eMedicine Specialties > Dermatology > Parasitic Infections

Leishmaniasis

Author: Julie R Kenner, MD, PhD, Consultant, Clinical Research, Medical Affairs, VaxGen, Inc; Private Practice, Kenner Dermatology Center
Coauthor(s): Peter J Weina, MD, PhD, COL, Director, Division of Experimental Therapeutics, Leishmania Diagnostics Laboratory
Contributor Information and Disclosures

Updated: Jul 5, 2007

Introduction

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

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.

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