Which pleural fluid studies should be ordered?

From the Guidelines

When evaluating pleural fluid, I recommend ordering a comprehensive panel including cell count with differential, protein, LDH, glucose, pH, Gram stain, culture, cytology, and amylase, with at least 25 mL and ideally 50 mL of pleural fluid submitted for initial cytological examination, as suggested by the British Thoracic Society guideline for pleural disease 1.

Key Tests

• Cell count with differential to assess for infection or malignancy
• Protein and LDH to differentiate between transudative and exudative effusions using Light's criteria
• Glucose and pH to assess for complicated parapneumonic effusion or malignancy
• Gram stain and culture to identify bacterial infection
• Cytology to diagnose malignancy, with higher yield from larger fluid volumes
• Amylase to assess for pancreatic disease or esophageal rupture

Specialized Tests

• Adenosine deaminase and mycobacterial cultures for TB
• Triglycerides for chylothorax
• Rheumatoid factor for rheumatoid effusions
• NT-proBNP for heart failure

Volume of Pleural Fluid

• At least 25 mL and ideally 50 mL of pleural fluid should be submitted for initial cytological examination 1
• Larger fluid volumes (>60 mL) may increase the diagnostic yield of cytology, but the submission of more than 50 mL of pleural fluid may not significantly increase the diagnostic yield 1

Clinical Context

• pH below 7.2 suggests complicated parapneumonic effusion requiring drainage 1
• Glucose below 60 mg/dL indicates infection, rheumatoid arthritis, or malignancy
• Cytology is essential for suspected malignancy, with higher yield from larger fluid volumes (>60 mL) 1
• Amylase elevation suggests pancreatic disease or esophageal rupture

Recommendations

• Pleural fluid samples should be processed by direct smear and cell block preparation, and microbiological samples should be sent in both white top containers and volumes of 5–10 mL inoculated into (aerobic and anaerobic) blood culture bottles, as recommended by the British Thoracic Society guideline for pleural disease 1.
• In cases where volume available does not allow 5–10 mL inoculation, volumes of 2–5 mL should be prioritised to blood culture bottles rather than a plain, sterile container 1.

From the Research

Pleural Fluid Studies

The following studies should be ordered for pleural fluid analysis:

• Cell count and differential 2
• Tests for protein, LDH, glucose, adenosine deaminase, cytology 2
• pH and bacterial and mycobacterial cultures if infection is a concern 2
• Gram stain and cultures, glucose, amylase, lactic acid dehydrogenase, cytology, and a marker for tuberculous pleuritis for exudative pleural fluids 3
• Carcinoembryonic antigen (CEA), C reactive protein (CRP), and lactate dehydrogenase (LDH) assay for patients with a history of cancer and suspicion of malignant pleural effusion 4

Diagnostic Utility of Pleural Fluid Studies

The diagnostic utility of pleural fluid studies is as follows:

• Adenosine deaminase levels >35 IU/L usually indicate tuberculosis in lymphocyte-predominant pleural fluid 2
• Adenosine deaminase levels >45 IU/L or gamma interferon levels >3.7 U/ml suggest tuberculous pleuritis 3
• Pleural fluid pH < 7.2 or glucose < 60 mg/dL identify complicated parapneumonic effusions 2, 5
• Conventional cytology may reveal malignant cells in 60% of patients with malignant effusions 2
• Natriuretic peptide assays improve the accuracy of a diagnosis of cardiac pleural effusion 2
• Pleural fluid mesothelin levels > 20 nmol/L are highly suggestive of mesothelioma 2
• Combination of pleural fluid cytology, CEA, and CRP assay together has a high diagnostic accuracy for malignant pleural effusion 4

Factors to Distinguish Between Diseases

The following factors can help distinguish between diseases with high pleural fluid adenosine deaminase levels:

• Pleural fluid lactate dehydrogenase (LDH) levels < 825 IU/L are beneficial for the diagnosis of tuberculosis 6
• Neutrophil predominance or cell degeneration, white blood cell count ≥ 9200/µL or C-reactive protein levels ≥ 12 mg/dL help in diagnosing pleural infection 6
• Pleural fluid amylase levels ≥ 75 U/L and a pleural fluid ADA/total protein (TP) ratio < 14 help in diagnosing malignant pleural effusion 6
• High serum LDH and high serum/pleural fluid eosinophils help in diagnosing malignant lymphoma and autoimmune diseases, respectively 6