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Etiology and PathogenesisTop
1. Etiologic agent: Over 20 species of obligatory intracellular protozoa of the genus Leishmania (family Trypanosomatidae). Most cases of visceral leishmaniasis are caused by L donovani and L infantum. Cutaneous leishmaniasis is mainly due to infection with L tropica, L major, L mexicana and L braziliensis. Sporadically, visceral leishmaniasis develops in individuals infected with L mexicana and L tropica, and cutaneous leishmaniasis, in those affected by L infantum invasion.
2. Pathogenesis: Promastigotes are introduced into the host’s bloodstream with a bite from a phlebotomine sandfly and phagocytized by macrophages from peripheral blood. Then they transform into amastigotes and multiply inside numerous phagocytes in the blood, bone marrow, liver (Kupffer cells), spleen, lymph nodes, and skin (Langerhans cells), which results in the development of clinical manifestations. Infected cells containing parasites burst and release amastigotes, which infect new phagocytes. In cutaneous leishmaniasis only the skin is affected and parasites multiply inside macrophages and Langerhans cells at the site of the insect bite. Protozoa causing leishmaniasis can escape innate and cell-mediated immune responses of an infected individual. Complex strategies enabling the parasite’s survival in the host’s body even after clinically effective treatment include the neutralization of complement system fragments, inhibition of release of superoxide radicals and nitrogen oxide from macrophages, and inhibition of CD4+ cell induction.
3. Reservoir and transmission: Leishmaniasis is transmitted by phlebotomine sandflies of the genus Phlebotomus (Africa, Asia, Southern Europe) or Lutzomyia (South and Middle Americas). Transmission may occur through transfusion of blood or transplant of organs from an infected person or through IV use of illicit drugs with shared infected needles or syringes; congenital infection is also possible. The reservoir includes animals (eg, dogs, rodents, marsupials) and infected humans.
4. Risk factors: Staying within a region endemic for Leishmania spp, performing activities that pose risk of exposure to vector bites. An increasing number of cases of cutaneous leishmaniasis with an atypical course have been observed among travelers receiving long-term anti–tumor necrosis factor (TNF) therapy.
5. Incubation and contagious period: The incubation period ranges from several weeks to years (usually 2-6 months) for visceral leishmaniasis and from several weeks to months for cutaneous leishmaniasis. Infected individuals can be a source of infection to vectors even for years.
EpidemiologyTop
Leishmaniasis occurs in >90 countries in hot and tropical climate zones, in rain forests in Middle and South Americas as well as in deserts and steppes in Africa and West Asia. Local infections have also been diagnosed in Southern Europe.
Etiologic agents associated with the 2 clinical types of leishmaniasis vary geographically:
1) Visceral leishmaniasis: L donovani: East and Central Africa, Iran, India, China. L infantum: North Africa, Southern Europe, Near East, China, South and Middle Americas (in Americas this species is called L chagasi). Over 90% of cases of visceral leishmaniasis occur in India, Bangladesh, Sudan, Ethiopia, and Brazil.
2) Cutaneous leishmaniasis: L tropica: Greece, Turkey, Near East, South Asia. L major: North and Central Africa, Near and Middle East, South Asia. L mexicana and L braziliensis group (Viannia species): South and Middle Americas; these species also cause mucosal leishmaniasis. Over 70% of cases are diagnosed in Brazil, Colombia, Algeria, Syria, Pakistan, and Afghanistan.
No exact prevalence rates of leishmaniasis have been reported. The incidence of cutaneous leishmaniasis is estimated at 0.7 to 1.2 million cases per year, and visceral leishmaniasis, at 0.1 to 0.4 million cases per year. The number of cases of cutaneous leishmaniasis imported from nonendemic countries is on the rise; most infections have been observed in travelers to Bolivia and Costa Rica. Outbreaks of leishmaniasis most frequently occur in regions affected by armed conflicts and associated migration (eg, in recent years in Syria).
Clinical Features and Natural HistoryTop
The course of Leishmania spp infection depends on numerous factors, such as parasite species, strain virulence as well as the host’s genetic predisposition, immune response variability, and nutrition. Infections may be asymptomatic. In some cases clinical manifestations may develop even years after contraction, at the time of the host’s immune deficiency, eg, associated with HIV infection or immunosuppression.
The 2 main types of disease are visceral leishmaniasis and cutaneous leishmaniasis.
1. Visceral leishmaniasis (kala-azar): Signs and symptoms include fever (irregular, high grade, sometimes with 2 peaks during the day, accompanied by chills), weight loss and cachexia (appears early in the disease course and progresses rapidly), appetite loss, splenomegaly (with features of hypersplenism) and hepatomegaly, cough, epistaxis, diarrhea, vomiting, edema, enlarged lymph nodes, jaundice (rarely).
Visceral leishmaniasis usually follows a subacute course and is associated with slowly worsening (over weeks or months) nonspecific symptoms such as fatigue, fever, weight loss, and splenomegaly. An acute onset with rapid symptom progression is rare.
2. Cutaneous leishmaniasis: Within 2 to 4 weeks (or later) single or multiple inflammatory nodules (resembling furuncles) or ulcerations develop at the site of an insect bite, mainly on exposed skin areas (on the extremities, face, pinnae of the ears). Satellite lesions may appear around the primary lesion. Localized cutaneous leishmaniasis is the most typical presentation, with a crusted, exudative chronic ulcer (2-5 cm in diameter) with slightly raised, volcano-like margins and features of healing (fibrosis, sometimes accompanied by deformities). Extensive lesions can be painful. Lymph nodes near the affected area may sometimes be enlarged. Rare forms of the disease include diffuse and recurrent cutaneous leishmaniasis.
3. Mucosal leishmaniasis associated with Viannia species and L mexicana occurs as a complication of skin lesions only in South and Middle Americas, follows a chronic course, and may result in destruction of the nasal septum, lips, soft palate, and larynx.
DiagnosisTop
1. Identification of the etiologic agent:
1) Microscopic examination for the detection of amastigotes in a Giemsa-stained specimen obtained from skin lesions (skin scrapings, biopsy of ulcer margins) or organs of the reticuloendothelial system in visceral leishmaniasis (splenic aspiration: sensitivity >95%; bone marrow or liver biopsy: sensitivity of 70%-85%). Peripheral blood smear has low sensitivity.
2) Molecular studies (polymerase chain reaction [PCR]) of the same types of specimens as collected for microscopic examination and of blood.
3) Culture for the isolation of the parasite.
4) Serologic studies (enzyme-linked immunosorbent assay [ELISA] and immunofluorescence) are of limited use in the diagnostic workup of cutaneous leishmaniasis but are useful in the diagnosis of the visceral form.
5) Intradermal testing allows for the assessment of the host’s local response to nonviable promastigotes injected into the dermis; it is used in the diagnostic workup of cutaneous leishmaniasis in South America.
2. Other: Laboratory blood tests may show thrombocytopenia; leukopenia; normocytic anemia; polyclonal hypergammaglobulinemia; hypoalbuminemia; hyperbilirubinemia; and increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).
Microscopic identification of Leishmania spp serves as a basis for diagnosis. However, due to frequent diagnostic difficulties, use of multiple methods is recommended in order to increase the identification rate. No applicable diagnostic algorithms have been developed.
1. Visceral leishmaniasis: Malaria, histoplasmosis, schistosomiasis, lymphoid and myeloproliferative neoplasms, amebic liver abscess, infective endocarditis, cirrhosis, tuberculosis.
2. Cutaneous leishmaniasis: Bacterial skin infections (contagious impetigo, ecthyma, anthrax, nocardiosis, actinomycosis, yaws, mycobacterioses), dermatomycoses, myiasis, skin neoplasms, other skin diseases (gangrenous dermatitis, nodular prurigo, sarcoidosis, lichen planus).
TreatmentTop
1. Visceral leishmaniasis: Parenteral amphotericin B, pentavalent antimony compounds (sodium stibogluconate, meglumine antimoniate), and oral miltefosine (dosage: see Table 1). Drug susceptibility of Leishmania spp varies depending on the region. Liposomal amphotericin B has the highest efficacy and best safety profile. Paromomycin has also been used to treat visceral leishmaniasis, but currently it is manufactured only in few countries (eg, India). The majority of experts recommend combination treatment in countries endemic for leishmaniasis, which prevents drug resistance and reduces disease duration and treatment costs; however, no universal multidrug regimens have been developed to date.
2. Cutaneous leishmaniasis: In some patients lesions may resolve spontaneously. Treatment facilitates wound healing and decreases the risk of recurrence and development of secondary lesions in other locations. In patients who do not meet the diagnostic criteria for cutaneous complex leishmaniasis (see Table 2), consider topical treatment with pentavalent antimony compounds (0.5-2-mL injection into the skin lesion every 3-7 days for up to 3 weeks) or paromomycin ointment or cream. Systemic treatment is indicated in other cases of localized cutaneous leishmaniasis and in the rare cases of recurrent and diffuse disease; in those patients use oral imidazole antimycotic drugs (ketoconazole, fluconazole, itraconazole, and miltefosine) and parenteral pentavalent antimony compounds and amphotericin B (dosage: see Table 1). Pentamidine is a second-line drug.
Supportive treatment includes cryotherapy and thermotherapy.
ComplicationsTop
Post-kala-azar dermal leishmaniasis (PKDL) is manifested by a maculopapular rash that occurs at 6 months to several years after treatment of visceral leishmaniasis. In some cases macules and nodules resemble leprosy. PKDL has been described in patients from the Horn of Africa and South Asia. In Africa in the majority of cases manifestations are mild and resolve spontaneously. Patients with PKDL may be a source of infection to insects transmitting leishmaniasis.
Special ConsiderationsTop
Visceral leishmaniasis in pregnancy is associated with an increased risk of fetal death and possible congenital infection in a newborn. Treatment includes amphotericin B and pentavalent antimony compounds. Miltefosine is contraindicated in pregnant patients.
Leishmania spp and HIV interfere with similar cell-mediated immune response mechanisms, which negatively affects clinical outcomes in patients with coinfection. Visceral leishmaniasis in patients with HIV infection may follow a severe and/or atypical course, with insufficient response to treatment. The largest number of cases of coexistence of HIV infection and visceral leishmaniasis has been observed in Southern Europe, but this is most likely associated with good access to diagnostic tools and efficient reporting systems. Amphotericin B is a first-line agent for patients with HIV infection and visceral leishmaniasis, but higher doses than normal may be required. Secondary pharmacological prophylaxis is recommended after treatment, particularly in individuals with <200 CD4+ cells/mL. No universal regimens have been established so far.
PrognosisTop
Prognosis in cutaneous leishmaniasis is usually good. In numerous cases in endemic regions lesions resolve spontaneously. Mucosal leishmaniasis may lead to irreversible destruction of the nasal septum, lips, soft palate, and larynx, and carries the risk of secondary bacterial infections, which may be life threatening. Visceral leishmaniasis is a progressive disease. If undiagnosed and left untreated, it may cause death. Prognosis is especially poor in patients with HIV coinfection.
PreventionTop
None.
1. Protection against bites of insects transmitting the parasite.
2. Limiting the reservoir of the parasite, including treatment of infected individuals, also those with PKDL.
Tables and FiguresTop
|
Agent |
Dosage | |
|
Visceral leishmaniasis | ||
|
|
Liposomal amphotericin B |
3 mg/kg IV once daily for 5 days, then after 14 and 21 days from initiation of treatment until the total dose of 21 mg/kg is achieved |
|
Antimony(V) compounds (sodium stibogluconate, meglumine antimoniate) |
20 mg of antimony/kg IV or IM once daily for 28 days | |
|
Miltefosine |
2.5 mg/kg PO in 2-3 divided doses for 28 days | |
|
Cutaneous leishmaniasis | ||
|
|
Fluconazole |
200 mg PO once daily for 6 weeks |
|
Ketoconazole |
600 mg PO once daily for 4 weeks | |
|
Miltefosine |
2.5 mg/kg PO (up to 150 mg) in 3 divided doses for 28 days | |
|
Antimony(V) compounds (sodium stibogluconate, meglumine antimoniate) |
20 mg of antimony/kg IV or IM once daily for 10-20 days | |
|
Liposomal amphotericin B |
3 mg/kg IV once daily for 6-7 days | |
|
Pentamidine isethionate |
Drug of choice (4 mg of salt/kg IV or IM at an interval of 48 h) for cutaneous leishmaniasis caused by Leishmania (Viannia) guyanensis | |
|
IM, intramuscular; IV, intravenous; PO, orally. | ||
|
1. Infection with a Leishmania species associated with risk of mucosal leishmaniasis, mainly in Bolivia, Peru, and Brazil 2. >4 cutaneous lesions sized >1 cm 3. Cutaneous lesions sized ≥5 cm 4. Subcutaneous nodules 5. Enlarged regional lymph nodes (>1 cm) 6. Size or location of skin lesions making treatment difficult 7. Involvement of the face, fingers or toes, genitalia 8. Immunosuppression in the infected individual 9. Unsuccessful topical treatment after 2-3 months of treatment completion |
|
Adapted from Clin Infect Dis. 2016 Dec 15; 63(12): 1539-1557. |
|
ASTMH, American Society of Tropical Medicine and Hygiene; IDSA, Infectious Diseases Society of America. |
Figure 10.9-1. Crusted ulcers on the pinnal surface in cutaneous leishmaniasis.
