Gastric Acidity

Ingested pathogenic bacteria and other pathogens first must survive passage through the stomach to infect the small or large intestine. In this regard, gastric acidity is the first line of defense.⁷ Most bacterial pathogens are highly susceptible to low pH, and thus exposure to gastric acid significantly reduces the number of viable bacteria after their ingestion. Gastric juice with a pH of less than 4.0 is rapidly bactericidal, whereas bacteria survive prolonged exposure to gastric juice from patients who are achlorhydric.⁸ In experimental studies of cholera in healthy adults, clinical infection did not develop when as many as 10¹⁰ cholera bacteria were ingested, whereas as few as 10⁴ Vibrio cholerae were able to produce disease when organisms were administered with sodium bicarbonate⁹; even fewer bacteria were necessary to produce clinical illness when organisms were directly instilled into the duodenum. Naturally occurring cholera also occurs more often in achlorhydric patients.¹⁰ The gastric barrier also may be important in preventing other enteric infections such as salmonellosis¹¹ and shigellosis.¹²

Intestinal Motility

Organisms surviving the milieu of the stomach enter the small intestine where normal propulsive motor activity clears them. Some bacteria, including Clostridium difficile, Clostridium perfringens, and heat-stable enterotoxin-producing Escherichia coli, elaborate toxins that impair intestinal motility.¹³ In experimental animals it is often necessary to restrict intestinal motility with pharmacologic agents or with ligatures to allow enteropathogens to establish infection.¹⁴

Intestinal Microflora

The normal intestinal microflora, primarily in the colon, resist colonization of the intestine by newly introduced bacteria. Products elaborated by the resident microflora, including lactic acid and short-chain fatty acids, are toxic to many bacterial pathogens, and when the intestinal microflora are altered in instances such as administration of an antibiotic, colonization resistance is lessened and the host may be more susceptible to intestinal infection (e.g., C. difficile).¹⁵ Alteration of intestinal flora by antibiotics also increases susceptibility to salmonellosis.^16,17

Mucus

Mucus, in concert with intestinal motility, provides a physical barrier to bacterial proliferation and mucosal colonization. Gastric mucus can act in conjunction with gastric acidity as the first line of enteric defense. Differences in the carbohydrate composition of intestinal mucus between immature and mature rats suggest that this difference plays a role in the reduced host defense of the immature animal.¹⁸

Systemic and Local Immune Mechanisms

The mucosa’s antibacterial immune response is quite complex and important in combating enteric pathogens. Secretory antibody in the intestine appears before serum antibody does in response to intestinal infection with Shigella.¹⁹ In cholera, there is a better correlation between the level of coproantibody and immune protection than there is with serum antibody and resistance to enteric infection with this pathogen²⁰; however, both mucosal and systemic immune systems provide important protection against pathogenic bacteria. These immune responses may be directed against multiple targets. For example, the immune response against cholera may be directed against the toxin or the bacterium and originate from either the mucosal immune system (secretory IgA) or from the serum (IgG). Regardless, both serum and secretory antibodies exert their protective effects at the intestinal level, even though the serum components are produced outside the intestine.

Others

Breast-feeding also serves as a defense mechanism against bacterial enteropathogens. Breast-fed infants are less susceptible to bacterial diarrhea than are formula-fed infants.^21,22 Multiple factors are responsible for this protection. Breast milk contains secretory IgA antibodies against specific enteropathogens that survive passage through the infant’s gastrointestinal tract.²³ Other components such as lactoferrin, lysozyme, and lactoperoxidase also have anti-infective properties, and breast milk glycolipids can interfere with toxin or microbial adherence.²⁴

Adherence

The ability of bacteria to adhere to host mucosal cells is a critical virulence factor in enterotoxin-producing and invasive bacteria as well as in enteroadherent E. coli (EAEC) and enteropathogenic E. coli (EPEC). Bacterial adherence to host mucosal cells may be the predominant virulence factor, as in the case of EPEC; one of two important factors (adherence plus toxin elaboration), as in the case of enterotoxigenic organisms; or only one of several factors required for expression of full pathogenicity, as seen with invasive organisms. Bacteria that cause disease by adhesion alone do not elaborate any of the traditional enterotoxins, but rather they adhere tightly to the mucosa of both the small and large intestine.²⁵ The classic EPEC and the EAEC²⁶ are typical of this group. Other organisms, including enterotoxigenic E. coli (ETEC) and the invasive Salmonella and Shigella species, also must adhere to the intestinal surface to be fully pathogenic.

Studies on the mechanism by which EPEC cause diarrhea show that they attach to the intestinal mucosa in a characteristic manner, producing ultrastructural changes known as attaching-effacing lesions²⁷ that lead to elongation and destruction of microvilli.^25,28 This pattern of bacterial binding to enterocytes also has been referred to as attaching and effacing adherence²⁷ and the particular morphologic alteration as pedestal formation (Fig. 107-1).²⁵

Figure 107-1. Electron micrograph of enteropathogenic Escherichia coli (EPEC) adherent to the jejunal mucosa and demonstrating the attaching and effacing lesion, also called pedestal formation. Tightly adherent E. coli are obliterating the brush border.

The laboratory counterpart of mucosal colonization is adherence in tissue culture to various cell lines such as Hep-2 and HeLa. A characteristic form of localized adherence is observed only with classic EPEC serotypes. These events occur in the following three phases²⁹:

The presence of a plasmid in EPEC serves to increase intimin production; this process is needed for localized adherence to occur.³¹ EPEC strains with localized adherence produce acute diarrhea when these strains are administered to normal volunteers.³² The role of the eaeA gene as a virulence factor in human EPEC infection has been confirmed in volunteer challenge studies.³³

Enterotoxigenic organisms also require expression of bacterial adherence for proliferation of the organisms and colonization, as well as for full expression of toxicity.³⁴ ETEC adhere to the surface of the small bowel epithelium without penetrating the epithelial layer and do so by mechanisms different from those used by EPEC. The most important mechanism by which enterotoxigenic bacteria adhere to the intestinal mucosa is related to specific protein antigens on the surface of the bacterial cell known as pili or fimbriae, also referred to as adherence antigens or colonization factor antigens.³⁵ These pili bind to specific receptor sites on the surface of the intestinal cell via specific ligand-receptor interactions.

The antigenic structure of the adherence pili determines the host specificity of the ETEC strains. For example, those bearing a K88 antigen are pathogenic for piglets, whereas others bearing K99 antigen cause disease in calves and lambs. ETEC adhesion antigens for humans include type 1,3,P and BFP pili.

Evidence that these colonization factors (e.g., pili and lectins) are important to the pathogenesis of E. coli diarrheal disease in animals is derived from the observations by Moon³⁶ that loss or gain of fimbriae by genetic manipulation results in the loss or gain of the ability to adhere to and colonize the intestine. Adherence not only permits colonization but also can facilitate the delivery of enterotoxin to the epithelium and might even enhance the ability of the organism to elaborate enterotoxin.^34,36

Enterotoxin Production

Enterotoxins are polypeptides, secreted by bacteria, that alter intestinal salt and water transport without affecting mucosal morphology.^5,37,38 Many organisms elaborate enterotoxins (e.g., V. cholerae, Shigella, ETEC, and Staphylococcus aureus), and several enterotoxins may be elaborated by a single organism. Although most enterotoxins affect the small intestine, the colon also may be a target organ.

Several enterotoxin-producing organisms cause food poisoning and induce disease without requiring intestinal colonization, such as S. aureus and C. perfringens; their toxins are ingested preformed in food, thus accounting for their characteristic brief incubation period.

Whether the enterotoxin is ingested preformed or is first expressed within the intestinal lumen, the toxin-enterocyte or toxin-colonocyte interaction begins with the binding of the enterotoxin to a specific mucosal receptor. The toxin-receptor interaction increases the concentration of an intracellular mediator, resulting in alteration of salt and water flux. Thus far, three intracellular mediator systems have been shown to be involved in the pathogenesis of enterotoxigenic diarrhea: adenylate cyclase and cyclic adenosine monophosphate (cAMP), the guanylate cyclase and cyclic guanosine monophosphate (cGMP) systems, and intracellular calcium.^39,40 Alterations in these mediator systems have similar effects on transport processes to decrease the coupled influx of sodium and chloride and to stimulate the active secretion of chloride from the cell into the intestinal lumen. Other intracellular mediator systems involved in the pathogenesis of bacterial diarrhea include protein kinase C and arachidonic acid metabolites, among others.

Cholera toxin (molecular weight ≈84,000 kDa), which stimulates adenylate cyclase, is a prototypical enterotoxin (Fig. 107-2 and Chapter 99), the toxin-enterocyte interaction of which is well understood. Cholera toxin is composed of an A subunit surrounded by five B subunits that bind the toxin to a ganglioside (GM₁) receptor on the brush border membrane of the villus epithelial cell. The A subunit, which consists of two parts (A₁ and A₂) linked by a disulfide bond, slowly penetrates the brush border membrane and is cleaved into its two component peptides. Reduction of this bond releases the active A₁ peptide that traverses the cell to the basolateral membrane, where it stimulates the ribosylation of G_s, the stimulatory subunit of a heterotrimeric G protein. This action results in the irreversible activation of G_s and an increase in cytosolic cAMP. This cAMP in turn activates cAMP-dependent kinases that inhibit NaCl-coupled transport and stimulate chloride secretion.

Figure 107-2. Subunit structure of cholera toxin (choleragen) (see text). mw, molecular weight.

(From Fishman PH. Action of cholera toxin: Events on the cell surface. In Field M, Fordtran JS, Schultz SG, editors. Secretory Diarrhea. Bethesda, Md: American Physiological Society; 1980. p 86.)

In addition to cholera toxin, other important enterotoxins are those elaborated by E. coli.^41,42 Two classes of E. coli enterotoxins are known: heat-labile (LT) and heat-stable (ST) toxins. LT, which exists in two forms (LT-1 and LT-2),⁴² is a large molecular-weight protein that causes diarrheal disease similar to, but less severe, than, cholera. The subunit structure and mechanism of action of LT-1 and LT-2 also are similar to those of cholera toxin; although cholera toxin and LT bind to a glycolipid receptor, specifically GM_1, an additional glycoprotein receptor might exist for LT.⁴² Heat-stable enterotoxins (ST_as) also may be elaborated by E. coli and bind to brush border receptors on enterocytes and colonocytes, a receptor guanylate cyclase, to increase intracellular levels of cGMP. ST_b is an unrelated enterotoxin elaborated by some E. coli pathogenic for pigs. Other organisms that elaborate highly homologous heat-stable enterotoxins include Yersinia enterocolitica, Citrobacter, and non-O1 vibrios.⁴²

Cytotoxin Production

Cytotoxins are polypeptides that cause cell injury, inflammation, intestinal secretion through inhibition of protein synthesis or via a cascade involving one or more inflammatory mediator substances, and cell death. Examples of organisms that produce cytotoxins include C. difficile (see Chapter 108),¹⁵ some EPEC, enterohemorrhagic E. coli (EHEC), and Shigella.⁴³ The mechanisms by which cytotoxins cause cell injury, inflammation, and intestinal secretion are numerous and complex and include inhibition of protein synthesis, disruption of cellular actin and tight junction integrity, mitochondrial damage, and adenosine triphosphate depletion among others.

Mucosal Invasion

The mechanism of mucosal invasion involves invasion of enterocytes or colonocytes by the infecting organisms with subsequent intracellular multiplication, resulting in cell injury and possibly cell death. Shigella species are classic examples of invasive enteropathogens. Salmonella species, Campylobacter jejuni, Y. enterocolitica, and some (enteroinvasive) strains of E. coli invade intestinal cells and pass into the lamina propria, where they elicit an inflammatory response and cause mucosal ulceration.^4,6

Unlike enterotoxigenic organisms that favor colonization of the small intestine, invasive organisms primarily, but not exclusively, colonize the colon. In salmonellosis, the ileum is colonized in addition to the colon; in shigellosis, the small intestine is colonized transiently early in the course of the disease when watery diarrhea rather than dysentery is the predominant symptom.⁴⁴ Subsequently, colonization occurs in the colon and bloody diarrhea ensues. In the cases of Shigella and Salmonella species, the ability to invade the gastrointestinal mucosa is of primary importance in establishing the enteric infection.^45,46

Bacterial invasion alone is not sufficient to establish disease; other properties of invading organisms also are required. In the case of Shigella species, the organisms must multiply intracellularly. Thus, strains of Shigella flexneri that can invade but cannot multiply do not cause disease when fed to a susceptible host.⁴⁵ Intracellular multiplication of Shigella organisms also involves lateral spread to adjacent intestinal cells and their death. In the cases of Salmonella species and Y. enterocolitica, however, the organisms penetrate into the lamina propria and can disseminate to extraintestinal sites. As a consequence of mucosal invasion and of the intramucosal multiplication of the organisms, an acute inflammatory reaction develops and mucosal ulceration can occur. Gross ulceration of the colonic mucosa commonly occurs in shigellosis, which accounts for dysenteric stools, but it is much less common with Salmonella and Yersinia infections. Yersinia infection more commonly manifests with microscopic and minute ulcerations involving both the ileum and colon.

Some of the mechanisms by which invasive organisms induce intestinal secretion include increased intracellular calcium and products of inflammation, such as prostaglandin and leukotriene metabolites, serotonin, substance P, interleukin (IL)-1, and reactive oxygen metabolites, among others.

Others

Other bacterial virulence factors, not as yet well defined, can modulate infectivity or the spectrum of illness, including the ability of bacteria to respond to chemotactic signals released by the mucosa, bacterial elaboration of mucolytic enzymes to enable bacterial penetration of the intestinal cell, resistance to phagocytosis, and elaboration of substances that interfere with intestinal motility. The importance of these factors in modifying virulence is uncertain and they are not discussed further.

Noninflammatory Diarrhea

Patients with noninflammatory diarrhea usually present with large-volume watery stools without blood or pus, or they present with severe abdominal pain. These patients generally have few systemic signs or symptoms, and fever usually is absent. Abdominal cramping, nausea, and vomiting can occur. The most likely causes are viruses (rotavirus, norovirus), enterotoxigenic E. coli, V. cholerae, staphylococcal and clostridial food poisoning, and Giardia and Cryptosporidium infections. Noninflammatory diarrheas generally do not require extensive evaluation. Pathogens causing noninflammatory diarrhea usually infect the small intestine and merely adhere to the mucosal surface without invading the epithelium or causing acute inflammation. Most of these organisms (e.g., cholera, rotavirus) elaborate enterotoxins that stimulate intestinal secretion, occasionally resulting in profound dehydration.

Inflammatory Diarrhea

Patients with inflammatory diarrhea usually present with numerous small-volume stools that may be mucoid, grossly bloody, or both. Such patients may appear toxic and usually are febrile. Abdominal cramping may be severe. Because of the small stool volumes, these patients are less likely to be dehydrated than those with noninflammatory diarrhea. Physical findings might point to a specific diagnosis (Table 107-3).

Table 107-3 Clinical Finding(s) That Suggest the Causative Organisms for Some Inflammatory Diarrheas

Organisms causing inflammatory diarrheas usually affect the colon and either invade or elaborate cytotoxins, resulting in an acute inflammatory reaction with disruption of the epithelial barrier, mucus, red blood cells, and white blood cells in the stool (Table 107-2). Microbes causing this syndrome include Shigella, Campylobacter, EHEC, C. difficile, Salmonella, Yersinia, and Entamoeba histolytica. Fecal leukocytes (or positive stool lactoferrin test) indicate an acute inflammatory process, and sheets of polymorphonuclear leukocytes (PMNs) usually indicate colitis. The acute inflammatory diarrheal syndrome also can have an noninfectious etiology, for example, ulcerative colitis, Crohn’s disease, radiation or ischemic colitis, and diverticulitis. Table 107-4 lists the organisms that may be associated with the presence of fecal leukocytes.⁴⁷

Table 107-4 Fecal Leukocytes in Intestinal Infections

Proctitis Syndrome

Proctitis syndrome is characterized by frequent painful bowel movements containing blood, pus, and mucus. The sensation of tenesmus, often with rectal pain, usually is prominent. Infectious causes include Shigella, herpes simplex virus type 2, and Neisseria gonorrhoeae, Treponema pallidum (syphilis), and Chlamydia (lymphogranuloma venereum). The importance of this syndrome is that many of the causes have specific treatments. Noninfectious causes include idiopathic ulcerative proctitis, Crohn’s proctitis, radiation proctitis, and solitary rectal ulcer syndrome.

Fecal Leukocytes

A particularly useful technique to focus the differential diagnosis is microscopic examination of the stool for PMNs (see Table 107-4). Invasive pathogens that primarily affect the colon, such as Shigella and Campylobacter, produce a “sea of polys,” as well as red blood cells. The toxigenic organisms, viruses, and food-poisoning bacteria cause a watery stool that harbors few formed elements. Stool tests for lactoferrin or calprotectin (proteins made by PMNs) in fecal specimens are available and provide a rapid and sensitive alternative to microscopy for identifying PMNs and, by inference, inflammatory diarrhea.⁴⁸

Salmonella, Yersinia, Vibrio parahaemolyticus, and C. difficile diarrhea have unpredictable and variable numbers of fecal leukocytes, depending on the degree of colonic involvement; most cases show only occasional PMNs. An acute exacerbation of ulcerative or Crohn’s colitis can produce a stool with many PMNs, thereby resembling bacillary dysentery. Although fecal microscopic examination is neither infallible nor even helpful in all cases, it is inexpensive and yields immediate information that can guide antibiotic therapy. Although the fecal lactoferrin and calprotectin tests are slightly more expensive than microscopy for fecal leukocytes, they have several advantages, including ease, rapidity, and the absence of a requirement for a fresh stool specimen.

Stool Cultures

Stool cultures are ordered too frequently. In most microbiology laboratories, routine stool cultures are processed for Shigella, Salmonella, and Campylobacter. Other enteric pathogens such as Yersinia, Vibrio, and E. coli O157:H7 are not sought routinely. Therefore, if clinical suspicion is high, the microbiology department needs to be notified to search for these pathogens. Because of sporadic shedding of pathogens (nontyphoidal Salmonella spp., Salmonella typhi) and because most episodes of acute diarrhea are caused by viruses, undetectable pathogens, or noninfectious causes, stool cultures are not usually positive. At Massachusetts General Hospital, the isolation rate of bacterial pathogens from 2000 fecal cultures in 1980 was 2.4%.⁴⁹ In patients with severe diarrhea requiring hospitalization, the bacterial isolation rate from feces is somewhat higher, ranging from 27% to 43%,^50,51 and up to 58% in a study that used more-advanced techniques.⁵² Even in patients hospitalized for dysentery, the rate of positivity for microbiologic diagnosis is only 40% to 60%. In community patients with severe acute gastroenteritis (more than four fluid stools per day, lasting at least three days and with at least one associated symptom), the yield of a stool culture and ova and parasite examination increased to 88%.⁵³ In outbreaks of gastroenteritis in the United States, only one half of the cases have a confirmed etiology, of which two thirds are bacterial in origin. These figures suggest that many cases of acute diarrhea are caused by unidentified pathogens.

When parasitic or protozoal infection is suspected, stool examination for cysts, trophozoites, larvae, or eggs should be performed. When either Giardia or cryptosporidia is suspected, a stool enzyme-linked immunosorbent assay (ELISA) for antigens of these organisms should be requested. ELISA also is done for rotaviruses or noroviruses, but this test rarely is required in adults. It is not appropriate to request stool cultures and stool examination for ova and parasites for every patient with diarrhea. These tests should be performed only when the clinical suspicion is high that parasitic infection is the cause of diarrhea and the results of the stool tests will change management and influence outcome.

Endoscopy

Endoscopy may be useful to obtain aspirates and biopsies of the small intestine to detect Giardia, cryptosporidia, microsporidia, Isospora belli, or Mycobacterium avium-intracellulare. Flexible sigmoidoscopy can be useful in evaluating patients with proctitis, tenesmus, or sexually transmitted diseases or in identifying the pseudomembranes of C. difficile. In HIV-infected patients, colonoscopy with multiple biopsies is used to detect cytomegalovirus ulcers, which may be confirmed by the presence of inclusion bodies on biopsy.

An algorithm for the diagnosis of acute diarrhea is presented to help determine which patients should be treated symptomatically and which require further diagnostic studies and treatment (see Fig. 107-3). Approximately 90% of cases of acute diarrhea fall into the “No” category.

Microbiology

Vibrio cholerae is a Gram-negative, short, curved rod that looks like a comma. It is actively motile by means of a single polar flagellum. Vibrios are strongly aerobic and prefer alkaline and high-salt environments.

The terminology and classification of V. cholerae are complex. Agglutination by antisera against the O1 antigen (cell wall polysaccharide) is used to characterize vibrios into O1 or non-O1 groups. They are then classified into serotypes based on the subspecificity of O1 antigen (A, B, C: Ogawa [A, B]; Inaba [A, C]; Hikojima [A, B, C]). Biotype refers to different phenotypic qualities (e.g., production of hemolysins, agglutination of various species of erythrocytes, resistance to polymyxin).

Toxigenic V. cholerae that agglutinates in O1 antiserum is the main cause of epidemic cholera. There are two major biotypes of V. cholerae O1: classic and El Tor. The latter strain is responsible for the current pandemic that began in 1961. El Tor vibrios are somewhat hardier than others in nature. Clinical disease is similar with both biotypes, although on average, El Tor infections are milder. The major serotypes associated with clinical disease are Inaba and Ogawa; a rare third type is Hikojima. The El Tor Inaba type was responsible for the 1991 outbreak in South America. There also are unique O1 cholera strains (e.g., V. parahaemolyticus and V. vulnificus) that cause endemic disease along the Gulf Coast of the United States.⁵⁴

A newly described toxigenic non-O1 strain, now designated V. cholerae O139 Bengal, was responsible for an epidemic that started in southern India and Bangladesh in late 1992 and spread rapidly to many countries in Southeast Asia.^55,56 This strain was classified as a new serogroup because it did not react with antisera to the previously identified 138 serogroups.⁵⁶

Cholera Toxin

All wild strains of V. cholerae, including O139, elaborate the same enterotoxin, a protein molecule with a molecular weight of 84,000 kDa (see Fig. 107-2).⁵⁷ The structural genes for the cholera toxin are encoded by a filamentous bacteriophage.⁵⁸ Like the diphtheria toxin, the cholera toxin is composed of two types of subunits. Each toxin molecule contains five B subunits that encircle a single A subunit. The B subunit is responsible for binding to the receptor on the mucosa. The A subunit is responsible for activation of adenylate cyclase located on the basolateral cellular membrane (see earlier). A second 10 to 30 kDa LT, zonula occludens toxin, has been described that alters intestinal permeability by acting on intestinal epithelial cell tight junctions.⁵⁹

Epidemiology

For many centuries, the Bay of Bengal had been considered the “cradle of cholera.” Western countries were relatively free of cholera epidemics until the 19th century, but since then, with the worldwide spread of the disease, six pandemics (across continents) have been reported. We are currently in the seventh pandemic, which started in 1961 in Indonesia and then made its way to the Philippines, Hong Kong, Japan, Korea, Thailand, India, Pakistan, and the Middle East, passing across the African continent to engulf the entire region, and, in 1991, spreading to South America. Although the overall number of cases of cholera in Latin America has subsided since 1991, outbreaks of V. cholerae have continued to occur sporadically throughout sub-Saharan Africa. During 1999, more than 200,000 cases of cholera were reported from Africa, accounting for 81% of the global total of cholera cases.⁶⁰

Cholera occurs sporadically along the Gulf Coast of the United States, primarily in Texas and Louisiana.⁶¹ Among the millions of American travelers to endemic areas in foreign countries, only 41 imported cases of cholera were reported in the United States from 1961 to 1990, and none was associated with secondary spread. The epidemic in South America resulted in 151 cases of cholera in the United States: 26 cases in 1991, 103 in 1992, and 22 in 1993; only one death was reported.⁶²

The organism associated with the current pandemic is an El Tor biotype which generally causes a milder disease than that seen with the classic strains and has a higher frequency of inapparent infection.

The South American epidemic that began in Peru in January 1991 reached more than one million cases in its first three years. From 15,000 to 20,000 cases of cholera were reported each week during the peak of the epidemic, for a national incidence of 1 : 1000 persons. Unboiled drinking water, unwashed fruits or vegetables, and food or water from street vendors were implicated risk factors in this explosive outbreak.^63,64

The epidemic of V. cholerae O139 Bengal that began in southern India and Bangladesh in late 1992 affected adults predominantly.⁵⁶ The clinical features of infection with the O139 Bengal strain were virtually indistinguishable from infection caused by V. cholerae O1.^65,66

Contaminated water and food are the major vehicles for the spread of cholera. Infection by person-to-person contact is uncommon, and rarely do physicians, nurses, ward attendants, and laboratory workers who come in contact with the microorganism acquire clinical disease. The inoculum required to cause acute cholera is large, approximately 10⁹ organisms. Even this number usually does not cause disease in a healthy person without some agent, such as a proton pump inhibitor or hydrogen pump blocker, to buffer gastric acidity. People with low gastric acidity, often associated with malnutrition, are more easily infected than those with normal acidity.

Humans are the only host for cholera vibrios. The carrier rate is approximately 5% after acute exposure, although long-term carriers are much less common. Cholera vibrios are harbored in the gallbladder, like S. typhi.

Pathogenesis

The clinical syndrome of cholera is caused by the action of the toxin on intestinal epithelial cells. Cholera toxin increases adenylate cyclase activity to result in elevated levels of cAMP in the intestinal mucosa, and this in turn causes intestinal secretion. Fluid loss in cholera originates in the small intestine. The most sensitive areas are the upper intestine, particularly the duodenum and upper jejunum; the ileum is less affected, and the colon usually is in a state of absorption and is relatively insensitive to the toxin. Diarrhea results because the large volume of fluid produced in the upper intestine overwhelms the absorptive capacity of the colon.

Attachment of V. cholerae to the intestinal mucosa is mediated by various surface components, including a fimbrial colonization factor known as toxin-coregulated pilus. The toxin-coregulated pilus attachment protein might play an important role in producing naturally occurring protective antibodies against V. cholerae.⁶⁷

Despite the derivation of the term cholera (Greek: chole, bile), the appearance of choleric stools resembles rice water; that is, the stool has lost all pigment and becomes a clear fluid with small flecks of mucus. The electrolyte composition (Table 107-5) is isotonic with plasma, and the effluent has a low protein concentration. On microscopic examination there are no inflammatory cells, only small numbers of shed mucosal cells.

Table 107-5 Electrolyte Concentrations of Choleric and Nonspecific Fecal Fluid and of Intravenous Fluids Used to Treat Infectious Diarrheas

Cholera vibrios do not invade the mucosal surface, and bacteremia is virtually unknown in this disease. A biopsy specimen of the mucosa during acute cholera shows evidence of dehydration, with maintenance of normal architecture, in sharp contrast to the invasive and ulcerating lesions associated with Salmonella and Shigella.

Clinical Features

Like many other infectious diseases, there is a spectrum of clinical manifestations with V. cholerae, from an asymptomatic carrier state to a desperately ill patient with severe dehydration. The initial stage is characterized by vomiting and abdominal distention and is followed rapidly by diarrhea that accelerates over the next few hours to frequent large volumes of rice-water stools. All the clinical symptoms and signs can be ascribed to fluid and electrolyte losses. Patients present with profound dehydration and hypovolemic shock, usually leading to kidney failure. The stool is isotonic with plasma, although there is an inordinate loss of potassium and bicarbonate, with resultant hypokalemic acidosis (see Table 107-5). Mild fever may be present, but there are no signs of sepsis.

Immunologic Responses

After recovery from acute cholera, two serum antibodies can be demonstrated: a vibriocidal antibody directed against somatic antigen and an antitoxin antibody against the enterotoxin. Vibriocidal titers rise and fall rapidly after infection, and by six months only 1% of patients have high serum levels. In areas of high prevalence, such as the Indian subcontinent, the level of vibriocidal titer rises with age; by the 10th year of life, 50% of people have measurable titers. Protection is related to the presence and actual level of vibriocidal antibody. From these observations, it follows that acute cholera in endemic areas is a disease largely of young children, primarily those who lack vibriocidal antibody. Antitoxin titers rise somewhat slowly after acute infection and remain elevated for many months.

The susceptibility of adults in areas endemic for the O139 Bengal strain of cholera indicates that the afflicted populations are immunologically naive and that prior exposure to V. cholerae O1 does not provide cross-protective immunity. Nevertheless, volunteer challenge studies indicate that an initial infection with O139 Bengal provides protection against recurrent disease.⁶⁵

Elevation in titers of vibriocidal antibody may be caused either by actual infection with vibrios or by asymptomatic carriage of vibrios. In field situations, the clinical case rate is approximately 0.26%; that is, for every clinical case of cholera there are approximately 400 asymptomatic people who have had contact with the organism, as demonstrated by an elevation in vibriocidal antibody titers.

Treatment

Treatment of acute cholera is based on the physiologic principles of restoring fluid and electrolyte balance and maintaining intravascular volume. These objectives can be accomplished with intravenous solutions or oral fluids that contain electrolytes in isotonic concentrations (see Table 107-5). Particular attention is paid to administration of bicarbonate and potassium, which are lost excessively in choleric stool. Various oral rehydration solutions (ORSs) have been developed for treating mild to moderate cases; ORS is especially useful in developing countries (Table 107-6).⁶⁸

Table 107-6 Compositions of Some Oral Hydration Beverages

The simple therapeutic principles of fluid replacement and antibiotics can save many lives. This knowledge has been available only since approximately 1970; before then, the mortality rate for cholera was 50% to 75%. Application of these physiologic principles reduces the mortality rate in adults to less than 1%. Indeed, the mortality rate in the Peruvian epidemic was less than 1%. Children with cholera still have a mortality rate of 3% to 5% because of a lack of fluid reserve in young children.

Antimicrobial agents are useful ancillary measures to treat cholera because their use leads to reductions in stool output, duration of diarrhea, fluid requirements, and Vibrio excretion.⁶⁹ Tetracycline is recommended at a dose of 40 mg/kg per day orally up to a maximum of 4 g/day in four divided doses for two days; there is no proven value in lengthening the duration of treatment to four days. Single-dose therapy with ciprofloxacin results in a successful clinical response in 94% of patients infected with V. cholerae.^70,71 As a result of rising rates of resistance, tetracycline and doxycycline often are less effective than the fluoroquinolones.^71,72 Alternative drugs include trimethoprim-sulfamethoxazole (TMP-SMX) and furazolidone.

Vaccines

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