Vibrio cholerae: The bacterium that causes cholera (SEM image)
Cholera, also called Asiatic cholera or epidemic cholera, is a severe diarrheal disease that affects humans and is caused by the bacterium Vibrio cholerae. Cholera is transmitted and spread to humans through consumption of water and food contaminated with the bacteria.
Cholera is a fairly preventable disease, traced to both personal and human responsibility. Contamination with the bacteria Vibrio cholerae most often occurs due to a lack of proper sanitation (clean water). Infected human feces in the water supply can spread the disease, as can crops treated with infected human feces. Certain seafood, if eaten raw or undercooked and obtained from contaminated water supplies, can contain the bacteria as well. Rarely is cholera spread by human to human contact. Both personal actions (such as good hygiene, boiling and filtering water, care regarding foods consumed, etc.) and social actions (sewage treatment, water chlorination, warnings around contaminated water sources, etc.) can prevent disease outbreaks.
Cholera is an acute illness, meaning that it has a sudden onset and a tendency to have a short course. In its most severe forms, cholera is one of the most rapidly fatal illnesses known if no treatment is provided. Fortunately, however, the cholera disease is not only preventable but also treatable with re-hydration and antibiotics.
Cholera is no longer a major health threat in the United States and other developed countries due to the enforcement of proper sanitation practices. Developing countries, on the other hand, continuously face the threat of cholera outbreaks. Referred to as a "poor man's disease," cholera is actively found in third world countries like India, Pakistan, Cambodia, and so forth. According to the World Health Organization, a single outbreak of cholera in these countries can affect anywhere from 0.2-1 percent of the local population.
The term, "cholera" is also used to refer to a variety of diseases that affect domestic animals. Characterized by severe gastroenteritis, these diseases affect animals such as hogs, chickens, and turkeys.
Symptoms of the cholera disease usually manifest one to three days after ingestion of contaminated food or water. Most cases of cholera are mild; however, one in 20 patients will suffer severe symptoms. Symptoms include those of the general gastrointestinal tract (GI tract), specifically upset stomach and massive, watery diarrhea. Symptoms may also include terrible muscle and stomach cramps, along with vomiting and fever in the early stages. In later stages of the disease, the diarrhea typically becomes "rice water stool" (almost clear with flecks of white) and ruptured capillaries may turn the skin black and blue. Sunken eyes and cheeks, with blue lips, are also commonly seen.
Cholera symptoms are caused by massive body fluid loss induced by the enterotoxins that V. cholerae produces. Enterotoxins are frequently cytotoxic and kill cells by altering the permeability of the epithelial cells of the intestinal wall by creating more pores in the cell membranes. V. cholerae, which produces the cholera toxin, is a Gram negative, anaerobic, rod-shaped bacterium. The enterotoxin acts on the mucosal epithelium lining of the small intestine and is responsible for the characteristic massive diarrhea of the disease.
The cholera toxin interacts with G proteins and cyclic AMP in the intestinal lining to open ion channels and alter cell permeability. As ions flow into the intestinal lumen (lining), body fluids (mostly water) flow out of the body due to the principle of osmosis. This leads 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 20 liters (or 20 percent of body weight) of liquid diarrhea in an adult, resulting in massive dehydration. This radical dehydration can bring death within a day through collapse of the circulatory system.
Anyone can get cholera; however, infants, children, and the elderly are more susceptible to the fatal consequences of cholera since they become dehydrated faster.
In its most severe forms, cholera is one of the most rapidly fatal illnesses known if no treatment is provided: A healthy person may become hypotensive within an hour of the onset of symptoms and may die within 2-3 hours. More commonly, however, without rehydration treatment, which is the most common treatment method, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days. Fortunately, the cholera disease is treatable. In general, patients must receive as much fluid as they lose, which can be up to twenty liters, due to diarrhea.
Treatment of cholera typically consists of aggressive rehydration to replace lost fluids and electrolytes with commercial or hand-mixed sugar-salt solutions. A 1 teaspoon (tsp) salt + 8 tsp sugar in 1 liter of clean/boiled water is commonly used. This simple and cost-effective solution created by the World Health Organization for oral rehydration has proven useful as a treatment method not only for cholera but other similar diseases. Massive injections of liquid given intravenously via an IV are used in advanced cases of dehydration. Without rehydration, the death rate can be as high as 10-50 percent, due to the serious dehydration that cholera produces.
Tetracycline antibiotics, used usually only in more severe cases, may have a role in reducing the duration and severity of cholera, although drug-resistance is beginning to occur, and their effects on overall mortality are questioned. Other antibiotics that have been used include ciprofloxacin and azithromycin, although again, drug-resistance has now been described.
Without treatment the death rate from cholera is as high as 50 percent; but with treatment, the death rate can be well below 1 percent. Typical recovery time for patients is between three and six days.
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 travelers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation practices, if instituted in time, are usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:
In general, public health education and good sanitation practices are the limiting factors in preventing transmission.
A vaccine is available for travelers and residents of areas where cholera is known to be an active threat. Unfortunately, it is not very effective. Currently, the United States Center for Disease Control and Prevention (CDCP) does not recommend the vaccine for travelers, since it, at most, provides 25-50 percent immunity against the disease for a maximum of up to six months. The practice of proper sanitation methods and common precautions discussed above are advised.
Recent epidemiological research suggests that an individual's susceptibility to cholera (and other diarrheal infections) is affected by their blood type: Those with type O blood are the most susceptible, while those with type AB blood are the most resistant.
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. V. cholerae are sensitive to acid, and the stomach's acidic environment serves as the first line of defense against the cholera disease. Decreased acidity due to a weak immune system or use of medications that decrease or block acid production in the stomach promote V. cholerae survival and cause more severe symptoms of the disease.
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. 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.
Cholera is rarely spread directly from one person to another, but rather through the fecal-oral route. Persons infected with cholera endure 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 sources used by other people. Cholera is transmitted through population centers by the ingestion of feces-contaminated water that is 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, groundwater, or the drinking water supply, the bacteria spreads easily and rapidly.
Also, any infected water and any foods washed in the water can cause an infection. Shellfish populations living in the affected waterway is a common example. V. cholerae occurs naturally in the plankton of fresh, brackish (water that is saltier than fresh water, but not as salty as seawater), and salt waters, attached primarily to copepods in the zooplankton. Both toxic and non-toxic strains exist. Non-toxic strains, however, can acquire toxicity through a lysogenic bacteriophage. Coastal cholera outbreaks typically follow algal blooms. This makes cholera a zoonosis, or an infectious disease that is able to be transmitted from one type of animal to another, or from animals, both wild and domestic, to humans.
Most of the V. cholerae bacteria in the contaminated water that a potential host drinks do not survive the very acidic conditions of the human stomach. But the few bacteria that manage to survive the stomach's acidity conserve their energy and stored nutrients during the perilous passage through the stomach by shutting down much of their 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 mucus that lines the small intestine in order to get to the intestinal wall where they can thrive. So they start up production of the hollow cylindrical protein flagellin in order to make flagella, the curly whip-like tails that the bacteria 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. Responding to the changed chemical surroundings, they stop producing the protein flagellin and again conserve energy and nutrients by changing the mix of proteins that they manufacture. On reaching the intestinal wall, the bacteria 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—if proper sanitation measures are not in place.
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 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. Of particular interest have been the genetic mechanisms by which cholera bacteria switch on the protein production of the toxins that interact with host cell mechanisms which then 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 through which osmosis can pull up to 20 liters of water through the intestinal cells, which then creates the massive amounts of diarrhea. 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.
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 were able to 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 a complex cascade of regulatory proteins exists that controls the 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 the infected intestine. 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."
Cholera was originally endemic to the Indian subcontinent, with the Ganges River likely serving as a contamination reservoir. It spread by trade routes (both land and sea) to Russia, then to Western Europe, and then from Europe to North America. It is now no longer considered an issue in Europe and North America, due to water filtration and chlorination of the water supply.
A persistent myth states that the 1885 epidemic in Chicago killed 90,000 people from cholera and typhoid fever. 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.
In the past, people traveling 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.
Cholera has claimed the lives of several well known people over its long history. Some were positively affected by the disease while others have only been speculated to have passed away due to cholera. For example, the crying and pathos in the last movement of Pyotr Ilyich 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 (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, such a connection was quite plausible …."
Other famous people who succumbed to the cholera disease include:
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.
The major contributions to fighting cholera were made by physician and self-trained scientist John Snow (1813-1858), who found the link between cholera and contaminated drinking water in 1854, and also by 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 in 1885, identified V. cholerae with a microscope as the bacillus causing the disease. 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.
Cholera has been used in the laboratory for the study of the evolution of virulence.
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