Populated landscape in the Nepalese Himalayas.

Has the move of leishmaniasis to high altitudes exceeding 1,500 metres resulted from the parasite’s adaptation or that of its vector?

© IRD/CNRS - Thibaut Vergoz, Preshine 2017

Atypical leishmaniasis cases in Nepal defy science and medicine

IRD scientists and their Nepalese and Indian partners are working to address a new and atypical form of leishmaniasis that is raising concerns. The cases raise questions about the ecology of the Leishmania parasite responsible for this pathology, its vector, the immunity of newly affected populations, the appropriateness of the treatments generally used to fight this neglected tropical disease (NTD) and the causes of this unexpected outbreak.

Is this yet another harmful effect of global warming? A human pathogen in South Asia appears to have changed its habits, particularly in Nepal and India. Two species of Leishmania parasites responsible for cases of leishmaniasis in Nepal, usually encountered in the plains, are now rampant in high altitude regions. “More significantly, the infection caused by one of these species, Leishmania donovani, produces an atypical clinical form,” says Rachel Bras-Gonçalves, IRD immunologist with the INTERTRYP Unit. “And it has created complex scientific and health issues.”

Phlebotomine sand flies, particularly the hematophagous female of the species, are responsible for transmitting leishmaniasis

© IRD - Patrick Landmann, Vectopôle

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Leishmaniasis is a vector-borne disease transmitted by phlebotomine sand fliesbiting midges similar in morphology to mosquitoes. The parasite is transmitted by infected females who feed on blood to produce eggs and caused by the protozoa Leishmania, of which over twenty species are pathogenic to humans. This disease affecting poor populations is found mainly in isolated rural villages, with rudimentary housing and little access to modern care facilities. The illness is a serious public health problem, especially in tropical and subtropical regions, with over one billion people on all five continents at risk of infection.

Cutaneous and visceral forms

Depending on the species of Leishmania, the infection can cause cutaneous symptoms (ranging from forms that heal on their own to more severe diffuse or mucocutaneous lesions with disfiguring and stigmatising effects leading to psychosocial distress) or visceral symptoms that are fatal if left untreated.

Cutaneous symptoms of leishmaniasis can be especially incapacitating and stigmatising.

© Wikipédia - CDC - Dr. D.S. Martin

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In Nepal, the visceral leishmaniasis associated with Leishmania donovani infection has been endemic in the lower tropical plain of Terai, south and southeast of Kathmandu, since the 1950s. “But recently, people have started to develop an unusual skin form caused by this species of parasite outside this area, even in high altitudes – above 1,500 metres – where Leishmania donovani had not previously been observed,” the scientists says.

Rural inhabitants of the Nepalese Plains are no longer the only group suffering from leishmaniasis in the country.

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The role of Leishmania donovani in causing these dermatological forms of the disease has been formally confirmed by PCR testsan in vitro DNA amplification technique used to identify an organism by detecting its characteristic sequences conducted in the research laboratory by Professor Krishna Manandhar, biologist at Tribhuvan University in Kathmandu. "The clinical diagnosis of cutaneous leishmaniasis is challenging," he explains. It is mainly accomplished by performing clinical examinations of the lesions, microscopic observations of the samples and using a rapid antigen testtest used to detect the possible presence of antigen, molecules specific to a pathogen, in a sample, confirming infection of the pathogen in question., which is not always very sensitive.  And there is often still some lingering doubt given the similarity of the symptoms with those of other skin diseases such as leprosy and cutaneous tuberculosis.”

The first cases of cutaneous leishmaniasis caused by Leishmania donovani were therefore misdiagnosed and initially mistaken for these diseases or skin cancer and were treated as such as the first line of treatment.

What treatment should be used?

Leishmania donovani is one of the 20 species of this intracellular parasite that are pathogenic to humans.

© Wikipedia - CDC - Dr. L.Moore, Jr

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These new symptoms of the disease are posing a challenge for healthcare providers since distinct types of treatment are administered for the typical skin forms and the visceral forms. The dilemma is therefore whether to treat it as cutaneous leishmaniasis or, on the contrary, use WHO-recommended treatments for Leishmania donovani infections, which usually result in a visceral form. Or should we look for more specific treatment for these atypical cases? Scientists and doctors are currently working on the issue.

Leishmaniasis, once a disease restricted to rural plains in Nepal, has also been prevalent in high-altitude urbanised areas for several years.

© IRD/CNRS - Thibaut Vergoz, Preshine 2017

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The emergence of leishmaniasis at these high altitudes and the skin forms caused by Leishmania donovani also raises many questions from a scientific perspective:  did the parasite acclimatise to the mountainous areas? Or was it the phlebotomine sand fly, the vector responsible for its transmission to humans? Could it be both? And what role has climate change played in this expansion of the disease's geographical scope.

In Nepal, leishmaniasis was once confined to low-lying tropical plains.

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“As for the singularity of the clinical form, is the parasite responsible for this or is it  linked to the fact that these populations have never encountered the pathogen? Do they have specific immunological characteristics that might explain why the infection is expressed in a cutaneous and non-visceral form with this species of parasite? All these avenues of research will need to be explored to address the phenomenon and prepare for possible epidemics of leishmaniasis,” Rachel Bras-Gonçalves concludes. Prevention and control efforts for this NTD are included in UN Sustainable Development Goal n°3 “Health and well-being for all” and they can only be implemented by committing the necessary human and financial resources.