Symptoms of shigellosis include abdominal pain, tenesmus, watery diarrhea, and/or dysentery (multiple scanty, bloody, mucoid stools). Other signs may include abdominal tenderness, fever, vomiting, dehydration, and convulsions.
Structure, Classification, and Antigenic Types
Shigellae are Gram-negative, nonmotile, facultatively anaerobic, non-spore-forming rods. Shigella are differentiated from the closely related Escherichia coli on the basis of pathogenicity, physiology (failure to ferment lactose or decarboxylate lysine) and serology. The genus is divided into four serogroups with multiple serotypes: A (S dysenteriae, 12 serotypes); B (S flexneri, 6 serotypes); C (S boydii, 18 serotypes); and D (S sonnei, 1 serotype).
Infection is initiated by ingestion of shigellae (usually via fecal-oral contamination). An early symptom, diarrhea (possibly elicited by enterotoxins and/or cytotoxin), may occur as the organisms pass through the small intestine. The hallmarks of shigellosis are bacterial invasion of the colonic epithelium and inflammatory colitis. These are interdependent processes amplified by local release of cytokines and by the infiltration of inflammatory elements. Colitis in the rectosigmoid mucosa, with concomitant malabsorption, results in the characteristic sign of bacillary dysentery: scanty,. unformed stools tinged with blood and mucus.
Inflammation, copious mucus secretion, and regeneration of the damaged colonic epithelium limit the spread of colitis and promote spontaneous recovery. Serotype-specific immunity is induced by a primary infection, suggesting a protective role of antibody recognizing the lipopolysaccharide (LPS) somatic antigen. Other Shigella antigens include enterotoxins, cytotoxin, and plasmid-encoded proteins that induce bacterial invasion of the epithelium. The protective role of immune responses against these antigens is unclear.
Shigellosis is endemic in developing countries were sanitation is poor. Typically 10 to 20 percent of enteric disease, and 50% of the bloody diarrhea or dysentery of young children, can be characterized as shigellosis, and the prevalence of these infections decreases significantly after five years of life. In developed countries, single-source, food or water-borne outbreaks occur sporadically, and pockets of endemic shigellosis can be found in institutions and in remote areas with substandard sanitary facilities.
Shigellosis can be correctly diagnosed in most patients on the basis of fresh blood in the stool. Neutrophils in fecal smears is also a strongly suggestive sign. Nonetheless, watery, mucoid diarrhea may be the only symptom of many S sonnei infections, and any clinical diagnosis should be confirmed by cultivation of the etiologic agent from stools.
Prevention of fecal-oral transmission is the most effective control strategy. Severe dysentery is treated with ampicillin, trimethoprim-sulfamethoxazole, or, in patients over 17 years old, a 4-fluorquinolone such as ciprofloxacin. Vaccines are not currently available, but some promising candidates are being developed.
Gram-negative, facultative anaerobes of the genus Shigella are the principal agents of bacillary dysentery. This disease differs from profuse watery diarrhea, as is commonly seen in choleraic diarrhea or in enterotoxigenic Escherichia coli diarrhea, in that the dysenteric stool is scant and contains blood, mucus, and inflammatory cells. In some individuals suffering from shigellosis, however, moderate volume diarrhea is a prodrome or the sole manifestation of the infection. Bacillary dysentery constitutes a significant proportion of acute intestinal disease in the children of developing countries, and this infection is a major contributor to stunted growth of these children. Shigellosis also presents a significant risk to travelers from developed countries when visiting in endemic areas, and sporadic food or water-borne outbreaks occur in developed countries.
The pathogenic mechanism of shigellosis is complex, involving a possible enterotoxic and/or cytotoxic diarrheal prodrome, cytokine-mediated inflammation of the colon, and necrosis of the colonic epithelium. The underlying physiological insult that initiates this inflammatory cascade is the invasion of Shigella into the colonic epithelium and the lamina propria. The resulting colitis and ulceration of the mucosa result in bloody, mucoid stools, and/or febrile diarrhea.
Shigellosis has two basic clinical presentations: (1) watery diarrhea associated with vomiting and mild to moderate dehydration, and (2) dysentery characterized by a small volume of bloody, mucoid stools, and abdominal pain (cramps and tenesmus) (Table 22-1). Volunteer challenge studies show that shigellosis can be evoked by an extremely small inoculum (10-100 organisms), and the time of onset of symptoms is somewhat influenced by the size of the challenge. The salient point is that shigellosis is an acute infection with onset of symptoms usually occurring within 24-48 hours of ingestion of the etiologic agent. The average duration of symptoms in untreated adults is 7 days, and the organism may be cultivated from stools for 30 days or longer.
The clinical features of shigellosis are summarized in Figure 22-1. Watery diarrhea occurs as a prodrome, or as the sole clinical manifestation, in a majority of patients infected with S sonnei. Diarrhea is often a prodome of the dysentery characterizing infection with other species of Shigella. Recently discovered enterotoxins secreted by S flexneri may contribute to the diarrheal phase as the etiologic agents traverse the small intestine. However, diarrhea is most common in patients who have colitis involving the transverse colon or cecum. These patients evidence net water secretion and impaired absorption in the inflamed colon. In patients experiencing dysentery, involvement is most severe in the distal colon, and the resulting inflammatory colitis is evidenced in frequent scanty stools reflecting the ileocecal fluid flow. Dysentery is also characterized by the daily loss of 200-300 ml of serum protein into the feces. This loss of serum proteins results in depletion of nitrogen stores that exacerbates malnutrition and growth stunting. Depletion of immune factors also increases the risk of concurrent, unrelated infectious disease and contributes to substantial mortality.
FIGURE 22-1 Pathogenesis of shigellosis in humans.
Possible complications of shigellosis include bacteremia, convulsions and other neurological complications, reactive arthritis, and hemolytic-uremic syndrome. Bacteremia occasionally accompanies S dysenteriae serotype 1 infections in malnourished infants, but this complication is uncommon in otherwise healthy individuals. Convulsions have been reported in up to 25% of Shigella infections involving children under the age of 4 years. Both high fever and a family history of seizures are risk factors for a convulsive episode. Ekiri syndrome, an extremely rare, fatal encephalopathy has also been described in Japanese children with S sonnei or S flexneri infections. Reactive arthritis, a self-limiting sequela of S flexneri infection, occurs in an incidence as high as 2% in individuals expressing the HLA-B27 histocompatibility antigen. Hemolytic-uremic syndrome, characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, is a rare complication in children infected with S dysenteriae serotype 1.
Structure, Classification, and Antigenic Types
Organisms of the genus Shigella belong to the tribe Escherichia in the family Enterobacteriaceae. In DNA hybridization studies, Escherichia coli and Shigella species cannot be differentiated on the polynucleotide level; however, the virulence phenotype of the latter species is a distinctive distinguishing feature. Enteroinvasive E coli (EIEC), are very similar to shigellae biochemically and they also evoke diarrhea and/or dysentery. Some EIEC are also serologically related to shigellae. For example, EIEC serotype O124 agglutinates in S dysenteriae serotype 3 antiserum.
The genus Shigella is differentiated into four species: S dysenteriae (serogroup A, consisting of 12 serotypes); S flexneri (serogroup B, consisting of 6 serotypes); S. boydii (serogroup C, consisting of 18 serotypes); and S sonnei (serogroup D, consisting of a single serotype). Serogoups A, B, and C are very similar physiologically while S. sonnei can be differentiated from the other serogroups by positive b-D-galactosidase and ornithine decarboxylase biochemical reactions. The identification of shigellae by species in the clinical laboratory is usually accomplished by slide agglutination using commercially available, absorbed rabbit antisera.
The rectosigmoidal lesions of shigellosis resemble those of ulcerative colitis. With frequencies indicated in Figure 22-2, there is proximal extension of erythema, edema, loss of vascular pattern, focal hemorrhage, and adherent layers of purulent exudate. Biopsy specimens from affected areas are typically edematous, with capillary congestion, focal hemorrhage, crypt hyperplasia, goblet cell depletion, mononuclear and polymorphonuclear (PMN) cell infiltration, shedding of epithelial cells and erythrocytes, and microulcerations.
FIGURE 22-2 Gross pathology of shigellosis.
The pathogenic mechanism that underlies these pathological manifestations is diagrammed in Figure 22-3. This cartoon incorporates experimental observations from tissue cultures and from animal models of shigellosis such as rabbit ligated ileal loops injected with virulent organisms. In the latter model, Shigella infection is initiated at the membranous (M) cells that are associated with macroscopic lymphoid follicles (Peyer's patches). Biopsy studies in rhesus monkeys suggest that shigellae also infect microscopic lymphoid follicles of the primate colon. During the early stages of infection, bacteria are transcytosed through the M cells into the subepithelial space. In the subepithelial space, the organisms are phagocytosed by resident macrophages. However, virulent shigellae are not killed and digested in the macrophage phagolysome. The bacteria lyse the phagosome and initiate apoptosis (programmed cell death). During this process, the infected macrophage releases the inflammatory cytokine IL-1, which elicits infiltration of PMN.
FIGURE 22-3 Histopathology of acute colitis following peroral infection with shigellae. The organisms are initially ingested by membranous (M) cells that are associated with lymphoid microfollicles in the colon. After transcytosis through the M cell, the bacteria are deposited into the subepithelial space where they are phagocytosed by macrophages. The macrophage phagosome is subsequently degraded, and the intracellular shigellae cause release of IL-1 that evokes an influx of polymorphonuclear leukocytes (PMN). Eventually the infected macrophages undergo apoptosis (programmed cell death), and the bacteria are released onto the basolateral surface of adjacent colonic enterocytes. In addition, PMN transmigration through the epithelium disrupts tight junctions, allowing shigellae to migrate into the subepithelial space. The bacteria infect enterocytes by induced endocytosis, and the endocytic vacuoles are subsequently degraded. The intercellular shigellae attach to actin in the enterocyte junctional complex, multiply, and spread to contiguous enterocytes by induced actin polymerization. Ultimately, the infected enterocytes die, and the resulting necrosis of the epithelium, in conjunction with the continuing inflammatory response, constitutes the lesions of shigellosis.
Transmigration of infiltrating PMNs through the tight junctions of local epithelial cells and into the intestinal lumen allows the reverse migration of shigellae from the lumen into the subepithelial spaces. These organisms then infect the columnar epithelial cells by inducing endocytic uptake at the basolateral surface. Immediately after infection of enterocytes, intracellular shigellae lyse endocytic vacuoles and attach to the actin cytoskeleton in the area of the junctional complex. As these organisms multiply within the enterocyte cytoplasm, occasional daughter cells induce polar nucleation of filamentous actin resulting in a "tail" that propels the shigellae into protrusions impinging on contiguous enterocytes. Plasma membranes enveloping the organisms are again lysed, and the organisms are deposited within the contiguous host cell resulting in intercellular bacterial spread.
In summary, shigellosis can be characterized as an acute inflammatory bowel disease initiated by the uptake of only a few organisms into lymphoid follicles. Intracellular replication and intercellular spread leads to an amplified inflammatory cascade at the initial site of entry, and as this inflammation persists and expands, the infiltration of PMN facilitates the entry of additional bacteria into the epithelium. The inflammatory infiltrate can also cause detachment of sheets of epithelial cells in areas devoid of lymphoid structures or bacterial cells.
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