Overview of pulmonary eosinophilia

INTRODUCTION — Eosinophilic lung diseases are a heterogeneous group of disorders that share the feature of abnormally increased numbers of eosinophils within the pulmonary airways and parenchyma [1-3].

The major causes of pulmonary eosinophilia will be reviewed here (table 1 and table 2). Pleural fluid eosinophilia and the differential diagnosis of blood eosinophilia and eosinophilia of other tissues are discussed separately. (See "Pleural fluid eosinophilia" and "Approach to the patient with unexplained eosinophilia" and "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs' and "Infectious causes of peripheral eosinophilia".)

DEFINITION — The defining characteristics of pulmonary eosinophilia include the following [4-6]:

●Peripheral blood eosinophilia (absolute eosinophil count ≥500 eosinophils/microL) with abnormalities on pulmonary imaging studies

●Increased eosinophils in bronchoalveolar lavage (BAL) fluid (eg, >10 percent)

●Lung tissue eosinophilia demonstrated in transbronchial or open lung biopsies

Peripheral blood eosinophils are, by no means, uniformly increased in all types of eosinophilic lung diseases [7,8], and conventional chest radiographs may fail to detect lung parenchymal disease [9].

CAUSES AND CLINICAL FEATURES

Helminth infections — Helminth infections elicit several pathophysiologically distinct forms of pulmonary eosinophilia depending on the behavior of the organisms in the lung and the associated host immune response [1]. (See "Eosinophil biology and causes of eosinophilia", section on 'Parasites and other infections' and "Infectious causes of peripheral eosinophilia".)

Transpulmonary passage of helminth larvae (Löffler syndrome) — Three types of helminths, Ascaris (A. lumbricoides, A. suum), hookworms (Ancylostoma duodenale, Necator americanus), and Strongyloides stercoralis, have life cycles in which infecting larvae reach the lungs via the bloodstream, penetrate into alveoli, mature, and ascend the airways before descending the alimentary tract into the small bowel [10]. (See "Ascariasis", section on 'Epidemiology'.)

The syndrome of transient pulmonary radiographic opacities and peripheral blood eosinophilia was originally described by Löffler; Ascaris infection acquired from the use of contaminated human night-soil as fertilizer was determined to be the cause [11]. Subsequent investigations have confirmed that Ascaris is the most common cause of Löffler syndrome worldwide (figure 1). (See "Ascariasis".)

Migrating larvae of hookworms and Strongyloides are less likely to elicit symptoms or pulmonary eosinophilia [10]. (See "Hookworm infection" and "Strongyloidiasis".)

Symptomatic patients most often complain of an irritating, nonproductive cough and burning substernal discomfort that is aggravated by coughing or deep breathing. Dyspnea, wheezing, fever, and blood-tinged sputum containing eosinophil-derived Charcot-Leyden crystals may also be present (picture 1).

The chest radiograph may show round or oval opacities ranging in size from several millimeters to several centimeters in both lung fields; these lesions are more likely to be present when blood eosinophilia exceeds 10 percent. The opacities are migratory and may become confluent in perihilar areas but usually clear spontaneously and completely after several weeks.

Definitive diagnosis of ascariasis at the time of pulmonary symptoms requires detection of Ascaris, Strongyloides, or hookworm larvae in the respiratory secretions. Stool examinations are generally negative at the time of pulmonary symptoms and thus not useful in the diagnosis of Löffler syndrome.

Pulmonary parenchymal invasion — Several helminths can directly invade the pulmonary parenchyma and produce long-lasting pulmonary manifestations rather than briefly passing through the lungs en route to the gastrointestinal (GI) tract as described above. These latter organisms include Paragonimus lung flukes and cestodes (ie, Echinococcus, Taenia solium) [12]. (See "Paragonimiasis", section on 'Pulmonary paragonimiasis' and "Echinococcosis: Clinical manifestations and diagnosis", section on 'Lung involvement'.)

●Paragonimiasis – Paragonimus lung flukes can invade the lungs and produce pleural effusions or eosinophil-enriched inflammatory infiltrates [10]. Endemic areas are listed in the table (table 3). Symptoms can include recurrent hemoptysis and chocolate-colored sputum, which is composed of a mixture of blood, inflammatory cells, and Paragonimus eggs (figure 2). Blood eosinophilia tends to be prominent in the early stages of disease but minimal with established disease. In contrast, the immunoblot or enzyme-linked immunosorbent assay (ELISA) for antibodies to Paragonimus is more useful later in infection.

Paragonimus lung lesions are typically nodular with surrounding areas of ground glass (image 1). The lesions are usually peripheral and are common in the mid- and lower lung zones, in contrast to tuberculosis, which is in the differential diagnosis of hemoptysis but more likely to cause apical cavities. The diagnosis of paragonimiasis is typically made by finding eggs in the sputum or bronchoalveolar lavage fluid (picture 2) or by a positive ELISA. (See "Paragonimiasis", section on 'Diagnosis'.)

●Echinococcosis and cysticercosis – Leakage or rupture of pulmonary cysts in echinococcosis (Echinococcus granulosus, Echinococcus multilocularis) or cysticercosis (Taenia solium) can also cause pulmonary eosinophilia. Antibodies to echinococcus (figure 3) can be detected by enzyme-linked immunosorbent assay (ELISA), while the enzyme-linked immunoelectrotransfer blot assay (EITB) may be useful in the diagnosis of cysticercosis when neuroimaging studies are not diagnostic (table 4). (See "Epidemiology and control of echinococcosis", section on 'Epidemiology' and "Echinococcosis: Clinical manifestations and diagnosis" and "Cysticercosis: Epidemiology, transmission, and prevention", section on 'Epidemiology' and "Cysticercosis: Clinical manifestations and diagnosis".)

Heavy hematogenous seeding — Heavy hematogenous seeding of helminth larvae or eggs can lead to lung deposition and an eosinophilic pulmonary response. This type of hematogenous spread is not essential for the parasite life cycle, in contrast to the "normal" transpulmonary migration noted above. In the case of strongyloidiasis, prior treatment with glucocorticoids may be a risk factor. Pulmonary symptoms such as cough, wheezing, and dyspnea may result, and blood eosinophilia is common.

The syndrome can arise in several settings, including the following [10,13]:

●Ascarids and hookworms – Ascarids (eg, Toxocara canis, Toxocara cati, Ascaris suum), which typically cause visceral larva migrans, and hookworms, which cause cutaneous larva migrans, can also spread hematogenously to the lungs when large numbers of larvae are released into the blood stream (figure 1 and figure 4) [14]. (See "Ascariasis", section on 'Early phase: Pulmonary manifestations' and "Toxocariasis: Visceral and ocular larva migrans" and "Hookworm-related cutaneous larva migrans", section on 'Pulmonary disease'.)

The majority of individuals with ascariasis live in Asia, Africa, and South America. Toxocariasis occurs worldwide. (See "Ascariasis", section on 'Epidemiology' and "Toxocariasis: Visceral and ocular larva migrans", section on 'Epidemiology'.)

●Trichinellosis – While serious pulmonary disease due to Trichinella infection is rare, pulmonary involvement can occur when large numbers of Trichinella larvae are spread hematogenously. Trichinellosis occurs worldwide, although the specific species and prevalences vary (figure 5). Trichinellosis should be considered in patients with periorbital edema, myositis, and eosinophilia.

The diagnosis is typically based on the history, clinical presentation, and peripheral blood eosinophilia. Serologic testing can be used to confirm the diagnosis, but does not become positive for two to eight weeks after infection. (See "Trichinellosis", section on 'Pulmonary disease' and "Trichinellosis", section on 'Diagnosis'.)

●Schistosomiasis – Schistosomiasis is associated with pulmonary eosinophilia in two settings. Schistosomal adult worms can spread to the lungs via collateral vessels following anthelminthic therapy, particularly in patients with portal hypertension. In addition, eosinophilic pneumonia may occur in the early phase (three to six weeks) after infection with schistosomes; patients may experience cough and shortness of breath, and chest computed tomographic (CT) scanning may detect multiple small nodules and, less commonly, ground glass opacities [15].

The diagnosis is typically based on the history, clinical presentation, and peripheral blood eosinophilia since serologic testing and stool examination for ova are typically negative at the time of acute symptoms. Areas of the world with endemic schistosomiasis are shown in the map of the distribution of schistosomiasis. (See "Schistosomiasis: Epidemiology and clinical manifestations".)

●Strongyloides – Hyperinfection and dissemination of Strongyloides larvae may produce invasion of a number of organs (including the lungs) separate from the transpulmonary passage, which is required for the helminthic life cycle (figure 6). Hyperinfection is typically associated with immunosuppression, but can occur in the absence of demonstrable immunosuppression. Typical manifestations include dyspnea, wheezing, cough, and fever. The chest radiograph usually shows diffuse ground glass opacities. The diagnosis can be made by the presence of eggs or larvae in bronchoalveolar lavage (BAL) fluid. Serologic testing by ELISA for IgG antibodies to Strongyloides is often positive, while stool examination is often negative. (See "Strongyloidiasis" and "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pulmonary complications'.)

Tropical pulmonary eosinophilia — Tropical pulmonary eosinophilia results from a distinct immune response to the bloodborne microfilarial stages of the lymphatic filariae, Wuchereria bancrofti and, less commonly, Brugia malayi [16-18]. These organisms are spread by mosquito bites. The typical symptoms are cough, breathlessness, wheezing, fatigue, and fever.

Pulmonary function tests may show a mixed restrictive and obstructive abnormality with a reduction in diffusion capacity [18]. Chest radiographs typically show diffuse opacities (image 2), although approximately 20 percent of affected patients have a normal chest radiograph [18,19]. CT scans are more sensitive than chest radiography; typical findings include reticular and small nodular opacities, bronchiectasis, air trapping, calcification, and mediastinal adenopathy [18,19].

The diagnosis is based on the finding of typical respiratory symptoms and radiographic abnormalities in patients with a history of residence or travel in a filaria-endemic region (eg, Indian subcontinent, South East Asia, Africa, South America) with associated dramatic peripheral eosinophilia (frequently >3000/microL), markedly elevated serum IgE (frequently >1000 units/mL), and serology showing markedly elevated antifilarial IgG antibodies. (See "Tropical pulmonary eosinophilia".)

An identical but nonfilarial syndrome of tropical pulmonary eosinophilia of uncertain etiology has also been recognized [20].

Fungal and mycobacterial infections — Primary coccidioidal infection can be associated with eosinophilic pneumonia [21,22]. Symptomatic infection due to Coccidioides most frequently manifests as a community-acquired pneumonia (CAP) approximately 7 to 21 days after exposure. (See "Primary pulmonary coccidioidal infection".)

Most patients who are suspected to have coccidioidomycosis are evaluated with serologic testing, although antibody testing may be negative early in the course of disease; enzyme-linked immunoassays for specific IgM and IgG are probably the most sensitive screening tests. Differentiation from idiopathic eosinophilic pneumonia can be difficult because organisms may be absent from cultures and open lung biopsy specimens [23]. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Detection of anticoccidioidal antibodies'.)

Pulmonary and peripheral blood eosinophilia have been reported in disseminated cryptococcal infection [24-26]. (See "Cryptococcus neoformans infection outside the central nervous system".)

Pulmonary mucormycosis (Cunninghamella bertholletiae) has been associated with eosinophilia in peripheral blood and bronchoalveolar lavage in a case report [27]. (See "Mucormycosis (zygomycosis)".)

Pulmonary eosinophilia rarely complicates pulmonary tuberculosis [28].

Viral infection — Acute eosinophilic pneumonia has been described in SARS-CoV-2 infection [29,30].

Medications and toxins — Pulmonary eosinophilia has been reported following the ingestion or inhalation of a variety of medications and toxins. The importance of identifying drug or toxin-induced pulmonary eosinophilia cannot be overemphasized as many cases will resolve with withdrawal of the offending agent.

The various clinical presentations of drug-induced pulmonary eosinophilia include asymptomatic pulmonary infiltration with eosinophils, chronic cough with or without dyspnea and fever, acute eosinophilic pneumonia, and drug reaction with eosinophilia and systemic symptoms (DRESS) [31,32]. DRESS should be suspected when the patient has a skin eruption, fever, facial edema, enlarged lymph nodes, and a history of initiation of a culprit medication two to six weeks prior to disease onset (table 5). The diagnosis is based on the combination of clinical features, cutaneous and systemic findings, and laboratory testing, as described separately.

●Common culprit medications – Nonsteroidal anti-inflammatory drugs (NSAIDs), antimicrobials (daptomycin, minocycline, nitrofurantoin), mesalamine, and sulfasalazine are the most common classes of drugs associated with pulmonary eosinophilia [31,32]. Other implicated agents include anticonvulsants, antidepressants, angiotensin converting enzyme inhibitors, beta blockers, hydrochlorothiazide and other sulfa-containing compounds, radiographic contrast media, L-tryptophan, methotrexate, allopurinol, amiodarone, and bleomycin [32,33].

●Implicated toxin exposures – A number of toxin exposures have been associated with pulmonary eosinophilia including [34-42]:

•Aluminum silicate and particulate metals [34]

•Sulfite-exposed grape workers [35]

•Scorpion stings [36,43]

•Inhalation of heroin, crack cocaine, or marijuana [37,44,45]

•Inhalation of organic chemicals during rubber manufacture [38]

•Inhalation of dust or smoke, as in exposure to fireworks, firefighting, tobacco smoking [39-41,46]

•Abuse of 1,1,1-trichloroethane (Scotchgard) [42]

●Outbreaks – Rare outbreaks of pulmonary eosinophilia have been described. The largest of these, the "toxic oil syndrome," affected >20,000 people in Spain in 1981, and was associated with ingestion of rapeseed oil contaminated with aniline derivatives [47]. A similar outbreak, "eosinophilia-myalgia syndrome" occurred in 1989, in association with L-tryptophan ingestion. Although the predominant complaints were neuromuscular, >50 percent of the affected individuals had cough or dyspnea and 17 percent had pulmonary involvement [48].

Idiopathic acute eosinophilic pneumonia — Idiopathic acute eosinophilic pneumonia (AEP) is a type of eosinophilic pneumonia associated with the rapid development of acute respiratory failure in a previously healthy patient. AEP is often associated with recent initiation or resumption of cigarette smoking, vaping [49], and less commonly with heavy inhalational exposure to smoke, fine sand, or dust. Clusters of AEP have occurred in military troops [46] and firefighters [39]. (See "Idiopathic acute eosinophilic pneumonia", section on 'Etiology' and "E-cigarette or vaping product use-associated lung injury (EVALI)".)

Most patients present with an acute febrile illness of less than seven days' duration, characterized by a nonproductive cough, dyspnea, and a variety of nonspecific radiographic changes (image 3A-B). Peripheral eosinophilia is rare at presentation, but may develop during the course of the disease. Hypoxemic respiratory insufficiency and diffuse pulmonary opacities on imaging are frequently identified at presentation and often require mechanical ventilation. (See "Idiopathic acute eosinophilic pneumonia", section on 'Clinical features'.)

The diagnosis is based on the clinical presentation, imaging findings, flexible bronchoscopy with bronchoalveolar lavage that reveals ≥25 percent eosinophils, and the absence of infection or other known precipitant (table 1). Lung biopsy is reserved for situations when the diagnosis is uncertain. Histopathologic findings include diffuse alveolar damage, hyaline membranes, and marked numbers of interstitial and lesser numbers of alveolar eosinophils (picture 3A-B). (See "Idiopathic acute eosinophilic pneumonia", section on 'Diagnosis'.)  

Chronic eosinophilic pneumonia — Chronic eosinophilic pneumonia (CEP) is an idiopathic disorder characterized by an abnormal accumulation of eosinophils in the lung [7]. CEP occurs predominantly in women and nonsmokers; cases have been reported following radiation therapy for breast cancer [50-52]. The syndrome often presents as a subacute illness with a constellation of symptoms including cough, fever, progressive breathlessness, weight loss, wheezing, and night sweats; asthma accompanies or precedes the illness in 50 percent of cases. Peripheral blood eosinophilia is common, but may be absent in 10 to 20 percent of patients [7,50]. (See "Chronic eosinophilic pneumonia".)

The chest radiographic finding of bilateral peripheral or pleural-based infiltrates described as the "photographic negative" of pulmonary edema is virtually pathognomonic for the disease (image 4 and picture 4), but is found in fewer than one-third of cases [7]. Pleural effusions [53] and cavitation [54] are infrequent findings. BAL eosinophilia ≥25 percent is suggestive of CEP. Nodular bronchial mucosal lesions that reveal necrotizing eosinophilic inflammation have been reported in association with CEP [55]. Histopathology of lung biopsy specimens reveals interstitial and alveolar eosinophils and histiocytes, including multinucleated giant cells (picture 5). Fibrosis is minimal, and organizing pneumonia is a commonly associated finding [7].

The diagnosis is based upon the combination of a subacute presentation, characteristic radiographic findings, and peripheral blood or BAL eosinophilia and the absence of infection or drug-induced pulmonary eosinophilia (table 1). (See "Chronic eosinophilic pneumonia", section on 'Diagnosis'.)

Eosinophilic granulomatosis with polyangiitis — Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) is a vasculitic disorder often characterized by sinusitis, asthma, and prominent peripheral blood eosinophilia [56]. In addition to the lungs, the skin and the cardiovascular, gastrointestinal, renal, and neurologic systems may also be involved. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Peripheral blood eosinophilia over 1500 cells/microL (or greater than 10 percent of the total leukocyte count) is part of the diagnostic criteria for EGPA, but much higher levels (>5000 eosinophils/microL) are common. Antineutrophil cytoplasmic antibodies (ANCA) are found in less than 50 percent of EGPA patients with pulmonary involvement and, when present, are most often of the myeloperoxidase (MPO) perinuclear staining pattern. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Laboratory tests'.)

Chest radiograph abnormalities in patients with EGPA are quite diverse, but most commonly consist of transient and patchy opacities without lobar or segmental distribution (image 5A-C). Pathognomonic findings on lung biopsy include eosinophilic infiltrates, an eosinophilic vasculitis (especially of the small arteries and veins), interstitial and perivascular necrotizing granulomas, and areas of necrosis (picture 6A-C). However, tissues from patients presenting with new onset EGPA may not exhibit all of the classic pathologic features of this syndrome, but rather may resemble the eosinophilic infiltration without vasculitis typical of CEP or hypereosinophilic syndrome [57]. In some patients with EGPA, a diagnosis of CEP precedes the onset of the vasculitic syndrome.

The diagnosis of EGPA is typically suspected based on the clinical findings (ie, eosinophilia ≥1500/microL, asthma, paranasal sinus disease). A positive MPO-ANCA is strong evidence in favor of the diagnosis. Definitive diagnosis typically requires a tissue biopsy from the most accessible site of disease, prior to the initiation of systemic glucocorticoid therapy. The diagnostic criteria for EGPA are described separately. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Diagnostic criteria'.)

Allergic bronchopulmonary aspergillosis/mycosis — Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction that occurs when airways become colonized by Aspergillus [58]. Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction can lead to bronchiectasis, fibrosis, and respiratory compromise. Immunologic responses elicited by Aspergillus fumigatus in the airways are responsible for this syndrome (table 6) (see "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis").

Although most of the published data relate to ABPA, a similar syndrome, allergic bronchopulmonary mycosis (ABPM) has been reported in response to other fungal pathogens, including Alternaria, Penicillium, Curvularia, and Schizophyllum sp [59,60].

The clinical picture of ABPA/ABPM is dominated by underlying asthma (or cystic fibrosis), complicated by recurrent episodes of bronchial obstruction, fever, malaise, expectoration of brownish mucous plugs, peripheral blood eosinophilia, and hemoptysis. Wheezing is not always evident, and some patients present with asymptomatic pulmonary consolidation. High resolution computed tomography (HRCT) scan of the thorax may show widespread proximal cylindrical bronchiectasis with upper lobe predominance and bronchial wall thickening. While central bronchiectasis with normal tapering of distal bronchi is considered a classic manifestation of ABPA/ABPM, this finding is neither sensitive nor specific for the disorder (image 6). (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Imaging'.)

Histologic findings in patients with ABPA/ABPM include asthmatic bronchiolitis, eosinophilic pneumonia, bronchocentric granulomatosis, and mucoid impaction of bronchi [61]. On occasion, bronchocentric granulomatosis presents with pulmonary eosinophilia in the absence of endobronchial fungi [62]. (See "Bronchocentric granulomatosis".)

Miscellaneous causes — A number of other conditions are less commonly causes of pulmonary eosinophilia. Examples include:

Hypereosinophilic syndromes — The hypereosinophilic syndromes (HES), some of known and some of idiopathic etiology, are associated with marked peripheral eosinophilia and eosinophilic involvement of diverse organs such as the heart, GI tract, lungs, brain, and kidneys [63,64]. Hypereosinophilia is defined as a blood eosinophil count >1500 cells/microL; a hypereosinophilic syndrome is defined by the association of hypereosinophilia with eosinophil-mediated organ damage and/or dysfunction. Pulmonary symptoms (eg, cough and breathlessness) are seen in up to 65 percent of patients [65]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Other idiopathic lung diseases — Lung diseases, such as idiopathic pulmonary fibrosis, sarcoidosis, and hypersensitivity pneumonitis, can be associated with modest degrees of eosinophilia in the BAL fluid and on biopsy [66]. Less commonly, pulmonary eosinophilia occurs in association with cryptogenic organizing pneumonia, rheumatoid arthritis, Sjögren's disease, radiation-induced lung injury, and graft-versus-host disease (table 2) [4,67,68]. Pulmonary eosinophilia can also be associated with lung allograft rejection [69]. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Eosinophilic BAL'.)

Neoplasms — Peripheral and/or localized pulmonary eosinophilic infiltration occasionally occurs in conjunction with undifferentiated lung carcinomas or lung metastases of cervical tumors; squamous carcinomas of the vagina, penis, skin, or nasopharynx; adenocarcinomas of the stomach, large bowel or uterine body; or transitional cell bladder carcinoma [70]. Pulmonary eosinophilia may also occur when lymphoma, acute eosinophilic leukemia, or the Sézary syndrome involves the lung [71]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Acute eosinophilic leukemia'.)

DIAGNOSTIC APPROACH — The diagnostic approach to patients with suspected pulmonary eosinophilia must be dictated by the specific clinical findings and the setting in which they occur [72]. Every patient should undergo a thorough history and physical examination.

History and physical examination

When obtaining the history, attention should be paid to the following:

●Medication and chemical exposures, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and antibiotics, as well as exposures to dust, smoke (eg, firefighting, tobacco smoke, vaping), or chemicals. (See 'Medications and toxins' above.)

●Travel and immigration histories, including residence in or travel to regions endemic for Coccidioides and varied parasites (more frequently encountered outside of the United States, although Ascaris and Strongyloides are found in rural areas in the southeastern US).

●History of ingestion of poorly cooked pork, wild boar, or other wild animal meats associated with complaints of muscle pain, tenderness, swelling, and weakness. (See 'Heavy hematogenous seeding' above and "Trichinellosis", section on 'Epidemiology'.)

●Respiratory history and findings, including antecedent or concomitant asthma, as found in allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM), eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), and sometimes chronic eosinophilic pneumonia (CEP) or helminthic etiologies. Duration of any antecedent symptoms should be considered. Acute eosinophilic pneumonia (AEP) is characteristically abrupt in onset, whereas CEP develops insidiously over months. Asthma in EGPA may begin years before the development of vasculitic lung involvement.

●Presence of symptoms or signs of extrapulmonary organ involvement, since these may be indicative of systemic diseases, including EGPA, hypereosinophilic syndromes, and neoplasms. (See "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs'.)

A key component of the physical examination is looking for cutaneous lesions that might indicate a certain diagnosis or provide an opportunity for a less invasive biopsy site. Stigmata of rheumatic diseases (eg, muscle weakness, joint swelling, or erythema) should be sought.

Lung examination is nonspecific, although wheezes would be more consistent with EGPA, CEP, or ABPA, while crackles would be more likely with drug-induced pulmonary eosinophilia, AEP, or less commonly CEP.

Blood eosinophilia — The presence of an elevated peripheral blood absolute eosinophil count (AEC; ie, ≥500 cells/microL) helps to support the diagnosis of a number of the entities discussed above. However, the magnitude of blood eosinophilia is not a reliable means to distinguish between the possible etiologies of pulmonary eosinophilia, and the absence of blood eosinophilia does not exclude the majority of these conditions.

A bacterial pneumonia is typically associated with an eosinopenic response, in part due to heightened endogenous glucocorticoid production. Thus, even mild or moderate blood eosinophilia in a patient with an acute or subacute pulmonary disease should prompt evaluation for one of the disorders considered above.

Some of the conditions that have pulmonary eosinophilia are not associated with peripheral blood eosinophilia, such as acute eosinophilic pneumonia and sometimes chronic eosinophilic pneumonia. Additionally, concomitant or recent glucocorticoid therapy can suppress blood eosinophilia.

Serologic and other laboratory tests — Serologic testing can be helpful in the diagnosis of some pulmonary eosinophilic disorders. However, some test results may not be rapidly available, and patients with a recent infection may not have developed antibodies, thus limiting the utility of serologic testing in the evaluation of an acutely ill patient.

Selection of serologic tests is guided by the likely exposures (based on geographic residence and travel) and disease patterns. As examples:

●Strongyloidiasis – Enzyme-linked immunoassay (ELISA) for antibodies to Strongyloides. It is important to identify patients with strongyloidiasis, as treatment with systemic glucocorticoids in a patient with undiagnosed infection can cause disseminated, and potentially fatal, bacterial infection. The sensitivity and specificity of serologic testing is variable, as described separately. (See 'Heavy hematogenous seeding' above and "Strongyloidiasis".)

●Ascariasis – Serologic testing not clinically useful. (See "Ascariasis", section on 'Diagnosis'.)

●Trichinellosis – ELISA or other serologic test. (See "Trichinellosis", section on 'Serologic tests'.)

●Filariasis – Testing for anti-filarial antibodies. (See 'Tropical pulmonary eosinophilia' above.)

●Paragonimiasis, echinococcosis, cysticercosis – ELISA or immunoblot for specific antibodies. (See 'Pulmonary parenchymal invasion' above.)

●Coccidioidomycosis – Enzyme-linked immunoassays for IgM and IgG specific for Coccidioides antibodies. (See 'Fungal and mycobacterial infections' above.)

●EGPA (Churg-Strauss) – Antineutrophil cytoplasmic antibodies (ANCA). (See 'Eosinophilic granulomatosis with polyangiitis' above.)

●Allergic bronchopulmonary aspergillosis – Total serum IgE, Aspergillus-specific IgE and IgG. (See 'Allergic bronchopulmonary aspergillosis/mycosis' above.)

●Serologic studies for systemic rheumatic diseases are obtained based on the finding of suggestive features on the history and physical examination.

Sputum examination for ova and parasites can be useful in patients with a suggestive clinical presentation and travel or residence in areas endemic for helminths, such as Paragonimus, Ascaris, Strongyloides, or hookworms. (See 'Helminth infections' above.)

Imaging — Radiographic imaging of the chest, especially by high resolution computed tomography (HRCT), can provide valuable findings early in the investigation of the patient. The ability of HRCT scans to differentiate among the causes of pulmonary eosinophilia has been evaluated in a series of 111 patients with eosinophilic lung disease [73]. The three diseases that could be diagnosed with greatest certainty by HRCT were CEP, ABPA, and AEP.

●Characteristic CT findings of CEP include: bilateral consolidative opacities and areas of ground-glass attenuation, involving predominantly the peripheral regions of the middle or upper lung zones [50,73-75].

●Common CT findings of ABPA consist of bronchiectasis, mucous plugging, bronchial wall thickening, atelectasis, consolidation, areas of ground-glass attenuation, and upper and central lung predominance [73]. The first three of these findings are the most indicative of ABPA.

●CT findings in AEP include ground-glass attenuation, consolidation, poorly defined nodules, interlobular septal thickening, and pleural effusions (image 7). The triad of interlobular septal thickening, bronchovascular bundle thickening, and pleural effusions are most suggestive of this diagnosis [73].

●CT findings in EGPA [76], drug-induced pulmonary eosinophilia [77], hypereosinophilic syndrome (HES), and simple pulmonary eosinophilia are varied and diverse. Thus, a radiologic diagnosis of these entities is rarely possible [73].

With all of the eosinophilic lung diseases, radiographic findings need to be combined with clinical and other features to guide the approach to diagnosis [73].

Flexible bronchoscopy — Unless the history and noninvasive evaluation identify a provocative agent (eg, helminth infection, medication) as a likely cause of an eosinophilic lung disease, flexible bronchoscopy with bronchoalveolar lavage (BAL) is usually necessary.

●Bronchoalveolar lavage – BAL fluid should be evaluated for the total and differential leukocyte counts. Since mild to moderate airway eosinophilia can occur in a number of common conditions, including asthma, a cut-off of ≥25 percent for the diagnosis of AEP or CEP has been suggested, although the specificities of these criteria have not been evaluated prospectively (table 2) [78].

If the patient has been in an area endemic for coccidioidomycosis or has clinical and radiographic findings suggestive of ABPA, fungal cultures should be obtained (and the laboratory alerted to the possibility of coccidioidomycosis). Examination of the BAL fluid for ova and larvae is appropriate for patients with residence or travel to endemic areas for the various helminths. Bacterial and mycobacterial cultures should also be performed. (See 'Fungal and mycobacterial infections' above.)

●Transbronchial biopsy – In general, transbronchial biopsy is less likely to secure a confident diagnosis than surgical lung biopsy. However, when EGPA (Churg-Strauss) is suspected, a definitive diagnosis can sometimes be made on a transbronchial biopsy, thus avoiding a more invasive lung biopsy procedure. (See 'Eosinophilic granulomatosis with polyangiitis' above.)

Lung biopsy — For causes of pulmonary eosinophilia other than infection, medication, or toxin, it is important to establish and document the nature of the disease. While EGPA, AEP, CEP, and often HES will respond to glucocorticoid therapy, establishing a firm pathologic diagnosis upfront is prudent given the side effects of long-term glucocorticoid treatment and the options for second-line therapy in glucocorticoid-refractory disease. Moreover, since EGPA has the potential to involve and damage other organs, documenting this vasculitis has important implications for the future management of the patient.

As with the general evaluation of interstitial lung disease a surgical approach is typically preferred over a transbronchial biopsy due to the small size of transbronchial specimens. Video-assisted thoracoscopic surgery (VATS) can substitute for a thoracotomy to provide tissue. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Role of lung biopsy' and "Role of lung biopsy in the diagnosis of interstitial lung disease".)

MANAGEMENT — The management of pulmonary eosinophilia depends on the underlying cause. An overview is provided in the following sections.

Infectious causes

●Transpulmonary passage of helminth larvae (Löffler syndrome) - Specific treatment of Löffler syndrome is generally not necessary, although anthelminthic therapy for intestinal infection after resolution of respiratory symptoms may be appropriate. (See "Hookworm infection", section on 'Treatment' and "Strongyloidiasis", section on 'Management' and "Anthelminthic therapies" and "Ascariasis", section on 'Early phase: Pulmonary manifestations'.)

●Parenchymal invasion by Paragonimus, Taenia solium, Echinococcus – Treatment of parenchymal invasion by Paragonimus or tapeworms requires antihelminthic therapy selected based on the specific infection and is discussed separately. (See "Paragonimiasis", section on 'Treatment' and "Echinococcosis: Treatment" and "Tapeworm infections", section on 'Treatment'.)

●Heavy hematogenous seeding of helminth larvae or eggs – Treatment of heavy hematogenous seeding is based on reduction or eradication of the parasite with specific therapy depending on the organism; occasionally systemic glucocorticoids are used to stem the inflammatory response.

(See "Ascariasis", section on 'Treatment' and "Trichinellosis", section on 'Treatment' and "Schistosomiasis: Treatment and prevention", section on 'Treatment' and "Strongyloidiasis", section on 'Severe disease'.)

●Tropical pulmonary eosinophilia – Initial treatment usually consists of oral diethylcarbamazine (DEC); occasionally, systemic glucocorticoids are used to treat accompanying wheezing and bronchoconstriction. Treatment is described separately. (See "Tropical pulmonary eosinophilia", section on 'Treatment'.)

●Coccidioidomycosis – Use of antifungal agents for pulmonary coccidioidomycosis depends on the severity of disease risk of dissemination or complications, as described separately. (See "Primary pulmonary coccidioidal infection", section on 'Management'.)

●Mucormycosis – Mucormycosis (zygomycosis) requires specific antifungal therapy and sometimes surgical debridement. (See "Primary pulmonary coccidioidal infection", section on 'Management'.)

●Tuberculosis – Treatment of tuberculosis is described separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Noninfectious causes

●Medications and toxins – Pulmonary eosinophilia due to drugs or toxins is largely treated with cessation of the implicated agent. For patients with severe respiratory impairment or drug reaction with eosinophilia and systemic symptoms (DRESS), a course of prednisone is usually indicated, as noted in the following examples: (See "Amiodarone pulmonary toxicity", section on 'Treatment' and "Nitrofurantoin-induced pulmonary injury", section on 'Treatment' and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Treatment'.)

●Idiopathic acute eosinophilic pneumonia – Acute eosinophilic pneumonia (AEP) is usually treated with systemic glucocorticoids due to the degree of respiratory impairment. (See "Idiopathic acute eosinophilic pneumonia", section on 'Treatment'.)

●Chronic eosinophilic pneumonia – Chronic eosinophilic pneumonia (CEP) is typically treated with systemic glucocorticoids, as fewer than 10 percent of patients spontaneously recover or improve. Case reports suggest that biologic agents targeting eosinophils (eg, anti-interleukin [IL]-5 agents) may be useful in preventing relapse in CEP, but further study is needed [79-81]. (See "Chronic eosinophilic pneumonia", section on 'Treatment'.)

●Eosinophilic granulomatosis with polyangiitis – Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) requires prompt treatment guided by the vasculitis disease activity, comorbidities, and response to initial therapy with systemic glucocorticoids. Additional therapy (eg, cyclophosphamide, azathioprine, methotrexate, anti-interleukin-5 antibodies, IgE antibodies) may be needed. (See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)

●Hypereosinophilic syndromes – Some of the hypereosinophilic syndromes require immediate treatment (algorithm 1), some require treatment but not urgently, and others, such as asymptomatic familial eosinophilia and hypereosinophilia of unknown significance (asymptomatic), can be safely monitored. The indications for treatment and choice of agents are discussed separately. (See "Hypereosinophilic syndromes: Treatment".)

●Allergic bronchopulmonary aspergillosis – Treatment of allergic bronchopulmonary aspergillosis (ABPA) aims to control episodes of acute inflammation and to limit progressive lung injury. The roles of systemic glucocorticoids and antifungal agents vary with the disease activity. Antieosinophil biologics may have a role in the treatment of eosinophilic pneumonia with fungal sensitization, including ABPA [82]. (See "Treatment of allergic bronchopulmonary aspergillosis", section on 'Treatment'.)

Pulmonary eosinophilia of undetermined cause — Although most of the varied etiologies of pulmonary eosinophilia (with the exception of strongyloidiasis) will improve on glucocorticoids, the empiric use of systemic glucocorticoids for the treatment of pulmonary eosinophilia remains controversial in many settings. In general, systemic glucocorticoid administration is reserved for patients with acute respiratory distress and hypoxemia due to idiopathic acute eosinophilic pneumonia (AEP) or a medication or toxin-elicited acute pulmonary eosinophilia. It should be noted, though, that AEP can resolve spontaneously without glucocorticoid therapy [83]. Glucocorticoids may be indicated during anthelminthic therapy for patients with dyspnea due to bronchoconstriction.

For other chronic or potentially systemic causes of pulmonary eosinophilia, we suggest NOT giving empiric glucocorticoids, at least until a diagnostic biopsy has been performed. Glucocorticoids given prior to a biopsy may suppress tissue eosinophilia and alter the histopathology, obscuring the chance to obtain a definitive diagnosis.

Following a biopsy, glucocorticoids may be given as clinically indicated pending biopsy results, as long as Strongyloides is not suspected. Patients with gastrointestinal Strongyloides infection can develop massive dissemination of filariform larvae to the lungs and other organs, called hyperinfection syndrome, with even a short course of systemic glucocorticoid therapy. For patients with possible Strongyloides infection, empiric treatment for Strongyloides with ivermectin without waiting for the results of laboratory testing is prudent prior to systemic glucocorticoid administration. (See "Strongyloidiasis".)

SUMMARY AND RECOMMENDATIONS

●The defining characteristics of pulmonary eosinophilia include peripheral blood eosinophilia (ie, ≥500 cells/microL) with radiographic evidence of pulmonary parenchymal disease; histopathologic evidence of lung tissue eosinophilia in a transbronchial or open lung biopsy specimen; and increased eosinophils in bronchoalveolar lavage fluid (eg, >10 percent). (See 'Definition' above.)

●A number of helminth infections are associated with pulmonary eosinophilia. The following patterns have been described:

•Transpulmonary passage of Ascaris, hookworms, and Strongyloides, also known as Löffler syndrome. (See 'Transpulmonary passage of helminth larvae (Löffler syndrome)' above.)

•Pulmonary parenchymal invasion by Paragonimus lung flukes or cestodes (eg, Taenia solium). (See 'Pulmonary parenchymal invasion' above.)

•Heavy hematogenous seeding of helminthic larvae or eggs (eg, hookworms, Ascaris, Trichinella, Schistosoma, Strongyloides). (See 'Heavy hematogenous seeding' above.)

•Tropical pulmonary eosinophilia results from a distinct immune response to the bloodborne microfilaria (eg, Wuchereria bancrofti, Brugia malayi). (See 'Tropical pulmonary eosinophilia' above.)

●Nonhelminthic infections, such as Coccidioidomycosis and, less commonly, Mycobacterium tuberculosis, can be associated with pulmonary eosinophilia. Eosinophilic pneumonia has also been reported in the setting of COVID-19. (See 'Fungal and mycobacterial infections' above.)

●Pulmonary eosinophilia can follow the inhalation or ingestion of a variety of toxins (eg, tobacco smoke, rubber manufacture) and medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], amoxicillin, amiodarone, anticonvulsants, angiotensin converting enzyme inhibitors]. A listing of medications associated with pulmonary eosinophilia can be found at Pneumotox. (See 'Medications and toxins' above.)

●The classic presentation of idiopathic acute eosinophilic pneumonia (AEP) is the rapid onset of acute respiratory failure in a previously healthy patient. The diagnosis is based on the clinical presentation, diffuse radiographic opacities, and bronchoalveolar lavage with ≥25 percent eosinophils, and the absence of infection or other known precipitant (table 1). (See 'Idiopathic acute eosinophilic pneumonia' above.)

●In chronic eosinophilic pneumonia (CEP), peripheral blood eosinophilia is common, but can be absent in 10 to 20 percent. Bilateral peripheral or pleural-based opacities are a classic finding on chest radiograph, but not always present. Bronchoalveolar lavage (BAL) eosinophilia ≥25 percent (often ≥40 percent) further supports CEP. (See 'Chronic eosinophilic pneumonia' above.)

●Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) is a vasculitic disorder characterized by sinusitis, asthma, and prominent peripheral blood eosinophilia. Antineutrophil cytoplasmic antibodies (ANCA) are found in less than 50 percent of EGPA patients with pulmonary involvement. For patients with a negative ANCA, the diagnosis may require a tissue biopsy from the most accessible site of disease. (See 'Eosinophilic granulomatosis with polyangiitis' above.)

●Allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) typically develops in patients with asthma, but can also complicate cystic fibrosis. The diagnosis is based upon several clinical, radiographic, and immunologic criteria that are described separately (table 6). (See 'Allergic bronchopulmonary aspergillosis/mycosis' above and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Diagnosis'.)

●Pulmonary eosinophilia can be a feature of hypereosinophilic syndromes (HES), defined as an absolute eosinophil count >1500 cells/microL with evidence of end organ eosinophilic manifestations. A number of systemic diseases that are not usually associated with eosinophilia can have a modest degree of eosinophilic infiltration in the lung (eg, idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia, systemic rheumatic diseases, malignancy). (See 'Miscellaneous causes' above.)

●The diagnostic approach to patients with pulmonary eosinophilia is dictated by the specific clinical findings and the setting in which they occur. The history, physical examination, radiographic, and laboratory findings are used to formulate a differential diagnosis and determine the need for invasive diagnostic testing. (See 'Diagnostic approach' above.)

●The management of pulmonary eosinophilia depends on the underlying cause. The various helminth infections are typically treated with anthelminthic agents, depending on the specific organism and phase in the lifecycle. Noninfectious processes, such as AEP, CEP, and EGPA, are treated with systemic glucocorticoids and sometimes additional immunosuppressive or anti-eosinophil agents. (See 'Management' above.)

●For patients with pulmonary eosinophilia of undetermined cause, we suggest NOT giving empiric glucocorticoids, at least until a diagnostic biopsy has been performed. Glucocorticoids given prior to a biopsy may suppress tissue eosinophilia and alter the histopathology, obscuring the chance to obtain a definitive diagnosis. (See 'Pulmonary eosinophilia of undetermined cause' above.)