Shigella infection: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Shigella species are a common cause of diarrhea worldwide.

Issues related to the epidemiology, microbiology, clinical manifestations, complications, and diagnosis of Shigella infection will be reviewed here. Issues related to treatment and prevention of Shigella infection are discussed separately. (See "Shigella infection: Treatment and prevention in adults" and "Shigella infection: Treatment and prevention in children".)

EPIDEMIOLOGY

Burden of disease

Worldwide — Worldwide, 188 million cases of Shigella occur annually, with 164,000 associated deaths [1]. Shigella is the most common cause of invasive (bloody) diarrhea among children in resource-limited settings [2]. In a study among children <6 years of age in the Peruvian Amazon, an incidence of 0.34 episodes of Shigella diarrhea per year was observed [3].

In many resource-limited settings, S. flexneri is the predominant species [4]. S. sonnei is the second most prevalent; however, S. sonnei appears to be emerging in economically transitional regions [5]. As an example, S. sonnei has become the most common isolate in Vietnam [6,7] and could become the predominant species in other parts of Southeast Asia. (See 'Microbiology' below.)

S. dysenteriae is rarely isolated in surveillance; its decline is likely due to improvements in sanitation and antimicrobial access [5]. S. boydii infections are uncommon outside the Indian subcontinent [5].

United States — In the United States, Shigella cases occur most commonly from June to October, and predominantly affects children [8]. Shigella infection is associated with poverty (incidence rate ratio 3.6) and crowded living conditions (incidence rate ratio 1.8) [9]. In 2022, the incidence of shigellosis in the United States was 4.9 cases per 100,000 population, about three to four times less frequent than Campylobacter or Salmonella infection [10].

Most cases of shigellosis in the United States are caused by Shigella sonnei (>75 percent), Shigella flexneri is the next most frequent isolate [11,12]. Disease caused by S. sonnei tends to be less severe than that caused by S. flexneri.

In the early 1900s, Shigella dysenteriae 1 (the Shiga bacillus) was the most common isolate in the United States and Europe, but is now rare. In the United States, S. dysenteriae 1 infection is generally limited to imported cases from Mexico and Central America [13] or from laboratory contamination [14]. (See 'Microbiology' below.)

Transmission — Shigella organisms can survive transit through the stomach since they are less susceptible to acid than other bacteria. For this reason, the inoculum required for the development of clinical disease is quite low; as few as 10 to 100 organisms can cause disease [15]. Humans are the only natural reservoir for disease.

Shigella bacteria are transmitted by the fecal-oral route; this includes transmission within households or between close contacts, transmission through sexual contact, and outbreaks related to contaminated food and water:

●Household or close contact transmission – Fecal-oral transmission from individuals with symptomatic infection is the most common mechanism of transmission. The secondary attack rate for family members or caregivers in the same household as the index case is 20 percent, and is highest when the index case is between one and four years of age [16].

In resource-rich settings, outbreaks occur most commonly in child care centers and in settings with crowded living conditions such as residential institutions [17,18]. Issues related to prevention of infection in child care centers are discussed separately. (See "Shigella infection: Treatment and prevention in children", section on 'School or daycare'.)

●Sexual transmission – Outbreaks of shigellosis have occurred among men who have sex with men (MSM) [19-22]. In one study including 151 episodes of gastroenteritis among MSM in which a pathogen was identified, 31 percent involved Shigella [23]. In resource-rich settings, intercontinental transmission as well as domestically-acquired Shigella infection have been reported among with MSM [21,24-26].

Outbreaks of extensively drug resistant (XDR) strains of Shigella have been reported worldwide, including in the United States. Approximately 80 percent of XDR cases have occurred in men, many of whom reported male-to-male sexual contact [27-29]. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance'.)

●Contaminated food, drinking water, or recreational water – Outbreaks occur due to common source contamination of food, drinking water, or recreational water [30]. Fecal contamination can occur during cultivation of produce; raw vegetables are the most common mode of foodborne transmission implicated in outbreaks [31].

In one review of untreated recreational water outbreaks in the United States between 2000 and 2014, 14 of the 90 outbreaks with confirmed etiology (15 percent) were caused by Shigella [32]. Updated information on foodborne outbreaks may be found on websites maintained by the United States Centers for Disease Control and Prevention and the US Food and Drug Administration.

Drug resistance — Shigella species have emerged with resistance to several antibiotics. The United States Centers for Disease Control (CDC) defines XDR Shigella bacteria as strains with resistance to azithromycin, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and ampicillin.

Issues related to antimicrobial resistance are discussed further separately. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance'.)

MICROBIOLOGY — Shigella are nonmotile, facultatively anaerobic, gram-negative rods. They are members of the family Enterobacteriaceae, genus Shigella.

●Species – There are four species of Shigella: S. dysenteriae (serogroup A), S. flexneri (serogroup B), S. boydii (serogroup C), and S. sonnei (serogroup D). Groups A, B, and C cannot be distinguished biochemically; S. sonnei can be differentiated from the other serogroups by the expression of ornithine decarboxylase.

The microbiology of shigellosis varies with geography. (See 'Burden of disease' above.)

The spectrum of disease severity varies depending on the infecting species. (See 'Signs and symptoms' below.)

●Toxin elaboration – Shigella strains elaborate three distinct enterotoxins: the virulence plasmid-encoded ShET2 (produced by all four species) [33], chromosomally-encoded ShET1 (produced by S. flexneri 2a) [34-36], and Shiga toxin (produced by S. dysenteriae 1) [37]. S. sonnei and S. flexneri isolates that produce Shiga toxin have been identified [38,39]. These enterotoxins induce intestinal secretion of solutes and water. With the exception of Shiga toxin, the contribution of each of these toxins to the disease process is probably minor, since nontoxigenic strains cause significant disease.

CLINICAL MANIFESTATIONS

Incubation period — The incubation period for shigellosis ranges from one to three days, with an average of two days [40].

Signs and symptoms — The illness typically begins with constitutional symptoms such as fever, anorexia, and malaise. Initially diarrhea is watery, but subsequently may contain blood and mucus. Tenesmus is a common complaint. Nausea and vomiting are notably absent in most patients [41].

The frequency of symptoms is as follows [41-45]:

●Fever – 30 to 40 percent

●Abdominal pain – 70 to 93 percent

●Mucoid diarrhea – 70 to 85 percent

●Bloody diarrhea – 35 to 55 percent

●Watery diarrhea – 30 to 40 percent

●Vomiting – 35 percent

Shigella is an infection of the colon, particularly the rectosigmoid portion. Stool frequency is typically 8 to 10 per day but may be substantially greater. Significant fluid loss is uncommon (average approximately 30 mL/kg per day). This is in contrast to infections involving the small bowel, which are typified by large volumes of watery diarrhea associated with abdominal cramping, bloating, gas, and weight loss [46].

The spectrum of disease severity varies depending on the infecting species. S. sonnei commonly causes mild disease, which may be limited to watery diarrhea, whereas S. flexneri or S. dysenteriae 1 commonly cause dysenteric symptoms (bloody diarrhea) [45,47,48]. (See 'Microbiology' above.)

The disease course is generally self-limited in immunocompetent individuals, lasting no more than seven days (in the absence of antibiotic therapy). The typical disease course varies with age group. In one review including 318 infants and children hospitalized with shigellosis in Bangladesh, infants had fewer days with diarrhea (four versus six) and were more likely to have watery (as opposed to bloody) stools, hyponatremia, abdominal distension, and acidosis than older children [49]. Older children were more likely to have a leukemoid reaction than infants. The mortality rate for infants was twice that of older children.

Intestinal complications — Shigella is an infection of the colon, particularly the rectosigmoid portion. Rarely, intestinal complications can occur in the setting of Shigella infection (table 1):

●Proctitis or rectal prolapse – In infants and young children, severe inflammation of the rectum and distal colon induced by organism invasion into the colonic mucosa may lead to proctitis or rectal prolapse [45].

●Toxic megacolon – Toxic megacolon occurs primarily in the setting of S. dysenteriae 1 infection. The pathogenesis of this complication is uncertain; it occurs in the setting of pancolitis and seems to be related to the intensity of inflammation rather than being mediated by Shiga toxin. In one study, the incidence of toxic megacolon among patients with diarrhea in Bangladesh was 3 percent [15].

●Intestinal obstruction – Severe colonic disease may result in intestinal obstruction. In one series of 1211 patients with shigellosis, the incidence was 2.5 percent [50]. The patients with obstruction were more likely to be infected with S. dysenteriae 1 and were more severely ill, with higher white blood cell count and lower serum sodium concentration.

●Colonic perforation – Colonic perforation is an extremely rare complication of shigellosis; it occurs principally in infants or severely malnourished patients and is associated with infection due to S. dysenteriae 1 or S. flexneri. In one epidemic of S. dysenteriae 1 in Central America, colonic perforation was seen at autopsy in 1.7 percent of cases [51].

Systemic complications — Shigellosis may be associated with a number of systemic complications (table 1).

Bacteremia — The incidence of bacteremia has been reported to be 0 to 7 percent [52-55]. Signs that may occur in the setting of bacteremia include leukocytosis, hypothermia or temperature >39.5°C, severe dehydration, and lethargy [55].

Bacteremia is more common among children <5 years of age and adults >65 years than among older children or younger adults [52,55,56]. Among 22 cases of bacteremia described among adults, one-third of patients were older than 65 years of age, and more than half had an underlying disease (most commonly diabetes) [54].

HIV infection does not appear to confer significant predisposition to Shigella bacteremia. Among adults in Soweto, South Africa, the rate of HIV infection nearly doubled between 1996 and 2006, while the rate of Shigella bacteremia remained stable (approximately 0.2 per 1000 adults; 0.8 per 100 children) [56].

Bacteremia is associated with an increased risk of death [55]. Young, malnourished children are at greatest risk. Additionally, the mortality rate associated with Shigella bacteremia may be higher in the setting of HIV infection. In a study of systemic shigellosis in South Africa, patients with HIV infection were more likely to die than patients without HIV infection (29 of 78 versus 5 of 40 of cases were fatal, respectively) [57].

Fluid, electrolyte, and nutrition disturbances — Substantial volume depletion is uncommon in shigellosis because the stool volume is usually low. In one review of 412 patients with shigellosis, 36 percent had mild dehydration, 12 percent had moderate dehydration, and 2 percent had severe dehydration [41]. In another series, hyponatremia (serum sodium <120 mEq/L) was observed in 29 percent of patients hospitalized with diarrhea due to S. dysenteriae 1 [58]. Hyponatremia is generally due to the syndrome of inappropriate antidiuretic hormone secretion, not volume depletion [15,58].

Protein-losing enteropathy may be observed. In one report that used stool alpha-1 antitrypsin levels as an indicator of protein excretion, protein loss was high during the acute phase in patients with dysentery (bloody diarrhea), remained high in patients who failed treatment, and fell to normal values in those who were recovered [59].

Increased catabolism due to fever, stool protein loss, malabsorption, and decreased intake associated with anorexia can exacerbate pre-existing malnutrition.

Leukemoid reaction — A leukemoid reaction (white blood count ≥50,000/mm³ or more) has been observed in Bangladesh among approximately 4 percent of patients, most commonly in children between 2 and 10 years of age (and not at all in children younger <1 year of age) [60]. The white blood cell count in these patients ranged from 50,000 to 195,000/mm³ and was accompanied by an increased number of immature forms. In this study, the mortality rate also was increased among patients with a leukemoid reaction (21 versus 7 percent).

In contrast, a study conducted in the United States found no association between disease severity and a high white blood cell count [42].

Neurologic disease

●Seizures

•Epidemiology – Seizures are the most common neurologic complication associated with Shigella infection and occur almost exclusively among children <15 years of age. In one study including 68 children hospitalized for acute gastroenteritis with convulsions, Shigella infection was associated with increased risk of seizures (odds ratio 3.38, 95% CI 1.50-7.59) [61].

Seizures tend to be generalized and are not associated with specific neurologic deficits, but have been associated with a higher risk of death [62,63]. The reported prevalence of seizures among children with shigellosis has ranged from 5 to 45 percent; among patients of all ages hospitalized with shigellosis, the prevalence is about 10 percent [15,62,63].

Seizures have been observed during infection with all serotypes of Shigella.

•Associated clinical and laboratory findings – The occurrence of seizures is associated with fever (often greater >39°C [102.2°F]), increased proportion of immature leukocytes, low serum sodium, and high serum potassium. Analysis of cerebrospinal fluid is typically normal; up to 15 percent may have mild lymphocytic pleocytosis with up to 12 cells.

•Mechanism – Neurologic complications of Shigella infection were previously thought to be induced by circulating Shiga toxin produced by S. dysenteriae 1, though this is not likely to be true [37]. In one study including five children with shigellosis and seizures or encephalopathy, cytotoxic activity was not detected in serum or spinal fluid (although it was present in stool, at levels 1000-fold below that of cultured S. dysenteriae 1) [64]. The stool cytotoxic activity was not neutralized by anti-Shiga toxin antibodies, no patient had neutralizing antibodies to Shiga toxin, and DNA hybridization studies of the Shigella isolates that probed for the gene encoding Shiga toxin were negative.

●Other neurologic complications – Other neurologic findings have been described in up to 40 percent of children hospitalized with Shigella infection, including encephalopathy with lethargy, confusion, and headache [65]. Obtundation, coma, and posturing are rare. In cases of fatal encephalopathy, cerebral edema has been observed at autopsy.

A particularly lethal form of shigellosis, known as the Ekiri syndrome, was responsible for 15,000 deaths per year in Japan during the pre-World War II era [15]. The Ekiri syndrome was associated with S. sonnei infection and was characterized by the rapid development of seizures and coma in patients with high fever and few dysenteric symptoms. The mechanism of the fulminant course remains unclear.

Reactive arthritis — Reactive arthritis is an uncommon complication that may be observed following S. flexneri infection, either alone or in association with conjunctivitis and urethritis. In a study of US military personnel, reactive arthritis occurred in 0.5 percent of cases of Shigella gastroenteritis [66]. (See "Reactive arthritis".)

The arthritis is a sterile inflammatory arthritis. Symptoms develop one to two weeks following symptoms of dysentery (bloody diarrhea), regardless of whether antibiotic treatment was administered. Approximately 70 percent of patients with arthritis are HLA-B27 positive [67]. A 5 amino acid peptide encoded on a 2 Md Shigella plasmid has been associated with reactive arthritis in two separate studies [68,69]. This peptide has sequence similarity to the HLA B27 alpha 1 domain, suggesting that molecular mimicry may play a pathogenetic role in arthritis. (See "Pathogenesis of spondyloarthritis".)

Sterile reactive arthritis has also been described following infection with Campylobacter jejuni, Salmonella enteritidis, Salmonella typhimurium, Yersinia enterocolitica, and Yersinia pseudotuberculosis [70].

Hemolytic-uremic syndrome (HUS) — HUS has been described most commonly in the context of infection due to Shiga toxin-producing Escherichia coli (STEC) infections; less frequently, it has also been associated with Shigella dysenteriae type 1 infection [71].

Retrospective data suggest that antibiotic use in the setting of S. dysenteriae 1 infection does not induce development of HUS, and that treatment with antibiotics may reduce its likelihood. In a review of several studies including 128 adults and 250 children with S. dysenteriae 1 infection treated with antibiotics, one child developed HUS [72]. The increased risk of HUS with antibiotic treatment for STEC infection but not S. dysenteriae 1 infection may be due to a difference in the genomes of these two organisms. In S. dysenteriae 1, the phage that carries the Shiga toxin genes is unable to undergo lysogenic conversion, whereas the phage that carries these genes within pathogenic E. coli is not defective [73,74].

Issues related to hemolytic-uremic syndrome are discussed further separately. (See "Overview of hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)

Other manifestations

●Vaginitis or vulvovaginitis – In young girls, Shigella can cause vaginitis or vulvovaginitis, with or without diarrhea [75]. The vaginal discharge is usually painless and may be bloody. Symptoms may persist for several months.

●Keratitis – Shigella is a rare cause of keratitis; it should be considered as the cause of keratitis or conjunctivitis in young children with recent diarrheal illness or exposure [76].

●Myocarditis – Acute myocarditis has been associated with acute S. sonnei gastroenteritis in two children [77].

DIAGNOSIS

Clinical suspicion — Shigella should be suspected in the setting of relevant clinical manifestations (watery or bloody diarrhea, abdominal pain, tenesmus, and fever). These manifestations may occur in the presence or absence of relevant epidemiologic exposure, such as contact with an individual with recent shigellosis (such as a household member, a member of a residential institution, or sexual partner) or exposure to food or water implicated in a shigellosis outbreak.

Presence of white blood cells and red blood cells on direct microscopic stool examination (if available; this test is no longer performed in many laboratories) should also raise suspicion for Shigella infection.

Diagnostic evaluation — Stool culture is the preferred tool for diagnosis of Shigella since it provides an isolate for subsequent susceptibility testing. Stool molecular panels are capable of detecting an array of bacterial pathogens; however, they are not able to assess antimicrobial susceptibility of the identified pathogens. Therefore, if Shigella is identified via molecular testing, reflex culture and susceptibility testing should be performed. (See 'Antimicrobial susceptibility testing' below.)

For patients with Shigella infection associated with sexual transmission, evaluation for other sexually transmitted infections should also be pursued. (See "Screening for sexually transmitted infections".)

●Stool culture – Shigella is a fastidious organism; it requires prompt handling and optimally should be inoculated onto agar at the bedside or soon after collection. A stool culture may have higher yield than culture from a rectal swab; the best yield is from a mucoid part of stool [78]. If transport is required, the best medium is buffered glycerol saline (BGS) [79].

Shigella is cultured by routine techniques in most clinical microbiology laboratories. Initial inoculation should be on more than one low selectivity medium, such as MacConkey or eosin methylene blue. Colonies that appear suspicious on low selectivity media are usually subcultured onto highly selective media such as SS (Salmonella-Shigella), XLD (xylose-lysine-deoxycholate), HE (hektoen enteric), or deoxycholate citrate agar (picture 1). All these media contain lactose, as well as a color indicator. Shigella do not ferment lactose (they are lactose non-fermenters).

Further classification can be pursued including identification of serogroup and serotype, although these are rarely important to clinical management, and these studies are not performed in most clinical laboratories.

●Molecular testing – A variety of molecular diagnostics techniques, including multiplex molecular panels, may be used for detection of Shigella in stool [80]. Polymerase chain reaction has been used to detect Shigella-specific DNA sequences, frequently a group of Shigella-specific genes known as invasion plasmid antigen H (ipaH), which enables the detection of as few as 10 to 100 S. flexneri organisms (as compared with 10(6) organisms detected by routine culture) [81,82]. These molecular assays are becoming increasingly available in clinical laboratories [80,83].

Antimicrobial susceptibility testing — Antimicrobial susceptibility testing should be performed on all Shigella isolates to inform antibiotic selection. Identifying drug-resistant infections can also inform appropriate public health measures. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance' and "Shigella infection: Treatment and prevention in children", section on 'Antibiotic resistance'.)

Antimicrobial susceptibility testing is especially important for Shigella infections because of the rising rate of antimicrobial resistance. In particular, susceptibility testing for ciprofloxacin should assess drug dilutions of 0.12 mcg/mL or lower, and clinicians should request the minimum inhibitory concentration (MIC) to ciprofloxacin if it is not routinely provided with the susceptibility testing results [84].

Issues related to antibiotic resistance are discussed further separately. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance' and "Shigella infection: Treatment and prevention in adults", section on 'Directed therapy'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for Shigella infection includes infection with Salmonella, Campylobacter, Yersinia, enteroinvasive E. coli, E. histolytica, or Clostridioides difficile, as well as noninfectious inflammatory bowel disease [85]. (See "Approach to the adult with acute diarrhea in resource-abundant settings" and "Approach to the adult with acute diarrhea in resource-limited settings" and "Diagnostic approach to diarrhea in children in resource-abundant settings" and "Approach to the child with acute diarrhea in resource-limited settings".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology

•Burden of disease – Shigella species are a common cause of diarrhea worldwide, and a major cause of morbidity and mortality. Shigella is the most common cause of invasive (bloody) diarrhea among children in resource-limited settings. (See 'Burden of disease' above.)

•Transmission (see 'Transmission' above)

-Shigella organisms can survive transit through the stomach since they are less susceptible to acid than other bacteria. For this reason, the inoculum required for the development of clinical disease is quite low; as few as 10 to 100 organisms can cause disease.

-Shigella bacteria are transmitted by the fecal-oral route; this includes transmission within households or between close contacts, transmission through sexual contact, and outbreaks related to contaminated food and water.

•Drug resistance – Shigella species have emerged with resistance to several antibiotics. Issues related to antimicrobial resistance are discussed further separately. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic resistance'.)

●Microbiology (see 'Microbiology' above)

•Species – Shigella are nonmotile, facultatively anaerobic, gram-negative rods. There are four species: S. dysenteriae, S. flexneri, Shigella boydii, and S. sonnei.

•Geographic variability – In many resource-limited settings, S. flexneri is the predominant species; S. sonnei is the second most prevalent. In the United States, most cases are caused by S. sonnei; S. flexneri is the next most frequent isolate.

•Association with disease severity – S. sonnei commonly causes mild disease, which may be limited to watery diarrhea, whereas S. flexneri or S. dysenteriae 1 commonly cause invasive (bloody) diarrhea.

●Clinical manifestations

•Incubation period – The incubation period for shigellosis ranges from one to three days. (See 'Incubation period' above.)

•Signs and symptoms – Symptoms include diarrhea (watery or bloody), abdominal pain, tenesmus, and fever. The disease course is generally self-limited in immunocompetent individuals, lasting no more than seven days (in the absence of antibiotic therapy). (See 'Signs and symptoms' above.)

•Complications (table 1):

-Intestinal complications – Intestinal complications of Shigella infection include proctitis, rectal prolapse, toxic megacolon, intestinal obstruction, and colonic perforation. (See 'Intestinal complications' above.)

-Systemic complications – Systemic complications of Shigella infection include bacteremia, fluid/electrolyte/nutrition disturbances, leukemoid reaction, neurologic disease (seizures, encephalopathy), and reactive arthritis. Infrequently, hemolytic uremic syndrome has been associated with Shigella dysenteriae type 1 infection. (See 'Systemic complications' above.)

●Diagnosis

•Clinical suspicion – Shigella should be suspected in the setting of relevant clinical manifestations, which may occur in the presence or absence of relevant epidemiologic exposure. (See 'Clinical suspicion' above.)

•Diagnostic evaluation – Stool culture is the preferred tool for diagnosis of Shigella since it provides an isolate for subsequent susceptibility testing. Stool molecular panels are capable of detecting an array of bacterial pathogens; however, they are not able to assess antimicrobial susceptibility of the identified pathogens. Therefore, if Shigella is identified via molecular testing, reflex culture and susceptibility testing should be performed.

For patients with Shigella infection associated with sexual transmission, evaluation for other sexually transmitted infections should also be pursued. (See 'Diagnostic evaluation' above.)

•Antimicrobial susceptibility testing – Antimicrobial susceptibility testing is especially important for Shigella infection because of the rising rate of antimicrobial resistance. In particular, ciprofloxacin susceptibility testing should assess drug dilutions of 0.12 mcg/mL or lower, and clinicians should request the minimum inhibitory concentration (MIC) for ciprofloxacin if it is not routinely provided with the susceptibility testing results. (See 'Antimicrobial susceptibility testing' above.)