AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The word cholera is derived from a Greek term that means "flow of bile." Cholera is caused by Vibrio cholerae, the most feared epidemic diarrheal disease because of its severity. Dehydration and death can occur within hours of infection.

Robert Koch discovered V cholerae in 1883 during an outbreak in Egypt. The organism is a comma-shaped, gram-negative aerobic bacillus whose size varies from 1-3 µm in length by 0.5-0.8 µm in diameter. Its antigenic structure consists of a flagellar H antigen and a somatic O antigen. The differentiation of the latter allows for separation into pathogenic and nonpathogenic strains. V cholerae O1 and V cholerae O139 are associated with epidemic cholera. V cholerae O1 is classified into 2 major biotypes: classic and El Tor. Currently, El Tor is the predominant cholera pathogen. Organisms in both biotypes are subdivided into serotypes according to the structure of the O antigen, as follows:

• Serotype Inaba - O antigens A and C
• Serotype Ogawa - O antigens A and B
• Serotype Hikojima - O antigens A, B, and C

Pathophysiology

The infectious dose of bacteria required to cause clinical disease varies by the mode of administration. If ingested with water, the infectious dose is 10³-10⁶ organisms. When ingested with food, fewer organisms (10²-10⁴ organisms) are required to produce disease.

The use of antacids, histamine receptor blockers, and proton pump inhibitors increases the risk of cholera infection and predisposes patients to more severe disease as a result of reduced gastric acidity. The same applies to patients with chronic gastritis secondary to Helicobacter pylori infection or those who have undergone a gastrectomy.

V cholerae O1 and V cholerae O139 cause clinical disease by producing an enterotoxin that promotes the secretion of fluid and electrolytes into the lumen of the small intestine. The enterotoxin is a protein molecule composed of 5 B subunits and 2 A subunits. The B subunits are responsible for binding to a ganglioside (monosialosyl ganglioside, GM1) receptor located on the surface of the cells that line the intestinal mucosa.

The activation of the A1 subunit by adenylate cyclase is responsible for the net increase in cyclic adenosine monophosphate (cAMP). cAMP blocks the absorption of sodium and chloride by the microvilli and promotes the secretion of chloride and water by the crypt cells. The result is watery diarrhea with electrolyte concentrations isotonic to those of plasma.

Fluid loss originates in the duodenum and upper jejunum; the ileum is less affected. The colon is usually in a state of absorption because it is relatively insensitive to the toxin. However, the large volume of fluid produced in the upper intestine overwhelms the absorptive capacity of the lower bowel, resulting in severe diarrhea.

The enterotoxin acts locally and does not invade the intestinal wall. As a result, few neutrophils are found in the stool.

Frequency

United States

Among the millions of Americans who travel to endemic areas in foreign countries, only 42 imported cases of cholera were reported from 1965-1991. However, in August 1986, 4 cases of cholera were acquired in Louisiana and 1 case was acquired in Florida. These patients were hospitalized with severe diarrhea and had stool cultures that yielded toxigenic V cholerae O1 Inaba. Although the vehicle of transmission was not specifically identified, the patients had consumed seafood within 5 days prior to symptom onset. Toxigenic V cholerae O1 El Tor Inaba appears to have an environmental reservoir on the US Gulf Coast.

Sixty-one cases of cholera were reported from January 1, 1995, through December 31, 2000, in 18 states and 2 US territories. Thirty-seven were travel-associated cases; the other 24 cases were acquired in the United States.¹ Individuals living in the United States most often acquire cholera through travel to cholera-endemic areas or through consumption of undercooked seafood from the Gulf Coast or foreign waters.

In 2005, 12 cases were reported to the World Health Organization (WHO) and, of these, 8 were imported.

International

Since 1817, 7 cholera pandemics have occurred. The first 6 occurred from 1817-1923 and were probably the result of V cholerae O1 of the classic biotype. The pandemics originated in Asia, with subsequent spread to Europe and the Americas.

The seventh pandemic was caused by V cholerae O1 El Tor, which was first isolated in Egypt in 1905. The pandemic originated from the Celebes Islands, Indonesia, in 1961; this pandemic affected more countries and continents than the previous 6 pandemics. The last extension of this pandemic was into Latin America. The total number of cases officially reported from 1997 through March 26, 1998, was 120,867; 89% of these cases were reported in Africa.

In 2002, all regions of the world continued to report cholera caused by V cholerae O1 El Tor; that year, 142,311 cases and 4564 deaths were reported to the WHO by 52 countries. Compared with 2001, the number of reported cases almost doubled. 

Between 2002 and 2004, the number of cases reported to the WHO decreased worldwide. In 2005, however, the number reported increased 30% to a total of 131,943 cases in 52 countries. 

In October 1992, an epidemic of cholera emerged from Madras, India, as a result of a new serogroup, O139 (also known as Bengal). This Bengal strain has now spread throughout Bangladesh and India and into neighboring countries in Asia. Some experts regard this as an eighth pandemic. Thus far, 11 countries in Southeast Asia have reported isolation of this Vibrio serogroup.

Mortality/Morbidity

If untreated, the disease rapidly results in dehydration and can result in death in more than 50% of infected individuals. The mortality rate is increased in pregnant women and children.

Age

People of all ages are susceptible, although infants are protected through maternally transmitted antibodies during breastfeeding. An attack of the classic biotype of V cholerae usually protects against recurrent infection by either biotype, but El Tor cholera does not protect against further attacks.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

After a 24- to 48-hour incubation period, symptoms begin with the sudden onset of painless watery diarrhea that may quickly become voluminous and is often followed by vomiting. The patient may experience accompanying abdominal cramps. Fever is typically absent. The diarrhea has a "rice water" appearance and a fishy odor. In patients with severe disease, the stool volume can exceed 250 mL/kg in the first 24 hours. Without replacement of fluids and electrolytes, hypovolemic shock and death ensue.

Physical

Clinical signs of cholera parallel the level of volume contraction. The amount of fluid loss and the corresponding clinical signs of cholera are as follows:

• With 3-5% loss of normal body weight - Excessive thirst
• With 5-8% loss of normal body weight - Postural hypotension, tachycardia, weakness, fatigue, and dry mucous membranes or dry mouth
• With greater than 10% loss of normal body weight - Oliguria; glassy or sunken eyes; sunken fontanelles in infants; weak, thready, or absent pulse; wrinkled "washerwoman" skin; somnolence; and coma
• Pediatric patients
• • In pediatric patients, the primary signs are similar to those in adults.
  • Children with severe cholera may present with signs that are rarely seen in adults. A child with cholera is usually very drowsy, and coma is not uncommon.
  • In addition, pediatric patients may have convulsions that appear to be related, in part, to hypoglycemia because patients exhibit some response to intravenous dextrose.
  • Another significant difference from the adult presentation is that children are often febrile.

Causes

• Cholera is transmitted via the fecal-oral route. Owing to the relatively large infectious dose, transmission occurs almost exclusively via contaminated water or food. Toxigenic V cholerae O1 has been shown to survive in crabs boiled for 8 minutes, but not in crabs boiled for 10 minutes. Transmission via direct person-to-person contact is rare.
• V cholerae is unable to survive in an acidic environment. Therefore, any condition that reduces gastric acid production increases the risk of acquisition. In addition, although the pathophysiology is not understood, individuals with blood group O are at increased risk of developing El Tor cholera.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Rotavirus infections

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• An elevated hematocrit value due to hemoconcentration may be found in nonanemic patients. Neutrophil leukocytosis may be found, especially in severe cases.
• Patients have elevated blood urea nitrogen and creatinine levels consistent with prerenal azotemia. A reduced bicarbonate level (<15 mmol/L) and an elevated anion gap occur as a result of increases in serum lactate, protein, and phosphate levels. The arterial pH is usually low (approximately 7.2). Calcium and magnesium levels are usually high as a result of hemoconcentration, and potassium levels are either normal or low. Hypovolemia may cause hyperglycemia secondary to systemic release of epinephrine, glucagon, and cortisol.
• In endemic areas, biochemical confirmation and characterization of the isolate are usually unnecessary. However, these tasks may be worthwhile in areas where V cholerae is an uncommon isolate.
• Diagnosis may be confirmed via identification of V cholerae in the stool. The organism may be detected directly with dark-field microscopy examination of a wet mount of fresh stool; chaotic motility is observed. The serotype may be determined by immobilization with Inaba-specific or Ogawa-specific antiserum.
• Laboratory isolation requires a selective medium. V cholerae grows as a flat, yellow colony on thiosulfate-citrate-bile salts-sucrose agar or taurocholate-tellurite-gelatin agar.
• More recently, polymerase chain reaction (PCR) has been used with a high degree of sensitivity and specificity.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The management of cholera "sicca" is difficult because the evaluation of the degree of dehydration is overshadowed by the accumulation of fluid in the intestinal lumen.
• The primary goal of therapy is to replenish fluid losses caused by diarrhea and vomiting. Reserve the intravenous route of rehydration for patients who purge more than 10-20 mL/kg/h and for patients with severe dehydration.
• Rehydration is accomplished in 2 phases, rehydration and maintenance.
• • The goal of the rehydration phase is to restore normal hydration status, which should take no more than 4 hours. Set the rate of infusion in severely dehydrated patients at 50-100 mL/kg/h. Lactated Ringer solution is preferred over isotonic sodium chloride solution because saline does not correct metabolic acidosis.
  • The objective of the maintenance phase is to maintain normal hydration status by replacing ongoing losses. The oral route is preferred, and the use of oral rehydration solution (ORS) at a rate of 500-1000 mL/h is recommended.
• Practical guidelines for the treatment of cholera are as follows:
• • Evaluate the degree of dehydration upon arrival.
  • Rehydrate the patient in 2 phases. These include rehydration (for 2-4 h) and maintenance (until diarrhea abates).
  • Register output and intake volumes on predesigned charts and periodically review these data.
  • Only use the intravenous route (1) during the rehydration phase for severely dehydrated patients for whom an infusion rate of 50-100 mL/kg/h is advised, (2) for moderately dehydrated patients who do not tolerate the oral route, and (3) during the maintenance phase in patients considered high stool purgers (ie, >10 mL/kg/h).
  • During the maintenance phase, use ORS at a rate of 800-1000 mL/h. Match ongoing losses with ORS administration.
  • Discharge patients to the treatment center if oral tolerance is greater than or equal to 1000 mL/h, urine volume is greater than or equal to 40 mL/h, and stool volume is less than or equal to 400 mL/h.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Drug Category: Antibiotics

Although not necessarily curative, treatment with an antibiotic to which the organism is susceptible diminishes the duration and volume of the fluid loss and hastens clearance of the organism from stool. Pharmacotherapy plays a secondary role in the management of cholera.

Emerging drug resistance in certain parts of the world is a concern, as some V cholerae strains contain plasmids that confer resistance to many antibiotics. In areas of known tetracycline resistance, therapeutic options include ciprofloxacin and erythromycin. Strains resistant to ciprofloxacin have been reported from Calcutta, India.

Chemoprophylaxis of household contacts is not necessary.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• John Snow was the first to demonstrate that the transmission of cholera was significantly reduced when uncontaminated water was provided to the population. Water can be made safer to drink by boiling or adding chlorine, although both methods are expensive and difficult to implement during epidemics.
• Education on specific hygiene practices is important in the prevention of cholera.
• Difficulties in implementing such practices have stimulated the century-long search for vaccines. Experience with the parenteral vaccine has been disappointing. Because of a better understanding of the immune response to natural infection, researchers now know that the oral route of administration is better.
• Cholera vaccination is no longer officially required for any international traveler, and the International Certificate of Vaccination no longer provides a special section for recording cholera immunization. The risk of an international traveler from a developed country contracting cholera is small (1 case in 500,000 travelers).
• The vaccines currently available are described as follows:
• • The cholera vaccine developed by Wyeth-Ayerst Laboratories is a parenteral, whole-cell, inactivated vaccine directed only at V cholerae O1. It is considered ineffective and obsolete, but it may be useful in certain (rare) high-risk populations in whom no other vaccine is available, who have minimal access to medical care, and who can receive booster shots. The vaccine should not be used to treat contacts of persons with imported cases or to control the spread of infection. Repeated vaccination is occasionally required or advised for laboratory workers and for airline and ship crews. However, such groups are unlikely to acquire or transmit cholera. Because information on the long-term safety of repeated vaccination is limited, such practices should be discontinued for airline and ship crews except when resolutely demanded by some countries for international travel. This vaccine is not recommended for infants younger than 6 months.
  • CVD 103-HgR is a cholera vaccine developed by the Swiss Serum and Vaccine Institute in Berne, Switzerland. This vaccine is available in Europe, Latin America, and, since 1997, Canada. The vaccine is composed of attenuated V cholerae O1 prepared by recombinant DNA. It has been tested in industrialized countries and in developing countries that have endemic, epidemic, and little or no cholera. The vaccine is highly protective against moderate and severe cholera, and it is very well tolerated and extremely immunogenic. Also, the rate and extent of vaccine excretion is minimal.
  • The WC/rBS cholera vaccine is currently available in Sweden and Latin America. This vaccine is composed of killed, whole-cell V cholerae O1 in combination with the purified recombinant B subunit of the cholera toxin (WC/rBS). The vaccine stimulates both antibacterial and antitoxic antibodies and attempts to stimulate the intestinal mucosal immune response similar to that induced by natural infection.

Complications

• If a patient is adequately treated with fluid and electrolytes, complications are averted and the self-limited process resolves in a few days.
• Potential complications include dehydration and volume loss that lead to acute tubular necrosis and renal failure. Hypovolemic shock and death ensue.

Patient Education

• Education in environmental control is critical for the prevention of cholera. The source of V cholerae in nature is human excrement, and the most common vehicle of infection is water. Environmental control must focus on keeping these elements apart.
• In the developed world, much has been done in public health planning and in the engineering of water conservation and sewage disposal. However, in developing countries, contamination of water by human excrement is a daily hazard. Members of these populations experience a constant cycle of infection, excretion, and reinfection. Education about the sterilization of water and hand-washing techniques is critical but difficult.
• Contamination via food is also an important consideration. The source of this contamination is impure water used to wash or flush vegetables and fruit. Water contamination occurs via sewage or soil that is used to fertilize crops. In this situation, training food handlers is necessary.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The use of quinolones is contraindicated in children with cholera.
• Cholera is endemic in parts of the United States and should be considered in cases of protracted secretory diarrhea in the correct epidemiological setting.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Steinberg EB, Greene KD, Bopp CA, Cameron DN, Wells JG, Mintz ED. Cholera in the United States, 1995-2000: trends at the end of the twentieth century. J Infect Dis. Sep 15 2001;184(6):799-802. [Medline].
2. Centers for Disease Control and Prevention. Toxigenic Vibrio cholerae 01 infections--Louisiana and Florida. MMWR Morb Mortal Wkly Rep. Sep 26 1986;35(38):606-7. [Medline].
3. Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 6^th ed. Philadelphia, Pa: Churchill Livingstone; 2004.
4. Seas C, DuPont HL, Valdez LM, Gotuzzo E. Practical guidelines for the treatment of cholera. Drugs. Jun 1996;51(6):966-73. [Medline].
5. Thompson RF, Bass DM, Hoffman SL. Travel vaccines. Infect Dis Clin North Am. Mar 1999;13(1):149-67, vii. [Medline].
6. Woodruff AW. A Synopsis of Infectious and Tropical Diseases. 3^rd ed. Bristol, England: Wright; 1987:186-90.

Article Last Updated: Nov 20, 2007