Cholera

Cholera is a disease that causes foul-smelling diarrhea that looks like rice water.

Cholera is an acute infectious disease caused by a bacterium, Vibrio cholerae (V. cholerae), which usually results in painless, watery diarrhea in humans. Some affected individuals have copious amounts of diarrhea and develop dehydration so severe it can lead to death. Most people who get the disease ingest the organisms through food or water sources contaminated with V. cholerae. Although symptoms may be mild, some previously healthy people will develop copious diarrhea within about one to five days after ingesting the bacteria. Severe disease requires prompt medical care. Hydration (usually by IV with a rehydration solution for the very ill) of the patient, and antibiotics in some individuals, is the key to surviving the severe life-threatening form of the disease. Subtypes of V. cholerae that may cause severe cases to include 01 and 0139.

The World Health Organization (WHO) has maps of current and past areas with cholera outbreaks (see WHO reference). It is estimated that about 1.4 million to 4.3 million people are infected worldwide each year, with approximately 28,000-142,000 deaths per year. Only about one in 10 people infected with cholera develop the typical signs and symptoms. Outbreaks of cholera in 2015-2016 include South Sudan, the United Republic of Tanzania, and Kenya, with over 216 deaths and most recently, 121 people diagnosed with cholera in Iraq, their first outbreak since 2012, and in Cuba, the first outbreak in over 130 years.

The term cholera has a long history (see history section below) and has been assigned to several other diseases. For example, fowl or chicken cholera is a disease that can rapidly kill chickens and other avian species with a major symptom of diarrhea. However, the disease-causing agent in fowl is Pasteurella multocida, a gram-negative bacterium. Similarly, pig cholera (also termed hog or swine cholera) can cause rapid death (in about 15 days) in pigs with symptoms of fever, skin lesions, and seizures. This disease is caused by a pestivirus termed CSFV (classical swine fever virus). Neither one of these animal diseases is related to human cholera, but the terminology can be confusing.

Cholera has likely been affecting humans for many centuries. Reports of the cholera-like disease have been found in India as early as 1000 AD. Cholera is a term derived from Greek khole (illness from bile) and later in the 14th century to colere (French) and choler (English). In the 17th century, cholera was a term used to describe a severe gastrointestinal disorder involving diarrhea and vomiting. There were many outbreaks of cholera, and by the 16th century, some were being noted in historical writings. England had several in the 19th century, the most notable being in 1854 when Dr. John Snow did a classic study in London that showed the main source of the disease (resulting in about 500 deaths in 10 days) came from at least one of the major water sources for London residents termed the "Broad Street pump." The pump handle was removed, and the cholera deaths slowed and stopped. The pump is still present as a landmark in London. Although Dr. Snow did not discover the cause of cholera, he did show how the disease could be spread and how to stop a local outbreak. This was the beginning of modern epidemiologic studies. The last reference shows the map Dr. Snow used to identify the pump site.

V. cholerae was first isolated as the cause of cholera by Filippo Pacini in 1854, but his discovery was not widely known until Robert Koch (who also discovered the cause of tuberculosis), working independently 30 years later, publicized the knowledge and the means of fighting the disease. The history of cholera repeats itself. The U.S. National Library of Medicine houses original documents about multiple cholera outbreaks in the U.S. from the 1820s to the 1900s, with the last large outbreak in 1910-1911. Since the 1800s, there have been seven cholera pandemics (worldwide outbreaks). The seventh pandemic of cholera started in 1961 and lasted until 1975; some researchers think the occasional outbreaks (even up to the present time) represent remnants of the seventh pandemic.

Cholera riots occurred in Russia and England (1831) and Germany (1893) when the people rebelled against strict government isolation (quarantines) and burial rules. In 2008, cholera riots broke out in Zimbabwe as police tried to disperse people who tried to withdraw funds from banks and were protesting because of the collapse of the health system that began with a cholera outbreak. Similar but less violent public protests have occurred when yellow fever, typhoid fever, and tuberculosis quarantines have been enforced by health authorities.

Multiple outbreaks continue into the 21st century, with outbreaks in India, Iran, Vietnam, and several African countries over the last 10 years. Some recent outbreaks occurred in Haiti and Nigeria in 2010-2011, and South Sudan, Tanzania, Iraq, Kenya, and Cuba in 2015-2016, and Yemen in 2017-18. From 2017-to 2018, the WHO has listed 1,084,191 suspected cases of cholera with 2,267 associated deaths in war-torn Yemen.

Why is cholera history repeating itself? The answer can be traced back to Dr. Snow's studies that show a source (water-borne or occasionally food) contaminated with V. cholerae can easily and rapidly transmit the cholera-causing bacteria to many people. Until safe, clean water and food are available to all humans, cholera outbreaks will likely continue to happen.

Cholera is caused by the bacterium Vibrio cholerae. This bacterium is Gram-stain-negative, comma-shaped, and has a flagellum (a long, tapering, projecting part) for motility and pili (hairlike structures) used to attach to tissue. Although many V. cholerae serotypes can produce cholera symptoms, the O groups O1 and O139, which also produce a toxin, cause the most severe symptoms of cholera. O groups consist of different lipopolysaccharides-protein structures on the surface of bacteria that are distinguished by immunological techniques.

The toxin produced by these V. cholerae serotypes is an enterotoxin composed of two subunits, A and B; the genetic information for the synthesis of these subunits is encoded on plasmids (genetic elements separate from the bacterial chromosome). In addition, another plasmid type encodes for a pilus (a hollow hairlike structure that supports bacterial attachment to human cells and facilitates the movement of toxins from V. cholerae into human cells). The enterotoxin causes human cells to extract water and electrolytes from the body (mainly the upper gastrointestinal tract -- small intestine) and pump it into the intestinal lumen where the fluid and electrolytes are excreted as diarrheal fluid. The enterotoxin is similar to toxin formed by bacteria that cause diphtheria in that both bacterial types secret the toxins into their surrounding environment where the toxin then enters the human cells. The bacteria are usually transmitted by drinking contaminated water, but the bacteria can also be ingested in contaminated food, especially seafood such as raw oysters.

Everyone who drinks or eats food that has not been treated to eliminate V. cholerae (liquids need to be chemically treated, boiled, or pasteurized, and foods need to be cleaned and cooked), especially in areas of the world where cholera is present, is at risk for cholera.

Outbreaks occur when there are disasters or other reasons for a loss of sanitary human waste disposal and the lack of safe fluids and foods for people to ingest. Haiti, a country that had not seen a cholera outbreak in over 50 years, had such circumstances develop in 2010 after a massive earthquake destroyed sanitary facilities and water and food treatment facilities for many Haitians. Post-earthquake, V. cholerae bacteria eventually contaminated primary water sources, resulting in over 530,000 people diagnosed with cholera that resulted in over 7,000 deaths. This cholera outbreak spread to Haiti's neighbor, the Dominican Republic. The Vibrio cholerae strain was closely related to a strain found in Nepal and leads some individuals to blame Nepalese troops (United Nations aid troops) that helped with the earthquake disaster as the source of the Haiti cholera outbreak. In 2010, the United Nations Secretary-General, Ban Ki-moon, apologized for the outbreak that first developed near a U.N. base.

In third-world countries, hunger can lead people to inadvertently eat contaminated food and/or drink contaminated water, thus raising the risk of cholera infecting malnourished populations.

There is some evidence that V. cholerae can survive in salt water and have been isolated from shellfish; eating raw oysters is considered a risk factor for cholera, especially in underdeveloped countries and occasionally even in developed countries. A few people are diagnosed with cholera every year in the U.S. Most of the individuals diagnosed are travelers who were exposed to cholera outside the country, but occasionally, isolated cases are traced to contaminated seafood, usually from states that border the Gulf of Mexico.

Some individuals are at higher risk to become infected than others. People who are malnourished or immune-compromised are more likely to get the disease. Children ages 2-4 seem more susceptible than older children, according to some investigators. In addition, researchers have noted that patients with blood type O are twice as likely to develop cholera as others. The reason for this blood type susceptibility is not completely understood. People with achlorhydria (reduced acid secretion in the stomach) and people taking medicines to reduce stomach acid (H2 blockers and others) are also more likely to develop cholera because stomach acid kills many types of bacteria, including V. cholerae.

Figure 1: Rice-water stool from a patient with cholera; note the flecks of mucus precipitated at the bottom of the cup that resembles rice grains. SOURCE: CDC

Figure 2: Washerwoman hands (loss of skin elasticity) are a sign of the dehydration seen in cholera. SOURCE: CDC

The symptoms and signs of cholera-related disease are watery diarrhea that often contains flecks of whitish material (mucus and some gastrointestinal lining [epithelial] cells) that are about the size of pieces of rice. The diarrhea is termed "rice-water stool" (See figure 1) and smells "fishy." Although many bacterial infections may cause diarrhea, the volume of diarrhea with cholera can be enormous; high levels of diarrheal fluid, such as 250 cc per kg or about 10 to 18 liters over 24 hours for a 154-pound adult, can occur. People may go on to develop one or more of the following symptoms and signs:

• Watery diarrhea (sometimes in large volumes)
• Rice-water stools (see figure 1)
• Fishy odor to stools
• Vomiting
• Rapid heart rate
• Loss of skin elasticity (washerwoman hands sign; see figure 2)
• Dry mucous membranes (dry mouth)
• Low blood pressure
• Thirst
• Muscle cramps (leg cramps, for example)
• Restlessness or irritability (especially in children)
• Unusual sleepiness or tiredness

Other symptoms that may occur, especially with more severe diseases, include the following:

• Abdominal pain (cramps)
• Rectal pain
• Fever
• Severe vomiting
• Dehydration
• Low or no urine output
• Weight loss
• Seizures
• Shock
• Death

Those infected require immediate hydration to prevent these symptoms from continuing because these signs and symptoms indicate that the person is becoming or is dehydrated and may go on to develop severe cholera. People with severe cholera (about 5%-10% of previously healthy people; higher if a population is compromised by poor nutrition or has a high percentage of very young or elderly people) can develop severe dehydration, leading to acute renal failure, severe electrolyte imbalances (especially potassium and sodium), and coma. If untreated, this severe dehydration can rapidly lead to shock and death. Severe dehydration can often occur four to eight hours after the first liquid stool, ending with death in about 18 hours to a few days in undertreated or untreated people. In epidemic outbreaks in underdeveloped countries where little or no treatment is available, the mortality (death) rate can be as high as 50%-60%.

Because most individuals have either mild or no symptoms, these people are either not treated or treated by their primary care physician. However, in some children and in individuals who have more severe diseases, besides the primary care physician or pediatrician, an infectious-disease specialist, a critical care specialist, a gastroenterologist, and/or an internist may be needed to help the team manage and treat the patient.

In addition, specialists in travel medicine and/or epidemiology can help individuals avoid cholera and/or can give advice about prevention, treatment, and prognosis to those individuals traveling to or living in endemic areas.

Preliminary diagnosis is usually done by a caregiver who takes a history from the patient and observes the characteristic rice-water diarrhea, especially if a local outbreak of cholera has been identified. The diarrhea fluid is often teeming with motile, comma-shaped bacteria (presumptively V. cholerae) that can be seen with a microscope. The definitive diagnosis is made by isolation of the bacteria from diarrhea fluid. All state health department laboratories in the U.S. can perform tests for Vibrio cholerae. Readers may see terms like serotypes Inaba, Ogawa, and Hikojima to describe V. cholerae; they simply indicate which O antigens (O antigens designated A, B, or C) are found on these strains of V. cholerae. PCR tests have also been developed to detect the genetic material of cholera, but currently, they are not as widely used as the immunologic tests based on type-specific antiserum.

A definitive diagnosis helps to distinguish cholera from other diseases caused by other bacterial, protozoal, or viral pathogens that cause dysentery (gastrointestinal inflammation with diarrhea).

The CDC (and almost every medical agency) recommends rehydration with ORS (oral rehydration salts) fluids as the primary treatment for cholera. ORS fluids are available in prepackaged containers, commercially available worldwide, and contain glucose and electrolytes. The CDC follows the guidelines developed by the WHO (World Health Organization) as follows:

*Repeat once if the radial pulse is still very weak or not detectable

• Reassess the patient every one to two hours and continue hydrating. If hydration is not improving, give the IV drip more rapidly. 200 mL/kg or more may be needed during the first 24 hours of treatment.
• After six hours (infants) or three hours (older patients), perform a full reassessment. Switch to ORS solution if hydration is improved and the patient can drink.

In general, antibiotics are reserved for more severe cholera infections; they function to reduce fluid rehydration volumes and may speed recovery. Although good microbiological principles dictate it is best to treat a patient with antibiotics that are known to be effective against the infecting bacteria, this may take too long a time to accomplish during an initial outbreak (but it still should be attempted); meanwhile, severe infections have been effectively treated with tetracycline (Sumycin), doxycycline (Vibramycin, Oracea, Adoxa, Atridox, and others), furazolidone (Furoxone), erythromycin (E-Mycin, Eryc, Ery-Tab, PCE, Pediazole, Ilosone), or ciprofloxacin (Cipro, Cipro XR, ProQuin XR) in conjunction with the following antibiotics in conjunction with IV hydration and electrolytes:

• Tetracycline (Sumycin)
• Doxycycline (Vibramycin, Oracea, Adoxa, Atridox, and others)
• Furazolidone (Furoxone)
• Erythromycin (E-Mycin, Eryc, Ery-Tab, PCE, Pediazole, Ilosone)
• Azithromycin (Zithromax)
• Sulfamethoxazole/trimethoprim (Bactrim, Septra)
• Ampicillin
• Ciprofloxacin (Cipro, Cipro XR, ProQuin XR)
• Norfloxacin (Noroxin)

Many antibiotics are listed; however, because of widespread antibiotic resistance, including multi-resistant Vibrio strains, antibiotic susceptibility testing is advised so the appropriate antibiotic is chosen. In addition, quinolones (for example, ciprofloxacin, and norfloxacin) should not be used in children if other antibiotics can be effective because of possible musculoskeletal adverse effects.

It takes about 100 million V. cholerae bacteria to infect a healthy adult. Because of this high number, significant contamination of food or water is required to transmit the disease, and direct person-to-person transmission is thought to be uncommon except in outbreaks. In outbreaks, cholera-causing bacteria become highly contagious indirectly and directly by the fecal-oral route because of widespread fecal contamination of food, water, and items like contaminated bedding and clothing.

The incubation period (time period from exposure to the bacteria to the development of symptoms) may vary from a few hours (about six to 12 hours) to five days, with the average incubation period being about two to three days. About six to 12 hours is considered a very rapid incubation period and may suggest that rapid/immediate intervention is required for recovery.

The contagious period for cholera begins as soon as organisms are excreted in the feces. This can occur as early as about six to 12 hours after exposure to the bacteria and can last for about seven to 14 days. Some individuals who are asymptomatic (infected but not having symptoms) will also excrete contagious organisms for about seven to 14 days.

Yes, cholera can be prevented by several methods. Developed countries have an almost zero incidence of cholera because they have widespread water-treatment plants, food-preparation facilities that usually practice sanitary protocols, and most people have access to toilets and hand-washing facilities. Although these countries may have occasional lapses or gaps in these methods, they have prevented many disease outbreaks, including cholera.

Individuals can prevent or reduce the chance they may get cholera by thorough hand washing, avoiding areas and people with cholera, drinking treated water or similar safe fluids, and eating cleaned and well-cooked food. In addition, there are vaccines available that can help prevent cholera, although they are not available in the U.S., and their effectiveness ranges from 50%-90%, depending on the studies reported. The vaccines are oral cholera vaccines because injected vaccines have not proved to be very effective. Two vaccines (Shanchol and Dukoral) are composed of killed V. cholerae bacteria and don't contain the enterotoxin B subunit. Unfortunately, both offer protection for only about two years, although one report suggests that Shanchol is about 65% effective over five years. Both vaccines are usually given in two doses, about one to six weeks apart. Unfortunately, the vaccines have limited availability; their recommended use is for people going to areas of known outbreaks with the likely possibility the person may be exposed to cholera. Some researchers suggest this limited oral vaccine availability should be changed and cite data that oral vaccines may help limit outbreaks, even after they have begun.

Research is ongoing; a research study in Haiti will try to determine if a two-dose vaccine in people will suffice to protect a difficult to treat (rural poor) population from cholera and thus save many lives. Over 30 universities are researching this disease (cholera's epidemiology, pathology, immunology, vaccine production, and other problems) currently worldwide.

In 2015, about 2 million doses of oral cholera vaccine were shipped to various outbreak areas, and currently, available information suggests that there was a significant reduction in transmission of endemic cholera; the study will be concluded in 2018.

In June 2016, the U.S. FDA (Food and Drug Administration) approved the first vaccination available in the United States to prevent cholera. The vaccine is termed Vaxchora and is manufactured by PaxVax Bermuda LTD. It can be used in adults aged 18-64 who are traveling to cholera-affected areas of the world. The vaccine is a live, attenuated (weakened) dose of V. cholerae serogroup 01, the most prominent cause of cholera worldwide. The vaccine is administered orally in about 3 ounces of fluid. It is about 80% effective in individuals challenged with Vibrio bacteria three months after vaccination. The vaccine (one-dose or single-dose) should be administered at least 10 days before the individual travels to a cholera-endemic area.

The prognosis (outcome) of cholera can range from excellent to poor, depending on the severity of the dehydration and how quickly the patient is given and responds to treatments. Death (mortality) rates in untreated cholera can be as high as 50%-60% during large outbreaks but can be reduced to about 1% if treatment protocols (see above treatment section) are rapidly put into action. In general, the less severe the symptoms and the fewer times people have dehydration symptoms, the better the prognosis; in many people, if dehydration is quickly reversed, the prognosis is often excellent.