Pleural effusion laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]; Nate Michalak, B.A., Dushka Riaz, MD

Overview

When the cause of the pleural effusion is unknown a thoracentesis is indicated. This will obtain 50 mL of fluid to be analyzed and it is best for the procedure to be done under ultrasound guidance. The analysis will then provide a differential diagnosis which will affect treatment modalities. Currently, the foundation of the clinical workup is the differentiation between exudates and transudates.

Laboratory Findings

Once a pleural effusion is diagnosed, the cause must be determined. Pleural fluid is drawn out of the pleural space in a process called thoracentesis. A needle is inserted through the back of the chest wall into the pleural space. Approximately 75% of patients may be diagnosed by analysis of the pleural fluid in conjunction with the clinical presentation. The fluid may then be evaluated for the following:

1. Chemical composition including protein, lactate dehydrogenase (LDH), albumin, amylase, pH and glucose
2. Gram stain and culture to identify possible bacterial infections
3. Cell count and differential
4. Cytology to identify cancer cells, but may also identify some infectious organisms
5. Other tests as suggested by the clinical situation - lipids, fungal culture, viral culture, specific immunoglobulins

Electrolyte and Biomarker Studies

• Definite diagnoses can be made by specific analyses of fluid.

  • Culture
  • Cytology
  • Lupus erythematosus (LE) cells
  • Antinuclear antibody (ANA) >1 (systemic lupus erythematosus)
  • Amylase and severe acidosis (esophageal rupture)
  • KOH prep
  • Triglycerides (>110mg/dL = chylothorax)
  • Hematocrit (pleural fluid to blood >0.5)
  • Creatinine (urinothorax)
  • Protein <1g/dL
  • Glucose 300 to 400 (peritoneal dialysis).

• Appearance of fluid: milky, bloody, or clear.
• Transudate

  • Imbalance between hydrostatic and oncotic pressure in chest.
  • May also be movement of fluid from abdominal cavity or retroperitoneal space.

• Exudate:

  • Results from pleural and lung inflammation (resulting in a capillary protein leak) or impaired lymphatic drainage of pleural space (i.e. slow removal of protein from pleural space).
  • Can also result from movement of fluid form peritoneal space.

• If at least one of the following is present, the fluid is typically exudate; if none is present, the fluid is typically transudate:

  • Pleural fluid protein/serum protein ratio >0.5
  • Fluid/serum lactic dehydrogenase (LDH) ratio >0.6
  • Fluid LDH greater than 2/3 the upper limits of normal of the serum LDH

• Additional notes:

  • Tuberculosis (TB) effusion virtually always have a protein above 4.0 g/dL.
  • Pleural fluid protein in the 7 to 8 g/dL range may be indicative of Waldenstrom macroglobulinemia and multiple myeloma.
  • LDH above 1000 is usually found in empyema, rheumatoid pleuritis, and sometime malignancy.
  • Pleural fluid in pneumocystis carinii pneumonia (PCP) has fluid/serum LDH greater than 1 and fluid/serum protein ratio less than 0.5
  • Glucose levels lower then 60mg/dL or fluid/serum ratio < 0.5 is not seen in transudates and limits exudates to the following: rheumatoid pleuritis, Parapneumonic effusion, empyema, malignant effusion, TB, lupus pleuritis, oresophageal rupture.
  • A pH less than 7.30 with normal blood pH is typically found with same diagnosis as low glucose.
  • Normal pleural fluid is around pH 7.6 due to a bicarbonate gradient between pleural fluid and blood.
  • Amylase levels greater than the upper limit of normal for serum or a pleural fluid to serum ratio >1 narrows an exudate to acute pancreatitis, chronic pancreatic effusion, esophageal rupture, or malignancy.
  • Pleural fluid C-reactive protein (CRP) is superior to serum CRP in determining pleural fluid etiology. Quantitative measurement of pleural fluid CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with malignant pleural effusion.

Transudate vs. Exudate

The first step in the evaluation of pleural fluid is to determine whether the effusion is a transudate or an exudate. Transudative pleural effusions are caused by systemic factors that alter the balance of the formation and absorption of pleural fluid (e.g. left ventricular failure, pulmonary embolism, or cirrhosis), while exudative pleural effusions are caused by alterations in local factors that influence the formation and absorption of pleural fluid (e.g. bacterial pneumonia, cancer, or viral infection).

According to Light's criteria transudative and exudative pleural effusions are differentiated by comparing chemistries in the pleural fluid to those in the blood. According to a meta-analysis, two-test or three-test rule for defining exudative pleural effusions have comparable specificity and sensitivity with light's criteria. It has an advantage over light's criteria in that there is no need to take blood sample and compare with pleural fluid sample before an exudative effusion can be defined.

Twenty-five percent of patients with transudative pleural effusions are mistakenly identified as having exudative pleural effusions by Light's criteria. Therefore, additional testing is needed if a patient identified as having an exudative pleural effusion appears clinically to have a condition that produces a transudative effusion. In such cases albumin levels in blood and pleural fluid are measured. If the difference between the albumin levels in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), it can be assumed that the patient has a transudative pleural effusion.

If the fluid is definitively identified as exudative, additional testing is necessary to determine the local factors causing the exudate.

The details of the various criteria have been summarized in the table below.

Diagnostic Criteria	Laboratory tests	Suggestive of Exudate
Light's Criteria	Pleural fluid protein to Serum protein ratio	> 0.5
	Pleural fluid LDH to Serum LDH ratio	> 0.6
	Pleural fluid LDH level	> 0.67 ULN
Two-test rule	Pleural fluid LDH level	> 0.45 ULN
	Pleural fluid cholesterol level	> 45 mg/dL
Three-test rule	Pleural fluid protein level	> 2.9 g/dL
	Pleural fluid cholesterol level	> 45 mg/dL
	Pleural fluid LDH level	> 0.45 ULN
* ULN=Upper Limit of Normal; LDH=Lactate Dehydrogenase

Exudative Pleural Effusions

Once identified as exudate, additional evaluation is needed to determine the cause of the excess fluid, and pleural fluid amylase, glucose, and cell counts are obtained. The fluid is also sent for Gram staining and culture, and, if suspicious for tuberculosis, examination for TB markers (adenosine deaminase > 45 IU/L, interferon gamma > 140 pg/mL, or positive polymerase chain reaction (PCR) for tuberculous DNA).

Pleural fluid amylase is elevated in cases of esophageal rupture, pancreatic pleural effusion, or cancer. Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis. If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative, and cancer is still suspected, either a thoracoscopy, or needle biopsy of the pleura may be performed.

COMPLES score

This is newly developed score for differentiating between tuberculous effusions with low pleural pH or glucose and complicated parapneumonic effusions. The components are:

• Pleural fluid adenosine deaminase (ADA) (<46 IU/L [0 points]
• The percentage of mononuclear cells (MNC %), ≥100 IU/L (6 points), 46-100 IU/L (4 points); MNC % <10 % (0 points), 10-50 (3 points), >50 (8 points)
• pH <7.07 (0 points), 7.07-7.20 (3 points), >7.20 (5 points),
• Age ≥30 (0 points), <30 years (3 points)

A score of 12 or more points is highly sensitive and specific for complicated tuberculous pleural effusion.