Cholera
Cholera is an infection of the small intestine by some strains of the bacterium Vibrio cholerae. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and muscle cramps may also occur. Diarrhea can be so severe that it leads within hours to severe dehydration and electrolyte imbalance. This may result in sunken eyes, cold skin, decreased skin elasticity, and wrinkling of the hands and feet. Dehydration can cause the skin to turn bluish. Symptoms start two hours to five days after exposure.
Cholera is caused by a number of types of Vibrio cholerae, with some types producing more severe disease than others. It is spread mostly by unsafe water and unsafe food that has been contaminated with human feces containing the bacteria. Undercooked seafood is a common source. Humans are the only animal affected. Risk factors for the disease include poor sanitation, not enough clean drinking water, and poverty. There are concerns that rising sea levels will increase rates of disease. Cholera can be diagnosed by a stool test. A rapid dipstick test is available but is not as accurate.
Prevention methods against cholera include improved sanitation and access to clean water. Cholera vaccines 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 E. coli. The primary treatment is oral rehydration therapy—the replacement of fluids with slightly sweet and salty solutions. Rice-based solutions are preferred. Zinc supplementation is useful in children. In severe cases, intravenous fluids, such as Ringer's lactate, may be required, and antibiotics may be beneficial. Testing to see which antibiotic 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 pandemic as of 2010[update], it is rare in the developed world. Children are mostly affected. Cholera occurs as both outbreaks and chronically in certain areas. Areas with an ongoing risk of disease include Africa and Southeast Asia. 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 Sanskrit. The study of cholera in England by John Snow between 1849 and 1854 led to significant advances in the field of epidemiology. Seven large outbreaks have occurred over the last 200 years with millions of deaths.
Play mediaSigns and symptoms
The primary symptoms of cholera are profuse diarrhea and vomiting 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 litres (3 to 5 US gal) 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 dehydration and electrolyte imbalances. Estimates of the ratio of asymptomatic to symptomatic infections have ranged from 3 to 100. Cholera has been nicknamed the "blue death" because a person's skin may turn bluish-gray 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. Kussmaul breathing, a deep and labored breathing pattern, can occur because of acidosis from stool bicarbonate losses and lactic acidosis associated with poor perfusion. Blood pressure drops due to dehydration, peripheral pulse is rapid and thready, and urine output decreases with time. Muscle cramping and weakness, altered consciousness, seizures, or even coma due to electrolyte imbalances are common, especially in children.
Cause
Transmission
Cholera bacteria have been found in shellfish and plankton.
Transmission is usually through the fecal-oral route of contaminated food or water caused by poor sanitation. 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 oysters in waters infected with sewage, as Vibrio cholerae accumulates in planktonic crustaceans and the oysters eat the zooplankton.
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, groundwater or drinking water supplies. Drinking any contaminated water and eating any foods washed in the water, as well as shellfish living in the affected waterway, can cause a person to contract an infection. Cholera is rarely spread directly from person to person.
V. cholerae also exists outside the human body in natural water sources, either by itself or through interacting with phytoplankton, zooplankton, or biotic and abiotic 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 'viable but non-culturable' (VBNC) or more conservatively 'active but non-culturable' (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 toxicity through a temperate bacteriophage.
Susceptibility
About 100 million bacteria must typically be ingested to cause cholera in a normal healthy adult. This dose, however, is less in those with lowered gastric acidity (for instance those using proton pump inhibitors). 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 blood type, with those with type O blood being the most susceptible. Persons with lowered immunity, such as persons with AIDS or malnourished 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 health care provider.
The cystic fibrosis genetic mutation known as delta-F508 in humans has been said to maintain a selective heterozygous 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 intestinal epithelium, thus reducing the effects of an infection.
Mechanism
When consumed, most bacteria do not survive the acidic conditions of the human stomach. The few surviving bacteria conserve their energy and stored nutrients during the passage through the stomach by shutting down protein production. When the surviving bacteria exit the stomach and reach the small intestine, they must propel themselves through the thick mucus 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 flagella to move. The bacteria stop producing the protein flagellin to conserve energy and nutrients by changing the mix of proteins that they express in response to the changed chemical surroundings. On reaching the intestinal wall, V. cholerae start producing the toxic proteins 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 cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits form a five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, 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 endocytosis. Once inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human partner protein called ADP-ribosylation factor 6 (Arf6). Binding exposes its active site, allowing it to permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP 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 horizontal gene transfer. Virulent strains of V. cholerae carry a variant of a temperate bacteriophage called CTXφ.
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 turn on the protein 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 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 E. coli 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 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, 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
Amplified fragment length polymorphism fingerprinting of the pandemic isolates of V. cholerae has revealed variation in the genetic structure. Two clusters 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, antibiotic resistance is increasing within cholera bacteria. In Bangladesh, for example, most cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin. Rapid diagnostic assay methods are available for the identification of multi-drug resistant cases. New generation antimicrobials have been discovered which are effective against cholera bacteria in in vitro studies.
Diagnosis
A rapid dipstick 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 epidemic situations, a clinical diagnosis may be made by taking a patient history 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 serogroup 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 World Health Organization (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 sanitation practices are followed. In developed countries, due to nearly universal advanced water treatment 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 developing countries.
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 sanitized by washing in hot water, using chlorine bleach 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.
- Sewage and fecal sludge management: 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 human excreta. Provision of sanitation and hygiene is an important preventative measure. Open defecation, release of untreated sewage, or dumping of fecal sludge from pit latrines or septic tanks into the environment need to be prevented. In many cholera affected zones, there is a low degree of sewage treatment. Therefore, the implementation of dry toilets that do not contribute to water pollution, as they do not flush with water, may be an interesting alternative to flush toilets.
- Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to decontaminate the water (boiling, chlorination etc.) for possible use.
- Water purification: All water used for drinking, washing, or cooking should be sterilized by either boiling, chlorination, ozone water treatment, ultraviolet light sterilization (e.g., by solar water disinfection), 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. Cloth filters or sari filtration, though very basic, have significantly reduced the occurrence of cholera when used in poor villages in Bangladesh 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.
Handwashing with soap or ash after using a toilet and before handling food or eating is also recommended for cholera prevention by WHO Africa.
Dumping of sewage or fecal sludge from a UN camp into a lake in the surroundings of Port-au-Prince is thought to have contributed to the spread of cholera after the Haiti earthquake in 2010, killing thousands.
Example of a urine-diverting dry toilet in a cholera-affected area in Haiti. This type of toilet stops transmission of disease via the fecal-oral route due to water pollution.
Cholera hospital in Dhaka, showing typical "cholera beds".
Surveillance
Play mediaSurveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. 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.
Vaccination
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. Dukoral, 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 Centers for Disease Control and Prevention (CDC) for most people traveling from the United States to endemic countries. The vaccine that the US Food and Drug Administration (FDA) recommends, Vaxchora, is an oral attenuated live vaccine, 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, as of 2010[update], 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 HIV, in countries where this disease is endemic. If people are immunized broadly, herd immunity results, with a decrease in the amount of contamination in the environment.
WHO recommends that oral cholera vaccination be considered in areas where the disease is endemic (with seasonal peaks), as part of the response to outbreaks, or in a humanitarian crisis during which the risk of cholera is high. Oral Cholera Vaccine (OCV) has been recognized as an adjunct tool for prevention and control of cholera. The World Health Organization (WHO) has prequalified three bivalent cholera vaccines—Dukoral (SBL Vaccines), containing a non-toxic B-subunit of cholera toxin and providing protection against V. cholerae O1; and two vaccines developed using the same transfer of technology—ShanChol (Shantha Biotec) and Euvichol (EuBiologics Co.), which have bivalent O1 and O139 oral killed cholera vaccines. Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists.
Sari filtration
Developed for use in Bangladesh, the "sari filter" is a simple and cost-effective appropriate technology method for reducing the contamination of drinking water. Used sari cloth is preferable but other types of used cloth can be used with some effect, though the effectiveness will vary significantly. Used cloth is more effective than new cloth, as the repeated washing reduces the space between the fibers. Water collected in this way has a greatly reduced pathogen count—though it will not necessarily be perfectly safe, it is an improvement for poor people with limited options. 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 nylon 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 oral rehydration therapy (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, intravenous rehydration may be necessary. Ringer's lactate 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 Bangladesh Liberation War, 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 acidosis, the potassium 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
Antibiotic 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.
Doxycycline is typically used first line, although some strains of V. cholerae have shown resistance. Testing for resistance during an outbreak can help determine appropriate future choices. Other antibiotics proven to be effective include cotrimoxazole, erythromycin, tetracycline, chloramphenicol, and furazolidone. Fluoroquinolones, such as ciprofloxacin, also may be used, but resistance has been reported.
Antibiotics improve outcomes in those who are both severely and not severely dehydrated. Azithromycin and tetracycline may work better than doxycycline or ciprofloxacin.
Zinc supplementation
In Bangladesh zinc 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 2010 epidemic in Haiti 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 as of 2010[update]. This occurs mainly in the developing world. 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 epidemic and endemic in many areas of the world. In October 2016, an outbreak of cholera began in war-ravaged Yemen. 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 feces and lack of treatment of drinking water greatly facilitate its spread, but bodies of water can serve as a reservoir, and seafood shipped long distances can spread the disease. Cholera was not known in the Americas for most of the 20th century, but it reappeared towards the end of that century.
History
