Cholera

Coordinates	53°45′15″N17°46′32″N
Name	Cholera
Caption	Scanning electron microscope image of Vibrio cholerae
Diseasesdb	29089
Icd10
Icd9
Medlineplus	000303
Emedicinesubj	med
Emedicinetopic	351
Meshid	D002771

Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission is primarily through consuming 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 rehydration solution and if these are not tolerated, intravenous fluids. Antibiotics are beneficial in those with severe disease. Worldwide it affects 3-5 million people and causes 100,000-130,000 deaths a year as of 2010. Cholera was one of the earliest infections to be studied by epidemiological methods.

Signs and symptoms

The primary symptoms of cholera are profuse painless diarrhea and vomiting of clear fluid.

If the severe diarrhea and vomiting are not aggressively treated it can, within hours, result in dehydration and electrolyte imbalances. Transmission is primarily due to the fecal contamination of food and water due to poor sanitation. 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.

Individuals' susceptibility to cholera is affected by their blood type, with those with type O blood being the most susceptible.

Transmission

Cholera is typically transmitted by either contaminated food or water. In the developed world, seafood is the usual cause, while in the developing world it is more often water. The source of the contamination is typically other cholera sufferers when their untreated diarrheal discharge is allowed to get into waterways or into groundwater or drinking water supplies. Drinking any infected 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. Both toxic and nontoxic strains exist. Nontoxic strains can acquire toxicity through a lysogenic bacteriophage. Coastal cholera outbreaks typically follow zooplankton blooms, thus making cholera a zoonotic disease.

Mechanism

Most bacteria, when consumed, do not survive the 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 walls, where they can thrive. V. cholerae bacteria start up production of the hollow cylindrical protein flagellin to make flagella, the curly whip-like tails they rotate to propel themselves through the mucus of the small intestine.

Once the cholera bacteria reach the intestinal wall, they no longer need the flagella propellers to move. 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 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, causing diarrhea in the infected person and allowing the bacteria to colonize the intestine.

Diagnosis

In epidemic situations, a clinical diagnosis may be made by taking a history and doing a brief examination. Treatment is usually started without or before confirmation by laboratory analysis.

A rapid dip-stick test is available to determine the presence of V. cholerae.

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

Enrichment media

# Alkaline peptone water at pH 8.6 # Monsur's taurocholate tellurite peptone water at pH 9.2

Plating media

# Alkaline bile salt agar (BSA): The colonies are very similar to those on nutrient agar. # Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios produce small translucent colonies with a greyish black center. # TCBS medium: This the mostly widely used medium; it contains thiosulphate, citrate, bile salts and sucrose. Cholera vibrios produce flat 2–3 mm in diameter, yellow nucleated colonies.

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 Vibrio and its inhibition by appropriate antisera. Diagnosis can be confirmed, as well, as serotyping done by agglutination with specific sera.

Prevention

in Dhaka, showing typical cholera beds.]] 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. 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 infected fecal waste water produced by cholera victims and all contaminated materials (e.g. clothing, bedding, etc.) is essential. All materials that come in contact with cholera patients should be sterilized 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: antibacterial treatment of general sewage by chlorine, ozone, ultraviolet light or other effective treatment before it enters the waterways or underground water supplies helps prevent undiagnosed patients from inadvertently spreading the disease.

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, 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.

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 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. For prevention to be effective it is important that cases are reported to national health authorities. Dukoral, an orally administered, inactivated whole cell vaccine, has an efficacy of 85%, 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 the third world. One injectable vaccine was found to be effective for two to three years. The World Health Organization (WHO) recommends immunization of high risk groups, such as children and people with HIV, in countries where this disease is endemic.

Electrolytes

As there frequently is initially acidosis, the potassium level may be normal, even though large losses have occurred. Fluoroquinolones, such as norfloxacin, also may be used, but resistance has been reported.

In many areas of the world, antibiotic resistance is increasing. In Bangladesh, for example, most cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin. New generation antimicrobials have been discovered which are effective against in in vitro studies.

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 the first sign of symptoms.

Epidemiology

, 1832. The outdated public health advice demonstrates the lack of understanding of the disease and its actual causative factors.]] It is estimated that cholera affects 3-5 million people worldwide, and causes 100,000-130,000 deaths a year as of 2010. In the early 1980s, death rates are believed to have been greater than 3 million a year. Cholera remains both epidemic and endemic in many areas of the world.

History

The word cholera is from kholera from χολή kholē "bile". Cholera likely has its origins in the Indian subcontinent; it has been prevalent in the Ganges delta since ancient times.

From a local disease, cholera became one of the most widespread and deadly diseases of the 19th century, killing an estimated tens of millions of people. In Russia alone, between 1847 and 1851, it is estimated that the death toll exceeded one million. In the United States, there were 150,000 cholera deaths during the second pandemic. In the two decades between 1900 and 1920, perhaps eight million Indians died of cholera.

Cholera became the first reportable disease in the United States due to the significant effects it had on health. In modern international maritime signal flags, the quarantine flag is yellow and black.

Cholera morbus

The term cholera morbus was used in the 19th and early 20th centuries to describe both nonepidemic 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.

Research

The Russian-born bacteriologist Waldemar Haffkine developed the first cholera vaccine around 1900. The bacterium had been originally isolated forty five years earlier (1855) by Italian anatomist Filippo Pacini, but its exact nature and his results were not widely known.

One of the major contributions to fighting cholera was made by the physician and pioneer medical scientist John Snow (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 etiology of the disease. In two pioneering epidemiological field studies, he was able to demonstrate 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 infrastructures between the mid-1850s and the 1900s. This eliminated the threat of cholera epidemics from the major developed cities in the world. In 1885, Robert Koch identified V. cholerae with a microscope as the bacillus causing the disease..

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 draw upon the resources of the host population and rapidly kill 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 the bacterium creates a hyperinfected 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.

Notable cases

Tchaikovsky's death has traditionally been attributed to cholera, most probably contracted through drinking contaminated water several days earlier. Since the water was not boiled and cholera was affecting St. Petersburg, such a connection was quite plausible ...." Tchaikovsky's mother died of cholera, and his father became sick with cholera at this time but made a full recovery. But, some scholars, including English musicologist and Tchaikovsky authority David Brown and biographer Anthony Holden, have theorized that his death was a suicide.

Other famous people believed to have died of cholera include:

* Charles X, King of France James K. Polk, eleventh president of the United States Carl von Clausewitz, Prussian soldier and German military theorist Elliott Frost, son of American poet Robert Frost

References

Further reading

External links

Cholera - World Health Organization

What is Cholera? - Centers for Disease Control and Prevention

Steven Shapin, "Sick City: Maps and mortality in the time of cholera", The New Yorker May 2006. A review of Steven Johnson, “The Ghost Map: The story of London’s most terrifying epidemic — and how it changed science, cities, and the modern world”

Cholera Epidemic in NYC in 1832 New York Times 15 April 2008

The Cholera Timebomb in The DRC - slideshow by The First Post

Category:Gastroenterology Category:Intestinal infectious diseases Category:Neurotoxins Category:Foodborne illnesses Category:Bacterial diseases Category:Waterborne diseases Category:Pandemics Category:Biological weapons Category:Neglected diseases Category:Microbiology Category:Cholera