Leishmaniasis in infants and children

Leishmaniasis in Infants and Children Murray Wittner, MD, PhD, and Herbert B. Tanowitz, MD Leishmaniasis is a group of diverse diseases caused by hemoflagellate protozoa of the genus Leishmania. These infections are found in the tropical and subtropical world and are transmitted by sandflies. These organisms parasitize macrophages in visceral organs, mucosa, and skin. Three major clinical syndromes are recognized: visceral, cutaneous, and mucocutaneous leishmaniasis. In each of these disease entities, especially visceral leishmaniasis, children often are affected. Leishmaniasis has emerged as an AIDSassociated opportunistic infection in endemic areas, especially in the Mediterranean basin. The diagnosis is based on identification of organisms on biopsy or culture, but molecular and immunologic methods are becoming more accepted. Pentavalent antimony compounds have been the most reliable therapy for leishmaniasis for more than 50 years. However, in recent years other drugs have been found to be efficacious. Copyright 娀 2000 by W.B. Saunders Company

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eishmaniasis consists of a group of diverse diseases that affect viscera, skin, and/or mucous membranes with a wide spectrum of clinical activity caused by vector-borne, obligate, intracellular hemoflagellates of the genus Leishmania.1 Three major clinical syndromes are recognized: visceral (VL), cutaneous (CL), and mucocutaneous leishmaniasis (MCL). The clinical manifestations of leishmaniasis appear to depend on a complex set of factors, including tropism and virulence of the parasite strain and the susceptibility of the host, that may be genetically determined. Each species of Leishmania has wellrecognized clinical variants that cause similar disease patterns in the same host species. Cell-mediated immunity appears to be a major factor modulating these diseases.

Organism Leishmania species are obligate intracellular protozoan parasites. The species infecting humans usually are indistinguishable from one another morphologically at both the light microscopic and ultrastructural levels. The intracellular stage, the amastigote, resides within a parasitophorous vacuole of the macrophage host. They are round or oval bodies ranging from 2 to 4 µm in diameter, possess a single nucleus and kinetoplast, and lack a free flagellum. In this environment, they multiply by binary fission, eventually destroying the host cell. When sandfly vectors feed on infected individuals, they ingest infected cells from blood or tissue. Amastigotes are liberated in the fly’s midgut, and

From the Department of Pathology, Albert Einstein College of Medicine, Bronx, NY. Address correspondence to Murray Wittner, MD, PhD, Professor of Pathology and Parasitology, Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461. Copyright 娀 2000 by W.B. Saunders Company 1045-1870/00/1103-0009$10.00/0 doi:10.1053/pi.2000.6231

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within a few hours, transformation to the promastigote stage occurs. These are elongated flagellates, 15 to 25 µm by 1.5 to 3.5 µm, with an anterior, free flagellum measuring 15 to 28 µm in length. Binary fission then begins, and large numbers of promastigotes are produced that gradually move forward to the pharynx, buccal cavity, and mouthparts. At 8 to 20 days, these organisms are dislodged into the bite wound when the female sandfly (Phlebotomus sp, Lutzomyia sp) next takes a blood meal. Promastigotes have surface molecules that bind to several macrophage receptors. The engulfed promastigotes within the parasitophorous vacuole transform into amastigotes. Transmission is believed to occur by contamination of the bite wound. Once they have been inoculated, many of the promastigotes do not survive because mammalian tissue fluids contain cytolytic substances. Organisms that are phagocytized transform into amastigotes and initiate replication. The parasites are seen readily in tissues or smears by light microscopy, especially with Giemsa or Wright stain. In Novey, MacNeal, Nicolle (NNN) culture medium at 24°C, they grow, assuming the promastigote or insect form. The taxonomic status of the genus is based on molecular biological techniques that have been employed to characterize the strains and species of clinical isolates.

Epidemiology The true incidence of leishmaniasis is not known. However, the World Health Organization (WHO) has estimated that 350 million individuals are at risk and that the disease is endemic in more than 80 countries.2 The estimated incidence of VL is 500,000 cases per year, and for CL and MCL, it is 1.5 million cases per year. Although the parasite most commonly is transmitted via the bite of the sandfly vector, it may be transmitted also as a result of a laboratory accident, direct person-to-person transmission, and blood transfusion. In addition, there is evi-

Seminars in Pediatric Infectious Diseases, Vol 11, No 3 ( July), 2000: pp 196-201

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Leishmaniasis in Infants and Children dence that it may be transmitted either in utero or during the peripartum period.

Visceral Leishmaniasis

often is related to old or eroded termite mounds where adolescents often congregate.

Old World (Cutaneous) Leishmaniasis

VL is caused by various organisms in the L (Leishmania) donovani complex (Table 1). They include L (L) donovani, L (L) chagasi, and L (L) infantum. Recently, strains of L (L) tropica from the Middle East have been found to cause this syndrome. It is transmitted by the sandfly vector, Phlebotomus. VL, or kala-azar, is found in a broad belt that extends from the Mediterranean through Asia to the east coast of China, at a latitude of between 30° and 48°N. Sudan and India account for many cases. In the Western Hemisphere, L (L) chagasi is found in Brazil, northern Argentina, Paraguay, Venezuela, Colombia, Guatemala, and Mexico. A Mediterranean type of VL usually is caused by L (L) infantum. This organism infects infants and young children (1 to 4 years), and dogs, foxes, or feral animals are the reservoirs. In recent years, numerous cases in the pediatric age group have been reported from France3 and Morocco.4,5 This type extends from the Mediterranean littoral through central Asia into China. L (L) chagasi is present in South America, where foxes and dogs are reservoir hosts. L (L) donovani predominates in Indian children between 5 and 15 years of age. Humans are the only known reservoir. An African type of VL exists in which rodents are the reservoir hosts. The Nile rat in the Sudan and probably the gerbil in Kenya are the reservoirs. In Kenya, VL

Old World (cutaneous) leishmaniasis (CL) is caused by L (L) major (rural), L (L) tropica (urban), and L (L) aethiopica. It is found throughout the Middle East, along the Mediterranean basin, Africa, India, and southwestern Asia. In humans, L (L) tropica produces self-limited skin ulcers in which amastigotes are found in macrophages in and about the lesions. These parasites almost never visceralize in humans. Recent reports described L (L) tropica isolates from patients with VL. Jackals, dogs, or rodents are believed to be natural reservoirs of infection. As with VL, various phlebotomine species of sandflies transmit the infection. Contact transmission is possible and is the basis of the long-time practice in middle and central Asia of immunizing with organisms of low virulence, to prevent possible disfigurement by a natural infection. Cutaneous leishmaniasis (CL), or Oriental sore (Delhi boil, Aleppo button), often is classified into ‘‘wet’’ and ‘‘dry’’ types. The wet or rural form is caused by L (L) major and is found chiefly in various rodents on the edge of deserts. The dry or urban type is preponderantly anthropronotic, is caused by L (L) tropica, and is transmitted by sandflies that frequently feed on humans and dogs. The dry or urban form of CL is characterized by a long incubation period, long duration of active infection, and large numbers of parasites in the dermis.

Table 1. Leishmania Infecting Humans and Their Clinical Syndromes, Distribution, Reservoirs, and Vectors Species L. donovani complex L. donovani L. infantum L. chagasi L. tropica complex L. tropica L. major L. aethiopica L. mexicana complex L. mexicana L. amazonensis L. venezuelensis L. braziliensis complex L. braziliensis

Clinical Syndrome

Geographic Distribution

Visceral

India, Pakistan, Nepal SubSaharan Africa, East Africa

Visceral (infantile) Visceral

Mediterranean littoral Central Asia, Middle East China South and Central America

Cutaneous (dry, urban Oriental sore) Cutaneous (moist, rural Oriental sore) Cutaneous; DCL

Middle East, Mediterranean littoral, Southwest Asia Middle East, Southwest Asia, subSaharan Africa Ethiopia, Kenya

Cutaneous; DCL rare Cutaneous; DCL Cutaneous Cutaneous; MCL

L. panamensis L. guyanensis

Cutaneous; MCL rare Cutaneous

L. peruviana

Cutaneous

Abbreviation: DCL, diffuse cutaneous leishmaniasis. Reprinted with permission.32

Major Reservoirs

Major Vectors

Humans Rodent, dog, ? humans Dog, fox Fox, jackal, dog Dog Dog, fox

P. perniciosus, P. major P. caucasicus, P. major P. chinensis, P. sergenti Lutzomyia longipalpis

Dog, humans

P. sergenti, P. papatasi

Gerbil

P. papatasi, P. caucasicus

Hyrax

P. longipes, P. pedifer

Mexico, Guatemala, Belizc Amazon basin of Brazil Venezuela

Rodent Rodent, marsupial Unknown

Lu. olmeca olmeca Lu. flaviscutellata Lu. olmeca bicolor

Brazil, Peru, Ecuador, Bolivia, Venezuela, Paraguay, Colombia Panama, Costa Rica, Colombia Guyana, French Guyana, Surinam, Brazil Peru, Argentina

Rodent

Lu. wellcomei

Sloth Sloth, anteater

Lu. trapidoi Lu. umbratilis

Dog

Lu. peruensis, Lu. verrucarum

Phlebotomus argentipes P. orientalis, P. martini

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By contrast, the moist or rural type has a relatively short incubation period, with rapid healing and few parasites in the skin. L (L) aethiopica is restricted to the mountain valleys of the Rift Valley of Ethiopia and Kenya, where the rock and tree hyraxes are infected regularly. Humans become infected when they intrude into these areas. This form of CL usually is self-limiting, although in a small number of individuals, nonhealing diffuse CL has been reported.

American Cutaneous and Mucocutaneous Leishmaniasis American cutaneous disease is closely tied to the forests of South, Central, and North America, and each variety has its own distinct epidemiological, pathological, and clinical picture. With regard to the American cutaneous forms, two main groups of organisms are distinguished: the L (L) mexicana and L (Viannnia) braziliensis complexes. L (L) mexicana is transmitted by species of sandflies of the genus Lutzomyia. Many rodent reservoir hosts exist. This species is found in Mexico, Guatemala, and Belize. L (V) braziliensis is transmitted by various species of Lutzomyia and Psychodopygus in Brazil and in the forest areas east of the Andes. L (V) guyanesis is transmitted by species of Lutzomyia in Guyana, Surinam, Brazil, and Venezuela.

Clinical Manifestations Visceral Leishmaniasis The clinical prepatent period of VL varies widely (6 weeks to 6 months) but has been reported to be as early as 10 to 14 days and as long as 10 years. A primary skin nodule is observed infrequently, but it is a more regular feature of African leishmaniasis. Infantile VL begins either suddenly with high fevers and vomiting or insidiously with irregular daily fever, anorexia, weight loss, lassitude, and pallor. Double daily spikes are a characteristic sign, with the temperature reaching more than 40°C. Splenomegaly is gradual and evident by the end of the first month. If the symptoms continue unabated, the spleen may extend to the umbilicus or even into the pelvis. Diarrhea or frank dysentery is not unusual, and blood occasionally is observed. A general bleeding diathesis often becomes evident shortly before death. After several months, if the disease is untreated, patients usually die. In less fulminating cases, the clinical course is more protracted, usually ending fatally after a year or two. Infantile VL has been associated with alterations in lipoprotein metabolism.6 As a result of the child’s general debility, death often results from such intercurrent infections as pneumonia, amebic or bacillary dysentery, malaria, or cancrum oris in more than 90 percent of cases. A handful of presumed congenital VL cases have been reported. These infants were born of infected mothers, and in some, evidence of parasitism of the placenta was found. However, whether these cases represent congenital infection or peripartum infection is unclear because sophisticated serological techniques were not available.7,8 In older age groups, the disease tends to assume a more chronic course, with marked emaciation, brittle hair, massive splenomegaly, lymphadenopathy, and a dusky slate-gray complexion. Hyperglobulinemia, leukopenia, eosinopenia, thrombo-

cytopenia, and anemia typically are found. The elevated globulin levels are caused by an increase in IgG. Cutaneous manifestations of kala-azar are encountered frequently. In India, the dark-gray appearance of the skin is known as kala-azar (black sickness). In some cases of inadequately treated VL, a skin condition termed post-kala-azar dermal leishmaniasis may ensue if all parasites are not eradicated. In Indian VL, this complication is encountered in 15 to 20 percent of cases and appears several years after therapy. In African disease, it is much less common, occurring often during therapy in about 2 to 3 percent of cases, and heals spontaneously in a few months. The lesions are characterized by the appearance of hypopigmented, erythematous, or nodular lesions of the skin of the face, chest, neck, and buttocks. At times, the nodular lesions of the face may resemble lepromatous leprosy. The lesions are believed to represent a modified form of L (L) donovani infection in which the parasites no longer invade the viscera and are localized to the skin. These lesions seem to be related to the host’s immune response. This change to dermal tropism is said to coincide with recovery from visceral disease and to disappear with relapse. Infections with L (L) chagasi cause VL in young children. Recently, atypical cutaneous leishmaniasis has been reported in older children with this infection.9 VL is an important opportunistic infection in patients infected with HIV-1.10 Although most of these patients have typical manifestations, atypical presentations are not uncommon. In that regard, splenomegaly may be absent, amastigotes may be found in macrophages of virtually any organ, and aplastic anemia (myelophlistic) has been observed in some cases. In addition, latent infection may become evident after immunosuppression for various reasons, such as chemotherapy for malignant disease. The diagnosis may be particularly difficult inasmuch as the clinical presentation can be atypical with low-grade fever, fatigue, cough, and gastrointestinal complaints. Atypical visceral disease caused by L (L) tropica occurred in individuals who participated in Operation Desert Storm in the Persian Gulf.11 Untreated VL is fatal in 75 to 85 percent of infantile and 90 percent of adult cases. Properly treated at an early stage, 85 to 95 percent of cases can be cured. The prognosis for patients who have pancytopenia or bleeding diatheses or who fail to develop a suitable cell-mediated immunologic response to infection usually is poor.

Old World (Cutaneous) Leishmaniasis The disease caused by L (L) tropica usually begins with a pruritic, red, vesicular papule that appears weeks to months after the bite of a sandfly. The papule gradually enlarges, often measuring 1 to 2 cm in diameter. When the surface of the papule dries, it encrusts and drops off, revealing a shallow ulcer. The ulcer gradually enlarges and characteristically has raised, sharp, indurated margins. Healing usually takes place in 3 to 18 months, often leaving an obvious hypopigmented or hyperpigmented depressed scar. It is not uncommon, however, for single or multiple papules to heal directly without extensive ulceration. If the lesions do not become infected secondarily, usually no complications occur.

Leishmaniasis in Infants and Children

New World Cutaneous and Mucocutaneous Leishmaniasis L (L) mexicana causes Chiclero ulcer, a single cutaneous lesion of the ear that may be self-limited or chronic. This species probably is the cause of the occasional cases of CL in the southern United States. Occasionally, patients have disseminated or diffuse disease. L (V) braziliensis causes destructive ulcerative lesions of the naso-oropharynx as a result of early or late metastases from a more superficial site. It causes single or multiple cutaneous ulcers over many parts of the body. It is believed to spread via lymphatics but does not visceralize. Mucosal involvement may occur in as many as 80 percent of infections, and up to 30 percent of these may eventually mutilate the mucous membranes of the mouth, nose, palate, larynx, and trachea and often are fatal. Lesions of the mucous membranes may occur years after a cutaneous ulcer has healed. Once mucous membrane involvement has become established, infection may be difficult to eradicate. L (V) panamensis causes single to several superficial ulcers that may metastasize along the lymphatics and may metastasize to the naso-oropharynx. L (V) peruviana is found in Peru and causes a single or a few self-healing ulcers known as uta.

Diffuse Cutaneous Leishmaniasis Diffuse cutaneous leishmaniasis (DCL) is uncommon and is associated with L (L) aethiopica infections in Africa and L (L) mexicana or L (L) amazonensis in Latin America. A separate species in the Dominican Republic has been associated with DCL. The initial lesion does not ulcerate, but amastigotes disseminate to skin macrophages, gradually forming nodules or plaques. DCL with visceral dissemination has been described in immunocompromised patients.

Pathology and Pathobiology Visceral Leishmaniasis The principal pathologic lesions of VL are the result of reticuloendothelial cell hyperplasia, especially in the spleen and liver. Bone marrow and lymph nodes are filled with infected macrophages, and a concomitant leukopenia and anemia develop. Kidneys may be filled with the infected macrophages, and invasion of the submucosa and mucosa of the digestive tract, especially in the duodenum and jejunum, results in hypertrophic, congested, and edematous villi. Small ulcerations and hemorrhages may occur. The spleen gradually enlarges, sometimes assuming enormous proportions, eventually extending into the pelvis. Splenic infarcts are common. The splenic capsule is thickened, and more deeply the splenic sinuses are dilated. Erythrophagocytosis results in sequestration of red blood cells. Kupffer cells of the liver are parasitized. Hyperplastic and centrilobular necrosis or fatty infiltration of the hepatic parenchyma often are observed. The bone marrow often is filled with parasitized histiocytes, which replace the normal marrow elements, resulting in a myelophthistic anemia. At the bite wound, a small pea-sized dermal lesion may form (ie, a leishmanioma); the parasites, initially localized in dermal macrophages, disseminate within the macrophages to the spleen,

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liver, bone marrow, and lymph nodes. The outcome of an infection appears to depend on the interaction of the host’s ability to raise a suitable cell-mediated immune response and the virulence of the invading organism. Experimentally, resistance appears to be determined by a single autosomal gene. The genetics of resistance in humans remains undefined but is the subject of intensive investigation. Experimental and human infections are likely controlled by CD4⫹ and CD8⫹ T cells and are related to the production of cytokines12 such as interferon-␥ (IFN-␥). Cytokines activate macrophages to kill intracellular amastigotes by oxidative and nonoxidative mechanisms. Studies in mice indicate that nitric oxide is an important factor in amastigote killing. If the infection is not eliminated by the host’s cellular immune response, it then becomes clinically evident. Within the affected organs, lymphocytogenesis and histiocytogenesis occur, with resultant hepatosplenomegaly and lymphadenopathy. Polyclonal B-cell activation occurs, causing hyperglobulinemia. The increase in IgG is nonspecific and is not protective. Resistance to VL is absent once the infection has become clinically evident. However, after chemotherapy-induced cure, acquired immunity emerges. Thereafter, cell-mediated immunity demonstrated by the Montenegro (leishmanin) skin test becomes evident. However, relapse with post-kala-azar dermal leishmaniasis is characterized by diminished cell-mediated immunity, dermal localization of parasites, and moderate hypergammaglobulinemia. A detailed discussion of the immunology of leishmaniasis is beyond the scope of this review. The reader is referred to recent publications.13,14

Old World (Cutaneous) Leishmaniasis Several forms of CL have been described and seem to be associated with the ability of the patient to develop cellmediated immune mechanisms. Whether these mechanisms are directly responsible for protection in humans remains uncertain. DCL may result from reduced cell-mediated immunity. Characteristically, lesions in DCL are filled with large parasite-containing histiocytes and there is an absence of lymphocytes. At the other extreme, in a small group of patients, cell-mediated immune response to infection with parasites is markedly exaggerated and lesions heal by scarring. At the edge of the scar, new lesions appear, so the disease seems to extend from the margins. Eventually, damage may be rather extensive and organisms are hard to find. This condition is known as leishmaniasis recidivans.

Diagnosis VL is diagnosed by finding the organism in stained smears of spleen aspirate, peripheral blood, or bone marrow.1 In Indian kala-azar, the parasites may be found regularly in peripheral blood monocytes (ie, buffy coat), but in African and Mediterranean forms, they may be difficult to find by this technique. In cutaneous forms of the disease, the biopsy material may be examined histologically and placed into culture. The lesions often are characteristic, so that the diagnosis should be suspected in a patient who has visited an endemic area.

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Blood, tissue, and marrow cultures grow on Novy-MacNealNicolle (NNN) or in Schneider’s insect medium. Serum albumin levels are low, and globulin levels are elevated because of an increase in IgG. Infantile VL has been associated with alterations in lipoprotein metabolism.6 Splenic puncture, bone marrow aspiration, and liver biopsy usually are the most rewarding procedures, although they are not without serious hazard in individuals with a bleeding diathesis. Splenic rather than bone marrow aspiration has been the most rewarding procedure. Contraindications include a soft or enlarging spleen. In children younger than 5 years, only a fully experienced physician should perform this procedure. Spleen and bone marrow aspirates should be placed in culture medium and smeared on slides, and saline-diluted aspirates should be inoculated into the peritoneal cavity of hamsters. Nonspecific tests reflecting the markedly elevated serum globulins, such as the formol gel and Sia water test, are helpful in acute disease and performed in the field. The leishmanin or Montenegro skin test is a measure of a cell-mediated response to leishmanial antigen. In VL, the test remains negative throughout the period of active disease. Once cure is effected, the test becomes positive. Thus, recovery from VL is characterized by the development of cell-mediated immunity. The leishmanin test usually is positive in patients with ulcerated skin lesions. However, a positive leishmanin skin test may help distinguish among a variety of skin lesions. Antileishmanial antibodies usually are present in blood and can be used to aid in the diagnosis. The fluorescent antibody test is highly specific, as are the indirect hemagglutination and gel diffusion tests. The complement-fixation test, however, is positive in only 65 to 70 percent of cases. Sera from patients with VL are known to have false-positive serological reactions when patients have antibodies to other parasites. Fluorescent antibody titers usually decrease after complete cure, so that a negative titer often is regarded as a sign of successful therapy. A positive serological test can occur as a result of past or inapparant infection. Conventional serological tests may be negative in patients with HIV disease. In ML, the fluorescent antibody test using amastigote antigen is most useful, being positive in 75 to 85 percent of cases, with declining titers after therapeutic cure. A direct agglutination test using promastigotes also is used frequently. A DNA-DNA hybridization or ‘‘dot-blot’’ test that is highly sensitive and species-specific in tissue or biopsy specimens has been used. Isozyme analysis of isolated organisms has been utilized to identify the species causing the infection. An enzyme-linked immunosorbent assay (ELISA) test that detects antibodies to a cloned recombinant antigen K39 of L chagasi was reported. The test was specific for active VL15 and detected antibodies in AIDS patients.16 A more recent study showed that the test could be applied to field situations.17

Therapy Visceral Leishmaniasis For many years, the treatment of VL and CL has been with pentavalent antimony agents.18,19 Sodium stibogluconate (Pentostam; Wellcome Foundation, UK) is available through the CDC Drug Service, Centers for Disease Control and Prevention and, generally, in English-speaking countries. Meglumine antimo-

niate (Glucantime; Rhone Poulenc, France) usually is available in French-speaking countries and Latin America. The recommended adult and pediatric dosage of pentavalent antimony is 20 mg/kg/d given IV or IM for 28 days. Pediatric dosing can be according to body surface area when treating children weighing less than 20 kg. Side effects are common. Myalgias and arthralgias are especially common during the latter part of therapy. Nausea, vomiting, headache, anorexia, and abdominal pain also occur. Elevated levels of serum amylase and lipase, indicating pancreatitis, occasionally is encountered and can be severe. Electrocardiogram changes, including decreased T wave amplitude, T wave inversion, prolongation of the corrected QT interval (QTc), and nonspecific ST-T wave changes, are seen. They resolve shortly after therapy has been completed. (Treatment should be discontinued if the QTc interval exceeds 0.5 seconds.) Deaths, presumably caused by arrhythmias, have been reported in patients who were receiving more than 20 mg/kg/d. Children appear to tolerate pentavalent antimonials better than do adults. Primary unresponsiveness, as well as relapses after pentavalent antimony therapy, occurs with all types of VL (ie, L (L) chagasi, L (L) donovani, L (L) infantum) but appears to be more common with the Indian form. In HIV-infected patients, almost 25 percent fail to respond to antimony therapy, and approximately 40 percent of responders relapse.20 Recently, the Food and Drug Administration (FDA) approved liposomal amphotericin B (AmBisome; Fujisawa, Deerfield, IL) for the treatment of VL. Other lipid formulations include amphotericin B lipid complex (Ambelcet; Liposome Company, Princeton, NJ) and amphotericin B cholesterol sulfate (Amphtec; Sequus, Menlo Park, CA).21-23 These compounds are taken up by cells of the reticuloendothelial system, where amastigotes organisms reside, and are less nephrotoxic, allowing for higher daily doses with shorter courses of therapy. The approved recommended regimen for immunocompetent VL patients (adults and children) is 3 mg/kg/d on days 1 through 5, 14, and 21. However, Berman21 recommends that liposomal amphotericin B (AmBisome) be administered on days 1 through 5 and 10 with the following daily doses: 3 to 4 mg/kg/d if the disease was acquired in Europe or Brazil; 3 mg/kg/d if the disease was acquired in Africa; and 2 to 3 mg/kg/d if the disease was acquired in India. Tolerance to these new lipid-amphotericin formulations has been excellent, with relatively few side effects. Treatment of VL in immunosuppressed or HIV-infected patients with amphotericin B lipid complex (AmBisome) has given an almost 100 percent cure rate.20 However, most of these patients relapse. The recommended treatment is 4 mg/kg/d on days 1 through 5, 10, 17, 24, 31, and 38; without maintenance therapy, almost all patients relapse. Because resistance to pentavalent antimonials is widespread in Bihar (India), amphotericin B generally is used and is highly efficacious. Parenteral pentamidine, 4 mg/kg three times weekly, has been used with limited success in antimony-resistant cases of VL. The aminoglycoside, paromomycin, was available in Europe for parenteral use as aminosidine until recently.24 Supplementary cytokine (IFN-␥) therapy along with antimony has been reported to accelerate or augment the healing response.25,26 In a recent clinical trial, miltefosine, an oral alkyl phospholipid initially developed as an oral antineoplastic agent, showed promise as an effective oral treatment of VL in India.27

Leishmaniasis in Infants and Children

Cutaneous and Mucocutaneous Leishmaniasis The prime considerations of whether and how to treat CL or MCL center around whether the patient is at risk of developing mucosal disease; whether the lesion may be cosmetically disfiguring, such as on the face; and whether the patient has multiple spreading or slow-healing chronic lesions. In general, parenteral (IV or IM) antimony provides the most reliable and effective therapy. Oral agents such as ketoconazole have moderate activity against cutaneous infections and have been used to treat small numbers of cases of L (L) mexicana in Guatemala and L (V) panamensis. Itraconazole, which is better tolerated than is ketoconazole, also may be less active. Limited data from Columbia suggest that short-course pentamidine is effective against the Vianna subspecies.28-31 Topical therapy with paromomycin ointment (15% paromomycin and 12% methylbenzethonium chloride in soft white paraffin) has been used for L (L) major in Israel. It may be useful in nonmetastasizing, self-limited cutaneous disease such as that caused by L (L) mexicana. Mucosal disease should be treated with pentavalent antimonials or amphotericin B. In the event of nasopharyngeal compromise with respiratory distress, steroids may be necessary to reduce edema and inflammation.

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