Historic Meanings of “Cholera”

Today the term cholera is restricted to suspected infections caused by Vibrio cholerae, sometimes called Asiatic cholera. Vibrio cholerae produces a very characteristic watery diarrhea sometimes described as ‘rice water’. This narrow definition wasn’t always so.

Since antiquity, cholera could refer to any diarrhea or dysentery. The term cholera comes from the Greek word cholē meaning bile. Cholera then was a flushing of bile from the body in an attempt to rebalance Galen’s four humors of the body (blood, bile, black bile, and phlegm) [1].

In 19th century American medical records,  it is common to see three types of cholera reported: cholera morbus, cholera infantum, and Asiatic cholera. Cholera morbus and cholera infantum were both terms for non-specific diarrhea and/or dysentery in adults and children under age five respectively.  Cholera morbus was sometimes called the summer complaint and was usually found in older children and adults from July to September [2]. It was caused by a variety of gastrointestinal pathogens with a significant contribution from contaminated food. Cholera infantum was given as the primary cause of death in children under age five in 19th century Illinois [2]. Physicians specifically associated it with the ages of teething and finger foods. Even given its non-specific definition, it was still probably over diagnosed due to paradigms of childhood illness. For example, early Illinois physicians  did not believe that children could contract malaria, then endemic in Illinois. Asiatic cholera is caused by Vibrio cholerae, epidemic in Illinois in 1832-1834, 1838, 1849-1852, 1866-1867, and 1892 [2]. Apart from discrete epidemic waves, Asiatic cholera was uncommon in America.

References:

[1] Männikkö, N. (Ed) (2011). Etymologia: Cholera. Emerging Infectious Disease, 17 (11) http://dx.doi.org/10.3201/eid1711.ET1711

[2]  Rawlings, Issac D. et al. (1927).The Rise and Fall of Disease in Illinois. State Department of Health.

Cradle of Cholera’s Seventh Pandemic Found

Cholera is a disease of seemingly endless fascination to epidemiologists for good reason. Vibrio cholerae emerged on a global stage in the 19th century just in time for the beginnings of modern medicine to grapple with it and for its transmission to prove the worth of epidemiological work. Although we understand its treatment and transmission well, it is still endemic in several regions, resulting in 3-5 million reported cases per year.

Like other relatively recently emerged pathogens, cholera has come in distinctive waves. Six discrete pandemics occurred between 1817 and 1923, it is believed from what is now known as the classic biotype. From 1923 to 1961 no pandemics occurred but evolution was far from standing still.  The seventh pandemic became apparent in the 1960s as the less severe El Tor biotype, that emerged sometime between 1827 and 1936, began to rapidly spread. The El Tor biotype transmits and survives better in the environment and human host than the classical biotype, including producing more asymptomatic and less severe infections.  El Tor represents an evolutionary leap forward for Vibrio cholerae on every level. We are still in the seventh pandemic. Preliminary characterization of the El Tor biotype’s mobile genetic units revealed too much diversity to reconstruct the pandemic.

Taking advantage of modern complete genome sequences, Mutreja et al (2011) collected and compared the complete genomic sequences of 136 isolates of the El Tor biotype collected over the last 40 years of the seventh pandemic plus 18 previously published genomes of El Tor and Classical biotypes. They were able to track three independent overlapping waves of cholera that are all descended from a 1950s ancestor in the Bay of Bengal. Each of these three descendant lineages left the Bay of Bengal independently for a transcontinental run.

Inferred transmission of the seventh cholera pandemic based on phylology. (Source: Mutreja et al, 2011, doi:10.1038/nature10392) Click to enlarge.

Each of the three waves can be distinguished genetically. The waves can be differentiated by the distinctive version of cholera toxin prophage carried by each clade. In addition, the first wave lacks the antibiotic cluster SXT/R391 and has obtained two VSP-2 genes. The acquisition of the SXT/R391 integrative and conjugative element (ICE) distinguishes the second wave beginning in 1978-1984. O139 strains of cholera are descended from the  second wave clone close to common ancestor of wave 1 and wave 2. The lineages within each wave have become quite complex but remain local enough not to produce waves of their own.

Each of the three waves reflects a clade of cholera that emerged from the Bay of Bengal and spread around the world, evolved into local lineages but then subsequently went extinct in non-endemic areas. Four discernible long distance transmissions have happened with the current outbreak in Haiti being the most recent. The overlapping nature and common source of these distinct waves reinforces the importance of the Bay of Bengal as cholera’s evolutionary cradle.

Considering the importance the Bay of Bengal for cholera, could other pathogens like Yersinia pestis, that has produced similar overlapping pandemic waves, also have an evolutionary cradle?  If so, then a sentinel  system set up around the cradle could give us crucial warning of an oncoming pandemic. The Bay of Bengal also serves as a lesson that knowing of the cradle is a far cry from controlling it.

Mutreja, A., Kim, D., Thomson, N., Connor, T., Lee, J., Kariuki, S., Croucher, N., Choi, S., Harris, S., Lebens, M., Niyogi, S., Kim, E., Ramamurthy, T., Chun, J., Wood, J., Clemens, J., Czerkinsky, C., Nair, G., Holmgren, J., Parkhill, J., & Dougan, G. Evidence for several waves of global transmission in the seventh cholera pandemic. (2011). Nature DOI: 10.1038/nature10392

Safa, A., Nair, G., & Kong, R. (2010). Evolution of new variants of Vibrio cholerae O1 Trends in Microbiology, 18 (1), 46-54 DOI: 10.1016/j.tim.2009.10.003

Cholera’s Chain of Infection

Cholera is the pandemic that just won’t go away. Worse yet, it preys on us when we are at our most vulnerable, after a natural or man-made disaster. We know how to prevent it but in times of natural disaster or in areas where infrastructure is inadequate, those conditions can be hard to maintain. A review of cholera’s chain of infection illustrates the challenges  of containing cholera.

The Organism

Vibrio cholerae (Public domain courtesy of Dartmouth Electron Microscopy Facility).

Scientific name: Vibrio cholerae

Common names: cholera, Asiatic cholera

The causative agent of cholera is Vibrio cholerae, a facultative, gram-negative bacterium. There are 155 known serogroups, differentiated by their O antigen. Only two serogroups, O1 and O139, are responsible for all epidemic and endemic cholera. The O1 serogroup can be further differentiated into three serotypes, Ogawa, Inaba, and (rarely) Hikojima, that can themselves be divided into two biotypes (genotypes), classical and El Tor (Faruque, Albert, & Mekalanos, 1998). V. cholerae O139, which is responsible for the on-going epidemic in Bangladesh and India, evolved from the El Tor biotype of serogroup O1 (Heymann, 2004). This chain of infection is restricted to serogroups O1 and O139, which have epidemic potential.

There are two major virulence factors of pathogenic V. cholerae. The primary virulence factor is cholera toxin responsible for the rice water diarrhea. The toxin gene is carried by a lysogenic bacteriophage (bacterial virus) ensuring that this mobile toxin gene will continue to create new pathogenic strains (Nelson et al, 2009). Haiti’s current outbreak by an altered El Tor strain with a classical B toxin gene is an example of the bacteriophage’s effect on V. cholerae‘s diversity. Biofilms are important in both the intestinal and aquatic environments.  V. cholerae’s other major virulence factor, toxin co-regulated pilus, binds together islands of bacteria (Nelson et al, 2009). Another bacteriophage carries an  island of antibiotic resistance genes (Nelson et al, 2009). However, antibiotics are usually not critical to cholera treatment because its not an invasive pathogen.

Reservoir

Cholera lifecycle between aquatic and human reservoirs. Source: Nelson et al, 2009. Click to enlarge.

There are two reservoirs for V. cholerae O1 and O139: humans and the aquatic environment. Humans are considered the primary reservoir and can be asymptomic carriers (Heymann, 2004). These bacteria are considered hyperinfective immediately upon release from the human body as defined by a significantly lower infectious dose required to cause an infection (Nelson et al, 2009). It has been shown that V. cholerae changes its gene transcription pattern shortly before release from the intestine as part of its ‘escape response’ to prepare it for survival in the aquatic environment (Nelson et al, 2009).

V. cholerae exists in both fresh water, such as the Ganges River delta, and marine environments.  In the Ganges River delta, where V. cholerae has been endemic for centuries (at least), it exists in wide variety of serotypes, toxigenic and non-toxigenic,  though only toxigenic O1 El Tor and O139 serotypes are found in symptomatic patients (Nelson et al, 2009).  An aquatic reservoir exists in Bangladesh where V. cholerae O139 has been shown to be a strain adapted to flourish in an environment changed by global warming (Koelle, Pascule, & Yunus, 2005). A poorly defined reservoir exists in the Gulf of Mexico associated with shellfish. Two cases of V. cholerae O1 were identified in a couple who ate poorly cooked shellfish after Hurricanes Katrina and Rita in Louisiana in 2005 (Straif-Bourgeois et al., 2006)

Portal of Exit

The portal of exit from the human reservoir is from the anus in fecal waste. Faruque et al. (2006) has shown that humans shed fragments of V. cholera biofilm into the environment. Symptomatic patients begin shedding hyperinfectious bacteria from before diarrhea begins and continue to shed for one to two weeks (Nelson et al, 2009). Asymptomatic cases are believed to shed bacteria for only a day (Nelson et al, 2009).  The portal of exit from the aquatic reservoir is in water used for drinking or food preparation, or in contaminated shellfish (Heymann, 2004).

Mode of Transmission

Whether the reservoir is human or aquatic, the primary mode of transmission is ingestion of water or food prepared with water containing V. cholerae. During an outbreak, there can be hand-to-mouth communication of V. cholerae (Heymann, 2004). Rare epidemics and sporadic cases of V. cholerae O1 have been contracted from eating poorly cooked shellfish in waters that have not been contaminated with sewage (Heymann, 2004). It is also a category B bioterrorism agent for water contamination (Boatwright & Greenfield, 2005).

Portal of Entry

The portal of entry is through the mouth in contaminated water or food.

Susceptible hosts

Previous infection produces variable immunity depending on the initial infection biotype (Heymann, 2004). Herd immunity appears to be a protective factor in endemic areas but its nature is not well understood.  In endemic areas hospitalizations are highest among young children, peaking around age 2 years (Nelson et al, 2009). In epidemics where there is no herd immunity cholera infects all age groups (Nelson et al, 2009).

V. cholerae responds differently to the human ABO blood groups. Paradoxically, blood group O has a lower risk of infection but those who are infected have more serious symptoms and worse outcomes (Nelson et al, 2009). The mechanism(s) at play here are not well understood. Blood group O’s “low prevalence in the Ganges River delta suggests that there is selection against this phenotype in a cholera-endemic area” (Nelson et al 2009: 694).

Vulnerable populations include anyone put at risk by dehydration.  This would include all infants, young children, pregnant women, the elderly, and people with other health conditions where hydration levels must be closely monitored. Fluid losses can be has high as 1 liter per hour causing rapid, severe dehydration and metabolic acidosis (Nelson et al, 2009).

Vaccine trials are underway. There is no approved cholera vaccine for the United States.

References

Boatwright, D. T. & Greenfield, R. A. (2005). Bioterrorism and threats to water safety: cholera and cryptosporidiosis. In Biodefense: Principles and Pathogens (pp. 587-618). Bronze, M. S. & Greenfield, R.A. (Eds). Norfolk, England: Horizon Bioscience.

Faruque SM, Albert MJ, & Mekalanos JJ (1998). Epidemiology, genetics, and ecology of toxigenic Vibrio cholerae. Microbiology and molecular biology reviews : MMBR, 62 (4), 1301-14 PMID: 9841673

Faruque SM, Biswas K, Udden SM, Ahmad QS, Sack DA, Nair GB, & Mekalanos JJ (2006). Transmissibility of cholera: in vivo-formed biofilms and their relationship to infectivity and persistence in the environment. Proceedings of the National Academy of Sciences of the United States of America, 103 (16), 6350-5 PMID: 16601099

Heymann, D. L. (Ed.). (2004). Cholera and other Vibroses: I. Vibrio cholerae serogroups O1 and O139. In Control of Communicable Disease Manual. (p. 103-111). 18th ed. Washington, DC: American Public Health Association.

Koelle, K., Pascual, M., & Yunus, M. (2005). Pathogen adaptation to seasonal forcing and climate change Proceedings of the Royal Society B: Biological Sciences, 272 (1566), 971-977 DOI: 10.1098/rspb.2004.3043

Nelson EJ, Harris JB, Morris JG Jr, Calderwood SB, & Camilli A (2009). Cholera transmission: the host, pathogen and bacteriophage dynamic. Nature reviews. Microbiology, 7 (10), 693-702 PMID: 19756008

Straif-Bourgeois, S., Sokol, T, Thomas, A, Ratard, R, Greene, KD, Mintz, E, et al. (2006). Two cases of toxigenic Vibrio cholerae 01 infection after hurricanes Katrina and Rita – Louisiana, October 2005, Morbidity & Mortality Weekly Report, 55, 31-32.

For more information see:

Todar, Kenneth. (2011) Vibrio cholerae and Asiatic Cholera, Todar’s Online Textbook of Bacteriology, retrieved February 2011.

Clonal origins of Haiti’s Cholera epidemic

Haiti had been free of cholera for 50 years when the earthquake struck in January 2010. The destruction of Haiti’s infrastructure by the earthquake made it vulnerable to infectious disease outbreaks but it was hoped that cholera would pass it by. As we all know by now, this unfortunately has not been the case. Cholera has spread extensively throughout the country and it is feared that with the vast infrastructure damage, it will become entrenched in Haiti.

Finding the source of the epidemic has been politically sensitive locally and internationally. While locals may be quick to accuse outsiders of increasing their misery, determining the exact origin of the bacteria is necessary to understand the outbreak and determine long-term response. Spread of Vibrio cholerae from the South American outbreak that started in Peru in 1991 or the gulf shore of the United States has been ruled out. Several groups have produced results that point toward a south Asian origin but no one has been able to conclusively prove that it came from Nepalese peacekeepers who have shouldered most the blame to date.

A forthcoming report by Ali et al in the April issue of Emerging Infectious Disease confirms a recent clonal origin for specimens taken within the first three weeks of the epidemic. Of the specimens  taken from 19 diarrhea patients in St Mark’s hospital, Artibonite, 16 patients had the altered El Tor biotype of  Vibrio cholerae O1 Ogawa with the classical cholera B toxin gene. Genetic analysis was unable to pinpoint an origin location for this strain. The lack of VNTR diversity suggests a clonal expansion of a point-source outbreak along the Artibonite river. Ali et al do not believe that this strain could have come from a long-standing environmental reservoir in Haiti because of the lack of diversity and the relatively recent origin of the El Tor  biotype.

Ali, A., Chen,Y.,  Johnson, J.A,  Redden, E., Mayette, Y.,   Rashid, M.H.,  Stine, O.C., and Morris,  J.G. (2011). Recent Clonal Origin of Cholera in Haiti. Emerging Infectious Disease, 17 (4 — April) : 10.3201/eid1704.101973

Expedited release of this article can be found here (as of Feb 20, 2011).

Enserink M (2011). Epidemiology. Despite sensitivities, scientists seek to solve Haiti’s cholera riddle. Science (New York, N.Y.), 331 (6016), 388-9 PMID: 21273460

Cholera in Illinois’ American Bottoms Region, 1849

This year is turning out to be a bad year for cholera. Major cholera outbreaks have erupted in Haiti, Pakistan, and in several African countries. Reports of all these outbreaks remind me of cholera epidemics in American history. In the 19th century cholera wasn’t as closely linked with disasters as it is today. Back then cholera was transmitted best by urban water systems, although it still swept through rural areas as well.

The 1850  federal mortality census  gives us a glimpse at the cholera epidemic that struck Illinois  during the summer of 1849. The American Bottoms region is the four counties in the St. Louis Metro East: Madison Co., St Clair Co, Monroe Co, and Randolph Co. It runs along the eastern shore of the Mississippi River from Alton to Kaskaskia. In 1849 the American Bottoms was mostly rural with a few good size towns (Alton, East St. Louis, Belleville, Cahokia). It is not hard to see the epidemic in a graph of deaths vs. months of 1849-1850.

From a slide presentation I did a few years ago. The American Bottoms region is the four counties now referred to as the St Louis Metro East.

In the mid-19th century summer was always the most deadly time of year in Illinois. The cholera epidemic was occurring against a backdrop of endemic malaria and typhoid fever, and high childhood morality.  In 1849-1850, “fevers” accounted for about 15% of all deaths and cholera for nearly 40% of all deaths.

As bad as the epidemic looks in the graph above, census taker Levi Sharp knows that it was actually far worse than the numbers suggest.

 

Mr Sharp reminds us of the problems with the federal mortality census. Relying on survivors, neighbors or next tenants will miss a lot of people. In an era when children were not mandated to attend school, it is likely that there were a fair number of children who few people knew existed, especially in rural areas.

The shape of the outbreak in St Clair county looks similar to the rest of the American Bottoms.

From a slide presentation I gave several years ago.

Cholera reached the American midwest as part of the second global pandemic. It came and went without people understanding the cause of the epidemic. It will still be a few years more until Dr John Snow discovers the link between cholera and water in 1854.