Pulmonary Medicine

Pleural Effusion General Approach/Considerations

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)

It should be noted that these mechanisms of pleural effusion are not exclusive from one another. For instance, in the absence of excess production, it would take 100 days for a 1.5 L effusion to accumulate if solely due to lymphatic obstruction, assuming a 15 mL/day pleural lymphatic clearance.

Traditionally, pleural effusions have been categorized as transudative or exudative. Transudates are typically “pressure-related” (hydrostatic or osmotic), are characterized by the presence of normal pleural membranes and defined by a low pleural fluid protein and lactate dehydrogenase (LDH) content. Exudates result from pleural diseases, such as inflammatory diseases, infection, malignancy, or drug reactions. Pleural fluid analysis typically reveals high pleural fluid protein and LDH content.

The clinical presentation of pleural effusions typically varies based on the transudative or exudative nature of the pleural fluid, and the acuity of pleural fluid accumulation. Patients with transudates generally present with dyspnea if the effusion is moderate to large in volume, more so if bilateral, as in congestive heart failure. Because pleural membranes are normal with transudative effusions, patients usually do not present with chest pain or inflammatory symptoms. 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 cause of a transudate, followed by hepatic hydrothorax. Although Light’s criteria remain useful, transudative effusions due to heart failure or cirrhosis may be misclassified as exudates (“pseudo-exudates”) in up to 30% of the cases. In these situations, the low pleural fluid-to-serum albumin ratio can be helpful to establish the diagnosis.

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 pleuritic chest pain, fever, dyspnea, and other varied symptoms that depend on the cause of the effusion. The differential diagnosis of exudative pleural effusions is broad, and includes lung infections, inflammatory conditions (connective tissue diseases and vasculitides), and malignancies (most common lung, breast and lymphoma). Drugs, such as nitrofurantoin or dasatinib among many others, can also cause pleural effusion. The diagnosis typically requires further diagnostic testing (cytology, bronchoscopy, bronchoscopy with lymph node biopsy, pleural biopsy, fluid and tissue culture, serologies) or drug discontinuation when appropriate.

Classification:

There are multiple approaches to classifying pleural effusions to simplify the diagnostic evaluation, but the traditional approach separates effusions into transudative or exudative. Transudative effusions have low pleural fluid content of protein and LDH, and they most commonly occur as a result of CHF or hepatic hydrothorax. Other less common causes of transudative pleural effusions include hypoalbuminemia, nephrotic syndrome, peritoneal dialysis, urinothorax, and trapped lung (see Table 1).

Exudative effusions occur as a result of a variety of thoracic and extrathoracic conditions and are characterized as having high protein and LDH content. Pneumonia and malignancy are the most common causes of exudative effusions. Exudates that virtually always present with symptoms include parapneumonic effusions, malignancy, lupus pleuritis, malignant mesothelioma, post-cardiac injury syndrome (PCIS), pulmonary embolism, tuberculous pleurisy, and viral pleurisy. Interestingly, benign asbestos pleural effusions (BAPE), rheumatoid effusion and chronic tuberculous empyema can occasionally present without significant symptoms.

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

Although the physical examination can raise suspicion for 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 (CT) in establishing the existence of a pleural effusion. Pleural ultrasound has revolutionized the approach to pleural effusions and can reveal septation and loculation not easily visualized on chest CT. Transudative effusions are always anechoic, while exudates may be anechoic or echogenic.

Once a pleural effusion is identified, a careful history, complete physical examination, and review of routine laboratory studies will often suggest the likely cause of a pleural effusion but in most instances, thoracentesis with pleural fluid analysis serves to establish the diagnosis.

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, decreased fremitus that occurs with an effusion solidifies 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. An estimated 1.5 million new pleural effusions are diagnosed each year in the US alone, among which 200,000 are malignant pleural effusions. 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 involvement and those affected are usually males with active arthritis. Worldwide, tuberculous effusions are common but they are much less common in the United States.

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

Patients with heart failure, cirrhosis and ascites, pneumonia, and underlying 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 identified on chest ultrasonography or CT scanning may suggest the presence of pleural infection or malignancy. Some findings may suggest that an effusion is exudative or transudative in nature, but most patients require thoracentesis and pleural fluid analysis to establish a diagnosis or at least to confirm a suspected working diagnosis.

After thoracentesis, pleural fluid is examined for its gross appearance. The presence of serous or serosanguinous fluid is nonspecific. A grossly bloody effusion is suggestive of chest trauma or malignancy, while milky fluid suggests a chylothorax or cholesterol (pseudochylous) effusion, and purulent fluid is pathognomonic of empyema. The presence of elevated triglycerides (>110 mg/dL) establishes the diagnosis of chylothorax. In equivocal cases, lipoprotein electrophoresis may reveal chylomicrons, diagnostic of chylous effusion. Pleural fluid tests appropriate in nearly all patients include total protein, LDH, total nucleated cell count and differential glucose, and pH.

A blood sample should also be obtained to measure total protein and LDH in order to compare results with pleural fluid values. Light's criteria establish an exudate 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 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 pleural fluid protein of 7-8 g/dL. A pleural fluid LDH greater than 1000 IU/L narrows the differential diagnosis to empyema, complicated parapneumonic effusion, cholesterol effusion, paragonimiasis, rheumatoid effusion, or body cavity lymphoma (potentially greater than 10,000 IU/L). When concern for pleural space infection exists, it is imperative to inoculate blood cultures bottles with pleural fluid at the bedside as the diagnostic yield is increased from 40% to 60%. Pleural adenosine deaminase has proven to be a meaningful biomarker in the diagnosis of pleural tuberculosis.

A pleural fluid pH less than 7.20 suggests complicated parapneumonic effusion or empyema, esophageal rupture, chronic rheumatoid effusion, cholesterol effusion, malignancy, TB effusion, acute lupus pleuritis, and paragonimiasis. A low pleural fluid glucose (<60 mg/dl) or pleural fluid to serum glucose ratio less than 0.5 suggests the same diagnoses that are suggested by a low pleural fluid pH.

When the context is evident, such as in heart failure or cirrhosis, pleural fluid analysis is sometimes obviated. However, even in these instances, additional tests may be of value, to exclude concurrent etiologies or spontaneous bacterial empyema for instance. A rare but interesting pathognomonic finding is the detection of beta-2-transferrin in a transudative effusion, which 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

  • Pleural fluid-to-serum albumin ratio when CHF or hydrothorax is suspected and misclassified by standard criteria

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 has supplanted other imaging modalities for the diagnosis of pleural effusion as less than 10 ml of pleural fluid can be identified, and may reveal additional important findings such as 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, but septations are not as visible as with ultrasound. Pleural infection enhances the pleural membranes on a contrast-enhanced CT scan, with the occasional diagnostic finding of “split-pleural” sign, nearly diagnostic of pleural space infection. 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.

Positron emission tomography has been evaluated for its use in differentiating malignant from benign pleural effusion, but is of relatively limited value with an estimated sensitivity of 80% and a specificity of 74%.

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.

Chest CT may 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, and allows a comprehensive evaluation of the complexity of the pleural effusion at the patient’s bedside.

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 hydrothorax.

Patients with exudative effusions often require additional diagnostic studies after thoracentesis and pleural fluid analysis. A closed-needle biopsy or pleuroscopy may be indicated if a tuberculous effusion is suspected but cannot be diagnosed. Closed pleural biopsies have little utility for other causes of exudative effusion, and pleuroscopy is preferred after 2 negative thoracenteses. CT or ultrasound-guided needle biopsy of the pleural can effectively diagnose or exclude pleural malignancy. Ultrasound guidance of pleural biopsy has been shown to be comparable compared to CT guidance. Pleuroscopy or, when not available, video-assisted thoracoscopic surgery with pleural biopsies, is the best option in undiagnosed exudative pleural effusions.

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% after an initial thoracentesis and increased to 75% after a second one. A third attempt is generally not recommended and pleuroscopy or image-guided pleural biopsy would then be considered. Sending more than 50 ml of pleural fluid to the cytology laboratory does not appear to increase the yield, unless molecular markers of response to novel targeted therapy for lung cancer are needed as well. 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. There is a small body of data to suggest that placement of indwelling pleural catheters is a viable option for those patients with recurrent benign pleural effusions refractory to all other treatments such as those due to cardiac, renal, or liver dysfunction. Considerable caution, particularly in patients eligible for solid organ transplant, should be the rule as pleural catheter-related infection could jeopardize a transplant opportunity. Some data suggest that solid organ transplant recipients may, however, benefit from tunneled catheters on selective basis.

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, 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 (<7.20) or, when unavailable, a low glucose (<40 mg/dL), presence of loculations, or large pleural fluid volumes suggest a complicated course. Several factors can significantly alter the reliability of pleural pH by increasing it (air in syringe or prolonged transport to the lab) or decreasing it (heparin or lidocaine in the syringe). These patients require pleural drainage with chest tube placement in addition to aggressive antibiotic therapy. There is no evidence to support that large bore chest tube is required for adequate drainage. Administration of intrapleural therapy (tissue plasminogen activator and deoxyribinuclease) is associated with improved drainage, decreased need for surgical referral, and decreased hospital time, though confirmatory studies with adequately powered patient important endpoints are warranted. For those individuals with ongoing signs of sepsis in spite of above therapy, surgical referral is indicated.

Antibiotics in pleural space infections should be targeted toward gram positive organisms. Streptococcus mitis (anginosis, intermedius and constellatus) is the most common organism in the community and Staphylococcus aureus is the most common organism in healthcare settings; additionally, consideration must be made for gram negative organisms and anaerobes – which may be difficult to obtain on culture. The incidence of pleural space infections in the US continues to rise steadily over the years.

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. The TIME2 trial which compared indwelling pleural catheter to chest tube talc pleurodesis demonstrated similar quality of life and dyspnea scores between both groups with decreased hospital time in those receiving indwelling pleural catheter. Post-hoc analysis of this study demonstrated similar cost to both. If the decision is made for talc pleurodesis, it should be noted that small bore chest tube (12Fr) may be associated with increased rates of pleurodesis failure when compared to large bore (24Fr). For patients undergoing talc pleurodesis, there is no difference in efficacy between talc slurry and thoracoscopic talc poudrage. Finally, in patients with indwelling pleural catheter, daily drainage of pleural fluid appears to lead to more rapid autopleurodesis and faster time to catheter removal.

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 chyle leak (lymphangiogram) and consideration of surgical thoracic duct ligation or, in expert centers, interventional radiology for lymphangiogram and thoracic duct interventions.

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, though it may vary considerably. There is a prognostic scoring system for malignant pleural effusion which has been validated in an international cohort. It is based on pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance score, neutrophil-to-lymphocyte ratio and tumour type (LENT score). This system provides valuable insight in prognostication in individuals with malignant pleural effusion.

Patients with uncomplicated parapneumonic effusions usually respond to antibiotic therapy of the underlying pneumonia, with the prognosis determined by the multiple factors including age, general health and nutrition, and whether infection is hospital or community acquired. Taking these factors into account, pleural infection is associated with a significant mortality rate nearing 30%. Prognostication for the individual can be challenging, however, a prognostic scoring system (RAPID) has been developed and may provide significant benefit if validated.

Interestingly, recent data suggest that individuals with transudative effusions also have a surprisingly high mortality – approaching 60% one year mortality in the case of bilateral effusions due to cardiac, renal, or liver failure.

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 measures. Older patients and more co-morbid conditions require comprehensive evaluation and a therapeutic plan.

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