Cholera

Etiology

Cholera is caused by Vibrio cholerae , a gram-negative, comma-shaped bacillus, subdivided into serogroups by its somatic O antigen. Of the >200 serogroups, only serogroups O1 and O139 have been associated with epidemics, although some non-O1, non-O139 V. cholerae strains (e.g., O75, O141) are pathogenic and can cause small outbreaks. A flagellar H antigen is present but is not used for species identification. The O1 serogroup is further divided into classical and the El Tor biotypes based on its biochemical characteristics. Since the turn of the 21st century, only O1 El Tor has been reported; hybrids and variants of V. cholerae O1 El Tor possessing classical genes have been reported worldwide. These hybrid and variant strains have been associated with more severe disease.

Each biotype of V. cholerae can be further subdivided into Inaba, Ogawa, and Hikojima serotypes based on the antigenic determinants on the O antigen. Inaba strains have A and C antigenic determinants, whereas Ogawa strains have A and B antigenic determinants. Hikojima strains produce all 3 antigenic determinants but are unstable and rare. Recent studies reveal that serotype switching results from a selection process as yet unidentified.

Epidemiology

The 1st 6 cholera pandemics originated in the Indian subcontinent and were caused by classical O1 V. cholerae . The 7th pandemic is the most extensive of all and is caused by V. cholerae O1 El Tor. This pandemic began in 1961 in Sulawesi, Indonesia, and has spread to the Indian subcontinent, Southeast Asia, Africa, Oceania, Southern Europe, and the Americas. In 1991, V. cholerae O1 El Tor first appeared in Peru before rapidly spreading in the Americas. Cholera becomes endemic in areas following outbreaks when a large segment of the population develops immunity to the disease after recurrent exposure. The disease is now endemic in parts of Africa and Asia and in Haiti.

In 1992 the first non-O1 V. cholerae that resulted in epidemics was identified in India and Bangladesh and was designated V. cholerae O139 . From 1992–1994, this organism replaced O1 as the predominant cause of cholera in South Asia but has since been an uncommon etiologic agent.

The hybrid El Tor strains were first identified sporadically in Bangladesh. In 2004, during routine surveillance in Mozambique, isolates of V. cholerae O1 El Tor carrying classical genes were identified. Since then, hybrid and variant El Tor strains have been reported in other parts of Asia and Africa and have caused outbreaks in India and Vietnam. Although the classical biotype has virtually disappeared, its genes remain within the El Tor biotype. The current circulating strain in Haiti is closely related to the South Asian strain.

Humans are the only known hosts for V. cholerae, but free-living and plankton-associated V. cholerae exist in the marine environment. The organism thrives best in moderately salty water but can survive in rivers and fresh water if nutrient levels are high, as occurs when there is organic pollution such as human feces. The formation of a biofilm on abiotic surfaces and the ability to enter a viable but nonculturable state have been hypothesized as factors that allow V. cholerae to persist in the environment. Surface sea temperature, pH, chlorophyll content, the presence of iron compounds and chitin, and climatic conditions such as amount of rainfall and sea level rise are all important environmental factors that influence the survival of V. cholerae in the environment and the expression of cholera toxin, an important virulence determinant.

Consumption of contaminated water and ingestion of undercooked shellfish are the main modes of transmission, with the latter more often seen in developed countries. In cholera-endemic areas, the incidence is highest among children <2 yr old; however, in epidemics, all age-groups are usually affected. Persons with blood group O, decreased gastric acidity, malnutrition, immunocompromised state, and absence of local intestinal immunity (prior exposure by infection or vaccination) are at increased risk for developing severe disease. Household contacts of cholera-infected patients are at high risk for the disease, because the stools of infected patients contain high concentrations of V. cholerae . Moreover, as V. cholerae organisms are shed, they enter into a hyperinfective state, requiring an infectious dose that is reduced by one-tenth to one-hundredth compared to organisms that were not shed by humans.

Pathogenesis

Large inocula of bacteria (>10 ⁸ colony-forming units) are required for severe cholera to occur; however, for persons whose gastric barrier is disrupted, a much lower dose (10 ⁵ CFUs) is required. After ingestion of V. cholerae from the environment, several changes occur in the vibrios as they traverse the human intestine: increased expression of genes required for nutrient acquisition, downregulation of chemotactic response, and expression of motility factors. Together these changes allow the vibrios to reach a hyperinfectious state, leading to lower infectious doses required to secondarily infect other persons. This hyperinfectivity may remain for 5-24 hr after excretion and is believed to be the predominant pathway for person-to-person transmission during epidemics.

If the vibrios survive gastric acidity, they colonize the small intestine through various factors such as toxin–co-regulated pili and motility, leading to efficient delivery of cholera toxin ( Fig. 228.1 ). The cholera toxin consists of 5 binding B subunits and 1 active A subunit. The B subunits are responsible for binding to the GM ₁ ganglioside receptors located in the small intestinal epithelial cells. After binding, the A subunit is released into the cell, where it stimulates adenylate cyclase and initiates a cascade of events. An increase in cyclic adenosine monophosphate leads to an increase in chloride secretion by the crypt cells, which in turn leads to inhibition of absorption of sodium and chloride by the microvilli. These events eventually lead to massive purging of electrolyte rich isotonic fluid in the small intestine that exceeds the absorptive capacity of the colon, resulting in rapid dehydration and depletion of electrolytes, including sodium, chloride, bicarbonate, and potassium. Metabolic acidosis and hypokalemia then ensue.