lymphatic filariasis

Lymphatic filariasis is transmitted by mosquitoes and is caused by two closely related nematodes, Wuchereria bancrofti and Brugia malayi, which are responsible for 90% and 10%, respectively, of the 90 million infections worldwide.

In endemic areas, which include parts of Latin America, sub-Saharan Africa, and Southeast Asia, filariasis causes a spectrum of diseases, including:

 (1) asymptomatic microfilaremia,
 (2) chronic lymphadenitis with swelling of the dependent limb or scrotum (elephantiasis),
 (3) tropical pulmonary eosinophilia.

As is the case with leprosy and leishmanial infections, some of the different disease manifestations caused by lymphatic filariae may be understood in the context of varying patterns of host T-cell responses to the parasites.

Pathogenesis

Infective larvae released by mosquitoes into the tissues during the blood meal develop within lymphatic channels into adult males and females, which mate and release microfilariae that enter into the bloodstream.

When mosquitoes bite infected individuals, they can take up the microfilariae and transmit the disease. Experiments in athymic (nude) mice suggest that adult filariae secrete factors that, by themselves, are capable of causing lymphatic dilation, lymphedema, and elephantiasis. In contrast, microfilariae, even in massive numbers in microfilaremic hosts, are not directly toxic to the host. The filarial genome project has led to the identification of a number of filarial molecules that can evade or inhibit immune defenses.

Brugia malayi produces (1) several surface glycoproteins with antioxidant function, which may protect from superoxide and free oxygen radicals; (2) homologues of cystatins, cysteine protease inhibitors, which can impair the MHC class II antigen-processing pathway; (3) serpins, serine protease inhibitors, which can inhibit neutrophil proteases, critical inflammatory mediators; and (4) homologues of TGF-β, which can bind to mammalian TGF-β receptors and may downregulate inflammatory responses.

Recent studies have revealed that endosymbiotic rickettsia-like Wolbachia bacteria infect filarial nematodes and might contribute to pathogenesis of disease.

Wolbachia appear to be needed for nematode development and reproduction, since antibiotics that eradicate Wolbachia impair nematode survival and fertility. It has been hypothesized that LPS from Wolbachia may stimulate inflammatory responses.

In chronic lymphatic filariasis, damage to the lymphatics is caused directly by the adult parasites and by a TH1-mediated immune response, which stimulates the formation of granulomas around the adult parasites. Microfilariae are absent from the bloodstream, because the immune response damages the adults such that they do not breed successfully. In contrast, there is an inadequate response to circulating parasites in microfilaremic individuals.

Because most microfilaremic individuals come from areas where filariasis is endemic, there is speculation that the inadequate response is caused by prenatal exposure to parasite antigens that may induce immunologic tolerance in the host.

Finally, there is an IgE-mediated hypersensitivity to microfilariae in tropical pulmonary eosinophilia. IgE and eosinophils may be stimulated by IL-4 and IL-5, respectively, secreted by filaria-specific TH2 helper T cells.

Morphology

Chronic filariasis is characterized by persistent lymphedema of the scrotum, penis, vulva, leg, or arm. Frequently, there is hydrocele and lymph node enlargement.

In severe and long-lasting infections, chylous weeping of the enlarged scrotum may ensue, or a chronically swollen leg may develop tough subcutaneous fibrosis and epithelial hyperkeratosis, termed elephantiasis. Elephantoid skin shows dilation of the dermal lymphatics with widespread lymphocytic infiltrates and focal cholesterol deposits; the epidermis is thickened and hyperkeratotic.

Adult filarial worms-live, dead, or calcified-are present in the scrotal draining lymphatics or nodes, surrounded by (1) mild or no inflammation, (2) an intense eosinophilia with hemorrhage and fibrin (recurrent filarial funiculoepididymitis), or (3) granulomas not dissimilar to those found in mycobacterial infections.

Organization of the endolymphatic exudate results in polypoid infoldings of the vessels with persisting eosinophilic and lymphocytic infiltrates. In time, hydrocele fluid, which often contains cholesterol crystals, red cells, and hemosiderin, induces thickening and calcification of the tunica vaginalis.

Lung involvement by microfilariae is marked by eosinophilia caused by TH2 responses and cytokine production (tropical eosinophilia) or by dead microfilariae surrounded by stellate, hyaline, eosinophilic precipitates embedded in small epithelioid granulomas (Meyers-Kouvenaar bodies). Typically, these patients lack any other manifestations of filarial disease.