Leishmaniasis (Leishmania)

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 ( Fig. 311.1 ). Fundamental to this transition are changes that take place in the terminal polysaccharides of the surface lipophosphoglycan , which allow forward migration of the infective parasites to be inoculated in the host skin during a blood meal. Metacyclic lipophosphoglycan also plays an important role in the entry and survival of Leishmania in the host cells. 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 10-20 million people in endemic tropical and subtropical regions on all continents except Australia and Antarctica ( Fig. 311.2 ). 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 waves. 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. 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. These parasites can also cause DCL. Members of the Viannia subgenus ( L. [V.] braziliensis, L. [V.] panamensis, L. [V.] guyanensis, and L. [V.] peruviana ) cause LCL and mucosal leishmaniasis (ML) from the northern highlands of Argentina northward to Central America. Some species, particularly L. (V.) braziliensis, rarely cause disseminated leishmaniasis (DL) . 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. tropica also has been recognized as an uncommon cause of visceral disease in the Middle East and India. VL in the New World is caused by L. (L.) infantum (formerly also called L. chagasi ), which is distributed from Mexico (rare) through Central and South America. L. infantum can also cause LCL in the absence of visceral disease in this same geographic distribution.

The maintenance of Leishmania in most endemic areas is through a zoonotic transmission cycle. In general, the dermotropic strains in both the Old and the New World are maintained in rodent reservoirs, and the domestic dog is the usual reservoir for L. infantum. 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 for vector-borne transmission, 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 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 outbreaks in Syria and Kabul, Afghanistan; 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 or climate change; (3) increase in anthroponotic transmission resulting from rapid urbanization in some focuses; and (4) increase in sandfly density resulting from a reduction in vector control programs.

Pathology

Histopathologic analysis of the skin lesions of LCL and DL show intense chronic granulomatous inflammation involving the epidermis and dermis with relatively few amastigotes. 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 (IL)-12–driven generation of a T helper 1 (Th1) cell response, with interferon (IFN)-γ inducing classic macrophage (M1) 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 (TGF)-β, which are inhibitors of macrophage-mediated parasite killing, and the generation of regulatory T cells and alternatively activated (M2) 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 reduced or altered Leishmania -specific cellular immune responses, with prominent generation of IL-10, 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 skin response to leishmanial antigens (Montenegro skin test ) or by antigen-induced production of IFN-γ in a whole blood assay. 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 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; however, latent infection can lead to active disease if the patient is immunosuppressed.

Clinical Manifestations

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