INTRODUCTION — Shigella species are a common cause of bacterial diarrhea worldwide, especially in resource-limited countries. Shigella organisms can survive transit through the stomach since they are less susceptible to acid than other bacteria; for this reason as few as 10 to 100 organisms can cause disease [1]. Ingested bacteria pass into the small intestine where they multiply; large numbers of bacteria then pass into the colon, where they enter the colonic cells. Given its relatively low infectious dose, Shigella transmission can occur via contaminated food and water and via direct person-to-person spread. (See "Shigella infection: Epidemiology, microbiology, and pathogenesis".)
The clinical manifestations, complications, and diagnosis of Shigella infection will be reviewed here. The treatment of this infection is discussed separately. (See "Shigella infection: Treatment and prevention in adults" and "Shigella infection: Treatment and prevention in children".)
CLINICAL MANIFESTATIONS
General features — Shigella is an infection of the colon, particularly the rectosigmoid portion of the colon. Patients with Shigella gastroenteritis typically present with high fever, abdominal cramps, and bloody, mucoid diarrhea [2-6]:
●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
The incubation period ranges from one to three days, with an average of two days [7]. The disease 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.
Stool frequency is typically 8 to 10 per day but may increase to up to 100 per day. Significant fluid loss is uncommon (average approximately 30 mL/kg per day); this is in contrast to small bowel infections, which are typified by large volumes of watery diarrhea associated with abdominal cramping, bloating, gas and weight loss [8]. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Approach to the child with acute diarrhea in resource-limited countries".)
The spectrum of disease severity varies depending on the serogroup of the infecting organism. Shigella sonnei commonly causes mild disease, which may be limited to watery diarrhea, whereas Shigella dysenteriae 1 or Shigella flexneri commonly causes dysenteric symptoms (bloody diarrhea) [6,9,10]. In an immunocompetent host, the course of disease is generally self-limited, lasting no more than seven days when left untreated.
The typical course of disease varies with age group. In a review of 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 [11]. Older children were more likely to have a leukemoid reaction than infants. The mortality rate for infants was twice that of older children. In another study conducted at the same institution, infants who were breast fed were less frequently infected and had a milder illness than infants who were not breast fed [2].
In the United States, severe disease is more likely to occur in Black males than in Black females or White males, with the highest incidence in those 18 to 49 years old [10]; whether the increased risk in this group is related to relatively higher rates of HIV infection in the same demographic is unknown.
Intestinal complications — Several intestinal complications can occur in the setting of Shigella infection; each is relatively rare (table 1).
Proctitis or rectal prolapse — In infants and young children, the severe inflammation of the rectum and distal colon that is induced by invasion of the organism into the colonic mucosa may lead to proctitis or rectal prolapse [6].
Toxic megacolon — Toxic megacolon occurs primarily in the setting of S. dysenteriae 1 infection. The pathogenesis of this complication is unclear; it occurs in the setting of pancolitis and seems to be related to the intensity of inflammation rather than being mediated by Shiga toxin. The incidence of toxic megacolon among patients admitted to the diarrhea treatment center in Bangladesh was 3 percent [12].
Intestinal obstruction — Severe colonic disease may result in intestinal obstruction. The incidence in one series of 1211 patients with shigellosis was 2.5 percent [13]. The patients with obstruction were more likely to be infected with S. dysenteriae 1 and were more severely ill, as evidenced by a significantly higher white blood cell count and lower serum sodium concentration than patients without evidence of obstruction.
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 fatal cases [14].
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 [15-17]. Signs that correlate with bacteremia are leukocytosis, hypothermia or temperature above 39.5°C, severe dehydration, and lethargy [18].
Bacteremia is more common among children younger than five years of age and adults older than 65 years than among older children or younger adults [15,18,19]. Among the 22 cases of bacteremia described among adults in the literature, one-third of patients were older than 65 years of age, and more than half had an underlying disease (most commonly diabetes) [20].
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 although the rate of Shigella bacteremia remained stable (approximately 0.2 per 1000 adults; 0.8 per 100 children) [19].
Bacteremia is associated with an increased risk of death [18]. 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, HIV-infected patients were substantially more likely to die than HIV-uninfected individuals (29 of 78 versus 5 of 40 fatal cases, respectively) [21].
Metabolic disturbances — Substantial volume depletion is uncommon in shigellosis because the stool volume is usually low. In a review of 412 patients with shigellosis, 36 percent had mild dehydration, 12 percent had moderate dehydration, and 2 percent had severe dehydration [2]. In another series, hyponatremia (defined as serum sodium below 120 mEq/L) was noted in 29 percent of patients hospitalized with diarrhea due to S. dysenteriae 1 [22]. Hyponatremia is generally due to the syndrome of inappropriate antidiuretic hormone secretion, not volume depletion [12,22].
Protein-losing enteropathy also may be observed. In one report that used the level of alpha-1 antitrypsin in stool as an indicator of protein excretion, protein loss was high during the acute phase in patients who had dysentery, remained high in patients who failed therapy, and fell to normal low values in those who were cured [23].
Increased catabolism secondary to fever, stool protein loss, decreased intake due to anorexia and malabsorption can exacerbate pre-existing malnutrition.
Leukemoid reaction — A leukemoid reaction (defined as a white blood count of 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 than one year of age) [24]. 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 [3].
Neurologic disease — 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) [25]. Seizures tend to be generalized and are not associated with specific neurologic deficits but have been associated with a higher risk of death [26,27]. 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 [12,26,27].
Analysis of cerebrospinal fluid obtained by lumbar puncture is typically normal, although up to 15 percent may have mild lymphocytic pleocytosis with up to 12 cells. The occurrence of seizures is associated with fever (often greater than 39°C [102.2°F]), increased proportion of immature leukocytes, low serum sodium, and high serum potassium. Seizures have been observed during infection with all serotypes of Shigella.
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 [28]. In a study of five children performed to determine whether seizures were associated with Shiga toxin, clinical specimens including stool, serum, and cell-free cerebrospinal fluid were examined in vitro for cytotoxic activity [29]. 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. 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.
Thus, although this study is too small to be conclusive, it did not demonstrate a relationship between Shiga toxin and seizures. Furthermore, the majority of patients who have seizures are infected with S. flexneri or S. sonnei, which do not express Shiga toxin. Taken together, these data suggest that other Shigella enterotoxins might contribute to the induction of seizures, although this possibility requires further study. The enterotoxin ShET1 has been identified in strains of S. flexneri 2a [30,31], and the enterotoxin ShET2 has been identified in members of all four serogroups [32], but the role of these or other as yet unidentified enterotoxins in Shigella-induced seizures is unknown.
In addition to seizures, other neurologic findings have been described in up to 40 percent of children hospitalized with Shigella infection, including encephalopathy with lethargy, confusion, and headache [33]. 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 [12]. 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 — Following S. flexneri infection, reactive arthritis is an uncommon complication that may be observed 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 [34]. (See "Reactive arthritis".)
The arthritis is a sterile inflammatory arthritis. Symptoms develop one to two weeks following symptoms of dysentery, regardless of whether or not the dysentery was treated with antibiotics. Approximately 70 percent of patients with arthritis are HLA-B27 positive [35]. A 5 amino acid peptide encoded on a 2 Md Shigella plasmid has been associated with reactive arthritis in two separate studies [36,37]. 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".)
There is one case report in which bacterial lipopolysaccharide antigen was detected in the synovial fluid of a patient with post-Shigella reactive arthritis; the significance of this finding is uncertain [38].
Sterile reactive arthritis has also been described following infection with Campylobacter jejuni, Salmonella enteritidis, Salmonella typhimurium, Yersinia enterocolitica, and Yersinia pseudotuberculosis [39].
Hemolytic-uremic syndrome — Although relatively uncommon, the hemolytic-uremic syndrome (HUS) is the most frequent cause of acute renal failure among infants and young children worldwide [40]. Ninety percent of cases of HUS in children follow a diarrheal prodrome; it is most often due to infection with Shiga-toxin producing Escherichia coli (STEC; particularly type O157:H7) but may also be induced by infection with S. dysenteriae 1 [6]. The other 10 percent of cases have a variety of etiologies, including drugs, malignancy, pregnancy, and collagen vascular disease. Thrombotic thrombocytopenic purpura is a related disorder with overlapping clinical findings that occurs more commonly in adults [41]. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
Patients present at the end of the first week and during the recovery phase of diarrheal or dysenteric symptoms with the combination of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (initially oliguric and then anuric). The patient may be considered to have thrombotic thrombocytopenic purpura if fever and transient neurologic symptoms are also present. Seizures occur in approximately 10 percent and stroke or cerebral edema in 5 percent.
The pathogenesis of HUS or TTP involves cytotoxic damage to the vascular endothelium. In most studies, Shiga-toxin production by S. dysenteriae 1 is thought to be directly involved. Additionally, strains of S. sonnei and S. flexneri that encode a Shiga toxin gene and produce Shiga toxin have been identified; at least so far, none of these strains were associated with HUS in the patients from whom they were isolated [42,43].
In the setting of infection due to STEC, antibiotic use may be associated with HUS [44,45]. In contrast, some 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. As an example, in a retrospective review of several studies including 128 adults and 250 children with S. dysenteriae 1 infection treated with antibiotics, only one child developed HUS [46]. This may be due to a difference in the genomes between S. dysenteriae 1 and STEC. 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 [47,48].
Other manifestations — In young girls, Shigella can cause vaginitis or vulvovaginitis with or without diarrhea [49]. The vaginal discharge is usually painless and may be bloody. Untreated Shigella vaginitis can persist for several months.
Shigella is a rare cause of keratitis and should be considered as the cause of keratitis or conjunctivitis in young children who have had a recent diarrheal illness or who have a recent exposure [50].
Acute myocarditis has been associated with acute S. sonnei gastroenteritis in two children [51].
DIAGNOSIS
Clinical suspicion — Shigella should be suspected in the setting of frequent, small volume, bloody stools, abdominal cramps, and tenesmus, particularly if accompanied by fever. Nausea and vomiting are notably absent in most patients [2].
The presence of white blood cells and red blood cells on direct microscopic examination of the stool is consistent with the diagnosis of Shigella, although most clinical microbiology laboratories no longer perform this assay. If available, these findings should raise suspicion of the diagnosis prior to the availability of microbiological testing results.
The differential diagnosis for this constellation of symptoms and signs includes infection with Salmonella, Campylobacter, Yersinia, enteroinvasive E. coli, or Clostridioides difficile, or noninfectious inflammatory bowel disease [1]. (See "Approach to the adult with acute diarrhea in resource-rich settings" and "Diagnostic approach to diarrhea in children in resource-rich countries".)
Organism identification
Stool culture — Stool culture is the preferred method for the diagnosis of Shigella, as it provides an isolate for subsequent susceptibility testing (see 'Susceptibility testing' below). Shigella is a fastidious organism; it requires prompt handling and optimally should be inoculated onto agar at the bedside or soon after collection. Culture from a stool sample may give a better yield than culture from a rectal swab [52]. The best yield is from a mucoid part of stool. If transport of the sample is required, the best medium is buffered glycerol saline (BGS) [53]. (See "Shigella infection: Epidemiology, microbiology, and pathogenesis", section on 'Stool culture'.)
Molecular testing — Many clinical microbiology laboratories are now using automated polymerase chain reaction (PCR) diagnostics on stool. These systems typically have the capability to identify any of multiple enteric bacterial pathogens from a homogenized stool sample in a few hours. However, they are not able to assess antimicrobial susceptibility of identified pathogens. If Shigella is identified on molecular testing of stool, a sample should also be submitted for culture and susceptibility testing. (See 'Susceptibility testing' below.)
Details on molecular testing for Shigella are found elsewhere. (See "Shigella infection: Epidemiology, microbiology, and pathogenesis", section on 'Molecular diagnostics'.)
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 children", section on 'Antibiotic resistance' and "Shigella infection: Treatment and prevention in adults", section on 'Antimicrobial 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 provided with the susceptibility testing results [54]. In the United States, an increasing proportion of isolates have an MIC to ciprofloxacin of 0.12 to 1 mcg/mL. Although MICs in this range are classified as susceptible, they are associated with resistance genes that confer reduced susceptibility to and lower response to therapy with fluoroquinolones in other Enterobacteriaceae. Patients who have infection with a Shigella isolate with a ciprofloxacin MIC in this range should be treated with another appropriate antibiotic whenever possible and, if treated with ciprofloxacin, should be followed closely to verify treatment success. (See "Shigella infection: Treatment and prevention in adults", section on 'Antibiotic selection'.)
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
●Shigella is a common cause of bacterial diarrhea. It is transmitted by direct person-to-person spread and, less commonly, through contaminated food and water. (See "Shigella infection: Epidemiology, microbiology, and pathogenesis".)
●The incubation period ranges from one to three days. Patients with Shigella gastroenteritis typically present with high fever, abdominal cramps, and bloody, mucoid diarrhea; tenesmus is common. Shigella gastroenteritis generally is self-limited, lasting no more than seven days in an untreated immunocompetent host. (See 'General features' above.)
●Intestinal complications of Shigella infection include proctitis, rectal prolapse, toxic megacolon, intestinal obstruction, and colonic perforation. (See 'Intestinal complications' above.)
●Systemic complications of Shigella infection include bacteremia, metabolic disturbances (hypovolemia, hyponatremia, protein-losing enteropathy), leukemoid reaction, neurologic disease (seizures, encephalopathy), reactive arthritis, and with Shigella dysenteriae 1 hemolytic uremic syndrome. (See 'Systemic complications' above.)
●Shigella should be suspected in patients with frequent, small volume, bloody stools, abdominal cramps, tenesmus, and fever, particularly if accompanied by fecal leukocytes. Definitive diagnosis is made by stool culture. Antimicrobial susceptibility testing should be performed on all isolates. If Shigella is identified by molecular testing, a stool sample should also be sent for culture and susceptibility testing. (See 'Diagnosis' above.)
●Treatment of Shigella is discussed separately. (See "Shigella infection: Treatment and prevention in adults" and "Shigella infection: Treatment and prevention in children".)
