Leishmanioses

Leishmaniasis is an obligate transmissible disease caused by protozoa of the genus Leishmania. The life cycle of leishmania proceeds with a change of hosts and includes two morphological forms: amastigote (without flagellum) and promastigote (with flagellum). In the amastigote form, leishmania parasitize in the cells (macrophages) of natural reservoirs (vertebrates) and humans; in the promastigote form, they live in various parts of the digestive tract of mosquitoes, which serve as their carriers and in nutrient media.

Leishmania carriers are dipterous insects: the Old World - mosquitoes of the genus Phlebotomus, the New World - the genus Lutzomya. The main natural reservoirs are rodents and representatives of the canine family.

The area of distribution of leishmaniasis includes countries with hot and warm climates. Human diseases have been registered in 76 countries in Asia, Africa, Southern Europe, Central and South America. In many countries, leishmaniasis causes significant socio-economic damage. In Russia, there are currently no local cases of leishmaniasis, but imported cases are registered annually, among those infected - people who have visited countries of the near and far abroad, endemic for leishmaniasis. At the same time, patients are identified among citizens of both foreign countries and the Russian Federation, who have returned from business or tourist trips to areas with a subtropical or tropical climate.

There are three clinical forms of leishmaniasis: cutaneous, mucocutaneous and visceral. In cutaneous leishmaniasis, the skin is affected; in mucocutaneous leishmaniasis, the skin and mucous membranes, mainly of the upper respiratory tract, sometimes with destruction of soft tissues and cartilage; in visceral leishmaniasis, the pathogen is localized in the liver, spleen, bone marrow and lymph nodes. In Russia, cutaneous and visceral leishmaniasis are most often registered.

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The development cycle of Leishmania

The infection process begins when promastigotes enter the host organism with the saliva of mosquitoes that bite the person on the face or limbs. The parasites are engulfed by dermal macrophages and soon transform into amastigotes or micromastigotes, which reproduce by transverse division, which ultimately leads to rupture of the macrophages. This process continues for a long time, since the released amastigotes are engulfed by new macrophages, which accumulate in the lesion and proliferate there. The affected macrophages facilitate further dissemination of the parasites. The subsequent development of the lesion depends on the individual characteristics of the parasite and the state of the immune reactions of the host organism. The situation is complicated by the fact that each taxon of Leishmania may include several different strains; however, usually each species or subspecies of Leishmania causes a fairly characteristic disease, which is included in one of the main groups.

The mosquito becomes infected with amastigotes of Leishmania when sucking blood from an infected vertebrate. In the mosquito's intestine, Leishmania pass into the promastigote stage, multiply by longitudinal division and develop within a week, turning into invasive forms that concentrate in the anterior sections of the intestine and in the mosquito's proboscis. Development of promastigotes in mosquitoes occurs at temperatures above 15 °C. When the carrier sucks blood again, promastigotes enter the blood of the vertebrate host, are phagocytosed by RES cells and turn into amastigotes.

Mosquitoes are small dipterous insects, ranging in size from 1.2 to 3.7 mm. They are distributed throughout the world in tropical and subtropical zones, in the belt between 50° N and 40° S. Mosquitoes live both in populated areas and in natural biotopes. In populated areas, mosquito breeding grounds are cellars, garbage dumps and other places where rotting organic matter accumulates. In natural conditions, mosquitoes hatch in rodent burrows, bird nests, caves, tree hollows, etc.

The peculiarities of the distribution of leishmania and its circulation in the territory endemic for leishmaniasis are closely connected with the peculiarities of the ecology of their carriers - mosquitoes. Thus, in the Old World leishmaniasis is widespread in dry (arid) territories - deserts, semi-deserts and oases; in the New World - these are (with rare exceptions) diseases of the humid tropical forest.

In populated areas of Central Asia, mosquitoes usually fly away only tens of meters from their breeding sites; in open areas, they spread up to 1.5 km. In the northern part of their range, mosquitoes have one generation and are active from June to August. In Central Asia, two generations usually develop, with a maximum population in early June and early August. In tropical countries, mosquitoes are active all year round. Mosquitoes are crepuscular and nocturnal insects; during 2-3 weeks of their life, females feed on blood and lay eggs 2-3 times.

Epidemiology of leishmaniasis

Leishmaniasis is one of the most important diseases in tropical pathology. According to the World Health Organization, leishmaniasis is common in 88 countries, and in 32 countries the disease is subject to mandatory registration. According to expert estimates, the number of people with leishmaniasis in the world is 12 million people. Every year, 2 million new cases occur. About 350 million people live in areas endemic for leishmaniasis and are at risk of infection.

Leishmaniasis is included in the WHO Special Programme for the Study and Control of Tropical Diseases. In some developing countries, leishmaniasis may act as a factor holding back economic development in certain areas.

There are several species of Leishmania pathogenic to humans, which are similar in their morphology, but differ in their antigenic, molecular biological and biochemical characteristics, as well as in the clinical picture and epidemiology of the diseases they cause.

Three main groups of leishmaniasis can be distinguished:

1. Cutaneous leishmaniasis.
2. Mucocutaneous American leishmaniasis.
3. Visceral leishmaniasis.

However, such a division cannot be considered absolute: in some cases, pathogens of visceral forms of the disease can cause skin lesions, and pathogens of cutaneous forms can cause lesions of internal organs.

Cutaneous leishmaniasis was first described by the English physician Rosske (1745). The clinical picture of the disease was covered in the works of the Russell brothers (1756), Russian military doctors N. A. Arendt (1862) and L. L. Reidenreich (Pendinsky Ulcer, 1888).

A major event was the discovery of the causative agent of cutaneous leishmaniasis by the Russian military doctor P. F. Borovsky (1898). This causative agent was also discovered by the American doctor J. H. Wright (1903). In 1990-1903, W. B. Leishman and C. Donovan discovered the causative agent of visceral leishmaniasis in the spleen of patients with Indian leishmaniasis, which was described by A. Laveran and F. Mesnil (1903) under the name L. donovani, and the causative agent of cutaneous leishmaniasis was named L. tropica in 1909.

Only in cutaneous leishmaniasis can the disease result in the development of intense sterile immunity and resistance to reinvasion. But even in this disease, the parasites can sometimes persist in the patient's body. For example, L. brasiliense can spread and affect the nasopharynx many years after the primary disease. L. tropica can cause chronic recurrent lesions, and in some patients with a complicated premorbid background, an anergic form of the disease, known as diffuse cutaneous leishmaniasis, can develop when invaded by L. mexicana or L. aethiopica. Immunity to reinvasion in the presence of a current invasion is called premunition (a synonym for non-sterile immunity).

Cutaneous leishmaniasis is characterized by skin lesions called leishmaniomas. Due to the proliferation of leishmania at the site of their introduction by mosquitoes, specific granulomas arise, consisting of plasma cells, neutrophils, and lymphoid elements. The vessels in the infiltrate area and beyond are dilated, swelling and proliferation of their epithelium are noted. The development of leishmanioma consists of three stages: tubercle, ulceration, and scarring. Spread of infection through the lymphatic vessels and development of lymphangitis and lymphadenitis are possible.

A distinction is made between anthroponotic and zoonotic cutaneous leishmaniasis.

Features of two types of leishmaniasis

Characteristics of infection	Type of infection
	Urban cutaneous leishmaniasis	Rural cutaneous leishmaniasis
	Synonyms
	Anthroponotic Ashgabat ulcer, yearling, late ulcerating form ("dry")	Zoonotic pendin ulcer, murgab ulcer, acute necrotizing form, desert type ("wet")
Incubation period	Long-term: 2-3-6 months, often 1-2 years or more	Short: usually 1-2-4 weeks, sometimes up to 3 months
Initial phenomena	A small papule-tubercle of flesh or brown color	Significant acute inflammatory, often furuncle-like infiltrate
Development of the process	Slow	Fast
Time of ulceration onset	After 3-6 months or more	In 1-2-3 weeks
Lymphangitis	Rare	Frequently
Tubercles of seeding	Relatively rare
Localization	On the face more often than on the lower limbs	On the lower limbs more often than on the face
Duration of the process until epithelialization	A year or more	2-6 months
Seasonality	2-6 months	Primary diseases occur in the summer-autumn months (June - October)
Epidemiological outbreaks	Rarely observed	They develop frequently
Sources of infection	Human (anthroponosis)	Wild rodents of the desert (zoonosis)
Distribution areas	Mainly in cities (Typus urbanus)	In rural areas, on the outskirts of cities and in desert areas
Number of parasites in granules	Many	Few
Virulence for white mice	Small	Big
Cross-immunity	To date, data have accumulated that indicate the presence of cross-immunity between the pathogens of the two types of cutaneous leishmaniasis.
Exciter	Leishmania tropica minor	L. tropica major
Skin test	From the 6th month from the onset of the disease	From the 2nd month
Main carrier	Ph. Sergenti	Ph. papatasi

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What causes leishmaniasis?

The causative agents of cutaneous leishmaniasis were described by Cuningham (1884) and Firth (1891). In 1898, P. F. Borovsky determined that these organisms were protozoa. In 1900, Wright observed similar parasites in the spleen of a patient with visceral leishmaniasis and in 1903 he published the first accurate description of these parasites and drawings.

In 1974, Jadin reported the presence of a small flagellum in the intracellular forms of some Leishmania (L. tropica, L. donovani, L. brasiliensis), revealed in a microelectron diffraction pattern. In this regard, along with the terms "amastigote", the term "micromastigote" is also encountered, denoting the same stage of the life cycle of Leishmania.

In the body of warm-blooded animals, amastigotes and micromastigotes of Leishmania are found in the protoplasm of cells of the reticuloendothelial system capable of phagocytosis. They have the appearance of small oval or round bodies measuring from 2 to 5 µm.

The protoplasm is stained according to Romanovsky-Giemsa in a grayish-blue color. In the central part or on the side there is an oval nucleus, which is stained in red or red-violet color. Near the nucleus there is a kinetoplast (a round grain or a short rod, lying eccentrically and stained more intensely than the nucleus, in a dark violet color). The presence of the nucleus and kinetoplast is the main feature that allows to distinguish leishmania from other formations (thrombocytes, histoplasms, yeast cells, etc.).

Leishmania promastigotes have an elongated spindle shape; their length is 10-20 μm, width - 3-5 μm. The nucleus, protoplasm and kinegoplasm are stained in the same colors as in amastigotes. In cultures, promastigotes often collect in clusters in the form of rosettes, with flagella facing the center (agglomeration phenomenon).

How to prevent leishmaniasis?

In endemic areas, leishmaniasis prevention is carried out differentially depending on the form of the disease in several directions. For anthroponoses (kala-azar, AKL), the main preventive measures are: identification and treatment of patients, mosquito control in populated areas. Much more complex and labor-intensive is the prevention of visceral leishmaniasis and ZKL, in which reservoirs of pathogens and sources of human infection are mainly wild animals. Preventive measures in foci of visceral leishmaniasis include: active identification and treatment of patients, detection and destruction of sick dogs in populated areas (treatment of valuable breeds is possible), limitation of the number of wild, predatory animals (foxes, jackals, etc.). Mosquito control is carried out in the vicinity of populated areas. Activities in ZKL foci, along with the identification and treatment of patients, are aimed at eliminating the main reservoir of the pathogen in nature - various types of rodents and the fight against burrowing mosquitoes.

In addition, to protect the population in foci of ACL and ZCL, prophylactic vaccinations with a live virulent culture of L. major are used.

A very effective measure for preventing leishmaniasis is protection from mosquito attacks. For this purpose, in the evening, immediately before sunset and throughout the night, it is advisable to use special mosquito-repellent substances - repellents, as well as a fine-mesh net.

Ukrainian citizens traveling outside the country may become infected with leishmaniasis when visiting neighboring countries during the active season of infection transmission (May - September): Azerbaijan (VL), Armenia (VL), Georgia (VL), South Kazakhstan (VL, ZKL), Kyrgyzstan (VL), Tajikistan (VL, ZKL), Turkmenistan (ZKL, VL), Uzbekistan (ZKL, VL). Crimea should also be considered endemic for visceral leishmaniasis, where isolated cases of visceral leishmaniasis have been registered in the past.

Among the countries of the far abroad, India poses the greatest danger in relation to kala-azar, where tens of thousands of cases of this disease are registered annually. Visceral leishmaniasis can most often be contracted in the countries of the Middle, Near East and the Mediterranean. Cutaneous leishmaniasis is dangerous for citizens traveling to the countries of the Middle, Near East and North Africa. In the countries of Central and South America, along with visceral, there are foci of cutaneous-mucous leishmaniasis.

The main preventive measure for citizens, even for a short time, traveling to the named regions, is protection from mosquito attacks. In addition, to prevent ZKL, vaccinations with a live culture and chemoprophylaxis with pyrimethamine can be recommended. It should be noted that vaccinations are contraindicated for children under 1 year old, patients with skin or chronic diseases (tuberculosis, diabetes, etc.) and people who have previously suffered from cutaneous leishmaniasis, and pyrimethamine is contraindicated in diseases of the hematopoietic organs, kidneys and pregnancy.