Cholera

Clinical Description

Vibrio cholerae is a species of bacteria. Some strains of Vibrio cholerae cause cholera, a severe diarrheal illness. Vibrio cholerae has many different types or serogroups, only two of which can cause epidemic cholera. Those two serogroups are called serogroup O1 and serogroup O139 (O139 is found only in Asia) and can cause epidemic cholera if they also produce the cholera toxin. The other serogroups are known collectively as non-O1 and non-O139 Vibrio cholerae. These serogroups can cause a diarrheal disease which is less severe than cholera and does not have epidemic potential. (Source: http://www.cdc.gov/cholera/non-01-0139-infections.html) This page covers serogroup 01 and serogroup 0139 cholera.


Identification of Vibrio cholerae (serotypes 01 and 0139)

An acute bacterial enteric disease characterized in its severe form by sudden onset, profuse painless watery stools (rice-water stool) provoked by an enterotoxin that affects the small intestine; nausea; and profuse vomiting early in the course of illness. In untreated cases, rapid dehydration, acidosis, circulatory collapse, hypoglycemia in children, and renal failure can rapidly lead to death. In most cases infection is asymptomatic or causes mild diarrhea, especially with organisms of the El Tor biotype; asymptomatic carriers can transmit the infection. In severe dehydrated cases (cholera gravis), death may occur within a few hours, and the case-fatality rate may exceed 50%. With proper and timely rehydration, this can be less than 1%.

Infectious Agent

Only Vibrio cholerae serogroups O1 and O139 are associated with the epidemiological characteristics of cholera. Serogroup O1 occurs as two biotypes—classical and El Tor—each of which occurs as three serotypes (Inaba, Ogawa and, rarely, Hikojima). The clinical illness caused by V. cholerae O1 of either biotype and by V. cholerae O139 is similar because these organisms elaborate an almost identical enterotoxin. In any single epidemic, one particular serogroup and biotype tends to be dominant, but serogroup switching is common. The current seventh pandemic is characterized by the O1 serogroup El Tor biotype, V. cholerae O1. The classical biotype has not been diagnosed outside of south Asia in many years, and V. cholerae O139 remains confined to South East Asia.

Before 1992, non-O1 strains were recognized as causing sporadic cases and rare outbreaks of diarrheal disease, but were not associated with large epidemics. However, in 1992–1993, large-scale epidemics of cholera-like disease were reported in India and Bangladesh, caused by a new organism, V. cholerae serogroup O139. This organism elaborates the same cholera toxin but differs from O1 strains in lipopolysaccharide (LPS) structure and in the production of capsular antigen. The clinical and epidemiological picture of illness it causes is typical of cholera, and cases should be reported as such. The epidemic O139 strain, which possesses the virulence factors of V. cholerae O1 El Tor, was apparently derived by a deletion in the genes that encode the O1 lipopolysaccharide antigen of an El Tor strain, followed by the acquisition of a large fragment of new DNA encoding the enzymes that allow synthesis of O139 lipopolysaccharide and capsule.

The reporting as cholera of illness due to non-O1 or non-O139 serogroups of V. cholerae is inaccurate and leads to confusion, even if these strains do possess the cholera toxin gene.


Diagnosis

Diagnosis is confirmed by isolating Vibrio cholerae of the serogroup O1 or O139 from feces. Ideally, in cases of sporadic infection, clinical isolates of V. cholerae O1 and O139 should be tested for the presence of the cholera toxin gene. Strains of V. cholerae O1 or O139 that do not possess cholera toxin can cause acute watery diarrhea, but do not cause cholera or epidemic disease. V. cholerae grows well on standard culture media, but the use of selective media, such as thiosulfate citrate bile-salts (TCBS) agar, is recommended. The strains are further characterized by O1 and O139 specific antisera. Strains that agglutinate in O1 antisera are further characterized for serotype. If laboratory facilities are not nearby or immediately available, Cary Blair transport medium can be used to transport or store a fecal or rectal swab. For clinical purposes, a quick presumptive diagnosis can be made by darkfield or phase microscopic visualization of the vibrios moving like “shooting stars,” inhibited by preservative-free, serotype-specific antiserum. For epidemiological purposes, a presumptive diagnosis can be based on the demonstration of a significant rise in titer of anti-cholera toxin or vibriocidal antibodies. In nonendemic areas, organisms isolated from initial suspected cases should be confirmed in a reference laboratory through appropriate biochemical and serological reactions, and by testing the organisms for cholera toxin production or for the presence of cholera toxin genes. One-step dipstick tests for rapid detection of V. cholerae O1 and O139 are available on the market, and have shown promise in initial field evaluations; however, these tests do not yield isolates for subtyping or antimicrobial resistance testing that may be useful for epidemiologic and treatment decisions. In epidemics, once laboratory confirmation and antibiotic sensitivity have been established, it is unnecessary to confirm all subsequent cases. Shift should be made to primary use of proposed WHO clinical case definitions, as follows:

.    Disease unknown in area: severe dehydration or death from acute watery diarrhea in a patient aged 5 or more
.    Endemic cholera: acute watery diarrhea with or without vomiting in a patient aged 5 or more
.    Epidemic cholera: acute watery diarrhea with or without vomiting in any patient.

However, monitoring an epidemic should include laboratory confirmation and antimicrobial sensitivity testing of a small proportion of cases on a regular basis.


Epidemiology

Mode of Transmission

Cholera is acquired through ingestion of an infective dose of contaminated food or water and can be transmitted through many mechanisms. Water is usually contaminated by feces of infected individuals and can itself contaminate, directly or through the contamination of food. Contamination of drinking water usually occurs at source, during transportation, or during storage at home. Food may also be contaminated by soiled hands, during preparation, or while eating. In funeral ceremonies transmission may occur through consumption of food and beverages prepared by family members after they handled the corpse for burial. V. cholerae O1 and O139 can persist in water for long periods and multiply in moist leftover food.

Beverages prepared with contaminated water and sold by street vendors, ice and even commercial bottled water have been incriminated as vehicles in cholera transmission, as have cooked vegetables and fruit “freshened” with untreated wastewater have also served as vehicles of transmission. Outbreaks or epidemics as well as sporadic cases are often attributed to raw or undercooked seafood. In other instances, sporadic cases of cholera follow the ingestion of raw or inadequately cooked seafood from non-polluted waters. Cases have been traced to eating shellfish from coastal and estuarine waters where a natural reservoir of V. cholerae O1, serotype Inaba, exists in an estuarine environment not characterized by sewage contamination. Clinical cholera in endemic areas is usually confined to the lowest socioeconomic groups.

Incubation Period

From a few hours to 5 days, usually 2–3 days.

Period of Communicability

As long as stools are positive, usually only a few days after recovery. Occasionally the carrier state may persist for several months. Antibiotics known to be effective against the infecting strains (e.g. tetracycline or doxycycline) shorten the period of communicability, but are recommended only for treatment of severely ill patients. Rarely, chronic biliary infection lasting for years, associated with intermittent shedding of vibrios in the stool, has been observed in adults.

Reservoir

The main reservoir is humans. Observations in Australia, Bangladesh and the USA have shown that environmental reservoirs exist, apparently in association with copepods or other zooplankton in brackish water or estuaries.

Susceptibility

Variable; gastric achlorhydria increases the risk of illness, and breastfed infants are protected. Severe cholera occurs significantly more often among persons with blood group O. Infection with either V. cholerae O1 or O139 results in a rise in agglutinating and antitoxic antibodies, and increased resistance to reinfection. Serum vibriocidal antibodies, which are readily detected following O1 infection, are the best immunological correlate of protection against O1 cholera, but comparably specific, sensitive and reliable assays are not available for O139 infection. Field studies show that an initial clinical infection by V. cholerae O1 of the classical biotype confers protection against either classical or El Tor biotypes; in contrast an initial clinical infection caused by biotype El Tor results in only a modest level of long-term protection that is limited to El Tor infections. In endemic areas, most people acquire antibodies by early adulthood. However, infection with O1 strains affords no protection against O139 infection, and vice-versa. In experimental challenge studies in volunteers, an initial clinical infection due to V. cholerae O139 conferred significant protection against diarrhea upon re-challenge with V. cholerae O139.

Occurrence

Cholera is one of the oldest and best-understood epidemic diseases. Epidemics and pandemics are strongly linked to the consumption of unsafe water and food, poor hygiene, poor sanitation and crowded living conditions. Conditions leading to epidemics exist in many developing countries where cholera is either endemic or a recurring problem in a large number of areas. Typical settings for cholera are peri-urban slums where basic urban infrastructure is missing. Outbreaks of cholera can also occur on a seasonal basis in endemic areas of Asia and Africa. In 2000–2001, for example, KwaZulu-Natal, South Africa experienced an outbreak that resulted in more than 125 000 cases with a low case fatality rate of less than 0.5%—a low rate that had never previously been observed in an outbreak of that magnitude.

Man-made or natural disasters such as complex emergencies and floods resulting in population movements and overcrowded refugee camps are potentially fertile ground for explosive outbreaks with high case fatality rates. In July 1994, an outbreak of V. cholerae El Tor among Rwandan refugees in Goma, Democratic Republic of Congo (DRC), resulted in more than 50 000 cases and 24 000 deaths over the course of little more than one month.

In 2006, 52 countries reported 236 896 cases of cholera and 6 311 deaths to WHO—an overall case fatality rate of 2.7%. These numbers represent a 76% increase in reported cases compared to 2005, and were the highest numbers reported since the late 1990s. Approximately 99% of all reported cases and all but a very few deaths were in sub-Saharan Africa. Reported case fatality rates by country ranged from 0 to 9%. Globally, actual numbers of cholera cases and deaths are likely to be much higher because of underreporting and poor surveillance.

During the 19th century, cholera spread repeatedly, through 6 pandemic waves, from the Gulf of Bengal to most of the world. During the first half of the 20th century, the disease was confined largely to Asia, except for a severe epidemic in Egypt in 1947. During the latter half of the 20th century, the epidemiology of cholera has been marked by: (1) the global spread of the seventh pandemic of cholera caused by V. cholerae O1 El Tor; (2) the recognition of environmental reservoirs of cholera, such as on the shore of the Gulf of Bengal and along the US coast of the Gulf of Mexico; and (3) the appearance for the first time of large explosive epidemics of cholera caused by V. cholerae organisms of a serogroup other than O1 (V. cholerae O139).

During the current (seventh) pandemic, which started in 1961, V. cholerae of the El Tor biotype spread worldwide from Indonesia, reaching the Asian mainland in 1963, and Africa in 1970, where it has remained endemic in many countries. Cholera reached Latin America in 1991 after nearly a century of absence, causing explosive epidemics along the Pacific coast of Peru and in many countries—by 1994, approximately one million cholera cases had been recorded in Latin America. Although the clinical disease was as severe as in other regions of the world, the overall case fatality rate in Latin America was low, at 1%, except in highly rural areas in the Andes and Amazon region where patients were often far from medical care.

In late 1992, the new serogroup of V. cholerae designated O139 Bengal emerged in Southern India and Bangladesh and spread rapidly throughout the region over the next few months, infecting several hundred thousand persons. During this epidemic period, V. cholerae O139 almost completely replaced V. cholerae O1 strains in hospitalized cholera patients and in samples of surface water. The epidemic continued to spread through 1994, with cases of O139 cholera reported from 11 countries in Asia. This new strain was soon introduced to other continents by infected travelers, but secondary spread outside of Asia has not been reported and V. cholerae O139 remains confined at time of writing to the southeastern areas of the Asian continent. It is not known whether this new strain has the potential to generate a new pandemic; however, the earlier explosive spread through Asia suggests that continued international surveillance is warranted.

Cases of cholera are regularly imported into industrialized countries. Several prospective studies using optimized bacteriological methods (TCBS medium) have shown that the incidence of traveler's cholera in travelers from industrialized countries is considerably higher than previously estimated. However, safe water and adequate sanitation limit the potential for outbreaks, and secondary transmission in developed countries is exceedingly rare.

Since 1973, the occurrence of laboratory and sporadic cases in the Gulf coast area of the USA, all due to a single indigenous strain, has led to the identification of an environmental reservoir of V. cholerae O1 El Tor Inaba in the Gulf of Mexico.


Prevention and Control

1)    Preventive measures:

a)    See the page on Typhoid.

b)    Traditional injectable cholera vaccines based on killed whole cell microorganisms provide only partial protection (50% efficacy) of short duration (3–6 months), do not prevent asymptomatic infection, and are associated with adverse effects. Their use has never been recommended by WHO, and they are no longer available in most countries.

Two oral cholera vaccines (OCV) that are safe and which provide significant protection for several months against cholera caused by O1 strains have been licensed in many countries. OCVs are mainly used by travelers from industrialized countries. The first is a single-dose live vaccine (strain CVD 103-HgR) which, although licensed, is not currently available, as the manufacturer ceased production in 2004. The second is a killed vaccine consisting of inactivated vibrios plus B-subunit of the cholera toxin, given on a 2-dose regimen. As of mid-2008, these vaccines were not licensed in the USA. A third killed whole-cell oral cholera vaccine containing no B-subunit has been produced via technology-transfer to Vietnam, though this vaccine is currently only licensed for use in that country.

A 2003–2004 mass vaccination trial in Mozambique showed that OCVs are effective in preventing cholera in the short-term in African populations with a high prevalence of HIV infection, and that large-scale vaccination campaigns are feasible. Additional questions, such as the duration of protection and cost-effectiveness, remain to be answered before widespread vaccination can be widely recommended. It has been suggested that herd immunity can be achieved with a 50–70% OCV coverage rate, a finding that—if supported by future observations in the field—would further support a scaling up of OCV use in endemic areas.

c)    Measures that inhibit or otherwise compromise the movement of people, foods or other goods are not epidemiologically justified and have never proved effective to control cholera.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Case report is no longer routinely required by the International Health Regulations [2005]; but the Regulations do make obligatory the reporting of outbreaks that have public health impact, are unusual or unexpected, or which pose a threat of international spread or trade or travel restrictions.

b)    Isolation: Hospitalization with enteric precautions is desirable for severely ill patients; strict isolation is not necessary. Less severe cases can be managed on an outpatient basis with oral rehydration. An appropriate antimicrobial agent can be administered to decrease the likelihood of further spread, but antimicrobials are clinically indicated for severe cases only as their injudicious use fosters the development of antimicrobial resistant strains. Cholera wards can be operated even when crowded without hazard to staff and visitors, provided standard procedures are observed for hand washing and cleanliness and for the circulation of staff and visitors. Fly control should be practiced.

c)    Concurrent disinfection: Of feces and vomit and of linens and articles used by patients, using heat, carbolic acid or other disinfectant. In communities with a modern and adequate sewage disposal system, feces can be discharged directly into the sewers without preliminary disinfection.

d)    Quarantine: Not applicable. WHO does not advise routine screening or quarantine of travelers coming from cholera affected areas. For more information, please see the WHO statement relating to international travel and trade to and from countries experiencing outbreaks of cholera, which can be found at: http://www.who.int/cholera/choleratravelandtradeadvice161107.pdf

e)    Management of contacts: Surveillance of persons who shared food and drink with a cholera patient for 5 days from last exposure. Chemoprophylaxis is rarely advisable—often by the time it can be delivered to contacts of an individual case, the targeted individuals have either already acquired the infection, or have little chance of acquiring it from the case in question. However, chemoprophylaxis of institutionalized populations, such as those in jail, which are rapidly accessible following the identification of an index case, has been successfully accomplished. The same antimicrobials used for treatment can be used for chemoprophylaxis, with attention to the resistance patterns of circulating strains. Mass chemoprophylaxis of whole communities is never indicated, as it is a waste of resources and can quickly lead to antibiotic resistance.

f)    Investigation of contacts and source of infection: Investigate possibilities of infection from polluted drinking water and contaminated food. Meal companions for the 5 days prior to onset should be interviewed. A search by stool culture for unreported cases is recommended only among household members or those exposed to a possible common source in a previously uninfected area.

g)    Specific treatment: The cornerstone of cholera treatment is timely and adequate rehydration. Patients presenting mild dehydration can be treated successfully by oral rehydration solutions (ORS) therapy. Only severely dehydrated patients need rehydration through intravenous routes to repair fluid and electrolyte loss through diarrhea. As rehydration therapy becomes increasingly effective, patients who survive hypovolemic shock and severe dehydration may manifest certain complications, such as hypoglycemia, that must be recognized and treated promptly.

Most patients with mild or moderate fluid loss can be treated entirely with oral rehydration solutions that contain: glucose 75 mmol/L; NaCl 75 mmol/L; KCl 20 mmol/L; and trisodium citrate dihydrate 10 mmol/L. This new formula of ORS was approved by a WHO expert committee in June 2002; it has a total osmolarity of 245 mOsm/L and is particularly effective for treatment of children with acute non-cholera diarrhea in both developing and industrialized areas. Mild and moderate volume depletion should be corrected with oral solutions, replacing over 4–6 hours a volume matching the estimated fluid loss (approximately 5% of body weight for mild dehydration and 7% for moderate dehydration). Continuing losses are replaced by giving, over 4 hours, a volume of oral solution equal to 1.5 times the stool volume lost in the previous 4 hours. In children, daily supplementation with 30mg elemental zinc during illness has been shown to reduce both duration and severity of cholera.

Severely dehydrated patients or patients in shock should be given rapid IV rehydration with a balanced multi-electrolyte solution containing approximately 130 mEq/L of Na+, 25 48 mEq/L of bicarbonate, acetate or lactate ions, and 10 15 mEq/L of K+. Useful solutions include Ringer lactate (4 grams NaCl, 1 gram KCl, 6.5 grams sodium acetate and 8 grams glucose/L), and “Dacca solution” (5 grams NaCl, 4 grams NaHCO3 and 1 gram KCl/L), which can be prepared locally in an emergency. The initial fluid replacement should be 30 mL/kg in the first hour for infants and in the first 30 minutes for persons over 1 year, after which the patient should be reassessed. After circulatory collapse has been effectively reversed, most patients can continue on oral rehydration to complete the 10% initial fluid deficit replacement and to match continuing fluid loss.

In severe cases, appropriate antimicrobial agents can shorten the duration of diarrhea, reduce the volume of rehydration solutions required, and shorten the duration of vibrio excretion. Adults are given a single 300 mg dose of doxycycline, or tetracycline 500 mg 4 times a day for 3 days. Children may be given 12.5 mg/kg of tetracycline 4 times daily, for 3 days (there is little risk of dental staining with short course tetracycline treatment). Where tetracycline-resistant strains of V. cholerae are prevalent, alternative antimicrobial regimens include furazolidone (100 mg 4 times daily for adults and 1.25 mg/kg 4 times daily for children, for 3 days); or erythromycin (250 mg 4 times daily for adults and 30 mg/kg 4 times daily for children, for 3 days). Ciprofloxacin, 250 mg once daily for 3 days, is also a useful regimen for adults. V. cholerae O1 and O139 strains are often resistant to cotrimoxazole or trimethoprim-sulfamet. Since individual strains of V. cholerae O1 or O139 may be resistant to any of these antimicrobials, knowledge of the sensitivity of local strains to these agents, if available, should always be used to guide the choice of antimicrobial therapy.

3)    Epidemic measures:

a)    Educate the population at risk concerning the need to seek appropriate treatment without delay.

b)    Provide effective treatment facilities.

c)    Adopt emergency measures to ensure a safe water supply. Chlorinate public water supplies, even if the source water appears uncontaminated. Chlorinate or boil water used for drinking, cooking and washing dishes and food containers, unless the water supply is adequately chlorinated and subsequently protected from contamination. Households that store drinking water should ensure that protective storage containers are used to prevent recontamination of treated water by hands or objects during storage.

d)    Ensure careful preparation and supervision of food and drinks. After cooking or boiling, protect against contamination by flies and unsanitary handling; leftover foods should be thoroughly reheated (70°C/158°F for at least 15 minutes) before ingestion. Persons with diarrhea should not prepare food or haul water for others. Food served at funerals of cholera victims may be particularly hazardous if the body has been prepared for burial by the participants without stringent precautions; this practice should be discouraged during epidemics.

e)    Initiate a thorough investigation designed to find the predominant vehicle(s) of infection and circumstances (time, place, and person) of transmission, and plan control measures accordingly.

f)    Provide appropriate safe facilities for sewage disposal.

g)    Parenteral whole cell vaccine is not recommended.

h)    Oral cholera vaccines can be used as an additional public health tool, but should not replace other recommended control measures, or detract from surveillance or clinical management of cases. The use of the currently available OCV is not recommended in populations currently experiencing an outbreak, due to the time required to administer—and receive full immunologic benefits from—the 2-dose regimen, and the heavy financial and logistical requirements.

4)    Disaster implications:

Outbreak risks are high in endemic areas if large groups of people are crowded together without sufficient quantities of safe water, adequate food handling, or sanitary facilities.

5)    International measures:

a)    Governments are required to report cholera cases due to V. cholerae O1 and O139, and outbreaks or epidemics of acute watery diarrhea, to WHO when they are unusual or unexpected, or when they present significant risk of international spread or of international travel or trade restrictions (International Health regulations 2005).

b)    Measures applicable to ships, aircraft and land transport arriving from cholera areas are to be applied within the framework of the revised International Health Regulations (2005).

c)    International travelers: No country is authorized under the International Health Regulations 2005 to require proof of cholera vaccination as a condition of entry, and the International Certificate of Vaccination no longer provides a specific space for the recording of cholera vaccination. Immunization with either of the new oral vaccines can be recommended for individuals from industrialized countries traveling to areas of endemic or epidemic cholera. As of mid-2008, no cholera vaccines are licensed and available in the United States. In countries where the new oral vaccines are already licensed, immunization may be particularly recommended for travelers with known risk factors such as hypochlorhydria (consequent to partial gastrectomy or medication) or cardiac disease (e.g. arrhythmia), and for the elderly or individuals of blood group O.

d)    Further information can be found at: http://www.who.int/csr/disease/cholera

e)    In addition, WHO Collaborating Centres provide support as required. More information can be found at: http://www.who.int/collaboratingcentres/database/en/

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.
 


Available Vaccines

WHO-Prequalified cholera vaccines

 

Common Disease Taxonomy: