Leishmaniasis a variety of disease manifestations focal distribution throughout world, especially tropics and subtropics new world: southern Texas to northern Argentina old world: Asia, Africa, middle east, Mediterranean transmitted by sand flies new world: Lutzomyia old world: Phlebotomus 350 million at risk 12 million infected 1.5-2 million clinical cases/year

Sandfly Transmission transmitted via mouthparts promastigotes regurgitated from anterior gut factors in saliva enhance infectivity immunosuppressive factor?

1) metacyclic promastigotes 2) phagocytosis by macrophage  amastigote 3) replication within macrophage 4) release and phagocytosis of amastigotes

Leishmania-Macrophage Interactions attachment and entry involves CR3 and surface molecules on parasite entry is typical phagocytosis phagosome fuses with lysosome survival within phagolysosome parasite is resistant to hydrolytic activities shut down of respiratory burst (ROI)

4) phagocytosis of amastigotes, or ingestion by vector 5) procyclic promastigotes replication attachment to epithelium 6) metacyclic promastigotes

Lypophosphoglycan (LPG) complex glycolipid covering surface of promastigotes mediates adherence to gut epithelia galactose-specific lectin LPG changes in metacyclics cap (galactosearabinose) increase disaccharide repeats glycocalyx 7 17 nm  complement resistance

Clinical Spectrum of Leishmaniasis Cutaneous Leishmaniasis (CL) most common form, relatively benign self-healing skin lesions (aka, localized or simple CL) Diffuse Cutaneous Leishmaniasis (DCL) rare cutaneous infection with non-ulcerating nodules resembling lepromatous leprosy Leishmaniasis Recivida rare hypersensitive dermal response Mucocutaneous Leishmaniasis (MCL) simple skin lesions that metastasize, especially to nose and mouth region Visceral Leishmaniasis (VL) generalized infection of the reticuloendothelial system, high mortality

Cutaneous Leishmaniasis Chiclero Ulcer (L. mexicana) incubation period: 2 weeks to several months chronic ulcerated, papular, or nodular lesion lesion is painless, non-tender, non-pruritic and usually clean occasionally satellite lesions and/or palpable lymph nodes Chiclero Ulcer (L. mexicana)

Cutaneous Leishmaniasis Chiclero Ulcer (L. mexicana) incubation period: 2 weeks to several months chronic ulcerated, papular, or nodular lesion lesion is painless, non-tender, non-pruritic and usually clean occasionally satellite lesions and/or palpable lymph nodes Chiclero Ulcer (L. mexicana)

Cutaneous Leishmaniasis incubation period: 2 weeks to several months chronic ulcerated, papular, or nodular lesion self-healing, months to years lesion is painless, non-tender, non-pruritic and usually clean occasionally satellite lesions and/or palpable lymph nodes

chronic ulcerated, papular, or nodular lesion occasionally satellite lesions

metastasis via blood or lymphatic systems especially L. braziliensis

Cutaneous Leishmaniasis incubation period: 2 weeks to several months chronic ulcerated, papular, or nodular lesion lesion is painless, non-tender, non-pruritic and usually clean self-healing, months to years occasionally satellite lesions and/or palpable lymph nodes

Old World CL L. tropica (oriental sore) SW Asia, N. Africa dry lesion urban/dogs L. major central Asia, middle East, Africa wet lesion rural/rodents L. infantum Mediterranea, Europe L. aethiopica highlands of Kenya and Ethiopia

Old World CL L. tropica (oriental sore) SW Asia, N. Africa dry lesion urban/dogs L. major central Asia, middle East, Africa wet lesion rural/rodents L. infantum Mediterranea, Europe L. aethiopica highlands of Kenya and Ethiopia hyper-pigmentation of scar

Old World CL L. tropica (oriental sore) SW Asia, N. Africa dry lesion urban/dogs L. major central Asia, middle East, Africa wet lesion rural/rodents L. infantum Mediterranea, Europe L. aethiopica highlands of Kenya and Ethiopia

Old World CL L. tropica (oriental sore) SW Asia, N. Africa dry lesion urban/dogs L. major central Asia, middle East, Africa wet lesion rural/rodents L. infantum Mediterranea, Europe L. aethiopica highlands of Kenya and Ethiopia

Diffuse Cutaneous Leishmaniasis scaly, not ulcerated, nodules chronic and painless numerous parasites in lesions seldom heal despite treatment L. aethiopica

Diffuse Cutaneous Leishmaniasis scaly, not ulcerated, nodules chronic and painless numerous parasites in lesions seldom heal despite treatment L. mexicana

Diffuse Cutaneous Leishmaniasis scaly, not ulcerated, nodules chronic and painless numerous parasites in lesions seldom heal despite treatment New World (sp?)

Leishmaniasis Recidivans aka, relapsing leishmaniasis or lupoid often due to inadequate treatment nodular lesions or rash around central healing can persist for decades variable expression not easily cured

Mucocutaneous Leishmaniasis primarily L. braziliensis (espudia) two stages simple skin lesion 2o mucosal involvement can occur long after primary lesion (up to 16 years) frequently in naso-pharyngeal mucosae metastasis via blood or lymphatic systems variable types and sizes of lesions chronic and painless

Mucocutaneous Leishmaniasis L. braziliensis (espudia) two stages simple skin lesion 2o mucosal involvement can occur long after primary lesion (up to 16 years) frequently in naso-pharyngeal mucosae metastasis via blood or lymphatic systems variable types and sizes of lesions chronic and painless

Mucocutaneous Leishmaniasis L. braziliensis (espudia) two stages simple skin lesion 2o mucosal involvement can occur long after primary lesion (up to 16 years) frequently in naso-pharyngeal mucosae metastasis via blood or lymphatic systems variable types and sizes of lesions chronic and painless

Mucocutaneous Leishmaniasis L. braziliensis (espudia) two stages simple skin lesion 2o mucosal involvement can occur long after primary lesion (up to 16 years) frequently in naso-pharyngeal mucosae metastasis via blood or lymphatic systems variable types and sizes of lesions chronic and painless tapir nose

Visceral Leishmaniasis 3 possibly related species L. donovani (Asia, Africa) India (kala azar) L. infantum (Mediterranean, Europe) L. chagasi (New World) reticuloendothelial system affected spleen, liver, bone marrow, lymph nodes onset is generally insidious progressive disease 75-95% mortality if untreated death generally within 2 years

Clinical Presentation incubation period generally 2-6 months can range 10 days to years fever, malaise, weakness wasting despite good appetite spleno- and hepatomegaly, enlarged lymph nodes depressed hematopoiesis severe anemia leucopenia thrombopenia  petechial hemorrhages in mucosa

Post Kala Azar Dermal Leishmaniasis due to inadequate treatment nodular lesions easily cured with treatment (in contrast to DCL)

L. infantum can cause either cutaneous or visceral disease zymodeme analysis reveals dermotropic and visceraltropic strains dermotropic strains result in visceral disease in AIDS patients

susceptible mice strains exhibit Th2 responses resistant mice strains exhibit Th1 responses Th1 response stimulates macrophages

Diagnosis of CL, MCL, DCL suspected because of: geographical presence of parasite history of sandfly bite + skin lesion: chronic, painless, ‘clean’ ulcer nasopharyngeal lesions nodular lesions amastigotes (scrapings, biopsy, aspirates) in vitro culture (promastigotes) inoculate into hamsters demonstration of parasite delayed hypersensitivity skin test serology?

make incision in active part of lesion

scrape cells from incision

prepare Giemsa-stained smear

aspiration and culture

promastigotes following in vitro culture

Delayed Hypersensitivity Skin Test aka leishmanin skin test, Montenegro reaction intradermal inoculation of leishmanin suspension of whole or disrupted promastigotes preferably from local area include negative control induration ± erythema in 48-72 hours

VL Diagnosis suspected because of: geographical presence of parasite history of sandfly bite prolonged fever, splenomegaly, hepatomegaly, anemia, etc. amastigotes in bone marrow aspirates in vitro culture of aspirates serological tests direct agglutination ELISA dipstick (39 kDa Ag)

Treatment pentavalent antimonials (eg., glucantime, pentostan) 20 mg/kg/day, 15-20 days pentamidine for Sb5+ failures amphotericin B

Control and Epidemiology New World Dermal zoonosis (arboreal mammals = reservoir) lowland forest occupational Old World Dermal urban = dog reservoir rural = rodent reservoir Visceral India (Ld): human-fly-human Africa (Ld): rodent reservoir others: dogs (with lesions) are usual reservoir depends on local transmission avoid sandfly bites bed nets insecticides destruction of dog reservoir ‘tropica vaccine’ historical inoculation in covered areas risk of recidiva or VL