2.6 Leishmaniases and phlebotomines

The pathogens Leishmania spec. are flagellates with a kinetoplast integrated into a mitochondrium inside of which the kinetoplast changes its position according to the morph of the flagellate. Leishmanias belong to the Trypanosomatids. In their mammalian hosts, they are obligatory intracellular kryptomastigot parasites. The vectors are sandflies or Phlebotomines (Diptera: Nematocera, family Psychodidae).

The disease has a broad spectrum and is classified according to geographical region and its main symptoms as the cutaneous Leismaniases of the Old World, the visceral types of the tropics and the muco-cutanous types of the New World (fig. 2.50, page 95). The different pathogens can be typed by an analysis of their isoenzymes and DNA. However, a stringent relationship is absent and specific zymodemes or DNA patterns cannot be assigned to certain courses of the disease.

According to their pathogenesis, the leishmaniases are differentiated as follows (fig. 2.51, page 97): Localised and limited: Cutaneous Leishmaniasis. Starting at the biting point, a necrotic focus grows for some months until it is arrested and heals spontaneously leaving a scar combined with protective immunity. Anthropo- and Zoonones attributable to L. tropica, L. major, L. brasiliensis panamensis, L .b. guyanensis, L .b. peruviana. In the guinea pig L. enrietti has been found.

Localised and progredient: Diffuse cutaneous Leishmaniasis. The pathogen remains limited to the skin but disseminates unlimitedly giving rise to symptoms similar to leprosy. No selfhealing. Anthropo- and zoonoses attributable to L. aethiopica, L. mexicana amazonensis, L. m. pifanoi.

Generalized and progredient: Visceral Leishmaniasis. Dissemination of the pathogen via blood and probably lymph vessels to internal organs (liver, spleen, bone marrow, intestine, adrenal gland) with obligatory death after several years. Following successful chemotherapy, protective immunity persists lifelong. Anthroponoses attributable to L. donovani donovani ("Kala Azar"), L. d. infantum, L. chagasi.

Localized and progredient: Muco-cutaneus Leishmaniasis. After entering the mucous tissues of the nose or mouth, the pathogen continuously destroys the cartilage but does not disseminate to other tissues "Espundia". Hunger leads to kachexia and death of the patient: L. brasiliensis. After a bite near the outer ear, the cartilage under the skin may also be affected "Chiclero": L. mexicana. The symptoms are variable because of the zoonotic character of the disease.

Diagnosis requires the identification of the pathogen microscopically in biopsy samples of the organ attacked (wall of the ulcer, bone marrow). Since this test is often negative, anamnestic exploration is important. For chemotherapy, preparations based on pentavalent antimony, Pentamidine and Amphotericin B, are used. Visceral Leishmaniasis caused by L. donovani infantum and caught in the Mediterranean area (typically are tourists with caravans and a dog) may develop over many years; fatal unless treated.

Development in the vector (phlebotomines) occurs suprapylorically (fig. 2.52, page 100, above). The kryptomastigotes are taken up with macrophages inside the midgut and exist freely within the peritrophic membrane. They transform into flagellate promastigotes that agglomerate for a short time (for the exchange of genes?). Afterwards, they colonize the anterior parts of the midgut, adhere to the walls of midgut and oesophagus, multiply and, after 7-10 days transform into metacyclic promastigotes, which are infective to mammals. They then block the passage of the intestine and are transmitted by regurgitation during feeding trials of the sandfly .

Development in the warmblooded host in cutaneous Leishmaniasis (fig. 2.52, page 100, below): Promastigotes, deposited into the skin of the warmblooded vertebrate host, induce Langerhans cells to migrate from the epidermis to the cutis in order to phagocytoze leishmanias. Some of the langerhans cells transport the leishmanias as developed kryptomastigotes to the regional lymph nodes for presentation to antigen-specific resting T-cells in the paracortex. The activated T-cells emigrate via lymph vessels and the circulating blood back into the lesion and recognize macrophages with internalized living leishmanias presenting antigens and stimulate their death. Other T-cells contact macrophages with killed stages, recognize other antigens expressed by them and inhibit the further killing of internalized leishmanias. The latter propagate by pathogenesis and may be taken up by the vector for further transmission.

The limited flight mobility of phlebotomines entails the focal distribution of leishmaniases. Originally, they were zoonoses, the natural reservoir of which was in the small burrowing mammals of steppes and savannahs. In the tropical rain forest, primarily tree-dwelling mammals, such as sloths, opossum, anteater and the kinkajou (Potos flavus), harbour Leismanias, establishing silvatic cycles (fig. 2.53, page 103). Wood cutters and workers in plantations are especially at risk of infection. Ground-living mammals are secondary reservoir hosts and create peridomestic cycles near human settlements (fig. 2.54, page 104). In pure domestic cycles, the dog may be involved. However, in India, visceral Leismaniasis appeared as an anthroponosis without participation of dogs. Phlebotominae are difficult to detect but show distinct characteristics (fig. 2.55, page 105).

Leismaniasis belongs to the immunologically most intensively investigated parasitic disease, if not the most investigated infectious diseases in general. Many of the human pathogenic Leishmanias may be investigated by using inbred mice strains. However, the cell-mediated immune responses do not follow common rules and is different in mice and in man. One important open question is how some Leismanias that are phagocytozed by macrophages survive, whereas others do not.

Leishmaniases are usually endemic, but visceral leishmaniasis sometimes appears epidemically (India, Sudan). The worldwide socio-economic losses calculated as DALYs (Disability Adjusted Life Years, see chapt. 8.4, page 298 ff) attains 8.6 million years for females and 1.2 million years for males, probably because of lower exposure. As a control measure, insectcides are sprayed inside housing and stables. To prevent local epidemics, an early diagnosis sometimes by non-specific measures (aldehyde test) is helpful, combined with the strict treatment of all cases of obscure fever and the removal of dogs.

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