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ShigellaInfections in Children: New Insights

Shai Ashkenazi, MD, MSc

Shigellosis, the acute enteric infection caused by bacteria of the genus Shigella, has a

worldwide distribution with an estimated annual incidence of 164.7 million cases, of which

163.2 million occur in developing countries, and 1.1 million deaths. Sixty-nine percent of all

episodes and 61 percent of all Shigella-related deaths involve children younger than 5

years old. In the United States, 10,000 to 15,000 cases of shigellosis are reported each

year. Although usually confined to the colonic mucosa, shigellosis sometimes can cause

extraintestinal complications. Recent publications have shed light on the clinical charac-

teristics ofShigella-induced bacteremia, surgical complications, urogenital symptoms, and

neurologic manifestations, and on the unique manifestations in the neonatal period. The

mainstay of treatment of shigellosis in children is correction of the fluid and electrolyte

loss, which often is achieved by the administration of oral rehydration solutions. Appro-

priate antibiotic therapy shortens the duration of both clinical symptoms and fecal excretion

of the pathogen. However, the increasing antimicrobial resistance of shigellae worldwide

constitutes a major problem. Regarding the pathophysiology of shigellosis and its compli-

cations, recent data not only elucidated the molecular mechanisms involved but also linked

manifestations of disease to the interplay of bacterial virulence factors and host responses.

The improved understanding of the pathophysiology is hoped to lead to innovative thera-

peutic approaches against shigellosis and new generations of vaccine candidates.

Semin Pediatr Infect Dis 15:246-252 2004 Elsevier Inc. All rights reserved.

Shigellais a genus of gram-negative bacilli that causes hu-man gastrointestinal infections, sometimes with extraint-estinal manifestations.

1

Four species (serogroups) are definedon the basis of serologic or biochemical reactions, namely,Shigella dysenteriae, serogroup A;Shigella flexneri, serogroupB;Shigella boydii, serogroup C; andShigella sonnei, serogroupD.1,2 Species classification has important therapeutic impli-cations because the species differ in both geographic distri-bution and antimicrobial susceptibility.1,3-5 In developedcountries, S. sonnei is the most common species; reports fromseveral locations show an increase in its relative prevalence inthe last several years.2,4,6-9 In developing countries,S. flexneriis most common, with outbreaks that often are caused by S.dysenteriae.1,2,9 The serogroups are further classified into atleast 37 serotypes and 13 subserotypes.1,2

To determine the global burden of Shigella infections,Kotloff and coworkers9 analyzed published reports from var-ious locations and then estimated the number of cases world-

wide according to the worlds population as categorized into

developed and developing countries and into age groups.9

They found that the annual number of Shigella episodesthroughout the world was 164.7 million, of which 163.2

million occurred in developing countries, with 1.1 million

deaths.9 Sixty-nine percent of episodes and 61 percent of all

shigellosis-related deaths involved children younger than 5

years of age. According to surveillance reports of the Centers

for Disease Control and Prevention, 10,000 to 15,000 cases

of shigellosis have been documented each year during the last

30 years in the United States, for annual incidence rates of 5

to 10 per 100,000.7 During this period, the relative preva-

lence ofS. sonnei, the most common species, has increased.7

This increase also was noted in other locations.4,6,8

Shigella infection spreads by the fecal-oral route. Becauseof the low infectious dose10 to 100 organismsperson-

to-person transmission probably is the most common.1,8

However, transmission by contaminated food, drinking wa-

ter, swimming pools, and flies also has been documented.2,10

The highest incidence of shigellosis is in young children,

usually those 1 to 5 years old.2-4,8,9 Recent studies have shed

new light on the pathophysiologic, clinical, therapeutic, and

preventive aspects ofShigellainfection in children. They are

discussed in detail below.

Department of Pediatrics A, Schneider Childrens Medical Center of Israel;

FMRC, Sackler Faculty of Medicine, TelAviv University, Tel Aviv, Israel.

Address reprint requests to: Shai Ashkenazi, MD, Professor of Pediatrics,

Director, Departmentof Pediatrics A, Schneider ChildrensMedical Cen-

ter of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel. E-mail:

[email protected].

246 1045-1870/04/$-see frontmatter 2004 Elsevier Inc. All rights reserved.doi:10.1053/j.spid.2004.07.005


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Pathophysiology

A key element in the pathogenesis of shigellosis is the ability

of the bacteria to invade colonic mucosa. The invasion pro-

cess depends on a 210- to 220-Kb plasmid, which is neces-

sary, but not sufficient, for full virulence.2,10,11 New data not

only have elucidated the molecular mechanisms involved but

also have revealed that manifestations of disease depend onthe interplay of bacterial virulence factors and host re-

sponses, which results in inflammation.12,13 In addition, new

insights have been reported on the cellular and molecular

effectors of the innate immune system that eradicate the bac-

teria during primary infection and prevent systemic dissem-

ination, sometimes at the price of local tissue destruction in

the colon.11,14-16

ShigellaDeterminants

of PathogenicityVirulence Plasmid

Sequencing the virulence plasmid of theS. flexneri5a strain

M90T has allowed investigators to identify the genes encod-

ing approximately 25 proteins secreted by the type III secre-

tion system.16 This secretion system, like that in some other

gram-negative bacteria, translocates the Shigella effector mol-

ecules from the bacterial cytoplasm to the membrane and

cytoplasm of the host cell.17A 31-kb segment of the virulence

plasmid, called the entry region or ipa/mxi-spa locus, com-

prises the pathogenicity island, which actually is sufficientfor

entry ofShigellainto intestinal epithelial cells, for apoptotic

death of macrophages, and for activation of polymorphonu-

clear leukocytes.18,19 The island is organized into two diver-

gently transcribed operons.15,18

One of the regions of the virulence plasma that is most

extensively studied is the invasive plasmid antigen (ipa) re-

gion.11,18 It contains four genes, ipaA to ipaD, that encode

four proteins, IpaA to IpaD, necessary for invasion.11,16,20

After the shigellae contact the host cells, IpaB and IpaC are

inserted as a single complex into the host membrane to form

a 25A pore, through which the other invasive proteins are

transported.21 IpaB is essential for inducing apoptosis in mac-

rophages;13

IpaB combined with IpaC, together with cyto-plasmic chaperon IpgC, are required for lysis of the cell mem-

brane, which is needed for cell-to-cell spread.22

The icsA (virG), virK, and sopA (icsP) genes play a role in

the ability of shigellae to move within the cytoplasm of in-

fected cells and to spread to other cells.23 They encode, re-

spectively, the outer membrane protein directly involved in

intracellular spread,24 the protein required for proper local-

ization of icsA,25 and the outer membrane protease that

causes cleavage of icsA.26 The virF gene regulates the virB

locus, which is required for positive regulation of the ipa

genes. The inv region is required for orientation of the Ipa

proteins into the outer membrane of the bacteria.11,27

Thefunction of the 5-copy ipaH gene has not been clarified yet.

Chromosomal GenesSeveral chromosomal loci participate in the pathogenic pro-cess by complementing the core virulence of the invasionplasmid genes and are, therefore, needed for full virulence.They can be categorized into two groups:

1. Genes regulating the expression of the plasmid viru-

lence genes. The virR gene encodes a histone-like mol-ecule controlling the temperature-dependent expres-sion of the Ipa and Mxi-Spa proteins, and thekeratoconjunctivitis provocation (kcpA) gene posi-tively regulates virG.11,28

2. Genes needed for bacterial survival in the intestine andfor resisting host defense mechanisms, such as thoseencoding lipopolysaccharides (LPS) and siderophores.Shigellae lacking complete LPS (rough colonies) areavirulent.2

ShigellaToxins

Shiga toxin, encoded chromosomally and found mainly inS.dysenteriaeserotype 1, is a potent protein-synthesis inhibitorthat targets primarily the vascular endothelium.29,30 Thistoxin mediates the severe complication of hemolytic-uremicsyndrome.29,31 A similar syndrome may be seen after infec-tions with enterohemorrhagic Escherichia coli, which produceclosely related toxins.30,31 In addition, Shiga toxin might playa role in the increased duration and severity of the diarrheacaused byS. dysenteriaeserotype 1.2,32

Shigella spp. also produce two enterotoxins, ShET-1 andShET-2.33 ShET-1 is produced mainly byS. flexneriserotype2a, whereas ShET-2 is produced by all Shigellaspp.33 These

enterotoxins may contribute to the high-volume, watery di-arrhea often seen in the initial stages of the disease.

Host Responsesto Shigella Infection

Interactions of shigellae with host cells trigger inflammatoryresponses that lead to the histopathological changes that oc-cur in the gut and the clinical presentation of shigellosis.12,15

Cytokine and chemokine responses have been shown by im-munohistochemistry studies of rectal samples both in thesera and locally.12,34 Although host responses cause the in-

flammation, they also are mandatory for controlling the in-fection.16 In a murine model, natural killer cell-mediatedinterferon-gamma production was found to be essential forhost resistance to shigellosis.14 Because the responses of thevarious host cells toShigellainfection are somewhat distinct,they are discussed briefly below.

Shigella and Intestinal Epithelial CellsShigellaecross the colonic epithelium through M cells in thefollicle-associated epithelium overlying the Peyer patches.2,15

At the dome area of the lymphoid follicle, the bacteria arephagocytized by macrophages, which are killed by apopto-

sis.13,35

With this strategy, shigellae reach the subepithelialtissue and invade the colonic epithelial cells through their

Shigella infections in children 247


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basolateral surface.11 During the initial step of the entry pro-cess, shigellae induce actin polymerization in the epithelialcells with the formation of filopodes.36 The process involvesactivation of the Rho family of GRPases.36,37 After entry, thebacteria disrupt their membrane-bound vacuole, proliferatein the cytoplasm, and use the actin-based motility, which isdependent on the IcsA (virG) protein.11,38 This process en-

ables their spread to neighboring cells by the formation offinger-like protrusions.15 In addition, intracellular shigellaeprogram the colonic epithelial cells to express pro-inflamma-tory cytokines, such as interleukin (IL)-6 and IL-8, augment-ing the local inflammation.12,39,40

Shigella and MacrophagesAfter crossing the colonic epithelium through the M cells,shigellae are taken up by local macrophages. They later es-cape from the phagosome and within 2 hours induce apopto-sis of the macrophages and an inflammatory reaction. 13,35,40

IpaB protein mediates the apoptosis by binding to caspase-1

or IL-1--converting enzyme, which cleaves the proinflam-matory cytokines IL-1- and IL-18 into their matureform.13,41 This inflammatory response has been shown to beimportant for eradicating the infection.15

Shigellaand LeukocytesThe massive recruitment of polymorphonuclear leukocytes ismediated mainly by postinvasion intracellular Shigella LPSvia transcription factors.15 The Shigella LPS also induce thetrafficking of toll-like receptor 4 (TLR4), the dominant me-diator of the innate immune response.16,42 The leukocytetransmigration disrupts the intestinal epithelium.15Although

this disruption initially contributes to virulence by aidingbacterial invasion, it actually limits the infection to the mu-cosa and submucosa and ultimately eradicates it because thebacteria are killed by polymorphonuclear leukocytes. Thisprocess has been well demonstrated in the severe combinedimmunodeficiency deficient mouse-human intestinal xeno-graft model.43

Clinical Features

Symptoms appear abruptly after an incubation period of 12hours to approximately 2 days and include high fever, gen-

eralized toxicity, anorexia, nausea, crampy abdominal pain,and diarrhea.1,3,10 Typically, the diarrhea initially consists ofhigh-volume watery stools (small bowel disease), which maybe followed by frequent, small-volume, bloody, mucousstools associated with urgency and painful defecation (largebowel disease).1,10 In children, most cases (50%) neverprogress to bloody stools, although in some patients, theinitial stools are bloody.1,3,10

Extraintestinal Complications of ShigellosisShigellaBacteremia

Although usually confined to the colonic mucosa, shigellosis

sometimes can cause extraintestinal complications. Bactere-mia or septicemia rarely occurs during shigellosis and has

been reported mainly in developing countries.2,44 For exam-

ple, according to one study from Bangladesh, 4 percent of

patients with shigellosis had Shigella bacteremia.44 Bactere-

mia occurred more frequently in malnourished young infants

and in patients infected withS. dysenteriaeserotype 1, and it

was associated with a significant mortality rate. A recent

study from southern Israel described 15 children with Shi-

gella bacteremia.45 Mean age was 20 months; 13 patients

(87%) failed to gain weight. Most (87%) of the isolates were

S. flexneri, and none wasS. dysenteriaeserotype 1. No deaths

were reported.45 Of note is that in patients with acquired

immunodeficiency syndrome (AIDS),46 shigellosis is not only

more common and more severe, but it also more often is

associated with bacteremia.47,48

Surgical Complications

Miron and coworkers49 reviewed reports published during a

40-year period of 57 children with surgical complications of

shigellosis. The complications were categorized into fourgroups: appendicitis with or without perforation (n 16,

28%); colonic perforation (n 10, 17%); intestinal obstruc-

tion (n 30, 53%); and intraabdominal abscesses (n 1,

2%).49 Thirteen children (23%) died, often despite having

received antimicrobial therapy. Many of the reports were

from developed countries.49

Pediatricians should be alerted to the risk of surgical com-

plications of shigellosis, despite their rarity, because of the

significant morbidity and mortality associated with a delayed

diagnosis. Establishing a diagnosis often is hampered by the

overlap of the signs and symptoms of shigellosis with those of

peritonitis.49 Some authors recommend avoiding laparotomyin the acute phase, even if signs of peritonitis are present,

unless the patient has evidence of perforation.49 Nonetheless,

the pediatric surgeon should be consulted as soon as perito-

nitis is suspected.

Neurologic Manifestations

The neurologic manifestations of shigellosis usually are asso-

ciated with a favorable outcome, although a study from Ban-

gladesh noted a 29 percent mortality rate in affected children

compared with 6 percent in those without neurologic symp-

toms.50

Seizures are the most common neurologic manifes-tation, followed by lethargy and disorientation or coma,

which often are referred to as encephalopathy.1,50,51 In the

minority of patients, the encephalopathy may be severe, un-

responsive to antibiotic therapy, and fatal, even in developed

countries.52 The pathogenesis has not been elucidated. In

developed countries, where hypoglycemia and electrolyte ab-

normalities do not play a significant pathogenic role, hypo-

natremia and early development of brain edema have been

reported.50,51,53 Complementary studies in a murine model

documented the early development of brain edema and the

major pathogenetic role of host response factors, such as

tumor necrosis factor alpha, IL-1, and nitric oxide produc-tion.54-56

248 S. Ashkenazi


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Urogenital SystemAlthough rare occurrences, vulvovaginitis and urinary tractinfections caused by Shigella spp. are well-documented.2,57

Recent publications from developed countries highlight theproblems in establishing the diagnosis and treating this in-fection.57,58 One case report from the United States describeda prepubertal child with chronic vulvovaginitis caused by S.

flexneri.58 Vaginal discharge and bleeding were the present-ing symptoms. Nonspecific vulvovaginitis and hemorrhagiccystitis initially were suspected, delaying the diagnosis. Fur-thermore, several empiric antimicrobial courses failed be-cause of the antimicrobial resistance of the pathogen. Finally,after 3 years, 14-day treatment with ciprofloxacin led to res-olution of the vaginal discharge. In another study, resistant S.sonnei caused a urinary tract infection that was cured onlyafter treatment with a third-generation cephalosporin.57

Thus, because of the rarity of their infections, their diagnosesoften are delayed, and because of the antibiotic resistance ofShigellae, empiric therapy often fails.57,58

Neonatal ShigellosisA recent publication emphasized the unique problem of shig-ellosis in the neonatal period.59 Newborn infections accountfor only 0.6 percent of all cases of shigellosis in the 0- to10-year age group. Only 1.6 percent of all infants exposed tothe infection become ill.2,4,59 This finding is explained by thepresence of maternal protective factors that pass through theplacenta or are transferred during breastfeeding.2,60

Neonates with shigellosis may have only low-grade feverwith mild diarrhea, often not bloody. Complications, how-ever, occur more commonly than in older children and in-

clude septicemia, meningitis, dehydration, colonic perfora-tion, and toxic megacolon.59 The mortality rate also is twiceas high as in older children, reaching 30 to 40 percent indeveloping countries, although less than 1 percent in devel-oped regions.59 On logistic regression analysis, predictorsof infant mortality in developing countries were gram-negative bacteremia, hyponatremia, hypoproteinemia, andileus.59

Diagnosis

Stool culture to isolate the pathogen is still the cornerstone of

diagnosis.2 This technique, however, has certain limitations:it takes a few days, the organisms may not survive transpor-tation, sensitivity is not higher than 80 percent, and the cul-ture may become negative in children given previous antibi-otic therapy.2

Additional diagnostic techniques show promise, but theyhave not been incorporated into practice yet. One large study(n 300) reported that improved direct polymerase chainreaction of stool specimens increased diagnosis by 50 percentcompared with culture.61 Other authors successfully identi-fied shigellae by microarrays using the gyrB genes.62 Thisnovel approach also renders it possible to identify simulta-

neously other enteric pathogens, such asSalmonellaspp. anddiarrheogenicEscherichia coli.62 Immune assay with mono-

clonal antibodies to the IpaC protein detected bothShigella spp. and enteroinvasive E. coli in 165 stool speci-mens, with high sensitivity and specificity.63

Treatment

Fluids and NutritionThe mainstay of treatment of shigellosis in children is correc-tion of the fluid and electrolyte loss, which often can beachieved by administering oral rehydration solutions.2,64

Early feeding, even with a high-protein diet, is important,especially in developing countries, to prevent malnutritionand encourage optimal growth.65

Antimicrobial TherapyAppropriate antimicrobial therapy of shigellosis shortens theduration of fever and diarrhea, and it apparently also reducesthe risk of developing complications.10 Concomitantly, theduration of excretion of the pathogen in stools is shortenedsignificantly, thereby reducing the spread of infection.10,66

However, the increasing antimicrobial resistance of shigellaeconstitutes a major problem.10Although initially susceptible,mostShigellaisolates currently are resistant to ampicillin andtrimethoprim-sulfamethoxazole (TPM-SMX). These antimi-crobial agents often are recommended for the treatment ofshigellosis,5 but they currently are inappropriate for empirictherapy unless local microbiologic data suggest susceptibil-ity. Table 167-76 shows the percent of resistance by geographiclocation. One should note that these values are based on allShigella isolates; S. sonnei, which is the most prevalent speciesin developed countries and relatively more common in chil-

dren,6 tends to be more resistant than is S. flexneri.5 Forexample, in Israel, between 1998 and 2000, 97 percent ofS.sonnei were resistantto TMP-SMX, compared with 69 percentofS. flexneri(P 0.0001).5

QuinolonesAlthough nalidixic acid proved to be efficacious against shig-ellosis in one pediatric clinical study, other studies fromBangladesh, Hong Kong, and Taiwan reported high resis-tance to this agent (Table 1).69,70,73 Rates of resistance in mostdeveloped countries are below 2 percent (Table 1).5,67,74 Thenew fluoroquinolones appear to have a high clinical and mi-

crobiological efficacy against shigellosis and frequently areused in adults with suspectedShigellainfections.10,66,69 Theyare not approved for children younger than 18 years of agebecause of a risk of drug-induced damage to the immature

joints.66 Some authors question this policy, owing to theproven effectiveness of quinolones in children77,78 and theapparent safety of a short course.10 Reduced susceptibility ofShigella spp., especially S. dysenteriaeserotype 1, to fluoro-quinolones has been reported and may be mediated by aproton motive force (pmf)-dependent efflux system.79,80

Cephalosporins

First- and second-generation cephalosporins, such as cepha-lexin, cefamandole, and cefaclor, are ineffective against shig-



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ellosis, often despite the susceptibility of the pathogen invitro.10 Their main limitation is the delayed fecal eradicationof shigellae. Third-generation cephalosporins hold promise.

Among this group, ceftriaxone has been the one investigatedmost extensively. Response was excellent, with two doses ofceftriaxone being as effective as five.10,81 Cefixime was effec-tive in children infected mostly withS. sonnei, but it was lesseffective in adults with severe shigellosis caused mostly by S.dysenteriaeandS. flexneri.10,82 Resistance to third-generationcephalosporins, mediated by extended-spectrum beta-lacta-mases, has been reported in several locations.10,83

AzithromycinAzithromycin, an azalide with a broad spectrum of antimi-crobial activity, was found to be efficacious in adults withshigellosis.69 In a comparison of azithromycin and cefiximein a controlled study of 75 children with culture-proven shig-ellosis in Paraguay,84 researchers noted a similar clinical effi-cacy for the two drugs but a better bacteriologic efficacy ofazithromycin (P 0.01), perhaps due to its better penetra-tion into cells.84

In summary, two parenteral doses of ceftriaxone is sug-gested as the treatment of choice for severe shigellosis inchildren, especially hospitalized patients. Oral treatment ofmilder cases is more problematic and depends on local resis-

tance patterns. One should remember that many of theagents discussed here are not approved yet by the Food andDrug Administration for the treatment of shigellosis.

Prevention

Clean running water, appropriate sanitation, control of flies,good personal hygiene, and breastfeeding are the main mea-sures to reduce the spread of shigellosis.2 Despite continuingefforts for the last 50 years, researchers so far have failed toproduce a vaccine against Shigella spp. Several strategies todevelop a Shigella vaccine are being studied. The current

status of vaccine development is addressed elsewhere in thisvolume with the other enteric vaccines (Nataro).

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Table 1 Antimicrobial Resistance ofShigellaIsolates in Various Geographic Locations According to Selected Publications from

1992 to 2003

Country

Years Isolates

Obtained

% Resistant to: Nalidixic

Acid RefAMP TMP-SMX

Israel 1998-2000 85 94 2 5

USA 1995-1998 63 59 0.3 67

USA 2001 80 47 2 68Bangladesh - 73 80 51 69

Hong Kong 1994-1995 72 76 32 70

Greece 1996-1998 46 29 - 71

Brazil 1988-1993 90 84 8 72

Taiwan 1982-1987 52 10 25 73

Canada 1990 52 34 0 74

Saudi Arabia 1985-1990 54 72 - 75

Thailand 1990 90 81 - 76

* AMP, ampicillin; TMP-SM, trimethoprim-sulfamethoxazol

250 S. Ashkenazi


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