Pleural effusion

• A pleural effusion is an abnormal collection of fluid in the pleural space, caused by too much formation or too little drainage.
• Transudates come from systemic pressure or protein problems such as heart failure, cirrhosis, nephrotic syndrome and hypoalbuminaemia.
• Exudates come from local inflammation or injury: infection (including parapneumonic effusion and empyema, tuberculosis), cancer, pulmonary embolism, pancreatitis, connective tissue disease, or trauma such as chylothorax and haemothorax.
• Imaging shows it, pleural fluid analysis (Light's criteria) tells you which kind it is, and drainage plus treatment of the cause relieves it.
• Parapneumonic effusions are drained when pH is under 7.2 or glucose under 3.4 mmol per litre, or when there is pus or loculation; large malignant effusions are managed with pleurodesis or an indwelling pleural catheter.

By the end of this page you should be able to:

1. Explain normal pleural fluid formation and clearance, and how an effusion becomes a transudate or an exudate.
2. List the common causes of transudative and exudative effusions and recognise the clues that suggest each.
3. Elicit and interpret the clinical features and imaging signs of a pleural effusion.
4. Apply Light's criteria, understand their limits, and interpret pleural fluid pH, glucose, LDH, protein, cell counts, ADA, amylase, triglycerides and cytology.
5. Use the criteria for drainage in parapneumonic effusion, understand intrapleural tPA and DNase, and manage malignant pleural effusion.
6. Outline treatment by cause, complications, and a practical approach in a low-resource setting.

Effusions are traditionally divided into transudates and exudates. A transudate forms when Starling forces are disturbed, with normal capillaries; an exudate forms when the pleura itself is inflamed or invaded and capillary permeability rises. Light's criteria, applied to pleural fluid and paired serum, separate the two with high sensitivity. In practice, the biochemical class is only a guide: a patient with heart failure can develop a pseudo-exudate after diuretics, and some conditions, such as pulmonary embolism or pericardial disease, can produce either. ^[1][5]

A few special forms are recognised by excess fluid composition rather than by transudate or exudate:

• Haemothorax: blood in the pleural space, usually after trauma, surgery, or vessel rupture.
• Chylothorax: lymph in the pleural space from thoracic duct injury or obstruction.
• Empyema: frank pus in the pleural space.
• Cholesterol (pseudochylous) effusion: lipid-rich fluid from chronic inflammation.

The pleural space is a potential space between the visceral and parietal pleura, normally containing only a thin film of serous fluid. That fluid lubricates the surfaces during breathing and maintains the negative intrapleural pressure that keeps the lung expanded against the chest wall. Fluid is formed continually by the parietal pleura and cleared by the visceral pleura and the lymphatics draining through the stomata of the parietal pleura. Because the pleura is smooth and the pressure gradients are small, even a modest imbalance between formation and clearance produces a measurable effusion.

Four mechanisms account for almost all effusions:

1. Raised hydrostatic pressure, as in heart failure, forces fluid out of normal capillaries faster than the lymphatics can return it. These are transudates.
2. Low plasma oncotic pressure, from hypoalbuminaemia or the nephrotic syndrome, reduces the force holding fluid in the vessels.
3. Increased capillary or pleural permeability, from infection, malignancy, embolism or autoimmune disease, allows protein-rich fluid to leak through. These are exudates.
4. Impaired lymphatic drainage, from malignancy or fibrosis, lets protein-rich fluid accumulate.

The symptoms a patient feels are mechanical. A large effusion reduces respiratory system compliance, displaces the diaphragm to a mechanically disadvantageous position, and creates ventilation-perfusion mismatch with mild hypoxaemia. Occasional patients with a massive effusion, occupying more than two-thirds of a hemithorax, develop mediastinal shift with impaired venous return and haemodynamic instability; this is rare. ^[1][2]

Pleural effusion is common worldwide. More than 1.5 million patients a year in the United States seek medical care for it. Non-malignant causes make up most of this load: congestive heart failure alone accounts for an estimated 500,000 effusions a year there. Malignant pleural effusion affects roughly 150,000 patients annually in the United States and 50,000 in the United Kingdom, with about 100,000 each year in Europe from lung cancer alone; its median survival is 3 to 12 months. Pleural infection is increasing in prevalence, with hospitalisation rates for empyema in US adults rising from 8.1 to 11.1 per 100,000 between 2007 and 2016. It predominantly affects men with an average age near 60 years. ^[1][4][2]

• Heart failure. The commonest cause of transudate and of non-malignant effusion generally; the fluid is usually small and bilateral, and more common on the right.
• Cirrhosis. Hepatic hydrothorax, usually right-sided, often without large ascites.
• Nephrotic syndrome and other severe hypoalbuminaemic states.
• Hypoalbuminaemia from chronic liver or renal disease, or severe malnutrition.
• Less common: peritoneal dialysis, hypothyroidism, nephrotic-range proteinuria.

The big three are parapneumonic effusion or empyema, malignancy and tuberculosis; these dominate most clinical series. Other exudates include:

• Pulmonary embolism or infarction can be either a transudate or an exudate.
• Pancreatitis or oesophageal perforation, with raised pleural amylase.
• Connective tissue disease: rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome.
• Intra-thoracic malignancy: metastatic adenocarcinoma, lung cancer, lymphoma, mesothelioma.
• Trauma and iatrogenic causes: haemothorax, chylothorax, post-cardiac injury syndrome.
• Drugs such as amiodarone, methotrexate, nitrofurantoin or beta-blockers.
• Asbestos-related pleural disease.

• Purulent or turbid fluid with a low pH suggests empyema.
• Bloody fluid in high volume suggests malignancy, pulmonary embolism, trauma, or mesothelioma; but many malignant effusions are serosanguinous.
• Milky, triglyceride-rich fluid suggests chylothorax.
• A cholesterol-rich, often thick fluid suggests pseudochylothorax (chronic rheumatoid or tuberculous effusion).
• Frank pus or a positive Gram stain makes the diagnosis of empyema.

Risk factors for pleural effusion in general include older age, comorbidity (diabetes, renal failure, cancer, immunosuppression, chronic lung disease), and exposure to asbestos or pleural disease drugs. Pleural infection is more common in men older than 60 years and in those with comorbidities. ^[1][5]

Parapneumonic effusion moves through recognisable stages. The exudative stage produces a simple, free-flowing effusion as adjacent lung inflammation raises capillary permeability. The fibrinopurulent stage adds bacterial invasion, neutrophil influx, falling pH and rising LDH, with fibrin septa forming loculations. Left untreated, the organising stage lays down a dense fibrous peel, producing fibrothorax or trapped lung. Early drainage prevents the last stage. ^[2]

Most patients present with breathlessness, which may be out of proportion to the volume of fluid: a review of malignant effusions found that up to a quarter of patients are not relieved by drainage, because the breathlessness is multifactorial. Pleuritic chest pain and cough are common, especially when infection or inflammation involves the pleura. Fever points to infection. Weight loss, night sweats and cachexia suggest malignancy or tuberculosis. Some effusions, particularly malignant ones, are found incidentally and 15 to 25% of patients are asymptomatic at presentation.

Examination:

• Reduced chest expansion on the affected side.
• Stony dull percussion note over the fluid.
• Reduced or absent breath sounds over the effusion.
• Reduced vocal fremitus and reduced vocal resonance.
• Tracheal or mediastinal shift away from a large or massive effusion (toward the effusion is not expected and suggests volume loss instead).
• Reduced tactile fremitus and decreased air entry at the apex of a very large effusion.
• Signs of the cause: raised jugular venous pressure, third heart sound and ankle oedema in heart failure; cervical lymphadenopathy and cachexia in cancer.

Vignette: a 67-year-old woman with hypertension presents with two weeks of worsening breathlessness and orthopnoea, dry cough for three months, tachypnoea and an oxygen saturation of 92% on air. Chest examination shows reduced air entry over the mid-to-lower right hemithorax with a stony dull percussion note and reduced chest excursion, and no tracheal deviation. The chest radiograph shows a large right-sided pleural effusion. ^[1]

The first question is whether the effusion is transudate or exudate. The second is whether the patient has a single cause or two (for example heart failure plus pulmonary embolism, which can coexist). A short table of common discriminators:

• Chest radiograph posteroanterior view reliably detects a pleural effusion of at least 200 mL; a lateral decubitus view detects as little as 50 mL. A typical effusion shows homogeneous radio-opacity with blunting of the costophrenic angle, flattening of the diaphragm and a meniscus. A massive effusion produces near-white-out of the hemithorax with tracheal or mediastinal shift. An erect chest radiograph may reveal the cause (consolidation, mass, pleural plaques).
• Lung ultrasound is the most sensitive bedside test and can detect effusions under 50 mL. It is essential for confirming small effusions, assessing complexity (septation, loculation) and guiding thoracentesis or chest tube insertion.
• Computed tomography of the thorax shows pleural and parenchymal disease, nodules, lymphadenopathy and suspected cancers or infections. Loculations, split pleura sign and pleural enhancement are reliable CT pointers to pleural infection; a collection over 30 mL helps separate complex from simple parapneumonic effusion. ^[1][2][4]

Diagnostic thoracentesis is the investigation of choice for any undiagnosed exudative effusion. It also relieves large effusions symptomatically. Samples should be sent for:

• Appearance (serous, bloody, purulent, chylous).
• Protein and LDH, with paired serum for Light's criteria.
• Cell count and differential; a lymphocyte-predominant exudate points to tuberculosis, malignancy or connective tissue disease.
• Glucose and pH.
• ADA, when tuberculosis is possible.
• Amylase if pancreatitis is suspected.
• Triglycerides and cholesterol when chylothorax or pseudochylothorax is possible.
• Gram stain and culture (aerobic and anaerobic; inoculation into blood culture bottles improves yield).
• Cytology for cancer (cell block plus conventional cytology allows immunohistochemistry and molecular testing).
• Optional specialised tests as indicated: NT-proBNP for possible heart failure, autoimmune markers for rheumatoid arthritis or systemic lupus erythematosus, fluid haematocrit for haemothorax.

An effusion is an exudate if one or more of the following holds:

• pleural fluid protein divided by serum protein above 0.5;
• pleural fluid LDH divided by serum LDH above 0.6;
• pleural fluid LDH above two-thirds of the upper limit of normal for serum LDH.

Sensitivity is 97.5% but specificity is only about 80%, because of pseudo-exudates. Diuretics concentrate pleural fluid by removing water faster than protein, converting a benign cardiac effusion into a false exudate: in one study pleural protein rose 43% and LDH 67% after diuresis. A very high pleural red cell count (above 10,000 x 10^6 per litre) or a recent invasive procedure can have the same effect. When the clinical picture strongly suggests a transudate (hypervolaemia, elevated NT-proBNP, heart failure) but Light's criteria call it exudate, calculate the serum-pleural protein gradient (above 3.1 g/dL) or serum-pleural albumin gradient (above 1.2 g/dL), both of which reclassify most pseudo-exudates; adding serum or pleural NT-proBNP above 1500 pg/mL further strengthens the diagnosis of a cardiac effusion. Heart failure accounts for more than 75% of all transudates and only 72% of cardiac effusions meet Light's criteria for a transudate in the first place, so these checks matter. ^[1][5]

Tuberculosis pleurisy deserves emphasis. The fluid is usually a lymphocyte-predominant exudate. Direct acid-fast smear has a yield of only about 10% in immunocompetent patients and 20% in HIV-positive patients; solid culture gives 12 to 30% and liquid culture up to 70%, but takes weeks. Therefore, a pleural ADA above 40 U/L in a lymphocyte-predominant effusion strongly supports tuberculosis, while a value under 40 U/L helps to exclude it. Nucleic acid tests have only moderate yield. ^[1][5]

For suspected malignancy, cytology has a sensitivity of 50 to 60%, better in adenocarcinoma (about 80%) and poor in mesothelioma. A second sample increases sensitivity modestly. The minimum volume for cytology is 60 to 75 mL. Non-expandable lung can be seen after drainage: a basal pneumothorax with failure of re-expansion. ^[4]

Pleuroscopic or image-guided pleural biopsy is used when cytology is negative but malignancy or tuberculous pleuritis is still likely: medical thoracoscopy has a diagnostic yield of 86% for exudates and above 90% for malignancy, ultrasound-guided pleural biopsy about 93% and CT-guided about 84%. ^[1][4]

The decision is clinical and biochemical. Empyema (pus or a positive Gram stain or culture) must be drained. A complicated parapneumonic effusion is defined by any of:

• pH under 7.2,
• glucose under 3.4 mmol/L (about 61 mg/dL; the commonly cited British and European threshold is under 2.2 mmol/L, about 40 mg/dL),
• LDH over 1000 IU/L,
• loculation or septation on imaging,
• large volume or ongoing fever.

By the European Respiratory Society definition, pleural infection is a collection with infective symptoms plus a low pH (under 7.2), a low glucose (under 2.2 mmol/L, about 40 mg/dL), or culture positivity; empyema is the presence of frank pus. Patients with an intermediate pH (7.2 to 7.4) are considered for drainage if LDH exceeds 900 IU/L or if other features support infection (fever, large volume, glucose at or below 4.0 mmol/L, CT enhancement, or septations on ultrasound). A pleural CRP above 10 mg/dL supports infection; pleural procalcitonin is not useful. Loculations on CT or ultrasound are themselves associated with the need for drainage. ^[1][2]

When the Royal College of Physicians/RAPID score is used in pleural infection, it combines renal function, age, fluid purulence, infection source (community versus hospital) and serum albumin. It stratifies patients into low (0 to 2), intermediate (3 to 4) and high (5 to 7) risk groups, the high-risk group carrying a 3-month mortality of about 30%. The RAPID score predicts mortality and length of stay but has not yet been shown to guide treatment. ^[2]

The three stages map directly on to treatment:

1. Exudative: simple, free-flowing, low LDH, normal pH and glucose; usually resolves with antibiotics alone.
2. Fibrinopurulent: infected fluid, low pH, rising LDH, loculations; needs drainage and antimicrobials.
3. Organising: fibrous peel, trapped lung; may need thoracoscopic or surgical decortication.

Unstable patients need resuscitation: oxygen for hypoxaemia, fluids or vasopressors for shock, and urgent drainage for a tension-like massive effusion. In a haemodynamically stable patient with a massive or severely symptomatic effusion, therapeutic drainage should be prompt.

Therapeutic thoracentesis removes a large volume (1 L or more). Current guidance supports 1 to 1.5 L at a time, because of the risk of re-expansion pulmonary oedema. Drainage of larger volumes is occasionally necessary in hospital with close monitoring. For prolonged drainage, small-bore drains of 10 to 14 Fr are as effective as large-bore drains and are less painful; ultrasound-guided Seldinger insertion is safe. Chest drainage should not exceed 500 mL per 8-hour shift (or about 1.5 L a day), to reduce the risk of re-expansion pulmonary oedema, and drains are usually removed once output is under 200 mL a day for two consecutive days; leaving a drain in beyond 7 days increases infection risk. ^[1]

• Simple or uncomplicated effusion: antimicrobials alone.
• Complicated or empyema: antimicrobials plus chest drainage.
• For loculated or refractory effusions, options are intrapleural fibrinolytic therapy, multiple drains, thoracoscopic or surgical decortication.
• The standard intrapleural regimen from the MIST-2 trial is alteplase 10 mg plus DNase 5 mg, each instilled twice daily for six doses, with 45 to 60 minutes of clamping and free drainage; 52 patients in MIST-2 showed benefit compared with either drug alone or placebo. Contemporary practice sometimes starts with lower alteplase doses (such as 5 mg or 2.5 mg with 5 mg DNase), escalating if there is insufficient response, because infection resolves in most cases. The MIST-2 regimen is effective but resource-heavy and not without bleeding risk.
• Clinically significant pleural bleeding with this combination occurs in 4.1% of patients (defined as a pleural fluid haematocrit reaching half the blood haematocrit during therapy, or 25 to 50% with clinical suspicion requiring intervention). Risk factors include systemic anticoagulation, a high RAPID score, elevated serum urea and low platelets; anticoagulation should be withheld before intrapleural therapy where possible. ^[2][3]
• Surgery versus fibrinolysis: the ERS/ESTS statement would start intrapleural alteplase and DNase within 48 hours of standard care as a potentially surgery-sparing option when treatment is failing, with surgical referral in parallel; the British Thoracic Society guideline instead favours surgery as first-line, except when the patient is unfit or there is a delay over 48 hours. There is no high-quality evidence that either reduces mortality. Postoperative mortality after surgery for pleural infection ranges from 1% to 12%; conversion from video-assisted thoracoscopic surgery to thoracotomy occurs in up to 8.4% of cases. Early surgery, within 3 days of diagnosis, is generally associated with better outcomes. ^[3]

Tuberculosis is treated with standard anti-tuberculosis therapy. In the absence of drug-resistant disease or HIV infection, the usual regimen is 2 months of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 20 mg/kg and pyrazinamide 25 mg/kg, followed by 4 months of rifampicin and isoniazid. In patients older than 75 years or with liver cirrhosis, a 9-month regimen (2 months of rifampicin, isoniazid and ethambutol, then 7 months of rifampicin and isoniazid) is less hepatotoxic because it avoids pyrazinamide. Complicated or refractory tuberculous effusions may need intrapleural fibrinolysis or thoracoscopic intervention. ^[1]

The aim is palliation: control breathlessness with the minimum number of minimally invasive interventions and as few hospital days as possible.

• Repeated symptom-guided thoracentesis for patients with short expected survival (under 3 months), rapid expected response to cancer treatment, or slow re-accumulation.
• Chemical pleurodesis (commonly graded talc slurry via a chest tube, or talc poudrage at thoracoscopy) for re-accumulating effusions in patients with an expected survival above 3 months, provided the lung re-expands. Pleurodesis succeeds in fewer than 80% of randomised studies, around 75% at 1 month falling to around 50% at 6 months; mesothelioma has a lower success rate. If talc slurry pleurodesis is planned, a drain larger than 12 Fr is recommended. Talc poudrage is only warranted if thoracoscopy is needed for another reason such as biopsy. Pleurodesis cannot be performed when the lung does not re-expand.
• An indwelling pleural catheter, tunneled and ambulatory, is the alternative for non-expandable lung or when home drainage is feasible. Spontaneous pleurodesis occurs in 30 to 60% of patients. Catheter drainage reduces re-intervention rates from 22% to 4 to 6% and avoids immediate hospitalisation days; it is cost-effective in those with shorter survival. Patients usually drain about three times a week; daily drainage improves breathlessness and accelerates pleurodesis. Catheter-related complications are uncommon but include infection, loculation and catheter tract metastases (particularly in mesothelioma).
• The American Thoracic Society guideline recommends the indwelling catheter as first-line for non-expandable lung and rates it equal to chest tube with talc pleurodesis in expandable lungs. The LENT and PROMISE scores assist prognostication but are imprecise for individuals. ^[4]

• Connective tissue disease: systemic treatment of the autoimmune disease (for example disease-modifying drugs for rheumatoid arthritis). ^[1]
• Transudates: diuretics and guideline-directed heart failure therapy; fluid restriction and dialysis for advanced renal failure; definitive treatment of cirrhosis. First-line for a cardiac effusion is optimal medical therapy, with invasive drainage reserved for refractory or unilateral effusions. ^[1][5]
• Pulmonary embolism: anticoagulation (see the pulmonary embolism topic) with drainage for symptomatic relief.
• Pericardial disease: treatment of the underlying pericarditis; effusions are usually small, bilateral and exudative and settle with therapy.
• Pregnancy and traumatic and post-surgical effusions are managed by cause.

Refer when the diagnosis is unclear, the effusion is exudative, or drainage is needed. Any mass on imaging, cytology showing cancer, or loculated infected fluid should prompt specialist and, where relevant, surgical review. Patients with pleural infection who need intrapleural therapy or surgery should be managed in centres able to provide them. After a first drainage, monitor the rate of re-accumulation and consider repeated therapeutic aspiration or a definitive procedure. ^[1]

• Re-expansion pulmonary oedema after rapid or large-volume re-expansion, sometimes fatal; risk factors include rapid removal, younger age, and collapse lasting over a week.
• Empyema and pleural infection during tube drainage.
• Fibrothorax and trapped lung after untreated or late-stage infection.
• Tube complications: non-oscillation from kinking, migration, obstruction or full re-expansion; an air leak from a misplaced drain; pain and skin infection.
• Catheter complications for indwelling pleural catheters, described above.
• Acute complications of thoracentesis (pneumothorax, bleeding) are reduced by ultrasound guidance.
• IPC self-drainage errors and catheter tract metastasis.
• Post-surgical complications after decortication, with mortality between 1% and 12%.

• Thoracic ultrasound is the single highest-yield tool: it confirms an effusion where X-ray is inconclusive, identifies small or loculated collections, and makes thoracentesis and small-bore drain insertion safe. Learn to recognise the patterns (anechoic, septated, turbid).
• If ultrasound is not available, careful percussion, auscultation and an erect chest film (PA detects about 200 mL; decubitus films detect 50 mL) still find most clinically important effusions.
• Diagnostic thoracentesis with basic tests (protein, LDH, glucose, pH by blood gas analyser or pH paper, cell count, Gram stain and AFB smear) gives the transudate versus exudate split and much of the cause. ADA and cytology can be added where available.
• Empyema needs a chest drain and antibiotics; small-bore drains (10 to 14 Fr) with Seldinger technique are acceptable and less painful. Keep drainage at or below 500 mL per 8-hour shift and remove drains when output falls below 200 mL a day for two days.
• In places without intrapleural fibrinolytics, surgery or medical thoracoscopy, early involvement of the nearest thoracic surgery service and timely referral are important; antibiotics and drainage alone cure a large proportion of simple parapneumonic effusions.
• Because tuberculosis is a leading cause of lymphocyte-predominant exudate in many regions, adding ADA or a structured diagnostic pathway reduces the need for expensive molecular or surgical tests.
• For malignant effusion where pleurodesis or indwelling catheters are unavailable, repeated therapeutic aspiration at home-based or outpatient follow-up is a reasonable palliative strategy.
• Check for HIV and manage nutritional status alongside treatment.

• Pleural effusion is a sign of disease, not a disease itself; transudates reflect systemic pressure or protein problems, exudates reflect local pleural or lung disease.
• Light's criteria are highly sensitive (97.5%) but their specificity is only about 80%, because of pseudo-exudates, especially after diuretics; confirm with albumin or protein gradients and NT-proBNP when the clinical picture suggests heart failure.
• Congestive heart failure is the commonest cause of transudate; effusions are often bilateral and right-sided.
• The three common exudates to rule out first are parapneumonic effusion or empyema, malignancy and tuberculosis.
• A pH under 7.2 or glucose under 3.4 mmol/L (about 61 mg/dL; the widely cited British and European threshold is under 2.2 mmol/L, about 40 mg/dL) with loculation or pus means a complicated parapneumonic effusion or empyema and indicates drainage.
• The intrapleural standard (MIST-2) combines alteplase 10 mg with DNase 5 mg, six courses twice daily, with 45 to 60 minutes of clamping; significant intrapleural bleeding occurs in 4.1%.
• Malignant effusions have a median survival of 3 to 12 months; options are repeated therapeutic aspiration (under 3 months expected survival), pleurodesis (above 3 months, expandable lung) or an indwelling catheter (non-expandable lung or home drainage).
• Tuberculous effusions are lymphocyte-predominant; ADA above 40 U/L supports the diagnosis and under 40 U/L helps to exclude it, given the poor direct smear yield.
• ADA should be interpreted with the lymphocyte fraction; cytology sensitivity is 50 to 60%, with better yield in adenocarcinoma.
• Ultrasound guides safe drainage, and small-bore 10 to 14 French drains are as effective and less painful than large-bore drains.
• Keep total drainage at or below 500 mL per 8-hour shift, with a maximum of 1.5 L per procedure, to reduce re-expansion pulmonary oedema.
• Pericardial and post-surgical effusions are usually small, settle with treatment of the cause, and only need drainage when symptomatic or large.

Congestive heart failure; cirrhosis and hepatic hydrothorax; nephrotic syndrome; hypoalbuminaemia; community-acquired pneumonia; lung cancer; mesothelioma; pulmonary embolism; tuberculosis; rheumatoid arthritis; systemic lupus erythematosus; acute pancreatitis; chylothorax; haemothorax; cardiac tamponade; pericarditis; respiratory failure and hypoxaemia.