Cholera

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Tarek Nafee, M.D. [2], Aysha Anwar, M.B.B.S[3], Sara Mehrsefat, M.D. [4], Priyamvada Singh, MBBS [5]

Cholera is an infection of the small intestine caused by the bacterium Vibrio cholerae. The main symptoms are profuse, watery diarrhea and vomiting. Transmission occurs primarily by drinking water or eating food that has been contaminated by the feces of an infected person, including one with no apparent symptoms. The severity of the associated diarrhea and vomiting can lead to rapid dehydration, an electrolyte imbalance, and, in some cases, death. The primary treatment is oral rehydration therapy, typically with oral rehydration solution (ORS), which serves to replace water and electrolytes. If this is not tolerated or does not provide fast enough improvement, intravenous fluids can also be used. Antibacterial drugs are beneficial in those with severe forms of the disease, as they shorten the duration and mitigate the severity of cholera. Worldwide, cholera affects 3–5 million people and causes 100,000–130,000 deaths a year. Cholera was one of the earliest infections to be studied with epidemiological methods.

The cholera-causing bacterium was originally isolated in 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, identified a link between cholera and contaminated drinking water.^[1] Dr. Snow proposed a microbial origin for epidemic cholera in 1849.

Most of the V. cholerae bacteria cannot survive the highly acidic conditions of the human stomach.^[2] The few bacteria that do manage to survive the stomach’s acidity conserve their energy and stored nutrients during passage through the stomach by largely shutting down protein production and subsequently restarting production in the more favorable environment of the small intestine. The toxins that interact with mechanisms of the host cell pump chloride ions into the small intestine, creating an ionic pressure that prevents sodium ions from entering the cell. The chloride and sodium ions create a saltwater environment in the small intestine, which, through osmosis, can pull up to six liters of water per day through the intestinal cells. This effect is responsible for the high frequency of diarrhea that is characteristic of cholera. The host can rapidly become severely dehydrated if an appropriate mixture of dilute saltwater and sugar is not taken to replace the blood’s water and salts lost in the diarrhea.

Vibrio cholerae is a gram negative bacterium with a curved-rod shape that causes cholera in humans.^[3] V. cholerae and other species of the genus Vibrio belong to the gamma subdivision of the Proteobacteria.  There are two major strains of V. cholerae, classic and El Tor, and numerous other serogroups.^{[3][4][5][6][7]}

Patients with cholera may have a history of consumption of contaminated food or water and travel to an endemic area. The symptoms usually develop within 24-48 hours of consumption of contaminated food. Patients present with sudden-onset, painless, odorless, rice-watery, large volume stool; abdominal cramps; vomiting; and fever. It should be differentiated from other infectious causes of diarrhea (e.g., rotavirus, E. coli, amoebic dysentry, giardiasis). It should also be differentiated from some non-infectious causes of diarrhea (e.g., VIPoma, tubulovillous adenoma, food poisoning).^{[8][9][10][11]}

Cholera affects an estimated 3-5 million people worldwide and causes 100,000-130,000 deaths a year as of 2010. Mortality due to cholera occurs mainly in the developing world.^[12] In the early 1980s, death rates are believed to have been greater than 3 million a year. It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism industries of endemic countries.^[13] Cholera remains both epidemic and endemic in many areas of the world. Although much is known about the mechanisms behind the spread of cholera, this has not led to a full understanding of what makes cholera outbreaks happen in some places but not others. Inadequate or nonexistent treatment of human feces and drinking water greatly facilitate the spread of cholera, while bodies of water can serve as reservoirs and seafood shipped over long distances can spread the disease. Cholera was not observed in the Americas for most of the 20th century, but it reappeared towards the end of that century and seems likely to persist.^[14]

Certain factors have been found to be associated with an increased risks of cholera. Among these are decreased immunity, decreased gastric pH, certain blood groups (people with type O blood are most prone, while people with type AB blood are least prone), and genetics are the most commonly associated factors.^[15][16][17] At particular risk are people residing in over-populated communities and refugee settings characterized by poor sanitation, unsafe drinking water, and, consequently, increased person-to-person transmission.^[18]

There are no screening guidelines for cholera.^[19]

Cholera infection can cause a severe diarrheal illness through the acute and substantial loss of water and electrolytes.^[3] The incubation period is very short (between 2 hours and 5 days); consequently, the number of cases in an area can rise extremely quickly. Delayed initiation of oral rehydration therapy or inadequate rehydration may lead to hypotension and electrolyte imbalance (mostly hypokalemia). Untreated dehydration may lead to hypotension, which can result in renal failure, hypovolemic shock, coma, and death. Untreated hypokalemia can lead to nephropathy and focal myocardial necrosis. Among children, hypoglycemia is common and can lead to seizures.^[18] If a patient with cholera is treated quickly and properly, the mortality rate is less than 1%. Without adequate treatment, the mortality rate rises to 50–60%.^[20][21]

A cholera patient’s history may involve the consumption of contaminated food or water and/or travel to an endemic area. Symptoms associated with cholera usually develop within 24-48 hour of infection. Patients present with sudden-onset, painless, odorless, rice-watery, large-volume stool; abdominal cramps; vomiting; and fever. If the severe diarrhea and vomiting are not aggressively treated, they can result in life-threatening dehydration and electrolyte imbalances within hours. The typical symptoms of dehydration include dizziness (due to low blood pressure), wrinkled hands (due to poor skin turgor), sunken eyes, muscle cramps (due to hypokalemia), and decreased urine output.^[8][22][23]

Signs of cholera on a physical examination depend on the patient’s level of dehydration. The patient may present with tachycardia, postural hypotension, somnolence, dry mucous membrane, sunken eyes, and/or oliguria. If the severe diarrhea and vomiting are not aggressively treated, they can result in life-threatening dehydration and electrolyte imbalances within hours. Typical symptoms of dehydration include dizziness (due to low blood pressure), wrinkled hands (due to poor skin turgor), sunken eyes, muscle cramps (due to hypokalemia), and decreased urine output.

Laboratory tests are not mandatory for the diagnosis and treatment of cholera. When cholera is suspected in an endemic area, treatment should be started as early as possible with fluid replacement and antibiotics. In areas where cholera is uncommon, it is worthwhile to perform lab tests. Tests used for the identification of organisms include direct microscopic examination of organism, dark field examination, gram staining, culture, antigen, polymerase chain reaction, and serotype tests.^{[24][25][26][27][28][29][5]}

There are no x-ray findings associated with cholera infection.^[24][25]

There are no CT scan findings associated with cholera infection.^[24][25]

There are no MRI findings associated with cholera infection.^[24][25][30]

Other diagnostic tests which may be used for cholera toxin detection include (EIS) microfluidic chips for flow immunoassay and lab-on-a-bubble surface enhanced raman indirect immunoassay for cholera.^[31][32]

In most cases, cholera can be successfully treated with oral rehydration therapy (ORT), which is highly effective, safe, and simple to administer. In severe cases with significant dehydration, intravenous rehydration may be necessary. Ringer’s lactate is the preferred solution, often with added potassium. Large volumes and continued replacement may be necessary until diarrhea has subsided.^[33][34] Ten percent of a person’s body weight in fluid may need to be given in the first two to four hours. Antibiotic treatments for one to three days shorten the course of the disease and reduce the severity of the symptoms.^[35] Patients can recover even without antibiotics, as long as sufficient hydration and electrolyte balance is maintained. Doxycycline is typically used as a first-line intervention,^[36] although some strains of V. cholerae have shown resistance.^[37] Zinc supplementation has been shown to reduce stool output and to reduce the duration and severity of symptoms.^[38]

Surgery is not recommended for the management of cholera.

Primary prevention of cholera can be achieved on an individual level by appropriate personal hygiene; use of sanitary water supply; appropriate preparation of food; as well as prompt identification, isolation, and treatment of new cases. Primary preventive methods may also be implemented on a community level through effective water sanitation, appropriate, and broad vaccination of the community to develop herd immunity, as well as early detection of an outbreak.^{[39][40][41][42][43][44]}

Secondary prevention of cholera includes prompt and appropriate diagnosis and treatment of patients with suspected cholera.^[33][34]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editors-In-Chief: Priyamvada Singh, MBBS [4]

The cholera-causing bacterium was originally isolated in 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, identified a link between cholera and contaminated drinking water.^[1] Dr. Snow proposed a microbial origin for epidemic cholera in 1849.

• The Russian-born bacteriologist Waldemar Haffkine developed the first cholera vaccine around 1900. The bacterium had originally been isolated 45 years earlier (1855) by Italian anatomist Filippo Pacini, but its exact nature and his results were not widely known.
• One major contribution to the fight against 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.^[1] 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 that human sewage contamination was the most probable disease vector in two major epidemics in London in 1854.^[2] His model was not immediately accepted by the scientific community, but it was accepted as the most plausible possibility as medical microbiology developed over the next several decades.
• Cities in developed nations made massive investments in maintaining clean water supplies 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 around the world. In 1883, Robert Koch identified V. cholerae with a microscope as the bacillus that caused cholera.^[3]
• Cholera has been a representative case in 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 the partition, both regions had cholera pathogens with similar characteristics. After 1947, India made more progress in the realm of public health than did 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, which 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 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 that 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.^[4]
• 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.^[5]

• 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 [5]. 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.^[6] 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 [6] and over 3,000 in New Orleans [7] as well as thousands in New York.^[7] 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.^[8]
• 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).[8]. Soho outbreak in London stopped by removing the handle of the Broad Street pump by a committee instigated to action by John Snow .^[9]
• 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.^[10] 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.^[11]
• 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 of a Cholera outbreak in Iraq.^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Tarek Nafee, M.D. [2], Sara Mehrsefat, M.D. [3], Priyamvada Singh, MBBS [4]

Vibrio cholerae is classified into more than 200 serogroups, which can cause epidemic cholera only if they also produce the cholera toxin. The two serogroups that fall into this category include serogroup O1 and serogroup O139.^[1][2]

Vibrio cholerae has many different types, or “serogroups.” Only two of these serogroups can cause epidemic cholera because they also produce the cholera toxin. Those two serogroups include:^[1][2]

• Serogroup O1
• Serogroup O139 (found only in Asia)

Serogroups which can cause a less severe diarrheal disease and does not have epidemic potential include:

• Non-O1 and non-O139 Vibrio cholerae (third most commonly reported group of Vibrio bacteria)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS, Aysha Anwar, M.B.B.S[2]

Cholera is mainly caused by two pathogenic serotypes of V. cholerae: O1 and O139. V. cholerae is usually transmitted via the fecal-oral route to the human host. Following ingestion, the V. cholerae must overcome the host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and osmolarity. After gaining access to small intestine, V. cholerae uses flagella to propogate through the mucus layer covering the small intestine and colonizes the small intestinal cells, using toxin-coregulated pilus (TCP) to form a biofilm. Diarrheal illness in the human host is mainly caused by production of enterotoxin.^{[1] [2][3][4][5][6][7][8][9][10]}

Cholera is mainly caused by two pathogenic serotypes of V. cholerae: O1 and O139. The pathogenesis underlying acute diarrheal illness is as follows:^{[1][2][3][4][5][6][7][8][9][10]}

• V. cholerae is usually transmitted via the fecal-oral route to the human host.
• Following ingestion, the V. cholerae must overcome host defense mechanisms such as gastric acidity, intestinal inhibitory factors, and changes in temperature and osmolarity.
• Infective dose varies from 102-106.
• The incubation period varies from a few hours to a few days.

• After gaining access to small intestine, V. cholerae uses flagella to propagate through the mucus layer covering small intestine and colonizes the small intestinal cells using toxin-coregulated pilus (TCP) forming a biofilm.

• Diarrheal illness in human host is mainly caused by production of enterotoxin.
• The production of enterotoxin protein in the small intestinal cells is the main mechanism responsible for causing acute diarrheal illness.
• It has 5B subunits and 2A subunits.
  • B subunits bind the enterocytes via GM1 ganglioside receptors and cause internalization of A subunits in the cells via endocytosis.
  • A subunits then bind and activate the adenylate cyclase enzyme in the enterocytes, increasing the levels of cAMP.
• Increased levels of enterotoxin cause activation of the cystic fibrosis transmembrane conductance regulator (CFTR), causing increased secretion of water, sodium, and chloride from enterocytes, which causes watery diarrhea.

The different virulence factors involved in the pathogenesis of V. cholerae involve activation of transcription factors such as ToxR, TcpP, and ToxT. Different toxins expressed by these transcription factors include:

• Zona occludens toxin (zot, causes invasion by decreasing intestinal tissue resistance)
• Accessory cholera toxin (ace, increases fluid secretion)
• Toxin-coregulated pilus (tcpA, essential colonization factor and receptor for the CTXf phage)
• NAG-specific heat-labile toxin (st)
• Outer membrane porin proteins (ompU and ompT)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS [2], Aysha Anwar, M.B.B.S[3]

Vibrio cholerae is a gram negative bacterium with a curved-rod shape that causes cholera in humans.^[1] V. cholerae and other species of the genus Vibrio belong to the gamma subdivision of the Proteobacteria.  There are two major strains of V. cholerae, classic and El Tor, and numerous other serogroups.^{[1][2][3][4][5]}

V. cholerae occurs naturally in the plankton of fresh water, brackish water, and saltwater, attached primarily to copepods in the zooplankton. Coastal cholera outbreaks typically follow zooplankton blooms. This makes cholera a typical zoonosis.^[2][6]

More than 200 serovars of Vibrio cholera have been identified. Two serogroups, O1 and O139, are mainly associated with major outbreaks of cholera.^[3]

There are two main biotypes of Vibrio cholerae:

• Classic
• E1 Tor

Each biotype is further associated with three serotypes based on difference in structure of O antigen:^[6]

• Serotype Inaba
• Serotype Ogawa
• Serotype Hikcojima

Features of Vibrio cholerae include:^[6]

• Gram negative
• Comma shaped organism
• Flagellated
• Halophillic
• Aerobic or facultatively anaerobic
• Two antigens, H and O

• O polysaccharide antigen
• H flagellar antigen

• Pathogenic factors

• Enterotoxin (cholera toxin)
• “Zona Occludans Toxin” (attacks the zona occludans or “tight” junctions joining epithelial cells)
• Other proteases such as mucinases and chitinases

The genome of V. cholerae consists of two chromosomes. The following genes may be associated with pathogenesis of Vibrio cholerae.^[5][7][8][9]

CtxAB genes

CT is encoded by the ctxAB genes on a specific filamentous bacteriophage. Transduction of this phage is dependent upon bacterial expression of the Toxin Coregulated Pilus (TCP), which is encoded by the V. cholerae pathogenicity island (VPI).

V. cholerae pathogenicity island (VPI)

VPI is generally only present in virulent strains and is laterally transferred. VPI was originally thought to encode a filamentous phage responsible for transfer. This theory was discredited by a study of 46 diverse V. cholerae isolates which found no evidence of VPI phage production. The generalized transduction phage CP-T1 has been shown to transduce the entire VPI, which is then integrated at the same chromosomal location. Also, VPI has been shown to excise and circularize to produce pVPI via a specialized mechanism involving VPI-encoded recombinases. It is not known whether pVPI is involved in CP-T1 transduction or if it is perhaps a component of an alternative VPI mobilization mechanism.^[5]

SXT/R391 ICE

SXT/R391 ICE is associated with the acquisition of antibiotic resistance by acquiring foreign DNA.^[7]

• 
  Crabs have been a repeated source of cholera in the United States and elsewhere, even though they are rarely eaten raw. From Public Health Image Library (PHIL). ^[10]
• 
  Typical Vibrio cholera contaminated water supply. From Public Health Image Library (PHIL). ^[10]
• 
  Scanning electron micrograph (SEM) depicts a number of Vibrio parahaemolyticus bacteria; Mag. 19058x. From Public Health Image Library (PHIL). ^[10]
• 
  Scanning electron micrograph (SEM) depicts a grouping of Vibrio vulnificus bacteria; Mag. 13184x. From Public Health Image Library (PHIL). ^[10]
• 
  Scanning electron micrograph (SEM) depicts a flagellated Vibrio vulnificus bacterium; Mag. 26367x. From Public Health Image Library (PHIL). ^[10]
• 
  Scanning electron micrograph (SEM) depicts a grouping of Vibrio vulnificus bacteria; Mag. 13184x. From Public Health Image Library (PHIL). ^[10]
• 
  Scanning electron micrograph (SEM) depicts a number of Vibrio cholerae bacteria of the serogroup 01; Magnified 22371x. From Public Health Image Library (PHIL). ^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS [2]

Patients with cholera may have a history of consumption of contaminated food or water and/or travel to an endemic area. Symptoms of cholera usually develop within 24-48 hour of infection. Patient presents with sudden-onset, painless, odorless, rice-watery, large-volume stool; abdominal cramps; vomiting; and fever. Cholera should be differentiated from other infectious causes of diarrhea such as rotavirus, E. coli, amoebic dysentry, and giardiasis. Cholera should also be differentiated from some non-infectious causes of diarrhea such as VIPoma, tubulovillous adenoma, and food poisoning.^[1][2][3][4]

Cholera must be differentiated from other conditions associated with acute onset diarrhea, including:^[1][2][3][4]

• It may be difficult to differentiate cholera from other infectious causes of diarrhea, especially if it is mild and in early stages.
• Fresh stool microscopy, stool culture, PCR, and other techniques help to differentiate these conditions. Stool tests are useful, cheap, and frequently used to differentiate cholera from other infectious conditions. Other tests (e.g., PCR, serotyping), though sensitive and specific, may not be performed due to prohibitive cost or lack of availability at many healthcare centers.

• Shigella patients present with acute, bloody diarrhea, whereas cholera patients have watery diarrhea.
• Shigella causes invasive diarrhea and thus presents with symptoms of fever, abdominal cramps, and rectal pain, which are not observed in patients with cholera.
• Vomiting is usually absent in shigella but is frequently seen in cholera.

• Bloody diarrhea, which is not seen in cholera, guides clinicians toward a diagnosis of dysentery.
• The volume of stool is not as high as seen in cases of cholera.

• The volume of stool is not as high as in cases of cholera.
• Stool microscopy is used to detect eggs and parasites.
• The stool of giardiasis patients produces a strong odor, whereas cholera patients usually have odorless stools.

• The volume of stool is not as high as in cases of cholera.
• Stool microscopy is used to detect eggs and parasites.

• The volume of stool is not as high as in cases of cholera.

• Patients present with a chronic history of diarrhea
• Volume of stool is not as high as in cases of cholera
• Negative stool examination and culture
• Fasting gut hormones confirm the diagnosis

• Colonoscopy and biopsy confirm the diagnosis
• Patients present with a chronic history of diarrhea
• Volume of stool is not as high as in cases of cholera
• Negative stool examination and culture

The table below summarizes the findings that differentiate watery causes of chronic diarrhea^[5][6][7][8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Sara Mehrsefat, M.D. [2], Tarek Nafee, M.D. [3], Priyamvada Singh, MBBS [4]Ahmed Younes M.B.B.CH [5]

In 2015, 172,454 cases and 1,304 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.^[1] In the early 1980s, mortality rates are believed to exceeded 3 million deaths a year. It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism of a country.^[2] Cholera remains both epidemic and endemic in many areas of the world. Although much is known about the mechanisms behind the spread of cholera, this has not led to a full understanding of what makes cholera outbreaks happen some places but not others. Lack of adequate treatment of human feces and/or drinking water greatly facilitates the spread of cholera. Bodies of water can serve as a reservoir of the disease. Seafood shipped over long distances can also spread the disease. Cases of cholera were not observed in the Americas for most of the 20th century, thought the disease reappeared towards the end of that century and seems likely to persist.^[3]

Date	Cases (confirmed and suspected)	Deaths	More details
June 11th, 2017	101,820	791 (0.7%)	Since the outbreak started in April 27, 2017, a total of 101,820 cases were suspected from which 791 died.[4] Most of the fatalities are children below 15 years (46% of cases) and elderly over 60 years (33% of cases). The disease is spreading in 19 out of 23 governorates in the country that is war torn.[5] The health system in the country is nearly destroyed which makes the mission to control the disease even harder. After 2 years of conflict, less than half of the healthcare centers are working. Medical supplies are entering Yemen in a rate that is third of what it used to be before the conflict. Moreover, infrastructure is terribly damaged preventing 14.5 million people from having access to clean water and sanitation. Efforts by WHO and UNICEF are made to control the outbreak especially in the “hotspots” or the most affected areas. 66.7 million US dollars are invested in the fight against the outbreak. Till the moment, 3.5 million people have been reached through disinfecting water tanks, chlorination of water and distributing hygiene kits.[4]
June 25th, 2017	200,000	1300 (0.65%)	Number of suspected cases has doubled so has the number of dead, making it the worst cholera outbreak in the recent history.[6] Numbers are expected to rise in the next few weeks. WHO and UNICEF are scaling up their efforts to contain the outbreak. Rapid response teams are going from house to house educating people about the effective measures for primary and secondary prevention. Local health workers (estimated 30,000 of them) have not been paid for 10 months due to the ongoing conflict and economic crisis, making the efforts to contain the infection more difficult.[6]
July 2nd, 2017	246,000	1500 (0.6%)	WHO is paying incentives to the local health workers who have not been paid for 10 months. WHO is setting up treatment centers in 10 governorates with the capacity of 50 each. Centers will be working around the clock in the efforts to fight the epidemic.
July 10th, 2017	297,438	1706 (0.57%)	After 10 weeks of the outbreak, the international committee of the red cross has declared that the recent outbreak is a disaster added to the economic collapse and the near famine in Yemen. The daily growth of the cases has decreased to 2%. However, new outbreak hotspots are discovered. The west region is the area most affected by the outbreak and that is due to the continuous war there. The spread of the disease is thought to be limited due to acquistion of “herd immunity” by the population from surviving patients. The mortality rate is controlled due to the early catching of the disease and the abundant network of rehydration points.
July 16th, 2017	326,082	1,743 (0.53%)	The outbreak has spread to 91% of the yemeni governorates. The plans to deploy cholera vaccines were suspended. According to WHO spokesperson, priority now comes to the measures to stop the progress of the outbreak such as ensuring clean water supply and treating patients. Up till now, about 2300 diarrhea treatment centers and 700 oral rehydration facilities were set up in the efforts to stop the spread of the outbreak. The limited numbers of vaccine doses can not cover the whole country and can cause more disputes between different regions of the country. This was another reason to suspend the plans to deploy the vaccines. Up till now, 42% of the infected population are children below 15 years and 32% of the deaths are 60 years or above.
July 22nd, 2017	462, 545	1817 (0.39%)	Cholera cases is now over 360,000 cases in three months only. The epidemic is declared the worst (in terms of the cases per one year) since the start of the modern recording system (highest number was in Haiti in 2011 and it recorded 340, 311 cases/year).[7][8] Oxfam estimates that the number of cases might rise above 600,000 cases making it the worst epidemic since 1949. Unicef states that most of the children do not have access to clean water or the proper medical care and that 17 million Yemenis do not know from where they are getting their next meal.
July 29th, 2017	408,583	1,885 (0.46%)	The rate of daily infected cases is now dropping and so is the case fatality rate. The outbreak is thought to have peaked 3 weeks ago. Despite the slowing of the spread, the number of daily cases remains high (5,000 to 6,000 cases per day) and the outbreak remains one of the worst in the recent history. The WHO is preparing for a massive campaign of vaccination in 2018 using 500,000 doses of oral cholera vaccine. WHO is targeting not only Yemen, but also Somalia, Kenya, Congo, Nigeria, Tanzania and South Sudan where cholera remains a concern.
August 5th, 2017	453,175	1,930 (0.42%)	Estimates that one million children are acutely malnourished with one fifth of them has severe malnutrition.[9] Malnourished children are three times more at risk to contract the infection because of the reduced immunity. Children below 15 years account for 44% of the new cases and 32% of the deaths.[10]
August 12th, 2017	473,701	1,953 (0.41%)	The outbreak is now affecting 96% (22/23) governorates and 89% (297/333) districts.[11] Seventy Percent of Yemen’s 28 million population live in these affected areas.[12] The overall number of suspected cases have been declining in the past five weeks, however, it has reached a plateau stage in the top 4 governorates affected.
September 5th, 2017	607,065[11]	2,047 (0.34%)	The number of cases hit the 600,000 mark. This is the double of the WHO estimates for the worst case scenario in April. The number of cases has been falling in August but some districts report sharp increase in the number of suspected cases for the past two weeks.[13] WHO investigates if the new rise of cases is due to cholera or due to another diarrheal illness. With the continuation of civil war, nearly 16 million Yemenis are deprived of clean water and proper sanitation.
September 29th, 2017	754,373[11]	2,119 (0.28%)	The outbreak is declared as the worst recorded cholera outbreak after the number of suspected cases exceeded the Haiti outbreak of 2010.[14] There number of cases are expected to reach one million by November this year.[15]

• In 2015, 172,454 cases and 1,304 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.^[1]
• Worldwide, cholera affects an estimated 1.4 to 4.3 million people and causes 28,000 to 142,000 deaths a year as of 2012.^[16][17]

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

Cholera occurs equally in males and females.

• In non-endemic areas, cholera occurs equally in all age groups.
• In endemic regions, children older than the age of 2 years are most commonly infected which cholera. Illness is uncommon before children reach 2 years of age, likely due to passive immunity.

In the United States, the occurrence of cholera is very low (0-5 cases per year) and is usually due to ingestion of contaminated food or infection during international travel. There has been a modest increase in imported cases since 1991 related to travel and ongoing epidemics.^[18]

The highest incidencce of cholera in the developing world occurs in the following regions:^[19][20]

• Africa: Zambia, Mozambique, Liberia, Democratic Republic of Congo, Niger
• Asia: Indonesia, Bangladesh, India
• The Americas: Dominican Republic, Haiti
• The Middle East: Yemen

• In 2015, the case fatality rates (CFRs) for cholera ranged from 0.0% to 11.7%; globally, the overall CFR was 0.8%.^[21]
• CFRs >1% were reported by 15 countries.
  • Of these 15 countries, CFR >5% were reported in Myanmar and Niger.
  • In Yemen, the case-fatality rate is reported to be between 4% to 5%.
• The average case fatality rate for Europe and the Americas is estimated to be around 1%.
• At the Treatment Center of the International Center for Diarrheal Disease Research in Bangladesh, less than 1% of patients with severe dehydration die.
• In Africa, a marked decline in case fatality rates has reported since 1970.
• in South America, low case fatality rates have been achieved.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS [2], Sara Mehrsefat, M.D. [3]

Certain factors have been found to be associated with an increased risk of contracting cholera. Among these decreased immunity, decreased gastric pH, certain blood groups (patients with blood group O are most prone, while patients with blood group AB are least prone), and genetics are the most commonly associated factors. The greatest risk occurs in over-populated communities and refugee settings characterized by poor sanitation, unsafe drinking water, and increased person-to-person transmission.^[1][2][3][4]

Risk factors for foodborne cholera may include:^[5][2]

• Consumption of contaminated water
• Consumption of rice products
• Consumption of specific vegetables or fruits

Risk factors for sporadic cholera include:

• Consumption of under-cooked shellfish

The greatest risk of developing cholera is present in over-populated communities affected by massive displacement and overcrowding, commonly due to natural disasters or political/economical instability (e.g., earthquakes, hurricanes, refugee camps) by means of:^[4]

• Poor sanitation
• Unsafe drinking water
• Increased person-to-person transmission

Recent epidemiologic research suggests that an individual’s susceptibility to cholera (and other diarrheal infections) is affected by his/her 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.^[6][7]

• Variants in the innate immunity protein BPIFB1 (LPLUNC1) are associated with susceptibility to cholera.^[3]
• 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.^[8] 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.

• Use of antacids

• Malnourished patients

• Retinol deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Tarek Nafee, M.D. [2], Priyamvada Singh, MBBS [3]

There are no screening guidelines for cholera.^[1]

There are no screening guidelines for cholera.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, MBBS [2], Sara Mehrsefat, M.D. [3]

Cholera infection can cause a severe diarrheal disease with acute and substantial loss of water and electrolytes.^[1] The incubation period is very short (2 hours to 5 days), which allows the number of cases in an area to rise extremely quickly. Delayed initiation of oral rehydration therapy or inadequate rehydration may lead to hypotension and electrolyte imbalance (mostly hypokalemia). If dehydration is left untreated, it may lead to hypotension, which can result in renal failure, hypovolemic shock, coma, and death. If hypokalemia is left untreated, it can lead to nephropathy and focal myocardial necrosis. Among the children, hypoglycemia is common and can lead to seizures.^[2] If patients with cholera are treated quickly and properly, the mortality rate is less than 1%. However, when cholera is left untreated, the mortality rate rises to 50–60%.^[3][4]

Cholera infection can cause a severe diarrheal disease with acute and substantial loss of water and electrolytes.^[1] The incubation period is very short (2 hours to 5 days), which allows the number of cases in an area to rise extremely quickly. Delayed initiation of oral rehydration therapy or inadequate rehydration may lead to hypotension and electrolyte imbalance (mostly hypokalemia). If dehydration is left untreated, it may lead to hypotension, which can result in renal failure, hypovolemic shock, coma, and death. If hypokalemia is left untreated, it can lead to nephropathy and focal myocardial necrosis. Among the children, hypoglycemia is common and can lead to seizures.^[2] If patients with cholera are treated quickly and properly, the mortality rate is less than 1%. However, when cholera is left untreated, the mortality rate rises to 50–60%.^[3][5]

Major complications of cholera include:^[6][2]

• Hypotension
• Hypovolemic shock
• Coma
• Renal failure
• Electrolyte imbalance
  • Hypokalemia
  • Hyponatremia
  • Hypocalcemia (occasionally)
• Metabolic acidosis
• Death

If people with cholera are treated quickly and adequately, the mortality rate is less than 1%. However, if cholera is left untreated, the mortality rate rises to 50–60%.^[3][7]

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