Leishmaniasis

Background: Leishmaniasis is a zoonotic infection caused by the protozoa belonging to the genus Leishmania. It is named for Leishman, who first described it in London in May 1903. Leishmaniasis is transmitted by sandflies (Phlebotomus species), and, 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 infecting humans mainly are the Leishmania donovani causing visceral leishmaniasis (kala azar) and cutaneous leishmaniasis caused by Leishmania tropica and Leishmania brasiliensis. Visceral leishmaniasis distributed all over the world but is predominantly is encountered in India, South America, Central Asia, Middle East, and Africa. Cutaneous leishmaniasis caused by L tropica is seen mainly along the shores of the Mediterranean, through the Middle East, central Africa, and parts of India. Cutaneous leishmaniasis caused by L brasiliensis is confined mainly to Central America and South America.

Leishmaniasis has a long history. Designs on pre-Columbian pottery and the existence of thousand-year-old skulls with evidence of leishmaniasis prove that the disease has existed in the Americas for a long time. It also has been present in Africa and India since the mid eighteenth century, at least. Geographical distribution of leishmaniasis is restricted to tropical and temperate regions (natural habitat of the sandfly). Leishmaniases are considered to be endemic in 88 countries (16 developed countries, 72 developing countries) on 5 continents of 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 number of cases 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 HIV adds a serious dimension to the problem. Leishmaniasis is spreading in several areas of the world as a result of the rapidly spreading epidemic of AIDS. The immune deficiency has lead to increased susceptibility to infections, including leishmaniasis. So far, co-infections have been reported in 33 countries worldwide 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 also may change asymptomatic Leishmania infections into symptomatic ones. Sharing of needles by intravenous drug users can spread not only HIV but also leishmaniasis.

Although cutaneous leishmaniasis exists 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.

Pathophysiology: Leishmaniasis infections are considered to be zoonotic diseases because the infection is being maintained in endemic areas in dogs, wild rodents, and other animals. Leishmania are obligatory intracellular parasites. Leishmania are transmitted by the bite of a tiny 2- to 3-millimeter insect vector, the sandfly belonging to the genera Phlebotomus and Lutzomyia . Of 500 known phlebotomine species, only about 30 of them have been positively identified as vectors of the disease.

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

Life cycle

The parasite exists in 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 . 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. During a period of 4-25 days, the parasite continues its development inside the sandfly, where it undergoes 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 entering the circulation are destroyed while others enter the cells of the reticuloendothelial system. Here they change into the amastigote form. The amastigote forms also multiply by binary fission, with the multiplication continuing until the host cell is packed with the parasites and ruptures, liberating the amastigotes into 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 the bite of sandfly. Different species of sandfly act as vectors in different parts of the world . The uncommon modes of transmission are through congenital transmission, through blood transfusion, and, rarely, through inoculation of cultures.

Pathogenesis

After inoculation by sandflies, the flagellates (promastigote form) bind to macrophages in 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 seen in this disease.

Leishmaniasis is a disease involving 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, it is soft and fragile, its vascular spaces are dilated and engorged with blood, and the reticular cells of Billroth are increased markedly 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.

Frequency:

• Internationally: Today, an estimated 12 million cases of leishmaniasis 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 (VL) occur each year.

  Of the 500,000 new cases of VL that occur annually, 90% are in Bangladesh, Brazil, India, Nepal, and Sudan. Mucocutaneous leishmaniasis occurs mainly in South America, with Bolivia, Brazil, and Peru accounting for 90% of the cases . Nearly 90% of all cases of cutaneous leishmaniasis occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria, with 1-1.5 million new cases reported annually worldwide.

History: Visceral leishmaniasis is caused by L donovani. The spectrum of illness ranges from asymptomatic infection to severe life-threatening infection also known as kala azar, Dumdum fever, Assam fever, and infantile splenomegaly in various parts of the world. It is the most severe form of leishmaniasis and usually is fatal within 2 years if left untreated. The incubation period usually is 3-6 months but can be months or years. Young malnourished children are the most susceptible to developing progressive infection.

The disease has an insidious onset with pyrexia, which is continuous or remittent and becomes intermittent at a later stage. It characteristically is described as a double rise in 24 hours. Waves of pyrexia may be followed by a period of no fever. Occasionally the disease may present with an acute onset. Children presenting later in the course of the disease may present with edema caused by hypoalbuminemia, hemorrhage caused by thrombocytopenia, or growth failure caused by features of chronic infection.

Although the patient has high fever, malaise is not seen, and usual accompaniments such as anorexia and coated tongue are unusual.

Fulminant forms of visceral leishmaniasis, which affect mainly children, have been reported from India, with manifestations that include pancytopenia and hepatic failure.

Physical: Splenic enlargement is another striking feature that often is considerable. The abdomen is protuberant because of the splenomegaly and the accompanying hepatomegaly. With progress of the disease, the spleen extends to well below the costal margin. The spleen is usually firm to hard, but soft spleen can be seen in acute disease.

Jaundice with mildly elevated enzyme levels is rarely seen and is considered a bad prognostic sign.

Lymphadenopathy is observed in the African and Chinese forms but rarely in the Indian form.

Anemia almost always is present and usually is severe. It is normochromic and normocytic and caused by various factors, including replacement of marrow by the parasites, splenic sequestration, hemorrhage, hemodilution, and hemolysis. Leukopenia also is observed and may contribute to secondary infections. Thrombocytopenia contributes to the hemorrhagic tendency observed in some cases.

The skin is dry, thin, and scaly, and hair is lost. As the disease progresses, the skin on the hands, feet, abdomen and face may become darkened, giving the name kala azar or black fever. Petechiae and ecchymosis may be seen in the extremities. Pedal edema is observed more commonly in children. Skin lesions, which contain parasites and appear as diffuse, warty, nonulcerative lesions, may occur in visceral leishmaniasis, especially in Africa. Mucosal lesions in the mouth and nose, which appear as nodules or ulcers and may lead to perforation of the nasal septum, have been described in Sudan but are rare elsewhere.

Hypergammaglobinemia, circulating immune complexes, and rheumatoid factors are present in sera of most patients with visceral leishmaniasis. Rarely, immunocomplex deposition in the kidneys may lead to mild glomerulonephritis. However, renal failure is not a feature of visceral leishmaniasis.

Unusual clinical presentations include pancytopenia without splenomegaly, generalized lymphadenopathy without hepatosplenomegaly, massive hepatic necrosis, and retinal hemorrhages. If untreated, death occurs within 2 years and often is caused by bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage or its sequelae.

A variant of visceral leishmaniasis has been described in US soldiers who participated in the gulf war. This is associated with light parasitic burden and mild symptoms including fever, malaise, and nausea.

• Post–kala azar dermal leishmaniasis follows the treatment of visceral leishmaniasis in approximately 10% of cases in India and 2% of cases in Africa. Lesions in India develop 1-2 years after treatment of the original disease and may persist for as long as 20 years. In Africa, they usually appear during or shortly after treatment and persist only for a few months. Recurrence of kala azar resistant to antimonials has been reported in dermal leishmanoid, with an incidence of 1 in 700 cases.

• Dermal lesions are categorized into 3 types, as follows:

• Depigmented macules are the earliest lesions and are seen in the trunk and extremities.

• Erythematous patches appear early in the course of disease and are seen in the nose, cheeks, and chin with a butterfly distribution. They are photosensitive, becoming prominent toward the middle of the day.

• Yellowish pink nodules appear mostly on the face and replace the earlier lesions. The absence of ulceration distinguishes these nodules from those of cutaneous leishmaniasis (oriental sore).

• Cutaneous leishmaniasis occurs mainly in 2 forms, oriental sore caused by L tropica and American cutaneous leishmaniasis caused by L brasiliensis. No difference in the pathology of the lesions caused by L tropica and L brasiliensis exists. Cutaneous leishmaniasis produces skin lesions mainly on the face, arms, and legs. Although this form is often self-healing, it can create serious disability and permanent scars. After recovery or successful treatment, cutaneous leishmaniasis induces immunity to reinfection by the species of Leishmania that caused the disease.

• Urban cutaneous leishmaniasis caused by subspecies L tropica causes a dry type of cutaneous ulcer in the face and has an urban distribution. Incubation period is approximately 2 months. It is common in Western India, North Africa, Mediterranean area, and Middle East. A similar disease in Mexico, Honduras, and Guatemala is known as the bay sore or chiclero ulcer. It is a chronic lesion occurring at the site of sand fly bite.

• Rural cutaneous leishmaniasis is caused by L tropica major and has a rural distribution. The moist type of cutaneous lesions are multiple, on the extremities, and are associated with marked local subcutaneous infiltration and regional lymphadenitis. Both lesions are common in Central Asia.

• Diffuse cutaneous leishmaniasis is associated with a deficient cell-mediated immunity that enables the parasite to disseminate in the subcutaneous tissues. It starts as a single lesion and spreads slowly over the face, ears, extremities, and buttocks until the whole body is affected. The lesions are neither destructive nor erosive but are disfiguring. The lesions are misdiagnosed as leprosy and are resistant to treatment.

• Mucocutaneous leishmaniasis, also called espundia in South America, causes disfiguring lesions to the face; it destroys the mucous membranes of the nose, mouth, and throat. The lesions commonly arise at the mucocutaneous junction around the nose and may spread inward, destroying tissues and leading to deformity. The lesions heal by scarring, causing the typical tapir or camel nose. It carries a significant mortality rate. Children rarely are affected.

Causes: Leishmaniasis is a zoonotic infection caused by the protozoa belonging to the genus Leishmania. Leishmaniasis is transmitted by sandflies (phlebotomus species), and, in the human host, Leishmania are intracellular parasites that infect the mononuclear phagocytes. Visceral leishmaniasis is caused by L donovani.