Leishmaniasis

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Leishmaniasis

Leishmaniasis is a chronic inflammatory disease caused by obligate intracellular protozoan parasites of the genus Leishmania, transmitted through the bite of infected female phlebotomine sandflies. It ranges in severity from a single self-healing skin lesion to a fatal systemic illness.

Etiology and Life Cycle

The parasite exists in two forms:

Promastigote - extracellular, flagellated form in the sandfly gut. When the fly bites, promastigotes are injected into the host dermis along with vasodilatory sandfly saliva (e.g., maxadilan) which potentiates infection.
Amastigote - intracellular, non-flagellated form within the phagolysosomal compartment of host macrophages. Amastigotes contain a unique organelle - the kinetoplast (a mass of mitochondrial DNA), making these parasites kinetoplastids.

Promastigotes are phagocytosed by macrophages; the phagolysosome's acidity (normally pH 4.5) would be lethal, but the parasites maintain the pH at 6.5 to survive. They then transform into amastigotes, which proliferate and spread to infect additional macrophages. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Main Species and Clinical Forms

Leishmania spp.	Subgenus	Distribution	Primary Disease	Alternative Name
L. donovani	Leishmania	South Asia, East Africa	Visceral	Kala-azar
L. infantum (chagasi)	Leishmania	Europe, Mediterranean, S. America	Visceral	-
L. major	Leishmania	Asia, N. Africa, Middle East	Cutaneous	Biskra nail
L. tropica	Leishmania	Asia, Europe	Cutaneous	Aleppo boil
L. aethiopica	Leishmania	Ethiopia	Cutaneous/Diffuse	-
L. mexicana	Leishmania	Central America	Cutaneous	Chiclero ulcer
L. braziliensis	Viannia	South America	Cutaneous/Mucosal	ML-Espundia
L. amazonensis	Leishmania	S. & Central America	Cutaneous/Diffuse	-

Goldman-Cecil Medicine, Table 319-1

Clinical Forms

1. Visceral Leishmaniasis (Kala-azar)

The most serious form - fatal in >95% of cases if untreated. Caused mainly by L. donovani and L. infantum.

Clinical features:

Irregular bouts of fever (often twice-daily "double quotidian" spikes)
Massive hepatosplenomegaly (spleen can weigh up to 3 kg)
Progressive weight loss, weakness
Pancytopenia (bone marrow invasion)
Lymphadenopathy
Hyperpigmentation of skin in South Asians - the origin of "kala-azar" (black fever in Hindi)
Hypoalbuminemia and edema

Microscopically, the spleen is packed with enlarged macrophages stuffed with amastigotes; normal splenic architecture is obliterated. The liver shows Kupffer cell infiltration and late fibrosis. There may also be an immune complex-mediated mesangioproliferative glomerulonephritis and, in advanced disease, amyloid deposition in the kidneys. - Robbins & Cotran

Post-kala-azar dermal leishmaniasis (PKDL): A rare sequela appearing 1-5 years after cure of VL (South Asian form) or concurrently (Sudanese/East African form). Characterized by dermal nodules or maculopapular rash.

Estimated global burden: 50,000-90,000 new cases/year; most in Brazil, East Africa, and South-East Asia. - Park's Textbook of Preventive & Social Medicine

2. Cutaneous Leishmaniasis (CL)

The most common form (600,000 to 1 million cases/year). Caused by L. major, L. tropica, L. mexicana, L. braziliensis, and others.

Lesion begins as a papule surrounded by induration, which evolves into a shallow, slowly expanding ulcer on exposed skin
Leaves permanent scars
Generally self-limiting but may persist for months to years
Predominantly in the Americas, Mediterranean, Middle East, Central Asia

3. Mucocutaneous Leishmaniasis (MCL / Espundia)

Mainly caused by L. braziliensis.

Moist, ulcerating lesions in the nasopharyngeal region
Leads to partial or total destruction of the mucous membranes of the nose, mouth, and throat - highly destructive and disfiguring
May reactivate after long intervals of apparent cure
90% of cases in Bolivia, Brazil, Ethiopia, and Peru

4. Diffuse Cutaneous Leishmaniasis (DCL)

Rare form; caused by L. aethiopica and L. amazonensis
Begins as a single skin nodule that spreads until the entire body surface is covered with nodular lesions
Microscopically: foamy macrophages stuffed with organisms
Associated with severe immunologic anergy to leishmanial antigens (dominant Th2 response)

Histopathology

Giemsa stain showing a tissue macrophage packed with Leishmania donovani amastigotes

Fig: Giemsa stain of a tissue macrophage with L. donovani amastigotes (dark oval bodies with visible kinetoplast). - Robbins, Cotran & Kumar

Pathogenesis and Immune Response

The outcome of infection depends critically on the Th1 vs Th2 immune response:

Response	Outcome
Th1 dominant (IFN-γ, IL-12, TNF-α)	Classical macrophage (M1) activation → intracellular killing via nitric oxide and ROS → parasite clearance
Th2 dominant (IL-4, IL-10, IL-13, TGF-β)	Alternative macrophage (M2) activation → parasite survival and spread

Key virulence mechanisms of Leishmania:

Lipophosphoglycan (LPG) on promastigote surface resists complement
Gp63 (zinc-dependent proteinase) cleaves host enzymes
Maintains phagolysosome pH at 6.5 (instead of normal 4.5) to survive intracellularly
Produces endonucleases that digest neutrophil extracellular traps (NETs)
Uses microRNAs to disrupt host cellular signaling
Stimulates iron entry into phagolysosomes via ZIP family transporters
Robbins, Cotran & Kumar; Goldman-Cecil Medicine

Diagnosis

Definitive: Demonstration of amastigotes on Giemsa-stained tissue smears/biopsy (spleen, bone marrow, lymph nodes for VL; skin/mucosa for CL)
Culture: On NNN (Novy-MacNeal-Nicolle) medium
PCR: Sensitive and specific; useful for species identification
Serology: rK39 rapid antigen test (widely used for VL in South Asia)
Montenegro skin test (leishmanin test): Delayed-type hypersensitivity test - negative in active VL; positive in healed or CL

Treatment

The choice of agent depends on species, geographic region (resistance patterns), and host factors.

Visceral Leishmaniasis

Drug	Class	Route	Notes
Liposomal Amphotericin B	Polyene antifungal	IV	Drug of choice in most regions; single-dose regimens used in India
Amphotericin B deoxycholate	Polyene	IV	Effective but more toxic than liposomal form
Miltefosine	Alkylphosphocholine	Oral	First oral drug for VL; interferes with phospholipids and induces apoptosis; teratogenic - avoid in pregnancy; nausea/vomiting common
Sodium stibogluconate	Pentavalent antimonial	IV/IM	Prodrug reduced to active trivalent form; resistance emerging in India; cardiac arrhythmias, pancreatitis, elevated LFTs
Meglumine antimoniate	Pentavalent antimonial	IV/IM	Similar to stibogluconate
Pentamidine	Diamidine	IM	Alternative agent
Paromomycin	Aminoglycoside	IM	Alternative; often used in combination

Cutaneous Leishmaniasis

Many cases are self-limiting and may not require systemic treatment
First-line systemic: Miltefosine 50 mg BID (if weight 30+ kg)
Parenteral: sodium stibogluconate, meglumine antimoniate, amphotericin B
Others: fluconazole, paromomycin

Mucocutaneous Leishmaniasis

Less responsive to treatment; relapses common
Options: liposomal amphotericin B, miltefosine, sodium stibogluconate, meglumine antimoniate, amphotericin B deoxycholate
Lippincott Illustrated Reviews Pharmacology; Goldman-Cecil Medicine; Katzung's Basic & Clinical Pharmacology

Epidemiology and Control

Endemic in tropical and subtropical regions of 98 countries
Worsening factors: asymptomatic carriers, PKDL, undernutrition, HIV co-infection (Leishmania-HIV co-infection greatly worsens prognosis)
Zoonotic reservoirs: rodents, canids (dogs/foxes) - most forms are zoonoses; Indian kala-azar is the major exception (anthroponotic)
Prevention: Insecticide-treated bed nets, sandfly control, reservoir host elimination, personal protection (repellents, protective clothing)
Epidemics occur with forced migration of non-immune populations into endemic areas (poverty-driven disease)
Park's Textbook of Preventive & Social Medicine; Robbins, Cotran & Kumar

Summary of key facts for exams:

Vector: female phlebotomine sandfly
Intracellular form in humans: amastigote (diagnostic form)
Extracellular form in sandfly: promastigote
Pathognomonic feature: kinetoplast (unique mitochondrial DNA organelle)
Most fatal form: visceral (kala-azar) - fatal if untreated
Most common form: cutaneous
Only oral drug: miltefosine (teratogenic!)
Drug of choice (VL): liposomal amphotericin B
Th1 response = protection; Th2 response = susceptibility

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