Leishmaniasis (Leishmania)

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Chapter 277 Leishmaniasis (Leishmania)

The leishmaniases are a diverse group of diseases caused by intracellular protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sandflies. Multiple species of Leishmania are known to cause human disease involving the skin and mucosal surfaces and the visceral reticuloendothelial organs. Cutaneous disease is generally mild but may cause cosmetic disfigurement. Mucosal and visceral leishmaniasis is associated with significant morbidity and mortality.

Etiology

Leishmania organisms are members of the Trypanosomatidae family and include 2 subgenera, Leishmania (Leishmania) and Leishmania (Viannia). The parasite is dimorphic, existing as a flagellate promastigote in the insect vector and as an aflagellate amastigote that resides and replicates within mononuclear phagocytes of the vertebrate host. Within the sandfly vector the promastigote changes from a noninfective procyclic form to an infective metacyclic stage. Fundamental to this transition are changes that take place in the terminal polysaccharides of the surface lipophosphoglycan (LPG), which allow forward migration of the infective parasites from the sandfly midgut to the mouth parts and inoculation of the host during a blood meal. Metacyclic LPG also plays an important role in the entry and survival of Leishmania in the mammalian host by conferring complement resistance and by facilitating entry into the macrophage by way of multiple receptors, including complement receptors 1 and 3. Once within the macrophage, the promastigote transforms to an amastigote and resides and replicates within a phagolysosome. The parasite is resistant to the acidic, hostile environment of the macrophage and eventually ruptures the cell and goes on to infect other macrophages. Infected macrophages have a diminished capacity to initiate and respond to an inflammatory response, thus providing a safe haven for the intracellular parasite.

Epidemiology

The leishmaniases are estimated to affect 10-50 million people in endemic tropical and subtropical regions on all continents except Australia and Antarctica. The different forms of the disease are distinct in their causes, epidemiologic characteristics, transmission, and geographic distribution. The leishmaniases may occur sporadically throughout an endemic region or may occur in epidemic focuses. With only rare exceptions, the Leishmania organisms that primarily cause cutaneous disease do not cause visceral disease.

Localized cutaneous leishmaniasis (LCL) in the Old World is caused by L. (Leishmania) major and L. (L.) tropica in North Africa, the Middle East, central Asia, and the Indian subcontinent. L. (L.) aethiopica is a cause of LCL and diffuse cutaneous leishmaniasis (DCL) in Kenya and Ethiopia. Visceral leishmaniasis (VL) in the Old World is caused by L. (L.) donovani in Kenya, Sudan, India, Pakistan, and China and by L. (L.) infantum in the Mediterranean basin, Middle East, and central Asia. L. infantum is also a cause of LCL (without visceral disease) in this same geographic distribution. L. tropica also has been recognized as an uncommon cause of visceral disease in the Middle East and India. In the New World, L. (L.) mexicana causes LCL in a region stretching from southern Texas through Central America. L. (L.) amazonensis, L. (L.) pifanoi, L. (L.) garnhami, and L. (L.) venezuelensis cause LCL in South America, the Amazon basin, and northward. Members of the Viannia subgenus (L. [V.] braziliensis, L. [V.] panamensis, L. [V.] guyanensis, and L. [V.] peruviana) cause LCL from the northern highlands of Argentina northward to Central America. Members of the Viannia subgenus also cause mucosal leishmaniasis (ML) in a similar geographic distribution. VL in the New World is caused by L. (L.) chagasi (now considered to be the same organism as L. infantum), which is distributed from Mexico (rare) through Central and South America. L. infantum/chagasi can also cause LCL in the absence of visceral disease.

The maintenance of Leishmania in most endemic areas is through a zoonotic transmission cycle. In general, the dermotropic strains in both the Old and New Worlds are maintained in rodent reservoirs, and the domestic dog is the usual reservoir for L. infantum/chagasi. The transmission between reservoir and sandfly is highly adapted to the specific ecologic characteristics of the endemic region. Human infections occur when human activities bring them in contact with the zoonotic cycle. Anthroponotic transmission, in which humans are the presumed reservoir, occurs with L. tropica in some urban areas of the Middle East and Central Asia, and with L. donovani in India and Sudan. Congenital transmission of L. donovani or L. infantum/chagasi has been reported.

There is a resurgence of leishmaniasis in long-standing endemic areas as well as in new foci. Tens of thousands of cases of LCL occurred in an outbreak in Kabul, Afghanistan, and severe epidemics with >100,000 deaths from VL have occurred in India and Sudan. VL is most prevalent among the poorest of the poor, with substandard housing contributing to the vector-borne transmission and undernutrition leading to increased host susceptibility. The emergence of the leishmaniases in new areas is the result of (1) movement of a susceptible population into existing endemic areas, usually because of agricultural or industrial development or timber harvesting; (2) increase in vector and/or reservoir populations as a result of agriculture development projects; (3) increase in anthroponotic transmission owing to rapid urbanization in some focuses; and (4) increase in sandfly density resulting from a reduction in vector control programs.

Pathology

Histopathologic analysis of the LCL lesion shows intense chronic granulomatous inflammation involving the epidermis and dermis. Occasionally, neutrophils and even microabscesses can be seen. The lesions of DCL are characterized by dense infiltration with vacuolated macrophages containing abundant amastigotes. ML is characterized by an intense granulomatous reaction with prominent tissue necrosis, which may include adjacent cartilage or bone. In VL there is prominent reticuloendothelial cell hyperplasia in the liver, spleen, bone marrow, and lymph nodes. Amastigotes are abundant in the histiocytes and Kupffer cells. Late in the course of disease, splenic infarcts are common, centrilobular necrosis and fatty infiltration of the liver occur, the normal marrow elements are replaced by parasitized histiocytes, and erythrophagocytosis is present.

Pathogenesis

Cellular immune mechanisms determine resistance or susceptibility to infection with Leishmania. Resistance is mediated by interleukin 12 (IL-12)–driven generation of a T helper 1 (Th1) cell response, with interferon-γ inducing classical macrophage activation and parasite killing. Susceptibility is associated with expansion of IL-4–producing Th2 cells and/or the production of IL-10 and transforming growth factor-β, which are inhibitors of macrophage-mediated parasite killing, and the generation of regulatory T cells and alternatively activated macrophages. Patients with ML exhibit a hyperresponsive cellular immune reaction that may contribute to the prominent tissue destruction seen in this form of the disease. Patients with DCL or active VL demonstrate minimal or absent Leishmania-specific cellular immune responses, but these responses recover after successful therapy.

Within endemic areas, people who have had a subclinical infection can be identified by a positive delayed-type hypersensitivity response to leishmanial antigens (Montenegro skin test). Subclinical infection occurs considerably more frequently than does active cutaneous or visceral disease. Host factors (genetic background, concomitant disease, nutritional status), parasite factors (virulence, size of the inoculum), and possibly vector-specific factors (vector genotype, immunomodulatory salivary constituents) influence the expression as either subclinical infection or active disease. Within endemic areas the prevalence of skin test result positivity increases with age and the incidence of clinical disease decreases with age, indicating that immunity is acquired in the population over time. Individuals with prior active disease or subclinical infection are usually immune to a subsequent clinical infection.

Clinical Manifestations

The different forms of the disease are distinct in their causes, epidemiologic features, transmission, and geographic distribution.

Localized Cutaneous Leishmaniasis

LCL (Oriental sore) can affect individuals of any age, but children are the primary victims in many endemic regions. It may present as 1 or a few papular, nodular, plaquelike, or ulcerative lesions that are usually located on exposed skin, such as the face and extremities (Fig. 277-1

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