Pediatric Leishmaniasis 

Leishmaniasis is a zoonotic infection caused by protozoa that belong to the genus Leishmania. The disease is named after Leishman, who first described it in London in May 1903. Leishmaniasis is transmitted by sandflies (Phlebotomus species). In the human host, Leishmania are intracellular parasites that infect the mononuclear phagocytes. The spectrum of human disease ranges from self-healing localized ulcers to widely disseminated progressive lesions of the skin, mucus membranes, and the entire reticuloendothelial system.

Epidemiology

The Leishmania species that infect humans are mainly Leishmania donovani, which causes visceral leishmaniasis (kala azar), and Leishmania tropica and Leishmania brasiliensis, which cause cutaneous leishmaniasis . Visceral leishmaniasis occurs worldwide but is predominantly encountered in India, South America, Central Asia, the Middle East, and Africa. Cutaneous leishmaniasis caused by L tropica is most common along the shores of the Mediterranean, throughout the Middle East, central Africa, and parts of India. Cutaneous leishmaniasis caused by L brasiliensis is mainly confined to Central America and South America.

Leishmaniasis has a long history. Designs on pre-Columbian pottery and thousand-year-old skulls with evidence of leishmaniasis prove that the disease has existed in the Americas for a long time. It has also been present in Africa and India since at least the mid eighteenth century. Geographical distribution of leishmaniasis is restricted to tropical and temperate regions (natural habitat of the sandfly). Leishmaniases are considered endemic in 88 countries (16 developed countries, 72 developing countries) on 5 continents: Africa, Asia, Europe, North America, and South America. A total of 350 million people are at risk. Geographical distribution of leishmaniasis is limited by the distribution of the sandfly, its susceptibility to cold climates, its tendency to take blood from humans or animals only, and its capacity to support the internal development of specific species of Leishmania.

The incidence of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. Poverty and malnutrition play a major role in the increased susceptibility to the disease. Extracting timber, mining, building dams, widening areas under cultivation, creating new irrigation schemes, expanding road construction in primary forests such as the Amazon, continuing widespread migration from rural to urban areas, and continuing fast urbanization worldwide are among the primary causes for increased exposure to the sandfly.

Another risk factor is the movement of susceptible populations into endemic areas, including large-scale migration of populations for economic reasons. In the city of Kabul, Afghanistan, which has a population of less than 2 million, an estimated 270,000 cases of cutaneous leishmaniasis occurred in 1996. The resurgence of visceral leishmaniasis has occurred because of deficiencies in the control of the vector (sandfly), absence of a vaccine, and lack of access to medical treatment because of the cost and increasing drug resistance to first-line treatment.

Coexistence of leishmaniasis with human immunodeficiency virus (HIV) infection is a serious concern. Leishmaniasis is spreading in several areas of the world because of the rapidly spreading epidemic of acquired immunodeficiency syndrome (AIDS). The immune deficiency has lead to increased susceptibility to infections, including leishmaniasis. Thus far, co-infections have been reported in 33 countries worldwide (see below).

Co-infection with HIV has lead to the spread of leishmaniasis, typically a rural disease, into urban areas. In patients infected with HIV, leishmaniasis accelerates the onset of AIDS by cumulative immunosuppression and by stimulating the replication of the virus. It may also change asymptomatic Leishmania infections into symptomatic infections. Sharing of needles by intravenous drug users can spread not only HIV but also leishmaniasis.

Although cutaneous leishmaniasis is found in many countries where L donovani is prevalent, the 2 parasites are not present in the same regions. In India, visceral leishmaniasis is confined to the eastern parts, and cutaneous leishmaniasis is limited to the dry western parts.

Leishmaniasis infections are considered zoonotic diseases because the infection is maintained in dogs, wild rodents, and other animals in endemic areas. Leishmania are obligatory intracellular parasites and are transmitted by the bite of a tiny 2-mm to 3-mm insect vector, the sandfly belonging to the genera Phlebotomus and Lutzomyia, shown below.

Only about 30 of the 500 known phlebotomine species have been positively identified as vectors of the disease.

The reservoir of infection for Indian kala azar is humans, whereas it is rodents for African kala azar, foxes in Brazil and Central Asia, and canines for the Mediterranean and Chinese kala azar.

Life cycle

The parasite has 2 forms: the amastigote form and the promastigote form. The amastigote form occurs in humans, whereas the promastigote form occurs in the sandfly and in artificial culture (see below).

Only the female sandfly transmits the protozoan, infecting itself with the Leishmania parasites contained in the blood it sucks from its human or mammalian host. Over 4-25 days, the parasite continues its development inside the sandfly, where it undergoes a major transformation into the promastigote form. A large number of flagellate forms (promastigotes) are produced by binary fission. Multiplication proceeds in the mid gut of the sandfly, and the flagellates tend to migrate to the pharynx and buccal cavity of the sandfly. A heavy pharyngeal infection is observed between the sixth and ninth day of an infected blood meal. A bite during this period results in the spread of leishmaniasis.

Following the bite, some of the flagellates that enter the circulation are destroyed, whereas others enter the cells of the reticuloendothelial system, where they change into the amastigote form. The amastigote forms also multiply by binary fission, with multiplication continuing until the host cell is packed with the parasites and ruptures, liberating the amastigotes into the circulation. The free amastigotes then invade fresh cells, thus repeating the cycle and, in the process, infecting the entire reticuloendothelial system. Some of the free amastigotes are drawn by the sandfly during its blood meal, thus completing the cycle.

Cutaneous leishmaniasis is caused by L tropica. Morphologically, it is indistinguishable from L donovani. The life cycle is exactly the same as that of L donovani except that the amastigote form resides in the large mononuclear cells of the skin.

Methods of transmission

The predominant mode of transmission is a sandfly bite. Different species of sandfly act as vectors in different parts of the world (see below).

Uncommon modes of transmission include congenital transmission, blood transfusion, and, rarely, inoculation of cultures.

Pathogenesis

After inoculation by sandflies, the flagellates (promastigote form) bind to macrophages in the skin. Two of the parasite surface molecules appear to play a prominent role in parasite-phagocyte interactions. The outcome of Leishmania infection appears to depend on the complex interaction between the parasite's virulence and the immune response of the host. Promastigotes activate complement through the alternate pathway and are opsonized. The most important immunological feature is a marked suppression of the cell-mediated immunity to leishmanial antigens. In persons with asymptomatic self-resolving infection, T-helper cells predominate, although immune suppression years later can result in disease. An overproduction of both specific immunoglobulins and nonspecific immunoglobulins also occurs. The increase in gamma globulin leads to a reversal of the albumin-globulin ratio commonly associated with this disease.

Leishmaniasis is a disease that involves the reticuloendothelial system. Parasitized macrophages disseminate infection to all parts of the body but more so to the spleen, liver, and bone marrow. The spleen is enlarged, with a thickening of the capsule, and is soft and fragile; its vascular spaces are dilated and engorged with blood. The reticular cells of Billroth are markedly increased and packed with the amastigote forms of the parasite. However, no evidence of fibrosis is present. In the liver, the Kupffer cells are increased in size and number and infected with amastigote forms of Leishmania. Bone marrow turns hyperplastic, and parasitized macrophages replace the normal hemopoietic tissue.

Genetic susceptibility to visceral leishmaniasis has been described in parts of Sudan. Susceptibility genes in chromosome 22q12 have been found in an ethnic group in Sudan that has a high prevalence rate of visceral leishmaniasis.

Frequency

International

An estimated 12 million cases of leishmaniasis currently exist worldwide, with an estimated 1.5-2 million new cases occurring annually. Approximately 1-1.5 million cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis occur each year.

Of the 500,000 new cases of visceral leishmaniasis that occur annually, 90% are in Bangladesh, Brazil, India, Nepal, and Sudan. See the map below.

Mucocutaneous leishmaniasis mainly occurs in South America, with Bolivia, Brazil, and Peru accounting for 90% of the cases. See the map below.

Nearly 90% of all cases of cutaneous leishmaniasis occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, Sri Lanka, and Syria, with 1-1.5 million new cases reported annually worldwide.