Cholera produces the most dramatic watery diarrhea known. Intestinal fluids pour out in voluminous bowel movements; this eventually leads to dehydration and electrolyte imbalance. These effects come from the action of cholera toxin se-creted by V.cholerae in the bowel lumen. Despite the profound physiologic effects, there is no fever, inflammation, or direct injury to the bowel mucosa.
Epidemic cholera is spread primarily by contaminated water under conditions of poor sanitation, particularly where sewage treatment is absent or defective. Even though con-valescent human carriage is brief, if the numerous vibrios purged from the intestines of cases are able to reach the primary water supply, the conditions for spread are established. The short incubation period (2 days) ensures that organisms ingested by others quickly enter the epidemic cycle. Even so, modern travel makes imported cases possible. One man developed diarrhea in Florida after eating ceviche (marinated uncooked fish) just be-fore departure from an airport in Ecuador.
Cholera is endemic in the Indian subcontinent and Africa. Over the past two centuries, its spread beyond this historic locale to other parts of Asia, Indonesia, and Europe has been described in eight great pandemics, each lasting 5 to 25 years. The current pandemic has brought cholera to the Western Hemisphere for the first time since 1911. Sporadic cases in the United States first appeared in the early 1970s and were traced to inade-quately cooked crabs and shrimp caught off the Gulf Coast of Louisiana and Texas. In 1991, Latin America was hit with epidemic cholera with cases reported from 21 countries from Peru to northern Mexico. In Peru alone, over 500,000 cases and 4500 deaths oc-curred in 2 years. The disease is now endemic, claiming thousands of lives every year. Virulent V.cholerae now lurks in coastal waters throughout the hemisphere and in the drinking water of locales with poor sanitation.
The dominant strain of the 20th century was the El Tor biotype, first isolated from Mecca pilgrims at the El Tor quarantine camp in 1905. This strain survives slightly longer in nature and is more likely to produce subclinical cases of cholera, both of which facilitated its spread. In 1992, the first cholera cases due to a serotype other than O1 were detected in India and Bangladesh. The new serotype (O139 Bengal) is fully virulent with the additional threat of enhanced ability to produce disease in persons whose immunity is due to exposure to the old serotype. This development is important for the global spread of cholera and for the vaccine strategies designed to prevent it.
The triggering of epidemics and the interepidemic survival of V.cholerae in the envi-ronment is incompletely understood but may be linked to crustaceans and theplankton population. V.cholerae in a dormant state can be demonstrated by immunofluorescence in plankton, and epidemics follow plankton blooms. Otherwise the organism is fragile, sur-viving only a few days in the environment unless maintained longer in marine and fresh-water crustaceans.
To produce disease, V.cholerae must reach the small intestine in sufficient numbers to multiply and colonize. In healthy people, ingestion of large numbers of bacteria is re-quired to offset the acid barrier of the stomach. Colonization of the entire intestinal tract from the jejunum to the colon by V.cholerae requires organism adherence to the epithe-lial surface, most probably by surface pili. The outstanding feature of V.cholerae patho-genicity is the ability of virulent strains to secrete CT, which is responsible for the disease cholera. The water and electrolyte shift from the cell to the intestinal lumen is the funda-mental cause of the watery diarrhea of cholera.
The fluid loss that results from the adenylate cyclase stimulation of cells depends on the balance between the amount of bacterial growth, toxin production, fluid secretion, and fluid absorption in the entire gastrointestinal tract. The outpouring of fluid and electrolytes is greatest in the small intestine, where the secretory capacity is high and absorptive capac-ity low. The diarrheal fluid can amount to many liters per day, with approximately the same sodium content as plasma but two to five times the potassium and bicarbonate con-centrations. The result is dehydration (isotonic fluid loss), hypokalemia (potassium loss), and metabolic acidosis (bicarbonate loss). The intestinal mucosa remains unaltered except for some hyperemia, because V. cholerae does not invade or otherwise injure the entero-cyte. Mutants lacking CT may still cause mild diarrhea due to recently discovered acces-sory toxins which cause fluid secretion or increase intestinal permeability.
The expression of the multiple virulence factors of V. cholerae is controlled in a complex but coordinated system involving environmental sensors and as many as 20 chromosomal genes divided between a pathogenicity island (PAI) containing CT and one containing TCP. The chief regulator is a transmembrane protein (ToxR ) that “senses” environmental changes in pH, osmolarity, and temperature which convert it to an active form. In the ac-tive state, ToxR can directly turn on CT genes as well as activate transcription of a second regulatory protein, ToxT. ToxT can then activate transcriptional of virulence genes in both PAIs, including TCP, CT, and accessory toxins.
Nonspecific defenses such as gastric acidity, gut motility, and intestinal mucus are impor-tant in preventing colonization with V. cholerae. For example, in persons who lack gastric acidity (gastrectomy or achlorhydria from malnutrition), the attack rate of clinical cholera is higher. Natural infection provides long-lasting immunity. The immune state has been associated with IgG directed against the cell wall LPS and with the production of secre-tory IgA by lymphocytes in the subepithelial areas of the gastrointestinal tract. The pre-cise protective mechanisms remain to be established.
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