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'''Cholera''' (or ''Asiatic cholera'' or ''epidemic cholera'') is a severe [[diarrhea]]l disease caused by the [[bacterium]] ''[[Vibrio cholerae]]''.<ref name=Sherris>{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | id = ISBN 0838585299 }}</ref> and transmitted to people by ingesting contaminated water or food.  The major reservoir for cholera was long thought to be humans, but some evidence suggests that it is the aquatic environment. It can kill if untreated, but often responds well to simple supportive treatment such as [[oral rehydration therapy]].


'''Cholera''' (or ''Asiatic cholera'' or ''epidemic cholera'') is a severe [[diarrhea]]l disease caused by the [[bacterium]] ''[[Vibrio cholerae]]''.<ref name=Sherris>{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | id = ISBN 0838585299 }}</ref> Transmission to humans is by ingesting contaminated water or food. The major reservoir for cholera was long assumed to be humans, but some evidence suggests that it is the aquatic environment. It is extremely deadly.
''V. cholerae'' is a [[Gram-negative bacteria]] which produces [[cholera toxin]], an [[enterotoxin]], whose effects on the [[mucosa]]l [[epithelium]] lining of the small intestine cause massive diarrhea.<ref name=Sherris /> In its most severe forms, cholera is one of the most rapidly lethal illnesses known: A healthy person may become [[hypotension|hypotensive]] within an hour of the first symptoms and may die within 2-3 hours if no treatment is provided.<ref name=Sherris /> More often, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without rehydration treatment.<ref name=McLeod_2000>{{cite journal |author=McLeod K |title=Our sense of Snow: John Snow in medical geography |journal=Soc Sci Med |volume=50  |pages=923-35 |year=2000 |id=PMID 10714917}}</ref><ref> WHO Cholera [http://www.who.int/topics/cholera/control/en/index.html]</ref>


''V. cholerae'' is a Gram negative bacteria which produces [[cholera toxin]], an [[enterotoxin]], whose action on the [[mucosa]]l [[epithelium]] lining of the small intestine is responsible for the characteristic massive diarrhea of the disease.<ref name=Sherris /> In its most severe forms, cholera is one of the most rapidly fatal illnesses known: A healthy person may become [[hypotension|hypotensive]] within an hour of the onset of symptoms and may die within 2-3 hours if no treatment is provided.<ref name=Sherris /> More commonly, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without rehydration treatment.<ref name=McLeod_2000>{{cite journal |author=McLeod K |title=Our sense of Snow: John Snow in medical geography |journal=Soc Sci Med |volume=50 |issue=7-8 |pages=923-35 |year=2000 |id=PMID 10714917}}</ref><ref> WHO Cholera [http://www.who.int/topics/cholera/control/en/index.html]</ref>
[[CIA transnational health activities|U.S. National Intelligence Council and CIA]] studies consider it a threat to world stability. It is on the [[CDC Bioterrorism Agents-Disease list]].


== Symptoms ==
== Symptoms ==
[[Symptoms]] include those of general GI tract (stomach) upset, and [[Diarrhea#Acute diarrhea|massive watery diarrhea]]. Symptoms may also include terrible muscle and stomach cramps, vomiting and fever in early stages. In a later stage the diarrhea  becomes "rice water stool" (almost clear with flecks of white) and ruptured capillaries may turn the skin black and blue with sunken eyes and cheeks with blue lips.  Symptoms are caused by massive body fluid loss induced by the [[enterotoxin]]s that ''V. cholerae'' produces. The main enterotoxin, known as '''[[cholera toxin]]''', interacts with [[G protein]]s and [[cyclic AMP]] in the intestinal lining to open [[ion channels]]. As ions flow into the intestinal [[lumen]] (lining), body fluids (mostly water) flow out of the body due to [[osmosis]] leading to massive diarrhea as the fluid is expelled from the body. The body is "tricked" into releasing massive amounts of fluid into the small intestine which shows up in up to 36 liters (or 20% of body weight) of liquid diarrhea in a six day period in adults with accompanying massive dehydration.<ref name=Rabbani_1996>{{cite journal |author=Rabbani GH |title=Mechanism and treatment of diarrhoea due to ''Vibrio cholerae'' and ''Escherichia coli'': roles of drugs and prostaglandins |journal=Danish medical bulletin |volume=43 |issue=2 |pages=173-85 |year=1996 |pmid=8741209}}</ref> Radical dehydration can bring death within a day through collapse of the circulatory system.
[[Symptoms]] include general GI tract (stomach) upset, and massive watery diarrhea. There can be severe muscle and stomach cramps, vomiting and fever in the early stages. Later, the diarrhea  becomes "rice water stool" (almost clear with flecks of white) and ruptured capillaries may turn the skin black and blue with sunken eyes and cheeks with blue lips.  Symptoms are caused by massive body fluid loss induced by the [[enterotoxin]]s that ''V. cholerae'' produces. The main enterotoxin, '''[[cholera toxin]]''', interacts with [[G protein]]s and [[cyclic AMP]] in the intestinal lining to open [[ion channels]]. As ions flow into the intestinal [[lumen]] (lining), body fluids flow out of the body due to [[osmosis]] leading to diarrhea as the fluid is expelled from the body. The body is "tricked" into releasing massive amounts of fluid into the small intestine which shows up in up to 36 liters (or 20% of body weight) of liquid diarrhea in a six day period in adults with accompanying severe dehydration.<ref name=Rabbani_1996>{{cite journal |author=Rabbani GH |title=Mechanism and treatment of diarrhoea due to ''Vibrio cholerae'' and ''Escherichia coli'': roles of drugs and prostaglandins |journal=Danish medical bulletin |volume=43 |pages=173-85 |year=1996 |pmid=8741209}}</ref> Radical dehydration can bring death within a day through collapse of the circulatory system.


== Treatment ==
== Treatment ==
[[Image:Cholera rehydration nurses.jpg|right|thumb|250px|Nurses encourage patients to drink large amounts of an oral rehydration solution to counteract the massive dehydration resulting from cholera.]] In general, patients must receive as much fluid as they lose, which can be up to 20 L, due to diarrhea.  
Treatment typically consists of aggressive [[rehydration]] (restoring the lost body fluids) and [[oral rehydration salt|replacement of electrolytes]] with commercial or hand-mixed sugar-salt solutions (1 tsp salt + 8 tsp sugar in 1 litre of clean/boiled water) or massive injections of liquid given intravenously via an IV in advanced cases. In general, patients must receive as much fluid as they lose, which can be up to 20 L. See: [[Oral rehydration therapy]] for easily made rehydration solutions and [[Ceralyte]]. Without rehydration, the death rate can be as high as 10-50%.


Treatment typically consists of aggressive [[rehydration]] (restoring the lost body fluids) and [[oral rehydration salt|replacement of electrolytes]] with commercial or hand-mixed sugar-salt solutions (1 tsp salt + 8 tsp sugar in 1 litre of clean/boiled water) or massive injections of liquid given intravenously via an IV in advanced cases. See: [[Oral rehydration therapy]] for easily made rehydration solutions and [[Ceralyte]]. Without rehydration, the death rate can be as high as (10-50%) due to the serious dehydration that cholera produces.
[[Tetracycline antibiotics]] may reduce the duration and severity of cholera, although drug-resistance is an increasing problem,<ref name="ExpertOpinPharmacother2003-Bhattacharya">{{cite journal | author=Bhattacharya SK, National Institute of Cholera and Enteric Diseases | title=An evaluation of current cholera treatment | journal=Expert Opin Pharmacother | year=2003 | pages=141-6 | volume=4 | id=PMID 12562304 }}</ref> and their effects on overall mortality are questioned.<ref name="PrimCareUpdateObGyns2001-Parsi">{{cite journal | author=Parsi VK | title=Cholera | journal=Prim. Care Update Ob Gyns | year=2001 | pages=106-109 | volume=8| id=PMID 11378428 }}</ref> Other antibiotics that have been used include [[ciprofloxacin]] and [[azithromycin]],<ref>{{cite journal | author=Saha D ''et al.'' | title=Single dose azithromycin for the treatment of cholera in adults | journal=New Engl J Med | volume=354  | pages=2452&ndash;62 | year=2006 }}</ref> although again, drug-resistance has now been described.<ref>{{cite journal | author=Krishna BVS ''et al.'' | title=Fluoroquinolone-resistant ''Vibrio cholerae'' isolated during a cholera outbreak in India | journal=Trans R Soc Trop Med Hyg | year=2006 | volume=100  | pages=224&ndash;26 | doi=10.1016/j.rstmh.2005.07.007 }}</ref>


[[Tetracycline antibiotics]] may have a role in reducing the duration and severity of cholera, although drug-resistance is occurring,<ref name="ExpertOpinPharmacother2003-Bhattacharya">{{cite journal | author=Bhattacharya SK, National Institute of Cholera and Enteric Diseases | title=An evaluation of current cholera treatment | journal=Expert Opin Pharmacother | year=2003 | pages=141-6 | volume=4 | issue=2 | id=PMID 12562304 }}</ref> and their effects on overall mortality are questioned.<ref name="PrimCareUpdateObGyns2001-Parsi">{{cite journal | author=Parsi VK | title=Cholera | journal=Prim. Care Update Ob Gyns | year=2001 | pages=106-109 | volume=8 | issue=3 | id=PMID 11378428 }}</ref> Other antibiotics that have been used include [[ciprofloxacin]] and [[azithromycin]],<ref>{{cite journal | author=Saha D, ''et al.'' | title=Single dose azithromycin for the treatment of cholera in adults | journal=New Engl J Med | volume=354 | issue=23 | pages=2452&ndash;62 | year=2006 }}</ref> although again, drug-resistance has now been described.<ref>{{cite journal | author=Krishna BVS, Patil AB, Chandrasekhar MR | title=Fluoroquinolone-resistant ''Vibrio cholerae'' isolated during a cholera outbreak in India | jounal=Trans R Soc Trop Med Hyg | year=2006 | volume=100 | issue=3 | pages=224&ndash;26 | doi=10.1016/j.rstmh.2005.07.007 }}</ref>
Without treatment the death rate is as high as 50%; with treatment the death rate can be well below 1%.<ref name=Sack_2004>{{cite journal |author=Sack D ''et al.'' |title=Cholera |journal=Lancet |volume=363 |pages=223-33 |year=2004 |id=PMID 14738797}}</ref>
 
Without treatment the death rate is as high as 50%; with treatment the death rate can be well below 1%.<ref name=Sack_2004>{{cite journal |author=Sack D, Sack R, Nair G, Siddique A |title=Cholera |journal=Lancet |volume=363 |issue=9404 |pages=223-33 |year=2004 |id=PMID 14738797}}</ref>


== Epidemiology ==
== Epidemiology ==
=== Prevention ===
=== Prevention ===
Although cholera can be life-threatening, it is nearly always easily prevented, in principle, if proper sanitation practices are followed. In the United States and Western Europe, because of advanced water treatment and sanitation systems, cholera is no longer a major threat. The last major outbreak of cholera in the United States was in [[1911]]. However, everyone, especially travellers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation practices, if instituted in time, is usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:
Although cholera can be life-threatening, it is nearly always easily prevented, in principle, if proper sanitation practices are followed. In the U.S.A. and Western Europe, because of advanced water treatment and sanitation systems, cholera is no longer a major threat. The last major outbreak of cholera in the U.S.A. was in 1911. However, everyone, especially travellers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation, if instituted in time, is usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:
* Sickbed: Proper disposal and treatment of the germ infected fecal waste (and all clothing and bedding that come in contact with it) produced by cholera victims is of primary importance.
* Sickbed: Proper disposal and treatment of infected fecal waste (and all clothing and bedding that come in contact with it) produced by cholera victims is of primary importance.
* Sewage: Treatment of general sewage before it enters the waterways or underground water supplies prevent possible undetected patients from spreading the disease.
* Sewage: Treatment of general sewage before it enters the waterways or underground water supplies prevent possible undetected patients from spreading the disease.
* Sources: Warnings about cholera contamination posted around contaminated water sources with directions on how to decontaminate the water.
* Sources: Warnings about cholera contamination posted around contaminated water sources with directions on how to decontaminate the water.
* Sterilization: Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections, when they do occur, from spreading. All materials (clothing, bedding, etc.) that come in contact with cholera patients should be sterilized in hot water using (if possible) chlorine bleach. Hands, etc. that touch cholera patients or their clothing etc. should be thoroughly cleaned and sterilized. All water used for drinking, washing or cooking should be sterilized by boiling or chlorination in any area where cholera may be present.  Water filtration, chlorination and boiling are by far the most effective means of halting transmission. [[Cloth filter]]s, though very basic, have greatly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water.  In general, public health education and good sanitation practices are the limiting factors in preventing transmission.
* Sterilization: Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections, when they do occur, from spreading. All materials (clothing, bedding, etc.) that come in contact with cholera patients should be sterilized in hot water using (if possible) chlorine bleach. Hands, etc. that touch cholera patients or their clothing etc. should be thoroughly cleaned and sterilized. All water used for drinking, washing or cooking should be sterilized by boiling or chlorination in any area where cholera may be present.  Water filtration, chlorination and boiling are by far the most effective means of halting transmission. [[Cloth filter]]s, though very basic, have greatly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water.  In general, public health education and good sanitation are the limiting factors in preventing transmission.


===Susceptibility===
===Susceptibility===
Recent [[epidemiology|epidemiologic research]] suggests that an individual's susceptibility to cholera (and other [[diarrhea]]l infections) is affected by their [[blood type]]: Those with [[type O blood]] are the most susceptible,<ref name=Swerdlow_1994>{{cite journal |author=Swerdlow D, Mintz E, Rodriguez M, Tejada E, Ocampo C, Espejo L, Barrett T, Petzelt J, Bean N, Seminario L |title=Severe life-threatening cholera associated with blood group O in Peru: implications for the Latin American epidemic |journal=J Infect Dis |volume=170 |issue=2 |pages=468-72 |year=1994 |id=PMID 8035040}}</ref><ref name=Harris_2005>{{cite journal |author=Harris J, Khan A, LaRocque R, Dorer D, Chowdhury F, Faruque A, Sack D, Ryan E, Qadri F, Calderwood S |title=Blood group, immunity, and risk of infection with ''Vibrio cholerae'' in an area of endemicity |journal=Infect Immun |volume=73 |issue=11 |pages=7422-7 |year=2005 |pmid=16239542}}</ref> while those with [[type AB]] are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B.{{Fact|date=February 2007}}
Recent [[epidemiology|epidemiologic research]] suggests that susceptibility to cholera (and other [[diarrhea]]l infections) is affected by [[blood type]]: Those with [[type O blood]] are most susceptible,<ref name=Swerdlow_1994>{{cite journal |author=Swerdlow D ''et al.''|title=Severe life-threatening cholera associated with blood group O in Peru: implications for the Latin American epidemic |journal=J Infect Dis |volume=170 |pages=468-72 |year=1994 |id=PMID 8035040}}</ref><ref name=Harris_2005>{{cite journal |author=Harris J ''et al.'' |title=Blood group, immunity, and risk of infection with ''Vibrio cholerae'' in an area of endemicity |journal=Infect Immun |volume=73 |pages=7422-7 |year=2005 |pmid=16239542}}</ref> while those with [[type AB]] are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B.


About one million ''V. cholerae'' bacteria must typically be ingested to cause cholera in normally healthy adults, although increased susceptibility may be observed in those with a weakened [[immune system]], individuals with decreased gastric acidity (as from the use of [[antacid]]s), or those who are [[malnutrition|malnourished]].
About one million ''V. cholerae'' bacteria must typically be ingested to cause cholera in normally healthy adults, although increased susceptibility may be observed in those with a weakened [[immune system]], individuals with decreased gastric acidity (as from the use of [[antacid]]s), or those who are [[malnutrition|malnourished]].


It has also been hypothesized that the [[cystic fibrosis]] genetic [[mutation]] has been maintained in humans due to a selective advantage: [[heterozygous]] carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to ''V. cholerae'' infections.<ref name=Bertranpetit_1996>{{cite journal |author=Bertranpetit J, Calafell F |title=Genetic and geographical variability in cystic fibrosis: evolutionary considerations |journal=Ciba Found Symp |volume=197 |issue= |pages=97-114; discussion 114-8 |year=1996 |pmid=8827370}}</ref> In this model, the genetic deficiency in the [[cystic fibrosis transmembrane conductance regulator]] channel proteins interferes with bacteria binding to the [[gastrointestinal]] epithelium, thus reducing the effects of an infection.
It has also been hypothesized that the [[cystic fibrosis]] genetic [[mutation]] has been maintained in humans due to a selective advantage: [[heterozygous]] carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to ''V. cholerae'' infections.<ref name=Bertranpetit_1996>{{cite journal |author=Bertranpetit J, Calafell F |title=Genetic and geographical variability in cystic fibrosis: evolutionary considerations |journal=Ciba Found Symp |volume=197 |pages=97-114; discussion 114-8 |year=1996 |pmid=8827370}}</ref> In this model, the genetic deficiency in the [[cystic fibrosis transmembrane conductance regulator]] channel proteins interferes with bacteria binding to the [[gastrointestinal]] epithelium, thus reducing the effects of an infection.


=== Transmission ===
=== Transmission ===
[[Image:Cholera.jpg|thumb|right|200px|[[Drawing]] of [[Death (personification)|Death]] bringing the cholera, in ''[[Le Petit Journal]]''.]]
Persons infected with cholera have severe diarrhea, loaded with bacteria that can spread to infect water supplies: cholera is transmitted from person to person mainly through ingestion of this contaminated water, and only rarely spread directly from person to person. Any infected water and any foods washed in the water, and [[shellfish]] living in the affected [[waterway]] can cause an infection.  ''V. cholerae'' occurs naturally in the [[plankton]] of [[fresh water|fresh]], [[brackish water|brackish]], and [[Seawater|salt water]], attached primarily to [[copepod]]s in the [[zooplankton]].  Both toxic and non-toxic strains exist.  Non-toxic strains can acquire toxicity through a [[lysogenic]] [[bacteriophage]].<ref name=Archivist_1997>{{cite journal | author =''Archivist'' | title = Cholera phage discovery | journal =Arch Dis Child  | year =1997 | volume =76 | pages = 274 | url=http://adc.bmj.com/cgi/content/full/76/3/274 }}</ref> Coastal cholera outbreaks typically follow [[algal bloom|zooplankton blooms]].  This makes cholera a [[zoonosis]].
 
Persons infected with cholera have massive diarrhea. This highly liquid [[diarrhea]], which is often compared to "rice water", is loaded with bacteria that can spread under unsanitary conditions to infect water used by other people. Cholera is transmitted from person to person through ingestion of [[feces]] contaminated water loaded with the cholera bacterium. The source of the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get into waterways or into [[groundwater]] or drinking water supply. Any infected water and any foods washed in the water, and [[shellfish]] living in the affected [[waterway]] can cause an infection. Cholera is rarely spread directly from person to person.  ''V. cholerae'' occurs naturally in the [[plankton]] of [[fresh water|fresh]], [[brackish water|brackish]], and [[Seawater|salt water]], attached primarily to [[copepod]]s in the [[zooplankton]].  Both toxic and non-toxic strains exist.  Non-toxic strains can acquire toxicity through a [[lysogenic]] [[bacteriophage]].<ref name=Archivist_1997>{{cite journal | author =''Archivist'' | title = Cholera phage discovery | journal =Arch Dis Child  | year =1997 | volume =76 | pages = 274 | url=http://adc.bmj.com/cgi/content/full/76/3/274 }}</ref> Coastal cholera outbreaks typically follow [[algal bloom|zooplankton blooms]].  This makes cholera a [[zoonosis]].


=== Biochemistry of the ''V. cholerae'' bacterium ===
=== Biochemistry of the ''V. cholerae'' bacterium ===
Most of the ''V. cholerae'' bacteria in the contaminated water that a potential host drinks do not survive the very acidic conditions of the [[stomach|human stomach]] <ref name=Hartwell>Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). ''Genetics: From Genes to Genomes.'' Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of [[gene expression]] to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).</ref> But the few bacteria that manage to survive the stomach's acidity conserve their [[nutrient|energy and stored nutrients]] during the perilous passage through the stomach by shutting down much protein production. When the surviving bacteria manage to exit the stomach and reach the favorable conditions of the [[small intestine]], they need to propel themselves through the thick [[mucous membrane|mucus]] that lines the small intestine to get to the intestinal wall where they can thrive. So they start up production of the hollow cylindrical protein [[flagellin]] to make [[flagella]], the curly whip-like tails that they rotate to propel themselves through the pasty mucus that lines the small intestine.
Most of the ''V. cholerae'' bacteria in contaminated water do not survive the acidic conditions of the [[stomach|human stomach]] <ref name=Hartwell>Hartwell LH ''et al.''(2004). ''Genetics: From Genes to Genomes.'' Mc-Graw Hill, Boston: p. 551-2, 572-4 (using the turning off and turning on of [[gene expression]] to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing chemical environments).</ref> But the few bacteria that survive the stomach's acidity conserve their [[nutrient|energy and stored nutrients]] during the passage through the stomach by shutting down much protein production. When the surviving bacteria exit the stomach and reach the [[small intestine]], they need to propel themselves through the thick [[mucous membrane|mucus]] that lines the small intestine to get to the intestinal wall where they can thrive. So they start producing the hollow cylindrical protein [[flagellin]] to make [[flagella]], the curly whip-like tails that they rotate to propel themselves through the pasty mucus that lines the small intestine.
 
Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move themselves any more, so they stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins that they manufacture, responding to the changed chemical surroundings. And on reaching the intestinal wall, they start producing the toxic proteins that give the infected person a watery [[diarrhea]] which carries the multiplying and thriving new generations of ''V. cholerae'' bacteria out into the drinking water of the next host&mdash;if proper sanitation measures are not in place.


[[Image:Cholera Toxin.png|thumb|Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc)]]
Once the bacteria reach the intestinal wall, they stop producing flagellin and start producing the toxic proteins that give the infected person a watery diarrhea which carries the multiplying and thriving new generations of ''V. cholerae'' bacteria.


Microbiologists have studied the [[gene expression|genetic mechanisms]] by which the ''V. cholerae'' bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.<ref name=DiRita_1991>{{cite journal |author=DiRita V, Parsot C, Jander G, Mekalanos J |title=Regulatory cascade controls virulence in Vibrio cholerae |journal=Proc Natl Acad Sci U S A |volume=88 |issue=12 |pages=5403-7 |year=1991 | url=http://www.pnas.org/cgi/reprint/88/12/5403 |id=PMID 2052618}}</ref> Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that ineract with host cell mechanisms to pump [[chloride]] ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The choride and sodium ions create a salt water environment in the small intestines which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive amounts of diarrhea.<ref name=Rabbani_1996 /> The host can become rapidly dehydrated if an appropriate mixture of dilute salt water and sugar is not taken to replace the blood's water and salts lost in the diarrhea.
Microbiologists have studied the [[gene expression|genetic mechanisms]] by which the ''V. cholerae'' bacteria turn off the production of some proteins and turn on the production of others as they pass through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.<ref name=DiRita_1991>{{cite journal |author=DiRita V ''et al.'' |title=Regulatory cascade controls virulence in Vibrio cholerae |journal=Proc Natl Acad Sci U S A |volume=88 |pages=5403-7 |year=1991 | url=http://www.pnas.org/cgi/reprint/88/12/5403 |id=PMID 2052618}}</ref> Of particular interest have been the genetic mechanisms by which the bacteria turn on production of the toxins that interact with host cell mechanisms to pump [[chloride]] ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The choride and sodium ions create a salt water environment in the small intestine which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive diarrhea.<ref name=Rabbani_1996 />  


By inserting separately successive sections of ''V. cholerae'' DNA into the DNA of other bacteria such as ''[[E. coli]]'' that would not naturally produce the protein toxins, researchers could find out the separate pieces of the mechanisms by which ''V. cholerae'' respond to the changing chemical environments of the stomach, mucous layers, and intestinal wall.  Researchers discovered that there is a complex cascade of regulatory proteins that control expression of ''V. cholerae'' virulence determinants. In responding to the chemical environment at the intestinal wall, the ''V. cholerae'' bacteria produce the TcpP/TcpH proteins which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins that cause diarrhea in the infected person and that permit the bacteria to colonize the intestine.<ref name=DiRita_1991 />Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."<ref name=Hartwell>p. 574</ref>
By inserting separately successive sections of ''V. cholerae'' DNA into the DNA of other bacteria such as ''[[E. coli]]'' that do not naturally produce the protein toxins, have found the mechanisms by which ''V. cholerae'' respond to the changing chemical environments of the stomach, mucous layers, and intestinal wall.  A complex cascade of regulatory proteins controls expression of ''V. cholerae'' virulence determinants. In responding to the chemical environment at the intestinal wall, the ''V. cholerae'' bacteria produce the TcpP/TcpH proteins which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins that cause diarrhea and that permit the bacteria to colonize the intestine.<ref name=DiRita_1991 />Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize the small intestine."<ref name=Hartwell />


== History ==
== History ==
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Cholera was originally [[endemic (epidemiology)|endemic]] to the Indian subcontinent, with the [[Ganges River]] likely serving as a contamination reservoir. It spread by trade routes (land and sea) to [[Russia]], then to [[Western Europe]], and from Europe to [[North America]]. It is now no longer considered an issue in Europe and North America, due to [[water filtration|filtering]] and [[chlorination]] of the water supply.
Cholera was originally [[endemic (epidemiology)|endemic]] to the Indian subcontinent, with the [[Ganges River]] likely serving as a contamination reservoir. It spread by trade routes (land and sea) to [[Russia]], then to [[Western Europe]], and from Europe to [[North America]]. It is now no longer considered an issue in Europe and North America, due to [[water filtration|filtering]] and [[chlorination]] of the water supply.


* 1816-1826 - '''First Cholera pandemic''': Previously restricted, the pandemic began in [[Bengal]], then spread across [[India]] by 1820. It extended as far as [[China]] and the [[Caspian Sea]] before receding.
* 1816-1826 - '''First Cholera pandemic''': Previously restricted, the pandemic began in [[Bengal]], then spread across [[India]] by 1820. It extended as far as China and the [[Caspian Sea]] before receding.
* 1829-1851 - '''Second Cholera pandemic''' reached Europe, [[London]] and [[Paris]] in 1832. In London, it claimed 6,536 victims (see: http://www.mernick.co.uk/thhol/1832chol.html); in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all of France [http://www.amicale-genealogie.org/Histoires_temps-passe/Epidemies/chol01.htm]. It reached Russia ([[Cholera Riots]]), [[Quebec, Canada|Quebec]], [[Ontario, Canada|Ontario]] and [[New York]] in the same year and the Pacific coast of North America by 1834.
* 1829-1851 - '''Second Cholera pandemic''' reached Europe, [[London, United Kingdom|London]] and [[Paris]] in 1832. In London, it claimed 6,536 victims (see: http://www.mernick.co.uk/thhol/1832chol.html); in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all of France [http://www.amicale-genealogie.org/Histoires_temps-passe/Epidemies/chol01.htm]. It reached Russia ([[Cholera Riots]]), [[Quebec, Canada|Quebec]], [[Ontario, Canada|Ontario]] and [[New York (disambiguation)|New York]] in the same year and the Pacific coast of North America by 1834.
* 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming 14,137 lives, ten times as many as the 1832 outbreak. In 1849 cholera claimed 5,308 lives in the port city of Liverpool England and 1,834 in Hull England. <ref>IBMS Institute of Biological Science [http://www.ibms.org/index.cfm?method=science.history_zone&subpage=history_choleraAn ]</ref> An outbreak in North America took the life of former [[President of the United States|U.S. President]] [[James K. Polk]]. Cholera spread throughout the Mississippi river system killing over 4,500 in St. Louis [http://www.stlgs.org/DBpublicationsNewsCholera.htm] and over 3,000 in New Orleans [http://www.rootsweb.com/~txpanola/epidemics.html] as well as thousands in New York <ref> The Cholera Years: The United States in 1832, 1849, and 1866 by Charles E. Rosenberg </ref> In 1849 cholera was spread along the California and Oregon trail as hundreds died on their way to the [[California Gold Rush]], [[Utah]] and [[Oregon]]. <ref> Trails of Hope: California, Oregon and Mormon Trails [http://overlandtrails.lib.byu.edu/ctrail.htm]</ref>  
* 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming 14,137 lives, ten times as many as the 1832 outbreak. In 1849 cholera claimed 5,308 lives in the port city of Liverpool England and 1,834 in Hull England. <ref>IBMS Institute of Biological Science [http://www.ibms.org/index.cfm?method=science.history_zone&subpage=history_choleraAn ]</ref> An outbreak in North America took the life of former [[President of the United States of America|U.S. President]] [[James K. Polk]]. Cholera spread throughout the Mississippi river system killing over 4,500 in St. Louis [http://www.stlgs.org/DBpublicationsNewsCholera.htm] and over 3,000 in New Orleans [http://www.rootsweb.com/~txpanola/epidemics.html] as well as thousands in New York <ref> The Cholera Years: The United States in 1832, 1849, and 1866 by Charles E. Rosenberg </ref> In 1849, cholera was spread along the California and Oregon trail as hundreds died on their way to the [[California Gold Rush]], [[Utah (U.S. state)|Utah]] and [[Oregon (U.S. state)|Oregon]]. <ref> [http://overlandtrails.lib.byu.edu/ctrail.htm ''Trails of Hope: California, Oregon and Mormon Trails'']</ref>  
* 1852-1860 - '''Third Cholera pandemic''' mainly affected Russia, with over a million deaths. In 1853-4, London's epidemic claimed 10,738 lives.
* 1852-1860 - '''Third Cholera pandemic''' mainly affected Russia, with over a million deaths. In 1853-4, London's epidemic claimed 10,738 lives.
* 1854 - Outbreak of cholera in Chicago took the lives of 5.5 per cent of the population (about 3,500 people).[http://www.chipublib.org/004chicago/timeline/riverflow.html]. [[Soho]] outbreak in London stopped by removing the handle of the [[Broad Street pump]] by a committee instigated to action by [[John Snow (physician)|John Snow]].<ref> On the Mode of Communication of Cholera (1855) by John Snow, M.D. (1813-1858) [http://eee.uci.edu/clients/bjbecker/PlaguesandPeople/week8a.html </ref>
* 1854 - Outbreak of cholera in Chicago took the lives of 5.5 per cent of the population (about 3,500 people).[http://www.chipublib.org/004chicago/timeline/riverflow.html]. [[Soho]] outbreak in London stopped by removing the handle of the [[Broad Street pump]] by a committee instigated to action by [[John Snow]] (1813-1858) .<ref>[http://eee.uci.edu/clients/bjbecker/PlaguesandPeople/week8a.html ''On the Mode of Communication of Cholera''](1855) by John Snow, M.D.</ref>
* 1863-1875 - '''Fourth Cholera pandemic''' spread mostly in Europe and [[Africa]].
* 1863-1875 - '''Fourth Cholera pandemic''' spread mostly in Europe and [[Africa]].
* 1866 - Outbreak in North America. <!-- taken from above paragraph. Not sure if this is separate from the 4th pandemic --> In London, a localized epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water treatment systems--the East End was not quite complete. William Farr, using the work of [[John Snow (physician)|John Snow]] et. al. as to contaminated drinking water being the likely source of the disease, was able to relatively quickly identify the East London Water Company as the source of the contaminated water. Quick action prevented further deaths. <ref> "The Ghost Map" by Steven Johnson, pg. 209 </ref>
* 1866 - Outbreak in North America. In London, a localized epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water treatment systems--the East End was not quite complete. William Farr, using the work of [[John Snow]] as to contaminated drinking water being the likely source of the disease, quickly identified the East London Water Company as the source of the contaminated water. Swift action prevented further deaths. <ref> "The Ghost Map" by Steven Johnson, pg. 209 </ref>
* 1881-1896 - '''Fifth Cholera pandemic '''; The 1892 outbreak in [[Hamburg, Germany]] was the only major European outbreak, about 8,600 people died in Hamburg, causing a major political upheaval in Germany, as control over the City was removed from a City Council which had not updated Hamburg's water supplies.  This was the last serious European cholera outbreak.
* 1881-1896 - '''Fifth Cholera pandemic '''; The 1892 outbreak in [[Hamburg, Germany]] was the only major European outbreak, about 8,600 died, causing a major political upheaval in Germany, as control over the city was removed from a City Council which had not updated Hamburg's water supplies.  This was the last serious European cholera outbreak.
* 1899-1923 - '''Sixth Cholera pandemic''' had little effect in Europe because of advances in public health, but Russia was badly affected again.
* 1899-1923 - '''Sixth Cholera pandemic''' had little effect in Europe because of advances in public health, but Russia was badly affected again.
* 1961-1970s - '''Seventh Cholera pandemic''' began in [[Indonesia]], called [[El Tor]] after the strain, and reached [[Bangladesh]] in 1963, India in 1964, and the USSR in 1966. From [[North Africa]] it spread into Italy by 1973. In the late 1970s there were small outbreaks in Japan and in the South Pacific. There were also many reports of a cholera outbreak near [[Baku]] in 1972, but information of this was suppressed in the USSR.
* 1961-1970s - '''Seventh Cholera pandemic''' began in [[Indonesia]], called [[El Tor]] after the strain, and reached [[Bangladesh]] in 1963, India in 1964, and the USSR in 1966. From [[North Africa]] it spread into Italy by 1973. In the late 1970s there were small outbreaks in Japan and in the South Pacific. There were also many reports of a cholera outbreak near [[Baku]] in 1972, but information about this was suppressed in the USSR.
* January 1991 to September 1994 - Outbreak in [[South America]], apparently initiated by ship discharged ballast water. Beginning in [[Peru]] there were 1.04 million identified cases and almost 10,000 deaths. The causative agent was an O1, El Tor strain, with small differences to the seventh pandemic strain. In 1992 a new strain appeared in Asia, a non-O1, [[nonagglutinable vibrio]] (NAG) named O139 Bengal. It was first identified in [[Tamilnadu]], India and for a while displaced El Tor in southern Asia before decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate between El Tor and the classic strain and occurs in a new serogroup. There is evidence as to the emergence of wide-spectrum resistance to drugs such as [[trimethoprim]], [[sulfamethoxazole]] and [[streptomycin]].
* January 1991 to September 1994 - Outbreak in [[South America]], apparently initiated by ship discharged ballast water. Beginning in [[Peru]] there were 1.04 million identified cases and almost 10,000 deaths. The causative agent was an O1, El Tor strain, with small differences to the seventh pandemic strain. In 1992 a new strain appeared in Asia, a non-O1, [[nonagglutinable vibrio]] (NAG) named O139 Bengal. It was first identified in [[Tamilnadu]], India and for a while displaced El Tor in southern Asia before decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate between El Tor and the classic strain and occurs in a new serogroup. There is evidence as to the emergence of wide-spectrum resistance to drugs such as [[trimethoprim]], [[sulfamethoxazole]] and [[streptomycin]].


=== Famous cholera victims ===
=== Famous cholera victims ===
The crying and pathos in the last movement of [[Pyotr Ilyich Tchaikovsky|Tchaikovsky]]'s last symphony made people think that Tchaikovsky had a premonition of death. "A week after the premiere of his [[Symphony No. 6 (Tchaikovsky)|Sixth Symphony]], Tchaikovsky was dead--6 Nov. 1893. The cause of this indisposition and stomach ache was suspected to be his intentionally infecting himself with cholera by drinking contaminated water. The day before while having lunch with [[Modest Tchaikovsky|Modest]] (his brother and biographer), he is said to have poured faucet water from a pitcher into his glass and drunk a few swallows. Since the water was not boiled and cholera was once again rampaging [[Saint Petersburg, Russia|St. Petersburg]], such a connection was quite plausible ...."<ref name=Neumayr>Meumayr A (1997). ''Music and Medicine: Chopin, Smetana, Tchaikovsky, Mahler : Notes on Their Lives, Works, and Medical Histories.'' Med-Ed Press: pp. 282-283 (summarizing various theories on what killed the composer [[Pyotr Ilyich Tchaikovsky|Tchaikovsky]], including his brother [[Modest Tchaikovsky|Modest]]'s idea that Tchaikovksy drank cholera infested water the day before he became ill).</ref>
The crying and pathos in the last movement of [[Pyotr Ilyich Tchaikovsky|Tchaikovsky]]'s last symphony made people think that Tchaikovsky had a premonition of death. "A week after the premiere of his [[Symphony No. 6 (Tchaikovsky)|Sixth Symphony]], Tchaikovsky was dead--6 Nov. 1893. The cause of this was suspected to be his intentionally infecting himself with cholera by drinking contaminated water. The day before while having lunch with Modest (his brother and biographer), he is said to have poured faucet water from a pitcher into his glass and drunk a few swallows. Since the water was not boiled and cholera was once again rampaging [[Saint Petersburg, Russia|St. Petersburg]], such a connection was quite plausible ...."<ref name=Neumayr>Meumayr A (1997). ''Music and Medicine: Chopin, Smetana, Tchaikovsky, Mahler : Notes on Their Lives, Works, and Medical Histories.'' Med-Ed Press: pp. 282-283 (summarizing various theories on what killed the composer [[Pyotr Ilyich Tchaikovsky|Tchaikovsky]], including his brother Modest's idea that Tchaikovksy drank cholera infested water the day before he became ill).</ref>
 
Other famous people who succumbed to the disease include:
 
* [[James K. Polk]] ex-President of the United States
* [[Mary Abigail Fillmore]], daughter of U.S. president [[Millard Fillmore]]
* Elliott Frost, son of American poet Robert Frost
* [[Nicolas Léonard Sadi Carnot]]
* [[Georg Wilhelm Friedrich Hegel]]
* Samuel Charles Stowe, son of [[Harriet Beecher Stowe]]
* [[Carl von Clausewitz]]
* [[George Bradshaw]]
* [[Adam Mickiewicz]]
* [[August von Gneisenau]]
* [[William Jenkins Worth]]
* [[John Blake Dillon]]
* Daniel Morgan Boone, founder of [[Kansas City, Missouri]], son of [[Daniel Boone]]
* [[James Clarence Mangan]]
* Mohammad Ali Mirza [[Dowlatshahi]] of [[Persia]]
* [[Ando Hiroshige]], Japanese ukiyo-e woodblock print artist.
* Juan de Veramendi, Mexican Governor of Texas, father-in-law of [[Jim Bowie]]
* [[Grand Duke Constantine Pavlovich of Russia]]
* William Shelley, son of [[Mary Shelley]]
* William Godwin, father of [[Mary Shelley]]
* Judge Daniel Stanton Bacon, father-in-law of [[George Armstrong Custer]]
* [[Inessa Armand]], mistress of [[Lenin]] and the mother of Andre, his son.
* [[Honinbo Shusaku]], famous go player renowned for his play.
 
[[Alexandre Dumas, père]], French author of [[The Three Musketeers]] and [[The Count of Monte Cristo]], also contracted cholera in the 1832 Paris epidemic and almost died, before he wrote these two novels.


=== Research ===
=== Research ===
The major contributions to fighting cholera were made by physician and self-trained scientist [[John Snow (physician)|John Snow]] (1813-1858), who found the link between cholera and contaminated drinking water in [[1854]] and Henry Whitehead, an Anglican minister, who helped John Snow track down and verify the source of the disease, an infected well in London. Their conclusions and writings were widely distributed and firmly established for the first time a definite link between germs and disease. Clean water and good sewage treatment, despite their major engineering and financial cost, slowly became a priority throughout the major developed cities in the world from this time onward. [[Robert Koch]], 30 years later, identified ''V. cholerae'' with a microscope as the bacillus causing the disease in 1885. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist [[Filippo Pacini]], but its exact nature and his results were not widely known around the world.
The major contributions to fighting cholera were made by physician [[John Snow]] (1813-1858), who found the link between cholera and contaminated drinking water in 1854 and Henry Whitehead, an Anglican minister, who helped John Snow track down the source of the disease to an infected well in London. Their conclusions established a definite link between germs and disease. Clean water and good sewage treatment, despite their cost, slowly became a priority throughout the major developed cities in the world from this time onward. [[Robert Koch]], 30 years later, identified ''V. cholerae'' as the bacillus causing the disease in 1885. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist [[Filippo Pacini]], but his results were not widely known.
 
Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in [[British India]] was partitioned into [[West Bengal]] (a state in India) and [[East Pakistan]] in 1947. Prior to partition, both regions had cholera pathogens with similar characteristics. After 1947, India made more progress on public health than East Pakistan (now [[Bangladesh]]). As a consequence, the strains of the pathogen which succeeded in India had a greater incentive in the longevity of the host and are less virulent than the strains prevailing in Bangladesh, which uninhibitedly draw upon the resources of the host population, thus rapidly killing many in it.


=== Other historical information ===
=== Other historical information ===
In the past, people travelling in ships would hang a yellow flag if one or more of the crew members suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an extended period of time, typically 30 to 40 days.<ref>{{cite journal | author =  Mackowiak PA | title = The Origin of Quarantine | journal = Clinical Infectious Diseases | year = 2002 | volume = 35 | pages = 1071&ndash;2 | url=http://www.journals.uchicago.edu/CID/journal/issues/v35n9/020760/020760.html }}</ref>
In the past, people travelling in ships would hang a yellow flag if one or more of the crew members suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an extended period of time, typically 30 to 40 days.<ref>{{cite journal | author =  Mackowiak PA | title = The origin of quarantine | journal = Clin Infect Dis | year = 2002 | volume = 35 | pages = 1071&ndash;2 | url=http://www.journals.uchicago.edu/CID/journal/issues/v35n9/020760/020760.html }}</ref>


==False report of cholera==
A persistent myth states that 90,000 people died in Chicago of cholera and [[typhoid fever]] in 1885. This has no factual basis. In 1885, a torrential rainstorm flushed the Chicago river and its attendant pollutants far enough into Lake Michigan that the city's water supply was contaminated. Fortunately, cholera was not present in the city and this is not known to have caused any deaths. It did, however, cause the city to become more serious about their sewage treatment.
A persistent myth states that [[Chicago 1885 cholera epidemic myth|90,000 people died in Chicago]] of cholera and [[typhoid fever]] in 1885. This story has no factual basis. In 1885 there was a torrential rainstorm that flushed the Chicago river and its attendant pollutants into Lake Michigan far enough that the city's water supply was contaminated. Fortunately, cholera was not present in the city and this is not known to have caused any deaths. It did, however, cause the city to become more serious about their sewage treatment.


== References ==
== References ==
 
{{Reflist|2}}[[Category:Suggestion Bot Tag]]
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== External links ==
{{commonscat|Cholera}}
 
* [http://www.who.int/cholera Cholera] - [[World Health Organization]]
* [http://www.cdc.gov/ncidod/dbmd/diseaseinfo/cholera_g.htm What is Cholera?] - [[Centers for Disease Control and Prevention]]
* [http://www2.ncid.cdc.gov/travel/yb/utils/ybGet.asp?section=dis&obj=cholera.htm Cholera information for travelers] - Centers for Disease Control and Prevention
* Steven Shapin, [http://www.newyorker.com/printables/critics/061106crbo_books "Sick City: Maps and mortality in the time of cholera"], [[The New Yorker]] May 2006. A review of Steven Johnson, “The Ghost Map: The Story of London’s Most Terrifying Epidemic — and How It Changed Science, Cities, and the Modern World”
*[http://www.itas.fzk.de/tatup/043/turn04a.htm short paper contrasting official responses to cholera in Hamburg, Soho and New York.]
* Kelley Lee and Richard Dogson, "Globalization and Cholera: implications for global governance." in Global Governance, 6:2 (Apr-June 2000)

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Cholera (or Asiatic cholera or epidemic cholera) is a severe diarrheal disease caused by the bacterium Vibrio cholerae.[1] and transmitted to people by ingesting contaminated water or food. The major reservoir for cholera was long thought to be humans, but some evidence suggests that it is the aquatic environment. It can kill if untreated, but often responds well to simple supportive treatment such as oral rehydration therapy.

V. cholerae is a Gram-negative bacteria which produces cholera toxin, an enterotoxin, whose effects on the mucosal epithelium lining of the small intestine cause massive diarrhea.[1] In its most severe forms, cholera is one of the most rapidly lethal illnesses known: A healthy person may become hypotensive within an hour of the first symptoms and may die within 2-3 hours if no treatment is provided.[1] More often, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without rehydration treatment.[2][3]

U.S. National Intelligence Council and CIA studies consider it a threat to world stability. It is on the CDC Bioterrorism Agents-Disease list.

Symptoms

Symptoms include general GI tract (stomach) upset, and massive watery diarrhea. There can be severe muscle and stomach cramps, vomiting and fever in the early stages. Later, the diarrhea becomes "rice water stool" (almost clear with flecks of white) and ruptured capillaries may turn the skin black and blue with sunken eyes and cheeks with blue lips. Symptoms are caused by massive body fluid loss induced by the enterotoxins that V. cholerae produces. The main enterotoxin, cholera toxin, interacts with G proteins and cyclic AMP in the intestinal lining to open ion channels. As ions flow into the intestinal lumen (lining), body fluids flow out of the body due to osmosis leading to diarrhea as the fluid is expelled from the body. The body is "tricked" into releasing massive amounts of fluid into the small intestine which shows up in up to 36 liters (or 20% of body weight) of liquid diarrhea in a six day period in adults with accompanying severe dehydration.[4] Radical dehydration can bring death within a day through collapse of the circulatory system.

Treatment

Treatment typically consists of aggressive rehydration (restoring the lost body fluids) and replacement of electrolytes with commercial or hand-mixed sugar-salt solutions (1 tsp salt + 8 tsp sugar in 1 litre of clean/boiled water) or massive injections of liquid given intravenously via an IV in advanced cases. In general, patients must receive as much fluid as they lose, which can be up to 20 L. See: Oral rehydration therapy for easily made rehydration solutions and Ceralyte. Without rehydration, the death rate can be as high as 10-50%.

Tetracycline antibiotics may reduce the duration and severity of cholera, although drug-resistance is an increasing problem,[5] and their effects on overall mortality are questioned.[6] Other antibiotics that have been used include ciprofloxacin and azithromycin,[7] although again, drug-resistance has now been described.[8]

Without treatment the death rate is as high as 50%; with treatment the death rate can be well below 1%.[9]

Epidemiology

Prevention

Although cholera can be life-threatening, it is nearly always easily prevented, in principle, if proper sanitation practices are followed. In the U.S.A. and Western Europe, because of advanced water treatment and sanitation systems, cholera is no longer a major threat. The last major outbreak of cholera in the U.S.A. was in 1911. However, everyone, especially travellers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation, if instituted in time, is usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:

  • Sickbed: Proper disposal and treatment of infected fecal waste (and all clothing and bedding that come in contact with it) produced by cholera victims is of primary importance.
  • Sewage: Treatment of general sewage before it enters the waterways or underground water supplies prevent possible undetected patients from spreading the disease.
  • Sources: Warnings about cholera contamination posted around contaminated water sources with directions on how to decontaminate the water.
  • Sterilization: Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections, when they do occur, from spreading. All materials (clothing, bedding, etc.) that come in contact with cholera patients should be sterilized in hot water using (if possible) chlorine bleach. Hands, etc. that touch cholera patients or their clothing etc. should be thoroughly cleaned and sterilized. All water used for drinking, washing or cooking should be sterilized by boiling or chlorination in any area where cholera may be present. Water filtration, chlorination and boiling are by far the most effective means of halting transmission. Cloth filters, though very basic, have greatly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water. In general, public health education and good sanitation are the limiting factors in preventing transmission.

Susceptibility

Recent epidemiologic research suggests that susceptibility to cholera (and other diarrheal infections) is affected by blood type: Those with type O blood are most susceptible,[10][11] while those with type AB are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B.

About one million V. cholerae bacteria must typically be ingested to cause cholera in normally healthy adults, although increased susceptibility may be observed in those with a weakened immune system, individuals with decreased gastric acidity (as from the use of antacids), or those who are malnourished.

It has also been hypothesized that the cystic fibrosis genetic mutation has been maintained in humans due to a selective advantage: heterozygous carriers of the mutation (who are thus not affected by cystic fibrosis) are more resistant to V. cholerae infections.[12] In this model, the genetic deficiency in the cystic fibrosis transmembrane conductance regulator channel proteins interferes with bacteria binding to the gastrointestinal epithelium, thus reducing the effects of an infection.

Transmission

Persons infected with cholera have severe diarrhea, loaded with bacteria that can spread to infect water supplies: cholera is transmitted from person to person mainly through ingestion of this contaminated water, and only rarely spread directly from person to person. Any infected water and any foods washed in the water, and shellfish living in the affected waterway can cause an infection. V. cholerae occurs naturally in the plankton of fresh, brackish, and salt water, attached primarily to copepods in the zooplankton. Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage.[13] Coastal cholera outbreaks typically follow zooplankton blooms. This makes cholera a zoonosis.

Biochemistry of the V. cholerae bacterium

Most of the V. cholerae bacteria in contaminated water do not survive the acidic conditions of the human stomach [14] But the few bacteria that survive the stomach's acidity conserve their energy and stored nutrients during the passage through the stomach by shutting down much protein production. When the surviving bacteria exit the stomach and reach the small intestine, they need to propel themselves through the thick mucus that lines the small intestine to get to the intestinal wall where they can thrive. So they start producing the hollow cylindrical protein flagellin to make flagella, the curly whip-like tails that they rotate to propel themselves through the pasty mucus that lines the small intestine.

Once the bacteria reach the intestinal wall, they stop producing flagellin and start producing the toxic proteins that give the infected person a watery diarrhea which carries the multiplying and thriving new generations of V. cholerae bacteria.

Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off the production of some proteins and turn on the production of others as they pass through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall.[15] Of particular interest have been the genetic mechanisms by which the bacteria turn on production of the toxins that interact with host cell mechanisms to pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The choride and sodium ions create a salt water environment in the small intestine which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive diarrhea.[4]

By inserting separately successive sections of V. cholerae DNA into the DNA of other bacteria such as E. coli that do not naturally produce the protein toxins, have found the mechanisms by which V. cholerae respond to the changing chemical environments of the stomach, mucous layers, and intestinal wall. A complex cascade of regulatory proteins controls expression of V. cholerae virulence determinants. In responding to the chemical environment at the intestinal wall, the V. cholerae bacteria produce the TcpP/TcpH proteins which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins that cause diarrhea and that permit the bacteria to colonize the intestine.[15]Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize the small intestine."[14]

History

Origin and Spread

Cholera was originally endemic to the Indian subcontinent, with the Ganges River likely serving as a contamination reservoir. It spread by trade routes (land and sea) to Russia, then to Western Europe, and from Europe to North America. It is now no longer considered an issue in Europe and North America, due to filtering and chlorination of the water supply.

  • 1816-1826 - First Cholera pandemic: Previously restricted, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
  • 1829-1851 - Second Cholera pandemic reached Europe, London and Paris in 1832. In London, it claimed 6,536 victims (see: http://www.mernick.co.uk/thhol/1832chol.html); in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all of France [3]. It reached Russia (Cholera Riots), Quebec, Ontario and New York in the same year and the Pacific coast of North America by 1834.
  • 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming 14,137 lives, ten times as many as the 1832 outbreak. In 1849 cholera claimed 5,308 lives in the port city of Liverpool England and 1,834 in Hull England. [16] An outbreak in North America took the life of former U.S. President James K. Polk. Cholera spread throughout the Mississippi river system killing over 4,500 in St. Louis [4] and over 3,000 in New Orleans [5] as well as thousands in New York [17] In 1849, cholera was spread along the California and Oregon trail as hundreds died on their way to the California Gold Rush, Utah and Oregon. [18]
  • 1852-1860 - Third Cholera pandemic mainly affected Russia, with over a million deaths. In 1853-4, London's epidemic claimed 10,738 lives.
  • 1854 - Outbreak of cholera in Chicago took the lives of 5.5 per cent of the population (about 3,500 people).[6]. Soho outbreak in London stopped by removing the handle of the Broad Street pump by a committee instigated to action by John Snow (1813-1858) .[19]
  • 1863-1875 - Fourth Cholera pandemic spread mostly in Europe and Africa.
  • 1866 - Outbreak in North America. In London, a localized epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water treatment systems--the East End was not quite complete. William Farr, using the work of John Snow as to contaminated drinking water being the likely source of the disease, quickly identified the East London Water Company as the source of the contaminated water. Swift action prevented further deaths. [20]
  • 1881-1896 - Fifth Cholera pandemic ; The 1892 outbreak in Hamburg, Germany was the only major European outbreak, about 8,600 died, causing a major political upheaval in Germany, as control over the city was removed from a City Council which had not updated Hamburg's water supplies. This was the last serious European cholera outbreak.
  • 1899-1923 - Sixth Cholera pandemic had little effect in Europe because of advances in public health, but Russia was badly affected again.
  • 1961-1970s - Seventh Cholera pandemic began in Indonesia, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966. From North Africa it spread into Italy by 1973. In the late 1970s there were small outbreaks in Japan and in the South Pacific. There were also many reports of a cholera outbreak near Baku in 1972, but information about this was suppressed in the USSR.
  • January 1991 to September 1994 - Outbreak in South America, apparently initiated by ship discharged ballast water. Beginning in Peru there were 1.04 million identified cases and almost 10,000 deaths. The causative agent was an O1, El Tor strain, with small differences to the seventh pandemic strain. In 1992 a new strain appeared in Asia, a non-O1, nonagglutinable vibrio (NAG) named O139 Bengal. It was first identified in Tamilnadu, India and for a while displaced El Tor in southern Asia before decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate between El Tor and the classic strain and occurs in a new serogroup. There is evidence as to the emergence of wide-spectrum resistance to drugs such as trimethoprim, sulfamethoxazole and streptomycin.

Famous cholera victims

The crying and pathos in the last movement of Tchaikovsky's last symphony made people think that Tchaikovsky had a premonition of death. "A week after the premiere of his Sixth Symphony, Tchaikovsky was dead--6 Nov. 1893. The cause of this was suspected to be his intentionally infecting himself with cholera by drinking contaminated water. The day before while having lunch with Modest (his brother and biographer), he is said to have poured faucet water from a pitcher into his glass and drunk a few swallows. Since the water was not boiled and cholera was once again rampaging St. Petersburg, such a connection was quite plausible ...."[21]

Research

The major contributions to fighting cholera were made by physician John Snow (1813-1858), who found the link between cholera and contaminated drinking water in 1854 and Henry Whitehead, an Anglican minister, who helped John Snow track down the source of the disease to an infected well in London. Their conclusions established a definite link between germs and disease. Clean water and good sewage treatment, despite their cost, slowly became a priority throughout the major developed cities in the world from this time onward. Robert Koch, 30 years later, identified V. cholerae as the bacillus causing the disease in 1885. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist Filippo Pacini, but his results were not widely known.

Other historical information

In the past, people travelling in ships would hang a yellow flag if one or more of the crew members suffered from cholera. Boats with a yellow flag hung would not be allowed to disembark at any harbor for an extended period of time, typically 30 to 40 days.[22]

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885. This has no factual basis. In 1885, a torrential rainstorm flushed the Chicago river and its attendant pollutants far enough into Lake Michigan that the city's water supply was contaminated. Fortunately, cholera was not present in the city and this is not known to have caused any deaths. It did, however, cause the city to become more serious about their sewage treatment.

References

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  2. McLeod K (2000). "Our sense of Snow: John Snow in medical geography". Soc Sci Med 50: 923-35. PMID 10714917.
  3. WHO Cholera [1]
  4. 4.0 4.1 Rabbani GH (1996). "Mechanism and treatment of diarrhoea due to Vibrio cholerae and Escherichia coli: roles of drugs and prostaglandins". Danish medical bulletin 43: 173-85. PMID 8741209.
  5. Bhattacharya SK, National Institute of Cholera and Enteric Diseases (2003). "An evaluation of current cholera treatment". Expert Opin Pharmacother 4: 141-6. PMID 12562304.
  6. Parsi VK (2001). "Cholera". Prim. Care Update Ob Gyns 8: 106-109. PMID 11378428.
  7. Saha D et al. (2006). "Single dose azithromycin for the treatment of cholera in adults". New Engl J Med 354: 2452–62.
  8. Krishna BVS et al. (2006). "Fluoroquinolone-resistant Vibrio cholerae isolated during a cholera outbreak in India". Trans R Soc Trop Med Hyg 100: 224–26. DOI:10.1016/j.rstmh.2005.07.007. Research Blogging.
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  10. Swerdlow D et al. (1994). "Severe life-threatening cholera associated with blood group O in Peru: implications for the Latin American epidemic". J Infect Dis 170: 468-72. PMID 8035040.
  11. Harris J et al. (2005). "Blood group, immunity, and risk of infection with Vibrio cholerae in an area of endemicity". Infect Immun 73: 7422-7. PMID 16239542.
  12. Bertranpetit J, Calafell F (1996). "Genetic and geographical variability in cystic fibrosis: evolutionary considerations". Ciba Found Symp 197: 97-114; discussion 114-8. PMID 8827370.
  13. Archivist (1997). "Cholera phage discovery". Arch Dis Child 76: 274.
  14. 14.0 14.1 Hartwell LH et al.(2004). Genetics: From Genes to Genomes. Mc-Graw Hill, Boston: p. 551-2, 572-4 (using the turning off and turning on of gene expression to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing chemical environments).
  15. 15.0 15.1 DiRita V et al. (1991). "Regulatory cascade controls virulence in Vibrio cholerae". Proc Natl Acad Sci U S A 88: 5403-7. PMID 2052618.
  16. IBMS Institute of Biological Science [2]
  17. The Cholera Years: The United States in 1832, 1849, and 1866 by Charles E. Rosenberg
  18. Trails of Hope: California, Oregon and Mormon Trails
  19. On the Mode of Communication of Cholera(1855) by John Snow, M.D.
  20. "The Ghost Map" by Steven Johnson, pg. 209
  21. Meumayr A (1997). Music and Medicine: Chopin, Smetana, Tchaikovsky, Mahler : Notes on Their Lives, Works, and Medical Histories. Med-Ed Press: pp. 282-283 (summarizing various theories on what killed the composer Tchaikovsky, including his brother Modest's idea that Tchaikovksy drank cholera infested water the day before he became ill).
  22. Mackowiak PA (2002). "The origin of quarantine". Clin Infect Dis 35: 1071–2.