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Evaluation of the Patient with a Pleural EffusionPCCSU Article | 01.15.08
By Steven A. Sahn, MD, FCCP
Dr.Sahn is Professor of Medicine and Director, Division of Pulmonary, Critical Care, Allergy and Sleep
Medicine, Medical University of South Carolina, Charleston, SC.
Dr.Sahn has disclosed no significant relationships with the companies/organizations whose products or
services may be discussed within this chapter.
Objectives
1. To understand the diagnostic value of pleural analysis.
2. To appreciate the value of pleural pH in narrowing the differential diagnosis of the exudate.
Key words: pleural effusion; pleural fluid analysis
Pleural effusions are a common occurrence that involve all specialities of medicine and surgery. The
annual incidence of new pleural effusions in the United States is estimated to be at least 1.5
million. 1 Thoracentesis is a relatively simple diagnostic procedure that can be performed in the office, at
the bedside, in the ICU, or in a dedicated procedure suite. Pleural fluid analysis in isolation may result in
only a small percentage of diagnoses with a high clinical likelihood that provides a strong argument for
generating a prethoracentesis diagnosis. If the clinician obtains a thorough history, performs a careful
physical examination, orders appropriate blood tests, and interprets the chest images thoughtfully prior
to thoracentesis, the likelihood of determining a likely clinical, if not definitive, diagnosis is greatly
enhanced. In this chapter, I will not only discuss discriminating information from the pleural fluid
analysis but also will address salient features of the history, physical examination, and radiographic
imaging that should lead to a logical prethoracentesis differential diagnosis.
History
Patients may be symptomatic or asymptomatic on presentation with a pleural effusion. Diagnoses in
which patients typically do not present with symptoms are listed in Table 1. For example, about half of
the patients with rheumatoid pleural effusion are asymptomatic,2 and 60 to 70% of patients with benign
asbestos pleural effusion (BAPE) have no symptoms.3 In contrast, as shown in Table 2, patients with
bacterial pneumonia, lupus pleuritis,4
postcardiac injury syndrome (PCIS),5
and congestive heart failure
virtually always have symptoms in association with their pleural effusions.
Dyspnea and chest pain are the most common symptoms of patients with a pleural effusion. Those with
a small pleural effusion and normal underlying lungs may have no perceptible symptoms. In contrast,
patients may present with a massive pleural effusion associated with contralateral mediastinal shift,
leading to dyspnea at rest. Pleuritic chest pain is the cardinal symptom of pleural inflammation and is
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typically accompanied by a pleural effusion.6 Pleuritic chest pain varies with the intensity of the
inflammation. Patients have described pleuritic chest pain as "stabbing," "shooting," or having a "stitch
in the side." This type of pain is exacerbated by deep inspiration, cough, or sneezing. Pleuritic chest pain
may be focused over the precise location of the inflammation or may be referred. With costal pleural
inflammation, the pain tends to be localized directly over the site of pleural involvement and is often
associated with tenderness on pressure and cutaneous hypersensitivity. When the lateral, anterior, and
portions of the posterior diaphragm are inflamed, pain is perceived diffusely over the lower thorax, back,
and abdomen. In contrast, inflammation of the central portion of the diaphragmatic pleura does not
result in local pain; pain is referred to the ipsilateral posterior neck, shoulder, and trapezius muscle.Central diaphragmatic pleural inflammation causes referred pain because the sensory fibers of the
phrenic nerve enter the spinal cord at the C4 level, which is the usual entry point of sensation from the
shoulder.6
Although the number of drugs associated with pleural disease is significantly fewer than those that are
presumed to cause parenchymal lung disease, drugs should always be considered as a possible cause of
a pleural effusion or pleural fibrosis, especially when the etiology of the effusion is problematic. 7 Some of
the drugs that have been associated with a pleural effusion, in more than a single case, include
bromocriptine, cyclophosphamide, dantrolene, isotretinoin, mesalamine, methotrexate, mitomycin,
nitrofurantoin, practolol, procarbazine, and valproic acid.
Physical Examination
Pleural fluid interferes with sound transmission from the lung to the stethoscope, as it separates thelung from the chest wall. Physical signs of a pleural effusion depend on the volume of pleural fluid and
the degree of lung compression. The status of the underlying lung and the patency of the bronchial tree
will modulate the physical findings. The physical examination results will be essentially normal when the
fluid volume is
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Bilateral effusions are most commonly transudates, as seen with congestive heart failure, nephrotic
syndrome, hypoalbuminemia, and constrictive pericarditis. The cardiac silhouette is virtually always
enlarged in congestive heart failure but may be of normal size with nephrotic syndrome and constrictive
pericarditis.16
Bilateral pleural effusions with a normal heart size are most likely related to malignancy
from a nonlung primary but can also occur with lupus pleuritis, rheumatoid pleurisy, hepatic
hydrothorax, and hypoalbuminemia.16
A chest radiograph with interstitial infiltrates raises the differential diagnosis of congestive heart failure,
rheumatoid disease,11 asbestos pleuropulmonary disease,3 lymphangiticcarcinomatosis,17lymphangioleiomyomatosis, 18 viral and mycoplasma
pneumonia,19
sarcoidosis,20
and Pneumocystis cariniipneumonia.21
Pleural effusions associated with
multiple pulmonary nodules suggest cancer (most common), Wegener granulomatosis,22
rheumatoid
disease,11 septic pulmonary emboli,23 sarcoidosis,20 or tularemia.24
Pleural Fluid Analysis
Virtually all patients with a newly discovered pleural effusion should undergo thoracentesis to confirm a
diagnosis. Exceptions include the patient who has typical congestive heart failure with a clinical diagnosis
that does not raise suspicion for an alternative diagnosis or a pleural effusion that is extremely small, as
with viral pleurisy. Observation is warranted in the previously mentioned examples; however, if the
clinical situation worsens or is atypical, a thoracentesis should be performed without delay. For example,
if a patient with congestive heart failure has pleuritic chest pain, fever, a unilateral effusion, a left
effusion greater than the right effusion, a normal cardiac silhouette, or an oxygen tension valve out of
proportion to the clinical situation, a thoracentesis should be done immediately.25 In a prospective studyof 129 patients with pleural effusion published 20 years ago, thoracentesis provided a definitive
diagnosis in only 18% and a presumptive diagnosis in 55%.26
In the remaining 27% of patients, the
pleural fluid findings were not helpful diagnostically because the values were compatible with two or
more clinical possibilities. However, in a number of these patients, the findings excluded possible
diagnoses, such as empyema. Over the years, health-care professionals have become better educated
about pleural fluid analysis; in conjunction with the clinical presentation, this should enable a definitive
or confident presumptive diagnosis in close to 95% of patients. Table 3 enumerates the diseases where
a diagnosis can be established "definitively" by pleural fluid analysis.27
Positive cytologic findings, pus in
the pleural space, or isolation of an organism from the fluid is obviously diagnostic. However, finding a
low pH and a high salivary amylase in the pleural fluid establishes the diagnosis of esophageal rupture in
the absence of malignancy. Other examples are the characteristic cytologic findings in a patient with
rheumatoid pleurisy28 or finding 2-transferrin in the pleural fluid,29 diagnostic for a duropleural fistula.
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Observation
The initial diagnostic step is to closely examine the pleural fluid as it is aspirated from the pleural space.
The color, character, and odor of the fluid may either be diagnostic or helpful in diagnosis (Table
4).27 Clear, straw-colored fluid suggests a transudate, but a paucicellular exudate cannot be excluded.
Sanguinous fluid (hematocrit value
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The character of the fluid can also suggest a diagnosis. If pus is aspirated, an empyema is established.
Pus is determined by the gross appearance of the fluid, which is a thick, viscous, yellow-white, opaque
fluid. If the pus has a putrid odor, an anaerobic infection is confirmed. If the pleural fluid appears to
contain debris, rheumatoid pleurisy with exfoliation of rheumatoid nodules from the visceral pleural
surface into the pleural space is a likely cause.28 If pleural fluid smells like ammonia, the diagnosis is
urinothorax, which is caused by obstructive uropathy.36
Exudates vs Transudates
The next deductive step in evaluating patients with a pleural effusion is to determine whether the
effusion is an exudate or transudate. Patients with transudative effusions have normal pleurae and
limited diagnostic possibilities, and the effusion is formed because hydrostatic pressures increase or
oncotic pressure decreases, or a combination of the two (Table 5).1,25 Rare causes of transudates
develop from an extravascular origin (pleural effusions of extravascular origin) and include urinothorax,
duropleural fistula, peritoneal dialysis, and extravascular migration of a central venous catheter withsaline infusion.35 In contrast, exudative effusions have a more extensive differential diagnosis, as these
effusions are caused by inflammation, infection, malignancy, and lymphatic abnormalities (Table 6).25,27
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It is important to distinguish between a transudate and an exudate accurately. The detection of an
exudative pleural effusion warrants additional diagnostic testing in most patients to determine the
underlying cause. Conversely, the patients clinical presentation is usually sufficient to determine the
cause of a transudative effusion without further testing.
An exudative effusion is defined by the presence of a high concentration of large, molecular weight
proteins compared with transudates. Although several tests have been suggested to separate
transudates from exudates, the two tests that appear to have the highest specificity and sensitivity are
the pleural fluid-to-serum total protein ratio and the pleural fluid LDH (lactate dehydrogenase) compared
with the upper limits of the normal serum LDH.37
The total protein ratio can be used because the pleural
fluid and serum values are related; however, because there is no correlation between pleural fluid and
serum LDH, the previously mentioned ratio should be used instead.38
If the pleural fluid-to-serum total
protein ratio is >0.50 or the pleural fluid LDH is >0.67 of the upper limit of normal serum LDH, the fluid
is most likely an exudate. If both total protein and LDH ratios are 0.50 and 0.67, respectively, the fluid
is most likely a transudate.1
Subsequent validation studies using pooled data from several primary
investigations reported that the above criteria have a sensitivity of 98% and a specificity of 74% inidentifying an exudative pleural effusion.
1However, the closer the values are to the cut-point, the fluid is
likely to be either a transudate or an exudate, while the further the value is from the cut-point, the more
likely the fluid is to be a transudate or an exudate. It should be recognized that treatment of the patient
may affect pleural fluid values; for example, in patients with congestive heart failure treated with
diuretics, either the protein or LDH ratio may be increased from the transudative range prior to diuresis
to the exudative range following diuresis. A more recent study by Joseph and colleagues,39 using
receiver operating characteristic curve analysis, found that the test with the highest sensitivity and
specificity for separating transudates and exudates was a pleural fluid LDH compared with the upper
limit of the normal serum LDH ratio of 0.82 (AUC = 0.89); this higher ratio decreases the incidence of
false exudates.
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Total Protein and LDH
The absolute concentrations of total protein and LDH may be of some diagnostic value. For example, a
tuberculous pleural effusion rarely has a total protein concentration 1,000 IU/L) for the serum LDH is typically seen only in complicated parapneumonic effusions
or empyema,42,43 rheumatoid pleurisy,44or pleural paragonimiasis.45
Nucleated Cells
The total nucleated cell count is rarely diagnostic but may provide useful information.1,25,46 Mostexudates have >1,000 nucleated cells/L, while transudates have a few hundred cells per microliter.
Pleural fluid nucleated cell counts >10,000/L are seen most commonly with parapneumonic effusions,
acute pancreatitis, subdiaphragmatic abscesses, liver, hepatic and splenic abscesses, and splenic
infarction. Nucleated cell counts >10,000/L at times can occur with pulmonary infarction, PCIS, and
lupus pleuritis. When the nucleated cell count is >50,000/L, the differential is limited to a complicated
parapneumonic effusion and empyema and rarely with acute pancreatitis and pulmonary infarction.
Chronic exudates typically have nucleated cell counts
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The predominant cell population is determined by the type of pleural injury and the timing of
thoracentesis in relation to the acute pleural injury. The acute response to any pleural injury, whether
infectious, immunologic, or malignant, is the attraction of neutrophils to the pleural space, initiated by
the chemotaxin interleukin-8.48,49
Within 72 h following the cessation of acute pleural injury,
mononuclear cells enter the pleural space from the peripheral blood and become the predominant
cells.50 This macrophage predominance is subsequently replaced by lymphocytes in effusions that persist
for >2 weeks. Therefore, a neutrophil-predominant exudate is the rule when the patient presents shortly
after the onset of symptoms, ie, acute bacterial pneumonia, acute pulmonary embolism with infarction,
and acute pancreatitis. In contrast, with the insidious onset of disease, as with malignancy andtuberculosis, a lymphocyte-predominant exudate is found. Transudative effusions are never neutrophil-
predominant (usually 10 to 15%, a second
diagnosis is likely. Transudative effusions are mononuclear-cell-predominant, a combination of
lymphocytes, macrophages, and mesothelial cells.
When the lymphocyte population is >80% of the total nucleated cells, the differential diagnosis of the
exudate is narrowed to those entities shown in Table 7.25,27 All the diagnoses listed in the table typically
have lymphocyte populations 80%; the lymphocyte population can occasionally be less but virtually
never 10% of the total nucleated
cell count. It appears that bone marrow eosinophils are attracted to the pleural space primarily by
interleukin-5.52Causes of PFE are shown in Table 8.27 The most common causes are pneumothorax and
hemothorax. Eosinophilicpleuritis is a common, early finding in patients requiring thoractomy or
thoracoscopy for treatment of spontaneous pneumothorax.53
In contrast to the rapid movement of
eosinophils into the pleura and pleural fluid in pneumothorax, eosinophils do not appear in the pleural
space for 1 to 2 weeks following hemothorax.54Furthermore, PFE is associated with peripheral blood
eosinophilia following trauma that does not clear until the pleural fluid resolves.55
About 30% of patients
with BAPE have PFE, which, at times, totals 50% of the nucleated cells. 56,57 It was previously thought
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that PFE virtually excluded the diagnosis of malignancy; however, recent studies have shown that the
prevalence of malignancy is similar in both eosinophilic and noneosinophilic pleural effusions. 58
Pleural fluid macrophages, which originate from the blood monocyte, are of no diagnostic
value.50 Mesothelial cells are exfoliated into normal pleural fluid in small numbers. Although common in
transudative effusions and some exudates, mesothelial cells are rarely found in tuberculous pleural
effusion, because of the extensive pleural involvement from the hypersensitivity reaction to tuberculin
proteins that inhibits mesothelial shedding.54,59 The paucity of mesothelial cells is also the typical finding
in other inflammatory processes, such as empyema, chemical pleurodesis, rheumatoid pleuritis, andchronic malignant effusions.54
A large number of plasma cells in pleural fluid suggests pleural involvement with multiple myeloma,
while a small number of plasma cells isnondiagnostic and has been observed in several nonmalignant
conditions.54
A few basophils are occasionally found in pleural fluid and are of no clinical significance.
However, when basophils represent >10% of the nucleated cells, leukemic involvement of the pleura is
likely.54
Pleural Fluid pH and GlucoseA limited number of diagnoses are associated with pleural fluid acidosis, which is defined as a pleural
fluid pH
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ranging from 7.45 to 7.55. The vast majority of exudative effusions have pH values that range from
7.45 to 7.30, while a small number of exudates are associated with pleural fluid acidosis (pH
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parapneumonic effusions.65 Using receiver operating characteristic curve analysis, it was observed that
the pleural fluid pH was lower in patients who had a complicated course and required pleural space
drainage. The primary studies recommended various cut-points for a complicated effusion that varied
from 7.10 to 7.30. While no single pH value can be used as a definitive cut-point for classifying patients
as having complicated or uncomplicated parapneumonic effusions, the pleural fluid pH serves as
adjunctive information that should be combined with the clinicians judgment in determining the need for
pleural space drainage.
A low pleural fluid pH (7.30.66
The explanation for these findings is related to the advanced
stage of malignant pleural metastasis that inhibits the end products of glycolysis from exiting the pleural
space.61
Finding a low pH is not an absolute contraindication to pleurodesis but should be considered in
the decision when contemplating treatment.
In the normal physiologic state, pleural fluid and blood glucose concentrations are equivalent, as glucose
is of low molecular weight and moves from blood to pleural fluid by simple diffusion across the
endothelial and mesothelial membranes. The same diseases associated with low pleural fluid pH also
have a low pleural fluid glucose concentration, which is defined as
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Amylase
An increased pleural fluid amylase level, defined as either a value greater than the upper limits of
normal serum or a pleural fluid/serum amylase ratio >1.0, is found with pancreatic disease,68-
71esophageal rupture,
72-74and malignancy.
70,75,76Both acute pancreatitis and a pancreaticopleural fistula
can cause an amylase-rich pleural effusion, the latter often having amylase levels >100,000 IU/L.75 An
increased pleural fluid amylase concentration occurs in 10 to 14% of patients with a malignant pleural
effusion. On isoenzyme analysis, the amylase in these malignant effusions is virtually all salivary-type.68,70,76 Adenocarcinoma of the lung is the most common malignancy associated with a salivary
amylase-rich pleural effusion followed by adenocarcinoma of the ovary.70,76
It has been demonstrated
that adenocarcinoma cells secrete a salivary-like isoamylase.75
Esophageal rupture is also characterized
by the presence of pleural fluid salivary isoamylase.
Triglycerides and Cholesterol
There are two types of lipid pleural effusions, chylothorax and a cholesterol effusion, also called a
chyliform effusion or pseudochylothorax. Table 11 provides detailed information that clearly
demonstrates the differences between these two lipid effusions. A chylothorax represents leakage of
chyle into the pleural space from the thoracic duct or one of its major tributaries.77,78
The most common
cause of a chylothorax is lymphoma, most commonly non-Hodgkin lymphoma. A cholesterol effusion is a
chronic form of lung entrapment that is most commonly associated with rheumatoid pleurisy and
tuberculosis.32,79
The diagnosis of chylothorax is highly likely when the pleural fluid triglyceride
concentration is >110 mg/dL and is highly unlikely if the triglyceride concentration is
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malignant cells cannot be detected in pleural fluid or pleural tissue and the effusion results from another
mechanism (ie, atelectasis)82; (2) the type of tumor (high adenocarcinoma positivity and low in Hodgkin
lymphoma)83,84; (3) the number of specimens submitted (yields tend to increase with additional
specimens, owing to exfoliation of fresher cells)84
; (4) the stage of pleural involvement (the more
advanced stage, the higher the diagnostic yield); and (5) the interest and expertise of the
cytopathologist.
Flow Cytometry
Flow cytometry can be helpful in the diagnosis of lymphoma of the pleura. Flow cytometry canspecifically define lymphocyte surface markers.85 Therefore, it can define clonality of a population of
lymphocytes to determine whether the cells are from T- or B-cell lineage. Therefore, flow cytometery is
most helpful in patients with a lymphocyte-predominant pleural effusion when lymphoma is in the
differential diagnosis.
Conclusion
For pleural fluid analysis to be most valuable, the clinician must have a solid prethoracentesis diagnosis
based on a patients history, physical examination, laboratory findings, and radiographic imaging. With a
presumptive clinical diagnosis in concert with a good working knowledge of pleural fluid analysis, a
definitive or confident clinical diagnosis can be determined in 95% of patients. Without this approach,
the clinician may be left with an unacceptable number of problematic or undiagnosed pleural effusions.
Poststudy Questions
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