Cholera

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]

Overview

Choleria is a severe bacterial gastrointestinal, diarrheal disease. In its most severe forms, cholera is one of the most rapidly fatal illnesses known. A healthy person may become hypotensive within an hour of the onset of symptoms and may die within 2-3 hours if no treatment is provided. More commonly, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without rehydration treatment.

Background

Cholera (or Asiatic cholera or epidemic cholera) is a severe diarrheal disease caused by the bacterium Vibrio cholerae. Transmission to humans is by ingesting contaminated water or food. The major reservoir for cholera was long assumed to be humans, but some evidence suggests that it is the aquatic environment.

V. cholerae is a Gram-negative bacteria which produces cholera toxin, an enterotoxin, whose action on the mucosal epithelium lining of the small intestine is responsible for the characteristic massive diarrhea of the disease. In its most severe forms, cholera is one of the most rapidly fatal illnesses known. A healthy person may become hypotensive within an hour of the onset of symptoms and may die within 2-3 hours if no treatment is provided. More commonly, the disease progresses from the first liquid stool to shock in 4-12 hours, with death following in 18 hours to several days without rehydration treatment.

Symptoms

Symptoms include those of general GA tract (stomach) upset and massive watery diarrhea. Symptoms may also include terrible muscle and stomach cramps, vomiting and fever in early stages. In a later stage the diarrhea becomes "rice water stool" (almost clear with flecks of white). Symptoms are caused by massive body fluid loss induced by the enterotoxins that V. cholerae produces. The main enterotoxin, known as cholera toxin, interacts with G proteins and cyclic AMP in the intestinal lining to open ion channels. As ions flow into the intestinal lumen (lining), body fluids (mostly water) flow out of the body due to osmosis leading to massive diarrhea as the fluid is expelled from the body. The body is "tricked" into releasing massive amounts of fluid into the small intestine which shows up in up to 36 liters of liquid diarrhea in a six day period in adults with accompanying massive dehydration. Radical dehydration can bring death within a day through collapse of the circulatory system.

Treatment

Nurses encourage patients to drink large amounts of an oral rehydration solution to counteract the massive dehydration resulting from cholera.

In general, patients must receive as much fluid as they lose, which can be up to 36 L, due to diarrhea.

Treatment typically consists of aggressive rehydration (restoring the lost body fluids) and replacement of electrolytes with commercial or hand-mixed sugar-salt solutions (1 tsp salt + 8 tsp sugar in 1 litre of clean/boiled water) or massive injections of liquid given intravenously via an IV in advanced cases. See: Oral rehydration therapy for easily made rehydration solutions. Without treatment the death rate is as high as 50%; with treatment the death rate can be well below 1%.

Tetracycline antibiotics may have a role in reducing the duration and severity of cholera, although drug-resistance is occurring. Oral tetracycline was recommended for reducing the period of vibrio excretion and need for parenteral fluid. Initially cholera vibrios were universally susceptible to all antibiotics active against gram negative bacilli, but since 1979 multiple drug resistant strain have become increasingly common and their effects on overall mortality are questioned. Other antibiotics that have been used include ciprofloxacin and azithromycin, although again, drug-resistance has now been described.

Epidemiology

Prevention

Although cholera can be life-threatening, it is nearly always easily prevented, in principle, if proper sanitation practices are followed. In the United States and Western Europe, because of advanced water treatment and sanitation systems, cholera is no longer a major threat. The last major outbreak of cholera in the United States was in 1911. However, everyone, especially travelers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation practices, if instituted in time, are usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:

Cholera hospital in Dhaka.

• Sickbed: Proper disposal and treatment of the germ infected fecal waste (and all clothing and bedding that come in contact with it) produced by cholera victims is of primary importance.
• Sewage: Treatment of general sewage before it enters the waterways or underground water supplies prevent possible undetected patients from spreading the disease.
• Sources: Warnings about cholera contamination posted around contaminated water sources with directions on how to decontaminate the water.
• Sterilization: Boiling, filtering, and chlorination of water kill the bacteria produced by cholera patients and prevent infections, when they do occur, from spreading. All materials (clothing, bedding, etc.) that come in contact with cholera patients should be sterilized in hot water using (if possible) chlorine bleach. Hands, etc. that touch cholera patients or their clothing etc. should be thoroughly cleaned and sterilized. All water used for drinking, washing or cooking should be sterilized by boiling or chlorination in any area where cholera may be present. Water filtration, chlorination and boiling are by far the most effective means of halting transmission. Cloth filters, though very basic, have greatly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water. In general, public health education and good sanitation practices are the limiting factors in preventing transmission.

Susceptibility

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

Transmission

Drawing of Death bringing the cholera, in Le Petit Journal.

Persons infected with cholera have massive diarrhea. This highly liquid diarrhea, which is often compared to "rice water," is loaded with bacteria that can spread under unsanitary conditions to infect water used by other people. Cholera is transmitted from person to person through ingestion of feces contaminated water loaded with the cholera bacterium. The source of the contamination is typically other cholera patients when their untreated diarrhea discharge is allowed to get into waterways or into groundwater or drinking water supply. Any infected water and any foods washed in the water, and shellfish living in the affected waterway can cause an infection. Cholera is rarely spread directly from person to person. V. cholerae occurs naturally in the plankton of fresh, brackish, and salt water, attached primarily to copepods in the zooplankton. Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a lysogenic bacteriophage. Coastal cholera outbreaks typically follow zooplankton blooms. This makes cholera a zoonosis.

Laboratory diagnosis

Stool and swab collected in the acute stage of the disease are useful specimens for laboratory diagnosis. A number of special media have been employed for the cultivation for Cholera vibrios. They are classified as follows:

Holding or transport media

1. Venkataraman-ramakrishnan (VR) medium
2. Cary-Blair medium: This the most popularly carrying media. This is a buffered solution of sodium chloride, sodium thioglycollate, disodium phosphate and calcium chloride at pH 8.4.

Enrichment media

1. Alkaline peptone water at pH 8.6
2. Monsur's taurocholate tellurite peptone water at pH 9.2

Plating media

1. Alkaline bile salt agar: The colonies are very similar to those on Nutrient Agar.
2. Monsur's gelatin Tauro cholate trypticase tellurite agar (GTTA) medium: Cholera vibrios produce small translucent colonies with a greyish black centre.
3. TCBS medium: This the mostly widely used medium. This medium contains thiosulphate, citrate, bile salts and sucrose. Also in oysters and lobster in some cases. Cholera vibrios produce flat 2-3 mm in diameter, yellow nucleated colonies.

Biochemistry of the V. cholerae bacterium

Most of the V. cholerae bacteria in the contaminated water that a potential host drinks do not survive the very acidic conditions of the human stomach But the few bacteria that manage to survive the stomach's acidity conserve their energy and stored nutrients during the perilous passage through the stomach by shutting down much protein production. When the surviving bacteria manage to exit the stomach and reach the favorable conditions of the small intestine, they need to propel themselves through the thick mucus that lines the small intestine to get to the intestinal wall where they can thrive. So they 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 pasty mucus that lines the small intestine.

Once the cholera bacteria reach the intestinal wall, they do not need the flagella propellers to move themselves any more, so they stop producing the protein flagellin, thus again conserving energy and nutrients by changing the mix of proteins that they manufacture, responding to the changed chemical surroundings. And on reaching the intestinal wall, they start producing the toxic proteins that give the infected person a watery diarrhea which carries the multiplying and thriving new generations of V. cholerae bacteria out into the drinking water of the next host—if proper sanitation measures are not in place.

Cholera Toxin. The delivery region (blue) binds membrane carbohydrates to get into cells. The toxic part (red) is activated inside the cell (PDB code: 1xtc)

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 separately, successive sections of V. cholerae DNA into the DNA of other bacteria such as E. coli that would not naturally produce the protein toxins, researchers 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."

History

Origin and spread

Cholera was originally endemic to the Indian subcontinent, with the Ganges River likely serving as a contamination reservoir. It spread by trade routes (land and sea) to Russia, then to Western Europe, and from Europe to North America. It is now no longer considered an issue in Europe and North America, due to filtering and chlorination of the water supply.

• 1816-1826 - First Cholera pandemic: Previously restricted, the pandemic began in Bengal, then spread across India by 1820. It extended as far as China and the Caspian Sea before receding.
• 1829-1851 - Second Cholera pandemic reached Europe, London and Paris in 1832. In London, it claimed 6,536 victims (see: http://www.mernick.co.uk/thhol/1832chol.html); in Paris, 20,000 succumbed (out of a population of 650,000) with about 100,000 deaths in all of France [6]. It reached Russia (Cholera Riots), Quebec, Canada, Ontario, Canada] and New York in the same year and the Pacific coast of North America by 1834.
• 1849 - Second major outbreak in Paris. In London, it was the worst outbreak in the city's history, claiming 14,137 lives, ten times as many as the 1832 outbreak. In 1849 cholera claimed 5,308 lives in the port city of Liverpool, England, and 1,834 in Hull, England. An outbreak in North America took the life of former U.S. President James K. Polk. Cholera spread throughout the Mississippi river system killing over 4,500 in St. Louis [7] and over 3,000 in New Orleans [8] as well as thousands in New York. In 1849 cholera was spread along the California and Oregon trail as hundreds died on their way to the California Gold Rush, Utah and Oregon.
• 1852-1860 - Third Cholera pandemic mainly affected Russia, with over a million deaths. In 1853-4, London's epidemic claimed 10,738 lives.
• 1854 - Outbreak of cholera in Chicago took the lives of 5.5 per cent of the population (about 3,500 people).[9]. Soho outbreak in London stopped by removing the handle of the Broad Street pump by a committee instigated to action by John Snow .
• 1863-1875 - Fourth Cholera pandemic spread mostly in Europe and Africa.
• 1866 - Outbreak in North America. In London, a localized epidemic in the East End claimed 5,596 lives just as London was completing its major sewage and water treatment systems--the East End was not quite complete. William Farr, using the work of John Snow et al. as to contaminated drinking water being the likely source of the disease, was able to relatively quickly identify the East London Water Company as the source of the contaminated water. Quick action prevented further deaths. Also a minor outbreak at Ystalyfera in South Wales. Caused by the local water works using contaminated canal water, it was mainly it's workers and their families who suffered. Only 119 died.
• 1881-1896 - Fifth Cholera pandemic ; The 1892 outbreak in Hamburg, Germany was the only major European outbreak; about 8,600 people died in Hamburg, causing a major political upheaval in Germany, as control over the City was removed from a City Council which had not updated Hamburg's water supplies. This was the last serious European cholera outbreak.
• 1899-1923 - Sixth Cholera pandemic had little effect in Europe because of advances in public health, but Russia was badly affected again.
• 1961-1970s - Seventh Cholera pandemic began in Indonesia, called El Tor after the strain, and reached Bangladesh in 1963, India in 1964, and the USSR in 1966. From North Africa it spread into Italy by 1973. In the late 1970s there were small outbreaks in Japan and in the South Pacific. There were also many reports of a cholera outbreak near Baku in 1972, but information about it was suppressed in the USSR.
• January 1991 to September 1994 - Outbreak in South America, apparently initiated when a ship discharged ballast water. Beginning in Peru there were 1.04 million identified cases and almost 10,000 deaths. The causative agent was an O1, El Tor strain, with small differences from the seventh pandemic strain. In 1992 a new strain appeared in Asia, a non-O1, nonagglutinable vibrio (NAG) named O139 Bengal. It was first identified in Tamil Nadu, India and for a while displaced El Tor in southern Asia before decreasing in prevalence from 1995 to around 10% of all cases. It is considered to be an intermediate between El Tor and the classic strain and occurs in a new serogroup. There is evidence of the emergence of wide-spectrum resistance to drugs such as trimethoprim, sulfamethoxazole and streptomycin.
• 2007 - The U.N. reported recently of a Cholera outbreak in Iraq.

Research

The major contributions to fighting cholera were made by physician and self-trained scientist John Snow (1813-1858), who found the link between cholera and contaminated drinking water in 1854 and Henry Whitehead, an Anglican minister, who helped John Snow track down and verify the source of the disease, an infected well in London. Their conclusions and writings were widely distributed and firmly established for the first time a definite link between germs and disease. Clean water and good sewage treatment, despite their major engineering and financial cost, slowly became a priority throughout the major developed cities in the world from this time onward. Robert Koch, 30 years later, identified V. cholerae with a microscope as the bacillus causing the disease in 1885. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist Filippo Pacini, but its exact nature and his results were not widely known around the world.

Cholera has been a laboratory for the study of evolution of virulence. The province of Bengal in British India was partitioned into West Bengal (a state in India) 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 which succeeded in India had a greater incentive in the longevity of the host and are less virulent than the strains prevailing in Bangladesh, which uninhibitedly draw upon the resources of the host population, thus rapidly killing many in it.

False report of cholera

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885. This story has no factual basis. In 1885 there was a torrential rainstorm that flushed the Chicago river and its attendant pollutants into Lake Michigan far enough that the city's water supply was contaminated. Fortunately, cholera was not present in the city and this is not known to have caused any deaths. It did, however, cause the city to become more serious about their sewage treatment.

Cholera morbus

The term cholera morbus was used in the 19th and early 20th century to describe both non-epidemic cholera and gastrointestinal diseases that mimicked cholera. The term is not in current use, but is found in many older references.

External links

• Cholera - World Health Organization
• What is Cholera? - Centers for Disease Control and Prevention
• Cholera information for travelers - 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”
• short paper contrasting official responses to cholera in Hamburg, Soho and New York.
• Kelley Lee and Richard Dogson, "Globalization and Cholera: implications for global governance." in Global Governance, 6:2 (Apr-June 2000)
• Nashville's cholera outbreak, Summer 1873

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