Leishmania

Background

Microbiology

• Diploid protozoa with dimorphic life cycle and no known sexual stage, related to Trypanosoma
  • Amastigote and promasigote forms
• The genus Leishmania is divided into subgenera Viannia and Leishmania
  • Viannia species develop in the hindgut before migradting to the midgut and foregut
  • Leishmania species develop in the midgut and foregut

Subgenus	Complex	Species	Reservoir	Distribution	Disease
Leishmania	L. donovani	L. donovani	humans	India	VL
		L. infantum	dogs	Mediterranean and China	VL
		L. chagasi/infantum	dogs	Central/South America	VL
	L. tropica	L. tropica	humans	East Mediterranean, Middle East, Central Asia	CL
	L. major	L. major	birds, gerbils, rodents	North and West Africa, Middle East, Central Asia	CL
	L. aethiopica	L. aethiopica	hyraxes	East Africa	CL
	L. mexicana	L. mexicana	forest rodents and marsupials	North, Central, and South America	CL
		L. amazonensis
Viannia	L. braziliensis	L. braziliensis	edentates, opossums, rodents, dogs	South and Central America	MCL
		L. peruviana	dogs, marsupials, rodents	Peru	CL
	L. guyanensis	L. guyanensis	sloths, arboreal anteaters	South America	CL
		L. panamensis	sloths	Central America and Colombia	MCL

Life Cycle

• Promastigote that is living in the sand fly digestive tract is transmitted into the skin of a mammalian host during a blood meal
• The promastigotes are phagocytized by macrophages in the dermis, where they transform into amastigotes (no flagellum) in the phagolysozome
• Amastigotes multiply, then rupture the containing macrophage and disseminate through lymphatics and vascular system
• Female sand fly ingests parasitized cells curing bloodmeal, where the amastigotes develop into flagellated promastigotes in their gut

Epidemiology

• Widely distributed in tropical, subtropical, and temperate regions
• Prevalence of about 12 million cases worldwide, with incidence of 500,000 cases of visceral leishmaniasis annually and 1-1.5m cases of cutaneous leishmaniasis
• Species and clinical syndromes vary geographically
  • In general, there is very little visceral leishmaniasis in the New World (except for rare cases in Brazil), but is common in all Old World areas including Asia, Africa, and the Middle East
  • Disseminated leishmaniasis, American mucosal leishmaniasis, and diffuse cutaneous leishmaniasis are exclusive to the New World (except rare DCL in Africa)
  • Visceral leishmaniasis:
    • Common species include L. donovani (Asia), L. infantum (southern Europe, Mediterranean), L. chagasi (Brazil).
    • 90% of human visceral infections occur in India, Bangladesh, Nepal, Sudan, Ethiopia and Brazil.
  • Cutaneous leishmaniasis:
    • Common species include L. major and L. tropica (Old World), L. mexicana, L. amazonensis, L. peruviana, L. guyanensis (New World), L. (Viannia) braziliensis (cutaneous and mucocutaneous).
    • 90% of human cutaneous infections occur in Afghanistan, Algeria, Iran, Saudi Arabia, Syria, Brazil, Colombia, Peru and Bolivia.
• Risk factors: HIV increases risk of VL
• Non-human reservoirs: dogs, primarily, but also other mammals
• Transmission is by the bite of infected sand flies, but it can also be acquired from blood transfusions, needle sharing, occupational exposures, congenital transmission, and apparently rare by sexual transmission

Pathophysiology

• The clinical syndrome is determined at least in part by the immune system response, much in the same way as leprosy
• Gets phagocytosed but it inhibits normal fusion with the lysosome, so survives and replicates in the macrophage until the phagocyte bursts, releasing the promastigotes
• Disseminates to skin and reticuloendothelial system

Clinical Manifestations

Cutaneous leishmaniasis (CL)

• Endemic in tropics worldwide
• Incubation period of 2 weeks to several months (range up to several years)
• Variety of cutaneous leisons, including small papules, papulonodules, dru crusted leions, and large, deep, mutilating ulcers, as well as plaques, satellite lesions, psoriasiform lesions, or verrucous lesions
  • Multiple lesion morphologies may be seen on the same patient
  • Ulcerative lesions are usually shallow and circular with well-defined, raised borders
  • No fat destruction, so less undermining
• Lesions are usually found on exposed parts of the body (i.e. where the sand fly can bite)

Old World CL

• Known as the oriental sore, bouton d'orient, bouton de Crete, bouton d'Alep, bouton de Biskra, Aleppo evil, Baghdad boil, and Delhi boil
• Most commonly caused by L. major, L. tropica, or L. aethiopica, but also rarely L. donovani and L. infantum
• Skin lesions can be single or multiple ulcers, atypical noduledisfiguring facial lesions, disseminated cutaneous leishmaniasis (L. aethiopica), post-kala-azar dermal leishmaniasis, and leismaniasis recidivans (L. tropica)
  • L. tropica tends to cause dry crusted slowly-enlarging lesions
  • L. major tends to cause moist, exudative lesions with a granulating base

New World CL

• May also be known as pian boid (bush yaws), uta, or chiclero's ulcer
• Most commonly caused by L. braziliensis, L. mexicana, L. panamensis, and others
• Lesions can include single or multiple ulcers, diffuse cutaneous leishmaniasis, and mucosal disease (L. braziliensis)
  • L. braziliensis tends to cause moist, exudative lesions with a granulating base

Mucocutaneous leishmaniasis

• A form of New World CL that also involves oral, nasal, pharyngeal, or laryngeal lesions
• Affects 2 to 5% of patients with L. braziliensis (rarely L. panamensis, L. guyanensis, or L. amazonensis)
• Usually occurs following resolution of a primary cutaneous ulcer, but can be concurrent
  • Incubation period range 1 month to 2 decades from primary lesion
• Initial complaint may be nasal stuffiness, discharge, discomfort, or epistaxis
• Can also have dysphonia
• Ulceration can result in destruction of the nasal cartilage and soft palate, and can result in a "tapir" nose
• Hypertrophy can resulting in nasal and labial protuberance called "espundia"
• Only rarely resolves spontaneously

Differential Diagnosis

• Painless wet ulcer from the topics is mostly leishmaniasis vs. Buruli ulcer
• Infectious
  • Bacterial: ecthyma, impetigo, syphilis, pinta, cutaneous anthrax, ulceroglandular tularemia, cutaneous actinomycosis
  • Fungal: including sporotrichosis, cutaneous blastomycosis/cryptococcus/histoplasmosis
  • Mycobacterial: M. ulcerans (Buruli ulcer; with fat necrosis), M. marinum, and leprosy
• Non-infectious
  • Skin cancer
  • Spider bites (brown recluse, eschar)
  • Pyoderma gangrenosum

Diagnosis

• Giemsa stain of biopsy, needle aspirate, or dermal scraping
• Demonstration of parasite in culture
• PCR
• Serology unhelpful
• Skin-based antigen testing unhelpful

Management

• For MCL incolving the pharynx or larynx, should get high-dose IV steroids for 1 to 2 days before starting antimicrobials

Visceral leishmaniasis (VL)

• Most common causative organism is the L. donovani complex, followed by L. infantum (L. chagasi)
• Also known as kala-azar in India, Dum Dum fever, and Assam fever
• Infantile splenomegaly is a Mediterranean VL caused by L. infantum
• Incubation period 2 to 8 months (range 10 days to more than 1 year)
• Risk factors include HIV, chronic steroids, methotrexate, anti-TNF-α inhibitors, and solid organ transplant
  • Can also have late reactivation after starting immunosuppressive medication
• There is a range of severity, from asymptomatic or self-limited illness to classic VL and death
• Classic pentad of kala-azar is characterized prolonged fever, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia
• Typically insidious onset of fever, weakness, anorexia, weight loss, and hepatosplenomegaly
  • Low-grade symptoms may be present for months before presentation to healthcare
  • Fevers may be intermitted, double quotidian, or continuous; usually do not appear toxic
  • Spleen enlarged but soft and nontender
• Lymphadenopathy only common in Sudan
• May have elevated liver enzymes and bilirubin
• Anemia almost always present
• May present atypically in AIDS (CD4 <50), with more GI involvement (mouth to small intestine, diarrhea), lung and pleural involvement, and bony marrow infiltration
  • More rapid onset with worse outcomes

Viscerotropic leishmaniasis

• Caused by L. tropica infection in Middle East
• Low-grade fever, malaise, fatigue, and sometimes diarrhea
• Mild splenomegaly

Post-kala-azar dermal leishmaniasis (PKDL)

• Following treatment of L. donovani leishmaniasis, many patients develop PKDL
  • In India, 5-10% of patients within 2 to 4 years
  • In Sudan, 50% of patients within 6 months
  • Rare in Latin America and the Mediterranean
  • More common after treatment with pentavalent antimony
• The skin lesions are chronic, lasting up to 20 years in India or up to a few months in Sudan
  • Generally self-limited in Sudan
• It presents with macular lesions that can be can be hyper- or hypopigmented, progressing to papules, nodules, and verrucous forms
• Lesions are on the face, trunk, extremities, oral mucosa, and occasionally genetalia
• Can mimic leprosy

Differential Diagnosis

• Acute form: malaria, enteric fevers, bacterial endocarditis, sarcoidosis, hemophagocytic syndromes, typhus, acute Chagas, acute schistosomiasis, miliary tuberculosis, and amebic liver abscess
• Subacute or chronic: brucellosis, prolonged Salmonella bacteremia, histoplasmosis, infectious mononucleosis, lymphoma, leukemia, myeloproliferative disorders, hepatosplenic schistosomiasis, and chronic malaria
• Late leishmaniasis: hematologic malignancies (hard spleen), disseminated histoplasmosis, tropical splenomegaly syndrome
• PKDL: leprosy, yaws, and syphilis

Diagnosis

• Often diagnosed clinically based on the pentad of fever, weight loss, hepatoplenomegaly, pancytopenia, and hypergammaglobulinemia
• Laboratory diagnosis is by demonstrating amastigotes in tissue, isolated promastigotes in culture, or with PCR
  • Samples can be from splenic aspiration (most sensitive), liver biopsy, lymph node aspirates, and bone marrow aspirates
  • Serology cross-reacts with T. cruzi and should not be relied on for definitive diagnosis

Investigations

• Rule out malaria and hematologic malignancy

Diagnosis

• Clinical diagnosis
• Histology
  • Biopsy of skin (aspirate or scraping) or splenic aspiration or bone marrow aspiration
  • Touch-prep of tissue or smear of fluid
  • Wright-Giemsa or DFA to stain for amastigote 2-5 μm
• Culture: NNN medium (rabbit-bloor agar plus other things)
• Molecular: PCR (best test in Canada, based on skin scraping or aspirate, or filter paper test)
• Immunology
  • Leshmenin skin test
  • RDT rapid antigen test

Management

• Specific therapies vary by species and region
• Despite clinical cure, viable parasites remain in scar tissue

Visceral leishmaniasis

• Predominantly intramuscular pentavalent antimony (SbV) (in resource-poor countries) or amphotericin B (in resource-rich countries)
• Amphotericin B
  • If immunocompetent, liposomal AmB 3 mg/kg/day on days 1 to 5, 14, and 21
  • If immunocompromised, liposomal AmB 4 mg/kg/day on days 1 to 5, 10, 17, 24, 31, and 38
• Pentavalent antimony
  • No longer recommended in India due to resistance
  • Typically prepared as sodium stibogluconate or meglumine antimoniate
  • Cardiac deaths have been associated with generic SbV
  • Given IM or IV for visceral leishmaniasis
  • Side effects include mild pancreatitis (anorexia, nausea, vomiting, and midepigastric pain), myalgias and arthralgias, headache, asthenia, and malaise
    • Also long QT, arrhythmias, sudden death, and torsade de pointe
    • Liver enzyme elevations are common
• Miltefosine
  • New drug useful for India
• Paromomycin
  • An aminoglycoside that is injected IM 11 mg/kg daily for 21 days
  • Non-inferior to amphotericin B in India, but more side effects

Post-kala-azar dermal leishmaniasis

• Difficult to treat
• Often treated with pentavalent antimony for 2 to 4 months, if tolerated
• Possibly treatable with amphotericin B

HIV coinfection

• Should start HAART within ~2 weeks, but beware IRIS

Cutaneous leishmaniasis

• Lesions don't always need treatment, as many will self-resolve
• The decision to treat or not depends on a number of factors: age and clinical course of lesion (resolving?), number of lesions, complexity, size of lesion, immune status of the patient, mucosal involvement, location L braziliensis (higher risk for late complications), and how bothersome the lesions are to the patient

Old World CL

• Good wound care
• Systemic treatment, possibly
  • If treatment is indicated, SbV 20 mg/kg/day IM for 20 days
  • Alternatively
    • Fluconazole 200 mg po daily for 6 weeks (L. major)
    • Itraconazole 200 mg/day po for 6 to 8 weeks (L. major > L. tropica)
    • Miltefosine 2.5 mg/kg/day for 28 days (L. major)
• Local treatment, possibly
  • Intralesional SbV
  • Paromomycin/methylbenzethonium cloride 15%/12% cream topically twice daily for 28 days (L. major)
  • Hyperthermic treatments and cryotherapy

New World CL

• SbV 20 mg/kg/day IM for 20 days
• Amphotericin B
• Pentamidine 4 mg/kg IM twice for L. guyanensis in French Guyana and Surinam (but not for other species)
• Ketoconazole 600 mg daily for 28 days (L. mexicana and L. panamensis, but not L. braziliensis)
• Miltefosine up to 50 mg po bid to tid for 28 days (possibly less useful against L. braziliensis but maybe not)
• Prefer not to use local treatment if there's a risk of Viannia subgenus, given risk of later mucocutaneous leishmaniasis

Diffuse cutaneous leishmaniasis

• Nothing works

Mucocutaneous leishmaniasis

• SbV, with variable response and frequent relapses
• Amphotericin for salvage
• Miltefosine 2.5 mg/kg/day for 28 days