■ To understand the composition and formation of pleural fluid
■ To know the mechanisms of injury to the pleura
■ To understand the aetiology, diagnosis, and management of primary and secondary pneumothoraces
■ To recognise the diagnosis and management of a tension pneumothorax
■ To learn the aetiology, diagnosis, and management of a pleural effusion
■ To understand the management of a malignant pleural effusion
■ To understand the management of pleural infection, including empyema
■ To appreciate asbestos-related pleural disease
■ To understand the aetiology, diagnosis, and management of malignant mesothelioma
ARDS adult respiratory distress syndrome
BTS British Thoracic Society
CAP community acquired pneumonia
CCF congestive cardiac failure
CPR cardiopulmonary resuscitation
CRP C-reactive protein
CT computed tomography
DNA deoxyribonucleic acid
EPP extra pleural pneumonectomy
FDG 18F-Fluorodeoxy glucose
HIV human immunodeficiency virus
HRCT high-resolution computed tomography
ICU intensive care unit
IGRA interferon gamma release assay
ILD interstitial lung disease
IMRT intensity modulated radiotherapy
LDH lactate dehydrogenase
LMWH low molecular weight heparin
MRI magnetic resonance imaging
MRSA methicillin-resistant Staphylococcus aureus
NIV non-invasive ventilation
NPSA National Patient Safety Agency
PCR polymerase chain reaction
PET-CT positron emission tomography with computed tomography
PLCH Pulmonary Langerhans cell histiocytosis
PleurX tunnelled pleural catheter
PSP primary spontaneous pneumothorax
RCT randomised controlled trial
SMRP soluble mesothelin-related protein
SP secondary pneumothorax
SPN solitary pulmonary nodule
SVCO superior vena cava obstruction
TB Mycobacterium tuberculosis
TED thromboembolic disease
VATS video-assisted thoracoscopic surgery
Normal pleura and pleural fluid
The pleura is a thin, serous membrane comprising of the visceral pleura, which covers the lungs and the mediastinum, and the parietal pleura which lines the inside of the thoracic cage and diaphragm. Chapter 2 has more details on the anatomy and physiology of the lung.
Pleural fluid is filtered from blood in the capillaries supplying the parietal pleura down a pressure gradient into the pleural space. Pleural fluid drains out of the pleural space through stomata in the parietal lymphatics which lie between the parietal mesothelial cells. These stomata merge into small lymphatic channels which form larger vessels which connect areas of the parietal, mediastinal and diaphragmatic pleura, ultimately draining into the mediastinal lymph nodes. In health, there is a thin layer of pleural fluid in the pleural space, approximately 1—5 ml and 10 μm thick, which acts as a lubricant, allowing expansion of the lungs without friction. There is a turnover of 1—2 L of pleural fluid each day. More pleural fluid is secreted at the apices of the lungs and more fluid is resorbed at the bases as there are a greater number of parietal lymphatics in the diaphragm and mediastinum.
In health, pleural fluid contains the same amount of protein and glucose as interstitial fluid, but a lower amount of sodium and a greater amount of lactate dehydrogenase (LDH). Pleural fluid also contains mesothelial cells, macrophages, and lymphocytes. The pH of healthy pleural fluid is 7.6. Water and small molecules move passively between the layers while larger particles are transported across by cytoplasmic transport mechanisms.
A pleural effusion is fluid in the pleural cavity. A pleural effusion occurs if more fluid is produced than is resorbed. A pleural effusion can be unilateral or bilateral.
Aetiology of pleural effusion
Analysis of pleural fluid and applying Light’s criteria can differentiate between an exudate and a transudate. Box 10.4 summarises what constitutes an exudate and a transudate. There are many different causes for an exudative and transudative pleural effusion.
Clinical assessment of a patient presenting with a pleural effusion
The main symptom associated with a pleural effusion is breathlessness. The patient may also complain of chest pain and other symptoms depending on the cause of the effusion. It is important to elicit the following information from the history: (Boxes 10.1 and 10.2).
Diagnostic pathway for management of a unilateral pleural effusion
Figure 10.1 shows the BTS diagnostic algorithm for investigation of a unilateral pleural effusion. There are several clinical signs that indicate a pleural effusion (Box 10.3).
Box 10.1 Symptoms of Pleural Effusion.
• Smoking history (pack years)
• History of asbestos exposure: a full and comprehensive occupational history is required
• Symptoms suggestive of infection
• Symptoms suggestive of malignancy
• Drug history
Box 10.2 Clinical Examination of patient with a pleural effusion.
• Clubbing of fingernails
• Clinical signs of pleural effusion can be detected when there is more than 300 ml of fluid
• Clinical signs of cardiac failure
Investigations for a pleural effusion
Chest X-ray (CXR): A pleural effusion with more than 300 ml fluid can be seen on a postero-anterior (PA) CXR as an area of whiteness. The fluid accumulates at the lung base because of gravitational forces, so the costophrenic angle is usually obliterated first. If the effusion is extensive, the CXR can show as a complete ‘white-out’ of the hemithorax. A small effusion, with only 50 ml of fluid, may be detected on a lateral decubitus CXR (Figure 10.2). A pleural effusion may be difficult to detect on a CXR taken when the patient is supine, for example, on the intensive care unit (ICU), as the fluid lies posteriorly. An ultrasound may be better at detecting fluid under these circumstances.
In a patient with congestive cardiac failure (CCF), bilateral pleural effusions can occur and there may be other radiological evidence of heart failure, such as an enlarged heart, Kerley B lines and fluid in the horizontal fissure.
Thoracic ultrasound is an essential investigation in the management of a pleural effusion as it is more sensitive than a CXR at identifying small effusions, including sub-pulmonic effusions (Figure 10.3). Thoracic ultrasound is also better at differentiating between pleural fluid and pleural thickening. Features such as septation seen on thoracic ultrasound may help distinguish between an exudate and a transudate and between a malignant and a benign pleural effusion with greater sensitivity than a contrast CT scan. Thoracic ultrasound is also essential for successful and safe thoracocentesis.
CT thorax with contrast should be conducted if the fluid is an exudate and if there are other abnormalities on the chest X-ray, such as a mass (Figure 10.4). Ideally, the CT scan should be done before the pleural fluid is completely drained. Septation, due to fibrin deposition, appears as suspended air bubbles. Contrast CT can reliably distinguish between an empyema and a lung abscess, as the former appears as a lenticular opacity with pleural enhancement around it. Contrast enhancement of the pleura can distinguish between benign and malignant pleural thickening, with malignant pleura showing areas of pleural nodularity. Mediastinal, parietal, and circumferential pleural thickening of >1 cm suggests a malignant process. Pleural enhancement can also occur when there is inflammation of the pleura secondary to infection. A CT thorax with contrast is essential if a surgical pleural biopsy is required and in the management of complicated pleural infections, including empyema.
An MRI is not routinely required in the management of a pleural effusion but can distinguish between a malignant and a benign pleural effusion when CT with contrast is contraindicated. An MRI can also give anatomical information about chest wall and diaphragmatic involvement when the effusion is secondary to malignancy, especially if surgery is being contemplated.
A PET-CT is not routinely used in the management of a pleural effusion as there are many false positives but, as with MRI, can be occasionally used for staging when there is a malignant pleural effusion.
Pleural Aspiration (Thoracocentesis)
This is an essential investigation in the diagnosis of a pleural effusion and should be conducted using direct ultrasound guidance as this increases the chance of successful aspiration, reduces the need for repeated aspiration, and reduces the risk of pneumothorax and injury to the heart, liver, and spleen. A 21G fine bore needle attached to a 50 ml syringe should be used. Appendix 10.A describes the methodology of pleural fluid collection. Table 10.1 describes the analysis of pleural fluid.
Figure 10.1 BTS diagnostic algorithm for investigation of a unilateral pleural effusion.
Box 10.3 Clinical signs of a pleural effusion.
• Reduced chest wall movement on the side of the effusion
• Reduced air entry on the side of the effusion
• Dullness on percussion on the side of the effusion: this is the most reliable clinical finding
• Decreased tactile vocal fremitus and vocal resonance on the side of the effusion
• Bronchial breathing above the effusion
• Tracheal deviation away from side of a large effusion
Classification of the fluid into either an exudate or a transudate is essential for diagnosis and further management. This can be done by applying Light’s criteria (Box 10.4).
Histological and microbiological analysis of pleura is essential in the management of an exudate as this can usually distinguish between malignancy, infection, and benign pleural fibrosis. Pleural biopsy can be obtained through an Abram’s needle, with a CT-guided biopsy or a VATS biopsy.
Figure 10.2 CXR showing a unilateral (right-sided) pleural effusion.
Figure 10.4 CT thorax showing a unilateral (rightsided) pleural effusion.
Figure 10.3 Thoracic ultrasound scan showing a pleural effusion with underlying lung atelectasis.
Result of pleural fluid analysis
Turbid suggests infection or empyema Pus suggests empyema
Milky suggests chylothorax or pseudo chylothorax
Blood-stained suggests malignancy, mesothelioma, pulmonary embolus with infarction, trauma, or post-cardiac surgery
Bloody: if the pleural fluid haematocrit is >50% of the blood haematocrit, then it is classified as a haemothorax.
Malodour suggests anaerobic infection
Pleural fluid protein and pleural fluid protein /serum protein ratio
Pleural fluid lactate dehydrogenase (LDH) and pleural fluid LDH/serum LDH ratio
Pleural fluid glucose will be low (<3.3 mmol/L) in a chronic effusion with a pleural fluid/ serum glucose ratio < 0.5.
Common causes of a low fluid glucose include empyema, malignancy, or mycobacterium tuberculosis infection.
Rheumatoid arthritis is associated with a very low fluid glucose level < 1.6 mmol/L
Malignant cells may be detected in 60% of malignant effusions
Differential cell count may be helpful, but is very non-specific and not diagnostic
Neutrophilia (>50%) suggests an acute process. This includes parapneumonic effusions secondary to a bacterial infection, pulmonary embolus, acute mycobacterium tuberculosis infection or benign asbestos pleural effusion
Lymphocytosis (>50%) suggests a chronic effusion secondary to mycobacterium tuberculosis infection or malignancy. Significant lymphocytosis (>80%) suggests mycobacterium tuberculosis infection, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, or post-cardiac bypass surgery.
Eosinophilia (>10%) is usually due to air or blood in the pleural space but could indicate parapneumonic effusions, eosinophilic granulomatosis with polyangiitis, lymphoma, drugs, parasitic infestation, pulmonary infarction, or benign asbestos pleural effusion
Mesothelial cells predominate in transudates
Gram stain Ziehl-Neelsen stain
Microscopy, culture, and sensitivity, including TB culture
Normal pleural fluid pH is 76
pH can vary significantly between locules in a complicated effusion
pH < 73 in chronic malignant effusions, rheumatoid arthritis, mycobacterium
tuberculosis infection and oesophageal rupture
pH < 72 is the best indicator of an empyema and the need for a chest drain pH > 76 when there is infection with proteus spp. which produces ammonia
Measurement Result of pleural fluid analysis
Other tests as
Adenosine deaminase if TB suspected (>45 IUl-1)
Polymerase chain reaction (PCR) for Mycobacterium tuberculosis
Interferon-gamma assay for Mycobacterium tuberculosis
Pancreatic amylase if pancreatitis is suspected or salivary amylase for oesophageal rupture
Chylomicrons will be seen with a chylothorax (milky effusion)
Pleural fluid triglyceride level will be >110 mg dl-1 in a chylothorax
Pleural fluid cholesterol will be elevated in a pseudo chylothorax
Box 10.4 Light’s criteria.
The fluid is an exudate if one or more of the following criteria are met:
• Pleural fluid protein/serum protein >0.5
• Pleural fluid LDH/serum LDH > 0.6
• Pleural fluid LDH > two-thirds of upper limit of normal serum LDH
Light’s criteria, used most often to differentiate between an exudate and a transudate, has a sensitivity of 98% and a specificity of 80%. It can falsely categorise a transudate as an exudate in 20% of cases, especially in patients with partially treated heart failure or those on diuretics as this increases the concentration of protein and LDH.
Measurement of N-terminal pro-brain natriuretic peptide in pleural fluid or serum can be helpful in borderline cases as this is raised in systolic and diastolic cardiac failure. Comparison of albumin and cholesterol in the pleural fluid to serum levels may also be helpful in differentiating between an exudate and a transudate.
An Abrams needle biopsy with a local anaesthetic is only recommended if mycobacterium tuberculosis is strongly suspected, if there is diffuse pleural enhancement on a contrast CT scan, and alternative methods of obtaining tissue are not feasible. Generally, this method of obtaining pleural tissue has a low yield and a high complication rate and is done much less now than it was a few years ago.
A CT-guided percutaneous pleural biopsy, which is less invasive than a surgical biopsy, can be performed if there is obvious pleural disease on imaging and if the patient is not fit for surgery. This has a better yield than an Abram’s blind biopsy and is much safer. A CXR is required after any invasive procedure to ensure that there is no iatrogenic pneumothorax.
A thoracoscopic pleural biopsy has the best yield and is a safe procedure. A therapeutic pleurodesis can be carried out at the same time if indicated, for example, for a malignant pleural effusion, avoiding two separate procedures. A medical thoracoscopic pleural biopsy with local anaesthetic and sedation can be carried out by a trained respiratory physician and is a safer procedure than a blind pleural biopsy, with a reasonable yield of 92% in experienced hands. The main complications are infection and haemorrhage.
A VATS pleural biopsy, carried out by a thoracic surgeon, is the investigation of choice for a patient with an exudate, so long as they can tolerate a general anaesthetic. The pleura can be directly visualised, and this gives the best yield of 95%, with a low complication rate. If there is a trapped lung, this can be freed, and a talc pleurodesis can be conducted at the same time as the biopsy.
Bronchoscopy is indicated if the patient with an exudative pleural effusion presents with haemoptysis, if aspiration pneumonia or inhalation of a foreign body is suspected, or if there are radiological changes suggestive of an endobronchial lesion.
Differential diagnosis of a transudate
A transudate occurs either due to an increase in the hydrostatic pressure in the parietal pleura or due to reduced oncotic pressure of the fluid, usually from hypoalbuminaemia. Table 10.2 lists the differential diagnosis of a transudate.
Table 10.2 Differential diagnosis of a transudate.
• Left ventricular failure: unilateral or bilateral pleural effusions
• Liver failure: right pleural effusion commoner then left. Ascites may be present
• Nephrotic syndrome
• Post cardiac surgery
• Constrictive pericarditis
• Meig’s syndrome: right>left, often associated with ascites, occurs with ovarian tumours
• Peritoneal dialysis
Management of a transudate
Management of a transudate is that of the underlying condition. Bilateral pleural effusions are usually transudates, most commonly secondary to CCF. The BTS guidelines do not recommend pleural aspiration in this situation unless there are atypical features, or the effusion does not respond to diuretics. CT thorax and pleural biopsy are not required in most cases of a transudate.
Differential diagnosis of an exudate
An exudate occurs when there is increased permeability of the capillaries, usually due to inflammation, with reduced fluid resorption. Table 10.3 lists the differential diagnosis of an exudate.
Management of malignant pleural effusion
Malignant cells reach the visceral pleura either haematogenously or through the lymphatic network and spread to the parietal pleural through pleural adhesions. Malignant cells, cytokines, and vascular endothelial growth factor (VEGF) increase endothelial permeability, disrupt the lymphatic network, and promote angiogenesis, thereby causing accumulation of fluid, which is often blood-stained. Involvement of the regional lymph nodes is usually associated with the presence of a pleural effusion.
Table 10.3 Differential diagnosis of an exudate.
• Malignancy: commonest cause in patients over 60 years
• Parapneumonic effusion: occurs in 50% of bacterial pneumonias and the commonest cause in patients <40 years
• Mesothelioma: often blood-stained fluid
• Pulmonary embolus
• Mycobacterium tuberculosis: lymphocytic effusion, acid-fast bacilli positive in 10% of cases and culture positive in 25% of cases. Pleural biopsy and culture often diagnostic
• Rheumatoid arthritis: low pleural fluid glucose <1.6 mmol/L
• Systemic lupus erythematosus
• Other connective tissue disorders
• Sarcoidosis: an effusion is very rare but when present will be lymphocytic
• Acute pancreatitis or pancreatic pseudocyst: increase in pancreatic amylase in the fluid
• Oesophageal rupture (Boerhaave’s syndrome): pH < 72 and an increase in salivary amylase
• Sub-phrenic abscess
• Eosinophilic granulomatosis with polyangiitis: increased eosinophils in pleural fluid
• Dressler’s syndrome: occurs post cardiac surgery, blood-stained fluid
• Post-myocardial infarction
• Chylothorax: chylomicrons in fluid with elevated triglyceride levels
• Cryptogenic organising pneumonia
• Yellow nail syndrome
• Familial Mediterranean fever
• Drug-induced: amiodarone, bromocriptine, methotrexate, phenytoin, nitrofurantoin
The presence of malignant cells in the pleura or pleural fluid suggests advanced metastatic disease with a median survival of 3—12 months, depending on the cancer. The commonest cause of a malignant pleural effusion in men is lung cancer (40%) and in women is breast cancer (17%). Other causes of a malignant pleural effusion include lymphoma, tumours of the gastrointestinal system, and tumours of the genitourinary system. In 10% of cases of a malignant pleural effusion, no primary malignancy is identified.
A large pleural effusion is most likely to be malignant, but in 25% of cases of a malignant pleural effusion, the patient is asymptomatic. Overall, 60% of malignant effusions can be diagnosed by pleural fluid cytology, with a greater diagnostic rate for adenocarcinoma of the lung than for mesothelioma or other types of lung cancers. Measurement of tumour markers in pleural fluid is not routinely done for lung cancer. Mesothelin levels may be elevated in epithelioid mesothelioma. A pH < 7.3 in a malignant pleural effusion confers a worse prognosis and a lower chance of successful pleurodesis.
Malignant pleural effusions recur within weeks after drainage and repeated aspirations are not ideal in most cases. There are several therapeutic options which will depend on the fitness of the patient and their overall prognosis. Patients who are relatively asymptomatic from their effusion can be observed.
In symptomatic patients who have a poor performance status and life expectancy of only a few weeks, repeated pleural aspirations can be carried out as a palliative procedure to remove some fluid to improve breathlessness. Patients who are not surgical candidates should have a small bore intercostal chest drain inserted to remove 500 ml to 1.5 L of fluid in a controlled way to avoid re-expansion pulmonary oedema. A low-pressure, high-volume suction device and regular flushing may be helpful. Chemical pleurodesis using talc, bleomycin or tetracycline should be considered as this will reduce the chance of recurrence, even if the effusion cannot be completely drained because of a trapped lung.
Patients who have a reasonable performance status and life expectancy of at least several months should have a VATS pleurodesis, as any trapped lung can be freed and the outcome is better, with fewer complications. A systematic review of 46 randomised controlled trials (RCTs) with 2053 patients concluded that talc pleurodesis was associated with fewer recurrences than bleomycin or tetracycline and that a thoracoscopic pleurodesis was better than a pleurodesis done via an intercostal chest drain.
Patients with a recurrent malignant pleural effusion who cannot have a medical or surgical pleurodesis because of poor performance status or a trapped lung, should have a tunnelled pleural catheter (PleurX) inserted. This will improve symptoms and allow the patient to go home. Rarely, when pleurodesis fails, a pleuroperitoneal shunt can be considered.
Pleural infection and empyema
Pleural infection is an infection in the pleural space. Empyema is frank pus in the pleural space.
The annual incidence of pleural infection in the UK and the USA is 80 000 cases. Pleural infections are commoner in the very young, the elderly, and commoner in men compared to women. The morbidity and mortality of pleural infection are high, especially for empyema, which has a mortality of 20%. Prompt diagnosis and management by an expert reduce the morbidity and mortality. Box 10.5 lists the risk factors for developing pleural infections and empyema.
Aetiology of pleural infection
Most pleural infections result from sub-optimally treated pneumonia, with progression of a parapneumonic effusion to frank empyema. Over 50% of patients with community acquired pneumonia (CAP) develop a parapneumonic effusion which usually resolves over a few weeks with prompt antibiotic treatment. If there is a delay in treatment or if there are underlying risk factors, some parapneumonic effusions can progress to pleural infection and empyema.
Box 10.5 Risk factors for developing pleural infection and empyema.
• Diabetes mellitus
• Alcohol abuse
• Gastro-oesophageal reflux
• Intravenous drug use
• Aspiration pneumonia
• Poor oral hygiene
Iatrogenic causes of pleural infection include any pleural intervention, especially repeated aspirations, thoracic surgery, oesophageal surgery, and oesophageal perforation.
Pathophysiology of pleural infection
Although the majority of parapneumonic effusions resolve with antibiotic treatment, some can progress through a fibrinopurulent stage to an empyema. Pro-inflammatory cytokines increase capillary vascular permeability resulting in fluid entering the pleural cavity. If the patient does not receive prompt antibiotics at this stage, then bacteria invade the pleural cavity, followed by neutrophils. There is activation of the coagulation cascade with deposition of fibrin, causing septation. The increased metabolic activity in the pleural space results in an increase in LDH, a decrease in the glucose content of the fluid, a lactic acidosis, and a decrease in the fluid pH. There is gradual organisation of the fluid with fibroblast proliferation and the formation of a pleural peel, which can encase the lung and reduce lung expansion.
Hypoalbuminaemia (<30 g l-1), thrombocytosis (platelet count >400 x 10 9 l-1) and hyponatraemia (sodium <130 mmol/L) predispose to the development of an empyema.
Pleural infection should be suspected in any patient with a pneumonia who fails to improve after 3 days of antibiotic treatment, with continuing fever and high CRP. Table 10.4 describes the process whereby a simple parapneumonic effusion becomes an empyema.
Appendix 10.A describes how pleural fluid should be collected for analysis.
Management of pleural infection
Pleural infections can be complicated, have a high morbidity and mortality, and should be managed by a respiratory physician and a thoracic surgeon. Poor prognostic factors include older age, co-morbid disease, poor nutrition, and a serum albumin of less than 30 g l-1.
■ Intercostal chest drainage
■ Surgical drainage
Antibiotics for pleural infection
Pleural fluid should be sent in a blood culture bottle as this increases the diagnostic yield of anaerobic infections. Samples will be culture positive in 60% of cases and this guides antibiotic treatment. When pleural fluid cultures are negative, blood cultures may be helpful in 15% of cases. Pleural fluid samples should always be stained for acid-fast bacilli (Ziehl-Neelsen stain) and sent for Mycobacterium tuberculosis culture.
Community acquired pleural infections are usually secondary to community acquired pneumonia. The commonest infections are Gram positive organisms, such as Streptococcus milleri and Staphylococcus aureus, which account for 65% of cases. Co-infection with anaerobic infections occurs in up to 76% of cases, often associated with aspiration pneumonia or poor dental hygiene and can have a more insidious onset. Gram-negative organisms, such as Enterobacteriaceae, Escherichia coli and Haemophilus influenza, can occur in patients with co-morbidities.
Hospital acquired pleural infections are often associated with pleural or other interventions. Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) infections account for two-thirds of these cases. Gram-negative infections, such as Escherichia coli, Enterobacter Spp and Pseudomonas Spp occur in older, immunocompromised patients and have a high morbidity and mortality. Fungal empyema, which is usually due to candida, is uncommon (<1%) and occurs in the immunocompromised.
Prompt antibiotics should be prescribed for empyema after discussion with the microbiologist, taking note of local prescribing guidelines and resistance patterns. Penicillin antibiotics with beta lactamase inhibitors, metronidazole and cephalosporins, which have good penetration into the pleural space, are usually the first choice. Patients with a penicillin allergy should be prescribed clindamycin. Macrolides are not usually required and aminoglycosides do not penetrate the pleural space well. Intravenous antibiotics should be given for at least 48 hours followed by oral antibiotics for up to 6 weeks, until there is complete resolution of symptoms, normalisation of inflammatory markers and radiological improvement. Intra-pleural antibiotics are not recommended.
Table 10.4 Pathophysiology of pleural infection.
Indications for chest drain insertion in pleural infection
A chest drain should be considered in all patients who show no clinical improvement after 3 days of treatment with antibiotics, with continuing fever, high respiratory rate, and high CRP (Figure 10.5). Indications for a chest drain include pleural fluid pH <7.2, frank pus in the pleural cavity, pleural fluid glucose of <2.2mmol/L, and features of a complicated effusion on thoracic ultrasound, such as septation and loculation.
The BTS and the National Patient Safety Agency (NPSA) recommend that a small bore (10—14F) chest drain is inserted using thoracic ultrasound guidance (Figure 10.6). Regular flushing with 20—30 ml of normal saline every 6 hours, together with suction of -20 cm H2O, is recommended.
Figure 10.5 CT thorax showing right-sided empyema with inserted drain.
Indications for surgery for pleural infection
There are no clear, evidence-based guidelines as to when a patient with an infective pleural effusion should be referred for surgery, although there is some evidence that surgery may have better longterm outcome than more conservative approaches.
Patients who have clinical evidence of persistent sepsis and radiological evidence of infection despite antibiotics and a chest drain for more than 4 or 5 days should be discussed with a thoracic surgeon. A patient who is compromised because of a fibrinous peel causing compression of the lung may also warrant surgical decortication. The thoracic surgeon will need to decide between a VATS procedure and a thoracotomy with decortication depending on the fitness of the patient, their comorbidities, and the extent of the pleural disease.
Intrapleural fibrinolytic drugs
The use of intrapleural fibrinolytic drugs in the management of pleural infection is controversial. A large British RCT did not find any long term benefit with intrapleural streptokinase, with no reduction in the need for surgical intervention, length of stay or mortality, but with significant side effects of fever and malaise. Some argue that this was because a heterogeneous group of patients, at various stages of organisation of the pleural fluid, were included. Several smaller RCTs using streptokinase and urokinase have reported benefits, with increased volume of fluid drained and reduced need for surgical decortication compared to placebo. A Cochrane meta-analysis with a small number of trials also concluded that intrapleural fibrinolytic drugs reduced the hospital stay, and resulted in radiological and symptomatic improvement.
Figure 10.6 Thoracic ultrasound scan of empyema with air-bubbles post aspiration.
The BTS recommendation is that intrapleural fibrinolytic drugs should not be given routinely to patients with pleural infection. However, fibrinolytic drugs could be used by experienced physicians in selected patients, for example, in elderly patients who have a complex, loculated effusion who are unfit for surgery.
Long term sequelae of pleural effusion secondary to pleural infection
Some 13% of patients with a pleural infection and empyema develop pleural thickening which can, over time, become calcified. In rare cases, a bronchopleural fistula can develop. An extensive fibro- thorax can cause breathlessness and a restriction in breathing. If severe, patients may require surgical decortication.
Empyema necessitans results from a disruption of the parietal pleura, with spontaneous discharge of the pleural contents into the subcutaneous tissue of the chest wall. The commonest cause is Mycobacterium tuberculosis. Actinomycosis and aspergillus can also be the causative organisms. A CXR will show a soft tissue density. Management is surgical drainage and a prolonged course of antibiotics.
Mycobacterium tuberculosis pleural effusion (tuberculous effusion)
An exudative pleural effusion with a high lymphocyte count and low glucose is a common presentation of mycobacterium tuberculosis infection. The number of organisms in the fluid is very low, and acid-fast bacilli will be detected in less than 5% of cases. The pleural fluid culture has a slightly better yield of 10—20%.
If a tuberculous effusion is suspected, it is essential to obtain pleural biopsies for microbiological staining and culture. This will be positive in 70% of cases and will give information about drug sensitivities and resistance, thus dictating therapy. If TB is suspected, the pleural fluid should be sent for adenosine deaminase testing, an enzyme present in lymphocytes, which is elevated (>45 U l-1) and has a sensitivity of 92% and specificity of 90%. This test may be a particularly useful in those with HIV or those who are immunosuppressed. Pleural fluid should also be sent for unstimulated interferon-gamma levels and PCR. Interferon-gamma release assays (IGRA) are more expensive and have not been validated for the diagnosis of pleural TB. TB is discussed in more detail in Chapter 8.
Rheumatoid arthritis pleural effusion
Although rheumatoid arthritis is commoner in women compared to men, pleural effusion associated with rheumatoid arthritis is commoner in men. Acute rheumatoid pleurisy can occur in 50% of cases and the exudate will have a very low glucose of <1.6 mmol/L, a high lymphocyte count, and low C4 complement levels. A chronic rheumatoid effusion may present as a pseudochylous effusion with a high cholesterol level and the presence of cholesterol crystals.
Pulmonary emboli and pleural effusion
A third of patients with a pulmonary embolus will develop either a unilateral, or bilateral small exudates. Pulmonary emboli should be suspected in patients whose symptoms of breathlessness are out of proportion to the size of the effusion. Thromboembolic disease is discussed in Chapter 11.
Chylothorax is the accumulation of chyle, which is lymphatic fluid of intestinal origin, in the pleural cavity. It appears as a milky pleural fluid which remains milky after centrifuging. It occurs as the result of damage to the thoracic duct, often after thoracic surgery (particularly oesophageal), malignancy or disorders of the lymphatic system. The diagnosis is confirmed by the presence of chylomicrons in the pleural fluid or elevated triglyceride levels of >1.24 mmol/L. Lymphangiography and a CT scan are essential to identify where the lymph is coming from. Management depends on the cause and includes conservative management, drainage of chyle with pleurodesis, a period of fasting, a high protein-low fat diet supplemented by medium chain triglycerides, octreotide analogues, such as somatostatin, and surgical repair of the thoracic duct.
Pseudo chylothorax can occur in rheumatoid arthritis and with mycobacterium tuberculosis infection. The fluid appears milky, as with a chylothorax, but there are cholesterol crystals in the fluid.
Benign asbestos pleural effusion
This condition, unlike the other asbestos-related pleural diseases, has a much shorter latency period, occurring 10—20 years after asbestos exposure. It is also dose-related, so more likely to occur with a greater exposure to asbestos. The patient is usually asymptomatic and presents with a small, unilateral, bloody, effusion, which resolves within 6—12 months, leaving diffuse pleural thickening. As the differential diagnosis for this presentation includes mesothelioma, patients will require surgical pleural biopsies, perhaps several, and long term follow-up before mesothelioma can be excluded.
Idiopathic pleural effusion
In about 8% of cases no obvious cause for the effusion is identified. Most of these will resolve spontaneously.
A pneumothorax is air in the pleural space, either from air leaking through a hole in the lung or from a penetrating chest injury. The sudden entry of air into the pleural space causes collapse of the underlying lung.
Primary spontaneous pneumothorax (PSP)
The incidence of primary spontaneous pneumothorax is 10/100 000/year, with a male to female ratio of 5 : 1. PSP occurs in patients with apparently normal lungs, although high resolution CT scan shows apical sub-pleural blebs and bullae in 90% of cases (Box 10.6). The aetiology of these blebs is unclear.
PSP is commonest in tall, thin men between the ages of 20—40 years because there is more negative intrapleural pressure at the apex of the lung causing the blebs to burst.
Box 10.6 Risk factors for primary spontaneous pneumothorax.
• Tall and thin
• Collagen vascular disease, for example, Marfan’s disease
• Occupational, for example, deep sea diving
Figure 10.7 CXR of a small, unilateral (right-sided) pneumothorax.
Those over 1.9 m in height have a greater incidence. Smoking increases the risk of a pneumothorax significantly, probably by the development of small bullae and secondary to obstruction of small airways (Figure 10.7, Figure 10.8). There is no association with physical exertion.
Secondary pneumothorax (SP)
SP occurs in individuals with underlying chronic lung disease. The incidence of SP is 17/100 000 in males and 6/100 000 in females. Patients with SP are considerably older than those with PSP, with more significant co-morbidities. They have little respiratory reserve, so are often unable to tolerate even a small pneumothorax. The morbidity and mortality of a secondary pneumothorax are, therefore, much greater, with patients developing respiratory failure. Box 10.7 lists those conditions that predispose to developing pneumothorax. Interventional procedures can also result in pneumothorax. Box 10.8 lists these.
Figure 10.8 CXR showing a large, left-sided pneumothorax with complete collapse of the left lung.
Box 10.8 Iatrogenic causes of pneumothorax.
• Percutaneous needle biopsy of lung
• Transbronchial biopsy
• Pleural aspiration
• Pleural biopsy
• Subclavian line insertion
• Central line insertion
• Percutaneous liver biopsy
• Mechanical ventilation on ICU
• Tension pneumothorax can occur after CPR, NIV or hyperbaric oxygen treatment
Box 10.7 Lung conditions predisposing to the development of a pneumothorax.
• Chronic obstructive pulmonary disease (COPD)
• Chronic asthma
• Interstitial lung disease (ILD)
• Lymphangioleiomyomatosis (LAM)
• Pulmonary Langerhans cell histiocytosis (PLCH)
• Cystic fibrosis
• Mycobacterium tuberculosis
• HIV, particularly with pneumocystis jiroveci infection
• Catamenial pneumothorax
Clinical presentation of pneumothorax
Box 10.9 details some important points in the history of pneumothorax.
Patients with a tension pneumothorax will present with collapse and cardiac arrest. This is a clinical diagnosis requiring immediate insertion of a needle. The emergency management of a tension pneumothorax is discussed later in the chapter.
The clinical history is not a reliable indicator of the size of the pneumothorax (Box 10.10). Patients with PSP may not be excessively breathless and 40—50% of patients wait for more than two days before they seek medical attention. These patients may be at risk of re-expansion pulmonary oedema when the lung is re-inflated. Patients with even a small secondary pneumothorax may be very breathless because of their underlying lung disease and older age. As the management depends on whether it is a primary or secondary pneumothorax, this distinction needs to be made at the beginning of treatment.
Box 10.9 Important points in the history.
• Pleuritic chest pain, sudden in onset and unilateral
• Associated symptoms, such as cough
• Smoking history
• Underlying lung disease
• Occupational history, such as diving
• Previous pneumothorax
Box 10.10 Clinical signs of pneumothorax.
• Decreased air entry on side of pneumothorax
• Hyper-resonance on side of pneumothorax
• Hamman’s sign, a click heard on auscultation due to movement of pleural surfaces with a left-sided pneumothorax
• Severe signs of respiratory distress with tracheal deviation, mediastinal shift, distended neck veins, cyanosis, and hypotension heralding cardiac arrest in a tension pneumothorax
Investigations for a pneumothorax
■ Chest X-ray: postero-anterior (PA), lateral or lateral decubitus
■ Oxygen saturation on air
■ Arterial blood gas on air
■ High-resolution computed tomography (HRCT). A PA CXR usually confirms the diagnosis of a pneumothorax. There will be an area of hypolucency, with a pleural line running parallel to the chest wall and no lung markings. There may also be blunting of the costophrenic angle due to bleeding into the pleural space. If there is doubt and the clinical suspicion is high, then a lateral or lateral decubitus CXR may be helpful. An expiratory CXR is not recommended. When there is underlying chronic lung disease, it may be difficult to distinguish between a small pneumothorax and a bulla. In these cases, it is essential to organise an urgent high-resolution CT thorax (HRCT) prior to any intervention.
The PaO2 is <10.9 kPa in 75% of patients with a pneumothorax and 16% of patients with secondary pneumothorax will develop type 2 respiratory failure, with PaO2 < 7.5 kPa and PaCO2 > 6.9 kPa.
Classification of pneumothorax
■ Small: if the rim of air is <2 cm between the edge of the lung and the chest wall at the level of the hilum.
■ Large: if the rim of air is >2 cm between the edge of the lung and the chest wall at the level of the hilum.
As the volume of the pneumothorax approximates to the ratio of the cube of the lung diameter to the diameter of the hemithorax, the appearance on the CXR underestimates the volume of lung involved. A 1 cm pneumothorax occupies 27% of the hemith- orax volume and a 2 cm pneumothorax occupies 49% of the hemithorax volume (Figure 10.9).
Management of pneumothorax
The management of a pneumothorax will depend on
■ Whether it is a primary or secondary pneumothorax
Figure 10.9 Measurement of the size of a pneumothorax from BTS Guidelines.
■ Whether the patient is symptomatic or not
■ The age of patient
■ Associated co-morbidities
■ The size of the pneumothorax, although this is less important than the amount of clinical compromise
Management of primary spontaneous pneumothorax (PSP)
Most young patients with a PSP have minimal symptoms and tolerate a pneumothorax well. Young patients (<50 years) with a small pneumothorax (<2 cm), who are not breathless, could be discharged from hospital with clear written advice about returning if they should become symptomatic (Box 10.11). These patients should be reviewed in the respiratory clinic with a repeat CXR to ensure that the pneumothorax has resolved and to identify any underlying lung abnormalities. An HRCT may be necessary to identify early, minor abnormalities. Patients should also be carefully assessed to identify any risk factors, including features of Marfan’s disease or other collagen vascular disease. Patients with asthma should have lung function testing and asthma treatment optimised. Smokers should be encouraged and supported to stop smoking, prescribed appropriate pharmacological support, and referred to a smoking cessation clinic.
Box 10.11 Written advice to patients on discharge after pneumothorax.
• Advise the patient to return immediately to the emergency department if the symptoms recur
• Advise the patient to stop smoking
• Advise the patient to avoid flying for at least one week after complete resolution of pneumothorax on CXR or two weeks for a traumatic pneumothorax
• Advise the patient to avoid deep sea diving unless they have had a definite bilateral surgical procedure and have satisfactory lung function test and CT scan at follow-up
• Patients with a SP may be at risk of a recurrent pneumothorax for one year. Patients who have had a definitive surgical procedure have a lower risk. Patients with lymphangioleiomyomatosis (LAM) are at increased risk
A small pneumothorax spontaneously resolves at a rate of 1—2% each day, with a median of 8 days for complete resolution. A large pneumothorax can take several weeks to resolve completely. The risk of recurrence is 40% in the first two years and is greater in those who smoke. The risk of recurrence increases with each subsequent pneumothorax, and up to 60% after a third pneumothorax.
Older patients with a small pneumothorax who are not breathless can be observed in hospital with high flow oxygen and have a repeat CXR to ensure that the pneumothorax has not enlarged.
Patients who are breathless should be admitted, given high flow oxygen (10 L min-1), given analgesia for the chest pain, and should undergo a simple aspiration with a 16F cannula inserted into the second intercostal space in the mid-clavicular line which is connected to a three-way tap. The cannula can also be inserted in the 8th, 9th or 10th intercostal space in the mid-axillary line. Aspiration should be continued until there is resistance to aspiration or until >2.5 L of air is aspirated as this suggests a persistent air leak from a bronchopleural fistula. Aspiration should also be stopped if the patient coughs or complains of worsening chest pain. A CXR should always be performed after an aspiration to ensure that there has been resolution of the pneumothorax. Inhalation of oxygen reduces the partial pressure of nitrogen in the blood and increases the absorption of air from the pleural cavity, thus expediting resolution.
Success rates for aspiration in PSP are between 50% and 69%. If the first aspiration is not successful, then a repeat aspiration is not recommended according to BTS Guidelines unless there was a technical reason for the failure. However, it is worth noting that a second aspiration is successful in a third of patients with a PSP. Aspiration is not recommended for very small pneumothorax of <1 cm as there is a risk of injury to the lung and the development of a larger pneumothorax.
Intercostal chest drain insertion for pneumothorax
If the aspiration fails, a small (8—14F) intercostal chest drain should be inserted in the triangle of safety using a Seldinger technique. There is no evidence that a large drain (20—24F) is any better than a small drain (8—14F). The drain should be attached to an underwater sealed unit. Swinging of the drain indicates that it is in the pleural space, and bubbling on inspiration and coughing will confirm the drainage of air. A CXR is necessary to ensure that the drain is in an optimal position.
Management of secondary pneumothorax (SP)
Most patients with SP will be symptomatic because of their underlying lung disease and poor respiratory reserve. The commonest cause of a SP is COPD. In these patients it can sometimes be difficult to differentiate between a small pneumothorax and a bulla and it would be catastrophic to put a chest drain into a bulla (Figure 10.10, Figure 10.11). These patients should have an urgent HRCT to confirm the presence of a pneumothorax and should be discussed with a respiratory physician prior to any intervention.
A small SP (<2 cm) could be managed with simple aspiration. However, the majority are likely to require an intercostal chest drain (as above for PSP). If there is a large and persistent air leak, a larger drain may be necessary, especially in a ventilated patient on ICU.
Rates of pneumothorax recurrence correlate with age and are particularly high in patients with severe emphysema, cystic fibrosis, LAM, and PLCH.
Figure 10.10 CXR showing a large, left-sided emphysematous bulla.
Figure 10.11 CT thorax showing a large, left-sided emphysematous bulla.
Management of patients with a chest drain for pneumothorax
Patients should be observed carefully on a specialist ward with nurses who are trained to manage chest drains. High flow oxygen should be prescribed if not contra-indicated by the development of type 2 respiratory failure. Analgesia should always be prescribed as chest drain insertion is painful. As the air in the pleural space comes out through the drain into the sealed bottle with sterile water, there will be bubbling of air. The chest drain should never be clamped because of the risk of creating a tension pneumothorax. Patients should be clinically reviewed daily to see whether their breathing is back to normal and whether their chest drain has stopped bubbling.
A CXR will be necessary to see if the lung has come up. If the chest drain is not swinging or bubbling but the CXR shows a persistent pneumothorax, then the drain should be checked to ensure that it is not kinked or that it has not been displaced.
Suction using a high volume, low pressure system (-10 to -20 cm H2O) is recommended if there is continued air leak (bubbling) 48 hours after chest drain insertion. This removes air from the pleural cavity and helps the parietal and visceral pleural surfaces to come together. Suctioning before 48 hours is not recommended as this may precipitate the development of re-expansion pulmonary oedema which can occasionally affect the contralateral lung. This serious, and occasionally fatal, complication is commonest in young patients who present late with a large pneumothorax and therefore have had the collapsed lung for several days. This can occur in up to 14% of cases and presents with cough and breathlessness. It usually resolves without treatment in most cases. Once the pneumothorax has resolved, the chest drain can be removed, sutures inserted if necessary, and a sterile dressing placed.
Complications of chest drain for pneumothorax
Complications of chest drain for pneumothorax include surgical emphysema, with air tracking subcutaneously due to pressure from the pleural space. This is more likely if there is an air leak, if the chest drain is displaced, or if there is significant underlying lung disease. A crackling sensation can be felt on palpating the chest wall and neck, and a crunch can be heard on auscultation. High flow oxygen and re-positioning of the chest drain will result in resolution in most cases. Severe surgical emphysema can cause upper airway obstruction and respiratory distress and may require skin incision decompression (Figure 10.12).
In a significant number of patients, particularly with a secondary pneumothorax, the pneumothorax will not resolve. These patients should be referred to a respiratory physician. A thoracic surgical opinion should be sought in patients who have a persistent air leak for more than 4 days.
Surgery for persistent pneumothorax
The aim of surgery is to repair the damaged pleura and obliterate the pleural space in patients with a persistent air leak or when the lung fails to re-expand several days after drain insertion. Surgical intervention may also be indicated in patients who have had more than two pneumothoraces on the same side, in those who develop bilateral pneumothoraces, or who have an underlying lung disease that predisposes to the development of a pneumothorax.
Figure 10.12 CXR showing surgical emphysema.
Open thoracotomy with resection of apical blebs, pleural abrasion, or apico-lateral pleurectomy has a recurrence rate of only 1% without compromising lung function. However, it is a major procedure with a hospital stay of a few days. VATS pleural abrasion with pleurectomy is better tolerated with a shorter hospital stay, but has a recurrence rate of 4%. Surgical pleurodesis with talc can also be considered although it is less effective than pleural abrasion and there is a risk of ARDS and emphysema. These procedures do not compromise future lung transplantation in patients with cystic fibrosis, LAM, or PLCH.
Patients who have a persistent air leak but are unfit for surgery could have a bedside chemical pleurodesis, although this has a failure rate of 10—20%. An alternative would be to have a Heimlich flutter valve which will allow the patient to mobilise and to go home.
A traumatic pneumothorax, usually the result of rib fractures, may be complicated by haemothorax and other injuries. Such patients should be looked after by the Trauma Team. Traumatic pneumothorax may also be complicated by pneumomediastinum and/or pneumopericardium. Figure 10.13 shows the BTS algorithm for the management of a primary and a secondary pneumothorax.
A tension pneumothorax occurs when air leaks into the pleural space during inspiration but is not able to re-enter the lung on expiration because the hole in the lung behaves like a valve. This results in accumulation of air in the pleural cavity which gradually compresses the lungs and the mediastinal structures, causing tracheal and mediastinal shift away from the side of the pneumothorax. Eventually the pressure on the heart impedes venous return with a reduction in cardiac output, resulting in a cardiac arrest, usually of the pulseless electrical activity type.
A tension pneumothorax is a medical emergency. The patient will present with severe dyspnoea, tachycardia, and will collapse. Clinical examination will reveal reduced air entry on the side of the pneumothorax with hyper-resonance on percussion and signs of mediastinal shift away from the side of the pneumothorax, such as deviated trachea and displaced apex beat.
Management of tension pneumothorax
As with all respiratory emergencies, the airways, breathing, and circulation should be assessed. If the clinical diagnosis is one of a tension pneumothorax, a 16G cannula attached to a 20 ml syringe containing 5 ml saline should be inserted into the second intercostal space in the mid-clavicular line on the side of the pneumothorax without delay. The plunger should be removed from the syringe and a hissing sound will indicate that it is in the correct position and that air is leaking out.
Intravenous access should be gained, the patient given high flow oxygen and arterial blood gas measurement obtained. A CXR should be performed to confirm the size of the pneumothorax once the patient is stable. An intercostal chest drain, using the Seldinger technique, should be inserted as soon as possible.
More than one pneumothorax, either on the same side or on the contralateral side, will warrant referral to the thoracic surgeon for consideration of VATS pleural abrasion, talc pleurodesis, pleurectomy, or bullectomy. The risk of recurrence of a primary pneumothorax is 54% within the first 4 years and increases up to 60% after the third pneumothorax.
Figure 10.13 BTS algorithm for management of primary and secondary pneumothorax.
Catamenial pneumothorax occurs during menstruation and may be due to pleural endometriosis. This should be considered in young women with recurrent pneumothoraces. Surgical intervention, together with hormonal management, may be required.
There is an increased risk of pneumothorax in pregnancy. The woman should be looked after by both the respiratory physician, and the obstetrician. Management should be conservative, if possible, or with simple aspiration. Patients should have a caesarean section with regional anaesthesia as near term as possible.
Asbestos-related pleural disease
Asbestos is a common cause of a variety of pleural diseases, benign and malignant. Patients should always be questioned in detail about their possible exposure to asbestos.
Benign pleural plaque
Benign pleural plaques, caused by thickening of the parietal pleura, are the commonest manifestation of asbestos exposure. The pleural plaques can occur all over the parietal pleural surface but are commonest on the postero-lateral chest wall, over the mediastinal pleura, and on the dome of the diaphragm. These occur in 50% of those exposed to asbestos and develop 20—30 years after exposure to asbestos, but not in a dose-dependent way. They can calcify heavily (Figure 10.14). Pleural plaques are usually asymptomatic and identified incidentally on a chest X-ray. Rarely, if the pleural plaques are extensive and calcified, they can result in restriction of the thoracic cavity and breathlessness (Figure 10.15). There is no evidence that pleural plaques predispose to the development of mesothelioma. Patients with benign pleural plaques are not eligible for compensation.
Figure 10.14 CXR showing benign, calcified, pleural plaques.
The differential diagnosis for unilateral calcified pleural plaque includes previous tuberculous effusion or secondary to a haemothorax.
Diffuse pleural thickening
Asbestos exposure can result in adhesion of the visceral and parietal pleura, with obliteration of the pleural space and fibrosis. This process can be extensive and involve much of the pleural surface, including the costophrenic angles, the apices, and the inter-lobar fissures. This occurs in a dose- dependent way and may follow recurrent asbestos pleurisy.
Patients with diffuse pleural thickening may present with breathlessness and pleuritic chest pain. A chest X-ray and a contrast CT scan will show smooth pleural thickening with no enhancement (Figure 10.16).
Pulmonary function testing may show a restrictive process. As the differential diagnosis for pleural thickening includes mesothelioma, these patients will need a pleural biopsy and careful monitoring. Management is symptomatic as there is no definite treatment that will reverse this process. Patients with diffuse pleural thickening are eligible for compensation (see Appendix 10.B).
Figure 10.15 CT thorax showing benign, calcified pleural plaques.
Figure 10.16 CT thorax showing left-sided pleural thickening.
Benign asbestos-related pleural effusion
Rounded atelectasis (folded lung/ Blesovsky syndrome)
Rounded atelectasis can develop secondary to any cause of pleural fibrosis, including asbestos. Contraction of fibrotic areas of the visceral pleura can entrap a segment of lung and twist it into a distinctive, rounded, pleural-based mass of 2.5—5 cm in diameter, which can appear like a solitary pulmonary nodule (SPN) (Figure 10.17, Figure 10.18). Patients are usually asymptomatic. A contrast CT scan shows a characteristic “comet- tail” appearance of vessels and bronchi converging towards lesion and adjacent thickened pleura (Figure 10.19). There may be volume loss in the affected lobe.
Figure 10.17 CT thorax showing round atelectasis with adjacent left-sided pleural thickening (mediastinal window).
Asbestosis, pulmonary fibrosis caused by inhalation of asbestos fibres, is discussed in Chapter 15.
Mesothelioma is a malignant tumour of the pleura with a poor prognosis and median survival of 8—14 months from diagnosis. In rare cases, the tumour can arise in the peritoneum, pericardium, or tunica vaginalis. Peritoneal mesothelioma, which occurs after prolonged asbestos exposure, presents with abdominal pain, ascites, and weight loss. It has a median survival of 7 months.
■ Incidence and prevalence: The Mesothelioma Register was established in the 1960s. The number of cases of malignant mesothelioma continues to increase, with approximately 2000 deaths per year in the UK. It is estimated that the number of new cases will peak around 2020, after which time numbers are likely to decrease in the UK, reflecting the ban on asbestos use in the 1970s. The prevalence of mesothelioma is likely to be much greater in developing countries where asbestos is still widely used.
■ Age: mesothelioma commonly presents in people aged between 50 and 70 years. It has been known to occur very rarely in children.
■ Male: Female: mesothelioma is commoner in men as it is due to occupational exposure to asbestos in 90% of cases. It accounts for 0.7% of all deaths in men born in the late 1930s and early1940s.
Figure 10.18 CT thorax showing round atelectasis with adjacent left-sided pleural thickening (parenchymal window).
Figure 10.19 Coronal reconstruction of CT thorax showing sub-pleural reticulation and multiple, bilateral, calcified pleural plaques.
Women exposed to asbestos while washing their husbands’ work clothes have also been known to develop mesothelioma. Ambient asbestos levels in the environment are low, but many old buildings, including schools, have asbestos.
■ Geographical variation: the incidence of mesothelioma is higher in areas of shipbuilding, railway construction, asbestos manufacture and building construction.
■ The responsibility of employers towards their employees in these industries is laid out in the Control of Asbestos Regulations 2006 (Statutory Instrument 2006 No. 2739).
Aetiology of mesothelioma
Asbestos, a naturally occurring material formed of crystalline hydrated silicates in fibrous form, was used extensively because it was cheap and resistant to acid, alkali, and heat. Box 10.10 lists the occupations associated with asbestos exposure. Inhalation of asbestos fibres can be attributed to be the cause of mesothelioma in up to 90% of cases. The latency period from first exposure to developing mesothelioma ranges from 15 to 67 years, with a median of 32 years, although the development is not dose-related.
Chrysotile, white asbestos with a serpentine structure, was the most commonly used asbestos type in construction. It clears rapidly from the lungs, so has a low risk of malignancy. Crocidolite, blue asbestos with an amphibole structure, takes longer to be degraded from the lungs and has a higher risk of malignancy, even with lower exposure. Erionite, a non-asbestos fibre found in rock in some areas of Turkey, appears to cause mesothelioma in up to 25% of residents in that region.
Pathophysiology of mesothelioma
It is postulated that asbestos fibres are inhaled, reach the terminal bronchioles, irritate the pleura, and damage the DNA, resulting in genetic changes. Mesothelioma arises from sub-mesothelial cells which proliferate and grow as a rind around the chest wall. The tumour invades locally into the mediastinum, pericardium, chest wall, and diaphragm. At an advanced stage, the tumour can spread haematogenously to distant sites.
Box 10.12 Occupations associated with asbestos exposure.
• Construction: insulation, fireproofing, electrical, lagging, plumbing, welding, carpentry
• Brake lining
• Milling asbestos fibres
A full occupational history, detailing all the jobs the patient has ever done, should be obtained. The patient should be questioned specifically about professions associated with asbestos exposure (Box 10.12). The chest pain may be referred to the shoulder or abdomen, may be pleuritic in nature, or have a neuropathic component if intercostal, thoracic, or brachial plexus nerves are involved. Box 10.13 lists the symptoms of mesothelioma and Box 10.14 lists the clinical signs of mesothelioma.
Investigations in the diagnosis of malignant mesothelioma
A CXR will show a unilateral pleural effusion in 90% of cases. The differential diagnosis includes benign asbestos pleural effusion and lung cancer (adenocarcinoma) with pleural metastases. The CXR may also show pleural thickening, a lobulated pleural mass, volume loss, and a contracted hemithorax. Bilateral pleural involvement is rare.
Box 10.13 Symptoms of mesothelioma.
• Dull, persistent, and progressively worsening chest pain
• Worsening breathlessness
• Weight loss
• Excessive sweating
Box 10.14 Clinical signs in mesothelioma.
• Clubbing of fingers (<1%)
• Signs consistent with a unilateral pleural effusion
• Volume loss on the side of the effusion
• Pericardial involvement resulting in cardiac tamponade
• Superior vena cava obstruction
A contrast CT scan usually shows a unilateral pleural effusion with enhancing, nodular, circumferential pleural thickening of >1 cm which may involve the mediastinal pleura, the pericardium, and the diaphragm. This can result in volume loss and contraction of the hemithorax. Mesothelioma can also appear as a lobulated pleural mass with lymphadenopathy (Figure 10.20, Figure 10.21). The CT scan is poor at distinguishing mediastinal nodal metastases from adjacent mediastinal pleural involvement. A mediastinoscopy will be required for accurate staging if surgery is being contemplated. Local invasion of chest wall can also be seen on a CT scan. In 20% of patients with mesothelioma, there will other radiological signs of asbestos exposure, such as pleural plaques or interstitial fibrosis.
An MRI may provide additional anatomical information when there is chest wall invasion. There will be enhancement with gadolinium-based contrast material. This may useful if surgery is being contemplated.
Figure 10.20 CT thorax showing right-sided malignant mesothelioma associated with external compression of the superior vena cava.
Figure 10.21 CT thorax showing right-sided malignant mesothelioma.
A PET-CT can be helpful when pleural biopsies have been negative as areas of FDG uptake may guide the surgeon to where to take further biopsies. A PET-CT is also important for accurate staging when surgery is being considered. However, false positive FDG uptake can occur with parapneumonic effusions and false negative results can occur with sarcomatoid mesothelioma.
Ultrasound guided pleural aspiration will reveal an exudate which is often blood-stained. Pleural cytology is positive in 50% of cases but it can be difficult to differentiate between reactive mesothelial cells, malignant mesothelial cells, and adenocarcinoma of the lung. Immunocytochemistry, using a panel of antibodies applied to cell blocks obtained from pleural fluid, may differentiate between mesothelioma cells and metastatic adenocarcinoma cells. Positive staining for calretinin, epithelial membrane antigen (EMA) and CK5/6 suggests epithelioid mesothelioma, whereas adenocarcinoma is CEA and TTF 1 positive.
Mesothelin levels may be elevated in the pleural fluid and blood of patients with malignant mesothelioma, although the sensitivity is only 48—84% and the specificity is 70—100%. False negative results occur in sarcomatoid mesothelioma and false positive results in adenocarcinoma, pancreatic carcinoma, lymphoma, and ovarian cancer. Soluble mesothelin-related protein (SMRP) levels are increased in mesothelioma with a sensitivity of 84%, but this is only used in clinical trials currently.
A pleural biopsy is necessary in most cases to establish a firm histological diagnosis of mesothelioma. This will determine the course of treatment, the prognosis, and is helpful when seeking compensation. A VATS pleural biopsy is usually definitive and has the best yield as the tumour appears as white nodules on the parietal pleura on direct visualisation. The VATS procedure also has the advantage that a pleurodesis can be carried out at the same time, reducing the risk of recurrence of the effusion.
If the patient is not fit for surgery, then a medical thoracoscopy with a local anaesthetic and sedation can be attempted. If this is not available, then a CT-guided pleural biopsy should be considered. A blind Abram’s biopsy is not recommended. The number of attempts at pleural aspiration should be limited as seeding of tumour in the subcutaneous tissue can occur, causing pain.
It is common to have negative pleural biopsies with mesothelioma, and repeat pleural biopsies may be required over a period of months to confirm the diagnosis if there is clinical suspicion. A mediastinoscopy may be required to sample mediastinal nodes as part of staging if surgery is being considered as CT and PET-CT are not good at detecting tumour involvement of mediastinal nodes.
Pathological types of malignant mesothelioma
■ Epithelioid (50—70%)
■ Sarcomatoid (10—15%)
■ Mixed (biphasic) (20—40%)
Within each of these histological types there are several subtypes, but these do not have any prognostic significance. Sarcomatoid mesothelioma has a particularly aggressive course and a poor prognosis, with median time from diagnosis to death of only 6 months. Poor prognostic features include trans-diaphragmatic spread, involvement of mediastinal lymph nodes, male gender, poor performance status, and sarcomatoid histology.
Management of malignant mesothelioma
Currently there is no curative treatment available, and limited evidence of benefit with surgery, chemotherapy, or radiotherapy. Once the diagnosis of mesothelioma is confirmed, the patient should be discussed at the lung multidisciplinary meeting and referred to a specialist centre with expertise in managing mesothelioma.
The patient and their relatives should be given verbal and written information about the diagnosis and prognosis, as well as information about compensation. The patient should be referred to the palliative care team for symptom control and be followed up by the lung cancer or mesothelioma nurse specialist. Patients with mesothelioma will benefit from counselling, rehabilitation, complementary therapies, referral to social services, and to Macmillan Cancer Support. After death, all patients should be referred for a Coroner’s post mortem.
See Appendix 10.B for details on obtaining compensation. See Chapter 9 for details on the lung MDT.
Pain should be managed with opioids, non-steroidal anti-inflammatory drugs (with proton pump cover) and steroids. Neuropathic pain can be managed with carbamazepine, amitriptyline, or gabapentin. When there is persistent pain due to chest wall invasion, the patient should be referred to a specialist pain service for consideration of nerve blocks (intercostal, paravertebral, or brachial plexus), intrapleural, epidural or intrathecal analgesic infusions or percutaneous cervical cordotomy. Transcutaneous electrical nerve stimulation (TENS) machines may help. Palliative radiotherapy has been shown to improve pain in 60—90% of patients.
Dyspnoea can be difficult to manage and does not respond to palliative radiotherapy. Opioids, steroids, and oxygen may be required. Drainage of the pleural effusion with talc pleurodesis, undertaken at the same time as the pleural biopsy, can improve breathlessness. If the patient is frail, pleurodesis can be done via a small bore (16—18F) intercostal drain. Sometimes, a chronic pleural effusion can result in a trapped lung which fails to expand. An indwelling pleural catheter, which can be managed at home, can be used although there is a risk of pleural infection. Pleuroperitoneal shunts are occasionally used when there is a trapped lung or when pleurodesis has failed, but are associated with a risk of shunt occlusion and infection.
Radical radiotherapy may improve local control of disease in 60—90% of patients. As the volume of disease in mesothelioma is considerable, irradiation to the pleura is limited by toxicity to the underlying lung and the mediastinal structures. This could be improved by using intensity modulated radiotherapy (IMRT). Prophylactic radiotherapy used to be offered to patients within 4 weeks of pleural aspiration or biopsy in order to reduce the risk of tumour seeding in the scar tissue. Recent trials do not support this practice.
Palliative radiotherapy improves pain in 50% of patients but does not improve symptoms of breathlessness.
All patients with histologically-verified malignant mesothelioma and a good performance status of 0—2 should be referred to an oncologist for consideration of chemotherapy. A combination of pemetrexed and cisplatin results in tumour regression and improvement in symptoms in 40% of cases and prolongs survival by 3 months. A combination of gemcitabine and cisplatin has also shown good response in recent trials.
The role of surgery in malignant mesothelioma is controversial. Radical extra-pleural pneumonectomy (EPP) involves removal of all macroscopic disease, a pneumonectomy with resection of all parietal and visceral pleura, the diaphragm, and pericardium. The operative mortality is 4—9% and more than 60% have serious complications. The recent Mesothelioma and Radical Surgery (MARS) randomised feasibility study found no benefit with EPP versus no EPP as part of trimodal therapy. Although only 50 patients participated in this study between 2005 and 2008, EPP was associated with a higher morbidity and mortality compared to the group not having surgery.
Debulking/cytoreductive surgery can be done by open thoracotomy or by a VATS procedure and involves removal of as much of the tumour as possible. This decortication may allow the reexpansion of the trapped lung and may reduce the re-accumulation of fluid.
The MesoVATS multicentre, randomised controlled trial compared VATS partial pleurectomy against talc pleurodesis. The results showed no difference in survival between the two groups. Partial pleurectomy was more expensive, and the patients had more complications with a longer hospital stay, but some improvement in symptoms at 6 months. Partial pleurectomy may be a more effective treatment for trapped lung.
Patients with mesothelioma and some other asbestos- related lung diseases are eligible for compensation. See Appendix 10.B for details on compensation.
■ Investigation of a unilateral pleural effusion includes contrast CT thorax, pleural aspiration, and pleural biopsy.
■ Pleural fluid analysis and applying Light’s criteria is the critical first step in management of a unilateral pleural effusion.
■ The commonest cause of an exudate in patients over 60 years is malignancy and in younger patients is infection.
■ The commonest cause of a transudate is CCF.
■ Parapneumonic effusions are common and occur in 50% of patients with CAP.
■ If a parapneumonic effusion is not treated optimally with antibiotics, or if the patient has risk factors, then this can progress to an empyema.
■ An empyema can be diagnosed if there is pus in the pleural cavity or if the pleural fluid pH < 72.
■ Empyema should be managed aggressively with intravenous antibiotics and intercostal chest drain insertion.
■ Patients with pleural infection who do not improve with antibiotics and chest drain will require surgery.
■ The management of a spontaneous pneumothorax will depend on whether it is primary or secondary, whether the patient is symptomatic or not, the age of the patient, the co-morbidities of the patient, and the size of the pneumothorax.
■ Primary spontaneous pneumothorax occurs in young patients with no obvious underlying lung disease and is commoner in tall thin men.
■ Primary spontaneous pneumothorax can be managed conservatively if the patient is not symptomatic, but will require intervention if the patient is breathless, regardless of the size of the pneumothorax.
■ Secondary pneumothorax has a higher morbidity and mortality and is more difficult to manage.
■ Most patients with a secondary pneumothorax will require intercostal chest drain insertion.
■ Patients with a chest drain should be managed on a specialist respiratory ward by a respiratory physician and specialist nurses.
■ If the pneumothorax does not resolve within 3-5 days, the patient should be referred to a thoracic surgeon for pleural abrasion, pleurectomy, pleurodesis, or bullectomy.
■ Patients who have recurrent pneumothoraces should be referred to the thoracic surgeon for pleural abrasion, pleurectomy, pleurodesis, or bullectomy.
■ Mesothelioma, a malignant tumour of the pleura, is associated with asbestos exposure and has a terrible prognosis.
■ Mesothelioma should be suspected in any patient presenting with chest pain and a unilateral pleural effusion, and/or pleural thickening.
MULTIPLE CHOICE QUESTIONS
10.1 Compared to interstitial fluid, pleural fluid has?
A Higher concentration of lactate dehydrogenase
B Higher concentration of neutrophils
C Higher concentration of sodium
D Lower concentration of glucose
E Lower concentration of protein
Pleural fluid has the same concentration of protein and glucose as interstitial fluid but a slightly lower concentration of sodium and a higher lactate dehydrogenase level. An increased neutrophil count in pleural fluid indicates an acute effusion secondary to bacterial infection.
10.2 A bilateral pleural effusion is most likely to be due to what cause?
A Congestive cardiac failure
B Meig’s syndrome
D Pulmonary embolus
E Rheumatoid arthritis
The commonest cause of a bilateral pleural effusion is congestive cardiac failure and it will be a transudate. Pleural aspiration is not necessary unless there are atypical features, or the effusion does not respond to diuretics. Meig’s syndrome can present with bilateral pleural effusions but is a rare condition. Bilateral effusions are rare in mesothelioma.
10.3 What is the ideal management of a simple parapneumonic effusion?
A Give intravenous antibiotics and insert a Seldinger intercostal chest drain
B Give intravenous antibiotics and refer to a thoracic surgeon for VATS debridement
C Give intravenous antibiotics and monitor closely
D Give intra-pleural antibiotics through a Seldinger intercostal chest drain E Give intra-pleural fibrinolytic drug through a Seldinger intercostal chest drain
The majority of parapneumonic effusions are secondary to bacterial pneumonia and will resolve with intravenous antibiotics without the need for an intercostal chest drain or surgery. Intra-pleural antibiotics have no proven benefit and intra-pleural fibrinolytic drugs are not indicated for most pleural infections.
10.4 Which of the following statements about an empyema is true?
A The commonest cause of an empyema is from a pleural intervention
B Empyema should always be managed by a thoracic surgeon with a VATS debridement
C A pH of <7.2 suggests that the pleural fluid is an empyema
D The mortality associated with an empyema is 1%
E Intra-pleural fibrinolytic drugs are always recommended as they break down the septation
Most empyemas arise from parapneumonic effusions that have not been optimally treated. A pH < 7.2 is an indication for drainage in the first instance and patients should be referred to a thoracic surgeon only if there is no improvement after s everal days. The use of an intrapleural fibrinolytic drug is controversial with insufficient evidence of long term benefit. Empyema has a significant mortality of up to 20% in immunocompromised patients.
10.5 According to the BTS pneumothorax guidelines, what should you do with a young patient with a primary spontaneous pneumothorax who is breathless?
A He can be discharged home if the pneumothorax is small, with follow-up in two weeks
B He should have an intercostal chest drain inserted without delay
C He should have an intercostal chest drain inserted and attached to suction to speed up recovery
D He should be observed on the ward and given high flow oxygen
E He should have simple aspiration in the first instance
The clinical state of the patient is more important than the size of the pneumothorax. Breathless patients should never be discharged home and will require an intervention. The first intervention is simple aspiration and an intercostal chest drain is indicated only if that fails. Suction is not recommended in the first 48 hours as it may precipitate re-expansion pulmonary oedema.
10.6 In a patient presenting with a unilateral pleural effusion, which of the following is most important?
A A bronchoscopy is always indicated.
B The differential cell count can be diagnostic
C Several samples of fluid should be sent for cytology
D The fluid protein and LDH to serum protein and LDH ratio should be measured
E Pleural fluid amylase level can be diagnostic
The essential investigation is pleural fluid analysis for the protein and LDH ratio compared to serum levels (Light’s criteria) as this distinguishes an exudate from a transudate and guides management. A bronchoscopy is only indicated if the patient has symptoms such as haemoptysis, or if there is a mass on the CXR. The differential cell count can narrow the differential diagnosis but will not be diagnostic. There is no benefit in sending more than two samples of fluid for cytology, and amylase levels are not routinely sent.
10.7 A 55-year-old man with emphysema presents to hospital with breathlessness and is found to have a 2 cm pneumothorax on the right side. How would you manage this patient?
A Simple aspiration as many times as necessary as chest drain insertion is dangerous when there are bullae
B Prescribe high flow oxygen and observe the patient carefully on the ward
C Insert a Seldinger intercostal chest drain, ensuring that it is a pneumothorax
D Insert a large bore chest drain as there is likely to be a significant leak
E Refer the patient to the thoracic surgeon for a VATS pleurodesis
Patients with a secondary pneumothorax who are symptomatic require intervention. Although one simple aspiration could be attempted, most patients with a secondary pneumothorax are likely to require a Seldinger chest drain. There is no evidence that a large drain is better and, in fact, may cause more complications. Thoracic surgical intervention should be considered if the pneumothorax does not resolve 3—5 days after insertion of the chest drain.
10.8 When managing a chest drain inserted for a secondary pneumothorax, what is the procedure?
A Swinging indicates that the drain is not working properly
B Persistent bubbling after 48 hours suggests a bronchopleural fistula
C The development of surgical emphysema is a life-threatening complication
D The drain should be clamped when the patient mobilises to avoid too much air leaking out
E The chest drain should be connected to a high pressure low volume suction device
Swinging of the drain indicates that it is correctly positioned in the pleural space. Surgical emphysema is usually a minor complication and resolves once the drain has been re-positioned. A bubbling chest drain should never be clamped as this might create a tension pneumothorax. A low pressure high volume suction device could be used, but only after 48 hours to prevent reexpansion pulmonary oedema. Persistent bubbling after 48 hours suggests the development of a bronchopleural fistula and thoracic surgery may be indicated.
10.9 In making a histological diagnosis of mesothelioma, what should you do?
A Pleural fluid cytology is diagnostic in most cases
B Repeat CT guided pleural biopsies are advised to ensure that the diagnosis is correct
C An MRI scan can be helpful in obtaining adequate samples
D A PET-CT is essential prior to obtaining biopsies as it has a high sensitivity and specificity
E A VATS pleural biopsy has the best yield and is the preferred investigation
A VATS pleural biopsy, done under direct visualisation, is the investigation of choice. Pleural fluid cytology is positive in only 50% of patients with mesothelioma and repeated biopsies can result in tumour seeding so should be avoided. MRI scan and PET-CT do not have a role in the histological diagnosis of mesothelioma.
10.10 What should a patient discharged home after a primary spontaneous pneumothorax be told?
A They must not participate in any physical activity for 4 weeks
B They should be able to fly on a commercial flight after 1 week if the chest X-ray is normal
C They must not fly in a helicopter for 6 weeks
D They can go scuba diving after 1 year
E Their risk of a recurrent pneumothorax is 10%
Patients with no chronic lung disease, and whose CXR confirms that the pneumothorax has resolved, are considered safe to fly after Iweek. There is no evidence that the development of a pneumothorax is related to physical exertion. Flying in a helicopter is safe as they do not fly at high altitude. Patients should not participate in any diving activity unless they have had a definitive surgical procedure, such as a pleural abrasion, pleurectomy or pleurodesis.
Appendix 10.A Analysis of pleural fluid
■ 2—5 ml of pleural fluid should be sent in a plain container for measurement of protein and lactate dehydrogenase (LDH). A blood sample should also be sent for total protein and LDH so that the fluid: serum ratio can be calculated (Light’s criteria).
■ 1—2 ml of pleural fluid should be sent in a fluoride oxalate tube for glucose measurement. A serum glucose sample should be sent at the same time.
■ 5 ml of pleural fluid should be sent in a plain container and 5 ml in anaerobic and aerobic blood culture bottles to the microbiology department for microscopy, culture, and sensitivity, including Ziehl-Neelsen stain and culture for tuberculosis if indicated.
■ 20—40 ml of pleural fluid (or more if available) should be sent in a plain universal container without delay. Samples taken out of hours should be refrigerated. Yield for malignancy increases if cell blocks formed by centrifuging and extracting the solid cellular portion are examined. Smears are also prepared from pleural fluid samples.
■ 5 ml pleural fluid in an anti-coagulated tube for differential cell count.
■ pH should be measured in non-purulent samples only as pus can damage the blood gas analyser.
0.5—1 ml of fluid should be drawn up into a hep- arinised blood gas syringe. Contamination with local anaesthetic must be avoided. Exposure to air must be minimised by keeping the syringe capped.
■ 1—2 ml of pleural fluid should be sent in an EDTA container to the Hematology department if a haemothorax is suspected.
Appendix 10.B Compensation for asbestos-related disease
Compensation is available for the following conditions:
■ Malignant mesothelioma.
■ Diffuse pleural thickening.
■ Asbestos-related pulmonary fibrosis (asbestosis). Pathological diagnosis is not mandatory but
helpful. The patient must identify occupational exposure or another source of asbestos to satisfy the ‘balance of probabilities’ test. The individual must also show that the employer was negligent in not maintaining appropriate standards required by common law and in breach of safety regulations.
The following compensation is available
1. Industrial Injuries Disablement Benefit (IIDB) is payable to individuals with asbestos- related illnesses, including mesothelioma, if they have been exposed to asbestos at work. It is not applicable if the patient was selfemployed. This payment is made weekly, monthly, or quarterly by the Department of Work and Pensions.
2. The Pneumoconiosis etc. (Worker’s Compensation) Act 1979 entitles the patient to a lump sum if they have been awarded Industrial Injuries Disablement Benefit and their employer is no longer in business or if the compensation claim has not been settled.
3. Diffuse Mesothelioma Scheme 2008 is for patients who cannot claim benefits under either of the above two schemes because their exposure to asbestos was not occupational but through contact with relatives who were exposed to asbestos (for example, wives washing their husbands’ work clothes) or individuals who were self-employed. The claim must be made within 12 months of the diagnosis of mesothelioma.
4. War Pensions Scheme is applicable if the individual was exposed to asbestos while working in the armed forces.
5. Common Law Claim is compensation from a previous employer or their insurers, usually through a specialist solicitor. Individuals will need accurate dates regarding their period of employment that resulted in exposure to asbestos. The individual will need to log a claim within three years of the time they first became aware of their illness.
As well as these compensation schemes, individuals may be entitled to statutory sick pay, incapacity and disability benefits, and employment and support allowance — called the Universal Credit from October 2013.
The next of kin of an individual who has died from mesothelioma can claim compensation for their relative’s pain and suffering and for financial losses within 6 months of death of the individual.
American Thoracic Society, Guidotti, T.L., Miller, A. et al. (2004). Diagnosis and initial management of nonmalignant diseases related to asbestos.
American Journal of Respiratory and Critical Care Medicine 170 (6): 691-715.
Bouros, D., Antoniou, K., and Light, R.W.(2006). Intrapleural streptokinase for pleural infection. BMJ (Clinical Research ed.) 332 (7534): 133-134.
British Thoracic Society (2007). BTS statement on malignant mesothelioma in the UK, 2007. Thorax 62 (Suppl 2): ii1-ii19.
British Thoracic Society, MacDuff, A., Arnold, A., and Harvey, J. (2010a). Management of spontaneous pneumothorax: British Thoracic Society pleural disease guideline 2010. Thorax 65 (Suppl 2): ii18-ii31.
British Thoracic Society, Roberts, M.E., Neville, E. et al. (2010b). Management of a malignant pleural effusion: British Thoracic Society pleural disease guideline 2010. Thorax 65 (Suppl_2): ii32-ii40.
British Thoracic Society Standards of Care Committee, Ahmedzai, S. et al. (2011). Respiratory diease: managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 66 (Suppl 1): i1-i30.
Davies, H.E., Davies, R.J.O., Davies, C.W.H., and on behalf of the BTS Group (2010). Management of pleural infection in adults: British Thoracic
Society pleural disease guideline 2010. Thorax 65 (Suppl 2): ii41-ii53.
Health and Safety Executive and Local Authorities Enforcement Liaison Committee (HELA) (2012) Control of Asbestos Regulations 2012: General enforcement guidance and advice, pp. 1-23, [online]. Available at: www.hse.gov.uk/foi/ internalops/ocs/200-299/oc265-50.pdf.
Hooper, C., Lee, Y.C.G., and Maskell, N. (2010). Investigation of a unilateral pleural effusion in adults: British Thoracic Society pleural disease guideline 2010. Thorax 65 (Suppl 2): ii4-ii17.
Light, R.W. (2002). Pleural effusion. New England Journal of Medicine 346 (25): 1971-1977.
Maskell, N.A., Davies, C.W., Nunn, A.J. et al. (2005). U.K. controlled trial of Intrapleural streptokinase for pleural infection. The New England Journal of Medicine 352 (9): 865-874.
Porcel, J.M. and Light, R.W. (2006). Diagnostic approach to pleural effusion in adults. American Family Physician 73 (7): 1211-1220.
Tan, C., Sedrakyan, A., Browne, J. et al. (2006). The evidence on the effectiveness of management for malignant pleural effusion: a systematic review. European Journal of Cardio-thoracic Surgery 29 (5): 829-838.
Zocchi, L. (2002). Physiology and pathophysiology of pleural fluid turnover. European Respiratory Journal 20 (6): 1545-1558.