AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Leishmaniasis is a protozoal disease capable of causing a spectrum of clinical syndromes ranging from cutaneous ulcerations to systemic infections. With the exception of Australia, the Pacific Islands, and Antarctica, the parasites have been identified throughout large portions of the world.

The protozoa are transmitted to mammals via the bite of the female sandfly of the genus Phlebotomus in the Old World and Lutzomyia in the New World. Humans are generally considered incidental hosts. For most species of Leishmania, an animal reservoir is required for endemic conditions to persist. Infections in wild animals are usually not pathogenic, with the exception of dogs, which may be severely affected.

Traditionally divided between Old World and New World parasites, more than 20 pathogenic species have been identified. Common Old World hosts are domestic and feral dogs, rodents, foxes, jackals, wolves, raccoon-dogs, and hyraxes. Common New World hosts include sloths, anteaters, opossums, and rodents.

Although uncommon in the United States, major epidemics currently exist in Afghanistan, Brazil, India, and Sudan. With the increase in international travel, immigration, overseas military exercises, and HIV co-infection, leishmaniasis is becoming more prevalent throughout the world.

Pathophysiology

Leishmaniasis can be divided into cutaneous, mucocutaneous, visceral, and viscerotropic forms. Cutaneous manifestations can be further subdivided into localized, diffuse, leishmaniasis recidivans, and post-kala-azar dermal leishmaniasis.

Parasites exist in the promastigote stage in sandflies and transform to the amastigote form in animal and human hosts. Rare cases of transmission through needle sharing, transfusions, pregnancy, and sexual intercourse have been reported.

Female sandflies can transmit the parasite 7-10 days after feeding on an infected host. The promastigotes migrate from the gut to the proboscis and are regurgitated during the next meal into the new host's tissue.

After inoculation, parasites infect the reticuloendothelial system and live in the intracellular lysosomal organelles of macrophages. Parasites may incubate for weeks to months before presenting as skin lesions or as a disseminated systemic infection involving the liver, spleen, and bone marrow. Pathogenesis appears related to T-cell cytotoxicity.

In India, visceral leishmaniasis caused by Leishmania donovani does not appear to have an animal reservoir and is thought to be transmitted via human-sandfly-human interaction. An animal reservoir for cutaneous leishmaniasis caused by Leishmania tropica has not been identified, although it has been found in some dogs in endemic areas.

The extent and presentation of disease depend on several factors, including the humoral and cell-mediated immune response of the host, the virulence of the infecting species, and the parasite burden. Infections may heal spontaneously or may progress to chronic disease, often resulting in death from secondary infection.

Frequency

United States

Endemic leishmaniasis is uncommon. Periodic cases of localized cutaneous and diffuse cutaneous leishmaniasis have been reported in southern Texas and Oklahoma.¹ The usual reservoir is the wood rat of the Southern Plains, but parasites have been identified in coyotes and domesticated dogs and cats. Spread by the sandfly vector Lutzomyia anthophora, cases are usually associated with exposure to the habitat of the wood rat.

Travelers, government workers, and military personnel from the United States are at risk overseas. Since 2001, more than 700 US military personnel have been diagnosed with cutaneous leishmaniasis and 4 with visceral leishmaniasis after serving in Afghanistan and the Middle East. Up to 1% of US forces serving in the Southwest Asian Theater may have been infected. During the first Persian Gulf War, an estimated 400 cases of cutaneous leishmaniasis and 12 cases of viscerotropic leishmaniasis were reported.² The etiological agent for most of these cutaneous leishmaniasis cases appears to have been Leishmania major.

The Centers for Disease Control and Prevention (CDC) was notified of 129 cases between 1985 and 1990 involving travelers from the United States who acquired the disease abroad. During World War II, more than 1000 cases of cutaneous leishmaniasis were reported among US service members serving in the Persian Gulf. Illnesses now attributed to leishmaniasis have been identified throughout military campaigns from World War I back to antiquity.

International

Leishmaniasis can be found in 88 countries in the intertropical and temperate regions of the world. Visceral leishmaniasis is endemic in 62 countries. The World Health Organization reports an annual incidence of 600,000 cases but estimates up to 1.5 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis occur each year. An estimated 12 million people are infected from a population of 350 million people who are at risk. Of these infections, approximately 25% are of visceral leishmaniasis, most of which come from the Indian subcontinent, Sudan, and Brazil. As of July 2005, an outbreak of a rapidly fatal form of visceral leishmaniasis in Ethiopia is causing concerns for an epidemic in the Horn of Africa. In contrast, most cases of localized cutaneous leishmaniasis come from Afghanistan, Saudi Arabia, Syria, Iran, and the Americas. In Kabul alone, an estimated 67,500 people are thought to be infected with cutaneous leishmaniasis.³

Old World leishmaniasis can be found in the Middle East, Indian subcontinent, Asia, Mediterranean, East Africa, and republics of the former Soviet Union. New World leishmaniasis exists throughout the Americas, with the exception of Canada, Chile, and Uruguay.

Visceral and cutaneous leishmaniasis in patients with AIDS have been increasingly appreciated as a potential opportunistic infection. Co-infection with HIV has been reported in more than 35 countries throughout southern Europe, the Mediterranean Basin, Central and South America, and India. Disease occurs in conjunction with severe immunosuppression. The incidence of co-infection has decreased in developed countries because of the widespread use of antiretroviral therapy.

Mortality/Morbidity

• Localized cutaneous leishmaniasis often spontaneously resolves in 3-6 months without therapy, although some infections persist indefinitely. Most cases of diffuse cutaneous leishmaniasis, post-kala-azar dermal leishmaniasis, and leishmaniasis recidivans are chronic and resistant to treatment and are associated with low mortality rates.
• Mucocutaneous leishmaniasis is chronic and progressive. Death can occur from secondary infection and after respiratory tract mucosal invasion. Respiratory compromise and dysphagia may lead to malnutrition and pneumonia.
• Visceral leishmaniasis is a progressive disease, with the mortality rate ranging from 75-95% if left untreated. With appropriate therapy and supportive care, the mortality rate is decreased to 5%. Death usually occurs from malnutrition and secondary infection. Tuberculosis, pneumonia, and dysentery are commonly implicated.

Sex

• Males have an increased incidence of infection.
• Male-to-female ratios of visceral leishmaniasis have been reported to be around 2:1.
• Males appear to have higher rates of infection because of increased environmental exposure to the habitat of the sandfly through occupation and leisure activity.

Age

• Leishmaniasis affects various age groups depending on the infecting species, geographic location, disease reservoir, and host immunocompetence.
• Visceral leishmaniasis is found in all age groups in India and Brazil, where an animal reservoir has not been identified. In areas with animal reservoirs, such as the Mediterranean Basin, visceral leishmaniasis mainly affects children.
• Cutaneous leishmaniasis affects all age groups. Reports from Afghanistan and Columbia show that adolescents and young adults are at risk the most. In Iran, most cases of the disease are found in infants.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Cutaneous leishmaniasis
• • Both New World and Old World species cause localized cutaneous leishmaniasis. Inoculation occurs after a sandfly bites an exposed part of the body (usually the legs, arms, neck, or face).
  • Incubation occurs over weeks to months followed by the appearance of an erythematous papule, which can evolve into a plaque or ulcer. New World disease usually presents with a solitary nodule, while Old World disease is associated with multiple lesions. Systemic symptoms are absent. Wound progression occurs over time and may exhibit localized lymphangitic spread.
  • Lesions are usually without pain or pruritus, although secondary bacterial infection may complicate the wound. Healing may occur spontaneously from 2-12 months and is followed by scarring and changes in pigmentation. New World disease may progress to mucocutaneous leishmaniasis.
  • Diffuse cutaneous leishmaniasis develops in an anergic host with poor immune response. Infection is characterized by a primary lesion, which spreads to involve multiple areas of the skin. Plaques, ulcers, and nodules may form over the entire body, resembling lepromatous leprosy. However, no neurologic or systemic invasion is involved. Infections are chronic and may recur after treatment. Although more common with New World species in Central and South America, Old World Leishmania aethiopica may progress to diffuse disease in east Africa.
  • Leishmaniasis recidivans may occur years after a localized cutaneous lesion has healed, commonly presenting on the face. New ulcers and papules form over the edge of the old scar and proceed inward to form a psoriasiform lesion. Infection may be from reactivation of dormant parasites or new infection from a different species. Infections tend to be resistant to treatment.
  • Post-kala-azar dermal leishmaniasis has predominantly been described in Africa and India. The Indian variant occurs several years after recovery from visceral leishmaniasis and is characterized by multiple, hypopigmented, erythematous macules. Over time, these can transform into large plaques and nodules that involve the face and trunk. The disease resembles lepromatous leprosy and requires intensive therapy. The African variant occurs shortly after treatment of visceral leishmaniasis and is characterized by an erythematous papular rash on the face, buttocks, and extremities. These lesions spontaneously resolve over the course of several months.
• Mucocutaneous leishmaniasis
• • Mucocutaneous disease is most commonly caused by New World species, although Old World L aethiopica has been reported to cause this syndrome. Infection by Leishmania viannia braziliensis may lead to mucosal involvement in up to 10% of infections depending on the region in which it was acquired. Initial infection is characterized by a persistent cutaneous lesion that eventually heals, although as many as 30% of patients report no prior evidence of leishmaniasis. Several years later, oral and respiratory mucosal involvement occurs, causing inflammation and mutilation of the nose, mouth, oropharynx, and trachea.
  • Progressive disease is difficult to treat and often recurs. With prolonged infection, death occurs from respiratory compromise and malnutrition. Mucocutaneous leishmaniasis may arise after inadequate treatment of certain Leishmania species.
• Visceral leishmaniasis
• • Visceral disease, the most devastating and fatal form, is classically known as kala-azar or black fever. It occurs with both New and Old World species and results from systemic infection of the liver, spleen, and bone marrow. The syndrome is characterized by the pentad of fever, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia.
  • Patients may report night sweats, weakness, and anorexia. Melanocyte stimulation and xerosis can occur, causing characteristic skin hyperpigmentation.
  • The incubation period varies after infection and may depend on the patient's age and immune status and the species of Leishmania. If left untreated, death frequently occurs from immunosuppression and secondary infections.
• Viscerotropic leishmaniasis
• • Viscerotropic disease caused by L tropica has been described in patients returning from the Middle East. These patients presented anywhere from 1 month to 2 years after exposure, with symptoms of malaise, fatigue, intermittent fever, cough, diarrhea, abdominal pain, and other gastrointestinal symptoms.
  • Viscerotropic leishmaniasis has an indolent but distinct clinical presentation and does not appear to progress to full visceral leishmaniasis. L tropica traditionally has been associated with cutaneous leishmaniasis, although several reports of visceral disease have been reported from Kenya, India, and Israel.

Physical

• Cutaneous leishmaniasis
• • The presentation varies depending on the stage of disease. Lesions are usually found in exposed areas. The skin lesion begins as a nontender, firm, red papule several centimeters in size at the site of the sandfly bite. In time, the lesion widens with central ulceration, serous crusting, and granuloma formation. The border often has a raised erythematous rim known as the volcano sign.
  • Lesions may be wet or dry and become fibrotic or hyperkeratotic with healing. Other findings include eczematous, psoriasiform, varicelliform, and verrucous lesions. The area surrounding the primary lesion may exhibit lymphangitic spread with palpable cords and subcutaneous nodules. This is common in New World lesions caused by L viannia braziliensis infections. Satellite lesions may be present. The lesions are generally painless and without pruritus. A generalized inflammatory reaction to migrating parasites may be present in the skin surrounding the sore. Overlying bacterial infection may complicate the natural history. Healing occurs over months to years, leaving a characteristic retracted hypopigmented scar.
  • Diffuse cutaneous leishmaniasis presents with disseminated, nontender, nonulcerating plaques and nodules covering the body similar in presentation to lepromatous leprosy. Generally a chronic disease, it may be resistant to therapy.
  • Leishmaniasis recidivans presents with lesions in the center or periphery of an old healed leishmaniasis scar. New ulcers may form years after the initial infection and often involve the cheek. Over years, these sores advance toward the center of the scar and form a psoriasiform plaque. It is often resistant to treatment.
  • Post-kala-azar leishmaniasis is initially characterized by a malar erythematous rash in conjunction with hypopigmented or reddish macules, following treatment for visceral leishmaniasis. Usually involving the face or trunk, the lesions progress to nontender plaques and nodules. Over time, these lesions join to form large raised growths similar to those of lepromatous leprosy. In Sudan, patients often present with a facial rash consisting of small papules resembling measles that spreads to involve other parts of the body. This syndrome may heal spontaneously, but relapse is common. Established disease is generally difficult to treat.
  • No systemic symptoms are evident.
• Mucocutaneous leishmaniasis
• • The initial skin lesion is often notable for its prolonged healing time and large size. In most cases, a healed scar can be identified based on careful examination. Months to years after the initial infection, patients may have rhinorrhea, epistaxis, and nasal congestion.
  • Examination reveals excessive tissue obstructing the nares, septal granulation, and perforation. Nose cartilage may be involved, giving rise to external changes known as parrot's beak or camel's nose.
  • The palate, uvula, lips, pharynx, and larynx may exhibit granulation, erosion, and ulceration with sparing of the bony structures. Hoarseness may be a sign of laryngeal involvement.
  • Other physical signs include gingivitis, periodontitis, and localized lymphadenopathy. In time, disfiguring facial deformities may occur, requiring plastic surgery. Optical and genital mucosal involvement have been reported in severe cases.
  • Death occurs from suffocation secondary to airway obstruction, respiratory infection, and aspiration pneumonia.
• Visceral leishmaniasis
• • In endemic areas, the diagnosis often is made based on the history and physical examination. Patients present with recurrent high fevers, wasting, anorexia, night sweats, diarrhea, and malaise. Physical examination reveals a patient who is thin and cachetic with abdominal distension and protuberance due to massive hepatosplenomegaly. The liver and spleen are usually soft and easily palpated, and the patient may experience intermittent abdominal distress. Epistaxis and petechiae from severe thrombocytopenia may occur. Lymphadenopathy and hair changes, such as alopecia and eyelash elongation, may be present. Characteristic patchy darkening of the face and trunk has been described. Although uncommon, xerosis may occur. Complications of visceral leishmaniasis include amyloidosis, glomerulonephritis, and cirrhosis.
  • In patients with HIV and visceral leishmaniasis co-infection, other atypical findings include gastrointestinal and respiratory involvement. Patients have presented with gastrointestinal ulcerations, masses, pleural effusions, and odynophagia. Spread outside of the reticuloendothelial system appears more common.
• Viscerotropic leishmaniasis
• • Patients have presented with an array of symptoms months to years after infection, including fever, rigors, fatigue, malaise, nonproductive cough, intermittent diarrhea, headache, arthralgias, myalgias, nausea, adenopathy, transient hepatosplenomegaly, and abdominal pain.
  • This disease does not appear to progress to visceral leishmaniasis.

Causes

• Localized cutaneous leishmaniasis
• • Old World
  • • L donovani - China, India, Bangladesh, Sudan
    • L tropica - Middle East, China, India, Mediterranean
    • L major - Middle East, Africa, India, Asia
    • L aethiopica - Ethiopia, Kenya, Namibia
    • Leishmania infantum - Asia, Africa, Europe
  • New World
  • • Leishmania leishmania mexicana - Central and South America, North America
    • L leishmania amazonensis - Dominican Republic, Central America, South America
    • L leishmania venezuelensis - Venezuela
    • L viannia braziliensis - Central America, South America
    • L viannia guyanensis - Guyana, French Guyana, Surinam, Brazil
    • L viannia panamensis - Costa Rica, Panama, Colombia, Ecuador
    • L viannia peruviana - Peru, Argentina
    • Leishmania donovani chagasi - Texas, Caribbean, Central America, South America
• Diffuse cutaneous leishmaniasis
• • Old World
  • • L aethiopica - Ethiopia, Kenya, Namibia
  • New World
  • • L leishmania mexicana - Central, South America, North America
    • L leishmania amazonensis - Dominican Republic, Central America, South America
• Leishmaniasis recidivans
• • Old World
  • • L tropica - Middle East, China, India, Mediterranean
  • New World
  • • L viannia braziliensis - Central America, South America
• Post-kala-azar leishmaniasis
• • Old World
  • • L donovani - China, India, Bangladesh
    • L infantum - Asia, Africa, Europe
  • New World
  • • L donovani chagasi - Central America, South America
• Mucocutaneous leishmaniasis
• • Old World
  • • L aethiopica - Ethiopia, Kenya, Namibia
  • New World
  • • L viannia braziliensis - Central America, South America
    • L viannia panamensis - Central America, South America
    • L viannia guyanensis - Guyana, French Guyana, Surinam, Brazil
    • Less often seen with L leishmania mexicana - Central America, South America, North America
    • Less often seen with L leishmania amazonensis - Brazil, Panama
• Visceral leishmaniasis
• • Old World
  • • L donovani - China, India, Bangladesh, Sudan
    • L infantum - Asia, Africa, Europe
  • New World
  • • L donovani chagasi - Central America, South America
• Viscerotropic leishmaniasis
• • Old World
  • • L tropica - Middle East

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Cutaneous leishmaniasis

Fungal – Paracoccidioidomycosis, chromoblastomycosis, sporotrichosis, blastomycosis
Bacterial – Staphylococcal and streptococcal infections, pinta, yaws, syphilis, tuberculosis, leprosy, cutaneous diphtheria, tularemia, tropical pyoderma, and other mycobacterioses
Viral - Orf
Inflammatory - Sarcoidosis, pyogenic granuloma, lupus
Neoplastic - Cutaneous T-cell lymphoma, basal cell carcinoma, squamous cell carcinoma, metastases
Psoriasis
Keloids

Mucocutaneous leishmaniasis

Paracoccidioidomycosis
Sporotrichosis
Histoplasmosis
Blastomycosis
Lethal midline granuloma
Carcinoma
Tuberculosis
Tertiary syphilis
Yaws
Rhinoscleroma

Visceral leishmaniasis

Leukemia
Lymphoma
Bacterial, fungal, parasitic, and viral infections, including HIV, malaria, tuberculosis, and typhoid fever

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Historically, the diagnosis of leishmaniasis has been confirmed by isolating, visualizing, and culturing the parasite from infected tissue. Over recent years, significant advances in polymerase chain reaction (PCR) techniques have allowed for the highly sensitive and rapid diagnosis of specific Leishmania species. Although currently limited to military and reference laboratories, leishmania PCR diagnosis is becoming more widely available in developing-world laboratories and field sites.
• Serological detection of antibodies to recombinant K39 antigen using a direct agglutination test, immunofluorescence assay, or enzyme-linked immunosorbent assay (ELISA) have been shown to be highly sensitive and specific in diagnosing visceral leishmaniasis.⁴ Recombinant K39 reactivity appears to correlate with active visceral disease caused by L donovani, L chagasi, and L infantum and is absent in cutaneous and mucocutaneous infections. Recent studies have confirmed its diagnostic utility in India and Brazil but have showed limited utility in Sudan because of regional species variance.^{5, 6, 7}
• Cutaneous and mucocutaneous forms generally display normal laboratory values.
• Visceral leishmaniasis  
• • Complete blood cell (CBC) count: Normocytic normochromic anemia, leukopenia with decreased neutrophils, and thrombocytopenia may occur due to parasitic bone-marrow infiltration. The severity of pancytopenia may vary with only 1 or 2 cell lines decreased.
  • Serum plasma electrophoresis (SPEP): An elevated serum immunoglobulin level with polyclonal spike may be present. Visceral leishmaniasis was traditionally diagnosed based on the addition of formaldehyde to a serum sample, which would increase the viscosity secondary to excessive immunoglobulins.
  • Liver function tests (LFTs): The patient may exhibit mild elevations in alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels.
  • Coagulation panel: Prothrombin and partial thromboplastin times are generally normal.

Other Tests

• Additional investigational diagnostic techniques include monoclonal antibody immunofluorescence, molecular analysis of kinetoplast DNA, rapid diagnostic antibody detection dipstick against rK39 antigen, and ELISA identification of exoantigens. Novel recombinant DNA-derived leishmania proteins are currently under intense review for their use in future rapid diagnostic kits.
• The Montenegro skin test is similar to the purified protein derivative (PPD) and has been used in the developing world to determine delayed-type hypersensitivity reactions. Injected intradermally, a 5-mm area of induration suggests past infection. In most cases, it is made locally from killed promastigotes. It is not approved for use in the United States.

Procedures

• For cutaneous leishmaniasis, take a punch or wedge biopsy sample from a cutaneous sore from the raised edge of an active lesion where parasites are present. Avoid samples from the necrotic center. Additional tissue can be obtained through saline aspiration, tissue scrapings, or slit incisions.
• For mucocutaneous leishmaniasis, tissue can be obtained through dental scrapings or mucosal granuloma biopsy, although parasites may be difficult to isolate.
• For visceral leishmaniasis, the safest way to obtain tissue is through bone-marrow aspiration, although splenic aspiration may be used in cases that are difficult to diagnose. Splenic aspiration has a higher sensitivity but should be attempted only by experienced physicians. Contraindications include low platelet count, abnormal prothrombin time, and a spleen palpable 4 cm or less below the costophrenic angle. Additional tissue can be obtained through liver biopsy and lymph node dissection.
• Once tissue is obtained, send touch preparations, tissue impression slides, and formalin-fixed paraffin sections for hematoxylin and eosin staining. Send touch preparations and aspirations for Giemsa staining, as well. Direct visualization of amastigotes with their red rodlike cytoplasmic kinetoplast is diagnostic and helps distinguish them from other parasites. Brown-Hopps staining has a higher sensitivity than other staining techniques.
• Culture tissue samples and aspirates to aid further in diagnosis and speciation. Specimens may be cultured on Nicolle-Novy-MacNeal (NNN) medium, rabbit blood agar, Schneider Drosophila medium, or a multitude of specialized media to induce promastigote growth. Additional cultures can be performed by inoculating tissue into the footpad and nose of hamsters. Cultures usually take a few days to 2 weeks to demonstrate growth. In animal models, growth may take months. Positive culture results occur approximately 75% of the time.
• With successful culture, the parasite can be sent to specialized facilities or the CDC for PCR, isoenzyme electrophoresis, or monoclonal antibody speciation.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The decision to treat medically depends on various factors. Given the associated morbidity, always treat visceral, mucocutaneous, and severe forms of cutaneous leishmaniasis. Given its potential to progress into mucocutaneous leishmaniasis, definitively treat New World cutaneous leishmaniasis caused by members of the Leishmania viannia subgenus. New World cutaneous leishmaniasis due to Leishmania mexicana is not associated with mucocutaneous leishmaniasis and may not require systemic treatment. Cutaneous leishmaniasis acquired in the Old World tends to resolve spontaneously, but patients with this infection should receive treatment if the lesions are disfiguring, painful, infected, over joints, or slow to heal.

• Therapies available in the United States are limited. The mainstays are the pentavalent antimony compounds first introduced in the 1930s. The 2 available preparations, sodium stibogluconate (Pentostam), produced in Great Britain, and meglumine antimonate (Glucantime), produced in France, have similar efficacy. Depending on the species and region, cure rates of 80-100% have generally been reported.
• • Sodium stibogluconate is available from the CDC as an investigational drug. Military personnel may receive sodium stibogluconate from the Walter Reed Army Medical Center. A 2002 randomized, double-blind, placebo-controlled study of intravenous sodium stibogluconate treatment in cutaneous leishmaniasis validated the efficacy of a 10-day course, with a significantly reduced side-effect profile over the standard 20-day course.⁸ This study included mostly patients infected with Leishmania viannia panamensis, and the results may not be applicable to infections caused by other species of Leishmania.
  • One study in Guatemala that involved a combination of intravenous stibogluconate and allopurinol showed improved efficacy against cutaneous L viannia panamensis infections compared with stibogluconate alone.⁹ However, this effect was not reproduced in the treatment of mucosal leishmaniasis. In many regions of the world, direct intralesional injection of pentavalent antimony is used to treat cutaneous disease, although this can be painful and is technically difficult.
• Other therapies include amphotericin B (AmBisome) and pentamidine.
• • Amphotericin B is effective against pentavalent antimony-resistant mucocutaneous disease and visceral leishmaniasis. Its use is limited because of its toxic adverse effect profile. The newer lipid preparations are better tolerated and are being used as first-line therapy against visceral leishmaniasis, but the response with cutaneous disease has been mixed. AmBisome is the only US Food and Drug Administration (FDA)–approved drug in the United States available for the treatment of visceral leishmaniasis. AmBisome is also useful to treat antimonial-resistant visceral disease. Single-dose treatment with AmBisome has shown a 91% cure rate in India but is still considered too expensive for general treatment.¹⁰
  • Intramuscular pentamidine is effective against visceral leishmaniasis but is associated with persistent diabetes mellitus and disease recurrence. Pentamidine is the drug of choice to treat L viannia guyanensis in French Guyana, where antimonial resistance is prevalent.¹¹
• Orally administered ketoconazole, itraconazole, fluconazole, allopurinol, and dapsone have been examined internationally, but none is as effective as the pentavalent antimony compounds. However, given their minimal adverse effect profile, these agents may be useful in accelerating the cure in patients with cutaneous leishmaniasis that does not progress to mucosal disease and tends to self-resolve.
• • Dapsone was shown to be effective in most cases of Indian cutaneous leishmaniasis after 6 weeks of therapy.¹²
  • Ketoconazole has a variable cure rate for New World cutaneous leishmaniasis, depending on the species. One study showed a 89% cure rate for individuals infected with L mexicana compared with 30% for L viannia braziliensis.⁹ Efficacy against L viannia panamensis in Panama and L major in Iran and Israel has been demonstrated, while no effect was noted against L tropica in India and Turkey.¹³
  • Fluconazole was effective against 79% of patients infected with uncomplicated cutaneous leishmaniasis caused by L major in Saudi Arabia.¹⁴
• The recent discovery of an affordable, orally administered, and well-tolerated therapy for visceral leishmaniasis has made mass treatment in the developing world a reality. Miltefosine is a phosphocholine analogue originally developed as an antineoplastic agent that interacts with membrane synthesis and signal production.  
• • Phase 2 and 3 drug studies in India showed orally administered miltefosine was 95-97% effective in curing patients with Indian visceral leishmaniasis.¹⁵ Oral treatment of 2.5 mg/kg/d lasting 4-6 weeks was generally well-tolerated.
  • Common adverse effects included gastrointestinal distress and elevated creatinine levels, which resolved with cessation of therapy.
  • Treatment of New World cutaneous leishmaniasis has met with variable levels of success. In Columbia, miltefosine treatment cured 91% of infections involving L viannia panamensis, similar to antimony therapy, while curing only 53% of infections involving L viannia braziliensis in Guatemala, well below historic antimony cure rates. However, another study in Bolivia showed oral miltefosine given for 28 days yielded an 82% cure rate compared with 88% for intramuscularly administered meglumine antimonate against L viannia braziliensis.¹⁶ The tolerance for oral miltefosine was so superior to intramuscularly administered meglumine antimonate that the researchers were unable to convince local treating physicians to continue treating the control group with the intramuscular therapy. Research is ongoing to determine which regional strains of New World cutaneous leishmaniasis will respond to oral miltefosine. 
  • The protective effect against subsequent mucocutaneous disease is unknown at this time. One study showed a 75% one-year cure rate among Bolivian patients who presented with mild mucocutaneous leishmaniasis. The particular strain of L viannia braziliensis affected an area known to have antimonial resistance. One-year cure rates were lower among patients with more severe disease. Long-term studies will be required to determine if a definitive cure was achieved.
  • Miltefosine did not prevent visceral relapse in patients co-infected with HIV but remained effective with retreatment and over prolonged periods of therapy.¹⁷
• Sitamaquine is another oral therapy in the research pipeline. Originally discovered by the Walter Reed Army Research Institute, this 8-aminoquinolone is currently undergoing phase 3 trials in Kenya and India.
• Topical paromomycin has been shown to be effective against cutaneous leishmaniasis caused by L major and L leishmania mexicana.
• • Because these species do not tend to cause visceral or mucocutaneous disease, this preparation can spare the patient systemic adverse effects associated with parenteral medications.
  • An ointment that contains 15% paromomycin and 12% methylbenzethonium chloride showed an even higher cure rate of 87% after 20 days of topical treatment for cutaneous L major.¹⁸ Unfortunately, the performance of this cream with infections caused by L tropica has been disappointing. Although not commercially available in the United States, this cream may be available from compounding pharmacies and is currently being used in Israel for the treatment of L major lesions.
  • Topical therapy is not recommended for treatment of New World species that are known to progress to mucocutaneous disease.
• Because Leishmania species are temperature-sensitive, local treatment with heat or cold provides an alternative to pharmaceutical therapy in some cases.  
• • Cryotherapy can be used on small, uncomplicated Old World lesions. A 15- to 20-second freeze-thaw-refreeze cycle repeated as needed over 1-2 weeks was sufficient to cure most cases of uncomplicated L tropica and L major infections.
  • In 2003, the FDA approved the ThermoMed device (ThermoSurgery Technologies, Inc) for the treatment of cutaneous leishmaniasis. This device heats the skin through radiofrequency waves directed to a specified area and depth. A recent study conducted in Afghanistan involving cutaneous disease caused by L tropica demonstrated a cure rate of 69% at 100 days after treatment.¹⁹ Although the lesions treated in this study were small, the initial results look promising. Further studies may demonstrate this to be a useful therapy for mild disease.

Surgical Care

• Severe mucocutaneous leishmaniasis may require orofacial surgery.
• Surgical removal is not recommended for cutaneous disease because of the potential for recurrence at the excision site.
• Surgery may exacerbate quiescent disease.

Consultations

• Given the importance of identifying the specific species, consider consulting an infectious disease specialist or a dermatologist for diagnosis and optimal therapy.

Diet

• Malnutrition has been shown to increase morbidity and mortality in mucocutaneous and visceral disease. Patients should receive nutritious, well-balanced meals.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications, recurrence, and the development of mucocutaneous forms of the disease.

Drug Category: Antiprotozoan

Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.

Drug Category: Antifungals/antiparasitics

When systemic agents are administered, monitor patients for adverse effects and complications common to the drug.

Drug Category: Antineoplastics/antiprotozoan

Miltefosine is a phosphocholine cytidylyl transferase (CTP) inhibitor with antimetastatic properties that induces apoptosis in cancer cells. The antiprotozoal effect is poorly understood.

FOLLOW-UP

Section 8 of 11  

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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Provide supportive care for patients with visceral and severe mucocutaneous leishmaniasis, as required.
• • At the onset of therapy, patients are admitted for laboratory and cardiac monitoring.
  • Use antibiotic therapy to treat superimposed bacterial wound infections.
  • An infectious disease specialist should be consulted for definitive diagnosis and treatment.

Further Outpatient Care

• Perform a follow-up evaluation for patients 6 weeks after last dose.
• Improvement in cutaneous disease is expected within the first couple of weeks.
• Patients with visceral disease should defervesce around 72 hours, with resolution of hepatosplenomegaly by 28 days.
• Severe leishmaniasis recidivans, mucocutaneous leishmaniasis, diffuse cutaneous leishmaniasis, and post-kala-azar leishmaniasis are often difficult to treat and may require prolonged therapy.
• Retreatment or second-line drugs may be required in patients with resistant disease.

Transfer

• Patients should receive treatment at facilities experienced with the use of pentavalent antimony compounds.

Deterrence/Prevention

• After successful treatment, patients generally acquire immunity from the Leishmania species with which they were infected.
• • In some areas of the world, children are superficially inoculated with infected material in concealed areas to induce infection, to promote immunity, and to prevent facial scarring.
  • Attempts to create a viable human vaccine along similar lines have been met with difficulty and have resulted in persistent cutaneous lesions. In May 2005, French researchers from the IRD Montpellier Research Centre successfully developed a novel vaccine against visceral leishmaniasis in dogs.²⁰ Using antigen proteins excreted by the parasite at the 100- and 200-mcg dose, 100% of the dogs (9 of 9) showed immunity over a period of 2 years after infection with L infantum. Immunity appears to be related to activation of the Th1 lymphocytes, allowing macrophages to produce nitric oxide and to clear the leishmania parasites. Researchers postulate that, by reducing the disease burden in dogs, the transmission cycle can be interrupted, indirectly reducing human infections. This new approach is currently being evaluated for incorporation into human vaccines.
• Reservoir eradication, vector control, and mass treatment of individuals who are infected have met with some success but are limited by cost and difficulty in coordinating efforts.
• Insect repellent, protective clothing, and permethrin-impregnated mosquito nets offer some protection for visitors to endemic areas. The female sandfly is small enough to pass through standard mosquito nets, thus requiring specially designed netting.

Prognosis

• Generally, the prognosis is excellent with appropriate therapy.
• Mortality in patients with visceral disease is reduced to approximately 5% with early therapy.
• • Without therapy, most patients with visceral disease die within 2 years.
  • In some endemic regions, pentavalent antimonial resistance is causing increased mortality rates.

Patient Education

• Educate patients about the possibility of recurrent disease and instruct them to schedule follow-ups as needed.
• Education on risk factors and the transmission of leishmaniasis can help reduce disease. Risk factors include the following:
• • Exposure to sandfly habitat
  • Age (depending on infecting species and geographic area)
  • Male sex
  • Adults who are immunologically naïve and entering endemic area
  • Patients who are immunosuppressed (eg, transplant recipients, chronic steroid use, malignancy)
  • Malnutrition
  • AIDS
  • People who use intravenous drugs in endemic areas

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Drug-resistant strains of leishmaniasis are appearing because of the unregulated use of pentavalent antimony compounds. Improper dosing and shortened duration of therapy are contributing factors.

Special Concerns

• The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Old World localized cutaneous leishmaniasis located on the trunk of a soldier stationed in Kuwait. This lesion was a 3-cm by 4-cm nontender ulceration that developed over the course of 6 months at the site of a sandfly bite. The patient reported seeing several rats around his encampment.
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Media file 2:  Old World cutaneous leishmaniasis located on the right arm of the same soldier as in Image 1. This 2-cm by 3-cm lesion was located at the exposed area where the sleeve ended. Note the satellite lesions.
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Media type:  Photo

Media file 3:  Active cutaneous Leishmaniasis lesion with likely secondary infection in a soldier.
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Media type:  Photo

Media file 4:  Cutaneous Leishmaniasis with keloid formation in an African American soldier.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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