Pleural effusion of extra-vascular origin (PEEVO)

INTRODUCTION — Pleural effusion of extra-vascular origin (PEEVO) refers to a pleural effusion that does not originate from the pleural vasculature. PEEVO comprises a wide variety of entities that are unusual. Due to their rarity, patients with PEEVO often have recurrent pleural effusion requiring multiple pleural drainages before a diagnosis is made. Thus, a high index of suspicion is needed to promote prompt diagnosis and appropriate management.

In this review, we describe various causes of PEEVO with a brief description of their epidemiology, pathogenesis, diagnosis, and treatment. The diagnostic investigation of pleural effusion, including effusions of unknown etiology, is described separately. (See "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

DEFINITION — PEEVO is characterized by the migration of fluid from the extrapleural space such as the abdomen, the genitourinary (GU) system, the biliary system, or the central nervous system. PEEVO can be either transudative (table 1) or exudative (table 2), depending upon the etiology. The biochemical characteristics that define transudative and exudative effusions are discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Our approach'.)

TRANSUDATIVE PEEVO — The presence of fluid in the pleural space that contains peritoneal dialysate, urine, central venous catheter infusate, cerebrospinal fluid, and glycine are all causes of PEEVO that have transudative characteristics (table 1). (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Our approach'.)

Peritoneal dialysis-associated pleural effusion — Peritoneal dialysis-associated pleural effusion (PDAPE) is an uncommon complication of peritoneal dialysis (PD) occurring in 1 to 10 percent of patients undergoing PD [1-5]. PDAPE should be suspected in patients undergoing PD who develop a right-sided pleural effusion that is transudative and has a high glucose level (eg, pleural fluid to serum glucose ratio >1; “sweet” pleural effusion). Treatment involves stopping PD for four to six weeks. PDAPE is described elsewhere in detail. (See "Noninfectious complications of continuous peritoneal dialysis", section on 'Pleural effusion due to pleuroperitoneal leak' and "Modalities for the diagnosis of abdominal and thoracic cavity defects in patients on peritoneal dialysis".)

Urinothorax — Urinothorax is defined by the presence of urine in the pleural space [6-9]. The most common cause of urinothorax is obstructive uropathy due to nephrolithiasis, ureteral stricture, extrinsic tumor, posterior urethral valves, or fibrosis (table 3) [6-9]. Less common causes include obstruction from large renal cysts or pregnancy, and surgical manipulation of or blunt trauma to the ureter. Injury or obstruction of the genitourinary (GU) tract can lead to the extravasation of urine into the perirenal or retroperitoneal space forming a urinoma (image 1). The urinoma may eventually spill into the pleural space either directly via transdiaphragmatic migration from diaphragmatic pores or indirectly through retroperitoneal-pleural lymphatic connections [8].

●Epidemiology – Urinothorax is rare. The prevalence is unknown with only case reports available in the literature. However, urinothorax is likely under reported because of the lack of knowledge and poor recognition by clinicians of this condition.

●Clinical features – Urinothorax typically develops quickly (hours/days) once the obstruction or trauma becomes severe enough for a urinoma to develop. Thus, urinothorax should be suspected in a patient with obstructive uropathy or recent GU trauma who develops dyspnea and chest pain.

●Diagnostic evaluation - The chest radiograph typically has a unilateral pleural effusion on the side of the GU tract obstruction or injury; however, contralateral and bilateral urinothorax have also been reported [10-13].

Pleural fluid analysis (PFA) mirrors that of urine typically revealing a transudative effusion (protein <1 mg/dL), hypocellularity, and low lactate dehydrogenase (LDH) levels due to an absence of inflammation with a low pH, and a glucose level similar to that of blood [8]. The effusion may have a distinctive smell of urine. When urinothorax is suspected, pleural and serum creatinine should be measured since a pleural fluid to serum (PF/S) creatinine ratio greater than 1 is supportive and greater than 1.7 is diagnostic.

Urinothorax is typically transudative with a low pH (urine typically has a pH less than 7.4) [14]. However, only half of cases have a low pH [8] and rarely, the pleural fluid is alkaline because of a concomitant urinary tract infection caused by a urea-splitting organism (eg, proteus sp). Occasionally, protein levels may be >1 mg/dL if there is a component of blood.

The diagnosis is supported by imaging studies showing the ipsilateral GU tract pathology, and a urinoma. Contrast-enhanced computed tomographic (CT) scan of the abdomen or ultrasonography should be done first to evaluate for the presence of obstructive uropathy and urinoma. In cases where the PFA and radiographic studies are inconsistent with the diagnosis but the clinical suspicion remains high, a technetium-99m renal scan that shows the migration of technetium-99-labeled albumin from the GU tract into the pleural space is diagnostic [15,16].

●Treatment - Management of urinothorax requires multidisciplinary effort between the urologist, interventional radiologist, and pulmonologist [7-9]. Initial drainage of pleural fluid is required for symptom relief and prevention of infection. Definitive treatment involves the relief and repair of GU tract obstruction or injury to prevent recurrent urinothorax. Surgical interventions such as video-assisted thoracoscopic pleurodesis or thoracotomy are not typically required since urinothorax resolves rapidly after the correction of GU tract pathology. Infection is not uncommon in patients with urinothorax, especially if the urine is infected from obstructive uropathy, and therefore drainage particularly important in such cases.

Extravascular migration of central venous catheter — A central venous catheter (CVC) may migrate into the pleural space during insertion if the guidewire or dilator perforates the posterior venous wall and the parietal pleura, or alternatively, it may occur after insertion if the catheter tip erodes into the intima of the vessel wall (eg, due to phlebitis) [17,18].

●Epidemiology – The true incidence of this complication is unknown with some case series suggesting rates of up to 6 percent of catheter placements [18-27]. In general, the left internal jugular and subclavian vein catheterization have the highest risk for misplacement and vascular perforation, compared with the right internal jugular or subclavian vein catheterization because of the horizontal course of the left brachiocephalic vein [19,21,28]. However, both right and left-sided catheters can be misplaced.

●Clinical features - Patients develop chest pain and/or dyspnea, and rarely epigastric discomfort. The diagnosis of pleural effusion due to CVC misplacement is often delayed, with some case series reporting delay of up to two days or longer [21]. Delay is thought to be due to slow development of the effusion and lack of awareness of misplacement into the pleural space as a complication, which may be difficult to appreciate on plain film radiography.

●Diagnostic evaluation – The typical radiographic presentation is the development of an ipsilateral pleural effusion; however, bilateral effusions have been reported [26,29]. A chest radiograph may show misplacement of the catheter tip (image 2); alternatively, computed tomography or ultrasonography may be necessary to confirm misplacement.

The pleural fluid analysis (PFA) should reflect the composition of the infusate. For example, in the case of saline, fluid is transudative with low pleural fluid protein (<1 g/dL), lactate dehydrogenase, and glucose as well as a low pH (approximately 7). The PFA may reveal exudative fluid if there is hemorrhage or if the patient is receiving total parenteral nutrition (TPN). Glucose can be high when TPN is being infused and appear milky if intravenous lipids are also being administered. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Tube feed or lipid leak'.)

●Treatment – Infusates should be immediately discontinued through the CVC as soon as this complication is suspected. The pleural effusion should be drained to relieve symptoms and to rule out CVC-related hemothorax from possible concomitant vascular trauma. Importantly, the clinician must assess for the type and extent of vascular injury before removing the CVC as removal of a malpositioned CVC can precipitate torrential bleeding; in such cases consultation with a vascular and/or thoracic surgeon may be necessary.

Pleural effusion containing cerebrospinal fluid — Cerebrospinal fluid (CSF) can enter the pleural space through a duropleural fistula (DPF), through a malpositioned ventriculoperitoneal (VP) shunt, or through a ventriculopleural (VPL) shunt [30]. While PEEVO due to a DPF and a VP shunt are pathological, in a VPL shunt, CSF is deliberately directed to the pleural space as a therapeutic procedure so a pleural effusion is expected.

●Duropleural fistula – A DPF is an abnormal communication between the dural membrane of the subarachnoid space and the parietal pleura. The CSF drains directly into the pleural space as a result of a pressure gradient between the subarachnoid space and negative pressure environment of the pleural space. A DPF is an uncommon complication of blunt trauma (eg, vertebral fracture), spinal cord tumor, neurosurgical (eg, transthoracic discectomy, laminectomy) or cardiothoracic surgical procedures [31-35].

•Clinical features - Pulmonary symptoms, such as dyspnea and chest pain, may vary depending upon the size of the effusion, which corresponds to the duration of the leak. A high degree of suspicion is needed since symptoms of the pleural effusion may be overshadowed by the symptoms of trauma or CSF leak. DPF should be suspected in a patient with risk factors who develops neurologic symptoms suggestive of a CSF leak, such as a postural headache, nausea, and vomiting [34,35]. (See "Post dural puncture headache", section on 'Clinical Features'.)

•Diagnostic evaluation – Radiographically, the pleural effusion may only be detected several days after the leak develops since the amount of CSF that is manufactured on a daily basis is low.

Typically, PFA reveals clear, water-like fluid that is paucicellular and transudative with a protein level <1 g/dL and low LDH level, unless blood from trauma is present [31,36]. The glucose concentration is generally slightly less than that of serum. When a CSF leak is suspected, the presence of beta-2 transferrin in the PFA is diagnostic [31,36]. Beta-2 transferrin is considered specific for CSF since its only other location for this protein is the perilymphatic fluid of the inner ear.

When the typical findings are absent and a PDF is suspected, radionuclide diethylenetriamine pentaacetate myelography is used to demonstrate a fistula between the subarachnoid and pleural spaces [37,38].

•Treatment – The optimal management is unknown. In some patients, conservative management with watchful waiting for spontaneous fistula closure and drainage of the effusion for symptomatic management (eg, suspected small leaks) will be successful (approximately one-third of cases); surgical repair is necessary when conservative management fails [33]. However, in other patients, drainage of the effusion with early surgical intervention to close the fistula may be necessary (eg, large symptomatic leaks). In a case series of 19 patients with post-traumatic DPF, 13 out of 19 (68 percent) ultimately required surgical intervention, with either a laminectomy or thoracotomy approach, to repair the CSF leak [39].

●Ventriculoperitoneal and ventriculopleural shunts – VP shunts can be misplaced into the pleural space during catheter insertion or after insertion when the catheter can migrate transdiaphragmatically into the pleural space [40,41]. The presentation and diagnostic evaluation is similar to patients with a DPF except the effusion occurs after the placement of a shunt (days, rarely weeks). When misplacement is confirmed, the shunt should be removed and replaced. VPL shunts, which are alternatives to VP shunts, are rarely used because of the higher incidence of catheter obstruction and occurrence of symptomatic pleural effusion, as well as the development of non-expandable lung [42-44]. (See "Normal pressure hydrocephalus", section on 'Shunt complications'.)

Glycinothorax — Glycinothorax is a term used for the accumulation of glycine-rich irrigation fluid accumulation in the pleural space due to leakage from a bladder wall perforation. Case reports suggest that glycinothorax is extremely rare [45,46]. Cases describe the development of acute respiratory failure and a large unilateral effusion after bladder wall perforation (eg, from a tumor) during transurethral surgery, leading to leakage of glycine-rich irrigation fluid into the abdominal cavity. It is assumed that the glycine-rich irrigant migrates from the abdomen directly into the pleural space. The pleural fluid is typically transudative and has a very high pleural fluid to serum of glycine (300:1), which is diagnostic [46]. When glycinothorax is suspected, bladder irrigation should be discontinued immediately and thoracentesis should be performed for the measurement of glycine and for symptomatic relief.

Hepatic hydrothorax — Patients with abdominal ascites, typically from portal venous hypertension, most often due to chronic liver disease may develop a pleural effusion, classically on the right. The effusion characteristics are typically transudative and similar to those of the underlying ascites but may have signs of infection if spontaneous bacterial peritonitis is present. Further details are provided separately. (See "Hepatic hydrothorax".)

EXUDATIVE PEEVO — PEEVO due to the presence of esophageal or gastric contents, enteral feeding formula, pancreatic fluid, or bile are classically exudative (table 2 and table 3). While it is unclear whether chylothorax or cholesterol effusions constitute PEEVO, they are included in this discussion for completeness. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Our approach'.)

Pleural effusion from esophageal and gastric perforation — Esophageal perforation is a life-threatening condition that is associated with high morbidity and mortality up to 40 percent [47,48]. Common causes of esophageal perforation include iatrogenic perforation after endoscopy/dilation at the site of luminal narrowing (stricture or gastroesophageal junction), perforation from esophageal or gastric malignancy, spontaneous perforation after vomiting (Boerhaave syndrome), and perforation due to trauma (blunt or penetrating) or the ingestion of caustic agents [49]. In such cases, the pathogenesis of the effusion may be due to emptying of visceral contents into the pleural space when there is concomitant mediastinal membrane rupture or due to a sympathetic inflammation in the pleural space when the mediastinal membrane is not ruptured. Details in this section focus on pleural effusion findings in patients with esophageal or gastric perforation. The clinical presentation and diagnosis and management of esophageal rupture is discussed separately. (See "Boerhaave syndrome: Effort rupture of the esophagus" and "Overview of esophageal injury due to blunt or penetrating trauma in adults" and "Surgical management of esophageal perforation".)

●Epidemiology – In a large series of patients with distal esophageal rupture, 14 percent of patients were found to have a pleural effusion and 8 percent with an empyema [50]. Pleural effusion is commonly seen with distal esophageal perforation because the distal esophagus comes in contact with the left mediastinal pleural membrane as the esophagus enters the thorax through the esophageal hiatus [30], while cervical esophagus perforation is commonly associated with subcutaneous air rather than a pleural effusion.

●Diagnostic evaluation – PEEVO from esophageal rupture should be suspected in patients who have dyspnea and chest pain after vomiting, endoscopy, or ingestion of caustic agents or similar symptoms in a patient with underlying esophageal malignancy. A pleural effusion may not be present on the initial chest radiograph such that serial chest radiography or thoracic ultrasonography over two to three days may be required in order to detect it. The pleural effusion is classically left-sided due to distal esophageal rupture but may be right-sided and/or associated with mediastinal air in mid- to upper- esophageal ruptures. The mediastinal pleura can be ruptured, especially in patients with Boerhaave syndrome (due to a rapid rise in intraluminal pressure). As a result, an intense inflammatory response leading to the rapid development of a pleural effusion with evidence of a purulent reaction can occur, and in some cases, a tension hydropneumothorax [51-54]. When the mediastinal pleural membrane is not ruptured, the accumulation of a sympathetic inflammatory effusion may be slower.

Patients with a pleural effusion suspected to be from a perforated esophagus should undergo thoracentesis or tube thoracostomy for diagnostic and therapeutic purposes. The pleural fluid analysis (PFA) typically shows an exudative effusion with signs of intense inflammation, pH between 5 and 7, glucose <60 mg/d, lactate dehydrogenase >1000 international units/L, and pleural fluid to serum amylase ratio >1 (salivary amylase) [52-55]. In some cases, pleural fluid may appear purulent with a putrid odor, particularly if an empyema is present. Food particles may be visible macroscopically or cytologically, which, when present, is diagnostic of an esophageal perforation, but this feature is unusual [56]. In atypical cases, esophageal rupture can cause a sympathetic reaction resulting in a small effusion with a pH >7.3 and an amylase level less than that of the serum [30]. In all cases, patients should concomitantly also undergo diagnostic investigation with endoscopy or esophagography to localize the perforation. (See "Overview of esophageal injury due to blunt or penetrating trauma in adults" and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Diagnostic evaluation'.)

●Treatment – Management involves drainage of the pleural effusion and repair of the perforation. (See "Overview of esophageal injury due to blunt or penetrating trauma in adults".)

Gastric perforation causing gastropleural fistula is rare because of separation of the stomach from the thoracic cavity by the strong muscular diaphragm. However, a gastropleural fistula can occur when the stomach is present within the thorax (eg, hiatal hernia, previous esophageal surgery) or when diaphragmatic integrity is compromised due to trauma, malignancy, or necrotic infection [57-61]. The presentation and management is similar to esophageal perforation.

Misplaced enteral feeding tube or parenteral feed — While in the past, large-bore enteral feeding tubes were associated with higher complication rates [62], pleural effusion from a misplaced enteral feeding tube is now rare due to the increased use of small-bore feeding tubes [63]. Misplacement presumably occurs through inadvertent perforation of the esophageal wall, particularly when excessive pressure is applied in a non-cooperative patient during placement [64-69]. Rarely, misplacement may occur when the feeding tube is misplaced into the airway and perforates the tracheal or bronchial wall (eg, intubated or sedated patient with minimal gag reflex).

Misplacement should be suspected if a patient develops acute chest pain and dyspnea soon after initiating enteral feeding.

When suspected, enteral feeding should be stopped immediately and the pleural effusion should be drained for diagnostic and therapeutic purposes.

The pleural fluid analysis may have similar characteristics and components to the enteral formula (eg, milky, lipid [triglyceride level >110 mg/dL], protein glucose, and electrolytes). Computed tomography of the chest may also be performed to locate the point of entry into the pleural space.

Once confirmed, surgical consultation should be obtained to consider repair of the esophageal or tracheobronchial perforation; importantly, the feeding tube should be left in place until surgical consultation occurs. Complications of feeding tube placement are discussed separately. (See "Inpatient placement and management of nasogastric and nasoenteric tubes in adults", section on 'Complications'.)

A pleural effusion may be exudative if parenteral nutrition (PN) is being infused through a misplaced central venous catheter; the fluid may appear milky if lipids are being infused. (See 'Extravascular migration of central venous catheter' above.)

Pancreaticopleural fistula — Chronic pancreatitis may be complicated by the formation of a pleural effusion due to the development of a pancreaticopleural fistula or the rupture of a pseudocyst with tracking of pancreatic fluid into the pleural space. Such effusions are exudative and characterized by a very high amylase level (pancreatic not salivary) in the pleural fluid (>100,000 international units/L), which is diagnostic [70,71]. Most cases are managed with a combination of octreotide and endoscopic and/or surgical repair of the fistula. The clinical presentation, diagnosis, and management of pleural effusion from chronic pancreatitis is described separately. (See "Overview of the complications of chronic pancreatitis", section on 'Pancreatic ascites/pleural effusion'.)

Bilothorax — The presence of bile in the pleural space is termed bilothorax (also known as cholethorax, bilithorax, pleurobilia, and thoracobilia) [72,73]. Bilothorax is a rare cause of PEEVO [74-80]. Bile salts are inherently alkaline and caustic to pleural and peritoneal tissue and cause an intense inflammatory reaction. Many cases are due to biliary tract injury or pathology that results in the development of a pleurobiliary fistula, while other cases are due to rupture of a subphrenic abscess into the pleural space [81]. Causes include biliary obstruction from a malignant or a benign stricture, perforation of the pleural sulcus from percutaneous hepatobiliary drain insertion, trauma to the hepatobiliary tree or diaphragm, or direct or lymphatic spread of infection from the liver (eg, amebiasis and echinococcosis) or subphrenic space (eg, pyogenic abscess) [72-80,82-86]. Often, a bilothorax is complicated by infection from biliary obstruction. The most common organisms infecting bilious effusions are gastrointestinal tract organisms, such as Escherichia coli, Enterobacter species, Klebsiella oxytoca, and Enterococcus faecalis [81]. Delay in diagnosis and management of bilothorax can be life threatening and may result in serious pleural complications such as the formation of complex fibrinous septations and eventually sepsis [72,73].

●Diagnostic evaluation – Bilothorax should be suspected in a patient with biliary tract or liver pathology who has fever, dyspnea, right upper quadrant abdominal or chest pain. Biliptysis (coughing up bile) is rare and may indicate a bronchobiliary fistula. Chest radiography may show an ipsilateral (ie, right-sided) pleural effusion, an elevated right hemi-diaphragm, and rarely, an air-fluid level in the liver. Abdominal imaging with ultrasonography or abdominal computed tomography may show biliary tract pathology with a subdiaphragmatic collection (termed a biloma) (image 3). The pleural fluid may appear as a turbid green color. The PFA typically shows an exudative effusion with features of infection (see "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis'). When bilothorax is suspected, pleural fluid bilirubin should be obtained; the pleural fluid to serum (PF/S) bilirubin ratio greater than one is highly suggestive of bilothorax, with higher ratios making the diagnosis more likely [81]. In most cases, a diagnosis of bilothorax can be established by the presence of bilious pleural effusion (PF/S bilirubin >1) in the right clinical context of hepatobiliary pathology. Rarely, a nuclear hepatobiliary scan demonstrating radiotracer in the pleural space is required to confirm the diagnosis [87].

●Treatment – Management requires a multidisciplinary approach between the pulmonologist and hepatobiliary specialist. Almost half of the bilious pleural effusions are infected and require immediate drainage of the effusion along with early administration of antibiotics. Typically, patients with bilothorax require either direct surgical closure of the pleurobiliary fistula, percutaneous drainage of the biliary tree, or endoscopic retrograde cholangiopancreatography to alleviate biliary obstruction.

Chylothorax and cholesterol effusions — It is unclear whether chylothorax or cholesterol effusions constitute true PEEVO or not but are described here for completeness. The presence of chyle (chylothorax) and cholesterol (cholesterol pleural effusion) in the pleural space are rare. They should be suspected when a pleural effusion is noted on a chest radiograph in a patient with a risk factor (table 4) or in a patient who presents with milky or turbid pleural fluid on thoracentesis. The demonstration of chyle (pleural fluid triglyceride concentration >110 mg/dL [1.24 mmol/L] and/or detection of chylomicrons) or cholesterol (pleural fluid cholesterol level ≥200 mg/dL [≥5.18 mmol/L], a cholesterol to triglyceride ratio >1 in the pleural fluid and absence of chylomicrons) is key diagnostically and treatment varies depending upon the underlying etiology. The presentation and treatment of these entities are provided separately. (See "Etiology, clinical presentation, and diagnosis of chylothorax" and "Management of chylothorax" and "Clinical presentation, diagnosis, and management of cholesterol pleural effusions".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pleural effusion".)

SUMMARY AND RECOMMENDATIONS

●Pleural effusion of extra-vascular origin (PEEVO) refers to a pleural effusion that does not originate from the pleural vasculature but rather migrates from the extrapleural space (eg, abdomen). PEEVO comprises a wide variety of entities that are unusual. Delay in diagnosis is common such that a high index of suspicion is needed to promote a prompt diagnosis and appropriate management. PEEVO can be either a transudative or exudative effusion, depending upon the etiology. (See 'Introduction' above and 'Definition' above.)

●Transudative PEEVO is caused by several conditions (table 3):

•Pleural effusion associated with peritoneal dialysis (PDAPE) should be suspected in patients undergoing peritoneal dialysis (PD) who develop a right-sided pleural effusion that is transudative and has a pleural fluid to serum glucose ratio >1. Treatment involves stopping PD for four to six weeks. (See 'Peritoneal dialysis-associated pleural effusion' above and "Noninfectious complications of continuous peritoneal dialysis", section on 'Pleural effusion due to pleuroperitoneal leak' and "Modalities for the diagnosis of abdominal and thoracic cavity defects in patients on peritoneal dialysis".)

•Urinothorax (urine in the pleural space) should be suspected in a patient with obstructive uropathy or recent genitourinary (GU) trauma who has a transudative pleural effusion with a low pH; the effusion may have an odor characteristic of urine and imaging may reveal a urinoma (image 1). A pleural fluid to serum creatinine ratio greater than 1 is supportive and >1.7 is diagnostic, but, occasionally, a technetium-99m renal scan that shows the migration of technetium-99-labeled albumin from the GU tract into the pleural space is needed. Treatment involves repairing the underlying GU pathology and drainage of the pleural effusion for symptomatic relief. (See 'Urinothorax' above.)

•An effusion due to a misplaced central venous catheter (CVC) results in an ipsilateral transudative pleural effusion that has the same composition as the infusate (image 2). The infusion should be stopped, the effusion drained, and the CVC can be removed after a vascular assessment has deemed that it is safe to remove the catheter. (See 'Extravascular migration of central venous catheter' above.)

•A duropleural fistula (DPF) should be suspected in a patient with symptoms of a cerebrospinal fluid leak that occurs in association with pathology that breaches the dural and parietal pleural membrane (eg, trauma, tumors, neurosurgery, cardiothoracic surgery). The pleural fluid is clear and watery, and has transudative characteristics. When a CSF leak is suspected, beta-2 transferrin should be measured since its presence is diagnostic. While some DPFs can be managed conservatively with pleural drainage only, others additionally need surgical repair. (See 'Pleural effusion containing cerebrospinal fluid' above.)

•Glycinothorax refers to the accumulation of glycine-rich irrigant fluid in the pleural space that can occur as a complication of bladder irrigation. Glycinothorax should be suspected in a patient who develops acute respiratory failure and a large pneumothorax on chest imaging. When glycinothorax is suspected, irrigation should be stopped and the pleural effusion drained; fluid which is typically transudative, should be sent for a glycine level since a pleural fluid to serum of glycine ratio of 300:1 is diagnostic. (See 'Glycinothorax' above.)

●Exudative PEEVO comprises several conditions (table 3):

•A pleural effusion due to a perforated esophagus should be suspected in a patient with risk factors for perforation (eg, endoscopy, tumors, vomiting) who develop a left-sided pleural effusion. Pleural fluid may be turbid and have a putrid odor and analysis typically shows an exudative effusion with signs of intense inflammation, pH between 5 and 7, glucose <60 mg/d, lactate dehydrogenase >1000 international units/L, and pleural fluid to serum amylase ratio >1 (salivary amylase). The presence of food particles macroscopically or microscopically is diagnostic. The effusion should be drained, and the perforation should be identified and repaired. (See 'Pleural effusion from esophageal and gastric perforation' above and "Boerhaave syndrome: Effort rupture of the esophagus" and "Overview of esophageal injury due to blunt or penetrating trauma in adults" and "Surgical management of esophageal perforation".)

•A pleural effusion due to a misplaced enteral feeding tube should be suspected if a patient develops acute chest pain and dyspnea soon after initiating enteral feeding. When suspected, enteral feeding should be stopped immediately and the pleural effusion should be drained. The pleural fluid analysis should have similar characteristics and components to the enteral formula (eg, lipid, protein glucose, and electrolytes). Once confirmed, surgical consultation should be obtained to repair the esophageal perforation and safely remove the feeding tube. (See 'Misplaced enteral feeding tube or parenteral feed' above.)

•A pancreaticopleural fistula should be suspected in a patient with chronic pancreatitis who has an exudative right-sided pleural effusion. The diagnosis is confirmed by the detection of a pancreatic amylase level >100,000 international units/L. Most cases are managed with a combination of octreotide and endoscopic and/or surgical repair of the fistula. (See 'Pancreaticopleural fistula' above and "Overview of the complications of chronic pancreatitis", section on 'Pancreatic ascites/pleural effusion'.)

•Bilothorax (bile in the pleural space) should be suspected when a patient with biliary pathology (eg, biliary strictures, liver abscesses) has a right-sided pleural effusion (image 3). The pleural fluid may appear as a turbid green color and analysis shows an exudative effusion with features of infection. When suspected, pleural fluid bilirubin should be obtained; the pleural fluid to serum (PF/S) bilirubin ratio greater than one is highly suggestive of the diagnosis but sometimes radionuclear imaging is needed to demonstrate the fistula. Since most effusions are infected, antibiotics should be started and the pleural fluid drained. The fistula generally needs to be surgically repaired and the underlying biliary obstruction (or infection) treated. (See 'Bilothorax' above.)

•The presence of chyle (chylothorax) and cholesterol (cholesterol pleural effusion) in the pleural space are rare and it is unclear whether they truly constitute PEEVO. They should be suspected when a pleural effusion is noted on a chest radiograph in a patient with a risk factor (table 4) or in a patient who presents with milky or turbid pleural fluid on thoracentesis. The demonstration of chyle (pleural fluid triglyceride concentration >110 mg/dL [1.24 mmol/L] and/or detection of chylomicrons) or cholesterol (pleural fluid cholesterol level ≥200 mg/dL [≥5.18 mmol/L], a cholesterol to triglyceride ratio >1 in the pleural fluid and absence of chylomicrons) is key diagnostically and treatment varies depending upon the underlying etiology. (See 'Chylothorax and cholesterol effusions' above and "Etiology, clinical presentation, and diagnosis of chylothorax" and "Management of chylothorax" and "Clinical presentation, diagnosis, and management of cholesterol pleural effusions".)