Homme de 28 ans prsentant 2 lsions papulo-nodulaires lgrement squameuses, indolores au niveau de la joue gauche. Sjour en Syrie, il y a quelques mois.

Leishmanioses cutanes (in Dermatologie, Saurat et al.)

Gnralits – Parasitologie

Il s'agit de maladies parasitaires tropisme cutan, lies l'inoculation de leishmanies par des piqres de phlbotome. La dissmination est mondiale avec environ 400 000 nouveaux cas par an. Seuls, l'Australie et l'Antarctique sont pargns.

La classification des leishmanioses est la suivante :

Leishmanioses viscrales : elles sont provoques par Leishmania donovani en Asie, L. infantum dans le bassin mditerranen et au Moyen-Orient, L. archibaldi en Afrique de l'Est et L. chagasi en Amrique. Elles peuvent comporter des lsions cutanes (leishmaniose post-kala-azar) ou se manifester par des lsions exclusivement cutanes (L. infantum).

Leishmanioses cutanes de l’Ancien Monde, elles sont provoques par L. major, responsable du bouton d'Orient dans sa classique forme humide ou rurale, L. tropica responsable d'une forme sche avec un rservoir humain et L. aethiopica pouvant tre l'origine des formes cutanes localises et diffuses.

Leishmanioses cutanes du nouveau Monde : elles svissent l'tat endmique en Amrique centrale et du Sud. On distingue :

- sous-genre Leishmania. Un complexe L. mexicana comprenant: L. mexicana mexicana donnant une forme ulcreuse; L. mexicana pifanoi responsable d'une forme cutane diffuse, L. mexicana venezuelensis l'origine d'une forme multiple. Un complexe L. amazonensis donnant des lsions cutanes solitaires;

- sous-genre Viannia (V). Un complexe brasiliensis : L. (V) brasiliensis brasiliensis responsable des formes cutanomuqueuses (espundia); L. (V) peruviana responsable de lsions isoles (Uta). Un complexe guyanensis : L. (V) guyanensis : pian-bois (leishmaniose ulcreuse); L. (V) panamensis : lsions cutanes avec diffusion lymphatique.

Pathognie

Le vecteur des leishmanioses est un moucheron de la famille des phlbotominae avec le genre Phlebotomus dans l'Ancien Monde et les genres Lutzomya et Psychodopygus dans le Nouveau Monde. Le phlbotome (mouche des sables) femelle est surtout actif la tombe de la nuit; il pique dans les habitations o l'air libre. La plus grande part des leishmanioses cutanes, l'exception de L. tropica, a un rservoir animal et l'homme est en quelque sorte un hte accidentel. Lors de la piqre de phlbotome, est inocule la leishmanie un stade flagell (prosmastiggote) qui envahit les macrophages dermiques en perdant le flagelle pour se transformer en un stade sans flagelle (amastigote). Celui-ci se multiplie l'intrieur des macrophages dermiques, est libr lors de sa mort pour coloniser d'autres macrophages. C'est le stade arnastigote qui est visualis par l'examen direct. La transmission interhumaine directe des leishmanioses cutanes est rarissime.

Clinique

Le diagnostic de leishmaniose cutane est envisager de faon systmatique devant toute lsion cutane chronique en zone d'endmie ou chez les voyageurs en provenance de ces zones. La notion de piqre d'insecte sur le site o sige la lsion suspecte, est le plus souvent impossible affirmer. Parfois, en cas d'incubation courte, on note une volution continue entre la piqre avec des ractions inflammatoires aigus et l'apparition d'une lsion chronique suspecte. Le plus souvent cependant, la priode d'incubation est longue (3 semaines 3 mois, voire davantage).

Le bouton d'Orient : Nous le prendrons comme type de description. Il se manifeste par l'apparition au niveau d'une rgion dcouverte (visage, membres) d'une lsion papuleuse, rouge, indolore, secondairement croteuse. D'apparence anodine, cette lsion rsistera aux traitements antiseptiques locaux pour constituer la phase d'tat une lsion papulo-nodulaire, infiltre, recouverte par une crote adhrente. L’ensemble a t compar un cne tronqu. L’ablation de la crote hrisse de prolongements sur sa face dermique met en vidence une ulcration anfractueuse avec des dbris ncrotiques. La lsion est peu douloureuse sauf en cas de surinfection bactrienne qui est inhabituelle. La raction ganglionnaire satellite est absente ou discrte. En l'absence de traitement, l'volution est chronique, la lsion s'affaisse progressivement en laissant une cicatrice plus ou moins inesthtique dans un dlai de quelques mois pouvant aller jusqu' deux ans. Le nombre de lsions cutanes est le plus souvent faible mais des lsions multiples rsultant de piqres simultanes sont possibles. Au voisinage de la lsion croteuse principale, dans un rayon de un deux centimtres, on peut parfois noter l'apparition de lsions papuleuses qui correspondent des dbuts de dissmination lymphangitique.

Formes cliniques

Formes sporotrichodes : elles rsultent de la dissmination par voie lymphatique des leishmanies et donnent naissance des abcs sur le trajet de drainage lymphatique. Le diagnostic diffrentiel devra se faire avec la mycobactriose atypique, la tuberculose et la sporotrichose. Ces formes semblent rsulter d'une altration des dfenses immunitaires de l'hte. Elles ont t dcrites avec L. major, L. tropica, L. (V) panamensis, L. (V) guyanensis.

Formes cutanes du bouton d'Orient: il tait classique autrefois de distinguer le bouton d'Orient forme humide due L. major des formes sches dues L. tropica dont le rservoir est plutt humain. Cette distinction n'a pas t confirme du moins dans les pidmies rcentes. Toutes les varits smiologiques sont possibles : formes ulcreuses, croteuses, vgtantes, inflammatoires, lupodes, etc.

Formes rcidivantes : une petite proportion de leishmanioses cutanes se caractrise par la rapparition de lsions cutanes actives en bordure d'une cicatrice antrieure. La ractivation peut survenir dans un dlai de 1 15 ans et l'volution sera chronique. L. tropica est en cause pour les foyers de l'Ancien Monde et L. (V) braziliensis pour le Nouveau Monde. Il existe galement des formes chroniques sans tendance la gurison aprs une volution de plus de 2 ans.

Leishmanioses cutanes du nouveau Monde: leur smiologie est identique celle du classique bouton d'Orient. Elles sont dues L. mexicana mexicana (ulcre du chiclero), L. (V) guyanensis (pian-bois), L. (V) peruviana (uta). Uatteinte du pavillon de l'oreille (L. mexicana) peut avoir une volution mutilante.

Leishmaniose cutanomuqueuse (espundia) : il s'agit d'une forme grave avec atteinte mutilante du massif centrofacial due L. (V) braziliensis braziliensis et peut-tre L. (V) panamensis. Cette forme peut tre prcde par une lsion cutane (70 % des cas) de sige ubiquitaire, elle survient dans un dlai de 2 10 ans aprs la lsion cutane avec atteinte initiale lective du cartilage nasal distal et extension locorgionale secondaire. Les lsions du massif facial sont soit ulcres et destructrices, soit vgtantes et granulomateuses.

Formes cutanes diffuses : ces formes pseudolpromateuses ont t dcrites avec L. aethiopica, L. mexicana amazonensis et L. mexicana pifanoi. Elles se caractrisent par une infiltration nodulaire ou en nappes du visage, des membres, pouvant en ralit atteindre tout le corps. Il n'y a pas d'atteinte nerveuse, ni d'atteinte viscrale.

Leishmanioses cutanes post-kala-azar : il s'agit de leishmanioses dermiques survenant dans les suites de leishmanioses viscrales en Afrique de l'Est et en Inde. L'ruption est micropapuleuse, discrte, avec une gurison spontane en Afrique, maculeuse et hypopigmente d'volution chronique dans les formes indiennes. L. infantum peut tre responsable de leishmanioses purement cutanes dans le Sud de la France.

Formes particulires de leishmanioses cutanes: l'immunodpression induite par le VIH favorise le dveloppement de leishmanioses viscrales. La dcouverte de corps de Leishman dans les macrophages dermiques est une constatation banale dans ce contexte. L'infection par le VIH peut galement entraner des rcidives locales de leishmanioses cutanes considres comme guries ou parfois des dissminations cutanomuqueuses avec des varits qui ne sont pas rputes pour possder ce pouvoir pathogne.

Diagnostic

Le diagnostic est voqu partir des caractristiques cliniques de la lsion, de la notion de sjour en pays d'endmie et de la rsistance aux traitements antiseptiques ou antibiotiques. Il sera confirm par le frottis avec coloration selon MayGrnwald-Giernsa (MGG), frottis ralis par crasement d'un fragment de tissu prlev en priphrie de l'ulcration. Les leishmanies sont facilement mises en vidence en position intracytoplasmique dans les cellules histiocytaires ou l'tat libre.

La biopsie cutane met en vidence une hyperplasie pseudopithliomateuse de l'piderme surmontant un granulome inflammatoire polymorphe au sein duquel la coexistence de cellules pithliodes et de plasmocytes est vocatrice. La coloration de MGG permet, sauf en cas de granulome trs tuberculode, de mettre en vidence les corps de Leishman.

L’intradermoraction de Montngro n'a gure d'intrt pour le diagnostic, mais permet de juger des ractions immunitaires de l'hte. La culture sur milieu NNN permet la confirmation de cas douteux. L’identification prcise de l'espce en cause n'est pas pratique en routine; elle peut tre importante dans les zones risque de leishmaniose cutanornuqueuse. L'identification repose sur l'analyse du DNA-mitochondrial.

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Leishmaniasis (in Pathology of the Skin, McKee,1997)CLINICAL FEATURESLeishmania is an organism related to the trypanosomes. The life cycle contains a flagellate phase (promastigote), which occurs in the intestine of its vector, a female Phlebotomus sand fly, and a phase in which the flagellum is retracted (amastigote). The latter is the form seen in the human host. Various mammals, including gerbils, rodents, dogs, jackals and foxes, may act as reservoirs of infection. The various species of Leishmania are distinguished on the grounds of biochemical and antigenic differences. Although leishmaniasis tends to be seen in Asia, Africa, the Americas and the Mediterranean countries it is being seen more often in non-endemic countries, particularly among refugees and returning holiday makers . There are eight main types of cutaneous presentation, with many local geographic and species variations. In endemic regions a significant number of people appear to have asymptomatic (subclinical) infection, so-called cryptic leishmaniasis. Cutaneous leishmaniasis has many local names, including oriental sore, Baghdad boil, Chiclero's ulcer and Aleppo boil. It is caused by Leishmania tropica, Leishmania major and Leishmania aethiopica and affects men, women and children. Mediterranean cutaneous leishmaniasis is caused predominantly by Leishmania donovani infantum. Lesions occur on any sites accessible to biting by the sandfly vector, most commonly the hands, arms and face. They present as an erythematous papule that enlarges over the course of a few weeks into an ulcerated and crusted nodule. Occasionally multiple lesions are seen. Lesions show a tendency to orientation along the skin creases and grossly the ulcers have been compared to a volcano in surface appearance and configuration . Variants may be hypoeshetic, psoriasiform, eczematous, varicelliform, verrucous or keloidal or present as macrocheilia. Regional lymphadenopathy may be a feature. In the Old World, these lesions may be "wet" or "dry":• The wet type has a short incubation period (two weeks) and occurs in rural areas. It is caused by L. major and develops like a suppurative folliculitis, which ulcerates, the surrounding oedematous, indurated erythema extending gradually to reaching a maximum of 6 cm. Small secondary nodules may be seen around this. Slow resolution with cribriform scarring occurs over 3-12 months.• The dry form is caused by L. tropica, has a longer incubation period (two months) and is mostly seen in urban areas. The initial lesion is a brown nodule and this becomes a plaque up to 2 cm across. It may ulcerate centrally with a firm crust. Resolution occurs with scarring over 12 months or longer.The American forms are caused by Leishmania mexicana and Leishmania braziliensis and their subspecies. The lesions of L. mexicana are usually like those of Old World cutaneous leishmaniasis, but some subvariants can cause destructive ulceration of the ear. Most infections with L. braziliensis are local and heal without much local damage. Chronic cutaneous leishmaniasis represents persistence (or spread) of an acute lesion for more than one year. Lesions are particularly seen on the face as erythematous plaques, which may resemble erysipeloid. The acute lesions may be followed by a relapsing chronic or lupoid stage (leishmaniasis recidivans) in which brownish papules develop close to the scar of the earlier stages. This occurs in 3-10% of patients. These papules extend to resemble lupus vulgaris; they may develop hypertrophic scars or become verrucous. They are extremely slow to resolve, even under treatment, and may persist for many years. It is thought that a change in local immunity results in reactivation of intracytoplasmic organisms. The leishmanin or Montenegro skin test for cellular immunity to Leishmania is strongly positive in nearly all cases. Skin infections with L. braziliensis are liable to recur as mucosal lesions, known as espundia (in which there is much tissue destruction), sometimes years later. The mucosal lesions occur most often in the nasal septum and mouth and rarely around the eyes, genitalia and anus. Patients may also develop "tapir nose" in which there is considerable damage to the nasal cartilage resulting in a free hanging nose . The mucosal lesion start as superficial erosions, but become deeply ulcerative and destructive. The Montenegro skin test is almost always positive. Diffuse cutaneous leishmaniasis, also known as pseudolepromatous leishmaniasis, is caused by variants of L. mexicana and L. aethiopica. The former occurs in Bolivia, Venezuela, Mexico and Brazil, while the latter is seen in Ethiopia. It develops as a consequence of an impaired cellular immune response. This form of leishmaniasis begins as a nodule, which grows and becomes surrounded by other similar lesions. This process is repeated until eventually, over many years, most of the skin becomes nodular. The nodules do not ulcerate and can closely resemble lepromatous leprosy. Although lesions may develop in the nasal mucosa these are not destructive like those of the mucocutaneous form of American leishmaniasis. Response to therapy is slow and relapse is common. The Montenegro test is invariably negative. L. major and L. braziliensis panamensis may develop a sporotrichoid spreading reaction. Visceral leishmaniasis (kala-azar, black fever) is due to infection by L. donovani and occurs widely in South America, Africa, the Mediterranean and in Asia. It may be a manifestation of HIV infection. Following inoculation, the organisms multiply in histiocytes; the onset of disease is insidious after 2-4 months. The macrophages of the liver and spleen take up the organisms, resulting in hepatosplenomegaly associated with lymphadenopathy, pancytopenia, irregular and intermittent fever and marked weight loss. In India, patients may develop an earthy-grey pigmentation, particulariy on the temples, around the mouth and on the hands and feet. A small number of patients who recover subsequently develop post kala-azar dermal leishmaniasis. This has been reported from India and East Africa. The lesions start as erythematous or hypopigmented macules, particularly on the face, and become nodular and coalesce so that they closely resemble lepromatous leprosy. The lesions are persistent, but resolve slowly on treatment. PATHOGENESIS AND HISTOPATHOLOGY

In all variants of the disease the amastigote form of the parasite multiplies within the histiocytes of the mammalian host. The host response is related to the number of amastigotes and the degree of cellular immunity. Large numbers of amastigotes are associated with an anergic response and many histiocytes without other inflammatory cells. Moderate numbers of amastigotes are usually associated with necrosis, which is an important mechanism for eliminating infection. Smaller numbers are associated with a good epithelioid granulomatous response after the necrosis phase. Some infections are eliminated by an effective granulomatous response without necrosis, while others are associated with focal necrosis and ulceration when organisms are released. In others there is more extensive necrosis. The events following necrosis depend on the rate at which an effective epithelioid granulomatous reaction develops. Healing is often relatively rapid once necrosis has occurred. In parallel with developing immunity the overlying epidermis shows pseudoepitheliomatous hyperplasia. Lymphocytes and plasma cells also become more numerous at the periphery of the granulomata. Scarring eventually replaces the granuloma. Histologically, the acute lesion (oriental sore) is characterised by hyperkeratosis and acanthosis although occasionally epidermal atrophy and parakeratosis are features. Ulceration is frequently seen. Liquefactive degeneration of the basal keratinocytes has been described [383]. The epidermis may show pseudoepitheliomatous hyperplasia and intraepidermal neutrophil microabscesses are not infrequent. The dermis typically contains an intense infiltrate of histiocytes, lymphocytes and plasma cells. Rarely a Grenz zone is evident. Neutrophils and eosinophils are usually sparse. Large numbers of amastigotes are evident and these may be seen within the overlying keratinocytes. Foci of dermal necrosis may be evident. Vascular changes are usually not seen. Recently perineural and intraneural chronic inflammatory changes associated with perineural Leishmania organisms have been described. The patient was found to be hyperaesthetic clinically. In chronic lesions the dermis contains large numbers of small non-caseating granulomata. Giant cells tend to be sparse. Leishman bodies are sparse or absent . Necrosis is very rare. Histologically mucocutaneous leishmaniasis is extensively necrotic, with many plasma cells, lymphocytes, neutrophils and macrophages, but few organisms. As with lepromatous leprosy, diffuse cutaneous leishmaniasis is characterised histologically by numerous macrophages distended with amastigotes and a lack of granuloma formation. There are few lymphocytes and plasma cells. These features indicate anergy, but not primary immunodeficiency. The features of post kala-azar dermal leishmaniasis are similar to those of the diffuse cutaneous variety; the overlying epidermis is atrophic, but is not usually ulcerated. The lupoid form of chronic cutaneous leishmaniasis may be difficult to diagnose because it represents an exaggerated tuberculoid response to very few organisms, (and as such closely resembles lupus vulgaris) or perhaps only leishmanial antigen; it is best distinguished from other tuberculoid diseases on the basis of its positive Montenegro skin test. In all other forms of cutaneous leishmaniasis the diagnosis is confirmed by the demonstration of amastigotes in a smear or skin section . The organisms are best revealed by Giemsa stain, as reddish cytoplasmic round to oval structures measuring 1.5 2.5 m to 4.5 6.8 m . They appear blue-grey on haematoxylin and eosin staining. A small rod-like similarly-stained kinetoplast may be visible. Many of the organisms are within macrophages, but some occur extracellularly. They are termed Leishman-Donovan bodies. These features must be distinguished from the similar bodies of histoplasmosis and, to a lesser extent, those of granuloma inguinale and rhinoscleroma. The clinical features will usually be distinctive; skin testing, serology and culture of the organisms will confirm the diagnosis.