Pleural effusion overview

# Overview
Pleural effusion is defined as the presence of excessive fluid in the pleural cavity resulting from transudation or exudation from the pleural surfaces. In normal conditions, the pleural space contains a limited amount of fluid (0.3 mLkg-1) maintained by a complex interplay of hydrostatic pressures and lymphatic drainage, which allows for steady liquid and protein turnover. Pathological processes may lead to the development of pleural effusions by causing disequilibrium between the rates of pleural fluid formation, pleural permeability and pleural fluid absorption. Pleural effusion may be secondary to pleural processes, pulmonary disorders, systemic conditions, and medications. A systematic approach with a comprehensive clinical history and physical examination is required for establishing the etiology.

# Historical Perspective
Pleural infection was first described by Hippocrates circa 460-370 B.C. During this time open chest drainage was the sole treatment modality and was associated with high mortality.
In 1300s, Guy de Chauliac also called Guido or Guigo de Cauliaco, a surgeon of medieval France, commented with surprise on the lack of ancient writings concerning thoracic wounds and the disagreements on the treatment of these wounds. Lanfranc of Paris, William of Bologna, and Roland of Parma advocated that open treatment of penetrating thoracic wounds using tents and drains allow blood and decaying organic materials to escape. However, Henri de Mondeville debated that immediate closure of wounds helps to prevent heat loss and air entry.
During the early 1500s, Giovanni da Vigo, an Italian surgeon and physician of Pope Julius II, was one of the first surgeons to discuss firearm wounds to the chest.
In 1873, Playfair gave the first description of a water-seal chest drainage system in the treatment of a child with thoracic empyema.
In 1875, Gotthard Bulau a German internist described the use of closed water-seal chest drainage to treat an empyema as an alternative to the standard rib resection and open tube drainage. He punctured the pleural membrane with trocar and introduced a rubber catheter into the pleural cavity. The free end of the catheter inserted in a bottle one-third full of solution allowing pus to flow freely from the chest into the bottle.
Closed chest tube drainage was experimentally practiced during the influenza epidemic in 191719 when open surgical drainage was associated with a high mortality rate. This coincided with World War I and the resultant crisis of streptococcal pneumonia and empyema.
In 1950, Vincenzo Monaldi an Italian pulmonologist suggested draining the thoracic cavity with a more superior approach at the second or third intercostal space.
The modern three chamber thoracic drainage system was first described by Howe in 1952 but not widely employed at the time.
Closed chest tube drainage became the standard of treatment from late 1950.

# Classification
Pleural effusion may be classified according to composition of pleural fluid by Light's criteria into two subtypes: exudate and transudate. An increase in plasma osmotic pressure or elevated systemic or pulmonary hydrostatic pressure are alterations that lead to the formation of transudate. In contrast, an exudate results from inflammation and infectious disease of the pleural surface, as seen in tuberculosis and pneumonia with effusion, or other disease of the pleural surface as seen in malignancy, pancreatitis, pulmonary infarction, or systemic lupus erythematosus.
Light's criteria classifies pleural fluid as an exudate if at least one of the following three criteria are fulfilled: 
- Pleural fluid protein/serum protein ratio greater than 0.5, or
- Pleural fluid LDH /serumLDH  ratio greater than 0.6, or
- Pleural fluid LDH greater than two-thirds the upper limit of the laboratory's normal serum LDH
Pleural effusion may also be classified according to the appearance of pleural fluid, and etiology of the pleural fluid:
- Serous fluid: hydrothorax
- Blood: hemothorax
- Chyle: chylothorax
- Pus: pyothorax or empyema

# Pathophysiology

## Anatomy/Physiology
Healthy individuals have less than 15 ml of fluid in each pleural space. Normally, fluid enters the pleural space from the capillaries in the parietal pleura, from interstitial spaces of the lung via the visceral pleura, or from the peritoneal cavity through small holes in the diaphragm. This fluid is normally removed by lymphatics in the visceral pleura, which have the capacity to absorb 20 times more fluid than is normally formed. When this capacity is overwhelmed, either through excess formation or decreased lymphatic absorption, a pleural effusion develops.
The lungs are surrounded by two membranes, the outer parietal pleura, which is attached to the chest wall, and the inner visceral pleura, which is attached to the lung. The two layers are continuous with one another. In between the two is a thin space known as the pleural cavity or pleural space. This is filled with pleural fluid, a serous fluid produced by the pleura. Each pleural membrane is made up of a layer of mesothelial cells, basement membrane, connective tissue, microvessels and lymphatics. The parietal pleura have lymphatic stomata, of 2 to 10 m in diameter, that open onto the pleural space. The pleural fluid lubricates the pleural surfaces and allow the layers of pleura to slide against each other easily during respiration. It also provides the surface tension that keeps the lung surface in contact with the chest wall. During quiet breathing, the cavity normally experiences a negative pressure (compared to the atmosphere), which helps to adhere the lungs to the chest wall, so that movements of the chest wall during breathing are coupled closely to movements of the lungs. The pleural membrane also helps to keep the two lungs away from each other and air tight, thus if one lung is punctured and collapses due to an accident, the other pleural cavity will still be air tight, and the other lung will function normally.
The parietal pleura has different names depending on its location, namely costal pleura, diaphragmatic pleura, cervical pleura, and mediastinal pleura. The visceral pleura covers the surface of lungs, including the interlobar fissures. There is no anatomical connection between the left and the right pleural cavities so in cases of pneumothorax, the other hemithorax will still be able to function normally. The parietal pleura is supplied with blood from systemic circulation (intercostals, internal thoracic and musculophrenic); it contains sensitive nerves (derived from the intercostal nerves and from the phrenic nerve) and cells with a dense cilliary layer.
The visceral pleura is supplied with blood from bronchial artery and from the pulmonary artery which divides into a net work of very delicate capillaries. Its nerve supply is derived from the autonomic nerves innervating the lung and accompanying the bronchial vessels. The lymphatic drainage of parietal and visceral pleura differ from each other. The mesothelial surface of parietal pleura is permeated by stomas that connect via lacunae to a lymphatic network in the adjacent submesothelial layers. The costal surface of the parietal pleura drains to parasternal and para vertebral nodes, while the diaphragmatic surface drains to the tracheobronchial nodes. The visceral pleura are devoid of lacunas and stomas and the underlying lymphatic vessels appear to drain the pulmonary parenchyma rather than the pleural space.
The parietal pleura has been proposed as the more important pleura for pleural liquid turnover in the normal physiologic state in absence of disease. Its microvessels are closer to the pleural surface and perfusion pressure is likely higher than the visceral pleura. It is approximately 30 to 40 m thick. Pleural fluid is filtered across the parietal mesothelium in the top of the pleural cavity and removed by lymphatic stomata in the more dependent mediastinal and diaphragmatic regions. The pleural lymphatics act as a feedback system that regulate pleural liquid volume and its protein composition around a low volume set point.
Healthy individuals have less than 15 ml of fluid in each pleural space. Normally, fluid enters the pleural space from the capillaries in the parietal pleura, from interstitial spaces of the lung via the visceral pleura, or from the peritoneal cavity through small holes in the diaphragm.  This fluid is normally removed by lymphatics in the visceral pleura, which have the capacity to absorb 20 times more fluid than is normally formed. When this capacity is overwhelmed, either through excess formation or decreased lymphatic absorption, a pleural effusion develops.
Pleural effusion results either from increased pleural fluid formation or decreased exit of fluid.

## Increased Pleural Fluid Formation
- Increased hydrostatic pressure (e.g. seen in congestive heart failure)
- Decreased colloid osmotic pressure (e.g. cirrhosis and nephrotic
syndrome)
- Increased capillary permeability (e.g. infection, neoplasm)
- Passage of fluid through openings in diaphragm (e.g. cirrhosis with ascites)
- Reduction of pleural space pressures (e.g. atelectasis)
- Increase in fluid conductance or protein permeability.

## Decreased Fluid Exit
- Reflects a reduction in lymphatic function.
- There are intrinsic and extrinsic factors.
- Intrinsic
Impaired ability of lymphatic vessels to transport fluid. May be due to inflammation, endocrine problems (hypothyroidism), direct injury (chemotherapy, radiotherapy), infiltration with cancer.
- Impaired ability of lymphatic vessels to transport fluid. May be due to inflammation, endocrine problems (hypothyroidism), direct injury (chemotherapy, radiotherapy), infiltration with cancer.
- Extrinsic
Limitation of respiratory motion (diaphragm paralysis, lung collapse), compression of lymphatics (pleural fibrosis, pleural granulomas), blockage (pleural malignancy), acute increased in systemic venous pressure (superior vena cava syndrome). In chronic increase in systemic venous pressure, the lymphatics can adapt.
- Limitation of respiratory motion (diaphragm paralysis, lung collapse), compression of lymphatics (pleural fibrosis, pleural granulomas), blockage (pleural malignancy), acute increased in systemic venous pressure (superior vena cava syndrome). In chronic increase in systemic venous pressure, the lymphatics can adapt.

# Causes
Common causes of transudative pleural effusion include: left ventricular failure, nephrotic syndrome, and cirrhosis, while common causes of exudative pleural effusions are bacterial pneumonia, cancer (with lung cancer, breast cancer, and lymphoma causing approximately 75% of all malignant pleural effusions), viral infection, and pulmonary embolism. Pulmonary embolism may lead to formation of either transudate or exudate however, an exudate is commonly observed.

# Differentiating Pleural Effusion from other Diseases
Evaluation of a patient with a pleural effusion requires a thorough clinical history and physical examination in conjunction with pertinent laboratory tests and imaging studies. Thoracentesis should not be performed for bilateral effusions in a clinical setting strongly suggestive of a transudate unless there are atypical features or they fail to respond to therapy. Pleural fluid should always be sent for protein, lactate dehydrogenase, Gram stain, cytology, and microbiological culture. Additional studies which may be indicated in selected cases include pH, glucose, acid-fast bacilli and tuberculosis culture, triglycerides, cholesterol, amylase, and hematocrit. Light's criteria is applied to distinguish the fluid between transudative or exudative. A  broad array of underlying conditions result in exudative effusions, while a limited number of disorders are assoicated with transudative effusions, which include congestive heart failure, cirrhosis, nephrotic syndrome, peritoneal dialysis, hypoalbuminemia, urinothorax, atelectasis, constrictive pericarditis, trapped lung, superior vena cava obstruction, and duropleural fistula.

# Epidemiology and Demographics
In the United States, up to one million patients develop parapneumonic effusions annually, and approximately 100,000 patients undergo pleurodesis for recurrent pleural effusions per year. Pleural effusion is reported to have an incidence of 0.32% in a study among the general population in central Bohemia. Congestive heart failure accounts for nearly 50% of cases, with malignancy, pneumonia and pulmonary emboli as the next three leading causes. However, the distribution of causes is largely dependent on the population being studied. For example, the incidence of pleural effusion among ICU patients is estimated to be 22.19  17%, whereas the prevalence of tuberculous pleural effusion remains steady with respect to the total number of TB cases (14.3%-19.3%). The incidence of parapneumonic effusions is constantly increasing, although, the microbial epidemiology of these effusions differs from pneumonia with a higher prevalence of anaerobic bacteria. The incidence of pediatric empyema increased from 1 per 100,000 children aged 0 to 14 years in 1998 to 10 per 100,000 in 2012, with a peak incidence of 13 per 100,000 in 2009 with Staphylococcus aureus as most frequent cause followed by S. pneumoniae. The age predominace of pleural effusion varies depending on the underlying cause. Greater than 60% of tuberculous pleural effusion commonly affects individuals between 15-44 years. Pleural effusions are the most common thoracic involvement findings in patients with POEMS syndrome, affecting more than 40% of cases with median age at the time of diagnosis of POEMS syndrome as 45.1 years. HIV infection, pleural empyema, and complicated parapneumonic effusion are mostly seen in middle-aged patients (53  17 years). Males are more commonly affected with tuberculous pleural effusion than females. The male to female ratio is approximately 3:2. Males are more commonly affected with pleural empyema and complicated parapneumonic pleural effusion than females. The male to female ratio is approximately 2:1. There is no racial predilection for pleural effusion. Development of tuberculous pleural effusion is common on endemic developing countries with TB infection.

# Risk Factors
Common risk factors in the development of pleural effusion include pre-existing lung damage or disease,  chronic smokers,  neoplasia (e.g. lung cancer patients),  alcohol abuse,  use of certain medications (e.g. dasatinib in the treatment of patients with chronic myelogenous leukaemia and immunosuppressive medicine), occupational exposure to asbestos, and surgery-related risk factors.

# Natural History, Complications, and Prognosis
Complications of pleural effusion can result from the disease itself or from complication of treatment procedure. These include: empyema, pneumothorax, reexpansion pulmonary edema and postcardiac injury syndrome. When left untreated, patients will develop worsening symptoms of respiratory distress with increasing accumulation of pleural fluid. The prognosis of pleural effusion depends upon the underlying disease. High expression of E-cadherin in pleural effusion cells predicts better prognosis in lung adenocarcinoma patients. Imbalance of regulatory T cells/T helper IL-17-producing cells in malignant pleural effusion partially predicts poor prognosis. Additionally, a high ratio of regulatory T/Th17 cells in malignant pleural effusion highly correlates with poor survival.

# Diagnosis

## Symptoms
Common symptoms of pleural effusion include chest pain, cough, and shortness of breath.

## Physical Examination
Physical examination findings for effusions are determined by the volume of pleural fluid and the extent of lung compression. Pleural fluid also interferes with transmission of low-frequency vibrations and results in diminished tactile fremitus, asymmetric chest expansion, decreased or absent fremitus posteriorly and laterally, dullness on percussion, decreased or absent breath sounds, and reduced vocal resonance.

## Laboratory Findings
The first step in the evaluation of pleural fluid is to determine whether the effusion is a transudate or an exudate. According to Light's criteria, transudative and exudative pleural effusions are differentiated by comparing chemistries in the pleural fluid to those in the blood. According to a meta-analysis, the two-test or three-test rules for defining exudative pleural effusions have comparable specificity and sensitivity with light's criteria. It has an advantage over light's criteria in that there is no need to take blood sample and compare with pleural fluid sample before an exudative effusion can be defined.
Twenty-five percent of patients with transudative pleural effusions are mistakenly identified as having exudative pleural effusions by Light's criteria. Therefore, additional testing is needed if a patient identified as having an exudative pleural effusion appears clinically to have a condition that produces a transudative effusion. In such cases albumin levels in blood and pleural fluid are measured. If the difference between the albumin levels in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), it can be assumed that the patient has a transudative pleural effusion.
If the fluid is definitively identified as exudative, additional testing is necessary to determine the local factors causing the exudate.
The details of the various criteria have been summarized in the table below.
The fluid may then be evaluated for the following: chemical composition (protein, lactate dehydrogenase (LDH), albumin, amylase, pH and glucose), Gram stain and culture to identify possible bacterial infections, cell count and differential, cytology to identify cancer cells or potentially some infectious organisms, and other tests as suggested by the clinical situation (lipids, fungal culture, viral culture, specific immunoglobulins).
- Additional notes:
Tuberculosis (TB) effusion virtually always have a protein above 4.0 g/dL.
Pleural fluid protein in the 7 to 8 g/dL range may be indicative of Waldenstrom macroglobulinemia and multiple myeloma.
LDH above 1000 is usually found in empyema, rheumatoid pleuritis, and sometime malignancy.
Pleural fluid in pneumocystis carinii pneumonia (PCP) has fluid/serum LDH greater than 1 and fluid/serum protein ratio less than 0.5
Glucose levels lower then 60mg/dL or fluid/serum ratio < 0.5 is not seen in transudates and limits exudates to the following: rheumatoid pleuritis, Parapneumonic effusion, empyema, malignant effusion, TB, lupus pleuritis, oresophageal rupture.
A pH less than 7.30 with normal blood pH is typically found with same diagnosis as low glucose.
Normal pleural fluid is around pH 7.6 due to a bicarbonate gradient between pleural fluid and blood.
Amylase levels greater than the upper limit of normal for serum or a pleural fluid to serum ratio >1 narrows an exudate to acute pancreatitis, chronic pancreatic effusion, esophageal rupture, or malignancy.
Pleural fluid C-reactive protein (CRP) is superior to serum CRP in determining pleural fluid etiology. Quantitative measurement of pleural fluid CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with malignant pleural effusion.
- Tuberculosis (TB) effusion virtually always have a protein above 4.0 g/dL.
- Pleural fluid protein in the 7 to 8 g/dL range may be indicative of Waldenstrom macroglobulinemia and multiple myeloma.
- LDH above 1000 is usually found in empyema, rheumatoid pleuritis, and sometime malignancy.
- Pleural fluid in pneumocystis carinii pneumonia (PCP) has fluid/serum LDH greater than 1 and fluid/serum protein ratio less than 0.5
- Glucose levels lower then 60mg/dL or fluid/serum ratio < 0.5 is not seen in transudates and limits exudates to the following: rheumatoid pleuritis, Parapneumonic effusion, empyema, malignant effusion, TB, lupus pleuritis, oresophageal rupture.
- A pH less than 7.30 with normal blood pH is typically found with same diagnosis as low glucose.
- Normal pleural fluid is around pH 7.6 due to a bicarbonate gradient between pleural fluid and blood.
- Amylase levels greater than the upper limit of normal for serum or a pleural fluid to serum ratio >1 narrows an exudate to acute pancreatitis, chronic pancreatic effusion, esophageal rupture, or malignancy.
- Pleural fluid C-reactive protein (CRP) is superior to serum CRP in determining pleural fluid etiology. Quantitative measurement of pleural fluid CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with malignant pleural effusion.

## Chest X Ray
Chest films acquired in the lateral decubitus position (with the patient lying on their side) are more sensitive, and can detect as little as 50 ml of fluid. At least 200ml-300ml of fluid must be present before upright chest films can detect signs of pleural effusion (e.g. blunted costophrenic angles).

## CT
CT scan may be helpful when the underlying cause of pleural effusion is not certain (e.g in malignant pleural effusion). In most cases, CT imaging may not provide additional information that would influence the clinical decision-making process. Routine use of high-resolution chest CT is recommended for early diagnosis and timely treatment of pleural disease in children with juvenile idiopathic arthritis.

## MRI
MRI is usually not needed to diagnose pleural effusion. However, in rare cases when CT scan is inconclusive, MRI may be needed.

## Other imaging findings
Ultrasonography is not needed in making diagnosis of pleural effusion. However, chest or upper abdominal ultrasound may show subpulmonic effusion.

# Treatment

## Medical Therapy
Treatment aims to remove the fluid (i.e. therapeutic thoracentesis), prevent fluid re-accumulation by way of pleurodesis, and treat the underlying cause (e.g. antibiotic therapy in infectious causes). In some malignant causes, chemotherapy may be needed.

## Surgery
The primary role of surgical therapy is to drain the pleural fluid and prevent fluid from building up again. Therapeutic aspiration may be sufficient; larger effusions may require insertion of an intercostal drain. Therapeutic thoracentesis is performed if the fluid collection is large and causing chest pressure, shortness of breath, or other breathing problems, such as hypoxia. Removing the fluid allows the lung to expand, making breathing easier. In people with cancer or infections, the effusion is often treated by using a chest tube for several days to drain the fluid.
Sometimes, small tubes may be left in the pleural cavity for an extended period of time to drain the fluid. Repeated effusions may require chemical (e.g. talc, bleomycin, tetracycline/doxycycline) or surgical pleurodesis.

## Prevention
There is no established method for prevention of pleural effusion. However, avoidance of some risk factors (e.g. smoking cessation, alcohol cessation, early treatment of pneumonia, and controlling heart failure) have demonstrated helpfulness.