No drug can cure a paradox. That basic truth is at the heart of a new Stanford-led study highlighting how poverty traps make it impossible to eradicate a potentially deadly disease with current approaches.
The study, published in the American Journal of Tropical Medicine and Hygiene, looks at why years of mass drug administration in Senegal have failed to dramatically alter infection rates of schistosomiasis, a parasitic disease that lurks in waterborne snails and affects more than 200 million people worldwide.
It finds that neither drugs nor people’s relatively sophisticated understanding of disease risks can overcome the inevitable exposure caused by imperatives of subsistence living.
The researchers call for greater focus on the role of socio-economic and environmental systems, and engaging communities in the design of disease control programs.
“The field of tropical medicine has focused primarily on mass drug administration programs,” said lead author Andrea Lund, a Ph.D. student in the Emmett Interdisciplinary Program in Environment and Resources within Stanford’s School of Earth, Energy & Environmental Sciences.
“These have worked in many places, but there are persistent hot spots where you need to come at the problem from social and environmental angles too.”
Although charity evaluation services consistently rank mass drug administration programs among the most effective developing world public health interventions, the efforts often fail to eradicate disease in the long run.
That’s because they don’t address the root causes that lead to reinfection time after time, according to Lund.
Obstacles to a cure
Schistosomiasis is a disease caused by a parasitic worm and transmitted to humans by freshwater snails that serve as the parasite’s intermediate host.
The disease is widespread across tropical latitudes, with the vast majority of cases in sub-Saharan Africa.
The snails release infective larvae into freshwater, where they burrow into people’s skin. Symptoms range from abdominal pain and diarrhea to infertility, permanent organ damage and bladder cancer.
Chronic schistosomiasis can affect cognitive development and labor productivity, according to some studies.
Nearly 40 years after being introduced, praziquantel – a drug used to clear schistosome parasites from people – has yet to make a dent in the global burden of the disease.
That’s because treated people often re-enter contaminated water, repeatedly exposing themselves to reinfection.
Lund is part of a team that has been trying to understand the obstacles to a cure and ways around them.
Led by Stanford disease ecologist Susanne Sokolow and biologist Giulio De Leo (both co-authors on the study), the group has shown that ecological tactics aimed at controlling schistosomiasis are the most effective way to reduce the disease’s prevalence.
The team received early funding from the Stanford Woods Institute for the Environment for a project to reintroduce native snail-eating prawns to local water sources, and has since established the Program for Disease Ecology, Health and Environment at Stanford with a grant from the Stanford Institute for Innovation in Developing Economies.
The program, supported by Woods and the Stanford Center for Innovation in Global Health, focuses on finding sustainable ecological solutions to a range of diseases.
For the study, Lund and her colleagues surveyed residents of villages along the Senegal River, a region with persistently high rates of schistosomiasis despite yearly school-based mass administration of praziquantel since 1999. P
eople explained how life in their rural, resource-poor area is inextricably intertwined with the river. Common livelihoods, such as agriculture and fishing, depend on contact with the waterway. So do chores, such as washing clothes, and hygiene practices, such as bathing and children’s play.
A 53-year-old man from one riverside village who spoke with one of the researchers summed up the catch-22: “That water, we cannot touch it. We cannot abandon it. If we abandon it, we will all become unemployed.”
“There is a feeling of inevitability around schistosomiasis infection, given the constraints of poverty,” said Sokolow, a senior research scientist at Woods.
“That jibes with the experience of the many years of efforts to distribute pills and carry out educational campaigns in the region without a huge drop in schisto transmission or infection. It’s the quintessential wicked problem.”
Residents expressed a relatively sophisticated knowledge about the environmental nature of schistosomiasis, including the fact that infection risks increase at midday – an observation borne out by the tendency of snails to release free-swimming parasite larvae into the water at the same time of day.
With this knowledge, some residents had developed personal strategies or village-wide policies – enforceable by fines – to minimize exposure by avoiding the river at certain times.
Good leadership and community engagement were among the strongest indicators of success in overcoming these obstacles.
This capacity to organize suggests that communities could take the lead in implementing environmental and social interventions – ranging from prawn re-introduction to the construction and maintenance of water and sanitation facilities or behavior change programs.
This would ensure interventions are locally acceptable and can be sustained over time.
This type of engagement with communities could reduce the amount of parasite transmission in the environment and improve outcomes of mass drug administration in areas where they have had limited success, according to the researchers.
“Ultimately, I see these findings making a case for further investment in environmental solutions – such as prawn re-introduction,” Lund said.
“This may be the only way to reduce the risk of schistosomiasis in settings where the disease burden remains high even in the presence of treatment programs.”
More information: Andrea J. Lund et al. Unavoidable Risks: Local Perspectives on Water Contact Behavior and Implications for Schistosomiasis Control in an Agricultural Region of Northern Senegal, American Journal of Tropical Medicine and Hygiene (2019). DOI: 10.4269/ajtmh.19-0099
Journal information: American Journal of Tropical Medicine and Hygiene
Provided by Stanford University
It is caused by trematode parasites of the genus Schistosoma;3 the adult male and female worms live within the veins of their human host, where they mate and produce fertilised eggs.
The eggs are either shed into the environment through faeces or urine, or are retained in host tissues where they induce inflammation and then die.
The eggs that reach freshwater will hatch, releasing free-living ciliated miracidia that then infect a suitable snail host.
In the snail, the parasite undergoes asexual replication through mother and daughter sporocyst stages, eventually shedding tens of thousands of cercariae (the form infectious for human beings) into the water.
The asexual portion of the lifecycle in the snail (figure 1) requires 4–6 weeks before infectious cercariae are released.
After cercariae penetrate the skin of the mammalian host, the maturing larvae (schistosomula) need about 5–7 weeks before becoming adults and producing eggs.
These intervals (in both the snail and human being) are termed prepatent periods, when the infection is ongoing but release of cercariae (from snails) or eggs (from humans) cannot be detected.
Cercariae can remain infective in freshwater for 1–3 days, but deplete their energy reserves greatly over a few hours.4
Eggs—whether excreted or retained in the body—die within 1–2 weeks after being released by the female worm.
Three main species of schistosomes infect human beings, Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum. S haematobium and S mansoni both occur in Africa and the Middle East, whereas only S mansoni is present in the Americas. S japonicum is localised to Asia, primarily the Philippines and China.
Three more locally distributed species also cause human disease: Schistosoma mekongi, in the Mekong River basin, and Schistosoma guineensis and Schistosoma intercalatum in west and central Africa (figure 2).
Each species has a specific range of suitable snail hosts, so their distribution is defined by their host snails’ habitat range. S mansoni and S haematobium need certain species of aquatic freshwater Biomphalariaand Bulinus snails, respectively. S japonicum uses amphibious freshwater Oncomelania spp snails as its intermediate host.
Adult male and female worms live much of this time in copula, the slender female fitted into the gynaecophoric canal of the male, where she produces eggs and he fertilises them (appendix).
Adult worms digest erythrocytes and although most of their energy is obtained by glucose metabolism,8,9 egg production is dependent on fatty acid oxidation10—both glucose and fatty acids being derived from the host.
They live within either the perivesicular (S haematobium) or mesenteric (S mansoni, S japonicum, and others) venules.
Schistosomes have no anus and cannot excrete waste products, so they regurgitate waste into the bloodstream.
Some of these expelled products are useful for blood-based and urine-based diagnostic assays.
S japonicum and S mekongi are zoonoses that also infect a wide range of mammalian hosts, including dogs, pigs, and cattle, which greatly complicates control and elimination efforts.
Although S mansoni can infect rodents and non-human primates, human beings are thought to be its predominant mammalian reservoir.
Understanding the schistosome lifecycle (figure 1) and the parasite’s movement between intermediate (snail) and definitive (mammalian) hosts is fundamental to the control and elimination of human schistosomiasis.
Environmental changes can either increase11 or decrease12 transmission. Changes in snail habitat and predators are crucial determinants of transmission, and prepatent periods can affect the efficacy of treatment regimens.13
Effective treatment of people (such that their excreta do not contain eggs), the prevention of sewage contamination of freshwater, the elimination of intermediate host snails, and the prevention of human contact with water containing infected snails can help to prevent transmission.
Although still in its infancy, studies of schistosome genomics will prove crucial for identification of candidates for drug targets and prophylactic vaccines.14
Schistosome populations are very genetically heterogeneous15,16 and genomic characterisation of human schistosomes can be used to establish epidemiological patterns of transmission, including insights into interspecies hybridisation among some schistosome species.
For example, in areas with high transmission of both S haematobium and the S bovis parasites of cattle, bidirectional introgressive hybridisation occurs, yielding schistosomes of mixed heritage in people and snails.17
The implications of these findings are unclear for human disease, but these populations of hybrid schistosomes could prove problematic if they can replace existing species and parasite strains or extend intermediate host ranges.