Introduction
Background
Leishmaniasis is a disease caused by an intracellular protozoa parasite, and it affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. The global incidence of leishmaniasis 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 approximately 2000 laboratory-confirmed cases (and at least double the number of unconfirmed cases) of cutaneous leishmaniasis and 5 laboratory-confirmed cases of visceral leishmaniasis in American soldiers alone from 2003-2008.1,2 In Colombia, the military fighting the Fuerzas Armadas Revolucionarias de Colombia (FARC) has seen more than 30,000 cases of leishmaniasis in the last 3 years. Of course, a significantly larger burden of diseases is borne by the local populations of these countries where Leishmania species are endemic. In these populations, 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 and, depending on the species of Leishmania involved, even a lethal systemic illness.
Sandfly. Courtesy of Kenneth F. Wagner, MD.
Comparison of a sandfly (left) and a mosquito (right). Their small size affects the efficacy of bed nets when used without permethrin treatment.
Infection with different Leishmania species can lead to a remarkably broad range of disease states. The clinical spectrum can range 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 contribute to the elucidation of the variety of clinical manifestations of an infection with even a single species of Leishmania. The particular species associated with certain disease states originally was determined based only on clinical manifestations and location found. In current practice, molecular techniques have shown a very different parasite-to-disease association than was ever appreciated previously.
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.
Also see Leishmaniasis (pediatric focus), Leishmaniasis (infectious disease focus), and Leishmaniasis (emergency medicine focus).
Pathophysiology
Mammalian reservoirs for the Leishmania parasite include rodents, canines, equines, monkeys, sloth, 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 is the sandfly, of the genus Phlebotomus in the Old World and of the genus Lutzomyia in the New World, and they ingest amastigotes when drawing a blood meal from an infected host. In the gut of the sandfly, the parasite transforms into flagellated promastigotes and multiplies.
Promastigotes in the gut of the sandfly migrate to the proboscis and are inoculated into a naive host during the insect's next blood meal. The promastigotes enter into or are ingested by the new host's macrophages, where they transform back into amastigotes, multiply, and eventually spread throughout the reticuloendothelial system. Clinical disease becomes apparent within weeks to months after infection, depending on the species of parasite and the host’s immune status.
Similar to the clinical diversity seen in Hansen disease (leprosy), leishmaniasis reflects a complex and still poorly understood 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 the 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.
Taxonomy of some of the medically important protozoans showing the relative relationship of the Kinetoplastida parasites generally, and Leishmania specifically.
Life cycles of the medically important Kinetoplastida illustrating the similarities and differences between the trypanosomes and Leishmania.
Frequency
United States
Most cases of leishmaniasis in the United States are imported from elsewhere. Predominately, the disease has traditionally been seen in graduate students and Peace Corps workers living in endemic areas for extended periods and returning to the United States after their studies or work abroad. Recently, however, the largest burden has been from returning veterans of Operation Iraqi Freedom.
Classic Leishmania major lesion from a case in Iraq shows a volcanic appearance with rolled edges.
Atypical appearance of Leishmania major lesion with local spread beyond the borders of the primary lesion. Many of the lesions in cases from Iraq show an atypical appearance.
Although sandflies are found in the United States as far north as upstate New York, and visceral leishmaniasis has been identified in foxhounds in a wide geographic distribution in the United States, virtually no human transmission is believed to occur in the majority of the United States (outside of Texas). The occurrence of 9 cases of Leishmania mexicana cutaneous leishmaniasis was described at the end of 2007. While endemic human leishmaniasis remains most common in Texas, isolated cases have been reported as far north as Pennsylvania, with no associated travel outside the patient’s home.
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). Leishmaniasis is known to exist in at least 88 different countries, with at least 350 million people at risk of acquiring the disease. The vast majority of cutaneous leishmaniasis cases occur in Afghanistan, Algeria, Brazil, Peru, Iran, Iraq, Syria, and Saudi Arabia, whereas most visceral leishmaniasis cases occur in India, Bangladesh, Nepal, Brazil, and the Sudan.3 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. This is not to say that the disease is without morbidity, especially in areas where even minimal facial disfiguring can condemn young girls to life without the prospect of marriage or acceptance in society. Even worse, these are areas of the world that have the highest burden of disseminated, recidivans, and post–kala-azar forms of cutaneous leishmaniasis. These forms can be exceedingly disfiguring cosmetically because of the degree of persistent involvement; however, these forms are not life threatening.
While cutaneous leishmaniasis is generally considered to be an innocuous disease, this illustrates that in some parts of the world, especially in tribal areas, even cutaneous disease can have a life altering effect on a person's life.
Mucocutaneous disease affecting the mucous membranes of the mouth, nose, and soft palate is especially debilitating and destructive. Found only in the New World and principally in South America, mucocutaneous leishmaniasis can result in extensive midfacial mutilation and, occasionally, death resulting from airway or nutritional compromise.
Visceral leishmaniasis (kala-azar) is a serious, potentially lethal systemic illness. Epidemics of kala-azar in impoverished communities can result in death in the majority of untreated patients. The fairly significant asymptomatic-to-symptomatic ratio varies from approximately 19:1 to even higher in some studies. The disease tends to affect individuals in poor states of health, with poor nutritional status, and with even the most minor decreased immune status much more severely than individuals with good health, good nutritional status, and intact immune systems.
For some of the same reasons, kala-azar also affects young children much more severely than older children and adults. Almost all visceral leishmaniasis infections, for example in Iraq, occur in children younger than 5 years and the most occur children younger than 1 year. Additionally, a well-described and feared interaction is kala-azar in combination with HIV infection, which leads to more severe and rapidly progressive fatal outcomes from both diseases acting synergistically.
Race
No racial preferences are recognized or described. Some minor associations with various racial groups have been noted, but these are confounded by and a result more strongly associated with occupational exposure.
Sex
No clear sex predilections are recognized; however, the prevalence is slightly higher in men than in women in most epidemiologic studies, 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 seen in association with visceral leishmaniasis.
Leishmania infantum infection has long been thought to be associated with an infantile form of visceral leishmaniasis, which can have devastating outcomes for children, particularly for those younger than 1 year. This 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.
Clearly, in some parts of the world, Leishmania donovani is a much more devastating disease in older children.
Clinical
History
The discovery of parasites in lesions of cutaneous leishmaniasis or visceral leishmaniasis 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.
- 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: 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: Analogous to lepromatous leprosy, individuals with diffuse cutaneous leishmaniasis 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: A relatively uncommon clinical variant of leishmaniasis, recidivans cutaneous leishmaniasis appears as a recurrence of lesions at the site of apparently healed disease years after the original infection. Recidivans cutaneous leishmaniasis lesions typically occur on the face, and recidivans cutaneous leishmaniasis 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.
- Post–kala azar dermal leishmaniasis: Endemic to India and the Sudan, this form of leishmaniasis develops months to years after the patient's recovery from visceral leishmaniasis. 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 post–kala azar dermal leishmaniasis 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.
- Mucocutaneous leishmaniasis: 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.
- Visceral leishmaniasis (kala azar): Leishmania parasites localize to the reticuloendothelial system, rather than to the skin, and produce a potentially lethal widespread systemic disease.
Physical
Localized cutaneous leishmaniasis usually manifests as a nonspecific ulcer that can mimic many other infectious and noninfectious skin conditions. The vast majority of cases patients spontaneously with scarring and never come to the attention of clinicians. Even in US troops stationed in Iraq, it is currently felt, by many most closely associated with the disease and familiar with the epidemiology in the military, that less than 25% of all disease ever concerns afflicted soldiers enough to seek medical attention.
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 (although very early in the disease large numbers of the parasites are frequently found). 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.
The general consensus is that less than 5% 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. However, no rigorous studies prove this commonly accepted rate. Without treatment though, even in this small number, destruction of the oral and nasopharyngeal mucosa can be quite devastating and relentless. Symptoms of visceral leishmaniasis 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).
A typical lesion of localized cutaneous leishmaniasis 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.
Cutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
Cutaneous leishmaniasis with sporotrichotic spread.
Patients with diffuse cutaneous leishmaniasis 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.
Disseminated cutaneous leishmaniasis. Courtesy of Jacinto Convit, National Institute of Dermatology in Caracas, Venezuela.
In recidivans cutaneous leishmaniasis, typically, psoriasiform plaques occur on the face and progress centrifugally, bearing a striking resemblance to lupus vulgaris. Similar to disseminated disease, recidivans cutaneous leishmaniasis may be resistant to therapy and result in a disfiguring clinical picture.
Recidivans leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
In post–kala azar dermal leishmaniasis, cutaneous lesions are polymorphous, ranging from hypopigmented or erythematous macules to papules and nodules that may coalesce. Similar to diffuse cutaneous leishmaniasis, post–kala azar dermal leishmaniasis closely resembles lepromatous leprosy. Prolonged intensive treatment is required to treat this disfiguring, but usually not lethal, form of leishmaniasis.
Post–kala azar dermal leishmaniasis. Courtesy of R. E. Kuntz and R. H. Watten, Naval Medical Research Unit, Taipei, Taiwan.
When left untreated, mucocutaneous leishmaniasis gradually spreads and results in extensive midfacial mutilation or, in some cases, in death.
Mucocutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
Mucocutaneous leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
The hallmarks of visceral leishmaniasis 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.
Visceral leishmaniasis. Courtesy of Kenneth F. Wagner, MD.
Causes
In the vast majority of cases, sandfly bites transmit leishmaniasis; however, infection potentially may be transmitted via a congenital route, through blood transfusions, or through contaminated needle sticks. Clear documentation of the potential of transfusion-associated leishmaniasis exists, although clear documentation of the actual occurrence of transfusion-related disease is less certain because most cases in the literature occur in endemic areas of the world.4,5
The different clinical manifestations and the commonly associated parasite species are listed below. Importantly, however, variation in these general associations often occur.
- Cutaneous leishmaniasis
- Localized cutaneous leishmaniasis
- Old World -Leishmania major, Leishmania tropica, Leishmania aethiopica, and L infantum
- New World – L mexicana, Leishmania venezuelensis, Leishmania amazonensis, L braziliensis, L panamensis, L guyanensis, Leishmania peruviana, and L eishmania 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 – L donovani and L infantum
- New World – L chagasi
- Localized cutaneous leishmaniasis
- Mucocutaneous leishmaniasis
- 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
Other diagnostic considerations
The differential diagnosis of localized cutaneous leishmaniasis is extensive and includes impetigo, pyoderma gangrenosum, deep fungal infection, mycobacterial infection, sarcoidosis, and squamous cell carcinoma.
Diffuse cutaneous leishmaniasis and post–kala azar dermal leishmaniasis closely resemble lepromatous leprosy. Recidivans cutaneous leishmaniasis may mimic cutaneous tuberculosis (lupus vulgaris, tuberculosis verrucosa cutis), psoriasis, deep fungal infection, or nummular dermatitis. Mucocutaneous leishmaniasis may simulate paracoccidioidomycosis, histoplasmosis, syphilis, yaws, rhinoscleroma, squamous cell carcinoma, and midline granuloma of the face.
Visceral leishmaniasis 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, visceral leishmaniasis 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 visceral leishmaniasis 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.3
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References
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Further Reading
Keywords
leishmaniasis, leishmaniosis, tropical disease, localized cutaneous leishmaniasis, diffuse cutaneous leishmaniasis, recidivans cutaneous leishmaniasis, post–kala azar dermal leishmaniasis, mucocutaneous leishmaniasis, visceral leishmaniasis, leishmanin skin test, sandfly,
