Pleural fluid analysis in adults with a pleural

effusion
Author: John E Heffner, MD
Section Editor: Fabien Maldonado, MD, MSc
Deputy Editor: Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2024. | This topic last updated: Feb 16, 2024.

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)'.)
● (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)'.)
● (See "Selection of modality for diagnosis and staging of patients with suspected
non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)'.)
● (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)'.)
● 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".)

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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