A number of causes of exudative pleural effusions have been recognized. Each is discussed below.
Twenty to 57% of patients hospitalized for community-acquired pneumonia develop a parapneumonic effusion,129,130 as defined by a pleural effusion caused by pneumonia. PF forms when inflammatory cells migrate to the pleural space from an adjacent zone of lung infection and release proinflammatory mediators that alter pleural membrane permeability and recruit additional inflammatory cells.131–133 An influx of protein-rich fluid creates an initially sterile, free-flowing effusion. Subsequent invasion of bacteria promotes a procoagulant effect in PF, which generates fibrin132–134 that deposits on pleural surfaces and begins the formation of intrapleural loculations and a pleural rind. Infected PF eventually evolves into pus and a frank empyema. Although the development of an empyema represents a continuous sequence of pathophysiologic events, it has been arbitrarily described as a three-stage process to assist management (Table 76-4).135 Parapneumonic effusions have also been classified as “uncomplicated” (treatable by antibiotics alone) or “complicated” (pleural space drainage is required).136,137
Table 76-4Stages of an Empyema |Favorite Table|Download (.pdf) Table 76-4Stages of an Empyema
|Exudative ||Increased permeability of pleural membranes with influx of inflammatory cells and protein-rich exudate. Most patients will respond to antibiotics without pleural drainage. |
|Fibrinopurulent || |
|Early Fibrinopurulent ||Increased procoagulant activity in the pleural space promotes deposition of fibrin with early septation of the effusion. Pleural fluid becomes more viscous with increasing LDH and decreasing glucose and pH. Some patients may respond to antibiotics alone but drainage becoming increasingly likely. |
|Late Fibrinopurulent ||Extensive fibrin deposition on pleural membranes causing loculations and pleural rind. Viable bacteria present with markedly increase PF LDH and low glucose and pH. Pleural fluid appears macroscopically purulent. Pleural fluid drainage and, possibly decortication, required. |
|Organizing ||Fibroblast proliferation generates a fibrous pleural peel that requires decortication. A trapped lung may occur if the empyema space is not obliterated. |
The incidence of pleural infections has increased during the last several decades across all age groups138–140 with 30-day mortality that ranges from 5% to 27% depending on the extent of intrapleural suppuration, patient age, and presence of comorbid conditions.138,140–142 Risk factors for parapneumonic effusions include diabetes, immunosuppression, alcoholism, cancer, poor dental hygiene, and increased severity of the index pneumonia.130
Signs and symptoms of a parapneumonic effusion merge with those of the underlying pneumonia with fever, productive cough, and dyspnea predominating. Pleuritic chest pain increases the probability of a parapneumonic effusion and, along with tachycardia and leukocytosis above 15,000/mm3, increases risk that the effusion is complicated.99 Subacute or chronic constitutional symptoms of malaise, anorexia, and weight loss with fetid breath represent characteristic findings of an anaerobic empyema. Failure of a patient with pneumonia to respond to antibiotics as expected suggests the possibility of a partially treated empyema.
Chest imaging identifies approximately 90% of clinically significant parapneumonic effusions.143,144 Most effusions are apparent as a dependent fluid collection with a meniscus on standard two-view chest radiographs. The only radiographic sign of an effusion, however, may be obscuration of a diaphragm that may be incorrectly attributed to lower lobe consolidation.144 Consequently, a parapneumonic effusion should be suspected and evaluated by US in the presence of a diaphragmatic silhouette sign. Presence of intrapleural air-fluid levels indicates a bronchopleural fistula with empyema. A loculated effusion in a nondependent location suggests a complicated parapneumonic effusion.
US has a higher sensitivity and specificity for detecting PF as compared with standard radiographs.145–148 Echogenic PF and septations suggest the presence of a complicated parapneumonic effusion in the fibrinopurulent or organizing stage and thereby increasing the likelihood that drainage will be required.149–152 Ultrasound also allows image-guidance for thoracentesis, which improves the success and safety of the procedure in the presence of pleural loculations.153,154 Contrast-enhanced chest CT can establish the presence, location, and extent of parapneumonic effusions for patients with complex PF collections and uncertain radiographic and US findings.3,143 Loculated empyemas with interlobar and paramediastinal fluid collections can only be imaged by chest CT. Characteristic CT findings include the “split pleura sign” (enhanced pleurae that surround a loculated effusion), pleural thickening, and increased attenuation of extrapleural subcostal fat.143 Chest CT can also differentiate between an empyema and a peripheral lung abscess adjacent to the chest wall.155 Ultrasound, however, is more sensitive as compared with chest CT for detecting septations.
Thoracentesis and PF analysis to provide diagnostic and therapeutic information are indicated when PF is greater than 1 to 2 cm in depth by US or decubitus radiographs.156,157 PF may appear grossly turbid, serosanguineous, or frankly purulent. A fetid odor suggests an anaerobic empyema. Appropriate PF tests with their clinical implications are listed in Table 76-5. PF procalcitonin levels do not provide value in guiding drainage decisions.158,159 Clinical practice guidelines recommend basing the decision to drain a parapneumonic effusion on a combination of clinical, imaging, and PF findings (see Chapter 127).160,161
Table 76-5Commonly Ordered Pleural Fluid Tests |Favorite Table|Download (.pdf) Table 76-5Commonly Ordered Pleural Fluid Tests
|Test ||Clinical Significance |
|Cell count and differential ||Leukocyte counts vary depending on the stage of empyema formation; frank empyemas may have low leukocyte counts because cells have undergone lysis. The effusions are neutrophil predominant although a mononuclear cell predominance may exist with partially treated parapneumonic effusions. |
|Protein ||Defines an exudate when >3.0 g/dL. Tuberculous effusions almost invariably >4.0 g/dL. Values >7.0 g/dL suggest Waldenström macroglobulinemia, multiple myeloma, or a cholesterol effusion. |
|LDH ||Defines an exudate in Light’s criteria rule; usually >1000 IU/L in empyemas. |
|Microbiologic staining and culture ||Microbiologic staining and culture with sensitivity blood culture bottles.162 Cultures positive in ~60% of patients who have signs of pleural infection.141,163 |
|pH and glucose ||Pleural fluid pH and glucose decrease because of intrapleural bacterial metabolism and inflammatory cell activity that utilize glucose and release lactic acid.164–166 A PF pH <7.20 and glucose <60 mg/dL suggest that a parapneumonic effusion is complicated and requires drainage.167 The studies upon which these recommendations are based, however, have extensive limitations in design.167 |
|Amylase (ordered in selected settings) ||Elevated in patients with empyema secondary to esophageal rupture (elevated salivary isoenzyme of amylase); elevated in pancreaticopleural fistula (elevated pancreatic isoenzyme of amylase). |
Uncomplicated parapneumonic effusions resolve after effective antibiotic therapy for the underlying pneumonia. Although it is widely accepted that complicated parapneumonic effusions by definition require drainage of infected PF, consensus does not exist regarding the initial approach to drainage.168 Insertion of an image-guided, small-bore (<15 Fr) intercostal catheter connected to suction and flushed with saline every 6 hours provides effective therapy for many patients.169–171 Limited data indicate that viscous effusions that fail to drain after catheter insertion may subsequently drain with intrapleural instillation of tissue plasminogen activator (tPA) to lyse fibrin adhesions and deoxyribonuclease (DNase) to thin PF.172–176 Up to 30% of complicated parapneumonic effusions, however, require surgical drainage either by VATS or thoracotomy, depending on the degree of loculation, extent of pleural peels and need for debridement or decortication, and operability of the patient.177 Studies have not validated any clinical or imaging findings that reliably identify patients who are unlikely to respond to catheter drainage and should be triaged directly to surgical drainage.163 Moreover, studies have not demonstrated advantages with surgery as a routine, first-line therapy for empyema.178,179 Regardless of the drainage approach adopted, unnecessary delays in draining infected PF increase hospital stay, morbidity, and mortality.180–183 Organized empyemas may require more extensive surgery to promote long-term open drainage and eventual closure of the empyema cavity.184
Tuberculous pleurisy can occur with primary infection or as reactivation disease.185 It accounts for 30% to 80% of all pleural effusions in developing countries and occurs in up to 30% of patients who present with pulmonary tuberculosis.186,187 Its prevalence is lower in developed nations accounting for 1% of all pleural effusions and occurring with pulmonary tuberculosis in only 3% to 5% of patients.186 HIV-positive patients, however, have a higher incidence of tuberculous pleurisy presenting with underlying pulmonary tuberculosis.188 Patients with tuberculous pleurisy commonly resolve their effusions spontaneously but present within 2 years with pulmonary tuberculosis.189,190
PF develops from an intrapleural hypersensitivity response to mycobacterial antigens released by rupture into the pleural space of a subpleural caseous focus.191,192 The number of viable acid-fast organisms in PF is insufficient to allow reliable diagnosis by standard PF staining and culture techniques. Patients present with subacute symptoms characterized by cough, pleuritic chest pain, dyspnea, and fever; although some patients present more acutely simulating bacterial pneumonia and others more indolently with weight loss and fatigue. Purified protein derivative skin tests are positive in only 50% of patients but usually convert to positive within 2 months.193,194 The effusion is usually unilateral encompassing less than two-thirds of the hemothorax.194 Standard chest radiographs and chest CT scans detect active parenchymal tuberculosis in 20% and 80% of patients, respectively.194,195
Any undiagnosed exudative pleural effusion should prompt consideration of tuberculous pleurisy with highest suspicion for lymphocyte predominant effusions (>60% lymphocytes) with protein concentrations >5 g/dL.196 Up to 17% of patients, however, have lymphocyte percentages <50%.196 The PF cell differential may be neutrophil predominant within the first 2 weeks of symptom onset.197 PF mesothelial cell percentages are nearly always <5%.198 PF glucose and pH mirror serum levels although some patients have PD levels lower than serum.
PF staining for acid-fast organisms has a low yield except in the presence of HIV-infection wherein 20% may be smear positive.199 Although PF culture has traditionally been reported to have a sensitivity <50%,194,200,201 studies using liquid culture techniques report a sensitivity of 63% to 75%.196,202 Sputum mycobacterial cultures may be positive in >50% of patients196,203 with positivity of either sputum and/or PF cultures in 79%.196
Adenosine deaminase (ADA) is found in increased concentrations in tuberculous effusions and some other inflammatory and neoplastic pleural conditions. In regions with a high prevalence of tuberculosis, a PF ADA >40 IU/L in a lymphocyte predominant effusion confirms tuberculous pleurisy,200,201,204–206 allowing a diagnosis for 90% of patients after a single thoracentesis.10 An ADA value <40 IU/L adequately excludes the diagnosis in high prevalence settings.207 In regions with low or intermediate prevalence of tuberculosis, PF ADA assay has insufficient sensitivity and specificity, and most patients with negative PF microbiologic evaluations require pleural biopsy.10,208–210 Although elevated ADA concentrations in the pleural space represent the ADA2 isoform, ADA2-specific PF assays provide only negligible benefits over ADA.211 Although several other biomarkers (interferon-gamma, interferon-gamma–induced protein of 10 kDa, and dipeptidyl peptidase [DPP] 4 levels in unstimulated PF) provide similar diagnostic value as compared with PF ADA,212–216 none has comparable availability for routine use.215,217,218 Commercially available T-cell interferon-gamma release assays performed on both blood and PF have inadequate diagnostic accuracy219,220 as do PF nucleic acid amplification tests.216,221,222
Pleural biopsy may be required in complicated settings. Tuberculous granulomata are diffusely distributed over pleural surfaces, which allows up to 70% to 87% of patients to be diagnosed by closed (blind) needle biopsy using an image-guided Abrams needle technique.194,200,200,223–226 This approach is appropriate when the pretest probability of tuberculosis is high for an undiagnosed exudative pleural effusion.201 Six pleural biopsies are recommended.201,224 For other patients, thoracoscopy provides a 100% diagnostic yield.200,201,208 Biopsied pleural tissue must be cultured for acid-fast organisms and examined for organisms and granulomata. Microscopic-observation drug-susceptibility culture as compared with Lowenstein–Jensen culture has a higher diagnostic yield.227
Drug therapy for tuberculous pleurisy is the same as for pulmonary tuberculosis with a four-drug regimen for susceptible organisms.228 Evidence does not support a role for adjunctive corticosteroids.229 When examined with chest CT after chemotherapy, nearly 70% of patients will have some degree of residual pleural thickening that may contribute to measureable pulmonary restriction.230 Some experts recommend therapeutic thoracentesis to prevent pleural fibrosis for moderate to large tuberculous effusions,228 although evidence of benefit is uncertain.231,232 Ultrasonographic detection of complex septated pleural space, CT evidence of extrapleural fat proliferation or loculated effusion, and long duration of symptoms at initiation of therapy may identify patients at greatest risk of pleural thickening 1 year later.230,233
Pleural Effusions Caused by Viral Infections
Acute viral respiratory infections may be associated with transient pleural effusions. The incidence of viral-related pleural effusions is unknown because most patients have a mild clinical course and do not undergo testing for viruses or imaging studies. Recent case series that review the chest studies of patients with documented viral pneumonias, however, demonstrate a low incidence of pleural effusions.234–236 The presence of a pleural effusion in a patient suspected with viral pneumonia and sufficiently ill to require hospitalization, therefore, should prompt consideration of a bacterial coinfection and a parapneumonic effusion. Notably, pneumonia due to swine-origin influenza A (H1N1) is commonly associated with pleural effusions.237,238
Fungal and Parasitic-Related Pleural Effusions
A wide spectrum of fungal infections causes pleural effusions in diverse clinical settings. Immunocompromised hosts may develop fungal empyema secondary to pleural seeding from a fungal pneumonia or more distant sites of infection. Common pathogens include Aspergillus239,240 and Cryptococcus species.240,241 Cryptococcal pleuritis suggests the presence of disseminated disease.241 In immunocompetent patients, chylothoraces may occur secondary to mediastinal granulomatous disease caused by Histoplasma capsulatum.242 Patients with allergic bronchopulmonary aspergillosis may develop eosinophilic pleural effusions242 or erosion of fungus balls into the pleural space.243,244 Finally, pulmonary fungal infections may lead to pleural effusions, which may be sterile or infected with fungal elements. Coccidioidomycosis represents the most common and distinctive endemic fungus presenting in this manner.245,246 Fifteen percent of patients hospitalized with acute pulmonary coccidioidomycosis have pleural effusions247,248 with nearly a quarter of patients progressing to empyema.248 PF is exudative with eosinophilia being commonly present.248
Anecdotal reports exist of a broad range of parasitic infestations associated with pleural effusions.249–257 Among these, pleural effusions related to rupture of an amebic liver abscess across the diaphragm into the pleural space producing an empyema258 and pulmonary infestation with Paragonimus (a genus of flatworms)254,256,259,260 are the most common. Amebic empyema is most commonly right sided, with PF having an anchovy paste or chocolate-milk appearance. A reactive pleural effusion can also occur secondary to transdiaphragmatic inflammation.257 Paragonimiasis produces pleural effusions and pulmonary parenchymal changes that may simulate malignancies or tuberculosis.256 Chest CT series indicate that pleural effusions are the most common intrathoracic imaging findings of the North American form of paragonimiasis (Paragonimus kellicotti).259 PF has a markedly increased LDH and may also assume characteristics of a chylothorax.251 Blood or PF eosinophilia are variable findings. Pulmonary echinococcosis can produce pleural effusions, hydropneumothorax, and secondary pleural hydatidosis when pulmonary or hepatic echinococcal cysts rupture into the pleural space.257,261 A reactive pleural effusion may also occur because lung echinococcal cysts are usually subpleural in location. PF may be an eosinophilic exudate262 or empyema.263 Other parasites rarely involve the pleural space.257
Up to 40% of patients with PTE have associated pleural effusions when examined by standard radiographs with 47% having effusions on chest CT images.264–268 Lung ischemia results in increased pleural membrane permeability with an influx of protein-rich fluid into the pleural space; effusions related to PTE are almost always exudates.265,269 Effusions are unilateral in 85% of patients with approximately equal distribution of right- versus left-sided locations occurring ipsilateral or contralateral to the site of the PTE.265,269 Less than 20% of effusions occupy more than one-third of the hemithorax264,265,269 with most only blunting the costophrenic angle. Delayed diagnosis may cause the effusions to loculate.265,270
PF findings are nonspecific with erythrocyte counts greater than 10,000/µL in 67% of patients, neutrophil predominance in 60%, and eosinophil counts >10% in 18%.269 Only 57% have bloody PF.269 Thoracentesis, therefore, has a limited role in evaluating PF for suspected PTE but has value for excluding other conditions, such as pleural infection or hemothorax. PF usually reabsorbs during anticoagulant therapy. The presence of a bloody effusion does not obviate systemic anticoagulation because hemothorax rarely occurs. When pleural bleeding does occur, it presents with sudden cardiopulmonary compromise usually during the first week of anticoagulation.271–273
Nonthrombotic Pulmonary Emboli
Septic emboli typically lodge in lung periphery, which can cause sterile or infected pleural effusions. Common causes of septic emboli include infected venous catheters,274 septic thrombophlebitis (e.g., Lemmiere syndrome),275 and right-sided endocarditis. Patients with intravenous drug addiction may present with pyopneumothorax.276,277 Common CT imaging findings include peripheral nodules with clearly identifiable feeding vessels and/or air bronchograms, metastatic lung abscesses, and subpleural, wedge-shaped densities with or without necrosis.278–280 PF reflects acute sterile inflammation or evidence of an empyema.281
Hemothorax is defined by the presence of bloody PF with a PF hematocrit (hct) >50% of the simultaneous blood hct value.282 Because erythrocytes undergo spontaneous lysis in the pleural space, a PF hct between 25% and 50% measured a few days after the onset of pleural effusion supports the diagnosis. Hemothoraces result from blunt and penetrating chest trauma, procedures that damage vasculature in or near the pleural space, and underlying conditions that promote spontaneous intrapleural hemorrhage (Table 76-6). Hemothorax carries a potential for unabated hemorrhage, respiratory compromise, and shock. Principles of management include drainage of the pleural space by thoracentesis in the absence of ongoing bleeding, or by chest tube to monitor ongoing bleeding rates, removal of intrapleural blood, and prevention of a subsequent trapped lung or empyema. Pleural drainage also apposes pleural membranes to tamponade pleural-based bleeding sites. Patients may require emergency thoracotomy or VATS to control bleeding and evacuate intrapleural clots.283
Table 76-6Causes of Hemothorax |Favorite Table|Download (.pdf) Table 76-6Causes of Hemothorax
|Condition ||Comments |
|Coagulopathy and bleeding diatheses ||Hemothorax due to primary coagulopathies, thrombocytopenia, anticoagulant therapy, or systemic and intrapleural fibrinolytic therapy rarely occur284–286 |
|Pneumothorax and ruptured lung bullae ||Hemothorax uncommon with spontaneous pneumothorax but can occur especially with ruptured lung bullae282 |
|Neurofibromatosis ||Rupture of friable vasculature in patients with neurofibromatosis may occur by vascular invasion or arterial dysplasia287 |
|Arteriovenous malformations ||Arteriovenous malformations rarely bleed into the pleural space with one-half of instances related to Osler–Weber–Rendu disease282 |
|Aneurysms ||Dissection or rupture of a major intra-thoracic artery is a common and usually clinically apparent cause of hemothorax288 Most commonly aortic but also pulmonary vasculature |
|Ehlers–Danlos disease ||Associated with internal mammary artery rupture289,290 |
|Connective tissue diseases ||Rare reports |
|Extramedullary hematopoiesis ||Rare reports |
|Endometriosis ||Varying degrees of hemorrhagic effusions or hemothorax |
|Exostoses ||Formation of new bone on the surface of existing bone creates sharp boney edges that can erode adjacent vascular structures and cause hemothorax291 |
|Postpartum ||Related to thoracic pressure changes during labor straining |
Catamenial hemothorax represents a unique form of hemothorax occurring in young, multiparous, and menstruating women with pelvic endometriosis.292,293 Two-thirds of patients have intrapleural endometriosis noted during VATS.293 Unilateral and right sided in 80% of instances, bilateral pleural effusions occasionally occur.293 Catamenial pneumothorax294 and hemoptysis293,295 may occur simultaneously with hemothorax. Intrapleural bleeding is usually mild and self-limited, which may delay diagnosis until the temporal relationship with menses is noted. Once diagnosed, most patients are sufficiently stable to allow medical management with hormonal therapies that provide only partial effectiveness.282,296 Patients with recurrent hemothorax may require surgical resection of intrathoracic endometriomas, although relapse commonly occurs.292
Pleural effusions can occur in granulomatous polyangiitis (GP, also termed Wegener granulomatosus) as a result of primary pleural involvement with necrotizing vasculitis or secondary to renal disease, pneumonia, or CHF as complications of vasculitis.297–299 Small patient series indicate that 10% to 20% of patients with GP have pleural effusions usually as incidental findings.298,300 Patients may rarely present, however, with a pleural effusion301,302 and massive effusions with bronchopleural fistulae have been reported.303 From the limited reports of PF analyses, the effusions are exudates with neutrophil predominance.304,305 Pleural biopsy may detect evidence of granulomatous vasculitis or only nonspecific fibrosis.306,307
Up to 30% of patients in the vasculitic phase of Churg–Strauss syndrome have pleural effusions, although most are small and asymptomatic.308,309 Massive effusions, however, have been reported.310 Only rare reports exist of PF analysis, which characterize the fluid as having increased eosinophils.310–312 One report noted a low pH and glucose.312 Effusions may respond to corticosteroid therapy.312
Pleural effusions rarely occur in patients with giant cell arteritis313–320 and may represent the presenting feature of the disease.313,315,316,320 PF is exudative with neutrophil predominance and a normal glucose, although lymphocyte predominance314 and transudative effusions have been reported.315 Pleural biopsy is nonspecific.317 The effusions respond to prednisone therapy.313,319
Behçet disease is a chronic, relapsing inflammatory disorder of unknown etiology. Vascular involvement represents the major risk for mortality with any sized vessel in the venous, arterial, or capillary circulation being potentially affected. Among a myriad of intrathoracic complications,321 Behçet disease can cause abnormalities of pleural membranes and various types of pleural effusions. High-resolution CT scans commonly detect pleural thickening and nodularity that may represent resolved pulmonary infarctions, spread of subpleural pulmonary inflammation, and/or pleural vasculitis.322–326 Pleural effusions commonly occur in patients with vascular obstruction and can be transudates in patients with superior vena cava (SVC) obstruction327 or chylothoraces in patients with thrombosis of the SVC or other major intrathoracic vessels.328–332 Effusions respond variably to corticosteroid therapy330,331 and may require anticoagulation, immunosuppressive drug therapy,333 and/or pleurodesis.330
Superior Vena Cava Syndrome
More than 60% of patients with SVC syndrome develop pleural effusions that are nearly always exudative in nature, with 18% being chylothoraces.334 The etiology of the effusions is unknown, but increased resistance to lymphatic duct drainage into the brachiocephalic vein may contribute to chylothorax.335 Effusions are equally right sided or left sided and most effusions occupy less than 50% of a hemithorax.335 The effusions usually resolve with resolution of the SVC syndrome.
Gastrointestinal and Intra-Abdominal Disorders
Pancreatitis and Pancreatic Fistulae
Pleural effusions are apparent in 50% of patients hospitalized with acute pancreatitis.336,337 Several potential mechanisms exist for PF formation, which include release of proinflammatory mediators from the pancreas into the circulation, transdiaphragmatic transit of parapancreatic inflammatory exudates, lipolysis of mediastinal fat, and early formation of pancreaticopleural fistulae.338,339 Early onset of pleural effusions represents a negative prognosticator for acute pancreatitis.337,340,341 The PF profile includes a neutrophil predominant exudate with an elevated amylase usually greater than twice the serum value.342
Predominantly left-sided effusions may develop in patients with chronic pancreatitis who develop a pseudocyst with a sinus tract through the retroperitoneum into the pleural space. Most patients are male (70%) with a history of chronic alcoholic pancreatitis (50%), but other causes of pancreatitis, such as choledocolithiasis, also occur.343 Patients present with dyspnea (65%), abdominal pain (29%), cough (27%), and chest pain (23%).344 PF pancreatic amylase is markedly elevated (>1000 IU/L). Visualization of the pancreaticopleural fistula with its drainage into the pleural space can be achieved by helical CT scanning, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography (MRCP) with MRCP being the most sensitive initial examination.343–348
No validated algorithm for treatment of pancreaticopleural fistula exists, but most centers initiate a sequential approach that begins with alimentary nutrition and observation supplemented with octreotide to suppress exocrine secretion.345,347–349 Thirty-five percent of patients will fail conservative therapy and require endoscopic placement of a pancreatic stent followed by surgery, if the stent is unsuccessful.343,344,346–348,350 Prolonged medical therapy only delays recovery, so patients should be evaluated for definitive operative intervention early in the course of treatment.343
Rupture or perforation of the esophagus with decompression of gastroesophageal contents into the pleural space represents a life-threatening condition. Esophageal disruption results from forceful vomiting (Boerhaave syndrome), esophageal lesions (retained foreign bodies or neoplasms), or esophageal instrumentation (endoscopy, gastric banding for weight loss).351 Boerhaave syndrome presents with chest pain and signs of sepsis with a rapidly progressing, usually left-sided effusion. Meckler’s triad of vomiting, chest pain, and subcutaneous emphysema suggests the diagnosis. Imaging studies demonstrate a rapidly progressing pleural effusion or hydropneumothorax often associated with mediastinal, paraesophageal, and/or subcutaneous emphysema.352,353 PF findings include high salivary amylase, low pH, low glucose, high LDH, and evidence of pleural infection. Cytologic examination may identify food particles and/or squamous epithelial cells.354 Gastrograffin-contrasted chest CT or endoscopy may localize the esophageal injury and fistula tract, but negative studies do not exclude the diagnosis. Adequate surgical debridement with drainage of the mediastinum and pleural space within 24 hours of presentation improves outcome in Boerhaave syndrome.355,356 Iatrogenic esophageal perforation may be managed more conservatively.357
Endometriosis involving the peritoneum complicated by ascites may rarely cause a pleural effusion that is characteristically right sided with bloody or chocolate-brown appearing PF.358,359 The effusions are linked temporally with menses and contain hemosiderin-laden macrophages. In contrast to catamenial hemothorax due to intrathoracic endometriosis, this condition is characterized by endometrial tissue that is confined to the abdominopelvic region with secondary flow of fluid into the pleural space.
Infradiaphragmatic abscesses and various ischemic and inflammatory lesions of abdominal organs (e.g., perihepatitis360 and splenic ischemia361) can cause exudative effusions that may become infected if intra-abdominal pathogens migrate into the pleural space. Depending on the location of the intra-abdominal locus of infection or inflammation, the effusions may be predominately right sided (e.g., hepatic abscess) or left sided (e.g., splenic abscess or infarction). CT scanning establishes the diagnosis in most instances and directs both pleural and abdominal drainage.
Bile can flow into the pleural space causing a right-sided pleural effusion as a complication of percutaneous biliary drainage,362–365 radiofrequency ablation or catheter embolization of liver lesions,366–368 or spontaneous pancreaticopleural or cholecystopleural fistulae.369,370 PF has a green tint with neutrophil predominance and a PF/serum bilirubin ratio >1.
Connective Tissue Diseases
As many as 30% of patients with systemic lupus erythematosus (SLE) experience pleuritis at some time during the course of their disease.371,372 Pleuritis is an independent predictor of mortality in lupus.371 Associated pleural effusions are usually small to moderate, but large effusions can occur. Usually bilateral, they have an equal side distribution when unilateral.373 Concomitant anti-Sm and anti-RNP antibody seropositivity, greater severity and longer duration of lupus, and young age at SLE onset are associated with a higher rate of pleural disease.371 Typical PF profiles are shown in Table 76-7.374,375 Detection of a positive PF antinuclear antibody (ANA) does not provide incremental diagnostic value to a positive serum ANA.376 Rarely, lupus pleuritis may progress to fibrothorax and trapped lung.377 Effusions respond to nonsteroidal anti-inflammatory drugs as initial therapy, or corticosteroids if necessary, in most patients, but pleuritis tends to recur, often on the contralateral side. Refractory massive pleural effusions rarely occur and may require high-dose steroids and cyclophosphamide, intravenous immunoglobulins, and occasionally pleurodesis.378
Table 76-7Pleural Fluid Test Results in Common Autoimmune Causes of Pleuritis |Favorite Table|Download (.pdf) Table 76-7Pleural Fluid Test Results in Common Autoimmune Causes of Pleuritis
|Finding ||Lupus Pleuritis ||Rheumatoid Arthritis |
|Appearance ||Clear ||Variably serous, purulent, milky, hemorrhagic |
|Protein ||Low in exudative range ||High in exudative range |
|Glucose ||Similar to serum ||Often low <30 mg/dL |
|Leukocytes ||3–5000/µL ||Usually <10,000/µL |
|Complement ||Low ||Low |
|Immune complexes ||High ||High |
|PF ANA ||Positive ||Variable |
|LDH ||Twice upper limits of normal for serum ||High |
|Rheumatoid factor ||Low ||Elevated |
Pleural involvement is the most frequent manifestation of RA in the chest and causes pleural effusions in up to 20% of patients.373,379 As many as 11% of patients within the first year of RA diagnosis have evidence of pleural thickening or pleural effusions on high-resolution CT imaging.380 Pleural effusions occur most often in men who have active arthritis, subcutaneous rheumatoid nodules, elevated rheumatoid factors, and radiographic evidence of underlying rheumatoid lung lesions.379 Patients with RA may rarely present with pleurisy.381 Pleural effusions are small to moderate in size, more often left sided, and asymptomatic.382 Symptomatic effusions warrant thoracentesis to exclude empyema that can occur spontaneously with RA pleural effusions.379 Sterile RA effusions have the pleural profile listed in Table 76-7. Effusions have a neutrophil predominance at onset but may convert to lymphocytic predominance in 7 to 11 days.383 PF cytology may demonstrate, elongated macrophages and multinucleated giant cells (tadpole cells), and granular debris.383 Sterile RA effusions often have a low glucose (<30 mg/dL) and pH (<7.20) that complicates differentiation from pleural infection. Pleural biopsy may demonstrate replacement of parietal pleural mesothelial cells with a palisade of macrophage-derived cells,383 but biopsy is usually not needed for diagnosis. Most effusions resolve spontaneously but some persist or progress to fibrothorax.379 No therapy has demonstrated value for RA pleural effusions. RA may also cause cholesterol effusions384 and bronchopleural fistulae.385
Although recurrent pleuritic chest pain commonly occurs in patients with Sjögren syndrome,386 pleural effusions rarely develop. Among 343 patients reported with Sjögren syndrome, only 9% had pulmonary manifestations, of which 4 patients had pleural effusions.386 Limited data indicate that the effusions associated with Sjögren syndrome are lymphocyte predominant exudates with high PF levels of anti–SS-A/SS-B antibodies.387 An effusion should suggest lymphoma, which occurs with increased frequency in Sjögren syndrome.
Up to 7% of patients with systemic sclerosis may have a pleural effusion that can result from pleural involvement with sclerodermal tissue changes or secondary causes of pleural effusions associated with scleroderma, such as CHF.388 PF is a lymphocyte predominant exudate unless it is a transudate due to associated CHF or renal failure.388,389
Mixed connective tissue disease (MCTD) has clinical features of SLE, scleroderma, and polymyositis–dermatomyositis and is defined by the presence of high serum titers of antibodies against uridine-rich RNA-small nuclear ribonucleoprotein (snRNP).390 Pleuropulmonary complications commonly occur in up to 50% of patients having pleural effusions and 20% having symptoms of pleurisy.391–393 Pleural effusions are usually incidental imaging findings, but may rarely be the presenting feature of the disease.394 The PF profile is poorly defined, but a report exists of a granulocyte predominant exudate.395
Exudative effusions with normal PF glucose levels have been rarely reported in patients with ankylosing spondylitis.396–399 Associated nonspecific pleuritis has been demonstrated on pleural biopsy specimens.399 Effusions may be transient399 or recurrent.396
Polymyositis and dermatomyositis cause interstitial lung disease in approximately 10% to 20% of patients and have the potential for provoking respiratory failure, especially in patients with the antisynthetase syndrome.400 Although pleural irregularities are noted in a high proportion of patients,401 pleural effusions rarely occur and, when present, invariably exist in association with interstitial lung disease and should prompt consideration of an alternative underlying diagnosis.402–404 The PF profile has been reported to be lymphocyte predominant with rare reports of increased eosinophils.402
Pleural effusions rarely occur in patients with sarcoidosis with a reported prevalence of 0.7% to 10%.405–411 A large case series reported 1.1% prevalence of sarcoid-related effusions in asymptomatic ambulatory patients examined by US.407 Thirty-three percent of patients examined by CT scanning have evidence of pleural thickening and subpleural nodules, which are assumed related to sarcoidosis.412,413 Sarcoid effusions are usually small to moderate sized, unilateral, and asymptomatic although large, symptomatic effusions can occur. Only 20% of effusions are bilateral.407 Most effusions are lymphocyte predominant exudates407,414 with one report of the lymphocyte populations having a high CD4/CD8 ratio.415 Chylothorax,409 eosinophilic effusions,416,417 trapped lung,418 and hemorrhagic effusions419 may occur. Pleural biopsy may demonstrate sarcoid granulomas.405,408,410 Most sarcoid effusions resolve spontaneously.
Both transudative and exudative effusions have been reported in patients with myxedema.420–425 Most of these effusions respond to thyroid replacement therapy.
Exudative or transudative pleural effusions can develop from infiltration of amyloid into parietal pleural surfaces, increasing capillary permeability and blocking reabsorption of PF through lymphatic stomata.426,427 Most effusions are associated with light chain amyloidosis. Pleural effusions can also occur through indirect mechanisms of amyloid-induced hypothyroidism, nephrosis, and CHF, the latter two of which may cause transudative effusions in this setting.428 Amyloid-related exudative effusions rarely resolve spontaneously and may require repeated thoracentesis or pleurodesis.
Extramedullary hematopoiesis involving the mediastinum and pleural membranes has been associated with exudative pleural effusions,429–432 hemothorax,433 and chylothorax.434 Detection of normoblasts435 and myeloblasts432 in PF suggests the diagnosis. Symptomatic effusions have been successfully managed by low-dose thoracic radiotherapy, pleurodesis, and hydroxyurea.429,430,434
A wide spectrum of drugs can cause pleural effusions through a variety of mechanisms. A listing of these drugs is available at http://pneumotox.com/indexf.php?fich=clin0&lg=en.
One unique form of drug-induced pleural effusions is represented by ovarian hyperstimulation syndrome (OHSS) that develops during induced ovulation with human chorionic gonadotropin hormone. This condition is characterized by massive increases in ovarian size, extravascular fluid shifts, and hemoconcentration that can result in shock and organ failure. Signaling by vasogenic molecules released from corpus lutae is thought to provoke increased epithelial membrane permeability.436,437 Unilateral and bilateral pleural effusions commonly occur during the full expression of the syndrome but also as isolated findings.438–441 Limited data exist regarding the PF profile, which is considered exudative.442 PF may contain high levels of cytokines.443 In most instances, OHSS is self-limited and spontaneous regression occurs although chest catheters may be required initially for draining large volumes of PF.444
Up to 3% of patients with an occupational exposure to asbestos will develop transient exudative pleural effusions, 445–447 termed benign asbestos pleurisy.446,448 Asbestos exposure may underlie many undiagnosed exudative pleural effusions.447,449 The pathophysiology of benign asbestos pleurisy is uncertain, but asbestos fibers can provoke pleural inflammation both by direct toxicity to mesothelial cells and also by indirect effects through stimulating the release of growth factors and inflammatory cytokines from the lung.450 Mean latency time from first asbestos exposure to pleural effusions is 30 years but ranges from 1 to 58 years.451 Symptoms of dyspnea, chest pain, and/or fever develop in only 35% to 50% of patients.447,451 Pleural effusions range from small to large and present most often as unilateral effusions with equal side distribution or as bilateral effusions in 15%.446,451 PF appears hemorrhagic in 50% of patients, and 25% have increased numbers of eosinophils.449,451 The effusions almost always follow a benign course with spontaneous resolution within 1 to 10 months (median 3 months),451 but some effusions recur.447 Patients with heavy asbestos exposure may have residual pleural thickening,445–447,449,452 which may require decortication if lung restriction occurs.
Lymphatics and Lipid-Related Effusions
Chylothorax is defined by the presence of chyle in the pleural space,453 which denotes a leakage of lymphatic fluid from the thoracic duct or its tributaries. Chyle contains lipids in transit from the digestive tract to the venous circulation via the cisterna chyli near the junction of the left jugular and subclavian veins. Disruption of these lymphatic channels anywhere along their course can result in a pleural effusion. Lymphatic fluid also contains a high content of lymphocytes and immunoglobulins. A classification of chylothorax and listing of common causes are shown in Table 76-8.
Table 76-8Causes of Chylothorax |Favorite Table|Download (.pdf) Table 76-8Causes of Chylothorax
|Classification ||Comments |
|Traumatic ||Account for 50% of chylothoraces with thoracic surgery most common cause.454 Also occur after neck surgery, central venous catheter and pacemaker insertion, blunt chest injury, traction injuries to the chest and neck, and sudden pressure changes with sneezing, vomiting, or labor and delivery. |
|Nontraumatic ||Lymphoma has decreased in incidence to 11% because of earlier lymphoma diagnosis.453 Less common causes include congenital or acquired lymphatic disorders, constrictive pericarditis, SVC syndrome, lymphangiomatosis, lymphangiectasias, lymphangioleiomyomatosis, Noonan syndrome, yellow nail syndrome, Down syndrome, granulomatous infections, and thyroid goiter453 |
|Idiopathic ||Small number idiopathic despite a complete diagnostic evaluation |
Chylothoraces usually present as unilateral effusions, but 20% may be bilateral. The thoracic duct ascends on the right side of the mediastinum crossing to the left side near the fifth thoracic vertebral body (T5). Consequently, a right- versus left-sided chylothorax suggests the presence of disruption to the thoracic duct below or above a T5 level, respectively. Because of the noninflammatory nature of chyle, patients do not experience pleuritic pain but present with dyspnea. The PF appears free flowing and nonloculated without pleural thickening on imaging studies. PF is grossly white, milky, and opalescent in 50% of patients but may be serous or serosanguineous when patients are fasting. PF analysis demonstrates a lymphocyte predominant exudate with an elevated protein but not LDH. A transudate may occur in 14% to 32% of patients,455 which suggests a coexisting condition such as CHF or hepatic hydrothorax.456 PF triglyceride concentration is usually above 110 mg/dL but 15% of patients have lower values that may be <50 mg/dL.455 PF triglyceride testing, therefore, has a high positive but low negative predictive value for chylothorax.455 In the absence of elevated triglyceride levels, analysis of PF for chylomicrons is indicated.
With an established diagnosis, some centers perform conventional lymphangiography or lymphoscintigraphy imaging studies to visualize thoracic lymphatics and identify the anatomical site of chyle leakage. The value of these studies for directing therapy, however, has not been established. No evidence-based algorithm exists for managing patients with chylothorax, and extensive practice variation exists. Generally accepted principles of care, however, encourage identification of the underlying etiology; guidance of therapy in a stepwise manner based on the severity of symptoms, size of the effusion, rate of fluid reaccumulation after thoracentesis, and the patient’s overall clinical condition, comorbidities, and ability to tolerate invasive procedures; and avoidance of prolonged PF drainage by chest tube, which results in nutritional depletion and immunosuppression.457
Observation may suffice for stable and small to moderate effusions with mild symptoms. Nonsurgical, conservative measures resolve 50% of traumatic chylothoraces but prove less successful for nontraumatic forms of the disease, which usually require surgery.458 Only two-thirds of patients with nontraumatic chylothoraces, however, respond to surgical interventions. Most patients with traumatic chylothorax respond to surgical interventions, if required.458 Dietary measures include restriction of fat except for medium chain triglycerides that are absorbed directly into the portal circulation. Available surgical interventions include pleurodesis, pleurectomy, thoracic duct repair or ligation, lymphovenous anastomosis, and pleuroperitoneal shunting. VATS for localizing and managing thoracic duct disruptions has improved outcomes as compared with open thoracotomy.459–461 Recent interest in percutaneous transabdominal embolization of the thoracic duct has developed.462,463 Patients nonresponsive to therapy or patients with terminal conditions may benefit from placement of a pleuroperitoneal shunt.464,465
Cholesterol pleural effusions, also termed pseudochylous or chyliform effusions, usually present as unilateral effusions with 30% of patients being asymptomatic.459 PF appears grossly turbid or milky due to high lipid content, largely composed of cholesterol and lecithin–globulin complexes. The pathogenesis of cholesterol effusions is unknown. Because they most often develop in patients with chronic (>5 years) exudative effusions and thickened pleural membranes, they have been considered a form of “trapped lung” wherein erythrocytes and neutrophils lyse and release their intracellular lipids that cannot be reabsorbed across thickened pleural membranes.459 Reports exist, however, of cholesterol effusions after shorter intervals of exudative effusions without pleural membrane thickening.384 The most common underlying conditions associated with cholesterol effusions include tuberculous pleurisy, chronic pneumothorax, chronic hemothorax, and chronic rheumatoid pleuritis.466 Less commonly associated conditions include pleural echinococcosis, paragonimiasis, and malignancies.
PF analysis demonstrates a cholesterol concentration >200 mg/dL and usually a neutrophil predominant exudate. The triglyceride concentration is usually but not always <110 mg/dL. If the triglyceride level is elevated, the PF cholesterol/triglyceride ratio is >1.0.459 Some PF samples demonstrate cholesterol crystals but chylomicrons are not present. Pleural biopsy may assist in diagnosing an underlying etiologic condition although biopsy samples are diagnostic in only 17%.467 Most patients with cholesterol effusions do not require therapy directed at the pleural space. Symptomatic effusions, however, may benefit from periodic therapeutic thoracentesis, pleurodesis, or rarely decortication. Some effusions may stabilize or resolve with drug therapy for underlying RA if present.384
Ten to 40% of patients with lymphangioleiomyomatosis develop pleural effusions that are almost always chylous.468 Chylothorax occurs as a consequent of obstruction or disruption of the thoracic duct or its tributaries, generalized oozing from pleural lymphatics, and/or transdiaphragmatic flow of chylous ascites.469 Effusions may be unilateral or bilateral,469 and chyloptysis may also occur.
Chylous effusions follow a variable clinical course. They most often progress in size and recur after thoracentesis,470 but may remain stable over years471 or resolve spontaneously.472 Symptomatic patients do not respond well to low-fat diets. Chemical or mechanical pleurodesis with or without thoracic duct ligation performed close to the diaphragm is successful in most patients, but pleurectomy with or without thoracic duct ligation may be required.469
The YNS is a rare, acquired disorder characterized by the triad of abnormal nails (yellowing, slow growth, ridging, onycholysis, excessive long-axis curvature, and/or diminished lunulae), lymphedema, and pleural effusions.453 Some patients have associated bronchiectasis, recurrent lower respiratory tract infections, and chronic sinusitis. The diagnosis is suspected by the presence of two of the triad findings in the absence of another more likely explanation. The etiology is unknown, but both anatomic and functional abnormalities of lymphatic ducts have been proposed.473–475 Histologic analyses of pleural membranes do not consistently detect lymphatic vessel abnormalities.476,477
Most (80%) patients have symmetric, lower extremity, nonpitting lymphedema, which is a finding in 30% of patients who present with pleural effusions. Lymphedema can also involve the face, arms, larynx, and peritoneal cavity producing ascites. Up to 40% of patients having pleural effusions are most often bilateral. The fluid is lymphocytic predominant with an elevated protein meeting exudative criteria, but often an LDH and cholesterol in the transudative range.476,478 Up to 30% of effusions are chylothoraces.476 Management is supportive with therapeutic thoracentesis for symptomatic effusions, pleurodesis or pleuroperitoneal shunting for recurrent effusions, and VATS with thoracic duct ligation for chylothoraces.479
Pleural effusions occur for a variety of reasons in patients with end-stage renal disease undergoing long-term hemodialysis. Approximately 50% of hemodialysis patients with acute respiratory complaints have pleural effusions when evaluated by CT.480 Although the most common etiologies of symptomatic effusions are cardiac failure, pneumonia, tuberculosis, malignancies, and volume overload;480–482 pleural effusions can develop as a direct consequence of uremia (uremic pleuritis).480
The onset or size of effusions related to uremic pleuritis does not correlate with the severity of underlying uremia or timing of hemodialysis.483 Most patients have chest pain, cough, dyspnea, and/or fever. PF is exudative with a predominance of lymphocytes. The diagnosis is one of the exclusion that requires careful consideration of alternative explanations, such as infection, heart failure, and malignancy. Most patients respond to continuation of hemodialysis, but some patients may develop pleural fibrosis with a trapped lung.110
Effusions after Cardiac Surgery
Most patients develop exudative pleural effusions after cardiac surgery in the immediate postoperative period as a direct consequence of the surgery itself in the absence of complications of the procedure, such as hemothorax or chylothorax. Effusions after coronary artery bypass graft surgery (CABG-related effusions) have received the greatest attention,484–487 but nonspecific exudative effusions also occur after cardiac valve replacement.488 CABG-related effusions have been separated into early (within 30 days of surgery) and late onset (30 days after surgery).489 The pathogenesis of these effusions is unknown but may relate to topical cardiac cooling, surgical interruption of lymphatic channels, direct surgical injury of the pleura, and/or pericarditis.487,490–492
Ninety percent of CABG-related effusions encompass <25% of a hemithorax and most are left sided and asymptomatic. Large effusions, however, may cause dyspnea, but chest pain and fever are uncommon.484 Because these effusions resolve spontaneously, thoracentesis is indicated only in certain instances based on the timing of onset, progression, and persistence of the effusion and any associated cardiopulmonary symptoms. Small- to moderate-sized effusions, effusions that develop within days of surgery, asymptomatic effusions, and nonprogressive effusions may be observed for resolution. Symptomatic, large, or progressive pleural effusions require thoracentesis either to manage dyspnea or to evaluate patients for the alternative diagnoses. PTE should be considered with appropriate studies.
When thoracentesis is performed, effusions that occur within the first 30 days of surgery are typically bloody in appearance and may contain >10% eosinophils.493,494 Late-onset effusions are nonbloody with lymphocyte predominance.493,494
Postcardiac injury syndrome (Dressler syndrome) develops 1 week or more after myocardial injury and is characterized by pericarditis, pulmonary infiltrates, and pleural effusions.495 Patients commonly have pericardial chest pain, fever, leukocytosis, and pleuropericardial friction rubs. Pleural effusions occur in 60% to 80% of patients and are typically small and unilateral, most often left sided.496,497 PF is hemorrhagic in 70% with a neutrophil predominant exudate during the acute presentation that evolves to lymphocyte predominance.496 The effusion usually resolves with anti-inflammatory drug therapy.
Iatrogenic Procedures and Treatments
Small exudative pleural effusions may occur in 10% of patients with radiation pneumonitis after external beam radiotherapy, with higher incidences in patients with esophageal cancer treated with extensive mediastinal radiation.498 In addition to direct effects on pleural membranes, lymphatic structures, and pulmonary parenchyma, radiotherapy can promote PF formation by causing constrictive pericarditis.63 The differential diagnosis includes pneumonia with parapneumonic effusions, venous thromboembolism, malignant pleural effusion, drug-induced effusions, and pericarditis. In contrast to malignant effusions, postirradiation effusions do not progress and tend to resolve over time.
Pleural effusions can occur after inadvertent transbronchial placement of a feeding tube into the pleural space.499,500 Cardiopulmonary collapse due to massive hydrothorax can occur if misplacement is not promptly recognized and infusates discontinued.501
Obstetrical and Gynecological
Postpartum Pleural Effusions
One case series demonstrated small, asymptomatic pleural effusions by chest radiographs in 46% of postpartum patients; the effusions had no relationship with method of delivery or antepartum complications.502 A subsequent study using US did not confirm these observations finding pleural effusions in only one patient, who had severe preeclampsia.503 Another study using US detected pleural effusions in 6 of 34 patients with moderate or severe preeclampsia.504 Considering these observations in aggregate, detection of small, asymptomatic effusions in a healthy woman during antepartum or postpartum periods should not trigger a diagnostic evaluation unless respiratory symptoms exist or other clinical features suggest a pathologic etiology for the effusion.
Meigs syndrome is defined by the presence of pleural effusions and ascites in a patient with a benign ovarian fibroma or fibrothecoma. The effusions and ascites resolve with resection of the ovarian tumor. The tumors generate large volumes of fluid that flow transdiaphragmatically into the pleural space causing usually right sided, exudative effusions.505 Meigs syndrome may be associated with marked elevations of serum CA125, which denotes ovarian cancer in other clinical settings.506–508