Seminar

Shigellosis
Karen L Kotloff, Mark S Riddle, James A Platts-Mills, Patricia Pavlinac, Anita K M Zaidi

Shigellosis is a clinical syndrome caused by invasion of the epithelium lining the terminal ileum, colon, and rectum by Published Online
Shigella species. Although infections occur globally, and in people of all ages, endemic infections among children aged December 15, 2017
http://dx.doi.org/10.1016/
1–4 years living in low-income and middle-income settings constitute most of the disease burden. The versatile S0140-6736(17)33296-8
manifestations of these highly contagious organisms range from acute watery diarrhoea to fulminant dysentery
Departments of Pediatrics and
characterised by frequent scant bloody stools with fever, prostration, and abdominal cramps. A broad array of uncommon, Medicine, Center for Vaccine
but often severe, intestinal and extraintestinal complications can occur. Despite marked reductions in mortality during Development, Institute for
the past three decades, there are roughly 164 000 annual deaths attributable to shigellosis. Intercontinental dissemination Global Health, University of
Maryland School of Medicine,
of multiresistant shigella strains, facilitated by travellers and men who have sex with men, has prompted new
Baltimore, MD, USA
recommendations for antibiotic therapy. Awareness of disease burden and the emerging threats posed by shigella have (Prof K L Kotloff MD); Naval
accelerated interest in development of shigella vaccines, many of which are being tested in clinical trials. Medical Research Center, Silver
Spring, MD, USA; Department
of Preventive Medicine and
Introduction lineage.6 S sonnei dominance in a population correlates Biostatistics, Uniformed
In 1892, the eminent physician Sir William Osler with economic development,4,7 for which several Services University of the
described dysentery as “one of the four great epidemic mechanisms have been proposed.8 One such mechanism Health Sciences, Bethesda, MD,
diseases of the world”. He further stated “In the tropics it is that people living in low-resource settings are naturally USA (Prof M S Riddle); Division
of Infectious Diseases and
destroys more life than cholera, and it has been more fatal immunised against S sonnei by exposure to faecally International Health, University
to armies than powder and shot.”1 Five years later, the contaminated surface water that contains Pleisiomonas of Virginia, Charlottesville, VA,
microbiologist Kiyoshi Shiga identified the cause of shigelloides O17,9 which has an O antigen virtually identical USA (J A Platts-Mills MD);
dysentery during an epidemic in Japan associated with to that of S sonnei.10 Second, the ubiquitous, free-living Department of Global Health,
Global Center for Integrated
high mortality.2 This bacterium, termed the Shiga bacillus, amoeba Acanthamoebae castellanii phagocytoses S sonnei Health of Women, Adolescents
is now classified taxonomically as shigella, a facultatively in nature, which provides an intracellular environment and Children (Global WACh),
anaerobic, non-motile Gram-negative rod, belonging to protected from chlorination and other sanitation University of Washington,
the family Enterobacteriacae. Shigella is an antigenically processes. S flexneri is lethal for A castellanii and cannot Seattle, WA, USA
(P Pavlinac PhD); and Enteric and
diverse pathogen that comprises four species (also called enjoy the same protective niche.11 Finally, S sonnei is more Diarrheal Diseases Programme,
groups or subgroups). Each species is subdivided into adept than S flexneri at acquiring antimicrobial resistance Bill & Melinda Gates
serotypes and subserotypes, distinguished by components from mobile genetic elements of other bacteria, thus Foundation, Seattle, WA, USA
(Prof A K M Zaidi SM)
of the lipopolysaccharide O antigen repeats. In addition imparting a selective survival advantage.8
to Shiga bacillus, now known as serotype 1 of Shigella S dysenteriae type 1 is notorious for emerging in Correspondence to:
Dr Karen L Kotloff, Departments
dysenteriae, there are 14 well established types of populations experiencing upheaval to produce explosive of Pediatrics and Medicine,
S dysenteriae, 15 of Shigella flexneri, and 19 of Shigella boydii, epidemics and pandemics with high case fatality in all Center for Vaccine Development,
but only one serotype of Shigella sonnei. age groups.12 Four S dysenteriae type 1 pandemics have Institute for Global Health,
erupted in the past 40 years, in central America (1968–72), University of Maryland School of
Medicine, Baltimore, MD 21201,
Factors that influence epidemiology south Asia (1980s), central Africa (1980s), and east Africa USA
Shigella species (1990s). Genomic analyses suggest that the pandemic kkotloff@medicine.
The epidemiology of shigella varies by offending species clone emerged in the 20th century and disseminated in umaryland.edu
(panel 1). S flexneri is the leading cause of endemic conjunction with the population movements, crowding,
shigellosis in low-income and middle-income countries,
causing nearly two-thirds of infections.3 S sonnei is the
second most common Shigella species in low-income Search strategy and selection criteria
and middle-income countries (causing around 25% of We searched Embase, PubMed, and Cochrane databases for
episodes), and is the leading species in high-income articles published between Jan 1, 2006, and Dec 31, 2016,
countries.4 The remaining isolates are either S dysenteriae with the terms “Shigella”, “dysentery”, and “bacillary
or S boydii. dysentery”, cross-referenced with the terms “microbiology”,
Whole-genome sequencing paired with phylogenomics “epidemiology”, “serogroup”, “serotype”, “seasonality”,
has provided a new framework for understanding the “pandemics”, “mortality”, “immunity”, “pathogenesis”,
evolution and epidemiology of shigella and has high­ “clinical manifestations”, “transmission”, “complications”,
lighted the distinct niches occupied by each species. “arthritis”, “elderly”, “diagnosis”, “antibiotic susceptibility”,
S flexneri has colonised endemic regions for long periods “antimicrobial therapy”, and “probiotics”. If there were fewer
with little global spread and multiple independent than 50 citations, the date limit was removed. We also
antimicrobial resistance acquisitions during the past referred to work in our personal collections of original
30 years.5 By contrast, S sonnei emerged from Europe in research papers and reviews from the period 1965–2017.
the late 1900s and disseminated intercontinentally via Only articles published in English were included.
travellers, driven mostly by a single multidrug-resistant

www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8 1

 Seminar
Panel 1: Key epidemiological features of shigella infection
Shigella species
• Shigella flexneri: the leading cause of endemic diarrhoea in
low-income and middle-income countries
• Shigella sonnei: the leading cause of endemic diarrhoea in
high-income countries
• Shigella dysenteriae: serotype 1 causes pandemics
precipitated by natural disaster and social disruption and
associated with high attack rates of severe disease in all
age groups; the remaining serotypes are uncommon
• Shigella boydii: relatively uncommon
Risk groups
• Children aged 1–4 years living in resource-restricted settings
• Travellers to endemic areas
• MSM
• Children in daycare and their household contacts
Incubation period
• 1–4 days, up to 8 days with S dysenteriae type 1
Transmission
• Primarily person-to-person because of the low infectious
inoculum
• Food and waterborne, or can initiate outbreaks that are
propagated by person-to-person spread
• Flies can disseminate in settings with faecal
contamination of the environment
Public health threats
• Intercontinental spread of antimicrobial resistant strains
facilitated by travellers and MSM
• Spread of genes encoding Shiga toxin production by
promiscuous mobile genetic elements, with the potential
to increase disease severity
MSM=men who have sex with men.
and poor hygienic conditions that accompanied the two
world wars.13 Given the circa 10-year periodicity of Shiga
epidemics, their inexplicable absence since the late 1990s
(with the exception of occurrences of ciprofloxacin-
resistant strains that produced one outbreak in India and
several sporadic cases in Bangladesh and Nepal14) should
be viewed with guarded optimism.
Reservoirs and transmission
Humans are the only natural host for shigella. As few
as ten S dysenteriae type 1 and 180 S flexneri or S sonnei
colony-forming units produced symptomatic infection
in volunteers.15 The low infectious inoculum facilitates
person-to-person spread by faecal–oral contact, which is
the predominant mode of transmission. Inadequate
sanitation and hygiene favour transmission. In the USA,
shigella outbreaks are commonly linked to young
children attending child-care facilities or schools.16 Day-
care centres can be reservoirs for spread of shigella to
2 www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8
the community, where secondary attack rates within
households can reach 33%.17
Food and water are less common sources of transmission
of shigella.18 Globally, foodborne shigella is estimated to
cause 1–3 million disability-adjusted life-years.19 These
outbreaks can disseminate rapidly, sometimes initiated by
a food or waterborne locus, and then propagated by
person-to-person contact.20
The importance of houseflies as a mechanical vector
for transmission in settings where disposal of human
faeces is inadequate is underappreciated.21 Fly control in
these settings can have a substantial impact on the
incidence of shigellosis.22
Spread of multiresistant shigella strains
Historically, shigella develops resistance to new
antibiotics within a decade of their release. High
frequencies of resistance to previous first-line drugs23,24
have made ciprofloxacin, azithromycin, and ceftriaxone
the drugs of choice for empirical therapy, but resistance
is now emerging to these newer drugs. A single clade
of S sonnei widespread in south Asia appears to be
driving the international dissemination of ciprofloxacin-
resistant organisms,25 causing importations and
establishing transmission in locations with low
endemicity, including Australia, Europe, and the USA.26
Azithromycin resistance surfaced more than a decade
ago27 and is spreading globally, particularly among men
who have sex with men (MSM) and HIV-positive
populations.28 Increasing resistance to third-generation
cephalosporins in Asia could leave few options for
effective therapy.29 Accordingly, the Centers for Disease
Control and Prevention (CDC)30 and WHO31 have
declared antibiotic-resistant shigella a serious threat
that requires new interventions.
Populations at risk
Endemic disease in children
Most shigellosis results from endemic disease among
children aged 1–4 years living in low-income and middle-
income countries. The Global Enteric Multicenter
Study32 (GEMS) of the cause of acute, medically attended
moderate-to-severe diarrhoeal disease among children
younger than 5 years living in sub-Saharan Africa and
south Asia found shigella (identified by culture) to be the
second most common aetiological agent among children
aged 12–23 months, and the most common aetiology in
children aged 24–59 months. Upon reanalysis of GEMS
samples with quantitative PCR, the attributable
incidence of shigella more than doubled.33 Shigella
was the major pathogen associated with dysentery
(attributable fraction 63·8%), but also the second most
common pathogen associated with watery diarrhoea
(attributable fraction 12·9%).33 These findings created a
new awareness that the burden of shigellosis as defined
by culture-based diagnostics probably represents an
underestimation.

Shigella among MSM
A unique epidemiological niche for shigella emerged
in the 1970s as a sexually transmitted infection among
MSM. In 2009, an outbreak of an unusual serotype
(S flexneri 3a) appeared in England and Wales among
MSM and disseminated intercontinentally within the
MSM population to regions considered low risk for
shigellosis.28 Behaviours such as unprotected sex, oro-anal
contact, multiple sexual partners, and encounters arranged
through networking applications facilitate the intense,
circumscribed nature of the epidemic.34 Concomitant HIV
infection might modulate transmission by causing
persistent or relapsing infection, or even re-infection with
the same serotype, because of altered immunity, resulting
in recirculation of the S flexneri 3a strain within the MSM
population.28 Although this strain was multidrug-resistant
before introduction into MSM, sublineages acquired
additional plasmid-mediated resistance to azithromycin
and ciprofloxacin, possibly from selective pressure exerted
by treatment of sexually transmitted co-infections.35
On the heels of multidrug-resistant S flexneri 3a, distinct
multidrug-resistant S sonnei and S flexneri 2a strains
emerged among MSM. These strains included clusters of
ciprofloxacin-resistant S sonnei in Australia,36 azithromycin-
resistant S flexneri in the USA,37 and azithromycin-resistant
S sonnei strains producing extended-spectrum β-lactamase
in the UK.38 Clinicians caring for MSM with diarrhoea or
dysentery must remain alert to the possibility of multidrug-
resistant shigellosis, its association with HIV, and the
impact of HIV co-infection on severity and infectivity of
shigellosis when formulating clinical management plans
and discussing control measures.
Shigella in travellers
Around 536 million people travel to low-income and
middle-income countries annually and 10–40% acquire
diarrhoea.39 Based largely on faecal cultures, an estimated
2–9% of travellers’ diarrhoea is due to shigella.39
Consequences of shigellosis during travel can include
introduction of antimicrobial-resistant shigella into new
populations,26 incapacitation of shigella victims,40 risk of
prolonged debilitation from post-infection complications,
such as reactive arthritis41 and irritable bowel syndrome,42
and the potential for outbreaks in tourist groups and
military deployment settings.
Global burden of disease
Morbidity
In 2010, around 188 million cases of shigellosis
occurred globally, including 62·3 million cases in
children younger than 5 years. In low-income and
middle-income settings, 2·0–7·0 cases of shigella per
100 child-years require clinical care, with the highest
risk among children aged 12–23 months.33 Incidence
rates in high-income countries are much lower, at
around 0·01 per 100 person-years among all ages and
0·02 per 100 person-years among children.43
www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8 3
Seminar
Mortality
Globally, shigella is the second-leading cause of
diarrhoeal deaths after rotavirus, responsible for roughly
164 300 annual deaths worldwide (12·5% of all diarrhoeal
deaths), 54 900 of which are among children younger than
5 years.44 Most deaths occur in south Asia and sub-Saharan
Africa. Although the number of cases has not diminished
substantially,45 these mortality estimates represent
substantial reductions compared with previous decades,
which is probably due to reductions in malnutrition,
dwindling measles incidence, increased access to oral
rehydration therapy, antibiotics, and micronutrients, and
the virtual disappearance of pandemic S dysenteriae type 1.
Pathogenesis
The molecular basis of shigella pathogenesis has been
reviewed elsewhere.46,47 After oral ingestion, shigella
survives the acidic environment of the stomach and the
competitive intestinal microbiota to reach the terminal
ileum, colon, and rectum, where it penetrates the
mucous layer. Processes that enable shigella to overcome
these barriers include proton consumption systems,
resistance to locally-produced antimicrobial peptides,
and production of mucinases.47
Shigella uses a range of bacterial effector proteins to
invade (eg, IpaA-D), replicate, and disseminate throughout
the intestinal epithelium (eg, VirG/IcsA). These effectors,
and the needle-like type III secretion system through
which they are injected into the host cell cytosol, are
encoded by a virulence plasmid common to all shigella
species. To initiate infection, shigella translocates through
M cells that overlie mucosal lymphoid nodules and is
engulfed by macrophages. After inducing macrophage
death and invading neighbouring epithelial cells, shigella
replicates and disseminates within the mucosa by
inducing cytoskeletal rearrangements. The ensuing host
innate immune response results in massive recruitment
of neutrophils and outpouring of inflammatory cytokines,
which ultimately clears the infection although at the cost
of epithelial abscesses, ulcerations, and destruction, and
enhanced shigella invasion via a disrupted epithelial
barrier. The molecular mechanisms underlying shigella
invasiveness have been reviewed in detail elsewhere.46
The ability of shigella to survive intracellularly and
evade phagocytic killing depends on effectors that
dampen inflammatory responses by inhibiting host cell
pro-inflammatory signalling pathways and cytokine
production, and modulation of B-cell and T-cell activities.
These mechanisms and other processes (eg, serotype
diversity) ultimately interfere with development of long-
term, broadly effective protection, as reviewed in detail
elsewhere.46,48
Enterotoxins are probable mediators of the watery
diarrhoea often seen during the early stages—or as the
sole manifestation—of shigellosis. Several enterotoxins
have been identified, including shigella enterotoxin 1,
which is found almost exclusively in S flexneri 2a,
 Seminar
and shigella enterotoxin 1/OspD3, which is found in
most serotypes.49 Shigella induces secretory diarrhoea in
the jejunum to facilitate transit to the invasion locus
in the colon. Watery diarrhoea could also result from the
inflammatory response in the colon.50
Historically, S dysenteriae type 1 was considered the
sole serotype to produce Shiga toxin, a potent
chromosomally-encoded cytotoxin that increases disease
severity. Haemolytic uraemic syndrome is attributed to
the prothrombotic effects of circulating Shiga toxin,
which binds to microvascular endothelial cells, resulting
in microangiopathic haemolysis, azotaemia, and neuro­
logical abnormalities. Clinical isolates of non-S dysenteriae
species have acquired Stx genes from horizontal transfer
of mobile genetic elements. Many shigella isolates were
linked to travel to Hispaniola and expressed Stx1
(virtually identical to shiga toxin of S dysenteriae type 1).51
Additional outbreaks that primarily resulted from
domestic transmission were reported in California
during 2014–15.52 Shigella acquisition of the putatively
more virulent Stx2 is rare.53 It is uncertain whether
Shiga toxin-producing strains are more virulent,
although the proportion of patients reporting bloody
diarrhoea during the California clusters (71%) was
higher than expected.
Immunity and vaccine development
Serotype-specific versus heterotypic immunity
In natural54 and experimental55 settings, findings that
an initial wild-type shigella infection prevented illness
following subsequent exposure provide a compelling
argument that vaccination is a feasible strategy for
shigellosis prevention. Protection in efficacy field
trials with early live oral non-invasive and parenteral
O-polysaccharide conjugate shigella vaccines offers
promise.56,57 In these instances, protection was serotype-
specific. Approaches that have conferred clinical
protection have reduced,55 but not prevented, intestinal
colonisation.56
An essential question facing vaccine developers is
whether heterotypic protection can be elicited across
shigella serotypes or species to simplify vaccine
construction. Cross-serotype protection is most relevant
for S flexneri because of its importance in endemic
paediatric diarrhoea. Observations of cross-protection
or cross-reactivity in animal models based on shared
type and group specific antigens between S flexneri 2a
and 3a and other S flexneri (except serotype 6) suggests
that serotypes 2a, 3a, and 6 could confer immunity to
all 15 S flexneri serotypes and subserotypes.58 These
observations might translate to humans.
The search for cross-species immunity has focused on
shared plasmid-encoded outer membrane proteins.
Although wild-type infection elicits immune responses
to some proteins (eg, IpaA-D and VirG/IcsA), cross-
species protection was not observed in challenge studies
involving non-human primates.59 Supporting evidence in
4 www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8
humans is limited to field trials in Romania60 and China61
in the 1970s and 1980s and requires re-examination.
Immune responses that correlate with clinical
protection
Oral bovine immunoglobulin colostrum concentrates
containing S flexneri 2a anti-lipopolysaccharide pre­vented
shigellosis in an experimental human challenge study.62
These results, together with the ameliorating effects of
breastfeeding on disease severity, are examples of
protection conferred at the mucosal level.63 Acc­ordingly,
gut-derived O-specific IgA antibody-secreting cells that
circulate in the bloodstream 7–10 days after oral
immunisation are a measure of intestinal priming that
has been correlated with vaccine efficacy in volunteers.64,65
Presence of serotype-specific serum anti-lipopoly­
saccharide antibodies correlated with protection in a
volunteer challenge model64,65 and among soldiers
deployed to endemic field settings.66 However, these
antibodies do not fully predict protection associated
with previous exposure.67 Other responses associated with
reduced disease severity following experimental challenge
with wild-type S flexneri 2a include functional (serum
bactericidal and opsonophagocytic killing) antibodies and
IpaB and VirG specific IgG.68
The role of cellular immunity in combating shigella
has been investigated. Interferon-γ responses in
patients recovering from shigellosis69 and in response
to live attenuated shigella vaccine candidates70 might
limit intracellular replication of shigella.71 A desirable
feature of a shigella vaccine is the ability to induce
enduring immunity by stimulating memory responses,
which has been observed following immunisation with
attenuated shigella vaccine candidates.72 Moreover,
vaccinated individuals who developed IgG and IgA
IpaB and lipopolysaccharide B cell memory responses
had less severe disease upon challenge with wild-type
S flexneri 2a compared to indiviuals who did not develop
these responses.73
Clinical presentation
The incubation period of shigellosis is typically 1–4 days,
but up to 8 days with S dysenteriae type 1.74 Asymptomatic
infection can occur, particularly in previously infected
individuals. The first manifestations of shigellosis are
usually fever, headache, malaise, anorexia, and vomiting,
followed several hours later by watery diarrhoea. Most
illnesses in otherwise healthy individuals are mild and
symptoms subside in a few days. In other people, there is
progression (within hours to days) to frank dysentery
with frequent small stools containing blood and mucus,
accompanied by lower abdominal cramps and tenesmus
(table). Patients with severe infection might pass more
than 20 dysenteric stools in one day. Abdominal pain,
often a prominent feature, might simulate appendicitis
or, in young infants and neonates, intussusception or
necrotising enterocolitis.75
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Shigella is not easily distinguished from other causes

Dysentery Watery diarrhoea
of diarrhoea, especially bacterial enteritides such as (n=757) (n=288)
campylobacter and non-typhoidal salmonella. Features
Fever 607 (80%) 207 (72%)
suggestive of bacterial diarrhoea include abrupt onset of
Abdominal cramps 616 (81%) 137 (48%)
diarrhoea, frequent stools (more than four per day), no
Vomiting 136 (18%) 89 (31%)
vomiting at onset, fever, blood in stool, and faecal
WHO-defined dehydration 95 (13%) 134 (47%)
leucocytes or a positive lactoferrin test.
Tenesmus 511 (68%) 32 (11%)
Rectal prolapse 19 (3%) 4 (1%)
Complications and extraintestinal manifestations
Shigella occasionally causes invasive infections such as Data unpublished or from the Global Enteric Multicenter Study.32
meningitis, osteomyelitis, arthritis, and splenic abscess.
Table: Acute clinical manifestations of shigellosis among children
Shigella sepsis, rare in otherwise healthy people, occurs
younger than 5 years
most often in young or malnourished infants and
children76 and people with HIV,77 and carries a poor
prognosis. Risk factors for death include young age,
number of stools before admission, malnutrition, hypo­ Panel 2: Clinical complications of shigellosis
natraemia, convulsions, and unconsciousness.78 Intestinal complications
Intestinal complications of shigellosis are uncommon • Rectal prolapse*
but often severe and include rectal prolapse, intestinal • Toxic megacolon
obstruction, toxic megacolon, and perforation; all these • Intestinal perforation
complications are more common with S dysenteriae type 1 • Intestinal obstruction
infections (panel 2).80 The most frequent extraintestinal • Appendicitis
manifestation is seizures, which are generally reported in • Persistent diarrhoea
5–30% of children hospitalised with shigellosis,81 and are
reported most often in young children with fever or Extraintestinal complications
metabolic derangements known to precipitate seizures.82 • Dehydration
A rare but devastating encephalopathy associated with • Severe hyponatraemia (serum sodium <126 mmol/L)*
shigellosis is Ekiri syndrome.83 Haematological • Hypoglycaemia
manifestations of shigellosis include leukaemoid reaction • Focal infections, for example, meningitis, osteomyelitis,
(neutrophil counts >50  000 per μL) and haemolytic arthritis, splenic abscesses, and vaginitis
uraemic syndrome.78 Shigella vaginitis is well described, • Sepsis, usually in malnourished or immunocompromised
particularly in prepubertal children.84 Pregnant women people
with shigella infection have had preterm labour (although • Seizure or encephalopathy
a causal relationship is not established), and can transmit • Leukaemoid reaction (peripheral leucocytes
the infection to the newborn.85 >40 000 per μL)*
Persistent diarrhoea and malnutrition are long-term Post-infectious manifestations
complications of shigellosis seen primarily among • Haemolytic uraemic syndrome*
children from low-income and lower middle-income • Reactive arthritis†
countries and those infected with S dysenteriae type 1.86,87 • Irritable bowel syndrome‡
These consequences can be compounded by the common • Malnutrition
occurrence of intestinal protein loss.88
*Significantly more common in episodes with Shigella dysenteriae type 1 than with all
Studies in high-income settings have linked shigella
other Shigella species among Bangladeshi children younger than 15 years during the
infection in adults to post-infectious irritable bowel 1990s (rectal prolapse [52% vs 15%], severe hyponatraemia [58% vs 26%], leukaemoid
syndrome characterised by altered stool frequency, form, reaction [22% vs 2%], and haemolytic uraemic syndrome [8% vs 1%]).78 †Typical acute
symptoms include asymmetric oligoarthritis (usually lower limb), enthesitis, dactylitis,
and passage, accompanied by abdominal pain.42 Symptoms and back pain. Extra-articular manifestations include conjunctivitis, uveitis, urethritis,
often resolve within 12 months, but a chronic course has and other genitourinary tract manifestations, oral, skin, and nail lesions, and rarely
been documented.42 The absolute risk of post-shigella cardiac abnormalities. ‡Irritable bowel syndrome follows around 4% of shigella
episodes in studies from high-resource settings.79
irritable bowel syndrome is around 4%;79 more severe
and longer illness is associated with a higher risk.89
A hypothesis for the association between shigella infection Reactive arthritis is an immune-mediated seronegative
and irritable bowel syndrome is that disruption of tight spondyloarthropathy that develops 1–4 weeks after shigella
junctions with commensal bacterial translocation in the infection in about 1–2% of individuals (usually adults),
context of shigella-induced severe inflammation results in particularly those with the HLA B27 haplotype.41 Although
dysregulation and persistent immune, proprioceptive, and the typical acute symptoms of asymmetric oligoarthritis
motility abnormalities.90 Post-infectious functional gastro­ (usually lower limb), enthesitis, dactylitis, and back pain
intestinal disorders following shigella infection have also generally resolve within 6–12 months, symptoms can
been described in children.91 persist and extra-articular manifestations can occur.

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 Seminar
Panel 3: Scenarios involving adults and children in which diagnostics and treatment
should be considered*
Clinical scenarios in which treatment is considered or planned
• Hospitalisation
• Moderate-to-severe illness
• Malnourished or immunocompromised child
• Invasive infection or suspected sepsis
• Prolonged dysentery
• Clinically failed empirical therapy
• At risk for Shiga toxin-producing organisms (eg, haemolytic uraemic syndrome in
patient or contact)†
• Intestinal comorbidities
Epidemiological scenarios where risk of resistance is elevated
• Returning traveller
• Men who have sex with men
Epidemiological scenarios in which treatment might be needed to control transmission
• Outbreak
• Household or sexual exposure to high-risk person
• Employment in health-care, day-care, or food handling settings
*Culture-independent diagnostic testing might yield a potential pathogen in a shorter amount of time to guide initial therapy;
however, this method does not provide susceptibility testing. Therefore, a stool culture with susceptibility testing should also
be performed in patients suspected of having a shigella infection who might be candidates for treatment. †Diagnostic testing
of patients with bloody diarrhoea in high-income countries can identify individuals with Shiga toxin-producing organisms,
in whom treatment might increase the risk of haemolytic uraemic syndrome (non-Shigella dysenteriae type 1 or Escherichia coli),
and individuals with S dysenteriae type 1 infection, in whom treatment might reduce the risk of haemolytic uraemic syndrome.
Diagnosis
Diagnostic assays
Conventional bacterial culture is the gold standard
for diagnosing shigella infection. When a delay between
stool collection and plating is anticipated, transport
media (preferably buffered glycerol saline) helps main­
tain organism viability. Cultivation of shigella allows
identification of antibiotic susceptibility, which is essential
in this era of increasing antimicrobial resistance.92 Since
2013, several nucleic acid-based diagnostic panels have
been approved by the US Food and Drug Administration
for detection of enteric pathogens, including shigella.93
Although these assays will not provide susceptibility data
to inform antimicrobial treatment, they might increase
the diagnostic yield and provide a more timely result that
could inform pathogen targeted therapies. Identification
of specific resistant gene targets that correlate closely with
phenotypic antibiotic resistance to shigella is an area of
active research that is needed before molecular tools can
replace culture completely.
When to test
Diagnostic tests should be done for clinical scenarios in
which treatment is warranted, or for groups such as
returning travellers and MSM with a high risk of
multidrug-resistant shigellosis, to ensure that treatment,
when needed, is based on susceptibility results (panel 3).
Patients who do not improve with treatment should
undergo repeat culture and sensitivity testing. Testing
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patients with bloody diarrhoea in high-resource countries
can identify those with Shiga toxin-producing organ­
isms (non-S dysenteriae type 1 or Escherichia coli), in
whom treatment might increase the risk of haemolytic
uraemic syndrome, although this remains a contro­versial
topic.94 Public health authorities should be notified
if shigella is identified in a patient with haemolytic
uraemic syndrome.
Treatment
Supportive care
The cornerstone of shigella treatment is maintenance of
hydration and electrolyte balance. In young children, oral
rehydration with a reduced osmolarity solution is
indicated to treat the WHO-defined category of some
dehydration, and is preferable to intravenous fluids unless
severe dehydration is present.95 Antimotility drugs are not
recommended in children with shigellosis and patients
who are debilitated, immunocompromised, or infected
with ciprofloxacin-resistant strains; these drugs might
prolong symptoms and pathogen shedding96 and have
been associated with abdominal distention in children
with diarrhoea.97 Although loperamide adjunctive therapy
could offer additional benefits compared to antibiotic
therapy alone in older children and adults with shigella
dysentery not caused by S dysenteriae type 1,97,98 it is not
recommended because of safety concerns.
Antimicrobial therapy
Evidence supports the use of antibiotics to treat shigella
dysentery (figure). Antibiotics reduce the duration of
fever and diarrhoea by 1–2 days, and pathogen shedding
is interrupted, reducing the risk of person-to-person
transmission. The benefit of antibiotics for non-
dysenteric shigella diarrhoea is unknown.
Oral ciprofloxacin and azithromycin are generally
considered as first-line therapy for shigellosis in adults
and children. Parenteral ceftriaxone is recommended for
severely ill or immunocompromised patients. In 2017,
WHO recommended that ciprofloxacin be the first
choice for treating adults and children with dysentery,
and azithromycin, cefixime, and ceftriaxone should
be considered as second choices.99 WHO suggested
trimethoprim-sulfamethoxazole as another second choice;
however, resistance is widespread to this drug combination
and other drugs that are otherwise considered efficacious
(eg, ampicillin, nalidixic acid, and pivmecillinam)101 but
are generally not recommended unless susceptibility is
known or expected based on local surveillance. For benefit
to exceed risk, treatment should be judicious and guided
by susceptibility results whenever possible because of the
threat of resistant strains. Notably, clinical breakpoints
(the standard method for definition of susceptibility cutoff
values) are not available for azithromycin, making
treatment decisions challenging.37 Minimal inhibitory
concentrations of at least 16 μg/mL (for S flexneri) and at
least 32 μg/mL (for S sonnei) are considered indicative of

decreased susceptibility102 but cannot be assumed to
predict treatment outcomes. Extensive use of nalidixic
acid is not advocated to avoid induction of cross-resistance
with ciprofloxacin. Concerns that antibiotic treatment of
Shiga toxin-producing E coli infections will trigger
haemolytic uraemic syndrome also might apply to
emerging Shiga toxin-producing shigella strains,52 but this
is not an issue for S dysenteriae type 1.103
In 2017, the CDC issued a health advisory100 with
recommendations that antibiotic treatment of shigella
in the USA be reserved for individuals who are
immunocompromised, have severe illness (eg, require
hospitalisation, or have invasive disease or compli­
cations), or are advised to take antibiotics by public health
authorities to prevent or mitigate outbreaks in certain
settings, for example, child care or food handling.
Although not addressed by the CDC, additional treatment
indications might be considered (eg, patients with
substantial discomfort, intestinal comorbidities, insti­
tutional settings, or household exposure to high-risk
individuals). WHO recommends antibiotic treatment for
all children with dysentery, with the assumption that most
cases are caused by shigella.
The CDC advisory100 described emerging shigella
strains in the USA with increased minimal inhibitory
concentration values for ciprofloxacin of 0·12–1·0 μg/mL.
Although laboratory standards might categorise these
strains as ciprofloxacin-susceptible, they can harbour
quinolone resistance genes conferring reduced suscept­
ibility. The CDC recommends that shigella strains with a
minimal inhibitory concentration of 0·12 μg/mL or
greater should not be treated with fluoroquinolones
because of concerns that these drugs might exacerbate
disease severity and prolong pathogen shedding, thereby
increasing the risk of secondary cases. Additional data are
needed to assess whether these minimal inhibitory
concentrations portend adverse outcomes.
Several principles guide the choice of antimicrobials to
treat shigellosis. First, the drug should achieve thera­
peutic concentrations in serum, but appreciable faecal
concentrations are not required.104,105 Non-absorbable
antibiotics with in-vitro activity against shigella, such as
oral rifaximin and gentamicin, have shown variable
results.106,107 Second, not all antibiotics that exceed serum
minimal inhibitory concentrations are effective. For
example, amoxicillin is better absorbed but appears less
efficacious than ampicillin.108
Short-chain fatty acids and other novel measures
In animal models, shigella-mediated downregulation of
the host endogenous antibacterial peptide—cathelicidin—
was reversed by treatment with the oral short-chain
fatty acid sodium butyrate and resulted in disease
amelioration.109 A randomised trial110 among children
with severe shigellosis found that ingestion of cooked
green banana (a substrate for production of butyrate
by intestinal bacteria) significantly improved disease
www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8 7
Seminar
Children Adults
First-line: First-line:
• Oral therapy • Oral therapy
- Ciprofloxacin* 15 mg/kg twice daily for 3 days - Ciprofloxacin* 500 mg once a day for 3 days
• Parenteral therapy for severe illness • Parenteral therapy for severe illness
- Ceftriaxone 50–100 mg once daily for 3 days, - Ceftriaxone 1 g every 24 h for 3 days,
intravenous or intramuscular intravenous or intramuscular
PLUS
• Zinc 20 mg (10 mg for infants <6 months) for
10–14 days, by mouth
If local strains are ciprofloxacin-resistant
Second-line oral therapy: Second-line oral therapy:
• Azithromycin* 12 mg/kg once on day 1, then • Azithromycin* 1 g (or 500 mg every 12 h) for
6 mg/kg once daily on days 2–4 (total course 1 day, oral
4 days), oral • Azithromycin* 500 mg on day one, followed by
• Cefixime 8 mg/kg once daily for 3 days, oral 250 mg once daily for 4 days, oral
• Trimethoprim-sulfamethoxazole: 4 mg/kg of • Cefixime 400 mg once daily for 3 days, oral
trimethoprim and 20 mg/kg sulfamethoxazole • Trimethoprim-sulfamethoxazole: 160 mg of
twice a day for 5 days (if susceptibility is known trimethoprim and 800 mg sulfamethoxazole twice a
or expected based on local data) day for 5 days (if susceptibility known or expected
based on local data)
Improving after 48 h of antibiotics?
Yes No
Finish therapy Is susceptibility known?
Yes No
Adjust therapy according to susceptibility results Choose different first-line or second-line therapy
not used previously
Improving after an additional 48 h of antibiotics?
Yes No
Finish therapy If amoebiasis is possible, give 5 days of oral
metronidazole†
• Children: 20 mg/kg three times per day
• Adults: 500–750 mg three times per day
Figure: Guidelines for treatment of suspected shigellosis99
Empirical therapy should be directed by hospital, clinical laboratory, or public health antibiograms whenever
possible. Minimal inhibitory concentrations of 0·12–1·0 μg/mL for ciprofloxacin might be considered susceptible
by laboratory standards but could harbour resistance genes known to confer decreased susceptibility.100
*Azithromycin and fluoroquinolones should be used with caution in patients taking the antimalarial artemether as
these drugs can prolong the QT interval on the electrocardiogram and trigger arrhythmias. †Per WHO
recommendations. Another acceptable regimen is a 7–10 day course of metronidazole followed by a luminal agent
such as paromomycin or diiodohydroxyquinoline.
out­comes compared to a rice-based control diet. However, For WHO recommendations see
rectal delivery of short-chain fatty acid to adults http://www.who.int/maternal_
child_adolescent/documents/
with severe shigellosis showed no clinical effect.111 child_hospital_care/en
Bacteriophages that lyse shigella have been proposed as a
method for decontaminating food and water112 and
preventing and treating shigellosis.113
Micronutrients
Small randomised trials have found a modest clinical
benefit associated with zinc therapy for shigellosis,
including reduced symptom duration and subse­quent
diarrhoeal incidence.114 Data are inconclusive regarding
the value of therapeutic vitamin A for treatment
of shigellosis.115
 Seminar
Infection control strategies
Handwashing interventions are associated with a
70% reduction in shigella transmission from index cases
to household members.116 Handwashing with soap and
water reduces shigella concentration on inoculated
hands by 2–3 logs.117,118 Although these trials observed a
larger reduction associated with antibacterial compared
to non-antibacterial soaps, the US Food and Drug
Administration has discouraged use of antibacterial
soaps because of safety concerns. Outside highly
controlled environments, the effect of sanitation and
hygiene interventions on shigella-specific diarrhoea
have not been quantified.
Recommended public health control measures
vary, frequently involving exclusion of ill people with
shigellosis from work, food preparation, and child­
care. Nonetheless, instituting hygiene practices and
segregating ill people is most important for interrupting
transmission during institutional outbreaks,119 even
when untreated asympto­matic individuals remain in
attendance.120 Physicians should query patients with
suspected shigellosis regarding their risk factors,
including day care attendance and sexual practices, to
provide the most relevant counselling about infection
control and to identify those at high risk for multidrug-
resistance.
Shigella vaccines in clinical development
Rationale
The high burden and severity of disease and the threat
of increasing antimicrobial resistance provide strong
support for vaccine development. Populations that might
benefit include infants and young children in low-income
and middle-income countries, travellers to endemic
settings, children attending day care, and MSM. The
following discussion is limited to vaccines that have
entered clinical trials. Detailed reviews of vaccines under
development have been published.121,122
Selection of vaccine antigens
Approaches to vaccine development include candidates
that target serotype-specific immunity and those that
contain antigens shared across Shigella species. GEMS
suggested that a vaccine containing S sonnei plus
S flexneri serotypes 2a, 3a, and 6 could provide direct
protection against 64% of shigella strains causing
moderate-to-severe diarrhoea in children from low-
income and middle-income settings.3 If heterologous
protection among S flexneri serotypes can be replicated
in humans,58 then a quadrivalent vaccine containing
S sonnei and S flexneri 2a, 3a, and 6 O-antigens could
provide overall coverage (direct plus cross-reactive) for
up to 88% of shigella strains. Inclusion of S dysenteriae
type 1 antigens could be considered if concerns for
recrudescence emerged. This approach forms the basis
of multivalent vaccine strategies pursued by numerous
developers.
8 www.thelancet.com Published online December 15, 2017 http://dx.doi.org/10.1016/S0140-6736(17)33296-8
Human models for vaccine efficacy
Insufficient definitive correlates of protective immunity
and an absence of animal models that simulate human
infection have hindered vaccine development. The
human challenge model of shigella was developed in the
1960s to address this gap.123 This model measures
protective efficacy by comparing the attack rate of illness
following ingestion of virulent shigella in groups of
vaccinated and unvaccinated people. The ability of this
model to detect protective efficacy against S sonnei and
S flexneri 2a has been validated by use of homologous
strain rechallenge studies55,124 that confirmed the
immunising ability of natural infection observed in the
field.54 Moreover, the S flexneri 2a streptomycin-dependent
vaccine, which was efficacious in field trials,56 conferred
significant protection in the challenge model.123
Live oral shigella vaccines
The evolving understanding of the molecular patho­
genesis of shigellosis guides the design of rational live
attenuated vaccines designed to mimic the immunising
potential of natural infection. A promising strategy
involves fundamental attenuating deletions in guaBA
(limiting bacterial intracellular replication) and in genes
encoding the shigella enterotoxins 1 and 2.70,125 A second
approach is to create a deletion in virG/icsA that cripples
the organism’s ability to spread within the intestinal
epithelium.65,126–128 A challenge confronting oral shigella
vaccines is their decreased immunogenicity in people
living in low-income and middle-income settings.129
Killed whole-cell oral shigella vaccines
Safety and efficacy of killed whole-cell vaccines in
prevention of cholera stimulated a similar approach
for shigella.130 In a phase 1 trial, a killed whole-cell
S flexneri 2a vaccine elicited immune responses similar to
those conferring protection in previous human challenge
studies.131
Shigella subunit vaccines
Robbins and colleagues132 pioneered the concept
that polysaccharide vaccines chemically conjugated to
proteins can be used to immunise infants and young
children against shigella and other pathogens that
colonise and invade through mucous membranes.
S sonnei conjugates were highly efficacious in field trials
involving adults57 and in children aged 3–4 years, but
efficacy was only 36% among children aged 2–3 years,
and was absent in children aged 1–2 years.133 Innovations
to enhance the immunogenicity of these constructs
include bioconjugate vaccines (enzymatic conjugation
of O-antigen repeat units to rEPA protein), which
better preserve integrity of the antigen,134 and synth­
esis of well-defined oligosaccharides conjugated to
protein carriers.92
Generalised modules for membrane antigens represent
a new platform for presentation of vaccine antigens as

vesicles formed naturally from lipopolysaccharide, outer
membrane proteins, and soluble periplasmic components
of shigella.135 The aim is to induce serotype-specific
immunity, although the presence of outer membrane
proteins could also stimulate cross-strain responses.
Three spaced doses of S sonnei alum-adjuvanted
generalised module for membrane antigens vaccine were
administered either intramuscularly, intranasally, or
intradermally in phase 1 trials. All routes were well-
tolerated, but only the intramuscular formulation
appeared immunogenic at the dosages given.136
Invaplex is a multicomponent vaccine comprising
serotype-specific antigens (lipopolysaccharide) and
conserved proteins (IpaB and IpaC).137 Although an initial
S flexneri 2a prototype was found to be safe and
immunogenic after intranasal administration,138 the
vaccine failed to protect in a human challenge model
(Riddle MS, unpublished). A second-generation vaccine
that uses recombinant Ipa proteins (InvaplexAR) has
completed phase 1 trials.
Conclusions and future directions
Shigella persists as a leading cause of morbidity and
mortality globally, disproportionately affecting young
children in low-resource settings. Factors that allow
shigella to elude control measures include a low infectious
inoculum and breaches in sanitation and hygiene, and
the success of treatment is stymied by global
dissemination of strains resistant to current first-line
therapy. Pandemic spread of multidrug-resistant shigella
strains fuelled by certain populations (eg, travellers and
MSM) and the threat of hypervirulent, Shiga toxin-
producing strains requires vigilant surveillance on a
global scale. The clinical consequences of rising minimal
inhibitory concentrations should be evaluated to guide
therapy. Adherence to available control measures is
essential, including judicious use of antibiotics targeting
more severe illness and in accordance with susceptibility
data, and strict adherence to appropriate hygienic
measures. Development of rapid diagnostics for pathogen
identification and susceptibility determination would be
useful, but uptake will depend on affordability and
technical requirements. Discovery of novel approaches
for prevention and therapy139 should be prioritised with
development of safe and effective vaccines.
Contributors
KLK did the literature searches and drafted the original and resubmitted
manuscripts, with contributions from all authors. All authors critically
reviewed the manuscript and approved the final version.
Declaration of interests
We declare no competing interests.
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