Leishmaniasis

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Leishmaniasis or leishmaniasis (technically also Latin Leishmaniosis and Leishmaniasis ) is an infectious disease occurring worldwide in humans and animals , which is caused by obligatory intracellular protozoan parasites of the genus Leishmania . Its distribution area is the tropics , especially Peru, Colombia and eastern Africa , but also the Mediterranean and Asia . Since the mid-1980s, the sand flies , which transmit leishmaniasis, possibly due to climate change , also increasingly appeared in Germany. In Germany there are increasing cases of leishmaniasis in animals and occasionally also in people who have never left Germany.

The pathogen Leishmania donovani was discovered in 1900 by William B. Leishman and Charles Donovan.

Leishmaniasis life cycle

transmission

Leishmania tropica

Sand flies (from the butterfly mosquito family ) transmit the infection . In the 1950s, the use of insecticides (mainly DDT ) against malaria-transmitting anopheles mosquitoes also decimated sand flies (Phlebotominae). In the meantime, the sand flies population has increased back to the original level, so that the number of leishmaniasis diseases in humans and animals is increasing in the Mediterranean region.

The increasing spread of the sand fly towards the north is associated with global warming and increasing globalization . That the Goethe University in Frankfurt and the Senckenberg Nature Research Society belonging Biodiversität- and Climate Research Center (BiK-F) in the summer of 2014 at casting using a sand fly the type Phlebotomus mascittii out the far northernmost evidence of a sandfly.

Leishmaniasis is endemic to 98 states and causes an estimated 1.5 million cutaneous infections and 0.5 million visceral infections annually.

The infection rate of dogs with leishmaniasis is very high in places , especially in the Mediterranean region : in Andalusia up to 42% of dogs are infected, in Sicily up to 80%. The rate of infection in humans and dogs depends on the local sandfly population , its level of contamination and biting habits.

Forms of human leishmaniasis

Classification according to ICD-10
B55.- Leishmaniasis
B55.0 Visceral leishmaniasis
B55.1 Cutaneous leishmaniasis
B55.2 Mucocutaneous leishmaniasis
B55.9 Leishmaniasis, unspecified
ICD-10 online (WHO version 2019)

There are many clinical pictures that can be assigned to the geographical distribution of the respective Leishmania species. They range from locally limited, often spontaneously healing solitary ulcers to fatal general illnesses . There are three different forms of leishmaniasis worldwide.

Internal leishmaniasis (visceral leishmaniasis)

In internal leishmaniasis or visceral leishmaniasis (also dum-dum fever , black fever or kala-azar ), the internal organs (Latin viscera : intestines) are affected. There is a swelling of the spleen that accompanies swelling of the liver ( tropical splenomegaly ). The pathogens are Leishmania donovani (the flagellate species discovered by Leishman and Donovan), in Europe Leishmania infantum . This disease probably originally spread from East Africa across the Middle East to India .

Paleomedicists around Albert R. Zink were only able to detect the mitochondrial DNA of Leishmania donovani in ancient Egyptian mummies from the Middle Kingdom onwards. The internal leishmaniasis was formerly referred to as ponos (in Hippokrates Πόνος) and "rib cake".

In 1977 a large epidemic with around 70,000 sick people was observed in India (North Bihar ). The term Kala-Azar comes from Hindi , refers to the brown-black pigmentation of dry skin in this disease, and means "black disease" or "black skin". Visceral leishmaniasis, however, is not limited to India and China . It also occurs in Europe, e.g. B. in the Mediterranean area from Portugal to Turkey , and is also represented in South America (there especially in Brazil).

In histology, the typically boat-shaped leishmanias can be seen in a macrophage. Without therapy, around 3% of cases of illness are fatal. The active ingredient miltefosine was approved as the first oral therapeutic agent in Germany in December 2004 .

Skin Leishmaniasis (Cutaneous Leishmaniasis)

Cutaneous leishmaniasis
Micrograph of leishmania in a leukocyte from a skin biopsy

The cutaneous leishmaniasis (also known as Hautleishmaniosis , Baghdad boil , oriental sore and Aleppo bump ) attacks as opposed to visceral leishmaniasis only the skin (Latin cutis ) and spared the internal organs. The transmitting sand or butterfly mosquitoes ingest the leishmania during a blood meal ; these go through a development cycle in the mosquito's intestines and later get into the proboscis. Infected mosquitoes pass them on when they bite. The pathogens are L. tropica major , L. tropica minor , L. tropica infantum and L. aethiopica .

After being bitten by the sand fly, there is initially a reddening, then itchy nodules develop on the skin, which transform into papules and form a non-painful ulcer. The size of the ulcers is usually between one and five centimeters. The reproduction of the parasites is often restricted to the site of the infection. Often the face is affected. Clinically, a distinction must be made between wet ( L. tropica major ), dry ( L. tropica minor ) and diffuse ( L. tropica infantum and L. tropica aethiopica ) leishmaniasis.

Therapy of the first two forms is usually not given, since the developing bump will heal by itself after six months to a year. The scars are often disfiguring. Diffuse skin leishmaniasis does not heal without treatment.

Miltefosine is available in Germany for systemic therapy , and paromomycin is also used as an intramuscular injection. Therapy with ointments containing cortisol is contraindicated (not recommended). In contrast, a Tunisian-American randomized, placebo-controlled phase 3 double-blind study in 2013 with 375 patients showed that an ointment with 15% paromomycin applied once a day for twenty days worked significantly better than the placebo ointment and showed a cure in 81% after 98 days, im Compared to 58% in the placebo group and 82% with an ointment with 15% paromomycin and an additional 0.5% gentamicin, which therefore had no additional effect. In contrast to intramuscular paromomycin therapy, there were no clinically significant kidney or hearing toxic side effects; systemic exposure was reduced to 10% by the application of the ointment. In the first few days after the start of therapy, an increased number of mild to moderate inflammatory (6%) and vesicular reactions (26%) were observed in the area of ​​the skin lesions, but no superinfections (which occurred in 10% of the placebo group).

Mucosal Leishmaniasis (Mucocutaneous Leishmaniasis)

Mucocutaneous leishmaniasis is known under various names (including Uta or Espundia ) in South America. In addition to the skin, it also affects the mucous membrane (Latin mucus : mucus). The pathogen is L. brasiliensis and is also transmitted by the butterfly mosquito. Clinically, there is a severe, destructive skin lesion that does not heal spontaneously.

Veterinary medicine

Leishmaniasis occurs primarily in domestic dogs in the area of pets . It belongs to the vector-borne diseases ( Companion Vector-borne Diseases , CVBD ). There are also descriptions of the disease for cats , rodents , cattle and domestic horses . The Leishmaniasis of the guinea pigs is the host-specific pathogen Leishmania enriettii causes and occurs only in South America.

etiology

Dogs and rodents appear to be the main reservoir for the pathogen. The transmission to humans or other mammals probably does not correspond to the original host range of the Leishmania. The parasite needs two hosts to develop . On the one hand, it is a stinging insect ( Phlebotomus sp. Or Lutzomyia sp.), In whose blood the approximately 10 to 15 µm ( micrometers ) long, flagellated and promastigote form develops and multiplies. Vertebrates, including humans, on the other hand, have the amastigote (uncultivated) shape, which is 2 to 5 µm in length and is much shorter , which preferentially settle inside the cells of macrophages - especially in the area of ​​the reticuloendothelial system . They do this because of their ability to neutralize the acidity of the phagosomes and to intercept free oxygen radicals inside the macrophages. It is here that they multiply through cell division .

The parasites are classified on the basis of their morphology , the host insect, the type of disease symptoms triggered and serological tests. In addition, zymodemes are differentiated according to the similarity of the enzymes active in the parasite and schizodemes according to special DNA fragment patterns ( RFLP patterns ) on the kinetoplasts .

Pathogenesis

In the intestine of the transmitting vector , after sucking infected blood, there is a strong increase in the form that has not yet been flagellated, which then transforms into a larger, flagellated parasite. By means of these flagella, the leishmanias migrate actively into the proboscis of the insect and from there are transferred to the mammal's tissue during the next blood meal. They are taken up by dendritic cells of the skin and local macrophages and multiply inside them. After they multiply, the parasites destroy the cell membrane and are then released in the organism, whereupon they attack cells of the body's defense system again. This mainly takes place in the lymph nodes, bone marrow, spleen and liver. The incubation period is very different and can be between one month and seven years.

The further course of the disease is determined according to the host's immune response . Resistant animals react to the infection with a cell-mediated immune response via T1 helper cells . If, on the other hand, a humoral immune response predominates, the pathogens that are still infectious despite the attachment of antibodies are in turn absorbed by macrophages and the infection spreads. With increasing duration of the disease, the immune response becomes more and more unspecific, which can ultimately lead to the formation of symptom complexes such as the visceral form, kidney failure or death due to an excess of circulating antigen-antibody complexes . In addition to this indirect damage, the parasite also causes direct damage, which can manifest itself in granulomatous inflammation of the skin, liver, kidneys, intestines, eyes and bones.

In cats, leishmaniasis is very often associated with diseases that damage the immune system, especially with the immunodeficiency syndrome in cats.

Clinic, diagnostics

Ulceration and loss of pigment on the nasal surface and purulent conjunctivitis
Canine skin lesion with central necrosis
Visceral leishmaniasis with severe emaciation

As a result of the fact that leishmanias can affect almost all organ systems in the body, the disease can be very diverse. A majority of the sick dogs, however, have skin disorders in common. Based on the distribution of this disorder, conclusions can be drawn about the prognosis of the disease:

  • Symmetrical hair loss and dandruff : with 60% of the cases the most common clinical picture, which predominantly develop in animals with an intact immune system ; Starting in the head, the disease spreads to the rest of the body (secondary sebadenitis ).
  • Skin ulcers over protruding bones, on the tip of the tail and ears and in the skin- mucous membrane transition: affects 20% of the infected animals and indicates a weakened immune system. On the one hand, the symptoms are caused directly by the parasites, but they can also be caused indirectly via a vasculitis caused by immune complexes .
  • Nodule formation in the skin: Macrophages that have migrated into the skin lead to the formation of nodules; other defense cells are only marginally involved. The disease occurs in about 12% of patients and indicates an inadequate immune defense.
  • Generalized skin degeneration with pustules in the area of ​​the trunk: at 4% the rarest form. The pustules are filled with a non-purulent fluid and some parasites. The pathogenesis of this form has not been clarified and there is no evidence of a connection with the immune competence of the diseased animal.
  • Recurrent or intermittent fever with two peaks per day (double-peaked fever) is an indication of visceral leishmaniasis.

In addition to the disorders described, the skin can develop other symptoms such as excessive keratinization , curvature of the claws , nail bed inflammation and loss of pigment in the nose and mouth area. The mucous membranes can also be affected.

In cats, ulcerated and nodular skin changes dominate the clinical picture. They occur in 3/4 of the cases. Eye diseases, anemia and kidney damage occur in over a third of the sick cats.

In addition to the skin disease, the internal organs are also often affected ( visceral leishmaniasis ). Depending on the organ involvement, the development of liver inflammation , intestinal inflammation , kidney failure , blood vessel inflammation , bone marrow inflammation , joint inflammation , nerve inflammation and muscle inflammation is possible.

As a result of the extremely diverse clinical picture, the diagnosis can be difficult, especially since the disease is not endemic in most parts of Germany and is therefore often not part of routine diagnostics. In addition, there is no reliable test for the disease.

In addition to the direct detection of parasites, the diagnosis is based primarily on examinations of the host's immune response. A direct detection of the leishmanias can take place by means of cytological or histological examinations, in which cells of the bone marrow, the lymph nodes or the skin are examined microscopically, which enables a direct identification of the mostly intracellular Leishmanias. As a further investigation, the genetic engineering method is PCR , which has a sensitivity and specificity of almost 100 percent for samples from the bone marrow.

Among the indirect detection methods, the serological determination of antibodies using the immunofluorescence test or ELISA has found the most widespread use. Although the sensitivity and specificity are also quite high here at around 80 percent, false negative results can occur in freshly infected animals that have not yet developed antibodies. This problem also exists with the intracutaneous test , which, however, under certain circumstances enables a statement to be made about the severity of the course of the disease. There is also the possibility of a stimulation test of the mononuclear cells of the blood.

Therapy of visceral leishmaniasis

Often a complete cure of the disease is not possible. The therapeutic approaches therefore focus - in addition to eliminating pathogens - above all on strengthening the body's own cellular defense .

Pentamidine

Pentamidine was developed in Great Britain in the late 1930s as a remedy for sleeping sickness. Despite frequent side effects, it still has its place in the therapy of leishmaniasis. It is administered intravenously as a second choice therapy instead of amphotericin B (preferably L-AmB ).

N -methylglucamine antimonate

N -methylglucamine antimonate (trade name Glucantime ) is currently the drug of choice in the treatment of leishmaniasis. The drug inhibits glycolysis and fatty acid breakdownprocesses taking place in the parasite. The dead leishmanias in turn stimulate the cellular defense. The drug is notabsorbed in the intestine and is therefore given by injection for 20 to 30 consecutive days. Painful swellings in the area of ​​the injection are described as side effects, and gastrointestinal complaints can also develop.

Sodium stibogluconate

Sodium stibogluconate (trade name: Pentostam ) can be used (as a second choice therapy instead of Amphotericin B ) in all forms of human leishmaniasis. Its effect is based on killing the amastigotes , but the underlying molecular process is still unknown. The recommended dose is 20 mg Sb per kg body weight (NSG contains 100 mg Sb / ml) daily over a treatment period of 28 days, with the injection being intravenous or intramuscular. Side effects can include nausea, headache, vomiting, arthralgias , myalgias, and anorexia . The intramuscular injection is also very painful. NGS must not be used in severe kidney, heart and liver diseases.

Miltefosine

Miltefosine (trade name Impavidol ), which is used as the second choice therapy instead of liposomal amphotericin B, has been shown to be effective against leishmania in studies. Miltefosine is approved in Germany for the treatment of leishmaniasis in humans, for dogs in southern Europe and in Switzerland.

Allopurinol

The active ingredient allopurinol , known from the therapy of gout, inhibits the synthesis of purines in the host organism. Since leishmanias are not able to produce these purines themselves and are therefore dependent on a supply from the host, their development is inhibited. It is administered orally and is usually combined with another drug, since allopurinol only has a parasitostatic effect.

Antibiotics

If resistance to a combination therapy or one of the above-mentioned active ingredients occurs, there is the option of using antimycotics and antibiotics (liposomal) amphotericin B (also as a first-choice agent) or aminosidine .

The Institute for OneWorld Health successfully tested the aminoglycoside antibiotic paromomycin against visceral leishmaniasis in clinical studies. Approval for this indication has now been obtained in India.

Other active ingredients

Case reports describe the successful use of the antimycotics ketoconazole and amphotericin B in lipid form as well as the anthelmintic levamisole , which has not yet been confirmed by studies.

In the dog in a study with a one-month administration of domperidone clinical improvement, an improvement of cellular immunity and in many animals, a reduction of antibody - titers are achieved.

Immunotherapy

To strengthen the body's own defenses, the use of recombinant interferon can be a therapeutic option, as this promotes the differentiation of lymphocytes into T 1 helper cells.

prophylaxis

An essential part of combating leishmaniasis is the prophylaxis of infection. The classic way here is to keep the vector (disease vector ) from biting the host (repellant effect). Good results are achieved with pyrethroids such as permethrin or deltamethrin .

The vaccine Canileish has been approved across Europe since March 14, 2011. It is designed to reduce the risk of infection and disease after exposure to leishmania in dogs that test negative for leishmania. Another vaccine, LetiFend , has been available since 2019 , which promises one year of protection with a single application.

research

The British parasitologist Ralph Lainson made numerous discoveries in the 1960s, first in what was then British Honduras (now Belize ) and later at the Wellcome Trust Parasitology Unit at the Evandro Chagas Institute in Belém , Brazil , which contributed significantly to the understanding of leishmaniasis. Discovered in 1987, Leishmania (Viannia) lainsoni was named after him.

The World Community Grid project Drug Search for Leishmaniasis was launched on September 7, 2011, with the aim of finding new drugs against resistant strains of the disease.

Other diseases transmitted by ectoparasites

literature

  • Écologie des leishmanioses, Montpellier 18–24 août 1974 , Center National de la Recherche Scientifique (CRNS), Paris 1977, ISBN 978-2-222-02042-4 .
  • N. Suttorp, M. Mielke et al. a .: Infectious diseases . Thieme, Stuttgart 2004, ISBN 3-13-131691-8 .
  • H. Hahn, D. Falke et al. a .: Medical microbiology and infectious diseases. 5th edition. Springer, Berlin / Heidelberg 2004, ISBN 3-540-26529-5 .

Guidelines

Web links

Commons : Leishmaniasis  - collection of images, videos and audio files

Individual evidence

  1. ^ TJ Naucke, C. Schmitt: Is leishmaniasis becoming endemic in Germany? In: International Journal of Medical Microbiology. 293.Suppl. 37 (2004), pp. 179-181.
  2. ↑ researchgate.net (PDF)
  3. ↑ Werner Köhler : Infectious diseases. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , pp. 667-671; here: p. 670.
  4. ↑ Horst Aspöck: Pathogens transmitted by arthropods of human infections in Central Europe - an update . (PDF) In: Mitt. Dtsch. General Applied Ent. . 16, 2008, pp. 371-392.
  5. ↑ Sand flies arrived in Hessen - pathogens can cause severe damage
  6. ^ World Health Organization: Control of the leishmaniases . WHO technical report series No. 949, WHO, Geneva
  7. ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, pp. 9-223, here: pp. 175 f. ( Kala-Azar ).
  8. ^ P. Desjeux: Leishmaniasis. In: Nature reviews. Microbiology. Sept. 2004, No. 2, p. 692, PMID 15378809
  9. ↑ SM Beverley: Protozomics: Trypanosomatid parasite genetics comes of age. In: Nature Reviews Genetics . Jan. 2003, No. 4, pp. 11-19, PMID 12509749
  10. ↑ BL Herwaldt: Leishmaniasis. In: The Lancet . Oct. 1999, No. 354, pp. 1191-1199, PMID 10513726
  11. ↑ F. Pratlong, J. Dereure et al. a .: Sudan: the possible original focus of visceral leishmaniasis. In: Parasitology. June 2001, No. 122, pp. 599-605. PMID 11444612
  12. ↑ Albert R. Zink a. a .: Letter: Leishmaniasis in Ancient Egypt and Upper Nubia. In: Emerging Infectious Diseases . Oct. 2006, Vol. 12, No. 10, full text
  13. ↑ Georg Sticker : Hippokrates: The common diseases first and third book (around the year 434-430 BC). Translated, introduced and explained from the Greek. Johann Ambrosius Barth, Leipzig 1923 (= Classics of Medicine. Volume 29); Unchanged reprint: Central antiquariat of the German Democratic Republic, Leipzig 1968, p. 107 ( A creeping fever with an enlarged spleen [...]. )
  14. ↑ Karl Wurm, AM Walter: Infectious Diseases. In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. 1961, p. 176.
  15. ↑ Afif Ben Salah, Nathalie Ben Messaoud, Evelyn Guedri, Amor Zaatour, Nissaf Ben Alaya, Jihene Bettaieb, Adel Gharbi, Nabil Belhadj Hamida, Aicha Boukthir, Sadok Chlif, Kidar Abdelhamid, Zaher El Ahmadi, Hechmi Morizni., Mourad Mokotni , Pierre Buffet, Philip L. Smith, Karen M. Kopydlowski, Mara Kreishman-Deitrick, Kirsten S. Smith, Carl J. Nielsen, Diane R. Ullman, Jeanne A. Norwood, George D. Thorne, William F. McCarthy, Ryan C. Adams, Robert M. Rice, Douglas Tang, Jonathan Berman, Janet Ransom, Alan J. Magill, Max Grogl: Topical Paromomycin with or without Gentamicin for Cutaneous Leishmaniasis. In: New England Journal of Medicine. 2013; Volume 368, edition 6 of February 7, 2013, pp. 524-532 doi: 10.1056 / NEJMoa1202657 .
  16. ↑ a b Ana Gallego-Fernandez et al .: Feline leishmaniosis: diagnosis, treatment and outcome in 16 cats. In: J. Feline Med. Surg. Volume 13, 2020. PMID 32053024 , doi : 10.1177 / 1098612X20902865
  17. ↑ Ernst-Günther Grünbaum, Ernst Schimke (ed.): Clinic of dog diseases . 3rd, revised edition. Enke, Stuttgart 2007, ISBN 978-3-8304-1021-8 , pp. 280-281 ( online ).
  18. ↑ Rüdiger Dörris: Medical Microbiology . Georg Thieme Verlag, ISBN 3-13-125313-4 , p. 527 .
  19. ↑ Marianne Abele-Horn (2009), p. 292.
  20. ↑ DPMAregister (accessed on January 8, 2013)
  21. ^ Marianne Abele-Horn: Antimicrobial Therapy. Decision support for the treatment and prophylaxis of infectious diseases. With the collaboration of Werner Heinz, Hartwig Klinker, Johann Schurz and August Stich, 2nd, revised and expanded edition. Peter Wiehl, Marburg 2009, ISBN 978-3-927219-14-4 , p. 292.
  22. ^ Franz von Bruchhausen (eds.), Siegfried Ebel, Eberhard Hackenthal and Ulrike Holzgrabe: Hager's Handbook of Pharmaceutical Practice: Volume 5: Substances LZ , 5th edition, Springer-Verlag, Berlin Heidelberg, 1999, ISBN 978-3-642- 63569-4 ; ISBN 978-3-642-58388-9 (eBook); doi: 10.1007 / 978-3-642-58388-9
  23. ↑ Marianne Abele-Horn (2009), p. 292.
  24. ↑ Marianne Abele-Horn (2009), p. 292.
  25. ↑ P. Gómez-Ochoa, JA Castillo, M. Gascón, JJ Zarate, F. Alvarez, CG Couto: Use of domperidone in the treatment of canine visceral leishmaniasis: a clinical trial. In: Veterinary journal (London, England: 1997). Volume 179, Number 2, February 2009, ISSN  1090-0233 , pp. 259-263. doi: 10.1016 / j.tvjl.2007.09.014 . PMID 18023375
  26. ↑ Adjuvanted vaccine for dogs against Leishmania infantum. European Medicines Agency, EMA / 296055/2010, ema.europa.eu (PDF).
  27. ↑ Ralph Lainson obituary in: The Guardian, May 18, 2015, accessed May 8, 2015.
  28. ↑ worldcommunitygrid.org