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Wednesday, August 19, 2015

Challenges Modeling Typhoid

Most of us in the United States have never received a vaccine for typhoid, yet only a few hundred cases per year occur in this country- the majority of which are recent travelers to endemic countries. It is not as if typhoid has never been a problem in the United States. Typhoid fever was a widespread illness in the 1800s affecting individuals across divisions of class and wealth. Typhoid, not pneumonia as was originally diagnosed, is believed to be responsible for killing our 9th and shortest-serving US president, William Henry Harrison, in 1841. Washington, DC had no sewer system at the time, and until 1850, raw sewage flowed onto grounds just upstream from the White House water supply.

Environmental transmission through ingesting contaminated water was the primary cause of typhoid illness in the United States. Typhoid was also transmitted through food, and often through asymptomatic carriers of the disease. The most famous example is Mary Mallon, an Irish cook for families in New York. Even as a typhoid carrier, transmission isn’t likely with effective food-safety and hand washing practices. But with Mary, the combination of her lack of acceptance of hand-washing and her famous peach ice cream led her to infect over fifty people, by some estimates. The widespread transmission of typhoid remained in the United States until the investment of infrastructure and regulations on water and sanitation systems in the early 1900s. This was the critical step in ridding the United States of its typhoid persistence, and remains the reason we do not see significant prevalence of typhoid in most developed countries today.

Typhoid fever is a bacterial infection caused by Salmonella enterica serovar Typhi. Tens of millions of cases occur each year, with over 200,000 deaths. Typhoid disproportionately affects the developing world, with countries in South Asia and Africa carrying the greatest burden. We are working with the Bill and Melinda Gates Foundation to evaluate the feasibility of control and elimination strategies for these high endemic areas. We do not yet have the ability to implement impenetrable and widespread water and sanitation systems in these areas. Thus, our approach has to involve understanding why typhoid persists in the population, and evaluate the best strategies to disrupt these mechanisms.

So, where do we intervene? Even without widespread sanitation systems, we may be able to identify the amplifying steps to environmental transmission, or weak points in these systems where a small change can make a big difference. In Santiago, Chile, for example, a dramatic decrease in typhoid incidence was seen after river water (which was pumped with raw sewage) was banned from being used for agricultural purposes. Kathmandu, Nepal is burdened with a persistent endemicity of typhoid that has been shown to likely be environmentally transmitted through water systems. With the increase in technology to genotype strains of typhoid, we may be able begin to target these amplifying steps more systematically in endemic scenarios.

Other interventions could be at the person-level. We have historical vaccines that are effective at preventing clinical typhoid, though there is evidence that individuals who have been vaccinated may still contribute to typhoid transmission if exposed. Significant work is being put into developing new vaccines but the efficacy of which has yet to be tested in human challenge studies. Early diagnosis and treatment of the disease is another person-level intervention that would have an impact on the persistence of typhoid in the environment. Individuals with the disease can shed bacteria

through their stool for weeks to months, and effective treatment can shorten this duration, thus lessening the contribution of these individuals to the infectious reservoir.

Individuals like Typhoid Mary also exist in these populations: a small proportion of infected individuals never clear their infection. Chronic carriers, an unfortunate and epidemiologically significant feature of typhoid fever, can contribute to the persistence of typhoid. These individuals are by most measurements perfectly healthy, yet can shed the typhoid bacteria through their stool for a lifetime. We do not know how many chronic carriers exist in these endemic populations, but putting in efforts to track down and treat these persistent sources of bacteria is another possible intervention to reduce the infectious reservoir of typhoid in a population.

Each of these mechanisms can contribute to the persistence of typhoid in endemic scenarios. Our work utilizes a combination of data analysis, epidemiology, and mathematical modeling in order to weigh the relative importance of each of these mechanisms. We work to understand how these dynamics may change from population to population, and plan to move forward in typhoid control in the most effective and impactful way.

Baker S, Holt KE, Clements AC, Karkey A, Arjyal A, Boni MF, Dongol S, Hammond N, Koirala S, Duy PT, Nga TV, Campbell JI, Dolecek C, Basnyat B, Dougan G, Farrar JJ. Combined high-resolution genotyping and geospatial analysis reveals modes of endemic urban typhoid fever transmission. Open Biol. 2011 Oct;1(2):110008.

Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ. 2004 May;82(5):346-53.

The New York TImes