Tweet
As an epidemiologist, I must make a special note at the beginning of this post. Modern epidemiology has its origin with this disease. It was the study of cholera, particularly in England during the middle of the 19th century, that laid the groundwork for the statistical analysis of public health data and applied surveillance. It was during a time when the miasma theory of disease transmission prevailed in the medical community. The widely recognized anethesiologist, Dr. John Snow, is largely credited with sparking and pursuing a paradigm shift in disease from one which defined illness as borne of bad, malodorous airs, or "miasmas", to one which would begin to recognize disease as infectious. This new conceptualization recognized disease as directly communicable between people or through vehicles (water, in the case of cholera) that are susceptible to contamination by human interaction.
While, Dr. Snow, was indeed at the forefront of pushing this new, germ theory of disease, the credit should not be allocated to him alone for 2 reasons. First, neither he nor any of his contemporaries could identify the agent that caused cholera, or any other disease for that matter, at the time of his investigations. Robert Koch would be the first to isolate and identify in 1877 a bacterial organism, Bacillus anthracis, that was pathogenic for human disease. In 1883, he subsequently identified Vibrio cholerae as the causative agent for cholera. Second, Dr. Snow did not always apply the greatest of rigor in his epidemiological analyses. It would instead be a priest, Henry Whitehead, who would employ exhaustive shoe-leather epidemiology in the Broad Street community as well as taking a more rigorous statistical approach to applied analysis of the resulting data. Dr. Snow's map of the Broad Street cholera outbreak of 1854 and the pump associated with the contaminated well are now iconic symbols of epidemiology and medical geography. This same map, now in the public domain, is the logo for my podcast, The Germlines:
The Pathogen. Cholera is caused by the gram-negative rod-shaped bacterium, Vibrio cholerae. V. cholerae is a distinctively curved (it's often identified as comma-shaped) bacillus with a flagellum:
Pathogenic V. cholerae is actually limited to a subset of strains within the species, rather than extending to all species members. The pathogenic strains are determined by antisera-specific agglutination and are referred to by their serogroup name. Most disease is caused by the O1 and O139 serogroups. Pathogenic V. cholerae are also classified according to biotype, classical or El Tor, and serotype, which consists of two distinct serotypes, Ogawa and Inaba, and one intermediate serotype, Hikojima. Prior to 1992 it was believed that only O1 strains were responsible for causing cholera. However, in 1992 a new serogroup, O139, emerged in South Asia and has been circulating there ever since but has not spread globally thus far. During human infection V. cholerae infects the small intestine and produces a toxin, known as cholera toxin (CT), which is responsible for the diarrheal disease associated with infection. V. cholerae is of only moderate infectivity as hundreds of millions of organisms are required to induce infection, and it is of low pathogenicity since 75% of infections with the classical biotype strains produce mild or subclinical disease and 93% of the El Tor biotype strains produce mild or subclinical disease. However, the virulence can be quite high: case-fatality in resource poor settings typically ranges from 5% to 10%, but can be as high as 20% during some epidemics if appropriate rehydration therapy is not available. In the best of circumstances the case-fatality is approximately 1%.
It is very important to note that Vibrio bacteria, in general, are free-living in water. They occupy various aquatic environments in various geographic locations, though, when free-living, they demonstrate a greater affinity for warmer more tropical climates. Vibrio species can be found in a range of mostly saltwater, and a few freshwater, environs, occupying a distinct ecologic niche in the water column. In addition, because they are ubiquitous in the marine environment they are frequently found in fish, and especially filter-feeding shellfish. Filter feeders (e.g. oysters, clams, cockles) can demonstrate very high levels of colonization, making them a potentially important reservoir for human infection in some circumstances. The image below, published by Nelson et al., 2009, in Nature Reviews Microbiology, shows the generalized V. cholerae life cycle in both the aquatic and human host settings:
While there is a high degree of genetic homogeneity among the various strains of pathogenic V. cholerae, the strains seem to have the ability to experience remarkable changes in specific gene expression as they transfer from the aquatic environment to the human gut. Studies have demonstrated that many of the pathogenic V. cholerae strains exhibit an increase in infectivity of up to 700 fold for up to 18 hours after passing out in the feces. This is a very interesting cross-niche adaption that V. cholerae has evolved to exploit two distinct ecologies (the ocean versus the human gut), while simultaneously relying on the interaction of these two ecologies for the bacterium's success in either one. We will discuss this concept more below.
The Disease. Simply put, it's watery diarrhea. But it is very bad diarrhea. Vomiting is also common.When diarrhea is present, it is a non-dysenteric diarrhea so there is no blood in the stool. Instead cholera diarrhea is characterized by a very liquid and grayish, "rice-water" stool, which can result in rapid and severe dehydration if the fluid loss is untreated. Cholera is really the only diarrheal disease that can cause severe dehydration resulting in death in healthy, immunocompetent adults. The disease is such a danger because so much fluid is lost so quickly: up to 1 liter per hour during acute infections. As such, rehydration therapy with a focus on re-establishing the electrolyte balance is imperative. The characteristic signs of the dehydration that attends the severe diarrhea are sunken eyes and cheeks and poor skin turgor:
The Epidemiology and the Landscape. Each year there are between 3 and 5 million incident cases of cholera globally, with approximately 100,000 associated deaths. Each of these deaths is 100% preventable as they are due to dehydration that can be easily treated with appropriate rehydration therapy. The map below was prepared by the World Health Organization (WHO) and shows the countries reporting annual cholera cases by their average case-fatality. Keep in mind that for any specific cholera epidemic, the actual case-fatality may be much higher depending upon the population affected, the local circumstances, the public health response to the source(s) of exposure, and the resources and knowledge available for rehydration therapy.
Cholera may or may not be an ancient disease. The documentation of this disease in populations largely comes down over the last 200 years through the writings of occupying colonizers of peoples in the tropical latitudes, and India in particular. Whether or not cholera emerged in a single location in the Bay of Bengal, which has been the canon of cholera discourse for generations, or existed endemically in multiple locations throughout the watered geography of the world, we cannot say. Either are possible. However, we can say that, during new periods of intense global shipping traffic due to trade and acquisitions of colonizing nations in the 18th and 19th centuries, cholera did spread globally across the world in a series of seven pandemics. However, the responsibility for this emergent disease and subsequent pandemics resides not in the tropical waters of south Asia or anywhere else, but rather in the large-scale movements of resources and people by the colonizers. I make this distinction because there is a very real discourse defined in the histories of cholera that allocates blame for this burgeoning global disease to subaltern populations. Thus we must read critically the standard documentations and chronologies of the seven pandemics as they are typically described. The first pandemic was referred to as the "Asiatic" cholera pandemic beginning in 1817 and running its course by 1824. The name is quite telling, and was, in part, directly responsible for the bureaucratization of lines between race, and between colonizer and colonized, in an emerging globalized world. This first pandemic extended between the Caspian Sea to the west and China to the east. Each subsequent pandemic lasted typically between 10 and 20 years then retreated into endemicity until the relevant V. cholerae strains were supplanted, thus beginning the next pandemic.
We are currently in the seventh pandemic, which began in 1961 and has been dominated by V. cholerae O1, El Tor. Its geographic spread is documented in this map, which also relied on genome sequencing of the bacterium in spatially diverse samples.
While the new serogroup, O139, emerged in the Bay of Bengal in 1992, this has not led to the emergence of an eighth pandemic.
As natural infection with V. cholerae does confer some immunity for a period, endemicity of infection or previous epidemic exposure is relevant to the severity of new epidemics in a given geographic area. In areas that have not had previous exposure to V. cholerae, essentially the entire population is susceptible. This translates to high incidence among both children and adults. Extremely fast transmission of rapid-onset, severe diarrhea across susceptible populations is characteristic of the typical cholera epidemic, and is one of the reasons why it has historically instilled such fear. A recent tragic example of such a situation is the cholera epidemic in Haiti, which began in 2010. Because cholera had been absent from the country for over a century, virtually everyone was susceptible when exposed. As of the middle of August, 2011, this outbreak had resulted in over 419,000 cases of cholera, of which more than 222,000 have been hospitalized and almost 6000 have died, according to the WHO. Again, explosive outbreaks of severe diarrhea among all age groups in susceptible populations is one of the key epidemiologic features of cholera. This unique dynamic may be due to a combination of a high level of susceptibility in the population with the shift in V. cholerae gene expression that leads to a hyperinfectious state of the bacterium when passed in human feces. Here again is the diagram from above to help illuminate the Vibrio life-cycle in this epidemiologic context:
So, cholera is unique because of the way in which ecologies and environments (particularly water and the human gut) converge to produce potentially massive epidemics. V. cholerae occupies specific ecologic niches, all of which are important in defining the landscape, or aqua-scape, epidemiology of cholera. First, it is free-living in the water column; second, it occupies a reservoir niche in fish and shellfish hosts; third, it occupies a niche in the human intestine, in which it undergoes changes in morphology (the production of the flagellum) and changes in infectivity. As such, its transmission is amplified by orders of magnitude, leading to rapid spread across susceptible populations. But always it's close connection with water is maintained: human fecal contamination of water sources account for the single greatest modality of transmission, and subsequently epidemic spread. Therefore, cholera is also firmly grounded in the human social landscape, being sharply delineated by the personal practice of hygiene at the level of the household and the public health practice of infrastructural sanitation at the level of the municipality.
Treatment. Oral rehydration salts mixed with water provide a universal and highly effective treatment. The goal is to reestablish the electrolyte balance in the person suffering the diarrhea episode. In order to stave off what can develop into deadly dehydration (in the case of cholera this can happen in a matter of hours), the individual must replace the fluid lost, AND the salts lost. This is precisely the goal of oral rehydration therapy. Packets of oral rehydration salts containing sodium chloride, potassium chloride, citrate and glucose can be obtained from almost any pharmacist or chemist in most areas of the world. These are simply mixed with water and consumed by the diarrhea-afflicted person. In addition, as much as can be tolerated by the ill person, normal nutrition intake should be maintained throughout the diarrhea episode. It may seem as though the food will go right through you, but the body does obtain some nutrients and this helps the immune system fight the infection. If dehydration is advanced, and/or if the individual is unable to keep fluids down due to vomiting, then intravenous administration of fluids will likely be necessary. With proper rehydration, no one should die from cholera.
Those suffering from cholera who are undergoing rehydration therapy should be closely monitored for fluid loss during the diarrhea illness. This is typically accomplished using a cholera cot, which is a basic cot with a plastic sheet covering and a hole in the middle that drains into a bucket placed below the hole:
This bucket should contain a measuring stick that quantifies the volume of fluid lost. In this way, health care providers can monitor the volume of fluid loss over time so rehydration therapy can be optimized.
Prevention and Control. Good sanitation and hygiene are the foundation of cholera prevention. Indeed, public sanitation and public health are both directly derived from the response to cholera in the latter half of the 19th century. However, even after more than 150 years, the world has not yet achieved anything close to an equitable distribution of safe water and so cholera epidemics can still strike with great force, as in Haiti in 2010 or in Zimbabwe in 2008. As such, improved infrastructure that can maintain adequate water resources is a first priority in cholera prevention. Secondarily, personal hygiene at the individual level of the household can also be very important in preventing the spread of cholera: consistent hand washing, boiling water, and thoroughly cooking food are all important in stopping the chain of transmission. However, these latter individual efforts, of course, require that adequate resources exist for such practices. Since both water and fuel for cooking or boiling water are often in short supply in the areas most at risk for widespread epidemics, these practices can be difficult to implement.
Finally, it is important to note that shellfish can be an important reservoir for cholera even in developed countries and should therefore be cooked thoroughly before eating. V. cholerae is endemic along the Gulf Coast of the United States and regular cases of cholera are seen in this area due to eating contaminated shellfish that have not been properly cooked. These isolated cases have not resulted in widespread epidemics because of the effective sanitation infrastructure in place along the Gulf Coast, which keeps any individual infections from contaminating larger water sources.
Here is a very nice animated video by the Department of Entomology at the University of Illinois demonstrating some cholera prevention strategies:
As an epidemiologist, I must make a special note at the beginning of this post. Modern epidemiology has its origin with this disease. It was the study of cholera, particularly in England during the middle of the 19th century, that laid the groundwork for the statistical analysis of public health data and applied surveillance. It was during a time when the miasma theory of disease transmission prevailed in the medical community. The widely recognized anethesiologist, Dr. John Snow, is largely credited with sparking and pursuing a paradigm shift in disease from one which defined illness as borne of bad, malodorous airs, or "miasmas", to one which would begin to recognize disease as infectious. This new conceptualization recognized disease as directly communicable between people or through vehicles (water, in the case of cholera) that are susceptible to contamination by human interaction.
While, Dr. Snow, was indeed at the forefront of pushing this new, germ theory of disease, the credit should not be allocated to him alone for 2 reasons. First, neither he nor any of his contemporaries could identify the agent that caused cholera, or any other disease for that matter, at the time of his investigations. Robert Koch would be the first to isolate and identify in 1877 a bacterial organism, Bacillus anthracis, that was pathogenic for human disease. In 1883, he subsequently identified Vibrio cholerae as the causative agent for cholera. Second, Dr. Snow did not always apply the greatest of rigor in his epidemiological analyses. It would instead be a priest, Henry Whitehead, who would employ exhaustive shoe-leather epidemiology in the Broad Street community as well as taking a more rigorous statistical approach to applied analysis of the resulting data. Dr. Snow's map of the Broad Street cholera outbreak of 1854 and the pump associated with the contaminated well are now iconic symbols of epidemiology and medical geography. This same map, now in the public domain, is the logo for my podcast, The Germlines:
The Pathogen. Cholera is caused by the gram-negative rod-shaped bacterium, Vibrio cholerae. V. cholerae is a distinctively curved (it's often identified as comma-shaped) bacillus with a flagellum:
Pathogenic V. cholerae is actually limited to a subset of strains within the species, rather than extending to all species members. The pathogenic strains are determined by antisera-specific agglutination and are referred to by their serogroup name. Most disease is caused by the O1 and O139 serogroups. Pathogenic V. cholerae are also classified according to biotype, classical or El Tor, and serotype, which consists of two distinct serotypes, Ogawa and Inaba, and one intermediate serotype, Hikojima. Prior to 1992 it was believed that only O1 strains were responsible for causing cholera. However, in 1992 a new serogroup, O139, emerged in South Asia and has been circulating there ever since but has not spread globally thus far. During human infection V. cholerae infects the small intestine and produces a toxin, known as cholera toxin (CT), which is responsible for the diarrheal disease associated with infection. V. cholerae is of only moderate infectivity as hundreds of millions of organisms are required to induce infection, and it is of low pathogenicity since 75% of infections with the classical biotype strains produce mild or subclinical disease and 93% of the El Tor biotype strains produce mild or subclinical disease. However, the virulence can be quite high: case-fatality in resource poor settings typically ranges from 5% to 10%, but can be as high as 20% during some epidemics if appropriate rehydration therapy is not available. In the best of circumstances the case-fatality is approximately 1%.
It is very important to note that Vibrio bacteria, in general, are free-living in water. They occupy various aquatic environments in various geographic locations, though, when free-living, they demonstrate a greater affinity for warmer more tropical climates. Vibrio species can be found in a range of mostly saltwater, and a few freshwater, environs, occupying a distinct ecologic niche in the water column. In addition, because they are ubiquitous in the marine environment they are frequently found in fish, and especially filter-feeding shellfish. Filter feeders (e.g. oysters, clams, cockles) can demonstrate very high levels of colonization, making them a potentially important reservoir for human infection in some circumstances. The image below, published by Nelson et al., 2009, in Nature Reviews Microbiology, shows the generalized V. cholerae life cycle in both the aquatic and human host settings:
The Disease. Simply put, it's watery diarrhea. But it is very bad diarrhea. Vomiting is also common.When diarrhea is present, it is a non-dysenteric diarrhea so there is no blood in the stool. Instead cholera diarrhea is characterized by a very liquid and grayish, "rice-water" stool, which can result in rapid and severe dehydration if the fluid loss is untreated. Cholera is really the only diarrheal disease that can cause severe dehydration resulting in death in healthy, immunocompetent adults. The disease is such a danger because so much fluid is lost so quickly: up to 1 liter per hour during acute infections. As such, rehydration therapy with a focus on re-establishing the electrolyte balance is imperative. The characteristic signs of the dehydration that attends the severe diarrhea are sunken eyes and cheeks and poor skin turgor:
Usually 2% - 5% body fluid loss is required before dehydration is clinically recognizable. In addition to the sunken eyes and poor skin turgor mentioned above, irritability, thirst, increased heart rate and respiration, and no urine volume are also characteristic of this stage. A 10% loss of body fluid marks severe dehydration and is characterized by low blood pressure, diminished pulse, increasingly poor skin turgor, delirium, and frequent loss of consciousness. At this stage the individual is no longer eager to drink and may not even be able to do so. This constitutes a medical emergency and requires immediate oral or intravenous (usually the latter) rehydration therapy.
The Epidemiology and the Landscape. Each year there are between 3 and 5 million incident cases of cholera globally, with approximately 100,000 associated deaths. Each of these deaths is 100% preventable as they are due to dehydration that can be easily treated with appropriate rehydration therapy. The map below was prepared by the World Health Organization (WHO) and shows the countries reporting annual cholera cases by their average case-fatality. Keep in mind that for any specific cholera epidemic, the actual case-fatality may be much higher depending upon the population affected, the local circumstances, the public health response to the source(s) of exposure, and the resources and knowledge available for rehydration therapy.
Cholera may or may not be an ancient disease. The documentation of this disease in populations largely comes down over the last 200 years through the writings of occupying colonizers of peoples in the tropical latitudes, and India in particular. Whether or not cholera emerged in a single location in the Bay of Bengal, which has been the canon of cholera discourse for generations, or existed endemically in multiple locations throughout the watered geography of the world, we cannot say. Either are possible. However, we can say that, during new periods of intense global shipping traffic due to trade and acquisitions of colonizing nations in the 18th and 19th centuries, cholera did spread globally across the world in a series of seven pandemics. However, the responsibility for this emergent disease and subsequent pandemics resides not in the tropical waters of south Asia or anywhere else, but rather in the large-scale movements of resources and people by the colonizers. I make this distinction because there is a very real discourse defined in the histories of cholera that allocates blame for this burgeoning global disease to subaltern populations. Thus we must read critically the standard documentations and chronologies of the seven pandemics as they are typically described. The first pandemic was referred to as the "Asiatic" cholera pandemic beginning in 1817 and running its course by 1824. The name is quite telling, and was, in part, directly responsible for the bureaucratization of lines between race, and between colonizer and colonized, in an emerging globalized world. This first pandemic extended between the Caspian Sea to the west and China to the east. Each subsequent pandemic lasted typically between 10 and 20 years then retreated into endemicity until the relevant V. cholerae strains were supplanted, thus beginning the next pandemic.
We are currently in the seventh pandemic, which began in 1961 and has been dominated by V. cholerae O1, El Tor. Its geographic spread is documented in this map, which also relied on genome sequencing of the bacterium in spatially diverse samples.
Transmission events inferred for the seventh cholera pandemic phylogenetic tree drawn on a global map
While the new serogroup, O139, emerged in the Bay of Bengal in 1992, this has not led to the emergence of an eighth pandemic.
As natural infection with V. cholerae does confer some immunity for a period, endemicity of infection or previous epidemic exposure is relevant to the severity of new epidemics in a given geographic area. In areas that have not had previous exposure to V. cholerae, essentially the entire population is susceptible. This translates to high incidence among both children and adults. Extremely fast transmission of rapid-onset, severe diarrhea across susceptible populations is characteristic of the typical cholera epidemic, and is one of the reasons why it has historically instilled such fear. A recent tragic example of such a situation is the cholera epidemic in Haiti, which began in 2010. Because cholera had been absent from the country for over a century, virtually everyone was susceptible when exposed. As of the middle of August, 2011, this outbreak had resulted in over 419,000 cases of cholera, of which more than 222,000 have been hospitalized and almost 6000 have died, according to the WHO. Again, explosive outbreaks of severe diarrhea among all age groups in susceptible populations is one of the key epidemiologic features of cholera. This unique dynamic may be due to a combination of a high level of susceptibility in the population with the shift in V. cholerae gene expression that leads to a hyperinfectious state of the bacterium when passed in human feces. Here again is the diagram from above to help illuminate the Vibrio life-cycle in this epidemiologic context:
So, cholera is unique because of the way in which ecologies and environments (particularly water and the human gut) converge to produce potentially massive epidemics. V. cholerae occupies specific ecologic niches, all of which are important in defining the landscape, or aqua-scape, epidemiology of cholera. First, it is free-living in the water column; second, it occupies a reservoir niche in fish and shellfish hosts; third, it occupies a niche in the human intestine, in which it undergoes changes in morphology (the production of the flagellum) and changes in infectivity. As such, its transmission is amplified by orders of magnitude, leading to rapid spread across susceptible populations. But always it's close connection with water is maintained: human fecal contamination of water sources account for the single greatest modality of transmission, and subsequently epidemic spread. Therefore, cholera is also firmly grounded in the human social landscape, being sharply delineated by the personal practice of hygiene at the level of the household and the public health practice of infrastructural sanitation at the level of the municipality.
Treatment. Oral rehydration salts mixed with water provide a universal and highly effective treatment. The goal is to reestablish the electrolyte balance in the person suffering the diarrhea episode. In order to stave off what can develop into deadly dehydration (in the case of cholera this can happen in a matter of hours), the individual must replace the fluid lost, AND the salts lost. This is precisely the goal of oral rehydration therapy. Packets of oral rehydration salts containing sodium chloride, potassium chloride, citrate and glucose can be obtained from almost any pharmacist or chemist in most areas of the world. These are simply mixed with water and consumed by the diarrhea-afflicted person. In addition, as much as can be tolerated by the ill person, normal nutrition intake should be maintained throughout the diarrhea episode. It may seem as though the food will go right through you, but the body does obtain some nutrients and this helps the immune system fight the infection. If dehydration is advanced, and/or if the individual is unable to keep fluids down due to vomiting, then intravenous administration of fluids will likely be necessary. With proper rehydration, no one should die from cholera.
Those suffering from cholera who are undergoing rehydration therapy should be closely monitored for fluid loss during the diarrhea illness. This is typically accomplished using a cholera cot, which is a basic cot with a plastic sheet covering and a hole in the middle that drains into a bucket placed below the hole:
This bucket should contain a measuring stick that quantifies the volume of fluid lost. In this way, health care providers can monitor the volume of fluid loss over time so rehydration therapy can be optimized.
Prevention and Control. Good sanitation and hygiene are the foundation of cholera prevention. Indeed, public sanitation and public health are both directly derived from the response to cholera in the latter half of the 19th century. However, even after more than 150 years, the world has not yet achieved anything close to an equitable distribution of safe water and so cholera epidemics can still strike with great force, as in Haiti in 2010 or in Zimbabwe in 2008. As such, improved infrastructure that can maintain adequate water resources is a first priority in cholera prevention. Secondarily, personal hygiene at the individual level of the household can also be very important in preventing the spread of cholera: consistent hand washing, boiling water, and thoroughly cooking food are all important in stopping the chain of transmission. However, these latter individual efforts, of course, require that adequate resources exist for such practices. Since both water and fuel for cooking or boiling water are often in short supply in the areas most at risk for widespread epidemics, these practices can be difficult to implement.
Finally, it is important to note that shellfish can be an important reservoir for cholera even in developed countries and should therefore be cooked thoroughly before eating. V. cholerae is endemic along the Gulf Coast of the United States and regular cases of cholera are seen in this area due to eating contaminated shellfish that have not been properly cooked. These isolated cases have not resulted in widespread epidemics because of the effective sanitation infrastructure in place along the Gulf Coast, which keeps any individual infections from contaminating larger water sources.
Here is a very nice animated video by the Department of Entomology at the University of Illinois demonstrating some cholera prevention strategies: