John Mekalanos on the Human Importation of Cholera

Special Topic of Cholera Interview, February 2011

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John MekalanosThe same situation occurred more recently with the cholera epidemic following the Pakistan earthquake. That was predictable in my opinion. When I heard in January 2010 that an earthquake had hit Haiti, the first thing that crossed my mind was "how long?" I knew cholera would happen, sooner or later, the only question was when.

It's also fair to say that I am not always right. When I heard of the tsunami in Indonesia, I thought for sure cholera would break out there and it didn't. Whether it is the climate or environment controlling the spread, as Dr. Colwell believes, or some human factor we don't understand, there is something missing in our ability to predict outbreaks perfectly. So we're wrong once in awhile. No question about it. But we are also right often enough to think about strategies for prevention that go beyond clean water.

SW: What are the conditions necessary for a cholera epidemic?

The ancient observers noticed cholera occurs when disasters happen, water is nearby, and a lot of people are living in unsanitary conditions. With those conditions, cholera is going to break out usually sooner or later. But that doesn't mean it can't happen sooner if it is accidently introduced into this setting by exposure to infected individuals. Europe lived in squalor for centuries before cholera was introduced there by the new trade routes to India and Asia. Quarantine was used for over a century because it was obvious that cholera spreads along the routes that infected people traveled. Pilgrims were not allowed to visit Mecca until they were housed for at least a couple of weeks in a quarantine camp.

Now we live in a world dominated by global traffic. With the exception of endemic disease, I would argue most epidemic disease occurring in previously cholera-free settings occurs after accidental human introduction of the virulent form of the pathogen. The clonality of the organism says this is the case. This is not to say that somebody in Italy or Louisiana can’t get cholera from eating a raw oyster. They do occasionally but the strain they get is seldom identical to the epidemic strain causing the disease in India or Africa. The gene sequences tell a clear story of the likely origin, be it local strain of low virulence or an imported killer.

"...importation of a strain into a new permissive environment should not be confused with the environment causing the epidemic."

In Haiti, admittedly, it took many months to break out. And the circumstances were just a shocker. Once I understood the circumstantial and microbiological data and, of course, the early genetic data coming from the Centers for Disease Control (CDC), Atlanta, I was one of the people who concluded that this was clearly an imported epidemic—although we all hoped that conclusion would be wrong. But I thought that it was pretty obviously that an importation had occurred and that there were plenty of humanitarian aid travelers to Haiti that could have brought it in. The genomic data generated with my colleagues now strongly support this conclusion.

As to where and when and how was it introduced by importation, that's for people to investigate further. If you ask me what the data say, I'll tell you that the data say that this strain was most likely imported to Haiti from South Asia. However, South Asian strains are finding their way to Africa too, so the final verdict is still out.

These strains are a particularly nasty variety that causes more severe disease and therefore likely more dramatic transmission by contamination of the water with human cholera stool. That should motivate people to make some decisions about what to do next in Haiti. We really need to stop this strain from leaving Hispaniola. Perhaps clean water and ultimately vaccination might do the job if we work fast as an international community.

SW: When you say an importation, does that mean imported by human travelers after the earthquake? So that raises the questions—who and how?

There has been a lot of denial on the part of the authorities associated with the UN humanitarian effort, but unfortunately the epidemiology is so far consistent with the conclusion that human travelers brought it in after the potable water infrastructure was smashed by the earthquake. Lots of things can now be done, none of which are definitive, but all will get us incrementally closer to the conclusion that this strain was imported, and perhaps exactly where it came from.

Some have argued that it probably came from the Nepalese UN security camp, implying that one or more of the Nepal peace-keeping troops were infected with a South Asian strain. The disease broke out near that camp, and evidence also has been reported that there was an accidental breakdown in sanitation practices at that camp. Cholera was epidemic in Nepal only weeks before the troops arrived so a subclinical infected individual could have easily brought the strain into that camp and after that improperly discarded human waste could have introduced the strain into the local river water and drinking supply. There has already been violence associated with this circumstantial evidence and that is unfortunate.

My colleagues and I have been very clear in saying that the genomic evidence says that this strain in Haiti has its origin in South Asia. True, Nepal is part of South Asia so it clearly needs more investigation and a commission has been established by the UN to look into the possibility. Whatever origin the strain has, in the end, this imported strain represents a particularly large and ominous threat to the Caribbean and Latin America and its introduction teaches us lessons.

When you have an imported epidemic of cholera like they now have in Haiti, you always have to worry about where it was imported from. In this case, it was an environment that has the most highly evolved pathogenic cholera—the Ganges River basin to the headwaters of the Himalayas, the river delta between Calcutta in India and Dhaka in Bangladesh. This represents the historical home of cholera. Descriptions in Sanskrit written 1,000 years ago describe epidemic disease with symptoms of cholera, killing most of the time and killing very rapidly. Centuries of selection has rendered the organisms from this region as being most fit to transmit the disease and persist in the environment. My colleague Shah Faruque in Bangladesh and I have been studying the organisms from this region for this precise reason.

A cholera patient being attended to at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh.
A cholera patient being attended to at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh.

From a historical perspective, cholera as a disease was not seen in the western world until British colonialism and other travelers brought the disease from the Indian subcontinent back to Europe in the 1800s. This disease has had a long history of importation by human activities tied to the Indian subcontinent. However, genomic evidence suggests that other importation can occur. CDC and we have recently found additional genomic evidence that the 1991 epidemic in Latin America may have occurred as a result on importation from Africa of all places. The genes tell the story.

To some extent that message has gotten lost in other messages over the last couple decades. Sure, V. cholerae is an environmental organism and changes in the environment such as global warming might change patterns of disease or the establishment of conditions that lead to endemic disease. However, importation of a strain into a new permissive environment should not be confused with the environment causing the epidemic. Importation is still a prerequisite most of the time and there are things we can do about importation that are a lot easier to tackle than stopping global warming.

I have to remind people again that all the genetic data, all the evidence to date, shows that the Haiti epidemic is another example of importation of cholera by human activity, and importation to a place where the disease didn't exist for over a hundred years. I think this is an important lesson to be learned, and I hope people learn it and act on it in the future. 

SW: Are you suggesting that global climate change is not a factor in the recent epidemics?

I'm not trying to argue against global warming playing a role. My simple point here is that it's not that relevant in this case. In 1991, cholera broke out in Peru, a devastating epidemic that spread throughout South America and into Central America. It's still endemic in many areas of Latin America. Any place that has difficulty in maintaining high water standards is going to suffer from cholera once the right pathogenic strain is introduced and there is enough susceptible humans to spread the disease.

The strain that was introduced in 1991 was again this extension of this 7th pandemic clone that was wreaking havoc in South Asia and Africa, which we refer to our in latest paper. That strain is very adaptive to establishing itself where an endemic cycle can be maintained.

I would emphasize that "maintained" means human amplification. I don't believe pathogenic strains of cholera can be maintained anywhere in a significant form without human amplification. That is where I part in my opinion with some of my well-credentialed colleagues.

Some of these same colleagues go one step further and think the environment plays such an overwhelming role in this disease that they're willing to blame epidemics of cholera on environmental effects—Peru in 1991, and Haiti in 2010—on El Niño in 1991 and the La Niña, the small warming, in 2010. Warmer water may help spread the disease, but the epidemic is started first by the introduction of a virulent strain into the naïve locale and second by the number of victims and susceptible individual sharing unsanitary water.

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