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09 JUL 2024
Kala-azar is a highly fatal infectious disease that is endemic to Bangladesh and more than 60 other countries across the world. It has historically been neglected in global health agendas as it tends to mostly affect poor and marginalized populations. Recently, Bangladesh celebrated the elimination of kala azar as a public health problem. According to the WHO’s 2021-2030 roadmap for neglected tropical diseases, elimination of kala azar as a public health problem in Bangladesh required reduction of the number of reported cases below 1 per 10 000 population in all kala-azar endemic upazilas of the country. Bangladesh has met this criterion since 2017 and obtained WHO recognition as the first country to eliminate kala-azar as a public health problem. The current vision and next step of the National Kala-azar Elimination Programme is to have zero kala-azar transmission in the country by 2030.
The disease
Kala-azar, also known as visceral leishmaniasis, is a severe form of leishmaniasis caused by parasites of the Leishmania species. Leishmaniaparasites are transmitted through bites of the females of several species of sandflies. Other forms of leishmaniasis affect the skin or mucous membranes.
Kala-azar affects multiple organs, leading to enlarged abdomen due to enlarged spleen and liver, weight loss, anemia and hemorrhage due to low blood cell and platelet count. Mud houses, poor sanitation, exposure to endemic areas, and high sandfly density in houses are risk factors for infection with Leishmania, and malnutrition and immunocompromised status are risk factors for infection progressing to severe disease, that is, kala-azar. It may occur within several weeks to months of exposure in up to 15-20% of Leishmania-infected individuals. If left untreated, kala-azar cases are usually fatal. The Global Burden of Disease study estimated that kala-azar caused almost 6,000 deaths globally in 2019, but this is likely to be an underestimate as many deaths occur outside medical facilities and go unreported.
A brief history
Western doctors first encountered the disease in Jessore in what was then British India, where it got the name of kala-azar (translating to black fever), possibly based on darkening of the skin on the extremities and abdomen that often occurs. In 2005, Bangladesh, Nepal, and India, with support from the WHO, set up the Kala-azar Elimination Programme. Early diagnosis and effective treatment were considered as means to reduce disease burden, and vector control and improved surveillance through active and passive case detection would be used to interrupt transmission. Rapid diagnosis relied on a then-novel test (the rK39 test) that detects a type of antibody produced by the patient against Leishmania parasites, while the initial treatment of choice was the easily administered oral drug miltefosine. Miltefosine has an efficacy of about 85% in the Bangladeshi population. Single-dose, intravenously administered liposomal amphotericin B was subsequently shown in a trial in Bihar, India, to have an efficacy of 96% in 2010. Following a feasibility study led by icddr,b’s Dr. Dinesh Mondal — which showed a 98% efficacy in rural Bangladesh — the Bangladeshi government adopted liposomal amphotericin B since 2013.
Controlling populations of the sandfly vector through insecticide-centered interventions — mostly indoor residual spraying with insecticides — and preventing sandfly bites using bed nets have been key strategies to interrupt transmission of the disease. In a 2013 article, Dr. Mondal and collaborators had reported in a study conducted across 72 villages that distribution of long-lasting insecticide-treated bed nets reduced incidence of kala azar by 66.5%.
Building partnerships between stakeholder organizations was one of the five  key strategies of the elimination campaign, and icddr,b scientists played an important role in establishing collaboration between CDC, DGHS, GoB and about 27 national and international research institutes and organizations, and development partners through innovations, discoveries and support for the NKEP.
As a result of strong political commitment, innovations for disease diagnosis, treatment, vector control and social mobilization, and effective partnership between CDC, DGHS, GoB, icddr,b and other national and international organizations and development partners in implementing strategies and innovations for kala-azar elimination, Bangladesh became the first country in the world to eliminate kala-azar as a public health problem in the country.
What now?
Elimination of this long endemic disease as a public health problem is a massive accomplishment for public health institutions —including icddr,b — in Bangladesh. Now, continued effective surveillance and control of the disease will be key to sustain its current status and possibly bring its transmission down to zero by 2030. Developing cost-effective methods for molecular diagnosis and post-elimination surveillance including in non-endemic areas will be key for early detection and prevention of eventual outbreaks, as will cheap, safe, and effective treatments for relapse kala-azar cases and patients with post kala-azar dermal leishmaniasis, the interepidemic reservoir of the disease. Looking beyond Bangladesh, kala-azar remains endemic in more than 60 countries, mostly clustering in parts of Brazil, Ethiopia, Kenya, Somalia, South Sudan, India, and Sudan. Globally, between 235 and 647 million people are at risk of the disease from living in areas where the sandfly vectors are common enough to maintain transmission. Methods and approaches that have found success in Bangladesh can inform strategies adopted by other countries to eliminate kala-azar.
Typical antibody-based diagnostic tests for kala azar are recommended to be performed on serum. This presents several challenges like refusal by patients to provide venous blood samples required for extracting serum, and a need for long-term storage and transportation if the facility is not equipped to extract serum from blood. Dried blood spots offer a less invasive and easily stored alternative that has previously been successfully used to diagnose HCV, HIV, phenylketonuria, and many other diseases and conditions. These are collected through finger-pricking onto a paper-like substrate and preserved by simply drying the substrate, A recent icddr,b study showed that two commonly used antibody-based tests showed complete agreement in results between whole blood and dried blood spot samples. This indicates that dried blood spots could serve as a suitable alternative to collecting venous blood samples for diagnostic testing and surveillance in resource-poor settings.
Challenges for kala-azar elimination include kala-azar relapse and post-kala azar dermal leishmaniasis (PKDL), which is a sequalae of kala azar characterized by skin hypopigmented, popular, nodular or mixed of all these lesions in mostly patients who have already treated for kala-azar. In the Indian subcontinent, PKDL occurs in 3-24% of patients who had been treated for kala-azar, with a median time of 2.3 years after treatment. An icddr,b study showed that similar to nodular PKDL cases, hypopigmented cases (the more common form in Bangladesh) are reservoirs and can transmit the parasite to the sandfly. Detection of PKDL is hindered by resemblance to other skin diseases such as leprosy and vitiligo. As the currently available serological tests cannot distinguish between past and current infections, it is difficult to diagnose relapse kala-azar cases and cases of PKDL without knowledge of the past history of kala-azar. Molecular methods based on detection of Leishmania DNA hold promise in detecting these cases and overcoming their diagnostic challenges. Common methods to extract and amplify (using PCR) DNA for detection require sophisticated equipment and reagents, and take several hours. In a recent study, icddr,b and international collaborators showed that a new DNA amplification method called the RPA (recombinase polymerase amplification) assay showed near-perfect agreement with a traditional qPCR-based test in detecting kala-azar infections from blood samples. The RPA assay is isothermal and takes 15 minutes, and does not require like more complex temperature settings like qPCR. The study also showed the effectiveness of a new 20-minute, equipment-free method of extracting DNA called SwiftDx. Thus, a SwiftDx-RPA approach could serve as an effective point-of-care diagnostic tool in the field, allowing rapid surveillance in remote areas with limited access to advanced laboratory equipment. This technology can set up in a Mobile Suitcase Lab — a new innovation developed in collaboration between Leipzig University and icddr,b — that can be taken to the field and powered by solar energy. The RPA assay was also successfully implemented in a 2024 study inside a small device that connects by Bluetooth to a smartphone and transmits diagnosis results in 20 minutes.
Bed nets, insecticides, and raising community awareness on kala-azar and its transmission have helped to reduce exposure to sandflies. A novel, further cost-effective measure involves incorporating insecticides into wall painting. icddr,b scientists recently showed in a study conducted in seven kala-azar endemic Bangladeshi villages that insecticidal wall painting, remains effective 24 months following application. The mean femalesandfly density reduction across the seven villages ranged from −56% to −83%, and sandfly mortality ranged from 81% to 99.5% during the 24-month period. Insecticidal wall painting was also equally effective or superior to routine indoor residual insecticide spraying, which is more resource-intensive and lasts four to six months before needing to be re-administered.
Such continued innovation in kala-azar surveillance and management is likely to play a key role not only in Bangladesh, but other kala-azar endemic regions across the world. The kala-azar elimination programme indeed holds lessons for controlling other neglected diseases that disproportionately affect resource-poor settings. Our findings can be taken to parts of Africa where kala-azar remains a big public health burden and be incorporated into ongoing and upcoming elimination programs. For instance, the rapid and sensitive RPA test developed and benchmarked by icddr,b could play a vital role in diagnosis of African kala-azar, especially as part of a mobile suitcase lab that improves access to the test.
Key contributions
Acknowledgements
icddr'b’s work on kala-azar detection, control, and elimination was made possible thanks to the excellent collaboration and financial support from TDR, WHO, Geneva, Switzerland, Bill and Melinda Gates Foundation, NTD, WHO, Geneva, Switzerland, FCDO (DFID), UK Aid, UK, JICA, Japan, CDC, Atlanta, USA , DNDi, Geneva, Switzerland, PATH, India / USA, IOWH , University of Tokyo and University of Nagasaki, Japan, IDRI, Seattle, USA, Thrasher Research Funds, USA, FIND, Geneva, Switzerland, UBS Foundation, Geneva, Switzerland, Liverpool School of Tropical Medicine, UK and University of Leipzig, Germany, Gilead Sciences, USA, Inesfly, Spain, Carlos III University, Madrid, Spain, MSF, Netherlands, Bayer (Ply) Ltd, Germany, Mott McDonald, UK, CROWN Agent, UK, Westergaard, Switzerland. Our vision is to continue to develop cost-effective therapeutic and preventive strategies including vaccine against VL and other diseases of public health importance.
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