Cholera

In 2015, 172 454 cases and 1304 deaths of cholera were reported to WHO worldwide. Outbreaks continued to affect several countries. Overall, 41% of cases were reported from Africa, 37% from Asia and 21% from the Americas. Cholera remains a major public health problem and affect primarily developing world populations with no proper access to adequate water and sanitation resources.

Cholera is an infection of the small intestine by some strains of the bacterium Vibrio cholerae.^[3] Symptoms may range from none, to mild, to severe.^[2] The classic symptom is large amounts of watery diarrhea that lasts a few days.^[1] Vomiting and muscle cramps may also occur.^[2] Diarrhea can be so severe that it leads within hours to severe dehydration and electrolyte imbalance.^[1] This may result in sunken eyes, cold skin, decreased skin elasticity, and wrinkling of the hands and feet.^[4] The dehydration may result in the skin turning bluish.^[7] Symptoms start two hours to five days after exposure.^[2]

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.^[1] Undercooked seafood is a common source.^[8] 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.^[1] Cholera can be diagnosed by a stool test.^[1] A rapid dipstick test is available but is not as accurate.^[9]

Prevention involves improved sanitation and access to clean water.^[4] 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.^[1] Rice-based solutions are preferred.^[1] Zinc supplementation is useful in children.^[5] 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.^[2]

Cholera affects an estimated 3–5 million people worldwide and causes 28,800–130,000 deaths a year.^[1][6] While it is currently classified as a pandemic, it is rare in the developed world. Children are mostly affected.^[1][10] Cholera occurs as both outbreaks and chronically in certain areas. Areas with an ongoing risk of disease include Africa and south-east Asia. While the risk of death among those affected is usually less than 5%, it may be as high as 50% among some groups who do not have access to treatment.^[1] Historical descriptions of cholera are found as early as the 5th century BC in Sanskrit.^[4] The study of cholera by John Snow between 1849 and 1854 led to significant advances in the field of epidemiology.

The primary symptoms of cholera are profuse diarrhea and vomiting of clear fluid.^[12] These symptoms usually start suddenly, half a day to five days after ingestion of the bacteria.^[13] The diarrhea is frequently described as “rice water” in nature and may have a fishy odor.^[12] An untreated person with cholera may produce 10 to 20 litres (3 to 5 US gal) of diarrhea a day.^[12] Severe cholera, without treatment, kills about half of affected individuals.^[12] If the severe diarrhea is not treated, it can result in life-threatening dehydration and electrolyte imbalances.^[12] Estimates of the ratio of asymptomatic to symptomatic infections have ranged from 3 to 100.^[14] Cholera has been nicknamed the “blue death” because a person’s skin may turn bluish-gray from extreme loss of fluids.^[15]

Fever is rare and should raise suspicion for secondary infection. Patients can be lethargic, and might have sunken eyes, dry mouth, cold clammy skin, decreased skin turgor, 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 losses and ion shifts are common, especially in children.^[12]

Cause

Vibrio cholerae, the bacterium that causes cholera

Transmission

Cholera has been found in two animal populations: shellfish and plankton.^[12]

Transmission is usually through the fecal-oral route of contaminated food or water caused by poor sanitation.^[1] Most cholera cases in developed countries are a result of transmission by food, while in the developing world it is more often water.^[12] 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.^[16]

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.^[17] 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 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.^{[medical citation needed]}

Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a temperate bacteriophage.^[18]

Susceptibility

About 100 million bacteria must typically be ingested to cause cholera in a normal healthy adult.^[12] This dose, however, is less in those with lowered gastric acidity (for instance those using proton pump inhibitors).^[12] Children are also more susceptible, with two- to four-year-olds having the highest rates of infection.^[12] Individuals’ susceptibility to cholera is also affected by their blood type, with those with type O blood being the most susceptible.^[12] Persons with lowered immunity, such as persons with AIDS or children who are malnourished, are more likely to experience a severe case if they become infected.^[19] 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.^{[medical citation needed]}

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.^[20] 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.

Mechanism

Drawing of Death bringing cholera, in Le Petit Journal (1912)

Emperor Pedro II of Brazil visiting people with cholera in 1855.

When consumed, most bacteria do not survive the acidic conditions of the human stomach.^[21] The few surviving bacteria 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 must propel themselves through the thick mucus that lines the small intestine to reach the intestinal walls where they can attach and thrive.^[21]

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 which 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.^{[medical citation needed]}

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).^[22] 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 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.^[23] 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 litres 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.^{[medical citation needed]}

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.^{[medical citation needed]} 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.^[23] 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.”^[23]

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.^[24]

Antibiotic resistance

In many areas of the world, antibiotic resistance is increasing. In Bangladesh, for example, most cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin.^[25] Rapid diagnostic assay methods are available for the identification of multi-drug resistant cases.^[26] New generation antimicrobials have been discovered which are effective against cholera bacteria in in vitro studies.^[27]

Diagnosis

A rapid dipstick test is available to determine the presence of V. cholerae.^[25] In those samples that test positive, further testing should be done to determine antibiotic resistance.^[25] 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.^[28]

Prevention

Cholera hospital in Dhaka, showing typical “cholera beds”

The World Health Organization (WHO) recommends focusing on prevention, preparedness, and response to combat the spread of cholera.^[29] They also stress the importance of an effective surveillance system.^[29] Governments can play a role in all of these areas, and in preventing cholera or indirectly facilitating its spread.

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.^[30][31] 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:^{[medical citation needed]}

• Sterilization: Proper disposal and treatment of infected fecal waste water produced by cholera victims and all contaminated materials (e.g. clothing, bedding, etc.) are essential. All materials that come in contact with cholera patients 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: 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 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 and/or ash after visiting toilets and before handling food or eating is also recommended for cholera prevention by WHO Africa