USMLE – Leishmaniasis
Leishmaniasis is a chronic inflammatory disease of the skin, mucous membranes, or viscera caused by obligate intracellular, kinetoplastid protozoan parasites transmitted through the bite of infected sandflies. Leishmaniasis is endemic throughout the Middle East, South Asia, Africa, and Latin America, so that numerous American soldiers were infected with Leishmania during operation Desert Storm. Leishmaniasis may also be epidemic, as is tragically the case in southern Sudan, where tens of thousands of persons have died of visceral leishmaniasis. Finally, leishmanial infection, like that with other intracellular organisms (mycobacteria, Histoplasma, Toxoplasma, and trypanosomes), is exacerbated by AIDS.
The infective stage of Leishmania is a slender, flagellated parasite released into the host dermis along with the sandfly saliva, which potentiates parasite infectivity. How far the amastigotes spread throughout the body is determined by the Leishmania species. Cutaneous disease is caused by Leishmania major and Leishmania aethiopica in the Old World and Leishmania mexicana and Leishmania braziliensis in the New World; mucocutaneous disease (also called espundia) is caused by L. brasiliensis; and visceral disease involving the liver and spleen is caused by Leishmania donovani in the Old World and Leishmania chagasi in the New World. One explanation for the tropism of Leishmania appears to be temperature, because parasites that cause visceral disease grow at 37 C in vitro, whereas parasites that cause mucocutaneous disease grow only at 34 C.
Leishmaniae are phagocytosed by macrophages, and acidity within the phagolysosome induces them to transform into round amastigotes that lack flagella but contain a single large mitochondrion-like structure called the kinetoplast. Leishmania amastigotes are the only protozoan parasites that survive and reproduce in macrophage phagolysosomes, which have a pH of 4.5. Amastigotes are protected from the intravacuolar acid by a proton-transporting ATPase, which maintains the intracellular parasite pH at 6.5. Leishmania parasites also have on their surface two abundant glycoconjugates anchored to lipid anchors, which appear to be important for their virulence. The first, lipophosphoglycans, are glycolipids that form a dense glycocalyx and bind C3b or iC3b. Organisms resist lysis by complement C5-C9, however, and are phagocytosed by macrophages through complement receptors CR1 (LFA-1) and CR3 (Mac-I integrin). Lipophosphoglycans may also protect the parasites within the phagolysosomes by scavenging oxygen radicals and by inhibiting lysosomal enzymes. The second glycoconjugate, gp63, is a zinc-dependent proteinase that cleaves complement and some lysosomal antimicrobial enzymes.
As is the case with M. leprae infection, the severity of disease caused by Leishmania is determined by the host immune response. Hosts with parasite-specific, cell-mediated immunity control the infection or make granulomas with few parasites present, whereas anergic hosts have diffuse lesions composed of macrophages stuffed with parasites. Leishmania parasites are cleared from the body by cell-mediated immune mechanisms, which is reflected by a positive, delayed type hypersensitivity reaction to extracts of Leishmania injected into the skin (leishmanin test). Parasite-specific CD4+ helper T lymphocytes of the TH-1 class may secrete interferon-gamma, which along with TNF-alpha secreted by other macrophages activates phagocytes to kill the parasites through toxic metabolites of oxygen or nitric acid (or both). In contrast, down-regulation of the immune response that leads to anergy and progressive disease may be caused by parasite-specific CD4+ helper T cells of the TH-2 class that secrete IL-4, which inhibits macrophage activation by interferon-gamma and inhibits secretion of TNF-alpha.
Leishmania species produce four different lesions in humans: visceral, cutaneous, mucocutaneous, and diffuse cutaneous. In visceral leishmaniasis, L. donovani or L. chagasi parasites invade macrophages throughout the reticuloendothelial system and cause severe systemic disease marked by hepatosplenomegaly, lymphadenopathy, pancytopenia, fever, and weight loss. The spleen may weigh as much as 3 kg, and the lymph nodes may measure 5 cm in diameter. Phagocytic cells are enlarged and filled with Leishmania, many plasma cells are present, and the normal architecture of the spleen is obscured. In the late stages, the liver becomes increasingly fibrotic. Phagocytic cells crowd the bone marrow and may also be found in the lungs, gastrointestinal tract, kidneys, pancreas, and testes. Often there is hyperpigmentation of the skin in the extremities, which is why the disease is called kala-czar or “black fever” in Hindi. In the kidneys, there may be an immune complex-mediated mesangioproliferative glomerulonephritis and in advanced cases amyloid deposition. The overloading of the reticuloendothelial system with parasites predisposes the patients to bacterial infections, the usual cause of death. Hemorrhages related to thrombocytopenia may also be fatal.
Cutaneous leishmaniasis, caused by L. major, L. mexicano. and L. braziliensis, is a relatively mild, localized disease consisting of a single ulcer on exposed skin. The lesion (often called tropical sore) begins as an itching papule surrounded by induration, changes into a shallow and slowly expanding ulcer with irregular borders, and usually heals by involution within 6 months without treatment. On microscopic examination, the lesion is granulomatous, usually with many giant cells and few parasites.
Mucocutaneous leishmaniasis, caused by L. braziliensis, is found only in the New World. Moist, ulcerating, or nonulcerating lesions, which may be disfiguring, develop in the larynx and at the mucocutaneous junctions of the nasal septum, anus, or vulva. On microscopic examination, there is a mixed inflammatory infiltrate with parasite-containing histiocytes in association with lymphocytes and plasma cells. Later the tissue reaction becomes granulomatous, and the number of parasites declines. Eventually, the lesions remit and scar, although reactivation may occur after long intervals by mechanisms not currently understood.
Diffuse cutaneous leishmaniasis is a rare form of dermal infection, thus far found only in Ethiopia and adjacent East Africa and in Venezuela, Brazil, and Mexico. Diffuse cutaneous leishmaniasis begins as a single skin nodule, which continues spreading until the entire body is covered by bizarre nodular lesions. These lesions, which resemble keloids or large verrucae, are frequently confused with the nodules of lepromatous leprosy, so patients may be incorrectly sent to leprosaria. The lesions do not ulcerate but contain vast aggregates of foamy macrophages stuffed with leishmania. Patients are usually anergic not only to leishmanin but also to other skin antigens, and the lesions often respond poorly to treatment.