Liquide Pleural
Liquide Pleural
Liquide 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
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".)
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.)
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 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)'.)
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'.)
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)).
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].
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
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).
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]:
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]:
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.)
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).
When assessing pleural fluid for the white cell count and differential, we
consider the following approach reasonable:
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].
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:
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:
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].
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.
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].
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'.)
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.
Patients with transudates and elevated triglyceride levels typically have hepatic
cirrhosis, nephrotic syndrome, amyloidosis, or obstruction of the superior vena
cava [134,135].
≥
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".)
FINALIZING A DIAGNOSIS
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)")
• 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.)
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