Approach to a patient with

pleural effusion
Presenter- Dr Fana Beyene ( R2)
Moderator- Dr Amsalu Bekele Internist, PCCM
April 2021
Contents
• Anatomy and physiology
• Sign and symptoms
• Radiographic evidence of pleural effusion
• Indications and contraindications of thoracentesis
• Diagnostic criteria
• Components of pleural fluid analysis
Normal pleural anatomy
• The term pleura is generally meant to encompass the parietal
pleura, the visceral pleura, and the intervening pleural space.
• The parietal and visceral pleura merge at the pulmonary hilum
and thus separate the thoracic cavity into two separate
hemithoraces
• mesothelial layer and connective tissue layers, where blood
vessels and lymphatic drainage lies which are important to
maintain dynamic of pleural fluid
• combined thickness of 0.2 to 0.4 mm, while the width of the
pleural space is 10 to 20 micrometers
• On the parietal pleura there are openings in the mesothelial cells called
stomata which leads to lymphatic channels, allowing passage for liquid from
pleural space to the lymphatic
• BVs supplying parietal pleural surface originate from the systemic arterial
circulation-primarily Inter Costal Artery and venous blood from the parietal
pleura drains to systemic venous system.
• Visceral pleura is supplied primarily by systemic aretries specifically bronchial
arterial circulation but venous drainage is in to pulmonary venous system
• Ultimately the fluid is transported to the right thoracic duct which empty in
to the systemic venous circulation
Mechanism of effusion
• In the normal pleural space, there is a steady state in which
there is a roughly equal rate of the formation (entry) and
absorption (exit) of liquid.
• Pleural fluid is the ultrafiltrate from pleural capillaries
• There are counteracting forces which are responsible for transport of
fluid these are hydrostatic plessure and colloid pressure
• A change in the magnitude of any of the factors can cause imbalance
in pleural fluid dynamics resulting in fluid accumulation
• An isolated increase in entry rate, unless large and sustained,
is unlikely to cause a clinically significant effusion because the
absorbing pleural lymphatics have a large reserve capacity to
deal with excess pleural liquid.
• An isolated decrease in exit rate is also unlikely to cause a
large effusion because the normal entry rate is low. Even if the
exit of liquid ceased entirely, accumulation of liquid would take
many days to become evident
• Both mechanisms contribute to effusion formation.
Symptoms
• Dyspnea
• Cough
• Chest pain
• Hemoptysis
Signs
• Inspection: resp distress, ipsilateral chest lag
• Palpation: trachea deviates away from effusion, decreased tactile
fremitus
• Percussion: stony dullness
• Auscultation: absent or decreased breath sounds, BBS at upper level,
pleural friction rub above fluid level
Radiographic evidence
Imaging
• Abnormalities of the pleural space can easily be detected by
conventional radiographic methods.
• At least 75 mL are needed to obliterate the posterior costophrenic
sulcus, and a minimum of 175 mL is necessary to obscure the
lateral costophrenic sulcus on an upright chest radiograph
• A pleural effusion of 500 mL will obscure the diaphragmatic contour
on an upright chest radiograph; if the pleural effusion reaches the
level of the fourth anterior rib, close to 1000 mL are present.
• On decubitus radiographs and computed tomography (CT) scans,
less than 10 mL, and possibly as little as 2 mL, can be identified 
• For quantitation on decubitus views, the rind of layering pleural
effusion is measured: small effusions are thinner than 1.5 cm,
moderate effusions are 1.5 to 4.5 cm thick, and large effusions
exceed 4.5 cm.
• Effusions thicker than 1 cm are usually large enough for
sampling by thoracentesis, since at least 200 mL of liquid are
already present
• Subpulmonic effusions — Subpulmonic pleural effusions
elevate the lung base, mimicking an elevated hemidiaphragm.
• "Rock of Gibraltar sign" well seen on the lateral chest
radiograph in patients with a subpulmonic pleural effusion
• On the left side, a marked separation (>2 cm) of the lung from
the stomach bubble suggests a subpulmonic effusion.
Loculated effusion
• Pleural effusions can also loculate as a result of adhesions.
• The angles of interface between the fluid and the chest wall are
obtuse
• The surface is usually smooth
• The content is homogeneous
• The fluid droops on upright images owing to its liquid content
and the effect of gravity
ULTRASONOGRAPHY
• Ultrasonography permits easy identification of free or loculated
pleural effusions, and it facilitates differentiation of loculated
effusions from solid masses.
• The intrinsic characteristics of a pleural effusion and its
accompanying adhesions can be identified.
• Thoracentesis of loculated pleural effusions is facilitated by
ultrasound guidance. However, computed tomography (CT) is
the method of choice for more complicated interventional
procedures, such as empyema drainage or biopsy of pleural
masses.
CT
• Computed tomography (CT) detects small pleural effusions..
less than 10 mL and possibly as little as 2 mL of liquid in the
pleural space.
• Thickening of the visceral and parietal pleura as well as
enhancement of the visceral and parietal pleura after injection
of intravenous contrast material (the "split pleura sign") suggest
the presence of inflammation and thus an exudative, rather than
transudative, effusion.
Other uses of CT
• Facilitating measurement of pleural thickness
• Distinguishing an empyema from a lung abcess
• Visualizing small pneumothoraces in supine patients
• Visualizing underlying lung parenchymal processes that are obscured on the
chest radiograph by a large pleural effusion
• Determining the exact location of pleural masses and characterization of their
composition
• Occasionally identifying peripheral bronchopleural fistulae
• Occasionally identifying a diaphragmatic defect in a cirrhotic patient with
hepatic hydrothorax
• Guiding thoracentesis and tube thoracostomy of loculated empyemas
• MAGNETIC RESONANCE IMAGINGMagnetic resonance
imaging (MRI) can display pleural effusions, pleural tumors, and
chest wall invasion. In selected cases, it can characterize the
content of pleural effusions
• FDG-PET SCANNINGThis modality has shown only modest
accuracy in discriminating malignant from benign pleural
effusions. While it can differentiate between exudative and
transudative pleural effusions, it is not routinely recommended
to facilitate the distinction between benign and malignant pleural
effusions.
Pleural fluid analysis
• Thoracentesis is a simple bedside procedure with imaging
guidance that permits fluid to be rapidly sampled, visualized,
examined microscopically, and quantified for chemical and
cellular content. 
• Indications
1. Diagnostic
2. Therapeutic
Diagnostic
• Most patients who have a newly detected pleural effusion
should undergo diagnostic thoracentesis to determine the
nature of the effusion (ie, transudate, exudate) and to identify
potential causes.
• exceptions -secure clinical diagnosis (eg, viral pleurisy), or
when there is clinically obvious heart failure (HF) without
atypical features.
Therapeutic
• commonly performed for symptom relief (eg, dyspnea) or if the
fluid has imaging characteristics of a complicated pleural
effusion.
• one-time therapeutic thoracentesis vs insertion of a small-bore
chest tube or catheter for one or more days is dependent upon
patient-related factors including, effusion size, character
(loculated or free flowing), and/or need for complete drainage
and institutional factors, operator preference, and availability of
expertise
Contraindications 
• Insufficient pleural fluid
• skin infection or wound at the needle insertion site
• severe bleeding diathesis. 
Pleural fluid analysis
• Tests routinely performed on pleural fluid include the following:
• Gross apperance
• Characterization ( Transudative vs Exudative)
• Chemical and biochemical analysis ( PH, protein, LDH, glucose,
cholestrol)
• Additional commonly performed tests in selected patients include
amylase, cholesterol, triglycerides, N-terminal pro-brain
natriuretic peptide (BNP), creatinine, adenosine deaminase, gram
and acid-fast bacillus (AFB) stain, bacterial and AFB culture, and
cytology.
Gross apperance
Diagnosis established by pleural fluid
analysis
Transudates
•   Transudates result from imbalances in hydrostatic and oncotic
pressures in the chest, as occur with CHF and nephrosis, or
conditions external to the pleural space.
• Movement of fluid from the peritoneal, cerebrospinal, or
retroperitoneal spaces, or from iatrogenic causes, such as
crystalloid infusion through a central venous catheter that has
migrated into the mediastinum or pleural space
Causes of transudative pleural effusion
Exudates
•  Exudative effusions present more of a diagnostic challenge
• Disease in virtually any organ can cause exudative pleural
effusions by a variety of mechanisms, including infection,
malignancy, immunologic responses, lymphatic abnormalities,
noninfectious inflammation, iatrogenic causes, and movement
of fluid from below the diaphragm 
Causes of exudative pleural effusion
Diagnostic criteria
• The Light's Criteria Rule is a traditional method of differentiating
transudates and exudates that measures serum and pleural fluid
protein and LDH
• According to the traditional Light's Criteria Rule, if at least one of
the following three criteria (ie, component tests of the rule) is
fulfilled, the fluid is defined as an exudate
●Pleural fluid protein/serum protein ratio greater than 0.5, or
●Pleural fluid LDH/serum LDH ratio greater than 0.6, or
●Pleural fluid LDH greater than two-thirds the upper limits of the
laboratory's normal serum LDH
• Light's criteria have been criticized for including both the pleural
fluid LDH/serum LDH ratio and the pleural fluid LDH because
they are highly correlated
• Proposed two-criteria and three-criteria diagnostic rules, which
require one criterion to be met to define an exudate
Two-test rule
•Pleural fluid cholesterol greater than 45 mg/dL
•Pleural fluid LDH greater than 0.45 times the upper limit of the
laboratory's normal serum LDH
Three-test rule
•Pleural fluid protein greater than 2.9 g/dL (29 g/L)
•Pleural fluid cholesterol greater than 45 mg/dL (1.165 mmol/L)
•Pleural fluid LDH greater than 0.45 times the upper limit of the
laboratory's normal serum LDH
Protein
•  Most transudates have absolute total protein concentrations below
3.0 g/dL (30 g/L)
• Acute diuresis in heart failure can elevate protein levels into the
exudative range… serum to pleural fluid albumin gradient greater than
1.2 g/dL or a protein gradient >3.1 g/dL, which correctly categorizes
their effusions as transudates + NT-proBNP
• Tuberculous pleural effusions virtually always have total protein
concentrations above 4.0 g/dL (40 g/L)
• When pleural fluid protein concentrations are in the 7.0 to 8.0 g/dL
range, Waldenström’s macroglobulinemia and multiple myeloma
should be considered 
LDH
• The level of pleural fluid LDH is one of the key criteria for
differentiating transudates and exudates.
• Pleural fluid LDH levels above 1000 IU/L are characteristically
found in empyema, rheumatoid pleurisy, and malignancies
• Pleural fluid secondary to Pneumocystis jirovecii pneumonia has
the characteristic finding of a pleural fluid/serum LDH ratio
greater than 1.0 and a pleural fluid/serum protein ratio of less
than 0.5. Such a pattern may also be suggestive of malignancy.
• Urinothorax is another cause of elevated pleural fluid LDH
associated with low pleural fluid protein levels
Cholesterol
• Pleural cholesterol is thought to be derived from degenerating
cells and vascular leakage from increased permeability.
• A pleural cholesterol level of greater than 45 mg/dL is not by
itself a definitive criterion for an exudate
• An elevated cholesterol >250 mg/dL defines a cholesterol
effusion (also known as pseudochylothorax or chyliform
effusion), which can develop in patients with long-standing
effusions
Triglycerides
•  Elevated pleural fluid triglyceride concentrations greater than
110 mg/dL supports the diagnosis of a chylothorax, a level less
than 50 mg/dL excludes a chylothorax with reasonable
likelihood, and an intermediate level between 50 and 110 mg/dL
should be followed by lipoprotein analysis of the pleural fluid
Glucose
• low pleural fluid glucose concentration (less than 60 mg/dL or a
pleural fluid/serum glucose ratio less than 0.5) narrows the
differential diagnosis of the exudate to the following possibilities
●Rheumatoid pleurisy
●Complicated parapneumonic effusion or empyema
●Malignant effusion
●Tuberculous pleurisy
●Lupus pleuritis
●Esophageal rupture
• The mechanism responsible for a low pleural fluid glucose
depends upon the underlying disease.
1. Decreased diffusion of glucose from blood to pleural fluid with
rheumatoid pleurisy or malignancy
2. Increased utilization of glucose by constituents of pleural fluid,
such as neutrophils, bacteria (empyema), and malignant cells
• The lowest glucose concentrations are found in rheumatoid
pleurisy and empyema, with glucose being undetectable in
some cases
Creatinine 
•  Pleural fluid creatinine represents a confirmatory test for urinothorax
when a transudate has a pleural fluid/serum creatinine ratio >1
pH 
• The pH of normal pleural fluid is approximately 7.60, due to a
bicarbonate gradient between pleural fluid and blood. Thus, a pH below
7.30 is abnormal.
• Transudates generally have a pleural fluid pH in the 7.40 to 7.55 range,
while the majority of exudates range from 7.30 to 7.45.
• urinothorax is the only transudate that can have a pleural fluid pH <7.40.
• The mechanisms responsible for pleural fluid acidosis (pH <7.30)
include;
1. Increased acid production by pleural fluid cells and bacteria
(empyema)
2. Decreased hydrogen ion efflux from the pleural space, due to
pleuritis, tumor, or pleural fibrosis. Specific examples include
malignancy, rheumatoid pleurisy and tuberculous pleurisy.
• A low pleural fluid pH has diagnostic, prognostic, and therapeutic
implications for patients with parapneumonic and malignant effusions.
• Patients with a low pleural fluid pH malignant effusion have a high
initial positive yield on pleural fluid cytology.
• shorter survival and poorer response to chemical pleurodesis
than those with a pH >7.30 …. The strength of these
associations do not provide prognostic value for individual
patients.
• Clinicians should not use a low pleural fluid pH as the sole
criterion for the decision to forego pleurodesis.
• A parapneumonic effusion with a low pleural fluid pH (≤7.15)
indicates a high likelihood of necessity for pleural space
drainage
Amylase
• Can assist when pancreatic or esophageal etiologies of an effusion
appear possible.
• pleural fluid amylase greater than the upper limits of normal for
serum amylase or a pleural fluid to serum amylase ratio greater
than 1, narrows the differential diagnosis of an exudative effusion to
the following major possibilities:
• Acute pancreatitis
• Chronic pancreatic pleural effusion
• Esophageal rupture
• Malignancy
• Pleural fluid amylase has low discriminative value for
differentiating benign from malignant effusions so it is not
routinely performed
• Other rare causes of an amylase-rich pleural effusion include
pneumonia, ruptured ectopic pregnancy, hydronephrosis, and
cirrhosis.
• Pancreatic disease is associated with pancreatic isoenzymes,
while malignancy and esophageal rupture are characterized by
a predominance of salivary isoenzymes
Adenosine deaminase
• ADA may be helpful to distinguish between malignant and
tuberculous pleurisy when an exudative effusion is lymphocytic, but
initial cytology and smear and culture for tuberculosis are negative.
• The level of ADA is typically greater than 35 to 50 U/L in
tuberculous pleural effusions and less than 40 U/L in 94 percent of
malignant pleural effusions.
• more valuable for ruling in the diagnosis of tuberculous pleurisy in
geographic locations with high prevalence of tuberculosis, although
the negative predictive value of ADA testing remains high in lower
tuberculosis prevalence regions
Cytology
• Can establish the diagnosis of malignant pleural effusions
• overall sensitivity of approximately 60 percent, which may increase
by 15 percent with a second thoracentesis pleural fluid sample
• The sensitivity of pleural fluid cytology varies depending on the
histological type of the underlying malignancy
• cytology has a sensitivity of 78 percent for adenocarcinoma, 53
percent for small cell carcinoma, and 25 percent for squamous cell
carcinomas
• The diagnostic yield of pleural fluid cytology does not appear to
depend on the volume of fluid sent
Cancer related biomarkers
•  Multiple biomarkers are expressed by cancer cells or their
environment.
• Modern immunohistochemistry techniques can detect these
biomarkers in pleural fluid and provide opportunities to diagnose
pleural malignancies when the results of standard cytology are
noncontributory.
• Although promising, clinical applicability of cancer-related
biomarkers to establish a diagnosis of pleural malignancy is limited
by the lack of standardized laboratory analysis methodologies and
a shortage of studies that validate positive studies.
• Nucleated cells
• ●Counts above 50,000/microL are usually found only in
complicated parapneumonic effusions, including empyema
• ●Exudative effusions from bacterial pneumonia, acute
pancreatitis, and lupus pleuritis usually have total nucleated cell
counts above 10,000/microL
• ●Chronic exudates, typified by tuberculous pleurisy and
malignancy, typically have nucleated cell counts below
5000/microL
Lymphocytic effusion
•  Pleural fluid lymphocytosis, particularly with lymphocyte counts
representing 85 to 95 percent of the total nucleated cells,
suggests tuberculous pleurisy, lymphoma, sarcoidosis, chronic
rheumatoid pleurisy, yellow nail syndrome, or chylothorax.
• Malignant pleural effusions will be lymphocyte-predominant in
over one-half of cases; however, the percentage of lymphocytes
is usually between 50 and 70 percent
• Some drug-induced pleural effusions, such as those caused
by dasatinib, are lymphocyte predominant
Eosinophilic effusions
• Pleural fluid eosinophilia (defined by pleural fluid eosinophils
representing more than 10 percent of the total nucleated cells) occurs
with both malignant and benign etiologies of pleural effusions.
• The differential diagnosis of pleural fluid eosinophilia includes
• ●Pneumothorax
• ●Hemothorax
• ●Pulmonary infarction
• ●Benign asbestos pleural effusion
• ●Parasitic disease
• ●Fungal infection (coccidioidomycosis, cryptococcosis, histoplasmosis)
• ●Drugs
• ●Catamenial pneumothorax with pleural effusion
• ●Malignancy (carcinoma, lymphoma, myeloma)
• ●Tuberculous pleurisy
• ●Parapneumonic effusions
• ●Chronic eosinophilic pneumonia
• Mesothelial cells — Mesothelial cells are found in small
numbers in normal pleural fluid, are prominent in transudative
pleural effusions, and are variable in exudative effusions. The
major clinical significance of mesothelial cells in exudates is that
tuberculosis is unlikely if there are more than 5 percent
mesothelial cells
THANK YOU
References
• Uptodate 2019
• Harrison’s principle of internal medicine