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UNIVERSITY OF GONDAR

COLLEGE OF MEDICINE AND HEALTH SCIENCES|

SCHOOL OF BIOMEDICAL AND LABORATORY SCIENCES


DEPARTMENT OF MEDICAL MICROBIOLOGY

Global Burden of Salmonellosis and Shigellosis in diarrheic Pediatric


Population

By: - Amare Alemu (bsc)


Advisors: - Setegn Eshetie (Bsc, Msc)
Tigist Engida (BSc, MSc)

December, 2017
Gondar, Ethiopia
ACKNOWLEDGEMENT
I would like to thank Setegn Eshetie and Tigist Engida to let me come up with this valuable
seminar topic and offering for their tremendous technical support. I would like to extend my
gratitude to School of Biomedical and Laboratory Sciences and Department of Medical
Microbiology for their technical support and enrolling me as MSc student.

I
Contents
ACKNOWLEDGEMENT .................................................................................................................................... I
Abbreviations ............................................................................................................................................... III
1.Introduction ................................................................................................ Error! Bookmark not defined.
1.1. Background ........................................................................................................................................ 1
2. Literature review ....................................................................................................................................... 3
2.1. Epidemiology...................................................................................................................................... 4
2.2. Transmission ...................................................................................................................................... 6
2.3. Pathogenesis ...................................................................................................................................... 7
2.4. Diagnosis ............................................................................................................................................ 9
2.5. Treatment, prevention and control ................................................................................................... 9
3. Significance of the review ....................................................................................................................... 10
4.Methods ...................................................................................................... Error! Bookmark not defined.
4.1. Search strategies .............................................................................................................................. 11
4.2. Study selection ................................................................................................................................. 11
5. Conclusion ............................................................................................................................................... 11
6. Reference ................................................................................................................................................ 13

II
Abbreviations
AIDS--------------------------------------Acquired Immuno Deficiency Syndrome
HCL----------------------------------------Hydrochloric Acid
HIV-----------------------------------------Human Immuno Virus
MLST---------------------------------------Multiple Loci Sequencing typing
PFGE -------------------------------------- Pulse-field Gel Electrophoresis
WHO---------------------------------------World health organization

Summary

III
1. Introduction
1.1. Background
Human diarrheal diseases have been recognized from the beginning of civilization and remain one of
the most prevalent public health problems of today. Gastrointestinal infections due to pathogenic
Enterobacteriaceae in particular Shigella and Salmonella species are significant causes of morbidity
and mortality worldwide; mainly children under the age of 5 years are at high risk (1, 2). Recently,
the World Health Organization (WHO) estimated that 1.1 million deaths per year are attributed to
shigellosis (3).

Salmonella and Shigella are members of the Enterobacteriaceae characterized by non-lactose


fermenters, gram-negative rods, non-spore formers and facultative anaerobes (4). The Shigella
species are non-motile, and non-gas producers’(4, 5) andSalmonella species are motile, produces
acid and gas from glucose, normally inhabit the intestines of animals and humans(3, 4).

The pathogenesis of salmonella species is characterized by the invasion of non-phagocytic cells.


Salmonella will penetrate into the intestinal epithelial cells by inducing their own uptake, in a
complex and active process that morphologically resembles phagocytosis(3, 5).They invade the
mucosa of the small and large intestines and produce inflammation. Invasion of intestinal epithelial
cells induces an inflammatory reaction which causes diarrhea due to Salmonella infections(3, 6).
The virulence factors associated with Salmonella species such as adhesion, invasion, and toxin genes
are clustered in certain areas of the chromosome known as “Salmonella pathogenicity islands (3, 7)

Most of the current knowledge on mechanisms of Shigella pathogenesis is derived from studies of S.
flexneri.The Shigella species enters and invade the intestinal mucosa by using M cells of the
intestinal epithelial cells as the portal of entry (8). The bacteria are highly infectious, since as few as
10 to 100 microorganisms are sufficient to cause disease (8,9,10). Because of delay in humoral
responses, complication and mortality rate due to shigellosis in children is higher than in other age
groups (10, 11). The highest susceptibility of this age group may be due to the fact that children less
than 2 months old produce little hydrochloric acid (gastric HCl), a natural barrier to many
microorganisms (10, 6).The severe tissue destruction caused by Shigella species results in an
impaired adsorption of water, nutrients, and solutes, which might cause the watery diarrhea as well as
the blood and mucus in stools characteristic of shigellosis A disturbance of electrolyte homeostasis

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and changes in membrane transport processes, such as uncontrolled ion and fluid secretion, are
typical of diarrheal disease. Shigella enterotoxins which are produced by several Shigella strains,
were found to induce fluid secretion into the intestine, thus accounting for the watery phase of
diarrhea (8).

The virulence plasmid is an essential virulence determinant of all Shigella species and encodes the
molecular machinery necessary for tissue invasion and the intracellular lifestyle. The Shigella species
have a lot of virulence factors that allow it to adhere to the epithelium of the intestine, survive
stomach acid, invade host cells, evade immune responses, and introduce toxins into the body.
Invasion of plasmid antigen B (IpaB) initiates binding to the host cell and initiating pathways that kill
macrophages upon infection, IpaC activates proteins to form the actin-polymerizing complex that
allows Shigella to move and spread within host cells (4, 7).Shigella virulence is based on the
presence of a large virulence inv plasmid, carrying an operon that encodes the type III-secretion-
system (T3SS) responsible for bacterial entry (12).

The Salmonella and Shigella are transmitted from person to person usually by asymptomatic carriers
and via contaminated food, flies, feces, fingers, and water (3,4, 7). A severe infection of diarrhea in
children is highly associated with risk factors such as poor environmental sanitation and hygiene,
poverty and malnutrition (10, 13).

Salmonellosis and shigellosis can be diagnosed by using culture and molecular techniques (4).
Prevention and control of salmonella rely on the strategies that prevent spread of the organism within
the community and from person to person. These include: hand-washing with soap, ensuring the
availability of safe drinking water, safely disposing of human waste, breastfeeding of infants and
young children, safe handling and processing of food, and control of flies and health education (5).

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2. Literature review
2.1. General Characteristics of Salmonella and shigella species
Salmonella and Shigella are members of the Enterobacteriaceae and characterized by non-lactose
fermenters, gram-negative rods, non-spore formers and facultative anaerobes (4). Shigella
species are non-motile, and non-gas producers(4,5) and Salmonella species are motile, produces
acid and gas from glucose (4).

Members of the genus Salmonella are ubiquitous pathogens found in humans and livestock, wild
animals, reptiles, birds, insects (Samuel chane). Salmonella is an important pathogen both for
humans and animals and causes severe infections (62). It causes infections in human and other
vertebrates. It is believed that it is an important cause of typhoid fever (enteric fever),
gastrointestinal enteritis, septicemia, and carrier states in human (4). It is a very complex group
and contains more than 2000 species and typed on the basis of serotyping and species typing (2
old, 62).

The genus Shigella encompasses four subgroups historically treated as species. Shigella species
are found only in the human intestinal tract (2 old) and are killed by drying (4). The natural
habitat of shigellae is limited to the intestinal tracts of humans and other primates, where they
produce bacillary dysentery. Microscopically and culturally shigellae are indistinguishable from
other enteric Gram-negative bacilli (2 old). Shigellosis is an acute intestinal infection, the
symptoms of which can range from mild watery diarrhea to severe inflammatory bacillary
dysentery (shigellosis in Brazil). Shigella is similar to enteroinvasive Escherichia coli (EIEC) in
that they both invade intestinal epithelial cells and release Shiga toxin, which causes cell
destruction (mark Gladwin ridiculous micro. Make it easy).

Classification and nomenclature

Salmonella was first discovered and isolated from the intestines of pigs by Theobald Smith in
1855 and Dr Daniel Elmer Salmon take the discovery credit. The nomenclature of Salmonella
is controversial and still evolving. Currently, the CDC and WHO collaborating centers classifies
Salmonella species into two broad groups; Salmonella enterica (type species) and Salmonella
bongori, based on differences in their 16S rRNA sequence analysis.

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On the other hand, Kauffman and White developed a scheme to further classify Salmonella by
serotype based on three major antigenic determinants: somatic (O), capsular (K) and flagella.
Virulence (Vi) antigens, a special subtype of K antigen, are found only in three pathogenic
serotypes: Paratyphi C, Dublin and Typhi. Salmonella: (A review on pathogenesis,
epidemiology and antibiotic resistance).

2.1. Epidemiology
Shigellosis is one of the most common diarrheal diseases in humans worldwide. Shigellosis is
endemic throughout the world where it is held responsible for some 165 million cases of severe
dysentery (4). In the early 1980s, diarrheal disorders were the biggest child killers, responsible
for an estimated 4·6 million deaths worldwide every year (Diarrhea in children: an interface
between developing and developed countries).

The devastating majority of these cases occur in the developing countries. Diarrhea was a
common cause of death among children under 5 years old (a systematic analysis for the Global
Burden of Disease Study 2015). There are approximately 1.4 million cases of salmonellosis per
year resulting in about 15,000 hospitalizations and 400 deaths per year in the United States of
America (The Salmonella Pathogenicity Island). 2·5 million children still die from these
illnesses every year, almost all of them in developing countries (Diarrhea in children: an
interface between developing and developed countries). Diarrhea, however, remains a prolific
killer of children. Some data suggest that in children younger than 5 years it accounts for 15% of
cause-specific proportional mortality. The burden of diarrheal illness sits firmly in the
developing world, both for morbidity and mortality. Malnutrition and the wholly inadequate
provision of safe water, sanitation, and hygiene highlight the stark inequalities that exist within
our world. A quarter of children in developing countries are still malnourished1·1 billion people
do not have access to safe drinking water, and 2·4 billion are without adequate sanitation.

The epidemiology of salmonella and Shigella species depends on the country: S. flexneri is
predominant in developing countries, whilst S. sonnei is most reported in developed countries
(14). S. sonnei has become dominant in some Asian countries. Due to international travel and
trade of animals and food products, there is a shift in the prevalence of specific shigellae strain
types and serovars in different places (2, 7, 14).

4
Shigella species, continue to have an important global impact, causing an estimated 1 million
deaths and 163 million cases of dysentery annually. Shigella species are the most important
causes of acute bloody diarrhea (dysentery) and account for about 15% of all deaths
attributable to diarrhea in children younger than 5 years (Diarrhea in children: an interface
between developing and developed countries). Based on a research conducted for 3-year period,
in a web-based surveillance, Salmonella enterica serovar Enteritidis was by far the most common
serotype reported from human isolates globally. In 2002, it accounted for 65% of all isolates,
followed by S. Typhimurium at 12% and S. Newport at 4% (16). S. Enteritidis represented 85%
of isolates in Europe but only 9% in Oceania. In Latin America and the Caribbean, S. Typhi
accounted for the greatest proportion of salmonellae (13%) (2,33,63). In Asia, from 2000
through 2002, Japan, Korea, and Thailand together reported S. Enteritidis as the most common
human serotype (17). In China, shigellosis is one of the top four notifiable infectious diseases,
with 1.7 million episodes of bacillary dysentery, and 200,000 patients admitted to hospitals each
year (18).

Salmonella which has 2500 different serotypes is a leading cause of food borne infections
worldwide (15). 1.4 million Cases of food-borne salmonella disease have been reported in USA
alone (19). There is a slight increase (4.2%) compared with 1996 and a large increase compared
with 2005 (12.3%); this could be attributed to increased reports from several states, including
Texas and California (33, 64). In the same time in USA, the national incidence of laboratory
confirmed Shigella was 3.5 per 100,000 populations. This was isolated frequently from children
< 5 years of age, who accounted for 31.1% of all isolates (19).

In endemic regions of developing countries, salmonellosis and shigellosis are predominantly a


pediatric disease (8, 20). These diseases are important cause of morbidity and mortality
especially in children (21). More than one million deaths occur in the developing world yearly
due to Shigella infection (66). Estimates suggest that during the 1990s, nearly 1.4 billion diarrhea
episodes occurred every year among children younger than 5 years of age in socioeconomically
developing countries (25).

In developing countries, a number of studies report the high prevalence of salmonellosis and
shigellosis, especially in under 5- children. Higher infection rates of Salmonella have been

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estimated in African countries annually (62). In a recent study carried out in a pediatric hospital
in the Democratic Republic of Congo, among the 1,528 children included in the study, 26.8%
were bacteremia and Salmonella accounted for 59% of all bloodstream infections

In 1994, an explosive outbreak among Rwandan refugees in Zaïre caused approximately 20,000
deaths during the first month alone. Between 1999 and 2003, outbreaks were reported in Sierra
Leone, Liberia, Guinea, Senegal, Angola, the Central African Republic and the Democratic
Republic of Congo (5).

The etiology and epidemiology of acute diarrheal disease on children in East Africa remain
largely undefined.

In Ethiopia, like other developing countries, salmonellosis and shigellosis are the common cause
of morbidity and mortality, particularly in children.

2.2. Transmission
Typhoid (enteric fever) and Non-typhoidal Salmonella (NTS, e.g. food poisoning) is an
important public health problem worldwide. Shigellosis (bacillary dysentery), the result of
infection with Shigella, is one of the most common diarrhea-related causes of morbidity and
mortality in children under 5 years in developing countries (22). Around 95% of these cases are
caused by consumption of contaminated food products, and S. Enteritidis is responsible for at
least 15% of these cases (salmonella pathogenicity island).

Primarily salmonella and shigella transmitted through ingestion of contaminated food and water
(23). Direct or indirect contact with infected animals and/or persons or from contact with pets
such as cats, dogs, rodents, reptiles, or amphibians can transmit the disease. Several recent
outbreaks have also been associated with consumption of contaminated plant products such as
sprouts, tomatoes, fruits, peanuts, and spinach (24).

Children living in areas with poor sanitation are at higher risk for fecal-oral transmission. Food
and water contamination will result in a higher risk of acquiring infection caused by Salmonella
and Shigella (25).

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2.3. Pathogenesis
Diarrhea poses a very serious problem in developing countries where it is the leading cause of
morbidity and mortality. As of other enteric bacteria salmonella and shigella species require a
mechanism to survive through the digestive tract and colonize a host and cause disease.
Salmonella species can infect both warm and cold-blooded hosts (4). By its ability of the
organism to avoid fusion of Salmonella containing vacuoles with dendritic cell lysosomes in the
intestine is the mechanism by which it can escape of killing. By surviving within macrophages,
Salmonella species will be carried to the spleen, lymph nodes and throughout the
reticuloendothelial system (17,).

The severity of Salmonella infections in humans varies depending on the serotype involved and
the health status of the human host. Children below the age of 5 years, elderly people and
patients with immunosuppression are more susceptible to Salmonella infection than healthy
individuals. (A review on pathogenesis, epidemiology and antibiotic resistance).

When the bacteria enter the digestive tract via contaminated water or food, they tend to penetrate
the epithelial cells lining the intestinal wall. SPIs encode for type III secretion systems, multi-
channel proteins that allow Salmonella to inject its effectors across the intestinal epithelial cell
membrane into the cytoplasm. The bacterial effectors then activate the signal transduction
pathway and trigger reconstruction of the actin cytoskeleton of the host cell, resulting in the
outward extension or ruffle of the epithelial cell membrane to engulf the bacteria. The
morphology of the membrane ruffle resembles the process of phagocytosis (A review on
pathogenesis, epidemiology and antibiotic resistance).

Following the engulfment of Salmonella into the host cell, the bacterium is encased in a
membrane compartment called a vacuole, which is composed of the host cell membrane. Under
normal circumstances, the presence of the bacterial foreign body would activate the host cell
immune response, resulting in the fusion of the lysosomes and the secretion of digesting
enzymes to degrade the intracellular bacteria. However, Salmonella uses the type III secretion
system to inject other effector proteins into the vacuole, causing the alteration of the
compartment structure. The remodeled vacuole blocks the fusion of the lysosomes and this
permits the intracellular survival and replication of the bacteria within the host cells. The
capability of the bacteria to survive within macrophages allows them to be carried in the

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reticuloendothelial system (RES) (A review on pathogenesis, epidemiology and antibiotic
resistance).

Shigella is the leading cause of infant diarrhea and mortality (death) in developing countries. In
shigella the infective dose is small and causes bacillary dysentery (4, 10). It infects the M cells in
the Peyer’s patches of the large intestine (4, 5). The capacity of the bacteria to cross the colonic
mucosa via M cells associated with Gastrointestinal Associated Lymphoid Tissue (GALT) and
reprogram epithelial cells to produce pro-inflammatory mediators, such as interleukin 8, which
play a major role in the strong inflammatory response facilitating further bacterial invasion. This
triggers an intense acute inflammatory reaction with infiltration by polymorph nuclear
leukocytes. The shigella species cause bacillary dysentery leading to watery or bloody diarrhea
(8). Patients develop diarrhea because the inflamed colon, damaged by the Shiga toxin, is unable
to reabsorb fluids and electrolyte (mark Gladwin ridiculous micro. Make it easy).

2.4. Virulence factors

The virulence factors of a pathogen are a multifactorial process that requires different general
class of determinants (pathogenicity islands). Some of these are virulence genes that are required
for physiological process for survival in host and non-host environments (pathogenicity islands).

Shigella virulence is based on the presence of a large virulence inv plasmid, carrying an operon
that encodes the type III-secretion-system (T3SS) responsible for bacterial entry (Virulence
Factors Associated with Pediatric Shigellosis in Brazilian Amazon). The T3SS is composed
of several proteins which connects the inner and outer bacterial membranes. As indicated in a
research in on Virulence Factors Associated with Pediatric Shigellosis inBrazilian Amazon, all
the isolates werepositive for the ipaBCD gene, as expected, whereas IpaB,IpaC, and IpaD are
key factors ofvirulent Shigella (shigellosis in brazil).

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2.5. Clinical manifestations

Based on the clinical patterns in human salmonellosis, Salmonella strains can be grouped into
typhoid Salmonella and non-typhoid Salmonella (NTS). In human infections, the four different
clinical manifestations are enteric fever, gastroenteritis, bacteraemia and other extraintestinal
complications, and chronic carrier state (A review on pathogenesis, epidemiology and
antibiotic resistance).

Shigellosis clinical manifestations may vary from asymptomatic to severe dysentery with several
complications. Infants were more common to have a history of non-bloody diarrhea, moderate to
severe dehydration, or bacteremia, but less common to have fever. Shigellosisin Jakarta

Shigellosis is an acute intestinal infection, the symptoms of which can range from mild watery
diarrhea to severe inflammatory bacillary dysentery (Virulence Factors Associated with
Pediatric Shigellosis in Brazilian Amazon).

2.4. Diagnosis
Salmonellosis and shigellosis cannot be distinguished reliably from other causes of bloody
diarrhea on the basis of clinical features alone. Routine microscopy must be performed and the
presence of PMNs suggests a bacterial etiology but does not necessarily indicate salmonellosis or
shigellosis; it may be C. jejuni or diarrheogenic E. coli. To identify accurately culture and
biochemical tests must be performed. Blood culture and bone marrow aspirate may be used if the
source and trained personnel are available (17). Molecular techniques are also more necessary to
identify them correctly. The most common methods currently in use are the pulse-field gel
electrophoresis (PFGE) and multiple loci sequencing typing (MLST) (4, 5, 17). The thirty
isolates of Shigella species were confirmed by conventional and 16S rRNA sequencing methods
(shigellosis in brazil).

2.5. Treatment, prevention and control


Prevention of salmonellosis and shigellosis can be primarily on measures to control the spread of
the organism within the community.

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1. Health education: - Teaching the child bearing mothers and school children about these
diseases and spreading the information in the local communities via health and religious
institutions, mass media, schools, and markets by using posters, drama etc.

2. Hand washing: - Hand-washing using soap is important after defecation, after cleaning a child
who has defecated, after disposing of a child’s stool, before preparing or handling food, and
before eating.

3. pure water supply: - The use of surface water for drinking, like water from a river, pond, or
open well, should be discouraged. To be used for drinking, it must be disinfected with chlorine
or it must be boiled.

4. breastfeeding: - breast feeding until 6 months must be promoted and continue breast feeding
with other nutrients for about 3 years are advisable.

5.Other prevention methods: -Other prevention methods should be promoted in the general
communities. In this regard health education must stress on the preparation and consumption of
safe food supply and on the disposal of environmental wastes. Vaccine trials should be carried
out to prevent it. But still there is no WHO recommended vaccine that is effective in preventing
shigella infections. Currently there is a trial against S. flexneri but still it is under development
(5). In other countries, heat-killed, phenol preserved whole cell salmonella vaccines containing a
mixture of culture of S. typhi and S.paratyphi have been used. But these were not effective.
Capsular (vi) polysaccharide replaces the existing vaccine. Now oral live-attenuated salmonella
vaccine is used (4, 17). Antibiotics and use of oral rehydration therapy in developing countries
has contributed significantly to reduce mortality from diarrheal dehydration (4).

3. Significance of the review


Salmonellosis and Shigellosis are endemic in most developing countries and is the most
important cause of bloody diarrhea worldwide. There is a need to estimate the magnitude of the
global burden of disease and death caused by Shigella and Salmonella in children specially in
under 5- children (4). Several recent efforts are carried out in modern medical and public health
in controlling this global threat; the consequences of which are most devastating in the
developing world. Understanding the global burden of infections caused by entero-pathogens

10
particularly due to Salmonella and Shigella is essential to design effective control and preventive
strategies.

4. Methods
4.1. Search strategies
Through computerized search using databases such as PubMed, goggle scholar, sci-hub and
different journal sites are assessed to download scientific papers around the world. Combination
of key words such as global burden of Shigella and Salmonella, diarrheal pediatric patients etc
are used to search journal articles.

4.2. Study selection


Estimates suggest that during the 1990s, nearly 1.4 billion diarrhea episodes occurred every year
among children younger than 5 years of age in socio-economically developing countries, of
which 123.6 million episodes required outpatient medical care and 9 million episodes required
hospitalization. Children living in socioeconomically underdeveloped areas will have more
overall diarrhea episodes which are caused by enteric pathogens mainly by Salmonella and
Shigella. Severe episodes with dehydration and a higher death rate occur in children living in
more economically underdeveloped areas (25). Therefore, studying these deadly pathogens in
diarrheic pediatric population in Gondar, Ethiopia is crucial to have information for designing
strategies for preventing and controlling shigellosis and salmonellosis in diarrheic pediatric
patients in the area.

5. Conclusion
Globally, Salmonellae and Shigella infections remain a major public health threat and the
significant cause of morbidity and mortality especially in the pediatric population. Diarrhea-
causing pathogens are the second leading cause of morbidity and mortality worldwide; mainly
children under the age of 5 years are at high risk. The highest susceptibility of this age group
may be due to the fact that children less than 2 months old produce little hydrochloric acid
(gastric HCl), a natural barrier to many microorganisms.

The risk to salmonellosis and shigellosis is increased due to absence of effective vaccines,
modifying handwashing behavior after defecating to control prolonged community outbreaks and

11
identifying high-risk groups and targeting prevention measures. The widespread occurrences of
Salmonella and Shigella are attributed to several factors including malnutrition and under
nutrition, HIV-AIDS, the close relationship between man and animals, the widespread field
slaughtering practices, the raw meat consumption habits in some societies, the unhygienic food
handling practices and poor water sources.

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17
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19
20
21
22
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24