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The Value of Pleural Fluid Analysis

STEVEN A. SAHN, MD

ABSTRACT: Pleural fluid analysis in isolation may have or confident clinical diagnosis can be expected in up to
clinical value. To have the greatest diagnostic impact, 95% of patients. The information in this report should
the clinician must formulate a prethoracentesis diagno- allow the clinician to achieve this goal. KEY INDEX-
sis based on the clinical presentation, blood tests, and ING TERM: Pleural fluid analysis. [Am J Med Sci
radiographic imaging. With this approach, a definitive 2008;335(1):7–15.]

effusion greater than the right effusion, a normal


P leural effusions commonly occur in patients un-
der the care of all specialties of medicine and
surgery. The incidence of pleural effusions in the
cardiac silhouette, or an oxygen tension decreased
out of proportion to the clinical situation, a thora-
United States is estimated to be at least 1.5 million centesis should be done immediately.2 In a prospec-
annually.1 Thoracentesis, a relatively simple diag- tive study of 129 patients with pleural effusion,
nostic procedure, can be performed in the office, at published 20 years ago, thoracentesis provided a
the bedside, in the intensive care unit, and in dedi- definitive diagnosis in only 18% and a presumptive
cated procedural suites. Pleural fluid analysis in diagnosis in 55%.3 In the remaining 27%, pleural
isolation will result in a low diagnosis rate and fluid analysis was not helpful diagnostically because
provides a strong indication for generating a pretho- the findings were compatible with 2 or more clin-
racentesis diagnosis. If the clinician obtains a thor- ical possibilities. However, in a number of these
ough history, performs a careful physical examina- patients, the findings excluded other possible diag-
tion, orders appropriate blood tests, and interprets noses, such as infection. Over the past 2 decades,
the chest images thoughtfully before thoracentesis, we have become more knowledgeable about pleural
the likelihood of determining a likely clinical, if not fluid analysis; and in conjunction with the clinical
definitive, diagnosis is greatly enhanced. This chap- presentation, the clinician should be able to estab-
ter will address discriminating information from pleu- lish a definitive or confident clinical diagnosis in
ral fluid analysis. However, the reader is referred to about 95% of patients after the initial thoracentesis.
review the salient features of the history, physical Table 1 enumerates the diseases where a diagnosis
examination, and radiographic imaging that should can be established “definitively” by pleural fluid
lead to a logical prethoracentesis diagnosis. analysis.4 Positive cytology, pus in the pleural space,
Virtually all patients who present with a new or isolation of organism from the fluid is obviously
onset pleural effusion should undergo a diagnostic definitive. However, finding a low pH (⬃7.00) and a
thoracentesis. Exceptions to this rule are a patient high salivary amylase in the pleural fluid estab-
with typical congestive heart failure or the patient lishes the diagnosis of esophageal rupture in the
with a very small pleural effusion as with viral absence of malignancy. Other examples are the
pleurisy. Observation is warranted in the previously characteristic cytology of a patient with rheumatoid
mentioned examples; however, if the clinical situa- pleurisy,5 the presence of ␤2 transferrin in the pleu-
tion worsens or becomes atypical, a thoracentesis ral fluid in cases of duropleural fistula,6 and total
should be performed without delay. For example, if protein of 0.5 g/dL and a glucose of 300 mg/dL in the
the patient with congestive heart failure has pleu- setting of peritoneal dialysis.
ritic chest pain, fever, a unilateral effusion, a left
Pleural Fluid Analysis
From the Department of Medicine, Division of Pulmonary, Crit- Observation
ical Care, Allergy and Sleep Medicine, Medical University of
South Carolina, Charleston, South Carolina. The initial diagnosis starts with an examination
Submitted August 28, 2007; accepted in revised form September of the pleural fluid as it is aspirated from the pleural
7, 2007. space. The color, character, and odor of the fluid may
Correspondence: Dr. Steven A. Sahn, Professor of Medicine and either be diagnostic or help narrow the differential
Director, Division of Pulmonary, Critical Care, Allergy and Sleep
Medicine, Medical University of South Carolina, 96 Jonathan diagnosis (Table 2).4 Clear, straw-colored fluid sug-
Lucas Street, Suite 812-CSB, P.O. Box 250630, Charleston, South gests a transudate, but a pauci-cellular exudate can-
Carolina 29425 (E-mail: sahnsa@musc.edu). not be excluded. Sanguinous fluid (hematocrit ⬍1%)

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Pleural Fluid Analysis

Table 1. Diagnoses That Can Be Established “Definitively” By Table 2. Appearance, Character, and Odor of Pleural Fluid
Pleural Fluid Analysis Helpful in Diagnosis

Diseases Diagnostic Pleural Fluid Tests Suggested Diagnosis

Acute pancreatitis Pancreatic isoamylase-rich effusion with Color of Fluid


PF/S amylase 3–5:1 and neutrophil Black Spores of Aspergillus niger
predominance Brown Long-standing bloody effusion; amebic
Biliopleural fistula PF/S bilirubin ⬎1.0 liver abscess rupture
Cholesterol Microscopy: cholesterol crystals Color of enteral Feeding tube has entered pleural
effusion tube feeding or space; extravascular catheter
Chylothorax Triglycerides ⬎110 mg/dL; presence of central venous migration into Mediastinum
chylomicrons line infusate
Complicated Positive Gram stain or culture; pH Green Biliopleural fistula
parapneumonic ⬍7.20; loculation Pale yellow (straw) Transudate, paucicellular exudates
effusion Red (bloody)
Duropleural fistula Presence of ␤2-transferrin Hematocrit ⬍5% Malignancy, BAPE, PCIS, pulmonary
Empyema Observation (pus, putrid odor) infarction, trauma
Esophageal High salivary isoamylase and pleural Hemothorax PF/S hematocrit ⬎0.5
rupture fluid acidosis (often as low as 6.00); White (milky) Chylothorax or cholesterol effusion
presence of food particles or squamous Yellow-green Rheumatoid pleurisy
cells Character of fluid
EVM of CVC Observation (milky if lipids are infused); Anchovy paste Amebic liver abscess rupture
glucose in pleural fluid/serum Debris Rheumatoid pleurisy
substantially ⬎1.0 Pus Empyema
Fungal effusion Positive KOH stain or culture Turbid Inflammatory exudates or lipid
Glycinothorax High PF/S glycine ratio after bladder effusion
surgery Satin-like sheen Cholesterol effusion
Hemothorax Hematocrit (pleural fluid-blood ratio Viscous Mesothelioma
⬎0.5) Odor of fluid
Lupus pleuritis Lupus erythematosus (LE) cells present Ammonia Urinothorax
Malignancy Positive cytology Putrid Anaerobic empyema
Pancreaticopleural Pancreatic isoamylase ⬎100,000 IU/L
fistula BAPE, Benign asbestos pleural effusion; PCIS, post–cardiac injury
Peritoneal dialysis Protein (⬍1 g/dL) and glucose (300–400 syndrome.
mg/dL)
Rheumatoid Characteristic cytology
pleurisy
Tuberculous Positive acid-fast bacillus (AFB) stain or nostic of a biliopleural fistula.11 If a central venous
effusion culture; ADA ⬎50 IU/L and catheter has migrated extravascularly into the me-
lymphocyte/neutrophil ratio ⬎0.75
Urinothorax PF/S creatinine ratio ⬎1 diastinum with subsequent rupture of the mediasti-
nal parietal pleura, the pleural fluid will be similar
ADA, Adenosine deaminase; EVM of CVC, extravascular migra- to the infusate (white if lipid is being infused).12
tion of central venous catheter; PF/S, pleural fluid/serum. The character of the fluid can also suggest a diag-
nosis. If pus is aspirated, an empyema is estab-
lished. Pus is determined by its gross appearance,
is not helpful diagnostically. However, when the which is a thick, viscous, yellow-white, opaque fluid.
fluid is grossly bloody and trauma is absent the If the pus has a putrid odor, an anaerobic infection is
differential diagnosis should include benign as- confirmed. If the pleural fluid appears to contain
bestos pleural effusion (BAPE), malignancy, post– debris, rheumatoid pleurisy with exfoliation of rheu-
cardiac injury syndrome, and pulmonary infarction. matoid nodules from the visceral pleural surface
A hemothorax (defined as a pleural fluid/serum he- into the pleural space is a likely cause.5 If the pleu-
matocrit ⱖ50%) is most commonly due to blunt or ral fluid smells like ammonia, urinothorax is likely,
penetrating chest trauma but may also occur with which is caused by obstructive uropathy.13
invasive procedures, anticoagulation with a hemor-
rhagic pulmonary infarction, and catamenial (asso- Exudates Versus Transudates
ciated with menses) hemothorax.7
When a white or milky fluid is aspirated from the The next deductive step in evaluating patients
pleural space, the diagnosis is either a chylothorax8 with pleural effusion is to determine whether the
or a cholesterol effusion,9 although an empyema effusion is an exudate or transudate. Patients with
may simulate this appearance. Centrifugation of the transudative effusions have normal pleurae and lim-
fluid will separate a lipid effusion from an empyema; ited diagnostic possibilities. A transudate develops
in the lipid effusion, the supernatant will remain because hydrostatic pressure increases or oncotic
white, while the empyema supernatant becomes pressure decreases, or a combination of the 2
clear. A yellowish-green tint suggests rheumatoid (Table 3).1,2 Rarely transudates can result from an
pleurisy,10 and green pleural fluid is virtually diag- extravascular origin and include urinothorax, duro-

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Table 3. Causes of Transudative Effusions Table 4. Causes of Exudative Pleural Effusions

Diagnosis Comment Connective Tissue Disease Lymphatic Abnormalities


Churg-Strauss syndrome Lymphangiectasis
Atelectasis Small effusion caused by increased Familial Mediterranean Lymphangioleiomyomatosis
intrapleural negative pressure; fever (chylothorax)
common in ICU patients Lupus pleuritis Noonan’s syndrome
Congestive heart failure Most common cause of Mixed connective tissue (chylothorax)
transudates; diuresis can disease Yellow nail syndrome
increase pleural fluid protein Rheumatoid pleurisy Malignancy
and lactate dehydrogenase Wegener granulomatosis Carcinoma
(LDH) Endocrine dysfunction Leukemia
Constrictive pericarditis Bilateral effusions with normal Hypothyroidism Lymphoma
heart size Ovarian hyperstimulation Mesothelioma
Duropleural fistula CSF in pleural space; caused by syndrome Miscellaneous
trauma and surgery Iatrogenic Meigs syndrome
EVM of CVC With saline infusion Drug-induced
Glycinothorax High PF/S glycine ratio following Other inflammatory
Enteral feeding tube in Acute pancreatitis
bladder irrigation with rupture pleural space
Hepatic hydrothorax Occurs in 6% with clinical ascites; ARDS
Esophageal perforation BAPE
up to 20% do not have clinical following Endoscopy/
ascites Pancreaticopleural fistula
dilation Post–cardiac injury syndrome
Hypoalbuminemia Edema fluid rarely isolated to Esophageal sclerotherapy
pleural space; small bilateral Pulmonary infarction
EVM of CVC Radiation therapy
effusions Hemothorax
Nephrotic syndrome Typically small and bilateral; Sarcoidosis
unilateral effusion with chest Infectious Uremic pleurisy
pain suggests pulmonary Actinomyces Trauma
embolism Atypical pneumonias Chylothorax
Peritoneal dialysis Small bilateral effusions common; Bacterial pneumonia Hemothorax
rarely large right effusion Fungal disease
develops within 72 h of Hepatic abscess
initiating dialysis Hepatitis
Superior vena caval Due to acute systemic venous Nocardia
obstruction hypertension Parasites
Trapped lung Unilateral effusion from imbalance Splenic abscess
in hydrostatic pressures from a Spontaneous esophageal
remote inflammatory process rupture
Urinothorax Unilateral effusion caused by Subphrenic abscess
ipsilateral obstructive uropathy Tuberculous effusion

EVM of CVC, Extravascular migration of central venous catheter.

pleural fistula, peritoneal dialysis, and extravascu-


lar migration of a central venous catheter with sa- is ⬎0.67 of the upper limits of normal serum LDH,
line infusion.12 In contrast, exudative effusions have the fluid is most likely an exudate. If both total
a more extensive differential diagnosis, as these protein and LDH ratios are ⱕ0.50 and ⱕ0.67, re-
effusions are caused by inflammation, infection, ma- spectively, the fluid is most likely a transudate.1,14
lignancy, and lymphatic abnormalities (Table 4).2,4 However, the closer the values are to these cut-
It is important to discriminate between a transu- points, the less likely that a distinction can be made,
date and an exudate. The diagnosis of an exudative while the further the values are from the cut-points,
pleural effusion warrants additional diagnostic testing the more likely the fluid is to be a transudate or an
in most patients to determine the underlying cause. exudate. However, it should be recognized that
Conversely, the patient’s clinical presentation is usu- treatment may affect pleural fluid values. For exam-
ally sufficient to determine the cause of a transudative ple, in patients with congestive heart failure treated
pleural effusion without further testing. with diuretics, either the protein or LDH ratio may
An exudative effusion is defined by the presence of be increased from the transudative range prior to
a high concentration of large, molecular weight pro- diuresis to the exudative range following diuresis. In
teins, which transudates lack. Although several these effusions, the albumin gradient (serum-pleural
tests have been suggested to separate transudates fluid albumin) ⬎1.2 g/dL, suggests that the effusion
from exudates, the 2 tests that appear to have the is a transudate.15 A recent study by Joseph and
highest specificity and sensitivity are the pleural colleagues16 using ROC (receiver operator charac-
fluid-to-serum total protein ratio and the pleural teristics) analysis found that the test with the
fluid LDH compared with the upper limits of the highest sensitivity and specificity for separating
normal serum LDH.14 If the pleural fluid-to-serum transudates and exudates was the ratio of pleural
total protein ratio is ⬎0.50 or the pleural fluid LDH fluid LDH to upper limits of the normal serum

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Pleural Fluid Analysis

LDH of 0.82 (AUC, 0.89). This higher ratio should Table 5. Exudates With at Least 80% Lymphocytes
decrease the incidence of false exudates.
Disease Comment

Total Protein and LDH Acute lung rejection New or increased effusion 2–6 weeks
after transplant
The absolute concentrations of total protein and Chylothorax 2,000–20,000 lymphocytes/␮L;
LDH in effusions may provide additional diagnostic lymphoma most common cause
Lymphoma Often 100% of nucleated cells are
value. For example, a tuberculous pleural effusion lymphocytes; diagnostic yield on
rarely has a total protein concentration ⬍4.0 g/dL, cytology or pleural biopsy higher
whereas total protein concentrations in malignancy with non-Hodgkin lymphoma
and parapneumonic effusions present with a wider Post–coronary artery Occurs ⬎2 months after surgery; not
range.2 A total protein concentration of ⱖ7.0 g/dL bypass graft associated with trapped lung
Rheumatoid pleurisy May be associated with unexpandable
suggests Waldenström macroglobulinemia,17 multi- (chronic) lung
ple myeloma18 or a cholesterol effusion.9 Pleural Sarcoidosis Usually ⬎90% lymphocytes
fluid LDH concentration greater than three times Tuberculous effusion Most common cause of lymphocyte
the upper limits of normal of the serum LDH (⬎1000 predominant exudate; usually 90%
to 95% lymphocytes
IU/L) is typically seen only in complicated parap- Yellow nail syndrome Typically a discordant exudate (by
neumonic effusions or empyema,19,20 rheumatoid protein only); occurs in 36% during
pleurisy,21 or pleural paragonimiasis.22 course of disease

Nucleated Cells
The total nucleated cell count alone is rarely di- shortly after the onset of symptoms, ie, acute bacte-
agnostic but may provide useful information.1,2,23 rial pneumonia, acute pulmonary embolism with in-
Most exudates have ⬎1000 nucleated cells/␮L, while farction, and acute pancreatitis. In contrast, with the
transudates have a few hundred cells/␮L. Pleural insidious onset of disease, as with malignancy and
fluid nucleated cell counts ⬎10,000/␮L are seen tuberculosis, a lymphocyte-predominant exudate is
most commonly with parapneumonic effusions, found. Transudative effusions are never neutrophil
acute pancreatitis, subdiaphragmatic hepatic or predominant and typically have ⬍5% neutrophils;
splenic abscess, and splenic infarction. Nucleated when the neutrophils percentage is ⬎10% to 15%, a
cell counts ⬎10,000/␮L at times can occur with pul- second diagnosis is likely. Transudative effusions are
monary infarction, post– cardiac injury syndrome, mononuclear cell predominant, a combination of lym-
and lupus pleuritis. When the nucleated cell count is phocytes, macrophages, and mesothelial cells.
⬎50,000/␮L, the differential diagnosis is limited to a When the lymphocyte population exceeds 80% of
complicated parapneumonic effusion and empyema the total nucleated cells, the differential diagnosis of
and rarely acute pancreatitis and pulmonary infarc- the exudate can narrowed to the diagnoses listed in
tion. Chronic exudates typically have nucleated cell Table 5.2,4 All typically have lymphocyte populations
counts ⬍5000/␮L, as seen with a tuberculous pleural ⱖ80%; however, the lymphocyte population can be
effusion24 and malignancy.25 When pus is aspirated less on occasion but virtually never ⬍50%. In con-
from the pleural space (empyema), the nucleated trast to most patients with lymphoma, only about
cell count may be as low as a few hundred cells per 60% of patients with metastatic carcinoma to the
microliter because the neutrophils have undergone pleura have a majority of lymphocytes, usually in
autolysis from the harsh pleural environment of the range of 50% to 75% of the total nucleated cell
acidosis and low oxygen tension. count. A lymphocyte predominant exudate is the
The predominant cell population is determined by most appropriate indication for percutaneous pleu-
the cause and phase of the pleural injury and the ral biopsy, which is the most sensitive (75% to 85%)
timing of thoracentesis in relation to the onset of diagnostic test for tuberculous pleural effusion24
pleural injury. The acute response to most pleural with the exception of thoracoscopy.
injury, whether infectious, immunologic or possibly Pleural fluid eosinophilia is defined as a pleural
malignant, is the attraction of neutrophils to the fluid eosinophil count ⬎10% of the total nucleated
pleural space, initiated by the chemotaxin interleu- cell count. It appears that bone marrow eosinophils
kin-8.26,27 Within 72 hours after the cessation of are attracted to the pleural space primarily by in-
acute pleural injury, mononuclear cells enter the terleukin-5.29 Causes of pleural fluid eosinophilia
pleural space from the peripheral blood and become are shown in Table 6.4 The most common are pneu-
the predominant cell as macrophages.28 This macro- mothorax and hemothorax. Eosinophilic pleuritis is
phage predominance is subsequently replaced by a common, early finding in patients requiring tho-
lymphocytes in effusions that persist for greater racotomy or thoracoscopy for treatment of spontane-
than 2 weeks. Therefore, a neutrophil-predomi- ous pneumothorax.30 In contrast to the rapid move-
nant exudate is the rule when the patient presents ment of eosinophils into pleural tissue and pleural

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Table 6. Exudates With Greater Than 10% Eosinophils (PFE) agnosis of malignancy; however, recent studies have
Disease Comment
shown that the prevalence of malignancy is similar
in both eosinophilic and noneosinophilic pleural ef-
BAPE 30% incidence of PFE; up to 50% fusions.35
eosinophils/total nucleated cells Pleural fluid macrophages, which originate from
Carcinoma Prevalence of PFE similar in malignant the blood monocyte, are of no diagnostic value.28
and nonmalignant effusions Mesothelial cells are exfoliated into normal pleu-
Churg-Strauss High PF eosinophil counts; associated
syndrome with blood eosinophilia ral fluid in small numbers. Although common in
Drug-induced Dantrolene, bromocriptine, transudative effusions and some exudates, me-
nitrofurantoin, valproic acid sothelial cells are rarely found in tuberculous
Fungal disease Histoplasmosis, coccidioidomycosis pleural effusion, because of the extensive pleural
Hemothorax PFE develops 1–2 weeks after involvement from the hypersensitivity reaction to
hemothorax
Lymphoma Hodgkin disease tuberculin proteins that inhibits mesothelial shed-
Parasitic disease Paragonimiasis, hydatid disease, ding.31,36 A paucity of mesothelial cells is also the
amebiasis, ascariasis typical finding in other inflammatory processes,
Pneumothorax Effusion in 10% to 20%; tissue such as empyema, chemical pleurodesis, rheuma-
eosinophilia and PFE occur
within hours toid pleuritis, and chronic malignant effusions.31
Pulmonary embolism Associated with infarction and A large number of plasma cells in pleural fluid
hemorrhagic effusion suggests pleural involvement with multiple myeloma,
Sarcoid Rare while a small number of plasma cells is nondiagnostic
Tuberculous effusion Rare and has been observed in several nonmalignant con-
BAPE, Benign asbestos pleural effusion. ditions.31 A few basophils are occasionally found in
pleural fluid and are of no clinical significance. How-
ever, when basophils represent ⬎10% of the nucleated
fluid after pneumothorax, after hemothorax eosino- cells, leukemic involvement of the pleura is likely.31
phils do not appear in pleural fluid for 1 to 2
weeks.31,32 Furthermore, pleural fluid eosinophilia Pleural Fluid PH and Glucose
is associated with peripheral blood eosinophilia fol-
lowing hemothorax that does not clear until the A limited number of diagnoses are associated with
pleural fluid resolves.32 About 30% of patients with pleural fluid acidosis, defined as a pleural fluid pH
benign asbestos pleural effusion have pleural fluid ⬍7.30, which should only be measured with a
eosinophilia, which can reach a level of 50% of the blood gas analyzer (Table 7).37,38 Pleural fluid pH
nucleated cells.33,34 It was previously believed that decreases because 1) there is an increased meta-
pleural fluid eosinophilia virtually excluded the di- bolic activity in pleural fluid as a result of neutro-

Table 7. Incidence, Pleural Fluid Range, and Clinical Comments on Diseases With Pleural Fluid Acidosis (pH ⬍7.30)

Estimated Incidence
Disease of pH ⬍7.30 (%) Range of pH Comments

Complicated parapneumonic 100 7.29–7.10 Nonpurulent effusion that usually requires pleural
effusion space drainage
Esophageal rupture 100 6.80–5.00 pH 6.00 and high salivary amylase
Rheumatoid pleurisy (chronic) 100 7.15–6.80 Associated with glucose ⬍30 mg/dL and LDH
⬎1000 IU/L
Malignant effusion 30–40 7.50–6.90 pH ⬍7.30: worse survival, increased yield on
cytology and pleural biopsy, poorer response to
pleurodesis
Lupus pleuritis 15–20 7.40–6.85 Associated with low glucose; diagnosis by LE cells
in PF
Tuberculous effusion 10–20 7.40–6.95 Associated with low glucose; when pH low, range
between 7.29 and 7.10; pleura severely
abnormal
Hemothorax ⬍10 7.50–7.17 Occurs when PF hematocrit approaches blood
hematocrit and pleura severely injured
Pancreaticopleural fistula Rare 7.50–7.28 Occurs with very high amylase and severe pleural
injury
Pulmonary infarction Rare 7.52–7.29 Occurs with grossly bloody PF and extensive
pleural injury
Diaphragmatic hernia with Single report 7.15 Acid products of infarcted bowel overwhelm efflux
capacity of pleura

LDH, Lactate dehydrogenase; LE, lupus erythematosus; PF, pleural fluid.

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phil phagocytes and bacterial metabolism (empy- A low pleural fluid pH (⬍7.30) is seen in approx-
ema); 2) the pleural membrane is abnormal (fibrotic imately one-third of patients presenting with a ma-
or inflamed) and impairs the efflux of hydrogen lignant pleural effusion.43 A low pleural fluid pH in
ions and CO2 from the pleural space into the this setting suggests that the patients will have a
circulation (rheumatoid pleurisy)38; and 3) a com- positive cytologic examination on initial testing, a
bination of the 2 mechanisms. The presence of a shorter survival time, and a poorer response to
low pleural fluid pH is helpful diagnostically and chemical pleurodesis than those with a pH ⬎7.30.43
also provides prognostic information. In the only The explanation for these findings is related to the
study of acid-base characteristics of normal hu- advanced stage of malignant pleural metastasis that
man pleural fluid, pleural fluid pH was measured inhibits the end products of glycolysis, CO2 and
at 7.64, 0.23 pH units greater than the simulta- lactic acid, from exiting the pleural space.38 How-
neously measured blood pH.39 We and others have ever, finding a low pH is not an absolute contrain-
measured an alkaline pH of ⬃7.60 in normal ani- dication to pleurodesis but should be considered in
the decision making.
mals.40,41 It appears that a bicarbonate gradient
In the normal physiologic state, pleural fluid and
between pleural fluid and blood explains the alka-
blood glucose concentrations are equivalent, as glu-
line pH of normal pleural fluid. Human transuda- cose is of low molecular weight and moves from
tive effusions have a pleural fluid pH ranging from blood to pleural fluid by simple diffusion across the
7.45 to 7.55. The vast majority of exudative effu- endothelial and mesothelial membranes. Diseases
sions have pH values that range from 7.45 to 7.30. with low pleural fluid pH may also have a low
Pleural fluid pH provides prognostic information pleural fluid glucose concentration, defined as ⬍60
and helps guide therapy in parapneumonic and ma- mg/dL or a pleural fluid/serum glucose ratio of
lignant effusions. A meta-analysis examined the ⬍0.5.44 As noted in Table 8, the only diagnoses with
prognostic value of pleural fluid pH in patients with a glucose of 0 mg/dL are chronic rheumatoid pleu-
parapneumonic effusions.42 Using ROC (receiver op- risy and empyema.
erator characteristics) analysis, it was observed that
pleural fluid pH was lower in patients who had a
complicated course and required pleural space Amylase
drainage. The primary studies recommended vari- An increased pleural fluid amylase, defined as
ous cut points for a complicated effusion that varied either a value greater than the upper limits of nor-
from 7.10 to 7.30. Although no single pH value can mal serum or a pleural fluid/serum amylase ratio
be used as a definitive cut-point for classifying pa- ⬎1.0, is found with pancreatic disease,45– 47 esopha-
tients into complicated and uncomplicated parap- geal rupture,48 –50 and malignancy.51,52 Both acute
neumonic effusions, pleural fluid pH should serve as pancreatitis and a pancreaticopleural fistula can
adjunctive information that should be combined cause an amylase-rich pleural effusion, the latter
with the clinicians’ judgment in determining the often showing amylase levels ⬎100,000 IU/L.53 An
need for pleural space drainage. increased pleural fluid amylase concentration occurs

Table 8. Incidence, Range of Glucose Concentration, and Clinical Comments on Diseases With Low Pleural Fluid Glucose

Estimated Incidence of Range of Glucose


Glucose Pleural Fluid/ Concentration
Disease Serum ⬍0.5 (mg/dL) Comments

Rheumatoid pleurisy 85–90% 0–118 Glucose ⬍30 mg/dL in 75%; PF triad of glucose
⬍30 mg/dL, pH 7.00 and LDH ⬎1000 IU/L;
may precede articular manifestations by 3
years
Empyema 80–90% 0–145 Low glucose not as sensitive marker as low pH
but correlation of glucose and pH is strong
Esophageal rupture 40–50% 15–120 Characteristic pH of 6.00 and high pleural fluid
amylase (salivary)
Malignant effusion 30–40% 15–167 Low glucose concentration with chronic effusion
in far-advanced pleural malignancy
Lupus pleuritis 20–30% 32–160 Transient; associated with severe pleural
inflammation; LE cells diagnostic
Tuberculous effusion 20–30% 10–140 No correlation between low glucose and clinical
course or pleural bacteriology

LDH, Lactate dehydrogenase; LE, lupus erythematosus; PF, pleural fluid.

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Sahn

Table 9. Differentiating a Cholesterol Pleural Effusion From a 90% of patients with a known malignancy.57,58 The
Chylothorax reasons for this variability include 1) the effusion
Chylothorax Cholesterol may be paramalignant, which is defined as a pleu-
ral effusion associated with a known malignancy
Incidence Uncommon (2%) Rare but malignant cells cannot be detected in the
Causes NHL, trauma, Lung entrapment: TB, pleural fluid or pleural tissue, and the effusion
surgery, LAM RA, empyema results from another mechanism (ie, atelectasis)59;
Onset Acute to subacute Insidious; develops over
years
2) the type of tumor (high positivity with adeno-
Symptoms Dyspnea None; dyspnea carcinoma and low in Hodgkin lymphoma)60,61; 3)
Appearance Serous, turbid, Milky; satin-like sheen the number of specimens submitted (yields tend to
milky, bloody increase with additional specimens owing to exfo-
Pleural fluid ⬎80% lymphocytes; Chol/TG ⬎1; PMNs; TP liation of fresher cells)61; 4) the stage of pleural
analysis TG/Chol ⬎1 ⬎5 g/dL
Diagnosis TG ⬎110 mg/dL; Cholesterol ⬎250 mg/dL; involvement (the more advanced stage the higher
chylomicrons; 300–1500 mg/dL the diagnostic yield); and 5) the interest and ex-
cholesterol 60–200 cholesterol crystals pertise of the cytopathologist.
mg/dL
Treatment Underlying disease; Observe, decortication
pleurodesis, Flow Cytometry
thoracic duct
ligation, octreotide Flow cytometry can be helpful in the diagnosis of
lymphoma of the pleura, as it can specifically
NHL, Non-Hodgkin lymphoma. define lymphocyte surface markers.62 It can define
the clonality of a population of lymphocytes to
determine whether the cells are from T- or B-cell
in 10 –14% of patients with a malignant pleural effu- lineage. Therefore, flow cytometry is most helpful
sion; on isoenzyme analysis, salivary-type amylase is in patients with a lymphocyte-predominant pleu-
predominant.47,52 Adenocarcinoma of the lung is the ral effusion when lymphoma is in the differential
most common malignancy associated with a salivary diagnosis.
amylase-rich pleural effusion, followed by adenocarci-
noma of the ovary.47,52 Adenocarcinoma cells have Conclusion
been documented to secrete a salivary-like isoamy-
lase.52 Esophageal rupture is also characterized by the For pleural fluid analysis to be most valuable, the
presence of pleural fluid salivary isoamylase.48 –50 clinician must have a well thought-out pre-thoracen-
tesis diagnosis based on the history, physical exami-
Triglycerides and Cholesterol nation, ancillary laboratory findings, and radiographic
imaging. With a presumptive clinical diagnosis in con-
There are 2 types of lipid pleural effusions, cert with a good working knowledge of pleural fluid
chylothorax and a cholesterol effusion, also termed analysis, a definitive or confident clinical diagnosis can
chyliform effusion or pseudochylothorax (Table 9). be determined in up to 95% of patients. Without this
A chylothorax represents leakage of chyle into the approach, the clinician may be left with an unaccept-
pleural space from the thoracic duct or one of its able number of problematic or undiagnosed pleural
major tributaries.54,55 The most frequent cause of effusions.
a chylothorax is malignancy, most commonly non-
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