HISTOLOGICAL SUBCLASSIFICATION OF IDIOPATHIC FORMS OF INTERSTITIAL LUNG DISEASE
Histological diagnosis Clinical diagnosis Notes
Usual interstitial pneumonia (UIP) Cryptogenic fibrosing alveolitis (CFA) See text
Poor response to corticosteroids
Non-specific interstitial pneumonia (NSIP) NSIP Uniform fibrosis and thickening of alveolar walls
Associated with underlying connective tissue disease and HIV infection
Good response to corticosteroids
Better prognosis than CFA
Respiratory bronchiolitis Respiratory bronchiolitis (interstitial lung disease) Invariable association with cigarette smoking
Accumulation of pigment-laden macrophages in respiratory bronchioles and adjacent alveoli
Good prognosis on stopping smoking
Diffuse alveolar damage (DAD) Acute interstitial pneumonia (AIP) Proteinaceous alveolar exudate, interstitial oedema and fibrosis, hyaline membranes
Desquamative interstitial pneumonia (DIP) DIP Alveolar wall thickening and mononuclear cell infiltration; alveoli filled with alveolar macrophages
Good initial response to corticosteroid therapy
Organising pneumonia Cryptogenic organising pneumonia (COP) Intraluminal organising fibrosis of distal airspaces, patchy distribution, preservation of lung architecture
Good response to corticosteroids
Macroscopically, the lungs show subpleural fibrosis and a honeycomb appearance, predominantly in the lower lobes and basolateral pleural regions. Microscopically, there is architectural disruption with temporal heterogeneity and characteristic fibroproliferative lesions representing the site of healing alveolar injury. There is variable mononuclear cell infiltration of the alveolar walls, fibrosis and smooth muscle proliferation.
CFA is predominantly a disease of the elderly, with a mean age at presentation of 69 years. Progressive exertional breathlessness is usually the presenting symptom, often accompanied by persistent dry cough. In 60% of patients digital clubbing is observed. Chest expansion may be poor and numerous bilateral end-inspiratory crepitations are audible on auscultation, particularly over the lower zones posteriorly.
Blood tests are of no value in confirming a diagnosis of CFA. However, rheumatoid factor and antinuclear factor can be detected in 30-50% of patients. The ESR and lactate dehydrogenase are elevated in most cases.
The chest radiograph shows diffuse pulmonary opacities which are usually most obvious in the lower zones and peripherally (see Fig. 13.46A, p. 552). The hemidiaphragms are high and the lungs appear small. In advanced disease the chest radiographs may show a 'honeycomb' appearance, in which diffuse pulmonary shadowing is interspersed with small cystic translucencies. 'Honeycomb lung' is also a characteristic feature of rare diseases such as Langerhans cell histiocytosis and tuberous sclerosis (see Box 13.84, p. 562). High-resolution CT can reveal a characteristic picture (see p. 552) and is particularly useful in early disease when chest radiograph changes may be slight or absent.
Pulmonary function tests show a restrictive ventilatory defect with proportionate reduction in VC and FEV1. The carbon monoxide transfer factor is low and there is an overall reduction in lung volume. In early disease there is arterial hypoxaemia on exercise; later, arterial hypoxaemia and hypocapnia are present at rest.
A firm diagnosis of CFA can usually be achieved on the basis of the history, clinical findings and characteristic high-resolution CT appearance (see Fig. 13.46B, p. 552). If doubt exists, an open lung biopsy is indicated. Bronchoalveolar lavage and transbronchial biopsy are generally unhelpful and do not allow the pathologist to differentiate between CFA and other forms of pulmonary fibrosis.
CFA has a high mortality rate, with survival beyond 5 years unusual; there are no RCTs of corticosteroids (or alternative immunosuppressive agents) in CFA but a proportion of patients do respond in terms of symptoms (50%) and lung function (25%) (see Box 13.77 for further details). Currently, such therapy is recommended in patients who are highly symptomatic or have rapidly progressive disease, have a predominantly 'ground-glass' appearance on CT or have a sustained fall of > 15% in their FVC or gas transfer over a 3-6-month period. The recommended initial treatment is combined therapy with prednisolone (0.5 mg/kg) and azathioprine (2-3 mg/kg).
Assessment of response to this treatment is by repeat measurement of lung volumes, transfer factor and chest radiograph. Immunosuppressive therapy should be withdrawn over a few weeks if there is no response. Should objective evidence of improvement be demonstrated the prednisolone dose can be reduced gradually to a maintenance dose of 10-12.5 mg daily.
The median survival time of patients with CFA is about 3.5 years. Most deaths occur in patients over the age of 55, with males predominating. The rate of disease progression varies considerably from death within a few months to survival with minimal symptoms for many years. Occasionally, the disease process may 'burn out', but in the majority of patients the disease is progressive, even in those who have responded to treatment. Lung transplantation (see p. 508) should be considered in young patients with advanced disease.
LUNG DISEASES DUE TO ORGANIC DUSTS
A wide range of organic agents may cause respiratory disorders (see Box 13.78). Disease results from a local immune response to animal proteins (e.g. bird fancier's lung) or fungal antigens in mouldy vegetable matter. The most common presentation has been termed extrinsic allergic alveolitis.
13.78 SOME EXAMPLES OF LUNG DISEASES CAUSED BY ORGANIC DUSTS
Disorder Source Antigen/agent
Farmer's lung* Mouldy hay, straw, grain Micropolyspora faenae
Bird fancier's lung* Avian excreta, proteins and feathers Avian serum proteins
Malt worker's lung* Mouldy maltings Aspergillus clavatus
Byssinosis Textile industries Cotton, flax, hemp dust
Inhalation ('humidifier') fever Contamination of air conditioning Thermophilic actinomycetes
Cheese worker's lung* Mouldy cheese Aspergillus clavatus Penicillium casei
Maple bark stripper's lung* Bark from stored maple Cryptostroma corticale
*Denotes lung disease presenting as extrinsic allergic alveolitis.
EXTRINSIC ALLERGIC ALVEOLITIS
In this condition the inhalation of certain types of organic dust produces a diffuse immune complex reaction in the walls of the alveoli and bronchioles.
The pathogenic mechanisms concerned in the production of extrinsic allergic alveolitis (EAA) are not fully understood. It is thought that the disease develops in sensitised individuals mainly through a type III Arthus reaction, although type IV mechanisms are probably also important. When the antigen is inhaled, the immune complexes formed in antibody excess are precipitated very rapidly. Deposition of these immune complexes results in complement activation, causing a localised inflammatory reaction in the alveolar walls. Immunofluorescence has shown IgG, IgA and complement to be fixed in the pulmonary tissues when biopsy specimens are examined in the acute stages. The presence of granulomata in the alveolar walls provides some evidence for a type IV response also being involved. Bronchoalveolar lavage fluid from patients with extrinsic allergic alveolitis usually shows an increase in the number of lymphocytes.
Some of the agents which produce EAA, their source, and the names given to the resulting disease are shown in Box 13.78. In the UK, 50% of reported cases of EAA occur in farm workers. If patients with this disorder continue to be exposed to the relevant antigen, they develop progressive lung fibrosis, leading to severe respiratory disability, pulmonary hypertension and cor pulmonale.
EAA should be suspected when anyone who is regularly or intermittently exposed to organic dust complains, within a few hours of re-exposure to the same dust, of influenza-like symptoms. These include headache, muscle pains, malaise, pyrexia, dry cough and breathlessness without wheeze. When exposure is continuous, as is the case with an indoor pet bird at home, the presentation can be with breathlessness without systemic symptoms, and if the cause is not recognised this may result in the formation of irreversible pulmonary fibrosis. For reasons that remain uncertain, there is a lower incidence of EAA in smokers compared to non-smokers.
In the acute stage of the disease widespread end-inspiratory crepitations are the rule and the chest radiograph shows diffuse micronodular shadowing, often more pronounced in the upper zones. High-resolution CT in patients with acute EAA shows bilateral areas of consolidation superimposed on small centrilobar nodular opacities and air-trapping on expiration. In more chronic disease, features of fibrosis with linear opacities and architectural distortion predominate. Pulmonary function studies reveal a restrictive ventilatory defect with preservation of (or an increase in) the FEV1/FVC ratio. The PaO2 is reduced and the PaCO2 is often below normal because of over-ventilation. Diffusion capacity is impaired.
The diagnosis of EAA is usually based on the characteristic clinical and radiological features, together with the identification of a potential source of antigen at the patient's home or place of work. Reduction in the carbon monoxide transfer factor is the most sensitive functional abnormality. The diagnosis may be supported by a positive precipitin test or by more sensitive serological tests based on the enzyme-linked immunosorbent assay (ELISA) technique. However, it is also important to recognise that the great majority of farmers with positive precipitins do not have farmer's lung, and up to 15% of pigeon breeders may have positive serum precipitins and yet remain healthy. Where the diagnosis is suspected but the cause is not readily apparent, it may be helpful to visit the patient's home or workplace. Occasionally, such as when a new agent is suspected, it may be necessary to prove the diagnosis by a provocation test; if positive, the inhalation of the relevant antigen is followed after 3-6 hours by pyrexia and a reduction in VC and gas transfer factor. Open lung biopsy may be necessary to establish a diagnosis.
Mild forms of extrinsic allergic alveolitis rapidly subside when exposure to the antigen ceases. In acute cases prednisolone should be given for 3-4 weeks, starting with an oral dose of 40 mg per day. Severely hypoxaemic patients may require high-concentration oxygen therapy initially. Most patients recover completely, but the development of interstitial fibrosis causes permanent disability when there has been prolonged exposure to antigen.
Not all inhaled organic dusts cause interstitial infiltration. In byssinosis the initial lesion caused by cotton dust inhalation is acute bronchiolitis associated with symptoms and signs of generalised airflow obstruction, more in keeping with asthma. Initially, symptoms tend to recur after the weekend break ('Monday fever') but eventually become continuous. There is usually no radiological abnormality. Recovery usually follows removal from the dust hazard. Smokers have a greater incidence of byssinosis than non-smokers.
INHALATION ('HUMIDIFIER') FEVER
Inhalation fever is characterised by self-limiting fever and breathlessness following exposure to organism-contaminated water from humidifiers or air-conditioning systems. An identical syndrome can also develop after disturbing an accumulation of mouldy hay, compost or mulch.
LUNG DISEASES DUE TO INORGANIC DUSTS
13.79 SOME LUNG DISEASES CAUSED BY EXPOSURE TO INORGANIC DUSTS
Cause Occupation Description Characteristic pathological features
Coal dust Silica Coal mining Mining, quarrying, stone dressing, metal grinding, pottery, boiler scaling Coal worker's pneumoconiosis Silicosis Focal and interstitial fibrosis, centrilobular emphysema, progressive massive fibrosis
Asbestos Demolition, ship breaking, manufacture of fireproof insulating materials and brake-pads, pipe and boiler lagging Asbestos-related disease Interstitial fibrosis, pleural disease, carcinoma of larynx and bronchus
Iron oxide Arc welding Siderosis Mineral deposition only
Tin oxide Tin mining Stannosis
Beryllium Aircraft, atomic energy and electronics industries Berylliosis Granulomata, interstitial fibrosis
13.80 SOME LUNG DISEASES CAUSED BY INORGANIC GASES AND FUMES
Cause Occupation Disease
Irritant gases (chlorine, ammonia, phosgene, nitrogen dioxide) Various (industrial accidents) Acute lung injury ARDS
Cadmium Welding and electroplating COPD
Isocyanates (e.g. epoxy resins, paints) Plastic, paints; manufacture of epoxy resins and adhesives Bronchial asthma Eosinophilic pneumonia
In certain occupations, the inhalation of inorganic dusts, fumes or other noxious substances may give rise to specific pathological changes in the lungs. The risk of these forms of occupational lung disease is highest in spray painters, shipyard and dock workers, miners and quarrymen, welders, electronic assembly workers and those that work in the construction industry or in chemical processing. Generally, prolonged exposure to inorganic dusts (see Box 13.79) leads to diffuse pulmonary fibrosis (the pneumoconioses), although berylliosis causes an interstitial granulomatous disease similar to sarcoidosis. The dusts themselves cause little direct damage to the lung parenchyma and the pathological result depends largely on the inflammatory and fibrotic responses to the particular dust. The fibrogenic properties of mineral dusts vary, silica being markedly fibrogenic whereas iron and tin are almost inert. The most important types of pneumoconiosis are coal worker's pneumoconiosis, silicosis and asbestosis.
Industrial inorganic gases and fumes can cause other, often more acute, respiratory diseases including pulmonary oedema and asthma (see Box 13.80).
Clearly, it is essential to elicit a detailed occupational history, both present and past, since a diagnosis of occupational lung disease can easily be overlooked and the patient may be eligible for compensation. It must also be emphasised that in many types of pneumoconiosis a long period of dust exposure is required before radiological changes appear, and these may precede clinical symptoms.
Notes on diagnosis and claims for benefits in pneumoconiosis, occupational asthma and other related occupational disease in Britain are contained in government pamphlets. New industrial processes are constantly being introduced and it is necessary to remain alert to the possibility that they may be associated with occupational lung disease.
COAL WORKER'S PNEUMOCONIOSIS
This disease follows prolonged inhalation of coal dust. The condition is subdivided into simple pneumoconiosis and progressive massive fibrosis for both clinical purposes and certification. It must be emphasised that for certification purposes in Britain the diagnosis rests at present on radiological and not clinical features.
Simple coal worker's pneumoconiosis
This is categorised radiologically into three grades, depending on the size and extent of the nodulation present. It does not progress if the miner leaves the industry.
Progressive massive fibrosis
In this form of the disease, large dense masses, single or multiple, occur mainly in the upper lobes. These may be irregular in shape and may cavitate. Tuberculosis may be a complication. The disease can be disabling, may shorten life expectancy and may progress even after the miner leaves the industry.
Cough and sputum from associated chronic bronchitis are frequently present. The sputum may be black (melanoptysis). Progressive breathlessness on exertion occurs in the later stages, and respiratory and right ventricular failure supervene as terminal events. There may be no abnormal physical signs in the chest but when present they are those of chronic obstructive airways disease.
Antinuclear factor is present in the serum of about 15% of patients with coal worker's pneumoconiosis. Rheumatoid factor is present in some patients in whom rheumatoid arthritis coexists, with rounded fibrotic nodules 0.5-5 cm in diameter. These are mainly in the periphery of the lung fields and the association is known as Caplan's syndrome. This syndrome may also occur in other types of pneumoconiosis.
This disease is becoming rare as the standards of industrial hygiene improve. It is caused by the inhalation of fine free crystalline silicon dioxide (silica) dust or quartz particles.
Silica is a most fibrogenic dust and causes the development of hard nodules which coalesce as the disease progresses. Tuberculosis may modify the silicotic process with ensuing caseation and calcification. The radiological features are similar to those seen in coal worker's pneumoconiosis, though the changes tend to be more marked in the upper zones. The hilar shadows may be enlarged; 'egg-shell' calcification in the hilar lymph nodes is a distinctive feature but does not occur in all patients. The disease progresses even when exposure to dust ceases. The patient should, therefore, be removed from the offending environment as soon as possible. Clinical features are also similar to those of coal worker's pneumoconiosis.
Intense exposure to very fine crystalline silica dust can cause a more acute disease similar to alveolar proteinosis (see p. 562) with over-production of surfactant by type II alveolar pneumocytes.
The main types of the fibrous mineral, asbestos, are chrysotile (white asbestos), which accounts for 90% of the world's production, crocidolite (blue asbestos) and amosite (brown asbestos). Exposure occurs in the mining and milling of the mineral and in a variety of occupations (see Box 13.79).
Asbestos exposure is a recognised risk factor for the development of a number of respiratory diseases (see Fig. 13.49), including carcinoma of the lung and larynx. Asbestos-related pleural disease is covered on page 572. Asbestosis itself is defined as diffuse fibrosis of the lungs caused by inhalation of asbestos particles. This condition may or may not be associated with fibrosis of the parietal or visceral layer of the pleura. Together with asbestos-related diffuse pleural fibrosis and mesothelioma, it qualifies an individual in the UK for industrial injury benefit. In contrast to the other forms of asbestos-related respiratory disease, asbestosis tends to develop in individuals exposed to significant levels of asbestos dust over a number of years.
Figure 13.49 Asbestos: the range of possible effects on the respiratory tract.
Asbestosis usually has an indolent course and may be present subclinically for many years before becoming symptomatic in late middle age with dyspnoea, digital clubbing and inspiratory crepitations audible over the lower zones of both lungs. The chest radiograph shows bi-basal reticular nodular shadowing and occasionally 'honeycombing'. Other features of asbestos exposure may also be present (e.g. pleural plaques). Pulmonary function abnormalities are a restrictive defect with decreased lung volumes and reduced gas transfer factor. The risk of bronchial carcinoma is extremely high, especially in patients who also smoke.
The diagnosis is usually easy to establish from the history of exposure to asbestos and the above clinical, radiological and pulmonary function abnormalities. Lung biopsy may be required to confirm the diagnosis (and exclude other treatable causes of interstitial lung disease) but should not be undertaken solely for the purpose of allowing patients to claim benefit.
No specific treatment is available. Corticosteroids are of no value in the management of asbestosis. Respiratory failure and cor pulmonale should be treated appropriately.
Improvements in standards of industrial hygiene are now enforced by law in many countries; such measures as wearing respirators, damping dust and efficient ventilation systems are already proving effective in a number of industries.
LUNG DISEASES DUE TO SYSTEMIC INFLAMMATORY DISEASE
THE ACUTE RESPIRATORY DISTRESS SYNDROME
See page 198.
RESPIRATORY INVOLVEMENT IN CONNECTIVE TISSUE DISORDERS
Fibrosing alveolitis is a recognised complication of most connective tissue diseases. The clinical features are usually indistinguishable from cryptogenic fibrosing alveolitis (see p. 555) and the response to immunosuppressive drugs is similarly unpredictable. Connective tissue disorders may also cause disease of the pleura, diaphragm and chest wall muscles (see Box 13.81 and Ch. 20). Pulmonary hypertension and cor pulmonale may result from advanced fibrosing alveolitis associated with connective tissue disorders and is particularly common in patients with systemic sclerosis.
Indirect associations between connective tissue disorders and respiratory complications include those due to disease in other organs, e.g. thrombocytopenia causing haemoptysis; pulmonary toxic effects of drugs used to treat the connective tissue disorder (e.g. gold and methotrexate); and secondary infection due to the disease itself, neutropenia or immunosuppressive drug regimens.
Fibrosing alveolitis is the most common pulmonary manifestation (rheumatoid lung). The clinical features, investigations, treatment and prognosis are similar to those of cryptogenic fibrosing alveolitis, although a rare variant of localised upper lobe fibrosis and cavitation has been described.
Pleural effusion is common, especially in men with seropositive disease. Effusions are usually small and unilateral but can be large and bilateral. Most resolve spontaneously. Biochemical testing shows an exudative effusion (see p. 501) with markedly reduced glucose levels and raised protein lactate dehydrogenase (LDH). Effusions that fail to resolve spontaneously may respond to a short course of oral prednisolone (30-40 mg daily) but some become chronic.
13.81 RESPIRATORY COMPLICATIONS OF CONNECTIVE TISSUE DISORDERS
Disorder Airways Parenchyma Pleura Diaphragm and chest wall
Rheumatoid arthritis Bronchitis, obliterative bronchiolitis, bronchiectasis, crico-arytenoid arthritis, stridor Fibrosing alveolitis, nodules, upper lobe fibrosis, infections Pleurisy, effusion, pneumothorax Poor healing of intercostal drain sites
Systemic lupus erythematosus - Fibrosing alveolitis, 'vasculitic' infarcts Pleurisy, effusion 'Shrinking lungs'
Systemic sclerosis Bronchiectasis Pulmonary fibrosis, aspiration pneumonia - 'Hidebound chest'
Dermatomyositis/polymyositis Bronchial carcinoma Fibrosing alveolitis - Intercostal and diaphragmatic myopathy
Rheumatic fever - Pneumonia Pleurisy, effusion -
Figure 13.50 Rheumatoid (necrobiotic) nodules. Thoracic CT just below the level of the main carina showing the typical appearance of peripheral, pleural-based nodules. The nodule in the left lower lobe shows characteristic cavitation.
Rheumatoid pulmonary nodules do not usually cause symptoms and are detected on chest radiographs performed for other reasons. They are usually multiple and subpleural in site (see Fig. 13.50). Solitary nodules can mimic primary bronchial carcinoma and when multiple the differential diagnosis includes pulmonary metastatic disease. Cavitation of nodules can raise the possibility of tuberculosis and cause pneumothorax. The combination of rheumatoid nodules and pneumoconiosis is known as Caplan's syndrome (see p. 558).
Bronchitis and bronchiectasis are both more common in rheumatoid patients. Rarely, the potentially fatal condition, obliterative bronchiolitis, may develop.
Systemic lupus erythematosus
Fibrosing alveolitis is a relatively uncommon manifestation of systemic lupus erythematosus (SLE). Pleuropulmonary involvement is more common in lupus than in any other connective tissue disorder. Up to two-thirds of patients have repeated episodes of pleurisy, with or without effusions. Effusions may be bilateral and involve the pericardium.
Some patients with SLE present with exertional dyspnoea and orthopnoea but without overt signs of fibrosing alveolitis. The chest radiograph reveals elevated diaphragms, and pulmonary function testing shows reduced lung volumes. This condition has been described as 'shrinking lungs' and is thought to be caused by diaphragmatic myopathy.
Most patients with systemic sclerosis eventually develop diffuse pulmonary fibrosis; at necropsy more than 90% have evidence of lung fibrosis. In some patients it is indolent, but when progressive, like cryptogenic fibrosing alveolitis, the median survival time is around 4 years. Pulmonary fibrosis is rare in the CREST variant of progressive systemic sclerosis but isolated pulmonary hypertension may develop.
Other pulmonary complications include recurrent aspiration pneumonias secondary to oesophageal disease. Rarely, sclerosis of the skin of the chest wall may be so extensive and cicatrising as to restrict chest wall movement seriously-the so-called 'hidebound chest'.
PULMONARY EOSINOPHILIA AND VASCULITIDES
This term is applied to a group of disorders of different aetiology in which lesions in the lungs produce a chest radiograph abnormality associated with an increase in the number of the eosinophil leucocytes in the peripheral blood. There is no satisfactory classification of this disparate group of disorders, but they can be divided into two main categories (see Box 13.82).
Some causes of extrinsic pulmonary eosinophilia are also given in the box. The most common disorder of this type in developed countries is allergic bronchopulmonary aspergillosis (see p. 540); in tropical countries the presence of microfilariae in the pulmonary capillaries (see p. 73) has to be considered.
CRYPTOGENIC EOSINOPHILIC PNEUMONIA
13.82 PULMONARY EOSINOPHILIA
Extrinsic (cause known)
e.g. Ascaris, Toxocara, Filaria
Nitrofurantoin, para-aminosalicylic acid (PAS), sulfasalazine, imipramine, chlorpropamide, phenylbutazone
e.g. Aspergillus fumigatus causing allergic bronchopulmonary aspergillosis (see p. 540)
Intrinsic (cause unknown)
Cryptogenic eosinophilic pneumonia
Churg-Strauss syndrome (diagnosed on the basis of four or more of the following features: asthma, peripheral blood eosinophilia of > 10%, mononeuropathy or polyneuropathy, pulmonary infiltrates, paranasal sinus disease or eosinophilic vasculitis on biopsy of an affected site)
Polyarteritis nodosa (see p. 1042; rare)
Cryptogenic eosinophilic pneumonia is more common in middle-aged females, and usually presents with malaise, fever, breathlessness and unproductive cough. The chest radiograph can show abnormal parenchymal shadowing which tends to be bilateral, peripheral and upper lobe in distribution. Unless corticosteroids have been given, the peripheral blood eosinophil count is almost always very high, and the ESR and total serum IgE are elevated. Bronchoalveolar lavage reveals a high proportion of eosinophils in the lavage fluid. Response to prednisolone (20-40 mg daily) is usually dramatic. Prednisolone treatment can usually be withdrawn after a few weeks without relapse, but long-term low-dose therapy is occasionally necessary to control the disease.
LUNG DISEASES DUE TO IRRADIATION AND DRUGS
The lungs are exposed during radiotherapy treatment of lung tumours and also tumours of the breast, spine and oesophagus. The pulmonary effects of radiation (see p. 219) are exacerbated by treatment with cytotoxic drugs, oxygen delivery and previous radiotherapy. Radiotherapy may cause acute damage to the lung, and also a chronic insidious scarring disease.
After pulmonary irradiation, acute radiation pneumonitis may present with cough and dyspnoea within 6-12 weeks. This acute form of lung damage may resolve spontaneously or respond to corticosteroid treatment. Chronic interstitial fibrosis presents later, usually with symptoms of exertional dyspnoea and cough. Established post-irradiation fibrosis does not usually respond to corticosteroid treatment.
13.83 DRUG-INDUCED RESPIRATORY DISEASE
Non-cardiogenic pulmonary oedema (ARDS)
I.v. ß-adrenoceptor agonists (e.g. treatment of premature labour)
Aspirin and opiates (in overdose)
Amiodarone, flecainide, gold, nitrofurantoin, cytotoxic agents-especially bleomycin, busulfan, mitomycin C, methotrexate
Antimicrobials (nitrofurantoin, penicillin, tetracyclines, sulphonamides, nalidixic acid)
Antirheumatic agents (gold, aspirin, penicillamine, naproxen)
Cytotoxic drugs (bleomycin, methotrexate, procarbazine)
Psychiatric drugs (chlorpromazine, dosulepin (dothiepin), imipramine)
Anticonvulsants (carbamazepine, phenytoin)
Others (sulfasalazine, nadolol)
Bromocriptine, amiodarone, methotrexate, methysergide
Via induction of SLE-phenytoin, hydralazine, isoniazid
Via pharmacological mechanism (ß-blockers, cholinergic agonists, aspirin and NSAIDs)
Idiosyncratic reaction (tamoxifen, dipyridamole)
Drugs may cause a number of parenchymal reactions, including ARDS (see Box 13.83), eosinophilic reactions and diffuse interstitial inflammation/scarring. Drugs can also cause other lung disorders including asthma (see p. 514), haemorrhage (e.g. anticoagulants, penicillamine) and occasionally pleural effusions and pleural thickening (e.g. hydralazine, isoniazid, methysergide). An ARDS-like syndrome of acute non-cardiogenic pulmonary oedema may present with dramatic onset of breathlessness, severe hypoxaemia and signs of alveolar oedema on the chest radiograph. This syndrome has been reported most frequently in cases of opiate overdose in drug addicts (see p. 176) but also after salicylate overdose, and there are occasional reports of its occurrence after therapeutic doses of drugs including hydrochlorothiazides and some cytotoxic drugs.
ISSUES IN OLDER PEOPLE
INTERSTITIAL LUNG DISEASE
Cryptogenic fibrosing alveolitis is the most common interstitial lung disease in old people and has a worse prognosis.
Chronic aspiration pneumonitis must always be considered in elderly patients presenting with bilateral basal shadowing on a chest radiograph.
Wegener's granulomatosis is a rare condition but is more common in old age. Renal involvement is more common at presentation and upper respiratory problems are fewer in older people.
The symptoms of asbestosis may appear for the first time in old age because of the prolonged latent period between exposure and the development of disease.
Drug-induced interstitial lung disease is more common in old age, presumably because of the increased chance of exposure to multiple drugs.
Sarcoidosis, idiopathic pulmonary haemosiderosis, alveolar proteinosis and eosinophilic pneumonia rarely present in old age.
Coexistent muscle weakness, chest wall deformity (e.g. thoracic kyphosis) and deconditioning may all exacerbate the extent of dyspnoea associated with interstitial lung disease.
Open lung biopsy is often inappropriate in the very frail and a diagnosis therefore frequently depends on clinical and high-resolution CT findings alone.
13.84 RARE INTERSTITIAL LUNG DISEASES
Disease Presentation Chest radiograph Course
Idiopathic pulmonary haemosiderosis Haemoptysis, breathlessness, anaemia Bilateral infiltrates often perihilar Diffuse pulmonary fibrosis Rapidly progressive in children Slow progression or remission in adults Death from massive pulmonary haemorrhage or cor pulmonale and respiratory failure
Alveolar proteinosis Breathlessness and cough Occasionally fever, chest pain and haemoptysis Diffuse bilateral shadowing, often more pronounced in the hilar regions Air bronchogram Spontaneous remission in one-third Whole lung lavage or granulocyte macrophage-colony stimulating factor (GM-CSF) therapy may be effective
Langerhans cell histiocytosis (histiocytosis X) Breathlessness, cough, pneumothorax Diffuse interstitial shadowing progressing to honeycombing Progressive leading to respiratory failure Poor response to immunosuppressive therapy Smoking cessation is important and may result in significant improvement
Neurofibromatosis Breathlessness and cough in a patient with multiple organ involvement with neurofibromas including skin Bilateral reticular nodular shadowing of diffuse interstitial fibrosis Slow progression to death from respiratory failure Poor response to corticosteroid therapy
Alveolar microlithiasis No symptoms Breathlessness and cough Diffuse calcified micronodular shadowing more pronounced in the lower zones Slowly progressive to cor pulmonale and respiratory failure May stabilise in some Disodium etidronate may be effective
Lymphangioleiomyomatosis Haemoptysis, breathlessness, pneumothorax and chylous effusion in females Diffuse bilateral shadowing CT shows characteristic thin-walled cysts with well-defined walls throughout both lungs Progressive to death within 10 years Oestrogen ablation and progesterone therapy of doubtful value Lung transplantation
Pulmonary tuberous sclerosis Very similar to lymphangioleiomyomatosis except occasionally occurs in men
Pulmonary fibrosis may occur in response to a variety of drugs, but is seen most frequently with bleomycin, methotrexate, amiodarone and nitrofurantoin. Eosinophilic pulmonary reactions can also be caused by drugs. The pathogenesis may be an immune reaction similar to that in extrinsic allergic alveolitis, which specifically attracts large numbers of eosinophils into the lungs. This type of reaction is well described as a rare reaction to a variety of antineoplastic agents (e.g. bleomycin), antibiotics (e.g. sulphonamides), sulfasalazine and the anticonvulsants phenytoin and carbamazepine. Patients usually present with breathlessness, cough and fever. The chest radiograph characteristically shows patchy shadowing. Most cases resolve completely on withdrawal of the drug, but if the reaction is severe, rapid resolution can be obtained with corticosteroids.
RARE INTERSTITIAL LUNG DISEASES
See Box 13.84.
pages 550 - 562
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013257
For problems or suggestions concerning this service, please contact: email@example.com
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > PULMONARY VASCULAR DISEASE
PULMONARY VASCULAR DISEASE
Deep venous thrombosis (DVT, see pp. 953-956) and pulmonary embolism (PE) can be usefully considered under the heading venous thromboembolism (VTE); 75% of pulmonary emboli derive from DVT in the lower limb and 60% of patients with DVT will have evidence of PE on scanning even in the absence of symptoms. Rarely, PE may occur due to amniotic fluid, placenta, air, fat, tumour (especially choriocarcinoma) and septic emboli from endocarditis affecting tricuspid or pulmonary valves. Pulmonary emboli occur in 1% of patients admitted to hospital and are responsible for about 5% of all hospital deaths. The prophylaxis of VTE is the same as DVT (see p. 956). Clinical presentation, physical signs and treatment of PE are best understood when classified on the basis of size, site and speed of onset (see Box 13.85).
Acute massive pulmonary embolism
The clinical features are of acute haemodynamic collapse with central chest pain, apprehension, a low cardiac output and syncope. The pathophysiology is due to acute obstruction of more than 50% of either the main or the proximal pulmonary artery, leading to an acute reduction of cardiac output and right ventricular dilatation. On examination there is a sinus tachycardia, hypotension and peripheral vasoconstriction. Tachypnoea is typically present with cyanosis and an elevated JVP. A right ventricular gallop may be heard with wide-splitting of the second heart sound. Other signs of pulmonary hypertension are not expected in acute massive pulmonary embolism.
13.85 CATEGORISATION OF PULMONARY THROMBOEMBOLI
Acute massive PE Acute small/medium PE Chronic PE
Pathophysiology Major haemodynamic effects: ? cardiac output; acute right heart failure; disordered ventilation-perfusion ratio Occlusion of segmental pulmonary artery ? infarction ± effusion Chronic occlusion of pulmonary microvasculature; pulmonary hypertension, right heart failure
Symptoms Sudden syncope, faintness, central chest pain, apprehension, severe dyspnoea Pleurisy, restricted breathing, haemoptysis Exertional dyspnoea Late-exertional syncope, symptoms of right ventricular (RV) failure
Cardiovascular Major circulatory collapse; tachycardia; hypotension; ? jugular venous pressure; gallop rhythm; P2 widely split (late) Tachycardia May be minimal early in disease Late-RV heave, loud, split P2 Terminal-signs of RV failure
Respiratory Severe cyanosis, otherwise no local signs Pleural rub, raised hemidiaphragm, crepitations, effusion (usually blood-stained)
Other ? Urine output Low-grade fever
Chest radiograph Often subtle; oligaemic lung fields, slight ? hilar shadows Pleuropulmonary opacities; pleural effusion; linear shadows; raised hemidiaphragm Enlarged pulmonary artery trunk; enlarged heart, prominent RV
ECG S1Q3T3 (see Fig. 13.52) T wave ? V1-V4 Right bundle-branch block Sinus tachycardia Signs of RV hypertrophy and 'strain'
Blood gases ? PaO2; ? PaCO2 (? PaCO2) Exertional ? PaO2 or desaturation (on formal exercise testing)
[Vdot]/[Qdot] scan Major areas of ? perfusion Perfusion defect(s) not matched on the ventilation scan May be no abnormality
Pulmonary angiography Definitive diagnosis Definitive diagnosis Usually diagnostic; may need lung biopsy to confirm diagnosis
Acute minor pulmonary embolism
Figure 13.51 Features of pulmonary thromboembolism/infarction on chest radiograph.
The majority of patients will present with so-called 'pulmonary infarction syndrome' with pleurisy, shortness of breath and haemoptysis. Clinically, there may be a pleural rub and signs of a pleural effusion. The chest radiograph (see Fig. 13.51) may show wedge-shaped opacity due to haemorrhage, pleural effusion or an elevated diaphragm. Some cases present with isolated breathlessness and these patients tend to have more extensive central thrombus if pulmonary angiography is performed.
Acute embolism in patients with chronic cardiopulmonary disease
Patients with a small degree of cardiopulmonary reserve may demonstrate a major and sudden deterioration in their clinical state even with small pulmonary emboli. The clinical features of PE may be obscured by the clinical features of the underlying disease and diagnosis can be difficult in this important situation. A high index of suspicion is required if successful investigation and management in this group of patients are to be achieved.
Chronic venous thromboembolism leading to thromboembolic pulmonary hypertension
This is a relatively rare but important condition which arises without a history of previous acute PE in over 50% of cases. Patients typically present with a history of exertional breathlessness, syncope and chest pain developing over months or years. On examination there are signs of pulmonary hypertension with a loud pulmonary component to the second heart sound and a right ventricular heave. The JVP is raised and there may be v waves indicating tricuspid regurgitation (see p. 462). Patients with severe pulmonary hypertension secondary to chronic pulmonary emboli should be considered for thromboendarterectomy, an operation that involves removal of the organised obstructing thrombus via an endarterectomy. The operation should be carried out in specialist centres; despite a significant operative mortality (10-20%), it has a high degree of success.
All patients presenting with suspected pulmonary embolism should undergo basic investigations including chest radiography, electrocardiography and arterial blood gases.
Although the chest radiograph may be normal or show non-specific changes, it is extremely valuable in excluding other diagnoses such as heart failure, pneumonia, pneumothorax or tumour. The common findings in PE include focal infiltrates, segmental collapse, raised hemidiaphragm and pleural effusion (see Fig. 13.51). A wedge-shaped pleural-based opacity, though well described, is rare. Hypovascularity as described in a large embolism is often difficult to detect. A normal chest radiograph in an acutely breathless and hypoxaemic patient increases the likelihood of PE.
ECG abnormalities in PE are common but usually comprise non-specific changes in the ST segment and/or T wave. The classic S1Q3T3 pattern (see Fig. 13.52) is rare and again not specific for PE. ECG is also useful in excluding other diagnoses such as acute myocardial infarction and pericarditis.
Arterial blood gases
Pulmonary embolism is characterised by ventilation-perfusion mismatch and reduced cardiac output with a low mixed venous oxygen saturation and hyperventilation. Arterial blood gases typically show reduced PaO2 and a normal or low PaCO2. Normal PaO2 and PaCO2 values may be found, particularly in small emboli. In acute massive PE, cardiovascular collapse typically results in a metabolic acidosis.
Figure 13.52 ECG from a patient with pulmonary embolism showing 'S1Q3T3' pattern. S wave in lead I, Q wave and inverted T wave in lead III.
D-dimer is a specific degradation product released into the circulation when cross-linked fibrin undergoes endogenous fibrinolysis (see p. 900). In patients with suspected PE a low plasma D-dimer (< 500 mg/ml measured by ELISA) has a 95% predictive power for excluding PE and hence the D-dimer can be used as an initial screening investigation (see Fig. 13.53). A positive D-dimer, however, does not positively diagnose PE since raised levels may be seen in a whole range of inflammatory conditions including pneumonia.
Figure 13.53 Algorithm for the investigation of patients with suspected pulmonary thromboembolism. Clinical risk is based on the presence of risk factors for VTE and the probability of another diagnosis.
Ventilation-perfusion ([Vdot]/[Qdot]) lung scanning (see p. 490) has been the most popular method of attempting to confirm the presence of PE by demonstrating the presence of 'non-matched' defects of perfusion. In practice, however, many patients presenting with a suspected PE have pre-existing chronic cardiopulmonary disease (such as COPD) which can seriously impair the diagnostic efficacy of ventilation-perfusion scanning and lead to indeterminate reports. The recognition of an over-reliance on ventilation-perfusion scanning and the recent acquisition of spiral CT imaging in most UK hospitals has led to increased use of CT pulmonary angiography. Ventilation-perfusion scanning remains useful in patients with no previous lung disease and should be carried out within 24 hours of presentation since some scans revert to normal very quickly and 50% do so by 1 week. Spiral CT angiography has good sensitivity and specificity for central or segmental thrombi and this is now considered the investigation of choice in patients presenting with isolated dyspnoea. Colour Doppler ultrasound of the leg veins remains the investigation of choice in patients with clinical DVT but may also be applied to patients presenting with features of PE alone since many will have identifiable proximal thrombus in the lower limbs. It is important to note that the sensitivity and specificity of ventilation-perfusion scanning in ruling pulmonary embolism in or out can be increased by the use of a simple clinical probability score indicating high or low clinical risk.
Echocardiography can be used to diagnose a major central PE and is valuable for excluding other conditions such as myocardial infarction, aortic dissection and pericardial tamponade. Changes only occur when there has been significant obstruction to the pulmonary circulation and this investigation should therefore be carried out only in patients with systemic hypotension. Accuracy can be increased by using the transoesophageal route, which is much more likely to show clot in either the right heart or the main pulmonary arteries.
Although conventional pulmonary angiography is said to be the 'gold standard' for the diagnosis of PE, there may be difficulties in interpretation, even with an experienced radiologist. While there are no absolute contraindications, particular care should be exercised in patients with known sensitivity to contrast media.
Opiates may be necessary to relieve pain and distress but should be used with great caution in the hypotensive patient. Resuscitation by external cardiac massage may be successful in the moribund patient by dislodging and breaking up a large central embolus. Oxygen should be given to all hypoxaemic patients in a concentration necessary to restore arterial oxygen saturation to over 90%. Diuretics and vasodilators should be avoided in the acute setting. Likewise, in the shocked patient inotropic agents are of limited value since in massive PE the hypoxic dilated right ventricle is near maximally stimulated by endogenous catecholamines.
Heparin should be given to all patients with a high clinical suspicion of PE whilst confirmatory test results are awaited. Low molecular weight heparin given subcutaneously has been demonstrated to be as effective as intravenous unfractionated heparin and it is much easier to administer (see p. 955). The dose is standardised for the weight of the patient and does not require monitoring by tests of coagulation. Heparin is effective in reducing mortality in PE by reducing the potential of further emboli. It should be administered for at least 5 days and anticoagulation continued using oral warfarin. Heparin should not be discontinued until the INR is over 2. The duration of warfarin therapy is under considerable discussion but should be continued for a minimum of 6 weeks for patients who have an identifiable and reversible cause for their DVT such as hip surgery, and for 3 months in patients with no identified cause. Patients with an underlying prothrombotic risk or a history of previous emboli should be anticoagulated for life. (For all anticoagulation control, see p. 955.)
ACUTE VENOUS THROMBOEMBOLISM (VTE)-use of subcutaneous low molecular weight heparins
'Low molecular weight heparins given subcutaneously in a weight-adjusted dosage are the treatment of choice for acute VTE.'
Columbus Investigations. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337:657-662.
Simonneau G, Sors H, Charbonnier B, et al. A comparison of low molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337:663-669.
Further information: www.acponline.org/journals/annals/15jun98/Imwhepar.htm
Patients with an acute massive PE and evidence of right ventricular dysfunction on echocardiography or of hypotension should be considered for urgent thrombolytic therapy when the diagnosis is confirmed. Streptokinase or alteplase (human tissue plasminogen activator or tPA) can be used. The latter is more expensive but less likely to lead to systemic side-effects and hypotension. A dose of 60 mg i.v. administered over 15 minutes is sufficient. Heparin should be given subsequently.
Patients with recurrent PE despite adequate anticoagulation control benefit from the insertion of a filter placed in the inferior vena cava below the origin of the renal vessels. Such filters may also be placed in patients with PE in whom anticoagulation is contraindicated (e.g. immediately following neurosurgery).
ACUTE MASSIVE VENOUS THROMBOEMBOLISM-role of thrombolysis
'In patients presenting with acute massive venous thromboembolism, thrombolytic therapy has been shown to cause more rapid restoration of haemodynamic instability and reduce the risk of recurrent emboli compared with the use of heparin.'
Thomas MD, Chauhan A, More RS. Pulmonary embolism-an update on thrombolytic therapy. QJM 2000; 93:261-267.
Konstantinides ST, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of haemodynamically stable patients with major pulmonary embolism. Results of a Multi-centre Registry. Circulation 1997; 96:882-888.
Further information: www.icsi.org/guide/VTE.pdf
SEVERE PULMONARY HYPERTENSION
Although respiratory failure due to intrinsic pulmonary disease is the most common cause of pulmonary hypertension (see p. 505), severe pulmonary hypertension may occur as a primary disorder or as a result of chronic repeated thromboembolic events. The primary disorder may be familial, sporadic or associated with an underlying cause such as previous ingestion of appetite suppressant drugs, HIV infection or underlying connective tissue disease, particularly limited cutaneous systemic sclerosis (see p. 1036).
The pathological features include hypertrophy of both the media and intima of the vessel wall, and the so-called plexiform lesion which represents a clonal expansion of endothelial cells. There is marked narrowing of the vessel lumen and this, together with the frequently observed in situ thrombosis, leads to an increase in pulmonary vascular resistance and pulmonary hypertension. The gene responsible for familial pulmonary hypertension has recently been identified as a member of the TGF-ß superfamily, BMPR2. Up to 30% of patients with sporadic pulmonary hypertension have also been found to have mutations in this gene.
PRIMARY PULMONARY HYPERTENSION-role of continuous epoprostenol (prostacyclin) infusion
'RCTs have demonstrated that continuous intravenous epoprostenol (prostacyclin) therapy produces sustained symptomatic and haemodynamic benefit and improved survival in patients with severe primary pulmonary hypertension.'
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334:296-301.
McLaughlin W, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273-277.
Further information: www.atsqol.org/pulmhyp.asp
Patients usually present with an insidious history of breathlessness on exertion and commonly the diagnosis is delayed for up to 2 years until the presence of severe pulmonary hypertension and right heart failure is evident. The prognosis of primary pulmonary hypertension was, until recently, very poor, with the majority of patients dying within 3 years of diagnosis unless they underwent heart-lung transplantation. The introduction of epoprostenol (prostacyclin) or iloprost therapy, given either as a continuous intravenous infusion through a central venous catheter or via the nebulised route, has dramatically improved exercise performance, symptoms and prognosis. All patients should undergo a trial of this therapy prior to consideration of heart-lung transplantation. Anticoagulation with warfarin has also been demonstrated to improve prognosis in severe pulmonary hypertension.
For issues in older people relating to haemostasis and thrombosis, see page 956.
ISSUES IN OLDER PEOPLE
The risk of thromboembolic disease rises by a factor of 2.5 over the age of 60 years.
In women aged over 60 years hormone replacement therapy increases the risk of thromboembolism by a factor of 2-4.
Prophylaxis for venous thromboembolism should be considered in all older patients who are immobile as a result of acute illness, except when this is due to acute stroke, as heparin increases the risk of haemorrhagic complications.
The prevalence of cancer among those with DVT increases with age, but the relative risk of malignancy with DVT falls with age; therefore intensive investigation is not justified if initial assessment reveals no evidence of an underlying neoplasm.
Older patients are more sensitive to the anticoagulant effects of warfarin, partly due to the concurrent use of other drugs and the presence of other pathology. Life-threatening or fatal bleeds on warfarin are significantly more common in those aged over 80 years.
Long-term anticoagulant therapy should not be given prophylactically to older people with chronic immobility, as there is no evidence that the latter increases the risk of thromboembolism.
pages 562 - 566
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013308
For problems or suggestions concerning this service, please contact: firstname.lastname@example.org
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > DISEASES OF THE NASOPHARYNX, LARYNX AND TRACHEA
DISEASES OF THE NASOPHARYNX, LARYNX AND TRACHEA
DISEASES OF THE NASOPHARYNX
This is a disorder in which there are episodes of nasal congestion, watery nasal discharge and sneezing. It may be seasonal or perennial.
Allergic rhinitis is due to an immediate hypersensitivity reaction in the nasal mucosa. The antigens concerned in the seasonal form of the disorder are pollens from grasses, flowers, weeds or trees. Grass pollen is responsible for hay fever (pollenosis), the most common type of seasonal allergic rhinitis in northern Europe; in the UK this disorder is at its peak between May and July.
Perennial allergic rhinitis may be a specific reaction to antigens derived from house dust, fungal spores or animal dander but similar symptoms can be caused by physical or chemical irritants-for example, pungent odours or fumes, including strong perfumes, cold air and dry atmospheres. The term 'vasomotor rhinitis' is often used for this type of nasal problem because in this context the term 'allergic' is a misnomer.
In the seasonal type there are frequent sudden attacks of sneezing, with profuse watery nasal discharge and nasal obstruction. These attacks last for a few hours and are often accompanied by smarting and watering of the eyes and conjunctival infection. In the perennial variety the symptoms are similar but more continuous and generally less severe. Skin hypersensitivity tests with the relevant antigen are usually positive in seasonal allergic rhinitis and are thus of diagnostic value, but these tests are less useful in perennial rhinitis.
The following symptomatic measures, singly or in combination, are usually effective in both seasonal and perennial allergic rhinitis:
an antihistamine drug such as loratadine 10 mg daily by mouth
sodium cromoglicate nasal spray, one metered dose of a 2% solution into each nostril 4-6-hourly
beclometasone dipropionate or budesonide aqueous nasal spray, one or two doses of 50 µg into each nostril 12-hourly.
Patients failing to respond to these measures may obtain symptomatic relief from intramuscular injection of a long-acting corticosteroid preparation; this form of treatment should be reserved for occasional use in patients whose symptoms are very severe and seriously interfere with school, business or social activities. Vasomotor rhinitis is often difficult to treat, but may respond to ipratropium bromide, administered into each nostril 6-8-hourly.
In the seasonal type an attempt should be made to reduce exposure to pollen-for example, by avoiding country districts and keeping indoors as much as possible with windows closed during the pollen season, especially when pollen counts are reported to be high. The prevention of perennial rhinitis consists of avoiding, as far as possible, exposure to any identifiable aetiological factors but this is often difficult or impossible.
Acute infections have already been described (see Box 13.38, p. 525). Other disorders of the larynx include chronic laryngitis, laryngeal tuberculosis, laryngeal paralysis and laryngeal obstruction. Tumours of the larynx are relatively common. For detailed information on these conditions, the reader should refer to a textbook of diseases of the ear, nose and throat.
The common causes of this condition are listed in Box 13.86.
13.86 SOME CAUSES OF CHRONIC LARYNGITIS
Repeated attacks of acute laryngitis
Excessive use of the voice, especially in dusty atmospheres
Heavy tobacco smoking
Mouth-breathing from nasal obstruction
Chronic infection of nasal sinuses
The chief symptom is hoarseness and the voice may be lost completely (aphonia). There is irritation of the throat and a spasmodic cough. The disease pursues a chronic course frequently uninfluenced by treatment, and in long-standing cases the voice is often permanently impaired.
The causes of chronic hoarseness are listed in Box 13.87.
These conditions must be considered in the differential diagnosis if hoarseness does not improve within a few weeks. In some patients a chest radiograph may bring to light an unsuspected bronchial carcinoma or pulmonary tuberculosis. If no such abnormality is found, laryngoscopy should be performed, usually by a specialist in otolaryngology.
13.87 CAUSES OF CHRONIC HOARSENESS
If hoarseness persists for more than a few days, consider:
Tumour of the larynx
Inhaled corticosteroid treatment
The voice must be rested completely. This is particularly important in public speakers. Smoking should be prohibited. Some benefit may be obtained from frequent inhalations of medicated steam.
Paralysis is due to interference with the motor nerve supply of the larynx. It is nearly always unilateral and, by reason of the intrathoracic course of the left recurrent laryngeal nerve, usually left-sided. One or both recurrent laryngeal nerves may be damaged at thyroidectomy or by carcinoma of the thyroid. Rarely, the vagal trunk itself is involved by tumour, aneurysm or trauma.
This always accompanies laryngeal paralysis, whatever its cause. Paralysis of organic origin is seldom reversible but when only one vocal cord is affected hoarseness may improve or even disappear after a few weeks, following a compensatory adjustment whereby the unparalysed cord crosses the midline and approximates with the paralysed cord on phonation.
A characteristic feature of organic laryngeal paralysis is a cow-like cough which results from the loss of the explosive phase of normal coughing consequent upon the failure of the cords to close the glottis. Difficulty in bringing up sputum, which some patients experience, is also explained on the same basis. A normal cough in patients with partial loss of voice or aphonia virtually excludes laryngeal paralysis.
Stridor is occasionally present but is seldom severe, except when laryngeal paralysis is bilateral.
Laryngoscopy is necessary to establish the diagnosis of laryngeal paralysis with certainty. The paralysed cord lies in the so-called 'cadaveric' position, midway between abduction and adduction.
The cause of laryngeal paralysis should be treated if that is possible. In unilateral paralysis the voice may be improved by the injection of Teflon into the affected vocal cord. In bilateral organic paralysis, tracheal intubation, tracheostomy or a plastic operation on the larynx may be necessary.
PSYCHOGENIC HOARSENESS AND APHONIA
Psychogenic causes of hoarseness or complete loss of voice may be suggested by associated symptoms in the history (see p. 254). However, laryngoscopy may be necessary to exclude a physical cause of the voice abnormality. In psychogenic aphonia only the voluntary movement of adduction of the vocal cords is seen to be impaired.
Laryngeal obstruction is more liable to occur in children than in adults because of the smaller size of the glottis. Some important causes are given in Box 13.88.
13.88 CAUSES OF LARYNGEAL OBSTRUCTION
Inflammatory or allergic oedema, or exudate
Spasm of laryngeal muscles
Inhaled foreign body
Inhaled blood clot or vomitus in an unconscious patient
Tumours of the larynx
Bilateral vocal cord paralysis
Fixation of both cords in rheumatoid disease
Sudden complete laryngeal obstruction by a foreign body produces the clinical picture of acute asphyxia-violent but ineffective inspiratory efforts with indrawing of the intercostal spaces and the unsupported lower ribs, accompanied by cyanosis. Unrelieved, the condition progresses rapidly to coma and death within a few minutes. When, as in most cases, the obstruction is incomplete at first, the main clinical features are progressive breathlessness accompanied by stridor and cyanosis. There is indrawing of the intercostal spaces and lower ribs on both sides with each inspiratory effort. In such cases the great danger is that complete laryngeal obstruction may occur at any time and result in sudden death.
Transient attacks of laryngeal obstruction due to exudate and spasm, which may occur with acute laryngitis in children (see p. 525) and with whooping cough, are potentially dangerous but can usually be relieved by the inhalation of steam.
Laryngeal obstruction from all other causes carries a high mortality and demands prompt treatment. The following measures may have to be employed.
Relief of obstruction by mechanical measures
When a foreign body is known to be the cause of the obstruction in children it can often be dislodged by turning the patient head downwards and squeezing the chest vigorously. In adults this is often impossible, but a sudden forceful compression of the upper abdomen (Heimlich manoeuvre) may be effective. In other circumstances the cause of the obstruction should be investigated by direct laryngoscopy which may also permit the removal of an unsuspected foreign body, or the insertion of a tube past the obstruction into the trachea. Tracheostomy must be performed without delay if these procedures fail to relieve laryngeal obstruction, but except in dire emergencies this operation should be performed in an operating theatre by a surgeon.
Treatment of the cause
In cases of diphtheria, antitoxin should be administered, and for other infections the appropriate antibiotic should be given. In angio-oedema complete laryngeal occlusion can usually be prevented by treatment with adrenaline (epinephrine) 0.5-1 mg (0.5-1 ml of 1:1000) intramuscularly, chlorphenamine maleate 10-20 mg by slow intravenous injection and intravenous hydrocortisone sodium succinate 200 mg.
See Box 13.38, page 525.
External compression by enlarged mediastinal lymph nodes containing metastatic deposits, usually from a bronchial carcinoma, is a more frequent cause of tracheal obstruction than the uncommon primary benign or malignant tumours. Rarely, the trachea may be compressed by an aneurysm of the aortic arch, or in children by tuberculous mediastinal lymph nodes. Tracheal stenosis is an occasional complication of tracheostomy, prolonged intubation, Wegener's granulomatosis or trauma.
Stridor can be detected in every patient with severe tracheal narrowing. Endoscopic examination of the trachea should be undertaken without delay to determine the site, degree and nature of the obstruction.
Localised tumours of the trachea can be resected, but reconstruction after resection may present complex technical problems. Endobronchial laser therapy, tracheal stents and radiotherapy are alternatives to surgery. The choice of treatment depends upon the nature of the tumour and the general health of the patient. Radiotherapy or chemotherapy may temporarily relieve compression by malignant lymph nodes, and tracheal stents introduced bronchoscopically may be of temporary value. Benign tracheal strictures can sometimes be dilated but may have to be resected.
This may be present in newborn infants as a congenital abnormality. In adults it is usually due to malignant lesions in the mediastinum, such as carcinoma or lymphoma, eroding both the trachea and oesophagus to produce a communication between them. Swallowed liquids enter the trachea and bronchi through the fistula and provoke coughing.
Surgical closure of a congenital fistula, if undertaken promptly, is usually successful. There is usually no curative treatment for malignant fistulae and death from over-whelming pulmonary infection rapidly supervenes.
pages 566 - 569
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013330
For problems or suggestions concerning this service, please contact: email@example.com
Home > 2 SYSTEM-BASED DISEASES > 13 Respiratory disease > DISEASES OF THE PLEURA, DIAPHRAGM AND CHEST WALL
DISEASES OF THE PLEURA, DIAPHRAGM AND CHEST WALL
DISEASES OF THE PLEURA
Pleurisy is not a diagnosis but simply a term used to describe the result of any disease process involving the pleura and giving rise to pleuritic pain or evidence of pleural friction. Pleurisy is a common feature of pulmonary infarction and may be an early manifestation of pleural invasion by pulmonary tuberculosis or a bronchogenic carcinoma.
Pleural pain is the characteristic symptom. On examination rib movement is restricted and a pleural rub is present. This may only be heard in deep inspiration or near the pericardium, where a so-called pleuro-pericardial rub may be present. The other clinical features depend upon the nature of the disease causing the pleurisy. Loss of the pleural rub and diminution in the chest pain may indicate recovery or herald the development of a pleural effusion.
Every patient must have a chest radiograph but a normal radiograph does not exclude a pulmonary cause for the pleurisy. A preceding history of cough, purulent sputum and pyrexia is presumptive evidence of a pulmonary infection which may not have been severe enough to produce a radiographic abnormality or which may have resolved before the chest radiograph was taken.
The primary cause of pleurisy must be treated. The symptomatic treatment of pleural pain is described on page 530.
See page 501.
This term describes the presence of pus in the pleural space. The pus may be as thin as serous fluid or so thick that it is impossible to aspirate even through a wide-bore needle. Microscopically, neutrophil leucocytes are present in large numbers. The causative organism may or may not be isolated from the pus. An empyema may involve the whole pleural space or only part of it ('loculated' or 'encysted' empyema) and is almost invariably unilateral.
Empyema is always secondary to infection in a neighbouring structure, usually the lung. The principal infections liable to produce empyema are the bacterial pneumonias and tuberculosis. Over 40% of patients with community-acquired pneumonia develop an associated pleural effusion ('para-pneumonic' effusion) and about 15% of these become secondarily infected. Other causes are infection of a haemothorax and rupture of a subphrenic abscess through the diaphragm. Despite the widespread availability of effective antibacterial therapy for patients with pneumonia, empyema continues to be a significant cause of morbidity and mortality even in developed countries. All too often, this reflects a delay in the diagnosis or instigation of appropriate therapy.
Both layers of pleura are covered with a thick, shaggy inflammatory exudate. The pus in the pleural space is often under considerable pressure and if the condition is not adequately treated pus may rupture into a bronchus causing a bronchopleural fistula and pyopneumothorax, or track through the chest wall with the formation of a subcutaneous abscess or sinus.
The only way in which an empyema can heal is by eradication of the infection, obliteration of the empyema space and apposition of the visceral and parietal pleural layers. This cannot occur unless re-expansion of the compressed lung is secured at an early stage by removal of all the pus from the pleural space. This cannot take place if:
the visceral pleura becomes grossly thickened and rigid due to delayed treatment or inadequate drainage of the infected pleural fluid
the pleural layers are kept apart by air entering the pleura through a bronchopleural fistula
there is underlying disease in the lung, such as bronchiectasis, bronchial carcinoma or pulmonary tuberculosis preventing re-expansion.
In all these circumstances an empyema tends to become chronic, and healing may not take place without surgical intervention.
An empyema should be suspected in patients with pulmonary infection if there is persistence or recurrence of pyrexia despite the administration of a suitable antibiotic. In other cases the illness produced by the primary infective lesion may be so slight that it passes unrecognised and the first definite clinical features are due to the empyema itself.
Once an empyema has developed, two separate groups of clinical features are found. These are shown in Box 13.89.
13.89 CLINICAL FEATURES OF EMPYEMA
Pyrexia, usually high and remittent
Rigors, sweating, malaise and weight loss
Polymorphonuclear leucocytosis, high CRP
Pleural pain; breathlessness; cough and sputum usually because of underlying lung disease; copious purulent sputum if empyema ruptures into a bronchus (bronchopleural fistula)
Clinical signs of fluid in the pleural space
The appearances are often indistinguishable from those of pleural effusion. When air is present in addition to pus (pyopneumothorax), a horizontal 'fluid level' marks the interface between the liquid and air. Ultrasound and CT are extremely valuable in defining the extent of pleural thickening and location of the fluid, and in the case of CT assessing the underlying lung parenchyma and patency of the major bronchi.
Aspiration of pus
This confirms the presence of an empyema. Ultrasound or CT is recommended to identify the optimal place to undertake pleuracentesis, which is best performed using a wide-bore needle. The pus is frequently sterile when antibiotics have already been given; the distinction between tuberculous and non-tuberculous disease can be difficult and often requires pleural histology and culture.
Treatment of non-tuberculous empyema
When the patient is acutely ill and the pus is thin an intercostal tube should be inserted under ultrasound CT guidance into the most dependent part of the empyema space and connected to a water-seal drain system. If the initial aspirate reveals turbid fluid or frank pus, or if loculations are seen on ultrasound, the tube should be put on suction (5-10 cm water) and flushed regularly with 20 ml normal saline. Although intrapleural fibrinolytic therapy is widely used in such situations there is currently insufficient evidence to support its routine use (see EBM panel). Finally, an antibiotic directed against the organism causing the empyema should be given for 2-4 weeks.
PARA-PNEUMONIC EFFUSIONS AND EMPYEMA-role of intrapleural fibrinolytic therapy
'There is currently insufficient evidence to support the routine use of intrapleural fibrinolytic therapy in the treatment of para-pneumonic effusions or empyema.'
Cameron R. Intra-pleural fibrinolytic therapy for parapneumonic effusions and empyema (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the treatment of empyema and complicated parapneumonic effusions. Chest 1997; 111:275-279.
An empyema can often be aborted if these measures are started early. If, however, the intercostal tube is not providing adequate drainage, which can happen when the pus is thick or loculated, surgical intervention is required. The empyema cavity is cleared of pus and adhesions, and a wide-bore tube inserted to allow optimal drainage. Surgical 'decortication' of the lung may also be required if gross thickening of the visceral pleura has developed and is preventing re-expansion of the lung.
Treatment of tuberculous empyema
Antituberculosis chemotherapy must be started immediately (see p. 538) and the pus in the pleural space aspirated through a wide-bore needle until it ceases to reaccumulate. Intercostal tube drainage is often required. In many patients no other treatment is necessary but surgery is occasionally required to ablate a residual empyema space.
Pneumothorax is the presence of air in the pleural space; it can either occur spontaneously, or result from iatrogenic injury or trauma to the lung or chest wall (see Box 13.90). The incidence of pneumothorax is highest in males aged 15-30 (see Fig. 13.54) where smoking, height and the presence of apical subpleural blebs appear to be the most important aetiological factors. Secondary pneumothorax is most common in older patients and those living in urban areas, and is associated with the highest mortality rates.
13.90 CLASSIFICATION OF PNEUMOTHORAX
Without evidence of overt lung disease. Air is usually introduced into the pleural space through rupture of a small subpleural emphysematous bulla or pleural bleb, or the pulmonary end of a pleural adhesion
Underlying lung disease, most commonly COPD and tuberculosis; also seen in asthma, lung abscess, pulmonary infarcts, bronchogenic carcinoma, all forms of fibrotic and cystic lung disease
Iatrogenic (e.g. following thoracic surgery or biopsy) or non-iatrogenic
Figure 13.54 Bimodal age distribution for hospital admissions for pneumothorax in England. The incidence of primary spontaneous pneumothorax peaks in males aged 15-30. Secondary spontaneous pneumothorax occurs mainly in males > 55 years.
Most episodes of primary spontaneous pneumothorax occur while the individual is at rest. Virtually all patients experience sudden-onset unilateral chest pain or breathlessness. In those with underlying chest disease, breathlessness can be severe and does not resolve spontaneously. In patients with a small pneumothorax the physical examination may be normal except for a tachycardia. A larger pneumothorax (> 15% of the hemithorax) results in decreased movement of the chest wall, a hyper-resonant percussion note and decreased or absent breath sounds.
A tension pneumothorax may develop if the communication between the pleura and lung persists but is small, and if it acts as a one-way valve which allows air to enter the pleural space during inspiration and coughing but prevents it from escaping. Very large amounts of air may be trapped in the pleural space and the intrapleural pressure may rise to well above atmospheric levels. This causes not only compression of the underlying deflated lung but also mediastinal displacement towards the opposite side, with consequent compression of the opposite lung and cardiovascular compromise (see Fig. 13.55C). Clinically, this results in rapidly progressive breathlessness associated with a marked tachycardia, hypotension and cyanosis.
Figure 13.55 Types of spontaneous pneumothorax. A Closed type. B Open type. C Tension (valvular) type.
Where the communication between the lung and pleural space seals off as the lung deflates and does not reopen, the pneumothorax is referred to as 'closed' (see Fig. 13.55A). In such circumstances the mean pleural pressure remains negative, spontaneous reabsorption of air and re-expansion of the lung occur over a few days or weeks, and infection is uncommon. This contrasts with an 'open' pneumothorax, where the communication fails to seal and air continues to transfer freely between the lung and pleural space (see Fig. 13.55B). An example of the latter is a bronchopleural fistula which, if large, can also facilitate the transmission of infection from the air passages into the pleural space, and empyema is a common complication. An open pneumothorax is most commonly seen following rupture of an emphysematous bulla, tuberculous cavity or lung abscess into the pleural space.
Figure 13.56 Haemopneumothorax. Chest radiograph of a patient with a right traumatic haemopneumothorax showing the characteristic visceral pleural line displaced from the chest wall (arrows), together with free fluid within the pleural cavity (not seen in patients with uncomplicated spontaneous pneumothorax).
The chest radiograph usually shows the sharply defined edge of the deflated lung with complete translucency between this and the chest wall and no lung markings (see Fig. 13.56). The practice of obtaining films in both inspiration and expiration has been abandoned as the latter do not improve the diagnostic yield. Care must be taken to differentiate between a large pre-existing emphysematous bulla and a pneumothorax; where any doubt exists, an emergency thoracic CT is indicated. Radiographs also show the extent of any mediastinal displacement and give information regarding the presence or absence of pleural fluid and underlying pulmonary disease. It is important to note that the absence of mediastinal shift on a chest radiograph does not exclude the presence of a tension pneumothorax, the diagnosis of which is largely clinical.
Figure 13.57 Management of spontaneous pneumothorax. (1) Immediate decompression is required prior to insertion of intercostal drain. (2) Aspirate in the 2nd intercostal space anteriorly in the mid-clavicular line using a 16 F cannula; discontinue if either resistance is felt, the patient coughs excessively, or > 2.5 litres of air are removed. (3) Beware: the post-aspiration chest radiograph is not a reliable indicator of whether a pleural leak remains and hence all patients should be told to attend again immediately in the event of noticeable deterioration.
It is now recognised that percutaneous needle aspiration of air is a simple, effective and well-tolerated alternative to intercostal tube drainage in young patients presenting with a moderate or large spontaneous pneumothorax (see Fig. 13.57). However, even a small pneumothorax may cause severe respiratory failure in patients with underlying chronic lung disease, and hence all such patients require intercostal tube drainage and inpatient observation. If required, an intercostal drain should be inserted in the 4th, 5th or 6th intercostal space in the mid-axillary line following blunt dissection through to the parietal pleura. The tube should be advanced in an apical direction, connected to an underwater seal or one-way Heimlich valve, and secured firmly to the chest wall. Clamping of the drain is potentially dangerous and never indicated. The drain should be removed 24 hours after the lung has fully reinflated and bubbling stopped. If bubbling in the underwater bottle stops prior to full reinflation, the tube is either blocked, kinked or displaced. All patients should receive supplemental oxygen as this accelerates the rate at which air is reabsorbed by the pleura.
Patients presenting with a spontaneous pneumothorax should not fly or dive for 3 months following full reinflation of the lung. They should also be advised to stop smoking and be informed about the risks of a further attack.
Recurrent spontaneous pneumothorax
Due to the seriousness of this condition surgical pleurodesis is recommended in all presenting with a secondary pneumothorax. This can be achieved by pleural abrasion or parietal pleurectomy at thoracotomy or thoracoscopy. In patients with their first primary spontaneous pneumothorax the risk of recurrence is high (approximately 30-50%), particularly in women and those who continue to smoke. Currently, chemical or surgical pleurodesis is recommended in all such patients following a second pneumothorax (even if ipsilateral) or in patients following their first pneumothorax where there is a persistent air leak (> 7 days). Patients who plan to continue activities that increase the risk of complications developing following a pneumothorax (e.g. flying or diving) should also undergo preventative treatment after the first episode of a primary spontaneous pneumothorax.
ASBESTOS-RELATED PLEURAL DISEASE
Benign pleural plaques
These areas of pleural thickening do not produce clinical symptoms and are usually identified on routine chest radiograph. They are often calcified and in the early stage are best seen on oblique films. They are most commonly observed on the diaphragm and anterolateral pleural surfaces (see Fig. 13.58).
Benign pleural effusion
This is considered to be a specific asbestos-related entity and may be associated with pleural pain, fever and leucocytosis. The pleural liquid may be blood-stained, and differentiation of this benign condition from a malignant effusion caused by mesothelioma can be difficult. The disease is self-limiting but may cause considerable pleural fibrosis which sometimes leads to breathlessness.
Diffuse pleural fibrosis
Diffuse pleural fibrosis is an important pleural manifestation of asbestos fibre inhalation and can restrict chest expansion and cause breathlessness. The restrictive defect caused by diffuse pleural fibrosis tends to progress and, like asbestosis and mesothelioma, qualifies a patient for industrial injury benefit in the UK.
Figure 13.58 Asbestos-related benign pleural plaques. Chest radiograph showing extensive calcified pleural plaques ('candle wax' appearance), particularly marked on the diaphragm and lateral pleural surfaces.
Mesothelioma of the pleura
Mesothelioma is a malignant tumour affecting the pleura (pleural mesothelioma) or, less commonly, the peritoneum (peritoneal mesothelioma). Blue asbestos (crocidolite) is thought to be the most potent cause of mesothelioma. A time lag of 20 years or more between asbestos exposure and the development of mesothelioma is typical. The incidence of this tumour has increased markedly over the past 20 years and this trend is predicted to continue until 2010. Asbestos exposure is also a recognised risk factor for the development of bronchogenic carcinoma.
Clinical presentation is frequently with chest pain. A pleural effusion, often blood-stained, may develop and cause breathlessness. Diagnosis rests on percutaneous or surgical biopsy of the pleura. Surgical resection is rarely indicated and most tumours are resistant to chemotherapy. Radiotherapy is, however, effective in preventing tumour growth through previous chest drain or biopsy sites. There is no curative treatment and chest wall pain is often difficult to control.
ISSUES IN OLDER PEOPLE
Spontaneous pneumothorax in the elderly is invariably associated with underlying lung disease and has a significant mortality. Surgical or chemical pleurodesis is advised in all such patients.
Rib fracture is a common cause of pleural-type pain in the elderly and underlying osteomalacia may contribute to poor healing, especially in the housebound with no exposure to sunlight.
Tuberculosis should always be considered and actively excluded in any elderly patient presenting with a unilateral pleural effusion.
Mesothelioma is more common in older than younger people due to a long latency between asbestos exposure (often > 40 years) and the development of disease.
Frail older people are particularly sensitive to the respiratory depressant effects of opiate-based analgesia and careful monitoring is required when using these agents for pleural pain.
DISEASES OF THE DIAPHRAGM
Abnormalities of the diaphragm are common and may be congenital or acquired. Both hemidiaphragms are displaced downwards and functionally impaired by diseases which cause pulmonary hyperinflation, notably emphysema. Diaphragmatic function can also be impaired in a variety of neuromuscular and connective tissue diseases (e.g. Guillain-Barré syndrome and polymyositis-see pp. 1180 and 1038) and with skeletal deformities such as thoracic scoliosis (see Box 13.91). Unilateral diaphragmatic palsy results from injury or damage to the phrenic nerve and should always alert the clinician to the possibility of intrathoracic malignancy (see below).
13.91 CAUSES OF ELEVATION OF A HEMIDIAPHRAGM
Phrenic nerve paralysis
Eventration of the diaphragm
Decrease in volume of one lung (e.g. lobectomy, unilateral pulmonary fibrosis)
Severe pleuritic pain
Large volume of gas in the stomach or colon
Large tumours or cysts of the liver
Congenital defects of the diaphragm can allow herniation of abdominal viscera. Posteriorly situated hernias through the foramen of Bochdalek are more common than anterior hernias through the foramen of Morgagni.
Eventration of the diaphragm
Abnormal elevation or bulging of one hemidiaphragm, more often the left, results from total or partial absence of muscular development of the septum transversum. Most eventrations are asymptomatic and are detected by chance on radiograph in adult life, but severe respiratory distress can be caused in infancy if the diaphragmatic muscular defect is extensive.
Other diaphragmatic abnormalities
These include defects of the oesophageal hiatus, congenital absence and duplication. The diaphragm may be involved in most primary muscle disorders.
Phrenic nerve damage leading to paralysis of a hemidiaphragm is most often produced by bronchial carcinoma but can also be idiopathic or the result of a number of neurological disorders, injury or disease of cervical vertebrae and tumours of the cervical cord. Trauma to the chest and neck, including road traffic and birth injuries, surgery and stretching of the phrenic nerve by mediastinal masses and aortic aneurysms may also lead to diaphragmatic paralysis.
Paralysis of one hemidiaphragm results in loss of approximately 20% of ventilatory capacity, but this is not usually noticed by otherwise healthy individuals.
Diagnosis is suggested by elevation of the hemidiaphragm on chest radiograph and is confirmed by screening or ultrasound examination, which show paradoxical movement of the paralysed hemidiaphragm on sniffing.
Other acquired diaphragmatic disorders
Hiatus hernia is common (see p. 775). Diaphragmatic rupture is usually caused by a crush injury and may not be detected until years later. Peripheral neuropathies of any type can involve the diaphragm, as can disorders affecting the anterior horn cells, e.g. poliomyelitis (see p. 1198). Connective tissue disorders such as systemic lupus erythematosus, and hypothyroidism and hyperthyroidism, may cause diaphragmatic weakness. Respiratory disorders which cause pulmonary hyperinflation, e.g. emphysema, and those which result in small stiff lungs, e.g. diffuse pulmonary fibrosis, decrease diaphragmatic efficiency and predispose to fatigue. Severe skeletal deformity, such as kyphosis, causes gross distortion of diaphragmatic muscle configuration and gross mechanical disadvantage.
DEFORMITIES OF THE CHEST WALL
Abnormalities of alignment of the dorsal spine and their consequent effects on thoracic shape may be caused by:
vertebral disease, including tuberculosis, osteoporosis and ankylosing spondylitis
neuromuscular disease such as poliomyelitis.
Simple kyphosis causes less pulmonary embarrassment than kyphoscoliosis.
Kyphoscoliosis, if severe, restricts and distorts expansion of the chest wall, causing maldistribution of the ventilation and blood flow in the lungs and impaired diaphragmatic function. Patients with severe deformity may develop type II respiratory failure (initially manifest during sleep), pulmonary hypertension and right ventricular failure; such patients can often be successfully treated with nocturnal and, if necessary, day-time, non-invasive ventilatory support (see p. 508).
In pectus excavatum (funnel chest) the body of the sternum, usually only the lower end, is curved backwards. The heart is displaced to the left and may be compressed between the sternum and the vertebral column; only rarely is there associated disturbance of cardiac function. The deformity may restrict chest expansion and reduce vital capacity. Operative correction is usually only indicated for cosmetic reasons.
Pectus carinatum (pigeon chest) is frequently caused by severe asthma during childhood. Very occasionally, this deformity can be produced by rickets or be idiopathic.
Beckett WS. Occupational respiratory diseases. N Engl J Med 2000; 342:406-413. Medline Similar articles Full article
Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345:1465-1472. Medline Similar articles Full article
Global Initiative for Chronic Obstructive Lung Disease (GOLD guidelines). National Institutes of Health, April 2001. Full article
Lim WS, Macfarlane JT. Hospital-acquired pneumonia. Clin Med 2001; 1:180-184. Medline Similar articles
Peppard PE, Young PT, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378-1384. Medline Similar articles Full article
Smoking cessation guidelines and their cost-effectiveness. Thorax 1998; 53(suppl). Full article
Tattersfield AE, Harrison TW. Inhaled steroids for COPD? Thorax 2001; 56(suppl 11):ii2-6.
www.brit-thoracic.org.uk British Thoracic Society website; has access to guidelines from recent years including community-acquired pneumonia, COPD, asthma, selection of patients with cancer for operation, pulmonary embolism etc.
www.cancerlinks.usa.com/lung.htm An American site which provides a good synopsis of thoracic oncology.
www.cancernews.com/lung/htm An American site which provides very good links to other relevant sites and is constantly updated.
www.lunguk.org British Lung Foundation site.
www.sign.ac.uk/guidelines/published/index.htm/#cancer Royal College site outlining the guidelines for the management of lung cancer, asthma, sleep etc.
www.thoracic.org Contains useful information and guidelines for management.
www.thoraxjnl.com Journal of the British Thoracic Society on-line Full article
pages 569 - 574
Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC013363
For problems or suggestions concerning this service, please contact: firstname.lastname@example.org