Cholera

Cholera is an infection of the small intestine caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea, vomiting and abdominal pain. Transmission is primarily through contaminated drinking water or food. The severity of the diarrhea and vomiting can lead to rapid dehydration and electrolyte imbalance. Primary treatment is with oral or intravenous rehydration solutions. Antibiotics may be beneficial, and in certain cases they are used. Cholera is a major cause of death in the world. Cholera was one of the earliest infections to be studied by epidemiological methods.

The primary symptoms of cholera are profuse diarrhea, severe dehydration, abdominal pain, and fever. Cholera may also cause blue skin and dehydration. A person infected with cholera may not always have these symptoms or any at all. Cholera may also cause vomiting. These symptoms start suddenly, usually one to five days after infection, and are the result of a toxin produced by the Vibrio cholerae bacterium that compels profuse amounts of fluid from the blood supply into the small and large intestines. An untreated cholera patient may produce around 10 liters of diarrhoeal fluid a day.

Most of the V. cholerae bacteria in the contaminated water consumed by the host do not survive the highly acidic conditions of the human stomach. The few bacteria that do survive 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. V. cholerae bacteria 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 mucus of the small intestine.

Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move any longer. The bacteria stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins which they manufacture 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 secretion of H2O, Na+, K+, Cl−, and HCO3− into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene transfer. Virulent strains of V. cholerae carry a variant of lysogenic bacteriophage called CTXf or 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 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 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 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. 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."

Recent epidemiologic research suggests that an individual's susceptibility to cholera (and other diarrhoeal infections) is affected by their blood type: those with type O blood are the most susceptible, 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. 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.

People infected with cholera suffer acute diarrhoea. This highly liquid diarrhoea, colloquially referred to as "rice-water stool," is loaded with bacteria that can infect water used by other people. Cholera is transmitted through ingestion of water contaminated with the cholera bacterium, usually from feces or other effluent. The source of the contamination is typically other cholera patients when their untreated diarrhoea discharge is allowed to get into waterways or into groundwater or drinking water supplies. Any infected water and any foods washed in the water, as well as shellfish living in the affected waterway, can cause an infection. Cholera is rarely spread directly from person to person. V. cholerae harbours naturally in the zooplankton of fresh,brackish, and salt water, attached primarily to their chitinous exoskeleton. Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage. Coastal cholera outbreaks typically follow zooplankton blooms, thus making cholera a zoonotic disease.

Cholera bacteria grown in vitro encounter difficulty subsequently growing in humans without additional stomach acid buffering. In a 2002 study at Tufts University School of Medicine, it was found that stomach acidity is a principal agent that advances epidemic spread. In their findings, the researchers found that human colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may contribute to epidemic spread of the disease. When these hyperinfectious bacteria underwent transcription profiles, they were found to possess a unique physiological and behavioural state, characterized by high expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes required for bacterial chemotaxis. Thus, the spread of cholera can be expedited by host physiology.

In epidemic situations, a clinical diagnosis is made by taking a history of symptoms from the patient and by a brief examination only. Treatment is usually started without or before confirmation by laboratory analysis of specimens.

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 Vibrio 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.

A number of special media have been employed for the cultivation for cholera vibrios. They are classified as follows:

Direct microscopy of stool is not recommended as it is unreliable. Microscopy is preferred only after enrichment, as this process reveals the characteristic motility of Vibrios and its inhibition by appropriate antiserum. Diagnosis can be confirmed as well as serotyping done by agglutination with specific sera.

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, cholera is no longer a major health threat. The last major outbreak of cholera in the United States occurred in 1910-1911. Travellers should be aware of how the disease is transmitted and what can be done to prevent it. 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 (and should be) halted:

A vaccine for cholera is available in some countries, but prophylactic usage is not currently recommended by the Centres for Disease Control and Prevention (CDC) for most travelers. During recent years, substantial progress has been made in developing new oral vaccines against cholera. Two oral cholera vaccines, which have been evaluated with volunteers from industrialized countries and in regions with endemic cholera, are commercially available in several countries: a killed whole-cell V. cholerae O1 in combination with purified recombinant B subunit of cholera toxin and a live-attenuated live oral cholera vaccine, containing the genetically manipulated V. cholerae O1 strain CVD 103-HgR. The appearance of V. cholerae O139 has influenced efforts in order to develop an effective and practical cholera vaccine since none of the currently available vaccines is effective against this strain. The newer vaccine (brand name: Dukoral), an orally administered inactivated whole cell vaccine, appears to provide somewhat better immunity and have fewer adverse effects than the previously available vaccine. This safe and effective vaccine is available for use by individuals and health personnel. Work is under way to investigate the role of mass vaccination.

Sensitive surveillance 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 provide guidance for improving cholera control activities for the most vulnerable. This will also aid in the developing indicators for appropriate use of oral cholera vaccine.

In most cases cholera can be successfully treated with oral rehydration therapy (ORT). ORT is highly effective, safe, and simple to administer: prompt replacement of water and electrolytes is the principal treatment for cholera, as dehydration and electrolyte depletion occur rapidly. In situations where commercially produced ORT sachets are too expensive or difficult to obtain, alternative homemade solutions (1 ltr. boiled water, 1 level tsp. salt, 8 level tsp. sugar, banana for potasium) using various formulas of water, sugar, table salt, baking soda, and fruit offer less expensive methods of electrolyte repletion. In severe cholera cases with significant dehydration, the administration of intravenous rehydration solutions may be necessary.

Antibiotics shorten the course of the disease and reduce the severity of the symptoms; however, oral rehydration therapy remains the principal treatment. Tetracycline is typically used as the primary antibiotic, although some strains of V. cholerae have shown resistance. Other antibiotics that have been proven effective against V. cholerae include cotrimoxazole, erythromycin, doxycycline, chloramphenicol, and furazolidone.Fluoroquinolones such as norfloxacin also may be used, but resistance has been reported.

Rapid diagnostic assay methods are available for the identification of multi-drug resistant V. cholerae. New generation antimicrobials have been discovered which are effective against V. cholerae in in vitro studies.

The success of treatment is significantly affected by the speed and method of treatment. If cholera patients are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%.

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 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 and seems likely to persist.

Amplified fragment length polymorphism (AFLP) fingerprinting of the pandemic isolates of Vibrio 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.

Cholera likely has its origins in and is endemic to the Indian subcontinent. The disease spread by trade routes (land and sea) to Russia, then to Western Europe, and from Europe to North America. Cholera is now no longer considered a pressing health threat in Europe and North America due to filtering and chlorination of water supplies, but still heavily affects populations in developing countries.

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885, but 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. However, because cholera was not present in the city, there were no cholera-related deaths. Nevertheless, the incident caused the city to become more serious about its sewage treatment.

The term cholera morbus was used in the 19th and early 20th centuries to describe both non-epidemic cholera and other gastrointestinal diseases (sometimes epidemic) that resembled cholera. The term is not in current use, but is found in many older references. The other diseases are now known collectively as gastroenteritis.

In the past, people traveling in ships would hang a yellow quarantine 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, typically 30 to 40 days. In modern international maritime signal flags the quarantine flag is yellow and black.

The Russian-born bacteriologist Waldemar Haffkine developed the first cholera vaccine around 1900. 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.

One of the major contributions to fighting cholera was made by the physician and pioneer medical scientist John Snow (1813–1858), who found a link between cholera and contaminated drinking water in 1854. 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 aetiology of the disease. In two pioneering epidemiological field-studies, he was able to demonstrate that human sewage 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 thirty years or so.

Cities in developed nations made massive investment in clean water supply and well-separated sewage treatment infractures was made between the mid-1850s and the 1900s. This eliminated the threat of cholera epidemics from the major developed cities in the world. Robert Koch, 30 years later, identified V. cholerae with a microscope as the bacillus causing the disease in 1885.

Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in British India was partitioned into West Bengal 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 that succeeded in India had a greater incentive in the longevity of the host. They have become less virulent than the strains prevailing in Bangladesh. These uninhibitedly draw upon the resources of the host population, thus rapidly killing many victims.

More recently, in 2002, Alam et al. studied stool samples from patients at the International Centre for Diarrhoeal Disease (ICDDR) in Dhaka, Bangladesh. 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 that the bacterium creates a hyper-infected state where genes that control biosynthesis of amino acids, iron 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.