Cholera

Introduction

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 non-toxigenic 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; the O139 serogroup was isolated to Asia and is now rarely reported.

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, cholera cases are caused by O1 El Tor organisms; classical appears to be extinct, although El Tor variants with characteristics of both classical and El Tor biotypes have emerged and are now commonplace; this hybrid variant may be more virulent.

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. In developing countries, climatological factors, namely warm air temperatures coupled with heavy rainfall (e.g., extreme weather events like hurricanes and floods) can overwhelm vulnerable sanitary infrastructure and drive incidence of epidemic cholera.

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 healthcare professionals during epidemics, has been reported and may be an important transmission pathway in some settings.

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

During 2017–2022, the United States had 39 confirmed cholera cases among people who traveled internationally in the week before illness. About two-thirds (27/39, 69%) of cases had a history of travel to South Asia or Africa. Pakistan (8/39, 21%), India (7/39, 18%), and Kenya (6/39, 15%) were the countries most frequently visited by cases. Other reported destinations included countries in the Eastern Mediterranean/Middle East, the Caribbean, and Western Pacific. Among the 9 international travel-associated U.S. cholera cases reported in 2017, 5 had a history of travel to Haiti or the Dominican Republic, the 2 Caribbean countries affected by a large cholera epidemic that began in Haiti in October 2010 and began receding in 2016. In 2022, cholera surged again in Haiti and, in 2023, there were 3 U.S. cholera cases among people who reported travel to Haiti.

There were no cholera cases associated with international travel in the United States in 2020 and only 2 in 2021, likely due to significantly constrained travel during the COVID-19 pandemic. However, the number of travel-associated cases quickly returned to pre-pandemic levels in 2022 with 9 reported cases. Since 2022, there has been a surge of cholera outbreaks worldwide, with over 29 countries reporting outbreaks or cases, including some that had not reported cases in years. In 2023, WHO assessed the global cholera risk as very high and declared a grade 3 (WHO's highest) emergency. Cholera is endemic to approximately 50 countries, primarily in South Asia, Southeast Asia, and Africa.

Travelers to areas where cholera is endemic or where an active epidemic is occurring are at risk for cholera infection. Healthcare and response workers in cholera-affected areas (e.g., during an outbreak, after a disaster) also might be at increased risk for cholera. People without access to safe water or food, who do not follow handwashing recommendations, or do not use latrines or other sanitation systems are at increased risk for infection. People who have inadequate gastric acidity (e.g., elevated pH secondary to an acid-blocking medication) 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 approximately 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 U.S. travelers, cholera can occur in travelers arriving from areas with ongoing transmission. Thus, laboratories and emergency room or urgent care physicians should be prepared to identify suspected cholera cases.

Currently available commercial rapid diagnostic tests (RDTs), which detect O1 and O139 antigens in human stool specimens using monoclonal antibodies, are useful for cholera outbreak detection and routine surveillance in endemic settings; RDTs are not used to guide clinical supportive care, which is based on the level of dehydration. Antigen-based RDTs do not yield an isolate for toxin detection, antimicrobial susceptibility testing, or subtyping. Some culture-independent diagnostic tests (CIDTs), used widely in clinical settings, include gene targets for V. cholerae but have demonstrated variable performance. Reflex culture to recover an isolate should always be performed when a possible V. cholerae diagnosis is derived from an RDT or CIDT in a non-endemic setting, and healthcare professionals should send the isolate to a public health laboratory for additional characterization. Before administering antimicrobial treatment, hospitals should collect patient stool samples and preserve samples in Cary-Blair medium for transport at ambient temperature.

Cholera can be confirmed by laboratory isolation and identification of toxigenic V. cholerae O1 recovered from a stool sample of a patient with acute, watery diarrhea. 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. Molecular methods (e.g., polymerase chain reaction, whole-genome sequencing) can detect V. cholerae and characterize its genetic profile and are increasingly used in reference laboratories. Cholera is a nationally notifiable disease in the United States, and all isolates obtained in the United States should be sent to 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 of adequate volumes will reduce case-fatality ratios to <1%. Antibiotics can reduce fluid requirements and duration of illness and are indicated in conjunction with aggressive hydration for severe cases and for patients who fail to respond to initial rehydration or with high stool output, HIV, severe acute malnutrition, or pregnancy.

Through the National Antimicrobial Resistance Monitoring System (NARMS), CDC performs antimicrobial susceptibility testing on V. cholerae isolates. During 2017–2019, the most recent years for which NARMS data are available, U.S. state health departments submitted 21 toxigenic V. cholerae O1 clinical isolates to CDC for testing. Patient travel destinations were Bangladesh, the Dominican Republic, Haiti, India, Japan (part of a trip with India as a second destination), Kenya, Nigeria, Pakistan, the Philippines, and Yemen. Most isolates (81%) had decreased susceptibility to both ciprofloxacin and nalidixic acid, but all were sensitive to azithromycin and tetracycline. Doxycycline and azithromycin are reasonable first-line drugs when treating travelers returning to the United States from abroad. Whenever possible, antimicrobial susceptibility testing should inform treatment choices because circumstances and geography influence susceptibility profiles. For instance, in outbreak settings, WHO's Global Task Force on Cholera Control recommends different antibiotic regimens, and resistance patterns can be specific to location and time. Accounting for such information, if available, might improve initial antibiotic selection.

Zinc supplementation reduces the severity and duration of cholera and other diarrheal diseases in children living in resource-limited areas.

Prevention

Food and water

Travelers should follow safe water and food precautions and frequently wash hands (see Food and Water Precautions for Travelers chapter). 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, Emergent BioSolutions Inc.), is licensed in the United States. A related vaccine was previously marketed under the names Orochol and Mutacol in other countries.

Indications

The Advisory Committee on Immunization Practices 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 with active cholera transmission. 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. Healthcare professionals 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 immunogenicity trials of CVD 103-HgR in children demonstrated CVD 103-HgR induced serum vibriocidal antibody seroconversion on day 11 in >97% of recipients aged 2–17 years; protective efficacy was not assessed. Duration of protection beyond that assessed at 90 days is uncertain.

Administration

Prepare and administer Vaxchora in a healthcare setting equipped to dispose of medical waste. To prepare Vaxchora, reconstitute the buffer component in 100 mL of cold or room temperature, purified, non-carbonated, non-flavored bottled or spring bottled water. Avoid using tap water, which, in the United States, usually contains chlorine and can kill the active agent. For children aged 2–5 years, discard half of the reconstituted buffer solution (50 mL) 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 and adverse reactions

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

In clinical safety trials involving adults aged 18–45 years, headache, tiredness, nausea, vomiting, or diarrhea were reported more commonly by CVD 103-HgR Vaxchora 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 recipients 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 women who are pregnant or lactating, or people who are immunocompromised. In people living with HIV, no difference in adverse events was reported between those who received an older formulation of the CVD 103-HgR vaccine and those who received placebo.

Precautions and 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, malaria chemoprophylaxis with chloroquine should begin ≥10 days after administration of Vaxchora. Two studies showed co-administration of atovaquone/proguanil with CVD 103-HgR failed to diminish the vaccine's immunogenicity. Antimicrobial drugs might decrease the immune response to CVD 103-HgR, so healthcare professionals 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 non-vaccinated close contacts. Healthcare professionals and travelers should use caution when considering whether to use the vaccine in people with close contacts who are immunocompromised.

Acknowledgements

The following authors contributed to the previous version of this chapter: Bruce Gutelius, Eric D. Mintz, and Talia Pindyck.