Pleural effusions

An increased (clinically significant) volume of fluid in the pleural space

Epidemiology

• Breakdown according to Shields:
  • 40% CCF
  • 20% parapneumonic effusion
  • 10% malignancy
  • 8% PE
  • 5% viral disease
  • 2.5% post-cardiac surgery
  • 1% GIT pathology
  • 0.1% TB
  • 0.1% malignant pleural mesothelioma
  • 0.1% asbestos-related benign pleural diseases

Aetiology

• Pleural infection (parapneumonic effusion - about 40%) and CCF (about 25%) are the most common causes, followed by things like chronic liver disease, renal disease, asbestosis, RA, SLE pleuritis, pancreatitis, PE and cardiac surgery.
• Transudative
  • Left heart failure (marked increase in permeability of visceral pleura, and interstitial lung oedema - not seen commonly in RHF)
  • Cirrhosis/hepatic failure
  • Nephrotic syndrome/renal failure
  • Hypoalbuminaemia
  • Fluid retention/overload
  • Pulmonary embolism (usually occupies less than one third of hemithorax and can be bilateral in 46% of cases, with dyspnoea out of proportion)
  • Lobar collapse/trapped lung (pleural dead space is filled by effusion fluid)
  • Meigs syndrome
• Exudative
  • Malignant
    • Primary lung
    • Metastatic
    • Lymphoma
    • Mesothelioma
  • Infectious
    • Bacterial (parapneumonic)/empyema (see separate topic)
    • TB
    • Fungal
    • Viral
    • Parasitic
  • Collagen vascular disease related
    • RA
    • Wegener granulomatosis
    • SLE
    • Churg-Strauss syndrome
  • Others
    • Chylothorax
    • Uraemia
    • Sarcoidosis
    • After CABG
    • Radiation/trauma
    • Dressler syndrome
    • PE with infarction
    • Asbestosis related
• Benign effusions (sometimes also called hydrothorax)
  • Systemic disease
    • Generally cause bilateral effusions
  • Local disease
    • Inflammation leads to both increased fluid filtration and decreased lymphatic drainage
    • Often causes unilateral moderate to large effusions

Causes of transudative pleural effusions

Causes of transudative effusions	Comment
Processes that always cause a transudative effusion
Atelectasis	Caused by increased intrapleural negative pressure
Cerebrospinal fluid leak into pleural space	Thoracic spinal surgery or trauma and ventriculopleural shunts
Heart failure	Acute diuresis can result in borderline exudative features
Hepatic hydrothorax	Rare without clinical ascites
Hypoalbuminemia	Edema liquid rarely isolated to pleural space
Iatrogenic	Misplaced intravenous catheter into the pleural space; post Fontan procedure
Nephrotic syndrome	Usually subpulmonic and bilateral
Peritoneal dialysis	Acute massive effusion develops within 48 hours of initiating dialysis
Urinothorax	Caused by ipsilateral obstructive uropathy or by iatrogenic or traumatic GU injury
Processes that may cause a transudative effusion, but usually cause an exudative effusion
Amyloidosis	Often exudative due to disruption of pleural surfaces
Chylothorax	Most are exudative effusions
Constrictive pericarditis	Bilateral effusions
Hypothyroid pleural effusion	From hypothyroid heart disease or hypothyroidism per se
Malignancy	Usually exudative, but 3 to 10 percent transudative possibly due to early lymphatic obstruction, obstructive atelectasis, or concomitant disease (eg, heart failure)
Pulmonary embolism	Most are exudative effusions
Sarcoidosis	Stage II and III disease
Superior vena caval obstruction	May be due to acute systemic venous hypertension or acute blockage of thoracic lymph flow
Coronavirus disease 2019 (COVID-19)	Limited data profile the nature of pleural fluid in COVID-19-related pleural effusions, although transudative effusions have been reported
Nonexpandable lung*	A result of remote or chronic inflammation

Causes of exudative pleural effusions

Infectious Bacterial pneumonia Tuberculous pleurisy Parasites Fungal disease Viral pneumonias (eg, influenza, coronavirus disease 2019 [COVID-19]) Nocardia, Actinomyces Subphrenic abscess Hepatic abscess Splenic abscess Hepatitis Spontaneous esophageal rupture Cholecystitis Iatrogenic or trauma Central venous catheter misplacement/migration Drug-induced (eg, nitrofurantoin, dantrolene, methysergide, dasatinib, amiodarone, interleukin-2, procarbazine, methotrexate, clozapine, phenytoin, beta blocker, ergot drugs) Esophageal perforation Esophageal sclerotherapy Enteral feeding tube in pleural space Radiofrequency ablation of pulmonary neoplasms Hemothorax Chylothorax Malignancy-related Carcinoma Lymphoma Mesothelioma Leukemia Chylothorax Paraproteinemia (multiple myeloma, Waldenstrom's macroglobulinemia) Paramalignant effusions Other inflammatory disorders Pancreatitis (acute, chronic) Benign asbestos pleural effusion Pulmonary embolism Radiation therapy Uremic pleurisy Sarcoidosis Postcardiac injury syndrome Acute respiratory distress syndrome (ARDS) Immunoglobulin G4-related disease (fibroinflammatory)

Increased negative intrapleural pressure with accompanying pleural malignancy or inflammation Lung entrapment Cholesterol effusion (eg, due to tuberculosis, rheumatoid arthritis) Connective tissue disease Lupus pleuritis Rheumatoid pleurisy Mixed connective tissue disease Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Granulomatosis with polyangiitis (Wegener's) Familial Mediterranean fever Endocrine dysfunction Hypothyroidism Ovarian hyperstimulation syndrome Lymphatic abnormalities Malignancy Chylothorax (eg, yellow nail syndrome, lymphangioleiomyomatosis, lymphangiectasia) Movement of liquid from abdomen to pleural space Pancreatitis Pancreatic pseudocyst Meigs' syndrome Chylous ascites Malignant ascites Subphrenic abscess Hepatic abscess (bacterial, amebic) Splenic abscess, infarction Miscellaneous Endometriosis Drowning Electrical burns Capillary leak syndromes Extramedullary hematopoiesis

Pathophysiology

• Disrupted balance between fluid production and absorption
  • The amount of pleural fluid is controlled by a balance of oncotic and hydrostatic pressure within the pleural space and pleural capillaries
  • Under normal circumstances, the net pressure moves fluid from the parietal pleura into the pleural space
  • Pleural space normally contains 0.3mL/kg of fluid
  • Normal turnover is about 0.15mL/kg/hour
  • Most pleural fluid is reabsorbed through lymphatics of the parietal pleura - protein cannot re-enter the relatively impermeable visceral pleura
• Causative factors:
  • Increased input:
    • Increased hydrostatic pressure
    • Increased negative intra-pleural pressure
    • Increased capillary permeability
    • Decreased plasma oncotic pressure
  • Decreased output:
    • Strong reduction in lymphatic drainage
• A pleural effusion represents a new equilibrium point between pressures acting across compartments - hence a larger imbalance will lead to a larger effusion
• Characterise as transudate or exudate
  • Transudates are protein-poor and result in change in fluid balance in the pleural space
  • Exudates are protein-rich and may be related to disruption of pleural or lymphatic reabsorption
• Volume
  • 300mL of fluid causes blunting of costophrenic angle on upright CXR
  • 500mL of fluid can be detected clinically

Symptoms:

• Dyspnoea (effusion causes compression and collapse of adjacent lung - most commonly lower lobe)
  • Volume of effusion
  • Degree of compression and collapse
  • Underlying lung function
• Chest pain
• Cough
• Massive pleural effusion can cause tension effusion - mediastinal shift and tension physiology (requires 1-3L)

Examination

• Asymmetrical decreased expansion
• Dullness to percussion
• Diminished or inaudible breath sounds
• Effusions <300mL will not show on physical exam

Diagnosis

• Pleural fluid only 3-test combination (favoured by UTD)
  • Any one of the following means exudate:
    • Pleural fluid protein >30g/L
    • Pleural fluid cholesterol >1.42mmol/L
    • Pleural fluid LDH >0.67 * serum LDH ULN (LDH ULN is typically ~280U/L)
• Light's criteria
  • Any one of the following means exudate:
    • Pleural fluid to serum protein ratio >0.5
    • Pleural fluid to serum LDH ratio > 0.6
    • Pleural fluid LDH > 0.67 * serum LDH ULN (LDH ULN is typically ~280U/L)
  • High sensitivity but only moderate specificity for exudates
  • 25% of transudates are incorrectly classified as exudates, particularly those due to heart failure when diuretics are given, or where erythrocytes are present in pleural fluid, which release LDH
• Visual characteristics
  • Serous
  • Bloody
  • Milky
  • Turbid
  • Frankly purulent
• Cytology (sensitivity and specificity 65-90%)
• Cell counts
• Gram stain and MCS
• TB testing
• Pleural and serum protein, glucose, LDH and pH

Other investigations

• Exclude medical conditions
  • BNP
  • eGFR
  • LFTs
  • TTE
• CT chest

Management:

• Treat the underlying disorder
• Drainage for symptomatic effusions
• Drainage for diagnostic purposes if complication is suspected

Treatment

• Benign effusions
  • Most benign pleural effusions are transudates, free-flowing, without loculation
  • Treat underlying cause (CCF, ascites, malnutrition)
  • Completely drain for diagnosis and treatment (14Fr or smaller if leaving a drain in)
  • CXR to confirm complete drainage
  • 'Trapped lung' may require decortication, especially if remaining symptomatic
  • If no improvement in symptoms, look for alternative causes
  • Recurrences
    • Consider repeat thoracentesis, tube thoracostomy or pleurodesis (mechanical vs chemical)
    • Don't need to continuously drain unless significant respiratory compromise is present
• Unilateral effusions
  • Parapneumonic, empyema, inflamed parietal pleura, chylothorax, haemothorax, pleural infection
  • Drain effusion and correct consequences
  • Indications for VATS:
    • Recurrent effusion following earlier drainage
    • Trapped lung (lack of re-expansion following drainage)
    • Loculated or multiloculated effusions
    • Parietal pleural tissue biopsies are required for diagnosis
    • Very large unilateral effusion (consider VATS vs drainage - higher recurrence rate and malignancy rate)
  • Role for VATS
    • Complete drainage of effusion
    • Parietal pleural biopsies
    • Re-expansion of lung and de-cortication if necessary
    • Pleurodesis
• Malignant pleural effusions
  • An effusion with positive cytopathology
  • Median survival 90 days (5 months in breast cancer, and longer in lymphoma)
  • Not all effusions associated with malignancy are caused by direct or metastatic pleural involvement (consider bronchial or lymphatic obstruction, hypoproteinaemia, and accumulation from infra-diaphragmatic involvement)
  • Consider pleurX catheter or pleurodesis
• Tension pleural effusion
  • Drain immediately
• Drainage
  • Need CT or USS prior to drainage, since CXR can get it wrong
  • Typically needle thoracocentesis under USS-guidance, with a catheter sometimes being left in
  • Dogma states don't remove more than 1-1.5L in one sitting to prevent re-expansion pulmonary oedema, however the veracity of this is unknown. Larger volumes can be removed if the benefits of symptom improvement are thought to outweigh the risks.
  • Those who respond well to drainage should also respond well for drainage of reaccumulations
  • Drain on the larger side, or the right side if both are equal

Survival with malignant pleural effusions according to cancer type

Cell type	Median survival in days (95% CI)	n
Mesothelioma	339 (267 to 422)	170
Hematological malignancy	218 (160 to 484)	35
Gynecological malignancy	230 (97 to 279)	59
Breast cancer	192 (133 to 271)	140
Renal cell carcinoma	114 (33 to 334)	22
Adenocarcinoma of unknown primary	87 (13 to 286)	11
Lung cancer	74 (60 to 92)	215
Other	71 (46 to 102)	33
Gastrointestinal cancer	61 (44 to 73)	61
Sarcoma	44 (19 to 76)	12
Melanoma	43 (23 to 72)	23
Urological cancer (bladder, prostate, testis, penile)	33 (22 to 168)	8
Overall	136 (119 to 167)	789

LENT score

	Variable	Score
L	LDH level in pleural fluid (IU/L)
	<1500	0
	>1500	1
E	ECOG PS
	0	0
	1	1
	2	2
	3 to 4	3
N	NLR
	<9	0
	>9	1
T	Tumor type
	Lowest risk tumor types Mesothelioma Hematological malignancy	0
	Moderate risk tumor types Breast cancer Gynecological cancer Renal cell carcinoma	1
	Highest risk tumor types Lung cancer Other tumor types	2
	Risk categories	Total score (median survival in days)
	Low risk	0 to 1 (319)
	Moderate risk	2 to 4 (130)
	High risk	5 to 7 (44)

LDH: lactate dehydrogenase; ECOG PS: Eastern Cooperative Oncology Group performance score; NLR: neutrophil to lymphocyte ratio.

Management of malignant and paramalignant pleural effusions

Option	Comment
Observation	For asymptomatic effusions; most will progress and require therapy
Therapeutic thoracentesis	Prompt relief of dyspnea; most effusions recur unless underlying tumor responds to chemo- or radiotherapy
Chest catheter drainage only	Most effusions will recur after catheter removal
Chest catheter drainage with chemical pleurodesis (eg, talc slurry)	Variable response rate with 60 to 90 percent of patients responding to talc pleurodesis
Thoracoscopy with talc insufflation	Control of effusion with similar frequency as chest catheter drainage with talc pleurodesis
Long-term indwelling pleural catheter	Control of effusion and improved symptoms in most patients. Some patients may experience pleurodesis after two weeks (median 11 weeks) of catheter drainage, which allows catheter removal.
Long-term indwelling pleural catheter with talc instillation	Control of effusion and symptoms with successful pleurodesis in 43 percent of patients without hospitalization
Pleural abrasion or pleurectomy	Requires thoracoscopy or thoracotomy. Effectively controls effusions in nearly all patients.
Pleuroperitoneal shunt	When other options have failed or are not indicated; may be useful for chylothorax
Chemotherapy	May be effective in some tumor types, such as breast cancer, lymphoma, and small cell lung cancer
Radiotherapy	Mediastinal radiation therapy may be effective in lymphoma and lymphomatous chylothorax

Traditional criteria for indwelling pleural catheter removal - <50mL drainage for three consecutive days