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Pleural effusion of undetermined etiology Author YC Gary Lee, MBChB, PhD

Section Editor Steven A Sahn, MD

Deputy Editor Helen Hollingsworth, MD

Last literature review version 17.3: September 2009 | This topic last updated: April 6, 2009 (More) INTRODUCTION — Pleural effusions can develop as a result of over 50 different pleuropulmonary or systemic disorders. The cause of a pleural effusion is not evident following diagnostic thoracentesis in up to 25 percent of patients [ 1,2] . Although no universally accepted definition exists for an "undiagnosed effusion," the evaluation and management of this condition will be reviewed here. The initial assessment of a patient with a pleural effusion is presented separately. ( See "Imaging of pleural effusions in adults" and see "Diagnostic evaluation of a pleural effusion in adults" and see "Diagnostic thoracentesis" ). HISTORY — The first step for the clinician is to revisit the patient's history, paying particular attention to drugs, occupational exposures, risk factors for pulmonary embolism or tuberculosis, and comorbid conditions. A careful drug history may reveal that the patient is taking nitrofurantoin , amiodarone , ovarian stimulation therapy, or a drug that can produce a lupus-like syndrome [ 3,4] . (See "Drug-induced lupus" ). Occupational asbestos exposure, which might suggest a benign asbestos pleural effusion, may have occurred many years earlier [ 5] . Benign asbestos effusions are usually unilateral, exudative, and about a third have an elevated eosinophil count [ 6] . Many systemic disorders (eg, lupus, hypothyroidism, amyloid, yellow nail syndrome) can cause an effusion and must not be overlooked. ( See "Pulmonary manifestations of systemic lupus erythematosus in adults" and see "An overview of amyloidosis" ). Patients with yellow nail syndrome typically have friable, yellow nails that grow slowly as well as lymphedema [7,8] . Abnormal nail fold capillaroscopy has also been reported [ 7] . Pleural fluid may originate from extrapleural sources, most commonly from transdiaphragmatic movement. A detailed history and examination for ascites and hepatic and pancreatic diseases are important. ( See "Hepatic

hydrothorax" ). TIME COURSE — Some effusions resolve spontaneously, but the time required for resolution varies depending upon the underlying etiology. Uncomplicated parapneumonic effusions and effusions from pulmonary embolism, tuberculous pleurisy, and postcardiac injury syndrome may persist for several weeks. ( See "Diagnosis of acute pulmonary embolism" and see "Parapneumonic effusion and empyema in adults" and see "Tuberculous pleural effusions in non-HIV infected patients" and see "Pleural effusions following cardiac surgery" ). Malignant pleural effusions, on the other hand, do not resolve spontaneously. ( See "Management of malignant pleural effusions" ). Benign asbestos pleural effusion, rheumatoid pleurisy, and radiation pleuritis often persist for months to years. Other effusions that may persist for years include those caused by lymphatic abnormalities (eg, yellow-nail syndrome and pulmonary lymphangiectasia) and trapped lung [ 9,10] . REANALYSIS OF PLEURAL FLUID — The pleural fluid should be analyzed carefully: vital diagnostic clues may lie in simple inspection (especially for chylous effusions) or the smell (in urinothorax), but are often overlooked. Most undiagnosed pleural effusions are exudative, because the differential diagnosis of a transudative effusion is limited and the cause can usually be recognized by the clinical presentation ( show table 1 ) (show table 2 ). A few points are worth noting when categorizing an undiagnosed effusion as a transudate or exudate: One common problem is that transudative pleural fluid from patients receiving diuretic therapy may have an elevated protein level and be mistaken as an exudate. In such cases, if the total protein gradient (serum minus pleural fluid) is greater than 3.1g/dL [ 11] , the fluid can be classified as a transudate. Alternatively, pleural fluid or serum pro-brain natriuretic peptide (proBNP) levels can be used to determine if the pleural fluid is a transudate [ 12] . (See "Diagnostic evaluation of a pleural effusion in adults" ). Constrictive pericarditis, which can be a sequel of prior cardiac surgery, infection, or remote radiation therapy, can also be difficult to diagnose. The resulting pleural effusion is typically transudative, but can be exudative with effusive constrictive pericarditis. ( See "Constrictive pericarditis" ). Effusions that are classically exudative can be transudative in some cases, particularly with malignancy [ 9,13] . (See "Diagnostic evaluation of a pleural effusion in adults" ). In patients with a lymphocytic effusion, further investigation should be considered for tuberculosis, sarcoidosis, lymphoma, and chylothorax. Pleural fluid adenosine deaminase may be helpful when tuberculosis

is suspected. Flow cytometry may be helpful in the evaluation of pleural lymphoma [ 7] . TRAPPED LUNG — The diagnosis of trapped lung should be suspected in any patient with a stable chronic pleural effusion, particularly if there is a history of pneumonia, pneumothorax, thoracic surgery, or hemothorax [ 9] . A trapped lung occurs when a remote inflammatory process causes a fibrin peel to form on the visceral pleural surface, thereby preventing the lung from expanding to the chest wall. This generates a negative pleural pressure favoring movement of fluid from the parietal pleural capillaries into the pleural space, until a new steady state is reached. Other causes of trapped lung include rheumatoid pleurisy, uremic pleurisy, tuberculosis, and malignancy. (See "Mechanisms of pleural liquid turnover in the normal state" and see "Mechanisms of pleural liquid accumulation in disease" ). DIAGNOSTIC EVALUATION — If clinical examination and pleural fluid analysis fail to result in a diagnosis, additional investigations with imaging and pleural biopsy will be needed. Bronchoscopy is rarely helpful in identifying the cause of an undiagnosed pleural effusion, unless the chest radiograph or CT show parenchymal abnormalities or the patient presents with hemoptysis [ 14-16] . Pleural pressure — Trapped lung is diagnosed in the appropriate clinical setting when the decrease in pleural pressure is at least 15 cm H20 per liter of fluid removed. The initial pleural pressure with a trapped lung is typically negative, but a positive pressure can also be observed [ 9] . (See "Diagnosis and management of trapped lung" ). Imaging — CT of the thorax with contrast should be performed in virtually all patients with an undiagnosed pleural effusion. Irregular or thickened pleura with contrast enhancement suggests pleural inflammation or malignancy and identifies optimal sites for CT guided needle aspiration or cutting needle biopsy. CT may also reveal signs of invasion of underlying or adjacent structures that would suggest malignant pleural disease. ( See "Imaging of pleural plaques, thickening, and tumors" ). CT pulmonary angiography may be considered if pulmonary embolism (PE) is a consideration, since pleural effusion is common with PE. In a study of 230 patients with pulmonary emboli, 47 percent had an effusion, all of which were exudates [ 17] . Positron emission tomography (PET)/CT has an emerging role: 18-fluorodeoxyglucose (FDG)-avidity confirms, but cannot differentiate between inflammatory and malignant disease. Focal increased uptake of FDG in the pleura and the presence of solid pleural abnormalities on CT are suggestive of malignant pleural disease. A PET-CT pattern composed of pleural uptake and increased effusion activity had an accuracy of 90 percent in predicting malignant pleural effusions in 31 patients with known extrapulmonary malignancy and a pleural effusion [ 18] . A negative PET/CT would favor a benign etiology. PET/CT may also highlight extrapleural

abnormalities that may be the cause of the effusion. Pleural biopsy — Pleural biopsy typically follows CT scan in undiagnosed pleural effusions. A number of techniques for pleural biopsy are available. Percutaneous techniques include closed pleural biopsy and CT guided cutting needle biopsy. The former is useful primarily when diseases such as tuberculosis are suspected (eg, because of a lymphocytic effusion or risk factors for TB). CT guided biopsy is useful when a pleural based mass is visible. Video assisted thoracoscopic pleural biopsy is increasingly used to diagnose malignancy when an obvious mass isn't visible on CT, when percutaneous biopsy is negative, or when patchy disease is suspected. Open pleural biopsy by thoracotomy has been used in the past [ but has been largely replaced by thoracoscopic pleural biopsy.

19] ,

Closed pleural biopsy — Closed pleural biopsy is useful in conditions where the pleura is diffusely involved (eg, TB pleuritis or non-caseating granulomata in rheumatoid pleuritis), but less so if involvement is patchy (eg, pleural malignancies). It can be considered in the setting of an undiagnosed lymphocytic effusion, particularly if the percentage of lymphocytes is greater than 80 percent. Closed pleural biopsy of the parietal pleura with a Cope or Abrams needle is operator-dependent. In a retrospective analysis of 75 patients who underwent percutaneous pleural biopsy, sufficient pleural tissue was obtained from 72 percent of patients when three samples were obtained, which increased to 80 percent with four to six samples [ 20] . For all diagnoses, the sensitivity, specificity, positive predictive value, and negative predictive values were 38, 100, 100, and 51 percent, respectively. Pneumothorax complicated 11 percent of procedures. The initial pleural biopsy in tuberculous pleuritis is positive in approximately 70 percent of cases. A greater number of biopsies taken at a single session (6 or more), or multiple, separate biopsy procedures can increase the sensitivity to 80 percent [ 21] . The combination of pleural fluid adenosine deaminase level and closed pleural biopsy may be adequate to establish a diagnosis of pleural tuberculosis [ 22] . (See "Tuberculous pleural effusions in non-HIV infected patients" ). CT guided cutting needle biopsy —CT guided cutting needle biopsy is typically used to diagnose malignancy when pleural based soft tissue masses are identified by CT scan. In a randomized trial, CT guided biopsy had a sensitivity of 87 percent (versus 47 percent with Abrams needle biopsy) in patients with suspected malignant effusions with negative cytology [23] . In another study of 85 cases, the sensitivity and specificity were 76 and 100 percent, respectively, for image guided biopsy for pleural

malignancies. A pneumothorax occurred in only 4 percent of cases [

24] .

Video assisted thoracoscopic (VATS) pleural biopsy —Thoracoscopic pleural biopsy has a diagnostic yield for malignant pleural effusions that is superior to percutaneous pleural biopsy [ 25] . Thoracoscopic pleural biopsy can also establish the diagnosis of tuberculous pleurisy, if percutaneous biopsy is non-diagnostic [ 22] . (See "An overview of medical thoracoscopy" , and see "Indications for diagnostic thoracoscopy" ). TUBERCULOUS PLEURISY — Tuberculous pleurisy affects all age groups and should not be overlooked [ 26] . An initial negative skin test does not exclude the diagnosis of pleural tuberculosis; the need for further diagnostic procedures in this setting is dictated largely by the likelihood of tuberculosis exposure. Elevated levels of pleural fluid adenosine deaminase and interferon-gamma increase the likelihood that a lymphocytic effusion is due to TB [ 27] . In PPD positive patients with an undiagnosed, lymphocyte-predominant exudate and no alternative likely etiology, empiric treatment for active tuberculosis may be considered. ( See "Tuberculous pleural effusions in non-HIV infected patients" and see "Tuberculous pleural effusions in HIV-infected patients" ). FOLLOW-UP — The cause of the pleural effusion may become obvious with follow-up of the patient [ 2,28-30] . One study monitored 143 patients who had a non-diagnostic pleural fluid analysis and pleural biopsy. Follow-up ranging from one to six years revealed that 29 (20 percent) had malignancy, and one had tuberculosis [ 28] . However, another study found neither malignancy nor tuberculosis during a mean follow-up of 33 months in 53 patients with nonspecific pleuritis [ 29] . In a retrospective study of 83 patients with undiagnosed "idiopathic" effusions, 47 resolved, 20 improved, and 16 persisted during follow-up [ 30] . Biochemical pleural fluid analysis did not predict these outcomes [ 30] . Overall, patients with idiopathic pleural effusions generally had favorable outcomes [ 2,30] . The optimal duration of follow-up has not been defined. SUMMARY AND RECOMMENDATIONS Although no universally accepted definition exists for an "undiagnosed effusion", the cause of a pleural effusion may not be evident following diagnostic thoracentesis in up to 25 percent of patients. ( See "Introduction" above ). The first step for the clinician is to revisit the patient's history, paying particular attention to drugs, occupational exposures, risk factors for pulmonary embolism and tuberculosis, and comorbid conditions. ( See "History" above ). Uncomplicated parapneumonic effusions and effusions from pulmonary embolism, tuberculous pleurisy, and postcardiac injury syndrome may

resolve spontaneously after several weeks, but malignant effusions virtually never resolve spontaneously. Benign asbestos effusions, rheumatoid pleurisy, radiation pleuritis, yellow nail syndrome, and trapped lung may persist for months to years. ( See "Time course" above ). A trapped lung occurs when a remote inflammatory process causes a fibrin peel to form on the visceral pleural surface, thereby preventing the lung from expanding to the chest wall. This can be diagnosed by measuring pleural pressure before and after fluid removal during thoracentesis; the decrease in pleural pressure is at least 15 cm H20 per liter of fluid removed. ( See "Trapped lung" above ). CT scan of the thorax with contrast should be performed in virtually all patients with an undiagnosed pleural effusion. Additional imaging modalities that may be helpful are CT pulmonary angiogram and positron emission tomography (PET)/CT scans. ( See "Imaging" above ). The decision whether to pursue more invasive procedures or simply observe the patient with an undiagnosed pleural effusion requires clinical judgment that is guided by the patient's presentation. As an example, the patient who is over 60 years of age, with abnormal CT of the pleura, is more likely to have a malignancy as the cause of an undiagnosed exudate. ( See "Diagnostic evaluation" above ). Closed pleural biopsy is most useful when the pleural abnormality is diffuse as in tuberculous pleurisy. ( See "Closed pleural biopsy" above ). CT guided cutting needle biopsy is useful when a pleural based soft tissue mass is identified by CT scan. ( See "CT guided cutting needle biopsy" above ). Video assisted thoracoscopic (VATS) biopsy is helpful for malignant effusions, because of the patchy distribution on the pleural surface, and for tuberculous effusions in the setting of a negative closed biopsy. (See "Video assisted thoracoscopic (VATS) pleural biopsy" above ). Tuberculous pleurisy can affect any age group and should not be overlooked. Clues to the diagnosis include risk factors for TB exposure and a lymphocytic effusion, especially when pleural adenosine deaminase and interferon-gamma are elevated. Empiric therapy for tuberculosis may be considered in patients with an undiagnosed, lymphocytic effusion and a positive tuberculin skin test . (See "Tuberculous pleurisy" above ). Use of UpToDate is subject to the Subscription and License Agreement .

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GRAPHICS

Causes of exudative pleural effusions Infectious Bacterial pneumonia Tuberculous pleurisy Parasites Fungal disease

Increased negative intrapleural pressure Atelectasis Trapped lung Cholesterol effusion

Connective tissue disease

Atypical pneumonias (viral, mycoplasma)

Lupus pleuritis

Nocardia, Actinomyces

Rheumatoid pleurisy

Subphrenic abscess

Mixed connective tissue disease

Hepatic abscess Splenic abscess Hepatitis Spontaneous esophageal rupture

Iatrogenic Drug-induced Esophageal perforation Esophageal sclerotherapy Central venous catheter misplacement/migration Enteral feeding tube in pleural space

Churg-Strauss syndrome Wegener's granulomatosis Familial Mediterranean Fever

Endocrine dysfunction Hypothyroidism Ovarian hyperstimulation syndrome

Lymphatic abnormalities Malignancy Chylothorax Yellow nail syndrome

Malignancy

Lymphangiomyomatosis

Carcinoma

Lymphangiectasia

Lymphoma

Movement of fluid from abdomen to pleural space

Mesothelioma

Leukemia

Pancreatitis

Chylothorax

Pancreatic pseudocyst

Paraproteinemia (multiple myeloma, Waldenstrom's macroglobulinemia)

Meigs' syndrome

Other inflammatory disorders

Chylous ascites

Carcinoma

Subphrenic abscess

Pancreatitis (acute, chronic) Benign asbestos pleural effusion

Hepatic abscess (bacterial, amebic)

Pulmonary embolism

Splenic abscess, infarction

Radiation therapy Uremic pleurisy Sarcoidosis Postcardiac injury syndrome Hemothorax Acute respiratory distress syndrome (ARDS)

Causes of transudative pleural effusions Comment Effusion always transudative Heart failure

Acute diuresis can result in pseudoexudate

Hepatic hydrothorax

Rare without clinical ascites

Nephrotic syndrome

Usually subpulmonic and bilateral

Peritoneal dialysis

Acute massive effusion develops within 48 hours of initiating dialysis

Hypoalbuminemia

Edema fluid rarely isolated to pleural space

Urinothorax

Caused by ipsilateral obstructive uropathy

Atelectasis

Caused by increased intrapleural negative pressure

Constrictive pericarditis

Bilateral effusions; may be exudative

Trapped lung

A result of remote or chronic inflammation; may be exudative

Superior vena caval obstruction

May be due to acute systemic venous hypertension or acute blockage of thoracic lymph flow

"Classic" exudates that can be transudates Malignancy

Due to early lymphatic obstruction, obstructive atelectasis, or concomitant disease (CHF)

Pulmonary embolism

23 percent incidence; due to atelectasis

Sarcoidosis

Stage II and III disease

Hypothyroid pleural effusion

From hypothyroid heart disease or hypothyroidism per se

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