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Epidemiology and clinical manifestations of leishmaniasis ]
INTRODUCTION — Leishmaniasis, caused by a heterogeneous group of protozoan parasites belonging to the genus Leishmania, results in a variety of different clinical syndromes. The classification and taxonomy of the organisms are confusing; several different approaches can be used: Leishmaniasis can be classified geographically into New World versus Old World disease. Infection can be divided into cutaneous, mucocutaneous, or visceral disease. Separation into subgenus, complexes, and species can be based upon taxonomy.
Specific organisms are often associated with a typical clinical picture. However, considerable overlap exists, and the relationship between the clinical syndromes and the different species is not always distinct. As an example, some Leishmania species are primarily dermatotrophic, while others are mainly viscerotropic. It has become increasingly clear that some species frequently associated with visceral leishmaniasis can produce skin lesions, and conversely, species usually found in the skin can disseminate viscerally. In addition, each clinical syndrome can be produced by multiple species. Thus, generalizations and classification can be difficult ( 1).
The epidemiology and clinical manifestations of leishmaniasis will be reviewed here, primarily using a syndromic approach to avoid the complicated taxonomy. Diagnosis and treatment issues are discussed separatelly
EPIDEMIOLOGY — Leishmania organisms are endemic in scattered foci in more than 80 countries on every continent except Australia and Antarctica. The overall prevalence of leishmaniasis is estimated to be 12 million cases worldwide, and the global yearly incidence of all clinical forms approaches 2 million new cases [1]. More than 20 Leishmania species have been identified. Most species cause disease predominantly in animals; humans become infected incidentally when they enter endemic areas. Although leishmaniasis occurs predominantly in individuals living in endemic regions, travelers to these areas can also be infected, even after less than one week of exposure
In addition, cutaneous leishmaniasis has reported in United States military personnel, primarily among those stationed in Iraq [7,30]. From August 2002 through April 2004 the Department of Defense reported 522 parasitologically confirmed cases of cutaneous leishmaniasis acquired in Iraq. Most infections were acquired near the borders of Iraq with Syria or Iran. All the 176 typed isolates were L. major. Approximately 75 percent of the lesions presented between August and September 2003, with further lesions peaking in presentation in September and October 2003.
The affected patients had a median of three lesions (range one to nine), with a diameter ranging from 3 to 40 mm. Most were on the arms or legs. The lesions were painless, centrally ulcerated, and peripherally indurated and erythematous. (See "Skin lesions in the returning traveler").
Sandfly vectors — Leishmaniasis is spread by the bite of a female sandfly. Sandflies of the species Lutzomyia serve as the vector in the New World, while the Phlebotomus species transmit infection in the Old World. Most sandflies typically bite at dusk, but certain vector species in parts of South America preferentially feed during daylight hours instead. Rodents and/or canines (wild or domestic) serve as the reservoir for most Leishmania species. However, in India and Bangladesh, L. donovani has no animal reservoir. Humans serve as both the natural reservoir and the host for infection in these countries.
Infection due to leishmaniasis occurs as a consequence of the interaction between the mammalian reservoirs, the sandfly vectors and humans. The disease is rural in some geographic areas and periurban or urban in others. Sandflies have a short flying range and thus must live close to animal reservoirs for perpetuation of transmission.
The mechanism of transmission from sandflies to humans is becoming better understood. In infected sandflies, the anterior midgut is blocked by parasite-derived promastigote secretory gel [8]. This blockade results in difficulty in feeding, resulting in multiple and longer feeding attempts and therefore a greater likelihood of transmission. In addition, both the gel and sandfly saliva, which are regurgitated with the metacyclic promastigotes during a bite, promote establishment of the parasite in the human host with exacerbation of the infection (see "Life cycle" below). The main active component in the gel is filamentous proteophosphoglycan.
Transmission to humans — Cutaneous and visceral disease can both have epidemic or endemic transmission patterns. Outbreaks tend to occur when susceptible hosts move into an area of endemic transmission or when a sandfly habitat is disturbed, such as with encroachment of settlements into forest areas .Both visceral and cutaneous leishmaniasis are increasing in prevalence globally because of urbanization, increases in rodent populations, decreased insecticide use, ecological changes resulting from war, and increased numbers of immunosuppressed and susceptible hosts
In addition to the usual means of transmission by the sandfly vector, disseminated forms of leishmaniasis can also be spread via shared needles, blood transfusions, vertically from the mother to fetus, or sexually [3].
LIFE CYCLE — Leishmania exist in nature in two morphologic states. They reside as intracellular pathogens within macrophages of mammalian hosts and as extracellular promastigotes within the gut of their sandfly vectors.
During the bite of a sandfly, flagellated metacyclic promastigote forms of the parasite are injected into the skin [10]. They are taken up by local tissue macrophages, within which the parasites transform into intracellular amastigotes [11]. Amastigotes multiply within the phagolysosomes of the macrophages. Infected macrophages either remain in the skin and cause cutaneous disease or disseminate throughout the reticuloendothelial system producing disseminated disease. The site of inoculation is often inapparent, but a small papule may form. In cutaneous syndromes, this papule grows and ulcerates to become the site of the lesion. By contrast, a local ulcer rarely develops in visceral syndromes.
If an uninfected sandfly bites an infected host, it takes up amastigotes residing within macrophages. These transform back into metacyclic promastigotes within the sandfly gut over a period of 4 to 14 days. They then migrate to the proboscis, the mouth part of the insect, thereby completing the life cycle.
CLINICAL SYNDROMES — Most infections with Leishmania are asymptomatic. The wide spectrum of disease that can be caused by Leishmania relates to intrinsic differences or differing virulence in the various parasite species, and genetic factors and differing immune responses of the host. When symptoms do occur, they can begin as soon as 7 to 10 days after exposure or be delayed by many years.
Leishmaniasis can be thought of as a spectrum of illness in similar terms to leprosy. (See "Overview of leprosy"). At one end, oligoparasitic disease associated with a marked cellular immune response (mucocutaneous leishmaniasis, post kala-azar dermal leishmaniasis, and leishmaniasis recidivans) At the other end, polyparasitic disease with macrophage predominance and no granulomatous inflammation (visceral leishmaniasis and diffuse cutaneous leishmaniasis) In the middle, intermediate forms (localized cutaneous leishmaniasis and viscerotropic infection)
Hosts who are malnourished or immunocompromised are more likely to have a high parasite burden and to develop symptoms.
Cutaneous syndromes — It is estimated that 1 to 1.5 million cases of cutaneous leishmaniasis occur annually; however, many more cases are not reported. More than 90 percent occur in Saudi Arabia, Iran, Afghanistan, Brazil, and Peru.
Cutaneous leishmaniasis is caused by organisms from the L. mexicana and L. braziliensis complexes, and by three ungrouped species, L. tropica, L. major and L. aethiopica. The typical incubation period between the time of the bite and clinical manifestations is one week to several months [12].
The cutaneous syndromes associated with Leishmania parasites include localized cutaneous leishmaniasis (LCL), mucosal leishmaniasis (ML), leishmania recidivans (LR), and diffuse cutaneous leishmaniasis (DCL).
Localized cutaneous leishmaniasis — Cutaneous lesions tend to occur on exposed areas of skin, beginning as a red papule that enlarges to form an ulcer with granulomatous tissue at the base and raised, heaped up margins (show picture 1). There is usually no surrounding induration. The ulcers are characteristically painless unless secondarily infected. Localized adenopathy may develop, especially in the early stages of the infection. Some individuals have multiple lesions, and lesions may occur in the distribution of lymphatic drainage. Nodular, psoriasiform, and verrucous forms arise less commonly.
LCL lesions typically undergo spontaneous resolution. The pace of this resolution varies according to the infecting Leishmania species and the immune reaction of the host. A residual hypopigmented, depressed scar at the site is common following cure.
The two main causes of LCL in the Old World are L. major and L. tropica. L. aethiopica can also cause localized cutaneous lesions; L. infantum, which is usually associated with visceral infection, occasionally provokes nodular skin lesions. In the New World, cutaneous lesions are caused predominantly by L. braziliensis, L. peruviana, L. guyanensis, L. panamensis, L. mexicana, and L. amazonensis. L. chagasi, which is typically associated with visceral leishmaniasis, also can have cutaneous manifestations, analogous to L. infantum.
There are some classic distinguishing clinical features between the Old and New World forms of cutaneous leishmaniasis. Old World cutaneous leishmaniasis typically has the following appearance, depending upon the inciting species: L. major tends to cause an exudative, "pizza-like" or "wet ulcer". The ulcer usually has a raised outer border, a granulating base, and an overlying white purulent exudate. After a typically short incubation period of one week to two months, the ulcer frequently grows to a size up to 6 cm in diameter over a short time period. Spontaneous healing typically also occurs quickly, usually within six months. Multiple lesions are common. L. tropica tends to evolve more slowly. It has a typical incubation period of two months to two years, and the ulcer does not usually grow larger than 1 to 2 cm. This ulcer is characterized as a "dry ulcer" because it usually has a central crust and no exudate. There may be satellite lesions, although single lesions are characteristic. Spontaneous resolution, when it occurs, happens more slowly, often taking one to two years. L. tropica can be associated with LR. L. aethiopica usually develops as a solitary lesion on the face with or without surrounding satellite papules that coalesce into spreading nodules or plaques. Lesions may spread along mucocutaneous margins but do not involve oral or nasal mucosa. These lesions typically show little inflammation and are more chronic than those seen with other Leishmania species, resolving slowly over many years. L. aethiopica can be associated with diffuse cutaneous leishmaniasis. L. infantum is usually associated with visceral leishmaniasis but can also be a cause of indolent, slow-growing nodular cutaneous lesions that can persist for years.
The lesions of New World cutaneous leishmaniasis tend to be difficult to distinguish by the etiologic leishmanial species. However, some classic features of certain species have been described. Primary lesions of L. braziliensis tend to be large, frequently with associated regional lymphadenopathy. A sporotrichoid pattern of multiple ulcers or subcutaneous nodules along the distribution of lymphatic drainage is common. The lymphadenopathy may appear prior to the development of an ulcer and may be accompanied by fever and malaise. Ulcers often heal within six months but may persist for one year or more. L. braziliensis can be associated with ML. L. mexicana generally produces small chronic ulcers, usually with only one or a few lesions. These tend to heal rapidly and spontaneously, often within three to four months. Lesions frequently occur on the ear, which relates to the biting habit of the vector. These lesions are referred to as "Chiclero's ulcers". L. mexicana and L. amazonensis can also be associated with DCL.
Leishmaniasis recidivans — LR refers to an uncommon syndrome caused by L. tropica infections in the Middle East. Following healing of the primary lesion, a few persistent organisms can cause new papules to form around the margins of the scar. These papules can ulcerate, heal, and reappear over decades. Thus, this syndrome is characterized by new lesions in the same area as an old scar, or by slowly] enlarging lesions that heal in the center. Patients tend to have a good cellular immune response, and few parasites are present in the lesion. A recent report described a patient who developed recurrence of LR 43 years after their initial symptoms [13].
Diffuse cutaneous leishmaniasis — Diffuse cutaneous leishmaniasis is a rare, syndrome that
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