eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Shigella Infection

Author: Jaya Sureshbabu, MBBS, DCh, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg), Registrar, Department of Pediatrics/Neonatology, Mid-Western Regional Hospital, Ireland
Coauthor(s): Poothirikovil Venugopalan, MBBS, MD, FRCP (Glasg), FRCPCH, Consulting Staff, Department of Child Health, University Hospital of Hartlepool, UK; Walid Abuhammour, MD, FAAP, Associate Professor of Pediatrics, Michigan State University; Director of Pediatric Infectious Disease, Department of Pediatrics, Hurley Medical Center; Ilyas Burny, MD, Staff Physician, Department of Pediatrics, Hurley Medical Center
Contributor Information and Disclosures

Updated: Jul 31, 2008

Introduction

Background

Shigella organisms are a group of gram-negative, facultative intracellular pathogens. They were recognized as the etiologic agents of bacillary dysentery or shigellosis in the 1890s. Shigella was adopted as a genus in the 1950s. These organisms are members of the family Enterobacteriaceae and tribe Escherichieae; they are grouped into 4 species: Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei, also known as groups A, B, C, and D, respectively. They are nonmotile and nonencapsulated. Group A has 13 serotypes, group B has 6 serotypes, group C has 18 serotypes, and group D has 1 serotype.

Geographic distribution and antimicrobial susceptibility varies with different species. S dysenteriae serotype 1 causes deadly epidemics, S boydii is restricted to the Indian subcontinent, and S flexneri and S sonnei are prevalent in developing and developed countries, respectively. S flexneri, an enteroinvasive gram-negative bacteria, is responsible for the worldwide endemic form of bacillary dysentery.

Pathophysiology

Shigella infection is a major public health problem in developing countries where sanitation is poor. Humans are the only natural reservoir. No natural food products harbor endogenous Shigella species, but a wide variety of foods may be contaminated.

Shigellosis is spread by means of fecal-oral transmission. Other modes of transmission include ingestion of contaminated food or water, contact with a contaminated inanimate object, and sexual contact. Vectors like the housefly can spread the disease by physically transporting infected feces.

The infectivity dose (ID) is extremely low. As few as 10 S dysenteriae bacilli can cause clinical disease, whereas 100-200 bacilli are needed for S sonnei or S flexneri infection. The reasons for this low-dose response are not completely clear. One possible explanation is that virulent Shigellae can withstand the low pH of gastric juice.

The incubation period varies from 12 hours to 7 days but is typically 2-4 days; the incubation period is inversely proportional to the load of ingested bacteria.

Bacterial shedding usually ceases within 4 weeks of the onset of illness. A chronic carrier state beyond 1 year is rare.

Virulence

Virulence in Shigella species involves both chromosomal-coded and plasmid-coded genes. Virulent Shigella strains produce disease after invading the intestinal mucosa; the organism only rarely penetrates beyond the mucosa.

The characteristic virulence trait is encoded on a large (220 kb) plasmid responsible for synthesis of polypeptides that cause cytotoxicity. Shigellae that lose the virulence plasmid are no longer pathogenic. Escherichia coli (E coli O157:H7) that harbor this plasmid clinically behave as Shigella bacteria.

Siderophores, a group of plasmid-coded genes, control the acquisition of iron from host cells from its protein-bound state. In the extraintestinal phase of infection by gram-negative bacteria, iron becomes one of the major factors that limits further growth. This limitation occurs because most of the iron in human body is sequestered in hemoproteins (ie, hemoglobin, myoglobin) or iron-chelating proteins involved in iron transport (transferrin and lactoferrin). Many bacteria can secrete iron chelating compounds, or siderophores, which chelate iron from the intestinal fluids and which bacteria then take up to obtain iron for its metabolic needs. These siderophores are under the control of plasmids and are tightly regulated by genes such that, under low iron conditions, expression of the siderophore system is high.

Regulatory genes control expression of virulence genes. Shiga toxin (Stx) is not essential for virulence of S dysenteriae type 1 but contributes to the severity of dysentery. Both plasmid-encoded virulence traits and chromosome-encoded factors are essential for full virulence of shigellae.

Regarding chromosomally encoded enterotoxin, many pathogenic features of Shigella infection are due to the production of potent cytotoxins known as Stx, a potent protein synthesis–inhibiting exotoxin. Shigella strains produce distinct enterotoxins. These are a family of cytotoxins that contain 2 major immunologically non–cross-reactive groups called Stx1 and Stx2. The homology sequences between Stx1 and Stx2 are 55% and 57% in subunits A and B, respectively.

These toxins are lethal to animals; enterotoxic to ligated rabbit intestinal segments; and cytotoxic for vero, HeLa, and some selected endothelial cells (human renal vascular endothelial cells) manifesting as diarrhea, dysentery, and hemolytic-uremic syndrome (HUS). Stx1 is synthesized in significant amount by S dysenteriae serotype 1 and S flexneri 2a and E coli (Shigella toxin–producing E coli [ShET]).

Stx1 and Stx2 are both encoded by a bacteriophage inserted into the chromosome. Stx1 increases inflammatory cytokine production by human macrophages, which, in turn, leads to a burst of interleukin (IL)-8. This could be relevant in recruiting neutrophils to the lamina propria of the intestine in hemorrhagic colitis and accounts for elevated levels of IL-8 in serum of patients with diarrhea-associated HUS.

Stxs have 2 subunits. Subunit A is a 32-kD polypeptide that, when digested by trypsin, generates A1 with a 28-kD fragment and another small fragment, A2, which is 4 kD. A1 fraction acts like N -glycosidase; it removes single adenine residue from 28S rRNA of ribosome and inhibits protein synthesis. The A2 fraction is a pentamer polypeptide of 7.7-kD protein and is required to bind the A1 fraction to the B subunit. The main function of the B subunit is the binding of toxins to the cell surface receptor, typically globotriaosylceramide (Gb3), on the brush border of intestinal epithelial cells.

In summary, events that occur on exposure to Shigella toxin are as follows:

• The B subunit of holotoxin binds to the Gb3 receptor on the cell surface of brush-border cells of the intestines.
• The receptor-holotoxin complex is endocytosed.
• The complex moves to Golgi apparatus and then to the endoplasmic reticulum.

The A1 subunit is released and it targets 28S RNA of the ribosome, inhibiting protein synthesis. Stxs may play a role in the progression of mucosal lesions after colonic cells are invaded, or they may induce vascular damage in the colonic mucosa. Stx adheres to small-intestine receptors and blocks the absorption of electrolytes, glucose, and amino acids from intestinal lumen. The B subunit of Stx binds the host's cell glycolipid in the large intestine and in other cells, such as renal glomerular and tubular epithelia. The A1 domain internalized by means of receptor-mediated endocytosis and causes irreversible inactivation of the 60S ribosomal subunit, inhibiting protein synthesis and causing cell death, microvascular damage to the intestine, apoptosis in renal tubular epithelial cells, and hemorrhage (as blood and mucus in the stool).

Chromosomal genes control lipopolysaccharide (LPS) antigens in cell walls. LPS plays an important role in resistance to nonspecific host defense encountered during tissue invasion. These genes help in invasion, multiplication, and resistance to phagocytosis by tissue macrophages. LPS enhances the cytotoxicity of Stx on human vascular endothelial cells. Shigella chromosomes share most of their genes with E coli K12 strain MG1655, and the diversity of putative virulence genes acquired by means of bacteriophage-mediated lateral gene transfer is extensive. As a result of convergent evolution involving the gain and loss of functions, Shigella species have became highly specific human pathogens with variable epidemiologic and pathologic features.

A 3-kb plasmid that harbors information for the production of bacteriocin by S flexneri strains has been described. The production of this bacteriocin may be related to dysenteric diarrhea these bacterial strains produce.

Intestinal adherence factor

Intestinal adherence factor favors colonization in vivo and in animal models. This is 97-kD outer-membrane protein (OMP) encoded by each gene on chromosomes. This codes for intimin protein, and an anti-intimin response is observed in children with HUS.

Pathology

The host response to primary infection is characterized by the induction of an acute inflammation, which is accompanied by polymorphonuclear cell (PMN) infiltration, resulting in massive destruction of the colonic mucosa. Apoptotic destruction of macrophages in subepithelial tissue allows survival of the invading shigellae, and inflammation facilitates further bacterial entry.

Gross pathology consists of mucosal edema, erythema, friability, superficial ulceration, and focal mucosal hemorrhage involving the rectosigmoid junction primarily.

Microscopic pathology consists of epithelial cell necrosis, goblet cell depletion, PMN infiltrates and mononuclear infiltrates in lamina propria, and crypt abscess formation. Invasion of M cells, the specialized cells that cover the lymphoid follicles of the mucosa, overlying Peyer patches may be the earliest event.

Frequency

United States

The reported incidence of Shigella infections was 2848 cases per 100,000 population in 2007.¹ Most cases are reported during summer months. S sonnei accounts for approximately 78% of all Shigella isolates in recent surveys from the Centers for Disease Control and Prevention (CDC); S flexneri and S boydii account for most of the remainder. S flexneri causes 18% of Shigella infections in the United States. S dysenteriae is rare in the United States. The highest incidence per 100,000 population for shigellosis (27.77 cases) was among children younger than 5 years.

The overall incidence of Shigella infection is 4.67 cases per 100,000 population, and the rate of HUS in pediatric patients younger than 15 years is 0.49 cases per 100,000 population. The estimated annual incidence of Shigella infection did not change significantly in 2007 compared with 2004-2006. More than 95% of Shigella infections may be asymptomatic. Hence, the actual incidence may be 20 times higher than reported.

International

Worldwide, the incidence of shigellosis is estimated to be 164.7 million cases per year, of which 163.2 million were in developing countries, where 1.1 million deaths occurred. About 60% of all episodes and 61% of all deaths attributable to shigellosis involved children younger than 5 years. The incidence in developing countries may be 20 times greater than that in developed countries. Although the relative importance of various serotypes is not known, an estimated 30% of these infections are caused by S dysenteriae.

Case-fatality rates for S dysenteriae infections may approach 30%. Patients with malnutrition are at increased risk of having complicated course. Shigella infection in malnourished children often causes a vicious cycle of further impaired nutrition, recurrent infection, and further growth retardation.

Mortality/Morbidity

Although shigellosis-related mortality is rare in developed countries, S dysenteriae infection is associated with substantial morbidity and mortality rates in the developing world.

• The overall mortality rate in developed countries is less than 1%.
• In the Far East and Middle East, the mortality rates for S dysenteriae infections may be as high as 20-25%.

Race

No racial predilection is known.

Sex

No sexual predilection is known.

Age

According to recent CDC reports, Shigella infection accounted for 28% of all the enteric bacterial infections.¹ Children younger than 5 years had 7% of total reported cases, a rate indicating a disproportionate disease burden in this population.

Clinical

History

• Populations that are at high-risk for shigellosis include the following:
  • Children in daycare centers
  • Orthodox Jews
  • Native Caucasians
  • Persons in custodial institutions
  • International travelers
  • Homosexual men
  • Persons in homes with inadequate water supply
  • People with human immunodeficiency virus (HIV) infection²
• Symptoms include the following:
  • Sudden onset of severe abdominal cramping, high-grade fever, emesis, anorexia, and large-volume watery diarrhea. Seizures may be an early manifestation.
  • Abdominal pain, tenesmus, urgency, fecal incontinence, and small-volume mucoid diarrhea with frank blood (fractional stools) may subsequently occur.
• Signs include the following:
  • Elevated temperatures (as high as 106 º F) are documented in approximately one third of cases, and a generally toxic appearance is noticed.
  • Tachycardia and tachypnea may occur secondary to fever and dehydration. Depending on the degree of dehydration, dry mucous membranes, hypotension, prolonged capillary refill time, and poor skin turgor may be present.
  • Abdominal tenderness is usually central and lower, although it may be generalized.
• Extraintestinal manifestations are as follows:
  • CNS symptoms include severe headache, lethargy, meningismus, delirium, and convulsions lasting less than 15 minutes, especially with S dysenteriae.³ Severe toxic encephalopathy is rare, but lethal complications occur when initial symptoms are followed by sensory obtundation, seizures, coma, and death in 6-48 hours. The pathogenesis of neurologic manifestations during shigellosis is unclear. However, data now clearly demonstrate that Stx is not responsible.
  • Regarding HUS, microangiopathic hemolytic anemia, thrombocytopenia, and renal failure have been reported with S dysenteriae because of vasculopathy mediated by Stx. The principal organ affected in Stx1-mediated HUS is the kidney. This is presumed to be the consequence of the high renal blood flow and abundant baseline expression and high inducibility of the Stx glycolipid receptor Gb_e in the glomerular microcirculation. Manifestations of the disease arise due to 2 primary pathogenetic mechanisms: direct Stx-mediated injury to vascular endothelial cells that leads to tissue ischemia and dysfunction and a systemic inflammatory response triggered by Stx-mediated release of a wide range of cytokines and chemokines, including IL-6, IL-8, and tumor necrosis factor-alpha.
  • Septicemia is rare, except in malnourished children with S dysenteriae infection. Septicemia is sometimes caused by other gram-negative organisms and is related to loss of mucosal integrity by Shigella infection.
  • Profound dehydration and hypoglycemia is more common with S dysenteriae infection.
  • Shigella sepsis may be complicated with disseminated intravascular coagulation (DIC), bronchopneumonia, and multiple organ failure in lethal cases.
  • Arthritis, urethritis, conjunctivitis syndrome is commonly observed in adults carrying human leukocyte antigen (HLA)-B27 histocompatibility antigen.
  • Cholestatic hepatitis, if present, is usually mild.
  • Myocarditis is identified with cardiogenic shock, arrhythmias, and heart block.
  • Rectal prolapse, toxic megacolon, and intestinal obstruction may be present.
  • Shigellosis in the first 6 months of life is rare probably due to presence of antibodies to both virulence plasmid-coded antigens and lipopolysaccharides in the breast milk. Shigellosis in the neonatal period results from mother-to-infant fecal-oral transmission during labor and delivery, usually from asymptomatic mothers.
  • Symptoms usually begin on the third day of life.
  • Septicemia and chronic diarrhea are common.
  • Fever may be absent.
  • Diarrhea is not usually bloody.
  • Intestinal perforation and mortality are more common in this group than in older children.
• Shigellosis in patients with HIV infection is often a protracted, chronic, relapsing disease (even when treated with antibiotics). Bacteremia may be a complication.

Physical

• Physical examination during acute illness reveals a febrile ill-appearing child. Fever with a temperature as high as 39-40 º C may be noted.
• The patient's hydration status should be carefully assessed. Especially note dryness of the oral mucosa, lack of tears, decreased urine output, and loss of skin turgor.
• Abdominal examination may reveal generalized mild-to-moderate tenderness with no guarding or rigidity.
• In a child who presents with febrile seizures, careful neurologic examination is mandatory to exclude meningitis.

Causes

• Shigella infection is spread by means of fecal-oral transmission.

• Search for CME/CE on This Topic »

• Gallbladder Disease (Pediatrics: Surgery)

• Green Banana Reduces Clinical Severity of Childhood Shigellosis: A Double-blind, Randomized, Controlled Clinical Trial