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Overview
Leishmania are obligate intracellular parasites distinguished by a slender body and polar flagellum. Leishmaniasis is caused by different species of Leishmania and results in a variety of clinical presentations dependent upon the infecting species. The most common forms of the disease are classified as cutaneal or visceral with accompanying disease manifestations. Cutaneal lesions may or may not heal depending on the infecting species and immune status of the host. Visceral leishmaniasis is often acute and highly lethal.
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Leishmania species are obligate intracellular parasites of mammals. Several strains can infect humans; they are all morphologically similar, resulting in some confusion over their proper speciation. Definitive identification of these strains requires isoenzyme analysis, monoclonal antibodies, kinetoplast DNA buoyant densities, DNA hybridization, and DNA restriction endonuclease fragment analysis or chromosomal karyotyping using pulse-field electrophoresis. The many strains can be more simply placed in four major groups based on their serologic, biochemical, cultural, nosologic, and behavioral characteristics. For the sake of clarity, these groups are discussed as individual species. Each, however, contains a variety of strains that have been accorded separate species or subspecies status by some authorities. The organisms can be propagated in hamsters and in a variety of commercially available liquid media.
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Species morphologically similar; differ in molecular features
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It is estimated that over 20 million people worldwide suffer from leishmaniasis, and 1 to 2 million additional individuals acquire the infection annually. Leishmania tropica in the Old World and Leishmania mexicana in the New World produce a localized cutaneous lesion or ulcer, known popularly as oriental sore or chiclero ulcer; Leishmania braziliensis is the cause of American mucocutaneous leishmaniasis (espundia); and Leishmania donovani and Leishmania infantum are the etiologic agents of kala azar, a disseminated visceral disease.
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✺ Cutaneous ulcer or visceral infection (kala azar) the primary diseases
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All five groups are transmitted by phlebotomine sandflies. These small, delicate, short-lived insects are found in animal burrows and crevices throughout the tropics and subtropics. At night, they feed on a wide range of mammalian hosts. Amastigotes ingested during a meal assume the flagellated promastigote form, multiply within the gut, and eventually migrate to the proboscis. When the fly next feeds on a human or animal host, the promastigotes are injected into the skin of the new host together with salivary peptides capable of inactivating host macrophages. Here, they activate complement by the classic (L donovani) or alternative pathway and are opsonized with C3, which mediates attachment to the CR1 and CR3 complement receptors of macrophages. After phagocytosis, the promastigotes lose their flagella and multiply as the rounded amastigote form within the phagolysosome. In stained smears, the parasites take on a distinctive appearance and have been termed Leishman–Donovan bodies. Intracellular survival is mediated by a surface lipophosphoglycan and an abundance of membrane-bound acid phosphatase, which inhibits the macrophage’s oxidative burst and/or inactivates lysosomal enzymes. Continued multiplication leads to the rupture of the phagocyte and release of the daughter cells. Some may be taken up by a feeding sandfly; most invade neighboring mononuclear cells.
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✺ All five groups transmitted by nocturnally feeding sandflies
✺ Complement activation mediates attachment to macrophages
✺ Intracellular survival by inhibiting macrophage killing mechanisms
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Amastigotes released from macrophages can infect feeding sandfly
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Continuation of this cycle results in extensive histiocytic proliferation. The course of the disease at this point is determined by the species of parasite and the response of the host’s T cells. CD4+ T cells of the TH1 type secrete interferon (IFN)-γ in response to leishmanial antigens. This, in turn, activates macrophages to kill intracellular amastigotes by the production of toxic nitric oxide. In the localized cutaneous forms of leishmaniasis, this immune response results in the development of a positive delayed skin (leishmanin) reaction, lymphocytic infiltration, reduction in the number of parasites, and, eventually, spontaneous disappearance of the primary skin lesion. In infections with L braziliensis, this sequence may be followed weeks to months later by mucocutaneous metastases. These secondary lesions are highly destructive, presumably because of the host’s hypersensitivity to parasitic antigens. Scrapings from these lesions show a noticeable absence of lymphocytes indicating that the cell-mediated immune response has been impaired.
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In localized cutaneous disease, cellular immune responses produce spontaneous cure
Mucocutaneous metastases in L braziliensis infections
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Some strains of L tropica and L mexicana fail to elicit an effective intracellular immune response in certain hosts. Such patients appear to have a selective suppressor T-lymphocyte–mediated anergy to leishmanial antigens. Consequently, there is no infiltration of lymphocytes or decrease in the number of parasites. The skin test remains negative, and the skin lesions disseminate and become chronic (diffuse cutaneous leishmaniasis). In infections with L donovani, there is a more dramatic inhibition of the TH1 response. The leishmanial organisms can disseminate through the bloodstream to the visceral organs, possibly because of a relative resistance of L donovani to the natural microbicidal properties of normal serum, and/or their ability to better survive at 37°C than strains of Leishmania, causing cutaneous lesions. Although dissemination is associated with the development of circulating antibodies, they do not appear to serve a protective function and may, via the production of immune complexes, be responsible for the development of glomerulonephritis. A simplified outline of the immune responses in different forms of leishmaniasis is presented in Table 53–2.
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✺ Lack of cellular immune response in disseminated and chronic infections
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LOCALIZED CUTANEOUS LEISHMANIASIS
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Cutaneous leishmaniasis is a zoonotic infection of tropical and subtropical rodents. It is particularly common in areas of Central Asia, the Indian subcontinent, Middle East, Africa, the Mediterranean littoral, and Central and South America. In the latter area, L mexicana infects several species of arboreal rodents. Humans become involved when they enter forested areas to harvest chicle for chewing gum and are bitten by infected sandflies. In the Eastern Hemisphere, the desert gerbil and other burrowing rodents serve as the reservoir hosts of L tropica. Human infection occurs when rural inhabitants come in close contact with the burrows of these animals. In the Mediterranean area, southern Russia, and India, human disease involves urban dwellers, primarily children. In this setting, the domestic dog serves as the reservoir, although sandflies may also transmit L tropica directly from human to human.
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Geographic distribution related to human and rodent reservoirs
Canine reservoir in urban disease
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LOCALIZED CUTANEOUS LEISHMANIASIS
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Lesions usually appear on the extremities or face (the ear in cases of chiclero ulcer) weeks to months after the bite of the sandfly (Figure 53–5). They first appear as pruritic papules, often accompanied by regional lymphadenopathy. In a few months, the papules ulcerate, producing painless craters with raised erythematous edges, sharp walls, and a granulating base. Satellite lesions may form around the edge of the primary sore and fuse with it. Multiple primary lesions are seen in some patients. Spontaneous healing occurs in 3 to 12 months, leaving a flat, depigmented scar. Occasionally, the lesions fail to heal, particularly on the ears, leading to progressive destruction of the pinna. A permanent strain-specific immunity usually follows healing. Multiple, disseminated nonhealing lesions may be seen in patients with acquired immunodeficiency syndrome (AIDS).
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✺ Chronic, self-limiting skin ulceration
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DIAGNOSIS AND TREATMENT
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In endemic areas, the diagnosis of localized cutaneous leishmaniasis is made on clinical grounds and confirmed by the demonstration of the organism in the advancing edge of the ulcer. Material collected by biopsy, curettage, or aspiration is smeared and/or sectioned, stained, and examined microscopically for the pathognomonic Leishman–Donovan bodies. Material should also be cultured in liquid media. The leishmanin skin test becomes positive early during the disease and remains so for life. Recently, it has been demonstrated that small numbers of Leishmania may be detected in tissue by NAA methods, and strains distinguished with probes to kinetoplast DNA. These techniques, though not widely available, permit direct, rapid, and specific diagnosis of all leishmanial infections.
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✺ Demonstration of Leishman–Donovan bodies or culture from tissue biopsy
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Patients with small, cosmetically minor lesions that do not involve the mucous membrane may be carefully followed without treatment. Pentavalent antimonial agents and liposomal amphotericin B have proved to be effective chemotherapeutic agents for individuals with more consequential lesions. Recently, ketoconazole and itraconazole, alone or in combination with the previously mentioned agents, have been found to be effective in some forms of cutaneous leishmaniasis. Paromomycin has also proved to be useful. What has become clear is that what works for one form of cutaneal leishmaniasis may not work for another. Combinations of thermotherapy and drugs have also been tried. Bacterial superinfections are treated with appropriate antibiotics. Prophylactic measures include the control of the sandfly vector by use of insect repellents and fine mesh screening on dwellings.
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MUCOCUTANEOUS LEISHMANIASIS
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Leishmania braziliensis causes a natural infection in the large forest rodents of tropical Latin America. Sandflies transmit the infection to humans engaged in military activities, road builders, opening jungle areas for new settlements, and others.
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✺ Rodent reservoir of L braziliensis
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MUCOCUTANEOUS LEISHMANIASIS
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A primary skin lesion similar to oriental sore develops 1 to 4 weeks after sandfly exposure. Occasionally, it undergoes spontaneous healing. More commonly, it progressively enlarges, often producing large vegetating lesions. After a period of weeks to years, painful, destructive, metastatic mucosal lesions of the mouth, nose, and occasionally the perineum, appear in 2% to 50% of the patients. Sometimes, decades pass and the primary lesion totally resolves before the metastases manifest themselves. Destruction of the nasal septum produces the characteristic tapir nose. Erosion of the hard palate and larynx may render the patient aphonic. In blacks, the lesions are often large, hypertrophic, polypoid masses that deform the lips and cheeks. Fever, anemia, weight loss, and secondary bacterial infections are common. Mucosal lesions caused by other Leishmania species may be seen after visceral dissemination in AIDS patients.
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✺ Primary lesion metastasizes to oral and nasal areas
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The diagnosis of mucocutaneous leishmaniasis is made by finding the organisms in the lesions as described for localized cutaneous leishmaniasis. Because the propensity to metastasize to mucocutaneous sites is specific to certain species and subspecies, precise identification of the responsible organism as described in the introduction is of clinical importance. The leishmanin skin test yields positive results, and most patients have detectable antibodies. As described for cutaneous leishmaniasis, it is now possible to provide a rapid, direct, species-specific diagnosis using NAA methods and probes to kinetoplast DNA.
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Detection of organisms as with cutaneous leishmaniasis
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Treatment is accomplished with the agents described later in the chapter for kala azar. Advanced lesions are often refractory and relapse is common. Cured patients are immune to reinfection. Control measures, other than insect repellents and screening of dwellings, are impractical because of the sylvatic nature of the disease.
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DISSEMINATED VISCERAL LEISHMANIASIS (KALA AZAR)
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Kala azar is caused by L donovani and L infantum. Leishmania donovani is found in East Africa and the Indian subcontinent, whereas L infantum is found in Europe, North Africa, and Latin America. Its epidemiologic and clinical patterns vary from area to area. In Africa, rodents serve as the primary reservoir. Human cases occur sporadically, and the disease is often acute and highly lethal. In Eurasia and Latin America, the domestic dog is the most common reservoir. Human disease is endemic, primarily involves children, and runs a subacute to chronic course. In India, the human is the only known reservoir, and transmission is carried out by anthropophilic species of sandflies. The disease recurs in epidemic form at 20-year intervals, when a new cadre of nonimmune children and young adults appears in the community. There appears to be a high incidence of visceral leishmaniasis in patients with HIV infection. Presumably, HIV-induced immunosuppression either facilitates acquisition of the disease and/or allows reactivation of latent infection.
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Marked geographic differences in reservoirs and disease severity
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After the host is bitten by an infected sandfly, the parasites disseminate in the bloodstream and are taken up by the macrophages of the spleen, liver, bone marrow, lymph nodes, skin, and small intestine. Histiocytic proliferation in these organs produces enlargement with atrophy or replacement of the normal tissue.
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✺ Parasites invade macrophages of reticuloendothelial system
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KALA AZAR: CLINICAL ASPECTS
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Most kala azar infections are asymptomatic; these become symptomatic years later during periods of host immunocompromise. Symptomatic disease most commonly manifests itself 3 to 12 months after acquisition of the parasite. It is often mild and self-limited. A minority of infected individuals develop the classic manifestations of kala azar. Fever, which is usually present, may be abrupt or gradual at onset. It persists for 2 to 8 weeks and then disappears, only to reappear at irregular intervals during the disease. A double-quotidian pattern (two fever spikes in a single day) is a characteristic but uncommon finding. Diarrhea and malabsorption are common in Indian cases, resulting in progressive weight loss and weakness. Physical findings include enlarged lymph nodes and liver, massively enlarged spleen, and edema. In light-skinned persons, a grayish pigmentation of the face and hands is commonly seen, which gives the disease its name (kala azar, black disease). Anemia with resulting pallor and tachycardia are typical in advanced cases. Thrombocytopenia induces petechial formation and mucosal bleeding. The peripheral leukocyte count is usually less than 4000/mm3; agranulocytosis with secondary bacterial infections contributes to lethality. Serum IgG levels are enormously elevated, but play no protective role. Circulating antigen–antibody complexes are present and are probably responsible for the glomerulonephritis seen so often in this disease.
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✺ Delayed onset, recurrent fever, chronic disease, diarrhea
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Severe systemic manifestations
Immune complex glomerulonephritis
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DIAGNOSIS AND TREATMENT
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The diagnosis of kala azar is made by demonstrating the presence of the organism in aspirates taken from the bone marrow, liver, spleen, or lymph nodes. In the Indian form of kala azar, L donovani is also found in circulating monocytes. The specimens may be smeared, stained, and examined for the typical Leishman–Donovan bodies (amastigotes in mononuclear phagocytes) or cultured in artificial media and/or experimental animals. As described for cutaneous leishmaniasis, a limited number of reference laboratories can provide a rapid, direct, species-specific diagnosis using NAA and probes to kinetoplast DNA. Results of the leishmanin skin test are negative during active disease but become positive after successful therapy.
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✺ Demonstration of Leishman–Donovan bodies or culture
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The mortality rate in untreated cases of kala azar is 75% to 90%. Treatment with pentavalent antimonial drugs lowers this rate dramatically. Initial therapy, however, fails in up to 30% of African cases, and 15% of those that do respond eventually relapse. Resistant cases are treated with the more toxic pentamidine, amphotericin B, or liposomal amphotericin B. Allopurinol and IFN-γ have proved to be useful adjunctive therapies in resistant cases. A new oral drug, miltefosine, has been shown to be very efficient and safe for both cutaneal and visceral leishmaniasis. Post-Kala azar dermal leishmaniasis, a condition marked by hypopigmented macules, papules, nodules, or facial erythema may appear many years after partial or even successful treatment of visceral leishmaniasis, particularly caused by L donovani. The lesions can be confused with those caused by leprosy. The lesions coincide with IFN-γ–producing cells causing skin inflammation as a reaction to persisting parasites in the skin. Patients need to be treated as those for visceral leishmaniasis. Control measures are directed at the Phlebotomus vector, with the use of residual insecticides, and at the elimination of mammalian reservoirs by treating human cases and destroying infective dogs.
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Up to 90% mortality rate without treatment