Old world cutaneous leishmaniasis B55.1

Localized infectious skin disease caused by leishmania, which develops after the bite of an infected mosquito (sand flies -Phlebotomus papatasi) and is characterized by phased clinical symptoms.

Leishmania spp; see Table

The incidence rates are 0.7-1.2 million per year worldwide.

90% of cases occur in the "Old World" (where the olive tree grows): Mediterranean regions, Africa (Algeria, Kenya, Northern Sudan, Ethiopia), Asia (Afghanistan, Iran, Syria), 10% in the "New World" (Texas, Brazil, Mexico, Bolivia, Peru).

The Leishmania species L. major, L. tropica, L. aethiopica, L. infantum (L. infantum = typical pathogen of leishmaniasis in Mallorca) cause predominantly the diseases of the "Old World".

L. mexicana and L. brasiliensis cause the leishmaniasis of the "New World".

In non-endemic countries, infections affect travelers or immigrants.

Humans are an accidental host. The natural reservoir of Leishmania is wild rodents, especially rabbits.

In Afganistan (deployment of the German Armed Forces) gerbils (Greater Gerbil) are the natural reservoir in the desert-like regions of North Afganistan. Sandflies are also found in the burrows of these rodents, so that a purely zoonotic transmission cycle exists here. Humans become hosts only accidentally.

In the area around Kabul, more than 200,000 people have contracted leishmaniasis (Leishmania tropica. The diseased human is the main reservoir. Vectors are also sandflies.

Cutaneous leishmaniasis is transmitted in the "old world" by the female sand or butterfly mosquito of the genus Phlebotomus; in the "new world" by Lutzomyia. Promastigotes are transmitted into the skin during the biting process.

Age at first manifestation:

• 5-9 years: 30% of infected persons
• < 20 years: 70% of infected persons

Predilection sites are the uncovered skin areas:

• face and neck: 60%.
• upper extremity: 35%
• lower extremity: 10%.

After the bite of the sand fly, erythema occurs first and then papules.

A distinction is made:

• Nodular form (regular picture): incubation period 2-3 weeks up to 1 year. After the bite of the sand fly, first an erythema forms and then a 0.1-0.3 cm large, reddish-brown, succulent, slowly growing, itchy red papule. Regional lymphadenitis possible. No general complaints. Within weeks gradual but steady growth to a reddish-brown, painful (light, sharp but not throbbing pain) nodules/nodules with a taut surface. Multiple nodules are rarer. Lymphangitis only complicates with bacterial overlay. The majority of nodules/nodules heal spontaneously after a period of several months without treatment, leaving scars. In infections caused by Leishmania tropica, pronounced local inflammatory reactions with marked swelling and erythema are observed.
• ulcerous form: development from the nodose form. Soft, encrusted ulcerations, usually healing spontaneously after one year (annual lump, self-limiting). Formation of prominent scars.
• Recurrent form (recurrent cutaneous leishmaniasis - see below: Recurrent cutaneous leishmaniasis
• Chronic hyperergic cutaneous leishmaniasis: This particular form of the disease is divided into a persistent and a recurrent form. It is characterized by reddish-brownish, lupoid plaques that resemble sarcoidosis or lupus vulgaris.
• Diffuse (anergic) cutaneous leishmaniasis: multiple, non-ulcerative papules and nodules that may spread symmetrically over the face and trunk during the course of the disease. Immunologically, there is a selective anergy of the immune system to leishmania with a high density of parasites in the lesions. Triggers are L. amazonensis, L. mexicana, L. guyanensis, L. aethiopica. In Ethiopia and Sudan this form occurs in about 20% of the patients.
• Mucocutaneous leishmaniasis: severe form of initial cutaneous leishmaniasis (Espundia). It develops from originally cutaneous foci that spread into the mucosal area.

Acanthotic, in places pseudoepitheliomatous surface epithelium with parakeratotic serum crust. Dense, diffuse, granulomatous infiltrate of neutrophil granulocytes, plasma cells, lymphocytes, epitheliodocytic histiocytes and multinucleated giant cells of varying density, penetrating the entire dermis. Especially in the Giemsa staining of fresh forms numerous intracellularly located pathogens are found.

Detection of Leishmania antigen by PCR (also possible on formalin-fixed material). Species differentiation (PCR, restriction fragment length polymirphism analysis) is possible but costly (only in special laboratories).

In older foci, the histiocytic component predominates with small, isolated or confluent epitheloid-cell nodules (DD: tuberculosis cutis luposa). The pathogen detection is then very sparse or even missing.

Clinical:

• Boils (highly acute event, painfulness, fluctuation)
• Basal cell carcinoma (missing inflammatory component)
• Eosinophilic granuloma (brown-red; follicular accentuation of the surface; histology is diagnostic)
• Ecthyma (highly acute, sharp-edged ulceration; localization usually lower extremity)
• Frambösie (country of origin)
• syphilitic primary effect (localization)
• lupoid rosacea (age of patient; mostly disseminated follicular papules and pustules; rosacea face)
• Tuberculosis cutis luposa (little raised plaques and atrophy; rather brown-red, never bright red; self-infiltrate).

Histological:

• Cutaneous B-cell pseudolymphoma (detection of germinal centres absent in leishmaniasis)
• Lupus vulgaris (important in cases of long-term leishmaniasis, as it is often difficult to detect the pathogen in such cases; the accompanying plasma-cell reaction is more likely to speak against tuberculosis)
• Histoplasmosis (granulomatous infiltrate; detection of spores in the PAS preparation).

The pathogens respond to different treatments: While local measures are often sufficient in the case of an infection caused by Leishmania species from Europe and Africa ("Old World"), systemic therapy is the first choice for cutaneous and mucocutaneous forms of the "New World".

In the case of individual lesions in cosmetically undisturbed localisation, spontaneous healing can be awaited (poor scar formation). Excision or cryosurgery are no longer recommended, as pathogens are removed from the lesion and thus the development of immunity is made more difficult. There is a risk of disseminating the pathogens that are already present in the lymph channels.

An effective antibiotic substance against L. major, which has been proven in several studies, is a 15% paromomycin ointment in 12% methylbenzethonium chloride (available as Leshcutan/Teva from the international pharmacy; approved in Israel; prepared in Vaselinum album in case of magistral formulation ). Applications 2 times/day over a period of 10-14 days. If necessary, repeat the therapy cycle after 14 days.

Local infiltration with antimony preparations: 1-3 ml megluminantimonate (e.g. glucantim) = 85 mg Sb/ml (depending on the size of the focus; with or without triamcinolone acetonide added); infiltration should be carried out first of all mainly in the peripheral area, as this is where the highest pathogen density is found. Later, inject also in the centre of the lesion. Perform the procedure 5 days a week; period: 4-5 weeks; usually quite painful procedure.

Alternatively (or in addition): Infrared therapy ( hyperthermia): 5 min. warm up to about 55 °C, if necessary repeat after 3 weeks (death of the pathogens; immune response is possible).

Alternatively, cryotherapy (liquid nitrogen in spray or contact procedures).

Alternative: In individual cases, success with photodynamic therapy (PDT) has been reported (2 irradiations per week for 4 weeks (Metvix; Waldmann PDT 1200 L, 100 J/cm2).

Antimony preparations (Antimony = Stibium = Sb): Basically the remedy of choice for infections with Leishmania brasiliensis! Sodium Stibogluconate (e.g. Pentostam) contains 10% Stibium (100 mg/ml); Megluminantimonate (e.g. Glucantime) contains 8.5% Stibium (85 mg/ml). Dosage: 20 mg/kg bw/day i.m. (painful) or slowly (10-20 min.) via small caliber needle i.v. Cave! Venous thrombosis! When administered i.v. the drug should be dissolved in 50 ml 5% glucose. Therapy duration: 20 days for cutaneous forms and 28-30 days for mucocutaneous forms. If toxic side effects occur, reduce the dose by 2 mg/kg bw Sb. Clinical healing often occurs 4-6 weeks after the end of treatment. Individual uncomplicated lesions of leishmaniasis can also be treated intralesionally (apply 1-3 ml of undiluted solution from the edge of the lesion! Perform the procedure 1-2 times/week. Duration of therapy: 3-6 weeks, depending on the acuteity of the lesion. Caution! Painfulness, toxicity to heart and liver!

Pentamidine diisethionate (e.g. pentacarinate): therapy of choice for diffuse cutaneous leishmaniasis and for those who fail the mucocutaneous forms. Dosage: 4 mg/kg bw/day once a week for at least 4 months. Recent studies also show efficacy in cutaneous leishmaniasis at a low dosage of 2 mg/kg bw i.m. every 2nd day up to a total number of 7 injections.

Liposomal amphotericin B (e.g. Ambisome): Drug of choice if pentavalent antimony is contraindicated or ineffective. ED: 0.5-1.0 mg/kg bw, every 2nd day, 20 doses in total.

Ketoconazole (e.g. Nizoral): drug of choice for infections by Leishmania mexicana, Leishmania panamensis and Leishmania major. Not or insufficiently effective for Leishmania brasiliensis, Leishmania tropica and Leishmania aethiopica. Dosage: 600 mg/day (evening) for 4 weeks.

Fluconazole (e.g. Diflucan): In studies very effective against infection with L. major. Dosage: 1 time a day 200 mg p.o. for 6 weeks

Miltefosine (Impavido): Adults and children from 3 LJ: 1,5-2,5 mg/kg bw/day for 28 days. Max. TD: 150 mg. With immunocompromised patients ( HIV-infected) a longer treatment may be necessary. Promising are also the therapeutic successes with cutaneous leishmaniasis in the New World. Approval for this indication is pending in Pakistan and Colombia. Recent reports indicate that miltefosine can also be successfully used in cutaneous L. of the Old World.

The course is usually without complications.

Rarely (!) accompanying lymphangitis, erysipelas or pyoderma.

Spontaneous healing of scars after about one year in the majority of infected persons

The disease leaves behind an immunity against the triggering species for several years.

Insecticides, suitable clothing, mosquito net to avoid mosquito bites. If necessary, removal of reservoirs (dogs, rodents).

Vector control is also important. Phlebotomus papatasi the sand fly has limited flight characteristics with a daily radius of action of only 50 m and a maximum flight altitude of 1.50m. Further prevention measures can be based on these characteristics.

• Resistance to treatment of leishmaniasis with antimony preparations has been observed more frequently.
• If necessary, culture and PCR should be performed in a special laboratory (e.g. Bernhard-Nocht-Instiut for tropical medicine / Hamburg).
• Note: A Giemsa-stained skin swab is a simple test method to detect amastigotes.

• In a 5-year-old girl, red, 0.4-0.7 cm high, slightly painful plaques and nodules appeared several months after a stay in Mallorca. The surface was partly smooth, partly crust-covered, flatly raised, blurred. Altogether 3 efflorescences were formed. The initial treatment with an ointment containing fusidic acid was unsuccessful.
• Laboratory: Completely inconspicuous.
• Histology: Typical findings with evidence of numerous intracellular pathogens, especially subepidermal.
• Diagnosis: Cutaneous leishmaniasis.
• Therapy: 5% paromomycin ointment in 12% methylbenzethonium chloride 2 times/day for 14 days. After 14 days repetition of the cycle. Including complete healing.

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