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 disease caused by protozoa, and it affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. The global incidence of this infectious disease has increased in recent years because of increased international leisure and military-related travel, human alteration of vector habitats, and concomitant factors that increase susceptibility, such as HIV infection and malnutrition. The recent conflicts in Iraq and Afghanistan have led to more than 1500 laboratory-confirmed cases of cutaneous leishmaniasis and 5 laboratory-confirmed cases of visceral leishmaniasis (VL) in American soldiers alone from 2003-2006. Of course, a larger burden is borne by the local populations of these 2 countries, as well as others, where Leishmania species are endemic and leishmaniasis contributes greatly to morbidity and mortality.

Infection is transmitted by the bite of a sandfly, which is usually one half to one third the size of a mosquito. The clinical spectrum of leishmaniasis ranges from a self-resolving cutaneous ulcer to a mutilating mucocutaneous disease to a lethal systemic illness.

Infection with many different Leishmania species can lead to disease, and the clinical spectrum can be quite broad, from insignificant pustules to fatal systemic disease. General understanding of this clinical spectrum, although once believed to be quite predictable, continues to evolve as new diagnostic techniques continue to add to understanding of the variety of clinical manifestations of an infection with even a single species of Leishmania. Diagnosis is often difficult because of the small size of the protozoa sequestered within macrophages of the skin, bone marrow, and reticuloendothelial system. Therapy has long been a challenge in the more severe forms of the disease and is made more difficult by the emergence of drug resistance. No effective vaccine for leishmaniasis is available.

Pathophysiology

Mammalian reservoirs for leishmanial parasites include rodents, canines, equines, monkeys, sloths, and humans. In mammalian hosts, the organism exists as a nonflagellated amastigote composed of a large nucleus and a kinetoplast, with an absent or greatly reduced flagellum, that resides in the phagolysosome of the macrophage. The vector sandfly, of the genus Phlebotomus in the Old World and of the genus Lutzomyia in the New World, ingests the amastigotes when drawing a blood meal from an infected host. In the gut of the sandfly, the protozoa multiply and transform into flagellated promastigotes.

The promastigotes migrate to the proboscis of the sandfly and are inoculated into the naive host during the insect's next blood meal. The promastigotes enter the new host's macrophages, where they transform back into amastigotes, multiply, and spread throughout the reticuloendothelial system. Clinical disease is apparent within weeks to months after infection.

Similar to Hansen disease, the clinical diversity of leishmaniasis reflects a complex interplay between the virulence of the infecting species and the host's immune response. At one extreme, localized cutaneous disease demonstrates a vigorous immune response, with most cases resolving without intervention. This form of disease exhibits a helper T-cell subtype 1 immune response, with interleukin 2, interferon-gamma, and interleukin 12 as the prominent cytokines that induce disease resolution. At the other extreme, with visceral or diffuse cutaneous disease, patients exhibit relative anergy to the Leishmania organism and have a prominent helper T-cell subtype 2 cytokine profile. The immunomodulation of leishmaniasis has become an area of intense study in the search for new treatments for this disease.

Frequency

United States

Most cases of leishmaniasis in the United States are imported from elsewhere. Sandflies are found in the United States as far north as upstate New York. VL has been identified in foxhounds in a wide geographic distribution in the United States. While endemic human leishmaniasis remains most common in south Texas, isolated cases have been reported as far north as Pennsylvania.

International

Leishmaniasis occurs in temperate and tropical climates in all parts of the world except Australia and Oceania (ie, Pacific islands of Melanesia, Micronesia, and Polynesia). The vast majority of cutaneous cases occur in Afghanistan, Algeria, Brazil, Peru, Iran, Iraq, Syria, and Saudi Arabia, whereas most visceral cases occur in India, Bangladesh, Nepal, Brazil, and the Sudan. The sandfly vector is adept at adjusting to climatic changes and to pressures of human habitation; therefore, vigilant epidemiologic tracking is required to monitor new patterns of disease prevalence.

Mortality/Morbidity

As many as 90% of localized cutaneous forms of leishmaniasis from several parts of the world heal spontaneously with minimal scarring. Disseminated, recidivans, and post–kala azar forms of cutaneous leishmaniasis can be disfiguring cosmetically because of the degree of persistent involvement; however, these forms are not life threatening. Mucocutaneous leishmaniasis (MCL) can result in extensive midfacial mutilation and, occasionally, death resulting from airway or nutritional compromise. VL (kala azar) is a serious, potentially lethal systemic illness. Epidemics of kala azar in impoverished communities can result in death in most of the untreated patients. Kala azar also affects young children much more severely than older children and adults, and kala azar in combination with HIV leads to more severe and rapidly progressive fatal outcomes from both concombinant diseases.

Race

No racial preferences are recognized.

Sex

No clear sex predilections are recognized; however, the prevalence is slightly higher in men than in women, possibly as a result of occupational contact with the sandfly vector.

Age

No specific age susceptibility is known for infection with Leishmania species in general; however, individuals at the extremes of age may be less able to mount effective immune responses to infection and therefore manifest clinical disease more often, especially VL. Leishmania infantum infection produces an infantile form of VL, which can have devastating outcomes for children, particularly for those younger than 1 year. An apparent predilection for the young appears to occur in highly endemic areas because of what may be protective immunity reducing the risk of reinfection in adults.

CLINICAL

Section 3 of 11  

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

History

The discovery of parasites in lesions of cutaneous leishmaniasis or VL was reported in the late 1800s and early 1900s. By the mid 1900s, the transmission and life cycle of the Leishmania organism had been scientifically confirmed. Since that time, many clinical syndromes and numerous (at least 20) morphologically similar species and subspecies of the protozoan have been, and continue to be, discovered. The taxonomy of Leishmania organisms is complex, and no single categorization is generally accepted.

The 2 simplest and most widely used disease categorization systems are based on clinical disease and geographic occurrence, as follows:

• Clinical disease: The 3 primary clinical forms of leishmaniasis are cutaneous, mucocutaneous, and visceral disease. Cutaneous leishmaniasis can be further divided into localized, diffuse cutaneous, recidivans, and post–kala azar dermal leishmaniasis (PKADL).
• Geographic occurrence: Old World leishmaniasis is caused by Leishmania species found in Africa, Asia, the Middle East, the Mediterranean, and India, and it produces cutaneous or visceral disease. New World leishmaniasis is caused by Leishmania species found in Central America and South America, and it produces cutaneous, mucocutaneous, and visceral disease.

The following forms of leishmaniasis have been identified:

• Localized cutaneous leishmaniasis (LCL): Crusted papules or ulcers occur several weeks to months (in rare cases) after sandfly bite inoculation on exposed skin. Lesions may be associated with sporotrichotic spread and usually heal spontaneously.
• Diffuse cutaneous leishmaniasis (DCL): Analogous to lepromatous leprosy, individuals with DCL cannot mount a cell-mediated immune response to the Leishmania parasite. Consequently, patients develop multiple, widespread cutaneous papules and nodules, and they are anergic to leishmanin skin testing (LST).
• Recidivans cutaneous leishmaniasis (RCL): A relatively uncommon clinical variant of leishmaniasis, RCL appears as a recurrence of lesions at the site of apparently healed disease years after the original infection. RCL lesions typically occur on the face, and RCL manifests as an enlarging papule, plaque, or coalescence of papules that heals with central scarring. Relentless expansion at the periphery may cause significant facial destruction similar to the lupus vulgaris variant of cutaneous tuberculosis.  
• PKADL: Endemic to India and the Sudan, this form of leishmaniasis develops months to years after the patient's recovery from VL. Cutaneous lesions demonstrate great variability, ranging from hypopigmented macules to erythematous papules and from nodules to plaques. As in leprosy, the wide clinical spectrum of PKADL reflects the immune response of the individual to the Leishmania organism. Lesions may be numerous and persist for decades. Isolated parasites from the lesions are identical to those that cause the original visceral disease.
• MCL: Predominantly a New World disease, this form of leishmaniasis may not manifest clinically until years after localized cutaneous disease apparently has healed. In a poorly understood manner, certain species of Leishmania migrate to the upper respiratory tract, where relentless destruction of the oropharynx and nose ensues. Gradually, the migration results in extensive midfacial destruction and, occasionally, in death.
• VL (kala azar): Leishmania parasites localize to the reticuloendothelial system, rather than to the skin, and produce a potentially lethal widespread systemic disease.

Physical

LCL usually manifests as a nonspecific ulcer that can mimic many other infectious and noninfectious skin conditions. The vast majority of cases heal spontaneously with scarring and never come to the attention of clinicians. In both the localized cutaneous and mucocutaneous forms of leishmaniasis, cell-mediated immunity to the parasite is vigorous and organism density in the skin and/or mucosa is low, especially in long-standing disease. Therefore, growing organisms in culture can be difficult, as can finding them in pathological specimens. Malnourished individuals are at greater risk of acquiring leishmaniasis and respond less well to treatment than those with adequate nutrition.

Approximately 1-3% of individuals infected by Leishmania brasiliensis, and a smaller percentage of individuals infected by Leishmania panamensis and Leishmania guyanensis, develop mucosal metastases several months to years after the apparent resolution of cutaneous disease. Without treatment, destruction of the oral and nasopharyngeal mucosae is relentless. Symptoms of VL can be confused with many other infectious diseases; however, in endemic areas, the typical patient has wasting and presents with massive splenomegaly, pancytopenia, hypergammaglobulinemia, and intermittent fevers (although they are less acutely ill than patients with malaria).

• LCL: A typical lesion begins as an inflammatory papule, which later progresses to an ulcer. This may be associated with sporotrichotic lymphatic spread. In the vast majority of cases, the ulcers heal spontaneously with scarring.
• DCL: Patients develop hundreds of papules, nodules, and plaques throughout the skin in a clinical picture that can be reminiscent of lepromatous leprosy. This form of leishmaniasis often is resistant to therapy and may assume a chronic course.
• RCL: Typically, psoriasiform plaques occur on the face and progress centrifugally, bearing a striking resemblance to lupus vulgaris. Similar to disseminated disease, RCL may be resistant to therapy and result in a disfiguring clinical picture.
• PKADL: Cutaneous lesions are polymorphous, ranging from hypopigmented or erythematous macules to papules and nodules that may coalesce. Similar to DCL, PKADL closely resembles lepromatous leprosy. Prolonged intensive treatment is required to treat this disfiguring, but usually not lethal, form of leishmaniasis.
• MCL: When left untreated, this form of leishmaniasis gradually spreads and results in extensive midfacial mutilation or, in some cases, in death.
• VL: The hallmarks of this form are fever, malaise, hepatosplenomegaly, anorexia, wasting, pancytopenia, and hypergammaglobulinemia. Occasionally, the skin becomes severely xerotic and hyperpigmented because of melanocyte stimulation. This form of leishmaniasis frequently is lethal if not treated.

Causes

In the vast majority of cases, sandfly bites transmit leishmaniasis; however, infection may be transmitted via a congenital route or through blood transfusions and contaminated needle sticks.

• Cutaneous leishmaniasis
  • Localized cutaneous leishmaniasis
    • Old World -  Leishmania major, Leishmania tropica, Leishmania aethiopica, and L infantum
       
    • New World - Leishmania mexicana, Leishmania venezuelensis, Leishmania amazonensis, L braziliensis, L panamensis, L guyanensis, Leishmania peruviana, and Leishmania chagasi
  • Diffuse cutaneous leishmaniasis
    • Old World - L aethiopica
      
    • New World - L mexicana, L amazonensis, and L venezuelensis
  • Recidivans cutaneous leishmaniasis
    • Old World - L tropica
      
      
    • New World - L braziliensis
  • Post–kala azar dermal leishmaniasis
    • Old World - Leishmania donovani and L infantum
      
      
    • New World - L chagasi
• Mucocutaneous leishmaniasis
  • Old World - L aethiopica (rare) and L major
     
  • New World - L mexicana, L amazonensis, L braziliensis, L guyanensis, and L panamensis
• Visceral leishmaniasis
  • Old World - L infantum, L donovani, and L tropica (rare; also may produce the atypical viscerotropic disease)
    
  • New World - L chagasi

The differential diagnosis of LCL is extensive and includes impetigo, pyoderma gangrenosum, deep fungal infection, mycobacterial infection, sarcoidosis, and squamous cell carcinoma.

DCL and PKADL closely resemble lepromatous leprosy. RCL may mimic cutaneous tuberculosis (lupus vulgaris, tuberculosis verrucosa cutis), psoriasis, deep fungal infection, or nummular dermatitis. MCL may simulate paracoccidioidomycosis, histoplasmosis, syphilis, yaws, rhinoscleroma, squamous cell carcinoma, and midline granuloma of the face.

VL may be confused with a variety of other infectious diseases or febrile systemic illnesses, including schistosomiasis, malaria, tropical splenomegaly syndrome, histoplasmosis, malnutrition, typhoid fever, brucellosis, miliary tuberculosis, lymphoma, leukemia, African trypanosomiasis, and bacterial endocarditis.

Coexisting infectious diseases and/or nutritional deficiencies may significantly impact the severity and outcome of leishmanial infection. In southern Europe, VL is emerging most notably as a serious opportunistic infection in individuals with HIV infection. Co-infection by HIV and leishmanial organisms is particularly common in southern Europe along the Mediterranean, where most adult patients (<70%) with VL have late-stage AIDS. Individuals with HIV infection and leishmaniasis have higher parasite loads, poorer responses to skin testing, lower responses to pentavalent antimony, and higher posttreatment relapse rates than those of their immunocompetent counterparts.

DIFFERENTIALS

Section 4 of 11  

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

WORKUP

Section 5 of 11  

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

Lab Studies

Cutaneous lesions
 
Skin scrapings can be obtained from the base of an active ulcer, or a 4-mm biopsy specimen can be obtained from the edge of a suggestive lesion or ulcer. A diagnosis to the genus Leishmania is made if amastigotes are identified in a touch preparation or histopathology section from cutaneous lesions or in biopsy specimens of infected tissue. Finding an organism in a tissue sample depends on the parasitic burden, the efficacy of the host's immune response, any coexisting bacterial contamination of the ulcer, and the age of the lesion (findings in older lesions are frequently nondiagnostic). The parasite consists of a nucleus and a kinetoplast surrounded by a cell wall. Visualization of all 3 features (ie, nucleus, cell membrane, and kinetoplast) is required to make a diagnosis based on microscopy findings.

Direct visualization of the organism is diagnostic but can be difficult in tissue sections because of its small size (2-4 mm) and because of subtle distinguishing characteristics on routine hematoxylin-eosin stains. Diagnosis is usually much easier using Giemsa-stained touch preparations. Regardless of the method of preparation, identification often requires an experienced pathologist and lengthy searches using high magnification, particularly when organisms are sparse. Giemsa, Brown-Hopps, Gram, or Leishman stains are all used to enhance Leishmania organisms on touch preparations, tissue aspiration, or biopsy samples.
 
The diagnostic sensitivity of microscopic identification of leishmanial amastigotes is typically 75-85% but may vary widely, depending on the size of the inoculum, the clinician's experience in sampling a proper area, the experience of the laboratory personnel in making smears or making tissue sections, and the observer's experience in finding the parasite. Most leishmania experts believe the ideal way to microscopically identify the parasite is with direct touch preparations from the lesion or biopsy tissue stained with Giemsa rather than with routine tissue sections.

Polymerase chain reaction (PCR) is now routinely used in experienced laboratories as a rapid diagnostic technique. Even in remote locations and under harsh conditions, this technique has proven its worth, as evidenced by the US military's recent experience with Leishmania infection in Iraq. Validated genus-specific PCR primers exist, and approval of this assay by the US Food and Drug Administration (FDA) is being sought so it can be used in worldwide facilities certified by the College of American Pathologists.  Species-specific PCR probes allow for rapid speciation in confirmed cases of leishmaniasis, and some are currently undergoing final validation. A word of caution is warranted, however, because many laboratories throughout the world offer species-level PCR diagnostics, but few have undergone the scientific rigor of complete validation necessary to assure accuracy of these species diagnostics. Many of these assays are suspect and may be misleading in their diagnoses.
 
In the United States, FDA approval of these assays should be sought or they should be performed in certified laboratories in order to be confident of the results. Difficult cases should be referred to reference laboratories in the United States for rapid diagnosis and speciation, such as the Walter Reed Army Institute of Research Leishmania Diagnostic Laboratory or the Leishmania Diagnostic Laboratory at the US Centers for Disease Control and Prevention (CDC).

In vitro cultures of tissue are regularly obtained to aid in diagnosis and to help identify difficult Leishmania species. This technique has approximately the same diagnostic sensitivity as that of pathologic evaluation, but special laboratory capabilities and technical skills are required. These are currently available in only 2 reference laboratories in the United States (ie, CDC, Walter Reed Army Institute of Research). The value of this method is that the species of the parasite can be identified on the basis of long-standardized isoenzyme patterns on cellulose acetate electrophoresis after the parasite is grown in vitro using both the New World methods of Kreutzer and the Old World methods of Dedet.

In vivo diagnosis of Leishmania organisms can also be achieved by inoculating clinical specimens into golden hamsters or certain highly susceptible mouse strains. Although results are not available for weeks to months, they are useful in diagnosing the disease, especially in difficult cases.  

Systemic leishmaniasis  

A variety of immunodiagnostic serologic tests have been developed to aid in the diagnosis of systemic leishmaniasis. The only successfully deployed serologic tests are limited to species of Leishmania that cause visceral disease. Limitations include false-negative serologic results due to inadequate titers of antibodies late in the course of the disease and false-positive results in the setting of other infectious or autoimmune diseases.

The most promising serologic test to date is an L chagasi recombinant amastigotes K39 (rK39)–based antigen test system that has been used with an enzyme-linked immunosorbent assay, a direct agglutination test, and even a nitrocellulose dipstick test. The degree of conservation of the K39 gene is high among isolates of the L donovani family, including L chagasi and L infantum. Therefore, this test is useful for most recognized cases of VL. Assays based on rK39 antigen are highly sensitive and specific and have been validated in several large studies worldwide. This currently is the only FDA-cleared rapid serologic test available that has undergone the necessary rigors of scientific testing to reliably trust for diagnosing VL. 

Ancillary tests important in the diagnosis of visceral leishmaniasis include determinations of the CBC count with differential; liver function tests; and lipase, amylase, gamma globulin, and albumin tests.

Other Tests

Skin testing

Similar to the purified protein derivative  test, Montenegro LST has been used for decades to determine previous or current exposure to Leishmania parasites. LST is not used to distinguish between active and resolved disease, but it can be useful in evaluating known naive populations that become immunologically responsive to leishmanial antigens. LST is not applicable to immunologically anergic patients with widely disseminated cutaneous disease. Because LST is not standardized, the FDA has not approved it; therefore, LST is not available as a diagnostic tool in the United States. 

Parasite speciation

Cellulose acetate electrophoresis is a well-standardized method for determining the species of parasites grown from clinical samples. Although this test is standardized, it requires experience and special facilities; therefore,  it is available only in highly specialized diagnostic facilities.

Procedures

Perform biopsy and obtain dermal scrapings and needle aspirates. Obtain bone marrow or splenic aspirates and analyze them for visceral disease.

Histologic Findings

LCL is characterized by irregular acanthosis, with or without epidermal ulceration, and dense dermal infiltrate of mixed inflammatory cells, particularly plasma cells, lymphocytes, and histiocytes. Early in the course of localized disease, organisms may be numerous and found readily in the cytoplasm of macrophages. As the lesion ages and as delayed-type immunity is up-regulated, the infiltrate is replaced by noncaseating granulomata in which few or no organisms can be seen. Ulcerated lesions are often secondarily infected by bacteria, in which case histologic changes may be nonspecific. Results with biopsy specimens obtained from old (>6 mo), partially treated, or low-burden infections are frequently nondiagnostic.

DCL occurs in individuals with poor cellular immunity to Leishmania parasites. Histologic diagnosis is straightforward in these cases. The dermis contains sheets of macrophages containing great numbers of amastigotes, with few lymphocytes or plasma cells.

PKADL has a variable histology that is determined by the degree of host immunity and the parasite load. Granulomatous histology is seen with low numbers of organisms, whereas diffuse histiocytic or xanthomatous infiltrates may be seen with numerous organisms.

RCL is usually difficult to confirm because of the rarity of organisms and because of its histologic similarity to lupus vulgaris.

Aspirates from bone marrow, lymph nodes, or the spleen are typically obtained to make a histologic diagnosis of kala azar. As with diagnosis with skin samples, diagnosis based on these aspirates depends on identification of Leishmania parasites, which are usually plentiful in macrophages.

TREATMENT

Section 6 of 11  

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

Medical Care

Tailor treatment to the individual because leishmaniasis is caused by many species or subspecies of the Leishmania protozoa, all of which have different degrees of virulence and clinical predilections. Consider the clinical pattern of disease, the geographic region in which the infection occurs, the immunologic status of the patient, and the previous attempts at treatment when therapy is started.

Although treatment was previously recommended for every case of leishmaniasis, this is no longer the conventional practice. Treatment must be a balance of risk versus benefit, especially in the case of L major from Iraq, which is generally a self-limited cutaneous illness that heals within 12 months, leaving minimal scarring. For lesions caused by this species, treatment is not generally necessary unless the lesion is in a cosmetically or functionally sensitive site. Cases due to L tropica (another Old World species) and some L major from certain regions of Afghanistan may have a more aggressive or chronic course (up to years); this organism (ie, L tropica) has been implicated in occasional cases of recidivans or viscerotropic leishmaniasis. As such, treatment may need to be more involved in cases caused by this species.

With New World leishmaniasis, as many as 10% of untreated individuals may have recurrences in the form of chronic ulcers, recidivans lesions, or mucocutaneous involvement. Multiple treatment options are used throughout the world. In addition to parenteral and oral medications (see Medication), local therapies for some forms of cutaneous leishmaniasis include (1) cryotherapy, (2) infiltration of sodium stibogluconate at 0.3-0.8 mL, (3) local heat therapy at 40-42°C (one novel FDA-cleared device is called the ThermoMed device; see Thermosurgery Technologies), and (4) various topical paromomycin preparations, typically 15% with 10% urea.

Surgical excision is not usually recommended because of the risk of relapse and the cosmetic disfigurement. In some areas of the world (eg, Russia, Middle East), live attenuated L major promastigotes have been used preemptively to immunize against Old World cutaneous leishmaniasis. This practice produces a modified form of the disease and results in a scar at the injection site. Immunity to subsequent L major infections usually is good; however, as with natural infection, cross-reactive immunity to other Leishmania species does not occur. Many more universally useful and cosmetically acceptable Leishmania vaccine formulations are under investigation. To date, no vaccines are commercially available.

Of primary importance in dealing with leishmaniasis is the treatment of malnutrition, concurrent systemic illness (eg, HIV disease, tuberculosis), or local infection (secondary bacterial). Despite successful clinical outcomes, the question of whether the parasites are completely eradicated is unclear because reactivation of leishmaniasis with immunosuppression has been reported.

Consultations

Consult an infectious disease specialist.

Diet

Advise patients to eat a nutritious diet.

MEDICATION

Section 7 of 11  

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

For 50 years, the mainstay of antileishmanial therapy has been pentavalent antimony (sodium stibogluconate or meglumine antimonate). This was previously used for all forms of the disease; however, recently, liposomal amphotericin B has replaced pentavalent antimony as the drug of choice for visceral disease. Pentavalent antimony is not marketed in the United States, but it can be obtained through the CDC under an Investigational New Drug application for civilian use and is also available at 2 medical centers in the US Department of Defense for military use, also under an Investigational New Drug application. Currently, however, efforts are underway to make this drug more widely available in the United States. VioQuest Pharmaceuticals, a New Jersey–based biopharmaceutical company, in partnership with the US  Army, has been granted orphan drug designation from the FDA with an eye toward licensure and marketing in the near future.

Cure rates for pentavalent antimony are 90-97% with 1-3 full intravenous treatment courses; however, the drawbacks are considerable. These drugs are expensive and difficult to obtain. They must be delivered parenterally, they have numerous adverse effects, they may have lot-to-lot variability, and they are becoming increasingly less effective because of the emergence of drug-resistant parasites (especially in certain countries such as India). In other parts of the world, intralesional injections have shown promise with less toxicity (although with much lower patient tolerability owing to the pain associated with the intralesional injections).

Alternative treatment regimens with acceptable cure rates are pentamidine, paromomycin, interferon-gamma plus antimony, and amphotericin B (and less toxic variations, eg, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion). However, few of these options are used in the United States, except for on antimony-resistant organisms. While much has been made of the use of azoles for the Iraqi L. major cutaneous disease, few practitioners in the field believe this is a prudent consideration for routine treatment of this disease.

Drug Category: Pentavalent antimonials

These are generally considered first-line therapy for cutaneous and mucocutaneous disease.

Drug Category: Antifungals

The major sterol in both Leishmania organisms and fungi is ergosterol. Antiergosterol agents, marketed as antifungals, have activity against Leishmania organisms.

Drug Category: Amebicidals

Paromomycin has a relatively favorable adverse effect profile, but it is not as effective as antimony or amphotericin B for visceral disease when used as monotherapy. Paromomycin can be used in combination with sodium antimony gluconate to reduce the total time of therapy, and it has better cure rates.

Drug Category: Cytokines

Interferon-gamma a T-helper subtype 1 cytokine used to enhance host immunity to Leishmania parasites.

FOLLOW-UP

Section 8 of 11  

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

Further Inpatient Care

In the United States, patients are often monitored as inpatients when pentavalent antimony is administered. Periodically evaluate cardiac conduction with ECG monitoring. Perform laboratory assessments of CBC counts; renal function; and amylase, lipase, and serum transaminases levels.

Alternate drug regimens require variable monitoring levels commensurate with their known adverse effects.

Further Outpatient Care

Disease varies in its response to treatment. Carefully monitor disease progression and resolution.

Deterrence/Prevention

Leishmaniasis is preventable by avoiding contact with the vector. The sandfly is most active from dawn to dusk, it is small enough to fit through standard mosquito netting, it makes no audible noise, and it is a relatively poor flyer. Effective prevention may be achieved by avoiding nighttime outdoor activities, by using topical insecticides (eg, diethyltoluamide [DEET]) on exposed skin surfaces, by using insecticide-impregnated clothing (permethrin stays in or on the material for many washings), by using fine-mesh mosquito netting treated with permethrin, and by sleeping with a fan on. 

Protective immunity after medical treatment or infection is 97-98% effective against disease caused by the same species of Leishmania. Deliberate scarification of the extremities with material from human lesions was once practiced to prevent scarring that may result from a later natural infection of the face. 

The treatment of infected persons and elimination of diseased reservoir vertebrates can reduce the source of infections.

Complications

Secondary bacterial infection may occur. Additionally, leishmaniasis may be disfiguring.

Prognosis

In well-nourished individuals with intact immune systems, recovery is expected after treatment with the appropriate medication.

Patient Education

Behavior modification to avoid vector contact, combined with insect control measures, significantly diminishes the risk of acquiring infection.

MISCELLANEOUS

Section 9 of 11  

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

Medical/Legal Pitfalls

Failure to make a timely diagnosis may result in significant morbidity or in mortality.

MULTIMEDIA

Section 10 of 11  

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

Media file 1:  Sandfly. Courtesy of Kenneth F. Wagner, MD.
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Media file 2:  Life cycle of the Leishmania parasite. Courtesy of the Armed Forces Institute of Pathology, Frank O. Raash†.
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Media file 3:  Cutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
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Media file 4:  Cutaneous leishmaniasis with sporotrichotic spread.
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Media file 5:  Disseminated cutaneous leishmaniasis. Courtesy of Jacinto Convit, National Institute of Dermatology in Caracas, Venezuela.
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Media file 6:  Recidivans leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
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Media file 7:  Post–kala azar dermal leishmaniasis. Courtesy of R. E. Kuntz and R. H. Watten, Naval Medical Research Unit, Taipei, Taiwan.
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Media file 8:  Mucocutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
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Media file 9:  Mucocutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
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Media file 10:  Visceral leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
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Media file 11:  Immunohistochemistry shows Leishmania organisms in macrophages under oil-immersion microscopy (World Health Organization G2D10 anti-Leishmania antibody stain, original magnification X330).
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Media file 12:  Leishmanial amastigotes in a macrophage. Left, Bone marrow aspirate under oil-immersion microscopy (World Health Organization G2D10 anti-Leishmania antibody stain, original magnification X330). Right, Artist's rendition. Courtesy of the Armed Forces Institute of Pathology, Frank O. Raash†.
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Media file 13:  Free amastigotes near a disrupted macrophase. Touch preparations like this (Giemsa stain, original magnification X1000), the amastigotes are easier to identify than on other preparations. These stains clearly demonstrate the cell membrane, nucleus, and kinetoplast; all 3 are required for definitive diagnosis.
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Media file 14:  Free amastigote in a touch preparation (Giemsa stain, original magnification X1000).
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Media file 15:  Classic Leishmania major lesion from a case in Iraq shows a volcanic appearance with rolled edges.
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Media file 16:  Atypical appearance of leishmaniasis major with local spread beyond the borders of the primary lesion. Many of the lesions in cases from Iraq show an atypical appearance.
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Media file 17:  Comparison of a sand fly (left) and a mosquito (right). Their small size affects the efficacy of bed nets when used without permethrin treatment.
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REFERENCES

Section 11 of 11

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

• Berman JD. Human leishmaniasis: clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis. Apr 1997;24(4):684-703. [Medline].
• Herwaldt BL. Leishmaniasis. Lancet. Oct 1999;354(9185):1191-9. [Medline].
• Kenner JR, Aronson NE, Benson PM. The United States military and leishmaniasis. Dermatol Clin. Jan 1999;17(1):77-92, viii. [Medline].
• Kenner JR, Aronson NE, Bratthauer GL, Turnicky RP, Jackson JE, Tang DB, et al. Immunohistochemistry to identify Leishmania parasites in fixed tissues. J Cutan Pathol. Mar 1999;26(3):130-6. [Medline].
• Lesho EP, Wortmann G, Neafie RC, Aronson NE. Cutaneous leishmaniasis: battling the Baghdad boil. Fed Pract. Oct 2004;59-67.
• Magill AJ. Leishmaniasis. In: Strickland GT, ed. Hunter's Tropical Medicine and Emerging and Infectious Diseases. 8^th ed. Philadelphia, Pa: WB Saunders; 2000:665-87.
• Magill AJ. Cutaneous leishmaniasis in the returning traveler. Infect Dis Clin North Am. Mar 2005;19(1):241-66. [Medline].
• Webb JG Jr. Memorandum: Guidance for the Management of Suspected Cutaneous Leishmaniasis in Operation Iraqi Freedom and Operation Enduring Freedom. Fort Sam Houson, Tex: United States Army Medical Command; September 10, 2004.

Article Last Updated: Jul 5, 2007