Shigella

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Chapter 191 Shigella

Theresa J. Ochoa, Thomas G. Cleary

Shigella causes an acute invasive enteric infection clinically manifested by diarrhea that is often bloody. The term dysentery is used to describe the syndrome of bloody diarrhea with fever, abdominal cramps, rectal pain, and mucoid stools. Bacillary dysentery is a term often used to distinguish dysentery caused by Shigella from amoebic dysentery caused by Entamoeba histolytica.

Etiology

Four species of Shigella are responsible for bacillary dysentery: S. dysenteriae (serogroup A), S. flexneri (serogroup B), S. boydii (serogroup C), and S. sonnei (serogroup D). There are 13 serotypes in group A, six serotypes and 15 subserotypes in group B, 18 serotypes in group C, and one serotype in group D. Species classification has important therapeutic implications because the species differ in both geographic distribution and antimicrobial susceptibility.

Epidemiology

It is estimated that there are approximately 165 million cases of shigellosis each year, resulting in >1 million deaths; most of these cases and deaths occur in developing countries. In the USA, approximately 14,000 cases per year are documented. Although infection can occur at any age, it is most common in the 2nd and 3rd years of life. Approximately 70% of all episodes and 60% of all Shigella-related deaths involve children <5 years old. Infection in the first 6 mo of life is rare for reasons that are not clear. Breast milk contains antibodies to both virulence plasmid-coded antigens and lipopolysaccharides in endemic areas, and breast-feeding might partially explain the age-related incidence.

Asymptomatic infection of children and adults occurs commonly in endemic areas. Infection with Shigella occurs most often during the warm months in temperate climates and during the rainy season in tropical climates. Both sexes are affected equally. In industrialized societies, S. sonnei is the most common cause of bacillary dysentery, with S. flexneri second in frequency; in preindustrial societies, S. flexneri is most common, with S. sonnei second in frequency. S. boydii is found primarily in India. S. dysenteriae serotype 1 tends to occur in massive epidemics, although it is also endemic in Asia and Africa, where it is associated with high mortality rates (5-15%).

Contaminated food (often a salad or other item requiring extensive handling of the ingredients) and water are important vectors. Exposure to both fresh and saltwater is a risk factor for infection. Rapid spread within families, custodial institutions, and child-care centers demonstrates the ability of shigellae to be transmitted from one individual to the next and the requirement for ingestion of very few organisms to cause illness. As few as 10 S. dysenteriae serotype 1 organisms can cause dysentery. In contrast, ingestion of 108-1010 Vibrio cholerae is necessary to cause cholera.

Pathogenesis

The basic virulence trait shared by all shigellae is the ability to invade intestinal epithelial cells. This characteristic is encoded on a large (220 Kb) plasmid that is responsible for synthesis of a group of polypeptides involved in cell invasion and killing. Shigellae that lose the virulence plasmid are no longer pathogenic. Escherichia coli that harbor a closely related plasmid containing these invasion genes (enteroinvasive E. coli) behave clinically like shigellae. The virulence plasmid encodes a type III secretion system (TTSS) required to trigger entry into epithelial cells and apoptosis in macrophages. This secretion system translocates effector molecules from the bacterial cytoplasm to the membrane and cytoplasm of target host cells. The TTSS is composed of approximately 50 proteins, including Mxi and Spa proteins involved in assembly and regulation of the TTSS, chaperones (IpgA, IpgC, IpgE, and Spa15), transcription activators (VirF, VirB, and MxiE), translocators (IpaB, IpaC, and IpaD), and approximately 25 effector proteins. In addition to the major plasmid-encoded virulence traits, chromosomally encoded factors are also required for full virulence.

Shigella passes the epithelial cell barrier by transcytosis through M cells and encounters resident macrophages. The bacteria evade degradation in macrophages by inducing apoptosis, which is accompanied by proinflammatory signaling. Free bacteria invade the epithelial cells from the basolateral side, move into the cytoplasm by actin polymerization, and spread to adjacent cells. Proinflammatory signaling by macrophages and epithelial cells further activates the innate immune response involving NK cells and attracts polymorphonuclear leukocytes (PMNs). The influx of PMNs disintegrates the epithelial cell lining, which initially exacerbates the infection and tissue destruction by facilitating the invasion of more bacteria. Ultimately, PMNs phagocytose and kill Shigella, thus contributing to the resolution of the infection.

Some shigellae make toxins including Shiga toxin and enterotoxins. Shiga toxin is a potent exotoxin that inhibits protein synthesis and is produced in significant amounts by S. dysenteriae serotype 1, by a subset of E. coli, which are known as Shiga toxin–producing E. coli (STEC), and occasionally by other organisms. This toxin mediates the severe complication of hemolytic-uremic syndrome (HUS). It is unclear whether the watery diarrhea phase of shigellosis is caused by one of the other enterotoxins. Targeted deletion of the genes for enterotoxins (ShET1 and ShET2) decreased the incidence of fever and dysentery in volunteers during vaccine-development studies. Lipopolysaccharides are virulence factors for all shigellae; other traits are important for only a few serotypes (e.g., Shigatoxin synthesis by S. dysenteriae serotype 1 and ShET1 by S. flexneri 2a).

The pathologic changes of shigellosis take place primarily in the colon, the target organ for Shigella. The changes are most intense in the distal colon, although pancolitis can occur. Shigellae cross the colonic epithelium through M cells in the follicle-associated epithelium overlying the Peyer patches. Grossly, localized or diffuse mucosal edema, ulcerations, friable mucosa, bleeding, and exudate may be seen. Microscopically, ulcerations, pseudomembranes, epithelial cell death, infiltration extending from the mucosa to the muscularis mucosae by PMNs and mononuclear cells, and submucosal edema occur.

Immunity

Innate immunity to Shigella infection is characterized by the induction of acute inflammation with massive recruitment of PMNs and subsequently massive tissue destruction. In humans, analysis of cytokine expression in rectal biopsies of infected patients at the acute phase of the disease has revealed upregulation of proinflammatory genes, such as those encoding interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and TNF-β, although antiinflammatory genes encoding IL-10 and TGF-β are also upregulated. Control of Shigella invasion in intestinal epithelial cells depends on interferon (IFN)-γ. Shigella-specific immunity elicited upon natural infection is characterized by the induction of a humoral response. Local secretory IgA and serum IgG are produced against LPS and some protein effectors (Ipas). Natural protective immunity arises only after several episodes of infection, is of short duration, and seems to be effective in limiting reinfection, particularly in young children.

Clinical Manifestations and Complications

Bacillary dysentery is clinically similar regardless of infecting serotype. There are some clinical differences, particularly relating to the greater severity and risk of complications with S. dysenteriae serotype 1 infection. Ingestion of shigellae is followed by an incubation period of 12 hr to several days before symptoms ensue. Severe abdominal pain, high fever, emesis, anorexia, generalized toxicity, urgency, and painful defecation characteristically occur. The diarrhea may be watery and of large volume initially, evolving into frequent, small-volume, bloody mucoid stools. Most children never progress to the stage of bloody diarrhea, but some have bloody stools from the outset. Significant dehydration is related to the fluid and electrolyte losses in feces and emesis. Untreated diarrhea can last 1-2 wk; only about 10% of patients have diarrhea persisting for >10 days. Persistent diarrhea occurs in malnourished infants, children with AIDS, and occasionally previously normal children. Even nondysenteric disease can be complicated by persistent illness.

Physical examination initially shows abdominal distention and tenderness, hyperactive bowel sounds, and a tender rectum on digital examination. Neurologic findings are among the most common extraintestinal manifestations of bacillary dysentery, occurring in as many as 40% of hospitalized children. Enteroinvasive E. coli can cause similar neurologic toxicity. Convulsions, headache, lethargy, confusion, nuchal rigidity, or hallucinations may be present before or after the onset of diarrhea. The cause of these neurologic findings is not understood. In the past, these symptoms were attributed to the neurotoxicity of Shiga toxin, but it is now clear that this explanation is wrong because the organisms isolated from children with Shigella-related seizures are usually not Shiga toxin producers. Seizures sometimes occur when little fever is present, suggesting that simple febrile convulsions do not explain their appearance. Hypocalcemia or hyponatremia may be associated with seizures in a small number of patients. Although symptoms often suggest central nervous system infection and cerebrospinal fluid pleocytosis with minimally elevated protein levels can occur, meningitis due to shigellae is rare. Based on animal studies, it has been suggested that proinflammatory mediators, including TNF-α and interleukin-1β, nitric oxide, and corticotropin-releasing hormone, all play a role in the enhanced susceptibility to seizures caused by S. dysenteriae.

The most common complication of shigellosis is dehydration. Inappropriate secretion of antidiuretic hormone with profound hyponatremia can complicate dysentery, particularly when S. dysenteriae is the etiologic agent. Hypoglycemia and protein-losing enteropathy are common. Other major complications include sepsis and disseminated intravascular coagulation, particularly in very young, malnourished children. Given that shigellae penetrate the intestinal mucosal barrier, these events are surprisingly uncommon.

Shigella and sometimes other gram-negative enteric bacilli are recovered from blood cultures in 1-5% of patients in whom blood cultures are taken; because patients selected for blood cultures represent a biased sample, the risk of bacteremia in unselected cases of shigellosis is presumably lower. Bacteremia is more common with S. dysenteriae serotype 1 than with other shigellae; the mortality rate is high (~20%) when sepsis occurs.

Neonatal shigellosis is rare. Neonates might have only low-grade fever with mild, nonbloody diarrhea. However, complications occur more commonly than in older children and include septicemia, meningitis, dehydration, colonic perforation, and toxic megacolon.

S. dysenteriae serotype 1 infection is commonly complicated by hemolysis, anemia, and HUS. This syndrome is caused by Shiga toxin–mediated vascular endothelial injury. E. coli that produce Shiga toxins (e.g., E. coli O157:H7, E. coli O111:NM, E. coli O26:H11) also cause HUS (Chapter 512).

Rectal prolapse, toxic megacolon or pseudomembranous colitis (usually associated with S. dysenteriae), cholestatic hepatitis, conjunctivitis, iritis, corneal ulcers, pneumonia, arthritis (usually 2-5 wk after enteritis), reactive arthritis, cystitis, myocarditis, and vaginitis (typically with a blood-tinged discharge associated with S. flexneri) are uncommon events. Although rare, surgical complications of shigellosis can be severe; the most common are intestinal obstruction and appendicitis with and without perforation.

On average, severity of illness and risk of death are least with disease caused by S. sonnei and greatest with infection by S. dysenteriae type 1. Risk groups for severe illness and poor outcomes include infants; adults >50 yr; children who are not breast-fed; children recovering from measles; malnourished children and adults; and patients who develop dehydration, unconsciousness, or hypo- or hyperthermia or have a history of convulsion when first seen. Death is a rare outcome in well-nourished older children. Multiple factors contribute to death in malnourished children with shigellosis, including illness in the first year of life, altered consciousness, dehydration, hypothermia, thrombocytopenia, anemia, hyponatremia, renal failure, hyperkalemia hypoglycemia, bronchopneumonia, and bacteremia.

The rare syndrome of severe toxicity, convulsions, extreme hyperpyrexia, and headache followed by brain edema and a rapidly fatal outcome without sepsis or significant dehydration (Ekiri syndrome or “lethal toxic encephalopathy”) is not well understood.

Differential Diagnosis

Although clinical features suggest shigellosis, they are insufficiently specific to allow confident diagnosis. Infection by Campylobacter jejuni, Salmonella spp, enteroinvasive E. coli, Shiga toxin–producing E. coli (e.g. E. coli O157:H7), Yersinia enterocolitica, Clostridium difficile, and Entamoeba histolytica as well as inflammatory bowel disease can cause confusion.

Diagnosis

Presumptive data supporting a diagnosis of bacillary dysentery include the finding of fecal leukocytes (usually >50 or 100 PMNs per high power field, confirming the presence of colitis), fecal blood, and demonstration in peripheral blood of leukocytosis with a dramatic left shift (often with more bands than segmented neutrophils). The total peripheral white blood cell count is usually 5,000-15,000 cells/mm3, although leukopenia and leukemoid reactions occur.

Culture of both stool and rectal swab specimens optimizes the chance of diagnosing Shigella infection. Culture media should include MacConkey agar as well as selective media such as xylose-lysine deoxycholate (XLD) and SS agar. Transport media should be used if specimens cannot be cultured promptly. Appropriate media should be used to exclude Campylobacter spp and other agents. Studies of outbreaks and illness in volunteers show that the laboratory is often not able to confirm the clinical suspicion of shigellosis even when the pathogen is present. Multiple fecal cultures improve the yield of Shigella. The diagnostic inadequacy of cultures makes it incumbent on the clinician to use judgment in the management of clinical syndromes consistent with shigellosis. Use of polymerase chain reaction (PCR) analysis of stool for specific genes such as ipaH, virF, or virA can detect cases not diagnosed by culture, but it is usually available only in research laboratories. In children who appear to be toxic, blood cultures should be obtained, especially in very young or malnourished infants because of their increased risk of bacteremia.

Treatment

As with gastroenteritis from other causes, the first concern in a child with suspected shigellosis should be for fluid and electrolyte correction and maintenance (Chapter 332). Drugs that retard intestinal motility (e.g., diphenoxylate hydrochloride with atropine [Lomotil] or loperamide [Imodium]) should not be used because of the risk of prolonging the illness.

Nutrition is a key concern in areas where malnutrition is common. A high-protein diet during convalescence enhances growth in the following 6 mo. A single large dose of vitamin A (200,000 IU) lessens severity of shigellosis in settings where vitamin A deficiency is common. Zinc supplementation (20 mg elemental zinc for 14 days) has been shown to significantly decrease the duration of diarrhea, improve weight gain during recovery and immune response to the Shigella, and decrease diarrheal disease in the subsequent 6 mo in malnourished children.

The next concern is a decision about the use of antibiotics. Although some authorities recommend withholding antibacterial therapy because of the self-limited nature of the infection, the cost of drugs, and the risk of emergence of resistant organisms, there is a persuasive logic in favor of empirical treatment of all children in whom shigellosis is strongly suspected. Even if not fatal, the untreated illness can cause a child to be quite ill for weeks; chronic or recurrent diarrhea can ensue. Malnutrition can develop or worsen during prolonged illness, particularly in children in developing countries. The risk of continued excretion and subsequent infection of family contacts further argues against the strategy of withholding antibiotics.

Shigella species have variable antimicrobial susceptibility. In general, S. flexneri tends to be more resistant than S. boydii. There are major geographic variations in antibiotic susceptibility of shigellae. In most developing countries and in some industrialized countries such as the USA, Shigella strains are often resistant to ampicillin and trimethoprim-sulfamethoxazole (TMP-SMX). Therefore, these drugs should usually not be used for empirical treatment of suspected shigellosis. Oral ampicillin (100 mg/kg/24 hr orally, divided 4 times/day) or TMP-SMX (10 mg/kg/24 hr orally of the TMP component in 2 divided doses) may be used if the strain is known to be susceptible (e.g., in an outbreak due to a defined strain). Amoxicillin is less effective than ampicillin for treatment of ampicillin-sensitive strains. Ceftriaxone (50 mg/kg/24 hr as a single daily dose IV or IM) can be used for empirical therapy, especially for small infants.

The oral 3rd-generation cephalosporin cefixime can also be used. Oral 1st and 2nd-generation cephalosporins are inadequate as alternative drugs despite in vitro susceptibility. Nalidixic acid (55 mg/kg/24 hr orally divided 4 times/day) is also an acceptable alternative drug when available. Azithromycin (12 mg/kg/24 hr orally for the first day, followed by 6 mg/kg/24 hr for the next 4 days) has proven to be an effective alternative drug for shigellosis. Ciprofloxacin (30 mg/kg/24 hr divided into 2 doses) used to be a back-up drug to treat shigellosis but is now the drug of choice recommended by WHO for all patients with bloody diarrhea, irrespective of their ages.

Although quinolones have been reported to cause arthropathy in immature animals, the risk of joint damage in children appears to be minimal and is outweighed by the value of these drugs for treatment of this potentially life-threatening disease. However, some experts recommend that these agents be reserved for seriously ill children with bacillary dysentery due to an organism that is suspected or known to be resistant to other agents, because overuse of quinolones promotes development of resistance to these drugs. Treatment in general is for a 5-day course.

Treatment of patients in whom Shigella infection is suspected on clinical grounds of should be initiated when they are first evaluated. Stool culture is obtained to exclude other pathogens and to assist in antibiotic changes should a child fail to respond to empirical therapy. A child who has typical dysentery and who responds to initial empirical antibiotic treatment should be continued on that drug for a full 5-day course even if the stool culture is negative. The logic of this recommendation is based on the proven difficulty of culturing Shigella from stools of ill patients during adult volunteer infection studies. In a child who fails to respond to therapy of a dysenteric syndrome in the presence of initially negative stool culture results, additional cultures should be obtained and the child should be re-evaluated for other possible diagnoses.

Prevention

Numerous measures have been recommended to decrease the risk of Shigella transmission to children. Mothers should be encouraged to prolong breast-feeding of infants. Families and day care personnel should be educated in proper handwashing techniques and encouraged to wash hands after using the toilet, changing diapers, or engaging in preparation of foods. They should be taught how to manage potentially contaminated materials such as raw vegetables, soiled diapers, and diaper-changing areas. Children with diarrhea should be excluded from child care facilities. Children should be supervised when handwashing after they use the toilet. Caretakers should be informed of the risk of transmission if they prepare food when they are ill with diarrhea. Families should be educated regarding the risk of swallowing contaminated water from ponds, lakes, or untreated pools.

There is not yet a vaccine that is effective for preventing infection by Shigella. Several candidate vaccines are under development, mostly against S. flexneri. Measles immunization can substantially reduce the incidence and severity of diarrheal diseases, including shigellosis. Every infant should be immunized against measles at the recommended age.

Bibliography

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