Meghan Perry / Wellcome Trust Research Fellow / Dundee
In this article, Dr Meghan Perry discusses some of the politics surrounding Neglected Tropical Diseases and gives us a run down on one of the most important, Visceral Leishmaniasis.
Neglected Tropical Diseases
Neglected Tropical Diseases are a group of tropical infections that do not include the Big Three of HIV, tuberculosis and malaria. Despite their huge impact, neglected tropical diseases have received minimal attention and research funding during the last century. They continue to present a big challenge to global public health.
At the beginning of this year, in a high profile meeting in London, the CEOs of nine leading pharmaceutical companies met with Bill Gates, Margaret Chan (the director general of the WHO), the World Bank and government officials to discuss how they could join forces. They pledged to fund the development of drugs that would bring the Neglected Tropical Diseases ‘to their knees with stunning speed’. Following the meeting Margaret Chan predicted the elimination or at least control of most neglected diseases by 2020.
This is amazing news in the world of tropical research. Effective, inexpensive and non toxic medications are desperately needed. However, they still only form a link in the chain of intervention, elimination and control. In fact, there are five key factors that are essential to control vector borne diseases: peace, long-term political commitment, finance, robust control methods and public health education.
For one of the NTDS, visceral leishmaniasis (VL, also known as kala-azar), Margaret Chan’s prediction will not be achievable until certain fundamental research questions relating to reservoir and vector control are answered and community and public health systems are strengthened. With VL’s scattered geography of endemicity in north eastern Asia, eastern Africa and north eastern Brazil needs and issues differ from country to country.
What is VL?
VL is the most severe of a range of conditions caused by the parasite Leishmania. It is a fatal disease transmitted by the bite of a sand fly (see the gallery). This tiny insect lives in temperate climates, breeding in and around the dark corners of poor quality thatched and mud housing, and near cattle (see diagram opposite). Worldwide, there are around 500,000 reported new cases per year with an annual death rate of about 50,000.
Patients present with signs of splenomegaly, enlarged lymph nodes (African VL only) and pancytopenia. This clinical picture can often be complicated by bacterial co-infection due to the parasite’s disabling of its host’s immune system. It is this co-infection that is often the cause of death.
The reservoir of the Leishmania parasite is any living mammal that can support infection and thus transmit the Leishmania parasite back to another biting sand fly. In Brazil, the principal reservoir is canine but elsewhere in the world VL is mainly spread from human to human. A full understanding of the different stages of human disease and their management is essential to control.
Effective treatment reduces the parasite reservoir. The first treatment developed for VL in the 1920s was injections of a drug based on the metalloid element antimony. This drug was highly toxic to the parasite but was poorly tolerated due to severe myalgia. It could also cause death in just under 1 in 100 treated patients from cardiotoxicity.
Antimony-based compounds are still being used effectively in Africa and Brazil. However in India, emergence of widespread treatment failure with antimony based drugs caused an epidemic and a public health crisis that peaked in the 1990s.
That crisis resulted in the development of less toxic drugs: the antifungal drug amphotericin B was employed to fight VL and a new oral medication, miltefosine, emerged. Unfortunately, miltefosine requires a lengthy course and, despite its relatively recent introduction, high relapse rates are being reported.
A relapsed patient is a reservoir of parasite. Following successful treatment patients can relapse in two different ways. In one, the traditional symptoms of VL can recur from weeks to years post-treatment.
In the other, the patient will develop ‘post kala-azar dermal leishmaniasis’ ( PKDL). Here the Leishmania parasite recurs in great numbers in macules and nodules that can cover a wide expanse of skin. PKDL is not uncomfortable, so patients often will not seek treatment, providing an important reservoir for infection.
Although PKDL is easily detected by trained health professionals, its treatment regime is ► long, arduous and toxic. Compliance levels are poor and there remains much room for development.
Only a small fraction of infections result in clinical VL. So, the largest reservoir of Leishmania parasite is thought to be asymptomatic VL patients.
Even with active case finding, detection and effective treatment of clinical VL, there will still be little impact on transmission due to the high prevalence of asymptomatic VL as a parasite source for the sand fly vector. Subclinical VL patients are not easy to identify. Until diagnostic testing improves and appropriate minimally toxic treatment regimes are identified, treating subclinical VL will not be a feasible control strategy.
Given that we are currently far away from the mass drug administration programmes effective for many other NTDs, the only alternative to bring about elimination would be vaccination. However, the holy grail of an antileishmanial vaccine is still in the developmental stages.
With these significant issues in reservoir control, vector control is paramount. In the 1950s and 1960s in India, an indoor residual spraying (IRS) programme for malaria almost eliminated VL due to the secondary effect of the insecticide DDT on sand flies.
Traditional IRS programmes are in progress around the world. Although effective, they are meeting with issues of sand fly resistance to DDT and, due to poor health education, lack of cultural acceptance.
The use of long lasting insecticidal bednets was shown to decrease incidence of VL in a trial in Sudan but a detailed trial in India looking at serological markers covering all stages of human disease as well as clinical VL, did not demonstrate any significant benefit. This contradiction throws up urgent research questions relating to sand fly feeding and breeding habits that need to be answered before vector control can be successful.
One solution could be an innovative approach to vector control which draws on more modern scientific methods.
A group in New Mexico have investigated the natural flora of the sand fly gut and found that paratransgenic manipulation of Bacillus subtilis alters the ability of the sand fly gut to support the growth of the Leishmania parasite and thus interrupts transmission. This promising method though is far from ready for the field and there are widespread ethical, ecological and environmental issues to be considered prior to implementation.
People and Politics
Visceral leishmaniasis is a devastating disease. Progress is being made to improve the lives of those who suffer from it but it is slow. Increased funding and development of good new treatment regimes, as promised by Bill Gates and partners, will improve the outlook. However for elimination to be successful attention should be paid to research into reservoir and vector control. It must also be remembered that without the cooperation, understanding and education of those who are at risk from VL and those who look after them, the impact of any research is diminished greatly.
Finally, if NTDs are kept on the global political agenda, then there is hope for the disease management and control that those affected both need and deserve.