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Tracking cholera in a drop of blood

February 20, 2019

Despite efforts to improve the availability of safe water and adequate sanitation, cholera continues to kill more than 100,000 people around the world every year. To combat this needless suffering, the World Health Organization Global Task Force for Cholera Control set a goal to eliminate cholera as a public health threat by 2030.

To accomplish this goal, new methods to count cholera cases are required. In response to this need, a multi-institutional, international team of researchers has developed a method that identifies individuals recently infected with Vibrio cholerae O1. The method uses six markers identified in the blood of cholera patients, achieving an unprecedented 93 percent accuracy. The results of the study are available online in the February 20 issue of the journal Science Translational Medicine.

"At this time, we do not have a good method to figure out who has had cholera and who hasn't," said Daniel Leung, M.D., M.Sc., an assistant professor in the Division of Infectious Diseases at University of Utah Health and co-author on the study. "Establishing a serosurveillance method overcomes many of the shortcomings of traditional surveillance approaches by providing a new way to track the spread of cholera in short-term outbreaks as well as assess long-term burden of cholera across different populations."

Currently, cholera surveillance is based almost entirely on clinical reporting of watery diarrhea, with few laboratory-confirmed cases. Only a fraction of cholera patients develop severe symptoms associated with the disease, like diarrhea, nausea, vomiting and dehydration. Many do not seek medical care and would not be counted in traditional surveillance efforts. An infected person, even in the absence of symptoms, sheds the bacteria for up to a week after infection, sometimes passing the disease to others, typically through contaminated water.

The research team analyzed more than 1,569 blood samples obtained from cholera patients, who received care at the icddr,b Dhaka Hospital, and their uninfected household members between December 2006 and December 2015.

In developing the method, the researchers monitored the concentration of six serum markers. The markers rise during the first two weeks of infection and then slowly wane with the passage of time. One marker, the vibriocidal antibody, was most predictive of recent infection. The researchers confirmed the validity of their method by testing North Americans who volunteered to be infected with cholera. The method produced similar results in this very different population.

"Our work shows that a drop of blood likely contains enough information to tell if someone was infected with the bacteria in the past year," said Andrew Azman, Ph.D., assistant scientist in Epidemiology at Johns Hopkins Bloomberg School of Public Health and lead author on the study. "It gives us another way to track cholera without having to fully rely on clinical data from the less than ideal health surveillance systems often available in cholera-affected countries."

When testing the method, the researchers conducted simulations of cholera transmission and were able to estimate the number of infections in hypothetical settings where cholera is common, and regions where it is episodic. These results help illustrate how this approach can be put to use in public health practice.

"After studying cholera immune responses for several decades to understand infection and plan immunoprophylactic strategies, we can now predict the exposure status of an endemic population," said Firdausi Qadri, Ph.D., senior scientist and head of the Mucosal Immunology and Vaccinology Unit, Infectious Diseases Division at icddr,b. "We are working on simpler sampling methods to further optimize procedures for analyzing large populations for antibody responses."

While this method is a positive step forward, it is based on data from a region where cholera is common, and validated by a small number of patients during challenge experiments in non-endemic regions. In addition, the method cannot differentiate between someone who has been infected with cholera or vaccinated against the disease. Currently, the team is working on validating the method in Haiti, where cholera fluctuates annually.

"Applying routine serosurveys like this method in cholera hotspots or after epidemics could help us better understand the true burden of this disease across populations, time, and space," said Leung.
Leung and Azman were joined in this work by Justin Lessler and Francisco Luquero at Johns Hopkins Bloomberg School of Public Health; Taufiqur Bhuiyan, Ashraful Khan, Fahima Chowdhury, Alamgir Kabir and Firdausi Qadri at International Centre for Diarrhoeal Disease Research; Marc Gurwith at PaxVax Inc.; Ana Weil, Jason Harris, Stephen Calderwood and Edward Ryan at Massachusetts General Hospital/Harvard Medical School/Harvard T.H. Chan School of Public Health. The work, titled Estimating Cholera Incidence with Cross-Sectional Serology, was supported by the Bill and Melinda Gates foundation and the National Institutes of Health.

University of Utah Health

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