Pleural Effusion, Empyema, and Pneumothorax

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Chapter 69 Pleural Effusion, Empyema, and Pneumothorax

Pleural Effusion

Pleural effusion, defined as the accumulation of fluid in the pleural space, is common and affects more than 3000 people per 1 million population each year. Pleural effusions develop when the rate of pleural fluid formation exceeds that of absorption and may be a complication of pleural, pulmonary, and systemic disease or associated with use of certain drugs. A systematic approach is required to determine the underlying cause.

Epidemiology and Pathophysiology


Thoracic Ultrasound Imaging

The availability of bedside thoracic ultrasound examination by clinicians has had a significant impact on pleural disease management in recent years. The 2010 British Thoracic Society Pleural Disease Guidelines strongly recommended the use of thoracic ultrasound imaging before procedures for pleural fluid. It is particularly useful for the detection (sensitivity approximately 100%), quantification (by depth), and characterization of pleural fluid (Figures 69-1 to 69-3; Table 69-2), as well as for guiding intervention. Ultrasonography is invaluable in the differentiation between pleural fluid and collapsed or consolidated lung, thereby avoiding unnecessary pleural procedures and associated complications.

Table 69-2 Pleural Fluid Sonographic Appearances

Sonographic Appearance Significance
Anechoic (black fluid) (see Figure 69-1) Transudative or exudative effusion
Septated (multiple lines within fluid) (see Figure 69-2) Exudative effusion; may suggest possible difficulties inserting chest tube; effusion may drain poorly, although not necessarily
Echogenic (echoes, often swirling, within fluid) (see Figure 69-3) Exudative effusion; heavily echogenic fluid suggestive of blood or pus

Thoracentesis guided by clinical examination alone could result in organ puncture in 10% of cases. Several large studies have demonstrated improved safety of pleural interventions performed under ultrasound guidance, particularly in reducing iatrogenic pneumothorax or organ puncture. A Mayo Clinic study showed a dramatic reduction (from 8% to 1%) in rate of thoracentesis-related complications since the unit initiated a “pleural safety program” that included pleural ultrasound training and mandated its use before thoracentesis. With adequate training in this modality, thoracic ultrasound imaging performed by respiratory physicians has been shown to have a safety profile comparable to that when performed by radiologists.

Ultrasound imaging has a high sensitivity (approximately 80%) for detecting pleural malignancy, which can manifest as thickening or nodularity on the visceral, parietal, and diaphragmatic pleural surfaces (see Figure 69-3). Detection of pleural nodularity mandates further investigation (e.g., with chest computed tomography [CT] and pleural biopsy), even if there are no further suspicious features. Ultrasonography also can identify abnormalities beyond the pleural cavity that may provide vital clues to the cause of the effusion, including peripheral lung tumors or abscesses, parenchymal consolidation and atelectasis, diaphragmatic paralysis or elevation, pericardial effusion, and rib and liver metastases and enables evaluation of supraclavicular and cervical lymphadenopathy (Figure 69-4).

Pleural interventions may be guided by site marking or real-time needle visualization; the latter is required to sample small or loculated effusions. The Royal College of Radiologists (in the United Kingdom), the American College of Chest Physicians, the American College of Surgeons, and the American College of Emergency Physicians are among the many agencies that have published ultrasound training guidelines for clinicians. Appropriate training is essential, because potential pitfalls with performance and interpretation of pleural ultrasound studies are recognized.

Computed Tomography and Magnetic Resonance Imaging

CT with pleural phase contrast enhancement highlights pleural abnormalities and aids discrimination of benign from malignant disease (see Chapter 7). Specific “pleural” CT protocols should be adopted for optimal pleural enhancement and abnormality detection; recent data suggest that images should be acquired 60 seconds after injection of 150 mL of an intravenous contrast agent at 2.5 mL/second. The presence of contraction of the hemithorax, mediastinal pleural involvement, and circumferential pleural thickening (especially greater than 1 cm and with nodularity) all are suggestive of pleural malignancy (Figure 69-5) but cannot adequately differentiate mesothelioma from metastatic pleural cancers. Magnetic resonance imaging (MRI) can help delineate malignant chest wall involvement and is valuable in selected cases, particularly when (probably benign) pleural abnormalities are to be followed clinically by serial imaging in younger patients.

Positron Emission Tomography

Positron emission tomography (PET)-CT scanning (see Chapter 8) is beginning to emerge as a useful tool in pleural disease management. PET-CT cannot adequately differentiate between benign and malignant effusions, because of the tracer 18F-fluorodeoxyglucose (FDG). FDG-enhanced PET imaging is confounded by avid pleural uptake of FDG in the presence of pleural inflammation (including that due to previous talc pleurodesis and pleural infection). However, FDG-PET may have a role in guiding pleural biopsy in patients with diffuse pleural abnormality to increase sensitivity (Figure 69-6). FDG-PET also may identify nonpleural sites that allow tissue sampling to confirm malignancy (e.g., lymphadenopathy or liver metastases). Recent data suggest a role for FDG-PET in monitoring disease response to therapy in malignant mesothelioma, as well as a potential prognostic role.

PET scanning using various novel molecular tracers is in early-phase trials for evaluation of pleural malignancies. For instance, PET scanning using labeled thymidine, essential for deoxyribonucleic acid (DNA) synthesis, can identify sites of cell proliferation activity and is not confounded by inflammation (Figure 69-7). New tracers targeting specific cell biology processes (e.g., annexin, a marker of apoptosis) are likely to provide valuable insight to disease pathobiology.

Diagnostic Approach

Investigation of a pleural effusion should be performed using a systematic approach (Figure 69-8), aiming to minimize the number of pleural procedures required to make a diagnosis and thereafter allow definitive treatment.

Thoracentesis, preferably imaging-guided, should be the initial investigation in pleural effusions of uncertain origin. If small (less than 1 cm in depth) effusions require sampling, this procedure should be undertaken using real-time radiologic guidance. Thoracentesis is generally safe and complications are uncommon but include vasovagal syncope (0.6%), pneumothorax, infection, and bleeding. Removal of large amounts of fluid may precipitate reexpansion pulmonary edema, often heralded by cough, chest discomfort (at which point the procedure must be terminated), or acute dyspnea. Pleural manometry has been advocated but is not widely available. If initial pleural fluid analysis is inconclusive, additional investigations are often required, including further imaging, repeat thoracentesis, and thoracoscopic or percutaneous pleural biopsy (see Chapters 13 and 74).

Pleural Fluid Analysis

Pleural fluid analysis can help determine the diagnosis or direct further investigations. Recent years have seen a significant increase in the tests and biomarkers available for pleural fluid analysis, but the exact role(s) of many of them in the diagnostic algorithm are still to be defined. An understanding of the indications and limitations of the individual tests is essential for clinicians to provide an efficient and cost-effective service.

Separation of Exudates and Transudates

Exudative pleural effusions most commonly are defined by Light’s criteria (Box 69-1), using the fluid-to-serum ratio of protein and lactate dehydrogenase, which has an accuracy of 96%. Numerous other markers and criteria have been tested (including measurement of pleural fluid cholesterol values), but none has proved superior. Distinguishing exudates from transudates may narrow the scope of the differential diagnosis and streamline further investigations, although such categorization has limitations: It does not provide the diagnosis and fails to identify concurrent transudative and exudative causes of fluid formation. Research in recent years has focused on disease-specific markers that may provide a definitive diagnosis.

Differential Leukocyte Count

The cellular portion of physiologic pleural fluid consists predominantly of macrophages and monocytes. In disease states, the differential cell count of the pleural fluid may be helpful in determining the cause (Box 69-2). Acute pleural inflammation or injury generates chemotaxins, such as interleukin 8, and attracts neutrophils to the pleural space. A neutrophil-predominant effusion is commonly seen with acute bacterial pneumonia or pulmonary infarction. A lymphocyte-rich fluid is more common in disease of insidious onset such as tuberculosis (TB) or malignancy. Tuberculous effusions occasionally (less than 10%) may be neutrophilic. An increased eosinophil count (more than 10% of total leukocytes) is often nonspecific. Most commonly, eosinophil effusions develop secondary to presence of intrapleural air or blood (including pneumothorax or previous interventions) but can also be associated with a range of other diseases, such as Churg-Strauss syndrome or drug-induced pleuritis.

pH and Glucose

Pleural fluid pH (or glucose) measurement can aid disease management. Low glucose levels are associated with a similar spectrum of diseases that give rise to low pH effusions (e.g., infection and connective tissue diseases) (Box 69-3) and are equally informative except in patients with hyperglycemia.

Physiologic pleural fluid pH is approximately 7.6 and reflects bicarbonate accumulation within the pleural cavity. Pleural fluid pH should be measured using a blood gas analyzer, and care should be taken to avoid exposure of the fluid to free air or to residual lidocaine, which will potently raise or lower the fluid pH, respectively. pH meters and litmus paper have been shown to give unreliable values. Low pleural fluid pH (e.g., less than 7.3) coexistent with a normal blood pH may result from increased metabolism of leukocytes, bacteria, or tumor cells or hydrogen ion accumulation.

In malignant pleural effusions, a low pH is associated with more extensive tumor involvement of the pleura, a higher chance of positive findings on cytologic examination, a lower success rate for pleurodesis, and a poorer prognosis. In parapneumonic effusion, a low pH (less than 7.2) predicts the need for chest tube drainage, and pH below 7.2 is now often used as a cutoff point to diagnose pleural infection (complicated parapneumonic effusion) in the presence of a compatible clinical history. A recent study of 308 patients confirmed that pleural fluid pH (or glucose) measurements were superior to other biomarkers tested (pleural fluid procalcitonin, C-reactive protein, lipopolysaccharide-binding protein, and triggering receptor expressed on myeloid cells-1 [sTREM-1]) in distinguishing between simple and complicated parapneumonic effusions.

Disease-Specific Tests

The diagnosis of a malignant effusion should be established only by histocytopathologic confirmation of malignant cells in the pleural fluid or tissue. Pleural fluid cytologic examination is the first line of investigation in suspected cases and has a sensitivity up to 60% (dependent on tumor type, extent of disease, and experience of the cytologist). Immunocytochemical analysis plays an invaluable role in cytologic assessment of pleural fluid, improving the differentiation between benign and malignant effusions and between different malignancies (particularly metastatic adenocarcinoma versus mesothelioma). If malignancy is suspected, generally little incremental benefit is obtained from cytologic analysis of pleural fluid on more than two occasions.

Mesothelioma, the most common primary malignant tumor of the pleura, often is challenging to diagnose. Research in recent years has proposed several potential adjunct diagnostic biomarkers. Mesothelin is a U.S. Food and Drug Administration (FDA)-approved diagnostic and prognostic marker for mesothelioma, although it is not recommended as a sole diagnostic marker (having sensitivity of 48% to 84% and specificity of 70% to 100%). False-negative results may occur with sarcomatoid mesothelioma, which often does not express mesothelin. A raised mesothelin level also can be found with other malignancies (most commonly, pancreatic or ovarian carcinoma but also lung adenocarcinoma and lymphoma). Hence, in patients with elevated pleural fluid or blood mesothelin, further investigations should be considered even if cytologic examination demonstrates no malignant cells. Megakaryocyte-potentiating factor (MPF), which originates from the same precursor protein as for mesothelin, has been shown to have a similar diagnostic performance for detection of mesothelioma. After initial interest in the use of osteopontin for mesothelioma identification, subsequent data have shown it to have a lower diagnostic accuracy than mesothelin.

Other tumor markers and pleural fluid cytokine measurements are neither sensitive nor specific enough for clinical use. Cytogenetic evaluation may be a helpful addition to characterize chromosomal markers of hematolymphoid and mesenchymal malignancies. Flow cytometry of the pleural aspirate should be considered if lymphoma is a possibility.

Gram staining and culture of pleural fluid should be performed in an appropriate clinical setting. Direct inoculation of bottled culture media (“blood culture bottles”) along with separate microbiologic analysis of pleural fluid in a universal container has been shown to increase microbial yield. In cases characterized by presence of frank pus, the diagnosis of empyema is secured, but Gram staining and culture may help to identify the causative organism(s) and to guide therapy.

Testing for tuberculosis should be conducted if clinically indicated, particularly if the fluid is lymphocyte-predominant (more than 50% of total leukocytes). Direct smears and aspirate cultures have low sensitivities (less than 5% and 10% to 20%, respectively) because tuberculous pleuritis usually develops as a type IV hypersensitivity reaction, with low mycobacterial load in the pleural cavity. Demonstration of caseating granulomas by closed or thoracoscopic pleural biopsy clinches the diagnosis. Debate exists regarding the role of adenosine deaminase (ADA), interferon-γ, interferon-γ release assays (IGRAs), and polymerase chain reaction (PCR) techniques in diagnosing tuberculous pleuritis. ADA, an enzyme present in lymphocytes, commonly is measured in disease-endemic countries, and a high pleural fluid ADA level suggests tuberculous effusions, with a sensitivity of greater than 90%. False-positive results have been reported (especially with empyema, rheumatoid effusions, and lymphoma). In nonendemic areas, a low ADA measurement may help rule out tuberculous pleuritis in some patients. Assays for the isoenzyme ADA2, which predominates in tuberculous effusions, are not widely available. Unstimulated interferon-γ pleural fluid levels perform about as well as ADA for diagnosis in this setting but are more expensive. Peripheral blood and pleural fluid IGRAs have been shown to be of limited clinical value in the diagnosis of tuberculous pleural effusions.

A raised amylase level (above the serum upper limit of normal or if the pleural fluid–to–serum ratio is more than 1) in an appropriate clinical setting can help confirm effusions from esophageal rupture and pancreatic diseases (acute pancreatitis or pseudocyst). Isoenzyme analysis may further differentiate the source of amylase (salivary or pancreatic) but is rarely needed. A raised amylase is present in some malignant (usually adenocarcinomas) effusions.

In suspected cases of chylothorax, lipoprotein electrophoresis for chylomicrons or a triglyceride concentration greater than 1.24 mmol/L (110 mg/dL) confirms the diagnosis. The presence of cholesterol crystals at microscopy with a pleural fluid cholesterol level more than 5.17 mmol/L (200 mg/dL) is diagnostic of a pseudochylothorax. Chylomicrons are not found in pseudochylothorax fluid.

Pleural fluid levels of rheumatoid factor and antinuclear antibody mirror serum values and add little to clinical management of rheumatoid or systemic lupus erythematosus–related pleuritis. Complement levels can be reduced but are of little clinical value. Very low pleural fluid glucose levels typically are seen in patients with a rheumatoid effusion, and differentiation from empyema fluid may be difficult.

β2-Transferrin is found in cerebrospinal fluid, and its presence in pleural fluid confirms presence of a duropleural fistula. Raised creatinine values are seen in urinothorax.

Pleural Biopsy

Histologic examination (with or without culture) of pleural tissue can aid in the diagnosis of specific pleural diseases. Tissue can be collected percutaneously (by “blind” or imaging-guided biopsy) or under direct vision (by thoracoscopy or thoracotomy), each with its relative merits (see Chapters 13 and 74).


Therapeutic objectives in patients with a pleural effusion include treatment of underlying disease, palliation of symptoms, and prevention of fluid recurrence.

Symptom Control

Preventing Fluid Reaccumulation


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