A. Major Causes [1]

1. Congestive heart failure
2. Pneumonia
3. Cancers
4. Pulmonary Embolus
5. Viral disease
6. Coronary artery bypass surgery
7. Cirrhosis with ascites

B. Pleural Transudate [2]

1. Definition
   1. Protein <50% of serum (usually <3gm/dL)
   2. LDH < 200 units or <60% serum LDH
   3. Cells usually <1000/µL
2. Congestive Heart Failure (CHF)
   1. Right more often than left sided pleural effusions
   2. Very low protein levels
   3. Use of diuretics in CHF will increase protein concentrations in pleural effusions [3]
   4. Exudative effusions are well documented in CHF patients [4]
   5. Very high pro-BNP levels (>5000pg/mL) in pleural fluid usually indicate CHF [12]
3. Primary Pulmonary HTN (veno-occlusive disease)
4. Liver Cirrhosis [5]
   1. Also called hepatic hydrothorax
   2. Right sided (85%) versus left sided (13%)
   3. Occasionally (~2%) bilateral pleural effusions
   4. Serum proteins usually low, <2.5gmdL
   5. Total protein pleural fluid to serum ratio <0.5
   6. Cell counts <1000/µL
   7. pH 7.40 to 7.55 (slightly alkaline)
   8. Pleural fluid amylase concentration < serum amylase concentration
5. Nephrotic syndrome
   1. Hypoalbuminemia with Albuminuria
   2. Anasarca: generalized edema with ascites
   3. Hypercholesterolemia
   4. Coagulopathy
6. Atelectasis
7. Constrictive Pericarditis
8. Fluid overload in renal failure / dialysis
9. Pulmonary venous obstruction [2]

C. Pleural Exudate

1. Definition
   1. Protein >3g/dL or >50% of serum OR
   2. Ratio of pleural fluid LDH > to serum LDH >0.6 OR
   3. Pleural fluid LDH level >67% upper limit of normal
   4. pH usually < 7.4 (not required)
2. Tuberculosis (TB)
   1. May be direct infection or post-primary TB
   2. May or may not show chest X-ray evidence of primary or previous TB
   3. Represents inflammatory response of pleura to subpleural focus of infection
   4. Presentation may be asymptomatic, or weight loss, anorexia, fevers, and pleurisy
   5. Patients with TB pleurisy have >95% PPD positive tests
   6. Exudate usually shows protein >5gm/dL
   7. White cells, mainly lymphocytic in chronic cases; methothelial cells usually <5%
   8. pH almost always <7.4 (higher pH usually excludes TB)
   9. Interferon gamma (IFNg) >3.7 IU/mL in pleural fluid strongly suggests TB [11]
   10. Cultures are ~50% sensitive on each specimen sent; AFB stain positive in ~10%
   11. Pleural biopsy may show granulomas but is ~30% sensitive overall
3. Tumor
   1. Most commonly lymphoma, bronchogenic Cancers, SCLC, Breast Ca, Methothelioma
   2. Often have RBC >100,000
   3. Lymphocyte predominant WBC
   4. Often have >10% non-hematic cells in effusion
   5. Cytologic examination is positive in 70-90% of cases (increased with serial specimens)
4. Pulmonary Embolism (Infarction)
   1. A not infrequent and often overlooked presentation of pulmonary embolism
   2. High protein levels often found
   3. WBC usually <10,000/µL
5. Other infections
   1. Empyema - WBC often >50,000/µL; frank pus; pH <7.2
   2. Parapneumonic effusion (may also be transudate)
   3. Fungal Infections - immunocompromised hosts in most cases
6. Complication of CABG Surgery [6]
   1. Small pleural effusions are fairly common (~50%)
   2. Large pleural effusions (>25% of hemithorax) occur in ~1% of patients
   3. Large effusions may be bloody (~40%) and/or contain eosinophils
   4. Manage by therapeutic thoracocenteses
7. Collagen Vascular Disease
   1. Rheumatoid Arthritis [8]
   2. Systemic Lupus - WBC 3000-5000, glucose normal, protein low, pleural ANA+, RF-
   3. Systemic Sclerosis - often with significant pulmonary hypertension
   4. Mixed Connective Tissue Disease
8. Rheumatoid Pleuritis [7]
   1. Effusions usually bilateral but may be unilateral
   2. Glucose typically very low in pleural fluid (<50mg/dL)
   3. Rheumatoid nodules - often found in lungs and pleura (may be seen on CT or biopsy)
   4. Pleural fluid complement levels decreased
   5. Pleural fluid often rheumatoid factor (RF) positive
9. Yellow Nail Syndrome
   1. Triad of Yellow Nails, Lymphedema, Exudative Pleural Effusions
   2. Due to lymphatic obstruction (blocked lung drainage)
   3. Often with bronchiectasis, recurrent pneumonia, infections
10. Abdominal Pathology
    1. Pancreatitis - pleural fluid amylase is elevated, often >100,000U/L
    2. Chylous Effusion - triglycerides > 110mg/dL of pleural fluid (mily fluid)
    3. Splenic Infarction - very high pleural fluid WBC
11. CHF may cause exudative effusions (may be due in part to diuretic use) [3,4]

D. Evaluation

1. History of infections, especially pulmonary; TB exposure
2. PPD placement, two step if needed
3. Chest Radiography (X-Ray) Including Bilateral Ducubitus Positioning
   1. Determine quantity and loculation of fluid
   2. Attempt to locate a pulmonary mass associated with effusion
   3. Can determine location by which markings in chest radiograph are lost
   4. This is called the silhouette sign
   5. Heart border is lost with anterior fluid
   6. Border of diaphragm is lost with for posterior fluid
4. Pleural Fluid Sampling [8]
   1. Procedure is called thoracocentesis
   2. Diagnostic thoracocentesis indicated for >10mm thick effusion on ultrasound or X-ray
   3. May delay diagnostic thoracocentesis 24-48 hours if likely cause is CHF
   4. Generally safe procedure where needle is inserted into pleural space
   5. Major risks are pain and pneumothorax; infection very uncommon
   6. Pneumothorax is most common, rate 3-20%
   7. Routine chest X-ray has been recommended after thoracocentesis
   8. Pneumothorax symptoms should be sought after test: continued pain, shortness of breath
   9. In the absence of any symptoms of pneumothorax routine chest X-ray not needed [8]
   10. May remove a large amount of fluid (therapeutic thoracocentesis, see below)
5. Pleural Fluid Analysis
   1. Chemistries: pH, LDH, Glucose, protein, amylase, (triglycerides)
   2. Cell Counts with Differential
   3. Cytologic Examination - excellent for malignancy detection
   4. Suspected Collagen Vascular Disease: Pleural ANA, RF, Complement Levels
6. Blood Tinged Pleural Fluid (>100,000/µL RBC)
   1. Trauma
   2. Malignancy
   3. Pulmonary Embolism
   4. Postcardiac Surgery Injury Syndrome (Dressler's Syndrome)
   5. Asbestos Pleurisy
7. Pleural Fluid Eosinophilia
   1. >10% Eosinophils in differential
   2. Rare in tuberculosis (TB) and unusual in malignancy
   3. Infections: Parasites, Fungus
   4. Pneumothorax and Hemothorax
   5. Asbestos Pleurisy
8. Pleural Biopsy
   1. Helps with pleural malignancy, TB, sarcoidosis, rheumatoid nodulosis, fungal diseases
   2. Previous standard uses reverse bevel needle (such as Abram's needle) without imaging
   3. High incidence of complications including pneumothorax, hemothorax, empyema
   4. CT guided cutting-needle biopsy is superior to Abram's needle for malignancy diagnosis [10]
   5. CT guided biopsy likely safer (as well as more sensitive) than Abram's needle

E. Treatment

1. Treat Underlying Cause
   1. CHF patients should receive diuresis and observation for 24-48 hours
   2. If no improvement effusion, consider diagnostic ± therapeutic thoracentesis
   3. Main problems are in patients with malignant effusions
2. Therapeutic Thoracocentesis (Pleurocentesis)
   1. Goal is re-expansion of affected lung
   2. In general, 500mL to 1 Liter or less of fluid is removed
   3. Main risk of procedure is pneumothorax
   4. May also insert small-caliber chest tube with one-way valve for drainage at home [9]
   5. In general, <1000-1500 mL or less fluid should be removed at any time [1]
   6. Removal of >500 mL of fluid increases risk of post-atelectatic pulmonary edema
3. Recurrent pleural effusions may require pleuradesis [9]
   1. Create adhesions between visceral and parietal pleura
   2. Administer talc, bleomycin or tetracycline into the pleural space
   3. Talc (2-10gm) administration reduces fluid accumulation in >70% of cases
   4. Talc is most effective agent, and is safe, with no increase in acute lung injury or ARDS [13]
   5. Very painful procedure
4. Intrapleural streptokinase of no clinical benefit in treating pleural infection [14]

References

1. Light RW. 2002. NEJM. 346(25):1971
2. Muthuswamy P, Alausa M, Reilly B. 2001. NEJM. 345(10):756 (Case Discussion)
3. Romero-Candeira S, Fernandez C, Martin C, et al. 2001. Am J Med. 110(9):681
4. Gotsman I, Fridlender Z, Meirovitz A, et al. 2001. Am J Med. 111(5):375
5. Lazaridis KN, Frank JW, Krowka MJ, Kamath PS. 1999. Am J Med. 107(3):262
6. Light RW, Rogers JT, Cheng D, et al. 1999. Ann Intern Med. 130(11):891
7. Quinn DA and Mark EJ. 2002. NEJM. 346(11):843 (Case Record)
8. Aleman C, Alegre J, Armadans L, et al. 1999. Am J Med. 107(4):340
9. Szeijo LM and Sterman DH. 2001. NEJM. 344(10):740
10. Maskell NA, Gleeson FV, Davies RJO. 2003. Lancet. 361(9366):1326
11. Villena V, Lopez-Encuentra A, Pozo F, et al. 2003. Am J Med. 115(5):365
12. Procel JM, Vives M, cao G, et al. 2004. Am J Med. 116(6):417
13. Janssen JP, Collier G, Astoul P, et al. 2007. Lancet. 369(9572):1535
14. Maskell NA, Davies CWH, Nunn AJ, et al. 2005. NEJM. 352(9):865