Approach

The first step in diagnosis is confirmation of the pleural effusion (suspected clinically or on chest x-ray) by ultrasound. Diagnostic aspiration (which may be included in therapeutic aspiration) establishes whether it is a transudate or an exudate, which then determines the potential etiology. This subdivision, along with relevant history, dictates further specific tests.[12][16]

Pleural aspiration animated demonstration
Pleural aspiration animated demonstration

Video demonstrating how to perform a pleural aspiration

History and examination

Symptoms of dyspnea, cough, and pleuritic chest pain, with typical exam findings of absent or decreased breath sounds, dullness to percussion, decreased or absent tactile fremitus, and decreased vocal transmission over the base of the lung, strongly suggest a fluid collection.

Further history and examination may reveal the underlying cause. A past medical history of congestive heart failure (CHF), renal failure, cirrhosis, previous malignancy, lupus pleuritis, or rheumatoid arthritis may be associated with pleural effusions. Full occupational history with particular relevance to asbestos exposure is essential. Full drug history is also important. The most common drugs implicated include tyrosine kinase inhibitors, nitrofurantoin, dantrolene, ergot alkaloids, valproate, propylthiouracil, and isotretinoin. Use of exogenous gonadotropins for ovarian stimulation, such as in in-vitro fertilization may cause pleural effusion. The presence of risk factors for thromboembolism, such as family history, recent long-distance travel, leg trauma, systemic lupus erythematosus (SLE), or immobilization, may be present in cases of pulmonary embolism. Fever and cough productive of purulent sputum suggests pneumonia. Age >50 years, coupled with a history of cigarette smoking and unexplained weight loss may indicate an underlying malignancy. Imaging findings should be interpreted in the context of clinical history and exam.[7]

Initial investigations

A posteroanterior chest x-ray and lateral view (now less commonly done) is the first test for this condition. It may confirm the clinical suspicion of, or incidentally reveal, a pleural effusion, but should usually prompt pleural ultrasound.[12][17]

Routine blood tests, blood culture, and sputum Gram stain and culture are indicated if clinical presentation and chest x-ray suggest pneumonia.[18][19]

Thoracic ultrasound (TUS) has long been used to assess suspected pleural effusion.[20][21][22][23]​​​ It is commonly used as a point of care test to guide intervention with strong evidence suggesting this improves safety and can guide management decisions.[17][20][24][25][26]​​

Except for patients with clear evidence of heart failure (suspected in patients with a past history of ischemic or other heart disease and suggestive clinical exam, including an elevated jugular venous pressure and pitting edema of the legs, or echocardiographic evidence, or elevated serum brain natriuretic peptide [BNP] or N-terminal pro-brain natriuretic peptide [NT-pro-BNP]), thoracentesis/pleural aspiration is indicated to identify and diagnose the underlying cause.[12] The procedure can be done quickly and easily at the bedside but must be ultrasound-guided to improve yield and safety.[7]​ Chest x-ray after thoracentesis is not routinely indicated unless air is drawn during the procedure or the patient develops symptoms, such as increased dyspnea, cough, or chest pain.[27]

Establish whether the effusion is a transudate or an exudate.

Presentation with bilateral effusions or associated ascites are strongly associated with transudates.[20][28][29]​​​ On TUS this makes the fluid appear anechoic, however this is not specific.[30]​ In contrast, effusions which are exudates will almost always appear echogenic, complex, or both.[30] 25 to 50 mL of pleural fluid should be submitted for cytologic analysis. If only smaller volumes are available, these may be sent but clinicians should be aware of the reduced sensitivity.[7]​ The pleural lactate dehydrogenase (LDH) and protein levels, and serum LDH and protein, should be measured to determine whether the effusion is a transudate or exudate using the Light criteria (where one or more of the following suggest an exudate: pleural fluid protein divided by serum protein >0.5; pleural fluid LDH divided by serum LDH >0.6; and pleural fluid LDH >two-thirds of the upper limit of laboratory normal range for serum LDH).[12] Pleural fluid cholesterol analysis has been used to distinguish exudates from transudates but is not used routinely.[31][32]​​​ In one meta-analysis to determine the best means for differentiating exudates from transudates, diagnosis of an exudate was most accurate with pleural fluid cholesterol >55 mg/dL or pleural fluid to serum cholesterol ratio of >0.3.[3]

A transudate is likely to be caused by CHF, cirrhosis, or nephrosis. An exudative effusion will require further studies. In congestive cardiac failure, diuretic therapy, which is the mainstay of treatment, can cause elevated levels of pleural fluid protein and LDH, resulting in a misclassification of pleural effusions as exudative in up to 25% of cases.[33] In cases where no cause for an exudative effusion can be identified, or congestive cardiac failure is suspected, there is some evidence that the sequential application of the pleural fluid LDH, followed by the serum-to-pleural fluid protein, and then the serum-to-protein albumin gradients may assist in diagnosis.[34] Pleural fluid N-terminal pro-brain natriuretic peptide (NT-pro-BNP) should be considered in patients with pleural effusions, suspected of having CHF, however this is not superior to serum NT-pro-BNP so should not be used routinely.[7][35]​​​ A laboratory cutoff value of 1500 picograms/mL is commonly used.[36]

Chylothorax

Chyle (a sterile, odorless, alkaline, milky fluid) is sometimes difficult to differentiate from empyema, but if chylothorax is suspected, lipid analysis of the pleural fluid should be performed. The presence of chylomicrons on microscopy confirms a chylothorax and a high triglyceride level, usually >110 mg/dL is diagnostic.[37] Chylothorax can usually be excluded if the triglyceride level is <50 mg/dL.[16]

Blood tests and cultures

Total and differential cell count, glucose, pH, and cytology are recommended; routine cultures are not useful or cost effective, but if a parapneumonic effusion is suspected or there is frank pus, then this is a valuable test.[38] Clinicians should be aware that using pleural cytology for the diagnosis of malignant pleural effusion can be unreliable, as it has a low sensitivity of 58%.[39]​ Pleural fluid should be inoculated into aerobic and anaerobic blood culture bottles at the same time as standard culture as this increases microbial yield.[40] Pleural fluid pH <7.20 is highly suggestive of pleural infection or complex parapneumonic effusion (CPPE); clear pleural fluid for pH can be collected anaerobically with heparin and measured in a blood gas analyzer.[41] (Avoid putting turbid fluid or frank pus through the analyzer. Note that manufacturers of blood gas analyzers may void their warranty if any fluid other than blood is processed through the machine.) In the absence of readily available pleural fluid pH measurement, an initial pleural fluid glucose <3.3 mmol/L may be used as an indicator of high probability of CPPE/pleural infection and can be used to inform decision to insert an intercostal drain in the appropriate clinical context.[7]

If the cell count is predominantly lymphocyte-dominant, then a test for markers of tuberculosis (TB) in the pleural fluid, such as adenosine deaminase, should be requested.[42][43] Eosinophilic pleural effusions (defined as >10% of pleural white cells) account for 10% of exudates and are nonspecific. Causes include malignancy (26%), idiopathic (25%), related to pleural air or blood (13%), parapneumonic (13%), and TB (7%), along with other less common miscellaneous causes. Likelihood of malignancy is inversely correlated with eosinophil count.[44] Interferon-gamma measurement in pleural fluid is sensitive and specific for the diagnosis of tuberculous pleurisy.[45][46]​​​[47] T-cell gamma interferon assays (IGRA) on blood or pleural fluid are not sensitive or specific enough to be clinically useful for diagnosis of TB pleurisy.[48]

Subsequent imaging studies

Thoracic computed tomography (CT) scans are useful to define the size and location of the effusion, show loculations, and identify additional pathology that requires further investigation (e.g., a lung mass or pleural thickening). A simple CT-scan scoring system to distinguish malignant effusions from benign effusions has been validated in two small populations.[49] If there is suspicion of TB, thoracic CT is indicated for detecting subtle parenchymal changes, as well as mediastinal lymphadenopathy, which may represent a target for transbronchial nodal aspiration via bronchoscopy. CT follow-up should also be considered for patients presenting with pleural infection to exclude occult malignancy if there are ongoing symptoms, or other clinically concerning features.[7]​ Magnetic resonance imaging (MRI), which provides better imaging of soft tissues than CT, can reveal tumor invasion of the chest wall or diaphragm, and can distinguish between benign and malignant effusions (using differences in signal intensity). MRI is, however, not routinely indicated in investigation of pleural effusion, and first-line cross-sectional imaging should be CT.​[17][50]

If no cause is established, pulmonary embolus should be ruled out by further pulmonary imaging, such as a helical CT scan. Pleural effusions due to pulmonary emboli are usually small and unilateral exudates.[51] 

Bronchoscopy, thoracoscopy, and tissue biopsy

Bronchoscopy is not routinely indicated in the investigation of pleural effusion. However, if the cause of an exudative effusion cannot be established, bronchoscopy can be used to exclude small malignant endobronchial lesions. Bronchoscopy should be performed after pleural fluid drainage to ensure optimum diagnostic conditions.

Thoracoscopy for diagnostic purposes is indicated if the patient is not improving, the cause of the effusion is unknown, TB is suspected, or cytology is negative when pleural malignancy is suspected. If malignancy is confirmed, then thoracoscopy can also be therapeutic and complication rates tend to be low.[12][52]​ Thoracoscopy is traditionally carried out by surgeons, but medical rigid or semi-rigid thoracoscopy is a safe, simple, and accurate alternative.[53] One meta-analysis of the usefulness of semi-rigid thoracoscopy in undiagnosed exudative pleural effusions (following thoracentesis with or without blind pleural biopsy) found a pooled sensitivity of 91%, with a specificity of 100%.[54]

Closed pleural biopsy is used after ultrasound exam in undiagnosed exudative effusions for suspected TB or malignancy when thoracoscopy is not available. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) suggest that biopsy is the definitive test for diagnosis and treatment planning of malignant pleural effusion.[55] Nonimage guided pleural biopsies should not be conducted.​[7]

Procalcitonin

Procalcitonin is now commonly used as a biomarker for the diagnosis of bacterial infections.[56][57][58]​​ Higher levels of procalcitonin have been detected in severe bacterial infections.[56][58]​ Do not order procalcitonin without an established, evidence-based protocol.[59]

It may have a function in guiding when to use antibiotics for the treatment of lower respiratory tract infection; however, this is unclear. A Cochrane review of the use of procalcitonin to guide initiation and duration of antibiotic treatment in people with acute respiratory tract infections found it lowered the risk of mortality, and led to lower antibiotic consumption and lower risk for antibiotic-related side effects in all patients.[56] Further research is required to establish its use in clinical practice. In a separate analysis of 1656 patients, 826 were randomly assigned to a group where the decision on whether to provide antibiotics was based on the results of a procalcitonin assay (830 patients were given usual care).[57] The assay results did not result in less use of antibiotics. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean 4.2 and 4.3 days, respectively; difference −0.05 days; 95% CI −0.6 to +0.5; P = 0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference −1.5 percentage points; 95% CI, −4.6 to +1.7; P <0.001 for non-inferiority) within 30 days. 

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