Cholera overview

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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]

## Overview

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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.

## Historical Perspective

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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.

## Pathophysiology

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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.

## Causes

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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]

## Differentiating Cholera from other Diseases

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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]

## Epidemiology and Demographics

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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]

## Risk Factors

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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]

## Screening

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There are no screening guidelines for cholera.[19]

## Natural History, Complications and Prognosis

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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]

## Diagnosis

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### History and Symptoms

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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]

### Physical Examination

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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 Findings

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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]

### X ray

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

### CT

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

### MRI

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

### Other diagnostic tests

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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]

## Treatment

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### Medical Therapy

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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

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Surgery is not recommended for the management of cholera.

### Primary Prevention

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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

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

## References

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1. ↑ Rosenberg, Charles E. (1987). The cholera years: the United States in 1832, 1849 and 1866. Chicago: University of Chicago Press. ISBN 0-226-72677-0.
2. ↑ Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM, and Veres RC (2004). Genetics: From Genes to Genomes. Mc-Graw Hill, Boston: p. 551-552, 572-574 (using the turning off and turning on of gene expression to make toxin proteins in cholera bacteria as a "comprehensive example" of what is known about the mechanisms by which bacteria change the mix of proteins they manufacture to respond to the changing opportunities for surviving and thriving in different chemical environments).
3. ↑ 3.0 3.1 3.2 Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. ISBN 0838585299.CS1 maint: Extra text: authors list (link) CS1 maint: Extra text (link)
4. ↑ Wilcox, Bruce A., and Rita R. Colwell. "Emerging and reemerging infectious diseases: biocomplexity as an interdisciplinary paradigm." EcoHealth 2.4 (2005): 244-257.
5. ↑ 5.0 5.1 Harris JB, LaRocque RC, Qadri F, Ryan ET, Calderwood SB (2012). "Cholera". Lancet. 379 (9835): 2466–76. doi:10.1016/S0140-6736(12)60436-X. PMC 3761070. PMID 22748592.CS1 maint: Multiple names: authors list (link)
6. ↑ Huq A, Sack RB, Nizam A, Longini IM, Nair GB, Ali A; et al. (2005). "Critical factors influencing the occurrence of Vibrio cholerae in the environment of Bangladesh". Appl Environ Microbiol. 71 (8): 4645–54. doi:10.1128/AEM.71.8.4645-4654.2005. PMC 1183289. PMID 16085859.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
7. ↑ Karaolis DK, Johnson JA, Bailey CC, Boedeker EC, Kaper JB, Reeves PR (1998). "A Vibrio cholerae pathogenicity island associated with epidemic and pandemic strains". Proc Natl Acad Sci U S A. 95 (6): 3134–9. PMC 19707. PMID 9501228.CS1 maint: Multiple names: authors list (link)
8. ↑ 8.0 8.1 Sack DA, Sack RB, Nair GB, Siddique AK (2004). "Cholera". Lancet. 363 (9404): 223–33. PMID 14738797.CS1 maint: Multiple names: authors list (link)
9. ↑ Krejs GJ (1987). "VIPoma syndrome". Am J Med. 82 (5B): 37–48. PMID 3035922.
10. ↑ Guerrant RL, Van Gilder T, Steiner TS, et al.; Infectious Diseases Society of America. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32(3):331–351.
11. ↑ Scallan, Elaine, et al. "Foodborne illness acquired in the United States—unspecified agents." Emerg Infect Dis 17.1 (2011): 16-22.
12. ↑ Reidl J, Klose KE (2002). "Vibrio cholerae and cholera: out of the water and into the host". FEMS Microbiol. Rev. 26 (2): 125–39. doi:10.1111/j.1574-6976.2002.tb00605.x. PMID 12069878. Unknown parameter `|month=` ignored (help)
13. ↑ Sack DA, Sack RB, Chaignat CL (2006). "Getting serious about cholera". N. Engl. J. Med. 355 (7): 649–51. doi:10.1056/NEJMp068144. PMID 16914700. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
14. ↑ Blake, PA (1993). "Epidemiology of cholera in the Americas". Gastroenterology clinics of North America. 22 (3): 639–60. PMID 7691740.
15. ↑ Glass RI, Holmgren J, Haley CE, Khan MR, Svennerholm AM, Stoll BJ; et al. (1985). "Predisposition for cholera of individuals with O blood group. Possible evolutionary significance". Am J Epidemiol. 121 (6): 791–6. PMID 4014172.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ Rabbani GH, Greenough WB (1999). "Food as a vehicle of transmission of cholera". J Diarrhoeal Dis Res. 17 (1): 1–9. PMID 10892490.
17. ↑ Larocque RC, Sabeti P, Duggal P, Chowdhury F, Khan AI, Lebrun LM; et al. (2009). "A variant in long palate, lung and nasal epithelium clone 1 is associated with cholera in a Bangladeshi population". Genes Immun. 10 (3): 267–72. doi:10.1038/gene.2009.2. PMC 2672110. PMID 19212328.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ 18.0 18.1 World Health Organization. Assessing the Outbreak response and improving preparedness (2004) http://apps.who.int/iris/bitstream/10665/43017/1/WHO_CDS_CPE_ZFk_2004.4_eng.pdf
19. ↑ U.S Preventive Services Task force. Cholera https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=cholera Accessed on October 7th, 2016
20. ↑ Sack DA, Sack RB, Nair GB, Siddique AK (2004). "Cholera". Lancet. 363 (9404): 223–33. doi:10.1016/S0140-6736(03)15328-7. PMID 14738797. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
21. ↑ Todar, Kenneth. "Vibrio cholerae and Asiatic Cholera". Todar's Online Textbook of Bacteriology. Retrieved 2010-12-20.
22. ↑ Weil AA, Khan AI, Chowdhury F, Larocque RC, Faruque AS, Ryan ET; et al. (2009). "Clinical outcomes in household contacts of patients with cholera in Bangladesh". Clin Infect Dis. 49 (10): 1473–9. doi:10.1086/644779. PMC 2783773. PMID 19842974.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
23. ↑ Morris JG, Wilson R, Davis BR, Wachsmuth IK, Riddle CF, Wathen HG; et al. (1981). "Non-O group 1 Vibrio cholerae gastroenteritis in the United States: clinical, epidemiologic, and laboratory characteristics of sporadic cases". Ann Intern Med. 94 (5): 656–8. PMID 7235397.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
24. ↑ 24.0 24.1 24.2 24.3 http://www.cdc.gov/cholera/laboratory.html Accessed on October 7, 2016
25. ↑ 25.0 25.1 25.2 25.3 Alam M, Hasan NA, Sultana M, Nair GB, Sadique A, Faruque AS; et al. (2010). "Diagnostic limitations to accurate diagnosis of cholera". J Clin Microbiol. 48 (11): 3918–22. doi:10.1128/JCM.00616-10. PMC 3020846. PMID 20739485.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
26. ↑ Page AL, Alberti KP, Mondonge V, Rauzier J, Quilici ML, Guerin PJ (2012). "Evaluation of a rapid test for the diagnosis of cholera in the absence of a gold standard". PLoS One. 7 (5): e37360. doi:10.1371/journal.pone.0037360. PMC 3364251. PMID 22666350.CS1 maint: Multiple names: authors list (link)
27. ↑ Rahman M, Sack DA, Mahmood S, Hossain A (1987). "Rapid diagnosis of cholera by coagglutination test using 4-h fecal enrichment cultures". J Clin Microbiol. 25 (11): 2204–6. PMC 269441. PMID 3693549.CS1 maint: Multiple names: authors list (link)
28. ↑ BENENSON AS, ISLAM MR, GREENOUGH WB (1964). "RAPID IDENTIFICATION OF VIBRIO CHOLERAE BY DARKFIELD MICROSCOPY". Bull World Health Organ. 30: 827–31. PMC 2555074. PMID 14215188.CS1 maint: Multiple names: authors list (link)
29. ↑ Lyon WJ (2001). "TaqMan PCR for detection of Vibrio cholerae O1, O139, non-O1, and non-O139 in pure cultures, raw oysters, and synthetic seawater". Appl Environ Microbiol. 67 (10): 4685–93. PMC 93220. PMID 11571173.
30. ↑ Dick MH, Guillerm M, Moussy F, Chaignat CL (2012). "Review of two decades of cholera diagnostics--how far have we really come?". PLoS Negl Trop Dis. 6 (10): e1845. doi:10.1371/journal.pntd.0001845. PMC 3469466. PMID 23071851.CS1 maint: Multiple names: authors list (link)
31. ↑ Chiriacò MS, Primiceri E, D'Amone E, Ionescu RE, Rinaldi R, Maruccio G (2011). "EIS microfluidic chips for flow immunoassay and ultrasensitive cholera toxin detection". Lab Chip. 11 (4): 658–63. doi:10.1039/c0lc00409j. PMID 21127822.CS1 maint: Multiple names: authors list (link)
32. ↑ Schmit VL, Martoglio R, Carron KT (2012). "Lab-on-a-bubble surface enhanced Raman indirect immunoassay for cholera". Anal Chem. 84 (9): 4233–6. doi:10.1021/ac300242k. PMID 22468564.CS1 maint: Multiple names: authors list (link)
33. ↑ 33.0 33.1 Lankarani KB, Alavian SM (2013). "Lessons learned from past cholera epidemics, interventions which are needed today". J Res Med Sci. 18 (8): 630–1. PMC 3872598. PMID 24379835.
34. ↑ 34.0 34.1 Hahn S, Kim S, Garner P (2002). "Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhoea in children". Cochrane Database Syst Rev (1): CD002847. doi:10.1002/14651858.CD002847. PMID 11869639.CS1 maint: Multiple names: authors list (link)
35. ↑ Kabir I, Khan WA, Haider R, Mitra AK, Alam AN (1996). "Erythromycin and trimethoprim-sulphamethoxazole in the treatment of cholera in children". J Diarrhoeal Dis Res. 14 (4): 243–7. PMID 9203786.CS1 maint: Multiple names: authors list (link)
36. ↑ Sack DA, Islam S, Rabbani H, Islam A (1978). "Single-dose doxycycline for cholera". Antimicrob Agents Chemother. 14 (3): 462–4. PMC 352482. PMID 708024.CS1 maint: Multiple names: authors list (link)
37. ↑ Towner KJ, Pearson NJ, Mhalu FS, O'Grady F (1980). "Resistance to antimicrobial agents of Vibrio cholerae E1 Tor strains isolated during the fourth cholera epidemic in the United Republic of Tanzania". Bull World Health Organ. 58 (5): 747–51. PMC 2395989. PMID 6975183.CS1 maint: Multiple names: authors list (link)
38. ↑ Roy SK, Hossain MJ, Khatun W, Chakraborty B, Chowdhury S, Begum A; et al. (2008). "Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial". BMJ. 336 (7638): 266–8. doi:10.1136/bmj.39416.646250.AE. PMC 2223005. PMID 18184631.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
39. ↑ Waldman RJ, Mintz ED, Papowitz HE (2013). "The cure for cholera--improving access to safe water and sanitation". N Engl J Med. 368 (7): 592–4. doi:10.1056/NEJMp1214179. PMID 23301693.CS1 maint: Multiple names: authors list (link)
40. ↑ Sepúlveda J, Valdespino JL, García-García L (2006). "Cholera in Mexico: the paradoxical benefits of the last pandemic". Int J Infect Dis. 10 (1): 4–13. doi:10.1016/j.ijid.2005.05.005. PMID 16326125.CS1 maint: Multiple names: authors list (link)
41. ↑ Sepúlveda J, Bustreo F, Tapia R, Rivera J, Lozano R, Oláiz G; et al. (2006). "Improvement of child survival in Mexico: the diagonal approach". Lancet. 368 (9551): 2017–27. doi:10.1016/S0140-6736(06)69569-X. PMID 17141709.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
42. ↑ Graves PM, Deeks JJ, Demicheli V, Jefferson T (2010). Graves, Patricia M, ed. "Vaccines for preventing cholera: killed whole cell or other subunit vaccines (injected)". Cochrane Database Syst Rev (8): CD000974. doi:10.1002/14651858.CD000974.pub2. PMID 20687062.CS1 maint: Multiple names: authors list (link)
43. ↑ Sinclair D, Abba K, Zaman K, Qadri F, Graves PM (2011). "Oral vaccines for preventing cholera". Cochrane Database Syst Rev (3): CD008603. doi:10.1002/14651858.CD008603.pub2. PMID 21412922.CS1 maint: Multiple names: authors list (link)
44. ↑ "Cholera vaccines". Health topics. WHO. 2008. Retrieved 2010-02-01.

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