The Cholera Pandemic, Still with Us after Half a Century: Time to Rethink

The recent outbreaks of cholera in Haiti, Pakistan, and Zimbabwe suggest that our current global action plans against cholera are failing. This issue contains two important articles that will help inform our discussions on ways to respond to the global cholera situation. Cholera is a severely dehydrating illness caused by Vibrio cholerae, a Gram-negative organism. V. cholerae exists in environmental aquatic reservoirs, and, as a result, cholera is not an eradicable disease, but it is controllable. Humanity has recognized seven cholera pandemics since 1817, all originating in Asia. The most recent pandemic began in 1961 in Indonesia, making it at half a century the longest cholera pandemic on record. As opposed to burning out after 5–20 years as all previous pandemics have done, this pandemic, if anything, seems to be picking up speed. Cholera outbreaks are occurring with increasing frequency and severity, as demonstrated by the recent major outbreaks in Nigeria, Angola, Pakistan, Vietnam, Zimbabwe, and now Haiti. This is on top of all the endemic infections that largely go ‘‘unnoticed’’. In fact, cholera is now endemic in approximately 50 countries worldwide, and V. cholerae infects 3–5 million individuals each year, killing approximately 100,000, only a minority of whom die in outbreaks that garner media attention. Cholera can kill a healthy person within 12–24 hours of onset of diarrhea and can cause explosive outbreaks; thus, it has the ignominious distinction of probably being the pathogen that can kill the most number of humans in the shortest period of time. Cholera outbreaks are associated with chaos, and they severely stress health care systems and communities. Humanity’s response to cholera led to the development of oral rehydration solution (ORS) and evidence-based approaches to rehydration therapy. ORS perhaps represents the paradigmatic successful interface of basic science and biomedical science and a cost-effective, inexpensive public health intervention. ORS costs pennies, can be made locally or in a rural house, requires minimal or no training for production and administration, can be used in extremely adverse circumstances, and mitigates dehydrating illness and death for all causes of diarrhea, not just cholera. It is estimated that ORS has saved the lives of 40 million individuals since it was first endorsed by the World Health Organization (WHO) in the 1980s. In part because of this success of ORS, response efforts to cholera over the last 30 years have largely focused on treating individuals who become afflicted in the short-term, and trying to provide safe water and improved hygiene in the longterm. However, as we mark a half century for this pandemic, we must stop and ask: is this still the best approach? Despite heroic efforts by many, 13% of the world’s population still lacks access to safe water. To translate this statement, safe water would have to be provided every day for 10 years to an additional 240,000 people who currently lack safe water each day to eliminate this disparity. And this assumes that people with currently tenuous access to safe water do not slip backward, and that somehow we also provide safe water to the 1–3 billion people who will be joining us on the planet in the next few decades. As such, the provision of safe water to all of the world’s population is truly a long-term solution, and one a realist would say will take decades. A second piece of data that needs to be considered as we mark the 50th anniversary of the start of this pandemic is that the causative agent of our current pandemic is different from those that caused the first six pandemics. V. cholerae O1 can be divided into two major biotypes. Earlier pandemics for which we have data were caused by what is referred to as the ‘‘classical’’ biotype, but the current pandemic is caused by the ‘‘El Tor’’ biotype. Compared to classical organisms, V. cholerae El Tor are much better at surviving in the environment, and are more likely to result in asymptomatic carriage in humans. The latter means that people can introduce the infection into a new zone unknowingly, and the former means that once a zone is involved, it may well become endemic for cholera. These facts may explain in part why our current pandemic extends much longer than all previous ones. It also means that outbreaks can be prolonged (as evidenced by Zimbabwe), and that there will be no quick fixes. The El Tor variant has also undergone two major modifcations over the last 20 years. First, an El Tor O1 strain acquired a new lipopolysaccharide structure, forming a new variant serotype, O139. Since immunity to cholera is largely serotype specific, this meant that a new variant had evolved that could infect and kill individuals thought to be immune to cholera by previous exposure to O1. O139 spread rapidly in the 1990s through 11 Asian countries, but then was largely replaced by its cousin O1 El Tor again (for unclear reasons). More recently, El Tor has undergone another genetic event to create what is being referred to as a ‘‘hybrid’’ strain, an El Tor variant expressing classical cholera toxin. Cholera caused by the hybrid strain may be more clinically severe, and the hybrid is rapidly replacing the old El Tor strain in many areas. The prevalence of the hybrid strain may explain why we are seeing case fatality rates of 1%–5% (or higher) in recent outbreaks, as opposed to the ,1% historically accepted as the goal for response teams.