Tropical Pulmonary Eosinophilia

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Diagnosis and reasoning

This patient has presented with a non-productive, paroxysmal, nocturnal cough associated with breathlessness and wheezing - a relatively nondescript presentation. However, note the presence of a significantly elevated eosinophil count, ranging in the tens of thousands. This degree of eosinophilia is uncommon and unusual, with a relatively small range of potential causes; these can be broadly classified into infectious and noninfectious etiologies. Important infectious etiologies include Loeffler's syndrome due to ascariasis or strongyloidiasis; Tropical Pulmonary Eosinophilia (TPE) due to filarial infection; toxocariasis; and certain fungal infections. Non infectious conditions include idiopathic hypereosinophilic syndrome, acute eosinophilic pneumonia, Churg-Strauss syndrome, and Allergic Bronchopulmonary Aspergillosis (ABPA). Note the appearance of his chest x-ray; the scattered reticulonodular infiltrates seen here are unfortunately a non-specific finding which might be due to any of the diseases considered above. His physical examination also reveals only scattered wheezes, which again are not diagnostically helpful. Thus, a structured investigative approach is essential for differentiation. Given that he is a recent migrant from India, it makes sense to start off by excluding the tropical diseases which might present in this manner. Of these, Loeffler's syndrome is considered the commonest; while stool microscopy shows no evidence of ova or the adult stages of intestinal parasites, it is important to note that the sensitivity of this test is rather low. Likewise, serology for toxocara also turns out to be negative. However, the assay for filaria specific antibodies turns out to be more helpful by becoming positive; this strongly points towards TPE. The diagnosis of TPE is based on the presence of 4 pre-treatment criteria (a history of nocturnal cough and dyspnoea, pulmonary infiltrates on chest x-ray, leukocytosis with peripheral eosinophilia 3,000/mm3, and elevated serum IgE levels and filaria specific antibodies), and 1 post-treatment criterion: clinical improvement with Diethylcarbamazine (DEC). Assessment of serum IgE levels in this patient shows them to be elevated; note that thus, all 4 pre-treatment diagnostic criteria are fulfilled, clinching the diagnosis. DEC is the current drug of choice for the management of TPE; it is effective against adult worms as well as microfilariae. Concomitant therapy with corticosteroids is of proven benefit in reducing airway inflammation, and can be justified in this patient. Note that if other causes of a TPE-like syndrome (such as strongyloidiasis) were suspected, corticosteroids are best avoided as dissemination of infection may result. There is no requirement for supplemental oxygen, as the patient is not dyspneic right now. The antihelminthic drug Ivermectin, has no proven effect on the adult filarial worm or TPE, however, it is known to act against microfilariae.


Discussion

Tropical Pulmonary Eosinophilia (TPE) is the pulmonary manifestation of occult filariasis, where there is an immunological response to filarial parasites, Wuchereria bancrofti and Brugia malayi. Filariasis and TPE are endemic in the tropics - particularly in the Indian subcontinent, South America and certain regions of Africa. It should be appreciated that only 1% of individuals infected with the filarial parasite develop TPE; it tends to occur more frequently in young men, with a 4:1 male to female ratio. Filariasis is a mosquito borne parasitic infection, affecting mainly the lymphatic system of humans. Different species of mosquitos act as vectors; Culex, Mansonia, Anopheles and Aedes species are among the more common. As the mosquito takes a blood meal from a human host, many microfilariae are ingested. These undergo several morphological changes within the mosquito, ultimately developing into L3 larvae, which are deposited onto human skin, when the mosquito bites. The L3 larvae develop into adults, within the human lymphatic system. Adult parasites produce large numbers of microfilariae, that get into the blood or lymph channels of the host. The mechanism of lung injury in TPE is an inflammatory reaction to trapped microfilariae within the lung tissue. Antigenic material released by the parasites evoke an intense eosinophilic response which destroys the microfilariae, preventing their release into the systemic circulation. Lung fibrosis that occurs due to a chronic inflammatory reaction during this process, gives rise to the clinical manifestations. Dry cough, breathlessness and wheezing, occur due to bronchospasm and mucosal oedema, while the collection of exudates in alveoli and smaller bronchioles results in crepitations found on chest examination. Note that, extrapulmonary as well as systemic manifestations often accompany the pulmonary features. Fever, fatigue, malaise, weight loss, lymphadenopathy and hepatosplenomegaly, are among the more common. Examination of the chest frequently reveals scattered rhonchi or crepitations; however, in 20% of patients, no signs are present. TPE is commonly misdiagnosed as bronchial asthma, and treated with bronchodilators, resulting in only partial resolution of symptoms. Thus, the importance of eliciting a travel history in patients responding poorly to conventional asthma medications cannot be underemphasized. Considering baseline investigations, a complete blood count will often reveal leukocytosis with predominant eosinophils; an erythrocyte sedimentation rate (ESR) if performed, will generally be elevated. Chest radiography may demonstrate diffuse reticulonodular opacities or miliary mottling, mainly in the mid and lower lung fields. Day and night blood samples for detection of microfilariae are usually negative, as the immunological response against the antigen rapidly clears them from the circulation. However, serum IgE levels typically show a marked elevation, while filaria specific antibodies can be detected by special techniques. One point to appreciate is that many of the serological tests cross-react with similar helminth antigens; thus, development of more specific assays is currently underway. At present the diagnosis of TPE relies upon several clinical and investigative criteria: - a history of nocturnal cough and dyspnoea - pulmonary infiltrates in the chest x-ray - leukocytosis with eosinophilia of > 3 ×109/L - elevated serum IgE levels and filaria specific antibodies - clinical improvement with Diethylcarbamazine (DEC) The world health organization (WHO) recommends DEC for the treatment of TPE; while most patients show marked clinical improvement following initiation of therapy, up to 20% of them may relapse following treatment. Note that Ivermectin is used for the prevention of filariasis, in certain regions with a high incidence of onchocerciasis (such as certain areas of Africa); this is because DEC cannot be used as it causes a severe adverse reaction if given in the presence of onchocerciasis. Concomitant addition of steroids (prednisolone), has proven benefit towards reducing the degree of airway inflammation. However, the ideal dose and duration which yields the maximum benefit is yet to be determined. The WHO aims to eliminate filaria and TPE in the near future; the main mode of control is to prevent transmission via the filarial vector Culex quinquefasciatus. Thus, annual mass drug administration schedules and vector control strategies are carried out in populations most at risk of filariasis, with DEC and albendazole recommended as preventive therapy. It is noted that most patients with TPE demonstrate a rapid and remarkable response if treatment is initiated early. However, despite treatment, some patients progress to chronic TPE, with irreversible deterioration of lung functions.


Take home messages

  1. TPE is a rare cause of hyper-eosinophilic airway hyperresponsiveness, and should be suspected in individuals from, or who have traveled to an endemic region.
  2. TPE is often misdiagnosed as bronchial asthma.
  3. DEC is the drug of choice for treatment of TPE, with the majority of patients showing a good response.

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