LEISHMANIASIS

LEISHMANIASIS

Current Diagnosis

• Infected tissues must be sampled for microscopy demonstration of Leishmania organisms in Giemsa-stained impression smears or cultures. Polymerase chain reaction (PCR) detection of Leishmania DNA increases diagnostic sensitivity.

• Different tissue samplings are performed depending on the clinical form of leishmaniasis: For visceral leishmaniasis, aspirate or biopsy specimens are obtained from spleen, bone marrow, the liver, or enlarged lymph nodes. For cutaneous and mucocutaneous leishmaniasis the material is obtained by skin lesion scraping or biopsy.

• Serology is useful when the diagnosis of visceral leishmaniasis proves difficult with other methods.

Current Therapy

• The therapy of leishmaniasis relies on a limited number of drugs, most of which are old and relatively toxic. Systemic drug administration requires hospitalization and monitoring of the patient.

• The pentavalent antimony (Sb) drugs sodium stibogluconate (Pentostam)10 and meglumine antimoniate (Glucantime)2 are equivalent and used in all clinical forms of leishmaniasis. Dosage is Sb 20 mg/kg/day IM for 21 to 28 days. In cases of uncomplicated cutaneous leishmaniasis, use intralesional administration intermittently over 20 to 30 days.

• Liposomal amphotericin B (Ambisome) is the gold standard for treating visceral leishmaniasis. Dosage: Total dose of 18 to 21 mg/kg IV using one of the following schedules: 3 mg/kg/day on days 1 to 5 and 10; 3 mg/kg on days 1 to 5, day 14, and day 21; 10 mg/kg/day for 2 days.

• Amphotericin B desoxycholate (Fungizone) is used in visceral leishmaniasis1 and mucocutaneous leishmaniasis. Dosage is 0.5 mg/kg IV every other day for 14 days.

• Other parenteral drugs: Pentamidine isethionate (Pentam 300)1 is used to treat some forms of New World cutaneous leishmaniasis; dosage is 2 mg/kg IM every other day for 7 days. Paromomycin (aminosidine) sulfate2 is used for Indian visceral leishmaniasis; dosage is 11 mg/kg/day IM for 21 days.

• Miltefosine (Impavido)5 is recommended for visceral leishmaniasis therapy in India and Ethiopia and for cutaneous leishmaniasis therapy in Colombia and Bolivia. Dosage is 2.5 mg/kg/day (not exceeding 100 mg/day) PO for 28 days.

10 Available in the United States from the Centers for Disease Control and Prevention.

2 Not available in the United States.

1 Not FDA approved for this indication.

5 Investigational drug in the United States.

Epidemiology

Leishmaniases are diseases caused by members of the genus Leishmania, protozoan parasites infecting numerous mammal species, including humans. The flagellated forms (promastigotes) are transmitted by the bite of phlebotomine sand flies and multiply as aflagellated forms (amastigotes) within cells of the mononuclear phagocyte system. The diseases range over the intertropical zones of America and Africa and extend into temperate regions of Latin America, Southern Europe, and Asia. About 20 named Leishmania species and subspecies are pathogenic for humans, and 30 sand fly species are proven vectors. Each parasite species circulates in natural foci of infection where susceptible phlebotomines and mammals coexist. The epidemiology and clinical manifestations of the diseases are largely diverse, being usually grouped into two main entities: zoonotic leishmaniases, where domestic or wild animal reservoirs are involved in the transmission cycle and humans play a role of an accidental host, and anthroponotic leishmaniases, where humans are the sole reservoir and source of the vector’s infection.

Visceral leishmaniasis (VL) is caused by Leishmania donovani in the Indian subcontinent and East Africa (anthroponotic entity) and by L. infantum (L. chagasi) in the Mediterranan basin, parts of Central Asia, and Latin America (a zoonotic entity with domestic dogs acting as the main reservoir host). Several species of Leishmania cause cutaneous leishmaniasis (CL) or mucocutaneous (MCL) leishmaniasis. The most common are L. major (rural zoonotic entity) and L. tropica (urban anthroponotic entity) in the Old World and L. mexicana, L. braziliensisL. amazonensis, L. panamensis, L. guyanensis, and L. peruviana (sylvatic zoonotic entities) in the New World.

Globally, 80 Old World and 21 New World countries are endemic for human leishmaniasis, with an estimated yearly incidence of 0.7 million to 1.2 million cases of CL forms and 0.2 million to 0.4 million cases of VL forms. Overall estimated prevalence is 12 million people with a disability-adjusted life years burden of 860,000 for men and 1.2 million for women. The disease affects the poorest people in the poorest countries: 72 are developing countries, of which 13 are among the least developed. The incidence is not uniformly distributed in endemic areas: 90% of CL cases are found in only seven countries (Afghanistan, Algeria, Brazil, Iran, Peru, Saudi Arabia, and Syria), whereas 90% of VL cases occur in rural and suburban areas of five countries (Bangladesh, India, Nepal, Sudan, and Brazil). These figures, however, must be regarded as underestimates; currently, it appears that the global incidence of human leishmaniases is higher than before, owing to environmental and human behavioral factors contributing to the changing landscape of these diseases.

Risk Factors

Risk factors for leishmaniasis are primarily associated with geographically and temporally defined human exposure to phlebotomine vectors. In the Old World, colonization and urbanization of desert areas have been identified as the major risk factor for outbreaks of zoonotic CL. Tourists and military personnel are often exposed to L. major or L. tropica infections in rural or urban endemic settings of North African and Middle Eastern countries. In the New World, the colonization of the primary forest associated with activities of deforestation, road building, mining, and tourism is responsible for the domestication of sylvatic cycles of CL and MCL agents. Increase in density and geographic range of phlebotomine vectors resulting from climate changes, together with the increased mobility of infected pet dogs, has been identified as a cause of northward spreading of zoonotic VL in Europe.

Individual risk factors play a major role in VL disease. Most of the L. donovani and infantum infections are asymptomatic or subclinical in well-nourished immunocompetent persons. Malnourished persons, infants younger than 2 years, and severely immunosuppressed adults are at high risk for acute VL when exposed to infection. Before the era of HAART (highly active antiretroviral therapy), the AIDS epidemics in southern Europe caused more than 2000 HIV and VL co-infection cases among men aged 39 years on average. Other conditions have been reported that influence the clinical outcome of VL, such as immunosuppressive therapies following organ transplantation, corticosteroid and anti–tumor necrosis factor α (TNF-α) treatments for immunologic disorders, hematologic neoplasia, and chronic conditions of hepatic cirrhosis. However, most acute VL episodes in adults remain unexplained. Other factors associated with impaired immune response to Leishmania (e.g., genetic factors) are probably involved.

Pathophysiology

Ingestion of metacyclic promastigotes inoculated by the vector in the skin is mediated by several types of receptors found in resident macrophages, monocytes, neutrophils, and dendritic cells. Leishmania lipophosphoglycan, the most abundant surface glycoconjugate, is the main factor of virulence. Once in the cell phagolysosome, amastigotes survive from hydrolase activity through pH acidification while selectively inhibiting production of reactive oxygen species.

Multiplication of parasites, infection of new cells, and dissemination to tissues are contrasted by the host’s inflammatory and specific immune responses. Even in most susceptible natural mammal hosts, the majority of infections are efficiently controlled, giving rise to asymptomatic latent infections. Leishmaniases have typical immunological polarity: Cure or control are associated with robust cellular immune responses driven by production of interleukin (IL) 12, whereas acute or chronic diseases are characterized by the absence of such responses and the presence of high levels of nonprotective serum antibodies, a condition often associated with high levels of IL-10 production. In spite of this polarity, analysis of cytokine patterns in tissues reveals a less-polar situation, as both TH1 and TH2 cytokines were found to be secreted in specimens from tissues infected with CL, MCL, and VL.

Prevention

There are no human vaccines available for the immune protection against leishmaniasis. Promising data on safety and immunogenicity have been provided for the only Leishmania candidate vaccine under development, consisting of the recombinant polyprotein antigen LEISH-F1 with MPL-SE as adjuvant. Preventive measures are thus limited to the individual protection from sand fly bites or to community protection through reservoir control. Individual protection is through the use of repellents or insecticide-impregnated nets. Reservoir control measures are largely diverse, depending on the epidemiologic entity of leishmaniasis. Examples related to zoonotic entities with synanthropic reservoir hosts are the destruction of rodent populations around human dwellings (e.g., to control zoonotic CL due to L. major) and the fight against canine infections through the mass use of topical insecticides or drug treatments (e.g., to control zoonotic VL due to L. infantum). Early diagnosis and treatment of human cases is the main control measure against anthroponotic entities of VL (L. donovani) and CL (L. tropica).

Clinical Manifestations

Visceral Disease

VL, also known as kala-azar, results from the multiplication of Leishmania in the phagocytes of the reticuloendothelial system. In endemic settings, the ratio of incident asymptomatic infections to incident clinical cases varies from 4:1 to 50:1 depending on the epidemiologic type (anthroponotic VL is normally more virulent) and the poverty of the affected country. Classic VL manifests as pallor, fever, and hard splenomegaly; hepatomegaly is less common.

Laboratory findings document pancytopenia and hypergammaglobulinemia. The clinical incubation period ranges from 3 weeks (exceptional) to more than 2 years, but 4 to 6 months is average. Patients report a history of fever resistant to antibiotics; on physical examination, the spleen is typically appreciated 5 to 15 cm below the left costal margin. Symptomatic VL is 100% fatal when left untreated.

Cutaneous Disease

CL results from multiplication of Leishmania in the phagocytes of the skin. In the classic course of the disease, lesions appear first as papules, advance slowly to nodules or ulcers, and then spontaneously heal with scarring over months to years. The clinical incubation period ranges from 1 week (exceptional) to several months; lesions caused by L. major and L. mexicana tend to evolve and resolve quickly, whereas those caused by L. braziliensis, L. tropica, and dermotropic strains of L. infantum can have longer periods of incubation and spontaneous healing.

Mucosal Disease

MCL results from parasitic metastasis in the nasal mucosal that eventually extends to the oropharynx and larynx. It can develop from CL lesions caused by L. braziliensis and L. panamensis. Typically, MCL evolves slowly (3 years on average) and does not heal spontaneously.

Diagnosis

The standard diagnosis method for all forms of leishmaniasis is still the microscopy demonstration of Leishmania organisms in Giemsa- stained impression smears or cultures from samples of infected tissues. In general, sensitivity increases when both staining and culture are performed. Polymerase chain reaction (PCR) detection of Leishmania DNA on samples further increases the diagnostic sensitivity and also might allow species identification by target DNA sequencing or restriction fragment length polymorphism analysis.

Different tissue samplings must be performed depending on the clinical form of leishmaniasis. For VL, aspirate or biopsy specimens are obtained from the spleen, bone marrow, the liver, or enlarged lymph nodes. Higher diagnostic yields are obtained with spleen aspirates (more than 98%), although bone marrow aspirates (80% to 98% of yield) are usually preferred. For CL and MCL, material is obtained by scraping tissue juice from a nodular lesion or from the edge of an ulcer or by taking punch biopsies of inflamed tissue.

Diagnostic yields of about 80% are obtained with impression smears and cultures during the first half of the natural course of the lesion. After that, standard parasitologic diagnosis becomes more difficult and PCR remains the only reliable method.

Serology is useful when the diagnosis of VL proves difficult with other methods. Commercially available dipstick tests using recombinant antigen K39 can be employed in decisions for or against treatment. Negative serology results are common in CL and MCL, as well as in VL when patients are severely immunosuppressed.

Differential Diagnosis

Visceral Disease

The differential diagnosis depends on the local disease pattern associated with endemic areas. In many of them it includes chronic malaria, disseminated histoplasmosis, hepatosplenic schistosomiasis, typhoid fever, brucellosis, tuberculosis, endocarditis, relapsing fever, and African trypanosomiasis. Other cosmopolitan diseases include syphilis, lymphomas, chronic myeloid leukemia, sarcoidosis, malignant histiocytosis, and liver cirrhosis.

Cutaneous Disease

A typical history of CL—an inflammatory, slowly developing, and painless skin lesion associated with recent exposure to sand fly bites— can strongly support a clinical diagnosis of disease. However, there is an extensive differential diagnosis, which includes acute or chronic forms of CL. For the former, insect bites, furuncular myiasis, and bacterial tropical ulcers are the most common; for the latter, keloid, lupus vulgaris, discoid lupus erythematosus, and sarcoidosis.

Treatment

The therapy of leishmaniasis relies on a limited number of drugs, most of which are old and relatively toxic compounds. Systemic drug administration requires hospitalizing and monitoring the patient.

Pentavalent Antimonials

Organic salts of pentavalent antimony (Sb) are still the mainstay therapy for all clinical forms of leishmaniasis. Two preparations are available that are equal in efficacy and toxicity when used in equivalent Sb doses: sodium stibogluconate (Pentostam),10 available in English-speaking countries, and meglumine antimoniate (Glucantime),2 available in Southern Europe and Latin America. The recommended dosage of Sb is 20 mg/kg/day for 21 to 28 days, given intramuscularly or intravenously. Treatment should be prolonged for 40 to 60 days in areas with documented Sb-resistant VL (e.g., in Bihar State, India). The drugs can be administered intralesionally in cases of uncomplicated CL, intermittently over 20 to 30 days. Systemic toxicity caused by the antimonials relates to the total dose administered and includes anorexia, pancreatitis, and changes on electrocardiography (e.g., prolongation of the QT interval), which can precede dangerous arrhythmias.

Amphotericin B Drugs

Liposomal amphotericin B (Ambisome) is the current gold standard for VL treatment, being highly effective and nontoxic. However, the high cost of the drug precludes its use in developing countries where leishmaniasis is endemic. Liposomal amphotericin B is given intravenously at the total dose of 18 to 21 mg/kg, with various treatment schedules similarly effective: 3 mg/kg/day on days 1 to 5 and 10; 3 mg/kg on days 1 to 5, 14, and 21; or 10 mg/kg/day for 2 days.

Amphotericin B desoxycholate (Fungizone) is a relatively toxic compound used in Sb-resistant VL1 and MCL, administered intravenously at the low dosage of 0.5 mg/kg every other day for 14 days. Doses in excess of 1 mg/kg/day commonly result in severe infusion-related side effects (fever, chills, and bone pain) and delayed side effects (toxic renal effects).

Other Parenteral Drugs

Other parenteral drugs include old second-line drugs whose use is limited. Pentamidine isethionate (Pentam 300)1 is a toxic compound used to treat some forms of New World CL resistant to Sb therapy and is given intramuscularly at the low dose of 2 mg/kg every other day for 7 days. Treatment in excess of this dosage can result in common side effects such as myalgias, nausea, headache, and hypoglycemia.

Paromomycin (aminosidine) sulfate injection2 (manufactured by Gland Pharma, India, on behalf of Institute of One World Health) is an old aminoglycoside that is being reevaluated as a first-line drug for Indian VL. It is given intramuscularly at the dose of 11 mg base per kg per day for 21 days. Elevation of alanine aminotranferease (ALT) and aspartate aminotransferase (AST) liver enzymes is usually seen during therapy.

Miltefosine, the First Oral Drug for Leishmaniasis

Miltefosine (Impavido)5 is a hexadecylphosphocholine originally developed as an anticancer agent. It is the first recognized oral treatment for leishmaniasis and is available in Germany and India. So far, it is recommended for VL therapy in India and Ethiopia and for CL therapy in Colombia and Bolivia. The drug is administered at 2.5 mg/kg/day (not exceeding 100 mg/day) for 28 days. Miltefosine administration does not require the patient to be hospitalized for monitoring. Mild gastrointestinal toxicity may be common. The drug is contraindicated in pregnancy.

Monitoring

In VL patients, fever recedes by day 3 to 5 of treatment, and well- being returns by the first week. Hematologic indices start to improve during the second week. Hemoglobin, serum albumin, and body weight are the most useful indicators of progress. The spleen tends to normalize 1 to 2 months after the end of therapy, although it can take up to 1 year to regress completely. Parasitologic assessment of cure is not normally necessary. Relapses can occur after apparent clinical cure from 2 to 8 months after treatment has been discontinued.

In CL patients, clinical response to drugs is rapid, but complete reepithelialization of lesions is observed in only one third of patients by the end of 3- to 4-week treatment courses.

References

1.     Alvar J., Aparicio P., Aseffa A., et al. The relationship between leishmaniasis and AIDS: The second 10 years. Clin Microbiol Rev. 2008;21:334–359.

2.    Alvar J. Vélez ID, Bern C, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7:e35671.

3.     Aronson N., Herwaldt B.L., Libman L., et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). Clin Infect Dis. 2016;63:e202–e264.

4.    Berman J.J. Treatment of leishmaniasis with miltefosine: 2008 status. Expert Opin Drug Metab Toxicol. 2008;4:1209–1216.

5.     Bern C., Adler-Moore J., Berenguer J., et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis. 2006;43:917–924.

6.      Bhattacharya S.K., Sinha P.K., Sundar S., et al. Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis. 2007;196:591–668.

7.    Chappuis F., Sundar S., Hailu A., et al. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol. 2007;5:873–882.

8.    González U., Pinart M., Rengifo-Pardo M., et al. Interventions for cutaneous and mucocutaneous leishmaniasis. Cochrane Database Syst Rev. (2):2009 CD004834.

9.       Gradoni L., Soteriadou K., Louzir H., et al. Drug regimens for visceral leishmaniasis in Mediterranean countries. Trop Med Int Health. 2008;13:1272.

10.       Gramiccia M., Gradoni L. The current status of zoonotic leishmaniases and approaches to disease control. Int J Parasitol. 2005;35:1169–1180.

11.    Sundar S., Agrawal N., Arora R., et al. Short-course paromomycin treatment of visceral leishmaniasis in India: 14-day vs 21-day treatment. Clin Infect Dis. 2009;49:914–918.

10  Available in the United States from the Centers for Disease Control and   Prevention.

2  Not available in the United  States.

1  Not FDA approved for this  indication.

2  Not available in the United States

5  Investigational drug in the United  States.

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