Comments by Ralph R. Frerichs are posted below at the end of this article.

Source: Howard Hughes Medical Institute, December 9, 2010.

Scientists Trace Origin of Recent Cholera Epidemic in Haiti

The strain of cholera currently sweeping through post-earthquake Haiti originated in South Asia, conclude scientists who did a rapid genetic analysis of bacteria collected from Haitian patients. The finding supports the notion that the cholera bacteria fueling the outbreak arrived on the island via recent visitors.

The mostly likely explanation for the sudden appearance of cholera in Haiti is transmission of V. cholerae by an infected human, food, or other contaminated item from a region outside of Latin America to Haiti, conclude Howard Hughes Medical Institute (HHMI) investigator Matthew Waldor and co-authors in the New England Journal of Medicine (NEJM), which fast-tracked and published the genetic analysis online December 9, 2010.

While cholera is endemic in many parts of the world, including regions of Latin America, until October, Haiti had historically been spared from the intestinal disease. But in mid-October, an outbreak flared in northern Haiti and quickly swept across the country. By December 3, the bacteria had sickened more than 93,000 people, killing some 2,100. The World Health Organization anticipates that the outbreak will last a year or longer.

"The scientific question for us was, 'How did cholera come to Haiti?' It hadn't been there for more than a hundred years," says Waldor, a microbiologist and infectious disease specialist whose laboratory at Brigham and Women's Hospital studies cholera and other pathogenic gut bacteria.

Waldor obtained two samples of Vibrio cholerae, the bacterium that causes cholera, from two Harvard Medical School colleagues, Stephen Calderwood and Jason Harris, who traveled to Haiti in November to assess the outbreak. Waldor then established a collaboration with Pacific Biosciences, which manufactures powerful DNA sequencing machines that can rapidly scan and identify millions of bases of genetic material. A team of scientists there, led by Eric Schadt, sequenced the complete genomes of the cholera bacteria in the samples. Waldor received the V. cholerae samples on November 8 and had the bacterial DNA sequence from Pacific Biosciences in hand by November 12.

The DNA readout showed that the two Haitian strains of V. cholerae -- isolated from different patients -- were essentially identical, supporting the idea of a single origin of the nation-wide outbreak. The two strains were also essentially identical to three other Haitian outbreak samples that had been sequenced (but not analyzed) by the Centers for Disease Control and Prevention (CDC). The HHMI, Harvard, and Pacific Biosciences team then compared the genome of the Haitian strain to the genomes of 23 other V. cholerae strains from various parts of the world that were stored in the genetic data repository GenBank. Surprisingly, the Haiti strain bore the strongest resemblance to strains that are currently circulating in South Asia. Conversely, the Haitian strains differed significantly from the bacteria currently circulating in Latin America. Some cholera experts had suggested that endemic Latin American V. cholerae -- found in Peru and elsewhere -- was the most likely source of the Haitian outbreak.

"The big conclusion is that the Haiti cholera epidemic is caused by a strain that was most likely introduced into Haiti from South Asia, and not from some strain that washed up environmentally from Latin America," Waldor says.

Waldor and colleagues then examined the genes of the Haitian bacteria for clues to the potency of its toxin production and antibiotic resistance. Interestingly, they found that the strain contains a version of the gene that produces cholera toxin -- and hence, the symptoms of the disease -- that differs from that found in strains from Latin America at three amino acid locations. Two of these three amino acid changes were present in the now extinct "classical" V. cholerae, a type of V. cholerae that characteristically produces more severe disease. The team concluded from these data that the Haitian strain may be more virulent than the average strain of V. cholerae. That means the strain may cause more severe diarrhea and lead to a higher death rate than usually seen. But examination of the antibiotic resistance genes showed some good news: The strain should be responsive to tetracycline antibiotics. Rehydration is the first-line of therapy, but antibiotics, which are currently being used sparingly in Haiti, can help shorten the length of illness as well as limit the dissemination of the pathogen and so are also an important treatment option.

Waldor says that the CDC assessed Haiti's public health system after the earthquake in January 2010 and concluded that the risk of a cholera outbreak was low because there is no endemic cholera in Haiti. "That thinking obviously was not correct," he says, "because the possibility of transfer of virulent V. cholerae strains by human activities wasn't considered."

Waldor adds that world health officials should consider measures to prevent the introduction of the cholera bacterium into other disaster sites worldwide, which often suffer from inadequate sanitation, a key factor in the spread of cholera, which is transmitted via feces.

"I think we could prevent future 'Haitis' by restricting travel from regions where cholera is epidemic to the disaster zone," says Waldor. "Alternatively you could give vaccines or antibiotics to people from endemic areas, regardless of symptoms, so they couldn't inadvertently transmit cholera."

Waldor also advocates a vaccination campaign throughout Haiti and neighboring Dominican Republic to stanch the current epidemic, a point he made with colleagues in an editorial published in the November 24, 2010, issue of NEJM. Waldor says such a campaign would require manufacturers to ramp up production of the vaccine, which is currently in limited supply, but could damp down the outbreak and prevent it from escaping the island into Latin America. In early December, Waldor discussed a vaccination campaign on a conference call with 80 other cholera experts from the World Health Organization, the National Institutes of Health, and other institutions and non-profit organizations. "I think we got some traction," Waldor says. "There are logistical and cost and other issues for any large vaccination campaign. But there was a lot of enthusiasm for the idea."

Comments by Ralph R. Frerichs on: "Scientists Trace Origin of Recent Cholera Epidemic in Haiti"

The abstract of the New England Journal of Medicine article is presented here:

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December 9, 2010 (10.1056/NEJMoa1012928)

The Origin of the Haitian Cholera Outbreak Strain

Chen-Shan Chin, Ph.D., Jon Sorenson, Ph.D., Jason B. Harris, M.D., William P. Robins, Ph.D., Richelle C. Charles, M.D., Roger R. Jean-Charles, M.D., James Bullard, Ph.D., Dale R. Webster, Ph.D., Andrew Kasarskis, Ph.D., Paul Peluso, Ph.D., Ellen E. Paxinos, Ph.D., Yoshiharu Yamaichi, Ph.D., Stephen B. Calderwood, M.D., John J. Mekalanos, Ph.D., Eric E. Schadt, Ph.D., and Matthew K. Waldor, M.D., Ph.D.

BACKGROUND

Although cholera has been present in Latin America since 1991, it had not been epidemic in Haiti for at least 100 years. Recently, however, there has been a severe outbreak of cholera in Haiti.

METHODS

We used third-generation single-molecule real-time DNA sequencing to determine the genome sequences of 2 clinical Vibrio cholerae isolates from the current outbreak in Haiti, 1 strain that caused cholera in Latin America in 1991, and 2 strains isolated in South Asia in 2002 and 2008. Using primary sequence data, we compared the genomes of these 5 strains and a set of previously obtained partial genomic sequences of 23 diverse strains of V. cholerae to assess the likely origin of the cholera outbreak in Haiti.

RESULTS

Both single-nucleotide variations and the presence and structure of hypervariable chromosomal elements indicate that there is a close relationship between the Haitian isolates and variant V. cholerae El Tor O1 strains isolated in Bangladesh in 2002 and 2008. In contrast, analysis of genomic variation of the Haitian isolates reveals a more distant relationship with circulating South American isolates.

CONCLUSIONS

The Haitian epidemic is probably the result of the introduction, through human activity, of a V. cholerae strain from a distant geographic source. (Funded by the National Institute of Allergy and Infectious Diseases and the Howard Hughes Medical Institute.)

SOURCE INFORMATION

From Pacific Biosciences, Menlo Park, CA (C.-S.C., J.S., J.B., D.R.W., A.K., P.P., E.E.P., E.E.S.); the Division of Infectious Diseases, Massachusetts General Hospital (J.B.H., R.C.C., S.B.C.), Channing Laboratory, Brigham and Women's Hospital (Y.Y., M.K.W.), the Departments of Pediatrics (J.B.H.), Medicine (R.C.C., Y.Y., S.B.C., M.K.W.), Microbiology (W.P.R., S.B.C., J.J.M., M.K.W.), and Molecular Genetics (W.P.R., S.B.C., J.J.M., M.K.W.), Harvard Medical School, and the Howard Hughes Medical Institute (M.K.W.) -- all in Boston; and Fondation pour le Developpement des Universites et de la Recherche en Haiti, Port-au-Prince, Haiti (R.R.J.-C.).

Address reprint requests to Dr. Schadt at eschadt@pacificbiosciences.com.

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The discussion section of the NEJM article provides additional thoughts in the opening two paragraphs on the "climate causal" hypothesis versus the "human causal" hypothesis.

The V. cholerae strain responsible for the expanding cholera epidemic in Haiti is nearly identical to so-called variant seventh-pandemic El Tor O1 strains that are predominant in South Asia, including Bangladesh. The shared ancestry of the Haitian epidemic strain and recent South Asian strains of V. cholerae is distinct from that of circulating Latin American and East African strains of V. cholerae (i.e., the microbe was likely not brought to Haiti from elsewhere in Latin America or from East Africa). Patterns of DNA from Haitian strains and V. cholerae strains in a large collection held by the CDC, as determined by means of pulsed-field gel electrophoresis, also suggested that the Haitian strains of V. cholerae are most similar to recent South Asian V. cholerae strains (i.e., the organism was brought to Haiti from some where in South Asia, a region that includes Nepal).

Our comparative analysis of the H1 and H2 strains and three CDC isolates indicate that the Haitian cholera epidemic is clonal. Collectively, our data strongly suggest that the Haitian epidemic began with introduction of a V. cholerae strain into Haiti by human activity from a distant geographic source (i.e., the findings further support the "human causal" hypothesis).

Our data distinguish the Haitian strains from those circulating in Latin America and the U.S. Gulf Coast and thus do not support the hypothesis that the Haitian strain arose from the local aquatic environment (i.e., the findings do not support the "climate causal" hypothesis). It is therefore unlikely that climatic events led to the Haitian epidemic, as has been suggested in the case of other cholera epidemics. Understanding exactly how this South Asian variant strain of V. cholerae was introduced to Haiti will require further epidemiologic investigation (i.e., the analysis does not identify the exact human source who brought the microbe from somewhere in South Asia to Haiti).

Information about Matthew K. Waldor, M.D., Ph.D., the main spokesperson for the NEJM article team, is presented here:

Dr. Waldor is also Edward H. Kass Professor of Medicine at Harvard Medical School and an attending physician in infectious diseases at Brigham and Women's Hospital, Boston. As an undergraduate at Yale University, he studied philosophy and biology. He carried out his doctoral work with Larry Steinman and received his M.D. and Ph.D. degrees from Stanford University. After an internal medicine residency at Brigham and Women's Hospital and an infectious disease fellowship at Massachusetts General Hospital, he did postdoctoral research with John Mekalanos at Harvard University.

The above article and interview with Dr. Waldor support the "human causal" hypothesis that Vibrio cholerae was brought to Haiti from South Asia, although the mechanism of how this took place was not revealed by the anaysis. Dr. Waldor, in addressing the Haiti cholera outbreak, finds himself in a similar situation as was Dr. John Snow during the 1850s in London, England. Snow presented much about cholera, but was not 100% conclusive or pursuasive. Nevertheless he made some important policy suggestions that helped those who followed to prevent future outbreaks. Nearly 160 years later, Dr. Waldor and his colleagues also lack completed information on sequence of events that led to a cholera outbreak, but this time in Haiti. Nevertheless, Waldor has made important policy suggestions, which, if followed, should help prevent future occurrences. Specifically, he stated...

"I think we could prevent future 'Haitis' by restricting travel from regions where cholera is epidemic to the disaster zone," says Waldor. "Alternatively you could give vaccines or antibiotics to people from endemic areas, regardless of symptoms, so they couldn't inadvertently transmit cholera."

Return to Cholera in Haiti and the Modern "John Snow" site