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Pleural effusion

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CONTENTS

approach to pleural effusion of unclear etiology

differential diagnosis

pleural radiology

pleural fluid analysis (PFA)

specific disease processes

other pleural topics

initial considerations when approaching a pleural effusion of unclear etiology

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A thorough, stepwise approach will guide the optimal selection of diagnostic and therapeutic maneuvers. 

1) history & exam

ask about recent events, e.g.:

  • MI or cardiac procedure (Dressler syndrome, post-CABG effusion).
  • Pneumonia (empyema).
  • GI surgery or procedures (postoperative effusion, abscess, PE, chylothorax, esophageal perforation).
  • Trauma (hemothorax, chylothorax, duropleural fistula).

review medical history, e.g.: 

  • Cirrhosis (hepatic hydrothorax, spontaneous bacterial pleuritis).
  • Renal failure (associated with several types of effusion, discussed here: ⚡️).
  • Heart failure.
  • Rheumatologic disorders (pleuritis, pulmonary arterial hypertension, opportunistic infection with parapneumonic effusion).
  • Cancer (associated with several types of effusion, discussed here: ⚡️).

history of present illness:

  • Constitutional symptoms? (fever, night sweats).
  • Pleuritic chest pain? (suggests exudative effusion).
  • Productive cough?
  • Abdominal pain? (pancreatitis, abscess).
  • Weight gain? Peripheral edema? (heart failure).

medication review:

  • Immunosuppressives?
  • Anticoagulants?
  • Diuretics?
  • Drugs that can cause pleural effusion? Most common are below: (longer list ⚡️)
    • Amiodarone.
    • Clozapine.
    • Ergot alkaloids, including bromocriptine, ergotamine.
    • Methotrexate.
    • Nitrofurantoin.
    • Phenytoin, valproic acid.
    • Tyrosine kinase inhibitors, including dasatinib.

examination:

  • Objective fever?
  • Abdominal tenderness?
  • Peripheral edema?
2) review of chest radiograph, POCUS, & prior radiology

points of interest on POCUS

  • Echotexture of effusion (e.g., septations?)?
  • Pericardial effusion?
  • Evidence of heart failure?
  • Ascites?

points of interest on chest radiograph

  • Parenchymal lung disease?
  • Tracheal shifts towards/away from effusion?

specific findings that can help focus the differential diagnosis:

3) blood tests 

For an undifferentiated effusion, the following studies may be considered:

  • Basic chemistries (including total protein and LDH, which help with interpreting thoracentesis results).
  • Complete blood count with differential.
  • Coagulation studies in selected patients (e.g., anti-Xa level for patients on oral Xa-inhibitors).
  • D-dimer (if PE is a consideration).
  • NT-pro-BNP (if suspecting heart failure).
  • Blood cultures (if concern for empyema, pneumonia, or endocarditis).
  • CRP (C-reactive protein) may help risk-stratify the likelihood of severe infection (discussed further below ⚡️).
4) CT scan

CT scan may help evaluate for subtle parenchymal lung disease and clarify the anatomy of the effusion. CT scan may also be required to evaluate for pulmonary embolism (the 4th most common cause of pleural effusion). 

which scan to order

  • CT angiogram is the test of choice if pulmonary embolism needs to be excluded.
  • If pulmonary embolism has been excluded, delayed pleural-phase IV contrast may be helpful.

sequencing of CT scan and effusion drainage

  • CT scan before effusion drainage may provide the best resolution of the pleura (e.g., to evaluate for pleural thickening or nodularity). This may also help with pre-procedural planning for the drainage of complex or loculated effusions.
  • CT scan after effusion drainage may provide the best resolution of the underlying lung parenchyma.

findings of interest on CT scan: 

  • Effusion:
    • Loculation?
    • > 16 HU suggests hemothorax.
    • Pleural thickening/nodularity?
    • Pleural enhancement with delayed-phase contrast?
  • Parenchymal lung disease?
  • Any evidence of malignancy?
  • Evidence of cardiac disease:
    • Left atrial dilation may support heart failure.
    • Pericardial effusion?
    • Pericardial thickening?
    • Contrast reflux into the IVC?
  • Ascites? Cirrhosis?
  • (General approach to CT interpretation: 📖)
5) thoracentesis?

As a general rule of thumb, a new effusion of unknown etiology that is moderate-large in size should undergo diagnostic sampling. However, there is room to personalize the approach for an individual patient. 

considerations regarding whether to pursue thoracentesis

  • Concern for empyema is an indication for sampling (e.g., fever, loculations, large size, rapid growth, intercurrent pneumonia).
    • Cirrhosis may cause spontaneous bacterial empyema 📖, so the presence of cirrhosis is an indication for thoracentesis to exclude this possibility.
  • Features suggesting an exudate would favor thoracentesis or drainage, for example:
    • Pleuritic chest pain.
    • Constitutional symptoms.
    • Loculations/septations.
    • Unilateral effusion.
  • Therapeutic drainage may be helpful if the effusion is large and appears to be causing significant respiratory dysfunction.
  • Safety of draining the effusion?
    • Small effusions are often technically drainable, but the risk of iatrogenic harm is larger.
    • Severe coagulopathy isn't an absolute contraindication, but may increase risk.
  • Chronicity of the effusion: The longer the effusion has been present and stable, the lower the likelihood that drainage will be beneficial.

alternative approaches to consider

  • Trial of diuresis: If the effusion is likely related to heart failure or volume overload, then close observation with diuresis is often a reasonable course of action.
  • Serial observation: Empyema will typically expand over time. Serial ultrasonography or chest radiography may be used to follow the effusion and ensure that it is not growing. If the effusion does grow in size, then it may become safer to drain (because it presents a larger target for thoracentesis).

pleural fluid labs to order: 📖

causes of pleural effusion

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list of all causes

key:

  • Fuschia = transudative.
  • Green = exudative.
  • Brown = either transudative or exudative.
  • Underlined etiologies are more common.

cardiovascular

  • Pulmonary embolism (85% exudative, 15% transudative). 📖
  • Post-cardiac injury syndrome, post-CABG effusion.
  • Heart failure and/or volume overload.
  • Constrictive pericarditis.
  • Superior vena cava syndrome.
  • PAH (pulmonary artery hypertension). 

neoplastic

  • MPE (metastatic pleural effusion)
    • Mesothelioma.
    • Lung cancer.
    • Metastatic cancer.
  • Meigs syndrome. 📖

infectious

  • Empyema & parapneumonic effusion. 📖
  • Tuberculosis. 📖
  • Fungal infection.
  • Viral infection.

rheumatologic

  • Connective tissue disease:
    • Lupus. 📖
    • Rheumatoid arthritis. 📖
    • Sjogren syndrome.
  • Sarcoidosis. 📖
  • GPA (granulomatosis with polyangiitis).
  • AEP (acute eosinophilic pneumonia).
  • EGPA (eosinophilic granulomatosis with polyangiitis). 📖

drugs & exposures

  • Medications 📖
  • Radiotherapy (if effusion is small, unilateral, lasting for up to 6 months after therapy).
  • BAPE (benign asbestos pleural effusion). 📖

infradiaphragmatic

  • Nephrologic:
    • Uremic pleuritis. 📖
    • Peritoneal dialysis (transdiaphragmatic migration).
    • Urinothorax. 📖
    • Nephrotic syndrome. 
    • Glomerulonephritis.
  • Gastrointestinal:
    • Hepatic hydrothorax. 📖
    • Spontaneous bacterial empyema. 📖
    • Pancreatic disease (pancreatitis, pancreaticopleural effusion). 📖
    • Esophageal perforation (e.g., Boerhaave syndrome).
    • Cholecystitis.
    • Hepatic or splenic abscess.
    • Bilothorax. 📖
  • OB/GYN:
    • Meigs syndrome. 📖
    • Ovarian hyperstimulation syndrome.
    • Endometriosis.
    • Postpartum (usually benign).
  • Peritonitis.
  • Abscess (e.g., subphrenic, hepatic, splenic).
  • Status post abdominal surgery.

postoperative or post-traumatic

  • Postcardiac injury syndrome. 📖
  • Post-CABG. 
  • Esophageal rupture.
  • Hemothorax. 📖

other

  • Hypothyroidism. 
  • IgG4 pleuritis.
  • Lymphatic abnormality:
    • Chylothorax. 📖
    • Yellow nail syndrome. 📖
    • LAM (lymphangioleiomyomatosis).
  • Trapped lung 📖 or bronchial obstruction causing atelectasis.
  • Hypoalbuminemia (if extremely severe).
  • Pleural amyloidosis.
  • Neurologic:
    • Duropleural fistula (e.g., disc surgery, trauma).
    • Ventriculoperitoneal shunt with migration into the pleura.
more common causes of transudates

most common transudates

  • Heart failure (~80% of transudates). (23374395)
  • Hepatic hydrothorax (~13% of transudates). (23374395)
  • Renal dysfunction:
    • Volume overload.
    • Nephrotic syndrome.
    • Glomerulonephritis.
    • Peritoneal dialysis.

less common transudates

  • Hypothyroidism.
  • Constrictive pericarditis (may have normal NT-pro-BNP).
  • Superior vena cava syndrome. (23374395)
  • Pulmonary embolism (15% are transudates).
  • Pulmonary hypertension.
  • Trapped lung, atelectasis.
more common causes of exudates

most common exudates

  • Infection (including bacterial, viral, fungal, or mycobacterial).
  • MPE (malignant pleural effusion).
  • Pulmonary embolism.
  • Autoimmune pleuritis (e.g., rheumatoid arthritis, lupus).

less common exudates

  • Medications.
  • Postcardiac injury syndrome; post-CABG effusion.
  • Uremic pleuritis.
  • Chylothorax.
  • Abdominal disease:
    • Pancreatitis.
    • Cholecystitis.
    • Abscess (subphrenic, hepatic, splenic).
    • Esophageal perforation.

pleural POCUS

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detection of an effusion

  • POCUS is sensitive for a free-flowing effusion >100 ml in size.
  • Loculated effusions may be missed if they are located in an unusual location.

characterization of bilateral effusions

  • In patients with bilateral effusions, care should be taken to evaluate the qualities of the effusions on both sides. Rarely, patients with bilateral effusions may have different etiologies, termed “Contarini syndrome” (e.g., heart failure and empyema).

specific signs that may be rarely encountered

  • Pleural nodularity suggests malignancy.
  • Hemothorax:
    • Increasing density of fluid in the most dependent areas may suggest blood (hematocrit sign).
    • Clotted blood has a distinctive appearance.

pleural effusion on chest X-ray

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frontal upright radiograph of a free-flowing effusion

  • Costophrenic angles:
    • (#1) Subtle blunting of the costophrenic angle is seen first. This may occur after accumulation of ~250 ml pleural fluid.
    • (#2) As more fluid builds up, a rounded edge of the lung may be seen (meniscus sign). This usually requires at least 500 ml of pleural fluid. (Folch 2023)
  • Fluid in the fissures.
    • Right minor fissure is most often seen.
    • “Incomplete fissure sign” may result from fluid in the major fissure (figure below). This generates a sharp curvilinear interface that is more dense laterally. (Walker 2019) 
Incomplete fissure sign (18430885)

supine radiograph of a free-flowing effusion

  • Posterior layering of a free-flowing effusion may cause hazy opacity (without costophrenic angle blunting).
  • If fluid tracks around the lung apex, it may interpose between the chest wall and the lung to produce an “apical cap.” (Shepard 2019) This is seen only in large effusions. 
subpulmonic effusion

basics

  • A subpulmonic effusion occurs if fluid accumulates below the lung base, without spilling into the costophrenic angle (such that the costophrenic angle appears normal).
Subpulmonic effusion demonstrating a lateral peak of the “diaphragm” with dense opacity underneath. (Courtesy of Ian Bickle, Radiopaedia)

radiologic clues to diagnose a subpulmonic effusion

  • (1) The apex of the “diaphragm” shifts laterally (this is not actually the true diaphragm, but rather a pseudo-diaphragm generated by the interface between the effusion and the lung tissue). (Shepard 2019)
  • (2) No blood vessels are seen below the dome of the pseudo-diaphragm.
  • (3) The dome of the pseudo-diaphragm appears more opaque than normal.
  • (4) For a left-sided subpulmonic effusion: there may be >2 cm between the stomach bubble and the pseudo-diaphragm (normally, the distance is <1 cm).
  • (5) Fluid seen in the fissure may also support the diagnosis of pleural effusion.

radiographic differential diagnosis

  • Elevated hemidiaphragm.
  • Diaphragmatic eventration.
  • Hepatomegaly/splenomegaly.
  • Ascites.
  • (Bedside ultrasonography should rapidly sort this out)
pseudotumor
  • This refers to focal accumulation of fluid within a fissure, which may mimic a lung mass.
  • Pseudotumor most often involves the right minor fissure.
  • Common causes include heart failure, cirrhosis, or renal failure. (Folch 2023) 
  • This appears as a smooth, biconvex lesion (unlike most lung masses).
  • Lateral X-ray may help with diagnosis (or CT scan if necessary).
  • Lesion should generally resolve with treatment of heart failure (e.g., diuresis).

radiologic subtyping of pleural effusion

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chronic pleural effusion

clinical significance of a chronic effusion

  • Chronic effusion might be roughly defined as persisting for >6 months. (23374395)
  • Chronic pleural effusion is unlikely to be causing acute symptoms.
  • Increasing chronicity suggests that nothing needs to be done emergently about the effusion.
  • Drainage is less likely to cause clinical improvement (e.g., the underlying lung tissue may be trapped).

causes of chronic effusion include

  • Unexpandable lung (including trapped lung).
  • Yellow nail syndrome.
  • Cholesterol effusions.
  • Benign asbestos pleural effusion.
  • Uremic pleurisy.
  • Rheumatoid pleurisy.
  • post-CABG effusion.
  • Radiation pleuritis.
rapidly growing and/or rapidly recurring pleural effusion

This may be roughly defined as growth or recurrence within ~1-3 days. Of course, hemothorax may grow much faster than that. 

  • Hemothorax.
  • Empyema or complex parapneumonic effusion.
  • Peritoneal sources:
    • Hepatic hydrothorax.
    • Malignant ascites.
    • Meigs syndrome.
  • Fistulae:
    • High-output chylothorax.
    • Pancreaticopleural fistula.
  • Trapped lung. (23374395)
pleural plus pericardial effusions
  • Infection:
    • Viral:
      • Influenza.
      • Coxsackievirus.
    • Tuberculosis.
  • Malignancy (carcinoma, lymphoma, leukemia).
  • Inflammatory processes (serositis):
    • Lupus.
    • Rheumatoid arthritis.
    • Stills disease, juvenile idiopathic arthritis, familial Mediterranean fever.
    • Post-cardiac injury syndrome.
    • GVHD (graft versus host disease).
  • Medications (e.g., methotrexate, mesalamine).
  • Metabolic:
    • Uremia.
    • Hypothyroidism.
pleural effusion plus ascites
  • Ascitic fluid with transmigration via diaphragmatic imperfections, most often:
    • Hepatic hydrothorax.
    • Heart failure.
    • Constrictive pericarditis.
    • Meigs syndrome.
  • Generalized serositis:
    • Pseudo-pseudo-Meigs syndrome in the context of lupus.
massive effusion (~entire hemithorax)
  • Statistically most likely:
    • Malignancy (~60%).
    • Complicated parapneumonic effusion or empyema (~20%). (23374395)
  • Other possibilities include:
    • Hepatic hydrothorax.
    • Tuberculous pleuritis.
    • Hemothorax.
    • Heart failure.
bilateral effusions may suggest:
  • Transudates:
    • Heart failure.
    • Hepatic hydrothorax.
    • Nephrotic syndrome.
    • Hypoalbuminemia.
    • Renal failure.
  • Malignancy (widespread malignancy, including abdominal/pelvic malignancy).
  • Lupus and other autoimmune disorders.
  • Bilateral pulmonary emboli. (37433578)
loculated effusion

diagnosing a loculated effusion

  • A loculated effusion is defined as having adhesions within the pleura that prevent fluid from freely flowing within the pleural space.
  • Loculation is revealed by fluid that doesn't respect gravity.
  • If there is doubt about whether the effusion is loculated, this may be determined by:
    • (1) If POCUS shows septations within the pleural effusion, this supports a loculated effusion.
    • (2) A lateral decubitus X-ray may be used to determine if fluid shifts in response to gravity.

common causes of a loculated effusion

  • Complicated parapneumonic effusion or empyema.
  • Tuberculosis.
  • Hemothorax.
  • Malignancy.
  • Pulmonary embolism with diagnostic delay >10 days. (23374395)
  • Chronic pleural adhesions due to a prior pleural injury (e.g., pleurodesis). In this case, any effusion (transudative or exudative) will generate a loculated effusion.
contrast enhancement of pleural surfaces (with delayed-phase pleural contrast)

Pleural phase contrast involves scanning the patient 60-90 seconds after contrast injection (late venous phase), to allow for maximal pleural soft tissue enhancement. (Folch 2023; 23374395)

causes of contrast enhancement include:

  • Complex parapneumonic effusion or empyema.
  • Tuberculosis.
  • Malignancy. (23374395)
pleural thickening 

basics

  • Pleural thickening is defined as the pleura being visible on CT scan (either noncontrast or contrast scan). Normally, the pleura should not be visible.
  • Diffuse pleural thickening may cause blunting of the costophrenic angle.
  • If pleural thickening is seen in combination with an effusion, this strongly suggests that the effusion is exudative.

causes of pleural thickening

  • Asbestos-related
    • Discrete pleural plaques.
    • Diffuse pleural thickening.
    • Mesothelioma.
  • Rheumatologic:
    • Rheumatoid arthritis.
    • Lupus.
    • Sjogren syndrome.
    • Systemic sclerosis.
    • Dermatomyositis.
    • Granulomatosis with polyangiitis.
    • Ankylosing spondylitis.
    • Periodic fever syndromes.
    • Adult-onset Still disease.
    • IgG4-related disease.
  • Malignancy:
    • Mesothelioma.
    • Malignant pleural effusion.
  • Infection:
    • Complex parapneumonic effusion or empyema.
    • Tuberculosis.
  • Medications:
    • Bromocriptine.
    • Cabergoline.
    • Tyrosine kinase inhibitors.
  • Iatrogenic:
    • Post-CABG effusion.
    • After thoracic radiotherapy.
    • Following prior pleurodesis: Talc pleurodesis often causes focal pleural thickening and nodularity, which are often high attenuation. Thickening is usually seen in the posterior basal pleura or apices, but can extend into the fissures. Some residual effusion may be seen as well. (27509157) 
  • Other:
    • Hemothorax (<1% of cases).
    • Uremic pleural effusion.
    • Amyloidosis. (Murray 2022)

initial approach to determining the cause of pleural thickening

  • Historical & medication review (to evaluate for known factors listed above).
  • Thoracentesis, with attempt to remove all fluid.
    • Evaluate whether fluid removal causes clinical improvement.
    • Evaluate whether it is possible to expand the lung (or whether the lung is trapped).
    • Pleural fluid analysis to evaluate for the underlying etiology.
  • CT scan:
    • Evaluate for signs of malignancy (e.g., nodular pleura).
    • Evaluate for signs of asbestos exposure.
    • High attenuation thickening suggests a narrower differential (prior hemothorax, prior empyema, asbestos-related pleural disease, status post pleurodesis). (27509157) 
hydropneumothorax

diagnosis of hydropneumothorax

  • Hydropneumothorax is defined as a combination of a pleural effusion plus pneumothorax.
  • The key finding on upright chest radiograph is a horizontal air-fluid interface that extends the length of the hemithorax. This generates a very distinctive sharp, horizontal line.
  • The radiological differential diagnosis includes lung abscess, or lung cyst/bullae containing fluid. Hydropneumothorax may generally be differentiated from a lung abscess or cyst because it is larger.
  • POCUS may be utilized to demonstrate the presence of a hydropneumothorax, based on detection of an air-fluid interface (called a hydropoint; discussed further here 🌊).

causes of hydropneumothorax

  • Bronchopleural fistula (e.g., due to infection or malignancy).
  • Spontaneous pneumothorax with pleural effusion.
  • Gas-forming pleuropulmonary infection.
  • Trauma.
  • Esophageal rupture. (23374395)

thoracentesis or pigtail drain insertion in coagulopathy

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Society of Interventional Radiology Consensus Guidelines:

  • Thoracentesis and nontunneled pigtail chest tubes are classified as low bleeding risk procedures.
  • Checking PT/INR is not routinely recommended.
  • Preprocedural interruption of DOAC hasn't been identified as a risk factor for hemorrhage.
  • Platelet transfusion is recommended if platelets are <20 b/L. (2019; 31229333)

bottom line

  • Studies have generally indicated that thoracentesis and pigtail chest drain insertion are safe in patients with coagulopathy. (23952852, 31303429)
  • The most important safety measure is the use of procedural techniques which avoid arterial laceration (discussed below).
  • Severe coagulopathies may still require caution, for example:
    • (1) Severe thrombocytopenia (<20 b/L).
    • (2) Severe hypofibrinogenemia (e.g., status post thrombolysis).
    • (3) Overdose of oral anticoagulant (e.g., accumulation in the context of acute kidney injury).

techniques to minimize bleeding risk

  • Avoiding thoracentesis near the spine (the intercostal artery position may be more variable there).
  • Staying close to the upper edge of the rib.
  • When possible, ultrasound may be used to visualize the intercostal artery. This allows for pre-procedure identification of aberrant vessels and avoidance of them.
  • As the syringe is advanced, apply continuous negative suction. If arterial blood appears in the syringe, pull out the syringe! Do not advance into the pleura (this could create an arterial-pleural fistula).

pleural fluid labs to order

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initial pleural fluid labs

  • Basic labs to check on all specimens:
    • ✅ Cell count and differential.
    • ✅ Glucose.
    • ✅ LDH (lactate dehydrogenase).
    • ✅ Total protein.
    • ✅ pH (this must be obtained in a syringe without any air bubbles or heparin, and analyzed by the laboratory STAT). 📄
      • pH is reasonable to send with the initial laboratory studies, because it's generally impossible to add on later.
    • ❗️Hold fluid for additional tests.
  • Other studies to commonly consider in the first round:
    • ✅ Gram stain and bacterial culture – only if infection is suspected.
      • Collection of pleural fluid in blood culture bottles improves yield.
    • ✅ For patients with heart failure or cirrhosis (especially for those receiving diuresis), evaluation for a pseudoexudate is needed:
      • Albumin level.

additional labs to consider

  • Additional microbiological studies:
    • Fungal stain & culture.
    • Acid-fast bacilli stain and culture; adenosine deaminase (ADA).
  • Additional evaluation for malignancy:
    • Cytology.
    • Flow cytometry if concern for lymphoma.
  • Additional labs for milky fluid 🥛:
    • Triglyceride level.
    • Cholesterol level.
  • Labs that evaluate for anomalous connections:
    • Amylase (positive in pancreatic disease, esophageal rupture, malignancy).
    • Creatinine (may reveal urinothorax).
    • Bilirubin (obtain if pleural fluid is green or black; pleural fluid bilirubin that is higher than serum bilirubin indicates bilothorax).
    • Beta-2 transferrin (if suspect duropleural fistula).
diseases suggested by pleural fluid appearance

looks like water 🚰

  • Duropleural fistula.
  • Central line misplacement with infusion of crystalloid.

milky or whitish ⚪️

  • Causes:
    • Chylothorax.
    • Cholesterol effusion (pseudochylothorax).
    • Empyema.
    • Misplaced central line that is infusing a white fluid (e.g., total parenteral nutrition, propofol, or clevidipine).
    • Feeding tube perforation into the pleura, with enteral nutrition infused into the pleura.
  • Evaluation:
    • Pleural fluid analysis: usual tests plus pleural fluid triglyceride and cholesterol levels.
    • Review placement of lines/tubes in the patient's thorax.
    • Review of prior imaging (a cholesterol effusion will be chronic).

serosanguinous 🔴

  • Definitions vary, including:
    • Fluid appears grossly serosanguinous (bloody, but not frank blood).
    • RBC count of 5,000-10,000/uL.
    • A more rigorous definition might be: blood in the pleural fluid with a RBC count or hematocrit <50% of corresponding blood values (i.e., not satisfying the criteria of hemothorax).
  • Common causes of a serosanguinous pleural effusion:
    • Most common:
      • Malignancy.
      • Pulmonary embolism with lung infarction.
      • Trauma/iatrogenic (including blunt trauma, post-CABG effusion).
    • Pneumonia.
    • Coagulopathy.
    • Uremia.
    • Tuberculosis.
    • Benign asbestos pleural effusion.
    • (Bloody effusions can occur in heart failure as well.)

greenish 🟢

  • Biliary fistula.
  • Rheumatoid arthritis.

brown 🟤

  • Catamenial effusion (a manifestation of thoracic endometriosis).
  • Amoebic liver abscess.
  • Empyema.

black ⚫️

  • Malignancy:
    • Metastatic melanoma.
    • Lung cancer (usually adenocarcinoma).
  • Pancreatic pseudocyst with pancreaticopleural fistula.
  • Fungal empyema due to Rhizopus oryzae or Aspergillus niger.
  • Crack cocaine use.
  • Rheumatoid pleurisy.
  • Hemothorax that is subacute in nature (with subsequent hemolysis and metabolism of heme).
  • Bronchopleural fistula; Boerhaave hydropneumothorax. (33664836)

viscous

  • Malignancy:
    • Mesothelioma.
    • Multiple myeloma with pleural involvement. ⚡️
    • Mucin-producing tumor with pleural involvement, e.g.:
      • Melanoma (fluid may be dark due to melanin pigmentation).
      • Lung cancer.
      • Abdominal or gynecological cancers.
  • Empyema.
  • Chylothorax.
  • IgG4 disease. (34468286; 37038561)

particulate matter

  • Empyema.
  • Esophageal fistula (food particles). (Folch 2023)

sorting out exudate vs. transudate

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Light's criteria

Light's criteria

  • [#1] (Pleural fluid protein / serum protein*) >0.5
    • Note: in reality this is a bit more complicated: 📄
      • >0.56 is increasingly suggestive of exudate.
      • <0.41 is increasingly suggestive of transudate.
      • 0.41-0.56 is a grey area (likelihood ratio 0.3 – 1.5).
    • ⚠️ A cutoff of >0.6 may be more accurate in effusions suspected to be due to heart failure or hepatic hydrothorax, especially following diuresis (see the discussion of pseudoexudate below ⚡️). (22372660)
  • [#2] (Pleural fluid LDH / serum LDH*) >0.6
  • [#3] Pleural fluid LDH >200 IU/L (or technically >0.66 times the upper limit of normal for serum, but in practice the 200 IU/L cutoff is used). (ERS handbook 3rd edition; 29466146)
  • *Serum values may be obtained a few days before or after the thoracentesis. (23374395)

performance

  • One criterion has a sensitivity of 99% and specificity of 83% for detecting an exudate.
    • 30% of heart failure effusions and 18% of hepatic hydrothorax will be incorrectly classified as exudates (“pseudoexudates”); discussed further below. ⚡️ (36273933, 23374395)
  • Two criteria have a sensitivity of >90% and a specificity of >99% for detecting an exudate.
Heffner's criteria

two or three criteria should be examined:

  • [#1] Pleural fluid protein >2.9 g/dL. (Transudates are usually <2 g/dL, whereas exudates are usually >3 g/dL)
  • [#2] Pleural fluid LDH is >~150 U/L (>0.45 times the upper limit of normal for serum).
  • [#3] Optional: Pleural fluid cholesterol is >45 mg/dL.

performance

  • The presence of ≧1 criterion has a high sensitivity for detection of exudate (~98%), similar to Light's criteria.
  • Heffner's criteria may be useful if pleural fluid chemistries are available without access to simultaneous blood levels.
pseudoexudate

definition of a pseudoexudate

  • A pseudoexudate is a transudative effusion that undergoes volume contraction leading to fluid concentration, causing the protein level to rise slightly into the “exudative” range according to Light's criteria. Usually the concentration of protein and/or LDH are only slightly above the cutoff ratio for an exudate (e.g., effusion/serum protein ratio of 0.5-0.6). (Murray 2022)
  • A pseudoexudate is especially likely following diuresis.
  • The most common causes of a pseudoexudate are:
    • Heart failure (30% of effusions meet criteria for an exudate). (23374395)
    • Hepatic hydrothorax (18% of effusions meet criteria for an exudate). (23374395)
    • Bloody pleural fluid due to a traumatic tap (>10,000 erythrocytes/uL). (23374395)

diagnosis of a pseudoexudate

  • If the clinical context and laboratory studies are typical for a pseudoexudate, then further testing may not be necessary to formally prove the diagnosis (e.g., known cirrhosis with effusion/serum protein ratio of 0.52).
  • Tests to evaluate for pseudoexudate:
    • Serum – pleural fluid albumin gradient >1.2 g/dL (~90% sensitive and specific for transudate).
    • Serum – pleural fluid protein gradient >3.1 g/dL (somewhat less accurate than albumin gradient, but may be more readily available).
    • Pleural fluid cholesterol >45 mg/dL supports the presence of a true exudate. (Folch 2023)
    • NT-pro-BNP may help support the presence of effusion(s) due to heart failure. ⚡️
discordant exudates
  • Usually protein and LDH are elevated in parallel, but there are some situations where they are discordant.
    • LDH is an intracellular enzyme. Elevated LDH within the pleural fluid reflects inflammation and cellular turnover. LDH may be useful to serially evaluate the amount of pleural inflammation over time. (Murray 2022)
  • LDH-discordant exudate (with only elevation of LDH): consider (Murray 2022)
    • Malignant effusion.
    • Parapneumonic effusion.
    • Urinothorax.
  • Protein-discordant exudate (with only elevation of protein): consider
    • Effusion due to capillary leak (e.g., ovarian hyperstimulation syndrome).
    • Effusion due to lymphatic dysfunction (e.g., chylothorax, yellow nail syndrome).
    • Trapped lung.
  • Effusions associated with unusually high protein levels:
    • Pleural fluid protein >4-5 g/dL suggests tuberculous pleuritis. (Murray 2022; Fishman 2023) 
    • Pleural fluid >7-8 g/dL should suggest multiple myeloma ⚡️ or Waldenstrom macroglobulinemia. (Folch 2023)

pleural fluid cell count and differential

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normal pleural fluid differential cell count

  • 0-2% neutrophils.
  • <10% eosinophils.
  • 7-11% lymphocytes.
  • 61-77% macrophages.
  • 9-30% mesothelial cells.

normal absolute cell count

  • There is little data available.
  • A normal concentration might be ~1.7 million/L. (10988124)
eosinophilic pleural effusion (>10% Eos)
  • Blood or air in the pleural space, e.g.:
    • Pneumothorax (eosinophilia appears within 3 days). (Murray 2022)
    • Hemothorax (may take 1-2 weeks to develop).
    • CABG (first month postoperative).
    • PE (if associated with lung infarction and bloody pleural effusion).
    • Repeated thoracentesis.
  • Malignancy (up to 40% of eosinophilic pleural effusions).
    • Carcinoma (5% may have pleural eosinophilia, most often lung cancer).
    • Lymphoma (rarely seen in Hodgkin disease).
  • Infections:
    • Parasitic disease (e.g., paragonimiasis, echinococcosis, filariasis, toxocariasis, amebiasis, ascariasis).
    • Fungal disease (e.g., histoplasmosis, coccidioidomycosis).
    • Psittacosis.
    • Tuberculous pleurisy (~7% may have eosinophilia). (34022019)
  • Drug-induced (e.g., dantrolene, bromocriptine, nitrofurantoin, valproic acid). 📖
  • Rheumatologic:
    • EGPA (eosinophilic granulomatosis with polyangiitis).
    • Rheumatoid arthritis.
  • BAPE (benign asbestos pleural effusion) 📖
  • Idiopathic (in one third of eosinophilic effusions, no cause is found).
lymphocyte-predominant effusion 

Lymphocytic effusions are generally associated with more chronic disease processes. Overall, malignant pleural effusion is a common cause. 

causes of lymphocyte-predominant effusion

  • Processes which may cause >80% lymphocytes:
    • Tuberculosis.
    • Post-cardiac injury syndrome (including post-CABG effusion).
    • Lymphoma/leukemia, including:
      • CLL (chronic lymphocytic leukemia).
      • Primary effusion lymphoma (often in patients with HIV).
    • Chylothorax.
    • Yellow nail syndrome.
    • Rheumatoid arthritis.
    • Sarcoidosis.
    • Acute lung transplant rejection.
    • Uremic pleural effusion.
  • Processes which usually cause less dramatic lymphocyte predominance (~50-80%)
    • Any chronic effusion (e.g., trapped lung, heart failure).
    • Malignancy (including bronchogenic carcinoma, mesothelioma).
    • Pulmonary embolism.
    • IgG4-related pleural effusion.

labs to consider in the evaluation of a lymphocytic effusion:

  • Serum:
    • Rheumatoid factor.
    • ANA (antinuclear antibody).
    • IgG4 level.
    • IGRA assay for tuberculosis (interferon-gamma release assay).
  • Pleural fluid:
    • Cytology.
    • Flow cytometry. (27831797)
    • Adenosine deaminase (ADA) +/- tuberculosis PCR.
    • Triglyceride level.

evaluation for the persistent lymphocytic effusion of unclear etiology

  • The primary concern is missing a diagnosis of malignancy or tuberculosis.
  • [#1] Initial steps:
    • The first step is generally to perform 2-3 thoracenteses with evaluation of cytology and cell block. Two thoracenteses will optimize yield for malignancy if they are performed adequately with high-volume specimens and careful processing.
    • Consider alternative diagnoses and send appropriate studies (listed above).
  • [#2] If nondiagnostic, next steps could include:
    • Additional imaging (e.g., CT chest/abdomen/pelvis, or PET-CT scan to evaluate for other sites of malignancy). This may identify lymph nodes or tissue masses that are biopsy targets.
    • Watchful waiting (especially if the patient is clinically well and pleural fluid LDH is decreasing on serial thoracentesis – which implies a gradual resolution of pleural inflammation). (Murray 2022)
    • Image-guided biopsy (e.g., CT-guided biopsy of an area of nodularity seen on CT scan). If there is CT evidence of pleural thickening or nodules that present a biopsy target, image-guided biopsy has the same yield as thoracoscopy (while being less invasive). (Fishman 2023)
    • VATS inspection and biopsy of the pleura.
  • Spontaneous resolution will occur in many patients with idiopathic exudative effusion without an apparent definitive diagnosis. Therefore, it is reasonable to defer further invasive evaluation if the patient is clinically stable. The optimal approach may depend on the specifics of any individual patient's situation and patient preferences.
neutrophil predominant effusion (>50%) 

Neutrophilic predominance is generally associated with acute disease processes.

causes include

  • Empyema or parapneumonic effusion.
  • TB in rare situations:
    • Early tuberculous pleural effusion.
    • Chronic tuberculous empyema.
  • Pulmonary embolism.
  • Acute pancreatitis.
  • Intra-abdominal abscess.
  • Malignant effusion.

hypoglycemic and acidotic effusions

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The same disease processes usually tend to reduce both the pH and the glucose. Low pH with normal glucose may rarely reflect a urinothorax, but more often it is due to poor collection technique or laboratory error. LDH >1,000 U/L is often seen in these disorders as well.

discussion of glucose, pH, and LDH >1000 IU/L

low pleural fluid glucose

  • Glucose is normally the same in the pleura and the blood. (31315808)
  • Hypoglycemia is defined as either:
    • Pleural fluid glucose <60 mg/dL (<3.33 mM). This may be considered as equivalent to a pH <7.20. (Folch 2023)
    • (Pleural fluid glucose)/(plasma glucose) ratio <0.5-0.6.
    • 💡 In patients with hyperglycemia, pleural hypoglycemia may be missed because the absolute glucose level falls within normal levels.

pleural fluid pH

  • How to measure pleural fluid pH:
    • Pleural fluid must be obtained in any syringe without any air bubbles or heparin, and analyzed by the laboratory STAT. 📄
    • It is not necessary to use a blood gas syringe (although a blood gas syringe is totally fine).
    • It is not necessary to transport the specimen on ice (as long as it is processed STAT).
  • Normal pleural fluid pH is ~7.60.
  • pH <7.20 is generally considered as an indication for chest tube insertion in the context of a complex parapneumonic effusion or empyema (more on this below 📖).
  • Factors which may artificially affect pleural pH:
    • Artificial elevation: air contamination in the sample.
    • Artificial reduction: contamination with heparin or lidocaine. (Folch 2023)

LDH >1,000 U/L

  • LDH >1,000 U/L tends to be associated with a similar group of processes as those with low pH and low glucose.
  • Causes of LDH >1,000 include:
    • Empyema and complex parapneumonic effusion.
    • Rheumatoid arthritis.
    • Malignant pleural effusion.
causes of acidic & hypoglycemic pleural effusions
  • (1) Fluid is usually acidic & hypoglycemic:
    • Empyema or complicated parapneumonic effusion.
    • Esophageal rupture.
    • Chronic rheumatoid pleurisy.
  • (2) Fluid may occasionally be acidic & hypoglycemic:
    • Tuberculous effusion or empyema (glucose <30 mg/dL is common in tuberculosis, but rare in carcinoma). (28185620)
    • MPE (malignant pleural effusion).
    • Lupus pleuritis.
    • Urinothorax (may cause low pH with normal glucose).

hemothorax

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definition

  • Hemothorax is defined as a pleural effusion with a hematocrit, a hemoglobin concentration, or a RBC count >50% of the corresponding value of blood.
    • If the blood RBC count isn't available: The pleural fluid red blood cell count per uL divided by 100,000 yields an estimate of the hematocrit (e.g., 2 million RBC/uL is equivalent to roughly a hematocrit of 20%). (Murray 2022; 23374395) 
  • If a hemothorax is allowed to persist over time, pleural fluid RBC levels may fall. Blood may cause inflammation, which draws fluid into the pleura, thereby diluting the RBC concentration to 25-50% of blood levels. (Folch 2023)
causes of hemothorax

traumatic

  • Blunt trauma, including CPR (especially with multiple rib fractures).
  • Penetrating trauma.

nontraumatic

  • Pneumothorax is a common cause (if there are any lung adhesions to the chest wall, tension on these adhesions may cause bleeding). (Murray 2022)
  • Aortic dissection (usually left-sided hemothorax).
  • Pulmonary arteriovenous malformation rupture.
  • Malignancy, including pleural malignancy (especially angiosarcoma, germ cell tumors, hepatocellular carcinoma, thymoma, schwannoma). (Folch 2023)
  • Intrathoracic endometriosis.

iatrogenic

  • Thoracentesis.
  • Central line or chest tube placement.
  • Lung biopsy.
clinical presentation
  • Hemorrhage into the pleural space may present similarly to pneumothorax (e.g., dyspnea, hypoxemia, shock).
  • The physiology of pneumothorax and hemothorax are similar, with the exception that a patient with hemothorax may also be suffering from intravascular volume depletion due to hemorrhage.
radiology of hemothorax

ultrasonography of hemothorax

  • The presence of clots suggests hemothorax (these are occasionally seen on ultrasonography).
  • Serial POCUS examination may be helpful to evaluate whether the hemothorax is expanding.

CT scan findings in hemothorax:

  • Effusion density of 16 Hounsfield units or greater suggests hemothorax. (Murray 2022)
  • Hematocrit sign:
    • Blood may layer out, with an interface between the cellular and liquid components.
    • Layering out requires the presence of unclotted blood – either due to active hemorrhage or coagulopathy.
management

(#1) Initial management steps

  • Coagulation should be evaluated, and any anticoagulants should be reversed (as able).
  • Chest tube insertion:
    • Indications for chest tube placement are controversial. For small and stable hemothorax (<~300 ml), observation without drainage is likely adequate. Indications for tube insertion may include: larger hemothorax, hemopneumothorax, or expansion over time.
    • Small-bore, pigtail chest tubes generally yield equivalent outcomes compared to larger bore surgical chest tubes. Especially for more stable patients, a pigtail chest tube is preferred.

(#2) Interventional management of ongoing bleeding

  • Interventional radiology: Embolization of the intercostal artery may be considered if there is suspicion or CT evidence of intercostal artery laceration.
  • Surgery: Indications may include high-volume or ongoing blood loss (>~1500 ml), or a large volume of intrathoracic clot (e.g., >~500 ml). Cutoff values are somewhat arbitrary, so when in doubt a surgical consultation should be obtained.

(#3) Removal of intrathoracic clotted blood

  • How important is it to remove intrapleural clotted blood?
    • This is controversial, requiring assessment on a patient-by-patient basis.
    • Fibrothorax or trapped lung doesn't usually result from hemothorax, even if there is retained clot within the pleura. (Murray 2022) 
    • Intrathoracic blood may cause pulmonary dysfunction, depending on the volume and anatomic location.
  • If removal of clotted blood is felt to be important, this can be achieved via the following techniques:
    • (1) Surgery, typically VATS (video-assisted thoracic surgery).
    • (2) Instillation of a thrombolytic agent via a chest tube. (31777566)
      • This may carry a risk of inciting rebleeding. Thus, intrapleural thrombolysis should generally be performed after the bleeding has settled (e.g., there is little ongoing blood output from the chest tube).
      • One approach to achieve this involves instillation of 50 mg alteplase in 100 ml saline into the chest tube, after which the tube is clamped for 1 hour. Rolling the patient during this dwell time may theoretically assist in distribution of alteplase throughout the pleura. Chest tube output and thoracic imaging should be monitored carefully. Ideally, improvement should be seen within three daily treatments of intrapleural thrombolytic therapy. (Surgicalcriticalcare.net)
complications of hemothorax
  • Empyema may occur, especially among patients with retained hemothorax (>~300 ml).
  • Pneumonia may occur among patients with traumatic hemothorax (although this may not causally be related to the hemothorax).

cholesterol effusion (pseudochylothorax)

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basics

  • Cholesterol effusion is defined by the presence of cholesterol crystals in the pleura. (Murray 2022)
  • A cholesterol effusion results from a longstanding exudative effusion (e.g., >5 years). Eventually cells lyse into the pleural space, releasing cholesterol.

causes

  • ~80% of cases are due to either:
    • Tuberculosis.
    • Rheumatoid arthritis (cholesterol effusion may precede other clinical manifestations of rheumatoid arthritis).
  • Rare causes:
    • Malignancy (e.g., lung cancer, hematologic malignancies).
    • Status post CABG surgery.
    • Bacterial empyema.
    • Trauma.
    • Parasitic infection (paragonimiasis, echinococcosis). (36338249)

clinical presentation

  • Patients are usually asymptomatic.

radiology

  • Effusion is usually unilateral.
  • Prior radiographs may reveal a chronic effusion.
  • The pleura is usually thickened, and might even be calcified.

pleural fluid analysis

  • The gross appearance is usually milky, but there may be a turbid or even “motor oil” appearance. (Murray 2022)
  • Basic labs reveal a lymphocyte-predominant exudate. (Murray 2022)
  • Cholesterol is usually >200 mg/dL (but this has only 75% sensitivity).
    • Cholesterol/triglyceride ratio >1 has higher sensitivity for cholesterol effusion. Triglyceride level can be >110 mg/dL, but the triglyceride level should be lower than the cholesterol level.
  • Cholesterol crystals may occasionally be seen.

management

  • Treat any underlying process if possible (including investigations for tuberculosis and rheumatoid arthritis, if the cause of the cholesterol effusion is unclear).
  • Chronic inflammation will often cause a trapped lung, so therapeutic thoracentesis may not be effective.

chylothorax

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clinical presentation of chylothorax

  • Chyle is bland, so it doesn't cause pleural irritation. The effusion will thus present with dyspnea.
  • Effusions due to iatrogenic thoracic duct injury will typically present within a week after injury.
radiology of chylothorax
  • 80% of effusions are unilateral, but 20% are bilateral.
    • Lesions below T6 tend to cause right-sided effusions.
    • Lesions between T4-T6 may affect either side or cause bilateral effusions.
    • Lesions above T4 tend to cause left-sided effusions.
    • (Figure showing the anatomy of the thoracic duct: 🌊)
  • A CT scan can occasionally show a reduced fluid density (but this often doesn't occur due to the protein content of the chyle).
pleural fluid analysis of chylothorax

general pleural fluid analysis

  • Appearance:
    • Classically described as milky or like a strawberry milkshake.
    • Chylothorax can also be clear (especially while a patient is fasting) or bloody.
  • Typically, a protein-discordant exudate (elevated protein levels, without LDH elevation).
    • LDH is usually normal. If LDH is elevated in a chylothorax, this suggests a coexisting inflammatory process or lymphoma. (Murray 2022)
    • Protein is usually 2-3 g/dL.
    • Transudative effusion may result from a combination of chylothorax plus another cause of a transudative effusion (e.g., cirrhosis or heart failure).
  • Cells:
    • >70-80% lymphocytes.
    • Total white blood count ranges from ~400-7,000 cells/uL.
  • pH is ~7.4-7.8.
  • Glucose is normal (similar to plasma; ~78-200 mg/dL).

interpretation of pleural fluid triglyceride level

  • >110 mg/dL (>1.24 mM)
    • This is 99% diagnostic of chylothorax.
    • 86% of chylothorax will have a triglyceride level in this range (with a mean of 750 mg/dL). (Folch 2023)
    • Other causes of elevated pleural fluid triglyceride levels:
      • Esophageal-pleural fistula, with ingestion of a substance containing triglycerides. 📖
      • Systemic hypertriglyceridemia (in whom pleural/serum ratio >1 supports chylothorax).
      • Cholesterol effusion.
  • 50-110 mg/dL (0.56 – 1.24 mM)
    • This is a gray zone. Chylothorax is less likely, but it has not been excluded.
    • Ideally, chylomicron levels could be evaluated directly (as discussed below).
    • Alternatively, consider repeating pleural fluid analysis after a fatty meal.
  • <50 mg/dL (<0.56 mM) excludes chylothorax with 95% sensitivity.

cholesterol level

  • Cholesterol may be ~60-220 mg/dL.
  • The cholesterol level should be lower than the triglyceride level (otherwise, consider the possibility of a cholesterol effusion).

chylomicron detection via lipoprotein electrophoresis

  • Theoretically, this is the gold standard test for diagnosing chylothorax.
  • Approaches to achieve this:
    • (1) Lipoprotein electrophoresis.
    • (2) Microscopy of pleural fluid stained with lipid-soluble dye (e.g., Sudan stain). (Folch 2023)
  • Unfortunately, these tests may be difficult to obtain. (26448352)
causes of chylothorax

[#1/4] lymphatic laceration

  • Iatrogenic:
    • Central line insertion.
    • Pacemaker implantation.
    • Surgical procedures near the thoracic duct (e.g., surgeries involving the esophagus, lung, neck/thyroid, heart, upper abdomen, or spine).
  • Trauma:
    • Blunt or penetrating trauma to the thorax or neck.
    • Spine fracture or hyperextension injury.
    • Posterior rib fracture.
    • Increased intrathoracic pressure (e.g., childbirth, severe coughing or emesis).

[#2/4] lymphatic obstruction

  • Extrinsic lymphatic obstruction:
    • Mediastinal mass that obstructs lymphatics, e.g.:
      • Non-Hodgkin lymphoma.
      • Lung cancer.
      • Esophageal cancer.
    • Thoracic radiotherapy. (31777567)
    • Retrosternal goiter.
    • Tuberculosis, sarcoidosis, or histoplasmosis (fibrosing mediastinitis).
  • Primary lymphatic disorders:
    • Lymphangioleiomyomatosis (LAM).
    • Yellow nail syndrome (section below).
    • Diffuse pulmonary lymphangiomatosis (section below).
    • Amyloidosis.
    • Filariasis.

[#3/4] hemodynamic alterations

  • Increased venous pressure:
    • Heart failure with systemic congestion and elevated central venous pressure, e.g.:
      • Restrictive cardiomyopathy.
      • Constrictive pericarditis.
    • SVC (superior vena cava) syndrome.
    • Subclavian thrombosis.
  • Cirrhosis (increased portal pressure may increase lymphatic flow).

[#4/4] other

  • Chylous ascites with trans-diaphragmatic movement of fluid.
  • Necrotizing pancreatitis. (28620431)
  • Idiopathic.
investigation of chylothorax
  • A contrasted CT scan of the chest +/- abdomen may be considered to exclude a mass lesion or thrombosis involving the SVC (superior vena cava).
  • Lymphangiography involves injecting Lipidol (aka Ethiodol, an oil-based contrast agent) into an inguinal lymph node or the thoracic duct. Magnetic resonance lymphangiography may be used in some centers. Discussion with the radiology department may help clarify the optimal technique at your center. Contrast agents themselves may induce an inflammatory, granulomatous reaction within the lymphatic ducts, which may promote closing the leak. (Folch 2023)
management of chylothorax

overall management strategy

  • This depends on the etiology and clinical context.
  • Whenever possible, treat any underlying disease.
  • A high-output chylothorax (>1 liter/day) may require more aggressive management, especially if this persists despite conservative management. Complications of large-volume chyle loss over time may include:
    • Hypocalcemia.
    • Hyponatremia.
    • Immunodeficiency.
    • Fat-soluble vitamin deficiency.
    • Volume depletion. (28620431)
  • Management options include various combinations of the following therapies:

[#1/4] pleural drainage

  • Either thoracentesis or chest tube may be utilized. Given the likelihood of ongoing drainage, a pigtail drain is generally preferred for a known chylothorax. (Folch 2023)
  • Ideally, drainage will be needed for only a short period of time. Prolonged drainage may cause a variety of complications:
    • Malnutrition, with hypolipidemia.
    • Hypovolemia with electrolyte abnormalities (including metabolic acidosis).
    • Immunodeficiency (due to loss of lymphocytes).
    • Malabsorption of some medications (e.g., cyclosporin A, digoxin, possibly amiodarone).

[#2/4] reduce the flow of chyle

  • Nutritional manipulations, which may include:
    • Fasting plus TPN (total parenteral nutrition). In traumatic or postoperative cases, a limited period of total parenteral nutrition may allow for healing of the thoracic duct injury.
    • Fat-free diet plus supplementation with oral medium-chain triglycerides (which are absorbed into the blood without traveling through the lymphatics).
  • Octreotide +/- midodrine might reduce chyle flow. (Midodrine: 30044748; Octreotide: 25784759)
    • Octreotide dosing is often ~150 mcg sq three times daily. (25784759, de Moraes 2024)

[#3/4] procedures to repair or ligate the thoracic duct

  • Ideally, via interventional radiology (or less optimally, via surgery).
  • Thoracic duct embolization may have a success rate of up to 90% for traumatic chylothorax or 50% for nontraumatic chylothorax. (Fishman 2023) Complications may include lower extremity swelling or chronic diarrhea. (31777567)
  • VATS surgery may be utilized to close the fistula from within the pleura in a relatively noninvasive fashion. Pleurodesis may also be performed during this procedure to improve the likelihood of success further.
  • Lymphangiography itself may have a therapeutic effect (discussed above in the section on radiology).

[#4/4] pleurodesis

  • This may be used to obliterate the pleural space entirely.
  • Pleurodesis may be an option where other treatments are unavailable (e.g., the patient is a poor surgical candidate).
  • Pleurodesis may be best suited for managing a low-output chylous effusion (because a high-output effusion will reduce the likelihood of successful pleurodesis). (Folch 2023) If pleurodesis is performed, success may be optimized by combining it with the modalities described above to temporarily reduce chyle flow. 
  • Further discussion of pleurodesis: 📖
related topic – chyloptysis

clinical presentation

  • Expectoration of milky-white sputum.
  • Often associated with chylous pleural effusion (but not always). (33160542)

diagnosis

  • Chyloptysis may be diagnosed based on the presence of triglycerides in sputum. (33160542)

causes & investigation

  • May be caused by disorders which cause obstruction of lymphatic ducts.
  • See the list of causes of lymphatic obstruction above.
  • Investigation is similar to the investigation of chylothorax, as discussed above.

yellow nail syndrome

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basics

  • Yellow nail syndrome is an idiopathic syndrome, of unclear etiology.

epidemiology

  • Range of onset varies widely, usually manifesting in middle or older age. (27157230)
  • May be associated with:
    • Thyroid disease (including thyroiditis, thyroid enlargement, and hypothyroidism).
    • Connective tissue diseases, including rheumatoid arthritis. (34488967)

clinical presentation

  • Yellow nail syndrome is often described as a triad (#1-3 below), but it may be more useful to consider a pentad of the most common features: (31149856)
  • #1: Yellow or green nails (90% of patients)
    • Nails may be thickened, slow growing, dystrophic, friable, and/or separate from the nail bed (onycholysis). (31149856; 27157230)
    • Ask patients if they are wearing nail polish.
  • #2: Lymphedema (80% of patients)
    • Edema is typically nonpitting. (34488967)
    • This primarily involves the legs, but may also affect fingers, eyelids, or breasts.
    • Lymphedema may cause recurrent cellulitis.
  • #3: Pleural effusion in ~1/3 of patients:
    • Usually bilateral. (27157230)
    • Varies from small to massive.
  • #4: Bronchiectasis in about half of patients:
    • Chronic bronchitis, chronic cough.
    • Recurrent pneumonia.
  • #5: Chronic sinusitis in ~60% of patients. (31149856)
  • Other potential manifestations:
    • Protein-wasting enteropathy with hypoalbuminemia. (34488967)
    • Other sites of fluid accumulation: Ascites, pericardial effusion. (27157230)

radiology

  • Pleural effusion:
    • Effusion is variable in size, but often bilateral and small-to-moderate.
    • Effusions may be chronic over months or years.
  • Bronchiectasis may be seen.
  • Lymphangiography results are mixed. Some patients are found to have hypoplasia, dilations, and collateral lymphatic networks. However, other patients with yellow nail syndrome seem to have normal lymphatic anatomy. (34488967)

pleural fluid analysis

  • Fluid may appear straw-colored or milky/chylous. (34488967)
  • (1) About one third are chylous.
  • (2) Most effusions are non-chylous.
    • These are usually protein-discordant exudates (isolated elevation of protein level).
    • They are usually lymphocyte-predominant.

management

  • There is no specific therapy. The disease tends to follow a relapsing-and-remitting course, with the potential for spontaneous improvements.
  • Chylous pleural effusion(s):
    • Some aspects of chylothorax management may be relevant (e.g., nutritional shifts towards mixed-chain fatty acids). This is discussed further above. 📖
    • Pleurodesis may be considered for refractory, symptomatic effusion.
  • Bronchiectasis, if present, should be treated as described in the chapter on non-CF bronchiectasis. 📖
  • Lymphedema may be managed with high-pressure elastic stockings.

diffuse pulmonary lymphangiomatosis (DPL)

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basics

  • Diffuse pulmonary lymphangiomatosis (DPL) is a developmental lymphatic abnormality causing a proliferation of complex anastomosing lymphatic channels that expand the typical lymphatic routes within the chest. (33160542)

epidemiology

  • Usually presents in late childhood, but is reported in patients up to 80 years old. (33160542)

clinical presentation

  • Chyloptysis and/or chylothorax may occur.

radiology

  • Chest imaging can be normal.
  • Pleural effusion may be seen.
  • Parenchymal lymphatic congestion may cause a combination of ground-glass opacities (GGO) and septal thickening (crazy paving) that closely resembles pulmonary alveolar proteinosis.

management

  • There is no specific therapy.
  • A diet low in cholesterol and long-chain triglycerides is a safe and conservative initial management. (33160542)

empyema and complex parapneumonic effusion

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definitions

  • Uncomplicated parapneumonic effusion: A simple effusion associated with pneumonia that will resolve without chest tube drainage.
  • Complicated parapneumonic effusion: An infected effusion that requires chest tube drainage to resolve. However, in many cases, bacterial culture and Gram stain may be negative (so the infection is presumed to have involved the pleural space).
    • The clinical criteria used to differentiate uncomplicated vs. complicated parapneumonic effusions are discussed further below. 📖
  • Empyema: Pleural fluid is grossly purulent. Empyema usually arises from adjacent pneumonia (such cases represent a subset of complicated parapneumonic effusions). However, empyema may arise de novo without adjacent pneumonia (e.g., due to hematogenous bacterial translocation of oral anaerobes directly into the pleura).
  • 💡 There is tremendous confusion regarding exactly how to define empyema. In clinical practice, the terms “empyema” and “complicated parapneumonic effusion” are often interchangeable. The treatment is essentially the same – so the precise terminology isn't very important.
epidemiology of empyema and complex parapneumonic effusion

epidemiology of effusions complicating pneumonia

  • ~30% of pneumonia patients develop uncomplicated parapneumonic effusion.
  • ~3% of pneumonia patients develop complicated parapneumonic effusion.

causes of pleural space infection include:

  • Bronchopulmonary source: (20511475)
    • Pneumonia.
    • Aspiration.
    • Adjacent lung abscess.
    • Bronchopleural fistula.
    • Bronchiectasis.
    • Endobronchial obstruction (e.g., malignancy or foreign body).
  • Esophageal perforation.
  • Extension from mediastinal, deep neck-space infection, vertebral osteomyelitis, or infra-diaphragmatic sepsis.
  • Hematogenous seeding of infection.
  • Iatrogenic (e.g., pleural instrumentation, thoracic surgery).
clinical presentation
  • Empyema may cause dyspnea, pleuritic chest pain, and constitutional symptoms (e.g., fevers and night sweats).
    • (Note that empyema by itself usually does not cause septic shock.)
  • Complex parapneumonic effusions often result from underlying pneumonia. In this situation, the underlying pneumonia often dominates the initial presentation. Development of an effusion may be difficult to discern (because the patient already has hypoxemia, fever, and dyspnea).
radiology of empyema & complex parapneumonic effusion

thoracic ultrasonography

  • POCUS is a front-line evaluation to determine effusion size and loculation.
  • Ultrasonography is more sensitive than CT scan for revealing internal septations.

role of CT scan in empyema

  • Role for CT scan:
    • (1) Confirm diagnosis of empyema.
    • (2) Evaluate for an underlying cause of the empyema (e.g., esophageal perforation, peripheral lung abscess, bronchial obstruction).
    • (3) Evaluate for complications of empyema (e.g., chest wall involvement with empyema necessitans).
  • CT scan may be protocoled with pleural-phase contrast (scanning 60-90 seconds after injection of contrast). (Folch 2023)

CT scan findings in empyema

  • Size: Empyemas are often large, and generally expand over time without therapy.
  • Loculation is usually seen.
  • Contrast enhancement on a pleural-phase contrast CT scan should always be seen. (Murray 2022) 
  • Pleural thickening is seen in ~90% of patients. (Walker 2019)
  • Split pleura sign: Visceral and parietal pleura split apart at the acute edge of a lenticular (lens-shaped) pleural effusion. The visceral and parietal pleura should be thickened. Contrast enhancement may accentuate the split-pleural sign, but it is not necessarily required to see this sign. A classic appearance of the split pleura sign strongly supports the presence of empyema. (Shepard 2019) However, other causes of pleural thickening 📖 may also cause a split pleura sign (e.g., long-standing rheumatoid pleural effusion). (Folch 2023)
  • Increased attenuation of extra-pleural fat (>2 mm) adjacent to the fluid may be seen. (Folch 2023; 37433578) 
  • Lymphadenopathy may occur in ~40% of patients, but this is generally not dramatic (i.e., <2 cm). (Walker 2019; Folch 2023) 

lung abscess versus empyema

  • Lung abscess that abuts the pleura may be confused with empyema. Some characteristics that may help sort these entities out are listed below. However, it is possible for these two pathologies to occasionally coexist simultaneously (e.g., a lung abscess ruptures into the pleural space, leading to empyema formation).
  • Shape and configuration:
    • Lung abscess is often spherical. The abscess may have a narrow contact with the chest wall.
    • Empyema is typically lenticular (lens-shaped). Empyema usually has broad contact with the chest wall.
  • Walls:
    • Abscess usually has thick, irregular walls.
    • Empyema may have a thinner and more uniform wall.
  • Interaction with lung tissue:
    • Lung abscess may replace lung tissue. Thus, the boundary between the abscess and the lung may be indistinct. Furthermore, the abscess doesn't compress lung tissue.
    • Empyema has a distinct boundary with adjacent lung. Adjacent lung tissue is compressed (which may cause bronchovascular structures to be draped around the empyema).
pleural fluid analysis & clinical definition of a complicated parapneumonic effusion

Several criteria are used to predict the need for chest tube drainage (which clinically defines a complex parapneumonic effusion).

(1) pH and glucose are often considered as the primary indicators for chest tube drainage

  • pH:
    • pH is generally felt to be the strongest predictor of requiring chest tube drainage. However, pH must be measured properly (discussed above ⚡️). If the pH isn't consistent with other pleural fluid parameters such as glucose and LDH, the validity of the pH level should be questioned.
    • pH <7.20 indicates a high risk of complex parapneumonic effusion. This is generally regarded as an indication for chest tube insertion.
    • pH >7.38 indicates a very low risk of complex parapneumonic effusion. (37433578)
    • pH between 7.21-7.38: complicated parapneumonic effusion is less likely, but it remains possible. British Thoracic Society guidelines recommend chest tube placement in this situation if other parameters are worrisome (especially LDH >900 IU/L). (37433578)
  • glucose:
    • Glucose should generally track in parallel with pH.
    • If pH wasn't measured, glucose levels may be used as a surrogate measurement instead of pH.
    • Glucose <~60 mg/dL (<~3.3 mM) is an indication for chest tube insertion if pH wasn't measured. (BTS guidelines; 37433578)
    • Glucose <72 mg/dL (<4 mM) may support the insertion of a chest tube if the pH is between 7.21-7.28 and the LDH is >900 mg/dL. (37433578)
  • ⚠️ Not all acidic/hypoglycemic effusions are due to bacterial infection. The differential diagnosis of hypoglycemic and acidic effusions is here: ⚡️

(2) ancillary indicators that support drainage:

  • Especially in cases where the pH and glucose values are borderline or discordant with one another, additional indices should be considered that may suggest the need for chest tube insertion:
  • LDH > 900 IU/L. (37433578)
  • Fluid is grossly purulent.
  • Gram stain and/or culture is positive for bacteria.
  • Radiographic features: (37433578)
    • Effusion size:
      • Larger effusion supports the benefit of drainage.
      • Depth <2 cm on a CT scan was 97% predictive of not requiring intervention in one series. (20029043)
      • Serial imaging that shows a rapidly expanding effusion supports the need for drainage.
    • CT or POCUS reveals loculations.
    • Pleural contrast enhancement on CT scan.
OVERVIEW OF DIAGNOSIS & TREATMENT FOR EMPYEMA/COMPLEX PARAPNEUMONIC EFFUSION

Treatment and diagnosis generally occur simultaneously. For example, POCUS plus chest radiography usually allows us to immediately suspect that an effusion will be a complex parapneumonic effusion or empyema. In this situation, immediate insertion of a pigtail chest tube serves both diagnostic and therapeutic purposes. Despite the scramble to achieve chest tube drainage, an organized approach is still essential:

diagnostic evaluation

  • (1) Radiology:
    • POCUS is a front-line study that may help with rapid triage and decisions for immediate drainage.
    • CT scan is generally obtained early in the hospital course (either initially or following chest tube insertion and drainage).
  • (2) Pleural fluid analysis:
    • Standard studies should be sent. ⚡️
    • 💡 Inoculation of blood culture bottles at the bedside increases the diagnostic yield from 40% to 60%. (21459855; Folch 2023)
  • (3) Basic laboratory studies:
    • Blood cultures (15% yield, including cases where pleural fluid is sterile). (Folch 2023)
    • Sputum Gram stain & culture (if concomitant pneumonia).
    • Urine pneumococcal antigen.
    • CRP (C-reactive protein):
      • (i) Diagnosis: CRP has been demonstrated to outperform procalcitonin for the diagnosis of empyema. (26449328) One study found that among patients with community-acquired pneumonia, 97.8% of patients who had empyema or complex parapneumonic effusion had a CRP >100 mg/L. (19131449) 
      • (ii) Therapy: Baseline CRP may help track the response to treatment over time and determine the appropriate duration of antibiotic therapy (discussed further in the section below).
    • Albumin should be checked to help prognosticate (RAPID score below).
  • (4) Prognosticate with the RAPID score ⚡️: Anyone with a RAPID score of 3 or higher should be taken extremely seriously, as they have a very high mortality. This may imply a lower threshold to obtain definitive CT imaging, repeat imaging early, and early surgical consultation.

management

  • (1) Drainage:
    • Insertion of a pigtail chest tube within <24 hours is usually front-line therapy.
    • Immediate initiation of pleural lytic therapy with tPA/DNAse is often pursued (unless the effusion immediately drains out completely).
    • Re-evaluate after 24-48 hours and consider more aggressive treatment if necessary (e.g., additional drains or surgical decortication).
  • (2) Antibiotic.
  • (3) Treatment of any underlying cause of the empyema (e.g., endobronchial obstruction).
  • (4) Prevent worsening deconditioning and malnutrition. Patients are often frail and hospitalization for an empyema may be prolonged.
    • Aggressive nutritional support (avoid unnecessary NPO orders).
    • Physical therapy.
[1/2] treatment: interventional management

chest tube insertion

  • Current guidelines recommend drainage within <24 hours. (Folch 2023) It's important to understand why prompt drainage is important for empyema and complex parapneumonic effusions: 
    • A common misconception is that drainage of empyema is needed to prevent septic shock. In actuality, the pleura functions to contain infection – so empyema rarely causes septic shock.
    • The reason to promptly drain these effusions it that over time they become more densely loculated and harder to drain. Initially, there is a window of time when they can be drained easily. If these effusions are allowed to fester, then they become more densely loculated – potentially requiring surgical decortication to fully resolve.
  • In most cases, drainage will begin with placement of a pigtail chest drain.

intrapleural fibrinolytics

  • The MIST2 trial demonstrated that the combination of intrapleural tissue plasminogen activator (tPA) plus DNase reduced surgical referral and hospital length of stay. (21830966) Subsequent studies have supported the use of tPA/DNase. This has led many centers to adopt prompt tPA/DNase administration following pigtail chest tube insertion.
  • Dose and duration of therapy
    • The MIST2 trial involved administering tPA 10 mg plus DNase 5 mg administered intrapleurally twice daily (total treatment course of six doses over three days).
    • Some patients will respond robustly to 1-2 doses, with near complete effusion drainage. In that case, ongoing tPA/DNAse administration may be unnecessary.
  • Pleural bleeding following lytic therapy:
    • This occurs in 2-3% of patients and is generally not severe. However, it may interfere with ongoing lytic therapy.
    • Risk factors for bleeding include anticoagulation, uremia, and thrombocytopenia (<100 b/L).
    • For patients at above-average risk of bleeding, consider holding or dose-reducing systemic anticoagulation during intrapleural lytic therapy. (36229045)
  • Contraindications to intrapleural fibrinolytics may include: (36229045)
    • Major hemorrhage or trauma.
    • Major surgery in the previous five days.
    • Prior pneumonectomy on the infected side.
    • Severe coagulopathy, severe renal disease, anticoagulation therapy, severe liver disease.
    • Bronchopleural fistula.
  • 💡 If TPA/DNase is contraindicated, consider the use of saline flushes or irrigation as discussed below.

intrapleural saline flushes or irrigation

  • If thrombolytics aren't utilized, instillation of 30 ml saline q6hr into the chest tube is generally recommended to help maintain the patency of small-bore chest tubes. (20696693) Without irrigation, small-bore tubes often obstruct over a period of days.
  • A recent randomized controlled pilot trial demonstrated that chest tube irrigation with 250 ml of normal saline three times daily was superior to the use of smaller volume flushes. (26022948) This trial requires replication in a larger study. It raises an intriguing possibility that tPA/DNase may be useful primarily due to the volume of fluid infused, rather than any chemical properties of tPA/DNase.

determining response to therapy

  • Chest tube drainage usually won't achieve immediate and complete resolution. Especially on CT scan, some small pockets of pleural fluid often persist following drainage. Radiological improvement can lag behind clinical improvement.
  • If the patient is improving clinically and residual pleural fluid volume is low/moderate, then no additional procedures may be needed.
  • CRP may also be used to determine response to therapy (discussed further in the section below regarding duration of antibiotic therapy).

interventional management of refractory empyema

  • If tube drainage fails to be effective after 48 hours, surgical consultation should be obtained. Treatment options include either the placement of additional chest drains, or surgical decortication.
  • The precise indication for surgery is unclear.
    • Residual pleural thickening and fluid collections will often resolve over time, with ongoing antibiotic therapy. (Murray 2022) Thus, surgery shouldn't be required for these reasons. However, surgical decortication may reduce the hospital length of stay, by achieving definitive control of larger effusions.
    • Sepsis that is refractory to chest tube drainage is technically an indication for surgery (with a goal of definitive source control). However, it is extremely uncommon that empyema would actually cause sepsis.
[2/2] treatment: antibiotics 

antibiotic selection in community-acquired empyema

  • An empyema should be treated with antibiotics that provide coverage for anaerobic and aerobic bacteria. Atypical coverage is generally unnecessary. (Folch 2023)
  • The most common causes of community-acquired empyema are gram-positive bacteria and anaerobes: (15745977)
    • 24% Streptococcus anginosus group (formerly Streptococcus milleri group).
    • 21% Streptococcus pneumoniae.
    • 20% Anaerobes.
    • 10% Staphylococcus aureus.
    • 8% Enterobacteriaceae.
  • Anaerobes are difficult to culture and often coexist with aerobic pathogens, so anaerobic coverage should generally be continued, even if an aerobic pathogen has been isolated. An exception to this is Streptococcus pneumoniae, which is not known to coexist with anaerobes. (ERS handbook 3rd ed.)
  • Potential regimens: (36229045)
    • Ampicillin-sulbactam is generally a good choice (which may be easily transitioned to oral amoxicillin/clavulanic acid).
    • Ceftriaxone + {metronidazole or clindamycin} is an alternative.
    • Moxifloxacin has the advantage of being a single agent, but it has neuromuscular toxicities associated with fluoroquinolones.

antibiotic selection in hospital-acquired empyema

  • Initial treatment may require coverage of MRSA and hospital-acquired gram-negative organisms.
  • Potential initial regimens could include: (36229045)
    • {Piperacillin-tazobactam or meropenem} plus linezolid.
    • Cefepime + {metronidazole or clindamycin} + vancomycin.
  • Specifics will depend on local antibiograms and details of the patient's history.
  • Antibiotics may be adjusted based on culture data and MRSA nares PCR results.

antibiotic duration

  • Duration of therapy is not well known. Treatment is generally extrapolated from that of lung abscess, which is probably inappropriate (since lung abscess involves nonviable necrotic tissue, whereas empyema does not). It's probable that this has promoted unnecessarily long durations of antibiotic therapy for empyema.
  • General consensus is that treatment should last between 2-6 weeks. (37433578) Duration may be personalized based on clinical, biochemical, and radiological response (e.g., the success of therapeutic drainage and whether there was viscous, purulent material). (36229045)
  • The ODAPE trial of two-week versus three-week therapy was stopped prematurely due to under-recruitment. It did, however, suggest that two weeks of treatment may be adequate. (36229045)
  • CRP (C-reactive protein levels) 📖 appears to be sufficient as a biochemical marker of treatment response.
    • Failure for CRP to fall by >50% suggests treatment failure. (ERS 2023; 36229045) 
    • If CRP falls by >50% and also reaches a level <100 mg/L, this supports an adequate response to therapy. (Murray 2022)
  • Radiological improvement is generally delayed, so treatment duration should be largely based on clinical improvement and CRP levels. (36229045)
prognosis with the RAPID score

calculation of the RAPID score 🧮

  • BUN
    • <14 mg/dL (5 mM) = 0 points.
    • 14-23 mg/dL (5-8 mM) = 1 point.
    • >23 mg/dL (>8 mM) = 2 points.
  • Age:
    • <50 = 0 points.
    • 50-70 = 1 point.
    • >70 = 2 points.
  • Purulent pleural fluid:
    • Yes: 0 points.
    • No: 1 point.
  • Infection source:
    • Community-acquired: 0 points.
    • Hospital-acquired: 1 point.
  • Albumin:
    • ≧ 2.7 g/dL = 0 points.
    • <2.7 g/dL = 1 point.

interpretation of the RAPID score

  • 0-2 = Low risk (1.5% 3-month mortality).
  • 3-4 = Medium risk (9-18% 3-month mortality).
  • 5-7 = High risk (30-48% 3-month mortality).

tuberculous pleural effusion

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basics

  • Timing of effusion in the context of overall TB infection:
    • Effusion most commonly occurs ~3-6 months after initial exposure as a component of primary tuberculosis. About 25% of patients may develop pleural effusion, typically ~3-4 months after developing skin reactivity to tuberculosis (PPD conversion). Without treatment, 65% of these patients will experience disease reactivation within five years. (ERS handbook 3rd ed.)
    • Effusion can also accompany postprimary tuberculosis (in ~15% of cases). In the United States, effusion due to TB is more likely to be due to reactivation.
  • The pathophysiology involves the rupture of a subpleural infectious focus into the pleural space, leading to a robust cell-mediated immune response. Few tuberculosis bacilli are present, with the effusion being largely driven by an inflammatory phenomenon.
  • Like other forms of extrapulmonary tuberculosis, tuberculous pleural effusion is more common among patients with immunocompromise (especially HIV).
clinical findings
  • Patients usually have an acute or subacute illness with:
    • Ipsilateral pleuritic chest pain.
    • Dry cough.
    • Constitutional symptoms (e.g., fever, night sweats, weight loss).
  • The natural course of the effusion is to resorb and disappear gradually. (28185620)
chest imaging

effusion

  • The location is almost always unilateral, typically ipsilateral to any parenchymal infiltrate.
    • Bilateral effusions are seen in only 3% of tuberculous pleuritis. (Folch 2023) Bilateral effusions in tuberculosis usually imply miliary spread or some alternative etiology. (28185620)
  • The effusion is usually small to moderate in size, but large effusions causing dyspnea can occur.
  • Visceral and parietal pleura are uniformly thickened during active infection. (34774172)
  • On ultrasound, the effusion is usually highly complex with internal septations. In the context of a lymphocyte-predominant effusion, complex septations predict the presence of tuberculosis. (37433578)

parenchymal infiltrate

  • Chest radiographs may show an infiltrate in ~1/3 of patients.
  • A CT scan may reveal an infiltrate consistent with active pulmonary TB in ~75% of patients.
  • Parenchymal infiltrates may be appreciated only after draining the effusion. (34774172)
diagnostic studies

basic pleural fluid analysis

  • Fluid is usually straw-colored, but it may be slightly bloody.
  • The fluid is exudative:
    • Protein levels are generally quite elevated (averaging 5-6 mg/dL, and almost invariably >3 mg/dL). (Folch 2023, de Moraes 2024) In general, pleural fluid protein >4-5 g/dL suggests tuberculous pleuritis. (Murray 2022; Fishman 2023) 
    • Lactate dehydrogenase is elevated (with mean values of 734-1184 U/L). (Folch 2023)
  • Glucose and pH may be low 📖, but usually are not.
  • Cellular analysis:
    • Leukocyte count usually ranges from 1,000-6,000 cells/mm. (36273933)
    • 90% of patients may have a lymphocyte-predominant effusion (with up to >90% lymphocytes).
    • Up to 10% of effusions may be neutrophil-predominant (especially early on, within a few days of an acute presentation).
    • The differential cell count usually doesn't include mesothelial cells or shows <5%. (28185620; 26449328) Eosinophilic pleural effusion may rarely occur. (34022019)

pleural fluid ADA (adenosine deaminase)

  • ADA is found in monocytes, macrophages, lymphocytes, and neutrophils. It has good performance for pleural tuberculosis.
  • Sensitivity (~90% using 40 IU/L cutoff; ~95% using 30 IU/L cutoff): (34774172)
    • ADA <40 IU/L generally excludes tuberculous pleuritis (especially if the effusion is lymphocytic). (Fishman 2023) 
    • Causes of false-negative ADA:
      • Early pleural TB. (26449328)
      • Impaired cell-mediated immunity (e.g., HIV, aging). (Murray 2022)
  • Specificity:
    • Causes of ADA elevation:
      • Tuberculosis (>90%).
      • Empyema or complex parapneumonic effusions (60%).
      • Rheumatoid arthritis.
      • Lymphoma (~15%).
      • IgG4-related disease.
    • ADA >40 IU/L is ~90% specific for tuberculosis.
    • Elevated ADA plus lymphocyte predominance increases the specificity for TB (>95%).
    • If rheumatoid arthritis or empyema is unlikely, an elevated ADA level supports the diagnosis of tuberculous pleural effusion more robustly.
    • If ADA is extremely high (>250 U/L), empyema or lymphoma is more likely than tuberculosis. (23374395)
  • LDH/ADA ratio:
    • Various studies have used cutoff values ranging from 10-16.
    • A low LDH/ADA ratio (<10-16) favors tuberculosis, whereas a high LDH/ADA ratio (>10-16) favors an alternative diagnosis (e.g., malignancy). (34774172)

microbiological analyses 

  • Sputum AFB smear is positive in roughly ~20% of patients. Induced sputum may be positive even in patients without apparent parenchymal lung disease. (Murray 2022)
  • Pleural fluid:
    • AFB smear yield is low (~5%).
    • PCR has a sensitivity of ~40% and a specificity of ~98%. (34774172)
    • Culture yield may be ~50%. (28185620)

systemic tests for tuberculosis

  • Since the pathophysiology of a tuberculous pleural effusion involves a delayed-type hypersensitivity reaction to TB, evaluation of the systemic immune response to TB makes sense.
  • Interferon-gamma release assays have ~85% sensitivity and ~85% specificity for pleural tuberculosis. (34774172)
  • Tuberculin skin test:
    • The vast majority of HIV-negative patients with tuberculous effusion have a positive skin test, but only 41% of HIV-positive patients have a positive skin test. (Folch 2023)
    • If the skin test yields >10 mm of induration, effusions should be presumed to be tuberculous until proven otherwise. (28185620)

pleural biopsy

  • Pleural biopsy has a yield of ~85% (especially if tissue is sent for TB PCR and culture). (34774172)
    • Histology showing granulomas may support the diagnosis of tuberculosis.
    • Positive culture may provide definitive diagnosis and sensitivities.
  • Given the invasiveness of this procedure, biopsy should be applied only to patients selected based on less invasive testing (e.g., ADA, interferon-gamma release assays).
management & prognosis

management

  • Treatment is similar to the management of active pulmonary tuberculosis. Unfortunately, culture yield is relatively low, so in some cases, antibiotic selection may need to be empiric.
  • Chest tube drainage is rarely needed.

prognosis

  • If untreated, slow resolution usually occurs. This can be falsely reassuring. Unfortunately, such patients are at very high risk (~65%) of developing postprimary tuberculosis within the next five years. (Fishman 2023)
  • Residual pleural thickening may cause trapped lung.

chronic tuberculous empyema

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basics

  • Chronic tuberculous empyema is a rare entity that is distinct from tuberculous pleural effusion. It reflects a chronic, active infection in the pleural space. It occurs due to inability of the immune system to resist the infection.
  • Chronic tuberculous empyema usually occurs in the context of progressive, extensive parenchymal infection with cavitation. (28185620)

clinical features

  • This is a chronic process with few symptoms (marked thickening of the pleura contains bacilli within the empyema cavity). It may present in various ways:
  • [1] Incidental detection on chest imaging.
  • [2] Bronchopleural fistula development:
    • Empyema erodes into the lung.
    • This may cause acute fever, dyspnea, and copious mucopurulent sputum production.
  • [3] Empyema necessitans:
    • Empyema may erode into the skin, with subsequent purulent drainage.
    • Other sites of potential invasion may include the esophagus, vertebral column, or pericardium.

chest imaging

  • (1) Effusion:
    • Effusion is usually moderate to large in size.
    • There is usually loculation, along with a thick and often calcified rind.
    • Erosion of the empyema into the chest wall (empyema necessitans) may cause soft tissue edema. The communicating fistula itself is usually too small to see.
  • (2) Pulmonary parenchymal disease is usually evident as well.

pleural fluid analysis

  • Pleural fluid is exudative, typically with LDH >1,000 IU/L and protein >5 g/dL.
  • Usually pH is <7.2 and glucose is <20 mg/dL.
  • Cellular analysis:
    • Nucleated cell counts are high (e.g., >100,000/uL).
    • Nearly all cells are lymphocytes. (Murray 2022)
  • AFB smear of the pleural fluid is usually positive.

management

  • The usual antibiotic therapy is necessary, but probably insufficient. Antibiotics may penetrate the pleura poorly, leading to the development of antimicrobial resistance.
  • Chest tube or surgical decortication is needed to manage the empyema. This may be challenging because, due to the chronicity of the empyema, there is often trapped lung.

malignant pleural effusion

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epidemiology

general epidemiology of malignant pleural effusions

  • Malignant pleural effusion is one of the most common causes of pleural effusions.
  • Malignancy is especially likely among patients with:
    • Older age.
    • There is no other obvious etiology.
    • Low risk of tuberculosis.
    • Massive effusion.

causative malignancies: 

  • Lung (~35%):
    • Especially adenocarcinoma (often peripheral, invades vasculature).
    • Usually ipsilateral to the tumor.
    • ♂ Lung cancer is the most common cause of malignant effusion in men.
  • Breast (15%):
    • Breast cancer causes an effusion in ~50% of patients eventually.
    • Breast cancer is generally diagnosed prior to the development of malignant effusion.
    • Effusion is usually ipsilateral to the tumor (although bilateral effusion may result from hepatic involvement and hematogenous dissemination).
    • ♀ Breast cancer is the most common cause of malignant effusion in women.
  • Lymphoma (10%):
    • Effusion is common in both Hodgkin and non-Hodgkin lymphomas.
    • Imaging may also reveal mediastinal lymph node involvement. (Shah 2019)
  • Genitourinary (10%; includes ovarian cancer).
  • Gastrointestinal (10%; includes pancreas, gastric).
  • Other (15%)
    • Sarcoma.
    • Melanoma.
    • Seminoma.
    • Thymoma.
    • Metastatic cancer of unknown primary (10%). (Murray 2022; 12728148, 27876589)
symptoms
  • Dyspnea is the most common symptom.
  • A dry cough may occur.
  • Chest pain may reflect invasion of the parietal pleura +/- chest wall.
  • Constitutional symptoms (e.g., weight loss) suggest more advanced malignancy.
radiology

chest radiograph

  • Typical appearance:
    • (1) Unilateral in 85% (often ipsilateral to a primary lung or breast cancer). (Fishman 2023; 23374395)
    • (2) Moderate to massive in size. Massive effusion suggests malignancy, but there are numerous other causes of massive effusion (listed here: ⚡️).
    • (3) Non-loculated.
  • If a massive effusion occurs without a contralateral shift of the mediastinum, this suggests a more complex process. Possibilities include:
    • (a) Central bronchial obstruction causing secondary atelectasis, with a resultant effusion.
    • (b) Fixed mediastinum caused by cancer and/or lymph nodes.
    • 💡 Massive effusion without mediastinal shifting suggests that fluid drainage may not entirely re-inflate the lung.

ultrasonography

  • If seen, the following features are highly suggestive of malignancy: (Fishman 2023)
  • 🚩 Parietal pleural thickening >1 cm.
  • 🚩 Nodular pleural thickening.
  • 🚩 Diaphragmatic nodularity or thickening >7 mm.

CT scan

  • Red flags that suggest malignant effusion (including mesothelioma) are listed below. Unfortunately, about half of malignant effusions have no concerning features on CT scans. (Walker 2019)
  • 🚩 Nodular pleural thickening.
  • 🚩 Parietal pleural thickening >1 cm.
  • 🚩 Mediastinal pleural thickening/involvement.
  • 🚩 Circumferential pleural thickening. (2106209) 

PET scan

  • PET scan could have several benefits, especially for patients who are reluctant to undergo pleural biopsy.
  • (1) Detection of pleural malignancy:
    • Nodular or focal thickening with increased activity suggests malignancy.
    • Sensitivity and specificity are fair (in the 85% range). (Folch 2023)
  • (2) Detection of malignancy elsewhere in the body: PET scan may reveal an unexpected primary tumor elsewhere in the body.
  • (3) Guidance of biopsy site: areas of high PET activity would be expected to have a higher yield on biopsy.
pleural fluid analysis

pleural fluid analysis

  • Exudative in >95% of cases.
    • Transudates may reflect a paramalignant effusion (discussed further below).
  • Gross appearance:
    • Effusions may be serosanguinous in about half of cases. Malignancy causes about half of serosanguinous effusions. (Murray 2022)
    • Serosanguinous appearance usually indicates tumor involvement of the pleura. (Folch 2023)
  • Cell count & differential:
    • Total nucleated cell count is often <5,000/uL. (Folch 2023) 
    • Lymphocytes usually account for 50-80% of the leukocytes. >80% lymphocytes may occur in lymphomatous effusion, but this overall suggests a different range of diagnoses: 📖
    • Eosinophilia (>10%) is commonly seen. 📖
  • Acidic/hypoglycemic chemistry profile: 📖
    • A third of malignant effusions have pH <7.3 and/or glucose <60 mg/dL.
    • Clinically, this implies:
      • Extensive burden of cancer cells in the pleura.
      • Higher diagnostic yield from cytology.
      • Reduced success rate of pleurodesis. (Folch 2023)
  • Pleural fluid amylase: 📖
    • 10% of malignant pleural effusions have elevated amylase (defined as above the upper limit of normal for serum amylase level). Elevation of amylase level is usually only mild.
    • Elevated amylase is most often seen with lung or ovarian cancer. (Folch 2023)
    • Elevation reflects salivary amylase, so pleural fluid lipase levels should be normal.
    • Given its low sensitivity, amylase shouldn't be routinely measured as a component of investigating suspected malignant pleural effusion. (Folch 2023)

cytology performance overall

  • Average diagnostic yield from successive thoracenteses:
    • 1st thoracentesis has a sensitivity of ~60%.
    • 2nd thoracentesis increases the total sensitivity by ~20%. (33714593) 
    • 3rd thoracentesis doesn't improve sensitivity much (~5%). However, if the initial two procedures weren't performed with adequate volume and laboratory attention to the possibility of malignancy, then a third thoracentesis could have a higher yield. (26449328)
  • Yield depends on the type of malignancy: (Folch 2023; 30262573)
    • Ovarian cancer: ~90% sensitivity.
    • Lung adenocarcinoma: ~80% sensitivity.
    • Breast & gastrointestinal carcinomas: ~70% sensitivity.
    • Small cell lung cancer: ~50% sensitivity.
    • Hematologic malignancy: ~40% sensitivity.
    • Squamous cell lung cancer: ~30% sensitivity.
    • Mesothelioma: ~10% sensitivity.
  • 💡 Yield may be improved by removing larger volumes of fluid (at least 50-75 ml) and communicating with the laboratory about the suspicion of malignancy.

cell block

  • Centrifugation of the pleural fluid may yield a cell-rich pellet that is processed similarly to a histology specimen. (Folch 2023)
  • Cell blocks may often allow for immunohistochemical and molecular analysis. (Folch 2023) 
  • Performing both liquid-based cytology slides plus a cell block may increase diagnostic yield. (Folch 2023)

flow cytometry should be checked if:

  • Clinical suspicion of hematological malignancy.
  • Known history of lymphoma or multiple myeloma.
  • Lymphocytic effusion of unknown etiology.

biomarkers

  • Pleural biomarkers for malignancy include CEA, CYFRA 21-1, CA 19-9, CA 15-3, CA 125, and CA 72-4.
  • The sensitivity of any individual biomarker for malignant effusion is generally low (e.g., ~25-50%), but specificity is often high (>90%). (Folch 2023)
  • Role in clinical practice?
    • Biomarker utilization might be especially useful in a patient with a known primary tumor, as this could guide the selection of 1-2 biomarkers.
    • One study found an 18% increase in diagnostic yield when adding a panel of CEA, CA 125, CA 15-3, and CYFRA 21-1. (15596670)
  • Mesothelin as a biomarker for mesothelioma is discussed below. ⚡️
overall diagnostic strategy

differential diagnosis of effusion in the context of known cancer

  • Pneumonia with parapneumonic effusion.
  • Pulmonary embolism.
  • “Paramalignant” effusion is a secondary consequence of the malignancy without direct pleural involvement by the tumor:
    • Lymphatic involvement (may cause chylothorax).
    • Venous obstruction (e.g., superior vena cava syndrome).
    • Bronchial obstruction by tumor, with subsequent atelectasis or pneumonia leading to an effusion.
    • Pericardial involvement. (23374395)
  • Iatrogenic:
    • Medications (including chemotherapy).
    • Radiation pleuritis.

diagnostic approach 

  • Initial approach:
    • Two thoracenteses with cytologic analysis.
    • Evaluate for competing diagnoses.
  • For persistent lymphocytic effusion of unclear etiology: this is discussed further above on lymphocyte-predominant effusions. 📖
approach to management

(#1) start with a diagnostic/therapeutic thoracentesis

  • A large-volume thoracentesis should be attempted, with a goal of complete drainage of the effusion (further discussion of the safety of large-volume thoracentesis here: 🌊). This will reveal three essential pieces of information:
  • (1) Is the lung tissue re-expandible or trapped?
    • If the lung is re-expandible, then complete drainage should be possible. Subsequently, chest imaging will reveal a completely inflated lung.
    • If the lung not re-expandible, then the patient may experience central chest discomfort during the procedure which requires stopping the thoracentesis. A pneumothorax ex vacuo may also occur. (Further discussion of trapped lung is here: ⚡️).
  • (2) Does the patient get symptomatic relief from fluid drainage?
    • Lack of clinical improvement following drainage suggests trapped lung or another pulmonary disorder (e.g., pulmonary embolism, lymphangitic carcinomatosis).
    • ⚠️ Lack of improvement following drainage suggests that therapy directed towards the effusion will not provide meaningful benefit. Other causes of dyspnea should be evaluated.
  • (3) How rapidly is the fluid reaccumulating?
    • If fluid reaccumulation is extremely gradual, then intermittent thoracentesis could be a reasonable initial therapeutic strategy. Serial thoracentesis may be sensible for patients with extremely gradual fluid reaccumulation and very short life expectancy (<1 month). This may have the advantage of allowing for prompt discharge home from the hospital. (Murray 2022)
    • If fluid accumulation is rapid, then more aggressive treatment measures may be needed.

(#2a) If drainage improves symptoms & lung cannot re-expand:

  • The primary therapeutic options here are either serial thoracentesis or an indwelling pleural catheter.
  • If the expected survival is extremely short, serial thoracentesis may be considered.
  • For most patients, an indwelling pleural catheter will be a reasonable option.

(#2b) If drainage improves symptoms & lung can re-expand:

  • The primary options here are:
    • Chemical pleurodesis alone.
    • Indwelling pleural catheter alone.
    • Indwelling pleural catheter plus pleurodesis.
  • Advantages and disadvantages of these options are discussed below. These three therapies are all reasonable treatment options. Ultimately, informed decision-making and individual patient preference should guide the optimal treatment. Logistic considerations are also important (e.g., will the patient be able to manage an indwelling pleural catheter properly?).
chemical pleurodesis

The main alternative to an indwelling pleural catheter is chemical pleurodesis (usually using talc).

prerequisites for pleurodesis include

  • Estimated survival of >3 months.
  • Established diagnosis of malignant pleural effusion.
  • Thoracentesis or chest tube drainage that results in adequate lung inflation with improvement of symptoms. (There shouldn't be substantial unexpandable lung). (ERS handbook 3rd ed.)

advantages of pleurodesis

  • More widely available (doesn't require interventional radiology and/or interventional pulmonology).
  • If successful, pleurodesis solves the problem permanently (without requiring ongoing chest tube management). This avoids the psychological effects of having a semipermanent tube drain in situ. (37433578)

disadvantages of pleurodesis

  • Typically pleurodesis requires hospital admission for a few days.
  • Pleurodesis can be painful and cause fever.
  • Pleurodesis with talc may carry a small risk of hypoxemic respiratory failure.
  • Pleurodesis fails to be effective in ~30% of patients (especially if the pleural fluid is acidic and hypoglycemic). (Fishman 2023) Consequently, pleurodesis is associated with an increased requirement for further pleural procedures (as compared to indwelling pleural catheter). (37433578)

For patients with malignant pleural effusion, pleurodesis is usually performed via a chest tube (rather than surgical pleurodesis). Further technical details: ⚡️

chronic indwelling tunneled pleural catheter

basics

  • An indwelling pleural catheter is often used for patients who achieve symptomatic benefit from fluid drainage.
  • Catheter insertion should ideally be performed as an outpatient procedure, thereby minimizing time spent in the hospital. Unfortunately the international collapse of modern healthcare is often causing this to wind up being an inpatient procedure (which negates much of the benefit of the indwelling pleural catheter).
  • Over time, about half of patients may experience spontaneous pleurodesis – wherein the visceral and parietal pleura adhere together, thereby obviating recurrence of the effusion. (Shah 2019) If pleurodesis occurs, the malignant effusion is effectively “cured” and the catheter may be removed. Daily drainage increases the likelihood of pleurodesis, as compared to drainage every other day. 
  • An indwelling tunneled catheter is often the best treatment option for patients who have lung entrapment and clinically improve following fluid removal (lack of contact between the lung and parietal pleura makes pleurodesis impossible for these patients).

advantages of an indwelling pleural catheter

  • Shorter hospital length of stay (if insertion may be achieved promptly, ideally as an ambulatory patient).
  • Fewer repeat pleural procedures.

contraindications to an indwelling pleural catheter

  • Dyspnea wasn't relieved by drainage of the effusions.
  • Patient is unable to care for the catheter.
  • Very short life expectancy (days to weeks) – in which case serial thoracentesis may be better.
  • Coagulopathy.
  • Pleural infection.
  • Cellulitis or severe skin disorder overlying the effusion.
  • Multiloculated effusion.
  • Severe immunosuppression.

potential complications

  • Infection (<5%):
    • Cellulitis may be more common than empyema. Initially, cellulitis may be treated solely with antibiotics, without immediate removal of the pleural catheter.
    • Empyema:
      • Diagnosis is challenging (e.g., loculated acidotic pleural effusions may be caused by either malignancy or infection; positive cultures from the catheter may reflect either colonization or infection).
      • Treatment may often be achieved using antibiotics, without removal of the catheter. (ERS handbook 3rd ed.)
  • Fluid loculations (~10%):
    • These may limit the ability of the catheter to effectively drain the pleura.
    • Fibrinolytic therapy may be successful in managing loculations.
  • Catheter displacement (~2%).
  • Catheter occlusion leading to dysfunction.
  • Tumor tracking along the catheter (typically with mesothelioma).
  • Pneumothorax or bronchopleural fistula.

indwelling pleural catheter plus pleurodesis

  • An emerging technique is to combine an indwelling pleural catheter with talc pleurodesis.
  • Theoretically this could combine the best of both worlds:
    • The patient could spend little time in the hospital.
    • If pleurodesis is successful, then the malignant pleural effusion would be permanently eliminated (allowing for discontinuation of the chest tube).
prognosis
  • Overall prognosis is poor, with a median survival ranging from 3-12 months. (ERS handbook 3rd ed.)
  • The LENT score is a validated prognostic tool for patients with malignant pleural effusion. It may be calculated here: 📖
  • Underlying malignancy drives the prognosis, for example: (25100651)
    • Overall: median survival of ~~4.5 months.
    • Lung cancer, gastrointestinal cancers: median survival of ~~2.5 months. (29466146)
    • Breast cancer: median survival of ~~6 months.
    • Hematologic malignancies: median survival of ~~7 months.
    • Mesothelioma: median survival of ~~11 months.
    • ⚠️ Newer therapies such as checkpoint inhibitors and targeted therapies may extend survival, so statistics, including those above, may not be accurate.

mesothelioma

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epidemiology

causes

  • >90% of cases are due to asbestos exposure (with a typical latency of 20-40 years).
  • Thoracic radiotherapy (e.g., for lymphoma or testicular cancer).
  • Chronic pleural disease.

general epidemiology

  • Most patients are >50 years old.
  • With decreases in asbestos exposure, the median age is increasing over time (currently, it may be ~75 years old). In the United States, mesothelioma is expected to have peaked between 2010-2020. (Shah 2019)
  • Mesothelioma is more common in men (~80%) due to epidemiological exposure patterns.
clinical manifestations

initial presentation

  • ~60% present with non-pleuritic chest pain, which can be severe.
    • Pain may be diffuse initially, with increasing focality over time.
    • Pain may reflect chest wall invasion.
  • ~25% present with dyspnea.
  • ~20% present with cough.
  • Constitutional symptoms may occur (weight loss, fever, night sweats, fatigue).

advanced disease manifestations

  • Involvement of the contralateral hemithorax and/or peritoneum may occur. (Shah 2019)
  • Cardiac involvement (with pericardial effusion, arrhythmias).
  • Superior vena cava syndrome.
  • Esophageal obstruction.
  • Spinal cord compression.
  • Brachial plexopathy.
radiology of mesothelioma

chest radiograph & basic findings

  • Mesothelioma is usually unilateral (but is contralateral in ~15%).
  • Effusion occurs in ~85%. The initial radiographic finding is often a large unilateral effusion.

radiographic signatures of asbestos exposure

  • Pleural plaques are seen in ~20%.
  • Some patients may have parenchymal asbestosis.
  • These features are not required for the diagnosis of mesothelioma.

CT findings in mesothelioma

  • Pleural thickening is seen in 92% of cases. (Folch 2023) 
    • Red flags for pleural malignancy in general:
    • 🚩 Nodular pleural thickening.
    • 🚩 Parietal pleural thickening >1 cm.
    • 🚩 Mediastinal pleural thickening/involvement.
    • 🚩 Circumferential pleural thickening. (2106209) 
  • Chest wall invasion may occur. This can include rib destruction and/or pericardial effusion.
  • “Frozen hemithorax” may occur: a large pleural effusion occurs without a mediastinal shift (or with a mediastinal shift towards the effusion).
  • Lymphangitic involvement of the lung parenchyma can occur (similar to lymphangitic carcinomatosis).
  • Hilar and/or mediastinal lymphadenopathy may be seen. (Shepard 2019)
mesothelin levels
  • Mesothelin levels may be highly elevated by mesothelioma. Non-mesothelioma malignancies may cause lesser degrees of mesothelin elevation (e.g., lung or ovarian cancer). Benign processes generally don't elevate mesothelin levels.
  • Pleural mesothelin levels may be more useful than serum levels. Mesothelin is renally excreted, so renal dysfunction elevates serum levels. (Murray 2022)
  • In one study, pleural mesothelin levels >20 nM were 67% sensitive and 95% specific for mesothelioma. (25505814) As such, elevated mesothelin levels may suggest mesothelioma, but negative results don't exclude mesothelioma.
  • Pragmatically, access to this laboratory test appears to be limited.
pleural fluid analysis

basic pleural fluid analysis

  • The effusion may be massive and often bloody.
  • Effusion is typically lymphocyte-predominant and exudative (often with protein >4 g/dL and LDH >600 IU/L).
  • In advanced disease, low pH and low glucose may occur (this is a poor prognostic indicator).

cytology

  • Cytology is challenging because it is difficult to sort out mesothelioma from reactive mesothelial cells. Sensitivity ranges from 20-75%, with higher sensitivities for epithelioid mesothelioma. (Shah 2019) 
  • Large clusters of cells (>15 cells/group) and marked cytologic atypia may support a mesothelioma diagnosis. (Folch 2023)
  • If mesothelioma is suspected clinically, this should be communicated with the pathology department to optimize cytological yield. 
  • Advances in molecular markers may improve performance. Markers for mesothelioma are listed in the section below.
tissue biopsy
  • An invasive biopsy may be necessary to secure the diagnosis.
  • Biopsy technique:
    • VATS biopsy is an option.
    • Percutaneous interventional radiology biopsy may be ideal if there is sufficient pleural thickening or mass. (28138725)
    • An endobronchial ultrasound-guided biopsy may be utilized if there is accessible lymphadenopathy. (31812210)
  • Immunohistochemical markers for mesothelioma are as follows. These may help differentiate mesothelioma from adenocarcinoma:
    • Calretinin
    • WT1 (Wilms tumor antigen).
    • Cytokeratin 5 and cytokeratin 6.
    • D2-40 (podoplanin).
treatment

extrapleural pneumonectomy should not be done

  • The MARS RCT showed increased mortality among patients who underwent extrapleural pneumonectomy. (21723781)
  • The morbidity and mortality of surgery are high.
  • Available evidence indicates that mesothelioma should not be operated upon (outside of the context of a randomized controlled trial).

chemotherapy

  • Combination chemotherapy may extend survival by ~3 months (e.g., cisplatin-pemetrexed or cisplatin-raltitrexed). (12860938, 16192580)
  • The addition of bevacizumab (a VEGF inhibitor) on top of platinum/pemetrexed therapy improved median survival by three months (albeit with increased adverse effects). (26719230)
  • Checkpoint inhibitors: the CheckMate 743 trial in 2021 evaluated 713 patients with mesothelioma randomized to a combination of nivolumab plus ipilimumab versus chemotherapy (cisplatin/carboplatin plus pemetrexed). Checkpoint inhibitor therapy extended overall survival by 4 months and improved two-year survival (41% vs. 27%). The grade 3-4 treatment-related adverse events rate was the same between both treatment arms.  (33485464)

palliative radiotherapy

  • Available evidence doesn't support the use of radiotherapy to treat pain in mesothelioma. (24314815) However, it is possible that newer radiotherapy techniques could be perform better.
  • Palliative radiotherapy may be utilized for chest wall invasion that is causing pain or tumor that is causing compression of vital structures.

malignant pleural effusion management

  • Management is similar to that of malignant pleural effusion due to other causes, as discussed in the section above. (23299964)
  • ⚠️ Tumor tends to spread along the site of pleural punctures, so it is desirable to limit the number of pleural procedures that are performed.
prognosis
  • Mesothelioma is almost always fatal, with a median survival of ~8-14 months following diagnosis. (31812210)
  • Poor prognostic indicators include:
    • Sarcomatoid or mixed histology.
    • Higher disease stage.
    • Poor performance status.
    • Advanced pleural fluid features (low pH, low glucose, very high LDH).
    • Chest pain.
    • Fever, weight loss.
    • Age >65-75 years old.

IgG4-related pleural effusion

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IgG4 disease may cause a lymphocytic effusion with elevated adenosine deaminase that can be confused with a tuberculous effusion. Serum and pleural IgG4 levels may not be elevated, so the diagnosis may require pleural biopsy revealing plasma cell infiltration). (Murray 2022)

radiology

  • Pleural effusion may be massive.
  • Extensive pleural thickening may occur.

pleural fluid analysis

  • Effusion may be lymphocytic with elevated adenosine deaminase (ADA) levels. This may cause confusion with a tuberculous effusion.

pleural biopsy

  • Pleural biopsy should show infiltration by IgG4-positive plasma cells (e.g., storiform fibrosis, lymphoplasmacytic infiltrate, obliterative phlebitis). (26510025)

amyloid pleural effusion

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basics

  • Pleural effusion occurs in ~5% of systemic AL-type amyloidosis.
  • Direct involvement of the pleura with amyloid plaques may occur.

radiology

  • Effusion may be unilateral or bilateral.
  • Effusion is often moderate to large volume.
  • CT scan may reveal areas of pleural thickening or pleural plaques. (Folch 2023)

pleural fluid analysis

  • Effusion is transudative in 2/3 of cases. (Folch 2023) 

thoracoscopy and pleural biopsy

  • Biopsy may reveal pleural plaques. Histology reveals amyloid deposition (with apple green birefringence under polarized light).

differential diagnosis

  • Pleural effusion due to other organ-system involvement from amyloidosis:
    • Cardiac dysfunction (this is a more common cause of effusion among patients with AL amyloidosis).
    • Nephrotic syndrome (due to amyloidosis).
    • Liver dysfunction.
    • Hypothyroidism. (Folch 2023)
  • Pleural involvement from amyloid.

treatment

  • Outcome is usually dominated by overall status of systemic AL amyloidosis (and whether the patient is well enough to undergo chemotherapy for this).
  • Initially therapeutic thoracentesis may be adequate, but eventually patients may require pleurodesis or placement of an indwelling pleural catheter.
    • Pleurodesis has been described to be successful in patients producing <100 ml/day fluid, but unsuccessful in patients producing >200 ml/day fluid. (15928500)

myelomatous pleural effusion

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basics

  • Myelomatous pleural effusion is a rare complication of multiple myeloma seen in ~3% of patients. It may be the presenting feature of multiple myeloma in roughly half of patients.
  • Most effusions are unilateral.
  • Effusion results from malignant cells infiltrating the pleura (so this is one form of malignant pleural effusion). In some cases, a plasmacytoma may involve the pleura. (30704934)

pleural fluid analysis

  • Fluid may appear serous or bloody.
  • Pleural effusions are generally exudative and lymphocyte-predominant.
  • In some cases, unique features may suggest a myelomatous pleural effusion:
    • Fluid is unusually viscous.
    • The protein level may be unusually high (>7-8 g/dL).
  • Diagnosis is usually based on cytopathology and/or flow cytometry. Pleural biopsy is another option.
  • The difference in free light chain concentrations between the blood versus pleural fluid could theoretically be useful (by implying the local synthesis of free light chain).

differential diagnosis: causes of effusion in a patient with multiple myeloma

  • Exudative:
    • Myelomatous pleural effusion (discussed above).
    • Infection (multiple myeloma increases the risk of infection).
    • Uremic pleural effusion.
  • Transudative:
    • Protein-losing enteropathy 2/2 amyloidosis causing low albumin levels.
    • Nephrotic syndrome.
    • Amyloidosis involving the pleural space.
    • Heart failure (which can reflect cardiac amyloidosis).
    • POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) may cause a transudative effusions due to increased vascular permeability from high VEGF levels. (30704934)

management of myelomatous pleural effusion

  • Myelomatous pleural effusion is a poor prognostic sign indicative of aggressive myeloma. Historically, the median survival may be on the order of 2-4 months.
  • The multiple myeloma may be treated with systemic chemotherapy.
  • The pleural effusion may be treated similarly to other malignant pleural effusions (as described above).

rheumatoid arthritis related effusion

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epidemiology

  • Pleural effusion occurs in ~5% of patients with rheumatoid arthritis.
  • Effusions usually occur 5-10 years after the onset of joint disease. However, rarely effusions can occur up to 3 years before the onset of other features of rheumatoid arthritis.
  • Effusion usually occurs in:
    • Older patients (nearly all are >35 years old). (Murray 2022)
    • Men (80% of patients with rheumatoid pleural effusion). (Murray 2022)
    • Moderate-to-severe arthritis.
    • Patients with subcutaneous rheumatoid nodules.

symptoms

  • Effusions are frequently asymptomatic.
  • ~20% of patients may experience pleuritic chest pain and, less often, fever. (Murray 2022)
  • Occasionally, effusions can develop acutely in the context of a flare of rheumatoid arthritis. (Murray 2022) However, in general rheumatoid pleural involvement doesn't seem to parallel the activity of joint involvement. (Folch 2023)

imaging

  • Effusions are usually unilateral and small-moderate in size.
  • Pleural thickening and/or nodules may be seen. (Shah 2019)
  • About a third of patients may have parenchymal evidence of rheumatoid lung disease (i.e., interstitial lung disease or rheumatoid nodules).

pleural fluid analysis

  • Effusion appearance is highly variable (e.g., yellow-green, serous, milky, hemorrhagic, or purulent; debris may be seen).
  • Most effusions have a reduced glucose level (<60 mg/dL). If encountered, the combination of glucose <30 mg/dL, pH <7.2, and LDH >1,000 IU/L is highly suggestive of rheumatoid arthritis after infection is excluded.
  • During active rheumatoid pleurisy, effusions may contain up to ~15,000 cells (mostly neutrophils). However, cell counts are usually lower than in parapneumonic infection or empyema (<5,000/mm3). (Folch 2023) Eventually, quiescent effusions due to trapped lung may contain only a few hundred cells (mostly lymphocytes).
  • Cytology may show large, elongated macrophages (“comet-tail cells” or “tadpole-shaped”), which are considered to be diagnostic.
  • Chronic effusions may eventually transition into a cholesterol effusion. ⚡️

additional diagnostic studies

  • Patients with effusions usually have a high serum rheumatoid factor titer. Of course, this supports the diagnosis of rheumatoid arthritis (but doesn't necessarily prove that the pleural effusion is caused by rheumatoid arthritis).

differential diagnosis

  • The main differential diagnostic consideration is empyema or complex parapneumonic effusion. Patients with rheumatoid arthritis may be at increased risk of parapneumonic effusion, so care should be taken to exclude this (e.g., including analysis of pleural fluid Gram stain and culture).

treatment

  • Underlying rheumatoid arthritis should be treated as appropriate.
  • Treatment directed specifically at the effusion is often unnecessary. However, if the effusion is large and persistent then it should be drained. (Fishman 2023)
  • Theoretically, anti-inflammatory therapy could reduce the risk of progression to lung entrapment and pleural fibrosis – but this remains unproven.

lupus pleuritis

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basics

  • Symptoms and presentation are similar between spontaneous lupus and drug-induced lupus. Thus, medication lists should be reviewed for drugs which may cause lupus erythematosus (e.g., hydralazine, procainamide, isoniazid, phenytoin, chlorpromazine).

epidemiology

  • Pleural effusion is the most common pulmonary manifestation of lupus. About half of patients with lupus will eventually experience pleuritis.
  • Pleuritis may be the presenting symptom of lupus in ~5% of patients.

symptoms & disease pattern

  • Effusion is typically associated with a lupus flare (e.g., most patients have arthritis/arthralgias or cutaneous symptoms). Patients may also have simultaneous lupus nephritis and/or acute lupus pneumonitis.
  • Pleuritic chest pain occurs in almost all patients. Pain is often severe enough to prompt presentation to the hospital. (Folch 2023)
  • Fever occurs in most patients.
  • Other symptoms may include cough and dyspnea.

imaging

  • Pleural effusions:
    • Size is usually small-moderate, but massive effusions can occur.
    • Location: 50% are bilateral, 25% are right-sided, and 25% are left-sided.
  • Pericardial effusion may occur simultaneously in 15% of patients (pleuropericarditis). (Fishman 2023) This narrows the differential diagnosis considerably (as listed above ⚡️).

pleural fluid analysis

  • Effusions are exudative and occasionally serosanguinous.
  • LDH is rarely higher than 500 U/L. (Folch 2023)
  • Occasional effusions may be highly inflammatory (e.g., with glucose <60 mg/dL and pH <7.3), but pH is usually >7.35 and glucose is usually >60 mg/dL.
  • Initially there is a neutrophil predominance (with up to 20,000 cells/uL), which may later transition to lymphocytic predominance.
  • Pleural fluid ANA appears to have high sensitivity for lupus pleuritis, albeit with limited specificity. (Folch 2023) However, it's unclear whether this test can be run by most laboratories.
  • Cytological evaluation for “lupus erythematosus cells” has unclear performance. (Folch 2023)

additional diagnostic studies

  • If the diagnosis of lupus is unclear or unknown, serum ANA levels may help clarify this.
  • Pleural biopsy has limited value (it may show nonspecific, chronic inflammation).
    • Immunofluorescence may show bound ANA and diffuse staining with anti-IgG, anti-IgM, and anti-C3 antibodies. (Folch 2023) However, this testing is unlikely to be performed in cases where lupus is not specifically suspected.

differential diagnosis: there are numerous causes of pleural effusion in lupus

  • Lupus pleuritis.
  • Infection, including empyema (many patients will be on immunosuppressive medications).
  • Heart failure (including that due to myocardial infarction, which is increased in lupus).
  • Nephrotic syndrome.
  • Uremic pleuritis.
  • Pseudo-pseudo-Meigs syndrome (triad of transudative pleural effusion, ascites, and elevated CA-125 without any ovarian pathology, which may occur in the context of lupus).
  • Pulmonary embolism.

management

  • Treatment intensity depends on clinical context and disease severity. Initial treatment may involve oral prednisone, with a rapid taper once symptoms improve. If acute lupus pneumonitis, lupus nephritis, or other organ system involvement is present, this may require additional management. Steroid-sparing agents for pleural effusion include azathioprine or hydroxychloroquine. (Folch 2023) Rheumatology consultants may help with ongoing medication management, including steroid-sparing immunosuppressives.
  • Rarely, if effusions are large and refractory to medical therapy, pleurodesis may be needed. (Fishman 2023) 
  • Any potentially causative drugs that could be inciting medication-induced lupus should be discontinued.

hepatic hydrothorax

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basics

  • Hepatic hydrothorax refers to a transudative effusion caused by cirrhosis (with some definitions requiring a size of >500 ml). (Folch 2023) Hepatic hydrothorax results from ascitic fluid being drawn into the pleura through tiny defects in the diaphragm.

epidemiology

  • Affects ~5-15% of patients with cirrhotic portal hypertension. (Murray 2022; Folch 2023)
  • Hepatic hydrothorax accounts for 2-3% of all pleural effusions. (Folch 2023)

clinical presentation

  • Dyspnea is the predominant symptom, but cough may also occur.
  • Most patients with hepatic hydrothorax will have clinically evident ascites (especially evident when utilizing ultrasound or CT scan to evaluate for ascites). Unfortunately, ~10% of patients with hepatic hydrothorax lack ascites (because the negative intrathoracic pressure pulls all of the ascitic fluid into the chest). (26449328)

radiology

  • Effusions are more often on the right side (80-85%), but they can be left-sided (13-18%), or bilateral (2-3%). (15999054, Fishman 2023)
  • Size is variable, ranging from small to massive.

pleural fluid analysis

  • Pleural fluid analysis usually reveals a transudative effusion (often with a total protein <1 g/dL). However, a pseudoexudate may occur, especially among patients who have undergone diuresis (further discussion of pseudoexudate is above: ⚡️).
  • The cell count is low and predominantly monocytic. Alternatively, if there are >250 neutrophils/uL then the diagnosis of spontaneous bacterial pleuritis (aka, spontaneous bacterial empyema) needs to be considered. 📖

diagnosis

  • ⚠️ Thoracentesis is generally indicated to exclude spontaneous bacterial empyema.
  • Hepatic hydrothorax is largely a diagnosis of exclusion. Of course, other evidence of portal hypertension does support the diagnosis (e.g., ascites, splenomegaly, esophageal varices).
  • Heart failure should be excluded (e.g., using echocardiography).
  • The differential diagnosis of pleural effusion plus ascites is discussed here: ⚡️
management

Management is overall similar to the management of ascites, since that is the underlying physiological process. 

reduction of portal pressure (preferred therapies)

  • Diuresis:
    • This is front-line therapy for patients who are volume overloaded and able to tolerate diuresis.
    • Typically, furosemide plus spironolactone are utilized (often starting with a ratio of 40 mg furosemide to 100 mg spironolactone daily). (Fishman 2023) Diuretics may be titrated up to a dose of 160 mg furosemide and 400 mg spironolactone daily, if necessary and tolerated. (Folch 2023)
  • Midodrine could theoretically cause splanchnic vasoconstriction, thereby reducing portal pressures. This might be useful, especially in the context of patients with hepatorenal physiology (among whom midodrine might promote tolerance and efficacy of diuresis, as a component of “squeeze and diurese” strategy).
  • TIPS (Transjugular Intrahepatic Portosystemic Shunt) may be effective for refractory effusions, with a success rate of ~75%. (Folch 2023) However, TIPS may be contraindicated by such conditions as hepatic encephalopathy, MELD score above >20-25, or pulmonary hypertension. 
  • Liver transplantation is the ideal management, if possible.

pleural interventions (not preferred but may be necessary)

  • Thoracentesis: for large effusions that are causing respiratory distress, therapeutic drainage may be necessary. Paracentesis may also be utilized for patients with tense abdominal ascites. Of course, these are only temporary solutions. Fluid removal should ideally be combined with diuresis (to prevent immediate reaccumulation of fluid).
  • Short-term pigtail chest tube placement is ideally avoided, since this may lead to drainage of large quantities of fluid (causing protein and lymphocyte depletion). However, pigtail chest tube placement may occasionally be necessary as a management of respiratory failure to bridge the patient to other treatments (e.g., achievement of euvolemia after several days of diuresis and/or transhepatic intraportal shunting). After careful consideration, the risks of a pigtail chest tube may be outweighed by benefits, such as avoiding intubation and avoiding repeated thoracentesis.

refractory disease: pleurodesis vs long-term indwelling pleural catheter

  • Long-term IPC (indwelling pleural catheter) may be considered in very selected patients, for whom other therapies are not available or have failed. Following placement of an indwelling pleural catheter, one third of patients may experience spontaneous pleurodesis. (31129701) 
  • Pleurodesis:
    • Video-assisted thoracoscopic surgery to repair defects in the diaphragm and perform pleurodesis is an option, but patients with refractory hepatic hydrothorax are usually poor surgical candidates.
    • Medical pleurodesis (e.g., with talc) may carry an elevated failure rate due to rapid fluid reaccumulation. However, this may be an option if other treatments fail or are unavailable. (33304406)

elevated pleural fluid amylase & pancreatic causes of effusion

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definition of elevated pleural fluid amylase level:

  • Normally, pleural fluid amylase should be the same as the serum level.
  • Elevated pleural fluid amylase is defined as a pleural fluid amylase level higher than the upper limit of normal for serum amylase. (Folch 2023)

There are five main causes of elevated pleural fluid amylase:

1) esophageal rupture
  • Clinically, the patient is acutely ill (e.g., chest pain, sepsis).
  • Pleural fluid analysis:
    • Pleural fluid usually shows reduced glucose and pH (often pH <7.0).
    • Pleural fluid may demonstrate particulate food particles, and/or polymicrobial bacteria on Gram stain/culture.
  • CT scan should usually reveal evidence of esophageal perforation. The evaluation for esophageal perforation is discussed further in the chapter on pneumomediastinum: 📖
2) acute pancreatitis
  • The clinical picture is usually dominated by the pancreatitis. In the context of pancreatitis, pleural effusion is a poor prognostic sign. (Folch 2023)
  • Pleural fluid analysis:
    • Pleural fluid is usually a neutrophilic exudate.
    • Glucose level is normal.
    • Amylase level may be elevated.
3) pancreaticopleural fistula

Pancreatitis and pseudocyst formation may eventually lead to a fistula between the pancreas and the pleural space. This is usually a chronic complication of pancreatitis. (Fishman 2023)

clinical presentation

  • Patients have a history of recent pancreatitis.
  • Pleural effusion may cause dyspnea, cough, and chest pain.
  • The effusion is usually left-sided and massive, with rapid recurrence following thoracentesis.

diagnosis

  • Serum amylase and lipase often aren't very high.
  • Pleural fluid amylase is extremely high (>4000 U/ml).
  • Pleural fluid lipase is also highly elevated.
  • MRCP (magnetic resonance cholangiopancreatography) is the most sensitive imaging modality to find a fistulous tract between the pancreatic ductal system and the pleura. (Fishman 2023)

management

  • Interventional gastroenterologic therapy is preferred (e.g., interruption of the fistula, or internal drainage of a pseudocyst).
4) pancreatic ascites
  • This is similar to a pancreaticopleural fistula, but it involves a rupture with leakage of pancreatic duct contents into the peritoneal cavity (“pancreatic ascites”). Subsequently, this fluid migrates through diaphragmatic defects into the pleural space.
  • Clinical presentation is similar to that of a pancreaticopleural fistula. In most cases, the simultaneous presence of ascites may provide a clue to the diagnosis.
  • Diagnosis may be aided by diagnostic paracentesis and thoracentesis, which should demonstrate elevation of amylase and lipase in both fluid cavities.
  • Treatment often involves stenting of the pancreatic duct.
5) malignant pleural effusion
  • Discussed further above: ⚡️

bilothorax

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diagnosis

  • Bilothorax is defined largely on the basis of a pleural fluid bilirubin greater than the serum bilirubin.

pathophysiology

  • (1) May involve leakage of bile into the peritoneum, and thence into the pleura.
  • (2) May result from a direct pleurobiliary fistula.

causes include:

  • Liver trauma (e.g., shearing/laceration).
  • Iatrogenic:
    • Biliary surgery.
    • Percutaneous transhepatic biliary drainage.
    • ERCP.
  • Biliary tract obstruction.
  • Liver abscess.
  • Hepatic tumor invasion of the pleura.

pleural fluid analysis

  • Pleural fluid color will be obviously abnormal (e.g., bilious or black).
    • Differential diagnosis: other causes of black pleural fluid: ⚡️
  • Pleural fluid bilirubin is greater than serum bilirubin.

management

  • Chest tube drainage is a rational therapy, since bile may cause pleural inflammation and adhesion formation. (30932703)
  • Biliary tract decompression should be performed if indicated (or other management of the underlying hepatic disorder).
  • Bile is a medium conducive to bacterial growth, so empyema may occur (requiring antibiotic therapy and chest tube drainage). (30932703)

Meigs syndrome

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basics

  • Meigs syndrome is due to a benign ovarian tumor that stimulates ascites formation and pleural effusion. Criteria for Meigs syndrome include the following: (Folch 2023)
    • (1) Benign ovarian tumor (fibroma, thecoma, granulosa cell tumor, or Brenner tumor).
    • (2) Ascites.
    • (3) Pleural effusion.
    • (4) Resolution of ascites and pleural effusion following resection of the tumor.
  • Ascites seems to result from secretion of fluid by the tumors, possibly in relationship to up-regulation of vascular endothelial growth factor (VEGF). Pleural effusion results from ascitic fluid migrating through defects in the diaphragm into the pleura (similar to hepatic hydrothorax).

clinical presentation

  • This generally occurs in postmenopausal women, with a peak incidence around 60 years old. (Folch 2023)
  • Patients may have weight gain/loss, bloating, ascites, and dyspnea.
  • CA125 level is often elevated, which may cause confusion in distinguishing this from ovarian cancer. (27305196)

radiology

  • Effusion is usually on the right (but can be left-sided or bilateral).
  • Effusion is usually larger than 1/3 of the hemithorax. (Fishman 2023)
  • Ovarian tumors are nearly always >10 cm large. (Folch 2023)

pleural fluid analysis

  • Occasionally, fluid may appear bloody.
  • Fluid is usually exudative. 80% of effusions have a protein >3.5 mg/dL. (Folch 2023)

differential diagnosis

  • Pseudo-Meigs syndrome:
    • This is defined as a triad of cytologically negative pleural effusion, ascites, and some other benign or malignant gynecologic tumor. Resection of the tumor causes resolution of the effusions. (Folch 2023)
    • This might include, for example, a low-grade ovarian malignant tumor without metastasis. Different sources disagree about precisely which tumor types are Meigs syndrome vs. pseudo-Meigs syndrome (some stating that Meigs syndrome refers solely to ovarian fibromas). (Folch 2023)
  • Pseudo-pseudo-Meigs syndrome (aka Tjalma syndrome): Lupus may cause a pleural effusion, ascites, and elevation of CA-125 in the absence of ovarian pathology (“pseudo-pseudo Meigs syndrome”). This is due to generalized serositis.
  • The differential diagnosis of pleural effusion plus ascites is discussed here: ⚡️

initial evaluation

  • Pleural fluid analysis including cytology.
  • CT scan of the chest/abdomen/pelvis to evaluate for malignancy.
  • Pelvic ultrasound.

management

  • Investigation and management focuses on evaluation and removal of the underlying gynecological lesion. Removal of the ovarian mass will cure the pleural effusion.
  • Chest tube drainage may be needed for 2-3 weeks in some cases, since even after resection of the ovarian lesion the effusion may not resolve immediately. However, serial thoracentesis is usually adequate. (Folch 2023)

pleural effusion in the context of renal dysfunction

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The differential diagnosis may include the following entities (along with other common pathologies, such as parapneumonic effusion). It's essential to realize that not all effusions in a patient with renal failure are due to volume overload. Consequently, not all effusions in a patient with dialysis will respond to hemodialysis (indeed, rapid resolution following a hemodialysis session would be rather unusual).

three common etiologies

volume overload / heart failure

  • Reasons for increased risk of volume overload:
    • Renal dysfunction may directly lead to volume retention.
    • Renal failure is a risk factor for diastolic dysfunction.
    • A high-output arteriovenous fistula may increase central venous pressure. (Folch 2023)
  • Chemical and radiologic features would be expected to mirror heart failure, as discussed further here: ⚡️

uremic pleuritis

  • Causes of pleural effusion:
    • (1) Active uremic pleuritis.
    • (2) Trapped lung due to prior chronic pleuritis.
  • (Further discussion of uremic pleuritis is below: ⚡️)

hemothorax

  • Reasons for increased risk of hemothorax in patients with renal failure:
    • Uremia causes platelet dysfunction.
    • Patients with renal failure commonly have additional comorbidities which may require additional anticoagulant therapies (e.g., coronary disease).
    • Heparin may be utilized as a component of dialytic therapy.
    • Renal failure may cause the accumulation of some anticoagulant medications (e.g., NOACs).
  • Further discussion of hemothorax is above: ⚡️

three uncommon etiologies

peritoneal dialysis

  • Pleural effusion occurs in ~2% of patients undergoing peritoneal dialysis. (Fishman 2023) Dialysate passes from the peritoneum into the thorax via tiny holes in the diaphragm (similar to hepatic hydrothorax). Effusion usually occurs during the first month of peritoneal dialysis, but it may also arise up to eight years after starting peritoneal dialysis. (Folch 2023)
  • Radiology: Effusion is usually unilateral and massive, typically on the right.
  • Pleural fluid analysis:
    • The effusion is transudative (protein level <1 g/dL).
    • Diagnosis is based on a pleural fluid glucose which is greater than the serum glucose level. (Fishman 2023)
  • Management:
    • Peritoneal dialysis may need to be temporarily interrupted for 4-6 weeks (with a shift to hemodialysis). (23374395)
    • VATS surgery to repair the diaphragmatic imperfections followed by pleurodesis may allow resumption of peritoneal dialysis. (Fishman 2023)

nephrotic syndrome

  • Pleural effusions may occur in about one fifth of patients with nephrotic syndrome. (Murray 2022) Effusions are related to sodium retention and hypervolemia.
  • Pleural effusions are usually seen only when the serum albumin is <2 g/dL. (Fishman 2023)
  • Effusions are usually bilateral, often subdiaphragmatic in location. (Murray 2022)
  • Note that nephrotic syndrome increases the risk of other types of pleural effusion:
    • (1) Pulmonary embolism, which may cause pleural effusion.
    • (2) Chylothorax (due to thrombosis of the superior vena cava, or due to chylous ascites formation with fluid translocation into the thorax).
    • (3) Infection, as a consequence of immunoglobulin depletion (including spontaneous bacterial empyema).

urinothorax

  • Rare cause of pleural effusion, which may be caused by urinary obstruction.
  • Further discussion of urinothorax here: ⚡️

uremic pleuritis

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basics

  • Pathophysiologically, uremic pleuritis may represent an inflammatory and fibrotic reaction to uremic toxins. (Folch 2023)

epidemiology

  • Pleuritis may occur in ~3-15% of patients with uremia.
  • This is typically seen in a patient on chronic dialysis.

clinical presentation

  • Symptoms can include fever, pleuritic chest pain, and cough.
  • Effusions can be asymptomatic.
  • Dyspnea is uncommon.
  • Uremic pericarditis may also be present in about 50% of patients.

imaging

  • Effusion is usually unilateral (80%) and small-to-moderate in size. However, at times effusions can be bilateral and massive.
  • POCUS findings:
    • (1) Pleural effusion may reveal septations, fibrinous bands, and often debris. (Folch 2023)
    • (2) Pericardial effusion should be sought on bedside POCUS. If found, this supports the diagnosis of uremia.

pleural fluid analysis

  • The gross appearance may be serous or serosanguinous.
  • Effusions are generally exudative, with normal glucose and pH >7.3
  • Nucleated cells are typically <1,500, with a lymphocyte predominance.

differential diagnosis of effusion in a patient with uremia

  • This is discussed above ⚡️

treatment

  • Initial management:
    • The primary therapy is dialytic treatment of the uremia. Effusions will usually resolve over 4-6 weeks.
    • Dialysis will not rapidly resolve the effusion, so if the effusion is causing respiratory distress then therapeutic drainage is needed.
  • Chronic management:
    • Refractory effusions may require talc pleurodesis, indwelling pleural catheter, or pleural decortication. (Folch 2023)
    • Failure to adequately treat uremic pleuritis may eventually lead to trapped lung.

urinothorax

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epidemiology

  • Urinothorax is extremely rare.

causes of urinothorax: 

  • Most often urinothorax is due to obstructive uropathy with hydronephrosis (including malignancy, retroperitoneal fibrosis).
  • Iatrogenic urinary tract disruption (e.g., percutaneous nephrostomy, renal biopsy, lithotripsy, urologic surgery).
  • Trauma.

clinical presentation

  • Cough, dyspnea, and pleuritic chest pain may occur.
  • Constitutional symptoms usually occur (fever, chills, and fatigue). (32386649)

radiology

  • Effusion is unilateral in 87% of cases, usually right-sided (58%).
  • The effusion will generally be ipsilateral to the obstructed/manipulated kidney.
  • Urinothorax is usually a free-flowing effusion, but loculation may rarely occur if the urine contains inflammatory debris. (32386649)

pleural fluid analysis

  • Gross appearance is usually straw colored or serosanguinous. (32386649) The pleural fluid may look and smell like urine.
  • Pleural fluid creatinine > serum creatinine is the defining feature of urinothorax. Pleural fluid creatinine / serum creatine ratio may vary from 1.1-16.
    • Pleural fluid creatinine > serum creatinine is sensitive, but not specific for urinothorax. ~10% of other effusions meet this criterion (including some empyemas).
  • Protein is usually quite low (<1 g/dL).
  • LDH is variable (LDH is often low, but it can be elevated).
  • Glucose is typically low. (Folch 2023)
  • pH is variable, depending on the patient's acid-base status and renal acid excretion:
    • pH may be acidic (<7.3). Urinothorax is the only cause of a transudative effusion with low pH (all other causes of acidic effusion are exudative).
    • pH may be as high as 8 (if the urine is alkalotic).

treatment

  • Treatment centers around resolution of the underlying urologic problem. Once the urologic obstruction is resolved, the pleural effusion should rapidly improve.

post-cardiac injury syndrome (PCIS)

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basics

  • PCIS is a general term for combinations of pleuropericardial disease that occur weeks to months after cardiac injury (pleuritis, pericarditis, +/- pneumonitis), often with fever.
  • PCIS usually occurs about 2-3 weeks after injury. (Murray 2022)

causes & epidemiology of PCIS

  • s/p MI (Dressler syndrome):
    • Affects ~1% of patients with MI. (Sadhu 2023)
    • Occurs between one week to three months after MI (most frequently after 1-2 weeks). (ESC 2023, 37622654)
  • s/p Cardiothoracic surgery (postpericardiotomy syndrome, may occur in ~25%).
  • s/p Cardiac trauma (e.g., contusion from blunt trauma).
  • s/p Pacemaker or ICD implantation.
  • s/p Ablation for tachyarrhythmias.
  • s/p PCI (percutaneous coronary intervention).
  • s/p TAVI (transcatheter valve implantation).

clinical presentation

  • Fever occurs in most patients.
  • Pericarditis:
    • May cause pleuritic chest pain and friction rub.
    • Tamponade is rare.
  • Pleuritis (dyspnea occurs in ~60% of patients).

radiology & POCUS

  • Pleural effusion (~80%):
    • Effusion is usually left-sided or bilateral.
    • Effusion is small.
  • Pericardial effusion (~50%).
  • Pneumonitis with lung infiltrates may occur in about half of patients.

pleural fluid analysis

  • Fluid is exudative.
  • pH is >7.20 and glucose is >60 mg/dL. (Folch 2023)
  • Initially:
    • Pleural fluid may be serosanguinous.
    • There may be a neutrophilic predominance.
  • Over several weeks:
    • Serosanguinous transitions into a serous fluid.
    • Lymphocyte predominance emerges.

serum labs

  • Systemic inflammatory markers are usually elevated (e.g., CRP and ESR).

differential diagnosis often includes

  • Early post-MI pericarditis (usually occurs within four days after transmural MI). 📖
  • MI (especially re-infarction in patients with prior MI).
  • Ventricular free wall perforation with hemopericardium (suggested if pericardial effusion >1 cm).
  • Post-cardiac surgery pleural effusion (discussed further below).
  • Viral or idiopathic pericarditis.
  • Pulmonary embolism.
  • Heart failure.
  • Pneumonia.

diagnostic approach

  • Diagnosis of the pericarditis component may be approached similarly to the general criteria for pericarditis. 📖

treatment

  • Pericardial tamponade is rare, but the pericardial effusion may require drainage.
  • Pericardial effusion isn't a contraindication to the use of antithrombotics and/or anticoagulants if these are otherwise indicated. (37622654)
  • Anti-inflammatory medication:
    • High-dose aspirin is useful in post-MI or post-cardiac surgery patients (due to concern that NSAID may increase infarct size). The dose is generally 750-1000 mg PO q8hr for 2 weeks, followed by tapering by 250-500 mg every 2 weeks. (Folch 2023, 37622654)
      • Alternatively, NSAIDs may be useful in non-MI patients.
    • Proton pump inhibitor should be given to prevent gastric ulceration.
    • Adjunctive colchicine is generally recommended for three months among patients with pericarditis. (30987913, 37622654) Further discussion of colchicine in pericarditis: 📖
    • Steroid is usually reserved for failure of other medical therapies. Steroid will work rapidly, but there is a high recurrence rate.
  • Usually inflammation settles within 1-2 weeks. Unfortunately, recurrence is common and may occur in a delayed fashion (up to ~2 years later).

effusion post-CABG (coronary artery bypass graft)

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Early effusions are usually neutrophilic, whereas later effusions are usually lymphocytic. However, it's conceivable that these represent two different stages within the evolution of usual post-CABG effusions. 

perioperative effusion (<1 week)

  • Causes may include diaphragmatic dysfunction, atelectasis, and pleural injury during surgery (with an increased risk following harvesting of the internal mammary artery).
  • Effusions are usually small, left-sided, and resolve within two weeks of conservative management. (Folch 2023)

early effusions (1-4 weeks) tend to be bloody & neutrophilic

  • Timing: Occur within a month of surgery.
  • Pleural fluid analysis:
    • Fluid is bloody.
    • Differential cell count often shows neutrophilia.
    • Pleural fluid and/or blood eosinophilia may occur.
    • Pleural fluid LDH is high.
  • Management: Effusions usually respond to 1-2 therapeutic thoracenteses. (Murray 2022)

later effusions (>1 month) tend to be serous & lymphocytic 

  • This probably represents a variant of post-cardiac injury syndrome. (23374395)
  • Timing: Usually reach maximal size >1 month after surgery.
  • Pleural fluid analysis:
    • >50% lymphocytosis.
    • Relatively low LDH level.
  • Management: Effusions usually respond to 1-2 therapeutic thoracenteses, but may be recurrent.

other possibilities:

  • Post-cardiac injury syndrome:
    • Features that may suggest PCIS:
      • Patients are more likely to be symptomatic (e.g., fever, chest pain).
      • Pericardial and/or lung parenchymal involvement.
    • This is discussed in more detail in the section above.
  • Empyema (in the perioperative period).
  • Heart failure.
  • Pulmonary embolism.
  • Chylothorax.

pleural effusion due to PE

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basics

  • Pulmonary embolism is estimated to be the fourth leading cause of pleural effusion in the United States (behind cancer, infection, and heart failure). (Fishman 2023) Therefore, pulmonary embolism merits routine consideration for any patient presenting with pleural effusion.
  • Pleural effusion occurs in ~30% of patients with pulmonary embolism. (Folch 2023)
  • The mechanism of effusion generation is usually pulmonary infarction (necrosis of distal lung tissue, as a complication of the pulmonary embolism).

clinical presentation

  • Patients may exhibit dyspnea that is out of proportion to what would be expected based on the small size of the effusion.
  • Other clinical symptoms of pulmonary infarction may occur:
    • Pleuritic chest pain or hemoptysis are common.
    • Cough or low-grade fever may occur.

radiology

  • Effusion:
    • Usually small (90%). (Folch 2023)
    • Usually unilateral (85%), but can be bilateral (15%).
    • Effusion is usually free-flowing, but loculated effusion can occur if the diagnosis has been delayed for more than 10 days after symptoms developed. (Walker 2019, 23374395)
  • Pulmonary infarct(s) are usually seen as well (especially with CT imaging).
    • Further discussion of imaging in pulmonary infarction here: 📖

pleural fluid analysis

  • Appearance is variable, but often serosanguinous.
  • Basic chemical analysis shows an exudate in ~90%. (Folch 2023)
    • ⚠️ A transudative effusion doesn't exclude the possibility of PE.
  • Differential cell count:
    • Neutrophil-predominant (although over time the neutrophil count may decrease).
    • Pleural eosinophilia (>10% of cells) may also occur.

differential diagnosis

  • The combination of effusion, pleuritic chest pain, fever, and pulmonary infiltrates may mimic a bacterial pneumonia combined with a parapneumonic effusion.

management

  • Treat the PE in the usual fashion. Neither mild-moderate hemoptysis nor serosanguinous effusion is a contraindications to anticoagulation.
  • Specific treatment for the effusion is usually unnecessary. The effusion should remain relatively small (<1/3 of the hemithorax) and should start to resolve within about three days. If the effusion is failing to behave as expected, then alternative diagnoses should be considered (e.g., recurrent pulmonary emboli, infection, or hemothorax). (Murray 2022)

pleural effusion due to heart failure

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basics

  • Heart failure is the most common cause of transudative effusion.
  • Heart failure is extremely common, so many patients may have a pleural effusion due to a combination of heart failure plus a second process. This can create a confusing picture, since the heart failure “dilutes” the effusion.

radiology

  • Effusions are often bilateral: POCUS or CT scan may be used to reveal small effusions which are missed on chest radiograph. On CT scan, effusions are present on the right side in 83% of patients and the left side in 77% of patients. (Folch 2023)
  • Effusions are usually small to moderate in size. (23374395)
  • Other parenchymal features of heart failure are often seen:
    • CT scan findings may include septal thickening (as discussed here: 📖).
    • POCUS findings may include bilateral B-lines.
  • CT scan revealing left atrial dilation supports the presence of heart failure: 📖

pleural fluid analysis

  • Effusions should be transudative. However, pseudoexudative effusions are frequently encountered (discussed here: ⚡️).
  • The most consistent findings on pleural fluid analysis: (26449328)
    • (Serum albumin – pleural albumin) gradient >1.2 g/dL (94%).
    • LDH below two thirds of the upper normal limit for serum (93%).
    • Pleural/serum LDH ratio <0.6 (84%).
    • Cholesterol <45 mg/dL (84%).
    • Pleural/serum protein ratio <0.5 (83%).
    • (Serum protein – pleural protein) gradient >3.1 g/dL (80%).
    • Pleural protein <3 g/dL (78%).
  • Pleural fluid may occasionally appear bloody (15%), which is a nonspecific finding. (26449328)

serum NT-pro-BNP

  • NT-pro-BNP with a cutoff value of 1500 pg/mL has a sensitivity and specificity of ~95%. Values >1,500 pg/ml have a positive likelihood of 15, whereas values below 1,500 pg/ml have a negative likelihood ratio of 0.06. (21092122) However, values very close to the binary cutoff (~1,500 pg/ml) are less informative. 
    • Levels of NT-pro-BNP are similar in the pleural fluid and the serum. Overall, it is generally logistically easier to measure NT-pro-BNP from the serum.

constrictive pericarditis

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basics

  • Pleural effusion occurs in about half of patients with constrictive pericarditis. This may occasionally be the most obvious finding on initial presentation.
  • Constrictive pericarditis is a rare etiology of pleural effusion which is difficult to diagnose.
  • The precise pathophysiology of effusion generation is unclear.
  • Some patients may develop constrictive pericarditis following an obvious insult to the pericardium (e.g., thoracic radiotherapy, cardiothoracic surgery). However, most cases are idiopathic – so constrictive pericarditis should be suspected regardless of whether there is a known injury to the pericardium.

clinical presentation

  • Presenting symptoms may include dyspnea and peripheral edema.
  • On examination, systemic vascular congestion is usually present (e.g., dilation of the jugular vein and inferior vena cava). Ascites and peripheral edema may be seen.

chest radiograph

  • Pericardial calcification is noted in about half of cases.
  • Effusions may be bilateral (60% of patients), right-sided (30% of patients), or left-sided (10% of patients). (21540221)

CT scan

  • Pericardial thickening may be seen in ~80% of patients.
  • Contrast reflux into the inferior vena cava can be a useful sign of right ventricular insufficiency, if seen.

pleural fluid analysis

  • Reported cases show a similar frequency of exudative and transudative effusions. (21540221)

blood tests

  • Brain natriuretic peptide levels are usually only slightly elevated.

management

  • Surgical stripping of the pericardium is curative.

drug related effusion

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Definitive proof linking any drug to effusions is often difficult to obtain. Below is a list of drugs which have been implicated in causing pleural effusions. (Shah 2019) More information at pneumotox.com.

antibiotics

  • Daptomycin.
  • Isoniazid (drug-induced lupus effusion).
  • Metronidazole.
  • Nitrofurantoin (may rarely cause eosinophil or lymphocyte-predominant effusion). (Folch 2023)

medications for neurologic/muscular conditions

  • Chlorpromazine.
  • Clozapine: Commonly associated with drug-induced pleural effusion, including eosinophilic effusion.
  • Dantrolene.
  • Fluoxetine has been associated with eosinophilic pleural effusion.
  • Ergot alkaloids: bromocriptine, ergotamine, dihydroergotamine, pergolide, methysergide. These are strongly associated with pleural effusion. (Folch 2023)
  • Phenytoin.
  • Valproic acid: Effusion is not a rare side effect. Various forms of effusion are reported, including exudative lymphocytic or eosinophilic effusion, transudative effusion, and drug-induced lupus. (Folch 2023)

anticancer drugs

  • All-trans retinoic acid.
  • Bleomycin.
  • Busulfan.
  • Etoposide.
  • Gemcitabine.
  • Imatinib.
  • Interleukin-2 (IL-2) may induce a capillary leak syndrome.
  • Methotrexate.
  • Mitomycin.
  • Procarbazine.
  • Taxanes.
  • Tyrosine kinase inhibitors:
    • Dasatinib has a ~25% incidence of effusion, which may take a while to resolve after discontinuation. (29406237) This may rarely involve chylothorax.

others

  • Amiodarone (may cause isolated effusion).
  • Hydralazine (drug-induced lupus effusion).
  • Mesalamine has been associated with eosinophilic pleural effusion.
  • Minoxidil.
  • Procainamide (drug-induced lupus effusion).
  • Quinidine (drug-induced lupus effusion).
  • Thiazolidinediones (glitazones) may promote heart failure & transudative effusion.
  • TNF-inhibitors (may cause drug-induced lupus effusion).

benign asbestos pleural effusion (BAPE)

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epidemiology

  • BAPE is rare, with an incidence of perhaps ~3% among asbestos workers. (Murray 2022)
  • Latency until development of BAPE is shorter than other complications of asbestos (usually ~10-15 years). However, effusions can develop after a latent period of >40 years.
  • BAPE is more likely to occur following more severe exposure.

clinical presentation

  • Most patients are asymptomatic.
  • Patients can have pleuritic chest pain, chest tightness, dyspnea, and fever.

radiology

  • Effusion is usually small to moderate.
  • Effusion is usually left-sided (although it can occur bilaterally).
  • Round atelectasis may be supportive of the diagnosis.
  • Other evidence of asbestos-related pulmonary disease may occasionally be seen:
    • Pleural plaques are seen in ~20% of patients, which may serve as a useful indicator of asbestos exposure. However, BAPE frequently occurs before pleural plaques develop (BAPE typically has a latency of ~10-15 years, whereas plaques usually develop after >20 years).
    • Parenchymal asbestosis is seen in <10% of patients.

pleural fluid analysis

  • About half of effusions may appear bloody.
  • Effusions are exudative.
  • Cell count often shows a neutrophilic predominance. However, about half of patients may have elevated eosinophil levels as well (>10% eosinophils).
  • Glucose levels are normal.

diagnosis of BAPE

  • Diagnostic criteria may be as follows: (Murray 2022)
    • History of asbestos exposure (direct or indirect).
    • Exclusion of other causes (especially infection, PE, or malignancy – including mesothelioma).
    • Follow-up of at least 2-3 years of surveillance for the emergence of a malignancy (thereby verifying that the effusion is benign).
  • Differentiation from mesothelioma may be difficult. Biopsies via CT guidance or thoracoscopy may help exclude malignancy. (Murray 2022)

treatment & prognosis

  • There is no known treatment.
  • Prognosis is generally favorable, although various disease courses may occur:
    • Spontaneous resolution usually occurs after ~3 months.
    • Recurrent effusions occur in about a third of patients (more often contralaterally than ipsilaterally).
    • Patients can develop pleural fibrosis and diffuse pleural thickening, with subsequent dyspnea.
    • Contraction/tethering of the visceral pleura may lead to round atelectasis.

duropleural fistula

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causes

  • Trauma:
    • Blunt trauma.
    • Penetrating trauma.
  • Surgery:
    • Spinal surgery
    • Thoracotomy or thoracoscopy.

symptoms

  • Dyspnea.
  • Intracranial hypotension (e.g., headache, dizziness, nausea).

pleural fluid analysis resembles CSF

  • Basic properties:
    • Color is clear.
    • Protein is extremely low (<1 g/dL).
    • LDH is generally low.
    • Glucose is often below the serum glucose level. (Folch 2023)
  • Beta-2 transferrin levels provide definitive confirmation (95% sensitive, 100% specific). (Folch 2023)
  • ⚠️ Trauma may cause bleeding, which obscures the watery nature of the pleural fluid.

imaging evaluation

  • Localization of the fistula may be obtained with CT myelography. This is a rare study, so communicate with radiology to determine the optimal test.

management

  • Due to the rarity of this condition, there is no definitive treatment algorithm.
  • Consult with neurosurgery or orthopedic/spine surgery to determine if surgical closure would be appropriate.
  • Placement of a chest tube to suction could theoretically lead to excessive CSF removal, with exacerbation of CNS hypotension.

lung entrapment & trapped lung

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definitions & basics

unexpandable or nonexpendable lung

  • Definition: Despite attempts to drain the pleural space, it is not possible to achieve apposition of the visceral and parietal pleura.
  • Causes of unexpandable lung:
    • (1) Trapped lung – discussed below.
    • (2) Entrapped lung – discussed below.
    • (3) Endobronchial obstruction causing lobar atelectasis.
    • (4) Pulmonary parenchymal fibrosis.
  • General clinical features of unexpandable lung:
    • Pneumothorax ex vacuo often results from thoracentesis. This occurs when fluid is removed but the lung cannot re-expand, leading to the generation of highly negative pressures in the pleura. An alveolus subsequently ruptures, leading to pneumothorax. Pneumothorax ex vacuo is not generally a dangerous process (e.g., there is very little risk of progression to tension pneumothorax).
    • There may be a lack of mediastinal shift away from the effusion.

trapped lung

  • Definition: Unexpandable lung due to a visceral fibrotic pleural peel as a result of a resolved inflammatory insult.
  • Trapped lung is a chronic state that cannot resolve spontaneously.
  • Clinically, trapped lung is frequently asymptomatic. However, it can be a cause of chronic dyspnea or exercise limitation.

lung entrapment

  • Definition: Unexpandable lung due to an active pleural process (e.g., malignancy or inflammation) that is causing the visceral pleural membrane to be compressed.
  • Outcome of lung entrapment:
    • (1) The pleural process may resolve, with normalization of the lung.
    • (2) The pleural process may progress to fibrosis (producing a chronic trapped lung).
  • Treatment of the underlying disease process may promote resolution (rather than fibrosis).
  • Clinically, lung entrapment is encountered far less often than trapped lung (because lung entrapment represents a transitional state).
epidemiology

causes of trapped lung & lung entrapment

  • These are caused by the same set of disorders (processes which cause prolonged and significant inflammation within the pleural space).
  • Causes of trapped lung are the same processes which may cause pleural thickening (since trapped lung is merely one form of pleural thickening). These are listed here: 📖

epidemiology of trapped lung 

  • Trapped lung is uncommon (accounts for <5% of pleural effusions).
  • Trapped lung usually manifests several months to years after the original pleural injury.
clinical features

clinical response of unexpandable lung to thoracentesis 

  • Thoracentesis to drain an effusion provokes central anterior chest discomfort (this is due to the development of negative pressure in the thorax). Pain may be described as sharp and pressure-like, sometimes radiating to the neck. (Folch 2023) This discomfort resolves if air is intentionally introduced through the thoracentesis needle (thereby producing a therapeutic pneumothorax).
  • Thoracentesis often causes an unexpected pneumothorax (“pneumothorax ex vacuo” due to generation of excessive negative pressure in the thorax).
  • (If a chest tube is inserted, it will not result in lung reinflation.)

differences between trapped lung versus lung entrapment

  • Clinical symptoms at time of presentation:
    • Lung entrapment: dyspnea and pleuritic chest pain may reflect fluid accumulation and active pleural inflammation.
    • Trapped lung is generally chronic and minimally symptomatic.
  • Clinical improvement following thoracentesis ?
    • Lung entrapment: Patients with lung entrapment may have dyspnea due to a combination of unexpandable lung plus compression by pleural fluid accumulation. Thus, drainage of pleural fluid may cause some lung expansion and some clinical improvement (although it won't completely re-expand the lung).
    • Trapped lung: thoracentesis won't cause clinical improvement.
radiology

radiologic features of either lung entrapment or trapped lung

  • Thoracentesis will often provoke a pneumothorax (“pneumothorax ex vacuo”).
  • The differential diagnosis of a post-procedure pneumothorax also includes iatrogenic lung injury or accidental introduction of air through the thoracentesis needle. Radiographic features that support the presence of pneumothorax ex vacuo due to lung entrapment or trapped lung:
    • (1) Follow-up chest radiograph (or especially CT scan) may show thickening of the visceral pleura.
    • (2) Air may focally accumulate at the base of the lung, or in a loculated fashion (whereas iatrogenic pneumothorax would generally cause a free-flowing pneumothorax).

radiology of lung entrapment

  • Active inflammation and fluid accumulation may cause contralateral mediastinal shift. (Folch 2023)
  • Active pleural inflammation may cause contrast enhancement on a CT scan with pleural-phase contrast.

radiology of trapped lung

  • Review of prior radiographs show that the effusion is chronic and stable in size over time.
  • There is no mediastinal shift.
  • The effusion may be loculated.
  • If pneumothorax ex vacuo occurs, a subsequent CT scan may reveal thickening of the visceral pleura (air is needed in the pleura in order to observe this). (29884273)
pleural fluid analysis (PFA)

PFA in lung entrapment

  • Active inflammation is present, causing an exudative pleural effusion.

PFA in trapped lung

  • Absence of inflammation may cause a transudative pattern. However, protein is often in an exudative range, with LDH frequently in a transudative range.
  • The cell count is usually low (<500/uL), often with lymphocytosis (>50%).
management

management of lung entrapment 

  • The inflammatory process should be treated if possible (treatment will vary, depending on the underlying process).
  • In some cases (e.g., malignant pleural effusion), if fluid re-accumulation is causing significant dyspnea then a tunneled pleural catheter may be helpful.
  • Surgery is generally not indicated, since this process may resolve over time. However, if the disease progresses to trapped lung, then surgery may be re-considered.

management of trapped lung

  • Trapped lung is generally best left alone, if possible.
  • Most patients are asymptomatic, so no treatment is needed.
  • There is no role for an indwelling tunneled pleural catheter or for therapeutic thoracentesis.
  • Surgery:
    • Thoracotomy with decortication can be performed in efforts to remove or disrupt the fibrous membrane overlying the visceral pleura.
    • Surgery can be successful, but carries a high morbidity and mortality.

pleural manometry

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Pleural manometry is not supported by available evidence:

  • Manometry cannot accurately predict whether complete lung expansion will occur when draining a pleural effusion. (31472154, 32395275)
  • A randomized controlled trial found that monitoring of pleural pressures with manometry didn't prevent cough or dyspnea during thoracentesis. (30772283)

There is currently no good rationale to perform pleural manometry. Instead of predicting whether lung expansion is possible, it is better to empirically determine whether lung expansion is possible (e.g., by attempting to completely drain the pleural effusion, or through placement of a pigtail chest drain). Attempting complete drainage of large pleural effusions is generally safe (as discussed further here 🌊).

There are also many additional pragmatic barriers to the use of pleural manometry:

  • Manometry requires that trapped lung is suspected prior to the thoracentesis procedure (whereas in reality, trapped lung is often diagnosed retrospectively following the thoracentesis).
  • Pleural manometry usually isn't readily available.

(If pleural manometry is encountered on a board examination: trapped lung is suggested if the pleural pressure falls by >15 cm per liter of fluid removed.)

pleurodesis

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patient selection

indications for pleurodesis

  • [1] Pleural effusion management:
    • Malignant pleural effusion or nonmalignant pleural effusion (including heart failure, hepatic hydrothorax, nephrotic syndrome, peritoneal dialysis, chylothorax, and lupus). (Folch 2023)
    • General criteria for use of pleurodesis for pleural effusions: (Folch 2023)
      • (1) Symptomatic pleural effusion.
      • (2) Therapeutic drainage causes clinical improvement.
      • (3) Recurrence despite maximal treatment of the underlying condition.
      • (4) Lung re-expansion following drainage.
  • [2] Pneumothorax or persistent air leak: discussed further here 📖

contraindications to pleurodesis

  • ⚠️ Inability to achieve complete lung inflation. Chemical pleurodesis requires that the lung can be fully reinflated and opposed to the chest wall. If it is impossible to completely reinflate the lung (e.g., despite placing the chest tube to suction), then pleurodesis is contraindicated.
    • Pleurodesis can be performed despite an ongoing air leak, provided that complete lung inflation is achievable. (Fishman 2023)
    • Pleurodesis isn't an option for trapped lung (where it's impossible to achieve complete apposition of the visceral and parietal pleura).
  • ⚠️ Poorly functioning chest tube: It is essential that the chest tube is functioning properly.
  • ⚠️ Plans for future thoracic surgery. Pleurodesis may make subsequent thoracic surgery more challenging. This predominantly is relevant for patients who may be lung transplant candidates. Doxycycline could have a slight advantage here, as the degree of pleural symphysis and density of adhesions may be less than with talc. (Fishman 2023)
  • ⚠️ Unresolved pleural space infection.
  • ⚠️ Low pH: pH below 7.15-7.3 predicts failure of pleurodesis (relative contraindication). (Folch 2023)

potential complications

  • Common complications:
    • Chest pain.
    • Fever
      • Usually low-grade.
      • Usually begins 4-12 hours post-procedure and may last up to 3 days.
      • Reported in up to 69% of patients. (Folch 2023)
    • Gastrointestinal symptoms. (Folch 2023)
  • Rare complications:
    • Empyema.
    • Acute lung injury (following talc pleurodesis).
choice & dose of sclerosant administration 

High-quality evidence is lacking to compare various agents. (9432409, 8205870) 

talc

  • Talc is generally believed to be more effective. For malignant pleural effusions, a Cochrane Database network meta-analysis suggested that doxycycline was associated with a higher failure rate than talc, but this was statistically nonsignificant (odds ratio for failure of 2.51, 95% confidence interval 0.81-8.40). (32315458)
  • Talc carries a very low risk of precipitating hypoxemic respiratory failure (including ARDS), due to migration of talc particles out of the pleura. Modern talc preparations that contain a larger particle size have reduced this risk. (Fishman 2023) Risk of respiratory failure may be minimized by:
    • (1) Not exceeding a dose of 5 grams.
    • (2) Avoiding bilateral talc pleurodesis.
    • (3) Avoiding talc administration following significant pleural injury or numerous pleural biopsies. (Folch 2023)
  • Dose of talc:
    • The dose is typically 3-5 grams in 50-200 ml of normal saline, usually 4 grams. (32525474) Four grams may be reasonable for a pleural effusion (to balance efficacy versus the risk of hypoxemic respiratory failure). (23374395)
    • Two grams may be sufficient to treat spontaneous pneumothorax. (Folch 2023)

doxycycline

  • Advantages of doxycycline:
    • (1) Doxycycline might be preferred among patients with a substantial ongoing air leak, due to the theoretical risk that talc could enter the lung parenchyma and cause pneumonitis. However, one study did demonstrate successful utilization of talc in this context. (20172150)
    • (2) Doxycycline may be preferred if the patient is a potential candidate for future lung transplantation (see discussion above).
    • (3) Doxycycline carries no risk of causing hypoxemic respiratory failure.
  • Disadvantages of doxycycline: efficacy may be lower than talc.
  • Dose of doxycycline: Dose may typically be 500-1,000 mg doxycycline in 50-100 ml of normal saline.
protocol for bedside pleurodesis

[1] pretreatment to reduce pain

  • [a] Systemic analgesia:
    • Start acetaminophen prior to the procedure (e.g., 1 gram Q6hr scheduled).
    • Premedicate with opioid analgesia (either PO or IV).
  • [b] Lidocaine should be administered into the pleura ~10 minutes before pleurodesis.
    • Use 3 mg/kg (up to 250 mg maximum dose).
    • 1% lidocaine contains 10 mg of lidocaine per ml. Thus, the dosing of 1% lidocaine is 0.3 ml/kg (up to 25 ml maximum volume).

[2] administration of sclerosant agent

  • Instill the scleosant agent (talc or doxycycline; dose discussed above).
  • Then flush 20 ml of normal saline into the pleural catheter. (32525474)

[3] the next two hours 

  • Clamp the chest tube for two hours.
  • There is no need to rotate the patient in bed.
  • If the patient cannot tolerate chest tube clamping (e.g., due to pneumothorax with air leak), the tube may be hung over an IV pole (to prevent tension pneumothorax, without preventing the sclerosant from immediately draining out of the chest).

[4] suction for 24 hours

  • Open the chest tube and place it on -20 cm suction for at least 24 hours.
  • Suction is essential to achieve maximal apposition of the pleural and the chest wall.
  • Chest radiograph should be performed ~18-24 hours after talc instillation. (32525474)

[5] chest tube removal

  • The chest tube may be removed after >24 hours, after the fluid drainage has decreased to <150-250 ml/day. (Folch 2023, 32525474)
  • For doxycycline: If chest tube output continues to be high (>300 ml/day), consider repeating pleurodesis.
discussion of some additional technical details

pleurodesis via chest tube vs. thoracoscopic surgery

  • There is little evidence that pleurodesis is more effective if performed via surgery, as compared to performed via a chest tube.
    • Pleurodesis may be achieved by applying talc through a chest tube, or via thoracoscopy. A multicenter RCT of malignant pleural effusion found that the success rate was identical regardless of whether talc was introduced via chest tube or thoracoscopy. (31804680) Thoracoscopy had been touted for its ability to distribute talc more widely, but this doesn't seem to matter. Pleurodesis results from a generalized inflammatory reaction in the pleura, rather than from using talc to serve as localized “glue” that holds the visceral and parietal pleura together. (Murray 2022)
  • If a patient requires VATS surgery for some other indication (e.g., bleb resection for pneumothorax, or pleural biopsy), then pleurodesis may be performed at the end of the surgical procedure.

choice of chest tube for pleurodesis

  • Use of a larger bore chest tube (24 French vs. 12 French) was not shown to affect the rate of successful pleurodesis among patients with a malignant pleural effusion. (26720026) 

questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

Guide to emoji hyperlinks 🔗

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Books:

  • Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
  • Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
  • Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
  • Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
  • Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
  • Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
  • Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.
  • Folch E, Tabba M, and slate J. Principles and Practice of Pleural Diseases. (2023)

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.


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We are the EMCrit Project, a team of independent medical bloggers and podcasters joined together by our common love of cutting-edge care, iconoclastic ramblings, and FOAM.

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