Leishmaniasis is a parasitic infection endemic to more than 90 countries worldwide. As travel to endemic areas increases, dermatologists need to keep this entity in the differential for any chronic skin lesion in persons who may have had a possible exposure for any duration. It can be difficult to diagnose because manifestations are varied and sometimes subclinical. This article discusses the current state of epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment options. A special focus is placed on cutaneous manifestations and their treatment.
Key points
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Leishmaniasis is a parasitic infection transmitted by the bite of a sandfly, which is endemic to tropical and subtropical regions.
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The incidence of cases is rising with increased travel to these areas.
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Polymerase chain reaction is emerging as the diagnostic test of choice, because it quickly and accurately identifies the infecting species.
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Treatment recommendations vary, but pentavalent antimonials remain the preferred choice in most centers.
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Travelers to endemic countries should be counseled appropriately, because there is no vaccine to prevent this infection.
Introduction/overview
Leishmaniasis is a tropical disease caused by an intracellular parasite of the genus Leishmania . The vector of transmission is the sandfly, which deposits one of the 20 disease-causing protozoan species during a blood meal. Clinical presentation depends on the complex interplay between the host cell-mediated immune response, and the specific protozoa and vector species. There are four generally accepted classifications of clinical disease: (1) cutaneous leishmaniasis (CL), (2) diffuse CL (DCL), (3) mucocutaneous leishmaniasis (ML), and (4) visceral leishmaniasis (VL). This disease is also often classified according to the world regions in which it occurs. Old World (OW) leishmaniasis exists in the Eastern Hemisphere and is endemic in Asia, Africa, and southern Europe. New World (NW) leishmaniasis is endemic to the Western Hemisphere, extending from south-central Texas to Central and South America (except Chile and Uruguay). The disease is not found in Australia, Antarctica, or the Pacific islands.
It is difficult to obtain accurate numbers on disease incidence. It is believed to be underreported because it can be subclinical and is a disease primarily affecting the impoverished parts of the world. Estimates suggest that there are 12 million people infected, with 2 million new cases annually, most of which are cutaneous and mucocutaneous infections. Leishmaniasis is the second leading cause of parasite-related death (after malaria) causing 20,000 to 30,000 deaths annually.
Although this disease historically is limited to the tropics and subtropics, there are several factors contributing to its dissemination to new areas. These include climate change, urbanization, deforestation, increased travel for tourist and work-related reasons, immigration from endemic countries, and military operations. In the United States, leishmaniasis is typically diagnosed among travelers to endemic areas, military personnel, and immigrants. However, CL acquired in Texas and Oklahoma has been reported. Long-term stay in endemic countries is a risk factor, but travelers may become infected in 12 hours in an endemic area. The lack of familiarity with this disease in nonendemic countries leads to delays in its diagnosis and selection of proper treatment.
Introduction/overview
Leishmaniasis is a tropical disease caused by an intracellular parasite of the genus Leishmania . The vector of transmission is the sandfly, which deposits one of the 20 disease-causing protozoan species during a blood meal. Clinical presentation depends on the complex interplay between the host cell-mediated immune response, and the specific protozoa and vector species. There are four generally accepted classifications of clinical disease: (1) cutaneous leishmaniasis (CL), (2) diffuse CL (DCL), (3) mucocutaneous leishmaniasis (ML), and (4) visceral leishmaniasis (VL). This disease is also often classified according to the world regions in which it occurs. Old World (OW) leishmaniasis exists in the Eastern Hemisphere and is endemic in Asia, Africa, and southern Europe. New World (NW) leishmaniasis is endemic to the Western Hemisphere, extending from south-central Texas to Central and South America (except Chile and Uruguay). The disease is not found in Australia, Antarctica, or the Pacific islands.
It is difficult to obtain accurate numbers on disease incidence. It is believed to be underreported because it can be subclinical and is a disease primarily affecting the impoverished parts of the world. Estimates suggest that there are 12 million people infected, with 2 million new cases annually, most of which are cutaneous and mucocutaneous infections. Leishmaniasis is the second leading cause of parasite-related death (after malaria) causing 20,000 to 30,000 deaths annually.
Although this disease historically is limited to the tropics and subtropics, there are several factors contributing to its dissemination to new areas. These include climate change, urbanization, deforestation, increased travel for tourist and work-related reasons, immigration from endemic countries, and military operations. In the United States, leishmaniasis is typically diagnosed among travelers to endemic areas, military personnel, and immigrants. However, CL acquired in Texas and Oklahoma has been reported. Long-term stay in endemic countries is a risk factor, but travelers may become infected in 12 hours in an endemic area. The lack of familiarity with this disease in nonendemic countries leads to delays in its diagnosis and selection of proper treatment.
Etiopathogenesis
Leishmania infection is acquired through the bite of the female sandfly of the genera Phlebotomus (OW) and Lutzomyia (NW). At the time of the blood meal, the flagellated motile promastigote form of leishmania is deposited and quickly phagocytosed by macrophages, dendritic cells, and neutrophils. Inside the host cells, the promastigote transforms into the aflagellate amastigote form. It then multiplies by binary fission and proceeds to infect other cells. The cycle is completed when the sandfly feeds again consuming the amastigotes, which transform back into the promastigote form in the gut of the sandfly. The promastigotes then migrate to the proboscis of the sandfly and are ready to repeat the cycle with the subsequent bite.
The major reservoirs of this disease are animals, such as dogs and rodents. The female sandfly is most active from dusk to dawn, and bites typically occur on the exposed skin of the arms, legs, neck, and face. The sandfly is smaller than a mosquito, has a painless bite, and does not make an audible noise. Infection also can be transmitted through needle sharing, blood transfusion with infected blood products, or transplacentally.
The major infecting species of OW and NW leishmaniasis and the associated clinical disease classification are included in Table 1 . It is generally regarded that OW species cause self-limiting disease and may not require treatment, whereas some NW species have a propensity to affect mucosal surfaces and thus necessitate more aggressive parenteral treatment ( Fig. 1 ).
| Region | Complex | Species | Clinical Manifestation |
|---|---|---|---|
| Old World | Leishmania donovani | L donovani | CL, VL, PKLD, ML (rare) |
| L infantum | CL, VL (children), PKLD, ML (rare) | ||
| L chagasi | CL, VL (children), PKLD, ML (rare) | ||
| Leishmania tropica | L tropica | CL, ML (rare), VL (rare) | |
| L major | CL, ML (rare) | ||
| L aethiopica | CL, DCL | ||
| New World | Leishmania mexicana | L mexicana | CL, DCL (rare) |
| L amazonensis | CL, DCL, ML, VL (rare), PKLD (rare) | ||
| L venezuelensis | CL, DCL (rare) | ||
| Leishmania (Viannia) braziliensis | L braziliensis | CL, ML, VL | |
| L guyanensis | CL, ML | ||
| L panamensis | CL, ML | ||
| L peruviana | CL |
Immunology
The health status of the individual, the species of Leishmania , and the vector of transmission are thought to be factors in determining the clinical presentation resulting from infection. It is the interplay of these elements that fashions the individual immunologic response and generates the clinical picture. The current understanding of the complex overlapping immunologic regulatory pathways is imperfect but is growing and is the subject of more detailed reviews. This article provides a limited overview of key factors involved in the immunologic response.
A classic simple T-helper (Th) cell type 1/2 model has been used for years to explain the disease. Promastigotes transmitted by the sandfly bite are processed by dendritic cells and presented to naive T-cells, which in turn produce a pattern of cytokines resulting in the formation of differentiated and expanded T-cell populations: Th1, Th2, and T-reg cells. Th1 CD4 + cells are activated and produce interleukin-2, interferon-γ, and tumor necrosis factor. Interferon-γ activates macrophages, which then engulf and kill the protozoa. T-reg cells then are activated and modulate the ongoing antimicrobial response thereby limiting damage to the host. However, should the Th2 CD4 + response predominate, Th1 response would be inhibited and infection would persist and spread.
The disease process is more complex. In addition to leishmania, some sandflies also may carry bacteria and viruses that can be transmitted with the bite and precipitate a proinflammatory response possibly enabling disease persistence. The best example is the recent discovery that ML-causing species harbor leishmania RNA virus-1, which may facilitate evasion of host protective immune response. Infected monocytes and fibroblasts may permit organisms to elude immune-mediated disease control. The heavily parasitized cells noted in DCL caused by L amazonensis infection occur in the setting of antigen-specific impaired cell activation. This organism seems to be unique in its ability to resist host-derived toxic molecules and drugs used in the treatment of leishmaniasis. The recently identified Th17 CD4 + cell population produced by the primed naive T cells is known to be important in protection against infections and participate in inflammatory and autoimmune diseases. Although interleukin-17 produced in a regulated manner by Th17 CD4 + cells may prevent L donovani from progressing to kala-azar, excessive interleukin-17 production can be associated with the destructive presentation and features of ML in patients infected with L braziliensis . With respect to impact of overall host health, patients with coexisting human immunodeficiency virus (HIV) infection are at increased risk of VL.
In that most leishmania infections are subclinical or self-limited, the immune system is well designed to control disease. Nevertheless the various expressions and manifestations of the disease demonstrate that a weak immune response is permissive with respect to disease progression, whereas an exuberant immune response can produce destructive results. Research sorting out this interplay of vector, organism, and host parameters is ongoing.
Clinical presentations
The clinical manifestations of leishmaniasis occur on a full spectrum ranging from asymptomatic to lethal. This depends on the infecting species, vector, immune status of the host, age, nutritional status, inoculation site and dose, and genetic background of the host. Fortunately, subclinical and self-healing CL is common. However, an inappropriate immune response leads to uncontrolled parasite replication and subsequent nonhealing forms.
No matter which species causes the infection, cutaneous lesions begin as solitary, well-circumscribed papules at the site of inoculation. These papules may then enlarge to form nodules and plaques that sometimes have associated scale but often become ulcerated. Ulcers are typically painless unless secondarily infected by bacteria or fungi. Satellite lesions and sporotrichoid (lymphangitic) spread have been reported. Regional lymphadenopathy may be associated with the initial presentation and may persist after the cutaneous lesions have cleared ( Figs. 2–7 ).
Coinfection with pre-existing HIV is common, particularly in cases of VL, and further complicates the clinical picture and treatment. Immunocompromised individuals have been reported to have atypical and more severe manifestations. Because T-cell activation is a key component in immunoregulation of leishmaniasis, HIV-infected patients and those with iatrogenic T-cell suppression caused by corticosteroids, chemotherapy, anticytokine agents, and transplant drugs are most vulnerable.
Cutaneous Leishmaniasis
This is the most common form of leishmaniasis and is characterized by one or more lesions that develop weeks to months after a bite. Ulcers often have raised indurated borders with central erosion, which may be covered by a crust. These may become painful if superinfected or overlying a joint. The ulcers often heal spontaneously from the center over a period of months and may leave behind atrophic, cribriform scars with a hyperpigmented halo. Leishmania parasites may persist in healed CL scars and in lymph nodes despite treatment, possibly resulting in reactivation during a period of immunosuppression. Failure of the host to limit parasite replication by local granuloma formation leads to less typical presentations, such as sporotrichoid spread, erysipeloid, and psoriasiform eruptions.
Diffuse Cutaneous Leishmaniasis
Also known as anergic or lepromatous leishmaniasis, this form is characterized by disseminated skin-colored papules or nodules usually sparing the trunk. Because of its propensity for numerous facial lesions, it is often likened to leonine facies of lepromatous leprosy. Ulceration is not characteristic of this form. Reported incidence in Brazil is 2.4% and has increased three-fold over a period of 20 years according to one study.
Mucocutaneous Leishmaniasis
ML, often regarded as “metastatic” CL, develops as an uncommon sequela of NW cutaneous disease 1 to 2 years or more after clinical healing of primary lesions. Progression to ML is generally not seen with OW infection, but the reasons for this remain unclear. Early manifestations include persistent nasal congestion and bleeding, and pharyngeal symptoms, such as hoarseness. Visualization reveals erythema and edema that eventually progresses to ulceration with a mucopurulent exudate. The mucosa of the eyes or genitals is rarely involved. Ultimately ML leads to mutilating destruction of mucous membranes of the nose, mouth, throat, and surrounding tissues. There is a paucity of data on the risk of progression to ML, but literature indicates it may develop in about 1% to 10% of NW CL cases. Associated risk factors seem to be male gender, incomplete or missed antimony treatments, large and multiple lesions particularly above the waist, HLA-DR2 and HLA-DQx3 genetic background, and malnutrition. Adequate treatment of the primary CL infection likely prevents ML. Complete ear, nose, and throat examination is indicated in confirmed cases of ML-causing strains.
Visceral Leishmaniasis
Also known as kala-azar (black sickness), this type of leishmaniasis develops months to years following inoculation and is a result of infected macrophages disseminating through the reticuloendothelial system. It is characterized by fevers, significant weight loss, anorexia, weakness, pallor, cough, diarrhea, epistaxis, hepatosplenomegaly, lymphadenopathy, and growth retardation in children. In certain patient population, significant hyperpigmentation can be noted which accounts for the name “black sickness”. Laboratory abnormalities include normocytic anemia, thrombocytopenia, neutropenia, transaminitis, hypoalbuminemia, and hypergammaglobulinemia. If left untreated, it is usually lethal within 2 years. Death usually results from infection, severe anemia, or hemorrhage. It exists both in the NW and OW, but six countries (Bangladesh, Brazil, Ethiopia, India, Sudan, and South Sudan) account for greater than 90% of cases.
A possible sequela of subclinical and untreated VL is post–kala-azar dermal leishmaniasis, which appears as diffuse hypopigmented macules, malar rash, papules, nodules, and plaques in all parts of the body. It is regarded as an active source of kala-azar infection and is almost exclusively found in East Africa and India, where L donovani is the etiologic agent.
Histopathology
The histopathologic finding of CL depends in large part on the stage of development of the lesion. Acute lesions have a dense dermal infiltrate of parasitized histiocytes, lymphocytes, plasma cells, and variable numbers of neutrophils. With increased lesion chronicity, small tuberculoid granulomas begin to replace the reducing number of parasitized histiocytes and decreased lymphoplasmactytic infiltrate. The overlying epidermis may show ulceration, neutrophil microabscesses, acanthosis, or atrophy, also depending on the lesion stage and biopsy site. Mucosal lesions may show nonspecific chronic inflammation and only a few parasitized histiocytes. Pseudoepitheliomatous hyperplasia may be prominent, particularly at the periphery of some lesions. With cutaneous involvement of visceral leishmaniasis (post–kala-azar dermal leishmaniasis), the epidermis is atrophic and nonulcerated, and follicular plugging is frequently present in lesions on the face. This form of dermal leishmaniasis demonstrates a nodular to diffuse dermal lymphohistiocytic infiltrate with variable numbers of organisms present.
The histopathologic features also depend greatly on the host response and degree of cellular immunity. Similar to the leprosy, large numbers of organisms and a primarily histiocytic infiltrate indicates an anergic response (DCL), whereas small numbers of organisms are associated with necrosis and a granulomatous response (self-healing CL). The recidivans or lupoid form of chronic CL represents an exaggerated tuberculoid response to very few organisms, and resembles lupus vulgaris with tubercles surrounded by lymphocytes but no necrosis and only sparse plasma cells. When leishmania organisms are sparse, the granulomatous infiltrate may be histologically misdiagnosed as sarcoidosis, foreign body granuloma, granuloma annulare, or granulomatous rosacea.
In all variants of leishmaniasis, the amastigote form of the organism multiples within the histiocytes of the human host. Amastigotes are round-to-ovoid structures and measure approximately 2 to 4 μm in impression smears or touch preparations, but may be only 1 to 3 μm in histologic sections because of shrinkage during tissue processing. Although the morphologic features may be better appreciated with a Giemsa stain, the organisms appear as basophilic dotlike structures within the vacuolated cytoplasm of histiocytes in hematoxylin-eosin–stained sections and tend to localize to the periphery of the parasitized histiocytes, the so-called marquee sign. Leishmania amastigotes have a prominent nucleus and an eccentric rod-shaped kinetoplast. They are termed Leishman-Donovan bodies and must be differentiated from other organisms that are parasitized by histiocytes, including histoplasmosis, granuloma inguinale, and rhinoscleroma. In particular, histoplasma organisms are of similar size, but the cytoplasm of the cell is retracted from the thick poorly staining cell wall to produce a halolike appearance. Additionally unlike leishmania amastigotes, histoplasmosis does not have a kinetoplast and stains positively with fungal stains, such as Gomori methenamine silver and periodic acid–Schiff.
Leishmania promastigotes are not seen in the human host, but may be found in the sandfly vector or in culture media. The promastigote form is more elongated, measuring 10 to 15 μm long. Promastigotes have a prominent central nucleus with an anterior kinetoplast and a single long flagellum that emerges from the anterior end of the organism ( Figs. 8–11 ).
Evaluation and management
There are several diagnostic modalities currently in use, and selection of the proper method is based on convenience and availability. In the United States, the Centers for Disease Control and Prevention can offer assistance with diagnosis and treatment ( Table 2 ).
| CDC Branch | Contact | Services |
|---|---|---|
| CDC Parasitic Disease Division www.cdc.gov/parasites/contactus.html | 404-718-4745 | Assistance with diagnosis and treatment options obtainable |
| CDC Laboratories | 770-488-4475 | Request media for culture, PCR |
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