Expert Review of Respiratory Medicine

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The diagnosis of pleural effusions

José M Porcel, M Azzopardi, CF Koegelenberg, F Maldonado, NM Rahman &

YCG Lee

To cite this article: José M Porcel, M Azzopardi, CF Koegelenberg, F Maldonado, NM Rahman &
YCG Lee (2015): The diagnosis of pleural effusions, Expert Review of Respiratory Medicine, DOI:
10.1586/17476348.2015.1098535

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Published online: 08 Oct 2015.

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 Review

The diagnosis of pleural

effusions
Expert Rev. Respir. Med. 00(00), 1–15 (2015)

José M Porcel*1, Pleural effusions arise from a variety of systemic, inflammatory, infectious and malignant
5 M Azzopardi2, conditions. Their precise etiological diagnosis depends on a combination of medical history,
CF Koegelenberg3, physical examination, imaging tests and pertinent pleural fluid analyses; including specific
biomarkers (e.g., natriuretic peptides for heart failure, adenosine deaminase for tuberculosis,
F Maldonado4,
or mesothelin for mesothelioma). Invasive procedures, such as pleuroscopic biopsies, may be
NM Rahman5 and required for persistently symptomatic effusions which remain undiagnosed after the analysis
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10 YCG Lee2
1
Pleural Medicine Unit, Department
of Internal Medicine, Arnau de
Vilanova University Hospital,
Biomedical Research Institute of
Lleida, Lleida, Spain
2
Respiratory Department, Sir Charles
Gairdner Hospital, Perth, Western
Australia
3
Division of Pulmonology,
Department of Medicine,
15 Stellenbosch University and
Tygerberg Academic Hospital, Cape
Town, South Africa
4
Division of Allergy, Pulmonary and
Critical Care Medicine, Vanderbilt
University, Nashville, TN, USA
20 5
Oxford Centre for Respiratory
Medicine, Oxford University Hospitals
NHS Trust, Oxford, UK
*Author for correspondence:
jporcelp@yahoo.es
25
30
35
40
of one or more pleural fluid samples. However, whenever parietal pleural nodularity or
thickening exist, image-guided biopsies should first be attempted. This review addresses the
current diagnostic approach to pleural effusions secondary to heart failure, pneumonia,
cancer, tuberculosis and other less frequent conditions.
KEYWORDS: chylothorax ● empyema ● heart failure ● hepatic hydrothorax ● malignant pleural effusion ● mesothelioma
● pleural effusion ● tuberculosis
Introduction which include history and physical examina- 45
It is estimated that pleural diseases affect over tion, pleural fluid analysis, imaging and pleural
3,000 people per million population.[1] biopsy; a flow diagram is summarized in
Establishing the precise etiology of a pleural Figure 1. The current article will focus on the
effusion should ideally follow logical, non-com- diagnostic approach to specific etiologies of
plex diagnostic algorithms. Few evidence-based pleural effusions. 50
clinical guidelines, however, are available to the
practicing physician,[2,3] which, in addition to Diagnosis of cardiac effusions
the lack of good quality randomized controlled HF-related effusions should be suspected in
studies, make management of pleural effusions any patient presenting with shortness of breath
heterogeneous.[4] and one or more of the following characteris-
Pleural effusions may result from an increase tics: previous history of HF, paroxysmal noc- 55
in the rate of pleural fluid formation, a decrease turnal dyspnea, orthopnea, S3 gallop, jugular
in fluid reabsorption or, most commonly, both venous distension, positive abdomino-jugular
processes. Although numerous potential causes test, displaced apical impulse, and radiological
of pleural effusions have been reported, in clin- cardiomegaly, cephalization of the vessels and
ical practice only a few account for most cases. interstitial or alveolar edema.[7] In contrast, 60
For instance, in a series of more than 3,000 the most useful finding for excluding HF is a
consecutive patients with pleural effusions sub- B-type natriuretic peptide (BNP) level lower
jected to a diagnostic thoracentesis, the four than 100 pg/mL.
main causes, in order of frequency, were cancer Routine chest radiographs reveal effusions in
(27%), heart failure (HF) (21%), pneumonia about 45% of patients with an acute decom- 65
(19%) and tuberculosis (TB) (9%).[5] pensated HF, a percentage which doubles when
However, HF can be considered the leading more sensitive techniques such as transthoracic
etiology of pleural effusions, since many ultrasonography or computed tomography
patients with a clinical diagnosis of HF do (CT) are employed. On chest films, effusions
not undergo a pleural aspiration. Readers are are bilateral in nearly 60% of the cases, right- 70
referred to other reviews [3,6] for the stage sided unilateral in 30%, and unilateral on the
investigation of an undiagnosed effusion, left in those remaining [7] (Figure 2).

www.tandfonline.com 10.1586/17476348.2015.1098535 © 2015 Taylor & Francis ISSN 1747-6348 1

 Review Porcel et al.
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Figure 1. Approach to the diagnosis of pleural effusions.[1,6]
ADA, adenosine deaminase; CT, computed tomography; LDH, lactate dehydrogenase; NT-proBNP, amino terminal fraction of pro-brain
natriuretic peptide; PAH, pulmonary arterial hypertension; PE, pulmonary embolism; PF, pleural fluid; PF/S, pleural fluid to serum; US,
ultrasonography.
Figure 2. Chest X-ray showing bilateral pleural effusions,
cardiomegaly, vascular redistribution and interstitial
edema in a patient with heart failure.
Occasionally, they may become loculated into a lung fissure,
thus giving the appearance of an intraparenchymal mass that
disappears with diuretics (vanishing tumors). On ultrasonogra-
phy, the presence of symmetric bilateral B-lines or comet-tail
artifacts, which are suggestive of an alveolar-interstitial
2 Expert Rev. Respir. Med. 00(00), (2015)
syndrome, along with a pleural effusion is indicative of a
decompensated HF in an adequate clinical context.
Ultrasonography may also help to monitor volume overload
through the evaluation of the effusion’s size and the caliber of
the inferior vena cava and its collapsibility.
In patients with a clinically evident acute decompensated HF,
a pleural tap is unnecessary. However, a thoracentesis is indi-
cated if any of the following characteristics are present: chest
pain, fever, unilateral pleural effusions (particularly if left-sided),
bilateral pleural effusions of disparate sizes, absence of cardio-
megaly on chest radiographs or no response to diuretics. When
aspirated, pleural fluid is usually yellowish or serous, though its
appearance may also be watery (<15%) or even bloody
(15%).[8]
The most consistent findings on pleural fluid analysis are, in
descending order of prevalence [7,8] as follows: a serum to
pleural fluid albumin gradient (serum albumin minus pleural
fluid albumin) greater than 1.2 g/dL (94%), lactate dehydro-
genase (LDH) less than two-thirds of the upper normal limit for
serum (93%), pleural fluid to serum LDH ratio less than 0.6
(84%), cholesterol less than 45 mg/dL (84%), pleural fluid to
serum protein ratio less than 0.5 (83%), serum to pleural fluid
protein gradient greater than 3.1 g/dL (80%) and protein levels
lower than 3 g/dL (78%).
Traditionally, HF-related effusions have been considered to
fall into the transudative category according to Light’s cri-
teria, which classify an effusion as a transudate if it meets the

Box 1. Light’s criteria for discriminating pleural exudates from transudates.[1,6]
An exudative pleural effusion meets one or more of the following criteria, while a transudate meets none
● Pleural fluid protein divided by serum protein >0.5
● Pleural fluid lactate dehydrogenase (LDH) divided by serum LDH >0.6
● Pleural fluid LDH >2/3 (67%) the upper normal limit for serum LDH
three conditions listed in Box 1. Light’s criteria are signifi-
cantly superior to pre-thoracentesis clinical judgment in iden-
tifying pleural transudates (75% vs. 56% in one study).[9]
However, these criteria may misidentify a cardiac effusion as
an exudate, usually by a small margin, in up to 30% of cases.
[10] This is particularly likely if the patient has been receiv-
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ing diuretics before the thoracentesis or the pleural fluid is
bloody. Clinically, if a patient appears to have a cardiac
effusion, but pleural fluid meets borderline exudative criteria,
additional tests can be assessed to verify its transudative
nature. Notably, in more than 80% of misclassified HF-
related effusions, the serum to pleural fluid albumin gradient
is greater than 1.2 g/dL and the serum or pleural fluid
concentrations of the natriuretic peptide NT-proBNP exceed
1500 pg/mL.[11] A gradient between the protein levels in the
serum and the pleural fluid of more than 3.1 g/dL performs
significantly worse than the two previous parameters in that it
is only able to correctly categorize around 50% of the mis-
labeled cardiac effusions.[11] Ultimately, there is still a small
percentage of cardiac fluids that generally meet only one of
Light’s three criteria for exudates, which remain misclassified
after applying albumin gradients or NT-proBNP concentra-
tions. Their diagnosis relies on clinical grounds and appears
evident when other causes of exudates have been reasonably
excluded and the effusion clears with diuretic therapy.
Diagnosis of hepatic hydrothorax
Hepatic hydrothorax (HH) is a pleural effusion that complicates
portal hypertension. It results from the transfer of ascites to the
pleural cavity through small diaphragmatic defects. About 6% of
patients with cirrhosis and ascites develop HH.[12] They are
frequently men (65%) with either alcoholic liver disease or
chronic hepatitis C (>80%).[13] HH should be suspected in
any patient with pleural effusion and a previous history of
cirrhosis or, alternatively, one or more of the following char-
acteristics: presence of ascites, thrombocytopenia, spider nevi
lesions on physical examination, or a combination of simple
laboratory tests (i.e., alanine aminotransferase:aspartate amino-
transferase ratio, platelet count and prothrombin international
normalized ratio) into the Bonacini cirrhosis discriminant score
(a scoring greater than 7 makes cirrhosis likely).[14]
Notably, about 10% of patients with HH have no clinically
or echographically detected ascites.[12,13] Effusions are typi-
cally right-sided (75%) and occupy half or more of the hemi-
thorax in 70% of the cases. Pleural fluid analysis is mandatory
www.tandfonline.com
The diagnosis of pleural effusions Review
since an etiology other than HH is found in 30% of cirrhotic
patients who develop pleural effusions (e.g., spontaneous bacter-
ial pleuritis (SBP), pneumonia, TB, cancer). The pleural fluid is
predominantly a transudate (82%).[12] For those patients with
a clinical picture consistent with HH whose pleural fluids meet
Light’s exudative criteria, a pleural fluid to serum albumin ratio
less than 0.6 may help to reclassify them as true transudates.[10]
The spontaneous infection of a pre-existent HH is termed
SBP. It complicates 10–15% of HH and, interestingly, 40–50%
of these patients do not have an associated spontaneous bacterial
peritonitis.[1] SBP should be suspected whenever a patient with
HH presents with fever, chest pain, new or worsening hepatic
encephalopathy, or unexplained deterioration of renal function.
The fluid in SBP is still a transudate, but with a high number of
neutrophils. The diagnosis is established if the pleural fluid
culture is positive and pneumonia has been excluded. If pleural
fluid cultures are negative, the diagnosis is also accepted when
the pleural fluid neutrophil count exceeds 500 cells/μL.[1]
Diagnosis of malignant effusions
Malignant pleural effusions (MPEs) represent an advanced and
usually incurable stage of cancer; the median survival being only
4–6 months for metastatic cancers and 9 months for mesothe-
lioma.[1] In ~25% of patients diagnosed with an MPE, the
effusion (and the associated breathlessness) is the first presentation
of cancer. For patients with known malignancies, the diagnosis of
a new MPE implies disease progression and alters management.
Lung cancer is one of the most common malignancies causing
MPEs worldwide. One in four lung cancer patients develop an
MPE.[15] Diagnosing pleural involvement during initial clinical
staging renders the patient ineligible for curative resection. For
patients who have undergone curative resection for early stage
cancer, the finding of occult malignant visceral pleural invasion
denotes a poorer prognosis.[16] Pleural lavage performed during
lung resection may show malignant cells in the absence of an
effusion, predicting a higher risk of cancer recurrence and
poorer outcome (median survival 12 months vs. 49 months
for those with a negative lavage).[17] Recent data suggest that
lung cancer cells in the pleural fluid may have discordant
mutation statuses from the primary tumor,[18] a finding that
may influence management.
Not every effusion in a cancer patient is malignant. Para-
malignant pleural effusions may arise from the indirect effect of
cancer (e.g., pneumonia from bronchial obstruction, pulmonary
emboli and lymphangitis). Separating malignant and non-
3
 Review Porcel et al.

malignant effusions has significant implications for management Magnetic resonance imaging (MRI) has a sensitivity of 98%
and prognosis. A high clinical index of suspicion for MPE is and specificity of 92% [23] in detecting pleural malignancy and
important in the workup of a new pleural effusion. Clinical can yield additional information, particularly on the regional
symptoms are, however, often non-specific and may be absent. spread of disease. Malignant pleural disease is suggested by high
signal intensity (relative to adjacent structures) on T2-weighted
images and contrast enhancement on T1-weighted images. MRI
Imaging
is at least as good as CT in detecting malignant features such as
Other than the pleural effusion itself, additional radiological
pleural thickening and nodularity and tumor invasion of the
features of interest include fluid loculations, trapped lung,
chest wall and mediastinum.[24] In mesothelioma, MRI has
pleural thickening and parenchymal pathology. Thoracic ultra-
been shown to excel at detecting diaphragmatic and bony inva-
sound can be useful in detecting pleural malignancy (with 73%
sion.[24] Perfusion MRI is a new technique that uses gadoli-
sensitivity and 100% specificity), especially if it demonstrates
nium contrast enhancement to assess tumor vasculature and the
parietal pleural thickening (>1 cm), pleural nodularity and
anti-angiogenic effects of chemotherapy, and may be superior to
diaphragmatic thickening (>7 mm).[19]
morphologic assessment in measuring early treatment response.
The hallmark features of pleural malignancies on CT include
[24,25]
pleural nodularity, mediastinal and circumferential parietal
thickening, and pleural thickening more than 1 cm (Figure 3).
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Pleural fluid analysis

In a retrospective study of 211 patients, these features had
The imaging features, however, are not useful in defining his-
positive (PPV) and negative (NPV) predictive values of 80%
tological types of pleural malignancies. Histocytological analysis
and 65%, respectively.[20] Recently, a simple chest CT scan
remains necessary to confirm a cancer diagnosis, define the
scoring system, which included the evaluation of pleural nodu-
histological tumor type and, wherever appropriate, permit mole-
larity or thickening ≥1 cm (5 points), the presence of liver
cular testing.
metastases, abdominal masses and lung nodules/masses (3 points
Thoracentesis is usually the first diagnostic step in the
each), and the absence of pleural loculations, pericardial effu-
workup of an MPE. No biochemical features accurately define
sions or cardiomegaly (2 points each), has proved to be reliable
MPEs. Most are exudates according to Light’s criteria, but up to
in identifying malignant effusions when 7 or more points are
8% may be transudates (usually from concurrent diseases).[26]
reached (sensitivity 74%, specificity 92%, likelihood ratio posi-
Case reports suggest that a distinct color of the pleural fluid
tive 9.4 and likelihood ratio negative 0.28).[21]
(black or brown) may be indicative of malignant type.[27,28]
Fluorodeoxyglucose avidity in positron emission tomography
The reported diagnostic yield of pleural fluid cytology varies
(PET) is moderately sensitive for pleural malignancy but can also
(commonly in the range of 50–72%) depending on tumor type
be seen in infection, inflammation and after pleurodesis. In a
and load, and experience of the cytologist.[3,5,6] In experienced
meta-analysis, the pooled test characteristics of hybrid PET-CT
hands, diagnostic yields of >70% can be achieved from cytology
imaging systems using semi-quantitative interpretations yielded
even for mesothelioma.[29] Negative cytology analyses in MPEs
81% sensitivity and 74% specificity.[22] PET may detect extra-
are often due to the appearance of the neoplastic cells not being
pleural sites of cancer involvement and can also be a guide to the
distinguishable enough to allow for a definitive diagnosis, or else
best site for pleural biopsies in selected patients. Novel PET tracers
the absence of malignant cells in the fluid. For this reason, a
and molecular imaging are under active investigation.
second or third thoracentesis only marginally improves the
diagnostic yield (~20% and 5%, respectively).[5] Likewise, stu-
dies have shown that submitting >60 mL of fluid for cytological
examination does not improve the yield.[30]
The measurement of pleural fluid levels of conventional
tumor markers (e.g., CEA, CA125, CA15-3 and CYFRA21-1)
is of limited use.[31] Newer clinically validated diagnostic bio-
markers, such as mesothelin,[32] fibulin-3,[32] survivin [33]
and CD163+CD14+ tumor-associated macrophages,[34] have
emerged, but do not replace the need for cytological or histolo-
gical confirmation of malignant cells in present-day practice. In
particular, a raised pleural fluid mesothelin level (in the absence
of renal impairment) is highly suggestive of pleural malignancy,
most commonly mesothelioma but also of other cancers (espe-
cially ovarian and pancreatic).[35]

Pleural tissue biopsy

Figure 3. Malignant pleural thickening (arrowheads) on CT If a pleural fluid analysis is non-contributory, then a pleural
scan in a patient with a lymphomatous effusion. tissue biopsy should be considered. For patients with pleural

4 Expert Rev. Respir. Med. 00(00), (2015)


thickening, imaging-guided biopsies (by CT or ultrasound) have
been shown to be superior to blind percutaneous (e.g., Abrams)
biopsies.[36] Malignant infiltration of the parietal pleura is
often patchy, hence blind pleural biopsy adds <10% yield to
pleural fluid cytology. Chang et al. found that ultrasound-
guided pleural biopsies with Tru-cut needles were more sensitive
at diagnosing pleural malignancy (70% vs. 44%) than Abrams
needle biopsies.[37] Maskell et al. randomized 50 patients with
suspected malignant effusions to either a CT-guided cutting
needle biopsy or an Abrams biopsy and found a higher diag-
nostic yield with the former (sensitivity 87% vs. 47%, respec-
tively).[38] CT has the advantage of detecting smaller lesions for
biopsy but is less mobile than ultrasound.[36] In a randomized
trial, the diagnostic yield of a CT-guided pleural biopsy was
comparable to that of a thoracoscopic biopsy for detecting
malignancy in patients with pleural thickening ≥1 cm on CT
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(96% vs. 95% respectively), but thoracoscopy was superior if
the pleural thickening was <1 cm.[39]
Thoracoscopy offers direct visual-guided biopsies of macro-
scopic abnormalities not apparent radiologically and thus has a
high diagnostic yield. The opportunity to perform talc poudrage
at the time of thoracoscopy can be an added advantage. Surgical
(video-assisted thoracoscopy) and medical (pleuroscopy) thora-
coscopies have similar yields. The choice of rigid vs. flexi-rigid
pleuroscopy is summarized elsewhere.[40] Of note, thoraco-
scopy is not a “gold standard” as false negatives are known to
occur (~10%), most commonly in mesothelioma patients.[1] If
the clinical concern of pleural malignancy (especially mesothe-
lioma) is high, or if the blood or pleural fluid mesothelin levels
are elevated, the patients should be re-evaluated or placed under
close surveillance, even if thoracoscopic biopsies were non-
malignant.
Diagnosis of parapneumonic effusions
The early identification of patients with a pleural infection and
the differentiation between a non-infected and infected pleural
collection in the context of symptoms suggestive of infection are
key diagnostic aspects. The clinical outcome from an infected
pleural space remains very poor—around 20% of patients either
die or require invasive surgery for this condition.[41,42] As
pleural fluid progresses from the initially infective stage to the
later fibrinopurulent stage, earlier identification and institution
of correct management is likely to result in a better outcome.
Background and definitions
Pleural effusion in the context of pneumonia is common, with
around 50% of patients with pneumonia having ultrasono-
graphic evidence of effusion.[43] However, the minority
(around 7%) of patients with pneumonia has an infected pleural
collection,[44] and therefore, tools to differentiate this condi-
tion are needed. For the purposes of this article, the term
“pleural infection” will be used to denote any pleural space
with evidence of active bacterial infection. This is traditionally
known as a “parapneumonic effusion”, and while it is true that
the majority of pleural infection cases are related to pneumonia,
www.tandfonline.com
The diagnosis of pleural effusions Review
it is increasingly recognized that the lung may be relatively
normal (seen in 30% of cases in the MIST2 study).[42] It is
therefore likely that pneumonia is sufficient, but not always
necessary, to cause infection of the pleural space.
Parapneumonic effusion has traditionally been separated into
the “complicated” and “uncomplicated” subtypes, and there is a
degree of confusion amongst clinicians as to what this classifica-
tion indicates. The differentiation is based on the seminal work
of Heffner et al. [45], where patients with pleural infection were
classified into those with a “complicated clinical course” (i.e.,
requiring the need for chest drainage or surgery) and those who
did not require such intervention to recover from their infection
(i.e., treatment with antibiotics only). Thus, the designation
“complicated” refers to the predicted clinical course of a patient,
and its diagnosis used as a surrogate for interventions such as the
use of intercostal drainage. With the increasing use of thoracic
ultrasound, it has been assumed that sonographic “complexity”
(i.e., the presence of fibrin, echogenic fluid or septations) is
synonymous with a “complicated” parapneumonic effusion as
above. While there is some evidence that sonographic features
may predict poorer clinical outcome in pleural infection, there is
no direct evidence to date that radiographic markers are able to
reliably predict which patients will run a clinically complicated
course.[46] Therefore, the accurate identification of patients
with pleural infection requires the clinician to have an apprecia-
tion of what the above terms represent, and an index of suspi-
cion such that patients with potential pleural infection are
assessed for this disease both clinically and using pleural fluid
sampling.
It has been established that there are no reliable clinical or
radiological predictors for the presence of pleural infection.
[2,46] Attempts have been made to risk stratify which patients
with pneumonia are more likely to develop the complication of
pleural infection, and a prospective observational study has
addressed this issue.[44] Using multivariate modeling, indepen-
dent factors were a low serum albumin, low serum sodium, a
high platelet count, a C-reactive protein level above 100 mg/L
and a history of drug or alcohol abuse. Prospective validation is
required before use in clinical practice.
The presence of effusion in the context of clinical suspicion of
infection therefore mandates pleural fluid sampling.[46] In cur-
rent practice, this should always be conducted using ultrasound
guidance, with evidence demonstrating high procedural success
and low complication rates when using this technique.[1,6] As
pleural infection may result in a loculated, septated pleural space
with abnormal anatomy including tethered lung and displaced
diaphragm, the use of ultrasound guidance is particularly impor-
tant in this context.
Pleural infection diagnostic markers
There are a number of pleural fluid diagnostic markers which
suggest pleural infection. Due to this complexity, decision trees
are common in guidelines, with an excellent example in the
2010 British Thoracic Society Guidelines on the Management
of Pleural Infection.[46]
5
 Review Porcel et al.
Empyema
The presence of pus in the pleural space upon thoracentesis is
diagnostic of empyema. This is a macroscopic diagnosis made at
the bedside after the aspiration of the abnormal fluid. It should
be noted that other causes of heavily fibrinous effusions can
cause this appearance, and conditions such as chylothorax may
look similar to empyema. Specific pleural fluid tests should be
undertaken if this is suspected—but bench centrifugation of the
fluid will easily differentiate these conditions, with empyema
demonstrating a supernatant and a fibrinous phase, whereas
chylothorax will show no difference post-centrifugation.[6]
Microbiological positivity
In the absence of pus, and in a patient with a radiologically
established pleural effusion in the context of symptoms sugges-
tive of infection, further pleural fluid analysis is required. Pleural
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fluid should always be submitted for Gram’s stain and micro-
biological analysis—the presence of positive microbiology is
diagnostic of pleural infection. Microbiological analysis of
pleural fluid is not 100% sensitive [5] and institution of drai-
nage and appropriate antibiotic therapy should not wait for
culture results. Therefore, this test is not usually used in real
time to diagnose a “complicated” collection requiring drainage.
The presence of positive pleural fluid microbiology is helpful in
focusing antibiotic therapy, but this result may not be available
for some days.
Pleural metabolic markers
In those patients with non-purulent pleural fluids, further tests
are required to differentiate those with evidence of early bacter-
ial infection, in the absence of positive microbiology and at the
point of thoracentesis. Pleural fluid forms in association with
pneumonia which causes the production of pro-inflammatory
cytokines within the pleural space, such as TNF-alpha, IL-6 and
IL-8.[47,48] As the infection progresses, translocation of bac-
teria is thought to occur from the infected lung into the pleural
space. This results in a more metabolically active pleural milieu,
and markers of this activity are used to identify those patients
with early biochemical evidence of pleural infection.
A number of markers have been assessed in this context, with
pleural fluid glucose, LDH and pH being the most well studied,
and indeed the most reliable and robust for clinical use.[49] The
definitive meta-analysis performed by Heffner et al.[45] demon-
strates that pleural pH is the most reliable marker of those
patients who undergo a complicated clinical course. A pleural
pH threshold of less than or equal to 7.2 is taken as the optimal
cutoff and is advocated in guidelines as the correct clinical
threshold for instituting drainage.[2,46]
The pleural pH is not 100% sensitive and should be inter-
preted in the correct clinical context.[49] There are a number of
conditions which lower the pleural pH to this threshold includ-
ing esophageal perforation, advanced MPE, TB pleuritis and
rheumatoid pleuritis.[6] In addition, a few patients with initially
“normal” pleural pH will progress to require surgical drainage,
6 Expert Rev. Respir. Med. 00(00), (2015)
[49] and repeat sampling should be considered in the correct
clinical context.
There are a number of situations in which the pleural pH
may be an unreliable marker of complicated parapneumonic
effusion.[50] This includes the rare cases of urea splitting organ-
isms (such as Proteus mirabilis), a pleural infection in which the
pleural pH may be raised rather than suppressed. Ultrasound-
guided thoracentesis studies have demonstrated different pleural
pHs in different areas of multi-septated pleural collections,[51]
and hence the presence of septations on ultrasound should raise
suspicion that the pH may not be a reliable treatment indicator.
Finally, the conditions of measurement of pleural pH have to be
carefully controlled to ensure a reliable result.[50] Litmus paper
has been demonstrated to be unreliable, and although handheld
pH analyzers have been shown to be accurate, their use is not
widespread. Pleural pH should always be measured using a
blood gas analyzer—and as long as one avoids analyzing puru-
lent material (which is of no clinical value), there is no sub-
stantial evidence to indicate that this damages the analyzers. A
number of conditions have been identified which render the
pleural fluid unreliable for analysis—these include delaying
analysis by more than 1 h, failing to exclude all air bubbles
from the sampling syringe and the presence of even small
volumes (0.1 mL) of residual local anesthetic or heparin.[50]
In all of these conditions, the pleural fluid glucose appears to be
consistent and robust (with a threshold of <3.0 mmol/L assum-
ing the patient is not diabetic).
Pleural microbiology
Even in the context of purulent pleural fluid, microbiological
analysis is only positive in around 60% of cases.[5] This means
that microbiology alone cannot be relied on as a “rule out” test
for pleural infection, and that a significant proportion of
patients will require empirical antibiotic therapy for their treat-
ment. Attempts have been made to increase pleural fluid micro-
biological yield. Based on data from peritoneal dialysis patients
with bacterial peritonitis, the use of inoculation of pleural fluid
into bacterial blood culture bottle systems (such as the
BACTEC system) has been assessed. A prospective trial with a
control group of HF patients demonstrated that using this
method can increase the microbiological yield by up to 20% if
used in addition to submitting fluid in a plain microbiology
container, and this often included the identification of strepto-
coccal species and gram negatives.[52] Although the blood
culture bottle results only directly influenced antibiotic treat-
ment in 4% of cases, this study was not powered to address a
change in clinical outcome. The results suggest that this should
be part of routine clinical care of patients with suspected pleural
infection.
Radiology
There are a number of radiological markers which make pleural
infection more likely, but no single predictor which can act as a
reliable diagnostic test. The presence of non-gravity-dependent
pleural collections on an erect chest radiograph is highly

suggestive of loculated or septated fluid, which indicates pleural
infection in the correct clinical context. Venous-contrast-
enhanced thoracic CT is reliable in the differentiation of pleural
infection and lung abscess. Infected pleural collections often
display the “split pleura sign”, in which the parietal and visceral
pleural surfaces brightly enhance and are separated by pleural
fluid.[1,6] However, a metabolically active pleural space of any
cause may result in this appearance. CT is helpful in the
identification of underlying lung consolidation (seen in around
70% of pleural infection cases) and other potential causes such
as an obstructed main bronchus.
On ultrasonography, the presence of heavily echogenic mate-
rial may suggest an empyema, but is also seen with hemothorax
and any cause of a heavily proteinaceous collection. There is
increasing interest in the predictive value of sonographically
detected septations, with retrospective studies reporting an
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increased use of fibrinolytic, higher surgical rate and mortality
and a higher need for intensive care in patients with septated
effusions compared to those without.[49] However, prospective
and blinded studies are required before the true utility of septa-
tion recognition at ultrasound is known.
Novel biomarkers
A number of potential biomarkers have been assessed in the
differentiation of complicated parapneumonic effusions from
“simple” or malignant effusions. These include procalcitonin,
triggering receptor expressed on myeloid cells (sTREM-1), lipo-
polysaccharide-binding protein and C-reactive protein. In a
large study, all of these markers were demonstrated to perform
less well than pleural fluid pH, glucose and LDH.[53] While
there has been significant interest in the use of procalcitonin, a
meta-analysis of 6 studies including 780 patients demonstrated
that the serum C-reactive protein is of higher diagnostic value
than serum procalcitonin in the diagnosis of complicated para-
pneumonic effusions.[54]
One context in which procalcitonin may be helpful is in the
differentiation of infected pleural effusion from post-pleurodesis
inflammation. In a proof of principle study, serum C-reactive
protein was demonstrated to rise significantly post-talc pleurod-
esis whereas procalcitonin was relatively unaffected.[55]
Although further data is needed, this may be helpful in cases
where infection is suspected post-pleurodesis.
Finally, a prognostic scoring system in pleural infection has
recently emerged which may be able to differentiate between
those with a good clinical outcome and those with a poor
outcome, including mortality.[56] The “RAPID” score uses
baseline parameters commonly collected in routine clinical prac-
tice, and includes serum markers (urea and albumin), as well as
the source of infection (hospital or community-acquired),
patient age and diastolic blood pressure. The score requires
prospective validation, but should it prove to be robust, may
permit more individualized and aggressive therapy in pleural
infection.
www.tandfonline.com
The diagnosis of pleural effusions Review
Diagnosis of tuberculous effusions
Globally, TB remains a frequent cause of pleural exudates, and
it is the most common cause of a lymphocytic effusion in HIV
patients in endemic areas.[57] It is therefore important to have a
high index of suspicion in patients who live or have emigrated
from high prevalence areas (≥125/100,000 population), parti-
cularly if they are immunocompromised or have constitutional
symptoms.
Imaging
TB effusions are frequently unilateral and may vary in size from
small to massive, occupying less than one-third of the hemi-
thorax in 80% of cases.[57] Parenchymal changes suggestive of
TB are present in up to 50% of chest radiographs and 80% of
CT.[58] On chest CT, parenchymal abnormalities may include
micronodules in the subpleural and peribronchovascular inter-
stitium, with interlobular septal thickening, suggesting lympha-
tic spread (Figure 4). The CT may also suggest TB empyema,
when the thickened visceral and parietal pleura separated by
fluid give rise to the “split pleura” during the fibrinopurulent
phase (Figure 5). On ultrasonography, the appearance of TB
effusions ranges from anechoic to complex septated or non-
septated to even homogeneously echogenic.
Diagnostic principles
The gold standard for the diagnosis of pleural TB remains the
detection of Mycobacterium tuberculosis in sputum, pleural fluid
or pleural biopsy specimens (by either microscopy and/or cul-
ture), or the histological demonstration of caseating granulomas
in the pleura containing acid-fast bacilli (AFB).[57] The diag-
nosis is, however, often inferred in patients from high burden
settings who present with pleural caseating granulomas (without
AFB) or a lymphocytic predominant exudate and high adeno-
sine deaminase (ADA) levels.[57]
Figure 4. A CT from a patient with confirmed pleural TB
(right-sided effusion, E) showing parenchymal involve-
ment as well (bilateral patchy consolidation in this parti-
cular case; arrows).
7
 Review Porcel et al.
Figure 5. This CT scan demonstrates moderate visceral (V)
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and parietal (P) thickening, which is often observed in
cases of TB empyema.
Sputum
Sputum is generally underutilized. A study from Brazil found a
single induced sputum TB culture had a sensitivity of 52%.[59]
The yield of sputum newer nucleic acid amplification tests
(NAAT) is not known.
Thoracentesis
Microscopy and culture
Microscopy will reveal AFB in <10%, which is more commonly
seen in patients with HIV and tuberculous empyema.[57] Solid
culture media historically yielded low sensitivities (12–30%), but
modern liquid media (e.g., the BACTEC MGIT semi-automated
system) have superior sensitivities (up to 70%).[60] A significantly
shorter time to positivity is an added benefit.[60] The volume
inoculated (100 mL vs. 5 mL) does not influence the sensitivity.
HIV-positive individuals are more likely to be culture-positive.[61]
Biochemistry analyses
The pleural fluid is straw-colored >80% and uniformly exudative.
None of the routine biochemistry findings are specific. ADA
levels are most useful in patients with a high suspicion for TB,
although a wide range of cutoff values (35–60 U/L) have been
reported.[57] The majority will have an ADA > 50 U/L. A cutoff
of 40 U/L has a sensitivity of 88–91% and specificity of 96–97%.
[57,62] An ADA > 50 U/L has a PPV of 97% in a high
prevalence setting.[63] The most meaningful cutoff value
depends not only on the pre-test probability for the disease, but
also whether ADA is being used to exclude or diagnose TB.[57]
In a high prevalence setting, an elevated ADA level might be
considered as a confirmatory test justifying treatment initiation.
In contrast, in low prevalence settings, the NPV remains high
even though the PPV of pleural ADA declines.[62] In popula-
tions with low TB prevalence, 97–98% of non-TB effusions will
have values <40 U/L, justifying pursuing alternative diagnoses.
[64] Common explanations for false-negative ADA levels include
8 Expert Rev. Respir. Med. 00(00), (2015)
early pleural TB, smoking and aging, whereas false-positive levels
can be found in rheumatoid effusions, malignant pleural effusions
(particularly lymphomas) and parapneumonic effusions.
Measuring different ADA isoenzymes has been shown to increase
the specificity from 91–92% to 96–99%.[57,65] ADA-2 is
increased in TB effusions, whereas ADA-1 is increased in bacterial
empyemas.
Nucleated cell count and cytology
A lymphocyte predominance (lymphocyte:neutrophil >0.75) is
present in 60–90%, depending on the timing of the thoracent-
esis.[57] Fluid collected in the first few days may exhibit a
neutrophil predominance, while lymphocytes tend to dominate
thereafter. The combined sensitivity, specificity, PPV and NPV
of a lymphocyte predominance and raised ADA levels are
88–89%, 95–100%, 88–100% and 69–88%, respectively.
[57,63] Eosinophilic predominance is rare, unless the patient
has had a pneumothorax or hemothorax. The presence of >5%
mesothelial cells is unusual.
Additional pleural fluid assays and biomarkers
Unstimulated pleural fluid interferon gamma (IFN-γ) is a useful
diagnostic aid, although its specificity is hampered by similar
factors that influence the specificity of ADA. A meta-analysis
reported that IFN-γ > 131.3 pg/mL had a sensitivity and specificity
of 89% and 97%, respectively.[66] A recent study found IFN-
γ > 107.7 pg/mL to be an excellent rule-in test and that, compared
to ADA, it has superior sensitivity and rule-out value in a TB-
endemic setting.[67] The test, however, is not yet widely available
and evidence for its utility in low TB burden settings is lacking.
NAAT have a high specificity, but a low sensitivity for pleural TB,
ranging from 25% to 62% in low vs. high prevalent settings.[57]
Pleural biopsy
Medical thoracoscopy allows direct visualization and biopsy of
the diseased pleura, has a sensitivity of 100% and is the pre-
ferred technique in most first world countries.[3,63]
Ultrasound-guided pleural biopsy has gained popularity, par-
ticularly in centers where access to thoracoscopy is limited
(which is the case in many high TB burden countries).[36]
Thoracoscopy is reserved in these settings for the small number
of cases where closed biopsy (the preferred procedure) is non-
diagnostic.[36] Ultrasound-guided pleural biopsy (with an
Abrams needle) has a sensitivity of up to 90%, provided at
least 6 specimens are obtained.[68] Surgical biopsy (either thor-
acoscopy or open) is rarely required.
Practical diagnostic approach
The pre-test probability should guide the practicing physician.
If the effusion is lymphocytic predominant with an
ADA > 40 U/L, and the TB prevalence is high, it is sensible
to initiate TB therapy without delay. It may be appropriate to
repeat thoracentesis in cases not diagnosed on the initial aspira-
tion. A recent study showed that 77.8% of cases could be
diagnosed on a second thoracentesis.[69] The same study

found that an image-assisted thoracentesis and a pleural biopsy
had a combined sensitivity of 89% in patients who previously
had a non-diagnostic thoracentesis, making it an acceptable
alternative to thoracoscopy in high prevalence settings.[69]
In a low prevalence population, it remains paramount to
perform pleural biopsies (unless M. tuberculosis is cultured
from fluid).[3] Thoracoscopy has a superior diagnostic yield
for both MPE and TB, and is therefore considered to be the
investigation of choice in pleural exudates when thoracentesis is
non-diagnostic.[3]
Diagnosis of uncommon pleural effusions
Chylothorax
The thoracic duct carries chyle (a lymphatic fluid enriched with
lipids absorbed from the gastrointestinal tract, lymphocytes and
proteins) from the cisterna chyli, which is a retroperitoneal
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reservoir posterior to the abdominal aorta, to the central venous
vasculature in the upper thorax, typically at the junction of the
left jugular and subclavian veins. Any disruption or obstruction
of the thoracic duct may result in chyle leakage with pleural
accumulation, that is, chylothorax.[70] As etiologies of chy-
lothorax have shifted from non-traumatic to traumatic causes,
the clinical context will often point toward the possibility of
chylous effusion, such as neck, thoracic or abdominal surgery,
central venous thrombosis due to pacemaker leads or cannula-
tion, or even chest trauma.[71]
This diagnosis is often considered when thoracentesis yields a
typical milky and opalescent fluid. Centrifugation will fail to clear
the fluid, as in pseudochylous effusions (see below), distinguish-
ing it from empyema that may occasionally have a similar appear-
ance. Chylothorax is confirmed by pleural fluid analysis
demonstrating the presence of chylomicrons (the gold standard),
or its surrogate, a triglyceride (TG) content >110 mg/dL.[70]
Cholesterol level is typically within normal limits. The appear-
ance may be misleading, as a significant proportion of chylous
effusions are serous or serohemorrhagic and, likewise, the TG
content is <110 mg/dL and <50 mg/dL in 15% and 3% of cases,
respectively, reflecting the nutritional status of the patient (with a
lesser lipid content in malnourished, fasting patients or with low-
fat diets).[70] Chylothoraces are typically lymphocyte-predomi-
nant, exudative effusions, and described in some studies as a
“protein-discordant” exudate (high protein, but LDH in the
transudative range).[72] Transudative chylothoraces have been
described in 15–30% of cases, such as in cirrhosis, portal hyper-
tension, constrictive pericarditis and amyloidosis.[70,72]
Chest CT is mandatory to assess for the presence of an
obstructive or infiltrative mediastinal process, and may reveal
pericardial thickening suggestive of constrictive pericarditis (an
echocardiogram may be necessary) or parenchymal cystic lesions
in the case of lymphangioleiomyomatosis, for instance. Upper
abdominal cuts may demonstrate cirrhosis, features of portal
hypertension or retroperitoneal lymphadenopathy, occasionally
responsible for chylous ascites with transdiaphragmatic pleural
extension. While lymphoscintigraphy has recently been recom-
mended, lymphangiogram using lipiodol will often clarify the
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The diagnosis of pleural effusions Review
etiology of chylothorax, identify the leakage site and occasion-
ally allow embolization of the culprit vessel.[73] Due to the high
viscosity of the contrast agent, diagnostic lymphangiograms
occasionally lead to resolution of the chylothorax.
Pseudochylothorax (cholesterol effusions)
Cholesterol effusions represent the main differential diagnosis of
chylothorax. They may be seen in a variety of clinical situations,
with typical etiologies being chronic pleural effusions secondary
to rheumatoid arthritis or TB.[74] The pathophysiology is
unclear, and the traditional hypothesis that cholesterol effusions
are due to cellular lipid membrane breakdown and accumula-
tion due to chronic pleural thickening has been challenged by
recent observations.[75] Hence, a thickened pleural may be
absent on chest CT. The diagnosis is established by the presence
of a high cholesterol content >200 mg/dL, and a cholesterol to
TG content >1. Given the predominance of TB and rheumatoid
arthritis-associated pleural effusions, investigations should be
pursued accordingly.
Urinothorax
Urinothorax is a peculiar type of pleural effusion rarely encoun-
tered in the setting of obstructive uropathy. The putative
mechanism responsible for urinothorax is transdiaphragmatic
diffusion of urine in the pleural space from the abdomen,
facilitated by the negative intrathoracic pressure generated dur-
ing breathing efforts. The fluid typically has the characteristic
odor of urine, is usually transudative and characterized by a
pleural fluid to serum creatinine ratio >1, which is sensitive but
not specific for urinothorax.[76] Notably, urinothorax is the
only known transudative pleural effusion with low pH. While
the clinical scenario typically suffices for the diagnosis, renal
scintigraphy may confirm the origin of the pleural fluid showing
accumulation of the tracer in the pleural space.
Amyloidosis
Pleural effusions in systemic amyloidosis are relatively rare, and
portend a poor prognosis with a median survival of 1.6 months in
the absence of treatment.[69] They are typically seen in primary
amyloidosis, although cases due to secondary amyloidosis have
been reported. They are usually transudative, and typically occur
in patients with cardiac amyloidosis. Interestingly, HF does not
appear to be sufficient to explain these effusions. In the largest
series, echocardiographic indices in patients with systemic amy-
loidosis and pleural effusions were not any worse than in those
without effusions.[77] Nephrotic syndrome and hypothyroidism
were also not more common, suggesting that direct pleural infil-
tration by amyloidosis is likely the main determinant of pleural
effusion, as confirmed by thoracoscopic biopsies. Chylothoraces
have also been described, and are likely secondary to direct
amyloid infiltration of the thoracic duct or its tributaries.
Duropleural fistula
Duropleural fistula is a vanishingly rare cause of transudative
effusion with very low protein (<0.05 g/dL) and LDH level,
9
 Review Porcel et al.
which may occur in blunt and penetrating trauma resulting in a
fistulous tract between the central nervous system and the
pleural space.[78] A high level of suspicion in the appropriate
clinical setting and a watery appearance of the pleural fluid
should prompt measurement of beta-2 transferrin, an isoform
of transferrin specific to the cerebrospinal fluid, which estab-
lishes the diagnosis. CT myelography may pinpoint the location
of the fistula.[78]
Undiagnosed pleural effusions
Standard diagnostic workup fails to establish the cause of
approximately 20% of pleural effusions.[1,3,6] The lingering
concerns of possibly threatening underlying etiology can be
distressing for patients and clinicians. Unfortunately, data on
the appropriate management of undiagnosed pleural effusions is
scarce.
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There are a number of factors that may contribute to the
difficulty in establishing the etiology of the “undiagnosed effu-
sions”. In some cases, the diagnosis, though obscure, can be
derived from pleural fluid or tissue analyses. In others, usually
from extrapleural causes, no pathognomonic features exist in
pleural fluid or tissue. Diagnostic clues from the pleural fluid or
tissues can be challenging to uncover. Pleural effusions of less
common etiologies might be overlooked. For example, pleural
effusion from cerebrospinal fluid leak is rare, but once suspected
can readily be diagnosed by demonstrating the presence of beta-
2 transferrin in the pleural fluid, as mentioned in the preceding
text. Alternatively, the diagnostic clue may not be detectable in
the fluid (e.g., absence of malignant cells); repeated thoracent-
eses would be unrewarding.
A thoracoscopic pleural biopsy provides a sampling of abnor-
mal pleural tissues under direct visual guidance. Pleural tissue
pathology, however, may not be generalized and sampling errors
can occur despite aggressive biopsies. Typical examples include
the sarcomatoid and desmoplatic subtypes of malignant
mesothelioma where tumor cells are often “hidden” within
fibrotic tissues. Imaging guided biopsies, especially with PET
input, may improve the yield in selected patients by locating the
metabolically active pleural lesions.
The pleura is secondarily affected in many systemic and
pulmonary diseases where pleural fluid and tissue changes are
non-specific; establishing the diagnosis may require exclusion of
other possible causes (Table 1). Nearly 50% of patients with
pulmonary emboli have radiological evidence of a pleural effu-
sion, for which there are no pathognomonic characteristics.[79]
Drug-induced pleural effusions are often diagnosed by obtaining
a detailed clinical history and demonstrating remission after
discontinuation of the drug.[1] Re-challenge of the suspected
drug may be required in some cases. Benign asbestos pleural
effusion and uremic pleuritis are other examples.[1]
In patients whose effusions remain undiagnosed, referral to
a specialist pleural service is recommended. The history, exam-
ination and diagnostic test results should be re-visited. The
threshold for repeating diagnostic tests, including pleural
biopsy, and the frequency of surveillance follow-up will be
10
Table 1. Important causes of undiagnosed pleural
effusions.[1,6]
Conditions that require specific tests Amyloidosis
on pleural fluid or tissue
IgG4 disease
Cerebrospinal fluid leak
Chylothorax/
pseudochylothorax
Lymphoma
Pancreatitis
Conditions where pleural Metastatic carcinomas
involvement is less diffuse and Mesothelioma
sampling errors are common
Systemic diseases (e.g.,
rheumatoid arthritis, SLE)
Conditions where pleural fluid and BAPE
tissue changes are not specific and Post-cardiac surgery
require exclusion of other causes
Trapped lung
Yellow nail syndrome
Pulmonary embolism
Uremic pleuritis
Thyroid disease
Drug-induced
Viral infections
BAPE, benign asbestos pleural effusion; SLE, systemic lupus erythematosus.
dictated by the clinical suspicion of a serious underlying
pathology. A history of malignancy, systemic diseases (e.g.,
rheumatoid arthritis), immunosuppression and significant
exposure to carcinogens (e.g., asbestos) are important consid-
erations.[6] A variety of gastrointestinal diseases, especially
pancreatitis and pancreaticopleural fistulas, may cause pleural
effusions and be overlooked.[1,6] An aggressive approach is
warranted in the setting of persistent symptoms, weight loss
and/or chest pain in particular; or if concerning pleural
abnormalities are present radiologically (e.g., mediastinal
pleural thickening) or during thoracoscopic inspection.
Elevated biomarker levels (e.g., mesothelin) would be highly
suspicious of a primary pleural malignancy and justify urgent
re-exploration.[35]
Follow-up studies of undiagnosed effusions have shown that
many cases will remain undiagnosed and only 5–8% will even-
tually be diagnosed with cancer.[80] Ferrer et al. prospectively
followed 40 patients with undiagnosed exudative effusions, of
which 80% remained undiagnosed after 62 months.[80] A
similar result was also found by Ryan et al. (60.8%).[81] If
the patient’s medical history could be taken into account, 14–
25% of thoroughly investigated effusions remain idiopathic.[82]
It is noteworthy that non-specific pleuritis on thoracoscopic
biopsies cannot be regarded as a clinical diagnosis. Several series
have consistently revealed mesothelioma as the most common
cause of “false negative” thoracoscopic biopsies reported as non-
Expert Rev. Respir. Med. 00(00), (2015)
 The diagnosis of pleural effusions Review

specific pleuritis.[83] No data exists to guide frequency and
duration of clinical and radiological follow-up, but most centers
will undertake monthly to tri-monthly surveillance initially for
up to 2 years.[1,3]
Most (>80%) undiagnosed effusions resolve spontaneously.
[80,82] The time to resolution may be suggestive of the etiol-
ogy.[84] For effusions that persist or for those that relapse after
initial resolution, repeated pleural drainage may be required and
insertion of an indwelling pleural catheter or talc pleurodesis
may be considered in selected cases of rapidly recurring
effusions.
Expert commentary
Aspiration of pleural fluid is one of the first and most important
steps in the assessment of patients with pleural effusions.
Table 2 summarizes the main pleural fluid parameters for estab-
lishing a differential diagnosis of this condition.

Table 2. Pleural fluid tests to evaluate the cause of pleural effusions.[1,3,6,8]

Test Test value Suggested diagnosis Comments
Routine
Red blood cell >100,000/μL Cancer, trauma A PF to blood hematocrit ratio >0.5 is diagnostic of
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count hemothorax
Neutrophils >50% of total Parapneumonics 20% of malignant and 10% of TB effusions are neutrophil-
leukocyte count predominant
Lymphocytes >50% of total Cancer, TB T lymphocytes predominate in TB, and B lymphocytes in
leukocyte count lymphoma
Eosinophils >10% of total Many causes Half of cases are idiopathic or due to cancer. If >30%
leukocyte count eosinophils, low probability of cancer
Protein >3 g/dL Exudate 85% of exudates have these protein levels, while 75% of TB
exceed 5 g/dL
LDH >2/3 of upper limits of Exudate Very high levels (× 5) may be found in complicated
normal for serum LDH parapneumonics and lymphomas
Glucose <60 mg/dL Complicated parapneumonics, Occasionally found in TB or malignancy (<10%).
pH <7.20 empyema, rheumatoid pleuritis Characteristic of TB empyema
ADA >35–40 U/L TB, empyema, lymphoma >90% of TB, 45% of complicated parapneumonics, 70% of
empyemas and 60% of lymphomas have high ADA levels
Bacterial Positive Infection Nearly 40% of empyemas are culture-negative
cultures
Mycobacterial Positive TB Solid media has low yield (20%), but liquid media is far
cultures superior (>60%)
Cytology Positive Cancer Overall sensitivity 60%. Cell blocks increase the diagnostic
yield and allow immunocytochemical staining
Optional
Triglycerides >110 mg/dL Chylothorax Levels <50 mg/dL virtually exclude chylothorax
Cholesterol >45 mg/dL Exudate Levels >200 mg/dL are typical of pseudochylothorax
Amylase × 5–10 the upper limits Pancreatitis, esophageal Pancreatic isoenzyme of amylase is elevated in pancreatitis;
of normal for serum rupture the salivary isoenzyme is elevated due to esophageal rupture
Albumin >1.2 g/dL Heart failure Useful for misclassified cardiac effusions
gradient
NT-proBNP >1500 pg/mL Heart failure Characterize nearly 95% of cardiac effusions
CEA >50 ng/mL Cancer 40% of malignant effusions exhibit these 100% specific
CA15-3 >75 U/mL cutoffs
Mesothelin >20 nmol/L Mesothelioma 70% sensitivity and nearly 90% specificity for discriminating
between mesothelioma and other effusions
NAAT for M. Positive TB Low sensitivity
tuberculosis
ADA, adenosine deaminase; CEA, carcinoembryonic antigen; LDH, lactate dehydrogenase; NAAT, nucleic acid amplification tests; NT-proBNP, amino terminal fraction of
pro-brain natriuretic peptide; PF, pleural fluid; TB, tuberculosis.

www.tandfonline.com 11
 Review Porcel et al.
HF is the leading etiology of pleural effusions. On the occasion
when thoracentesis is performed, the finding of a biochemical
transudate establishes the diagnosis. However, it should be recog-
nized that there still remains a small proportion of patients whose
pleural fluids meet Light’s exudative criteria and for which no
explanations other than HF exists. The disappearance of the
effusion with diuretics strongly points to its cardiac nature.
The diagnosis of MPE may be challenging due to the mod-
erate sensitivity of pleural fluid cytological analyses in general
(60%), and their low yield in neoplasms such as mesothelioma
or squamous cell lung cancer in particular (25–30%).[5]
However, the information provided by immunocytochemical
studies on pleural fluid cell blocks not only increases the diag-
nostic accuracy over that of cytology alone, but also enables the
pathologist to determine the tumor origin and may have ther-
apeutic implications (e.g., determination of epidermal growth
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factor receptor and anaplastic lymphoma kinase status in pleural
fluid samples of lung cancer patients). Thoracic ultrasound is
increasingly used at the bedside by respiratory physicians, not
only for diagnostic purposes, but also to guide and permit safe
pleural interventions. Ultrasound- or CT-guided pleural biop-
sies are currently being used in place of blind needle biopsies, or
even pleuroscopies, on patients with pleural nodularity or thick-
ening for which pleural malignancy or TB is suspected, but
undemonstrated by simpler methods.
In clinical practice, the identification of non-purulent com-
plicated parapneumonic effusions is based on simple pleural
fluid biochemical parameters, such as pH or glucose, since the
poorly sensitive bacterial cultures are not readily available for
speed decisions. Even more often than these fluid clues, the
demonstration of large (half or more of the hemithorax) or
loculated/septated effusions shifts clinical judgment towards
the insertion of an intercostal drain.[49]
Any lymphocyte-predominant exudate with high ADA levels
(>35–40 U/L) in areas with moderate to high burden of TB is
considered tuberculous until proved otherwise, and is an indica-
tion for antituberculous therapy while other diagnostic studies
are pending (e.g., fluid cytology).[85] In the few cases in which
pleural fluid ADA concentrations are below the diagnostic cut-
off or in low prevalence TB areas, closed pleural biopsies
(assisted by ultrasonography) suffice for achieving a confident
diagnosis.
Certain causes of pleural effusions may go unnoticed or be
difficult to diagnose unless there is a high index of suspicion.
These include pulmonary embolism, mesothelioma, benign
asbestos pleuritis, uremic pleuritis, drug-induced pleuritis and
non-milky chylothoraces. The finding of a non-specific pleuritis
on pleural biopsy is not always reassuring because a small
percentage of patients will ultimately have a mesothelioma dur-
ing follow-up.
Five-year view
Although the diagnosis of HF-related effusion is generally straight-
forward, measurement of serum or pleural fluid levels of the
12
natriuretic peptide NT-proBNP in atypical or doubtful cases
(e.g., unilateral large effusions, borderline exudates with low albu-
min gradient) may be justified and become more widespread. In a
recent meta-analysis of 12 studies, pleural fluid levels of NT-
proBNP had 94% sensitivity, 91% specificity, positive likelihood
ratio of 10.9 and negative likelihood ratio of 0.07 for identifying
cardiac effusions. Figures for serum NT-proBNP extracted from 4
studies were 92%, 88%, 7.8 and 0.10, respectively.[86]
Future advances in the non-invasive diagnosis of MPE are
expected, especially with reference to either new panels of
antibodies for immunocytochemical studies, or specific tumor
proteins and genetic fingerprints evaluated in pleural fluid
samples. Similarly, novel molecular PET radiotracers are
rapidly being developed, which may be relevant for diagnosis,
prognosis and therapy monitoring of pleural tumor involve-
ment. Overall, advances in cytopathology and image-guided
biopsies will likely reduce the need for classical medical
thoracoscopy.
In the future, it is possible that molecular microbiological
techniques such as 16s bacterial PCR will enable much higher
diagnostic yields in patients with parapneumonic effusions.[87]
However, this technique is not yet widely available and is
associated with the identification of a large number of organ-
isms, and may be oversensitive. Also, widely sensitive markers of
inflammation, such as C-reactive protein measured either in
serum or in pleural fluid, might represent a useful adjunct for
the identification of those non-purulent parapneumonic effu-
sions which ultimately need pleural drainage.[88]
Due to its NPV approaching 100% when less than 35–40 U/
L, ADA levels will probably be incorporated into the routine
diagnostic algorithms of pleural effusions in low prevalence TB
areas, as has been done in those which are moderate to high.
The introduction and increasing use of liquid culture media for
M. tuberculosis, which provides a much higher yield and faster
results than conventional solid media, may significantly raise the
number of secure TB diagnoses with the additional advantage of
informing on drug-resistant strains.[60]
Financial & competing interests disclosure
M Azzopardi is supported by the Western Australia Cancer & Palliative Care
Network clinical fellowship. YCG Lee is a National Health & Medical
Research Council (NHMRC) Career Development Fellow and receives research
funding from the NH&MRC, the New South Wales Dust Disease Board and
the Sir Charles Gairdner Research Advisory Committee. YCG Lee has been a
member of the advisory board for Sequana Medical, Carefusion, and Lung
Therapeutics Inc. He has received an unrestricted educational grant from
Rocket UK Ltd in support of clinical research. NM Rahman received an
unrestricted research grant from Roche UK to conduct the MIST study. The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript apart from those
disclosed.
Expert Rev. Respir. Med. 00(00), (2015)
 The diagnosis of pleural effusions Review

Key issues
● Cardiac effusions are a clinical diagnosis supported by the finding of a transudate or, alternatively, a borderline exudate with an albumin
gradient >1.2 g/dL or serum or pleural fluid levels of NT-proBNP >1500 pg/mL.
● Hepatic hydrothorax usually manifests as large right-sided pleural effusions in patients with a previous history of cirrhosis, or those with
abnormal physical findings, laboratory and/or abdominal imaging studies consistent with liver disease. Fluid is mostly a transudate, even
if it becomes infected (spontaneous bacterial pleuritis).
● There are about 40% false negative pleural fluid cytological results in malignant effusions. In these cases, image-guided parietal pleural
biopsy is the diagnostic method of choice, provided there are nodules or pleural thickening >1 cm.
● The diagnosis of complicated parapneumonic effusions relies on the aspiration of pus (empyema) or, in those cases in which the pleural
fluid is not purulent, on the demonstration of a marked acidosis (pH < 7.2), low glucose level (<60 mg/dL) or a positive microbiology in
pleural fluid specimens.
● A definitive diagnosis of pleural TB depends on the isolation of Mycobacterium tuberculosis in the sputum, pleural fluid or pleural biopsy
specimens, or the demonstration of caseating granulomas in the parietal pleura. However, lymphocytic exudades with a high ADA
content (>35–40 U/L) are generally accepted as tuberculous in the correct clinical context.
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● When the cause of a pleural effusion remains obscure after the standard initial workup, which may eventually include pleural biopsy,
medical history and all available diagnostic examinations should be revisited. Most of these effusions will resolve spontaneously.
● Chylothoraces, which are lipid-rich pleural effusions, may not have the typical milky appearance, especially in patients who are fasting or
malnourished.

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