Pleural effusion due to nonmalignant gastrointestinal disease

Abstract

Although pleural effusion is a frequent finding in clinical practice, determining its aetiology may be challenging, and up to 20% of cases remain undiagnosed. Pleural effusion may occur secondary to a nonmalignant gastrointestinal disease. A gastrointestinal origin is confirmed based on a review of the medical history of the patient, thorough physical examination and abdominal ultrasonography. In this process, it is crucial to correctly interpret findings on pleural fluid obtained by thoracentesis. In the absence of high clinical suspicion, identifying the aetiology of this type of effusion may be difficult. Clinical symptoms will be determined by the gastrointestinal process causing pleural effusion. In this setting, correct diagnosis relies on the specialist's ability to evaluate pleural fluid appearance, test for the appropriate biochemical parameters and determine whether it is necessary or not to send a specimen for culture. The established diagnosis will determine how pleural effusion is approached. Although this clinical condition is self-limited, many cases will require a multidisciplinary approach because some effusions can only be resolved with specific therapies.

Short abstract

The aetiology of pleural effusion secondary to nonmalignant gastrointestinal disease may be difficult to establish and its complications can be potentially severe, especially if early diagnosis and management are not established. Recent evidence is scarce. https://bit.ly/3Ffiw0U

Introduction

Pleural effusion (PE) is a condition commonly found in clinical practice. In Spain, the prevalence of PE is estimated to be 400 in 100 000 [1], and 1.5 million cases are diagnosed every year in the USA [2]. Although there are more than 50 known causes of PE (table 1) [3], over 75% of cases are due to heart failure, pneumonia, neoplasm and tuberculosis [4]. Accurate early diagnosis is crucial to improving prognosis. However, establishing a diagnosis may be challenging, and 20% of cases of PE remain undiagnosed [5].

TABLE 1.

Most frequent causes of pleural effusion

	Transudate	Exudate
Frequent	Heart failure	Malignant
	Hepatic hydrothorax	Parapneumonic
		Tuberculous
Less frequent	Nephrotic syndrome	Chylothorax
	Urinothorax	Pleural effusion of cardiac cause
	Peritoneal dialysis	Pleural effusion of vascular cause
	Trapped lung	Systemic disease
		Benign asbestosis
		Gastrointestinal diseases
Infrequent	Duropleural fistula	Gynaecological diseases
	Extravascular migration of central venous catheter	Lymphatic disorders
	Glycinothorax	Uraemic
	Ventriculoperitoneal and ventriculopleural shunt	Drugs
	Pulmonary veno-occlusive disease

In normal circumstances, there is a small amount of pleural fluid (PF) that allows the two layers of the pleura to glide past each other. This fluid is in continuous movement and is influenced by both hydrostatic and oncotic pressure within the pleural space and the capillaries of the two pleural layers. Reabsorption of PF occurs mainly through lymphatic drainage in the most dependent part of the parietal pleura. PE is mediated by a variety of mechanisms related to the increased production of PF, reduction of reabsorption or a combination of both [6]. Occasionally, PE originates in the abdominal cavity. PF enters the pleural space by traversing diaphragmatic defects [7–11].

The purpose of this review was to determine the mechanisms that mediate PE due to nonmalignant gastrointestinal diseases, define its clinical and radiological characteristics, and identify the diagnostic value of PF analysis.

Lessons for clinicians

• Gastrointestinal diseases should be considered in the differential diagnosis of pleural effusion (PE) of unknown origin.

• A good knowledge of pleural fluid biochemistry is critical for determining the aetiology of PE.

• This type of PE may require a multidisciplinary approach, because management can be complex and it can only be resolved with specific treatments.

• New, larger studies are needed to elucidate unknown aspects of the mechanisms involved in the development of these PEs, and their diagnosis and treatment.

Oesophageal diseases

PE is a complication that can occur in patients with oesophageal perforation [12]. In these cases, the oropharyngeal microbiota contaminates the mediastinal cavity, thereby causing mediastinitis, sepsis and pleural infection. Delayed diagnosis can be fatal, because this condition is associated with high morbidity and mortality rates. PE secondary to oesophageal perforation is a rare condition. As few as 85 cases were treated in a hospital over a 21-year period [12], and only 286 cases were reported in a national study in Denmark over a 9-year period [13]. The cause of perforation may be traumatic (iatrogenic or spontaneous), inflammatory or neoplastic. In three case series including 286, 127 and 559 patients, respectively, the percentage of all-cause iatrogenic PEs was 50.7%, 55% and 59%, respectively [13–15]. Spontaneous oesophageal rupture generally occurs at the level of the lower oesophagus, with a longitudinal tear affecting the left posterior aspect proximal to the diaphragm, given that the upper oesophagus is protected by striated muscles [16]. This explains why PE is left-sided in 70% of cases. These cases may occur as a result of vomiting followed by chest pain. Dyspnoea is another manifestation of oesophageal rupture. Right-sided PE occurs when the perforation is located in the middle portion of the oesophagus [17].

Symptoms mimic those of acute mediastinitis and pleural space infection, in which the bacterial flora of the oesophagus leaks into the mediastinal and pleural space following oesophageal perforation [18]. Some hours after the rupture, the patient experiences severe pleuritic epigastric pain, fever and dysphagia [19]. Diagnosis is established based on the most frequent radiological findings, including pneumomediastinum, mediastinal widening, mediastinal air-fluid level or subcutaneous emphysema [20]. Diagnostic imaging involves cervical, thoracic or upper abdominal radiography, depending on where the perforation is suspected. Up to 77% of patients develop pneumothorax [21]. PF is an anaerobic empyema with the following characteristics: very low pH (5–7); lactate dehydrogenase (LDH) >1000 IU·L⁻¹; elevated salivary amylase; glucose 0–60 mg·dL⁻¹; and the presence of squamous epithelial cells and, less frequently, food particles (table 2) [22–26].

TABLE 2.

Typical characteristics of pleural fluids secondary to nonmalignant gastrointestinal diseases

Condition	Appearance	pH	Nucleated cells	LDH (IU·L−1)	Glucose (mg·dL−1)	Other characteristics
Oesophagus
Oesophageal rupture	Purulent: empyema	5–7	Polymorphonuclear	>1000	0–60	Salivary amylase: high levels Squamous epithelial cells Sometimes food particles
Stomach
Gastropleural fistula	Serous/empyema	If empyema, low	Polymorphonuclear	>1000		Salivary amylase: high levels Squamous epithelial cells Sometimes food particles
Ménétrier's disease	Serous					Transudate
Cytomegalovirus infection	Serous					Same characteristics as Ménétrier's disease
Intestine
Ulcer perforation	Sometimes purulent	If empyema, low
Colopleural fistula	Sometimes fecaloid		Lymphocyte or eosinophil predominance
Ulcerative colitis treatment (anti-TNF drugs)						Tuberculous pleural effusion
Liver
Hepatic hydrothorax	Serous/milky					Transudate If chylothorax, triglycerides >110 mg·dL−1
Pyogenic liver abscess	Exudate/empyema		Polymorphonuclear			Elevated C-reactive protein
Liver amoebic abscess	Serous/empyema, sometimes anchovy paste, pleural			If empyema, >1000	Normal	Generally negative culture results
Viral hepatitis	Serous		Lymphocytes
Gallbladder
Biliopleural fistula	Serous/greenish (50% empyema)	Normal	Polymorphonuclear			Exudate Pleural fluid/serum bilirubin ratio >1 Presence of pleural glycoholic acid Sometimes biliotysis
Pancreas
Acute pancreatitis	Serous/sometimes haemorrhagic		Polymorphonuclear	>1000		Exudate Elevated amylase (higher than in blood)
Chronic pancreatitis	Serous		Polymorphonuclear	>1000		Exudate Elevated amylase (higher than in blood)
Pancreatic ascites	Serous					Elevated amylase and proteins
Spleen
Splenic abscess, infarction or haematoma	Serous/sometimes haemorrhagic		Polymorphonuclear			Exudate Amylase, same as in blood
Abdominal infection
Subphrenic abscess	Serous	Normal	Polymorphonuclear		Normal	Exudate
Peritoneum
Peritoneal dialysis	Serous					Transudate
Other diseases
Diaphragmatic hernia	Serous/empyema					Exudate
Liver transplant	Serous					Transudate or exudate
Epstein–Barr virus	Serous/rarely empyema		Lymphocytosis			Mostly exudates; sometimes transudates

LDH: lactase dehydrogenase; TNF: tumour necrosis factor.

Early diagnosis is crucial, because mortality reaches 60% when it is delayed for >24 h [27­–29]. The clinical sequence and findings of PF are strongly suggestive of oesophageal perforation. Chest ultrasonography also facilitates diagnosis by demonstrating a mobile left-sided PE with numerous hyperechoic pinpoints that is positive for the suspended microbubble sign (caused by a small amount of air trapped in pus) [30]. Final diagnosis is established by a contrast-enhanced oesophageal ultrasound demonstrating perforation. Contrast must be water-soluble (diatrizoate meglumine/diatrizoate sodium, brand name Gastrografin). Barium is of limited use because it is not absorbed when it enters the mediastinum or pleural space and may cause a granulomatous reaction and fibrosis [31]. Water-soluble contrasts also have some limitations, especially their hypertonicity, and may enter the tracheobronchial tree. This phenomenon causes high rates of false-negative results. In such case, barium is administered. Ultimately, in a consistent clinical setting, diagnosis can also be established based on a thoracic computed tomography (CT) scan demonstrating air at the level of the mediastinum [32].

The treatment of choice for oesophageal perforation includes mediastinal examination, oesophageal repair surgery, endoluminal therapies (endoscopic clip placement, self-expanding metal-coated stents and endoluminal wound vacuum systems) [33], and pleural and mediastinal drainage. In addition, mediastinitis and pleural infection are treated with parenteral antimicrobials. Although conservative management (parenteral antimicrobials and nasogastric tube alone) may be effective in some patients, early mediastinal examination (contrast oesophagram or CT scan) is crucial to reduce mortality [34].

Gastric diseases

Gastric disease rarely causes PE, and evidence on the incidence of this complication is limited. There are reports, however, of the presence of gastropleural fistulas secondary to gastric disease [35–40]. In a MEDLINE review of studies of gastropleural fistulas (1966–2000), the 25 cases reported were classified according to whether gastric perforation was intrathoracic (14 cases) or intra-abdominal (11 cases) or according to its aetiology (peptic ulcer (11 cases), trauma (seven cases), empyema (four cases), malignant tumour (three cases), surgery complications (including bariatric surgery), radiation (two cases) or gastric cancer (one case); three cases presented two causal factors) [41].

The most frequent symptoms associated with gastropleural fistula include fever, malaise, dyspnoea and left-sided chest pain. Thoracic radiography demonstrates a large left-sided PE with or without pneumothorax, with contralateral mediastinal displacement. There are scarce data available on the characteristics of PF. Less frequently, an empyema may be found. In this setting, pH is low, although that may be due to the acidity of gastric contents. In other cases, PF is an exudate, with LDH values >1000 IU·L⁻¹. If the aetiology is traumatic, amylase values may also be elevated. Food material can also be observed in PF (table 2). Diagnosis is established based on the finding of radiological contrast extravasation into the pleural space, or by upper digestive tract endoscopy. It requires fistula surgery.

Ménétrier's disease is a rare condition of unknown aetiology characterised by giant mucosal folds in the proximal portion of the stomach, decreased acid secretion and protein loss, which may cause severe hypoalbuminaemia. It usually affects children younger than 10 years, is more frequent in males and has a benign course that resolves in a few weeks with support measures [42]. When serum albumin levels decrease below 1.8 g·dL⁻¹, ascites and PE appear. PF is a transudate. Conversely, the disease is progressive and chronic in adults. Diagnosis is established by digestive endoscopy, or even solely by direct observation. Biopsy confirms diagnosis and excludes other diagnoses. In adults with persistent symptoms, gastric resection should be considered, given the good outcomes reported [43].

Infection of the gastrointestinal tract by cytomegalovirus is frequent and in immunocompromised patients may progress into severe disease. It is characterised by hypertrophic gastropathy, with associated severe protein loss secondary to foveolar hyperplasia of the gastric mucosa, as occurs in Ménétrier's disease. The resulting hypoalbuminaemia causes diffuse oedema with or without concomitant PE. In these cases, especially in adults, the disease may progress into chronic disease, with a poor prognosis. Treatment with ganciclovir may delay disease progression [44].

Intestinal diseases

PE may occur due to intestinal disease, including a perforated ulcer, and causes acute symptoms [45]. There are reports of PE related to Crohn's disease, an idiopathic inflammatory bowel disease characterised by the formation of fistulas between intestinal lesions and adjacent organs such as the lung or the pleura [46–48]. Cases of PE secondary to ulcerative colitis have also been reported [48]. In a series of patients with inflammatory bowel disease, 1.1% of patients with Crohn's disease (1 of 93) and 2.4% of patients with ulcerative colitis (4 of 167) developed PE [49]. The literature on the characteristics of PF is limited, although it is known to be lymphocytic or eosinophilic [46]. PF may also be faecaloid (table 2) [48]. These findings, along with the presence of sputum containing feculent material, should raise a high suspicion of PE due to intestinal disease [46]. Diagnosis is based on contrast-enhanced scans of the colon demonstrating the presence of fistulas. Although there are reports of conservative management having been successful [47], surgical management is the gold-standard treatment because it is usually effective. Finally, tumour necrosis factor α antagonists generally used for the treatment of inflammatory bowel disease may cause tuberculous PE [50].

Liver diseases

Hepatic hydrothorax (HH) refers to the presence of PE in a patient with liver cirrhosis and without underlying heart or lung disease [51]. The diagnostic criteria for HH are shown in table 3 [52]. HH occurs in 5–10% of patients with liver cirrhosis, and concurrent ascites are found in 80% of cases [53]. Several factors contribute to its development. On the one hand, the pressure gradient between the peritoneum and the pleural space causes the fluid to escape from the abdominal cavity into the thoracic cavity. On the other hand, diaphragmatic defects in the tendinous parts of the right diaphragm facilitate fluid leakage. In 80% of cases, HH develops on the right side, probably due to the “piston” effect of the liver [54]. Upon suspicion of HH, thoracentesis is necessary to 1) confirm that the PF is a HH, 2) exclude an alternative diagnosis and 3) exclude the presence of spontaneous bacterial empyema.

TABLE 3.

Diagnostic criteria for hepatic hydrothorax and spontaneous bacterial empyema

Diagnostic criteria for uncomplicated hepatic hydrothorax	Diagnostic criteria for spontaneous bacterial empyema
Cell count <500 cells·mm−3, polymorphonuclear cell count <250 cells·mm−3 and negative culture	Positive PF culture and polymorphonuclear cell count >250 cells·mm−3, or
Total protein concentration <2.5 g·dL−1 or PF/serum total protein ratio <0.5	Negative PF culture and polymorphonuclear cell count >500 cells·mm−3
PF/serum lactate dehydrogenase ratio <0.6	No evidence of pneumonia or parapneumonic effusion on chest radiography
Serum–PF albumin gradient >1.1 g·dL−1
Amylase in PF lower than in serum
pH 7.40–7.55
Glucose in PF same as in serum

PF: pleural fluid.

PF is usually a transudate. When diagnosis is uncertain, a PF/serum albumin ratio <0.6 [55] or a serum–PF albumin gradient >1.2 g·dL⁻¹ [56] may help identify it as a transudate. PF may occasionally be chylothorax [57], given that some patients with cirrhosis show a high hepatic venous pressure gradient, which results in high thoracic and hepatic lymph flow. This causes chylous ascites, which manifests in the form of elevated levels of triglycerides (>110 mg·dL⁻¹), both in ascitic fluid and PF (table 2) [58].

If HH is refractory to optimised medical treatment, then liver transplant is the ultimate treatment [59]. If contraindicated, other options include transjugular intrahepatic portal systemic shunting [51] or diaphragm repair surgery [60], although they are not very effective in the control of refractory HH [61]. If all options fail, therapeutic thoracentesis or indwelling pleural catheters can be used to control PE, although these options remain controversial [62]. In a recent randomised clinical trial [63], indwelling pleural catheters were not effective in controlling dyspnoea. However, this approach reduced the number of invasive procedures performed, which prevented the occurrence of the severe, albeit rare, complications associated with these procedures. Of note, complications were less frequent among patients who underwent therapeutic thoracentesis. The authors recommend that the decision should be made on a case-by-case basis considering patient preferences. In a recent review, the authors recommended that patients with refractory HH who are not candidates for liver transplantation should be treated with palliative intent. Thus, the authors suggest a tunnelled pleural catheterisation, unless it is contraindicated. In patients who cannot undergo definitive procedures, serial thoracentesis is recommended [64].

Spontaneous bacterial empyema (SBEM) is defined as spontaneous infection of a pre-existing hydrothorax, in the absence of pneumonia [65]. It is reported to occur in 15% of patients with HH [66] and in 2–2.5% of patients with cirrhosis. PF analysis is more reliable for diagnosis than ascitic fluid analysis, and the occurrence of PF is associated with increased morbidity and mortality (table 3). It should be differentiated from empyema secondary to pneumonia because they require different therapeutic approaches [67, 68]. In more than 40% of cases, SBEM occurs without spontaneous bacterial peritonitis and even without associated ascites [69]. Chest drainage is not recommended if the PF is not purulent, even if culture is positive, to prevent life-threatening fluid depletion, protein loss and electrolyte imbalance [70]. The management of SBEM may be challenging owing to liver dysfunction in cirrhotic patients, which is usually associated with kidney failure [65]. SBEM is associated with poor long-term survival (11 of 24 patients in a series (45.8%) died in 19 months) [71]. HH generally has a poor prognosis, with a 1-year survival rate of 43% [72].

Pyogenic liver abscess has an annual incidence of 3.6 cases per 100 000 (95% CI 3.5–3.7) [73], with the percentage of patients with concomitant PE ranging from 20% to 50% [74, 75]. The presence of PE is related to diaphragmatic inflammation resulting from an adjacent abscess and a larger liver abscess. As a result, the patency of diaphragmatic capillaries increases and fluid accumulates in the pleural space. In a series of 234 patients with liver abscess, 114 (48.7%) developed non-complicated PE, 36 required invasive procedures due to complicated PE and 10 (4.3%) had an empyema [76]. The most frequent symptoms include fever, chills, anorexia and abdominal complaints (although rarely located in the right hypochondrium). Patients usually have a history of hepatobiliary disease, with the potential presence of hepatomegaly [77]. Findings on blood analysis include anaemia, leukocytosis and elevated levels of alkaline phosphatase and bilirubin. Half of the organisms identified are Escherichia coli and Streptococcus spp., and infections are polymicrobial in 16% of cases [78]. PE is right-sided (53.5%) or bilateral (42.1%) [76] and is characterised by polymorphonuclear exudate with elevated C-reactive protein levels (table 2) [76, 77]. When a liver abscess is located near the right diaphragm and there is concomitant polymicrobial infection and biliary duct disease, the PE is more likely to be an empyema [76]. Abdominal CT reveals small liver abscesses (0.5 cm in diameter). Abdominal ultrasonography demonstrates the presence of fluid-filled hepatic lesions. Final diagnosis is established by CT or ultrasound-guided percutaneous biopsy [78]. Management consists of imaging-guided abscess drainage and antimicrobial therapy. In the presence of symptoms of peritonitis, laparoscopy is indicated. Mortality reaches 19% [78].

Amoebiasis is an infection by Entamoeba histolytica. Although infection generally develops in the intestine, most deaths are caused by extraintestinal amoebiasis, including liver and pleural amoebiasis [79]. It is unclear whether intestinal metastatic infection is due to the virulence of the pathogen or to some host-related factor. Thus, invasive disease is more frequent in children, pregnant women and alcoholic, malnourished or immunocompromised subjects [80]. In a case series including 501 cases with thoracic complications secondary to a hepatic amoebic abscess, 156 patients developed PE and pneumonitis [81]. Between 20% and 35% of patients with a hepatic amoebic abscess develop PE [81, 82]. If the amoebic abscess is located near the diaphragm, it may enter the diaphragm and cause PE, generally on the right side. If the abscess is in the left liver lobe, PE can be left-sided [83]. There is scare evidence on the characteristics of the PF. Although the fluid usually has a serous appearance, if the liver ruptures into the pleural space, an empyema may develop. In this case, the pus obtained by thoracentesis has a characteristic black colour, known as anchovy paste, which is pathognomonic of a hepatopleural fistula. In other cases, it may have a yellowish or greenish appearance (table 2) [84, 85]. In a series of three patients undergoing thoracentesis, a patient required chest drainage to relieve severe dyspnoea. In all cases, PF was an exudate, and Gram staining and bacterial culture test results were negative [82]. In another two-case series, in one patient the PF was serous and had the biochemical characteristics of an exudate, whereas in the other it was purulent and chocolate-like, with an LDH level of 3340 IU·L⁻¹ and normal glycaemia. Cultures were negative in both cases [86]. In these cases, PF culture is required to detect amoebas [85]. Finding trophozoites in the PF confirms diagnosis, especially if the liver abscess culture is negative [87]. The fistula is occasionally hepatobronchial and may cause a pulmonary abscess, with sputum having a similar appearance to that of the PF (anchovy paste). Both abdominal ultrasonography and CT demonstrate a liver abscess, but they do not distinguish whether it is pyogenic or amoebic [88]. In this context, a serological test may be useful. Treatment with metronidazole is effective in >90% of cases [89]. If PE causes dyspnoea, therapeutic thoracentesis alone is effective in the control of symptoms.

Hepatitis B may also cause PE. In a series of 2500 patients with hepatitis B, PE was detected clinically in only four patients [90]. PE seems to be induced by an autoinmune reaction that affects the skin, joints and, to a lesser extent, the pleura. PF is usually a lymphocytic exudate (table 2) [91].

Gallbladder diseases

PE is a frequent complication of laparoscopic cholecystectomy. In a series of 27 patients, PE was found on a chest CT scan performed 24 h after surgery in 33% of patients [92].

A wide range of diseases can cause biliopleural fistula, which allows direct communication between the bile duct and the pleural space (thoracobilia). Other causes include percutaneous biliary drainage, a palliative surgical intervention for obstructive jaundice that may cause bilious PE [23, 93]; complete bile duct obstruction; placement of a catheter between the ninth and tenth rib in the midaxillary line; and long-term percutaneous biliary drainage (between 7 days and 2 months) [94]. A possible mechanism by which long-term bile duct obstruction can cause a fistula is the development and rupture of an intrahepatic cholangitic abscess. This abscess occurs when a sub-diaphragmatic bile collection enters the thorax through the diaphragm [95]. Clinical symptoms include fever, right pleurisy chest pain and pain in the right upper quadrant and ipsilateral shoulder [96]. PE is almost exclusively right-sided. Chest radiography demonstrates PE on the right side and air-fluid levels in the liver. PF is greenish, with the characteristics of an exudate, with a predominance of polymorphonuclear cells and a pleural/serum total bilirubin ratio >1 [96]. In 50% of cases, empyema occurs as a complication (table 2). A recent review of 12 cases revealed that a PF total bilirubin to serum total bilirubin ratio >1 combined with the presence of pleural glycocholic acid has a high diagnostic yield [97]. Once stabilised, a magnetic resonance (MR) cholangiopancreatography is necessary to find the cause and site of biliary obstruction. It is managed through endoscopy or surgery, where appropriate, to close the fistula between the bile duct and the pleural space [96].

Pancreatic diseases

Pancreatic disease is the most common abdominal condition causing PE [98]. There are four types of nonmalignant pancreatic disease that cause PE: acute pancreatitis, pancreatic abscess, chronic pancreatitis with pseudocyst and pancreatic ascites.

In acute pancreatitis, nearly 50% of patients develop PE [94]. It is generally accepted that acute pancreatitis is more severe when accompanied by PE. In a series of 19 patients with severe acute pancreatitis, 84% had PE, whereas only 8.6% of the 116 patients with mild pancreatitis had PE [99]. PE occurs as a result of exudative fluid produced during acute pancreatic and diaphragmatic inflammation. The fluid is transferred from the inflammation site and interconnected lymphatic vessels on both sides of the diaphragm into the pleural space. Symptoms are predominantly abdominal, although the symptoms caused by PE (dyspnoea and pleuritic pain) may be more severe than abdominal symptoms. Chest radiography demonstrates PE (small to moderate fluid collection), diaphragm elevation and basal infiltrate [100]. Diagnosis is established based on the characteristic symptoms and elevated levels of amylase or lipase in blood. Thoracentesis is not required for diagnosis, unless the PE is large and the patient has dyspnoea. In this case, therapeutic thoracentesis can be performed. PF generally has a serous or serosanguineous appearance. It also has the biochemistry of a polymorphonuclear-predominant exudative effusion, with higher levels of amylase than in blood. Of note, in early phases, amylase concentrations may be normal (table 2) [101, 102]. Phospholipase A2 can also be elevated [103]. In this type of pleuritis, PE generally resolves in parallel with acute pancreatitis. A PE not subsiding at 2 weeks should raise suspicion of a pancreatic abscess or cyst.

IgG4-related disease is a chronic, systemic entity characterised by a lymphoplasmacytic infiltrate rich in IgG4⁺ plasma cells. Although primarily described in the pancreas, it can affect any organ. Thoracic involvement occurs in 50% of cases and can manifest in different ways. Pleural involvement, both pleural thickening and PE, occurs in 5–16% of cases. In this disease, the PF is an exudate with a predominance of lymphocytes, plasma cells and high concentrations of IgG4. Pleural biopsy shows a fibrosing pleurisy with lymphoplasmacytic inflammation and IgG4⁺ plasma cells [104].

Pancreatic abscess usually follows acute pancreatitis. In this case, at 15–20 days, the patient will develop fever, abdominal pain and leukocytosis. Diagnosis must be confirmed either by ultrasonography or abdominal CT because, if it is not established, mortality is very high. Nearly a third of pancreatic abscesses co-occur with PE [105]. Management consists of surgical drainage.

Pancreatic pseudocyst occurs in 10% of acute pancreatitis and is a collection of fluid and detritus rich in pancreatic enzymes located in the pancreas or proximal to it. In chronic pancreatitis, PE occurs secondary to pancreatic duct obstruction and may cause a pancreatic–pleural fistula, a rare complication. It is most frequently associated with chronic alcoholic pancreatitis, and the obstruction of the pancreatic duct causes a leakage of fluid into the pleural space [106]. PE can be the first sign of a fistula. If fluid leakage causes pseudocyst decompression, abdominal symptoms will be limited, with a predominance of PE symptoms (dyspnoea and chest pain) [107]. PF is similar to that in acute pancreatitis. Amylase concentrations are very high in the presence of a fistula (>1000 U·L⁻¹), although they may initially be normal (table 2) [102, 108]. PE develops on the left side, although it may be bilateral (15%) or right-sided (20%) [107]. PE occasionally occupies the whole hemithorax. A PE with a high content of amylase does not confirm the diagnosis of pancreatic disease [109]; therefore, determination is not useful when screening for concomitant abdominal disease. For this reason, routine amylase determination is not recommended [110, 111]. A history of pancreatitis with recurrent PE should raise suspicion of a pancreatic–pleural fistula [112]. Diagnosis is based on abdominal CT, which allows the pseudocyst and fistula to be visualised [109]. Retrograde endoscopy and MR cholangiopancreatography, the method of choice, are especially useful in finding the fistulous tract between the pancreas and the pleural space. MR cholangiopancreatography has higher sensitivity than CT for characterising the trajectory of a fistula tract. In addition, this technique helps to identify the anatomical relationship before surgery is considered [113]. In addition, unlike retrograde endoscopy, MR cholangiopancreatography is not invasive [106]. Conservative management (therapeutic thoracentesis and parenteral nutrition) solves 50% of cases. Here, the goal is two-fold, to reduce pancreatic enzyme secretion and the volume of fluid in the pseudocyst to subsequently close the fistulous tract. Another option is the administration of somatostatin, or one of its analogues, to inhibit pancreatic exocrine secretion [114]. If conservative management is not effective within 2 weeks, other options should be considered [106, 114]. Currently, endoscopic intervention (endoscopic retrograde cholangiopancreatography) together with stenting is the technique of choice over surgery, with success rates reaching 100% [115]. Surgery is reserved for patients in whom conservative medical treatment and endoscopic intervention fail [116].

Pancreatitis occasionally causes ascites originating from fluid leaking from the pseudocyst to the peritoneum. The fluid enters the pleural space through diaphragmatic defects. This occurs in 20% of cases, and the fluid has elevated levels of amylase and proteins [117]. In this type of patient, endoscopic retrograde cholangiopancreatography used in combination with pancreatography and pancreatic stenting is effective for total fluid drainage in 73.6% of cases [118].

Splenic diseases

Splenic abscess is rare but causes PE in 50% of cases [119]. It is generally left-sided, small and may present with pleurisy. The cause of abscess is a primary haematogenous spread, e.g. as occurs in endocarditis. However, it is also found in patients with an underlying disease causing splenic abnormalities, such as chronic haemolytic anaemia or falciform anaemia [120]. PF has a predominance of neutrophils (table 2) [121]. Treatment with antimicrobials combined with abscess percutaneous aspiration or drainage may be useful, especially if the patient is not a candidate for surgery. Nevertheless, splenectomy is the treatment of choice in most patients and is considered the definitive intervention.

Splenic infarctions occur as a result of embolism, hypercoagulability, splenic artery obstruction, vasculitis or infiltrative diseases, because splenic arteries only have an end, without collateral circulation. PEs associated with splenic infarction are small and develop when >80% of the spleen is involved [122, 123].

Splenic haematoma develops as a result of trauma. This type of event is rarely reported on the medical history of patients. In addition, some time may elapse between the trauma and the formation of the haematoma and establishing the association can be difficult. A splenic subcapsular haematoma may present with PE [124]. PF is haemorrhagic and solves spontaneously in 2 weeks, whereas the haematoma persists for longer [125].

Subphrenic abscess

PE occurs in 60–80% of cases of subphrenic abscess. These abscesses occur following a surgical procedure such as a splenectomy or gastrectomy in a time interval ranging from some weeks to several months from the intervention [126]. Sometimes, PE results from a perforated organ (e.g. the appendix), diverticulitis, cholecystitis or trauma. PE occurs when the underlying abscess causes diaphragmatic inflammation, which increases the patency of diaphragmatic capillaries, thereby allowing the passage of fluid into the pleural space. Symptoms include fever, abdominal pain and leukocytosis if the cause of the abscess is a surgical intervention. In other cases, thoracic symptoms predominate [127], with chest pain the most frequent symptom. The PE is usually small/moderate. PF is a polymorphonuclear exudate without relevant changes in pH and glucose (table 2). The radiological finding of a sub-diaphragmatic air-fluid level out of the gastrointestinal tract confirms the diagnosis of subphrenic abscess [126]. Diagnosis is delayed or remains unclear when the abscess is not associated with surgery. Abdominal CT is the diagnostic procedure of choice for subphrenic abscess [128]. Abdominal ultrasound also demonstrates air-fluid levels in cavities. However, it can be technically difficult to identify an abscess located on the left side because the lung, the ribs and gas in the gastrointestinal tract are superimposed [126]. Management of a subphrenic abscess requires the administration of adequate antimicrobials, given that infection is generally polymicrobial (with Escherichia coli, Staphylococcus aureus and anaerobic pathogens the most frequent microorganisms) [129]. Another therapeutic option is percutaneous or surgical abscess drainage; because similar outcomes have been reported [130], the first option is recommended. Mortality ranges from 20% to 45%, and it is generally due to delayed diagnosis or failure to establish a diagnosis (finding on autopsy). Therefore, to diagnose this type of abscess, it is important that, in the presence of a polymorphonuclear pleural exudate, abdominal scans are performed to detect the presence of extravisceral gas.

Diaphragmatic diseases

Bochdalek hernia resulting from inadequate closure of the posterolateral pleuroperitoneal membrane is the most common congenital diaphragmatic hernia, with an incidence of 1:2000 to 1:5000 live births [131, 132]. Up to 6% of Bochdalek hernias are found in adults [133].

The most frequently herniated organs include the stomach, spleen and small bowel [134]. The hernia may develop some months or years after the trauma that caused the diaphragmatic defect [135], although strangulation occurs suddenly.

PE may occur secondary to a herniation of an abdominal organ through the diaphragm or through a ruptured diaphragm after a blunt or penetrating trauma [136]. In the presence of atypical PE, diaphragmatic hernia should be considered. In these cases, PE is left-sided, given that the liver is on the right side and prevents herniation of adjacent organs. It occurs in patients with a strangulated diaphragmatic hernia [137]. The PE may be an empyema. Characteristic manifestations include left-sided abdominal pain due to diaphragm irritation. Diagnosis is established by a simple X-ray demonstrating the presence of bowel loops in the thoracic cavity, although contrast-enhanced imaging studies, CT and ultrasound are also useful. It is treated surgically to prevent ischaemic damage in the herniated organ [138].

Liver transplant

In two large series of 300 liver recipients each, PE occurred in 50–68% of cases [139, 140] and was right-sided or bilateral. These cases were associated with increased morbidity. However, nearly 80% of cases resolved within the first 3 months [139]. The cause of PE is unclear, but it may be caused by damage to the right diaphragm as a result of the dissection and retraction of the right upper quadrant. PE appears from the third day and solves spontaneously some weeks or months later. However, some PEs occurring after liver transplantation are related to a previous HH associated with ascites [59]. There is scarce evidence on the characteristics of PF. In a case series of 37 patients, PF was an exudate in 16 patients (43%) and culture was positive in seven patients (19%) [141]. In another series of 189 patients with PE, the mean values for the different parameters analysed (LDH, proteins, glucose, nucleated cell count and red blood cell count) suggest that in a high proportion of cases the PF was an exudate (table 2). Conversely, in another series, PF was prevailingly a transudate [139]. PF culture was positive in four patients (2.1%) [139]. This type of PE can be prevented during transplantation by irrigating the undersurface of the diaphragm surrounding the insertion of hepatic ligaments with fibrin to achieve a sealing effect. In a series of 25 cases in which this technique was used, none developed PE [142].

Peritoneal dialysis

In patients receiving peritoneal dialysis, dialysate may migrate from the peritoneal cavity into the pleural space through a pleuroperitoneal leak, thereby producing PE [143]. Although it only occurs in 1.5–3% of cases [144, 145], it is a severe complication that can lead to early interruption of peritoneal dialysis [145]. In 90% of cases, PE is on the right side [144] and the PF usually has the characteristics of a transudate (table 2) [143], although it may occasionally be an exudate [146]. Diagnosis is usually simple, and firstly leads to the temporary interruption of peritoneal dialysis or a reduction of peritoneal dialysate volume. Because the cure rate does not exceed 50% with conservative treatment, haemodialysis is often required. For cases refractory to conservative treatment, talc pleurodesis through video-assisted thoracoscopy with peritoneal dialysate can be effective [147].

Other diseases

Within the spectrum of Epstein–Barr virus infection, the form associated with haemophagocytic syndrome and chronic active Epstein–Barr virus infection may manifest in the form of hepatosplenomegaly, gallbladder wall thickening, ascites, PE and cardiomegaly [148]. The prevalence of PE of unknown aetiology depends on the definition employed. In a review of 20 cases of PE secondary to Epstein–Barr infection, Takei and Mody [149] observed that this infection explained some cases of idiopathic effusion. Polymorphous lymphocytosis is the most common cytological feature (70%), although PEs may also exhibit atypical characteristics (both in lymphocytes and in mesothelial cells). Immunophenotyping by flow cytometry is useful for cases with atypical lymphoid characteristics. PF is generally a one-sided exudate, most frequently on the left side, and is lymphocytic, although neutrophilic predominance does not exclude the diagnosis (table 2) [149, 150].

This review has some limitations. Some of the articles reviewed were based on retrospective data, with the associated risk of selection bias and lack of randomisation. In addition, many studies corresponded to small case series from which it is difficult to draw solid conclusions. Finally, there is a significant lack of prospective trials that allow results to be applied to a specific patient.

Conclusions

Determining the aetiology of PE caused by a gastrointestinal disease may be challenging due to the wide variety of causative gastrointestinal diseases. Understanding the diagnostic value of PF analysis is crucial to determining the aetiology of a PE. Figure 1 contains an algorithm for the diagnosis of these diseases. Although some effusions are self-limited, in most cases the management of PE will require a multidisciplinary approach, given that some effusions will only resolve with very specific treatments.

FIGURE 1.

Diagnostic algorithm of a nonmalignant pleural effusion of gastrointestinal origin. PE: pleural effusion; US: ultrasonography; GID: gastrointestinal disease; PF: pleural fluid; PMN: polymorphonuclear; HH: hepatic hydrothorax; DH: diaphragmatic hernia; CMV: cytomegalovirus; PF/S: pleural fluid/serum ratio; EPF: oesophagopleural fistula; GPF: gastropleural fistula; EBV: Epstein–Barr virus; LDH: lactate dehydrogenase; CRP: C-reactive protein.