Tropical pulmonary eosinophilia

INTRODUCTION — Tropical pulmonary eosinophilia (TPE) is a clinical manifestation of lymphatic filariasis, a parasitic infection caused by filarial nematodes (roundworms) that inhabit the lymphatics and bloodstream. Three species cause human lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Infection is transmitted by mosquito vectors; humans are definitive hosts.

TPE is caused by an immune hyper-responsiveness to microfilariae trapped in the lungs [1-4]. The syndrome has also been termed tropical eosinophilia or tropical filarial pulmonary eosinophilia. Rarely, a similar hyper-responsive pulmonary syndrome can be seen in the setting of intestinal helminth infection [5].

Issues related to TPE of filarial origin will be reviewed here. Other issues related to lymphatic filariasis are discussed separately. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis" and "Lymphatic filariasis: Treatment and prevention".)

EPIDEMIOLOGY — TPE can occur in any tropical area where filariasis occurs and is most common among young adults. It is more common in individuals from the Indian subcontinent and occurs four to seven times more frequently in males than in females [6,7]. Rare cases have been described in children [8].

The majority of cases of TPE occur in endemic areas; cases in nonendemic settings have also been described. In a review of 17 cases observed in Toronto, all received an incorrect diagnosis at presentation (most often asthma), and a median of two consultations was required before the diagnosis was established [9].

PATHOGENESIS — Available evidence suggests that the pulmonary disease reflects a robust immunologic response against bloodborne microfilariae that become trapped within the lung and reticuloendothelial organs [4]. TPE develops in less than 0.5 percent of patients with lymphatic filariasis; the explanation for this observation remains unclear.

The earliest histopathologic finding is histiocytic infiltration [6]. Approximately one month following infection, an eosinophilic interstitial infiltrate develops. In more severe cases, eosinophilic abscesses, eosinophilic bronchopneumonia, or eosinophilic granulomas may be observed. With chronic disease, there is an ongoing eosinophil interstitial infiltration and increasing pulmonary fibrosis [1]. Occasionally, microfilarial fragments may be identifiable in biopsied lung or reticuloendothelial tissues [6].

A mouse model of TPE has been developed that recapitulates these findings [10]. In this model, rapid microfilarial clearance was accompanied by dramatic lung eosinophilia, local production of interleukin (IL-) 4, IL-5, and eotaxin, functional impairment of alveolar macrophages, activation of alternatively activated lung macrophages, and eosinophil upregulation of antiapoptotic genes. Subsequent data using the same model suggests that acidic calcium-independent phospholipase A2 plays a key role in this process [11].

CLINICAL MANIFESTATIONS — The onset of clinical manifestations is usually gradual. Symptoms include a dry, hacking, nonproductive cough, which is frequently paroxysmal and nocturnal. Asthma-like attacks are associated with breathlessness and wheezing. Other symptoms include weight loss, fatigue, and malaise. Dyspnea on exertion is relatively uncommon.

Chest findings are minimal or absent in most patients. In some cases, rhonchi, crepitations (especially over the midzones and bases), and wheezing may be auscultated. Lymphadenopathy, hepatomegaly, and/or splenomegaly are observed in approximately 15 percent of patients [6]. Cor pulmonale is a rare complication [12].

DIAGNOSIS — The cardinal laboratory finding in TPE is blood eosinophilia, usually above 3000/microL [7]. An elevation in serum immunoglobulin E level is frequently observed, often above 1000 units/mL. The diagnosis can be confirmed by marked elevations in filarial antibody titers. Microfilariae are generally not detectable in peripheral blood, and circulating filarial antigen is undetectable in up to 50 percent of cases [13]. Bronchoalveolar lavage reveals an intense eosinophilic alveolitis in patients with active disease [3].

The major chest radiograph findings include increased bronchoalveolar markings, diffuse interstitial lesions (1 to 3 mm in diameter), and/or mottled opacities (usually most prominent in the lower lung fields) (image 1). Hilar lymphadenopathy and pleural effusions are rare. The chest radiograph is normal in 20 to 30 percent of cases [6]. High-resolution computed tomography can be useful and typically shows widespread ill-defined bronchocentric nodules and ground-glass infiltrates, although these findings are not specific for TPE and can occur in other types of inflammatory and infectious pneumonitis [14].

Pulmonary function tests (PFTs) typically demonstrate a predominantly restrictive pattern together with mild to moderate airway obstruction. In some cases, PFTs demonstrate a predominantly obstructive pattern with a mild restrictive component [6]. Airway obstruction is reversible with bronchodilators.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of TPE includes chronic eosinophilic pneumonia, drug hypersensitivity reactions, fungal pneumonia, and pulmonary syndromes associated with other helminths (most commonly Toxocara hookworm, Ascaris, and Strongyloides) [5]. Among these, strongyloidiasis is most important to exclude since corticosteroid administration can lead to fatal dissemination of infection. Although the imaging studies in TPE can mimic miliary tuberculosis [15], the presence of marked eosinophilia in TPE is an important distinguishing feature. (See related topics.)

TREATMENT — Standard treatment consists of diethylcarbamazine (DEC) given at 6 mg/kg/day in three doses for 12 to 21 days [16,17]. DEC is active against both the microfilariae and adult worms, and DEC therapy is associated with a dramatic and rapid improvement in signs and symptoms in most cases. The restrictive and obstructive defects typically return toward normal if DEC is administered in the first few years of disease, although a low-grade eosinophilic alveolitis may persist [18]. If DEC therapy is delayed, progressive interstitial fibrosis and irreversible impairment in pulmonary function can occur.

Corticosteroid therapy has been used as adjunctive therapy to reduce inflammation in the acute setting but is not definitive therapy for TPE.

Relapses occur in up to 20 percent of patients within the first five years of DEC therapy [6] and are treated with a repeat course of the same treatment regimen.

Other agents are used in the treatment of lymphatic filariasis, including doxycycline (which has efficacy against adult filarial worms via its action on their Wolbachia endosymbionts [18]), ivermectin (a rapid microfilaricide without efficacy on adult worms), and albendazole (which affects only adult worms). However, there are no published data describing any of these as either primary or adjunctive treatment for TPE.

Bronchospasm can generally be managed with bronchodilators, although short-term corticosteroids may be necessary in severe cases. (See "Lymphatic filariasis: Treatment and prevention", section on 'Treatment' and "An overview of asthma management".)

DEC is not distributed for use in the United States but can be obtained from the Centers for Disease Control and Prevention under an Investigational New Drug protocol (CDC Drug Service, Atlanta, GA 30333; telephone 404-639-2888). (See "Lymphatic filariasis: Treatment and prevention", section on 'Treatment'.)

SUMMARY AND RECOMMENDATIONS

●Tropical pulmonary eosinophilia (TPE) is a clinical manifestation of lymphatic filariasis, a parasitic infection caused by nematodes (roundworms) that inhabit the lymphatics and bloodstream. TPE is caused by an immune hyper-responsiveness to microfilariae that become trapped in the lungs. (See 'Introduction' above.)

●TPE can occur in any tropical area where filariasis occurs and is most common among young adults. It is more common in individuals from the Indian subcontinent and occurs four to seven times more frequently in males than in females. Rarely, a similar hyper-responsive pulmonary syndrome can occur in the setting of other helminth infections. (See 'Epidemiology' above.)

●The onset of clinical manifestations is usually gradual. Symptoms include a dry, hacking, nonproductive cough that is frequently paroxysmal and nocturnal. Asthma-like attacks are associated with breathlessness and wheezing. Other symptoms include weight loss, fatigue, and malaise. Dyspnea on exertion is relatively uncommon. (See 'Clinical manifestations' above.)

●The cardinal laboratory finding in TPE is blood eosinophilia, usually above 3000/microL. An elevation in serum immunoglobulin E level is frequently observed, often above 1000 units/mL. Chest radiographic studies typically show widespread ill-defined bronchocentric nodules and ground-glass infiltrates, although mediastinal lymphadenopathy and pleural effusions have been described. The diagnosis can be confirmed by elevations in filarial antibody titers. Microfilariae are generally not detectable in peripheral blood. (See 'Diagnosis' above.)

●For treatment of TPE, we recommend diethylcarbamazine (6 mg/kg/day in three doses for 12 to 21 days) (Grade 1B). Bronchospasm can be managed with bronchodilators and, in severe cases, short-term corticosteroids. (See 'Treatment' above.)