Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion

INTRODUCTION — Pleural effusions can develop as a result of over 50 different pleuropulmonary or systemic disorders of both benign and malignant etiologies. Consequently, the evaluation of patients with a pleural effusion is challenging since the differential diagnosis is broad. Making a prompt diagnosis is important so that serious conditions such as malignancy and tuberculosis are not missed.

This topic will provide an overview the diagnostic approach to a pleural effusion including the indications for thoracentesis. It will not include evaluation of the unstable patient with traumatic hemothorax. Pleural effusion imaging, pleural fluid analysis, and evaluation of traumatic hemothorax are discussed separately. (See "Ultrasound-guided thoracentesis" and "Imaging of pleural effusions in adults" and "Pleural fluid analysis in adults with a pleural effusion" and "Initial evaluation and management of blunt thoracic trauma in adults", section on 'Hemothorax'.)

INITIAL APPROACH

History and examination — The history and examination are critical for narrowing the differential and deciding what pleural fluid biomarkers should be obtained for initial pleural fluid analysis. Although pleural effusion has a wide array of etiologies, large series have shown that cancer, heart failure, and parapneumonic infections account for most cases [1]. Thus, we pay particular attention to comorbid conditions (particularly congestive heart failure) but also underlying lung disease and risk factors that might predispose a patient to pneumonia, tuberculosis (TB), and lung cancer.

●Comorbid conditions – We inquire about any heart, liver, or renal disease that may predispose patients to a pleural effusion due to fluid overload. We also inquire about lung conditions that may predispose a patient to parapneumonic effusion or malignant pleural effusion (eg, chronic bronchitis, bronchiectasis, immune deficiency).

The patient may have a known disorder that may raise the suspicion for other less common causes of a pleural effusion including systemic lupus erythematosus (pleuritic exudate), hypothyroidism (transudative pleural effusion), amyloidosis (exudative pleural effusion), pancreatitis (amylase-rich pleural effusion), lymphangioleiomyomatosis (chylous effusion), rheumatoid arthritis (cholesterol effusion), and immunoglobulin G4 (pleuritic exudate). (See "Pulmonary manifestations of systemic lupus erythematosus in adults" and "Overview of amyloidosis".)

When the pleural effusion is large or underling lung disease is severe, it may be difficult to distinguish symptoms due to an underlying pulmonary cause from those due to the pleural effusion. For example, dyspnea, cough, and chest pain can occur with a pleural effusion and underlying pneumonia. However, the contribution of pleural disease may be more apparent after therapeutic thoracentesis. (See "Ultrasound-guided thoracentesis".)

●Signs and symptoms of pneumonia or tuberculosis – We ask about symptoms of a respiratory tract infection such as cough, sputum production, hemoptysis, fever, history of aspiration, immunosuppression (eg, human immunodeficiency virus [HIV]).

We inquire about exposure to TB, travel to countries where TB is endemic, or past history of TB.

A recent history of pneumonia (eg, in the prior 6 months) should raise the suspicion for nonexpandable lung due to an undiagnosed parapneumonic pleural effusion that is undergoing organization. Slowly resolving pneumonia should also raise the suspicion for a malignant pleural effusion. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

A recent history of vomiting in a patient who is sick with suspected aspiration pneumonia may raise the suspicion for a ruptured esophagus due to Boerhaave syndrome (amylase-rich pleural effusion).

●Symptoms of or risk factors for malignancy – The patient may have a known history of active cancer or be receiving medications that can cause a pleural effusion. We ask about hemoptysis, weight loss, fatigue, night sweats, smoking, change in bowel habit, breast lumps, recent mammography, or skin abnormalities.

Other pertinent questions are focused on less common etiologies and may or may not be apparent on initial presentation. These include the following:

●Drug and occupational history – 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 (eg, hydralazine) [2,3]. (See "Drug-induced lupus".)

Patients may also be taking immunotherapy and have immunotherapy-related pleural effusion [4]. (See "Toxicities associated with immune checkpoint inhibitors".)

We inquire about potential asbestos exposure, which might suggest mesothelioma or a benign asbestos pleural effusion, even if exposure may have occurred many years earlier [5].

●Recent procedures – Recent procedures should prompt the clinician to suspect procedure-related pleural effusion such as central line insertion (catheter misplacement), bladder washes (glycinothorax), urinary or biliary intervention (urino- and bilo-thorax, respectively), cerebrospinal fluid (CSF) shunt placement (CSF shunt-related pleural effusion), or thoracoabdominal surgery (fluid overload, hemorrhage, cardiac surgery-related pleural effusion).

●Potential extra-pleural sources – Pleural fluid may originate from extrapleural sources, most commonly from transdiaphragmatic movement. A detailed history and examination for ascites (hepatic hydrothorax) and urinary tract obstruction (urinothorax) are important. Patients receiving peritoneal dialysis (PD) are at risk of developing a PD-related pleural effusion (table 1). (See "Pleural effusion of extra-vascular origin (PEEVO)".)

●Miscellaneous – Rare etiologies are often not initially apparent but may be considered after the initial pleural fluid analysis suggests a possible etiology (eg, milky fluid may suggest chylothorax (table 2)).

The patient may have a recent history of falls, which may prompt suspicion for hemothorax or a history of aggressive fluid resuscitation for shock or sepsis, which may suggest fluid overload.

Advanced thoracic imaging — In most patients, we perform advanced thoracic imaging, particularly bedside thoracic ultrasound, which is now widely available. Point-of-care thoracic ultrasonography can rapidly provide information on effusion size and the presence of loculations or pleural masses. Further information on thoracic ultrasonography is provided separately. (See "Bedside pleural ultrasonography: Equipment, technique, and the identification of pleural effusion and pneumothorax" and "Indications for bedside ultrasonography in the critically ill adult patient".)

While chest computed tomography (CT) is not necessary in every case of pleural effusion, it is useful in the following scenarios [6]:

●When the etiology is not obvious

●When the pleural effusion appears complex and loculated

●When malignancy or other diseases more apparent on CT are suspected (eg, lymphangioleiomyomatosis [LAM])

When CT is indicated, we typically obtain pleural-phase contrast enhancement scans. 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. (See "Imaging of pleural plaques, thickening, and tumors".)

Chest CT may also reveal underlying abnormalities that are directly related to the etiology of the pleural effusion and help narrow the differential. These include conditions such as a lung mass, hilar or mediastinal lymphadenopathy, pneumonic consolidation, cystic lung diseases, or old TB calcification patterns.

CT is also valuable in detecting extra-pulmonary clues to the causes of pleural effusions, such as fractured ribs, pericardial effusions (often obscured by pleural effusion on chest radiographs), esophageal abnormalities, ascites, and pathologies in upper abdominal organs (eg, pancreas).

THORACENTESIS INDICATIONS AND CONTRAINDICATIONS — Thoracentesis is a percutaneous procedure where pleural fluid is removed either through a needle (typically for small volumes [eg, <30 mL]), needle over catheter system, or a small-bore catheter. The location for this procedure is most often bedside in an inpatient setting, but the same technique can be used for those in an emergency room, operating room, or outpatient setting. Although referral of patients to interventional radiology services for image-guided thoracentesis may be convenient, referral is more costly and no safer than performing ultrasound-guided thoracentesis in the clinic or at the bedside by appropriately trained clinicians [7].

Indications — Thoracentesis may be diagnostic and/or therapeutic:

●Diagnostic (new effusion of unclear etiology) – Most patients who have a newly detected pleural effusion of unclear etiology should undergo diagnostic thoracentesis to determine the nature of the pleural effusion (ie, transudate, exudate) and to identify potential causes.

The exceptions are when there is only a small amount of pleural fluid with a secure clinical diagnosis (eg, pneumonia) or when there is clinically obvious congestive heart failure (CHF) with typical features (eg, bilateral pleural effusions and pulmonary edema) [8].

In a patient with suspected CHF, atypical features that should prompt consideration of diagnostic thoracentesis include the following:

•Features that suggest an alternate etiology for the effusion (eg, unilateral or bilateral effusions of significantly disparate sizes, especially if the effusion on the left is larger than on the right)

•Symptoms of pleurisy or fever

•Features suggestive of infection or cancer

•An echocardiogram that is not consistent with CHF

•A disproportionately wide alveolar-arterial oxygen gradient

•The lack of resolution with effective CHF therapy

For patients with pleural effusions who do not undergo thoracentesis, we follow them clinically and the effusion is followed radiologically. We have a low threshold to perform thoracentesis if the effusion does not respond as anticipated. This approach is based upon the rationale that up to one-third of patients with a clinically apparent cause of a pleural effusion, such as heart failure, have more than one etiology that can be readily distinguished by pleural fluid analysis (eg, heart failure plus either pneumonia or pulmonary embolism) [9].

●Therapeutic (symptom relief) – Therapeutic thoracentesis is commonly performed for symptom relief (eg, dyspnea) or if the fluid has imaging characteristics of a complicated pleural effusion (eg, loculations suggesting a parapneumonic pleural effusion). (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Choosing between a one-time therapeutic thoracentesis or insertion of a small-bore chest tube or catheter for one or more days is dependent upon patient-related factors including effusion size and character (loculated or free flowing), the need for complete drainage, institutional factors, operator preference, and availability of expertise.

●Prevention of complications – Thoracentesis is also indicated for patients with pleural conditions that risk pleural thickening and restrictive functional impairment, should they not be drained. Examples include pleural effusions due to post-primary or reactivation tuberculosis and hemothorax.

Contraindications — Contraindications to thoracentesis include the following:

●Insufficient pleural fluid – Thoracentesis is not justified for small free-flowing pleural effusions because of the low diagnostic yield and high risk of pneumothorax. The "safe window" for thoracentesis on ultrasonography has been estimated as a point where maximum pleural fluid depth is >1 cm adjacent to the parietal pleura [10]. (See "Ultrasound-guided thoracentesis", section on 'Locating fluid'.)

●Skin infection or wound at the needle insertion site – Active skin infection at the point of needle insertion is a contraindication due to the risk of introducing pleural space infection.

●Severe bleeding diathesis – It is not clear whether a bleeding diathesis should be corrected prior to the procedure or whether any specific laboratory result represents excessive bleeding risk that serves as a contraindication to thoracentesis [11-13].

While older retrospective series demonstrated increased risk of bleeding in patients with a coagulopathy (eg, International Normalized Ratio [INR] >2), thrombocytopenia (platelet count <50,000 platelets/mm³), or a serum creatinine concentration >6 mg/dL [14], case series performed in the era of ultrasound guidance do not demonstrate an increased risk of bleeding in these settings in most patients [11,15-18].

In the absence of data, decisions to reverse the coagulopathy or correct the thrombocytopenia should be individualized and based on perceived benefit-to-risk ratios and urgency of thoracentesis. The benefits should be weighed against the probability of bleeding into the pleural space as well as the ability of a patient to tolerate a hemothorax and a procedure to drain intrapleural blood, should that be needed. For instance, for patients with an indication that represents an urgent need for pleural fluid analysis, such as possible acute hemothorax, we proceed quickly to thoracentesis without correcting a bleeding diathesis. In contrast, if pleural fluid analysis is not immediately needed, such as for a patient with suspected pleural malignancy, we reverse a coagulopathy when the INR is >1.5 or administer platelets when the platelet count is <50,000 platelets/mm³.

Mechanical ventilation is not considered a contraindication to thoracentesis. While patients receiving mechanical ventilation who undergo ultrasound-guided thoracentesis may be at increased risk of pneumothorax, particularly tension pneumothorax [17,19-21], the rate is low. The use of positive end-expiratory pressure does not increase pneumothorax risk [19] (see "Ultrasound-guided thoracentesis", section on 'Complications'). However, the consequences of developing a post-procedural pneumothorax will be more significant in a patient already requiring ventilatory support. This needs to be factored into the benefit-to-risk calculation.

The technique of performing ultrasound-guided thoracentesis is provided separately. (See "Ultrasound-guided thoracentesis".)

INITIAL PLEURAL FLUID ANALYSIS — For patients who undergo diagnostic thoracentesis, we obtain general biomarkers (eg, cell counts and cell differential, total protein, lactate dehydrogenase, glucose, cholesterol) and condition-specific pleural fluid biomarkers (eg, pleural fluid culture and Gram stain when infection is suspected, cytology if malignancy is suspected, lipid analysis if chylothorax is suspected). Initial general and specific biomarkers that should be obtained and their interpretation are discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion".)

MAKING A PRELIMINARY DIAGNOSIS — In most patients, a diagnosis can be achieved using an approach that combines clinical evaluation and imaging with comprehensive pleural fluid analysis. Occasionally, a second thoracentesis may be needed for pleural fluid analysis especially when the first analysis increases the suspicion for a select diagnosis and additional condition-specific diagnostic markers need to be obtained (table 3).

The diagnosis is typically easily made in patients who clearly have a transudative (table 4) or an exudative (table 5) pleural effusion with positive condition-specific biomarkers in the right clinical setting. Common diagnoses that are made using this approach are listed in the tables (table 6 and table 7).

However, in some patients, the diagnosis is not clear and further evaluation is needed. This evaluation is provided below. (See 'Additional evaluation for unclear etiology' below and 'Etiology remains undetermined' below.)

ADDITIONAL EVALUATION FOR UNCLEAR ETIOLOGY — The cause of a pleural effusion is not evident in an estimated one-quarter of patients despite clinical evaluation and pleural fluid analysis [22]. The numbers vary among series significantly because it depends on the setting and patient population studied. These patients are often deemed as having an "undiagnosed pleural effusion," although no universally accepted definition exists for these patients. In this group of patients, the etiologic diagnosis can be challenging. As such, subspecialty consultation with a pulmonologist is reasonable to assess the need for all or any of the following options:

●We typically rereview the history and examination and reanalyze the pleural fluid. (See 'Retake the history and examination' below and 'Reanalyze pleural fluid' below.)

●If indicated, we perform additional imaging targeted at confirming suspected etiologies or excluding serious etiologies (eg, positron emission tomography [PET] or CT pulmonary angiography). (See 'Consider additional imaging' below.)

●If the etiology still remains undetermined at this point, we typically perform a pleural biopsy with the goal of confirming or excluding serious pathologies that can be diagnosed on pleural biopsy, such as cancer or tuberculosis (TB). (See 'Pleural biopsy' below.)

Retake the history and examination — For patients with pleural effusion of undetermined etiology, we rereview the history and examination to find etiologic clues that were potentially overlooked. We also consider the possibility of uncommon or rare etiologies (eg, yellow nail syndrome, lymphatic diseases, cholesterol effusion, and chylothorax). These details are provided above. (See 'History and examination' above.)

Reanalyze pleural fluid — This may involve recalculation of the criteria used to distinguish transudative (table 4) and exudative (table 5) effusions. This recalculation is particularly important in patients with results that are borderline or discordant (with clinical suspicion or each other). Reanalysis may also involve adding condition-specific biomarkers if needed and/or reanalyzing a fresh sample of pleural fluid.

●Distinguishing transudative and exudative effusions – Interpretation of pleural fluid biochemistry must take into consideration the clinical context. This is especially the case when pleural fluid analysis is borderline for transudate/exudate parameters and/or discordant with the clinical suspicion (eg, exudate in a patient with classic features of heart failure). In these circumstances, we use additional pleural fluid tests (eg, using a different formula or biomarker) and imaging analyses in conjunction with clinical judgment to distinguish transudative from exudative causes of pleural effusions.

For example, in patients with cardiac failure receiving diuretic therapy, the transudative pleural fluid may have an elevated protein level and be mistakenly classified as an exudate. Calculating a serum-to-pleural fluid gradient for albumin or protein may reclassify the effusion as a transudate. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Albumin and protein gradients'.)

In patients with borderline or discrepant results, we also consider the possibility that the pleural effusion has more than one cause [23]. One study of 130 patients with a unilateral pleural effusion found that 30 percent had more than one cause for the effusion [9]. If those causes contain concomitant transudative and exudative etiologies (eg, malignancy in a patient with heart failure), the resultant effusion can either be a transudate (table 4) or exudate. In such cases, it may not be possible to clearly distinguish a transudate from an exudate and additional biomarkers and/or pleural biopsy may be needed for diagnosis.

It is also important to note that in some cases of malignant pleural effusion, a proportion present with transudative effusion (eg, up to 10 percent), perhaps because there is another etiology for the effusion or because pleural involvement is early or minimal.

Further details regarding distinguishing transudative from exudative effusions are provided separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Classification as exudative or transudative'.)

●Add condition-specific biomarkers, when indicated – We consider obtaining additional specific biomarkers when the suspicion for a diagnosis becomes more apparent after the initial thoracentesis. As examples:

•When heart failure is suspected but the pleural fluid is borderline exudative, some experts measure the total protein or albumin gradient. While obtaining pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) is sometimes performed in this population, measuring pleural NT-proBNP has no added value over serum values. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Suspected heart failure-related pleural effusion'.)

•Similarly, if a cholesterol or chylous effusion is suspected, we obtain pleural fluid triglycerides and cholesterol levels and consider definitive tests such as chylomicrons (chylous effusion) and microscopic examination for cholesterol crystals (cholesterol effusion). (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Suspected chylous or cholesterol effusion'.)

•In patients with a lymphocytic effusion, further investigation should be considered for TB (eg, adenosine deaminase), lymphoma (cytometry, flow cytometry), chylothorax (triglycerides), and pseudochylothorax (cholesterol) [24]. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Interpreting individual biomarkers'.)

Specific biomarkers for select suspected conditions are discussed in more detail separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Condition-specific biomarkers'.)

●Repeat pleural fluid analysis – In some patients, repeating pleural fluid analysis is helpful if additional tests are needed (especially involving tests that cannot be performed on stored fluid). As examples:

•Repeating pleural fluid cytology may increase the chances of obtaining a diagnosis of a malignant pleural effusion modestly, although the yield may differ among cancer types. For example, pleural fluid analysis may be more useful in adenocarcinoma than in sarcoma or renal cell carcinoma. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases' and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)'.)

•Fresh sample may also be needed for repeat microbiologic culture and pH in patients with suspected parapneumonic effusion or flow cytometry in patients with suspected lymphoma. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis'.)

Consider additional imaging — In patients in whom a pleural effusion is suspected to be due to pulmonary embolism (PE), we perform imaging targeted at diagnosing PE (eg, CT pulmonary angiography). Two studies of 60 [25] and 230 [26] patients with PE showed that 47 to 48 percent had a pleural effusion, the majority of which were small and did not require drainage. Large effusions should alert clinicians to alternative or additional causes of fluid formation other than PE.

PET/CT may be indicated when malignancy is suspected, although a negative PET/CT does not exclude malignancy nor does a positive one confirm it [27]. Suspicious findings may help guide biopsy. PET/CT may also highlight extrapleural abnormalities that may be associated with the cause of the effusion (eg, bony metastases).

Ultrasonography can be helpful in the etiologic evaluation of pleural effusion and help guide biopsy under direct image-guidance. Pleural nodularity and thickening of the diaphragm (>7 mm) and pleura (>1 cm) are strong predictors of malignant pleural diseases with a positive predictive value of 100 percent if all are present [28]. (See 'Pleural biopsy' below.)

Magnetic resonance imaging may be useful when examining chest wall invasion by local tumors [29].

Imaging of the pleura is discussed in detail separately. (See "Imaging of pleural effusions in adults" and "Imaging of pleural plaques, thickening, and tumors" and "Bedside pleural ultrasonography: Equipment, technique, and the identification of pleural effusion and pneumothorax", section on 'Identification of malignant pleural disease'.)

ETIOLOGY REMAINS UNDETERMINED — If the etiology still remains undetermined following additional evaluation, we typically perform a pleural biopsy. The major goal of a pleural biopsy is to confirm or exclude serious conditions that can be diagnosed pathologically, such as cancer (including mesothelioma), tuberculosis (TB), or other infection.

Pleural biopsy

Choosing biopsy mode — A number of techniques for pleural biopsy are available. These include CT-guided (or ultrasound-guided) pleural biopsy, thoracoscopic pleural biopsy, closed pleural biopsy, and open pleural biopsy. Choosing among the available options is dependent upon factors including the suspected etiology, local expertise, and type of pleural involvement (eg, focal or diffuse, mass or ill-defined thickening). Open pleural biopsy by thoracotomy and closed pleural biopsy have been largely replaced by image-guided or thoracoscopic techniques [30]. In general, definitive diagnosis is more likely with thoracoscopic biopsy and is widely used. However, in communities where TB is endemic and tuberculous involvement is likely to be diffuse, closed biopsy is still commonly used. Data to support one of the other varies depending on the patient population being studied and the skill of the operator.

Diffuse pleural involvement: Closed pleural biopsy — For patients with conditions where the pleura is likely to be diffusely involved (eg, tuberculous or rheumatoid pleuritis), a closed pleural biopsy is useful. For patients in whom the pleural disease process is expected to be patchy, such as suspected malignant pleural effusions, we do not use a closed pleural biopsy since the yield is likely to be low. In general, multiple biopsies are performed to increase the diagnostic yield of the study (eg, four or fewer biopsies). If this expertise is not available and the disease thought to be diffuse, then image-guided or thoracoscopics pleural biopsy can be used to obtain pleural tissue.

Limited data and our experience support the value of closed pleural biopsy in patients suspected to have diffusely involved pleural disease. In a randomized trial of 89 patients with suspected TB pleuritis, closed pleural biopsy using an Abrams needle (of at least four tissue pieces) and ultrasound guidance yielded pleural tissue in 91 percent of cases and successfully diagnosed TB pleuritis in 82 percent of patients, which was superior to closed pleural biopsy using Tru-Cut needles (78 and 65 percent, respectively) [31]. In another trial the sensitivity of a closed biopsy using an Abrams needle was lower at 47 percent [32].

Pleural mass or thickening: Image-guided pleural biopsy — In patients whose pleural effusion is associated with pleural-based abnormalities (eg, pleural-based mass or thickening), we typically prefer image-guided biopsy since it has a higher yield than closed (blinded) percutaneous biopsy. The choice between ultrasound- and CT-guidance depends on local expertise and availability as well as patient factors.

Limited data support image-guided biopsy in patients with undiagnosed pleural effusion and pleural-based abnormality:

●Ultrasonography – In a randomized study of 150 patients with undiagnosed pleural effusion, ultrasound-guided biopsy had a sensitivity of 67 percent compared with 82 percent using CT-guided Abrams needle biopsy [33]. In contrast, in 196 patents with suspected TB pleuritis, ultrasound-guided pleural biopsy had similar diagnostic sensitivity as thoracoscopy (82 versus 90 percent), likely due to the diffuse nature of the disease [34].

●CT – A randomized trial of 124 patients with suspected malignant pleural diseases showed that CT-guided biopsy had a yield of 88 percent compared with 94 percent with thoracoscopy [35]. In another randomized trial of 50 patients with a pleural effusion and pleural thickening suspected to be malignant, the sensitivity of CT-guided cutting needle biopsy was greater than that of a closed Abrams biopsy (87 percent versus 47 percent) [32].

The efficacy of CT-guided biopsy in the setting of suspected cancer is discussed separately. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases'.)

Patchy pleural involvement: Thoracoscopic pleural biopsy — In patients whose pleural effusion is not associated with an obvious mass on CT or when percutaneous biopsy is negative or patchy disease is suspected, we typically prefer thoracoscopic pleural biopsy, especially when malignancy is suspected. When compared with closed or image-guided biopsy, thoracoscopy has the advantage of visual inspection and targeted biopsy of visually abnormal regions of the pleura. (See "Medical thoracoscopy (pleuroscopy): Equipment, procedure, and complications" and "Medical thoracoscopy (pleuroscopy): Diagnostic and therapeutic applications", section on 'Diagnostic evaluation of an exudative pleural effusion of unknown etiology'.)

Thoracoscopic pleural biopsy, in the form of video-assisted thoracoscopic surgery or pleuroscopy (also called medical thoracoscopy), has a diagnostic yield for malignant pleural effusions that is superior to percutaneous pleural biopsy [35,36]. However, a negative thoracoscopic biopsy does not fully exclude malignant pleural disease, especially mesothelioma and rarely, may need to be repeated to increase the chances of yielding a positive result. These data are discussed separately. (See "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases'.)

Biopsy results — Some biopsy findings provide a clear diagnosis. For example, microorganisms found on tissue specimens or tissue culture may confirm parapneumonic effusion while malignant cells confirm malignant pleural effusion.

Some pathologic findings found on pleural biopsy may be nondiagnostic but support the clinical suspicion (eg, noncaseating granulomas [sarcoidosis, rheumatoid pleuritis], pleuritis [connective tissue disease]). As such, they may not warrant additional testing or follow-up.

It should be emphasized that "chronic fibrinous pleuritis" and "nonspecific pleuritis" are descriptive pathologic terms and should not be considered a clinical diagnosis. We consider these patients as having an undiagnosed pleural effusion and manage them as such. Some are eventually diagnosed with malignancy during follow-up [37,38]. (See 'Follow-up and outcomes' below.)

Follow-up and outcomes — In many cases, an etiology is not identified, even after extensive investigations, including pleural biopsy. In this population, we observe both the patient and the effusion closely, paying attention to identifying "treatable" causes of a pleural effusion (eg, tuberculosis, lymphoma) [39]. We typically start with clinical evaluation and chest radiography in two to three weeks, sooner if the patient has new or progressive symptoms. We then follow the patient thereafter until the effusion improves, resolves, stabilizes, or worsens. The British Thoracic Society suggests follow-up for up to two years in patients with a undiagnosed pleural effusion [8].

●Improvement or resolution – If the pleural effusion improves without specific treatment, we continue to observe until complete resolution.

Overall, patients with idiopathic pleural effusions generally have favorable outcomes [40,41]. Many cases resolve or improve spontaneously, but the time required for resolution varies depending upon the underlying etiology while others persist and remain without a clear etiology [40-45]. In a retrospective study of 83 patients with undiagnosed "idiopathic" effusions, 57 percent resolved and 24 percent improved, and 19 percent persisted during follow-up [41]. Biochemical pleural fluid analysis did not predict these outcomes.

In such cases, a viral etiology is often presumed [46] but rarely proven. For example, in patients with coronavirus disease 2019 (COVID-19) who had a pleural effusion, most spontaneously improved and none demonstrated any evidence of the virus in pleural fluid [47]. (See "COVID-19: Clinical features", section on 'Imaging findings'.)

Uncomplicated parapneumonic effusions and effusions from pulmonary embolism, tuberculous pleurisy, and postcardiac injury syndrome may persist for several weeks. 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 those associated with nonexpandable lung [48,49]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults" and "Tuberculous pleural effusion" and "Evaluation and management of pleural effusions following cardiac surgery" and "Diagnosis and management of pleural causes of nonexpandable lung".)

●Progression or stable effusion – Among patients without a clear etiology, only a small proportion of patients develop a persistent or worsening pleural effusion (eg, <20 percent) during follow-up [41]. If patients show signs of symptomatic or radiologic progression, we typically repeat the evaluation most often beginning with repeat CT and pleural fluid analysis, followed by biopsy, if necessary. For patients with a stable pleural effusion during follow-up, we continue observation.

In a small proportion of patients, the cause of the pleural effusion may become obvious during follow-up, although the diagnoses are variable (eg, malignancy, tuberculosis). In one series of 53 patients who had nonspecific pleuritis after pleural fluid analyses and thoracoscopic biopsies, almost half received a diagnosis in the subsequent two years, typically parapneumonic effusion and congestive heart failure; only a small proportion (4 percent) were diagnosed with malignancy [44]. In another series of 52 patients with nonspecific pleurisy on thoracoscopic biopsy, a malignant diagnosis was revealed in 15 percent after a median follow-up of 35.5 months while 44 percent had benign disease [45].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pleural effusion".)

SUMMARY AND RECOMMENDATIONS

●Initial approach – Pleural effusions can develop as a result of over 50 different pleuropulmonary or systemic disorders of both benign and malignant etiologies. (See 'Initial approach' above.)

•We take a detailed history, perform a thorough examination, and obtain necessary imaging targeted at the most common etiologies, which are cancer, heart failure, and parapneumonic infections. We also pay attention to identifying other potential etiologies, including: comorbid conditions; drugs; occupational exposures; risk factors for pulmonary embolism, tuberculosis (TB), and malignancy; recent procedures; and extrapleural sources for a pleural effusion. This assessment is critical for narrowing the differential and deciding what pleural fluid biomarkers to obtain for initial pleural fluid analysis. (See 'History and examination' above and 'Advanced thoracic imaging' above.)

•Most patients who have a newly detected pleural effusion of unclear etiology should undergo diagnostic thoracentesis (eg, 50 mL). Exceptions include congestive heart failure with typical features, insufficient pleural effusion volumes, and the presence of contraindications. For patients with a moderate to large symptomatic pleural effusion, we suggest withdrawing a larger volume for symptom relief (Grade 2C). (See 'Thoracentesis indications and contraindications' above.)

•We obtain routine pleural fluid biomarkers (eg, cell counts and cell differential, total protein, lactate dehydrogenase, glucose, cholesterol) as well as select condition-specific pleural fluid biomarkers (eg, pleural fluid culture and Gram stain when infection is suspected, cytology if malignancy is suspected, lipid analysis if chylothorax is suspected). The selection and interpretation of pleural fluid biomarkers are discussed separately. (See 'Initial pleural fluid analysis' above and "Pleural fluid analysis in adults with a pleural effusion".)

●Preliminary diagnosis – In most patients, clinical findings together with chest imaging and pleural fluid analysis (usually one, sometimes two thoracenteses) are generally sufficient to make a preliminary diagnosis. The diagnosis is typically easily made in patients who clearly have a transudative (table 4) or an exudative (table 5) pleural effusion with positive condition-specific biomarkers in the right clinical setting. Common diagnoses that are made using this approach are listed in the tables (table 6 and table 7).

●Additional evaluation for undiagnosed pleural effusion – The cause of a pleural effusion is not evident in more than a quarter of patients after initial pleural fluid analysis. In such patients, subspecialty consultation with a pulmonologist is reasonable to assess the need for all or any the following options:

•Retake the history and examination and reanalyze the pleural fluid – We typically rereview the history and examination, consider the possibility of uncommon or rare etiologies, and reanalyze the pleural fluid. Reanalyzing the pleural fluid may involve recalculation of the parameters that distinguish transudative and exudative effusions, particularly in patients with borderline or discrepant results. It may also involve adding condition-specific biomarkers, if needed (eg, amylase for suspected pancreatic effusion), and/or reanalyzing a fresh sample of pleural fluid (eg, repeat cytology for suspected malignant pleural effusion). (See 'Retake the history and examination' above and "Pleural fluid analysis in adults with a pleural effusion", section on 'Condition-specific biomarkers' and "Pleural fluid analysis in adults with a pleural effusion", section on 'Classification as exudative or transudative' and 'Reanalyze pleural fluid' above.)

•Additional imaging – If indicated, we perform additional imaging targeted at confirming suspected etiologies or excluding serious etiologies (eg, positron emission tomography or CT pulmonary angiography). (See 'Consider additional imaging' above and "Imaging of pleural effusions in adults" and "Imaging of pleural plaques, thickening, and tumors".)

•Pleural biopsy – If the etiology still remains undetermined at this point, we typically perform a pleural biopsy with the goal of confirming or excluding serious conditions that can be diagnosed pathologically, such as cancer or TB. (See 'Pleural biopsy' above.)

-Choosing among the available options is dependent upon factors including the suspected etiology, local expertise, and type of pleural involvement (eg, focal or diffuse, mass or ill-defined thickening). (See 'Choosing biopsy mode' above.)

-Some biopsy findings are diagnostic (eg, cancer cells that indicate malignant pleural effusion) while others are nonspecific findings that may support the clinical suspicion (eg, noncaseating granulomas [sarcoidosis, rheumatoid pleuritis], pleuritis [connective tissue disease]). (See 'Biopsy results' above.)

•Follow up – For patients in whom an etiology is not identified despite extensive investigation, we observe the patient and the effusion closely for up to two years. We typically start with clinical evaluation and chest radiography in approximately two to three weeks, sooner if patients have new or progressive symptoms. (See 'Follow-up and outcomes' above.)

-If the pleural effusion improves without specific treatment, we continue to observe until complete resolution. Approximately three-quarters of patients resolve or improve and are often presumed to have a viral pleuritis or other benign condition.

-If patients show signs of progression, we typically repeat the evaluation, most often beginning with repeat chest CT and pleural fluid analysis, followed by biopsy, if necessary. Almost half of these patients receive a diagnosis during follow-up, although the diagnoses are variable (eg, malignancy, tuberculosis).