Pathogenesis

The manifestations of cutaneous leishmaniasis typically occur at the site where promastigotes

Cutaneous Disease

Early in cutaneous infection, amastigote-filled macrophages are the dominant finding (Ridley,

Fig. 13.3 Phase contrast photomicrograph of an L. (L.) donovani promastigote attached to a human monocyte-derived macrophage in vitro. Bar=10 ^m

1979; Ridley and Ridley, 1984). A necrotizing granulomatous response subsequently develops. There is focal necrosis and ulceration of the overlying skin. The mechanism of tissue necrosis has not been defined, but it is thought to be immune-mediated. Over time the number of amastigote-infected mononuclear cells decreases and the number of lymphocytes increases. After a period of months, the typical lesion heals, leaving a flat, atrophic scar as evidence of disease.

Data from experimentally infected animals and observations in humans suggest that amastigotes reach draining lymph nodes early in infection. This is particularly evident in a subset of patients infected with L. (V.) braziliensis, who present with tender regional adenopathy, fever and other constitutional symptoms before a skin lesion appears (Barral et al., 1992; Sousa et al., 1995).

Blood cultures have been positive in a few cases. As the skin lesions enlarge and then ulcerate, lymphadenopathy and constitutional symptoms resolve. Months to years later, a small percentage of those infected with L. (V.) braziliensis or related Leishmania (V.) spp. develop mucosal leishmaniasis involving the nose, oral pharynx or other mucosal structures.

Two variants of cutaneous leishmaniasis, diffuse cutaneous leishmaniasis and leishmaniasis recidiva, lie at the extremes of the spectrum of human disease. Diffuse cutaneous leishmaniasis, an anergic variant, is characterized by a predominance of amastigote-filled macrophages and relatively few lymphocytes. The lesions do not ulcerate and those affected fail to mount cellmediated immune responses. Lesions can persist for decades. Leishmaniasis recidiva is a chronic, ulcerative condition characterized by a granulo-matous response, with a predominance of lymphocytes and few amastigotes seen in macrophages. Those infected mount delayed-type hypersensitivity responses to leishmanial antigens, but the lesions can persist for years.

The spectrum of cutaneous leishmaniasis has been compared to that of leprosy. Persons with diffuse cutaneous leishmaniasis are similar to those with lepromatous leprosy, in whom large numbers of mycobacteria are observed within macrophages, while those with leishmaniasis recidiva are similar to those with tuberculoid leprosy, in whom there is a tissue-damaging granulomatous response but few parasites. However, as Ridley and Ridley (1984) have pointed out, in leprosy the histopathological findings are predictive of the clinical syndrome, while in simple cutaneous leishmaniasis the histopathology evolves from a predominance of amastigote-filled macrophages early in infection to a granulomatous response with lymphocyte predominance as the lesions age.

Visceral Disease

The majority of those infected with L. (L.) donovani and related species that are associated with visceral disease have asymptomatic, self-resolving infections and do not come to clinical attention. In humans who progress to typical visceral leishmaniasis and in the Syrian hamster model (Wilson et al., 1987), amastigotes disseminate to mononuclear phagocytes in the liver, spleen, bone marrow and other organs. A skin lesion is seldom apparent at the site of inoculation. Massive splenomegaly and hepatomegaly develop as monocytes are recruited to those organs and become infected. In persons who are immunocompromised by HIV, amastigote-infected macrophages are frequently observed in the gastrointestinal tract, lung and other organs (Figure 13.4).

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