Chapter 351. Leishmaniasis

The leishmaniasis comprise a group of clinical syndromes that include ulcerative skin lesions, destructive mucosal inflammation, and disseminated visceral infection caused by protozoan Leishmania species parasites, which are transmitted through the bite of female sand flies.The infection occurs in nature in a wide range of vertebrate hosts but is particularly common in canids; rodents; and primates, including humans.

Leishmaniasis is caused by an obligatory intracellular protozoan parasite that is of the Leishmania genus and belongs to the order Kinetoplastida and family Trypanosomtidae.4 To date, over 20 different species of Leishmania have reportedly infected humans. These have been grouped in different complexes, according to biochemical and genetic characteristics. Leishmania species traditionally have been classified according to biological, clinical, and epidemiological features as belonging to three major clinical disease groups (Table 351-1).4 Most populations affected by leishmaniasis, either alone or in association with human immunodeficiency virus (HIV) infection, live in developing countries where there is poor access to appropriate medical intervention; this defines leishmaniasis as a neglected disease.

Epidemiology

Worldwide, there are 12 million people infected with Leishmania, and 2 million new infections are reported every year; 1 to 1.5 million with the cutaneous form and 0.5 million with visceral disease. The disease is endemic in over 88 countries of tropical and subtropical regions around the world, including southern Europe, North Africa, the Middle East, the American continent, and the Indian subcontinent.1

The disease is associated with 2.4 million disability-adjusted life years and close to 70,000 deaths per year. Over 90% of the cutaneous form of leishmaniasis occurs in Afghanistan, Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru; 90% of visceral leishmaniasis occurs in India, Bangladesh, Nepal, Sudan, and Brazil.1 In the last two decades, the coinfection of leishmaniasis and HIV has been identified in 35 countries, mainly Mediterranean nations, the North African region, India, and Brazil. The adult group is the most affected, as this coinfection mainly strikes intravenous drug users (IVDU); however, there is evidence of mother-to-child transmission.5,6 Recently, leishmaniasis has gained importance within the United States due to infection of military personnel exposed to endemic areas in the Middle East.7 Global-warming models predict a dramatic rise in the incidence of leishmaniasis due to increase of vector range and propagation.8

Pathophysiology

The Leishmania parasite is transmitted through the bite of female sand flies. Most of Leishmania infections are zoonotic, as nearly all reservoir hosts are wild or domestic mammals, ranging from rodents and marsupials to primates. Humans become infected when accidentally exposed. Only two Leishmania species can maintain anthroponotic, human-human cycle: L donovani, which is responsible for visceral leishmaniasis (VL) in India and East Africa, and L tropica, which is responsible for cutaneous leishmaniasis (CL) in the Old World.5 Occasionally, sand flies are not involved in the transmission, and VL can be directly initiated by amastigotes via blood (shared needles, transfusion, transplacental spread) or organ transplantation.1,2

Leishmania organisms have two stages in their life cycle: (1) the amastigote found within human macrophages, which is the obligate host cell of the parasite, and (2) the promastigote form, found in the lumen of the sand fly gut; this form is injected into the human when the sand fly ingests a blood meal. The amastigote is a nonmotile, round or oval organism measuring 2 to 5 μm and containing a central nucleus and a small rod-shaped kinetoplast associated with a flagellar rudiment. The amastigote multiplies by longitudinal binary fission and spreads to new host cells after destruction of earlier infected cells (Fig. 351-1).1 Sand flies feeding on infected hosts ingest cells containing amastigotes, which rapidly transform into promastigotes; these multiply extracellularly in the lumen of the sand fly gut and progressively change to infective metacyclic promastigotes, which move forward to the pharynx, buccal cavity, and mouthparts of the insect. The promastigote form is 15 to 20 μm in length and 1.5 to 3.5 μm in width and has a single anterior flagellum, a single central nucleus, and a kinetoplast at the anterior end.1

After parasite inoculation into the host skin by an infected sand fly, metacyclic promastigotes rapidly attach to and enter cells of the mononuclear phagocyte system, where they transform into amastigotes that reside and multiply within phagolysosomes.1 Promastigote surface molecules, including the lipophosphoglycan and the glycoprotein gp63, play a key protective role during parasite escape from cytotoxic serum components. They function as ligands for macrophage receptors, facilitate survival within phagolysosomes, and modulate the T lymphocyte immune response.11 Although a clear humoral antibody response is induced during leishmanial infection in humans and experimental hosts, the protective immune response appears to be primarily cell-mediated. Acting in coordination, innate and acquired immune responses dictate overall outcome of infection, including spontaneous healing and prevention of reactivation; in addition, the infecting Leishmania species determine the clinical expression of the disease and the response to treatment.1

Two subsets of CD4+ cells with a distinct profile of cytokine production that influences the outcome of infection have been identified.Accordingly, T lymphocytes that produce interleukin-2 (IL-2) lymphotoxin; tumor necrosis factor-beta (TNF-β); and interferon-γ (INF-γ), which are known as TH1 cells, augment cell-mediated immune responses by activating macrophages to kill or inhibit parasite growth, resulting in resolution of L major infection in C57BL/6 mice.12 A macrophage cytokine, IL-12, promotes the expansion of TH1 cells and induction of INF-γ synthesis from natural killer cells and induces host resistance. On the other hand, T lymphocytes that produce IL-2, IL-4, IL-5, IL-6, IL-10, and IL-13, which promote antibody production, the TH2 cell subset, augment humoral responses and downregulate some cell-mediated immune responses; this leads to disseminated and fatal infection in BALB/c mice.1,11,12

Another mononuclear cell cytokine, transforming growth factor-β, exhibits potent downregulatory effects on macrophage function and influences the T lymphocyte cytokine pattern during Leishmania infection, favoring parasite survival.1 In murine models of disease, innate susceptibility to L major and L mexicana infections segregate according to genes that have been provisionally mapped on mouse chromosomes 11 and 4, respectively. Differences in resistance and susceptibility to L donovani infection are under the control of the Lsh gene, located on chromosome 1.4

In humans, a cell-mediated immune response to Leishmania antigens usually develops during both cutaneous and mucocutaneous diseases, and a direct correlation exists between delayed-type hypersensitivity, level of lymphoproliferative response, production of INF-γ, and healing. In visceral leishmaniasis, there is depression of the cellular immune response, and progression of disease is related to reduced lymphocyte proliferation and decreased production of IL-2 and INF-γ. Anti-Leishmania antibody titers are generally low in the sera of patients with cutaneous and mucocutaneous disease but are moderate to high in patients with visceral leishmaniasis.1 Thus, the spectrum of clinical manifestations associated with human leishmaniasis appears to correlate with differences in humoral and cell-mediated responses. In cutaneous disease, manifestations include diffuse cutaneous leishmaniasis, with multiple skin lesions containing abundant parasites; complete cutaneous anergy; and leishmaniasis recidivans with a low number of parasites and exaggerated hypersensitivity, which is responsible for tissue damage. However, an appropriate lymphocytic response usually develops in self-healing localized cutaneous disease.

Similarly, many cases of visceral leishmaniasis in patients with suitable immune responses are subclinical and self-healing. Following infection, delayed hypersensitivity is usually suppressed, specifically to leishmanial antigens and nonspecifically to tuberculin and other unrelated antigens, and nonspecifically to tuberculin and other unrelated antigens. Specific cellular immunity is regained slowly after successful treatment, and individuals who have recovered are considered immune to reinfection. Protective immunity generally develops only against the homologous species causing the initial infection, although there may be a degree of cross-reactive immunity between species that is not reciprocal.12

Clinical Manifestations and Diagnosis

Visceral Leishmaniasis

Visceral leishmaniasis typically is caused by organisms of the L donovani species complex (L donovani, L infantum, and L chagasi). L donovani is responsible for the disease in India, Bangladesh, Nepal, Sudan, China, Ethiopia, and Kenya; L infantum in the Mediterranean region and Middle East, and L chagasi in Central and South America.1 However, L tropica has been isolated sporadically from patients with typical visceral leishmaniasis or with post-kala-azar dermal leishmaniasis. In countries bordering the Mediterranean shoreline, infection usually occurs in children ages 1 to 4 years. Similarly, in South America, China, and southwest Asia, young children are likewise affected most frequently, but in Africa and India, visceral leishmaniasis is usually a disease of adolescents and young adults; men are infected twice as frequently as women, due probably to greater occupational exposure.1

After inoculation of metacyclic promastigotes by the vector, the infection begins locally in the dermal macrophages at the site of the sand fly bite and disseminates throughout the mononuclear-phagocytic system, particularly to the spleen, liver, bone marrow, and lymph nodes. As a result, after an incubation period ranging from 2 weeks to several months or years, the infection can present with a variety of clinical syndromes that range from asymptomatic infection to disseminated visceral leishmaniasis.1 The onset is generally insidious, with intermittent low-grade fever, sweating, weakness, weight loss, and progressive enlargement of the liver and spleen.1 Fever can be continuous, intermittent, or remittent, often reaching 40°C. In some patients, the course of disease is acute (eg, high fever, chills, malaise), and death can occur within a few weeks, but the disease may follow a subacute or chronic course and may be oligosymptomatic or floridly symptomatic. Anemia is invariably present and often severe and is due to bone marrow infiltration that compromises both the erythropoietic and the granulocytic series. Hypersplenism, autoimmunity, and iron deficiency can also be present.

In addition, jaundice, petechiae, ecchymoses, and purpura can also occur. Some patients have a prolonged illness characterized by nonspecific clinical manifestations or can have weight loss and cachexia, with marked abdominal distention secondary to splenomegaly and hepatomegaly (Fig. 351-2). Femoral and inguinal lymph nodes are moderately enlarged, but generalized lymphadenopathy is rare and can be present in patients only in certain geographic areas (eg, Sudan). Darkening of the skin, especially on hands, feet, abdomen, and forehead, commonly occurs in light-skinned patients, giving rise to the name kala-azar (black fever) in India. In dark-skinned individuals, warty eruptions can develop.1,2 Oral and nasopharyngeal mucosal lesions occasionally occur in patients in India, East Africa, and Sudan, appearing as nodules or ulcers of the gum, palate, tongue, or lip. Lesions of the nasal mucosa can perforate the septum.1,2 Mortality of untreated persons with established disease ranges from 75% to 95%, and death usually occurs within 2 years as a complication of intercurrent bacterial infections, hemorrhage, or progressive emaciation. Bacterial pneumonia can develop as a consequence of severe neutropenia, and pulmonary tuberculosis is a common complication.1,2

Some patients with visceral leishmaniasis develop a syndrome called post-kala-azar dermal leishmaniasis (PKDL), which is characterized by skin lesions (eg, macules, papules, nodules, or patches that are pigmented or depigmented) that typically are most prominent on the face. The syndrome may develop several years after therapy (eg, as has happened in India) or during or within a few months of therapy (eg, as has happened in East Africa). Lesions may be fleeting or persistent and sometimes are associated with relapse of the visceral infection. In settings such as India, where the dermal lesions can be persistent and associated with plentiful parasites, persons with PKDL serve as chronic reservoirs of infection.1

Since the first HIV/VL coinfection case was reported in 1985, the spread and overlap of both infections in the major foci of VL (India, Brazil, and eastern Africa) has become a serious worldwide concern.2 This is because both HIV and VL infection induce a deficit in humoral and cellular immune responses that limit the diagnostic value of serological tests for coinfected patients. In addition, patients with HIV may have a shorter duration of symptoms, a poor response to treatment, a higher rate of relapse after therapy, and higher mortality.1,2 Visceral leishmaniasis is now recognized as an opportunistic infection of HIV-infected individuals, as AIDS patients are at a hundred- to a thousandfold higher risk of visceral leishmaniasis,14 and coinfection generally occurs when patients’ CD4 cell count is less than 200 cells/mm3.2,14Following the introduction of highly active antiretroviral therapy (HAART) in southern Europe, the number of coinfected cases fell sharply, but access to HAART in developing countries, where the problem is expanding, remains inadequate.2

VL can also occur as an opportunistic infection in other immunosuppressed persons, including individuals with renal transplants and hematologic malignancies.15The differential diagnosis for VL includes other parasitic diseases (eg, malaria with tropical splenomegaly syndrome, African trypanosomiasis, and schistosomiasis), as well as mycobacterial and bacterial (eg, miliary tuberculosis, typhoid fever, brucellosis), fungal (eg, histoplasmosis), and noninfectious diseases (eg, leukemia, lymphoma).1,10

Cutaneous Leishmaniasis

Cutaneous leishmaniasis is widely distributed in diverse tropical and subtropical areas of the world. Over 90% of cases occur in Afghanistan, Algeria, Brazil, Iran, Iraq, Saudi Arabia, Sudan, Syria, and Peru.1 This leishmanial syndrome is divided into Old World cutaneous leishmaniasis, which is caused by L tropica (ie, “urban disease”), L major (ie, “rural disease”), and L aethiopica, and American (New World) cutaneous leishmaniasis, which typically is caused by organisms of the L mexicana and L braziliensis species complexes.1,10,16

Cutaneous leishmaniasis of the Old World is caused by L tropica, L major, and L aethiopica, all members of the L tropica complex and transmitted by sand flies of the genus Phlebotomus (P).10,16 New World cutaneous leishmaniasis is a zoonosis caused by members of the L mexicana complex and the subgenus Viannia (V), which are transmitted by sand flies of the genus Lutzomyia (Lu).4 The disease is endemic in the Americas, from southern Texas to most of Central and South America as well as the Caribbean, where it is restricted to tropical and subtropical regions from sea level to altitudes greater than 3600 feet.18,19 The infections occur in persons residing or working in rural areas and in travelers to forested regions (explorers, tourists, scientists, missionaries, hunters, and military personnel).20

Cutaneous leishmaniasis is mostly diagnosed in children between the ages of 2 and 3 years with equal sex distribution in endemic areas, although all ages are susceptible.16 When the illness is present in adult populations, men are infected more frequently than women, probably as a result of occupational exposure. After an incubation period that can range from 3 weeks to 6 months, the first sign of clinical disease appears as a small papule at the site of the sand fly bite, most commonly on exposed areas of the body (ie, face, ears, neck, arms, hands, legs, and feet), rarely on the trunk, and never on the palms, soles, or hairy scalp.1The lesions generally evolve from painless papules to nodules to depressed ulcerative lesions with raised indurate borders but may be persistently nodular16 (Fig. 351-3). Pain, pruritus, and regional adenopathy may develop, depending on the case severity or secondarily to bacterial infection. Independent of the etiologic agent, Old World cutaneous leishmaniasis is self-limited and confers lifelong protective immunity, at least to the homologous strain. New World CL lesions may heal in months to years and may cause an atrophic scar or may migrate through the lymphatic channels to produce distant nodules that cause sporotrichoid-like lesions, as is the case of species of the Viannia subgenus.

In any case, multiple skin lesions can result from the bites of multiple sand flies or can be a local dissemination of infection. Satellite lesions may form near a primary lesion and may ultimately merge with the primary lesion.1,16 On the other hand, dry lesions of L tropica infections are typically single and may not ulcerate. L aethiopica infections resemble the dry form but produce more chronic lesions lasting several years. L mexicana lesions occur on the face and ears (40% to 60% of the cases) and are usually single papules, nodules, or ulcers that heal spontaneously in about 6 months; however, ear lesions (chiclero ulcer) with destruction of the pinna are more persistent.22L (V) braziliensis produces large single or multiple lesions that heal in 6 to 18 months. Both L (V) guyanensis and L (V) panamensis produce multiple skin ulcers and involve lymphatic nodules, occasionally with nasopharyngeal lesions.1,10 Viscerotropic leishmaniasis, caused by L tropica infection was reported in military personnel in Saudi Arabia during Operation Desert Storm and also from Kenya and Israel.23 The differential diagnosis includes pyogenic nodules, insect bites, tertiary syphilis, yaws, tuberculosis of the skin, lupus vulgaris, and leprosy.

Two unusual variants of cutaneous leishmaniasis that cause difficult-to-treat chronic disease are diffuse cutaneous leishmaniasis (DCL), which is an anergic variant with plentiful parasites, and leishmaniasis recidivans, which is a hyperergic variant with scarce parasites.24Diffuse cutaneous leishmaniasis develops in some persons who are infected with L aethiopica or organisms in the L mexicana complex who have specific anergy to leishmanial antigens. This clinical form of leishmaniasis begins as a localized papule and disseminates to cause many persistent, nonulcerative, indurated skin lesions resembling lepromatous leprosy.1The histopathology shows few lymphocytes but abundant parasites in vacuolated macrophages. Leishmaniasis recidivans is a relapsing form of cutaneous disease that has been associated only with L tropica infections; it is found primarily in Iran, Iraq, and neighboring areas.

The lesions often begin on the face and may persist for 20 years or more. Satellite lesions appear at the margins of healing primary lesions, forming small, painless, hard papules. Parasites are rare, the delayed skin-test reaction is positive, and the condition is considered a hypersensitive reaction.16

Mucocutaneous Leishmaniasis

Mucosal leishmaniasis is the metastatic complication of cutaneous leishmaniasis in which nasal, buccal, pharyngeal, and sometimes laryngeal tissues become infected because of lymphatic or hematogenous dissemination of parasites; this occurs in up to 5% of individuals infected with L (V) braziliensis species complex, L panamensis, or L guyanensis. The disease occurs after several months to years (within 2 years of infection in 50% of cases) after the initial cutaneous lesion has healed. This illness should be considered in patients who develop persistent, unusual nasal symptoms such as epistaxis or nasal obstruction. Inflammation of the nasal, pharyngeal, and oral mucosa is followed by progressive ulceration and destruction of the nasal septum, nasal turbinate tissue, palate, lips, pharynx, and larynx. The uvula is swollen and subsequently can be destroyed. Rarely, trachea, bronchi, and esophagus can be involved. Untreated disease can progress to naso-oropharyngeal tract destruction, and patients may die from aspiration pneumonia, starvation, or secondary bacterial infection. Adequate treatment of the original cutaneous lesion(s) is assumed to further reduce the risk of developing metastatic disease. Parasitological confirmation is difficult, because amastigotes typically are scarce. Therefore, the diagnosis commonly is based on the clinical manifestations and on supportive laboratory data (eg, presence of antileishmanial antibodies, positive skin test).24 Differential diagnoses to consider include paracoccidioidomycosis, histoplasmosis, rhinoscleroma, syphilis, tertiary yaws, midline granuloma, sarcoidosis, and neoplasm.

Diagnosis

Visceral Leishmaniasis

The diagnosis of visceral leishmaniasis is confirmed parasitologically by demonstrating the parasite in stained smears (Fig. 351-4) or cultures of a splenic aspirate, bone marrow aspirate, liver biopsy specimen, lymph-node aspirate, biopsy specimen, or buffy-coat preparation. In Indian cases of kala-azar and in HIV-infected patients, parasites may be found more frequently than usual in circulating blood monocytes. Splenic aspiration has a higher diagnostic yield than bone marrow aspiration (ie, as high as 98% vs. 80–85%) and is less painful, but it is also potentially more dangerous.1 The indirect fluorescence antibody test (IFA) is positive in more than 95% of patients. The enzyme-linked immunosorbent assay and the direct agglutination test have sensitivities greater than 90%. Except for some HIV-infected or otherwise immunocompromised persons, as well as some persons who are infected with L tropica, most patients with active visceral infection have moderate to high titers of antileishmanial antibodies. In contrast, delayed-type skin-test reactivity is noted only after recovery.

Using peripheral blood in combination with PCR technique allows the detection of up to one Leishmania-infected macrophage in 8 mL of blood with 90% sensitivity and 100% specificity. In a study of Sudanese patients with visceral leishmaniasis, PCR was able to detect parasite DNA in 37 of 40 (92%) blood samples.1,25

Laboratory abnormalities include pancytopenia and a reversal of the albumin:globulin ratio because of hypergammaglobulinemia (primarily IgG) from a striking polyclonal B-cell activation and hypoalbuminemia. The transaminase values sometimes are modestly elevated. Bone marrow infiltration and hypersplenism partially explain the leukopenia and the anemia, which typically is normochromic and normocytic; Coombs-positive hemolysis, bleeding, and hemodilution also can contribute to the anemia. Patients with leukopenia typically have neutropenia, marked eosinopenia, and a relative lymphocytosis and monocytosis. As visceral dissemination occurs in the context of anergy to leishmanial antigens, the leishmanin skin test is negative and there is a lack of lymphocyte proliferation. On histopathology, the spleen is markedly enlarged and congested, with hyperplasia of reticuloendothelial cells, atrophy of paracortical zones and areas of infarcts, and fibrosis.1,25

Cutaneous and Mucocutaneous Leishmaniasis

For cutaneous leishmaniasis (CL), definitive diagnosis requires microscopic demonstration of the parasite by identification of amastigotes in lesion scrapings, aspirates, and biopsy specimens. Material from the ulcer base usually has the highest yield, but as lesions age, parasitological confirmation becomes more difficult because amastigotes become more scarce. For ulcerative lesions, one should examine multiple Giemsa-stained thin smears of lesion scrapings and should obtain cultures of lesion aspirates or biopsy specimens. Through this technique, the diagnosis can be established with certainty in approximately 70% of persons with CL and in up to 50% of persons with mucocutaneous leishmaniasis (MCL). Parasite culture in biphasic media is technically difficult and may last up to 30 days before becoming positive. However, combining microscopy evaluation and culture increases diagnostic sensitivity to more than 85%.

Species identification of isolated parasites by immunocytochemical methods, isoenzyme analysis, or DNA probes is available in research or in some field laboratories. Specific antibodies can be demonstrated in 70% to 80% of infected individuals by IFA or enzyme-linked immunosorbent assay (ELISA), but antibody levels decline over 4 to 5 months after successful therapy and fail to distinguish between previous and current infection in persons from endemic areas. However, ELISA, based on the detection of Leishmania-specific IgG, may be useful in clinical and epidemiological studies and control programs, as it can detect up to 89% of individuals with cutaneous leishmaniasis.26

The Leishmania skin-test reaction (Montenegro test) is positive in 80% to 100% of persons with cutaneous and mucocutaneous disease within 3 months of infection but is consistently negative in persons with disseminated cutaneous leishmaniasis and localized cutaneous leishmaniasis of less than 1 month in duration. A skin reaction is considered positive if induration is greater than 5 mm in diameter, but such a reaction is not species-specific, and cross-reactions with Trypanosoma and Leptomonas are frequent. This test has limited value in endemic areas, as it cannot distinguish between recent or previous exposure to the parasite.1,24

New approaches for detecting parasites include standard PCR on skin biopsy specimens, on aspirates, or on imprint smears on nitrocellulose paper, but its potential use in routine diagnosis has been hampered by the complexity of the procedures. PCR that uses oligonucleotide primers directed to Leishmania’s minicircle kinetoplast DNA (kDNA) is highly sensitive, as it measures femtogram quantities of DNA. It has a reported sensitivity of 87% and 100% for complex and species identification.24,25 Likewise, identifying parasite species with 95% sensitivity and 100% specificity using skin scrapings collected with a toothpick was demonstrated in Bolivia by using PCR–RFLP.27

A more rapid and highly specific diagnosis can be established with recently developed technologies such as real-time PCR, whereby primer sets coupled with a fluorescent probe allow monitoring of amplification of specific DNA sequences as the reaction occurs. With this method, up to 96% sensitivity was demonstrated on ethanol-preserved tissue of CL patients from Panama.28 Histopathologic analysis is the least sensitive method of diagnosis, although Giemsa staining improves detection over routine hematoxylin and eosin staining. The initial lesion is characterized by a large number of parasitized macrophages and by mild infiltration of granulocytes, mononuclear cells, and eosinophils in association with hyperplasia of the epidermis and necrosis of the dermis. Older lesions may have a heavy infiltration of lymphocytes and plasma cells and a granulomatous reaction with epithelioid, multinucleated giant cells with fewer parasites.1,24

In MC leishmaniasis, lesions show massive necrotizing inflammation with a variable number of lymphocytes, small histiocytes, plasma cells, and few amastigotes. There is an exaggerated, antigen-specific, cell-mediated immune reaction, and levels of serum antibodies are high.24

In diffuse cutaneous leishmaniasis, large numbers of infected mononuclear cells are seen, but lymphocytic infiltration is negligible. Both in vivo and in vitro antigen-specific cell-mediated immune reactions are absent. The antibody response, however, is conserved and often increased. Delayed-type skin-test reactivity to leishmanial antigens that is usually present in persons with simple cutaneous or leishmaniasis recidivans is absent in persons with diffuse cutaneous leishmaniasis.1,24

Treatment

All cases of visceral leishmaniasis and mucocutaneous leishmaniasis must be treated because the disease may be lethal without treatment. The treatment of CL may depend on the geographic distribution, the parasite species involved, and the clinical manifestations, because lesions due to different species vary in both their severity and their response to treatment.29 American CL tends to be more severe and longer lasting than Old World CL, in which case a large number of lesions heal rapidly without treatment. The rate of self-healing depends on several factors, including parasite load and virulence, host immune response, location of the lesion, and the presence or absence of secondary bacterial infection.29 Over 60% to 70% of cases caused by L major heal spontaneously within 3 months.1 In this case, an expectant approach with local care and prevention of bacterial infection may be appropriate for small single and uncomplicated lesions. This approach is particularly pertinent for those patients living in endemic areas, because spontaneous healing is associated with the development of protective immunity. On the other hand, lesions caused by L tropica infection do not self-heal rapidly and can be difficult to treat expectantly.1,29

Local treatment with paromomycin ointment combined with methylbenzethonium chloride seems promising, with a cure rate of 74% to 87% of early noninflamed lesions; however, it might cause local inflammatory reactions.29 Any case of Old World CL lesions on cosmetically or functionally important sites such as the face or hands, and any case in patients with associated lymphangitis, with multiple or persistent lesions, and with compromised immune systems should receive systemic treatment. Small single cutaneous lesions caused by L mexicana infection have a self-cure rate of over 75% at 3 months. However, observation alone has not been assessed formally, and a short 10-day course of parenteral antimonials is recommended.1

In American CL, the crucial step is to decide whether or not a member of the L braziliensis complex could be the infecting organism (ie, likely infection in Belize, Colombia, Costa Rica, Guiana, Honduras, Surinam, Panama, Venezuela, Brazil, the western slopes of the Andes, and the Argentinean highlands), because all such cases must be considered capable of progressing to mucocutaneous disease and therefore require adequate systemic therapy.1,29 Similarly, leishmaniasis recidivans and diffuse cutaneous leishmaniasis must receive systemic treatment.

Pentavalent antimonials (SbV) remain the drugs of choice for all clinical forms of leishmaniasis and for all regions, except for Bihar State in India, where only 35% of cases respond to treatment, and in southern Europe, where liposomal amphotericin B is the preferred drug because of lower toxicity and higher efficacy.1 In the rest of the world regions, two closely related pentavalent antimonials currently are used: sodium stibogluconate (GlaxoSmithKline) and meglumine antimoniate (Glucantime; Sanofi-Aventis).2 The recommended dosage of SbV is 20 mg/kg per day, given intramuscularly (IM) or intravenously (IV) without restricting the daily dose (as was previously done); treatment should last for 20 days in the case of CL and for 28 days in the case of MC and VL. In the United States, sodium stibogluconate is available through the CDC Drug Service (daytime: 404-639-3670; other times: 404-639-2888).10 In Latin America, meglumine may be the drug of choice in the treatment of MCL, as it offers a cure rate of 88%, which is superior to stibogluconate (51%) and similar to amphotericin B.30 Patients should be monitored weekly with serum hepatic enzyme levels and with electrocardiogram twice weekly. Freedom from clinical relapse for at least 6 months of follow-up is the best indicator of permanent cure. Cure rates with antimony therapy range from 80% to 95%, and relapses should be treated with the same drug for at least twice the previous duration.1,10 Patients with VL become afebrile within 4 to 5 days of therapy initiation, and the various hematologic abnormalities and hypoalbuminemia usually improve substantially during therapy; reappearance of eosinophils in the peripheral blood is a good sign. However, laboratory abnormalities may take weeks to months to resolve. Likewise, regression of splenomegaly may take months.

One of the major difficulties with SbV treatment compliance is the frequency and severity of adverse effects, characterized by pain at the injection site, myalgias, arthralgias, abdominal pain, nausea, thrombocytopenia, leukopenia, raised levels of amylase and lipase, and cardiotoxicity with electrocardiographic changes.1

Amphotericin B is the drug of choice for VL in Bihar India and for antimony-resistant mucocutanous disease. A dosage of 0.5 to 1.0 mg/kg daily, or every-other-day IV, for a total dose of 7 to 20 mg/kg is considered to be very effective (98–100% success rate).1,10 Liposomal amphotericin B is the preferred drug to treat HIV/VL coinfected patients; it is used in southern Europe to treat VL of immunocompetent patients because of fewer side effects.1,2 For immunocompetent individuals, the drug is given at a dose of 1 to 3 mg/kg for 5 days and has a cure rate up to 97%. In another study, amphotericin B lipid complex, at a dose of 3 mg/kg administered every other day for five injections, was 100% successful in patients with antimony-resistant kala-azar.1 For HIV/VL coinfected patients, doses of 1 mg/kg per day for a total dose of 20 mg/kg have been effective in up to 88% of cases.2,31 With this regimen, parasitological cure was achieved, and relapses were present most often in patients not receiving antiviral HAART treatment.2

Paromomycin, an aminoglycoside similar to aminosidine, was recently licensed in India to treat VL of immunocompetent patients. An IM dose of 15 mg/kg per day for 21 days achieved a cure rate of 93% to 97%.1,2 This broad-spectrum antibiotic has a good safety profile and is well tolerated; its main side effect is reversible elevation of liver enzymes in 1% of patients. Paromomycin is considered an alternative to amphotericin B in India and a potential substitute for antimony worldwide, due to its high efficacy level, minimum toxicity, and low cost.1,2 Indeed, this antibiotic might be a suitable drug for topical treatment of cutaneous disease, as ointment formulations of 15% paromomycin in combination with 12% methylbenzethonium chloride gave a cure rate of 74% to 85% in Old World CL.1,29

Miltefosine is the first oral treatment for VL, including antimony-resistant infection. A dose of 2.5 mg/kg per day for 28 days gave a cure rate of 94% to 96% for VL in India. However, variable cure rates had been reported for CL in Colombia (91%), Guatemala (53%), Afghanistan (63%), and Bolivia (88%).32,33 The agent is active in adults and children, and common adverse gastrointestinal reactions are transient. However, it has a potential teratogenic effect, which limits its use in pregnant or lactating women and women of childbearing age not taking contraceptives.2

Pentamidine was used to treat VL and CL at a dose of 2 to 4 mg/kg daily, or every-other-day IV or IM, for a total of 15 doses.29 However, the treatment has now been abandoned due to severe side effects (such as irreversible diabetes mellitus in up to 12% of the cases2)and poor efficacy.

Combined therapy of SbV with the immunomodulatory molecule imiquimod is currently under investigation for CL.34 Similarly, sitamaquine, an orally active 8-aminoquinoline analog, is under evaluation for VL treatment.34

Prevention

To date, no effective human vaccines are available, despite the great need due to drug resistance, toxicity of chemotherapy, and the increase of disease incidence in immunocompromised subjects. However, considerable effort has been devoted to vaccine development, generating several candidates based on parasite antigens—such as LACK, LeIF, TSA, LmSTI1, H1, CpA + CpB, KMP11, and NH36—that have proved their effectiveness in animal models.35

As there is no effective form of chemoprophylaxis against Leishmania, and an adequate method of vaccination is not yet available, the control of leishmaniasis depends on the prevalent local epidemiological characteristics. Measures of control include treating infected individuals, reducing reservoir hosts, and spraying to eliminate vector insects.1,37 Where humans are the sole reservoir, as in India, case detection and treatment, followed by DDT spraying for phlebotomine control, help to contain the spread of disease.35 On the other hand, where canines are important reservoirs, identifying, destroying, and replacing infected dogs has not been an effective control method, as new dogs were infected in a short time period.38

Similarly, when rodents or wild animals are involved, control is even more difficult. Vector control using bednets impregnated with pyrethroids or DDT and other residual insecticides had a significant effect in reducing visceral leishmaniasis in many parts of the world, as sand fly bites was reduced at a rate of 64% to 100%.1 Insect repellents, protective clothing, and fine mesh netting can provide temporary protection in areas where leishmaniasis is primarily zoonotic, as in the New World.1 Similarly, deltamethrin-soaked collars for dogs had a protective effect.