Shigella species are members of the Enterobacteriaceae family. The shigellae are gram-negative, aerobic, nonmotile bacteria that do not use lactose or use it only during prolonged
periods of incubation. The Shigella genus consists of four species (with more than 40 serotypes) that are biochemically differentiated. Group A, S. dysenteriae, has 13 serotypes. Group B, S. flexneri, has 6 serotypes and 13 subserotypes (1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6, X variant, and Y variant). Group C, S. boydii, has 18 serotypes; and group D, S. sonnei, has a single serotype. Although important differences in virulence genes and clinical features among Shigella serotypes exist, these organisms traditionally are discussed together because of their microbiologic and clinical similarities.

Shigellae are spread by the fecal-oral route. They are hardy organisms that can survive in water for as long as 6 months. Unlike most other agents that cause diarrhea, the inoculum size required to cause illness is very low. Some adult volunteers have become ill after ingesting only ten shigellae. Although shigellae are like other enteric pathogens in that they can be spread through contaminated food or water, they are atypical in that they are passed easily from person to person.

The peak incidence of symptomatic Shigella infection occurs during the first 4 years of life. Despite the small inoculum required to produce disease, infants in the first few months of life rarely are symptomatically infected. The reason is unclear. The exact incidence of Shigella infection is unknown because many infections are asymptomatic, and infections associated with illness not always are diagnosed or reported. The annual number of Shigella episodes worldwide was estimated to be 164.7 million, of which 163.2 million were in developing countries (with 1.1 million deaths) and 1.5 million in industrialized countries. More than one-half of the episodes and deaths occur in children younger than 5 years of age. Approximately 18,000 cases of Shigella are diagnosed each year in the United States.

Shigellosis often is seen in outbreaks involving day-care centers, nursing homes, prisons, troops, and cruise ships. Outbreaks of infection are difficult to control because of the low infectious dose and ease of person-to-person transmission. Some settings in the United States, such as custodial care institutions and Indian reservations, have unusually high isolation rates. Native Americans have a risk of acquiring shigellosis that is approximately four times that of the remainder of the population. Sexually transmitted shigellosis occurs among those having unprotected anal intercourse. Day-care centers are an important focus for outbreaks of shigellosis in the United States. The small inoculum required for production of disease, the pooling of susceptible children, and the frequent lack of adherence to basic hygienic procedures contribute to this situation.

In the developing world, where carriers are common, the frequency of infection is even greater, with infants routinely exposed to Shigella early in life. Studies by Leonardo Mata of 45 Guatemalan infants whose stools were cultured weekly during their first 3 years of life documented 1,032 positive cultures for Shigella species. Although these studies were done many years ago, the risk for children in the developing world probably has not decreased.

The peak occurrence in the United States is between July and October. In tropical regions, the peak period is during the rainy season.

Important geographic variations in the prevalent serotypes of Shigella exist. In the United States and other industrialized countries, most shigellosis is caused by S. sonnei, followed by S. flexneri. In most of the developing world, S. flexneri is seen more commonly than is S. sonnei. In some areas, S. dysenteriae serotype 1 causes epidemic disease.

The virulence of Shigella results from its ability to invade, multiply, spread to adjacent epithelial cells, and induce inflammation within the intestine. Shigella species infect the large intestine primarily. When the pathogen reaches the colon, bacteria are taken up by the M cells. After translocation, Shigella organisms are phagocytosed by dendritic cells and resident macrophages in Peyers patches. Shigella causes apoptosis of the macrophages, thus allowing access to the basal side of the epithelial cells, where bacteria can enter efficiently. The infected macrophages release large amounts of inflammatory cytokines. This early inflammatory process leads to disruption of the epithelial barrier, thereby facilitating further invasion of Shigella.

The most fundamental virulence property shared by all shigellae and by the enteroinvasive Escherichia coli is the ability to invade mammalian cells. Most of the genes responsible for invasion are located on the Shigella virulence plasmid. Shigella that lack this plasmid are avirulent. This plasmid carries two types of genes: the ipa and ipg genes encoding the entry-mediating proteins and the mxi and spa genes encoding the type III secretion system. This secretion system is found in many other pathogenic gram-negative bacteria; its function is to transport proteins from the bacterial cytoplasm into the host cell plasma membrane and cytoplasm on contact with host cells. In addition to the key plasmid-encoded invasion proteins, shigellae have chromosomally encoded traits that enhance their pathogenicity. The Shigella species also produce several toxins. Shiga toxin, a protein synthesis inhibitor produced in high amounts by S. dysenteriae serotype 1, may account for the severity of infection caused by this serotype compared with other shigellae. This toxin is involved in the pathogenesis of the hemolytic uremic syndrome (HUS), a major complication of infection with S. dysenteriae serotype 1. Enterotoxins also have been described that may contribute to the watery diarrhea.

The pathogenesis of the neurologic manifestations in shigellosis is as yet unclear. Data from animal models and epidemiologic studies previously linked Shiga toxin to the development of neurologic disturbances. However, Shiga toxin is not a neurotoxin. Children who have neurologic symptoms during shigellosis usually are infected with Shigella that do not produce Shiga toxin.

Immune responses to shigellae are both humoral and cellular. Volunteer studies show that tumor necrosis factor-alpha and interferon-gamma increase in stool within 24 to 48 hours of infection. Antibody-secreting cells are present in blood by 4 to 7 days after infection, and humoral antibody develops by 7 to 14 days. Antibodies to lipopolysaccharides and the invasion plasmid antigens are produced during natural infection. Some epidemiologic, serologic, and clinical data suggest that the concentration of serum immunoglobulin G (IgG) antibodies to the O-specific polysaccharide component of lipopolysaccharide is related to immunity to shigellosis.

Children with shigellosis have a persistent activation of the innate immune response in the convalescent phase. Children have delayed accumulation of mast cells and eosinophils and reduced neutrophil counts in the rectum, compared with adults. These factors may affect the clinical course in children.

The most obvious pathologic changes in shigellosis are those found in the colon. The rectosigmoid and distal segments of the colon typically are more involved than are proximal areas. Erythema, mucosal edema, friability, focal hemorrhages, and adherent mucopurulent pseudomembranes all may be found. The microscopic findings include edema, capillary congestion,
capillary thromboses, focal hemorrhages, crypt hyperplasia, crypt abscesses, goblet cell depletion, mononuclear and polymorphonuclear infiltrates, shedding of epithelial cells, and ulcerations. The cellular infiltrate persists for a month or more.

Shigella enteric infection has several typical clinical presentations. Some children have a biphasic illness, presenting with severe abdominal cramps associated with fever and watery diarrhea, followed in 24 to 48 hours by colitis with small-volume, bloody stools, whose passage is associated with tenesmus (an ineffectual urge to defecate) and pain. Other children present with a picture of colitis. In still others, watery diarrhea never progresses to the colitic phase. Approximately 40% of children with Shigella infection have blood in their stools, and 50% have emesis. Clinical presentation vary with Shigella species. Patients with S. sonnei infection usually have watery diarrhea, whereas those with S. flexneri, S. boydii, and S. dysenteriae infection typically have bloody diarrhea and more severe systemic symptoms. S. dysenteriae serotype 1 typically produces more severe colitis. The incubation period varies from 1 to 7 days but typically is 2 to 4 days.

Physical findings include fever (e.g., more than two-thirds have rectal temperatures higher than 38.9°C), evidence of toxicity, dehydration, and lower quadrant abdominal tenderness. Because the disease involves distal segments of colon more than proximal areas, rectal examination may demonstrate an unusual degree of tenderness. Without therapy, fever and diarrhea may persist for a week or more. Chronic diarrhea can occur not only in children with acquired immunodeficiency syndrome (AIDS), but also in immunologically normal children. Mild dehydration and electrolyte disturbances are common findings. Despite frequent bowel movements, less than 30 mL/kg/day of fluid is lost during the dysenteric phase. Hyponatremia and hypoglycemia are major metabolic abnormalities that are associated with adverse outcomes. Hyponatremia occurs most commonly with S. dysenteriae infection. Because stool sodium losses do not appear to account for the degree of hyponatremia, researchers have postulated that the abnormality is produced by inappropriate antidiuretic hormone secretion. The prevalence of hypoglycemia is higher among patients with shigellosis than among patients with diarrhea from other causes. The low concentrations of insulin and elevated concentrations of glucose regulatory hormones (e.g., growth hormone, glucagon, epinephrine, norepinephrine, cortisol) suggest failure of gluconeogenesis as the cause of hypoglycemia. Shigellosis causes protein-losing enteropathy, which can aggravate or provoke malnutrition and lead to death. Shigellosis probably is the most frequent enteric infection resulting in the progression of marginal malnutrition to overt protein-calorie malnutrition. Postshigellosis persistent diarrhea is not uncommon. A community-based study of Bangladeshi children found that, despite the use of nalidixic acid in dysenteric episodes, persistent diarrhea occurred in 23% of children with shigellosis.