Pleural fluid eosinophilia

INTRODUCTION — 

The accumulation of eosinophils in pleural fluid is termed pleural fluid eosinophilia (PFE; also called eosinophilic pleural effusion). PFE requires a comprehensive evaluation so that the underlying causes can be identified and the effusion treated.

The pathogenesis, etiology, and evaluation of PFE will be reviewed here. The general analysis of pleural fluid and evaluation of systemic eosinophilia and pulmonary parenchymal eosinophilia are discussed separately.

●(See "Pleural fluid analysis in adults with a pleural effusion".)

●(See "Approach to the patient with unexplained eosinophilia".)

●(See "Overview of pulmonary eosinophilia".)

DEFINITION AND INCIDENCE — 

PFE is defined as pleural fluid with a nucleated cell count containing >10 percent eosinophils [1-4]. It is estimated that approximately 10 percent of exudative pleural effusions are eosinophilic (normal range is 0 to 1 percent) [2,3,5,6].

PATHOGENESIS — 

The mechanisms that lead to the recruitment of eosinophils to the pleural space are unclear.

Pleural tissue does not normally harbor eosinophils. Thus, the development of PFE requires the recruitment of bone marrow-derived eosinophils (picture 1) [7].

One hypothesis is that stimulation of pleural mesothelial cells by nonspecific injury (eg, air, cancer, drugs) leads to the production of cytokines, chemokines, and adhesion molecules that recruit eosinophils to the pleural space [8,9].

●Eosinophil recruitment into tissues is dependent upon mediators, such as eotaxins (eotaxin-1 [CCL11], eotaxin-2 [CCL24], and eotaxin-3 [CCL26]), interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES) [10-13]. These mediators induce eosinophil proliferation and maturation in the bone marrow, migration into the circulation, adhesion to the endothelium, and migration across endothelial barriers into the pleural space.

●Soluble vascular cell adhesion molecule (VCAM)-1 is increased in eosinophilic pleural effusions compared with noneosinophilic effusions [14]. VCAM-1 and eosinophil very late antigen-4 mediate eosinophil-endothelial cell interactions to allow eosinophils to enter the pleural space [14].

Eosinophil survival in the pleural space is also thought to be mediated by cytokines, such as IL-3, IL-5, and GM-CSF [14,15]. Eosinophil apoptosis can be inhibited for up to two weeks when eosinophils are incubated with these cytokines; in contrast, eosinophils undergo apoptosis within two days when these cytokines are absent [16].

CLINICAL PRESENTATION — 

PFE features are nonspecific and present as the following:

●Incidental pleural fluid finding – In most cases, PFE is an incidental finding when a white cell count and differential or cytology are requested during routine pleural fluid analysis for a pleural effusion of unclear etiology. Further details are provided separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Cell counts and cell differential' and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

●Features of the pleural effusion and underlying etiology – Patients with PFE may have symptoms associated with the underlying etiology of PFE or the pleural effusion itself. For example, patients with infection-related PFE may have chest pain, fever, cough, and dyspnea; patients with parasitic-related PFE may have pulmonary or extra-pulmonary symptoms; and patients with pulmonary infarction may have hemoptysis. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Clinical features' and "Paragonimiasis", section on 'Clinical manifestations'.)

The time course for the development of pleural fluid varies with the etiology [7]. For example, PFE develops within hours after a spontaneous pneumothorax; 10 to 14 days after the onset of a traumatic or hemorrhagic pleural effusion [7]; and longer when due to malignancy, drugs, or asbestos exposure.

PFE is usually unilateral, but rare reports suggest that drug-associated PFE may be bilateral or recurrent [17]. Untreated infection may also be associated with recurrence [18].

There is no sex or age predilection for patients with PFE, but patients with idiopathic PFE classically present as middle-aged (eg, 40 to 50 years) males with a small- to moderate-sized unilateral pleural effusions [16].

PFE may occur in the presence or absence of peripheral blood eosinophilia. For example, direct pleural trauma and hemothorax, but not pneumothorax, are often associated with peripheral blood eosinophilia that develops days after the PFE. (See "Approach to the patient with unexplained eosinophilia" and "Eosinophil biology and causes of eosinophilia", section on 'Major causes of eosinophilia'.)

DIFFERENTIAL DIAGNOSIS — 

The spectrum of diseases associated with PFE is wide (table 1) and is affected by the diseases prevalent in the population being tested [2,3,6,19,20].

Common etiologies — The distribution of etiologies varies among studies. In a meta-analysis of 687 cases of PFE, the most common causes were the following [20]:

●Pleural malignancy (26 percent) – (See 'Malignancy' below.)

●Idiopathic (25 percent) – (See 'Idiopathic' below.)

●Pleural infections (13 percent) – (See 'Infections (parapneumonic pleural effusion)' below.)

●Pleural air or blood (13 percent) – (See 'Pleural trauma (air, blood, direct injury)' below.)

Malignancy — Malignancy is one of the most common causes of PFE with the incidence ranging from 6 to 40 percent in several studies (on average one-quarter to one-third) [2,3,19,21]. However, among patients with malignant pleural effusions, the prevalence of PFE is low (2.3 to 6.8 percent) [1,22].

The presence of eosinophils does not increase the risk for malignant pleural effusion since malignancy is diagnosed as frequently in eosinophilic pleural effusions as in noneosinophilic effusions [2,6].

Among the malignancies associated with PFE, lung cancer is the most common [3,19]. In a review of 153 pleural fluid samples demonstrating PFE, one-third were associated with malignancy and among these, one-half were due to lung cancer [19].

Although the likelihood of pleural malignancy appears to be inversely related to the percentage of pleural fluid eosinophils [19,20], there is no absolute eosinophil percentage cutoff that excludes malignancy [3,20]. Furthermore, the presence of ≥10 percent eosinophils cannot be considered an indicator of benignancy [19,23].

Infections (parapneumonic pleural effusion) — Parapneumonic pleural effusions caused by bacteria, fungi, mycobacteria, parasites, and viruses can cause PFE [3,18,19,24-37].

Parasitic infections are the most common infectious etiology to be associated with PFE and generally have a higher degree of PFE than other types of pleural infection [6,38].

●Paragonimiasis is the most common parasite associated with PFE and is endemic to southeast Asia [28,29,37]. (See "Paragonimiasis".)

●Other parasitic infections associated with PFE include the following [29-35,37]:

•Sparganosis – (See "Tapeworm infections", section on 'Visceral involvement'.)

•Toxocariasis – (See "Toxocariasis: Visceral and ocular larva migrans", section on 'Other presentations'.)

•Cutaneous myiasis – (See "Skin lesions in the returning traveler", section on 'Myiasis'.)

•Loiasis – (See "Loiasis (Loa loa infection)".)

•Lymphatic filariasis – (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Tropical pulmonary eosinophilia'.)

•Amebiasis – (See "Extraintestinal Entamoeba histolytica amebiasis", section on 'Pleuropulmonary infection'.)

•Ascariasis – (See "Ascariasis", section on 'Early phase pulmonary manifestations'.)

•Strongyloidiasis – (See "Strongyloidiasis", section on 'Acute infection'.)

•Echinococcosis – (See "Echinococcosis: Clinical manifestations and diagnosis", section on 'Lung involvement'.)

•Taenia solium – (See "Tapeworm infections", section on 'Clinical manifestations'.)

•Dracunculiasis – (See "Miscellaneous nematodes", section on 'Dracunculiasis'.)

•Clonorchis – (See "Liver flukes: Clonorchis, Opisthorchis, and Metorchis", section on 'Clinical manifestations'.)

While tuberculosis is typically associated with a low eosinophil count, rare reports suggest a high eosinophil count [25,26,38,39]. (See "Tuberculous pleural effusion".)

Fungal infections, specifically coccidiomycosis, can be associated PFE and should be considered as a potential cause in endemic areas [27,36].

Rarely, bacterial and viral parapneumonic effusion can be associated with pleural eosinophilia [19]. Eosinophils appear late in the course of a parapneumonic effusion, usually three weeks or more, and often after resolution of the pneumonia [24,40]. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Pleural trauma (air, blood, direct injury) — Pleural irritation with air or blood and direct injury are associated with PFE [2,19,41-43].

●Air in the pleural space (pneumothorax) – In many case series, spontaneous pneumothorax is a common cause of PFE [19,41]. An intense eosinophilic pleuritis occurs over a few hours following pneumothorax [44].

●Blood in the pleural space (hemothorax) – Bleeding into the pleural space may contribute to the development of PFE in the setting of thoracotomy, chest trauma, benign asbestos pleural effusion (BAPE), and pulmonary infarction [19]. As an example, nonspecific pleural effusions that develop within 30 days after cardiac surgery are typically hemorrhagic and often eosinophilic. They are more common when the pleura has been excised (eg, for internal mammary artery grafting). (See "Evaluation and management of pleural effusions following cardiac surgery", section on 'Pleural fluid characteristics'.)

Unlike PFE associated with spontaneous pneumothorax, eosinophils typically appear in pleural fluid by day 10, and eosinophilia appears in the peripheral blood a few days later [45,46].

●Trauma – Direct trauma to the pleural space in the form of thoracotomy, thoracoscopy, or other injury can cause PFE [19,23]. Whether repeated thoracentesis causes PFE is unclear since data are limited and conflicting [45,47]. The percentage of eosinophils does not appear to increase in successive thoracenteses [19,23].

Less common and rare etiologies

Drugs — Several drugs have been implicated in the development of PFE and are listed in the table (table 2) [17,48-62].

Concomitant blood eosinophilia has been described with valproic acid, nitrofurantoin, dantrolene, gliclazide, tizanidine, fluoxetine, and warfarin [48-56].

The latency between the development of PFE from first drug exposure is typically several months, with a range from a few days to one to two years (eg, nitrofurantoin) or even 12 years (eg, dantrolene) [7,48,63]. Herbal preparations (eg, kampo) have also been implicated in PFE [57].

Asbestos (benign asbestos pleural effusion) — BAPEs typically develop in the first two decades following asbestos exposure (earlier than malignant pleural mesothelioma, which typically presents 30 to 40 years after exposure). Approximately one-third of BAPEs have PFE, even as high as 50 percent of the total nucleated cell count [64]. Asbestos-related pleural disease is discussed separately. (See "Asbestos-related pleuropulmonary disease", section on 'Benign asbestos pleural effusion'.)

Pulmonary embolism — In patients with pulmonary embolism (PE), 18 percent of pulmonary effusions are eosinophilic [4,65,66]. Pleural effusions in PE are classically associated with pulmonary infarction that has pleural involvement; the effusions are often small and bloody, which may explain the presence of eosinophils. (See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism" and "Pulmonary embolism: Epidemiology and pathogenesis in adults", section on 'Infarction'.)

Rare causes — Rarely, PFE has been reported in association with acute and chronic eosinophilic pneumonia, rheumatoid pleurisy, eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome), and immunoglobulin G4-related disease [15,67-71]. Cirrhosis and heart failure are rare causes of transudative PFE [42]. (See "Chronic eosinophilic pneumonia" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Clinical features' and "Clinical manifestations and diagnosis of IgG4-related disease", section on 'Other manifestations'.)

Idiopathic — PFE is idiopathic in 8 to 35 percent of patients (on average a quarter) and varies with the definition [2,4,16,19,20,26,41,72,73]. At least some of these cases may be due to unidentified asbestos exposure, occult PE, viral infection, or a medication.

Among patients with pleural effusion, the likelihood of an idiopathic pleural effusion was significantly higher in PFE than in noneosinophilic pleural effusion [20].

EVALUATION TO NARROW THE DIFFERENTIAL — 

In most cases, the evaluation of PFE follows the evaluation protocol for pleural effusions (see "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion"). However, certain clinical features help determine the underlying PFE etiology (algorithm 1). These features are discussed in this section.

Retake the history and examination — For patients with PFE, we review the history and examination with the differential diagnosis above in mind (see 'Differential diagnosis' above) to find etiologic clues that were potentially overlooked, such as the following (table 3):

●A past medical history of a disorder known to be associated with PFE. This includes malignancy and parapneumonic effusion, and rarer conditions, such as acute and chronic eosinophilic pneumonia, rheumatoid arthritis, eosinophilic granulomatosis with polyangiitis (EGPA), and immunoglobulin (Ig) G4-related disease. (See 'Malignancy' above and 'Infections (parapneumonic pleural effusion)' above.)

●Risk factors for cancer including hemoptysis, weight loss, fatigue, night sweats, smoking, change in bowel habit, breast lumps, recent mammography, or skin abnormalities. (See 'Malignancy' above.)

●Any thoracic/pulmonary condition or procedures in the previous one to four weeks or signs of chest trauma that may have led to entry of air or blood into the pleural space (eg, motor vehicle accident, fall, recent chest surgery, symptoms of possible pulmonary embolism). (See 'Pleural trauma (air, blood, direct injury)' above.)

●History or signs of infection (eg, fever, sweats, or chills; recent upper or lower respiratory tract symptoms) or travel to or residence in endemic areas of fungi (eg, Coccidioides), tuberculosis, or parasites (eg, Paragonimus, Strongyloides, Dracuncula). Diarrhea and abdominal pain or new skin lesions following travel may support parasitic infection. Skin lesions may suggest fungal infection. (See 'Infections (parapneumonic pleural effusion)' above.)

●List of medications including dietary supplements (eg, L-tryptophan), herbal preparations, and vitamins. We also ascertain if medications are new or old. (See 'Drugs' above.)

●Asbestos exposure, which might suggest mesothelioma or a benign asbestos pleural effusion. (See 'Asbestos (benign asbestos pleural effusion)' above.)

●Joint examination for evidence of rheumatoid arthritis.

●Skin examination for new lesions that might suggest fungal or parasitic infection.

●Bilateral PFE, which may suggest a systemic disorder or drugs as the etiology.

Laboratory analysis — For patients with PFE, we typically obtain a complete blood count with differential (if not already performed), serum chemistries including liver function tests, and stool for ova and parasites. Evidence of peripheral blood eosinophilia may support certain etiologies, such as hemothorax, direct trauma to the pleural space, chronic eosinophilic pneumonia, hypereosinophillic syndromes, or IgG4-related disorder.

We do not routinely measure serologic studies for fungal or parasitic microbes. However, microbe-specific serology may be useful when select fungal and parasitic infections are suspected in patients with a history of travel to or residence in endemic areas [37]. (See 'Infections (parapneumonic pleural effusion)' above.)

Similarly, we do not routinely measure serology for autoimmune or collagen vascular disorders. However, disorder-specific serology may be useful in patients with features that suggest rheumatoid arthritis (cyclic citrullinated peptide), EGPA (antineutrophil cytoplasmic antibody), or IgG4-related disease (IgG4 levels). Diagnosis of these conditions are provided separately.

●(See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●(See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)", section on 'Evaluation'.)

●(See "Clinical manifestations and diagnosis of IgG4-related disease", section on 'Laboratory evaluation'.)

Pleural fluid reanalysis — We send pleural fluid for cytology (malignant cells and microbe staining) as well as for Gram stain, bacterial, fungal, parasitic, and mycobacterial culture. Obtaining a pH or other condition-specific biomarkers is reasonable when a select etiology is suspected (eg, rheumatoid arthritis) (table 4) (see "Pleural fluid analysis in adults with a pleural effusion"). The original sample may be used, but if not feasible, a new sample may be required. As examples:

●Case reports suggest that obtaining specific parasitic antibodies in pleural fluid may be helpful when parasite infection is suspected [37]. Similarly, IgG4 levels may be obtained when IgG4-related disease is suspected [70], although IgG4 staining on pleural biopsies may be necessary. (See 'Additional studies' below.)

●Pleural fluid patterns may support specific etiologies (table 4) but are rarely diagnostic unless malignant cells or an organism are identified on cytology or culture, respectively. Pleural fluid characteristics for etiologies that underlie PFE are discussed in the linked topics:

•(See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Making a preliminary diagnosis'.)

•(See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Thoracentesis and pleural fluid analysis'.)

•(See "Asbestos-related pleuropulmonary disease", section on 'Benign asbestos pleural effusion'.)

●Determination of whether the fluid is an exudate or transudate may also help narrow the differential. A list of transudative and exudative causes of PFE is provided in the table (table 1). Differentiating transudative from exudative effusions is discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion", section on 'Classification as exudative or transudative'.)

Although the likelihood of pleural malignancy appears to be inversely related to the percentage of eosinophils in the pleural space [3,19], the proportion of eosinophils in pleural fluid does not help differentiate between the different causes of PFE. Similarly, while parasitic infections tend to have a higher percentage of eosinophils than other infections, it is not specific for parasitic PFE.

Additional studies — In most cases, a preliminary or clinical diagnosis can be made without additional studies. However, in a small proportion of patients with an undetermined etiology of PFE, we perform chest computed tomography (CT) and evaluate the need for a pleural biopsy:

●Chest CT – If not already performed, we obtain chest CT with contrast optimized for pleural membrane visualization [74,75] to identify pleuroparenchymal pathology that explains the PFE finding.

●Pleural biopsy – We typically perform a pleural biopsy when a diagnosis cannot be made with less invasive testing. Diagnoses that can be made on biopsy include cancer, tuberculosis or other infection, or autoimmune/collagen vascular disease (eg, rheumatoid arthritis and IgG4-related disorder [71]). The role and type of pleural biopsy required are discussed separately. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion", section on 'Etiology remains undetermined'.)

After a comprehensive evaluation, a minority of patients have no apparent cause and are considered to have "true" idiopathic PFE. (See 'Idiopathic' above.)

ASSIGNING AN ETIOLOGIC DIAGNOSIS — 

The etiologic diagnosis of PFE is assigned based upon the strength of the clinical suspicion for a select disorder and available supporting data. In many cases, a diagnosis is made without a pleural biopsy. As examples:

●The diagnosis of trauma-related PFE is typically made in patients with a history of trauma (air, blood, injury) when diagnoses such as cancer (eg, low suspicion and negative cytology), infection (low suspicion and negative culture), or culprit drugs are reasonably excluded. The same approach is usually taken in those with parapneumonic effusions, known pleural malignancy, or asbestos-related disease, drugs, and pulmonary embolism.

●In a small proportion of patients, pleural biopsy is needed to confirm or exclude cancer, infection, or inflammatory disorder. (See 'Additional studies' above.)

●In some cases, resolution of the PFE when a drug is discontinued provides retrospective confirmation that the PFE was drug-related.

●In patients with idiopathic PFE, an etiology may become apparent if the patient undergoes repeat evaluation for recurrence.

TREATMENT AND PROGNOSIS — 

The cornerstone of management is treatment of the underlying disorder. This varies with the cause and is discussed in the appropriate topic reviews. (See "Overview of the initial treatment and prognosis of lung cancer" and "Management and prognosis of parapneumonic pleural effusion and empyema in adults" and "Treatment of secondary spontaneous pneumothorax in adults" and "Treatment of primary spontaneous pneumothorax in adults" and "Asbestos-related pleuropulmonary disease", section on 'Benign asbestos pleural effusion' and "Acute pulmonary embolism in adults: Treatment overview and prognosis".)

For drug-related PFE, we discontinue the offending agent. Treatment with oral glucocorticoids has been reported to speed resolution in a few cases [56,76,77].

We monitor all patients over the following weeks for resolution or recurrence.

●Resolution is expected in most patients with PFE when PFE is due to trauma, parapneumonic pleural effusion, drugs, benign pleural asbestos disease, PE, and inflammatory disorders. The response to therapy in patients with malignancy including mesothelioma depends on the response to cancer-specific therapy.

●Symptoms usually begin to improve within the first few days after drug discontinuation and the pleural effusion completely resolves over several months [48].

●Benign asbestos pleural effusions typically resolve spontaneously over the course of several weeks to months but can persist for up to a year. (See "Asbestos-related pleuropulmonary disease", section on 'Benign asbestos pleural effusion'.)

For patients with idiopathic PFE, the prognosis is excellent, and most resolve even when the effusion persists for months. However, in rare cases, the PFE may recur and a cause becomes apparent.

SUMMARY AND RECOMMENDATIONS

●Definition – Pleural fluid eosinophilia (PFE) is defined as pleural fluid with a nucleated cell count containing >10 percent eosinophils. Approximately 10 percent of exudative pleural effusions are eosinophilic. The development of PFE requires eosinophil recruitment from bone marrow since pleural tissue does not normally harbor eosinophils. (See 'Definition and incidence' above and 'Pathogenesis' above.)

●Etiologic differential – Etiologies of PFE are listed in the tables (table 1 and table 2). Common etiologies include pleural malignancy (most commonly lung cancer), pleural infections (most commonly parasitic), and pleural trauma in the form of air (pneumothorax), blood (hemothorax), or direct pleural injury (thoracoscopy/surgery). Drugs, asbestos exposure, and inflammatory disorders are less common. Approximately, one-quarter is idiopathic. (See 'Differential diagnosis' above.)

●Diagnostic evaluation – In most cases, the evaluation of PFE follows the evaluation protocol for pleural effusions. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

To help determine the etiology, we perform the following (algorithm 1 and table 3) (see 'Evaluation to narrow the differential' above):

•Clinical history and examination (see 'Retake the history and examination' above):

-A past medical history of a disorder known to be associated with PFE (table 1 and table 2)

-Risk factors or symptoms for cancer

-Any thoracic condition or procedures in the previous one to four weeks that may have led to entry of air or blood into or directly injured the pleural space

-History or signs of infection or travel to or residence in endemic areas of fungi, tuberculosis, or parasites

-Medication list including dietary supplements, herbal preparations, and vitamins

-Asbestos exposure

-Joint and skin abnormalities that suggest an underlying connective tissue disorder (CTD)

•Laboratory – Complete blood count with differential, serum chemistries including liver function tests, and stool for ova and parasites. We do not routinely measure serologic studies for microbes or CTD unless suspected. (See 'Laboratory analysis' above.)

•Pleural fluid – We send pleural fluid for cytology (malignant cells and microbe staining) as well as for Gram stain bacterial, fungal, and mycobacterial culture. Pleural fluid patterns for specific etiologies are shown in the table (table 4) to support an underlying etiology; however, these patterns are rarely diagnostic unless malignant cells or an organism are identified on cytology or culture, respectively. (See 'Pleural fluid reanalysis' above.)

●Additional studies – In most cases, a preliminary or clinical diagnosis can be made without additional studies. However, in a small proportion of patients, we perform chest CT to identify pleuroparenchymal pathology that may explain the PFE finding, and if no cause is identified, we obtain a pleural biopsy. (See 'Additional studies' above and 'Assigning an etiologic diagnosis' above.)

●Treatment and prognosis – The cornerstone of management is treatment of the underlying disorder. All patients are followed over the following weeks for resolution or recurrence. In most patients, resolution is expected provided the underlying disease is responsive.