Vibrio cholerae (Cholera)

Cholera is an acute diarrheal disease with great potential for epidemic spread. For centuries cholera has caused considerable morbidity and mortality, particularly in the most impoverished areas of the world, where it remains a major public health challenge. Epidemic cholera is caused by two toxin-producing serogroups of the bacterium Vibrio cholerae, O1 and O139. Severe cholera causes rapid loss of fluid and electrolytes, which, without prompt volume replacement and correction of electrolyte imbalances, can quickly be fatal.

The Pathogen And Microbiology

V. cholerae is a gram-negative bacterium of the family Vibrionaceae that can exist in a free-living state in oceans, rivers, lakes, and ponds. The organism is classified into over 200 serogroups based on somatic (O) antigen composition. Only toxigenic (cholera-toxin producing) strains of serogroups O1 and O139 cause cholera epidemics. Traditionally, V. cholerae O1 has been divided into biotypes (classical and El Tor) based on phenotypic markers and further subdivided into serotypes (Inaba, Ogawa, and rarely, Hikojima), which differ by a single methyl group. During epidemics, serotype switching from Ogawa to Inaba can occur. ^, V. cholerae O139 closely resembles the El Tor biotype but, unlike V. cholerae O1, possesses both a capsule and a distinct lipopolysaccharide and does not agglutinate with O1 antiserum. ^, Nontoxigenic and non-O1, non-O139 V. cholerae strains can cause diarrhea and septicemia (see Chapter 159 ).

V. cholerae is a curved, motile, gram-negative bacillus with a single polar flagellum and measuring 1.4–2.6 μm in length. V. cholerae is salt-tolerant and is best grown on a selective medium, such as thiosulfate citrate bile salts sucrose (TCBS) agar. After 24 hours of incubation at 37°C, V. cholerae colonies grown on TCBS agar are large (2–4 mm in diameter) and yellow with opaque centers and translucent edges. The organism ferments glucose and sucrose and is oxidase positive. Presumptive identification is based on slide agglutination with O1 or O139 antiserum. V. cholerae serogroup O1 isolates are further classified into three serotypes (i.e., Inaba, Ogawa, or Hikojima) based on agglutination in monovalent antisera to type-specific O-antigens. These serotypes are found among both classical and El Tor biotype strains. The two biotypes of V. cholerae serogroup O1 (i.e., classical and El Tor) were originally defined based on phenotypic traits but can also be differentiated by genetic markers. The classical biotype was predominant until the 1960s, when the El Tor biotype spread around the world during the seventh pandemic and gradually displaced it.

Virulence And Pathogenesis

Infection with toxigenic strains of V. cholerae O1 and O139 causes a spectrum of illnesses. A study in Bangladesh found that 59% of people infected with the classical biotype of V. cholerae O1 were asymptomatic compared with 75% of those infected with the El Tor biotype. Among people with symptomatic infection, 11% of those infected with the classical biotype compared with only 2%–5% of those with El Tor infections were hospitalized for severe cholera. The remainder had mild or moderate illness. ^, Mortality rates in severe cases can reach 50% in remote regions or among populations for whom treatment is not readily available. However, with prompt and appropriate volume resuscitation, the mortality rate should be <1%. More recently, “variant El Tor” strains that possess an integrated El Tor biotype phage but express the classical cholera toxin allele were described. ^, These were first noted in Bangladesh but spread quickly to India and have since become the dominant strain in Asia, sub-Saharan Africa, the Americas (Haiti), and the Middle East (Yemen). The classical cholera toxin genes increase toxin secretion and can lead to a higher proportion of infected persons presenting with severe illness, and a lower proportion of asymptomatic infections than typical El Tor strains.

V. cholerae O1 and O139 remain in the gastrointestinal tract and typically do not invade the bloodstream, though a few publications report sporadic cases of cholera bacteremia with each serogroup. The voluminous secretory diarrhea of cholera results from the concerted actions of two major virulence factors: cholera toxin and the toxin coregulated pilus. Cholera toxin, a protein encoded on the filamentous phage known as CTXϕ, is composed of an A subunit and five B subunits arranged in a circular form. Once the B subunit of cholera toxin phage has bound to intestinal cells, the A subunit activates adenylate cyclase, resulting in increased intracellular concentrations of cyclic adenosine monophosphate, which decreases sodium uptake and fuels secretion of chloride and bicarbonate into the gut lumen by the cystic fibrosis transmembrane conductance regulator; water follows this ion gradient passively. Isotonic fluid is secreted at a rate that exceeds the absorptive capacity of the colon, reaching 500–1000 mL/hr, which results in a net fluid and electrolyte loss primarily from the jejunum and ileum.

Immune Response And Susceptibility

Infection with V. cholerae O1 induces the development of serum antibacterial (vibriocidal) and antitoxin antibodies. The primary target of the vibriocidal response is the O-antigen of the V. cholerae lipopolysaccharide. This immune response is serogroup-specific and appears to be mediated by OSP-specific memory B cells. Cholera infection can induce long-lasting immunologic memory, though reinfection with the same or a different serogroup, biotype, or serotype is possible. ^, Surveillance data from cholera endemic regions suggest natural serotype-specific immunity to reinfection for at least 3 years. A study comparing the immune response of patients infected with V. cholerae O1 and O139 revealed that both serogroups elicited vibriocidal and cholera toxin-specific responses. However, previous infection with serogroup O1 did not protect against infection with serogroup O139. ^, Other host factors that contribute to the susceptibility of infection include age <5 years, low gastric acidity, and gut microbiota. People with blood group O are particularly likely to have severe cholera if infected, although the reason is largely unknown. One study in Bangladesh found that although people with blood group O were more likely to develop severe disease once they were infected, they were less likely to become infected with V. cholerae O1 in the first place.

The incubation period of cholera varies with the ingested dose and gastric acidity. In an observational cohort study in Bangladesh, young children were more likely to be infected with V. cholerae O1 (though not V. cholerae O139) and more likely to develop symptomatic illness with either serogroup. An abnormal gut microbiome also has been identified as a risk factor for V. cholerae . ^, Where toxigenic V. cholerae is prevalent, children who are not breastfed are infected more often than breastfed children. ^,

Epidemiology

Cholera can be endemic, epidemic, or pandemic. For centuries, cholera has remained endemic in countries bordering the Bay of Bengal and has spread in periodic pandemic waves. The modern era of cholera comprises 7 pandemics; the first 6 occurred between 1817 and 1923. Most of these pandemics originated in Asia, usually the Indian subcontinent, and subsequently extended to Europe, the Americas, and sometimes Africa. During the third pandemic, the English physician John Snow traced cholera in London to the Broad Street pump and documented waterborne disease transmission before the etiology of the disease was known. During the fifth pandemic, Robert Koch isolated V. cholerae from patients with diarrhea, thereby establishing the etiologic agent. Strains of the first six pandemics were documented or presumed to be of the classical biotype.

V. cholerae O1 El Tor Pandemic

The ongoing seventh pandemic, already the longest and most widespread, began in 1961, when V. cholerae O1, biotype El Tor, spread from a focus in the Sulawesi archipelago (formerly Celebes), Indonesia. In 1971, it reached both East and West Africa, where it remains endemic. In 1991, pandemic V. cholerae O1 reached the Americas, appearing in Peru and spreading swiftly through much of South and Central America. ^, Compared with epidemics of the 19th century, attack rates were higher, but mortality rates were lower. ^, From 1991 to 1996, >1.3 million cases of cholera and nearly 12,000 associated deaths were reported from 20 countries in Latin America, sparing the Caribbean. In stark contrast to the situation in Africa, cholera was nearly eliminated (and infant mortality, typhoid fever, and hepatitis A diminished) in Latin America within a decade because of investments in water and sanitation infrastructure. ^, During the Latin American epidemic, both infant mortality and cholera correlated with unsafe drinking water and poor sanitation. Cholera remains endemic in sub-Saharan Africa, the region with the lowest population coverage for improved water sources and sanitation, with persistent, widespread, and recurrent outbreaks in many countries.

In 2010, cholera was identified in Haiti, approximately 10 months after the devastating earthquake. Haiti had no documented history of epidemic cholera. An epidemiologic and laboratory investigation suggested a single-source introduction of V. cholerae O1, which was confirmed by investigation and isolated genetic testing, indicating UN Peacekeepers from Nepal. After its introduction, cholera became endemic and spread throughout Haiti and into parts of the Dominican Republic. ^, As of 2018, Haiti had reported a cumulative total of 819,085 cases and 9780 deaths resulting from cholera (case-fatality rate, 1.2%). ^, In 2019, following sustained efforts to improve access to safe water and sanitation, conduct cholera vaccination campaigns, increase clinicians’ awareness and knowledge of cholera treatment, and educate the public about cholera prevention, Haiti reported <1000 suspected cases, and only 3 confirmed cases of cholera; similar decreases have been reported by the Dominican Republic. This has led many to believe that cholera could be eliminated from Hispaniola by 2022.

In 2016, cholera was reported in Yemen, where an ongoing civil conflict has severely disrupted health, water, and sanitation infrastructure. By late 2019 in Yemen, 2,188,503 suspected cholera cases and 3750 deaths had been reported, the largest cholera epidemic in recent history.

In the US, 133 cases of cholera were reported to the Centers for Disease Control and Prevention (CDC) from 2007 through 2017. Cholera was associated with international travel in 117 (88%) cases and was domestically acquired in 13 (10%). Of the 13 patients with domestically acquired cholera, 12 (92%) reported seafood consumption, of whom 4 (33%) ate seafood from the US Gulf Coast. During the first 14 months of the cholera outbreak in Hispaniola, 40 (83%) of the 48 travel-associated cases were associated with travel to Haiti or the Dominican Republic.

In 2019, the latest year for which data were available, 31 countries notified the World Health Organization (WHO) of a total of 923,037 cholera cases and 1911 deaths (case-fatality rate, 0.2%). The ongoing outbreak in Yemen contributed 861,096 (93%) of all reported cases in 2019, with another 55,087 (6%) reported from 16 African countries. However, lack of standard reporting, concerns about political and economic ramifications of reporting cholera cases, barriers to accessing healthcare and rapid death before reaching healthcare facilities all contribute to underreporting. Recent modeling estimated that 2.86 million cholera cases (uncertainty range 1.3 million–4.0 million) occur annually in endemic countries, with an estimated 95,000 deaths (uncertainty range 21,000–143,000).

V. cholerae O139 Bengal Outbreaks

In 1992, a novel strain of V. cholerae was identified in Chennai, India. The strain did not agglutinate with antiserum to O1 antiserum or any of the other 137 previously known serogroups, and the strain spread rapidly to 11 countries in South Asia. ^, Designated V. cholerae O139 Bengal, it was the first non-O1 Vibrio to cause epidemic disease. Due to the lack of protection from V. cholerae O1, the proportion of adults affected was unusually high. Because of the general susceptibility of populations, concern was expressed that V. cholerae O139 Bengal could mark the beginning of the eighth pandemic of cholera. Thus far, however, O139 only transiently displaced O1 as the dominant serogroup and has remained confined to South and Southeast Asia, including Bangladesh, Pakistan, Nepal, and China. ^, The O139 episode highlights the potential for the emergence of novel toxigenic V. cholerae strains with the potential to escape prior natural or vaccine immunity.

V. cholerae Transmission

Brackish aquatic environments are the natural reservoirs of V. cholerae , including toxigenic and non-toxigenic strains of serogroups O1 and O139. When conditions are favorable, V. cholerae multiplies and can survive indefinitely, independent of human fecal contamination, in association with invertebrates (e.g., copepods, crabs, shrimp, and oysters) found in brackish waters. Endemic foci of V. cholerae O1 persist in several areas of the developed world, including the US Gulf Coast, where rare sporadic human cases can follow ingestion of water or undercooked shellfish. ^, However, most cases in the US and other resource-rich countries occur in travelers returning from areas of active transmission.

The introduction of cholera into an area where the drinking water supply is not protected from human fecal contamination can cause explosive epidemics. Infection typically follows the consumption of water or food contaminated with feces from one or more persons who are excreting V. cholerae . Waterborne transmission can result from contamination of municipal sources, shallow wells, or unsafe water storage containers in the home. ^, Foodborne transmission can occur through contaminated foods and beverages that are held at ambient temperatures or prepared with unsafe water or ice. Direct person-to-person spread of cholera can occur, especially in healthcare settings; however, this is not thought to be a major mode of transmission. ^,

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