Author(s): Talia Pindyck, Bruce Gutelius, Eric Mintz

Infectious Agent

Cholera is an acute bacterial intestinal infection caused by toxigenic Vibrio cholerae O-group 1 (O1) or O-group 139 (O139). Many other serogroups of V. cholerae, with or without the cholera toxin gene (including the nontoxigenic strains of the O1 and O139 serogroups), can cause a cholera-like illness. Only toxigenic strains of serogroups O1 and O139 have caused widespread epidemics and are reportable to the World Health Organization (WHO) as “cholera.” Toxigenic strains of V. cholerae O1 are the source of an ongoing global pandemic that began in 1961, but the O139 serogroup is localized to a few areas in Asia.

V. cholerae O1 has 2 biotypes, classical and El Tor, and each biotype can be divided into distinct serotypes, Inaba Ogawa, and rarely, Hikojima. The symptoms of infection are indistinguishable, but more people infected with the El Tor biotype remain asymptomatic or have only a mild illness. Globally, most cholera cases are caused by O1 El Tor organisms. In recent years, an El Tor variant with characteristics of both classical and El Tor biotypes has emerged in Asia and spread to Africa and the Caribbean. This is the strain responsible for the epidemic on Hispaniola, the island shared by Haiti and the Dominican Republic; compared to older El Tor strains, this newer variant appears to be more virulent, causing a greater proportion of severe episodes of cholera with the potential for higher death rates.

Transmission

Toxigenic V. cholerae O1 and O139 are free-living bacterial organisms found in fresh and brackish water, often in association with copepods or other zooplankton, shellfish, and aquatic plants. Cholera infections are acquired most often from untreated drinking water in which toxigenic V. cholerae naturally occurs or has been introduced from the feces of an infected person. Other common vehicles include raw or undercooked food, especially fish and shellfish. Other foods, including produce, are less commonly implicated. Direct person-to-person transmission, including to health care workers during epidemics, has been reported.

When in countries affected by cholera, travelers who consistently observe recommendations regarding safe drinking water, food preparation and consumption, handwashing, and sanitation have virtually no risk of acquiring the disease.

Epidemiology

Cholera is endemic to ≈50 countries, primarily in South and Southeast Asia and Africa. During 2007–2017, the United States had 117 confirmed cholera cases among people who traveled internationally in the week before illness; ≈16% reported travel to India or Pakistan. Other reported destinations included other countries in Southeast Asia, East and West Africa, and the Caribbean. Sporadic cases in the United States associated with travel to or from cholera-affected countries in Asia and Africa continue to occur.

More than half (70/117, ≈60%) of US cases during 2007–2017 were linked to travel to Haiti, the Dominican Republic, or Cuba, the 3 Caribbean countries affected by a large cholera epidemic that began in Haiti in October 2010. Ninety-four percent (66/70) of case-patients reported travel to either Haiti or the Dominican Republic sometime during 2010–2017. The other case-patients had been to Cuba sometime during 2013–2015.

In 2018 and 2019, the most recent years for which data are available, no cholera cases in the United States were associated with travel to Haiti or the Dominican Republic, and those 2 countries reported far fewer cholera cases to WHO during these 2 years than in previous years. Although efforts were underway to eliminate cholera from Hispaniola, in October 2022, the Pan American Health Organization reported a resurgence of the disease in Haiti. Before 2022, the last confirmed case of cholera in Haiti was in 2019, and in the Dominican Republic in 2018.

Travelers to areas where cholera is endemic or where an active epidemic is occurring are at risk for cholera infection. Health care and response workers in cholera-affected areas (e.g., during an outbreak, after a disaster) also might be at increased risk for cholera. People who do not follow handwashing recommendations, and/or do not use latrines or other sanitation systems are at increased risk for infection. People who have low gastric acidity have a greater risk for infection, and they, along with those with blood type O, are at greater risk for developing severe disease if infected.

Clinical Presentation

Cholera most commonly manifests as acute watery diarrhea in an afebrile person. The pathogen typically remains in the gastrointestinal tract and does not invade the bloodstream. Infection is often mild or asymptomatic, but it can be severe. Severe cholera (cholera gravis) occurs in ≈10% of cholera episodes and is characterized by profuse watery diarrhea, described as rice-water stools, often accompanied by nausea and vomiting that can rapidly lead to severe volume depletion.

Clinical findings include dry mucous membranes and loss of skin turgor, hypotension, tachycardia, and thirst. Additional symptoms, including muscle cramps, are secondary to the resulting electrolyte imbalances. Untreated cholera can cause rapid loss of body fluids, which can lead to severe dehydration, hypovolemic shock, and death within hours. The case-fatality ratio for untreated cholera can reach >50%, but with adequate and timely rehydration, the case-fatality ratio is <1%.

Diagnosis

In the United States, cholera traditionally is confirmed by isolation and identification of toxigenic V. cholerae O1 recovered from a stool sample of a patient with acute, watery diarrhea. Before administering antimicrobial treatment, collect patient stool samples and preserve samples in Cary-Blair medium for transport at ambient temperature. Selective media (e.g., taurocholate-tellurite-gelatin agar, thiosulfate-citrate-bile salts agar) also can be used for pathogen isolation.

Reagents for serogrouping V. cholerae isolates are available in most state health department laboratories. Antigen-based rapid diagnostic tests (RDTs) do not yield an isolate for toxin detection, antimicrobial susceptibility testing, or subtyping. Reflex culture to recover an isolate should always be performed when a V. cholerae diagnosis is derived from an RDT, and clinicians should send the isolate to a public health laboratory for additional characterization.

Currently available commercial RDTs, which detect O1 and O139 antigens in human stool specimens using monoclonal antibodies, are useful for cholera outbreak detection and response, but should not be used to diagnose individual patients. Molecular methods (e.g., PCR, whole-genome sequencing) can detect V. cholerae and characterize its genetic profile and are increasingly used in public health laboratories. Cholera is a nationally notifiable disease in the United States, and all isolates obtained in the United States should be sent to the Centers for Disease Control and Prevention (CDC) via state health department laboratories for identification and virulence testing.

Treatment

Rehydration is the cornerstone of cholera treatment. Administer oral rehydration solution and, when necessary, intravenous fluids and electrolytes; timely administration in adequate volumes will reduce case-fatality ratios to <1%. Antibiotics will reduce fluid requirements and duration of illness and are indicated in conjunction with aggressive hydration for severe cases and for patients with moderate dehydration and ongoing fluid losses.

Whenever possible, antimicrobial susceptibility testing should inform treatment choices. In most countries, doxycycline is recommended as the first-line antibiotic treatment for children, adults, and pregnant people. Previously, tetracycline antibiotics (including doxycycline) were not recommended for children due to concern for dental discoloration, or pregnant people due to concern for teratogenic effects. A recent systematic review among young children and pregnant people receiving doxycycline did not demonstrate a safety risk.

Multidrug-resistant isolates are emerging, particularly in South Asia, with resistance to quinolones, trimethoprim-sulfamethoxazole, and tetracycline. The strain from Hispaniola is also multidrug resistant; as of 2013, however, tested isolates were still sensitive to doxycycline and tetracycline. Macrolides, including erythromycin and azithromycin, are alternative agents for multidrug-resistant isolates. Zinc supplementation reduces the severity and duration of cholera and other diarrheal diseases in children living in resource-limited areas.

Prevention

Food & Water

Travelers should follow safe food and water precautions and frequently wash hands (see Sec. 2, Ch. 8, Food & Water Precautions). Antibiotic chemoprophylaxis is not recommended.

Vaccine

No country or territory requires vaccination against cholera as a condition for entry. CVD 103-HgR, a live, attenuated, single-dose oral cholera vaccine (Vaxchora, PaxVax), is licensed in the United States. The vaccine was previously marketed under the names Orochol and Mutacol in other countries.

Indications

The Advisory Committee on Immunization Practices (ACIP) recommends CVD 103-HgR vaccine for both pediatric and adult travelers (2–64 years old) visiting areas of active cholera transmission. An area of active cholera transmission is defined as a province, state, or other administrative subdivision within a country with endemic or epidemic cholera caused by toxigenic V. cholerae O1. It includes areas that are prone to recurrence of cholera epidemics that have had cholera activity within the past year. Locations where rare sporadic cholera cases have been reported are not considered active cholera areas.

CDC provides a list of countries for which cholera vaccine can be considered for travelers (see “Who is at risk?”). Cholera activity can occur in certain parts of a country or in certain settings, however, and information about places with cholera activity might be incomplete because of variations in surveillance and reporting. The vaccine is not routinely recommended for most travelers from the United States because they do not visit areas with active cholera transmission. Clinicians and travelers can find additional country-specific information on CDC’s Travelers’ Health website.

Efficacy

In clinical efficacy trials, adults aged 18–45 years who received Vaxchora were protected against severe diarrhea after oral V. cholerae O1 challenge at 10 days (vaccine efficacy 90%) and at 3 months (vaccine efficacy 80%) after vaccination. In adults aged 46–64 years, vibriocidal antibody seroconversion rates, the best available marker for protection against cholera, were comparable to the response seen in adults aged 18–45 years. Multicenter randomized clinical efficacy trials of CVD 103-HgR in children (published in 2020) demonstrated CVD 103-HgR induced serum vibriocidal antibody seroconversion on day 11 in >97% of recipients aged 2–17 years; efficacy was not assessed.

Administration

Prepare and administer Vaxchora in a health care setting equipped to dispose of medical waste. To prepare Vaxchora, reconstitute the buffer component in 100 milliliters (mL) of cold or room temperature, purified, non-carbonated, non-flavored bottled or spring bottled water. The package insert indicates that for children aged 2–5 years, half of the reconstituted buffer solution (50 mL) should be discarded before adding the active component (lyophilized V. cholerae CVD 103-HgR); after preparation, a single oral dose of Vaxchora for children aged 2–5 years is 50 mL. Patients should avoid eating or drinking for 60 minutes before and after taking Vaxchora vaccine. Administer Vaxchora as a single oral dose ≥10 days before potential cholera exposure.

Booster Doses

The safety and efficacy of revaccination with CVD 103-HgR have not been established.

Safety & Adverse Reactions

Serious adverse events were rare among recipients of Orochol and Mutacol, the previously marketed formulation of the CVD 103-HgR vaccine.

In clinical safety trials involving adults aged 18–45 years, headache, tiredness, and nausea, vomiting, and diarrhea were reported more commonly by CVD 103-HgR recipients than by placebo recipients within 7 days of vaccination. Among children and adolescents aged 2–17 years, adverse events more commonly reported by vaccine than by placebo recipients included abdominal pain, anorexia, headache, and tiredness. No vaccine-related serious adverse events were reported among participants aged 2–64 years.

Vaxchora is not currently licensed for use in children <2 years or adults >65 years of age. The safety and effectiveness of Vaxchora have not been established in pregnant or lactating people, or in immunocompromised people. No difference in adverse events were reported among HIV-positive recipients of an older formulation of the CVD 103-HgR vaccine and those who received placebo.

Precautions & Contraindications

Vaxchora is contraindicated in people with a history of severe allergic reaction to the ingredients of this or any other cholera vaccine. A study with the older formulation of CVD 103-HgR showed that concomitant use of chloroquine decreased the immune response to the vaccine; therefore, antimalarial prophylaxis with chloroquine should begin ≥10 days after administration of Vaxchora. Coadministration of mefloquine and proguanil with CVD 103-HgR did not diminish the vaccine’s immunogenicity. Antimicrobial drugs might decrease the immune response to CVD 103-HgR, so clinicians should not administer the vaccine to patients who have received antibiotics in the previous 14 days.

Vaxchora might be shed in the stool for ≥7 days, and the vaccine strain could be transmitted to nonvaccinated close contacts. Clinicians and travelers should use caution when considering whether to use the vaccine in people with close contacts who are immunocompromised.

CDC website: Cholera