Cholera

Cholera (or Asiatic cholera or epidemic cholera) is a severe diarrheal disease caused by the bacterium Vibrio cholerae. and transmitted to people by ingesting contaminated water or food. The major reservoir for cholera was long thought to be humans, but some evidence suggests that it is the aquatic environment. It can kill if untreated, but often responds well to simple supportive treatment such as oral rehydration therapy.

V. cholerae is a Gram-negative bacteria which produces cholera toxin, an enterotoxin, whose effects on the mucosal epithelium lining of the small intestine cause massive diarrhea. In its most severe forms, cholera is one of the most rapidly lethal illnesses known: A healthy person may become hypotensive within an hour of the first symptoms and may die within 2-3 hours if no treatment is provided. More often, 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.

U.S. National Intelligence Council and CIA studies consider it a threat to world stability. It is on the CDC Bioterrorism Agents-Disease list.

Symptoms

Symptoms include general GI tract (stomach) upset, and massive watery diarrhea. There can be severe muscle and stomach cramps, vomiting and fever in the early stages. Later, the diarrhea becomes "rice water stool" (almost clear with flecks of white) and ruptured capillaries may turn the skin black and blue with sunken eyes and cheeks with blue lips. Symptoms are caused by massive body fluid loss induced by the enterotoxins that V. cholerae produces. The main enterotoxin, 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 flow out of the body due to osmosis leading to 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 (or 20% of body weight) of liquid diarrhea in a six day period in adults with accompanying severe dehydration. Radical dehydration can bring death within a day through collapse of the circulatory system.

Treatment

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. In general, patients must receive as much fluid as they lose, which can be up to 20 L. See: Oral rehydration therapy for easily made rehydration solutions and Ceralyte. Without rehydration, the death rate can be as high as 10-50%.

Tetracycline antibiotics may reduce the duration and severity of cholera, although drug-resistance is an increasing problem, 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.

Without treatment the death rate is as high as 50%; with treatment the death rate can be well below 1%.

Epidemiology

Prevention

Although cholera can be life-threatening, it is nearly always easily prevented, in principle, if proper sanitation practices are followed. In the U.S.A. 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 U.S.A. was in 1911. However, everyone, especially travellers, should be aware of how the disease is transmitted and what can be done to prevent it. Good sanitation, if instituted in time, is usually sufficient to stop an epidemic. There are several points along the transmission path at which the spread may be halted:

• Sickbed: Proper disposal and treatment of 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 are the limiting factors in preventing transmission.

Susceptibility

Recent epidemiologic research suggests that susceptibility to cholera (and other diarrheal infections) is affected by blood type: Those with type O blood are 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

Persons infected with cholera have severe diarrhea, loaded with bacteria that can spread to infect water supplies: cholera is transmitted from person to person mainly through ingestion of this contaminated water, and only rarely spread directly from person to person. Any infected water and any foods washed in the water, and shellfish living in the affected waterway can cause an infection. 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.

Biochemistry of the V. cholerae bacterium

Most of the V. cholerae bacteria in contaminated water do not survive the acidic conditions of the human stomach But the few bacteria that survive the stomach's acidity 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. So they start producing 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 bacteria reach the intestinal wall, they stop producing flagellin and 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.

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 others as they pass 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 the bacteria turn on 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 choride and sodium ions create a salt water environment in the small intestine which through osmosis can pull up to six liters of water per day through the intestinal cells creating the massive diarrhea.

By inserting separately successive sections of V. cholerae DNA into the DNA of other bacteria such as E. coli that do not naturally produce the protein toxins, have found the mechanisms by which V. cholerae respond to the changing chemical environments of the stomach, mucous layers, and intestinal wall. 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 that cause diarrhea 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 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 [3]. It reached Russia (Cholera Riots), Quebec, Ontario 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 [4] and over 3,000 in New Orleans [5] 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).[6]. Soho outbreak in London stopped by removing the handle of the Broad Street pump by a committee instigated to action by John Snow (1813-1858) .
• 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 as to contaminated drinking water being the likely source of the disease, quickly identified the East London Water Company as the source of the contaminated water. Swift action prevented further deaths.
• 1881-1896 - Fifth Cholera pandemic ; The 1892 outbreak in Hamburg, Germany was the only major European outbreak, about 8,600 died, 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 this was suppressed in the USSR.
• January 1991 to September 1994 - Outbreak in South America, apparently initiated by 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 to 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 Tamilnadu, 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 as to the emergence of wide-spectrum resistance to drugs such as trimethoprim, sulfamethoxazole and streptomycin.

Famous cholera victims

The crying and pathos in the last movement of Tchaikovsky's last symphony made people think that Tchaikovsky had a premonition of death. "A week after the premiere of his Sixth Symphony, Tchaikovsky was dead--6 Nov. 1893. The cause of this was suspected to be his intentionally infecting himself with cholera by drinking contaminated water. The day before while having lunch with Modest (his brother and biographer), he is said to have poured faucet water from a pitcher into his glass and drunk a few swallows. Since the water was not boiled and cholera was once again rampaging St. Petersburg, such a connection was quite plausible ...."

Research

The major contributions to fighting cholera were made by physician 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 the source of the disease to an infected well in London. Their conclusions established a definite link between germs and disease. Clean water and good sewage treatment, despite their 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 as the bacillus causing the disease in 1885. The bacterium had been originally isolated thirty years earlier (1855) by Italian anatomist Filippo Pacini, but his results were not widely known.

Other historical information

In the past, people travelling in ships would hang a yellow 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 of time, typically 30 to 40 days.

A persistent myth states that 90,000 people died in Chicago of cholera and typhoid fever in 1885. This has no factual basis. In 1885, a torrential rainstorm flushed the Chicago river and its attendant pollutants far enough into Lake Michigan 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.