Pathology of Eosinophilic Pneumonia

The definition of eosinophilic pneumonia depends on the clinical context. In pathology, eosinophilic pneumonia refers to a histologic pattern of diffuse pulmonary infiltrates that contain prominent numbers of eosinophils with or without peripheral blood eosinophilia. Distinguishing the histologic pattern of eosinophilic pneumonia from clinical syndromes that also present with the histologic pattern of eosinophilic pneumonia (eg, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, simple eosinophilic pneumonia, acute eosinophilic pneumonia) is important. The pattern of eosinophilic pneumonia can occur due to infectious or noninfectious etiologies; that is why it is important to see the whole picture of clinical, radiologic, and histopoatholic information in each case. In this context, identification of eosinophilic pneumonia in lung biopsies may be helpful in the diagnosis and classification of these syndromes when the clinical features are atypical. Biopsies may also provide further information of potential etiologies.

This article reviews pathologic findings, epidemiologic, etiologic, prognostic, and therapeutic aspects of eosinophilic pneumonia in the context of the major clinical pulmonary eosinophilic syndromes, which are as follows:

• Chronic eosinophilic pneumonia

• Acute eosinophilic pneumonia

• Simple eosinophilic pneumonia

• Tropical pulmonary eosinophilia

The differential diagnosis discusses disorders in which eosinophilic pneumonia often occurs as part of a spectrum of pathologic findings. These entities include the following:

• Allergic bronchopulmonary aspergillosis

• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

• Infectious diseases

• Pulmonary Langerhans cell histiocytosis

Pulmonary eosinophilic syndromes are rare, and the exact incidence and prevalence are unknown. Epidemiologic features differ depending on the clinical syndrome and etiology.

Idiopathic chronic eosinophilic pneumonia

Idiopathic chronic eosinophilic pneumonia is reported to comprise anywhere from 0% to 2.5% of cases within the registries of interstitial lung disease. ^{[1, 2]} In an Icelandic study, the incidence in the general population was as high as 0.54 cases per 100,000 population per year. ^[3] The disease occurs most often in middle-age females, and females are affected more often than males by a ratio of 2:1. Patients range in age from 18 to 79 years, with a peak between 30 and 39 years. Idiopathic chronic eosinophilic pneumonia may occur in children, but it is rare. Approximately half of all patients have preexisting allergic conditions such as asthma, allergic rhinitis, drug allergy, and others. ^{[1, 4, 5, 6]}

Idiopathic acute eosinophilic pneumonia

The syndrome of idiopathic acute eosinophilic pneumonia is even more rare than that of chronic eosinophilic pneumonia. However, the incidence may be increased in certain conditions. Shorr et al reported an incidence of 9.1 cases per 100,000 population per year in military personnel deployed in or near Iraq. ^[7] In contrast to idiopathic chronic eosinophilic pneumonia, males appear to be affected slightly more often than females. A study by Philit et al found that the average age of patients was around 29 years, with a range of 15-86 years, and patients are usually not asthmatic. ^[8] Several studies report an increased percentage of patients who had recently started smoking prior to the development of acute eosinophilic pneumonia. ^{[8, 9, 10]}

Other pulmonary eosinophilic reactions - Simple eosinophilic pneumonia

Little information is available regarding the prevalence and incidence of eosinophilic reactions to drugs or as a secondary histologic manifestation of pulmonary infection, parasitic infection (eg, Löffler syndrome, simple eosinophilic pneumonia), or neoplasia or as a component of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

Tropical pulmonary eosinophilia

Tropical pulmonary eosinophilia syndrome is thought to represent a hypersensitivity reaction to microfilaria elaborated by Wuchereria bancrofti and Brugia malayi. It occurs predominantly in areas endemic to filariasis including India, Sri Lanka, Southeast Asia, and certain parts of China and Africa. It may sometimes also occur in Western countries as a result of immigration or travel. It appears to arise in less than 1% of patients with filariasis. ^{[11, 12, 13]} Young males between ages 15 and 40 years old are most often affected. The male to female ratio is 4:1. ^[13]

The etiology of eosinophilic pneumonia varies according to the presenting clinical syndrome. Etiologies also overlap but have different frequencies of association.

Chronic eosinophilic pneumonia

The syndrome of chronic eosinophilic pneumonia is often idiopathic but may occur as a manifestation of a pulmonary drug reaction ^{[14, 15]} or in association with fungal, parasitic, or bacterial infection, ^{[16, 17, 18, 19, 20]} underlying connective tissue disease, ^[21]   malignancy, ^[22]  or irradiation. Drug reactions are a particularly common cause of pulmonary eosinophilic infiltrates with hundreds of cases reported.

In a review, Allen et al provided a comprehensive list of drugs that may cause pulmonary eosinophilia. However, new agents are reported each year. ^[15]

Causes of chronic eosinophilic pneumonia are as follows:

• Idiopathic (most cases)

• Drugs (eg, antibiotics, amiodarone, heroin, infliximab, sertraline) ^{[15, 23, 24, 25, 26]}

• Infection, either fungal (eg, coccidiomycosis, aspergillus), parasitic, or bacterial

• Toxic inhalation (eg, nickel carbonyl vapor)

Acute eosinophilic pneumonia

The syndrome of acute eosinophilic pneumonia is also often idiopathic but may also occur as a manifestation of a drug reaction, underlying infection with bacteria, viruses or fungi, or as a result of toxic inhalation. ^{[8, 23, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]} There have also been case reports of an elderly woman who developed acute respiratory failure due to eosinophilic pneumonia following pneumococcal vaccination ^[37]  and of an elderly man who developed acute eosinophilic pneumonia in association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ^[38]

Causes of acute eosinophilic pneumonia are as follows:

• Idiopathic

• Toxic inhalation: Recent initiation of cigarette smoking, ^{[8, 9, 10]}  use of heat-not-burn cigarettes (HNBC), ^[36] nickel dust, ^[39] exposure to World Trade Center dust, ^[40] heroin smoking, ^[35] acetylene, ^[41] Scotch Gard, ^[42]  smoke from fireworks, ^[43] and turpentine oil. ^[44]  Marijuana smoking as well as use of synthethic cannabinoids, e-cigarrettes (vaping), ^{[45, 46]} and waterpipes have also been implicated. ^[47]

• Drug reactions: Trazodone, ^[48] ranitidine, ^[49] progesterone, ^[28] tenidap, ^[50] clomipramine and sertraline, ^[51]  calcium stearate (additive agent for oral antihistamine), ^[52] granulocyte macrophage–colony stimulating factor, ^[53] pentamidine isethionate, ^[54] gemcitabine, ^[55] amiodarone, ^[23] daptomycin, ^{[31, 56]} cocaine, ^[57] and L-tryptophan ^[58]

• Infection: Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), ^{[33, 59]} Trichosporon terrestre, ^[32] intravesical bacillus Calmette-Guérin (BCG), ^[60] aspergillosis, ^[34] toxocariasis, ^[61] and Candida ^[27]

In a prospective study that investigated the phenomena of why peripheral eosinophil count (PEC) tends to increase during the course of acute eosinophilic pneumonia (AEP) and also why an initially elevated PEC is associated with milder disease, the collected data suggested that serum interleukin (IL)-5 is an important cytokine involved in the recruitment of eosinophils from the peripheral blood into the lungs and that an initially elevated PEC is associated with a resolving state of inflammation. ^[62] The data also suggested that mast cells are potentially involved in the inflammatory process of AEP.

Simple eosinophilic pneumonia

Simple eosinophilic pneumonia (Löffler syndrome) often occurs in association with passage of larva due to Ascaris infection through the lung. 

Other causes of simple eosinophilic pneumonia are as follows:

• Other parasitic infections (eg, cutaneous larva migrans) ^[63]

• Pulmonary manifestation of drug reactions

In approximately one third of cases, no cause is identified. ^{[15, 64]}

Tropical pulmonary eosinophilia

The syndrome of tropical pulmonary eosinophilia most often occurs as a hypersensitivity reaction to microfilaria elaborated by W bancrofti and B malayi. ^{[11, 12, 13]} Occasional cases appear to be manifestations of helminthic infections (ie, ascariasis) or other parasites such as strongyloidiasis. ^{[65, 66]}

Secondary causes of eosinophilic pneumonia

As noted above, pulmonary drug reactions are a common secondary cause of eosinophilic pneumonia. In some disorders, eosinophilic pneumonia may occur as one component of a spectrum of pathologic findings. These disorders include allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and infection (bacterial, fungal, parasitic). Distinguishing features of these disorders are discussed in more detail in the Differential Diagnosis section.

Clinical syndromes of eosinophilic pneumonia are largely defined by the clinical and radiographic features accompanied by, when indicated, consistent pathologic findings on biopsy.

Idiopathic chronic eosinophilic pneumonia

In idiopathic chronic eosinophilic pneumonia, patients present with progressive dyspnea, high fever, peripheral blood eosinophilia, and peripheral pulmonary infiltrates on radiography. Patients often have a gradual onset of symptoms for several weeks to months prior to presentation, although occasional cases may present more acutely (< 10 d from onset of symptoms). Approximately half of patients have an underlying atopic condition, such as asthma, allergic rhinitis, drug allergy, or other features. ^{[1, 4, 5, 6]}

Chest radiographs typically show a peripheral infiltrate within the outer two thirds of the lung fields. In some cases (< 50%), the infiltrates correspond to Carrington’s description of the “photographic negative” of pulmonary edema. Findings on high-resolution computed tomography (CT) scanning include peripheral subpleural areas of consolidation and ground-glass attenuation in early stages with a predominance of nodules or reticular densities in later stages. ^{[67, 68]} See the images below.

Idiopathic acute eosinophilic pneumonia

In idiopathic acute eosinophilic pneumonia, young, otherwise healthy patients present with the development of acute respiratory failure. Symptoms include the acute onset of dyspnea, cough, fever, pleuritic chest pain, and myalgia, often progressing to respiratory failure within 1 week. Unlike in chronic eosinophilic pneumonia, patients lack peripheral blood eosinophilia and do not have a history of asthma. ^{[8, 69, 70, 71, 72, 73]}

Chest radiographs show diffuse bilateral infiltrates. High-resolution CT scanning shows diffuse areas of ground-glass attenuation, widening of interlobular septa, nodules, and pleural effusion. ^{[67, 68]}  (See the image below.) The presence of traction bronchiectasis on high-resolution CT images may potentially predict fatal acute eosinophilic pneumonia. ^[74]

Simple eosinophilic pneumonia

Symptoms of simple eosinophilic pneumonia (Löffler syndrome) are usually mild and self-limited. ^{[68, 75]} Transient pulmonary infiltrates are present on chest radiography but usually resolve in less than 1 month. High-resolution CT scanning shows transitory areas of ground-glass attenuation and peripheral airspace consolidation. ^{[67, 68]} This condition is only rarely biopsied. See the image below.

Tropical pulmonary eosinophilia

Symptoms of tropical pulmonary eosinophilia include a nonproductive paroxysmal cough, wheezing, and peripheral adenopathy. Associated marked peripheral blood eosinophilia is recognized (>3000/um), which may show diurnal fluctuations. Serum levels of immunoglobulin (Ig) E are elevated and filarial-specific IgE and IgG are present. ^[13] Pulmonary function studies show a restrictive or obstructive airways disease pattern. Chest radiography reveals reticulonodular opacities (predominantly in the middle and lower zones), miliary mottling, and hilar prominence. Approximately 20% of chest radiography findings may be normal. Findings on CT scanning include reticulonodular opacities, bronchiectasis, air trapping, calcification, and mediastinal lymphadenopathy. ^{[11, 12, 76, 77, 78]}

Histologic findings of eosinophilic pneumonia vary depending on the clinical syndrome and etiology. The description of histologic features is based on wedge or open lung biopsies. However, in clinically typical cases, findings on bronchoalveolar lavage (BAL) or transbronchial biopsy are often sufficient to establish the diagnosis.

Biopsies from patients with the clinical syndromes of chronic eosinophilic pneumonia and simple eosinophilic pneumonia usually histologically show areas of eosinophilic pneumonia.

Histologic features of chronic eosinophilic pneumonia are as follows:

• Consistent features: Diffuse infiltrate of eosinophils within alveolar spaces, variable number of macrophages (from few to many), and mixed interstitial infiltrate of eosinophils, lymphocytes, and plasma cells.

• Variable features: Nonnecrotizing small-vessel vasculitis with eosinophils and lymphocytes, eosinophilic microabscesses, rare scattered multinucleated giant cells or granulomas, foci of an organizing pneumonia pattern, scattered neutrophils, and eosinophilic granules and/or Charcot-Leyden crystals within macrophages

Histologic features of acute eosinophilic pneumonia are as follows:

• Consistent features: Diffuse infiltrate of eosinophils within the alveoli and interstitium and superimposed changes of acute and organizing diffuse alveolar damage (hyaline membranes, variable degrees of interstitial and organizing pneumonia)

• Variable features: Perivascular mixed eosinophilic inflammation without necrosis, occasional mucus plugging, and hyperplasia of type II pneumocytes

• Biopsies from patients with idiopathic acute eosinophilic pneumonia show variable areas of eosinophilic pneumonia with superimposed changes of diffuse alveolar damage. When eosinophilc are occasional and scattered, a diagnosis or acute interstitial pneumonia (AIP) should be considered.

Biopsies from patients with tropical pulmonary eosinophilia show areas of eosinophilic pneumonia sometimes accompanied by eosinophilic microabscesses and granulomas which may progress over time to fibrosis. Importantly, findings of other disorders, such as aggregates of Langerhans cells in pulmonary Langerhans cell granulomatosis, mucoid impaction or bronchocentric granulomatosis in allergic bronchopulmonary aspergillosis, or allergic granulomas in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) are absent.

Histopathologic features of biopsies from patients with chronic eosinophilic pneumonia, acute eosinophilic pneumonia, simple eosinophilic pneumonia, and tropical pulmonary eosinophilia are discussed in more detail below.

Chronic eosinophilic pneumonia

In chronic eosinophilic pneumonia, areas of eosinophilic pneumonia consist of intraalveolar infiltrates of eosinophils accompanied by variable numbers of histiocytes, fibrin, and proteinaceous debris. Eosinophilic granules or even Charcot-Leyden granules are sometimes present within histiocytes. Multinucleated histiocytes may occasionally be present. Scattered lymphocytes, plasma cells, and/or neutrophils may be part of the infiltrate but are not conspicuous. A mixed interstitial inflammatory infiltrate consisting of eosinophils, lymphocytes, and plasma cells is often present. Giemsa special stain may be used to highlight eosinophils. ^{[4, 6, 79, 80]} See the images below.

Some cases of chronic eosinophilic pneumonia may show eosinophilic abscesses. Eosinophilic abscesses consist of focal areas of necrotic eosinophils bordered by a poorly formed granulomatous rim. A nonnecrotizing small vessel vasculitis consisting of eosinophils and lymphocytes is often present but is also not conspicuous and, if present, should raise concern for allergic granulomatous angiitis (eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome]). A common, usually focal but nonspecific finding is areas of organizing pneumonia pattern (“BOOP”) consisting of buds of organizing connective tissue within alveolar airspaces.

Histiocytes may sometimes be more prominent than eosinophils, probably reflecting the duration of eosinophilic pneumonia or its course of resolution with treatment. An associated amorphous intraalveolar eosinophilic exudate may be present in some cases. ^{[4, 6, 80]} A summary of histologic features in chronic eosinophilic pneumonia is discussed above.

See the images below.

In addition to the pulmonary parenchymal findings, rare patients with chronic eosinophilic pneumonia may show tracheobronchial lesions. On bronchoscopy, these consist of whitish nodules along the tracheobronchial tree. Histologically, the nodules show tracheobronchial mucosa with squamous metaplasia, thickening of the submucosal basement membrane, and underlying collections of eosinophils. ^[81]

Acute eosinophilic pneumonia

Biopsies from patients with a clinical syndrome of acute eosinophilic pneumonia also show areas of eosinophilic pneumonia. However, in addition to eosinophilic pneumonia, superimposed features of diffuse alveolar damage are present in these biopsies. Biopsies reveal interstitial and intraalveolar infiltrates of eosinophils as well as hyaline membranes sometimes accompanied by an organizing intraalveolar fibrinous exudate. Varying degrees of organization may be noted, consisting of interstitial fibrosis, edema, and scattered interstitial lymphocytes. Hyperplastic type II pneumocytes are usually line-thickened alveolar septa. ^[82] A summary of histologic features in acute eosinophilic pneumonia is discussed above.

See the following images.

Simple eosinophilic pneumonia

In biopsies from patients with simple eosinophilic pneumonia (Löffler syndrome), the lung shows eosinophilic pneumonia characterized by numerous eosinophils within alveolar spaces and/or the interstitium. However, lung biopsies are rarely obtained, and the diagnosis is usually established clinically with documentation of the eosinophilia in the peripheral blood and identification of the pulmonary infiltrates by chest radiographs.

Tropical pulmonary eosinophilia

As in patients with simple eosinophilic pneumonia, the diagnosis of tropical pulmonary eosinophilia is usually established clinically. Rare reports of pathologic findings have described a nodular eosinophilic bronchopneumonia evolving to a fibrosing, predominantly nodular granulomatous infiltrate. ^[12] Microfilaria have rarely been demonstrated in the lung. ^[83]

Findings on ancillary tests: BAL and transbronchial biopsy

In typical cases of simple, chronic, or acute eosinophilic pneumonia or tropical pulmonary eosinophilia, findings on BAL or transbronchial lung biopsy may obviate the need for wedge biopsy. Although eosinophils in BAL fluid are sometimes increased in interstitial lung disease, this increase is usually below 10%. A finding of 20% or greater eosinophils within BAL is almost always associated with an eosinophilic alveolitis. ^[84] In one study, patients with either acute or chronic eosinophilic pneumonia had a mean percentage of BAL eosinophils of 42% and 35%, respectively. ^[85] Areas of eosinophilic pneumonia may also sometimes be identified on transbronchial biopsy.

The pathologic differential diagnosis of an eosinophilic pneumonia pattern includes the following:

• Acute eosinophilic pneumonia
• Desquamative interstitial pneumonia (DIP)
• Pulmonary Langerhans cell histiocytosis (pulmonary eosinophilic granuloma)

These patterns may be distinguished by consideration of their histologic features.

Acute eosinophilic pneumonia is distinguished from the pattern of chronic eosinophilic pneumonia by the presence of a background of diffuse alveolar damage (DAD). ^{[72, 82]} Some cases of eosinophilic pneumonia may show numerous intraalveolar macrophages in a pattern mimicking DIP. ^[86] Pulmonary Langerhans cell histiocytosis also often contains aggregates of eosinophils and macrophages. Unlike eosinophilic pneumonia, however, pulmonary Langerhans cell histiocytosis is a multifocal, interstitial patchy process that forms irregular stellate nodules with a bronchiolocentric distribution. Pulmonary Langerhans cell histiocytosis also, by definition, contains collections of Langerhans cells, which are not present in eosinophilic pneumonia. ^{[87, 88]}

Secondary causes of eosinophilic pneumonia

In biopsies that reveal eosinophilic pneumonia, secondary causes should be assessed by correlation with clinical and radiologic features, history of drug exposure, culture results, and appropriate use of special stains for bacteria and fungi (eg, Brown and Brenn, Grocott-Gomori methenamine silver [GMS], Ziehl-Neelsen).

Numerous examples of pulmonary eosinophilic pneumonia occurring in association with the use of drugs or inhalational agents are documented in the literature. ^{[15, 23, 28, 30, 31, 35, 39, 40, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 89, 90, 91]}  Areas of eosinophilic pneumonia may be either part of, or the predominate response to, an infectious agent such as coccidiomycosis, atypical mycobacteria, Paragonimus westermani, and others. ^{[18, 19, 20, 34, 61, 92, 93, 94, 95]} In some cases, features more typical of infection, such as prominent necrotizing granulomatous inflammation, may be present offering a clue to the underlying etiology. Cases in which no secondary cause is found are considered idiopathic.

Histologic features of other diseases should also be assessed, as eosinophilic pneumonia may occur as one component of a complex disease process. For example, areas of eosinophilic pneumonia are often present and prominent in allergic bronchopulmonary aspergillosis (ABPA) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). However, unlike in idiopathic variants of eosinophilic pneumonia, fungal hyphae, and/or areas of bronchocentric granulomatosis or mucoid impaction may be found in ABPA.

Even in cases of ABPA consisting predominantly of eosinophilic pneumonia, however, the identification of rare fungal hyphae on GMS stain allows its distinction from idiopathic chronic eosinophilic pneumonia. Likewise, allergic granulomas and a vasculitis are also often present in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), whereas they are absent in patients with idiopathic chronic eosinophilic pneumonia. See the images below.

Idiopathic chronic eosinophilic pneumonia

Most patients with idiopathic chronic eosinophilic pneumonia respond promptly to steroids, with complete resolution of the presenting symptoms within 2 to several weeks. ^{[1, 6, 64, 75]} Recurrence is fairly common, occurring in 58% of patients in one study. In these patients, the clinical course is often prolonged. ^[4] Anti-immunoglobulin (Ig) E therapy has been effective in some patients who have relapsed disease, allowing discontinuation of steroids. ^[96]

Idiopathic acute eosinophilic pneumonia

Patients with idiopathic acute eosinophilic pneumonia respond rapidly to treatment with steroids (within 1 wk). Occasional patients may spontaneously recover. The disease does not recur. Rarely, patients have died despite administration of steroids. ^{[8, 69, 70, 72]}

Simple eosinophilic pneumonia

Simple eosinophilic pneumonia (Löffler syndrome) is usually mild, self-limited, and requires no treatment. It responds well to steroids when necessary.

Tropical pulmonary eosinophilia

Untreated patients with tropical pulmonary eosinophilia may undergo periods of spontaneous remission but over several years show progressive chronic pulmonary insufficiency with increasing dyspnea. Current treatment consists of diethylcarbamazine (DEC), which kills both microfilaria and adult worms. Treatment results in marked improvement with a decrease in eosinophil counts over 7-10 days. However, as many as 20% of patients relapse and require higher doses of DEC. Approximately 12-25% of treated patients nonetheless develop mild chronic pulmonary insufficiency. ^[11] Antihelminthic agents (eg, piperazine citrate, mebendazole) are effective in patients with underlying helminthic infestations. ^{[66, 76]}

Secondary forms of eosinophilic pneumonia

The prognosis and treatment of patients with secondary forms of eosinophilic pneumonia depends on the underlying cause. Eosinophilic pneumonia occurring as a drug reaction requires identification and withdrawal of the implicated pharmaceutical agent. Eosinophilic pneumonia occurring in the context of allergic bronchopulmonary aspergillosis often results in chronic pulmonary impairment. Eosinophilic pneumonia occurring as part of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) responds well to steroids.