Leishmaniasis

Definition

Leishmaniasis, which is caused by protozoan parasites of the genus Leishmania, is generally transmitted between mammalian hosts by female phlebotomine sandflies. The parasite exists as an extracellular flagellated form, the promastigote, in the gut of the female sandfly, and as an intracellular form, the amastigote, in the phagolysosomal compartment of macrophages in the mammalian host. The disease in humans affects either the skin/mucosae or internal organs and ranges in severity from a single, self-curing skin lesion to widespread multilesional cutaneous involvement, or a potentially fatal visceral disease that affects the spleen, liver, and bone marrow.

Epidemiology

An estimated 1.0 million clinical cases of leishmaniasis occur each year, but this number is probably an underestimate because leishmaniasis is not a reportable disease in many of the endemic countries and territories where it is known to occur.

Infection is established in the mammalian host following a bite of the female sandfly belonging to either Phlebotomus spp in Europe, Asia, and Africa or Lutzomyia spp in the Americas. Different species of sandfly are associated with transmission of different Leishmania species. Most leishmaniasis is caused by 12 species ( Table 319-1 ). Most species that cause cutaneous leishmaniasis are acquired from another mammal (zoonotic transmission cycle), with the exception of Leishmania tropica, which is frequently transmitted between human beings (anthroponotic cycle). Visceral leishmaniasis is usually anthroponotic (in the case of Leishmania donovani ) or zoonotic (in the case of Leishmania infantum ). The predominant mammalian hosts (the reservoirs) are associated with different Leishmania species in diverse ecosystems ( Fig. 319-1 ).

Visceral leishmaniasis is caused by either L. donovani or L. infantum (which is identical to Leishmania chagasi in South America). These species have different geographic distributions, with the highest incidence found in the poorest communities in eight countries (India, Sudan, South Sudan, Ethiopia, Eritrea, Somalia, Kenya, and Brazil). An estimated 1 in 5 to 1 in 50 infections are symptomatic, depending on the parasite species and host immunity. Since 2005, an initiative in South East Asia has reduced the annual incidence of the disease by more than 90%, but the economic burden of infection remains enormous.

Cutaneous leishmaniasis is widely distributed, but its prevalence is difficult to estimate because of underreporting. Leishmaniasis is more common in children under age 16 years and in working-age men, but is uncommon in persons over age 65 years. This age prevalence may be related to the acquisition of immunity and to risk factors, including the presence of domestic animals, rodents, or other mammalian hosts. Ecologic conditions for sandflies, including shaded and humid habitats in crevices and mammal burrows, have been identified. Urbanization, deforestation, and migration have resulted in changing patterns of disease, with transmission occurring in peridomestic cycles. Other forms of transmission, such as through organ transplantation, blood transfusion, intravenous needles shared by drug users, transplacental or perinatal passage, or laboratory exposure, have been reported.

Pathobiology

The infection is initially established in the skin after the inoculation of infective metacyclic promastigotes by the sandfly. These infective forms have a glycoprotein coat (a lipophosphoglycan) that enables them to resist complement and attach to and invade host cells. Peptides in the saliva of sandflies (e.g., maxadilan) cause vasodilatation and erythema and help establish infection in the dermal layer of the skin. Early responses to infection involve neutrophilic infiltration and invasion of resident macrophages. Progress of the disease depends on the parasitic species and the host response. For both visceral leishmaniasis and cutaneous leishmaniasis, progression of the disease depends on the maintenance of a parasite-specific immunosuppressive state. During established disease, host cell macrophages polarize from a classic (M1 phenotype) to a nonclassic, alternatively activated (M2 phenotype). Following successful treatment, macrophages become classically activated and are then able to kill the intracellular parasites, which are sensitive to nitric oxide and oxygen radicals, in the phagolysosomal compartment. After the activation of macrophages, resolution of disease is enhanced by a helper T-cell type 1 (T _H 1) response following interaction between antigen-presenting cells (e.g., dendritic cells) with CD4 ⁺ and CD8 ⁺ T cells, as well as subsequent secretion of pro-inflammatory cytokines (e.g., interleukin-12 [IL-12], interferon-γ, tumor necrosis factor-α). In clinical forms such as active visceral leishmaniasis or diffuse cutaneous leishmaniasis, a mixed T _H 1/T _H 2 cell response occurs with the latter predominating, and downregulation of macrophage activity follows the production of cytokines such as IL-4, IL-10, IL-13, and transforming growth factor-β.

In patients with visceral leishmaniasis, the absence of a T-cell-specific immune response to leishmanial antigens is associated with uncontrolled progression of infection. Progression is linked to elevated levels of IL-10 and decreased production of interferon-γ. Genetic susceptibility to L. donovani in Sudan has been associated with a solute carrier family that regulates the activation of macrophages and with a polymorphism in the IL-4 gene.

In localized simple cutaneous leishmaniasis, patients show a T _H 1-type response and a delayed-type hypersensitivity response. Chronic infections show a T _H 2-type response, most predominantly in patients with diffuse cutaneous leishmaniasis, in whom there is complete anergy to leishmania antigen and no delayed-type hypersensitivity response. Patients with mucosal leishmaniasis have a T _H 1 or T _H 2 cell response or both, and they also have a strong or weak delayed-type hypersensitivity response.

Post–kala-azar dermal leishmaniasis, which is a rare sequela after cure of visceral leishmaniasis, is seen in two geographically distinct zones, the Sudanese/East African form and the South East Asian form. The Sudanese and South East Asian forms differ in that the former appears along with visceral leishmaniasis (para–kala-azar dermal leishmaniasis), whereas the latter appears 1 to 5 years later (post–kala-azar dermal leishmaniasis), The presence of alternatively activated M2 macrophages and a predominant CD8 T-cell milieu have been identified in the South East Asian form, whereas the immunopathology remains poorly defined in the Sudanese form.

Complex Manifestations of Visceral Leishmaniasis