Etiology
Leishmaniasis is a localized or systemic infectious disease, caused by the obligate intracellular (macrophage) protozoa of the genus Leishmania and transmitted to humans by the bite of infected female phlebotomine sand flies.[1][2] There are more than 20 Leishmania species, including Leishmania tropica, Leishmania major, Leishmania aethiopica, Leishmania infantum (synonym: Leishmania chagasi), Leishmania donovani, Leishmania mexicana, Leishmania amazonensis, and Leishmania venezuelensis, as well as the Viannia subgenus that includes Leishmania braziliensis, Leishmania guyanensis, Leishmania panamensis, and Leishmania peruviana.[1] A new subgenus, Mundinia, is associated with Leishmania martiniquensis, Leishmania orientalis, Leishmania enrietti.[34]
Transmission is either anthroponotic or zoonotic, depending on whether human or nonhuman mammals are reservoirs of the disease. Many sand fly and mammalian species have been implicated as leishmaniasis vectors and reservoir hosts, respectively.[1][2] Other modes of transmission (e.g., congenital, blood transfusion, organ/tissue transplantation, needle sharing, laboratory infection) occur, but are comparatively rare.[4][5]
Multiple Leishmania species can cause cutaneous leishmaniasis (CL).[1] Visceral leishmaniasis (VL) is caused by L donovani in East Africa and South Asia, or by L infantum (synonym: L chagasi) in Latin America, Europe, North Africa, and parts of Asia, with emerging foci of VL due to Leishmania martiniquensis in Thailand, French West Indies, and Guyana.[2][35][36][37] Most metastatic mucosal leishmaniasis (ML) cases are due to L braziliensis, but can also be caused by L guyanensis, L panamensis, L amazonensis, L aethiopica, and, in patients who are immunosuppressed, L infantum (synonym: L chagasi).[1] Post-kala-azar dermal leishmaniasis is due mostly to L donovani rather than L infantum(synonym: L chagasi).[6] Some CL species (e.g., L major) are known to cause more benign, self-healing lesions than other species (e.g., L braziliensis and L tropica).
Comparative studies focusing on different ethnic groups, natives, migrants, or family clustering have shown that human genetic components control CL susceptibility and resistance.[38] Thus, studies indicate a role of human leukocyte antigen (HLA) molecules in localized CL and ML leishmaniasis, and the role of tumor necrosis factor (TNF)-alpha in developing ML. Similarly, studies have demonstrated a genetic basis for VL susceptibility.[39][40][Figure caption and citation for the preceding image starts]: Female Phlebotomus papatasi sand flyWith kind permission from EdRowtonPhotography.com [Citation ends].
Pathophysiology
When biting their hosts to obtain a blood meal, infected female sand flies regurgitate the flagellated Leishmania promastigotes into the skin, which then invade or are phagocytosed by local or recruited host cells, primarily macrophages.[3][41][42]
Experimental studies have shown that sand fly saliva is vasodilatory, anticoagulatory, and immunogenic: this enhances erythema and increases parasite burden, lesion size, and parasite persistence, probably by shifting the immune response from a T helper 1-type to a T helper 2-type cell-mediated response.[43][44] Some limited data available in natural setting show that variation in sand fly saliva can determine clinical outcome of Leishmania infantum (synonym: Leishmania chagasi) infections.[45]
Within the phagolysosomes of resident macrophages, promastigotes become nonflagellated amastigotes.[46] This amastigote tissue form is found during human infection. Amastigotes replicate, and may then infect additional macrophages, either locally (e.g., in localized cutaneous leishmaniasis [CL]) or in distant tissues after dissemination (e.g., visceral leishmaniasis [VL] or mucosal leishmaniasis). It is unclear why some Leishmania species remain localized while others disseminate.[1][2][47][48] Dissemination from the dermis through the lymphatic and vascular systems leads to infection of other monocytes and macrophages. This results in infiltration of bone marrow, hepatosplenomegaly, and sometimes lymphadenopathy.
In advanced VL, bone marrow and spleen infiltration results in decreased production and increased consumption of blood cells (hypersplenism). Thus, anemia, leukopenia, and/or thrombocytopenia ensue. As the reticuloendothelial system is invaded, the monocytic cell line becomes increasingly susceptible to other infectious agents, as shown by the high frequency of superimposed bacterial infections (e.g., pneumonia, diarrhea, or tuberculosis).
Most human Leishmania infections remain asymptomatic.[1][2] The ratio of asymptomatic to symptomatic infections depends on the type of infecting Leishmania species and strain, host, and sand fly factors, and other noncharacterized factors. For example, this ratio is generally higher in L infantum (synonym: L chagasi) than in Leishmania donovani areas, reflecting the higher virulence of the latter. Other factors (e.g., malnutrition) influence infection and disease as highlighted by the observations that the ratio of asymptomatic to symptomatic L infantum (synonym: L chagasi) infections is different in Latin America than in Europe.[2] People with defective cell-mediated immunity, such as patients infected by HIV or with severe malnutrition, are at higher risk of developing the disease, sometimes years or decades after infection.[19][49][50] Other host determinants such as genetic factors may play an important role in the adaptive immune response.[38] The incubation period can be variable and depends on parasite species.[1][2] This typically is 1 to 3 months for CL, although longer periods are seen.[Figure caption and citation for the preceding image starts]: Female Phlebotomus papatasi sand flyWith kind permission from EdRowtonPhotography.com [Citation ends].[Figure caption and citation for the preceding image starts]: Life cycle of Leishmania species, the causal agents of leishmaniasisImage courtesy of CDC; A.J. da Silva, PhD; M. Moser [Citation ends].
[Figure caption and citation for the preceding image starts]: Skin touch preparation showing Leishmania tropica amastigotes. Intact macrophage is practically filled with amastigotes, several of which have a clearly visible nucleus and kinetoplast (arrows)Image courtesy of CDC; NCID; DPDx [Citation ends].
Classification
Leishmaniasis subtypes
Cutaneous
Localized cutaneous leishmaniasis
Diffuse cutaneous leishmaniasis
Disseminated leishmaniasis
Leishmaniasis recidivans
Mucosal leishmaniasis (sometimes classified as a separate subtype on its own)
Visceral
Visceral leishmaniasis (also known as kala-azar, mainly when associated with Leishmania donovani)
Post-kala-azar dermal leishmaniasis
Cutaneous leishmaniasis is sometimes categorized by geographic occurrence:[1]
Old World: caused by Leishmania species found in the Eastern hemisphere, including Africa, Southwest Asia, the Middle East, and the Mediterranean (e.g., Leishmania tropica, Leishmania major, Leishmania aethiopica, Leishmania infantum [synonym: Leishmania chagasi], and Leishmania donovani)
New World: caused by Leishmania species found in the Western hemisphere, including South and Central America (e.g., Viannia subgenus, including Leishmania braziliensis, Leishmania guyanensis, Leishmania panamensis, and Leishmania peruviana; as well as Leishmania mexicana, Leishmania amazonensis, Leishmania venezuelensis, and L infantum [synonym: L chagasi]; listing not exhaustive).
Clinical classification
The appropriate management is individualized for each CL patient. The Infectious Diseases Society of America (IDSA)/American Society of Tropical Medicine and Hygiene (ASTMH) guidelines classify cutaneous leishmaniasis as either simple or complex.[8]
Simple CL:
No mucosal involvement and parasite species not associated with ML
≤4 lesions <1 cm
Location feasible for local therapy and/or nonexposed skin (not cosmetically important)
Immunocompetent host
Lesions resolving without therapy.
Complex CL:
Parasite species caused by species associated with ML
Local subcutaneous nodules
Large regional adenopathy
>4 lesions generally >1 cm
Individual lesion ≥5 cm
Size or location makes local therapy infeasible and/or lesion of the face, fingers, toes, joints, or genitalia
Immunocompromised host
Failure of local therapy
Unusual syndromes (leishmaniasis recidivans, diffuse cutaneous leishmaniasis, or disseminated leishmaniasis).
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