Diseases of the pleural space in dogs and cats

Most of the pathological conditions affecting the pleural space can be classified, based on their aetiology, in three main categories:

• PLEURAL EFFUSIONS
• PNEUMOTHORAX
• PLEURAL NEOPLASIA (mesothelioma)

THE PLEURA

The pleura is a thin membrane that lines the entire thoracic cavity, lungs and mediastinum. It is composed of two major elements: the mesothelium and connective tissue.

The mesothelium cell layer is composed of a thin monolayer of flattened cells, rich in microvilli producing glycoproteins and phospholipids to reduce friction between organ surfaces. The mesothelium layer is supported by a network of connective and fibroelastic tissues, lymphatics and vessels. These course through the connective layer and are responsible for the normal physiologic functions of the pleural space.

The pleura consists of a parietal sheet, which lines the internal ribs surface, the diaphragm and the mediastinum, and of a visceral sheet, which covers the serosal surface of the lungs. The mediastinum, the space existing between each hemithorax, contains the heart, trachea, oesophagus, aorta and the thymus, and is continuous with the fascial planes of the neck cranially and the retroperitoneal space caudally. In healthy dogs and cats the mediastinal pleura is incomplete because of the presence of fenestrations that allow air and most effusions to pass freely between the right and the left hemithorax. Additionally, the parietal mesothelium presents few but large pores, the “stomas”, that allow direct lymphatic drainage removing particles (like proteins) and cells from the pleural space.

The parietal pleura receives its blood supply from the systemic circulation and contains sensory nerve endings, whereas the visceral pleura receives its blood supply from the low pressure pulmonary circulation and does not contain sensory nerve fibres.

In physiological conditions the pleural space between the parietal and visceral pleura is potentially and normally filled with 5-10 ml of serous fluid. This provides lubrication between organ surfaces during movement and mechanical coupling, which therefore allows direct transmission of forces between the chest wall and the lungs during normal respiratory phases.

Normal pleural fluid is a serous ultrafiltrate of blood with low protein content. This enters the pleural space through the parietal pleural arteriolar capillaries, thanks to a net filtration pressure. It is removed by an absorptive pressure gradient through the visceral pleural venous capillaries, by lymphatic drainage through the stomas of the parietal pleura and by cellular mechanisms. Pleural mesothelium cells are metabolically active and possess the cellular features necessary for the active transport of solutes, including the vesicular transport of proteins.

PLEURAL EFFUSIONS

Pleural effusion is defined as the abnormal collection of fluid in the thoracic cavity that can result from a large variety of disease processes.

These include:

• congenital disorders;
• cardiac diseases;
• primary thoracic or abdominal neoplasia;
• secondary thoracic metastasis;
• primary abdominal diseases;
• infections of the thoracic cavity;
• vascular disease;
• rodenticide poisoning;
• trauma.

The rate of production and absorption of physiological pleural fluid is dependent on Starling’s forces, on the degree of mesothelial and endothelial permeability and on lymphatic drainage integrity.

Therefore, the factors responsible for pleural effusion may be classified in three main categories:

• changes in transpleural pressure balance;
• increases in mesothelium and capillary endothelial permeability;
• impairment of lymphatic drainage._¹

STARLING’S FORCES AND PLEURAL FLUID PRODUCTION
The "Starling" forces are the oncotic and hydrostatic pressures involved in the movement (filtration) of fluids across the capillary membrane.

According to Starling's equation, the movement of pleural fluid between compartments depends on the following forces:

• systemic and pulmonary capillary hydrostatic pressure - the pressure that will force fluid out from the capillary;
• intrapleural hydrostatic pressure - the pressure that will force fluid out from the pleural space;
• systemic and pulmonary capillary oncotic pressure - the osmotic pressure that will force the fluids to enter the capillary from the pleural space;
• intrapleural oncotic pressure - the osmotic pressure that will force the fluids to enter the pleural space from the systemic and pulmonary capillaries.

In normal conditions, the summation of the outward force (caused by capillary hydrostatic pressure and intrapleural oncotic pressure) and the inward force (caused by capillary oncotic pressure and intrapleural hydrostatic pressure) is almost in equilibrium, with a slight imbalance of outward forces.

Parietal arteriolar capillaries have a hydrostatic pressure (HP) of 30 cm H2O, similar to that of the systemic circulation, whereas that of the visceral pleural venous capillaries depends on the pulmonary circulation, which is around 11 cm H2O. The intrapleural HP is around -5 cm H2O. Parietal and visceral oncotic pressures (OP) are equal (34 cm H2O) and greater than that of the intrapleural cavity (8 cm H2O). The difference between the parietal, intrapleural and visceral HP sets up a gradient that forces the pleural fluid across the pleural cavity and its absorption by the visceral capillaries.

The subtraction of the systemic capillary and intrapleural HP is 35 cm H2O (30 cm H2O – (- 5 cm H2O)), whereas the subtraction of the respective OP is 26 cm H2O (34 cm H2O – 8 cm H2O). Therefore, the net filtration pressure which determines the formation of pleural fluid is 9 cm H2O (hydrostatic pressure 35 cm H2O – oncotic pressure 26 cm H2O).

The subtraction of the pulmonary and intrapleural HP is 16 cm H2O (11 cm H2O- (-5 cm H2O)), whereas the subtraction of the respective OP is 26 cm H2O (34 cm H2O – 8 cm H2O). At this level the OP is higher than the HP, therefore the pleural fluid undergoes resorbtion by the visceral pleura with a net HP of 10 cm H2O (OP 26 cm H2O – HP 16 cm H2O).

CHANGES IN TRANSPLEURAL PRESSURE BALANCE
Imbalances of this filtration-absorption mechanism result in the accumulation of pleural fluid.

As aforementioned, effusion accumulation is correlated with increased hydrostatic pressure in microvascular circulation (congestive heart failure), decreased oncotic pressure in microvascular circulation (severe hypoalbuminaemia) or increased OP in the pleural space.

Increases in hydrostatic forces or decreases in oncotic pressures result in low protein “transudates”.

INCREASE IN MESOTHELIAL AND ENDOTHELIAL PERMEABILITY
Through the action of inflammatory mediators like cytokines and histamine, inflammatory conditions of the pleura damage the endothelial lining of capillaries, increasing their permeability and filtration coefficient. The result is an increased influx of fluids, proteins, cells and macromolecules into the pleural space.

IMPAIRMENT OF LYMPHATIC DRAINAGE
Lymphatic drainage impairment alters pleural fluid dynamics in two ways:

1) Thickening of the costal parietal pleura, which is a major lymphatic drainage point in dogs and cats;

2) Decreased protein absorption. Proteins can only leave the pleural space via the lymphatics. Increased levels of proteins in the pleural space lead to increases in the pleural OP and therefore  favour fluid movement into it.

Increased endothelial and mesothelium permeability and loss of effective lymphatic drainage is typically present with malignant effusion.

Increased outpouring by “capillaries or cells and/or blocking of lymphatics results in high protein “exudates”.

PHYSICAL FINDINGS IN PATIENTS WITH PLEURAL EFFUSION

The clinical presentation of patients with pleural effusion is related to a decreased lung expandability and impaired gas exchange. A restrictive breathing pattern, characterised by rapid and shallow ventilation, develops. Animals can often compensate in the presence of a slow accumulation of large effusion volumes, until decompensation is triggered by stress, anxiety and increased environmental temperature. Owners usually report exercise intolerance, shortness of breath, open-mouth breathing, increased respiratory rate and dyspnoea. In some cases patients are reluctant to lay down, are inappetent, pyretic, anaemic and lethargic. Other findings include weight loss, dehydration and cyanosis, decreased lung sounds and muffled heart sounds.

DIAGNOSTIC EVALUATION OF PLEURAL EFFUSIONS

RADIOLOGY

Radiography or ultrasonography often support the diagnosis of pleural effusion or pneumothorax. As these investigations could severely compromise dyspnoeic patients, oxygen supplementation, minimal handling and taking only one lateral view of the chest are recommended. In some cases the removal of pleural fluid or air via thoracocentesis is advised before taking radiographs. A stable patient may undergo survey radiography that includes right and/or left lateral and either ventro-dorsal or dorso-ventral views. Classic radiological signs of pleural effusion include blurring of the cardiac silhouette, presence of interlobar fissure lines and rounding of the lung margins at the costo-phrenic angles. Fluid within the pleural cavity may be free or encapsulated. This is commonly associated with pyothorax (Fig. 1).

EVALUATION OF PLEURAL EFFUSIONS

Evaluation of pleural effusion is recommended in order to determine the definitive aetiology of the condition.  Analysis of the fluid should include physical, chemical and cytological characteristics. Physical parameters include volume, colour, turbidity, viscosity and odour (Fig. 2)

A portion of fluid should be collected in EDTA tubes and submitted for PCV if haemorrhagic, total nucleated cell count, total protein and cytology. The remainder of the sample should be placed in a serum tube for biochemical analysis and in culture-transport media for aerobic and anaerobic bacterial, mycoplasma and fungal cultures.

CLASSIFICATION OF EFFUSIONS

Two different classifications of effusions have been described:

• classification by total protein, specific gravity and total nucleated cell count;_²
• classification by aetiology._^3,4

The classification by total protein and total nucleated cell count utilizes three categories: transudate, modified transudate and exudate._²

The classification based on the aetiology (O’Brien, Stockham and Scott 1988) divides effusions into:

• protein-poor transudates;
• protein-rich transudates;
• effusion resulting from vessel or viscus rupture (haemothorax and chylothorax);
• non-septic exudates;
• septic exudates (pyothorax);
• effusions resulting from cell exfoliation (neoplasia)._⁴

CLASSIFICATION OF PLEURAL EFFUSIONS

A clinically useful classification of pleural fluid includes transudates, serosanguineous, haemorrhagic, inflammatory, chylous and neoplastic effusions.

TRANSUDATES
Transudates are typically clear and colourless. They can be either protein-poor or protein-rich. In veterinary patients, hypoalbuminaemia is the primary cause of protein-poor transudative effusions. A decrease in serum albumin reduces the oncotic pressure of the vascular system, resulting in increased fluid leakage and decreased absorption. Causes of hypoalbuminaemia include decreased production (e.g. with hepatic dysfunction or nutritional deficiency) and increased loss (e.g. protein-losing conditions). Protein-rich transudates result from congestive heart failure because of increased hydrostatic pressure. Any chronic transudate may become modified over time. Idiopathic pleuritis is most often associated with modified transudate (Fig. 3)._¹

SEROSANGUINEOUS EFFUSIONS
Many conditions can result in serosanguineous effusion such as lung lobe torsion, diaphragmatic hernia, pericardial effusion and neoplasia (mesothelioma) (Fig. 4).

Lung lobe torsion and diaphragmatic hernias with liver incarceration result in venous and lymphatic occlusion. Lung lobe torsion causes an increase of the HP with increased pleural fluid production, whereas liver incarceration results in parenchyma congestion and subsequent fluid leakage. Lung lobe torsion can also be associated with chylous or modified transudative effusion. Cardiac tamponade in cases of pericardial effusion causes right heart failure and increased fluid production.

EFFUSION FROM RUPTURED VESSELS
The most common effusions in this category are the haemorrhagic and chylous effusions.

Patients with a history of blunt, penetrating or surgical trauma are predisposed to this typology of cavitary effusion, but other causes should also be considered.^_1,3

HAEMORRHAGIC EFFUSION
Haemorrhagic effusions are usually characterized by a PCV >10%. Haemorrhagic effusion should be considered in patients with no history of trauma, coagulopathy, lung lobe torsion or neoplasia. A thrombocyte count and coagulation profile should be provided for evidence of coagulopathy. In these cases cytology  does not often yield diagnostic findings due to haemodilution. Haemorrhagic effusions typically do not clot and if the haemorrhage is chronic haemosiderophages may be present._^1,3

In non-coagulopathic spontaneous haemothorax the most common aetiology is neoplasia (e.g. haemangiosarcoma, mesothelioma, osteosarcoma of the ribs, pulmonary carcinoma, chemodectoma). Neoplasia can erode into vessels, leading to significant haemorrhage.

CHYLOUS EFFUSION
Chylous effusion results from the loss of lymphatic drainage integrity and is characterized by a milky appearance (Figs. 5 and 6). Chyle is classified as a modified transudate. Although chylothorax is commonly idiopathic, any condition that increases HP in the cranial vena cava leading to mechanical or functional obstruction of the lymphatico-venous junction can determine dilation and leakage of thoracic lymphatics. Primary cardiac disease, lung lobe torsion and masses compressing the lymphatic drainage are the most common causes of chylous effusion. Chylothorax can also occur with trauma, however thoracic duct tears usually heal spontaneously. Cytology usually shows a lymphocyte-predominant population and non-degenerate neutrophils. The definitive diagnosis is made comparing serum triglycerides and cholesterol with those of the effusion. With chyle, the triglyceride concentration is higher and the cholesterol is lower in the effusion compared with serum values._^5,6

BARTONELLA SPP- ASSOCIATED EFFUSION
Bartonella spp. organisms affect vascular integrity and are therefore categorized within effusions from ruptured vessels. Bartonella spp invade and infect vascular endothelium, leading to increased permeability and fluid accumulation. This type of effusion is classified as a pure or modified transudate; when other causes of effusion have been excluded, fluid culture and PCR for Bartonella may be worthwhile._⁷

INFLAMMATORY EFFUSIONS
Inflammatory effusions have an increased white blood cell count and can be modified transudates or exudates. They can be non-septic or septic and cytology determines the predominant cell population present in the effusion.  Inflammatory effusions are considered septic if bacteria are detected on cytology and culture. Pleural septic exudate takes also the name of pyothorax or thoracic empyema.

Cytology of inflammatory exudates usually shows a high content of nucleated cells, macrophages and lymphocytes, however with septic inflammation neutrophils become degenerate.

Inflammatory effusions result from a local inflammatory response to foreign material. The foreign material can be exogenous (e.g. bacterial, viral, fungal, protozoal, parasitic or inert), neoplastic or endogenous.

Local inflammatory responses release cytokines which alter the mesothelial and endothelial permeability and lead to secondary vasodilation. This results in an increased permeability to macromolecules, induces chemotaxis of inflammatory cells into the effusion and increases fluid production. As these and fibrin accumulate within the effusion the intrapleural OP rises, the lymphatic stomas become obstructed resulting in drainage impairment and fluid accumulation exacerbation. Additional fluid resorbtion decreases because of chronic pleural thickening.

NON-SEPTIC INFLAMMATORY EFFUSION
Non septic inflammatory effusions may be caused by diaphragmatic herniation of abdominal organs, chronic chylothorax, lung lobe torsion, pancreatitis, neoplasia and infectious diseases like Feline Infectious Peritonitis (FIP).

The wet form of FIP presents as a non-septic exudative disorder. The fluid is straw to gold in colour, has a high total protein content (often > 4.5 g/dl, Hartmann 2003) and a low total nucleated cell count._⁸

FIP can be of difficult diagnosis. Hartmann et al. (2003) reported that effusion feline coronavirus antibodies (1:1600), effusion gamma-globulin concentrations >1.0 g/dl and effusion albumin-globulin ratios > or = 0.9 are all associated with FIP, but their sensitivity and specificity are between 75% and 85%. The Rivalta’s test is very sensitive for the globulin content of fluid, but the specificity for FIP is of only 80%. Performing the Rivalta’s test is very simple: one drop of acetic acid (98%) is added to 5ml of distilled water and mixed. One drop of effusion is then placed in the mixture. If the drop stays at the top of the fluid or slowly floats to the bottom imitating the shape of cigarette’s smoke, the test is considered to be positive. A positive Rivalta’s test can result from lymphosarcoma, septic exudate or FIP effusion. Lymphosarcoma and septic effusions can be usually differentiated from FIP by cytology and culture, respectively._⁸

SEPTIC INFLAMMATORY EFFUSION (PYOTHORAX)
Septic effusions usually result from bacterial contamination of the chest cavity. Cytology is often diagnostic because of the identification of intracellular bacteria. This finding remains the gold standard for the initial diagnosis of a septic effusion while culture is pending. If the patient has been previously treated with antibiotics it may be difficult to find intracellular bacteria and the culture may result negative (Figs. 7 and 8).

EFFUSION FROM CELL EXFOLIATION
Lymphosarcoma is the most common neoplasia that can lead to an exfoliative effusion characterised by an immature lymphoid cell population usually larger than neutrophils (Fig. 9).

Carcinomas, mesotheliomas and round cell neoplasms exfoliate cells into effusions more readily than sarcomas. Irritation of mesothelial cells exposed to foreign substances, cytokines or chronic effusions cause mesothelial activation, proliferation and exfoliation into the fluids. These cells can exhibit cytologic features such as anisocytosis, anisokaryosis and multinucleation, which makes the cytological differentiation between neoplastic and reactive mesothelial cells difficult. Mesothelioma can cause exfoliative effusions, but cytologic differentiation between reactive mesothelial cells and mesothelioma is again very difficult. Histologic evaluation of mesothelial proliferative lesions is generally necessary for the diagnosis of mesothelioma._³

References

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2. Rizzi TE, Cowell RL, Tyler RD, et al. Effusions:abdominal, thoracic, and pericardial. In: Cowell RL, Tyler RD, Meinkoth JH, et al, eds. Diagnostic cytology and hematology of the dog anf cat. 3^rd ed. St. Louis, MO: Mosby; 2008:235-55
3. O’Brien PJ, Lumsden JH. The cytologic examination of body cavity fluids. Semin Vet Med Surg (Small Anim) 1988; 3(2): 140-56
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8. Hartmann K, Binder C, et al. Comparison of different tests to diagnose feline infectious peritonitis. J vet Intern Med 2003; 17(6): 781-90