Pulmonary Medicine

Pathogenesis, Etiology, and Evaluation of Pleural Effusion

What every physician needs to know:

Pleural effusions occur as a consequence of a large variety of lung diseases but also as a result of systemic illnesses and primary disorders of the pleural space itself. There are five basic mechanisms that result in the development of a pleural effusion.

  • increased transpleural pressure gradient (e.g., congestive heart failure [CHF])

  • increased capillary permeability (e.g., parapneumonic effusion in patients with pneumonia)

  • impaired lymphatic drainage (e.g., malignant pleural effusions)

  • transdiaphragmatic movement of fluid from the peritoneal space (e.g., hepatic hydrothorax from ascites)

  • pleural effusions of extravascular origin (PEEVO) (e.g., chylothorax and peritoneal dialysis)

Pleural effusions can be either transudates or exudates. Transudates are characterized by the presence of normal pleural membranes and defined by a low pleural fluid protein and lactate dehyrdrogenase (LDH) content. Exudates result from pleural inflammation, infection, malignancy, or drugs. Exudates often present more diagnostic difficulties than transudates do.

The clinical presentations of pleural effusions usually vary depending on the transudative or exudative nature of the pleural fluid. Patients with transudates generally present with dyspnea if the effusion is moderate to large in volume and/or bilateral, as in the example of congestive heart failure. Because pleural membranes are normal with transudative effusions, patients usually do not present with chest pain, fever, or chills. Establishing the transudative nature of a pleural effusion simplifies patient evaluation because there are only fourteen causes of a transudate (Table 1). CHF is the most common transudate, followed by hepatic hydrothorax.

Table 1

Causes of transudative pleural effusions.
Amyloidosis
Atelectasis
Cerebrospinal fluid leak into pleural space
Constrictive pericarditis
Heart failure
Hepatic hydrothorax
Hypoalbuminemia
Hypothyroid pleural effusion
Iatrogenic
Malignancy
Nephrotic syndrome
Peritoneal dialysis
Pulmonary embolism
Sarcoidosis
Superior vena caval obstruction
Trapped lung
Urinothorax

The clinical presentation of patients with exudative effusions often includes chest pain, fever, dyspnea, and other varied symptoms that depend on the cause of the effusion. The possible causes of exudative effusions are highly diverse; lung infections, inflammatory disease like lupus, and malignancies--most commonly lung and breast cancer--are frequent causes. Drugs can also cause pleural effusions. The diagnosis typically requires further diagnostic testing (cytology, bronchoscopy, bronchoscopy with lymph node biopsies, pleural biopsies, culture, serologies) or drug discontinuation.

Classification:

There are multiple approaches to classifying pleural effusions to simplify the diagnostic evaluation, but the traditional approach requires separation into transudative or exudative effusions. Transudative effusions have low pleural fluid content of protein and LDH, and they most commonly occur as a result of CHF or hepatic hydrothorax. Table 1 lists the other causes of transudates.

Asymptomatic transudates include hypoalbuminemia, neprotic syndrome, peritoneal dialysis, urinothorax, and trapped lung. Exudative effusions, which have a high pleural fluid protein and LDH content, occur as a result of a diverse list of thoracic and extrathoracic conditions. However, parapneumonic effusions and malignant effusions are the most common causes of exudative effusions. Exudates that virtually always present with symptoms include bacterial pneumonia, malignancy, lupus, malignant mesothelioma, post-cardiac injury syndrome (PCIS), pulmonary embolism, tuberculous pleurisy, and viral pleurisy. Benign asbestos pleural effusions ( BAPE), rheumatoid effusion, and chronic TB empyema typically present without symptoms.

Are you sure your patient has a pleural effusion? What should you expect to find?

Although the physical examination can create suspicion of a pleural effusion, chest imaging is required to confirm its presence. A standard radiograph demonstrates blunting of the costophrenic angles, but it is less sensitive than chest ultrasonography or chest computerized tomography in establishing the existence of a pleural effusion.

Once a pleural effusion is identified, a careful history, complete physical examination, and review of routine laboratory studies often suggests the likely cause of a pleural effusion--for instance, a small to moderate effusion in an a febrile patient with decompensated heart failure is likely due to CHF--but in most instances, thoracentesis with pleural fluid analysis is required to establish an etiology to the effusion.

Beware: there are other diseases that can mimic a pleural effusion:

Patients with lung consolidation, as occurs with pneumonia, may have chest dullness that simulates a pleural effusion. However, the decreased fremitus that occurs with an effusion suggests the diagnosis. Fremitus may also be decreased in patients with lung consolidation and airway obstruction to the region of consolidation. In such patients, chest imaging is required to detect pleural fluid. Chronic pleural fibrosis may mimic a pleural effusion on standard radiographs, requiring chest ultrasonography or CT scanning to differentiate.

How and/or why did the patient develop a pleural effusion?

Pleural effusions are encountered commonly in clinical practice because of the large number of conditions associated with pleural fluid formation. The epidemic of CHF in the United States explains why CHF-related transudative effusions are the most common pleural effusions. Cigarette smoking leads to a high prevalence of lung cancer and malignant effusions. Smoking-related COPD increases the risk of pneumonia and parapneumonic effusions.

Pleural effusions occur in 30-50 percent of patients with lupus at some time during the course of their disease. In contrast, only 5 percent of patients with rheumatoid arthritis develop pleural effusions. Affected patients are usually males with active arthritis. Worldwide, tuberculous effusions are common but they are much less common in the United States than elsewhere.

Which individuals are at greatest risk of developing a pleural effusion?

Patients with heart failure, cirrhosis and ascites, pneumonia, and uncerlying cancer that is primary or metastatic to the lung have the greatest risk of developing pleural effusions.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Imaging studies may suggest the etiology of a pleural effusion. Various signs observable on chest ultrasonography or CT scanning may suggest the presence of pleural infection or malignancies. Some findings may suggest that an effusion is exudative or transudative in nature, but most patients require a thoracentesis and pleural fluid analysis to establish a diagnosis or at least to exclude a suspected working diagnosis.

After thoracentesis, pleural fluid is examined for its gross appearance. The presence of serous or hemorrhage-appearing fluid is a nonspecific finding. Grossly bloody effusion is suggestive of chest trauma or malignancy, while milky fluid suggests a chylothorax or cholesterol (pseudochylous) effusion, and purulent fluid establishes the presence of an empyema. Pleural fluid tests appropriate for nearly all patients include protein, LDH, total nucleated cell count, absolute neutrophil count (ANC), glucose, and pH.

A blood sample should also be obtained to measure total protein and LDH in order to compare results with pleural fluid protein and LDH values. Light's criteria establishes the presence of an exudate as defined by the presence of any one of three criteria:

  • pleural fluid-to-serum total protein ratio greater than 0.5

  • pleural LDH/upper limit of normal of serum LDH in the laboratory greater than 0.67

  • pleural fluid LDH greater than 0.6

Various patterns of pleural fluid findings may suggest specific diagnoses. For instance, tuberculous effusion and cholesterol effusion commonly have a total protein level greater than 4.0 g/dL. Waldenstrom macroglobulinemia, multiple myeloma, and rheumatoid pleural effusion may present with a PF protein of 7-8 g/dL. A pleural fluid LDH greater than 1000 IU/L narrows the differential diagnosis of exudate to an empyema, complicated parapneumonic effusion, a cholesterol effusion, paragonimiasis, rheumatoid effusion, or body cavity lymphoma, with the last often having values greater than 10,000 IU/L.

A pleural fluid pH less than 7.30 suggests complicated parapneumonic effusion or empyema, esophageal rupture, chronic rheumatoid effusion, cholesterol effusion, malignancy, TB effusion, acute lupus pleritis, and paragonimiasis. A low pleural fluid glucose (<60 mg/dl) or PF/s glucose ratio less than 0.5 suggests the same diagnoses that are suggested by a low pleural fluid pH.

A transudative effusion does not usually require additional pleural fluid tests because the cause of the effusion is apparent from the underlying condition, such as CHF or hydrothorax. However, occasionally, additional tests may be of value. For instance, detection of beta-2-transfer in a transudative effusion establishes the presence of a leak of cerebrospinal fluid into the pleural space.

Detection of an exudative effusion may require additional pleural fluid tests, as indicated by the clinical setting. Each test in the following list is followed by the suspected diagnoses that warrant the test:

  • Cytology - malignancy

  • Culture - pleural infection, tuberculosis, fungal infection

  • Ova and parasites - paragonimiasis

  • Pancreatic amylase - acute and chronic pancreatitis

  • Salivary amylase - esophageal rupture, adenocarcinoma of the lung

  • Adenosine deaminase - tuberculous pleural effusion

  • Mesothelin - malignant mesothelioma

  • Triglycerides (>110 mg/dl) or chylomicrons - chylothorax

  • Cholesterol (250 mg/dl) - cholesterol effusions

  • BNP - elevated in CHF after diuretic therapy, which can convert a transudate to an exudate

What imaging studies will be helpful in making or excluding the diagnosis of a pleural effusion?

Standard chest radiographs require collection of 200-500 ml of pleural fluid before blunting of the costophrenic angles on the posterior-anterior projection becomes detectable. A lateral chest radiograph allows detection of as little as 50 ml of pleural fluid. A supine radiograph may demonstrate findings like haziness of a hemithorax to suggest an effusion, but typical findings of an effusion that are apparent on an upright projection, such as the meniscus sign, are lacking.

However, chest ultrasonography can detect less than 10 ml of pleural fluid and can also show pleural thickening, pleural tumor deposits that can guide biopsy, intrapleural loculations, and fluid characteristics that suggest the presence of infection or malignancies. Chest CT provides the best spatial imaging for establishing the presence of a pleural effusion and its distribution within the thorax, as pleural infection enhances the pleural membranes on a contrast-enhanced CT scan. Other findings of empyema include edema of the extrapleural fat stripes. Chest ultrasonography is more sensitive than chest CT to intrapleural septation of pleural fluid loculations.

The presence of loculations on ultrasonography or CT suggest an infectious or inflammatory intrapleural process. A massive effusion that occupies the entire hemithorax suggests a malignancy. A massive effusion with contralateral shift of the mediastinal structures occurs in patients with non-lung primary malignancies, and ipsilateral shift suggests lung cancer. A normal heart size with bilateral effusions suggests malignancy, constrictive pericarditis, and CHF post-acute myocardial infarction.

Chest CT can aid in differentiating an empyema from a lung abscess, diagnosis of a pseudotumor that is due to pleural fluid in a fissure in patients with CHF, and paramediastinal fluid collections. Both CT and ultrasonography can guide thoracentesis and intrapleural catheter placement for patients with loculated effusions.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a pleural effusion?

Chest ultrasonography is the most sensitive study for making a diagnosis of pleural effusion.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a pleural effusion?

Most patients with transudative effusions have clinically apparent causes of pleural effusions from an underlying condition, such as CHF or ascites. However, additional diagnostic tests that assess the presence or severity of these underlying conditions may be required to confirm the source of the transudative effusion. Some patients with co-morbid ascites and CHF may benefit from a radionuclide study in which tagged albumin is injected into ascitic fluid to demonstrate its rapid transit into the pleural effusion in order to diagnose a hepatothorax.

Patients with exudative effusions often require additional diagnostic studies after thoracentesis and pleural fluid analysis. A closed-needle biopsy may be indicated if a tuberculous effusion is suspected but cannot be diagnosed. Closed pleural biopsies have little utility for other causes of exudative effusions. CT or ultrasound-guided needle biopsy of the pleural can effectively diagnose or exclude pleural malignancy. However, pleural biopsy by video-assisted thoracoscopic surgery or by a limited thoracotomy has the highest diagnostic accuracy in establishing the etiology of an exudative pleural effusion.

Open biopsy by thoracotomy may be necessary in patients with mesothelioma because of the large biopsy samples required to establish the diagnosis and specific mesothelioma cell type.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a pleural effusion?

Pleural fluid cytology has a diagnostic sensitivity of only 60-70 percent in patients suspected of having a pleural malignancy; sending 60 ml of pleural fluid to the cytology laboratory is sufficient. No tumor markers have achieved sufficient diagnostic accuracy in routine practice to establish the presence of a malignant pleural effusion, although mesothelin in blood or pleural fluid may have value for patients with mesothelioma. Flow cytometry with appropriate cell studies can establish the diagnosis of a malignant pleural effusion in most patients with underlying lymphoma

If you decide the patient has a pleural effusion, how should the patient be managed?

The first goal in managing a pleural effusion is to treat the underlying disease. Improvement of CHF or hepatic decompensation will subsequently decrease the volume of an associated transudative effusion. Parapneumonic effusions that are due to pneumonia may resolve with antibiotic therapy for the underlying pneumonia. In such cases, the effusion is termed an uncomplicated parapneumonic effusion.

If the parapneumonic effusion does not resolve, it is termed a complicated parapneumonic effusion, and it requires a pleural fluid drainage procedure. Clinicians are challenged to predict the course of a parapneumonic effusion to anticipate its complicated nature in order to initiate drainage early--in the first day or two of antibiotic therapy. A low pH, presence of loculations, or large pleural fluid volumes suggest a complicated course.

A malignant pleural effusion may respond to effective treatment of the underlying cancer, but most patients progress with the effusion, which eventually becomes symptomatic and requires palliation. Depending on the general condition of the patient, palliative therapy for a malignant effusion ranges from repeated thoracentesis, to drainage with a long-term intrapleural catheter, to pleurodesis. Pleurodesis can be performed by multiple techniques but obliteration of the pleural space is required to prevent fluid reaccumulation.

Tuberculous pleural effusions require the initiation of anti-tuberculous therapy. Although the effusion itself may resolve spontaneously, up to 65 percent of patients develop pulmonary or extra-pulmonary tuberculosis within the next five years.

An acute hemothorax requires insertion of a large-bore chest tube to monitor the rate of bleeding and expand the lung in order to tamponade the bleeding site. A surgeon should be consulted for an acute hemothorax.

Patients with chylothoraces may resolve spontaneously, but chylothoraces require drainage if they are large and associated with dyspnea. Patients may require parenteral nutrition to decrease chyle flow, and may require effort to identify the source of pleural fluid chyle and consideration of surgical thoracic duct ligation.

What is the prognosis for patients managed in the recommended ways?

The prognosis for patients with pleural effusions depends on the underlying cause. Patients with malignant pleural effusions have a median survival of approximately four months. Patients with uncomplicated parapneumonic effusions usually respond to antibiotic therapy of the underlying pneumonia, with the prognosis determined by the prognosis of the pneumonia. Patients with an empyema have a 20 percent mortality rate, with increased mortality with advanced age and underlying cancer.

What other considerations exist for patients with pleural effusions?

Pleural effusions present management challenges because therapy is frequently dictated by the underlying disease and associated comorbidities. Young patients with a single, reversible underlying condition usually have good clinical outcomes after diagnosis of an effusion. Young patients with more complex underlying conditions that are less amenable to therapy, such as malignant effusions, can be treated only by palliative care. Older patients and more co-morbid conditions require comprehensive evaluation and a therapeutic plan.

What’s the evidence?

Sahn, SA. "Pleural effusions of extravascular origin". Clin Chest Med. vol. 27. 2006. pp. 285-308.

Discusses the transudates and exudates that generate pleural effusions from an extravascular source.

Porcel, JM. "Pleural effusions from congestive heart failure". Semin Respir Crit Care Med. vol. 31. 2010. pp. 689-697.

The BNP or NT-pro BNP helps confirm the diagnosis of CHF, especially when the fluid develops an increased PF/serum protein ratio in the exudative range from diuretics.

Heffner, JE. "Management of the patient with a malignant pleural effusion.". Semin Respir Crit Care Med. vol. 31. 2010. pp. 723-733.

In the cancer patient, the effusion can be the direct result of the malignancy, a response to treatment, or related to another cause, such as CHF.

Sahn, SA. "Diagnosis and management of parapneumonic effusions and empyema". Clin Infect Dis. vol. 45. 2007. pp. 1480-1486.

Provides the time course and timely management for the optimal outcome of parapneumonic effusions.

Cohen, M, Sahn, SA. "Resolution of pleural effusions". Chest. vol. 119. 2001. pp. 1547-1562.

Discusses the resolution times with and without treatment of both transudates and exudates. This information helps narrow the differential diagnosis at the time of presentation.

Heidecker, J, Sahn, SA. "The spectrum of pleural effusions after coronary artery bypass grafting surgery". Clin Chest Med. vol. 27. 2006. pp. 267-283.

Discusses the presentation and timing of the multiple pleural effusions that can develop after CABG surgery and the response to treatment.

Alonso, JC. "Pleural effusion in liver disease". Semin Respir Crit Care Med. vol. 31. 2010. pp. 698-705.

Describes the pathogenesis, clinical presentation, diagnosis, and treatment of hepatic hydrothorax; addresses the therapeutic options based on the physiopathological stages of hepatic hydrothorax; and discusses the diagnosis and management of spontaneous bacterial pleuritis.

Good, JT, Taryle, DA, Maulitz, RM, Kaplan, RL, Sahn, SA. "The diagnostic value of pleural fluid pH.". Chest. vol. 78. 1980. pp. 55-9.

Reports on the diseases associated with a pleural fluid pH less than 7.30. The manuscript also provides the incidence and pH range of each of the diagnoses.

Huggins, JT, Sahn, SA, Heidecker, J, Ravenel, J, Doelken, P. "Characteristics of trapped lung: pleural fluid analysis, manometry, and air-contrast chest computed tomography.". vol. 131. 2007. pp. 206-213.

Discusses the pathophysiology, clinical presentation, radiologic imaging, and management of the unexpandable lung.

Sahn, SA. "Pathogenesis and clinical features of disease associated with a low pleural fluid glucose.". The pleura in health and disease.. 1985. pp. 267-285.

Reports on the pathogenesis, clinical findings, and pleural analysis in diseases associated with low pleural glucose. The only diseases associated with a pleural fluid glucose of zero are empyema and chronic rheumatoid pleurisy.
You must be a registered member of Renal and Urology News to post a comment.

Sign Up for Free e-newsletters