Leishmaniasis

1. 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

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

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

4. 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)

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

6. 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

8. 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

10. 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)

11. 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)

12. 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

13. chronic ulcerated, papular, or nodular lesion • occasionally satellite lesions

14. metastasis via blood or lymphatic systems • especially L. braziliensis

15. 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

16. 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

17. 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

18. 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

19. 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

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

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

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

23. 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

24. 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

25. 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

26. 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

27. 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

29. 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

30. 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

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

32. 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

33. susceptible mice strains exhibit Th2 responses • resistant mice strains exhibit Th1 responses • Th1 response stimulates macrophages

34. 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?

35. make incision in active part of lesion

36. scrape cells from incision

37. prepare Giemsa-stained smear

41. aspiration and culture

42. promastigotes following in vitro culture

43. 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

44. 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)

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

46. 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