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 (galactosearabinose)• increase disaccharide repeats

• glycocalyx 7 17 nm complement resistance

Clinical Spectrum of LeishmaniasisCutaneous 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

Some Leishmania Species Infecting Humans

New World Cutaneous,Mucocutaneous, and

Diffuse Leishmaniasis

Old World Cutaneous,Recidivans, and

Diffuse LeishmaniasisVisceral

Leishmaniasis

Mexicana ComplexL. mexicanaL. amazonensis

Braziliensis ComplexL. braziliensisL. panamensisL. guyanensis

L. tropica

L. major

L. aethiopica

L. infantum*

L. donovani

L. infantum*

L. chagasi**

*Both dermotrophic and viscerotrophic strains exist.**L. chagasi (Americas) may be the same as L. infantum (Mediteranean)

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

• 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

• 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

• due to inadequate treatment• nodular lesions• easily cured with treatment

(in contrast to DCL)

Post Kala Azar Dermal Leishmaniasis

Some Leishmania Species Infecting Humans

New World Cutaneous,Mucocutaneous, and

Diffuse Leishmaniasis

Old World Cutaneous,Recidivans, and

Diffuse LeishmaniasisVisceral

Leishmaniasis

Mexicana Complex

Braziliensis Complex

L. tropicaL. majorL. aethiopicaL. infantum*

L. donovaniL. infantum*L. chagasi**

• 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

• demonstration of parasite

• delayed hypersensitivity skin test

• serology?

• amastigotes (scrapings, biopsy, aspirates)

• in vitro culture (promastigotes)

• inoculate into hamsters

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

• 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

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