Three-Nation Effort, Including India, to Beat Kala Azar Faced With New Challenge

In 2005, India, Nepal and Bangladesh launched a joint kala azar elimination initiative to bring down the incidence to less than 1 case per 10,000 people by 2015. That goal has not been reached.

Leishmania donovani. Credit: Wikimedia Commons

Leishmania donovani. Credit: Wikimedia Commons

A South Asian drive to eliminate kala azar, a form of the disease called leishmaniasis, is already two years past its original deadline. And it could be tougher than initially thought as people who carry the parasite but do not show symptoms for up to (and sometimes beyond) three years serve as hidden reservoirs.

Leishmaniasis is caused by the parasite Leishmania donovani and spreads by the bites of certain types of sandflies. The disease prevails in parts of India, Nepal and Bangladesh, as well as in Latin America and Africa. An estimated 200,000 to 400,000 new cases are recorded every year worldwide. The South Asian trio of nations accounts for 67% of them.

When the infection strikes the skin, it’s called cutaneous leishmaniasis; mucosal when it strikes the mucous lining (mainly of the nose and mouth); visceral when it strikes the abdomen. Visceral leishmaniasis (VL) is more widely known as kala azar in India and South Asia. It affects the liver and the spleen and is known to recur after treatment, at which point it is called post-kala-azar dermal leishmaniasis (PKDL).

According to the World Health Organisation, “The disease affects some of the poorest people on earth, and is associated with malnutrition, population displacement, poor housing, a weak immune system and lack of financial resources.” It is also linked to environmental changes like deforestation, dams-building, irrigation and urbanisation.

Treatment often relies on drugs such as miltefosine and amphotericine. Spraying against sandflies can also control a spread.

In 2005, India, Nepal and Bangladesh launched a joint kala azar elimination initiative. Their goal was to bring down the incidence to less than 1 case per 10,000 people by 2015. That goal has not been reached. Since then, scientists have also begun to claim that persons who do not show symptoms – called asymptomatic persons – serve as hidden reservoirs of the parasite.

Infections without symptoms

According to research reported in the journal PLoS Neglected Tropical Diseases in January 2017, asymptomatic persons who are infected but do not show the symptoms “may drive the epidemic” and present “an important challenge to reach the goal of joint VL elimination initiative taken by three Asian countries.”

Scientists from the department of microbiology at the Calcutta School of Tropical Medicine surveyed eight tribal villages in Malda district, West Bengal, using rapid diagnostic kits. They found anti-leishmaniasis antibodies in 185 out of 26,013 people screened.

The team found 79 persons with the infection but without the symptoms. Of them, seven remained infected but had shown no symptoms even after three years.

“If there are no cases for two or more years, it does not mean that the area is free from leishmaniasis,” the researchers concluded, since the symptoms “may appear even after three years.” They presented these people as a significant challenge of the three-nation effort.

“The occurrence of asymptomatic carriers is indeed of concern,” Jean-Claude Dujardin, a professor at the Institute of Tropical Medicine, Antwerp, who has worked extensively on leishmaniasis, confirmed to The Wire. “Mathematical modelling studies showed that asymptomatics could be equally (and even more) important for transmission of Leishmania than PKDL, if they are indeed a source of infection for sand flies. Studies are currently in progress to verify experimentally if this is the case.”

According to him, those carrying the infection can be picked out with the right diagnostic tools – but that’s not the issue. The issue is what they’d be able to do with the information. “Treating them is currently not considered an option because of the cost and toxicity of the drugs, plus the risk of drug resistance.”

The Indian government – as well as the international medical charity Médecins Sans Frontières (MSF) – follow a treatment protocol that only involves the screening of symptomatic patients so they can treat those who are actually sick, for example.

Alan Pereira is MSF’s medical coordinator in India. He said that the limited number of studies from Bihar and West Bengal suggest that “asymptomatic VL is 4-17 times more prevalent than symptomatic VL.”

“A recent review of these studies estimated the risk of progression from asymptomatic to symptomatic to be between 1.5-23%, being higher in those with high antibody titres,” Pereira said. “Asymptomatic infections probably pose a challenge for elimination of Kala Azar from India. As of now, it is not known how infective such patients are in transmitting the disease. There are theoretical models that attribute a large burden of transmission on asymptomatic patients but it is based on several assumptions.”

He also clarified that the persistence of asymptomatic VL was the reason the international effort was focused on eliminating the disease, not eradicating it, and it calls for a robust surveillance system that continues for several years after elimination. This is to make sure it is sustained and that those progressing to symptomatic kala azar are diagnosed early.

Drug resistance and other challenges

Emerging drug resistance in infected persons is compounding the leishmaniasis problem. “Many studies showed that parasites may remain somewhere in the body even after successful treatment,” Dujardin said.  

A study in Nepal, which included Dujardin and was published in 2013, first showed that one in every five patients treated with miltefosine relapsed. The concluded that this was “alarming”.

“A new field of research is emerging around that topic – several authors suggest that leishmanial parasites can remain quiescent in the body. They don’t replicate and show a dramatically decreased metabolism,” Dujardin explained. “If such parasites are present, they could reactivate, for instance in cases of immune-suppression.”

In March this year, they wrote in the journal Trends in Parasitology that academics suggest drug-resistance studies should be involved at two different stages of drug development. First, the efficiency of novel compounds should be confirmed on sets of strains including recent clinical isolates with drug resistance. Next, experimental drug resistance should be generated to promising compounds at an early stage of their development. This is to further optimise them and monitor clinical trials.

Pereira said that other challenges that stood in the way of eliminating kala azar were reservoirs of parasites in patients with PKDL and those co-infected with HIV.

MSF is looking at addressing this knowledge gap by conducting operational research in highly endemic districts of Bihar to discern the prevalence of asymptomatic VL infection in HIV-positive patients and risk factors for progression to symptomatic VL.

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