Pleural fluid

Analysis of pleural fluid is important for the workup of a pleural effusion.

A pleural effusion is the most common manifestation of pleural disease and it may occur from a wide range of aetiologies. It refers to an abnormal collection of fluid with the pleural space. Pleural fluid may be aspirated and analysed to help determine the underlying cause.

Pleural effusions may be a manifestation of numerous conditions that requires a careful history, clinical examination, imaging (e.g. chest x-ray), and pleural fluid analysis to determine the cause. Sometimes the cause may be obvious (e.g. heart failure) and pleural aspiration is not necessary. For unilateral effusions and/or suspected exudates, pleural aspiration and fluid analysis are vital in the majority of cases.

For more information see our notes on Pleural effusions.

The causes of a pleural effusion can be broadly divided into transudates and exudates.

Specific causes of pleural effusion (e.g. haemothorax) usually have a clear cause (e.g. trauma). When referring to a simple pleural effusion (i.e. hydrothorax) the causes can be broadly divided into transudates and exudates.

Transudate

A transudate is a fluid with minimal protein or cellular content. It occurs due to alteration in hydrostatic and oncotic pressures leading to the fluid being ‘squeezed’ into the pleural space (ultrafiltration).

• Heart failure
• Hypoalbuminaemia
• Cirrhosis
• Constrictive pericarditis
• Nephrotic syndrome
• Peritoneal dialysis
• Meigs' syndrome (Ascites and pleural effusion in association with a benign ovarian tumour).

Exudate

An exudate is a fluid with a high protein and cellular content. It develops due to a variety of inflammatory conditions that affect vessel permeability and/or lymphatic drainage. Exudates are commonly due to infection or malignancy.

• Parapneumonic effusion (secondary to pneumonia)
• Malignancy (commonly breast or lung)
• Tuberculosis
• Pulmonary embolism
• Pancreatitis
• Radiation pleuritis
• Systemic inflammatory condition (e.g. systemic lupus erythematosus, rheumatoid arthritis)
• Trauma

A pleural paracentesis, or pleural ‘tap’, is important to obtain a sample of pleural fluid for analysis.

Pleural procedures should now always be performed with ultrasound guidance. A pleural paracentesis involves the insertion of a small needle under aseptic conditions through the intercostal space into the pleural space to take a small sample of fluid (e.g. 20-50 mL).

Several investigations can be requested on pleural fluid to determine the cause of the pleural effusion.

The basic set of investigations that should be conducted on pleural fluid include pH, gram stain, microscopy, culture, and sensitivity (MC&S), protein count, lactate dehydrogenase (LDH), and cytology. Other investigations are guided by the suspected cause (e.g. lipids, amylase). The reason for these tests is discussed in detail below.

pH

A sample of pleural fluid should be run through a blood gas machine to determine the pH. The pH of normal pleural fluid is alkalotic (pH 7.60) due to the high bicarbonate content.

A pH < 7.30 is abnormal and highly concerning for a complicated parapneumonic effusion or empyema. This is due to the increased acid production by pleural cells and bacteria. It strongly indicates the need for drainage.

Protein

The pleural protein content is essential to determine whether the effusion is a transudate or exudate. It should be measured alongside the serum protein content. If it is close to 30 g/L, Lights criteria should be applied (discussed below).

• Transudate < 25-30 g/L
• Exudate > 30-35 g/L

Lactate dehydrogenase

LDH is useful as part of Lights criteria to help further differentiate between transudates and exudates. High levels (i.e. >1000 IU/L) are often found in empyema.

Microbiology

A sample of pleural fluid should be sent to microbiology to analyse for an infection. An initial gram stain should be performed looking for any bacterial microorganisms. Subsequently, microscopy, culture, and sensitivity can be completed.

If tuberculosis is suspected, then a number of specific investigations can be requested:

• Acid-fast bacilli: specific stain looking for M. Tuberculosis organisms
• TB culture: traditional culture, can take days to weeks for a diagnosis
• TB PCR: nucleic amplification testing

Cytology

A large sample of pleural fluid should ideally be sent for cytology. This involves looking down a microscope at the fluid and assessing for any abnormal cells that may suggest malignancy. The sensitivity of cytology for a malignant pleural effusion is ~60% although this varies depending on the cancer type (highest for adenocarcinoma).

Glucose

A number of exudative pleural effusions cause a characteristically low pleural fluid glucose (<3.3 mmol/L). These include:

• Complicated parapneumonic effusion
• Empyema
• Malignant effusion
• Tuberculosis
• Systemic lupus erythematosus
• Oesophageal rupture

Glucose is typically low in infective and malignant causes of pleural effusions due to increased utilisation of glucose by microorganisms or malignant cells. The lowest levels of glucose are often found in empyema.

Haematocrit

Measurement of the pleural fluid haematocrit is important to determine whether the effusion is a haemothorax. If the effusion is bloody, haematocrit can be measured in EDTA container. Haematocrit >50% of the patients' peripheral blood hematocrit confirms haemothorax.

Amylase

Amylase may occasionally be measured in pleural fluid and compared to serum levels. Common causes of a raised amylase level in the pleural fluid include oesophageal rupture, acute or chronic pancreatitis, and malignancy. Amylase-rich fluid is defined as a level > serum ULN (upper limit of normal).

Lipids

Triglycerides may be requested in suspected chylothorax. A level > 110 mg/dL supports the diagnosis. Chylothorax may be secondary to trauma, malignancy, idiopathic or rare conditions. A pseudochylothorax is defined as a cholesterol level > 250 mg/dL of which tuberculosis and rheumatoid arthritis are commonly implicated.

Nucleated cell count

White cell counts can be assessed on pleural fluid samples to help determine the aetiology. Collectively these are termed ‘nucleated cells’ and their relative concentrations (i.e. percentage of the total population) can help the diagnosis. Examples include:

• Neutrophilia and high counts (>10,000/micoL): highly suggestive of complicated parapneumonic effusion or empyema.
• Marked lymphocytosis (85-95% of nucleated cells): suggestive of tuberculosis, lymphoma, sarcoidosis, or other chronic inflammatory conditions
• Eosinophilia (>10% of nucleated cells): may be seen in a variety of benign and malignant conditions

Over time, any longstanding pleural effusion tends to become populated by lymphocytes.

Analysis of the pleural fluid helps determine whether it is a transudate or exudate.

Pleural effusions can be categorised into transudates or exudates based on their protein content. The broad cut-off is around 30 g/L.

• Transudate: an extravascular fluid with low protein content (< 30 g/L)
• Exudate: an extravascular fluid with high protein content (>30 g/L)

When the level of protein is close to 30 g/L (~25-35 g/L), Light’s criteria can be applied to formally determine whether it is a transudate or exudate. This is critical to narrow the differential diagnosis and guide further investigations. To apply Lights criteria, the total protein and LDH level should be measured in both the pleural fluid and serum.

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 >2/3 the upper limits of laboratory normal value for serum LDH

The pleural fluid should be interpreted in the context of the history and clinical examination to help make a diagnosis.

When interpreting pleural fluid, the first step is to confirm whether it is a transudate or exudate based on the pleural fluid protein count.

• Transudate: < 30 g/L
• Exudate: > 30 g/L

If the protein content is between 25-35 g/L, then Lights criteria should be applied (discussed above). Once the fluid has been confirmed as a transudate or exudate, the other pleural tests can be used to help determine the diagnosis. We discuss the characteristic pleural findings for several common diagnoses.

Parapneumonic effusion

This refers to an effusion adjacent to an area of pneumonia.

• Appearance: may range from straw-coloured (simple effusion) to turbid (complicated effusion).
• Protein count: high protein count consistent with exudate
• Microbiology: positive gram stain and culture may be identified
• Glucose: typically low (< 3.3 mmol/L)

Empyema

This refers to a collection of pus within the pleural space.

• Appearance: evidence of pus on aspiration
• Protein count: high protein count consistent with exudate
• Microbiology: positive gram stain and culture may be identified
• Glucose: typically low (< 3.3 mmol/L)
• Other: characteristically low pH (< 7.30)

Tuberculous effusion

This refers to a pleural effusion secondary to mycobacterium tuberculosis infection.

• Appearance: typically straw-coloured. May be turbid or blood-stained depending on extent.
• Protein count: often very high protein count >40 g/L
• Microbiology: positive acid-fast bacilli and culture may be identified
• Glucose: typically low (< 3.3 mmol/L)

Heart failure

This refers to a pleural effusion secondary to heart failure.

• Appearance: pale yellow (straw-coloured), common to most transudates.
• Protein count: commonly low protein count consistent with transudate. Note that acute diuresis in heart failure can elevate the pleural fluid protein count into the exudate range. In this situation, a serum pleural albumin/protein gradient should be calculated.
• Microbiology: negative gram stain and cultures
• Glucose: typically normal level like most transudates

Malignant effusion

This refers to a pleural effusion secondary to malignancy.

• Appearance: variable appearance, commonly blood-stained
• Protein count: high protein count consistent with exudate
• Microbiology: negative gram stain and cultures
• Cytology: the presence of abnormal or atypical cells
• Glucose: typically low (< 3.3 mmol/L)

Last updated: August 2021