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Diagnostic approach of the patient with pleural effusion

Article  in  Revista Hospital Medicine and Clinical Management · August 2018

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Hosp Med Clin Manag. 2018;11:73-8 REVIEW ARTICLE

Diagnostic approach of the patient

with pleural effusion
Oscar Santes* and Jesús Morales-Maza
Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

ABSTRACT

Pleural effusion (PE) is an excess of fluid in the pleural cavity, resulting from an imbalance between its production,
absorption, or both. It is a common pathology, although its causes and incidence depend on the population stud-
ied. It is estimated that pleural disorders affect more than 3000 people per million inhabitants1. Although numerous
potential causes of PE have been reported, in clinical practice, only a few represent the majority of cases. For
example, in a study of more than 3000 patients with PE undergoing diagnostic thoracentesis, the four main causes
were cancer (27%), heart failure (HF) (21%), pneumonia (19%), and tuberculosis (9%)2. However, HF could be
considered the first cause of PE since most patients with a clinical diagnosis of HF do not undergo thoracentesis.
The lack of good-quality randomized clinical trials and the existence of few evidence-based guidelines result in
a heterogeneous approach and management of PE. The establishment of the exact etiology of a PE should ide-
ally follow a logical and simple diagnostic algorithm. The key elements to determine the causes of a PE are the
clinical evaluation, imaging studies, pleural fluid analysis and when appropriate, pleural biopsy. This review de-
scribes the stages in the investigation of PE etiology. (Hosp Med Clin Manag. 2018;11:73-8)
Corresponding author: Oscar Santes, oscar.santesj@gmail.com

Key words: Pleural effusion. Diagnosis. Pleural fluid analysis.

RESUMEN

El derrame pleural (DP) es un exceso de líquido en la cavidad pleural, generalmente resultado de un desequilibrio
entre su producción y absorción o en ambas. Es una patología común y sus causas e incidencia varían de acuerdo
con la población estudiada. Se estima que las patologías pleurales afectan a más de 3,000 personas por millón de
habitantes1. Aunque se han reportado numerosas causas potenciales de DP, en la práctica clínica solo unas pocas
representan la mayoría de los casos. Por ejemplo, en una serie de más de 3,000 pacientes con DP sometidos a
toracocentesis diagnóstica, las cuatro causas principales por orden de frecuencia fueron: cáncer (27%), insuficiencia
cardíaca (IC) (21%), neumonía (19%) y tuberculosis (9%)2. Sin embargo, la IC puede considerarse la principal etiología

Correspondencia:
*Oscar Santes
Department of Surgery
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Vasco de Quiroga, 15
Col. Belisario Domínguez, Del. Tlalpan Received for publication: 17-01-2018
C.P. 14080, Ciudad de México, México Accepted for publication: 14-06-2018
E-mail: oscar.santesj@gmail.com DOI: 10.24875/HMCM.18000102

73
Hosp Med Clin Manag. 2018;11:73-8

de DP, ya que muchos pacientes con diagnóstico clínico de IC no se someten a toracocentesis. La falta de estudios

Sin contar con el consentimiento previo por escrito del editor, no podrá reproducirse ni fotocopiarse ninguna parte de esta publicación.   © Permanyer 2018
clínicos aleatorizados de buena calidad y la existencia de pocas guías clínicas basadas en evidencia hacen que el
abordaje y el tratamiento de los DP sea heterogéneo. Establecer la etiología exacta de un DP debe seguir idealmente
un algoritmo diagnóstico lógico y no complejo. Los elementos clave para determinar la causa de un DP son la evalu-
ación clínica, el estudio de imagen, el análisis del líquido pleural y, cuando proceda, la biopsia pleural. Esta revisión
describe las etapas en la investigación de la etiología de un DP.

Palabras clave: Derrame pleural. Diagnóstico. Análisis del líquido pleural.

Table 1. Important features in the history of patients with

CLINICAL HISTORY AND PHYSICAL
EXAMINATION
The patient’s history and physical examination guide the
clinician in determining whether a pleural effusion (PE)
is a transudate or exudate. This critical distinction re-
duces the differential diagnosis and directs further in-
vestigations. A transudate is usually associated with
cardiac, renal or hepatic failure, and an exudate, with
conditions that cause excess inflammation such as ma-
lignancy or infection.
suspected or confirmed pleural effusion3
Severity, duration, and speed of symptoms onset
Presence of general symptoms (fever, sweating, and weight loss)
Thoracic injuries or interventions
History of malignancy
Recent hospitalizations
Previous exposure to tuberculosis
Occupational history (e.g., asbestos)
Tobacco use
Medications (methotrexate, amiodarone, phenytoin, nitrofurantoin,
beta blockers, L-tryptophan, and ergot alkaloids)
Uncontrolled heart, kidney, or liver failure
Recent illnesses

The form of presentation of a PE depends on several Table 2. Accuracy of common clinical findings in the diagnosis
of pleural effusion5
factors such as the size of the effusion, the amount/rate
of accumulated fluid, comorbidities, and the baseline Finding Sensitivity (%) Specificity (%)
respiratory reserve. Patients usually report dyspnea, Pleural rub 5.3 99
cough, or chest pain but may be asymptomatic4. On Asymmetric chest expansion 74 91
physical examination, pulmonary dullness to percussion Decreased vocal resonance 76 88
is the most reliable sign for suspecting PE (positive Decreased vocal fremitus 82 86
likelihood ratio = 8.7), while the absence of reduced Decreased respiratory sounds 42-88 83-90
Dullness to percussion 30-90 81-98
tactile thrill makes this diagnosis less probable (nega-
Crackles 56 62
tive likelihood ratio = 0.21)5. Other physical findings that
may be present are as follows: asymmetric thoracic ex-
pansion, decrease or absence of respiratory sounds,
and pleural rub (Table 2). silhouette of the ipsilateral hemidiaphragm, and appar-
ent fissure thickening as a result of pleural fluid leak-
age7. In the supine position, the volume tends to be
INITIAL IMAGING STUDIES underestimated, and the “normal” appearance does not
exclude the presence of a spill8.
When PE is suspected, a chest X-ray should be done to
confirm the diagnosis; the sensitivity reported is 65%
and the specificity is 81%. The posteroanterior radio- THORACIC ULTRASOUND
graph is abnormal in the presence of approximately 200
mL of pleural fluid. However, on a lateral radiograph, The thoracic ultrasound (US) has a diagnostic accuracy
only 50 mL can produce effacement of the posterior of 99.6% and allows assessing 70% of the pleural sur-
costophrenic angle6. In prostrate patients who undergo face9. It is particularly useful in the diagnosis of small
an anteroposterior radiography, an increase in the opac- effusions or in patients in the supine position (for exam-
ity of the hemithorax can be found with preservation of ple, ventilated and critically ill) due to low sensitivity of
vascular shadows, loss in the sharpness of the the radiography in this situations7.

74
 O. Santes, J. Morales-Maza: Diagnostic approach of the patient with pleural effusion
The US is effective in determining the nature of a PE; it
positively identifies exudative effusions when the pleural
fluid is complex, septate, or echogenic10. The findings sug-
gestive of malignancy include pleural thickness > 1 cm,
diaphragmatic thickness > 7 mm, and pleural nodular-
ity (sensitivity 42% and specificity 95% for each criteri-
on)11. The US detects septa with greater sensitivity than
tomography12.
The US is considered the standard of care for the safe
location and aspiration of pleural fluid because it im-
proves the success rate of thoracentesis. Several stud-
ies have shown that with US, the fluid can be obtained
in up to 88% of patients after a failed attempt without
using it. The US reduces the incidence of iatrogenic
pneumothorax (1.3-6.7% with US vs. 4-30% without US)
and decreases the incidence of visceral puncture by
10-15%, this effect is independent of the size of the
effusion. This benefit seems to disappear when the
method of “guided labeling, mobilization of the patient,
and subsequent puncture” is used, presumably due to
differences in the positioning of the patient during the
US and the following procedure7.
COMPUTED TOMOGRAPHY OF THE CHEST
Computed tomography (CT) is more useful in the study
of exudative PEs. Its main indication is in cases of pleu-
ral infection complicated with drainage failure or before
surgery. Ideally, CT should be done before total drain-
age of pleural fluid and with intravenous contrast7.
The same characteristics of the US that helps in the dif-
ferentiation of malignant from benign effusions are appli-
cable to CT. Thus, the existence of pleural nodules or
thickening usually > 1 cm strongly suggests the presence
of malignancy. However, although these findings are very
specific (> 90%), they are not sensitive enough (40%)13.
Virtually, all patients with empyema or tuberculosis
show parietal pleural thickening on CT. In infectious
effusions, evidence of multiple air zones within the pleu-
ral fluid suggests the presence of septa. Chest CT is
also effective in demonstrating parenchymal lung ab-
normalities hidden by the effusion, mediastinal lymph-
adenopathy, pericardial involvement, subdiaphragmatic
disease (e.g., liver metastases and gastric tumors),
and, by following a CT angiography protocol, pulmo-
nary embolism14.
THORACENTESIS
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The diagnostic aspiration of a small volume of pleural
fluid (50-100 mL) is indicated when the etiology of the
effusion is unknown. Drainage of larger volumes is re-
served for the treatment of symptoms related to the ef-
fusion (such as dyspnea), to improve the hemodynamic
compromise or to evacuate the pleural site of infection9.
The chest radiography may guide in the selection of
patients with pneumonia and associated PE. Aspiration
is required when a parapneumonic effusion is > 5 cm in
a supine lateral position (as this may cause treatment
failure); an effusion smaller than this usually resolves
without drainage15,16.
Patients with bilateral PE highly suggestive of transu-
dates should not undergo thoracentesis, unless they
have atypical features (e.g., fever, pleuritic chest pain,
and uneven size) or do not respond to treatment7.
There are no absolute contraindications to the procedure.
The relative contraindications for reasons that increase
the risk of bleeding are alterations of coagulation or treat-
ment with anticoagulants (INR > 1.5), thrombocytopenia
(< 50,000), and renal failure (serum creatinine > 6 mg/dL)9.
Complications of the procedure include pneumothorax
(1.3-6.7%), failure of the procedure, bleeding, and or-
gan injury (liver, spleen, and lung)7. In thoracentesis of
a large volume, pulmonary edema has been reported
as a complication due to a re-expansion (incidence 0.2-
14% and morbidity and mortality 20%), so the volume
of extraction should be limited to 1-1.5 L17.
The clinical guidelines recommend performing the pro-
cedure with the use of US7,18,19. Post-puncture radiog-
raphy is not indicated, unless it has been difficult to
obtain the fluid, when aspiration of air has occurred, in
case of multiple punctures, or when other symptoms
develop after aspiration7.
If thoracentesis is not successful, consultation with an
interventional radiology team or thoracic surgery team
is recommended.
PLEURAL FLUID ANALYSIS
The pleural fluid appearance can provide diagnostic
clues (Table 3)7. Routine pleural fluid studies include
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Hosp Med Clin Manag. 2018;11:73-8
Table 3. Suspected diagnosis according to physical characte-
ristics of the pleural fluid4
Finding Suspected diagnosis
Urine Urinothorax
Putrid odor Anaerobic empyema
Milky fluid Chylothorax or pseudochylothorax
Food particles Esophageal perforation
Black fluid Aspergillus spp. infection
Bile staining Cholothorax (biliary fistula)
Anchovy color (brown fluid) Ruptured amebic abscess
protein and lactate dehydrogenase (DHL) levels, cell
count, pH, glucose, Gram stain, culture, and cytology.
Protein and DHL
They are helpful to determine whether the extracted
pleural fluid represents a transudate or exudate and are
used to evaluate Light’s criteria (Table 4), which have a
diagnostic accuracy of 93-96%. In congestive heart fail-
ure (HF), treatment with diuretics increases the concen-
tration of protein, DHL, and lipids in the pleural fluid; in
this context, Light’s criteria may erroneously classify a
significant proportion of effusions as exudates (25%)20.
Other criteria highly specific in the diagnosis of exudate
include pleural cholesterol levels > 55 mg/dL, the ratio
of pleural cholesterol to serum cholesterol of > 0.3, and
a DHL > 200 U/L21.
Cell count
It is useful in ruling out differential diagnoses, although
it lacks specificity. The predominance of neutrophils
tends to indicate an acute process such as a parapneu-
monic effusion or pulmonary thromboembolism, where-
as the predominance of lymphocytes can be observed
in long-lasting effusions such as those of malignancy,
tuberculosis, and HF7.
pH
Under normal conditions, the pleural fluid pH is 7.6.
Pleural fluid acidosis reflects an increase in the produc-
tion of lactic acid and carbon dioxide due to the increase
in local metabolic activity, as well as a drop in the flow
of hydrogen ions through the abnormal pleural mem-
branes. Pleural fluid with a pH < 7.3 may suggest malig-
nancy, connective tissue diseases, esophageal perfora-
tion, or complicated infection; in isolation, it does not
distinguish between these causes. In parapneumonic
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Table 4. Light’s criteria to characterize pleural effusion as an
exudate20
Pleural fluid is an exudate if one or more of the following criteria are
met:
Pleural fluid protein divided by serum protein is > 0.5
Pleural fluid LDH divided by serum LDH is > 0.6
Pleural fluid LDH is > 2/3 than the normal top value of serum LDH
LDHs: Lactate dehydrogenases.
effusions, a pH < 7.2 indicates the need to place an
endopleural tube, especially when associated with high
DHL and glucose < 60 mg/dL. Situations related to tho-
racentesis capable of altering pH are the inclusion of air
in the sample (increases pH by 0.05) and local anesthet-
ic (decreases pH by 0.15)7. In cases of purulent fluid, it
should not be subjected to pH determination because
an endopleural tube placement is mandatory regardless
of the value14.
Glucose
In the absence of pleural disease, glucose crosses free-
ly between the pleural membranes and is equivalent to
the levels in serum. A low glucose in the pleural fluid
(< 60 mg/dL) may occur in complicated parapneumon-
ic effusions, empyema, rheumatoid pleuritis, or effusions
associated with tuberculosis, neoplasia, and esopha-
geal rupture. The most frequent causes of low glucose
levels are empyema and rheumatoid arthritis7.
Gram stain and culture
These tests help in the identification of the pathogen in
infectious PEs.
Cytology
Pleural fluid cytology has a sensitivity of 60% to diag-
nose malignancy. The required volume is 60 mL, and
the diagnostic yield of more than two samples taken on
different occasions is very low (65% in the first sample,
27% in the second, and 5% in the third sample); there-
fore, it is not recommended7.
Other tests
Other tests could be performed in the pleural fluid
guided by clinical suspicion, including determination
of adenosine deaminase, triglycerides, cholesterol,
amylase, hematocrit, N-terminal prohormone of brain
 O. Santes, J. Morales-Maza: Diagnostic approach of the patient with pleural effusion

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Table 5. Selected pleural fluid tests7,24

Hct Pleural fluid Hct divided by blood Hct ≥ 0.5 suggests hemothorax
Cr Pleural fluid Cr divided by serum Cr > 1 suggests urinothorax
NT-proBNP Serum value > 1500 pg/mL suggests heart failure
Adenosine deaminase Diagnosis of tuberculosis with a sensitivity of > 90%
Amylase Suspected esophageal rupture or pancreatitis. May be elevated in malignancy and ruptured ectopic pregnancy
Tg and cholesterol Help in the diagnosis and differentiation of chylothorax (presence of chylomicrons, Tg > 110 mg/dL, low cholesterol,
absence of cholesterol crystals) and pseudochylothorax (cholesterol > 200 mg/dL, presence of cholesterol crystals,
absence of chylomicrons)

Hct: hematocrit; Cr: creatinine; Tg: triglycerides; NT-proBNP: N-terminal prohormone of brain natriuretic peptide.

History and clinical examination

Chest X-ray

Yes Clinical picture suggestive of transudate?

Treat the cause
(congestive heart failure, hypoalbuminemia, dialysis)
No

No Ultrasound-guided Thoracentesis
Resolution of
Pleural fluid analysis: appearance, protein, LDH,
Pleural Efussion
Gram stain, culture, cytology and pH

Light´s criteria

Transudate Exudate

Treat the cause. Do the clinical characteristics and pleural Yes Treat
If the diagnosis is still unknown, carry out effusion analysis allow to establish a diagnosis? cause
complementary studies, for example:
NT-proBNP (Heart failure) No
TSH (Hypothyroidism)
Request a confirmed chest CT scan.
Urine proteína (Nephrotic Syndrome)
Consider the performance of selective studies
LFT (Liver Cirrhosis)
of pleural effusion (ADA, cholesterol, Tg,
amylase, tumor markers). Interconsultation with
Thoracic Surgery Team

Yes Treat
Etiology found
cause

Resolution of
Consider guided Consider video-assisted Pleural Efussion
pleural biopsy thoracoscopy

Re-consider treatable conditions such as, TB, No Diagnosis Yes Treat

chronic heart failure and malignancy. established cause
Close observation

Figure 1. Algorithm of diagnostic approach of pleural effusion.

natriuretic peptide, complement (C4), antinuclear anti- INVASIVE PROCEDURES

bodies, and rheumatoid factor7. Tumor markers do not
currently have a role in the routine investigation of PEs Percutaneous pleural biopsy guided by CT or thoraco-
(Table 5)22. scopy is indicated in the investigation of exudative PE

77
 Hosp Med Clin Manag. 2018;11:73-8
with suspicion of malignancy and results of previous
negative or inconclusive studies. Both procedures have
shown a good diagnostic performance (> 85%)3,23.
Bronchoscopy is not considered a routine study; it can
be justified if there is hemoptysis or imaging findings
are suggestive of bronchial obstruction7.
CONCLUSION
The diagnostic approach to PEs is based primarily on
the study of pleural fluid, based on the suspected diag-
nosis after a complete clinical history, physical evalua-
tion and an imaging study. To date, there are several
algorithms, but in our experience, the one developed by
the British Thoracic Society is the most representative7.
CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.
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