Occurrence. Various forms of leishmanioses occur in the warmer regions of 88 countries in Asia, Africa, Europe (Mediterranean countries!), and Latin America (Fig. 9.7). The annual number of new cases is estimated at 1.5-2 million (0.5 million VL, 1-1.5 million CL and MCL). Both geographic distribution and case numbers are reported to be on the increase (WHO, 2000).

Parasites and life cycle. The many (about 15) species of the genus Leishmania pathogenic to humans do not show morphological differences. They can be differentiated on the basis of biological criteria, laboratory analyzes (mainly isoenzyme patterns and DNA analysis), the different clinical pictures, and epidemiological facts (Table 9.4, p. 495).

In humans and other vertebrates, leishmanias parasitize in mononuclear phagocytic cells (macrophages, monocytes, Langerhans cells) in the amasti-gote form. The Giemsa-stained organisms are recognizable under a light microscope as round-to-oval cells 2-5 im in diameter with a nucleus and a small, rod-shaped kinetoplast (Fig. 9.8). A rudimentary flagellum, a single mitochondrion and other cell organelles are also rendered visible on the electron microscopic level (see also Trypanosoma).

The leishmania species are transmitted by female mosquitoes of the genera Phlebotomus (Old World) and Lutzomyia (New World) known as "sandflies" (Fig. 9.9 and 11.1). The amastigote stages of the parasite ingested by the insect with a blood meal are transformed in its intestine into slender, flagellate promastigote forms 10-15 im long, which multiply and migrate back into the proboscis. At tropical temperatures this process takes five to eight days. When infected sandflies take another bloodmeal the promastigote forms are inoculated into a new host (humans or other vertebrates). In the

Leishmania Promastigote Stages

Table 9.4 Selected Forms of Leishmanioses in Humans

(L.: subgenus Leishmania, V.: subgenus Viannia)

Visceral leishmanioses

Main localization: Internal organs, less often skin.

Incubation: In most cases 3-6 months, also: several weeks to years

Primary symptoms: Fever, splenomegaly, hypergammaglobulinemia, progressive anemia, leucopenia etc.

■ L. (L.) donovani: Asia: India, Bangladesh, southern Nepal. Mainly in adults.

Reservoir hosts2: humans. Vectors: Phlebotomus species.

■ L. (L.) donovani: Africa: Mainly Sudan, Ethiopia, Kenya. Reservoir hosts:

humans, dogs (Felidae, rodents?)2. Vectors: Phlebotomus species.

■ L. (L.) infantum: Mediterranean region (Iberian Peninsula to Turkey, northern

Africa), Middle East and central Asia, China. In children and adults; in adults cutaneous manifestations as well: Reservoir hosts: humans, dogs, wild Canidae. Vectors: Phlebotomus species.

■ L. (L.) chagasi3: Central and northern South America. Mainly in youths.

Reservoir hosts: humans, dogs, fox species, (opossum?). Vectors: Lutzomyia species.

Cutaneous leishmanioses (oriental sore)

Main localization: Incubation: Primary symptoms:


Weeks to months.

On skin accessible by Phlebotomus species, development of solitary or multiple, dry, later possibly ulcerating papules; rarely spread to lymph vessels and nodes. Healing with scarification. Solid immunity is conferred by infections with L. major and L. tropica.

Northern Africa, Middle East, Sahel Zone, western Asia. Incubation: up to 2 months. "Moist," (= "rural," or "zoonotic" ) form. Rapid growth of cutaneous lesion, later ulceration and healing within 6 months. Reservoir hosts: rodents. Vectors: Phlebotomus species.

Mediterranean region, southwestern Asia to India. Incubation: 2-24 months. "Dry," (= "urban," or "anthroponotic" ) form. Development of lesions and persistence longer than with L. major. Reservoir hosts: humans. Vectors: Phlebotomus species.

Table 9.4 Continued: Selected Forms of Leishmanioses in Humans

■ L. (L.) aethiopica: Ethiopia, Kenya. Cutaneous leishmaniosis. Reservoir hosts: rock hyrax and bush hyrax. Vectors: Phlebotomus species.

American cutaneous and mucocutaneous leishmanioses

Main localization: Primary symptoms:

Skin, mucosa.

Skin changes similar to oriental sore. Some forms tend to spread to mucosa and cause severe tissue destruction.

Southern US (Texas), parts of Central America and northern South America. Various Leishmania subspecies. Destructive cutaneous form. Reservoir hosts: woodland rodents. Vectors: Lutzomyia species.

Parts of Central and South America. Various Leishmania subspecies. Mucocutaneous form ("espundia"). Reservoir hosts: woodland rodents, sloth, opossum. Vectors: Lutzomyia species.

Peru (Andes). Cutaneous form ("uta"). Reservoir hosts: dogs. Vectors: Lutzomyia

1 Kala (Hindi) azar (Persian) = black disease (due to hyperpigmentation of skin caused by the infection) is the name given in India to the infection caused by L. (L.) donovani.

2 Reservoir hosts: Epidemiological^ significant hosts from which vectors can transmit parasites to humans. In parentheses with question mark: significance questionable.

3 L. chagasi and L. infantum have many similarities. It is therefore assumed that L. infantum was imported to South America in dogs from Europe.

host, they bind host components to their surface (IgM, complement, erythrocyte receptor) and, thus equipped, couple to macrophage receptors. They are then phagocytosed and enclosed in a phagolysosome, where they are protected from the effects of lysosomal enzymes inter alia by substances in their cell membrane. The promastigotes quickly (within 12-14 hours) transform into amastigote stages, which are finally surrounded by a parasitophorous vacuole within the phagolysosome and reproduce by binary fission. The amastigote forms are then released in a process resembling exocytosis and can infect new cells.

Clinical manifestations and immunology. The most important human forms of leishmanioses are summarized in Table 9.4. It is important to note that in CL and MCL the parasites generally remain restricted to the skin or skin and mucosa. CL lesions may persist for long periods, but tend to heal spontaneously, whereas a greater tendency to destructive changes is seen in MCL infections. By contrast, in VL the leishmania organisms can invade the entire

— Leishmania infantum: Life Cycle

Steps Exocytosis

mononuclear phagocytic system in various organs (spleen, liver, lymph nodes, bone marrow, blood monocytes, etc.), causing infections that are normally lethal without treatment.

Basic research using animal models has provided and explanation for these differences: the course of an infection is apparently dependent on the activation of various T lymphocyte subpopulations by Leishmania antigens. Activation of TH1 cells involves production of IFNy, which activates macrophages that exert a protective effect by killing Leishmania organisms by means of a nitric oxide-mediated mechanism. On the other hand, when TH2 cells are activated large amounts of 1L-4 and 1L-10 are produced, which inhibit NO activity, thus reducing or even preventing elimination of the parasites. Production of antibodies is also greatly increased, but they do not play a significant role in immune protection. Findings in patients are in accordance with these interpretations: in CL, high concentrations of IFNy were found, but in severe cases of VL the levels of 1L-4 and 1L-10 were raised and IFNy concentrations were low. The situation is similar in severe forms of MCL. It would appear that the cell-mediated immune response in CL protects efficiently, but the immune response in advanced VL and some forms of MCL is more or less suppressed. 1n cases where the immune defenses are additionally weakened by AIDS, a latent Leishmania infection may be activated and take a fulminant symptomatic course. In endemic regions, the risk to acquire a Leishmania infection is increased for AIDS patients by 100-1000 times. Most of the cases of AlDS-associated leishmaniosis (about 50%) registered to date (1990-1998) were reported from areas in which L. infantum is endemic in southwestern Europe (Italy, France, Spain, Portugal) (others from India, Africa, Latin America, etc.) (WHO, 1999). Besides L. infantum, coinfections with other Leishmania species have also been found in A1DS patients (e.g., L. do-novani, L. braziliensis, L. tropica).

Epidemiology. Table 9.4 refers briefly to the epidemiology of this disease. In central Europe, leishmaniosis deserves attention as a travelers' disease, especially the VL imported from Mediterranean countries. Major VL epidemics have occurred recently in various parts of the world, e.g., in southern Sudan with 100 000 deaths in a population of <1 million (WHO, 2000).

Diagnosis. An etiological diagnosis of VL is made by means of direct parasite detection in aspirate material from lymph nodes or bone marrow (in HIV patients also in the enriched blood leukocyte fraction) in Giemsa-stained smears (uncertain!), in cultures (in which promastigotes develop) or using PCR. Cultivation and PCR have about the same high level of sensitivity. Antibodies are detectable in nearly all immunocompetent patients (around 99%), but 40-50% of HIV-coinfected patients are seronegative (Table 11.5, p. 625).

Diagnosis of a cutaneous leishmaniosis is usually based on clinical evidence. Etiological verification requires direct parasite detection (see above)

in smears or excised specimens from the edges of the skin lesions. More reliably, the parasites can be detected by cultivation or PCR. Serological antibody tests are positive in only a small proportion of cases.

Therapy and prevention. Treatment of VL is usually done with pentavalent antimonials (meglumine antimonate, sodium stibogluconate) pentamidine, or amphotericin B. The recurrence rate is relatively high, especially in HIV patients. Miltefosine, a newly developed and well tolerated antitumor alkyl-phospholipid for oral application, has proved effective against VL. Various forms of CL (for instance L. major and L. tropica) can be influenced by injecting antimonial preparations into the lesions; mucocutaneous leishmaniosis (L. braziliensis) is treated systemically with antimonials (see above, ampho-tericin B, or pentamidine). An effective chemoprophylaxis has not yet been developed. It is therefore important to prevent Phlebotome bites with fine-meshed, insecticide-impregnated "mosquito nets" (p. 535). Control of the vectors involves use of insecticides and elimination of breeding places.

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