Shigellosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian; and João André Alves Silva, M.D. [2]

Shigellosis is a common foodborne or waterborne infectious illness caused by Shigella species, a gram-negative, non-motile, facultatively anaerobic, non-spore-forming rod. Shigella was first discovered by Dr. Kiyoshi Shiga following a bacillary dysentery outbreak in Japan in 1896. It is commonly spread by the fecal-oral route in regions of poor sanitation. Although individuals of all age groups may acquire shigellosis, high risk patients include young children, elderly patients, and immunocompromised patients. Clinical manifestations typically include diffuse, colicky abdominal pain, fever, and mucoid/bloody diarrhea that develop as early as 12 hours to 3 days following ingestion of Shigella and typically self-resolve within 5 to 7 days of symptom onset. If left untreated, the majority of patients recover spontaneously, but intestinal and systemic complications, such as post-infectious arthritis (Reiter’s syndrome) or hemolytic uremic syndrome (HUS), may develop in a few individuals. Individuals with suspected infection should undergo blood and stool work-up for appropriate diagnosis and choice of antimicrobial agents. The cornerstones of the treatment of shigellosis are fluid and salt replacement and antibiotic therapy. Antibiotic therapy is recommended among all patients and usually consists of a 3 day course of trimethoprim/sulfamethoxazole or ciprofloxacin in patients with a documented resistant strain. Although there is currently no vaccine for shigellosis, primary prevention consists of proper hand hygiene, as well as safe food and water practices.

Shigella was first discovered by Dr. Kiyoshi Shiga following a bacillary dysentery outbreak in Japan in 1896. Since then, several outbreaks have occurred.

A small inoculum of Shigella (10 to 200 organisms) is sufficient to cause shigellosis. Shigella is commonly spread by the fecal-oral route in regions of poor sanitation (foodborne or waterborne transmission). Shigella first invades the epithelial cells of the large intestine by using M cells as entry ports for transcytosis. Shigella then invades macrophages and induces cellular apoptosis, which results in inflammation, generation of proinflammatory cytokines, and recruitment of polymorphonuclear neutrophils (PMNs). Following transcytosis and macrophage apoptosis, Shigella avoids extracellular exposure and spreads intercellularly using actin polymerization processes (rocket propulsion). As PMNs invade the site of active inflammation, the integrity of the intestinal epithelial barrier is lost, and adsorption of fluids and nutrients is impaired, resulting in clinical manifestations of shigellosis (e.g. diarrhea). On gross pathology, hyperemia with development of ulcers and edema are typical findings. On microscopic pathology, infiltration of PMNs and inflammatory pseudomembranes are characteristic features.

Shigella species are classified into four serogroups: Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei.

Shigellosis is usually a foodborne or waterborne illness caused by an infection with Shigella species. Shigella is a gram-negative, non-motile, facultatively anaerobic, non-spore-forming rod.

Shigellosis must be differentiated from other diseases that cause fever, bloody diarrhea, dehydration, tachycardia and low blood pressure, such as Enterohemorrhagic E.coli (EHEC) infection, Ebola, Typhoid fever, Malaria, and Lassa fever.

Although individuals of all age groups may acquire shigellosis, the majority of affected individuals are children between the age of 2 to 5. There is no gender or racial predominance of shigellosis. More than 160 million cases are reported annually, of which more than 95% are reported in the developing countries. Shigella sonnei accounts for the majority of shigellosis cases in the developed (industrialized) countries, while Shigella flexneri accounts for the majority of shigellosis cases in the developing countries.

All individuals are at risk of developing shigellosis. Individuals at high risk of developing shigellosis or complications of shigellosis are young children between the age of 2 to 5, elderly individuals, and individuals who engage in anal sexual intercourse, HIV-positive individuals, and travelers to developing countries in regions of poor sanitation.

Clinical manifestations of shigellosis typically develop 12 hours to 3 days following ingestion of Shigella. Patients often first develop colicky, diffuse abdominal pain and fever, followed by diarrhea and tenesmus. If left untreated, shigellosis typically self-resolves within 5 to 7 days of onset of clinical manifestations in the majority of patients. High risk patient populations (young children, elderly, or immunocompromised patients) are at increased risk of developing complications, which may be intestinal or extra-intestinal. Classical complications include post-infectious arthritis (Reiter’s syndrome) and hemolytic uremic syndrome (HUS). Prognosis is generally excellent for immunocompetent individuals. Factors that are associated with poorer prognosis include prolonged duration of disease, development of complications, and infection of high risk patients.

Symptoms may range from mild abdominal discomfort to severe colicky, diffuse abdominal pain. Patients may initially have small volume watery diarrhea that precedes dysentery. The majority of patients report mucoid diarrhea, and up to 50% of patients report bloody diarrhea. Other common symptoms include fever, nausea and vomiting, and tenesmus.

Patients with shigellosis usually appear lethargic. Physical examination of patients with shigellosis is usually remarkable for diffuse abdominal tenderness in more than 70% of cases and fever in approximately 25% to 40% of cases. Less commonly, physical examination is remarkable for signs of dehydration, such as hypotension, tachycardia, and dry mucous membranes.

The majority of patients with shigellosis have no significant derangements in either blood or stool work-up. Common findings include leukocytosis with left shift on blood examination, and blood and/or mucus in stools on stool examination. Multiple blood and stool cultures are needed to rule out bacteremia and to obtain antibiotic susceptibility testing, but the majority of cases yield negative cultures. Hematology, renal, and liver function testing may be required in some cases to rule out the development of any complications associated with shigellosis, such as severe dehydration, cholestatic liver disease, or hemolytic uremic syndrome (HUS).

Other diagnostic studies, such as enzyme-linked immunoassay (ELISA), polymerase chain reaction (PCR), or colon/rectal biopsies, are not always necessary but may be required for the diagnosis of shigellosis in the minority of patients, such as high risk patients who are hospitalized and in need of urgent management).

The cornerstones of the treatment of Shigellosis are fluid and salt replacement and antibiotic therapy. For the majority of patients, oral fluid replacement is adequate and should consist of water, glucose, and electrolytes such as sodium, chloride, potassium and bicarbonate. IV fluids should be reserved for patients with severe disease who cannot tolerate oral therapy, and should be tailored to their lab findings. Antimotility agents should be avoided as they prolong the duration of the infection. Antibiotic therapy is recommended among all patients and usually consists of a 3 day course of either ciprofloxacin, azithromycin, or extended-spectrum penicillin antibiotics.

There is no vaccine to prevent shigellosis. Primary prevention consists of proper hand hygiene, as well as safe food and water practices. Special care should be taken when handling diapers as they may be an important source for the spread of Shigella.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Shigella was first discovered by Dr. Kiyoshi Shiga following a bacillary dysentery outbreak in Japan in 1896. Since then, several outbreaks have occurred.

• Shigella was first discovered by Dr. Kiyoshi Shiga, a Japanese scientist, following a bacillary dysentery outbreak in Japan in 1896.
• Shigella was then adopted as a genus with 4 species in 1950s.
• In 2000, Shigella was found to be phylogenically closely related to E. coli. Both species are thought to be derived from similar ancestral virulence plasmids.

Several Shigella outbreaks have been reported in USA in the past, including the following outbreaks:

• January, 2000: Senor Felix outbreak in Washington, California, Idaho, Arizona, New Mexico, Oregon, and Alaska. A total of 122 cases were reported.
• October, 2000: Viva Mexico outbreak in California, USA. A total of 221 cases were reported.
• January, 2001: Royal Fork outbreak in Washington, USA. A total of 8 cases were reported.
• May, 2001: Tomato outbreak in New York. A total of 118 cases were reported.
• August, 2004: Gate Gourmet outbreak in Hawaii. A total of 22 cases were reported.
• August, 2006: Filiberto’s outbreak in San Diego, USA. A total of 73 cases were reported.
• March, 2010: Subway Restaurant outbreak in Illinois, USA. A total of 328 cases were reported.
• March, 2015: Drug-resistant Shigella outbreak in Massachusetts, California, and Pennsylvania, USA.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

A small inoculum of Shigella (10 to 200 organisms) is sufficient to cause shigellosis. Shigella is commonly spread by the fecal-oral route in regions of poor sanitation (foodborne or waterborne transmission). Shigella first invades the epithelial cells of the large intestine by using M cells as entry ports for transcytosis. Shigella then invades macrophages and induces cellular apoptosis, which results in inflammation, generation of proinflammatory cytokines, and recruitment of polymorphonuclear neutrophils (PMNs). Following transcytosis and macrophage apoptosis, Shigella avoids extracellular exposure and spreads intercellularly using actin polymerization processes (rocket propulsion). As PMN invade the site of active inflammation, the integrity of the intestinal epithelial barrier is lost, and adsorption of fluids and nutrients is impaired, resulting in clinical manifestations of shigellosis (e.g. diarrhea). On gross pathology, hyperemia with development of ulcers and edema are typical findings. On microscopic pathology, infiltration of PMN and inflammatory pseudomembranes are characteristic features.

• A small inoculum of Shigella (10 to 200 organisms) is sufficient to cause shigellosis.^[1]
• Shigella is commonly spread by the fecal-oral route in regions with poor sanitation.^[1][2]
• Exposure to contaminated food (e.g. vegetables or meat) or water (drinking or swimming in untreated water) is associated with shigellosis. Contaminated food and water may have a normal appearance and smell.
• Epidemics may be foodborne or waterborne.^[1]
• Shigella can also be transmitted by flies and sexual contact.^[2]

The small inoculum may be attributed to the following features of the organism:

• Shigella contains acid resistance systems that enable the organism to survive the acidic environment in the stomach.^[3]
• Shigella can downregulate the expression of antibacterial proteins released by the host (human) intestinal mucosa.^[4]

Shigella migrates to the large intestine, where it causes infection via invasion of the epithelial barrier of the large intestine. Initially, Shigella uses M cells from the basolateral side of the intestinal epithelium as entry port.^[5] M cells are specialized cells that sample the gut lumen for pathogenic antigens and delivers these antigens to mucosal lymphoid tissue to activate an adequate immune response.^[6] Shigella is transcytosed across the epithelial layer of the intestinal M cells.

• Following transcytosis, Shigella enters macrophages and induces cellular apoptosis.^[7]
• Macrophage apoptosis results in the release of proinflammatory cytokines (IL-1-beta and IL-18), which signal intestinal inflammation and consequent activation of the innate immune system.^[8][9]

• Following apoptosis and inflammation, Shigella is released from the macrophages.^[10]
• Invasion of the intestinal epithelium continues from the basolateral side, and the bacteria further spreads to adjacent epithelial cells and avoids extracellular exposure by using intercellular actin polymerization processes (rocket propulsion).^[11]

• As Shigella infiltrates the epithelial cells, activation of nuclear factor kappa-B (NF-KB) by Shigella generates IL-8, which in turn mediates the recruitment of polymorphonuclear neutrophils (PMN) to the site of inflammation.^[12]
• PMN destroy the integrity of the intestinal epithelial barrier and allow more Shigella organisms to directly and more easily invade the intestinal epithelium. The loss of the intestinal epithelial cells results in impaired adsorption of other nutrients and fluids and leads to clinical manifestations of shigellosis (diarrhea).^[2]
• Shigella enterotoxin 1 (ShET1) and enterotoxin 2 (ShET2) are synthesized during the inflammatory process and are thought to account, at least in part, for fluid secretion that results in shigellosis-associated diarrhea.^[13]
• Other Shigella toxins, such as Shigella dysenteriae serotype 1 toxin, results in cytotoxicity and development of vascular lesions at the level of the colon, the kidneys, and the central nervous system. The cytotoxic activity of the toxin is thought to cause shigella-associated complications, such as hemolytic uremic syndrome (HUS).^[14]

Ultimately, more PMNs are recruited and Shigella organisms are killed.

On gross pathology, shigellosis is typically associated with acute-onset diffuse fibrinous exudative inflammation in the colon and/or the rectum. The following histopathological features may be observed:

• Ulcer formation and focal erosions
• Necrotizing inflammation
• Hyperemia
• Edema

On microscopic histopathological analysis, the following findings may be observed from samples of the colon, rectum, and occasionally the distal ileum:

• PMN infiltration
• Formation of patchy inflammatory pseudomembrane

The following video demonstrates the microscopic pathological features of shigellosis: {{#ev:youtube|1D1m4rybDrc}}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Shigella species are classified into four serogroups: Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei.

Shigella species are classified into four serogroups:^[1]

• Serogroup A: S. dysenteriae (12 serotypes)
• Serogroup B: S. flexneri (6 serotypes)
• Serogroup C: S. boydii (23 serotypes)
• Serogroup D: S. sonnei (1 serotype)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Shigellosis is usually a foodborne or waterborne illness caused by an infection with Shigella species. Shigella is a gram-negative, non-motile, facultatively anaerobic, non-spore-forming rod.

Shigellosis is usually a foodborne or waterborne illness caused by an infection with Shigella species.

• There are 4 Shigella species that are responsible for development of Shigellosis:

• Serogroup A: S. dysenteriae (12 serotypes)
• Serogroup B: S. flexneri (6 serotypes)
• Serogroup C: S. boydii (23 serotypes)
• Serogroup D: S. sonnei (1 serotype)

• Shigella is a gram-negative, non-motile, facultatively anaerobic, non-spore-forming rod.^[1]
• Shigella is closely related to E. coli, where both organisms are thought to be derived from similar vector plasmids. Unlike E. coli, Shigella cannot ferment lactose or decarboxylate lysine.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Yazan Daaboul; Serge Korjian

Shigellosis must be differentiated from other diseases that cause fever, bloody diarrhea, dehydration, tachycardia and low blood pressure, such as Enterohemorrhagic E.coli (EHEC) infection, Ebola, Typhoid fever, Malaria, and Lassa fever.

The table below lists the underlying bacterial pathogens known to cause acute diarrhea:^[1][2]

Shigellosis must be differentiated from other causes of watery chronic diarrhea^[3][4][5][6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Although individuals of all age groups may acquire shigellosis, the majority of affected individuals are children between the age of 2 to 5. There is no gender or racial predominance of shigellosis. More than 160 million cases are reported annually, of which more than 95% are reported in the developing countries. Shigella sonnei accounts for the majority of shigellosis cases in the developed (industrialized) countries, while Shigella flexneri accounts for the majority of shigellosis cases in the developing countries.

• In 2013, the average annual incidence of shigellosis in the United States was 4.82 cases per 100,000 individuals.

• Individuals of all age groups may acquire shigellosis.
• Children between the age of 2 to 5 and elderly patients are most susceptible to acquire shigellosis.^[1][2]
• Approximately 60% to 70% of all cases are reported in childcare/school settings or among families with small children.^[1][2]

• There is no gender predominance for shigellosis.

• There is no racial predominance for shigellosis.

• The total incidence of shigellosis in the developed countries is estimated to be approximately 1.5 million cases per year.^[1][2]
• Approximately 14,000 laboratory confirmed cases of shigellosis and an estimated 448,240 total cases occur in the United States each year.^[1][2]
• The majority of cases reported in USA are caused by Shigella sonnei (approximately 77%).^[1]

• The incidence of shigellosis in the developing world is estimated to exceed 160 million cases per year, among which shigellosis is responsible for approximately 1.1 million deaths per year.^[1]
• In the developing world, the most common cause of shigellosis is S. flexneri (approximately 60%).^[2]
• Epidemics of S. dysenteriae type 1 have been reported in Africa and Central America with case fatality rates that range between 5 to 15%.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

All individuals are at risk of developing shigellosis. Individuals at high risk of developing shigellosis or complications of shigellosis are young children between the age of 2 to 5, elderly individuals, and individuals who engage in anal sexual intercourse, HIV-positive individuals, and travelers to developing countries in regions of poor sanitation.

• Individuals living in regions of poor sanitation with inadequate supply of clean water are at risk of developing shigellosis.

• The majority of shigellosis cases are reported in childcare/school settings or among families with small children.^[1]

• Children between the age of 2 to 5 are most susceptible to shigellosis infection and to death associated with the infection.

• Individuals who engage in anal sexual intercourse are at risk of developing shigellosis.^[1]
• Shigella is transmitted via the fecal-oral route. Individuals who engage with anal sexual intercourse may be exposed to fecal residue.^[1]

• HIV-positive patients and patients with advanced cancers may develop severe and prolonged forms of shigellosis and are at high risk of developing bacteremia.^[1]

• Individuals with malnutrition may develop severe forms of shigellosis.

• Individuals who travel to developing countries are at risk of shigellosis following ingestion of contaminated food and water.^[1]
• Swimming in regions with poor sanitation during travel further increases the risk of developing shigellosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Clinical manifestations of shigellosis typically develop 12 hours to 3 days following ingestion of Shigella. Patients often first develop colicky diffuse abdominal pain and fever, followed by diarrhea and tenesmus. If left untreated, shigellosis self-resolves within 5 to 7 days of onset of clinical manifestations in the majority of patients. High risk patient populations (young children, elderly, and immunocompromised patients) are at increased risk of developing complications, which may be intestinal or extra-intestinal. Classical complications include post-infectious arthritis and hemolytic uremic syndrome (HUS). Prognosis is generally excellent for immunocompetent individuals. Factors that are associated with poorer prognosis include prolonged duration of disease, development of complications, and infection of high risk patients.

• Not all individuals develop clinical manifestations of shigellosis. Individuals may remain asymptomatic but transmit the organism to other individuals.

• Clinical manifestations of shigellosis typically appear approximately 12 hours to 3 days following ingestion of Shigella.
• Patients typically first develop colicky, diffuse abdominal pains associated with nausea and fever.
• Diarrhea and tenesmus (rectal spasms) typically follow. Diarrhea is often reported to be small in volume and may range from mild to severe.
• The diarrhea is usually watery at first, but patients may also develop dysentery.
• Children younger than 2 years of age may develop high-grade fevers and febrile seizures.

• If left untreated, clinical manifestations of shigellosis typically self-resolve within 5 to 7 days of development of clinical manifestations.
• In immunocompromised individuals and young children, shigellosis may be more severe and prolonged, necessitating hospitalization to reduce the risk of Shigella-associated complications.

• Rectal prolapse
• Proctitis
• Toxic megacolon
• Intestinal obstruction
• Colonic perforation

• Post-infectious arthritis (Reiter’s syndrome)
  • Approximately 2% of individuals infected with S. flexneri develop Reiter’s syndrome (triad of arthritis, uveitis, and urethritis).
  • Post-infectious arthritis may persist for several weeks to months and may become chronic.
  • Individuals with HLA-B27 subtype are predisposed to development of Reiter’s syndrome following shigellosis.
• Concomitant infections
  • Patients with dysentery lose proteins, including immune factors, in stools and are predisposed to concomitant infections that are not related to shigellosis.

• Bacteremia
  • Bacteremia is common among immunocompromised individuals, such as HIV-positive individuals and individuals with cancer and malnutrition.
• SIADH and SIADH-associated hyponatremia
• Seizure
  • Among children less than 2 years of age.
• Encephalopathy
  • Among children less than 2 years of age.
• Reactive arthritis
• Hemolytic uremic syndrome (HUS)
  • HUS is mediated by Shiga toxin that is typically present in S. dysenteriae.
  • HUS is characterized by the triad microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury.^[1]
• Bronchopneumonia

• Disseminated intravascular coaguloapathy (DIC)

• Cholestatic hepatitis
• Myocarditis
• Coma
• Death

• Generally, prognosis of shigellosis is excellent, and the majority of patients recover without sequelae.
• Factors associated with poorer prognosis include:
  • Prolonged duration of disease (> 7 days)
  • Development of complications
  • Patient risk factors (young children, elderly patients, or immunocompromised patients).

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