Leishmaniasis
KEY FEATURES
ESSENTIALS OF DIAGNOSIS
• Four clinical syndromes occur
- Visceral leishmaniasis (kala azar)
- Cutaneous leishmaniasis
- Mucocutaneous leishmaniasis (espundia)
- Diffuse cutaneous leishmaniasis
GENERAL CONSIDERATIONS
• Two species of sand flies transmit infection
- Phlebotomus (Old World leishmaniasis)
- Lutzomyia (New World leishmaniasis)
• Transmission
- Sand flies feed on wild animal reservoir (eg, rodents, marsupials) and domestic dogs and then bite humans
- Kala azar is transmitted directly from humans to humans
• Leishmaniae life cycles have two distinct forms
- In mammalian hosts, the parasite is in its amastigote form (Leishman-Donovan bodies, 2-5 μm) in mononuclear phagocytes
- The sand flies ingest the parasitized cells when they feed on an infected host
- In the sand fly vector, the parasite converts to, multiplies, and is then transmitted during feeding as a flaggellated extracellular promastigote (10-15 μm)
• There is overlap between the four clinical syndromes, and each syndrome is caused by more than one species
• Leishmania results in lifelong latent infection
• Cutaneous and visceral leishmaniasis have occurred in US military after exposure in Afghanistan and Iraq
• Leishmaniae can become opportunistic pathogens through reactivation or new infection
• In southern Europe, ~5% of people with AIDS have coinfections
• Diffuse cutaneous leishmaniasis
- State of deficient cell-mediated immunity
- Causative organisms: L mexicana complex (New World) and L aethiopica(Old World)
DEMOGRAPHICS
• In tropical and temperate zones, ~12 million persons are infected with leishmaniasis
• 1.5-2.0 million new cases occur yearly
• > 1 million are cutaneous and 500,000 visceral disease
• Approximately 50% are in children
CLINICAL FINDINGS
SYMPTOMS AND SIGNS
• Severity of infection ranges from subclinical (self-curing or easily treated cutaneous lesions) to persistent, disfiguring cutaneous and mucocutaneous lesions to potentially fatal visceral disease
• See Leishmaniasis, Visceral (Kala Azar)
• See Leishmaniasis, Cutaneous
• See Leishmaniasis, Mucocutaneous
• Diffuse cutaneous leishmaniasis
- There are widespread, leprosy-like skin lesions
- Skin lesions are generally progressive and refractory to treatment
• In patients with AIDS who have coinfection with Leishmania, splenomegaly may not occur in visceral disease
DIAGNOSIS
LABORATORY TESTS
• Definitive diagnosis is established by finding
- Intracellular nonflagellated amastigote
◊ In Giemsa-stained biopsies from skin, mucosa, liver, or lymph nodes
◊ From splenic aspirates (most sensitive site, but risky procedure), bone marrow, or lymph nodes
- Flagellated promastigote in culture of these tissues (requires up to 21 days)
• Occasionally, the organisms are seen in mononuclear cells of buffy coat Giemsa-stained smears
• In patients with AIDS, diagnostic criteria may be altered (Leishmania antibodies become undetectable; splenomegaly may not occur in visceral disease)
• Golden hamster or BALB/c mouse inoculation of the nose, footpad, or tail base may be used (requires 2-12 weeks of observation)
• Polymerase chain reaction has up to 100% specificity and sensitivity
• Species identification is by molecular, isoenzyme, and monoclonal antibody methods
• Serologic tests (ELISA, indirect fluorescent antibody, direct agglutination) and the leishmanin (Montenegro) skin test (not licensed in the United States) may facilitate diagnosis, but none is sensitive or specific enough to be used alone, to speciate, or to distinguish current from past infection
DIAGNOSTIC PROCEDURES
• Skin lesion specimens should be obtained through intact skin (cleansed with 70% alcohol) at a raised edge of an ulcer margin
- Can use local anesthesia
- To obtain tissue fluid for staining, press blood out of the site with two fingers, incise a 3-mm slit, and then scrape with the blade
• When doing a biopsy, an impression smear is made, a portion is macerated for culture, and the remainder is reserved for pathologic sections. For needle aspiration, sterile preservative-free saline is inserted with a 23- to 27-gauge needle; the aspirate is then cytospun at 800 × g for 5 min
TREATMENT
• See Leishmaniasis, Visceral (Kala Azar)
• See Leishmaniasis, Cutaneous
• See Leishmaniasis, Mucocutaneous
MEDICATIONS
• The drug of choice is sodium stibogluconate or meglumine antimoniate; resistance and treatment failures are increasing
• Generic sodium stibogluconate is as effective and safe as Pentostam
- Start with 200-mg Sb test dose followed by 20 mg Sb/kg/d (IV preferable to IM)
• Meglumine antimoniate (85 mg Sb/mL) is equal in efficacy and toxicity in equivalent Sb doses (20 mg Sb/kg/d)
• The drug is given QD
- 28 days for visceral and mucocutaneous leishmaniasis
- 20 days for cutaneous leishmaniasis
- Longer courses are indicated in regions where there is resistance
- Side effects likely to appear with cumulative doses
• Common side effects
- Gastrointestinal symptoms
- Fatigue, fever
- Myalgia, arthralgia
- Phlebitis, rash
• Rare side effects
- Hemolytic anemia
- Hepatitis, pancreatitis
- Renal and heart damage
• Therapy is discontinued if the following occur
- Aminotransferases 3-4 times normal levels
- Significant arrhythmias
- Corrected QT intervals > 0.50 s or concave ST segments
• Relapses should be treated at the same dose for at least twice the previous duration
• In the United States, only stibogluconate is available (obtain from the Parasitic Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333 404-639-3670)
• Second-line drugs are amphotericin B and pentamidine
Amphotericin B
• Visceral leishmaniasis
- AmBisome 3 mg/kg/d (parenteral) on days 1-5, 14, and 21; may be repeated
- Dosage for immunoincompetent persons is 4 mg/kg/d on days 1-5, 10, 17, 24, 31, and 38
- There may be comparable effectiveness with cumulative doses of 3.75 or 7.5 mg/kg, given in five divided doses, over 5 days
• Conventional amphotericin B deoxycholate 1 mg/kg daily by slow infusion (4-6 hours) for 20 days (used in India)
Pentamidine isethionate
• Pentamidine isethionate, 2-4 mg/kg IM (preferable) or IV, QD or QOD (15 doses for visceral and 4 doses for cutaneous leishmaniasis)
• For some forms of visceral leishmaniasis, repeat treatment may be necessary using up to twice the dose, but resistance may persist
Paromomycin (aminosidine)
• Cutaneous leishmaniasis: topical application in various formulations has variable success that differs by region
• One ointment is paromomycin 15%/methylbenzethonium chloride 12% in soft paraffin, applied BID for 15 days; skin reactions may occur. The ointment cannot be used in regions of mucocutaneous leishmaniasis as it does not prevent metastatic disease
• For refractory visceral leishmaniasis, parenteral paromomycin is promising, but may cause renal or otic toxicity
Miltefosine
• Oral drug; approved in India for treatment of visceral leishmaniasis
• Daily dose is 2.5 mg/kg in two divided doses for 4 weeks (95% cure rates)
• Promising efficacy for cutaneous leishmaniasis
• Side effects: vomiting (40%), diarrhea (20%), occasional transient elevations of aminotransferases and creatinine
• It cannot be used in pregnancy due to teratogenic potential
OUTCOME
FOLLOW-UP
• Patients should be monitored weekly for the first 3 weeks and twice weekly thereafter by serum chemistries, complete blood cell counts, and electrocardiography
PREVENTION
• Sand fly habitats are warm, humid, dark microclimates, including rodent burrows, rock piles, or tree holes; these are often in sylvatic areas near forests or semiarid ecosystems
• Peridomestic sand flies are found on debris close to buildings
• Biting is generally at twilight or at night but may occur in shaded areas during the day
• Partial protection is from permethrin applied to clothing, DEET repellent, avoidance of endemic areas (especially at night), use of mosquito coils, and use of fine-mesh insecticide-impregnated nets for sleeping (may be too warm for tropical use)
WHEN TO REFER
• All patients should be referred to a clinician with expertise in this disease