Cholera

Cholera is an of the  by some  of the  . Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery that lasts a few days. and may also occur. Diarrhea can be so severe that it leads within hours to severe and. This may result in, cold skin, decreased skin elasticity, and wrinkling of the hands and feet. Dehydration can cause the skin to turn. Symptoms start two hours to five days after exposure.

Cholera is caused by a number of of Vibrio cholerae, with some types producing more severe disease than others. It is spread mostly by and  that has been contaminated with  containing the bacteria. Undercooked is a common source. Humans are the only animal affected. for the disease include poor, not enough clean , and. There are concerns that s will increase rates of disease. Cholera can be diagnosed by a. A rapid is available but is not as accurate.

Prevention methods against cholera include improved sanitation and access to. s that are given by mouth provide reasonable protection for about six months. They have the added benefit of protecting against another type of diarrhea caused by . The primary treatment is —the replacement of fluids with. Rice-based solutions are preferred. is useful in children. In severe cases, s, such as, may be required, and s may be beneficial. the cholera is susceptible to can help guide the choice.

Cholera affects an estimated 3–5 million people worldwide and causes 28,800–130,000 deaths a year. Although it is classified as a, it is rare in the. Children are mostly affected. Cholera occurs as both and. Areas with an ongoing risk of disease include and. The risk of death among those affected is usually less than 5% but may be as high as 50%. No access to treatment results in a higher death rate. Descriptions of cholera are found as early as the 5th century BC in. The study of cholera in England by between 1849 and 1854 led to significant advances in the field of. have occurred over the last 200 years with millions of deaths.

Signs and symptoms
The primary symptoms of cholera are profuse and  of clear fluid. These symptoms usually start suddenly, half a day to five days after ingestion of the bacteria. The diarrhea is frequently described as "rice water" in nature and may have a fishy odor. An untreated person with cholera may produce 10 to 20 litre of diarrhea a day. Severe cholera, without treatment, kills about half of affected individuals. If the severe diarrhea is not treated, it can result in life-threatening and  imbalances. Estimates of the ratio of to symptomatic infections have ranged from 3 to 100. Cholera has been nicknamed the "blue death" because a person's skin may turn from extreme loss of fluids.

Fever is rare and should raise suspicion for secondary infection. Patients can be lethargic, and might have sunken eyes, dry mouth, cold clammy skin, or wrinkled hands and feet. , a deep and labored breathing pattern, can occur because of from   losses and  associated with poor. drops due to dehydration, peripheral pulse is rapid and thready, and urine output decreases with time. Muscle cramping and weakness, altered consciousness,, or even due to s are common, especially in children.

Transmission
Cholera has been found in two animal populations: and.

is usually through the of contaminated food or water caused by poor. Most cholera cases in developed countries are a result of transmission by food, while in the developing world it is more often water. Food transmission can occur when people harvest seafood such as s in waters infected with, as Vibrio cholerae accumulates in ic and the oysters eat the.

People infected with cholera often have diarrhea, and disease transmission may occur if this highly liquid stool, colloquially referred to as "rice-water", contaminates water used by others. A single diarrheal event can cause a one-million fold increase in numbers of V. cholerae in the environment. The source of the contamination is typically other cholera sufferers when their untreated diarrheal discharge is allowed to get into waterways, or  supplies. Drinking any contaminated water and eating any foods washed in the water, as well as living in the affected, can cause a person to contract an infection. Cholera is rarely.

V. cholerae also exists outside the human body in natural water sources, either by itself or through interacting with, , or and  detritus. Drinking such water can also result in the disease, even without prior contamination through fecal matter. Selective pressures exist however in the aquatic environment that may reduce the virulence of V. cholerae. Specifically, animal models indicate that the transcriptional profile of the pathogen changes as it prepares to enter an aquatic environment. This transcriptional change results in a loss of ability of V. cholerae to be cultured on standard media, a phenotype referred to as  (VBNC) or more conservatively  (ABNC). One study indicates that the culturability of V. cholerae drops 90% within 24 hours of entering the water, and furthermore that this loss in culturability is associated with a loss in virulence.

Both toxic and non-toxic strains exist. Non-toxic strains can acquire through a.

Susceptibility
About 100million bacteria must typically be ingested to cause cholera in a normal healthy adult. This dose, however, is less in those with lowered ity (for instance those using ). Children are also more susceptible, with two- to four-year-olds having the highest rates of infection. Individuals' susceptibility to cholera is also affected by their, with those with being the most susceptible. Persons with, such as persons with or  children, are more likely to experience a severe case if they become infected. Any individual, even a healthy adult in middle age, can experience a severe case, and each person's case should be measured by the loss of fluids, preferably in consultation with a professional.

The genetic  known as  in humans has been said to maintain a selective :  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 channel proteins interferes with bacteria binding to the, thus reducing the effects of an infection.

Mechanism
When consumed, most bacteria do not survive the conditions of the. The few surviving bacteria conserve their energy and stored s during the passage through the stomach by shutting down production. When the surviving bacteria exit the stomach and reach the, they must propel themselves through the thick that lines the small intestine to reach the intestinal walls where they can attach and thrive.

Once the cholera bacteria reach the intestinal wall, they no longer need the to move. The bacteria stop producing the protein to conserve energy and nutrients by changing the mix of proteins which they express in response to the changed chemical surroundings. On reaching the intestinal wall, V. cholerae start producing the that give the infected person a watery diarrhea. This carries the multiplying new generations of V. cholerae bacteria out into the drinking water of the next host if proper sanitation measures are not in place.

The (CTX or CT) is an ic complex made up of six s: a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a. The five B subunits form a five-membered ring that binds to s on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that s, while the A2 chain fits into the central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated. Once inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human partner protein called (Arf6). Binding exposes its active site, allowing it to permanently ribosylate the of the. This results in constitutive production, which in turn leads to the secretion of water, sodium, potassium, and bicarbonate into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin was introduced into V. cholerae by. Virulent strains of V. cholerae carry a variant of a  called.

Microbiologists have studied the 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 turn on the protein production of the toxins that interact with host cell mechanisms to pump ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride 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. The host can become rapidly dehydrated unless an appropriate mixture of dilute salt water and sugar is taken to replace the blood's water and salts lost in the diarrhea.

By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria, such as  that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which V. cholerae responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered a complex cascade of regulatory proteins controls expression of V. cholerae 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 genes that produce the toxins, causing diarrhea in the infected person and allowing the bacteria to colonize the 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."

Genetic structure
of the pandemic of V. cholerae has revealed variation in the genetic structure. Two have been identified: Cluster I and Cluster II. For the most part, Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the strains from the African continent.

Antibiotic resistance
In many areas of the world, is increasing within cholera bacteria. In, for example, most cases are resistant to , , and. Rapid diagnostic methods are available for the identification of  cases. New generation antimicrobials have been discovered which are effective against cholera bacteria in in vitro studies.

Diagnosis
A rapid test is available to determine the presence of V. cholerae. In those samples that test positive, further testing should be done to determine antibiotic resistance. In situations, a clinical diagnosis may be made by taking a  and doing a brief examination. Treatment is usually started without or before confirmation by laboratory analysis.

Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is V. cholerae O1. If V. cholerae O1 is not isolated, the laboratory should test for V. cholerae O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory.

Infection with V. cholerae O139 should be reported and handled in the same manner as that caused by V. cholerae O1. The associated diarrheal illness should be referred to as cholera and must be reported in the United States.

Prevention
The (WHO) recommends focusing on prevention, preparedness, and response to combat the spread of cholera. They also stress the importance of an effective surveillance system. Governments can play a role in all of these areas.

Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper practices are followed. In, due to nearly universal advanced and sanitation practices present there, cholera is rare. For example, the last major outbreak of cholera in the United States occurred in 1910–1911. Cholera is mainly a risk in.

Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. There are several points along the cholera transmission path at which its spread may be halted:
 * Sterilization: Proper disposal and treatment of all materials that may have come into contact with cholera victims' feces (e.g., clothing, bedding, etc.) are essential. These should be by washing in hot water, using   if possible. Hands that touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with chlorinated water or other effective antimicrobial agents.
 * and : In cholera-affected areas, sewage and fecal sludge need to be treated and managed carefully in order to stop the spread of this disease via . Provision of and  is an important preventative measure., release of untreated sewage, or dumping of fecal sludge from s or s into the environment need to be prevented. In many cholera affected zones, there is a low degree of . Therefore, the implementation of s that do not contribute to , as they do not flush with water, may be an interesting alternative to s.
 * Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to the water (boiling, chlorination etc.) for possible use.
 * : All water used for drinking, washing, or cooking should be sterilized by either boiling,, ozone water treatment, ultraviolet light sterilization (e.g., by ), or antimicrobial filtration in any area where cholera may be present. Chlorination and boiling are often the least expensive and most effective means of halting transmission. s or , though very basic, have significantly reduced the occurrence of cholera when used in poor villages in that rely on untreated surface water. Better antimicrobial filters, like those present in advanced individual water treatment hiking kits, are most effective. Public health education and adherence to appropriate sanitation practices are of primary importance to help prevent and control transmission of cholera and other diseases.

with soap or ash after using a and before handling food or eating is also recommended for cholera prevention by WHO Africa.

Surveillance
Surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during. Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provides guidance for improving cholera control activities for the most vulnerable. For prevention to be effective, it is important that cases be reported to national health authorities.

Vaccine
A number of safe and effective oral vaccines for cholera are available. The World Health Organization (WHO) has three prequalified oral cholera vaccines (OCVs): Dukoral, Sanchol, and Euvichol. , an orally administered, inactivated whole cell vaccine, has an overall efficacy of about 52% during the first year after being given and 62% in the second year, with minimal side effects. It is available in over 60 countries. However, it is not currently recommended by the (CDC) for most people traveling from the United States to endemic countries. The vaccine that the (FDA) recommends,, is an ,  that is effective as a single dose.

One injectable vaccine was found to be effective for two to three years. The protective efficacy was 28% lower in children less than five years old. However,, it has limited availability. Work is under way to investigate the role of mass vaccination. The WHO recommends immunization of high-risk groups, such as children and people with, in countries where this disease is. If people are immunized broadly, results, with a decrease in the amount of contamination in the environment.

Sari filtration
An effective and relatively cheap method to prevent the transmission of cholera is the use of a folded  (a long cloth garment) to filter drinking water. In Bangladesh this practice was found to decrease rates of cholera by nearly half. It involves folding a sari four to eight times. Between uses the cloth should be rinsed in clean water and dried in the sun to kill any bacteria on it. A cloth appears to work as well but is not as affordable.

Treatment
Continued eating speeds the recovery of normal intestinal function. The WHO recommends this generally for cases of diarrhea no matter what the underlying cause. A CDC training manual specifically for cholera states: "Continue to breastfeed your baby if the baby has watery diarrhea, even when traveling to get treatment. Adults and older children should continue to eat frequently."

Fluids
The most common error in caring for patients with cholera is to underestimate the speed and volume of fluids required. In most cases, cholera can be successfully treated with (ORT), which is highly effective, safe, and simple to administer. Rice-based solutions are preferred to glucose-based ones due to greater efficiency. In severe cases with significant dehydration, rehydration may be necessary. is the preferred solution, often with added potassium. Large volumes and continued replacement until diarrhea has subsided may be needed. Ten percent of a person's body weight in fluid may need to be given in the first two to four hours. This method was first tried on a mass scale during the, and was found to have much success. Despite widespread beliefs, fruit juices and commercial fizzy drinks like cola, are not ideal for rehydration of people with serious infections of the intestines, and their excessive sugar content may even harm water uptake.

If commercially produced oral rehydration solutions are too expensive or difficult to obtain, solutions can be made. One such recipe calls for 1 liter of boiled water, 1/2 teaspoon of salt, 6 teaspoons of sugar, and added mashed banana for potassium and to improve taste.

Electrolytes
As there frequently is initially, the level may be normal, even though large losses have occurred. As the dehydration is corrected, potassium levels may decrease rapidly, and thus need to be replaced. This may be done by consuming foods high in potassium, like bananas or coconut water.

Antibiotics
treatments for one to three days shorten the course of the disease and reduce the severity of the symptoms. Use of antibiotics also reduces fluid requirements. People will recover without them, however, if sufficient hydration is maintained. The WHO only recommends antibiotics in those with severe dehydration.

is typically used first line, although some of V. cholerae have shown. Testing for resistance during an outbreak can help determine appropriate future choices. Other antibiotics proven to be effective include, , , , and. s, such as, also may be used, but resistance has been reported.

Antibiotics improve outcomes in those who are both severely and not severely dehydrated. and may work better than  or.

Zinc supplementation
In Bangladesh supplementation reduced the duration and severity of diarrhea in children with cholera when given with antibiotics and rehydration therapy as needed. It reduced the length of disease by eight hours and the amount of diarrhea stool by 10%. Supplementation appears to be also effective in both treating and preventing infectious diarrhea due to other causes among children in the developing world.

Prognosis
If people with cholera are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%.

For certain genetic strains of cholera, such as the one present during the and the 2004 outbreak in India, death can occur within two hours of becoming ill.

Epidemiology
Cholera affects an estimated 3–5 million people worldwide, and causes 58,000–130,000 deaths a year. This occurs mainly in the. In the early 1980s, death rates are believed to have been greater than three million a year. It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism of a country. Cholera remains both and endemic in many areas of the world. In October 2016, an began in war-ravaged. WHO called it "the worst cholera outbreak in the world".

Although much is known about the mechanisms behind the spread of cholera, this has not led to a full understanding of what makes cholera outbreaks happen in some places and not others. Lack of treatment of human and lack of treatment of drinking water greatly facilitate its spread, but bodies of water can serve as a, and seafood shipped long distances can spread the disease. Cholera was not known in the for most of the 20th century, but it reappeared towards the end of that century.

History
The word cholera is from χολέρα kholera from χολή kholē "bile". Cholera likely has its origins in the as evidenced by its prevalence in the region for centuries.

The disease appears in the European literature as early as 1642, from the Dutch physician  description it in his De Medicina Indorum. (The "Indorum" of the title refers to the East Indies. He also gave first European descriptions of other diseases.)

Early outbreaks in the Indian subcontinent are believed to have been the result of poor living conditions as well as the presence of pools of, both of which provide ideal conditions for cholera to thrive. The disease first spread by s (land and sea) to in 1817, later to the rest of, and from Europe to  and the rest of the world. Seven s have occurred in the past 200 years, with the seventh originating in  in 1961.

The occurred in the Bengal region of India, near Calcutta starting in 1817 through 1824. The disease dispersed from India to Southeast Asia, the Middle East, Europe, and Eastern Africa. The movement of British Army and Navy ships and personnel is believed to have contributed to the range of the pandemic, since the ships carried people with the disease to the shores of the Indian Ocean, from Africa to Indonesia, and north to China and Japan. The lasted from 1826 to 1837 and particularly affected North America and Europe due to the result of advancements in transportation and global trade, and increased human migration, including soldiers. The erupted in 1846, persisted until 1860, extended to North Africa, and reached South America, for the first time specifically affecting Brazil. The lasted from 1863 to 1875 spread from India to Naples and Spain. The pandemic was from 1881–1896 and started in India and spread to Europe, Asia, and South America. The started 1899–1923. These epidemics were less fatal due to a greater understanding of the cholera bacteria. Egypt, the Arabian peninsula, Persia, India, and the Philippines were hit hardest during these epidemics, while other areas, like Germany in 1892 and Naples from 1910–1911, also experienced severe outbreaks. The originated in 1961 in Indonesia and is marked by the emergence of a new strain, nicknamed El Tor, which still persists  in developing countries.

Since it became widespread in the 19th century, cholera has killed tens of millions of people. In alone, between 1847 and 1851, more than one million people perished of the disease. It killed 150,000 Americans during the second pandemic. Between 1900 and 1920, perhaps eight million people died of cholera in India. Cholera became the first in the United States due to the significant effects it had on health. , in, was the first to identify the importance of contaminated water as its cause in 1854. Cholera is now no longer considered a pressing health threat in Europe and North America due to and  of water supplies, but still heavily affects populations in.

In the past, vessels flew a yellow flag if any crew members or passengers were suffering from cholera. No one aboard a vessel flying a yellow flag would be allowed ashore for an extended period, typically 30 to 40 days. In modern sets of, the quarantine flag is yellow and black.

Historically many different claimed remedies have existed in folklore. Many of the older remedies were based on the. Some believed that abdominal chilling made one more susceptible and flannel and s were routine in army kits. In the 1854–1855 outbreak in Naples homeopathic was used according to. T. J. Ritter's "Mother's Remedies" book lists tomato syrup as a home remedy from northern America. was recommended in the United Kingdom according to William Thomas Fernie.

Cholera cases are much less frequent in developed countries where governments have helped to establish water sanitation practices and effective medical treatments. The United States, for example, used to have a severe cholera problem similar to those in some developing countries. There were three large cholera outbreaks in the 1800s, which can be attributed to Vibrio cholerae's spread through interior waterways like the Erie Canal and routes along the Eastern Seaboard. The island of Manhattan in New York City touched the Atlantic Ocean, where cholera collected just off the coast. At this time, New York City did not have as effective a sanitation system as it does today, so cholera was able to spread.

Cholera morbus is a historical term that was used to refer to rather than specifically cholera.

Research
The bacterium was isolated in 1854 by Italian anatomist, but its exact nature and his results were not widely known.

Spanish physician developed a cholera inoculation in 1885, the first to immunize humans against a bacterial disease.

Russian-Jewish bacteriologist developed the first cholera vaccine in July 1892.

One of the major contributions to fighting cholera was made by the physician and pioneer medical scientist (1813–1858), who in 1854 found a link between cholera and contaminated drinking water. Dr. Snow proposed a microbial origin for epidemic cholera in 1849. In his major "state of the art" review of 1855, he proposed a substantially complete and correct model for the cause of the disease. In two pioneering epidemiological field studies, he was able to demonstrate human contamination was the most probable disease vector in two major epidemics in London in 1854. His model was not immediately accepted, but it was seen to be the more plausible, as medical microbiology developed over the next 30 years or so.

Cities in developed nations made massive investment in clean water supply and well-separated sewage treatment infrastructures between the mid-1850s and the 1900s. This eliminated the threat of cholera epidemics from the major developed cities in the world. In 1883, identified V. cholerae with a microscope as the bacillus causing the disease.

, working at the US in Southeast Asia, evaluated the pathophysiology of the disease using modern laboratory chemistry techniques and developed a protocol for rehydration. His research led the to award him its prize in 1967.

More recently, in 2002, Alam, et al., studied stool samples from patients at the in. From the various experiments they conducted, the researchers found a correlation between the passage of V. cholerae through the human digestive system and an increased infectivity state. Furthermore, the researchers found the bacterium creates a hyperinfected state where s that control biosynthesis of s, uptake systems, and formation of periplasmic nitrate reductase complexes were induced just before defecation. These induced characteristics allow the cholera vibrios to survive in the "rice water" stools, an environment of limited oxygen and iron, of patients with a cholera infection.

Health policy
In many developing countries, cholera still reaches its victims through contaminated water sources, and countries without proper sanitation techniques have greater incidence of the disease. Governments can play a role in this. In 2008, for example, the was due partly to the government's role, according to a report from the. The Haitian government's inability to provide safe drinking water after the 2010 earthquake led to an increase in cholera cases as well.

Similarly, South Africa's cholera outbreak was exacerbated by the government's policy of privatizing water programs. The wealthy elite of the country were able to afford safe water while others had to use water from cholera-infected rivers.

According to of the, if cholera does begin to spread, government preparedness is crucial. A government's ability to contain the disease before it extends to other areas can prevent a high death toll and the development of an epidemic or even pandemic. Effective disease surveillance can ensure that cholera outbreaks are recognized as soon as possible and dealt with appropriately. Oftentimes, this will allow public health programs to determine and control the cause of the cases, whether it is unsanitary water or seafood that have accumulated a lot of Vibrio cholerae specimens. Having an effective surveillance program contributes to a government's ability to prevent cholera from spreading. In the year 2000 in the state of Kerala in India, the Kottayam district was determined to be "Cholera-affected"; this pronouncement led to task forces that concentrated on educating citizens with 13,670 information sessions about human health. These task forces promoted the boiling of water to obtain safe water, and provided chlorine and oral rehydration salts. Ultimately, this helped to control the spread of the disease to other areas and minimize deaths. On the other hand, researchers have shown that most of the citizens infected during the 1991 cholera outbreak in Bangladesh lived in rural areas, and were not recognized by the government's surveillance program. This inhibited physicians' abilities to detect cholera cases early.

According to Colwell, the quality and inclusiveness of a country's health care system affects the control of cholera, as it did in the. While sanitation practices are important, when governments respond quickly and have readily available vaccines, the country will have a lower cholera death toll. Affordability of vaccines can be a problem; if the governments do not provide vaccinations, only the wealthy may be able to afford them and there will be a greater toll on the country's poor. The speed with which government leaders respond to cholera outbreaks is important.

Besides contributing to an effective or declining public health care system and water sanitation treatments, government can have indirect effects on cholera control and the effectiveness of a response to cholera. A country's government can impact its ability to prevent disease and control its spread. A speedy government response backed by a fully functioning health care system and financial resources can prevent cholera's spread. This limits cholera's ability to cause death, or at the very least a decline in education, as children are kept out of school to minimize the risk of infection.