- Author: Jaya Sureshbabu, MBBS, MRCPCH(UK), MRCPI(Paeds), MRCPS(Glasg), DCH(Glasg); Chief Editor: Russell W Steele, MD more...
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 were discovered over 100 years ago by a Japanese microbiologist named Shiga, for whom the genus is named. 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: Shigelladysenteriae, Shigellaflexneri, Shigellaboydii, and Shigellasonnei, also known as groups A, B, C, and D, respectively. They are nonmotile, non – spore forming, rod shaped, and nonencapsulated. Subgroups and serotypes are differentiated from each other by their biochemical characteristics (e.g., ability to ferment D-mannitol) and antigenic properties. Group A has 15 serotypes, group B has 8 serotypes, group C has 19 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, enteroinvasive gram-negative bacteria, is responsible for the worldwide endemic form of bacillary dysentery.
Shigella infection is a major public health problem in developing countries where sanitation is poor. Humans are the natural reservoir, although other primates may be infected. 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 (untreated wading pools, interactive water fountain), contact with a contaminated inanimate object, and certain mode of 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. Most isolates of Shigella survive acidic treatment at pH 2.5 for at least 2 h.
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. The disease is communicable as long as an infected person excretes the organism in the stool, which can extend as long as 4 weeks from the onset of illness. Bacterial shedding usually ceases within 4 weeks of the onset of illness; rarely, it can persist for months. Appropriate antimicrobial treatment can reduce the duration of carriage to a few days.
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 extra intestinal phase of infection by gram-negative bacteria, iron becomes one of the major factors that limit further growth. This limitation occurs because most of the iron in human body is sequestered in hemoproteins (i.e., 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. Stx is transported into nucleoli. Stx nucleolar movement is carrier-dependent and energy-dependent. 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 become 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.
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.
Shigella bacteria invade the intestinal epithelium through M cells and proceed to spread from cell to cell, causing death and sloughing of contiguously invaded epithelial cells and inducing a potent inflammatory response resulting in the characteristic dysentery syndrome. In addition to this series of pathogenic events, only S dysenteriae type 1 has the ability to elaborate the potent Shiga toxin that inhibits protein synthesis in eukaryotic cells and that may lead to extraintestinal complications, including hemolytic-uremic syndrome and death. Invasion of M cells, the specialized cells that cover the lymphoid follicles of the mucosa, overlying Peyer patches, may be the earliest event.
In 2013, the average annual incidence of shigellosis in the United States was 4.82 cases per 100,000 individuals. Most cases are reported during summer months. S sonnei accounts for approximately 78% of all Shigella isolates in recent surveys from the Center 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. Fifty reporting jurisdictions reported a total of 7,746 Shigella infections in 2012. The reporting jurisdictions with the highest incidence rates were Nebraska (13.2), New Jersey (7.6), and Minnesota (7.1). The highest incidence per 100,000 population for shigellosis (27.77 cases) was among children younger than 5 years.
State public health laboratories reported 7.746 laboratory confirmed Shigella infections to the CDC in 2012. Of the 7,746 laboratory confirmed isolates, 687 were identified to species level. Distribution by species was similar to previous years, with S sonnei accounting for the largest percentage of infections (75%), followed by S flexneri (12%), S boydii (0.8%), and S dysenteriae (0.3%).The reporting jurisdictions with the highest incidence rates were Nebraska (13.2 %), New Jersey (7.6%), and Minnesota (7.1%).
The overall incidence of Shigella infection in 2012 was 2.5 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. Compared with the previous 10 years (2002–2011), a larger portion of Shigella infections in 2012 were reported from January through March. More than 95% of Shigella infections may be asymptomatic. Hence, the actual incidence may be 20 times higher than reported. The CDC estimates that 450,000 total cases of shigellosis occur in the United States every year. The latest major outbreak is reported from Illinois in February 2010 due to S sonnei.
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.
Although shigellosis-related mortality is rare in developed countries, S dysenteriae infection is associated with substantial morbidity and mortality rates in the developing world.
Case fatality is as high as 15% among patients with S dysenteriae type 1 who require hospitalization; this rate is increased by delayed arrival and treatment with ineffective antibiotics. Infants, non-breastfed children, children recovering from measles, malnourished children, and adults older than 50 years have a more severe illness and a greater risk of death
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%.
No racial predilection is known.
No sexual predilection is known.
According to recent CDC reports, Shigella infection accounted for 28% of all the enteric bacterial infections. Children younger than 5 years had 7% of total reported cases, a rate indicating a disproportionate disease burden in this population.
Gomez HF, Cleary TG. Shigella species. Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone; 1997. 429-34.
Phalipon A, Sansonetti PJ. Shigella's ways of manipulating the host intestinal innate and adaptive immune system: a tool box for survival?. Immunol Cell Biol. 2007 Feb-Mar. 85(2):119-29. [Medline].
Edwards BH. Salmonella and Shigella species. Clin Lab Med. 1999 Sep. 19(3):469-87, v. [Medline].
Friedrich AW, Bielaszewska M, Zhang WL, et al. Escherichia coli harboring Shiga toxin 2 gene variants: frequency and association with clinical symptoms. J Infect Dis. 2002 Jan 1. 185(1):74-84. [Medline].
Richardson SE, Rotman TA, Jay V, et al. Experimental verocytotoxemia in rabbits. Infect Immun. 1992 Oct. 60(10):4154-67. [Medline].
Ingersoll MA, Zychlinsky A. ShiA abrogates the innate T-cell response to Shigella flexneri infection. Infect Immun. 2006 Apr. 74(4):2317-27. [Medline].
Keusch GT, Jacewicz M, Acheson DW, et al. Globotriaosylceramide, Gb3, is an alternative functional receptor for Shiga-like toxin 2e. Infect Immun. 1995 Mar. 63(3):1138-41. [Medline].
Schuller S. Shiga toxin interaction with human intestinal epithelium. Toxins (Basel). 2011 Jun. 3(6):626-39. [Medline].
Crim SM, Iwamoto M, Huang JY, Griffin PM, Gilliss D, Cronquist AB, et al. Incidence and trends of infection with pathogens transmitted commonly through food--Foodborne Diseases Active Surveillance Network, 10 U.S. sites, 2006-2013. MMWR Morb Mortal Wkly Rep. 2014 Apr 18. 63 (15):328-32. [Medline].
CDC. Vital signs: incidence and trends of infection with pathogens transmitted commonly through food--foodborne diseases active surveillance network, 10 U.S. sites, 1996-2010. MMWR Morb Mortal Wkly Rep. 2011 Jun 10. 60(22):749-55. [Medline].
Baer JT, Vugia DJ, Reingold AL, et al. HIV infection as a risk factor for shigellosis. Emerg Infect Dis. 1999 Nov-Dec. 5(6):820-3. [Medline].
Khan WA, Dhar U, Salam MA, et al. Central nervous system manifestations of childhood shigellosis: prevalence, risk factors, and outcome. Pediatrics. 1999 Feb. 103(2):E18. [Medline].
Ochoa TJ, Cleary TG. Shigella. Kliegman, Behrman, Jenson, Stanton, eds. Nelson Textbook of Paediatrics. 19th ed. Philadelphia, PA: Saunders Elsevier; 2011. 191-Pg 959-961. [Full Text].
Mitra AK, Alvarez JO, Wahed MA, et al. Predictors of serum retinol in children with shigellosis. Am J Clin Nutr. 1998 Nov. 68(5):1088-94. [Medline].
Nataro JP. Treatment of bacterial enteritis. Pediatr Infect Dis J. 1998 May. 17(5):420-1. [Medline].
Rahman MJ, Sarkar P, Roy SK. Effect of zinc supplementation as adjunct therapy on the systemic immune response in shigellosis. Am J Clin Nutr. Feb, 2005. 81(2):495-502. [Medline].
World Health Organization. Zinc in a diarrhoeal disease control programme. 2008. Available at http://whqlibdoc.who.int/publications/2008/9789241596473_eng.pdf. Accessed: June 19, 2012.
Christopher PR, David KV, John SM, Sankarapandian V. Antibiotic therapy for Shigella dysentery. Cochrane Database Syst Rev. 2010 Aug 4. CD006784. [Medline].
Basualdo W, Arbo A. Randomized comparison of azithromycin versus cefixime for treatment of shigellosis in children. Pediatr Infect Dis J. 2003 Apr. 22(4):374-7. [Medline].
Niyogi SK. Shigellosis. J Microbiol. 2005 Apr. 43(2):133-43. [Medline].
Heiman KE, Karlsson M, Grass J, Howie B, Kirkcaldy RD, Mahon B, et al. Notes from the field: Shigella with decreased susceptibility to azithromycin among men who have sex with men - United States, 2002-2013. MMWR Morb Mortal Wkly Rep. 2014 Feb 14. 63(6):132-3. [Medline].
Brooks M. Growing Concern Over Drug-Resistant Shigella in US. Medscape Medical News. Available at http://www.medscape.com/viewarticle/846038. June 06, 2015; Accessed: April 22, 2016.
Ciprofloxacin- and Azithromycin-Nonsusceptible Shigellosis in the United States. Centers for Disease Control and Prevention. Available at http://www.bt.cdc.gov/han/han00379.asp. June 4, 2015; Accessed: April 22, 2016.
Bowen A, Eikmeier D, Talley P, Siston A, Smith S, Hurd J, et al. Notes from the Field: Outbreaks of Shigella sonnei Infection with Decreased Susceptibility to Azithromycin Among Men Who Have Sex with Men - Chicago and Metropolitan Minneapolis-St. Paul, 2014. MMWR Morb Mortal Wkly Rep. 2015 Jun 5. 64 (21):597-8. [Medline].
Appannanavar SB, Goyal K, Garg R, Ray P, Rathi M, Taneja N. Shigellemia in a post renal transplant patient: a case report and literature review. J infect Dev Ctries. Feb 13, 2014. 8:237-239. [Medline].
World Health Organization. Implementing the new recommendations on the clinical management of diarrhea. 2006. Available at http://whqlibdoc.who.int/publications/2006/9241594217_eng.pdf. Accessed: June 19, 2012.
Katz DE, Coster TS, Wolf MK, et al. Two studies evaluating the safety and immunogenicity of a live, attenuated Shigella flexneri 2a vaccine (SC602) and excretion of vaccine organisms in North American volunteers. Infect Immun. 2004 Feb. 72(2):923-30. [Medline].
National Institute of Allergy and Infectious Diseases (NIAID). Safety and Immunogenicity of Two Live, Attenuated Oral Shigella Sonnei Vaccines: WRSs2 and WRSs3. Available at http://clinicaltrials.gov/ct2/show/NCT01336699. Accessed: June 6, 2014.
World Health Organization. Guidelines for the control of Shigellosis, including epidemics due to Shigella dysenteriae type 1. Available at http://whqlibdoc.who.int/publications/2005/9241592330.pdf. Accessed: June 19, 2012.
Plotz FB, Arets HG, Fleer A, et al. Lethal encephalopathy complicating childhood shigellosis. Eur J Pediatr. 1999 Jul. 158(7):550-2. [Medline].
Bennish ML, Khan WA, Begum M, et al. Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh. Clin Infect Dis. 2006 Feb 1. 42(3):356-62. [Medline].
Tzipori S, Sheoran A, Akiyoshi D, et al. Antibody therapy in the management of shiga toxin-induced hemolytic uremic syndrome. Clin Microbiol Rev. 2004 Oct. 17(4):926-41, table of contents. [Medline].
Gomez HF, Cleary TG. Shigella. Textbook of Pediatric Infectious Diseases. Philadelphia, PA: WB Saunders; 1998. 1207-317.
Bishop R, Strockbine N, Nygren B, Mintz E. Annual Summary-Shigella 2006. Centres for Disease Control and Prevention, US Department of Health and Human Services. Nov 2008. Available at http://www.cdc.gov/ncidod/dbmd/phlisdata/shigella.htm.
Huicho L, Sanchez D, Contreras M, et al. Occult blood and fecal leukocytes as screening tests in childhood infectious diarrhea: an old problem revisited. Pediatr Infect Dis J. 1993 Jun. 12(6):474-7. [Medline].
Kaminski RW, Oaks EV. Inactivated and subunit vaccines to prevent shigellosis. Expert Rev Vaccines. 2009 Dec. 8(12):1693-704. [Medline].
Martinez-Becerra FJ, Kissmann JM, Diaz-McNair J, et al. Broadly protective Shigella vaccine based on type III secretion apparatus proteins. Infect Immun. 2012 Mar. 80(3):1222-31. [Medline].
Nathoo KJ, Porteous JE, Siziya S, et al. Predictors of mortality in children hospitalized with dysentery in Harare, Zimbabwe. Cent Afr J Med. 1998 Nov. 44(11):272-6. [Medline].
Navia MM, Gascon J, Vila J. Analysis of the mechanisms of resistance to several antimicrobial agents in Shigella spp. causing travellers' diarrhoea. Clin Microbiol Infect. 2005 Dec. 11(12):1044-7. [Medline].
Oaks EV, Turbyfill KR. Development and evaluation of a Shigella flexneri 2a and S. sonnei bivalent invasin complex (Invaplex) vaccine. Vaccine. 2006 Mar 20. 24(13):2290-301. [Medline].
Pazhani GP, Ramamurthy T, Mitra U, et al. Species diversity and antimicrobial resistance of Shigella spp. isolated between 2001 and 2004 from hospitalized children with diarrhoea in Kolkata (Calcutta), India. Epidemiol Infect. 2005 Dec. 133(6):1089-95. [Medline].
Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000 Jun 29. 342(26):1930-6. [Medline].
Yang F, Yang J, Zhang X, et al. Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery. Nucleic Acids Res. 2005. 33(19):6445-58. [Medline].