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Pathogen + Vector
- Genus: Leishmania
- Many species â different clinical forms by species
- Vector: Sandfly â Phlebotomus (Old World â Asia, Africa, Mediterranean) + Lutzomyia (New World â Americas)
- Reservoirs: dogs, rodents, foxes, humans (anthroponotic in some areas)
Epidemiology
- 700,000 - 1 million new cases/yr globally (WHO)
- 26,000 - 65,000 deaths/yr (mostly VL)
- VL hot spots: India, Bangladesh, Nepal, Sudan, Ethiopia, Brazil
- CL: Brazil, Iran, Peru, Saudi Arabia, Syria, Afghanistan
- MCL: South America (Bolivia, Brazil, Peru)
Diagnosis
- Direct visualization:
- Bone marrow aspirate (most sensitive for VL)
- Splenic aspirate (highest sensitivity, but bleeding risk)
- Liver biopsy
- Skin biopsy (CL)
- Amastigote forms (intracellular, no flagella) on Giemsa stain
- Promastigote forms (extracellular, flagellated) in culture media (NNN â Novy-MacNeal-Nicolle)
- PCR â sensitive, species-specific
- Serology:
- VL: rK39 rapid test (highly sensitive + specific for VL caused by L. donovani)
- rK28 for L. infantum
- ELISA, IFA, DAT (direct agglutination test)
- Leishmanin skin test (Montenegro test) â for past exposure, not active
Treatment
Visceral Leishmaniasis
- Liposomal amphotericin B (AmBisome) â preferred (high efficacy, less toxicity)
- Single dose (10 mg/kg) for VL in India (used in mass campaigns)
- 3-5 mg/kg/day à 10-21 days for other endemic
- Miltefosine (oral) â alternative
- 50 mg PO bid à 28 days
- Teratogenic â pregnancy contraindicated
- Lactation contraindicated
- Pentavalent antimony (sodium stibogluconate, meglumine antimoniate)
- IV/IM Ã 28+ days
- Cardiac toxicity (QTc)
- Pancreatitis, hepatic, hematologic
- Increasing resistance in India
- Paromomycin + amphotericin combinations
- Pentamidine â historical
HIV + VL Co-Infection
- More severe + relapsing
- Liposomal AmB Ã longer course
- Maintenance / suppression often needed
- ART concurrent
Cutaneous Leishmaniasis
- Many self-limited; observation acceptable for simple ulcers
- Pentavalent antimony intralesional or systemic
- Miltefosine oral
- Liposomal AmB
- Cryotherapy + paromomycin topical for simple Old World CL
- Treatment more aggressive if:
- New World CL (mucocutaneous risk)
- Multiple lesions
- Facial / mucosal proximity
- Immunocompromise
Mucocutaneous Leishmaniasis
- Pentavalent antimony à 28+ days systemic
- Liposomal AmB alternative
- Miltefosine oral
- Surgical reconstruction often needed
PKDL
- L. donovani (Sudan, India)
- Miltefosine or liposomal AmB
- Long course
Prevention
- Sandfly avoidance (dusk + dawn protective measures)
- DEET + permethrin clothing
- Bed nets (fine mesh â sandflies smaller than mosquitoes)
- Insecticide-treated nets
- Vector control programs
- Treat human reservoir (PKDL)
- No human vaccine licensed; canine vaccines exist for L. infantum control
1ïžâ£ Leishmania Microbiology + Life Cycle
Morphology
- Amastigote: intracellular form (no visible flagellum), in macrophages
- Promastigote: extracellular form (free flagellum), in sandfly + culture
Life Cycle
- Sandfly bites infected mammal â promastigotes ingested
- Multiply in sandfly midgut
- Sandfly bites human â promastigotes injected
- Promastigotes enter macrophages (via complement)
- Inside macrophage â transform to amastigotes
- Multiply in macrophage phagolysosome
- Macrophage lyses â release amastigotes â infect new macrophages
- Tissue tropism varies by species:
- Skin macrophages: CL
- Mucosal: MCL
- Reticuloendothelial system (spleen, liver, bone marrow): VL
2ïžâ£ Cutaneous Leishmaniasis (CL)
Etiology + Geography
Old World
- L. major: arid + semi-arid (Mid East, N Africa, Central Asia)
- L. tropica: urban, anthroponotic
- L. aethiopica: highland Ethiopia
- Russia, Uzbekistan, Turkey, Iran, Saudi Arabia, Syria, Israel
New World
- L. mexicana: Central America
- L. braziliensis: Brazil + Andes (risk of mucocutaneous progression)
- L. amazonensis: Amazon Basin
- L. panamensis, L. peruviana, others
Clinical
- Sandfly bite site: papule â nodule â ulcer
- âOriental soreâ
- Painless typically
- Heals 6-18 months with scar
- 1-multiple lesions
- Some species cause anergic / diffuse CL in immunosuppression
- Mucocutaneous progression in 1-15% of New World L. braziliensis cases (years later)
Diagnosis
- Skin biopsy + Giemsa stain (amastigotes in macrophages)
- PCR of biopsy
- Serology less useful for CL
Treatment
- Simple Old World L. major / L. tropica:
- Often observation (self-limited)
- Cryotherapy + paromomycin topical
- Intralesional pentavalent antimony
- More aggressive treatment if:
- New World species (mucocutaneous risk)
- L. braziliensis complex (always treat systemically)
- Multiple lesions
- Facial / immune compromise
- Options:
- Pentavalent antimony systemic
- Liposomal AmB
- Miltefosine
- Fluconazole, ketoconazole (some Old World species)
- Pentamidine, paromomycin alternatives
3ïžâ£ Mucocutaneous Leishmaniasis (MCL / Espundia)
Etiology
- L. braziliensis complex (especially L. braziliensis, L. panamensis)
- New World Latin America
Pathogenesis
- CL primary lesion years prior
- Hematogenous spread to mucosal surfaces
- Inflammatory destruction
Clinical
- Nasal involvement first: nodules, ulceration
- Progressive destruction of nasal septum, palate, pharynx, larynx
- Disfigurement
- Airway compromise (severe)
- Self-limited unlikely
Diagnosis
- Skin / mucosal biopsy + Giemsa
- PCR
Treatment
- Pentavalent antimony à 28+ days systemic
- Liposomal AmB alternative
- Miltefosine
- Pentamidine (less effective)
- Surgical reconstruction for disfigurement (after parasite control)
4ïžâ£ Visceral Leishmaniasis (VL / Kala-Azar)
Etiology
- L. donovani (Indian subcontinent, Sudan, E Africa)
- L. infantum (Mediterranean, China, Latin America)
- L. chagasi (synonym of L. infantum in Latin America)
Epidemiology
- 90% of cases in 6 countries: India, Bangladesh, Nepal, Sudan, Brazil, Ethiopia
- WHO 2030 goal: eliminate VL as public health problem
- India: nearly eliminated (subnational targets met)
- E Africa (Sudan, Ethiopia) ongoing
Reservoirs
- Anthroponotic in India + Sudan (humans)
- Zoonotic in Mediterranean + Latin America (dogs primarily)
Pathogenesis
- Visceralization of amastigotes to spleen, liver, bone marrow
- Pancytopenia from marrow suppression + splenic sequestration
- Hepatosplenic enlargement
- Hypergammaglobulinemia (polyclonal IgG)
- Severe immunosuppression
Clinical
- Incubation 2-6 months (range 10 d - 2 yr)
- Prolonged fever (months)
- Massive splenomegaly + hepatomegaly
- Pancytopenia (anemia + thrombocytopenia + neutropenia)
- Lymphadenopathy
- Cachexia + weight loss
- Hyperpigmentation (âKala-azarâ = âblack sicknessâ)
- Hypoalbuminemia + edema
- Bleeding from thrombocytopenia
- Death typically from:
- Bacterial sepsis (immunosuppressed)
- Severe anemia
- Cardiac failure
- Severe bleeding
- 95%+ mortality untreated
Diagnosis
- rK39 rapid test â antibody to L. donovani recombinant antigen
- Sensitive + specific for VL (Indian + S American strains)
- Point-of-care
- Useful in field settings
- Bone marrow aspirate â high sensitivity (60-85%)
- Splenic aspirate â highest sensitivity (95%) but bleeding risk
- Lymph node aspirate (Sudan, where common)
- Liver biopsy (less common)
- Buffy coat smear of blood
- Culture: NNN media; slow
- PCR of marrow, blood, tissue â sensitive, species-specific
- Direct Agglutination Test (DAT), ELISA, IFA serology
Treatment
Liposomal Amphotericin B (Preferred)
- Single dose 10 mg/kg for Indian VL (used in mass campaigns; WHO endorsement)
- 3-5 mg/kg/day à 10-21 days for other endemic regions / severe
- Lower toxicity than antimony
- Effective + reduced renal toxicity
- WHO essential medicine
Miltefosine (Oral)
- 50 mg PO bid à 28 days
- Effective for VL + CL + MCL
- Pregnancy contraindicated (teratogenic)
- Lactation contraindicated (long half-life)
- Gastrointestinal side effects
- Cardiac side effects (QTc)
Pentavalent Antimony
- Sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime)
- IV/IM Ã 28-40 days
- Cardiac (QTc, T-wave changes)
- Pancreatitis (elevated amylase)
- Hepatic + hematologic
- Increasing resistance in India (L. donovani)
Paromomycin
- IM Ã 21 days
- Used in combinations
- Aminoglycoside
Combinations
- Liposomal AmB + miltefosine
- AmB + paromomycin
- Reduce treatment duration + improve cure rate
VL + HIV Co-Infection
- More severe + relapsing course
- Atypical presentations (limited fever)
- Treatment more aggressive + longer
- Liposomal AmB Ã longer (40 mg/kg total instead of 30)
- Maintenance / suppression often needed
- ART concurrent
Pregnancy + VL
- Liposomal AmB safe
- Pentavalent antimony â relative contraindication
- Miltefosine + pentamidine contraindicated
Pediatric VL
- L. infantum in Mediterranean (mostly pediatric)
- Severe disease
- Liposomal AmB
5ïžâ£ Post-Kala-Azar Dermal Leishmaniasis (PKDL)
Background
- Develops in 5-15% of VL patients after treatment
- Mostly L. donovani (Sudan, India)
- Latency: months to years post-VL
Clinical
- Hypopigmented macules + nodules + papules
- Especially face + extremities
- Long-standing
- Cosmetic concern + social stigma
Significance
- Reservoir for transmission in anthroponotic regions
- Public health importance
Treatment
- Miltefosine PO
- Liposomal AmB
- Long course
- May resolve spontaneously over years
6ïžâ£ Prevention
Personal
- DEET + picaridin repellents
- Long sleeves + pants at dusk-dawn (sandfly activity)
- Permethrin-treated clothing
- Fine-mesh bed nets (sandflies are smaller than mosquitoes â regular mosquito nets less effective)
- Insecticide-treated nets
Vector Control
- Spraying with pyrethroid insecticides
- Indoor residual spraying (IRS)
- Environmental management (eliminating breeding sites)
Reservoir Control
- Dog testing + treatment (Mediterranean, Latin America)
- Canine vaccine (CaniLeish, LeishVet) â for veterinary use to reduce transmission
Treatment of Human Reservoir
- PKDL patients
- VL active treatment + cure
No Human Vaccine
- Multiple candidates in clinical trials (Phase 1-2)
- Whole-killed, recombinant, attenuated, DNA, mRNA
- LEISH-F2 + GLA-SE adjuvant (in development)
- IDRI vaccines
WHO 2030 Elimination Strategy
- VL elimination as public health problem (< 1 case per 10,000 in endemic areas)
- India near elimination
- E Africa ongoing
- Mass drug administration in some areas
- Integrated vector management