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Pleural fluid analysis in adults with a pleural effusion

Pleural fluid analysis in adults with a pleural effusion
Literature review current through: Jan 2024.
This topic last updated: May 11, 2023.

INTRODUCTION — Thoracentesis with imaging guidance is a bedside or outpatient clinic procedure that permits pleural fluid to be rapidly sampled, visualized, and analyzed for chemical, microbiologic, and cellular content. A systematic approach to analysis of the fluid assists clinicians in narrowing the differential diagnosis or establishing the cause of an effusion. In addition to its diagnostic value, pleural fluid analysis also has predictive value (ie, estimates of the likelihood of a clinical response to pleural fluid drainage) and prognostic value (eg, likelihood of disease recurrence or progression in malignant pleural effusion).

The initial approach to pleural fluid analysis will be presented here. An initial approach to pleural effusions of uncertain etiology, pleural imaging, and the technique of thoracentesis are discussed separately. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and "Imaging of pleural effusions in adults" and "Ultrasound-guided thoracentesis".)

The diagnostic approach in specific patient populations is also discussed separately:

(See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

(See "Tuberculous pleural effusion".)

(See "Etiology, clinical presentation, and diagnosis of chylothorax".)

(See "Evaluation and management of pleural effusions following cardiac surgery".)

(See "Pleural effusion of extra-vascular origin (PEEVO)".)

(See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases'.)

(See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases'.)

(See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions" and "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Suspected pleural metastases'.)

(See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Thoracentesis'.)

(See "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pleural disease'.)

INDIVIDUALIZING THE APPROACH — For all patients with a pleural effusion, we perform initial pleural fluid analysis for the following:

Routine laboratory biomarkers (all patients). (See 'Routine pleural fluid biomarkers' below.)

Specific biomarkers when a specific disease is suspected based on clinical findings or gross fluid appearance. (See 'Condition-specific biomarkers' below.)

Concurrent serum tests, which are needed in some patients. (See 'Concurrent serum testing' below.)

Our approach considers the likely cause(s) of a pleural effusion and performs a comprehensive assessment early in the process to evaluate those potential causes. In our opinion, this reduces the time to diagnosis, decreases the need for repeat thoracentesis, and leads to prompt management. Several diagnoses can be established definitively by thoracentesis, which are listed on the table (table 1) [1].

Routine pleural fluid biomarkers — For every patient with a pleural effusion, we routinely perform all of the following tests on initial pleural fluid samples:

Cell counts and cell differential (see 'Cell counts and cell differential' below)

Total protein (see 'Total protein' below)

Lactate dehydrogenase (LDH) (see 'Lactate dehydrogenase' below)

Glucose (see 'Glucose' below)

Cholesterol (see 'Cholesterol' below)

Some experts also perform pleural fluid culture, Gram stain, and cytology, especially when pleural infection or malignancy appear possible diagnoses.

Some clinicians may not perform pleural fluid cholesterol routinely if they use Light's criteria to classify pleural effusions as exudative or transudative but should order concurrent serum LDH and protein levels instead. (See 'Classification as exudative or transudative' below and 'Light's criteria (three-test combination rule)' below.)

Condition-specific biomarkers — In select cases, we perform additional disease-specific biomarkers. We prefer that these be done at the time of the initial thoracentesis when the suspicion is strong enough to warrant them. However, when the suspicion for a specific condition has increased as a result of initial pleural fluid or other testing, some condition-specific biomarkers may be performed on an existing sample, while others may need a repeat thoracentesis. The latter approach is associated with diagnostic delay. For example, it has been shown that it may take a median of 26 days to receive a diagnosis of malignant pleural effusion (MPE) [2].

Suspected heart failure-related pleural effusion — In patients with pleural effusions suspected to be due to congestive heart failure (CHF), we do not routinely perform additional testing over and above routine tests unless the diagnosis is in doubt.

CHF-related pleural effusions are typically transudative (table 2). However, 25 to 30 percent of patients with CHF have their pleural effusion misclassified as exudative by combination test criteria, such as Light's criteria (see 'Light's criteria (three-test combination rule)' below). This misclassification is thought to be due to performance of thoracentesis after initial diuresis, elevated erythrocytes in the pleural space (the latter increases the LDH level), and/or inherent limitations of approaches to classifying pleural effusions [3-7]. In such cases, we measure the following:

Albumin or total protein gradient – Calculation of the serum-to-pleural fluid albumin or protein gradient may help distinguish a transudate from an exudate. (See 'Albumin and protein gradients' below.)

Although not performed by us, some clinicians also additionally perform pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP), although the diagnostic utility is no better than that of serum NT-proBNP. (See 'N-terminal pro-BNP' below.)

Suspected parapneumonic effusion or empyema — For patients with a suspected parapneumonic effusion (eg, cough, fever, radiograph infiltrates), we obtain the following:

pH – Pleural fluid for pH should be drawn directly from the pleural space (typically into an arterial blood gas syringe), placed immediately on ice, and measured within one hour in a blood gas analyzer [8-10]. Of note, mixing pleural fluid with air, lidocaine (from the anesthetic needle or syringe), or an excess of heparin can alter the measured pH. (See 'pH' below and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis' and "Ultrasound-guided thoracentesis", section on 'Fluid removal'.)

Gram stain and cultures – If specific microorganisms are suspected or need to be excluded, special transport tubes and media may be needed (eg, fungal or parasitic cultures). We place a sample of pleural fluid blood cultures bottles and a routine culture tube [11]. When the suspicion for pleural infection is high, antibiotics (or drainage) should not be delayed while waiting for the culture results. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults".)

Cytologic staining – When organisms requiring special stains are suspected or need to be excluded, we send pleural fluid for cytologic immunohistochemical stains (eg, actinomyces, nocardia, fungal).

Investigational biomarkers that are not routinely performed include procalcitonin, calprotectin, soluble urokinase plasminogen activator receptor, STREM-1, pleural vascular endothelial growth factor, interleukin 8, and nucleic acid amplification (NAA) for specific organisms [12-15].

Pleural fluid analysis for the diagnostic evaluation of parapneumonic pleural effusion and empyema is provided separately. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis'.)

Suspected tuberculous pleural effusion — When tuberculous (TB) pleural effusion is suspected (eg, patient with a pleural effusion who lives in an endemic region for TB), we obtain pleural fluid acid fast bacillus (AFB) smear and TB cultures as well as adenosine deaminase (ADA). We do not routinely perform pleural interferon gamma assays or NAA; we reserve NAA for patients in whom the diagnosis is in doubt.

AFB smear and TB culture – AFB and TB culture should always be performed since a positive culture is diagnostic. However, AFB and culture results are only positive in less than 50 percent of patients (higher if the fluid is grossly purulent) and may take up to eight weeks.

ADA – ADA results can be obtained more quickly than culture results and can therefore facilitate a presumptive diagnosis so that therapy can be promptly initiated, when indicated. Measurement of ADA is particularly helpful in regions with a high prevalence of TB and is most useful when the effusion is lymphocyte-predominant and initial AFB smear and culture are negative [16,17].

Interferon gamma assays – We do not routinely perform pleural fluid interferon gamma assays (eg, T-SPOT.TB and/or QuantiFERON assays) due to the lower cost and ready availability of ADA testing. Waning use has led to their limited availability. While some studies suggest greater diagnostic value of pleural fluid interferon gamma assays in differentiating malignant from TB lymphocytic exudates [18,19], data are limited and report varying diagnostic utility [20-27].

NAA – We do not routinely perform NAA testing (eg, Xpert MTB/RIF assay). While some clinicians routinely obtain NAA with AFB, culture and ADA, we reserve NAA testing for patients in whom the diagnosis is not definitive but remains suspected, understanding that it is only US Food and Drug Administration approved for sputum and not for pleural fluid.

Further details regarding pleural fluid evaluation and the value of pleural biopsy for the diagnosis of TB pleural effusion are provided separately. (See "Tuberculous pleural effusion", section on 'Pleural fluid analysis' and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Pleural biopsy'.)

Suspected malignancy — For patients with suspected MPE (eg, patient with tobacco exposure who has a large, new-onset pleural effusion), we perform cytology. The approach to patients with suspected pleural metastases from lung cancer is discussed separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)'.)

In patients with a high suspicion for mesothelioma, we often proceed directly to biopsy since pleural fluid analysis may have a low yield for the diagnosis of mesothelioma [28]. However, many clinicians perform thoracentesis since the diagnosis may not be suspected until later during the evaluation. (See "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma", section on 'Diagnosis'.)

For patients with suspected lymphoma or multiple myeloma, we also obtain flow cytometry and immunohistochemical staining, which, if positive, may help support the diagnosis [29-31]. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma", section on 'Flow cytometry/immunohistochemistry'.)

We do not perform other cancer biomarkers (eg, carcinogenic embryonic antigen). (See 'Cytology, flow cytometry, and cancer-related biomarkers' below.)

Suspected pancreatic- or esophageal rupture-related effusion — When pancreatic-related pleural effusion is suspected, we obtain pleural fluid pancreatic amylase (eg, chronic pancreatitis and a right-sided pleural effusion). When esophageal rupture is suspected, we obtain salivary amylase and pleural fluid pH (eg, patient with recurrent or violent vomiting and a pleural effusion). (See 'Amylase' below and 'pH' below.)

Suspected chylous or cholesterol effusion — A cholesterol pleural effusion may be suspected in a patient with risk factors (eg, chronic TB or rheumatoid pleuritis, milky fluid on gross appearance (table 3)) while chylothorax may be suspected in patients with a separate group of risk factors (eg, trauma, malignant tumors of the mediastinum, lymphangioleiomyomatosis, milky fluid on gross appearance (table 4)). In both scenarios, we typically obtain cholesterol and triglyceride levels. Rarely, fluid may be needed for lipoprotein analysis to determine the presence of chylomicrons (usually performed on a second thoracentesis or from fluid stored in the laboratory). (See 'Cholesterol' below and 'Triglycerides' below.)

Suspected rheumatoid or lupus pleuritis — In patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) who have a pleural effusion that is suspected to be due to the underlying disorder (ie, pleuritis), we typically request the following:

RA – Cytology for tadpole cells and laboratory analysis of rheumatoid factor

SLE – Cytology for lupus erythematosus cells (if available) and antinuclear antibody testing

Of note, most clinical laboratories no longer perform lupus erythematosus preparation tests, which are lengthy and complex and are considered by some experts as having low diagnostic utility [32,33]. Interpreting these studies is discussed below. (See 'Connective tissue disease biomarkers' below.)

Suspected hemothorax — When hemothorax is suspected, we perform a hematocrit on a fresh sample of pleural fluid ("pleurocrit") and collect it into a complete blood count (ie, lavender top) tube. Diagnosing hemothorax is discussed below. (See 'Cell counts and cell differential' below.)

Others — Other markers may be useful when specific conditions are suspected. For example, pleural effusions of extravascular origin may require specific biomarkers (table 5) (see "Pleural effusion of extra-vascular origin (PEEVO)"). Most of these conditions are typically rare but include the following:

Suspected urinothorax – Creatinine (concurrent serum creatinine level needed)

Suspected ventriculoperitoneal or ventriculopleural shunt-related effusion – Beta-2-transferrin

Suspected glycinothorax (eg, glycine bladder washout) – Glycine (concurrent serum glycine level needed)

Suspected bilothorax – Bilirubin (concurrent serum bilirubin level needed)

Concurrent serum testing — Concurrent serum tests are needed in the following patients:

If planning to use Light's criteria to distinguish exudative from transudative pleural effusions, blood should be drawn for total protein and LDH so that comparative measurements with pleural fluid levels can be made. No blood tests are needed if classification rules are used that require only pleural fluid bioassays. (See 'Light's criteria (three-test combination rule)' below and 'Pleural fluid only three-test combination (PFO3)' below.)

If a specific condition is suspected that requires comparative analysis of pleural fluid and serum biomarkers, corresponding blood testing should be performed (eg, red cell count [hemothorax], amylase [ruptured esophagus, pancreatic effusion], creatinine [urinothorax], bilirubin [bilothorax] (table 5)).

INTERPRETING PLEURAL FLUID FINDINGS

Gross appearance — Initial diagnostic clues can be obtained by gross inspection of pleural fluid as it is being aspirated from the patient's chest [1]. Observations that are helpful diagnostically are listed in the table (table 6). Gross features may also facilitate the inclusion of additional pleural fluid biomarkers for both diagnostic and prognostic purposes. As examples, it is appropriate to do the following:

Turbid fluid – Draw a pH and perform microbiologic testing

Milky fluid – Assay for lipids and cholesterol

Bloody fluid – Obtain a hematocrit ("pleurocrit") and cytology

Black fluid – Perform fungal and bacterial cultures, amylase, cytology, and hematocrit

Green fluid – bilirubin, cytology, and rheumatoid factor

Classification as exudative or transudative — Once routine biomarkers have been measured, we classify the pleural effusion as either a transudate or an exudate. This distinction is important since etiologies of transudates (table 2) and exudates (table 7) differ from one another.

However, despite this dichotomous classification, most experts recognize that overlap exists and the distinction can be challenging when the pleural fluid test results are borderline or when pleural tests are discordant with each other or with the clinical suspicion. Clinicians should understand that existing approaches have considerable limitations. Rather than accepting test result classifications as definitive, we interpret test results in the context of the patient's clinical findings and consider how much they alter the pretest probability of an exudate. (See 'Our approach' below and 'Alternate approaches' below.)

Transudates – Transudates result from imbalances in hydrostatic and oncotic pressures in the chest in patients with congestive heart failure (CHF), liver failure, and nephrosis. They can also be due to conditions external to the pleural space (eg, peritoneal, cerebrospinal fluid) or to iatrogenic conditions (eg, crystalloid infusion through a central venous catheter that has migrated into the mediastinum or pleural space). Transudates have a limited number of diagnostic possibilities that can usually be discerned from the patient's clinical presentation (table 2).

Exudates – In contrast, exudative effusions present more of a diagnostic challenge. Disease in virtually any organ can cause exudative pleural effusions by a variety of mechanisms, including infection, malignancy, immunologic responses, lymphatic abnormalities, noninfectious inflammation, iatrogenic causes, and movement of fluid from below the diaphragm (eg, acute or chronic pancreatitis, chylous ascites, and peritoneal carcinomatosis) (table 7).

Exudates result primarily from pleural and lung inflammation (resulting in increased entry of fluid and protein due to elevated capillary permeability), impaired lymphatic drainage of the pleural space (resulting in a decreased removal of pleural fluid and protein), or movement of fluid from the peritoneal space.

Approaches used to distinguish transudative from exudative pleural effusions, including our approach, and caveats associated with approaches in general, are reviewed below. (See 'Our approach' below and 'Alternate approaches' below and 'Limitations of one-, two-, and three-test classification systems' below.)

Our approach — Several approaches have been described to help classify pleural fluid as transudative or exudative. Our approach is the following:

For most patients with a pleural effusion who need pleural fluid analysis, we favor the "pleural fluid only" three-test combination rule (PFO3) that measures pleural fluid protein, cholesterol, and lactate dehydrogenase (LDH) and does not require serum tests (calculator 1). The rationale for this preference, description of the calculation, and comparison with Light’s criteria are discussed below. (See 'Pleural fluid only three-test combination (PFO3)' below.)

As alternatives, Light's criteria (a three-test combination rule that requires concurrent serum tests (calculator 2)), two-test combinations, and one-test rules are also appropriate. (See 'Light's criteria (three-test combination rule)' below and 'One- and two-test classification rules' below.)

When pleural fluid test results are discordant (eg, one criterion classifies the fluid as exudative while others classify it as transudative) or borderline or a classification result does not fit the clinical context (eg, an exudate in a patient with heart failure), we use a Bayesian approach that uses likelihood ratios (LRs) to derive a more precise estimate of the posttest probability of an exudate (calculator 3 and calculator 4). Bayesian approaches incorporate a patient's clinical context (ie, pretest probability of an exudate) to help clinicians avoid placing too much reliance on dichotomous approaches that can only classify pleural fluid as either exudative or transudative regardless of clinical context. (See 'Borderline or discordant results: Bayesian approaches' below.)

Data to support using any particular classification approach over another are limited. One meta-analysis of eight studies (1448 patients) examined multiple pleural fluid tests and combinations of tests to distinguish exudates from transudates and found that all individual tests except for one (pleural fluid bilirubin) had similar accuracy [34]. Another meta-analysis demonstrated similar classification accuracy between Light's criteria and several individual pleural fluid tests [35]. A single center database report found similar classification accuracies of several single and combination classification strategies analyzed [36].

Pleural fluid only three-test combination (PFO3) — We use PFO3, a three-test combination approach (calculator 1), as our preferred calculation [34,36]. A pleural effusion is considered an exudate if any one or more of the following are present:

Pleural fluid protein greater than 3.0 g/dL (30 g/L)

Pleural fluid cholesterol greater than 55 mg/dL (1.424 mmol/L)

Pleural fluid LDH greater than 0.67 times the upper limit of the laboratory's normal serum LDH

Our preference for PFO3 is based on the advantages of obviating a need for blood sampling and avoiding the duplicative use of highly correlated criteria (eg, pleural fluid LDH and pleural fluid-to-serum LDH ratios as found in Light's criteria) and data that report a similar accuracy to the traditional approach of Light's criteria [34,36].

Reports vary in the cutoff value used for pleural fluid cholesterol being between 45 to 55 mg/dL and pleural fluid LDH greater than 0.45 to 0.67 upper limits of normal [34,36,37]. Cutoff values have even varied within these ranges when reported from the same institution and investigative group at different times [36,37], demonstrating inherent imprecisions in identifying perfect cutoff points because of spectrum bias from differences in patient characteristics in different settings and times. The original derivation of PFO3 from a large meta-analysis proposed the following cutoff points: pleural fluid protein >2.9 g/dL, pleural fluid LDH >0.45 upper limits of normal, and pleural fluid cholesterol >45 mg/dL [34]. We use the cutoff values listed above because they derive from the largest (5299 patients) and most updated dataset from a single center that showed equal diagnostic accuracy of PFO3 compared with Light's criteria [36].

Alternate approaches

Light's criteria (three-test combination rule) — The Light's Criteria Rule is a commonly used three-test rule that measures serum and pleural fluid protein and LDH (calculator 2) [38].

According to the Light's Criteria Rule, if at least one of the following three criteria (ie, component tests of the rule) is fulfilled, the fluid is defined as an exudate [38]:

Pleural fluid-to-serum protein ratio greater than 0.5

Pleural fluid-to-serum LDH ratio greater than 0.6

Pleural fluid LDH greater than 0.67 (ie, two-thirds) the upper limits of the laboratory's normal serum LDH

Light's criteria have been criticized for including pleural fluid LDH in two separate criteria (ie, pleural fluid LDH and pleural fluid-to-serum LDH ratio) [34], which means that the two criteria are highly correlated, which decreases its diagnostic accuracy [34,37,39]. In addition, use of pleural fluid-to-serum ratios require simultaneous blood tests that increase costs and inconvenience to the patient. Data also suggest that omitting the pleural fluid-to-serum LDH ratio does not diminish the diagnostic accuracy of Light's criteria [3,36] or other two-test rules that also include pleural fluid-to-serum LDH ratio [40].

Light's criteria have a high sensitivity but a moderate specificity for exudative pleural effusions [36,41]. As a result, 25 to 30 percent of transudates are incorrectly classified as exudates, particularly those due to heart failure when diuretics are given or a high level of erythrocytes (which release LDH) are present in the pleural fluid [36,40,42]. Despite a high sensitivity, up to 10 percent of pleural effusions due to malignancy are classified as transudates by Light's criteria [43,44], although it is unclear whether this is from the inherent imperfection of all classification systems or the fact that some malignant effusions are transudates due to various mechanisms (eg, superior vena cava obstruction).

One- and two-test classification rules

Pleural fluid only two-test combination rule (PFO2) – Multiple studies have examined the discriminative properties of two-test combination rules for classifying pleural effusions that variably included pleural fluid cholesterol, protein, or LDH in various pair-wise combinations using different cutoff points for pleural fluid cholesterol and LDH [35,36,40,45]. If a two-test combination is to be used, we prefer using the following rule that classifies an effusion as exudative when one or both criteria are met [40]:

Pleural fluid cholesterol greater than 40 mg/dL (1.034 mmol/L)

Pleural fluid LDH greater than 0.60 times the upper limit of the laboratory's normal serum LDH

In support, one study reported that these criteria had an overall accuracy equivalent to Light's criteria (area under the receiver operating curve 0.87 versus 0.85, respectively) and had the advantage of avoiding blood draws [40].

One-test criteria – Limited data suggest that some single tests have sufficient accuracy when used individually to classify pleural effusion as exudative. As examples [35]:

Pleural fluid cholesterol greater than 55 mg/dL (1.424 mmol/L)

Pleural fluid-to-serum cholesterol ratio greater than 0.3

Pleural fluid LDH greater than 200 U/L

Total protein concentrations above 3.0 g/dL (30 g/L)

Pleural fluid LDH greater than 0.67 times the upper limit of the laboratory's normal serum LDH

Although the optimal cutoff point reported for pleural fluid LDH that indicates an exudate varies [46] with cutoffs ranging from 45 percent to 83 percent of the laboratory's upper limit of normal [34,36,47,48], most experts use a cutoff of greater than 0.67 (ie, two-thirds) the upper limits of the laboratory's normal serum LDH.

Several studies have examined the diagnostic sensitivity of one-test rules. One meta-analysis reported that when pleural fluid cholesterol greater than 55 mg/dL (1.424 mmol/L), pleural fluid-to-serum cholesterol ratio >0.3, and pleural fluid LDH greater than 200 U/L were used as a single-test criterion, each had only slightly lower sensitivities but higher specificities as compared with Light's criteria [35]. Other studies report a similar lower sensitivity and higher specificity when compared with two-test and three-test combination strategies [34,36]. However, confidence intervals of the overall diagnostic accuracy of each of these tests overlapped so none appeared clearly superior to any other.

For patients with suspected heart failure who have an atypical presentation and whose pleural effusion is suspected to be misclassified as an exudate, we use either one of the following single-test criteria to help recategorize the pleural effusion as a transudate [3,49]:

Serum-to-pleural fluid albumin gradient (ie, the difference between the serum and pleural values) greater than 1.2 g/dL (12 g/L)

Serum-to-pleural fluid protein gradient greater than 2.5 g/dL (25 g/L)

For such patients, it is unclear if the albumin or protein serum-to-pleural fluid gradients add to clinical decision-making over and above information gained from other assessments of cardiac performance, such as serum N-terminal pro-BNP (NT-proBNP) and echocardiography. (See 'Albumin and protein gradients' below and 'N-terminal pro-BNP' below.)

Limitations of one-, two-, and three-test classification systems — When interpreting pleural fluid biomarkers, it is important for the clinician to understand that cutoff points for pleural fluid test results are chosen intentionally to maximize sensitivity for exudates because the identification of exudative effusions has considerable prognostic importance (eg, cancer and parapneumonic effusion). However, this comes at the price of lowering the specificity because sensitivity and specificity are inversely coupled for all diagnostic tests (ie, as sensitivity increases, specificity decreases) [41,50]. Further increasing sensitivity at the expense of specificity is the commonly used classification strategy that combines two or more tests in "either-or" rules wherein only one component test result needs to be positive to make the rule positive. This results in the sensitivity of the combination test rule being higher than the sensitivity of the individual component tests of the rule, but the specificity of the rule is lower than its individual components [50]. This tradeoff of higher sensitivity for lower specificity is considered "desirable" since it is important that exudates not be missed. Some transudates, however, may be misclassified as an exudate because of the decreased specificity of the combination test rule [51]. (See "Glossary of common biostatistical and epidemiological terms".)

However, these classification systems all treat test results that are marginally close to cutoff points (eg, protein 3 g/dL [borderline]) the same as results that are at the extreme range of the test (eg, protein 7 g/dL [extreme]) (see 'Pleural fluid only three-test combination (PFO3)' above and 'Light's criteria (three-test combination rule)' above and 'One- and two-test classification rules' above) [52] and, as a consequence, may misclassify pleural fluid as exudates or transudates when values are near their cutoff points [34,36,37,50,53]. A meta-analysis demonstrated that even though the overall diagnostic accuracy of Light's criteria is >90 percent in most studies, diagnostic accuracy falls to 70 percent when any of the three criteria return results close to their cutoff points [53]. We use a Bayesian approach in such cases to help inform the likelihood of an exudate within a specific clinical context. (See 'Borderline or discordant results: Bayesian approaches' below.)

Borderline or discordant results: Bayesian approaches — Bayesian approaches use LRs and clinician pretest estimates (ie, pretest probability) to help inform them of the likelihood that a pleural effusion is an exudate by calculating a posttest probability. Rather than classifying effusions as exudates or transudates (ie, a dichotomous classification), a Bayesian approach removes this dichotomization and allows clinicians to combine their gestalt clinical suspicion that the patient has an exudate (high [eg, 90 percent], moderate/uncertain [eg, 50 percent], or low [eg, 10 percent]) with the pleural fluid test results to calculate a posttest probability of an exudate.

Dichotomous and continuous LRs for pleural fluid tests have been described for use in calculators. We prefer calculators that use continuous LRs since they are easier to use and likely more precise (calculator 3 and calculator 4):

Continuous LRs – Two studies have reported simple exponential equations for common pleural fluid tests that can be built into calculators to compute a unique LR for every discrete value across a test result's range (ie, continuous LR) [37,53]. This process gives clinicians a more precise estimate as to how much the pleural fluid test results increase or decrease the pretest estimate of the probability of an exudate than can be achieved by dichotomous approaches (eg, Light's or PFO3) and is our preferred Bayesian approach (calculator 3 and calculator 4).

Dichotomous LRs – Several studies have reported dichotomous LRs for common pleural fluid tests, although the cutoff values for each test differ among studies [34-36,40,52]. These LRs may be used in dichotomous calculators that allow computation of posttest probabilities with LRs derived from multiple test results (calculator 5).

Bayesian approaches using either dichotomous or continuous LRs help clinicians recognize that pleural fluid test values that fall only slightly above or below a single cutoff point marginally alter their pretest estimates of the probability of an exudate. Clinicians may use calculators based on continuous LRs for the PFO3 rule pleural fluid test values (calculator 4) or Light's criteria (calculator 3) rules. (See "Glossary of common biostatistical and epidemiological terms".)

Interpreting individual biomarkers — Individual pleural fluid biomarkers should be interpreted in the clinical context to help narrow the differential. Specific biomarker patterns together with clinical and imaging findings can lead to a diagnosis in the majority of patients (table 8).

Cell counts and cell differential — We typically evaluate both the white cell count and differential as well as the red cell count.

White cell count and differential – Because of associated challenges in collecting the small amount of pleural fluid that is present in healthy individuals, few studies have determined normal values for the white cell count and differential. However, one study in healthy adults that collected pleural fluid by lavage reported that the pleural fluid white cell count was <2000/microL, with a predominance of macrophages (approximately 75 percent) and lymphocytes (approximately 23 percent) [54]. Mesothelial cell, neutrophil, and eosinophil counts comprised the remainder (<1 percent each).

An elevated white cell count is typically encountered with pleural injury, inflammation, or infection. Timing influences the predominant cell type. For example, the early cellular response to pleural injury is neutrophilic. However, as the time from the acute pleural insult lengthens, the effusion develops a mononuclear predominance, provided that the pleural injury is not ongoing.

When assessing pleural fluid for the white cell count and differential, we consider the following approach reasonable:

Polymorphonuclear-predominant pleural effusion – The total pleural fluid nucleated cell count is virtually never diagnostic of a single entity. There are, however, some settings in which specific levels may have diagnostic importance [55-57]:

-Counts above 50,000/microL in an exudative pleural effusion are usually found only in complicated parapneumonic effusions, including empyema.

-Counts above 10,000/microL in an exudative pleural effusion are typically due to bacterial pneumonia, acute pancreatitis, and lupus pleuritis.

-Counts below 5000/microL are likely due to chronic exudates such as tuberculous (TB) pleurisy and malignancy.

Lymphocyte-predominant pleural effusion – Elevated lymphocyte content in pleural fluid may indicate a reactive or benign condition or a neoplasm [1,58-61].

-Lymphocyte counts representing 85 to 95 percent of the total nucleated cells suggests TB pleurisy or lymphoma (primary pleural lymphoma or systemic lymphoma) and, less commonly, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, chylothorax, or drug-induced pleural effusion. (See "Tuberculous pleural effusion" and "Primary effusion lymphoma" and "Etiology, clinical presentation, and diagnosis of chylothorax".)

-Malignant pleural effusions (MPEs; other than lymphoma) are lymphocyte-predominant in over one-half of cases; however, the percentage of lymphocytes is usually between 50 and 70 percent.

-Some viral- and drug-induced pleural effusions are lymphocyte predominant (eg, dasatinib-related).

Cytomorphologic examination of lymphocytes provides an essential clue to the underlying disease. Small versus large lymphocytes, cellular atypia, and a history of lymphoma warrant the initiation of specialized studies, such as immunophenotyping and molecular assays to exclude cancer [62].

Eosinophilic pleural effusion – Pleural fluid eosinophilia (defined by pleural fluid eosinophils representing more than 10 percent of the total nucleated cells) occurs with both malignant and benign etiologies [63]. The differential diagnosis of pleural fluid eosinophilia is listed in the table (table 9 and table 10) [63-66] and discussed in detail separately. (See "Pleural fluid eosinophilia".)

Eosinophils >15 percent may support a diagnosis of malignancy [63,67-69] and may decrease the likelihood of TB pleurisy in the absence of pneumothorax [69].

Eosinophilia may have prognostic significance. One study reported that lung cancer patients with pleural fluid eosinophilia had a better prognosis than those without eosinophilia [70].

Basophilia – Basophils greater than 10 percent of nucleated cells suggests leukemic involvement of the pleura [71].

Mesothelial cells – Mesothelial cells are found in small numbers in normal pleural fluid, are prominent in transudative pleural effusions, and are variable in exudative effusions. The major clinical significance of mesothelial cells in exudates is that tuberculosis is unlikely if there are more than 5 percent mesothelial cells [69].

Red cell count – Evidence of red blood cells (RBCs) in pleural fluid may reflect minor bleeding due to traumatic thoracentesis or inflammation. However, large amounts of RBCs may reflect hemothorax. The ratio of pleural fluid to blood hematocrit >0.5 is considered diagnostic of hemothorax. However, if patients undergo thoracentesis several days after active bleeding stops, some patients with hemothorax have values between 25 to 50 percent [72,73].

Patients with heart failure may have pleural fluid erythrocyte counts >10,000 cells/microL causing a serosanguinous appearance and artifactual elevation of pleural fluid LDH measurement, thereby misclassifying the effusion as exudative [74].

Total protein — The major reason for measuring the protein level in pleural fluid is to determine whether the fluid is exudative or transudative (see 'Classification as exudative or transudative' above). However, specific levels may have some diagnostic value. For example:

TB pleural effusions virtually always have total protein concentrations above 4.0 g/dL (40 g/L) [75]. (See 'Suspected tuberculous pleural effusion' above and "Tuberculous pleural effusion".)

Very high pleural fluid protein concentrations (eg, 7.0 to 8.0 g/dL [70 to 80 g/L]) may suggest Waldenström macroglobulinemia and multiple myeloma [76,77]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Extremely low pleural fluid concentrations (eg, <1 g/dL) suggest migration of a central venous infusion catheter or ventriculoperitoneal shunt into the pleural space, duro-pleural fistula, peritoneal dialysate, glycinothorax, hepatic hydrothorax, or urinothorax [78,79](See "Pleural effusion of extra-vascular origin (PEEVO)".)

Lactate dehydrogenase — The level of pleural fluid LDH is one of the key criteria for differentiating transudates from exudates (See 'Classification as exudative or transudative' above.)

Several specific disease associations have been noted with elevated pleural fluid LDH levels:

Pleural fluid LDH levels above 1000 international units (IU/L with upper limit of normal for serum of 200 IU/L) are characteristically found in empyema [80,81], rheumatoid pleurisy [82], pleural paragonimiasis [83], and sometimes malignancy.

Pleural fluid LDH levels are elevated in both TB pleural effusions and complicated parapneumonic pleural effusions (empyema), but values are lower in TB effusions (365 U/L versus 4037 U/L) [84], providing diagnostic value in discriminating between these two conditions [81,85]. (See 'Suspected tuberculous pleural effusion' above.)

A pleural fluid-to-serum LDH ratio greater than 1.0 and a pleural fluid-to-serum protein ratio of less than 0.5 is characteristic of Pneumocystis jirovecii [86] but can also be seen in malignancy, coronavirus disease 2019 (COVID-19) [87], and urinothorax [88]. (See 'Others' above.)

While in the past, pleural fluid LDH levels above 1000 IU/L have been proposed to predict the need for chest tube drainage for patients with parapneumonic effusions, data are limited and do not support this claim [89].

Glucose — Most pleural effusions have a pleural glucose level similar to that of blood. However, select conditions should be considered when the glucose level is low or high.

Low pleural fluid glucose – A low pleural fluid glucose concentration (less than 60 mg/dL [3.33 mmol/liter]) or a pleural fluid-to-serum glucose ratio less than 0.5 narrows the differential diagnosis of the exudate to the following possibilities [1]:

Rheumatoid pleurisy

Complicated parapneumonic effusion or empyema

MPE

TB pleurisy

Lupus pleuritis

Esophageal rupture

Normal saline infusate

Urinothorax

The lowest glucose concentrations are found in rheumatoid pleurisy and empyema, with glucose being undetectable in some cases. In comparison, when the glucose concentration is low in TB pleurisy, lupus pleuritis, and malignancy, it usually falls into the range of 30 to 50 mg/dL (1.66 to 2.78 mmol/L) [1].

The mechanism responsible for a low pleural fluid glucose depends on the underlying disease. Specific examples include:

Decreased diffusion of glucose from blood to pleural fluid with rheumatoid pleurisy [90,91] or malignancy [92].

Increased utilization of glucose by constituents of pleural fluid, such as neutrophils, bacteria (empyema), and malignant cells [93].

High pleural fluid glucose – Transudative pleural effusions with elevated pleural fluid glucose concentrations may be secondary to a misplaced central venous catheter that infuses glucose-containing fluids into the pleural space [78] or to migration of peritoneal dialysate fluid from the intraperitoneal space into the pleural space [94]. (See 'Others' above.)

pH — When interpreting pH, we suggest the following:

Normal pH – The pH of normal human pleural fluid inferred from animal models is approximately 7.60 [95]. Transudates generally have a pleural fluid pH in the 7.40 to 7.55 range, while the majority of exudates range from 7.30 to 7.45 [96].

Low pH – A pleural fluid pH below 7.30 with a normal arterial blood pH is found in patients with the following:

Acute lupus pleuritis

MPE

Complicated parapneumonic effusions/empyema

Chronic rheumatoid pleural effusions

Urinothorax

TB pleural effusions

Pancreatic-pleural fistula

Hemothorax

Inadvertent intrapleural infusion of normal saline

Esophageal rupture

Crystalloid infusion into the pleural space

Inadvertent infusion of normal saline and urinothorax are the only transudates that can have a pleural fluid pH <7.40 [88]. (See "Pleural effusion of extra-vascular origin (PEEVO)".)

A low pleural fluid pH has not only diagnostic but also therapeutic implications for patients with parapneumonic effusions [97]. As an example, a parapneumonic effusion with a low pleural fluid pH (≤7.15) indicates a high likelihood of necessity for pleural space drainage [89,98-100]. The differential diagnosis of pleural fluid acidosis and implications for patients with a parapneumonic pleural effusion are discussed separately. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis' and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Differential diagnosis'.)

A low pleural fluid pH also has prognostic and therapeutic implications for patients with MPE [97]. Patients with MPE who have a low pleural fluid pH have a high initial positive yield on pleural fluid cytology. They also tend to have a shorter survival and poorer response to chemical pleurodesis than those with a pH >7.30, [101-103]. However, we do not use a low pleural fluid pH as a criterion for the decision to forego pleurodesis since the strength of these associations are weak [102,103]. (See "Management of malignant pleural effusions".)

The mechanisms responsible for pleural fluid acidosis (pH <7.30) include:

Increased acid production by pleural fluid cells and bacteria (empyema) [93,104].

Migration of urine or infusion via misplaced catheters of low pH solutions (eg, normal saline) into the pleural space.

High pH – A high pleural fluid pH greater than the normal pleural fluid pH of 7.60 is usually due to sample error if the sample was not placed on ice or not immediately analyzed. Rarely, it may be associated with a misplaced catheter that is infusing bicarbonate or pleural space infection caused by urea-splitting organisms, such as Proteus species [105].

N-terminal pro-BNP — An NT-proBNP level >1500 pg/mL supports the presence of a transudative pleural effusion consistent with heart failure [3,4].

However, routinely measuring pleural fluid NT-proBNP has questionable value since it correlates well with serum values for NT-proBNP [106-108]. Meta-analyses report that the overall sensitivity and specificity of pleural fluid NT-proBNP for CHF was greater than 90 percent each [107,109]; however, measuring it in the blood was equally as effective [107]. (See "Natriuretic peptide measurement in heart failure".)

False positives can occur. For example, patients with septic shock or acute kidney injury can elevate NT-proBNP and, thereby, lower the specificity of NT-proBNP (73 percent) [110]. In addition, patients with true exudates due to parapneumonic effusions or MPEs may have elevated pleural fluid levels of NT-proBNP possibly from coexisting heart failure [110].

Albumin and protein gradients — In patients with heart failure, a serum-to-pleural fluid albumin gradient (ie, the difference between the serum and pleural values) greater than 1.2 g/dL (12 g/L) or a serum-to-pleural fluid total protein gradient >2.5 g/dL supports a transudative effusion [3,6,111]. One study reported that acute diuresis increased the concentration of all pleural fluid components, but the impact of albumin and protein gradients was lower than on individual components [6].

Microbiologic Gram stain and cultures — Positive Gram stain and cultures are generally diagnostic of a parapneumonic effusion, and frank pus is diagnostic of empyema. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Diagnosis'.)

Acid fast smear and tuberculous cultures — While acid fast smear can be positive for TB and non-TB mycobacteria, positive TB culture is definitively diagnostic. However, cultures can take up to eight weeks to become positive and are imperfect since less than 50 percent of patients are actually positive.

Adenosine deaminase — The most common diagnostic threshold used to establish a TB pleural effusion is a pleural fluid adenosine deaminase (ADA) level greater than 40 U/L [17]. The level of ADA is typically greater than 35 U/L in TB pleural effusions [112], and TB is rare when the ADA level is less than 40 U/L (ie, a high negative predictive value) [113]. However, the clinician should be aware that false-negative and false-positive results can occur (eg, malignancy, mesothelioma, lymphoma, uremic pleuritis, human immunodeficiency virus [HIV] infection, hemorrhagic effusions, empyema, rheumatoid pleurisy, and immunoglobulin G4-related pleural disease) [112,114,115]. Further details are provided separately. (See "Tuberculous pleural effusion", section on 'Pleural fluid analysis'.)

Cytology, flow cytometry, and cancer-related biomarkers

Cytology – Cytologic analysis of pleural fluid can establish the diagnosis of MPEs but has an overall sensitivity of approximately 60 percent [116,117], which may increase by 15 percent with a second thoracentesis sample [118]. Identification of benign etiologies may be evident on cytologic staining (eg, microorganisms and lymphangioleiomyomatosis).

The sensitivity of pleural fluid cytology for malignancy varies depending on the histologic type of the underlying cancer. One meta-analysis reported that pleural fluid cytology has a sensitivity of 85 percent for ovarian cancer, 78 to 83 percent for adenocarcinoma, 65 percent for breast cancer, 53 percent for small cell carcinoma, 29 percent for mesothelioma, and 25 percent for squamous cell carcinomas [117].

We prefer to collect a sufficient volume of pleural fluid to enhance the diagnostic yield of cytology and allow examination of a cell block [119]. High-quality studies to determine the minimum volume of submitted sample for accurate diagnosis are limited and report differing results [120-125]. Nonetheless, based on existing data, we send at least 75 mL for cytology, especially in the era of molecular profiling [126]. While the College of Pathologists guideline recommends sending as much fluid as is possible [125], even small volumes of pleural fluid can yield a diagnosis [127].

One factor that has complicated cytologic reporting for pleural fluid is the variation in the descriptions of diagnostic terminology. To standardize terminology, cytology experts have published the "International System for Reporting Serous Fluid Cytopathology" [128].

Further details on the value to pleural fluid analysis for the diagnosis of lung cancer are provided separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)' and "Procedures for tissue biopsy in patients with suspected non-small cell lung cancer", section on 'Thoracentesis-cytology'.)

Flow cytometry – For patients with suspected lymphoma (primary pleural or systemic), flow cytometry and immunohistochemical staining may supplement cytology that identifies lymphomatous cells.

Investigational cancer-related biomarkers – Clinical applicability of cancer-related biomarkers to establish a diagnosis of pleural malignancy is limited by the lack of standardized laboratory analysis methodologies and a shortage of studies that validate positive studies. No single pleural fluid biomarker is accurate enough for routine use in the diagnostic evaluation of pleural effusion [129,130]. The role of soluble mesothelin-related peptides in the diagnosis of pleural mesothelioma is discussed separately. (See "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma", section on 'Biomarkers under investigation'.)

Amylase — An amylase-rich pleural effusion is defined as either a pleural fluid amylase greater than the upper limits of normal for serum amylase or a pleural fluid-to-serum amylase ratio >2. When present, this narrows the differential diagnosis of an exudative effusion to the following major possibilities:

Acute pancreatitis

Chronic pancreatitis

Esophageal rupture

Malignancy

Other rare causes of an amylase-rich pleural effusion include pneumonia, ruptured ectopic pregnancy, multiple myeloma, hydronephrosis, and cirrhosis [131,132].

Pancreatic disease is associated with the pancreatic isoenzyme while malignancy and esophageal rupture are characterized by a predominance of the salivary isoenzyme [131]. Esophageal rupture is also associated with a very low pH (often as low as 6) and ingested vegetable or meat fragments on cytology.

Pleural fluid amylase, however, has low discriminative value for differentiating benign from malignant effusions, so it is not routinely performed in suspected cancer for this reason.

Cholesterol — Pleural cholesterol can be used for the following:

Classifying exudative from transudative pleural effusions – Measurement of pleural cholesterol has been used to differentiate transudative from exudative effusions. Elevated pleural cholesterol is included in the one-, two-, and three-test classification rules [34]. (See 'One- and two-test classification rules' above and 'Pleural fluid only three-test combination (PFO3)' above.)

Diagnosis of cholesterol pleural effusion – An elevated cholesterol >250 mg/dL defines a cholesterol effusion (also known as pseudochylothorax or chyliform effusion) (algorithm 1). (See "Clinical presentation, diagnosis, and management of cholesterol pleural effusions", section on 'Diagnosis'.)

The presence of cholesterol in pleural fluid is thought to be derived from degenerating cells and vascular leakage from increased permeability.

Triglycerides — An exudative pleural effusion with elevated triglyceride concentration greater than 110 mg/dL supports the diagnosis of a chylothorax. A level less than 50 mg/dL excludes a chylothorax with reasonable likelihood, and an intermediate level between 50 and 110 mg/dL should be followed by lipoprotein analysis of the pleural fluid for chylomicrons (algorithm 2) [133]. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Pleural fluid analysis'.)

Patients with transudates and elevated triglyceride levels typically have hepatic cirrhosis, nephrotic syndrome, amyloidosis, or obstruction of the superior vena cava [134,135].

Connective tissue disease biomarkers — For patients with connective tissue disease, interpreting pleural fluid cytologic and antibody findings may help differentiate rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) associated pleural effusion due to pleuritis from pleural effusion due to other causes.

RA – In patients with RA, cytologic evidence of elongated macrophages and distinctive multinucleated giant cells (tadpole cells) in a background of amorphous debris and the presence of rheumatoid factor in pleural fluid may be supportive of the diagnosis of rheumatoid pleuritis. However, the sensitivity and specificity of these findings have not been described. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Thoracentesis'.)

SLE – A pleural fluid antinuclear antibody (ANA) titer ≥1:160 is a sensitive tool (86 to 100 percent) for detecting lupus pleuritis in patients with a known diagnosis of SLE [136-140]. One study of 59 patients, 16 of whom had underlying lupus, reported a sensitivity of 91 percent, specificity of 83 percent, and negative predictive value of 97 percent for an ANA >1:80 in discriminating lupus from nonlupus pleuritis-related pleural effusion [141].

While in the past, positive pleural fluid lupus erythematosus cell preparation tests, pleural fluid ANA titers ≥1:160, and a pleural fluid-to-serum ANA ratio ≥1 were considered diagnostic of lupus pleuritis, it is now apparent none of these findings occurs solely in lupus pleuritis. For example, lupus erythematosus cells have been identified in patients with malignancy and RA [32,142,143]. Similarly, small case series report that pleural fluid ANA titer ≥1:160 can be found in exudative, parapneumonic and malignancy-associated effusions [136-139]. Even an extremely high pleural fluid ANA >1:640 can occur in malignant effusions [139].

Using the ratio of pleural fluid-to-serum ANA of ≥1 [136,138,139] or ANA staining pattern in pleural fluid does not provide any additional diagnostic value for the diagnosis of lupus pleuritis [137,139]. (See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

Others — The interpretation of other parameters such as creatinine (urinothorax), beta-2 transferrin (ventriculoperitoneal shunt), pleural fluid-to-serum glucose ratio (peritoneal dialysate pleural effusion), pleural fluid-to-serum bilirubin (bilothorax), and glycine (glycinothorax) can be found in the table (table 5). (See "Pleural effusion of extra-vascular origin (PEEVO)".)

FINALIZING A DIAGNOSIS — In most patients, a diagnosis can be achieved using an approach that combines clinical evaluation with pleural fluid analysis targeted at the suspected underlying disorder (table 8). This evaluation is discussed separately. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Additional evaluation for unclear etiology'.)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Pleural effusion (The Basics)")

Beyond the Basics topic (see "Patient education: Thoracentesis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

What tests to order – When deciding what tests to order in patients undergoing thoracentesis, we keep the following principles in mind:

Routine – In all patients, we perform pleural fluid analysis for routine laboratory tests including white and red cell count and differential, total protein, lactate dehydrogenase (LDH), glucose, and cholesterol. Some experts also perform pleural fluid culture, Gram stain, and cytology especially when pleural infection or malignancy appear possible diagnoses. (See 'Routine pleural fluid biomarkers' above.)

Condition-specific tests – When a specific disease is suspected based upon clinical findings or gross fluid appearance (table 6), we additionally perform specific biomarkers at the time of initial pleural fluid sampling (eg, triglycerides, cytology, Gram stain and culture, amylase, rheumatoid factor, bilirubin, creatinine, beta-2-transferrin). (See 'Condition-specific biomarkers' above and 'Gross appearance' above.)

Laboratory blood draws – When Light's criteria are being used to differentiate transudative from exudative effusion, we draw blood for total protein and LDH. We draw other laboratory tests if specific conditions listed in the table (table 5) are suspected (eg, cell count [hemothorax], amylase [ruptured esophagus, pancreatic effusion], creatinine [urinothorax], bilirubin [bilothorax]). (See 'Condition-specific biomarkers' above.)

Distinguishing transudates and exudates – This distinction is important since etiologies of transudates (table 2) and exudates (table 7) differ from one another. Data to support using any particular classification approach over another are limited and conflicting. (See 'Classification as exudative or transudative' above.)

Pleural fluid only three-test combination rule (PFO3) – For most patients with a pleural effusion of unclear etiology, we favor the PFO3 rule that measures pleural fluid protein, cholesterol, and LDH (calculator 1). Our preference for PFO3 is based on the advantages of obviating the need for blood sampling and avoiding the duplicative use of highly correlated criteria (ie, pleural fluid LDH and pleural fluid-to-serum LDH ratio) and data that suggest a similar sensitivity to the traditional approach of Light's criteria. (See 'Pleural fluid only three-test combination (PFO3)' above.)

Alternative rules – As alternatives, Light's criteria (a three-test combination rule that requires concurrent serum tests (calculator 2)), two-test combinations, and one-test rules are also appropriate. (See 'Alternate approaches' above.)

Bayesian approach – When pleural fluid test results are borderline or discordant with each other or with the clinical suspicion, we use calculators that use continuous likelihood ratios to derive a more precise estimate of the posttest probability of an exudate (calculator 3 and calculator 4). (See 'Borderline or discordant results: Bayesian approaches' above.)

Individual pleural fluid biomarkers – Individual pleural fluid biomarkers should be interpreted in the clinical context to help narrow the differential. Occasionally, additional testing may be needed to confirm or exclude a diagnosis. Common diagnoses that are made using this approach are listed in the tables (table 5 and table 8). (See 'Interpreting individual biomarkers' above and 'Finalizing a diagnosis' above.)

Follow-up – Further evaluation is discussed separately. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Additional evaluation for unclear etiology'.)

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Topic 6698 Version 36.0

References

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