neumo

1. PLEURA Pleural disease Key points Oliver J Bintcliffe Point-of-care ultrasound guidance should be used for all pleural procedures involving fluid If the pleural fluid protein concentration is 25e35 g/litre, Light’s criteria can be used to differentiate exudates from transudates PleuralfluidpHshouldbemeasuredinallnon-purulenteffusionsif infectionissuspected;pH<7.2indicatesaneedfortubedrainage Only 60% of malignant effusions can be diagnosed by cytology Image-guided pleural biopsy has a higher diagnostic yield than blind pleural biopsy for malignancy Indwelling pleural catheters are increasingly being used to manage symptomatic malignant pleural effusions, reducing hospitalization and enabling management in the community Pleural fluid specimens for microbiology should be sent in both a sterile tube (for Gram stain, acid- and alkali-fast bacilli and culture of Mycobacterium tuberculosis) and blood culture bot- tles to increase the microbiological yield Combination treatment with intrapleural tissue-type plasmin- ogen activator and DNase may be beneficial in patients with pleural infection resistant to standard medical therapy Heimlich valves allow ambulatory treatment for selected pa- tients with pneumothorax C Amelia O Clive C Nick A Maskell C Abstract Pleural disease encompasses a wide range of pathological processes, many of which are common and increasing in incidence. Patients with pleural disease are encountered by both respiratory specialists and general physicians, and a systematic approach to their management helps in targeting investigation and optimizing patient care. Research has led to recent advances in diagnostic strategies and therapeutic techniques in these patients. This review focuses on the clinical assessment, diagnosis and management of patients with pleural effu- sions, malignant pleural disease, pleural infection and pneumothorax, and provides practical suggestions regarding investigation and management. Keywords Empyema; malignant pleural effusion; parapneumonic effusion; pleural disease; pleural effusion; pneumothorax C C C C C C Investigating pleural effusions a heparinized syringe (to measure pH using a blood gas analyser) and sent for the following tests: ? biochemistry e lactate dehydrogenase (LDH), total pro- tein, glucose ? microbiology e Gram stain, identification of acid- and alcohol-fast bacilli (AAFB) and microbiological culture ? cytology ? pH. Pleural effusions are a common medical problem (Table 1). There are several underlying mechanisms, including: ? increased permeability of the pleural membrane ? increased pulmonary capillary pressure ? excess negative intrapleural pressure ? reduced tissue oncotic pressure ? obstructed lymphatic flow. The differential diagnosis is wide, so a systematic approach to investigation is necessary.1This should start with an accurate history, including a drug history (Table 2), and examination. Distinguishing pleural fluid exudate and transudate: in most cases, a pleural fluid total protein of less than 25 g/litre represents a transudate and more than 35 g/litre an exudate. However, if the serum total protein is low or the pleural fluid protein concentra- tion lies between these figures, differentiating the two can be more difficult. In these cases, measurement of serum and pleural fluid LDH and total protein allows Light’s criteria to be used to distinguish exudates and transudates more accurately (Table 4). Light’s criteria have good sensitivity and specificity (as high as 98% in some series). However, a small number of patients with malignancy will be categorized as having a transudate; in addition, patients with cardiac failure taking diuretics may have a higher fluid protein concentration, so the pleural fluid may be mislabelled as an exudate. Pleural aspiration: a diagnostic pleural fluid sample should be collected using a fine-bore (21 G) needle and a 50-ml syringe, using ultrasound guidance to locate a safe site to perform the procedure (Table 3).1 The appearance and odour of the fluid should be noted. The sample should be placed in sterile vials, blood culture bottles and Oliver J Bintcliffe MRCP is a Specialist Registrar in Respiratory and General Medicine and Clinical Research Fellow in pleural disease at the University of Bristol, UK. His research interests include pneu- mothorax and non-malignant pleural effusions. Competing interests: none declared. Differential cell counts: a differential count of a pleural fluid sample can be useful in narrowing the differential diagnosis, but the results are not disease-specific. Lymphocytic effusions are commonly seen in malignancy and tuberculosis (TB), after coro- nary artery bypass graft and with cardiac failure and chronic pleural effusions. Neutrophilic effusions usually signify a more acute disease process, such as pulmonary emboli (PEs) or parapneumonic effusions. Amelia O Clive PhD is a Specialist Registrar in Respiratory and General Medicine at North Bristol NHS Trust, UK. Her research interests include the management of malignant pleural disease. Competing interests: none declared. Nick A Maskell DM FRCP is a Professor in Respiratory Medicine at the University of Bristol, UK. His clinical and research interests include malignant pleural disease and pleural infection. Competing interests: Professor Maskell has received research funding from Care Fusion, Roche and Novartis. 249 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4

2. PLEURA Pleural procedures1 Causes of transudative and exudative pleural effusions Transudative Exudative Pleural procedures should not take place out of hours except in an emergency Pleural aspirations and chest drain should be inserted in a clean environment using full aseptic technique Bedside thoracic ultrasound guidance is strongly recommended for all pleural procedures involving pleural fluid The preferred site for pleural interventions is the triangle of safety (see below) Non-urgent pleural procedures should be avoided in anti- coagulated patients until the international normalized ratio is <1.5 Pleural fluid aspiration should be stopped when no more fluid can be aspirated or the patient becomes symptomatic, to reduce the risk of re-expansion pulmonary oedema. The total amount aspirated is often limited to 1.5 litres in the elderly. C Common Left ventricular failure Cirrhosis Hypoalbuminaemia Peritoneal dialysis Less common Hypothyroidism Renal impairment Mitral stenosis Pulmonary embolism Rare Constrictive pericarditis Superior vena cava obstruction Ovarian hyperstimulation Common Malignancy Parapneumonic effusions Less common Pulmonary infarction Rheumatoid arthritis Autoimmune diseases Benign asbestos effusion Post-myocardial infarction syndrome Rare Yellow nail syndrome Drugs (Table 2) C C C C C Table 1 pH: a low pleural fluid pH (<7.2) can indicate pleural infection requiring chest tube drainage. Other causes of low pH effusions include advanced malignancy, rheumatoid arthritis, TB, collagen vascular disease and oesophageal perforation. Pleural fluid glucose concentration correlates with pleural fluid pH and can be a useful alternative if pH cannot be measured. Cytology: malignant effusions can be diagnosed from a single pleural fluid cytology specimen in about 60% of cases. A second cytology specimen increases the yield slightly. Certain malignant cell types are diagnosed more readily by experienced cytologists, using immunocytochemistry; a cytological diagnosis is more likely in a malignant pleural effusion due to metastatic adeno- carcinoma than in mesothelioma for instance. Identify the ‘safe triangle for drain placement, as demarcated by the outer border of the pectoralis major, the anterior border of the latissimus dorsi and a horizontal line that meets the nipple anteriorly. In general, the drain should be sited in the 4th or 5th intercostal space within this triangle. Table 3 Pleural imaging: effusions greater than 200 ml can be detected on a postero-anterior chest radiograph, although smaller vol- umes can be detected using thoracic ultrasound. Ultrasound scanning can also differentiate more clearly between pleural fluid and thickening, assess septations and loculations within an effusion and help to identify a safe site for pleural procedures. Computed tomography (CT) can help to characterize pleural abnormalities further. Contrast enhancement aids differentiation between benign and malignant pleural thickening and is often visualized more clearly if some pleural fluid is still present (Figure 1). In addition, CT can identify other underlying causes of a pleural effusion, such as PEs, infection or tumours. Up to 40% of patients with PEs have a small pleural effusion with no specific biochemical characteristics; a high index of suspicion is required to make this diagnosis, and CT pulmonary angiography should be requested if the diagnosis is considered. Magnetic resonance imaging (MRI) is developing as an im- aging modality for pleural disease and can be useful in selected cases where clear soft tissue differentiation is required. Drug causes of pleural effusion Light’s criteria Common Rare Pleural fluid is an exudate if one or more of the following criteria are met: Pleural fluid protein:serum protein ratio >0.5 Pleural fluid LDH:serum LDH ratio >0.6 Pleural fluid LDH more than two-thirds of upper limit of normal serum LDH Amiodarone Nitrofurantoin Phenytoin Methotrexate Cabergoline Pergolide Dasatinib Carbamazepine Penicillamine Cyclophosphamide Bromocriptine C C C LDH, lactate dehydrogenase. Table 2 Table 4 250 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4

3. PLEURA failure of pleurodesis. Cytological analysis identifies tumour cells in 60% of malignant effusions, so histology is often required for diagnosis. This is particularly the case with suspected mesothe- lioma, in which pleural fluid cytology is frequently non- diagnostic. Blind pleural biopsies have a lower diagnostic yield and higher complication rate than CT-guided biopsy and are now rarely used. Use of local anaesthetic thoracoscopy is increasing and allows for complete drainage of the pleural effusion, tissue sampling for histology and pleurodesis in the same procedure. It provides an alternative to VATS under general anaesthetic if a less invasive approach is preferred, particularly for elderly pa- tients for whom a general anaesthetic can be more risky. In some cases, where the lung is tethered or the effusion heavily septated, a surgical procedure via multiple ports may be needed to release the trapped lung, break down septations and obtain tissue for histology. CT is mandatory for identifying the primary source and for staging (Figure 1). The precise role of other imaging modalities, such as MRI and positron emission tomography CT has yet to be established. Figure 1 Contrast-enhanced thoracic CT of an exudative pleural effusion, showing enhancement of the pleural tumour. Pleural biopsy techniques A pleural biopsy should be considered in patients who have a pleural effusion of unknown cause after initial investigations, particularly if malignancy or TB is suspected. The biopsy can be performed percutaneously, or at thoracoscopy. A blind pleural biopsy using an Abrams’ biopsy needle can be considered if TB pleuritis is suspected, as the pleural abnormality is more diffuse than in malignancy. However, at least four samples should be taken to maximize the diagnostic yield. If TB is suspected, the sample should be sent in saline for TB culture as well as for histology. If malignancy is suspected, however, pleural biopsy using an image-guided cutting needle has a higher diagnostic yield than blind pleural biopsy. Four samples should still be taken to opti- mize the diagnostic accuracy. Thoracoscopy is gaining popularity in the investigation and management of pleural disease as it is both diagnostic and thera- peutic.1It allows direct visualization of the pleura and can be per- formed under local anaesthetic thoracoscopic surgery (VATS)) anaesthesia. The sensitivity for ma- lignancy and TB is over 90%. During the procedure, all the pleural fluid can be removed and pleurodesis performed if necessary. Management The treatment modalities available to patients with malignant pleural effusions are expanding and depend on patient choice, clinical condition and availability.1Aside from treatment of the underlying malignancy, management strategies focus on fluid removal and prevention of reaccumulation. No current therapies target the underlying problem of excess fluid production directly, but this is the subject of continuing research. Treatment of the underlying malignant process can help to reduce pleural fluid production, particularly in chemoresponsive tumours such as breast cancer. Thoracocentesis allows instant relief of symptoms, but reac- cumulation frequently necessitates more definitive treatment. Chest drain insertion and pleurodesis is a well-established method of removing fluid and preventing recurrence. Talc is the preferred agent in pleurodesis and is effective in about 70% of patients. It can be given in the form of talc slurry through a chest tube, or as a ‘talc poudrage’ during thoracoscopy. The ef- ficacy of these procedures is the subject of a large, randomized controlled trial (TAPPS). Pleurodesis is unlikely to be successful when the lung is unable to fully re-expand (‘trapped lung’), because of a visceral pleural ‘peel’ of tumour or endobronchial obstruction. Indwelling pleural catheters (Figure 2) are gaining popularity in the management of malignant effusions, particularly in pa- tients with trapped lung or those who wish to avoid hospital admission.2The catheters are small chest tubes tunnelled under the skin that allow regular pleural fluid drainage to be carried out in the community. Spontaneous pleurodesis occurs in up to one- half of patients, after which the catheter can be removed. The combination of talc and an indwelling pleural catheter can in- crease the rate of pleurodesis; this is the subject of a randomized controlled trial (IPC-PLUS). The role of prophylactic radiotherapy in mesothelioma to prevent metastases along the procedure track following pleural interventions is not established but is the subject of two large multicentre randomized controlled trials (SMART, PIT). or general (video-assisted Malignant pleural effusion Malignant pleural effusion can result in disabling breathlessness for patients with advanced malignancy and confers a poor prognosis. It can be caused by mesothelioma (a primary pleural tumour) or metastatic disease. Lung, breast, ovarian, haemato- logical and gastrointestinal commonly metastasize to the pleura. Other conditions associated with an underlying malignant process can also cause a pleural effusion. These include PEs, superior vena cava obstruction, nodal enlargement restricting pleural fluid resorption and hypoalbuminaemia. tract cancer and melanoma Diagnosis Initial assessment with blood and pleural fluid analysis assists with diagnosis. Imaging using CT and ultrasound is also used. Malignant pleural effusions are exudates in 90% of cases. A low pleural fluid pH indicates extensive disease and helps to predict 251 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4

4. PLEURA Figure 2 (a) An indwelling pleural catheter, commonly used for the management of recurrent, symptomatic, malignant pleural effusions. (b) Trocar and cannula. Parapneumonic effusions and empyema choice of antibiotic. Prolonged courses of antibiotics may be required to ensure complete resolution. First-line antibiotic treatment for community-acquired pleural infection should include an aminopenicillin (e.g. amoxicillin) to cover organisms such as Streptococcus pneumoniae and Haemo- philus influenzae, as well as metronidazole or a b-lactamase in- hibitor (e.g. clavulanic acid), to ensure penicillin-resistant aerobes and anaerobes are covered.1 In hospital-acquired empyema broader cover is required for Gram-positive (including meticillin-resistant Gram-negative and anaerobic organisms.1 More than 65,000 patients develop pleural infection in the USA and UK each year. Mortality is about 15%. Hospital-acquired infection, particularly with Gram-negative bacteria, has a particularly poor prognosis. The microbiology of hospital- acquired infection also differs from that of community-acquired empyema (Figure 3), and they should be considered as sepa- rate entities in terms of epidemiology and recommended therapy. S. aureus), Epidemiology Pleural infection can occur at any age, but is most common in elderly patients and children. Men are affected twice as often as women, and the incidence (particularly of infection caused by Staphylococcus aureus) is increasing. The incidence is higher in patients with diabetes, rheumatoid arthritis or coincidental chronic lung disease, and in alcohol and substance abusers. Poor dentition is associated with anaerobic infection. Diagnosis In all suspected cases, pleural fluid aspiration and analysis should be undertaken. Biochemical pleural fluid markers (low pH, high LDH, predominant neutrophils, low glucose) are central in establishing a diagnosis. Gram staining and culture can aid antibiotic choice, although 40% of infected pleural effusions are culture-negative. Use of blood culture bottles increases the microbiological yield over universal containers alone and can aid assessment of poly- microbial infection. A pleural pH <7.2 identifies effusions requiring chest tube drainage. pH should be measured routinely in any potentially infectedpleuralfluid sample,unless itis obviouslypurulent. A low pleural fluid glucose concentration (<2.2 mmol/litre indicates the needforchesttubedrainage)isanalternativetopHasanindicator. Tuberculous effusions are usually unilateral and more than 50% will show evidence of parenchymal TB. These effusions are usually sterile, unless secondarily infected. Smears for acid-fast bacilli on pleural fluid are positive in only 5e10% of cases, and only 25e50% are positive on culture. A pleural biopsy is often required to confirm the diagnosis. Management Antibiotics: the clinical setting, pleural fluid culture results and local antibiotic prescribing policies help to inform the initial Figure 3 252 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4

5. PLEURA Chesttubedrainage:promptdrainageisrequiredinpatientswitha pleural fluid pH less than 7.2, septated appearances on ultrasound, positive pleuralfluidmicrobiologyorpurulentpleuralfluid.1Small Seldinger tubes are as effective as larger ones and are more comfortable for the patient; however, they need regular flushing with sodium chloride 0.9% (20 ml 8-hourly) to prevent blockage. Nutrition:adequatenutritionisimportant.Allpatientsshouldhave anutritionalassessmentanddietarysupplementation ifnecessary. Intrapleural fibrinolytics: there has been much debate about the role of intrapleural fibrinolytics in pleural infection, to break down fibrin septae and reduce the pleural rind, and thus improve fluid drainage and lung expansion. The MIST-2 trial, which assessed the use of intrapleural tissue-type plasminogen activator and DNase, showed that combined treatment improved drainage, reduced hospital stay and decreased referrals for thoracic surgery.3This treatment can have a role in patients who do not respond to standard therapy, or in those not fit for surgery, although its precise role has yet to be fully established. Figure 4 A chest X-ray showing a left-sided primary spontaneous pneumothorax. pneumothoraxislarge,simpleaspirationistherecommendedfirst- line treatment and can prevent a hospital admission. However, simple aspiration fails in 20e25% of patients, and insertion of a chest tube is then warranted in those who are symptomatic. Clinically stable patients with a large primary pneumothorax can also be appropriate for conservative treatment without aspiration; this hypothesis is the subject of a currently recruiting trial in Australia and New Zealand. Heimlich valves offer the potential for an outpatient-based treatment of pneumothorax, which may be appropriate in selected patients. These devices are the subject of a currently recruiting randomized controlled trial (RAMPP study). Recurrence of PSP occurs in about 40% of patients, usually within 5 years of the first event. If a recurrence occurs, patients should be referred to a thoracic surgeon for consideration of a definitive procedure such as pleurodesis or pleurectomy to prevent further events.4 Surgery: surgical referral may be necessary in patients with continuing signs of sepsis or failure of the effusion to resolve despite medical management. The aims of surgery are to treat infection by draining any residual fluid completely and to allow adequate lung re-expansion. Several surgical options are avail- able, including open thoracotomy with decortication, mini- thoracotomy, VATS and rib resection with open drainage (if patients are not fit enough for a more definitive procedure). Pneumothorax Pneumothorax is defined as air in the pleural space and can be spontaneous or traumatic (including iatrogenic). Recommended management depends on the size of pneumothorax and patient symptoms and whether the pneumothorax is primary or sec- ondary (Figure 5). Chest radiographs confirm the diagnosis (Figure 4) but do not accurately quantify pneumothorax size. CT is sometimes required to differentiate a pneumothorax from a subpleural bulla and confirm tube placement, particularly if the radiographic images are obscured by surgical emphysema.1 Secondary pneumothorax Secondary pneumothoraces occur in the presence of underlying lung pathology (particularly chronic obstructive pulmonary disorder (COPD)); symptoms are often more severe than in PSP because of a pre-existing impairment of respiratory function. If the patient develops a small secondary pneumothorax (<2 cm) and is asymptomatic, inpatient observation is reason- able. If symptoms are minimal, simple aspiration can be attempted, although this has a lower success rate than in PSP; inpatient observation for at least 24 hours after the aspiration is advised. Many patients with a secondary pneumothorax need inter- costal drain insertion. A small (<14 F) chest tube is usually sufficient, but if there is a persistent air leak (continuous bubbling of the drain >48 hours after insertion), significant surgical emphysema or the patient is mechanically ventilated, a larger bore chest tube may be indicated. Suction may also be helpful if the pneumothorax is slow to resolve and should be slowly titrated to a more negative pressure, depending on the patient’s symptoms, down to ?20 cmH2O. Primary spontaneous pneumothorax (PSP) PSPs occur in individuals without underlying lung disease. Subpleural blebs and bullae are found in up to 90% of patients at thoracoscopy and are thought to have a role in the pathogenesis of PSP. Smoking is a risk factor; the lifetime risk of PSP is 12% in men who smoked heavily compared with 0.1% in non-smoking men. Patients with primary pneumothorax tend to be taller than controls. The aim of treatment is to reduce symptoms and prevent recurrence. Administration of high-flow oxygen (10 litres/minute) can accelerate resorption of the pneumothorax by reducing the partial pressure of nitrogen in the pleural space. Observation alone isappropriateinpatientswithasmallPSP(<2cmbetweenthelung edge and chest wall) without significant breathlessness, as resorp- tion will occur over time. If the patient is symptomatic or the 253 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4

6. PLEURA Suggested management of pneumothorax pneumothorax No Yes Primary pneumothorax Known lung disease or Secondary pneumothorax smoking history? Consider symptoms, pneumothorax size and clinical stability Requires admission Yes Size >2 cm and/or breathlessness No Conservative management Consider Heimlich valve + ambulatory management if available Aspiration with cannula Aspiration or observation. (observe for minimum 24 hours) Failure Success Chest drain insertion Discharge home Thoracic surgical referral Early outpatient review as required Resolution Ongoing air leak Figure 5 Adapted from the British Thoracic Society Pleural Disease Guideline 2010. Tension pneumothorax: immediate intervention is necessary. A large-bore cannula should be inserted promptly into the second intercostal space in the mid-clavicular line and left in place until a chest tube can be positioned. Patients should be advised about smoking cessation and should not fly until the pneumothorax has entirely resolved on chest radiograph. Unless they undergo a definitive surgical pro- cedure, patients should not dive. A Iatrogenic pneumothorax: the incidence of iatrogenic pneumo- thorax is high and increasing. Percutaneous lung biopsy, trans- bronchial needle aspiration, pleural biopsy, thoracocentesis and central venous puncture are the principal causes. COPD and lung fibrosis are important risk factors. In most patients, the pneu- mothorax will resolve with observation alone, but others can require aspiration. KEY REFERENCES 1 British Thoracic Society Pleural Disease Guideline Group. BTS pleural disease guideline 2010. Thorax 2010; 65(suppl 2): ii1e76. 2 Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. J Am Med Assoc 2012; 307: 2383e9. 3 Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med 2011; 365: 518e26. 4 Tschopp JM, Bintcliffe O, Astoul P, et al. ERS task force statement: diagnosis and treatment of primary spontaneous pneumothorax. Eur Respir J 2015; 46: 321e35. Referral for surgery: open surgery with thoracotomy and pleur- ectomy is an effective method to reduce recurrence rates, though minimally invasive VATS with surgical talc pleurodesis or mechanical abrasion is now usually the preferred approach on account of reduced postoperative pain and shorter hospital stays. Indications for a surgical referral for pneumothorax include: ? persistent air leak (patients should be referred early, ideally within 5 days) ? second ipsilateral pneumothorax ? first contralateral pneumothorax ? bilateral spontaneous pneumothorax ? certain at-risk professions (e.g. pilots, divers). Patients with recurrent secondary pneumothorax who are not fit for surgery can be given alternative treatments including chemical pleurodesis (although the recurrence rate is high) or an ambulatory Heimlich valve. FURTHER READING Bintcliffe OJ, Hallifax RJ, Edey A, et al. Spontaneous pneumothorax: time to rethink management? Lancet Respir Med 2015; 3: 578e88. Clive AO, Bhatnagar R, Psallidas I, Maskell NA. Individualised manage- mentofmalignantpleuraleffusion.LancetRespirMed2015;3:505e6. Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller- Kopman D, Rahman NM. Pleural infection: past, present, and future directions. Lancet Respir Med 2015; 3: 563e77. 254 ? 2016 Elsevier Ltd. All rights reserved. MEDICINE 44:4