LeishmaniaLeishmania

• Genus Leishmania includes four clinically important malor pathogens in L.donovani, L.tropica, L.mexicana and L.braziliensis. Several strains of these species are known to affect humans.

• L.donovani complex includes L.donovani, infantum, chagasi, amazonensis.

• L.tropica complex includes L.tropica, aethiopica and major.

• L.mexicana complex includes L.mexicana, pifanoi, garnhami.

• L.braziliensis complex includes L.braziliensis, guyanensis, panamensis.

• They are all similar morphologically and only differ on a biochemical and epidimeological criteria.

• Leishmania species are obligate intracellular parasites of mammals. They live in macrophages as intracellular amastigotesin humans and other mammalian hosts and as extracellular promastigotes in the gut of their invertebrate sandfly vectors.

• The different Leishmania spp. present a wide range of clinical characteristics.

• The major clinical grouping, however are :• Visceral Leishmaniasis (Kala-Azar) caused by L.donovani,• Cutaneous Leishmaniasis caused by L.tropica (old world cutaneo

us Leishmaniasis like Oriental sore, Delhi boil etc…) and L.mexicana (new world Leishmaniasis like chiclero ulcer, bay sore etc…),

• Mucocutaneous Leishmaniasis (espundia) caused by L.braziliensis.

• Visceral Leishmaniasis has emerged as an opportunistic disease in HIV, organ transplant patients and in conditions with compromised cell-mediated immunity.

• L.donovani is the cause of visceral Leishmaniasis, Kala-azar, Dum-Dum fever, death fever, tropical splenomegaly and ponos (in Greece).

• Visceral Leishmaniasis is a vector borne disease. The vector is a sandfly in the genus Phlebotomus.

• Life cycle of L.donovani has two distinct phases: Amastigote and Promastigote.

• The parasite is engulfed by the reticuloendothelial cells of the mammalian host, where it can be found in the amastigote stage within the phagocytic cell.

• The amastigote multiplies by binary fission within the macrophage, until the cell is destroyed, and the liberated parasites are engulfed by other neighbouring mononuclear cells or ingested by the insect vector.

• In the digestive tract of the female sandfly, the parasites develop through a series of flagellated, intermediate stages to become metacyclic promastigotes.

• The promastigotes migrate to the pharynx, where they are innoculated into humans with salivary peptides capable of inactivating host macrophages when the infected sandfly attempts to take its blood meal.

• Opsonization by complement C3 on the activation of the Classical cascade pathway, mediates its attachment to the CR1 and CR3 complement receptors of the macrophages.

• Two parasite surface molecules : gp63 and a lipophosphoglycan play an important role in parasite-macrophage interaction.

• Following phagocytosis, the promastigotes lose their flagella and multiply as rounded amastigote within the phagolysosome.

• Intracellular survival is ensured by the lipophosphoglycan and membrane-bound acid phosphatase, that inhibit the macrophage’s oxidative burst and/or may also inactivate the lysosomal enzymes.

• Continuation of this cycle results in extensive proliferation.

• The progress of the disease is now determined by the species of parasite and the host response of the T helper cells.

• The T-cells secrete interferon-gamma in response to the Leishmanial antigens, which inturn activates the macrophages to kill intracellular amastigotes by the production of toxic nitric oxide.

• L.donovani, may also however, if able to inhibit the T-cell response, will disseminate through the blood stream to the visceral organs. Better resistance to the natural microbicidal properties of the serum and its ability to better survive at 37 degree centigrade helps in its dissemination, which accompanies the production of circulating antibodies, but do not have any protective function.

• The production of immune complexes, however may result in the development of transient glomerulonephritis.

• In persons with progressive visceral Leishmaniasis, evidence of leishmania-specific T-cell response is absent.

• There is no evidence of delayed-type hypersensitivity response to Leishmanial antigen when innoculated intradermally.

• Paradoxically, progressive visceral leishmaniasis produce high titer antibodies and there is even evidence of polyclonal B-cell proliferation.

• Persons with self-resolving infection with L.donovani and those undergone successful chemotherapy manifest protective T-cell responses.

• In most cases, even positive leishmanial skin tests are seen.These have protective immunity, but disease can occur if immunocompromised.

• Visceral Leishmaniasis is emerging as an important opportunistic infection with HIV-1 and the parasite may be a cofactor in its pathogenesis, brought about by the lipophosphoglycan inducing transcription of HIV in CD4+ cells.

• Pathogenesis:

• L.donovani spreads from the site of innoculation to multiply in the reticuloendothelial cells, especially macrophages in the spleen, lymph nodes, liver and the bone-marrow.

• Large numbers of amastigote-infected mononuclear phagocytes in the liver and the spleen result in progressive hypertrophy.

• The spleen may become massively enlarged as splenic lymphoid follicles are replaced by parasitized mononuclear cells.

• In the liver, there is a marked increase in the number and size of the Kupffer cells containing amastigotes.

• Infected macrophages also found in the bone marrow, lymph nodes ands other organs.

• Increased secretion of TNF-alpha may mediate catabolic and anorectic effectresulting in the patient becoming cachectic.

• Death in visceral leishmaniasis is often secondary to bacterial or viral infections in debilitated patients with advanced disease.

• Incubation period varies from 3-8 months.• Patients present with prolonged intermittent,

well tolerated fever, progressive weight loss, weakness, pronounced splenomegaly,hepatomegaly, leukopenia, anemia, thrombocytopenia and hypergammaglobulinemia.

• The skin becomes dry, thin and scaly with hair loss. Skin on hands, feet, abdomen and face may become grayish, hence the name Kala-azar (black sickness).

• Hemorrhage from more than one site. Petechiae and ecchymosesobserved on extremities.

• Secondary bacterial infections are common and death may result from bacterial pneumonia, septicemia tuberculosis, severe anemia or hemmorhage.

• Anemia almost always present and due to hemolysis, marrow replacement with Leishmania infected macrophages, hemorrhage, splenic sequestration of erythrocytes and effects of cytokines such as TNF-alpha.

• Leukopenia with WBC counts as low as 1000/mm3 is possible.• Hypergammaglobulinemia, circulating immune complexes and r

heumatoid factors are present in the sera in visceral leishmaniasis.

• The course of the disease runs for months to years.

• Laboratory diagnosis:

• Detecting amastigotes in bone-marrow, slpeen, lymph node biopsy.

• Serological indirect immunofluorescence tests helpful in most cases.

• Skin test with Leishmanial antigens negative during active disease, but recovered patients show positive skin tests..

• Treatment includes either liposomal Amphotericin B or sodium stibogluconate.

• Recovery results in permanent immunity.

• Prevention:• Nets, protective clothing, insect repellan

ts and insecticidal sprays.

• Cutaneous Leishmaniasis seen as lesions confined to the skin.

• Mucocutaneous Leishmaniasis manifests lesions confined to mucous membranes, cartilage and the skin.

• A granulomatous lesion transforming into a necrotic ulcer at the site of the bite is a common manifectation that can get superinfected with bacteria.

• Cutaneous lesions begin with a red papule at the bite site, enlarges slowly to form multiple satellite nodules that finally ulcerate. This can heal spontaneously in immuno-competent individuals.

• In immunocompromised, the lesions can spread to involve large areas of the skin infected with parasites.

• Mucocutaneous lesions begin with a papule at the bite site leading to the formation of metastatic disfiguring, granulomatous and ulcerating lesions, usually at the mucocutaneous junction of the nose and the mouth, destroying the nasal cartilage. Lesions, if heal, they do so very slowly.

• Death due to secondary infection.

• Laboratory diagnosis:

• Demonstrating presence of amastigotes in the skin lesions.

• The leishmanial skin test may become positive with the onset of ulcerative lesions.

• Treatment:

• Drug of choice is sodium stibogluconate.• Results are frequently unsatisfactory.