History’s Seven Deadliest Plagues
Joining Forces To Take On Neglected Tropical Diseases
T. Cruzi expressed in host vero cells, the green dots represent the amastigote stage, the mitochondria is red coloured, and the nucleus is blue.© Mizuki Hayashishita
Almost two billion people globally are affected by conditions such as Chagas disease, dengue fever, leishmaniasis, and schistosomiasis. These viral, bacterial and parasitic infections cause about 200,000 deaths annually, particularly in low-income nations in Africa, Asia and the Americas.
Despite their prevalence, these so-called neglected tropical diseases (NTDs) remain largely overlooked in the global health policy agenda. But at Nagasaki University's Institute of Tropical Medicine (NEKKEN) in Japan, they have been under the spotlight for almost a century.
At the university's research development stations across Asia, Africa and Latin America, researchers are collaborating with international partners to discover new ways to diagnose, control and treat neglected tropical diseases.
Decoding dengue
In Asia and Latin America, immunogeneticist, Kenji Hirayama, and his team are searching for the genetic factors that underpin the severity of dengue fever, a mosquito-borne viral illness that infects up to 400 million people each year.
While most people with dengue experience relatively mild symptoms, around 5% develop a severe version of the illness that can be fatal — severe dengue leads to serious bleeding, or dengue shock syndrome. "It's so variable and diverse," says Hirayama. "We are curious about the different types of reactions that happen across different groups."
In 2020, Hirayama and an international team conducted a genome-wide association study on almost 7,500 people of Latin American, South Asian and Southeast Asian ancestries to pin down whether certain genetic variants make some people more susceptible to severe forms of dengue.
They found that participants who had contracted severe versions carried several genetic variations that were not present in the control group, or among those who had endured a regular dengue infection. This genetic susceptibility held up across all three ancestries, suggesting that it is universal rather than a unique feature of a population or region.1
Carlos Ramos, a member of the Nagasaki University team, talking to a member of the public at El Bajio Hospital in Santa Cruz, Bolivia.© Nagasaki University
No one left behind
Another infection in Hirayama's sights is Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. It affects as many as seven million people at any one time, mostly throughout Latin America, and can result in chronic Chagas characterized by heart problems and digestive issues. "In Central America, heart disease is common, but in South America digestive issues are dominant," says Hirayama.
According to Hirayama's research, the reason symptoms vary across regions is not due to differences among T. Cruzi strains, but to genetic variations among patients. For instance, in a study the team conducted in Bolivia, human leukocyte antigens — a group of genes that play a role in the immune response — were found to be less common in Chagas disease patients with a dilated colon, also known as megacolon.2
Understanding the human genetics underpinning disease severity could hold the key to developing new treatment protocols and vaccines, particularly for chronically ill patients, says Hirayama.
Another approach involves improving diagnosis in remote, resource-limited regions. In 2020, Hirayama joined an international team of researchers and industry partners to evaluate whether a diagnostic test called loop-mediated isothermal amplification (LAMP) could be used to detect Chagas disease in newborn infants in maternity hospitals across Bolivia, Argentina and Paraguay. Developed by Japanese clinical diagnostics and equipment firm, Eiken Chemical, LAMP offers a low-cost, rapid, and highly specific alternative to current diagnostic methods, such as quantitative polymerase chain reaction (PCR). The project is funded by the Global Health Innovative Technology (GHIT) Fund, a Japan-based partnership of international public and private organizations, and Mundo Sano in Argentina.
In addition to diagnostics, the university is working on anti-Chagas drug development. This project is focussed on mitochondrial enzymes, and is led by Hirayama's colleagues, Kiyoshi Kita and Daniel Ken Inaoka. Such collaborations between industry, government, and academia are key to bringing effective diagnostic tools and treatments to people who need them the most, says Hirayama.
Tracing the spread
Africa accounts for almost 40% of the global neglected tropical disease burden. Satoshi Kaneko and his team are working to improve diagnosis, treatment and monitoring for diseases afflicting the region, such as schistosomiasis and leishmaniasis.
Eumycetoma is another target for Kaneko. This is a chronic skin infection caused by a variety of soil fungi and bacteria, mainly in Sudan. "We know that many people in rural areas are suffering from infection, but we don't know exactly how many," says Kaneko. Using a grant from the Japan Agency for Medical Research and Development (AMED), Kaneko is developing point-of-care diagnostic tests that can be used in rural areas that lack access to medical services.
But the big picture goal is to develop a surveillance system that can monitor multiple neglected tropical diseases at once, helping researchers better track and control their spread through communities. Currently, numerous surveillance monitoring systems are used to track individual diseases, but this is costly and impractical, as several neglected tropical diseases overlap geographically, says Kaneko. "It would be easier to monitor them all at once with one system," he says.
In 2014, Kaneko and colleagues developed a multiplex immunoassay system that could detect Immunoglobulin G antibodies to recombinant antigens derived from eight different pathogens, including Leishmania donovani — the parasite behind visceral leishmaniasis — in blood samples taken from communities in endemic areas. Now, the system has been expanded to detect between 10 and 20 infectious diseases in a single batch, allowing researchers to monitor infections in different locations, says Kaneko.3
More recently, a team led by Kaneko's colleague, Shinjiro Hamano, has been homing in on schistosomiasis, another parasite infection that's prevalent around Africa's Lake Victoria. While the disease has been detected in young children and infants, they are trying to uncover the risk factors underlying infections in this age group.
Kaneko also leads the Japan Alliance on Global Neglected Tropical Diseases (JAGntd), a network that connects international organizations, companies, and researchers working to control neglected tropical diseases. The alliance aims to reach the targets outlined in the World Health Organization's (WHO) Neglected Tropical Disease Roadmap, which seeks to prevent, control, and eradicate 20 diseases or disease groups by 2030.
The transition between the amastigote stage to the trypomastigote stage in T. Cruzi expressed in host vero cells.© Mizuki Hayashishita
Applied research
Partnering with public and private sectors is key for ensuring that research results make an impact, particularly in remote regions, says Kaneko. "We have to ensure that our research can be applied, such as in the development of diagnostic kits and treatments," says Kaneko.
To strengthen the university's focus on NTDs, Nagasaki University has recently established 'Dejima Tokku' which it describes as an "autonomous free research development complex designed for global infection control". A biosafety level 4 facility and a School of Tropical Medicine and Global Health (TMGH) are new additions to this complex and join already established basic and clinical research groups.
These activities are part of the vision of Shigeru Kohno, the president of Nagasaki University. He is expanding its health research community through the multi-disciplinary concept of "planetary health". Nagasaki University plans to continue as a vibrant research hub in Japan, say Hirayama and Kaneko.
References
1. Pare, G. Et al., eBioMedicine 51, 102584 (2020).
2. Del Puerto, F. Et al., PLoS Neglected Tropical Diseases 6, e1587 (2012).
3. Fujii, Y. Et al., PLoS Neglected Tropical Diseases 8, e3040 (2014).
Tropical Medicine Healthcare
The National School of Tropical Medicine at Baylor College of Medicine is located in subtropical Houston, Texas, an international hub and the most diverse city in the United States. NSTM's location in combination with the significant multi-cultural population creates a unique clinical environment with locally and internationally acquired tropical diseases.
Harris Health System Adult Tropical Medicine ClinicThe NSTM at Baylor College of Medicine established a Tropical Medicine Clinic at Harris Health System's Smith Clinic (https://www.Harrishealth.Org/locations-hh/Pages/smith-clinic.Aspx) in the Texas Medical Center in 2011. The clinic evaluates, diagnoses and manages adult patients with neglected tropical diseases. Neglected tropical diseases are infectious pathogens including parasites, fungi, viruses and bacteria that disproportionately affect person's living in resource limited tropical regions globally. Now commonly known as infections of poverty. New evidence indicates a hidden burden of tropical disease in the poorest parts of the United States, including South Texas. We are available to answer any questions you may have related to tropical diseases, particularly:
Reviewing a Decade of Outpatient Tropical Medicine in Houston, Texas. Julika Kaplan, Fernando Hernandez Centeno, Jesica Hayon, Maria Elena Bottazzi, Peter J. Hotez, Jill E. Weatherhead, Eva Clark, and Laila Woc-Colburn.
A referral by a healthcare provider to the adult tropical medicine clinic can be made by faxing the completed referral form with relevant medical history to (713) 440-1190.
Texas Children's Hospital Tropical Medicine ClinicThe NSTM at Baylor College of Medicine established a Pediatric Tropical Medicine Clinic at Texas Children's Hospital in 2020. Due to the high rate of childhood poverty in the southern United States and the subtropical climate, neglected tropical diseases are commonly identified in children. Chagas disease, cysticercosis, Dengue, tuberculosis, strongyloidiasis, soil-transmitted helminths and toxocariasis are among several endemic tropical diseases that can be locally acquired in Texas. The Pediatric Tropical Medicine clinic diagnoses and manages pediatric patients with tropical diseases including neglected tropical diseases and infections of poverty. Clinicians within the Pediatric Tropical Medicine clinic also evaluate pediatric patients with post-travel syndromes.
A referral by a healthcare provider to the pediatric tropical medicine clinic can be made by calling Texas Children's Hospital (832) 824-4330 or by completing the Infectious disease on-line referral form indicating Tropical Medicine Clinic.
International Tropical Medicine Case ConferenceIn 2022 the Baylor College of Medicine National School of Tropical collaborated with Houston Methodist, Universidad Peruana Cayetano Heredia (Lima, Peru), and Universidad San Francisco de Quito (Quito, Ecuador) to establish a quarterly International Case Conference. The objectives of the International Tropical Medicine Case Conference are to:
For information on how to participate in the International Tropical Medicine Case Conference email tropmed@bcm.Edu.
Ethiopia: The Impact Of Enhanced, Demand-Side Sanitation And Hygiene Promotion On Sustained Behavior Change And Health In Ethiopia
Neglected tropical diseases are a diverse group of parasitic, bacterial, and viral diseases affecting more than one billion people around the world, primarily those in poor regions without adequate sanitation. Some of the diseases, namely soil-transmitted helminthiasis, schistosomiasis, and trachoma, can be controlled with preventive drug treatments, but reinfection can rapidly occur. Eliminating these conditions requires that people have access to and use sanitation and hygiene infrastructure. In Ethiopia, millions of people are at risk of neglected tropical diseases and the Government of Ethiopia has made control and elimination a priority. Researchers will study the impact of an intervention that integrates specific sanitation and hygiene behavior change components into current government supported programming to encourage improved personal hygiene and sanitation practices. The evidence will help Ethiopia develop more effective programs, while providing researchers worldwide with new information on how to improve sanitation and hygiene.
Research area: Water Supply, Sanitation and Hygiene Country: Ethiopia Evaluation Sample: 76 kebeles (each kebele consists of one or two gotts, which are communities of 60 to 90 households). Timeline: 2017-2019 Intervention: Community-led total sanitation and hygiene program Researchers: Matthew Freeman, Emory University Partners: Amhara Regional Health BureauProblem In Ethiopia, millions of people are at risk of neglected tropical diseases (NTDs) and the Government of Ethiopia has made control and elimination a priority. In the Amhara region of Ethiopia, where the evaluation is taking place, several neglected tropical diseases are prevalent – including trachoma, soil-transmitted helminths, and schistosomiasis – and the spread of these diseases is exacerbated by people's poor water, sanitation, and hygiene practices.
Intervention The SIEF-supported research team, working together with the local health authority, developed a program for encouraging sustained behavior change around sanitation, personal hygiene, and keeping living areas free of animal and children's feces. The intervention is designed to complement existing government approaches for promoting use of improved water and sanitation actions to reduce transmission of neglected tropical diseases in the area. The activities are delivered through local volunteers, known as the Women's Development Army, and include community celebrations, public commitment ceremonies, and repeated household visits. The campaign is called Andilaye (which means togetherness in Amharic) and offers an aspirational message that emphasizes the need for collective action to make positive change in one's community.
Evaluation design Cluster-randomized controlled trial. The unit of randomization is the kebele, which is a group of gotts (gotts are communities of around 60 to 90 households). The study sample include 50 kebeles (each kebele has 1-2 gotts), with 25 kebeles randomly assigned to the intervention group that received the Andilaye intervention, and the remaining 25 assigned to the control, which receives the government's standard sanitation improvement package.
Eligibility Rural and peri-urban households in the Amhara region of Ethiopia.
Results Evaluation is ongoing
Next steps The team has completed the midline survey as of April 2018 and plans the endline survey in 2019.
Policy impacts The program is being implemented together with the Amhara Regional Health Bureau, which is paying the salaries of the health workers.
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