A Millennium Update on Pediatric

Diarrheal Illness in the Developing World

Miguel ORyan, MD,* Valeria Prado, MD,* and Larry K. Pickering, MD, FAAP
More than one billion diarrhea episodes occur every year among children younger than 5
years of age in socioeconomically developing countries causing 2 to 2.5 million deaths.
More than twenty viral, bacterial, and parasitic enteropathogens are currently associated
with acute diarrhea. Rotavirus and diarrheagenic Escherichia coli are the most common
pathogens responsible for acute diarrhea episodes in children; Shigella spp., Salmonella
spp, Campylobacter jejuni/coli, Vibrio cholerae, Aeromonas spp, and Plesiomonas spp.
occur more commonly in poorer areas and infections caused by protozoa and helminthes
occur mainly in areas where environmental sanitation is significantly deteriorated. Initial
clinical assessment of a child with diarrhea should focus on obtaining an accurate evaluation of hydration and nutritional status. Assessment of stool characteristics (e.g., liquid
non-bloody stools vs. dysenteric or bloody stools) is a key feature in determining potential
pathogens causing an acute diarrhea episode. Diagnostic guidelines are discussed in the
article. The major therapeutic intervention for all individuals with diarrhea consists of fluid
and electrolyte therapy. When antimicrobial therapy is appropriate, selection of a specific
agent should be made based upon susceptibility patterns of the pathogen or information on
local susceptibility patterns. Current guidelines for administering appropriate antimicrobial
treatment are provided in the article. Preventive measures include careful personal hygiene, especially promotion of hand washing. Immunizations currently or soon to be
available for Salmonella serotype Typhi, cholera prevention, and rotavirus are discussed.
Semin Pediatr Infect Dis 16:125-136 2005 Elsevier Inc. All rights reserved.

n the new millennium, diarrheal disease continues to be a

significant cause of morbidity and mortality worldwide.
Information available from the 1980s to date suggests that
the overall frequency of childhood diarrhea has remained
relatively constant, but with a steady decline of diarrheaassociated deaths.1 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, of which 123.6 million episodes
required outpatient medical care and 9 million episodes required hospitalization. Approximately 2 to 2.5 million diarrhea-associated deaths were estimated annually in this age
group, concentrated in the most impoverished areas of the
world.2,3 The highest age-mortality rate (8.5 per 1000/yr)
occurred in children younger than 1 year of age.3 These esti*Microbiology and Mycology Program, Institute of Biomedical Sciences,
Faculty of Medicine, University of Chile, Santiago, Chile.
National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Georgia.
Address reprint requests to: Miguel L ORyan, Associate Director, Institute of
Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile. E-mail: moryan@med.uchile.cl

1045-1870/05/$-see front matter 2005 Elsevier Inc. All rights reserved.

doi:10.1053/j.spid.2005.12.008

mates are somewhat lower than the more than 3 million

deaths from diarrhea reported 10 years before, indicating
that significant advances have had a positive impact on diarrhea-associated outcomes.1
Children living in socioeconomically underdeveloped areas will have more overall diarrhea episodes, severe episodes
with dehydration, and a higher death rate compared with
children living in more economically developed areas. These
events are a consequence of numerous conditions common
to poverty, including deficiencies in infrastructure (decreased accessibility to noncontaminated water and appropriate sewage disposal), crowding and exposure to farm animals (free roaming chickens and pigs), lower standards in
food handling and hygiene, decreased accessibility to medical care, and low educational level. Malnutrition, a well-recognized risk factor for death from diarrhea, occurs more
commonly in less economically developed countries.4-7
The concept developing country is an oversimplification
that tends to include a broad range of countries that have
important socioeconomic, cultural, and medical-care related
differences among them. For example, the Gross Domestic
Product (GDP) per capita/yr of developing regions ranges
125

M. ORyan, V. Prado, and L.K. Pickering

126
from 7.374 international dollars for Latin America to 4.327 in
Asia and 1.797 in sub-Saharan Africa.8 The risk of developing
gastrointestinal tract infections and severe disease in the
poorer countries will be significantly higher compared with
middle-income countries within the economically developing world. Even more, within the same continent and country there are cities where the standards are similar to those of
more developed countries. These differences need to be accounted for when seeking specific information on which to
make recommendations. For example, a pediatrician in the
United States asked to recommend diarrhea prevention strategies for a family moving to Santiago, Chile will make different recommendations than for a family moving to Dhaka,
Bangladesh. General information can be obtained at specific
web sites (www.cdc.gov/travel), but information obtained
should be supplemented with country-specific information
when possible. The need for the best local knowledge available to support recommendations is critical.
Unfortunately, accurate information on the impact of diarrheal disease in most areas within the developing world is
either not available or outdated, or the collection methods
used do not permit comparisons. Taking into account these
limitations, in general, a child in the developing world will
have more diarrhea episodes than will a child living in middle- or high-income countries. The range in the number of
diarrhea episodes per child/yr is wide and will vary depending on the risk factors indicated above. An 18-month-old
child living in a small shanty town hut in Bangladesh or the
Amazon area of Brazil, with poor sanitation and no access to
sewage systems, receiving water from a well or river, lacking
adequate nutrition, and sharing a bed with two or three siblings likely will have eight or more diarrhea episodes during
his or her first year of life. The same 18-month-old child
living in a rural area of Chile in a house of wood, with access
to clean water and relatively adequate disposal of sewage,
including stools, and receiving food that potentially could be
contaminated but that most probably will be cooked will
have two to three episodes of diarrhea per year.9,10
Breast-feeding plays a key role in prevention of diarrheal
disease in infants.11,12 Breastfed infants, especially infants
younger than 3 months of age, suffer fewer episodes of diarrhea than do infants who are not breastfed.13 Partial breastfeeding confers protection that is intermediate between that
gained by infants who are exclusively breastfed and that of
infants who are exclusively bottle-fed. Other measures such
as vitamin A and zinc supplementation have been shown to
have a positive impact in decreasing morbidity and mortality
associated with Shigella infections in Bangladesh.14
The relative contribution of different pathogens accounting for diarrhea episodes will vary depending on the specific
area of residence. Children living in areas with poor sanitation are at higher risk for fecal-oral transmission, and food
and water contamination will result in a higher risk of acquiring infection caused by enteric bacteria and parasites. In contrast, in areas of better sanitary conditions, bacteria are a less
common cause of diarrhea in children, with most cases being
caused by enteric viruses.15-17 Severe outcomes (hospitalization and death) associated with acute diarrhea show a diver-

gent pattern in areas with different levels of economic development. Unfortunately but not unexpectedly, 85 percent of
diarrheal deaths occur in the less privileged countries of the
world. In these low-income countries, diarrhea accounts for
as many as 21 percent of all deaths in children younger than
5 years of age.2,3 These figures are striking when compared
with the more economically developed world, where diarrhea is associated with fewer than 1 percent of deaths in
children.2 The leading cause of diarrhea-associated hospitalizations and death is dehydration. The risk of having severe
dehydration increases if episodes are more frequent or are
more severe and if the possibility of appropriately managing
dehydration, including accessibility to oral rehydration solutions and to emergency departments and hospitals, is not
readily available. In addition, the educational level of parents
is critical in preventing and recognizing severe illness. In this
context, children living in areas where specific pathogens
tend to cause severe diarrhea-vomiting episodes (eg, cholera)
and where accessing oral or IV rehydration is difficult will be
at the highest risk for the development of severe dehydration.
The possibility of dying will be highly concentrated in these
settings within the poorest areas of the world, mainly underdeveloped areas of Asia, sub-Saharan Africa, India, and Latin
America. Hospitalization rates for acute diarrhea will not parallel necessarily the trend observed for mortality rates. Hospitalization in many poor countries represents an opportunity that is not readily available. Conversely, in more
developed countries, hospitalization often represents a safety
measure that frequently is overused. Recent estimates suggest
that hospitalization rates for acute diarrhea are higher in middle- and high-income countries than in poorer countries.2

Relevant Pathogens
Causing Diarrhea
More than 20 viral, bacterial, and parasitic enteropathogens
are associated with acute diarrhea. Enteropathogens most
frequently reported are shown in Table 1. Case-control studies required to determine the true pathogenic role of different
microorganisms are scarce in the economically developing
world. Available information is based mostly on descriptive
studies that group children younger than 5 years of age and
that do not define clearly the severity of disease nor diarrhea
characteristics (watery versus dysenteric stools). Prevalence
of specific pathogens is dependent on these variables and,
thus, proposing age-adjusted prevalence rates for specific
pathogens is difficult. Certain generalizations can be made
and are discussed in the following section.

Enteric Viruses
Four enteric viruses cause diarrhea in humans: rotavirus,
astrovirus, human caliciviruses (divided into 2 genera, norovirus and sapovirus), and enteric adenoviruses. Independent
of economic development, rotavirus is the most common
cause of severe, acute nondysenteric diarrhea in most areas of
the world where it has been studied. Rotavirus causes from
25 to 70 percent of cases in children of gastroenteritis severe

Pediatric diarrheal illness in the developing world

127

Table 1 Enteropathogens Frequently Associated With Acute Diarrhea in Children

Microorganisms
Viruses
Rotavirus
Human calicivirus
Norovirus
Sapovirus
Astrovirus
Enteric adenovirus
Bacteria
Diarrheagenic E. coli
EPEC*
ETEC
STEC
EAEC
EIEC
Shigella spp.

Salmonella enteritidis
Campylobacter spp.
Vibrio cholerae
Parasites
Giardia lamblia
Entamoeba histolytica

Cryptosporidium parvum
Cyclospora cayetanensis
Isospora belli

Highlights
Most common cause of diarrhea in children <24 months of age
Causes outbreaks and sporadic cases of gastroenteritis
Outbreaks occur in closed populations; common source outbreaks associated with
ingestion of contaminated food and water
Less common; causes sporadic diarrhea episodes in children.
Infection usually occurs in children <4 years of age.
Diarrhea associated mainly with serotypes 40 and 41, most often in children.

Acute endemic and epidemic diarrhea in infants, occasionally associated with persistent
diarrhea
Infantile diarrhea in economically developing countries and travelers diarrhea in all ages
Bloody diarrhea and hemolytic uremic syndrome in children <5 years of age,
hemorrhagic colitis and thrombotic purpura following diarrhea in adults
Acute and persistent diarrhea in infants
Similar to disease caused by Shigella, spp
Common cause of watery diarrhea and dysentery in children 12-48 months of age; S.
flexneri is more common than S. sonnei in developing areas; significant antimicrobial
resistance worldwide
Zoonotic; common cause of foodborne outbreaks
Zoonotic; mainly due to contact with poultry
Severe watery diarrhea; O1 is endemic in South Asia and Africa, and O139 is epidemic
in Asia
Cause of diarrhea in all ages worldwide; asymptomatic shedding is common
Prevalent in economically developing countries; less common in children; E. dispar is
not pathogenic
Associated with large waterborne outbreaks; person-to-person transmission occurs
commonly
Outbreaks associated with food and water; direct person-to-person transmission has
not been documented
Infection more common in tropical and subtropical areas and in areas of poor sanitation

*EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic E. coli; STEC, Shigatoxin-producing E. coli; EIEC, enteroinvasive E. coli;
EAEC, enteroaggregative E. coli.

enough to require hospitalization.2,18-20 Rotavirus occurs

most commonly in children younger than 2 years of age and
uncommonly after they reach 5 years of age. In areas with low
economic development, infection occurs more commonly in
infants younger than 12 months of age compared with more
industrialized areas, where infection occurs more commonly
in children 12 to 24 months of age.21 Virtually all children are
infected by the time they reach 3 years of age.
Astrovirus, human caliciviruses, and enteric adenovirus
together represent as many as 20 to 30 percent of cases of
diarrhea in areas where bacterial infections are found less
commonly. In areas with less economic development, these
viruses also infect children, but their relative contribution to
the total number of cases is diluted in lieu of the higher rate of
bacterial infections. Enteric adenoviruses belonging to serotypes 40 and 41 have been associated with persistent diarrhea, generally in children younger than 4 years of age.20
Noroviruses have a worldwide distribution, are genetically
and antigenetically diverse, and cause both sporadic disease
and common-source outbreaks.17,20,22 Eight antigenic types

of astrovirus cause diarrhea in young children.23 All enteric

viruses can cause asymptomatic infection.

Bacterial Pathogens
Diarrheagenic Escherichia coli include the following clinically
relevant pathotypes: enteropathogenic (EPEC), enterotoxigenic (ETEC), shigatoxin-producing (STEC), enteroaggregative (EAEC), and enteroinvasive (EIEC). As a group, diarrheagenic E. coli are the most common bacteria detected in
studies from economically developing countries, causing 30
to 40 percent of acute diarrhea episodes in children.21,24-30
EAEC, EPEC and ETEC cause endemic watery diarrhea and
have been reported most frequently in children younger than
2 years of age.21,31 ETEC is a common cause of travelers
diarrhea in economically developing countries. EIEC causes
diarrhea generally with fever and blood indistinctive from
Shigella infections in all ages. STEC has been reported as a
common cause of bloody diarrhea from some developing
countries (mainly Chile and Argentina), but these findings
have not been universal. Geographic location and methods

128
used for establishing the diagnosis have an important influence on incidence and prevalence.32 For instance, in the
United States, E. coli O157:H7 is the STEC most frequently
reported, whereas in Argentina and Chile other non-O157
STEC strains cause most cases of bloody diarrhea and hemolytic uremic syndrome (HUS).32,33 STEC has been established
as the main etiologic agent of HUS.32 EAEC has been associated with persistent diarrhea.9
Enteric infections associated with Shigella spp., Salmonella
spp., Campylobacter jejuni/coli, and other bacteria (Vibrio cholerae, Aeromonas spp, Plesiomonas spp.) occur more commonly in areas where development and hygiene are inadequate.21 In these areas, children commonly shed these
organisms in the absence of diarrhea, confounding their
pathogenic role in acute diarrhea episodes.9,21-23,28,34 Severity
of Shigella infections can increase significantly in malnourished children, causing severe complications such as toxic
megacolon, intestinal perforation, and HUS associated with
S. dysenteriae type 1 infections. C. jejuni/coli is associated with
consumption of poultry and the presence of poultry in the
households; prevalence is variable among different areas,
with most cases occurring in children younger than 24
months of age. Campylobacter also can be shed asymptomatically.35-37
The principal reservoirs of nontyphoidal Salmonella organisms are animals, including poultry, livestock, reptiles, and
pets. The major vehicles of transmission are foods of animal
origin, including eggs, dairy products, and poultry, and are
most significant in areas where potentially contaminated
food products (mainly derived from poultry) are processed in
large scale. Foodborne outbreaks caused by nontyphoid
Salmonella strains affect children and adults worldwide.38
Differences in seasonal prevalence of specific pathogens
and epidemic curves need to be considered before proposing
probable microorganisms causing acute diarrhea in a child.
In general, rotavirus predominates during colder months,
although infection tends to occur year-round in tropical areas
and in some temperate climates. Bacterial infections predominate during warmer months. Salmonella enteritidis and
C. jejuni/coli infections can be epidemic in a given area during
a defined time period.37
V. cholerae needs to be considered among the possible
causes in children living in endemic areas (currently, south
Asia and Africa). V. cholerae O1, V. cholerae O139, and
S. dysenteriae 1 can cause epidemics and pandemics in areas
of extreme poverty and/or in areas with massive population
migrations associated with natural disasters or long-lasting
wars.39
Mixed infections can represent as many as 15 to 20 percent
of diarrhea episodes. The possibilities of coinfections occurring reflect the most common organisms circulating within a
community. Mixed infections are not necessarily more severe
compared with infections caused by a sole pathogen.9,21,24,26,27-29

Parasites
Infections caused by protozoa and helminths occur mainly in
areas where potable water is not readily available and/or

M. ORyan, V. Prado, and L.K. Pickering

where environmental sanitation is significantly deteriorated,
as occurs in markedly deprived areas of the economically
developing world. These infections decrease significantly in
areas that have solved these basic sanitary deficiencies.
Entamoeba histolytica can cause acute nonbloody and bloody
diarrhea, necrotizing enterocolitis, ameboma, and liver abscess and needs to be differentiated from morphologically
identical nonpathogenic strains such as Entamoeba dispar and
Entamoeba moshkovskii.40 These species are excreted as cysts
and trophozoits in stools of infected people, and infection is
initiated most commonly by ingesting fecally contaminated
water or food containing E. histolytica cysts.
Giardia lamblia is a binucleate flagellated protozoan parasite with trophozoite and cyst stages. Giardia is spread by the
fecal-oral route through ingestion of cysts, and infection is
limited to the small intestine and biliary tract. Outbreaks in
childcare centers have reflected person-to-person spread and
have demonstrated high infectivity.41-43 Foodborne and
waterborne transmission also occur. Infection often is
asymptomatic or mildly symptomatic. Symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive occurring typically in the
youngest children. Infection rates in the economically developing world are high, as exemplified by a study in slum areas
of Peru, where seroprevalence reaches 40 percent by the time
infants reach the age of 6 months.44
Cryptosporidium parvum is a spore-forming coccidian protozoon. Other spore-forming protozoa that cause diarrhea
are Isospora belli, Cyclospora cayetanensis, and Microsporidium
spp.45,46 Cryptosporidium spp. are ubiquitous and, because
Cryptosporidium infects a wide variety of animal species, infected individuals often have a history of animal contact.47
Person-to-person spread, particularly in household contacts
and child-care centers, is well-documented and shows that
the organism is highly infectious.48-50 Waterborne outbreaks
of cryptosporidiosis occur and can reach massive proportions.51 The clinical manifestations of illness in immunocompetent persons include watery diarrhea, abdominal pain, myalgia, fever, and weight loss.47,49,50,52,53 Infants infected early
in life may develop chronic diarrhea and malnutrition.54 Cyclosporiasis occurs worldwide but is endemic in some countries such as Peru and Haiti. Sporulation outside the host
produces infectious organisms; therefore, direct person-toperson transmission does not occur. Outbreaks have been
associated with contaminated food and water. Clinical signs
and symptoms include watery diarrhea, which usually is selflimited.55 Isosporiasis occurs more commonly in tropical and
subtropical climates and in areas of poor sanitary conditions.
Infection occurs by the fecal-oral route and has been linked to
contaminated food and water. Oocysts are passed unsporulated and require exposure to oxygen and temperature lower
than 37 C before becoming infective.56 Watery diarrhea is
the most common symptom. Two microsporidia species are
important causes of chronic diarrhea in immunocompromised people, especially people infected with human immunodeficiency virus (HIV).57

Pediatric diarrheal illness in the developing world

Clinical Considerations
and Diagnosis
Diarrhea is a manifestation of intestinal dysfunction that results in increased stool output resulting in loss of water,
electrolytes, and/or nutrients. The most commonly used definition of diarrhea is three or more loose stools during a
24-hour period, but physicians should consider the normal
regular evacuation pattern of the affected individual before
defining if he/she has diarrhea. In breastfed infants, for example, normal stool patterns include passages of six to eight
liquid stools per day. Fever, vomiting, abdominal cramps,
and dehydration of different magnitudes can accompany diarrhea. High fever and intense vomiting can be present in
viral and bacterial infections and are not pathognomonic of a
given pathogen. Acute diarrhea accompanied with urgency
to defecate and tenesmus suggests an inflammatory/invasive
process of the colon as described below.
Most cases of acute diarrhea will resolve within 7 days.
Persistent diarrhea lasting longer than 14 days has been associated with several infectious and noninfectious causes,
including EAEC, Yersinia enterocolitica, enteric adenovirus,
Isospora belli, Cyclospora cayetanensis, G. lamblia, Microsporidium, C. parvum, transitory lactose intolerance, and moderate to severe malnutrition.20,58-61 As indicated previously, the
risk of acquiring infection with several enteric pathogens increases in areas where potable water is not readily available.
Initial clinical assessment of a child with diarrhea should
focus on obtaining an accurate evaluation of hydration and
nutritional status. The first is critical for management because
morbidity and mortality are associated predominantly with
dehydration. Guidelines for evaluation and quantification of
dehydration can be found elsewhere.62,63 Malnutrition is a
risk factor for a poorer outcome, and physicians should ensure that appropriate actions are taken to avoid nutritional
deterioration that occurs during the acute diarrheal episode
(maintain oral protein/calorie intake). Limiting intake of milk
currently is not recommended for the great majority of children with acute diarrhea; this measure should be considered
only if lactose malabsorption causing persistent diarrhea is
suspected.
Assessment of characteristics of the stool is a key feature in
determining potential pathogens causing an acute diarrhea
episode. Liquid nonbloody stools are associated predominantly with a secretory/small intestinal dysfunction process,
whereas dysenteric (blood and pus) or bloody stools generally are associated with an inflammatory/invasive process of
the colon. Mucous can be present in both situations and
should be differentiated from pus. Table 2 lists the pathogens
most likely to be detected in children with moderate to severe
acute endemic diarrhea living in developing areas.
The ability to obtain an etiological diagnosis in a child with
diarrhea is highly dependent on the quality of the stool sample, the experience and skill of the microbiologist, and resources available for stool evaluation. Appropriate management of the stool sample requires collection of a recently
passed sample directly from the diaper or an appropriately

129
Table 2 Most Commonly Reported Microorganisms Associated With Acute Endemic Diarrhea in Economically Developing Areas by Age Groups and Diarrhea Characteristic*
All Episodes
<2 year

25 years

Watery/mucous
<2 year

25 years

Dysenteric/bloody
<2 year

25 years

Microorganisms
Rotavirus
EPEC, ETEC
Astrovirus, Caliciviruses, Enteric
Adenovirus
Shigella flexneri, Shigella dysenteriae
type 1
Campylobacter jejuni
STEC, EAEC
ETEC
S. flexneri, S. dysenteriae type 1
Rotavirus
Non-typhi Salmonella
Giardia lamblia
Rotavirus
EPEC, ETEC
Astrovirus, Caliciviruses, Enteric
adenovirus
ETEC
S. flexneri/S. dysenteriae type 1
Rotavirus

S. flexneri, S. dysenteriae type 1

STEC
C. jejuni
S. flexneri/S. dysenteriae type 1
STEC
Non-typhi Salmonella
Entamoeba histolytica

*List generated by consensus of authors based on literature review

and personal experience. The list order of the pathogens represents a gross approximation from higher to lower probability.
In areas where infection is endemic.
Associated with presence of animals (poultry) in the household.
Mainly in areas where hygiene is markedly deficient.

obtained rectal tube or swab sample. Areas of stools with pus,

blood, or mucous are optimal for sampling. All samples
should be inoculated immediately or placed into transport
media and immediately transported to the laboratory.
Once in the laboratory, the number and types of selective
media used and the number of suspicious colonies studied
will impact the ability to identify an enteric pathogen in
stools. A universal consensus guideline for stool evaluation is
not available, and different laboratories have established their
own guidelines.64,65 Culture techniques used in microbiology
laboratories should be able to identify Shigella, Salmonella,
Yersinia, and Campylobacter. Because selective media for
Campylobacter are expensive, identifying this microorganism
may be difficult in economically developing countries.66
Identifying other enteropathogens requires additional testing
not always available in diagnostic microbiology laboratories.
Enteric viruses such as rotavirus, enteric adenovirus, astrovirus, and the parasite G. lamblia can be detected by commercially available techniques with acceptable sensitivity and
specificity.18,67 Detection of E. coli pathotypes and calicivi-

M. ORyan, V. Prado, and L.K. Pickering

130
ruses are available in selected research or reference laboratories.15,68,69 Studies suggest that detection of low inoculumviable microorganisms such as Shigella spp. or differentiation
of E. histolytica from E. dispar can be improved significantly
by using genetic amplification techniques such as real-time
polymerase chain reaction (PCR), but the clinical and epidemiological relevance and applicability of detection based on
gene amplification in culture-negative individuals will require further clarification.70,71 The possibility of incorporating new molecular techniques for routine diagnostic testing
in most economically developing countries will require appropriate cost-benefit analyses of these new techniques.
Most episodes of diarrhea, independent of etiology, are
mild, self-limited, and not affected by specific antimicrobial
treatment. In addition, the numbers of different pathogens
that can cause acute diarrhea are significant, and diagnostic
testing is difficult to perform and expensive. This concern is
especially important in economically developing countries
where resources are limited. In addition, in most laboratories, stool culture results are reported 48 to 72 hours after
collection of the sample, a time period during which patients
with acute diarrhea may have been treated and most of whom
will have improved significantly with or without specific
treatment.
Considering the limitations of enteropathogen detection,
our current recommendation for physicians managing children with acute diarrhea is to focus diagnostic efforts on
children in whom the likelihood of obtaining a pathogen will
be reasonable and will make a difference for the child or
his/her potential contacts. Neonates and immunocompromised patients with diarrhea should be studied because they
have a higher risk for acquiring invasive or unusual pathogens. Individuals involved in foodborne or waterborne outbreaks and, when possible, children in childcare centers
should be studied for epidemiological and preventive reasons. Children with persistent diarrhea also should be studied, although the yield may be low. Children with moderate
to severe bloody diarrhea, especially children requiring hospitalization, should be studied to detect Shigella, STEC, Salmonella, Campylobacter, and E. histolytica in areas where these
infections are prevalent. Appropriate case-control studies
performed on a regular basis in different areas represent the
best strategy to define the most probable microorganisms
causing disease. These studies are an invaluable aid in empiric management of children with diarrhea residing in these
areas.
Stool assays for rapid identification of episodes likely to be
caused by an invasive organism have been proposed. Stool
leukocytes, lactoferrin, and occult blood have been the most
common fecal screening tests evaluated.72-75 In general, children with diarrhea who have one or more of these elements in
stools will have a higher probability of harboring an invasive
pathogen, but the clinical usefulness of these nonspecific
tests is limited. A metanalysis concluded that these tests perform moderately well in suggesting invasive pathogens such
as Shigella, Salmonella, EIEC, and Campylobacter in economically developed countries but poorly in developing countries.72 Considering that current guidelines support treat-

ment of moderate to severe invasive diarrhea caused by

Shigella spp. and not STEC, that the additional benefit of
microscopic over macroscopic/clinical findings in severe
cases is unclear, and that fecal screening tests do not help in
discriminating between these pathogens, we consider these
tests to be of limited benefit for most children in the economically developing world. To assist in the macroscopic evaluation of a stool specimen, screening tests could be considered
in a febrile child with severe watery diarrhea if Shigella is
suspected. A positive test could favor administering antimicrobial treatment while awaiting culture results. In a febrile
child with grossly bloody diarrhea, these tests will not provide benefit and will increase management costs of the episode unnecessarily.

Treatment
The major therapeutic intervention for all infants, children,
adolescents, and adults with diarrhea consists of fluid and
electrolyte therapy.76 Antimicrobial therapy is not indicated
for most patients with diarrhea because most enteric infections are self-limited or are caused by agents for which antimicrobial therapy is not available or effective. In addition,
concerns inherent with antimicrobial therapy include safety
and tolerability of antimicrobial agents, particularly in immunocompromised people, the young and the elderly; potential
enhancement of virulence factors; prolongation of the carrier
state; and development of resistance.77,78
Antimicrobial agents are given to patients with diarrhea
caused by select bacterial and protozoal pathogens (Table 3).
The purpose of this therapy is to reduce signs, symptoms,
and duration of disease; prevent morbidity and mortality;
eradicate fecal shedding of the causative organism; and eliminate transmission. Benefits and limitations of antimicrobial
therapy should be considered when approaching a patient
with gastroenteritis. When antimicrobial therapy is appropriate, selection of a specific agent should be made based on
susceptibility patterns of the pathogen or information on local susceptibility patterns obtained from active surveillance
studies if the first is not available. Because resistance among
enteric organisms can spread rapidly, constant monitoring of
susceptibility patterns is important for selecting appropriate
agents for therapy when indicated.

Bacterial Resistance
Enteric bacterial pathogens are becoming increasingly resistant to antimicrobial agents for many reasons, including inappropriate and excessive use of antimicrobial agents in humans79 and inclusion of various classes of antimicrobial
agents as growth promoters in feeds of livestock.80-82 Recent
use of an antimicrobial agent in a human, particularly within
the previous 4 weeks, is a documented risk factor for development of infection or colonization with resistant bacterial
pathogens.79
In many countries of the world, an increase in antimicrobial resistance patterns has occurred among the major bacterial enteric pathogens, including Shigella spp, E. coli patho-

Pediatric diarrheal illness in the developing world

131

Table 3 Antimicrobial Therapy for Enteric Pathogens

Organism

Drug of Choice

Campylobacter Spp.

Azithromycin or erythromycin

Clostridium difficile
Nontyphi Salmonella

Metronidazole
Cefotaxime
Ceftriaxone
Fluoroquinolone
Fluoroquinolone
Azithromycin

Shigella

Vibrio cholerae

Doxycycline if >8 years of age

TMP/SMX

E. histolytica

Metronidazole followed by Iodoquinol

G. lamblia

Metronidazole

Cryptosporidium parvum
Isospora belli
Cyclospora cavetanensis

Nitazoxanide
TMP/SMX
TMP/SMX

Alternative Drugs
Fluoroquinolone
Tetracycline
Gentamicin
Oral vancomycin
Ampicillin
TMP/SMX
Chloramphenicol
Nalidixic acid
TMP/SMX
Ceftriaxone
Fluoroquinolone
Chloramphenicol
Furazolidone
Tinidazole
Secnidazole
Ornidazole
Tinadazole
Quinacrine
Furazolidone
Paramomycin (pregnant women)
Paramomycin azythromicin

types associated with diarrhea, C. jejuni/coli, and Salmonella

spp. These resistance patterns frequently have shown a progressive increase over the course of time and have demonstrated resistance to several classes of antimicrobial agents.

ommended therapy of people infected with Shigella includes

fluoroquinolones, azithromycin, and extended-spectrum
cephalosporins. To optimize therapy, one should know local
susceptibility patterns.

Shigella Species

C. jejuni and C. coli

Shigella strains have become progressively resistant to multiple antimicrobial agents since the introduction of sulfonamides, and multiresistance is a global problem. Resistance of
S. flexneri and S. sonnei, the most frequent causes of shigellosis, has developed to tetracycline, chloramphenicol, streptomycin, ampicillin, kanamycin, and TMP-SMX less than 10
years after each was licensed for use in humans. Data from the
National Antimicrobial Resistance Monitoring System
(NARMS) in the United States show that in 2001 resistance of
Shigella isolates (70% of which were S. sonnei) to ampicillin
was approximately 80 percent and to TMP-SMX was 47 percent.83 None of the isolates was resistant to ceftriaxone, imipenem, or gentamicin, and only one isolate (0.3%) was resistant to ciprofloxacin. Susceptibility testing against
azithromycin was not performed. Similar resistance patterns
have been reported from England and Wales,84 Canada,85
and Germany.86 In economically developing countries, current data from Chile indicate that most Shigella spp. are resistant to ampicillin, TMP/SMX, tetracycline, and chloramphenicol and are susceptible to ciprofloxacin and extended
spectrum cephalosporins.87,88 Reports from Bangladesh,
where shigellosis is highly endemic, show a similar resistance
pattern.89 Outbreaks caused by multiresistant S. dysenteriae
type 1, including strains resistant to ciprofloxacin, has been
reported.90,91 Neither ampicillin nor TMP-SMX should be
considered appropriate empiric therapy for shigellosis. Rec-

More than 16 species of Campylobacter have been identified,

but not all of them infect humans. Most episodes of Campylobacter-associated diarrhea are caused by C. jejuni/coli
strains. Azithromycin, erythromycin, or fluoroquinolones
are the agents of choice for therapy of gastroenteritis caused
by C. jejuni/coli. Erythromycin resistance in most economically developed and developing countries generally is stable
at less than 5 percent,92-94 including strains isolated from
children.95,96 However, in some countries, higher resistance
rates to erythromycin have been reported.77,95,97 Strains that
demonstrate high-level resistance to erythromycin also manifest resistance to azithromycin and clarithromycin.97
Resistance to fluoroquinolones in human strains has
ranged from 3 to 96 percent. Data from NARMS in the United
States show that in 2001, 18 percent of C. jejuni/coli isolates
were resistant to ciprofloxacin.83 In studies from countries
throughout the world, including Austria, Canada, Germany,
Finland, Norway, and the Netherlands, resistance has increased from 9 to 30 percent.77 A high frequency of crossresistance has been reported among the fluoroquinolones.77,98-100 In several countries, the increase in
fluoroquinolone resistance coincided with initiation of administration of a fluoroquinolone compound to animal food
or use in veterinary animals.83,84,100 These studies highlight
the importance of being familiar with local or regional resistance patterns when making decisions about therapy.

M. ORyan, V. Prado, and L.K. Pickering

132
Table 4 Vaccines Currently or Soon-to-Be Available to Prevent Enteric Infections
Organism

Vibrio cholerae
Salmonella serotype typhi
Rotavirus

Vaccine

Type

CVD-103HgR
B-WC
Ty21A
ViCPS
Monovalent
Pentavalent

Live attenuated
Inactivated
Live attenuated
Polysaccharide
Live attenuated
Live attenuated

Salmonella Species
The type of syndrome produced by nontyphoidal Salmonella
strains dictates the selection and duration of antimicrobial
therapy. Problems with use of antimicrobial agents among
persons who are nontyphoidal Salmonella carriers or in patients who have mild gastroenteritis are lack of clinical effectiveness,101 conversion of intestinal carriage to systemic disease with bacteremia,102 production of bacteriologic and
symptomatic relapse,101,102 development or selection of resistant strains, and prolonged periods of fecal excretion.102 In
NARMS data from the United States, the 16 most common
serotypes accounted for 80 percent of isolates that were serotyped. The two serotypes most commonly identified, Typhimurium (23%) and Enteritidis (20%), showed differences
in resistance to five or more antimicrobial agents, 35 percent
and 1 percent, respectively. Only 2 percent of isolates were
resistant to TMP-SMX, 2 percent to ceftriaxone, and 0.2 percent to ciprofloxacin. Worldwide antimicrobial resistance to
Salmonella strains is a common finding,103-106 but specific
serotypes responsible for causing infection and the degree of
resistance of specific serotypes differ by geographic location.
Data collected from seven cities in Argentina reported resistance rates of 35 percent, 14 percent, and 42 percent against
ampicillin, chloramphenicol, and TMP/SMX, respectively.107

Shiga Toxin-Producing E. coli (STEC)

The STEC most commonly isolated in the United States is E.
coli 0157:H7. Other STEC types, such as O26:H11, O45,
O55:H7, O55:H10, O111:H8, O111:H30, O111:H34,
O113, O121, and O145, are found more commonly in other
countries.33 Antimicrobial resistance patterns of various animal and human STEC strains have been reported, with resistance noted to ampicillin, sulfamethoxazole, tetracycline,
streptomycin, and TMP-SMX.108 Resistance is associated
with country of origin or source of the isolates tested. In the
2001 NARMS data, of 277 E. coli 0157:H7 isolates tested, 9
percent were resistant to one or more antimicrobial agents, 5
percent were multidrug-resistant, 5 percent were resistant to
sulfamethoxazole, 5 percent to tetracycline, 2 percent to ampicillin, and 2 percent to streptomycin; none was resistant to
ceftriaxone, ciprofloxacin, amikacin, or imipenem.83 Data
from Chile for O157 and non-O157 STEC isolates obtained
from clinical and food origins showed that strains were 100
percent susceptible to ampicillin, TMP/SMX, ciprofloxacin,
chloramphenicol, tetracycline, aminoglycosides, and extended spectrum cephalosporins.109

Route of
Administration
Oral
Oral
Oral
Intramuscular
Oral
Oral

Age
>2 years
all ages
>6 years
>2 years
2,4 months
2,4,6 months

Antimicrobial therapy of children infected with STEC is

not recommended because of the potential for bacteriophage
induction with enhanced cytotoxin production, leading to
development of HUS by certain classes of antimicrobial
agents.110-112 A meta-analysis showed no benefit or increased
risk for sequelae from therapy of children with STEC intestinal infection.113

Effect of Resistance on Clinical

Manifestations and Treatment Options
Clinical manifestations of enteric infections include signs and
symptoms involving the gastrointestinal tract, dissemination
of organisms to sites outside the gastrointestinal tract, neurologic manifestations, and immune-mediated sequelae. People infected with enteric pathogens that are resistant to frequently used antimicrobial agents may manifest as either
clinical or bacteriologic treatment failures114-117 and may
have an extended duration of excretion of viable organisms.114,118

Prevention
The most important aspect in control of diarrheal disease is
hygiene, both general and personal. General issues deal with
clean water, clean food, and appropriate sanitation facilities.
Despite the high-quality water and food supplies available in
the United States and other socioeconomically developed areas of the world, outbreaks of foodborne and waterborne
disease continue to occur, generally due to improper handling and storage of food.119 Personal measures include careful personal hygiene, especially handwashing, and limited
use of antacids, antimotility drugs, and antimicrobial agents.
Promotion of handwashing has proven to be a highly effective measure in decreasing the incidence of diarrhea among
people living in high-risk areas, such as settlements in Pakistan.120 Appropriate diaper-changing facilities and techniques should be available and implemented in childcare
facilities. Breastfeeding in all areas of the world should be
promoted, implemented, and supported.
The number of immunizations available to prevent enteric
infections is scarce but expected to increase in the future with
development of new technologies including delivery mechanisms (Table 4).121 Vaccines against Salmonella serotype
Typhi are the only vaccines against enteric diseases commercially available in the United States (Table 4). Currently, two
vaccines are licensed for cholera prevention. The oral live

Pediatric diarrheal illness in the developing world

genetically attenuated CVD 103HgR (Orochol, Berna Biotech, Bern, Switzerland) has demonstrated 100 percent protection against severe cholera, but protection is not longlasting (14% of individuals living in endemic areas were
protected 4 years after vaccination). This vaccine is indicated
for individuals older than 2 years of age traveling to a choleraendemic area.122 The inactivated whole cell vaccine with B
subunit has proven to be safe and effective up to 3 years after
vaccination in Bangladesh. Two doses conferred 70 percent
protection in adults but only 25 percent in children.123 Live
genetically attenuated vaccines for Shigella are in different
stages of development. These vaccines are serotype-specific,
meaning that multivalent vaccines will be required to protect
against the most prevalent serotypes worldwide (eg, Shigella
dysenterie type 1, S. sonnei, and S. flexneri 2a, 3a, and 6).124
Vaccines to prevent rotavirus (RV) have been shown to be
effective,125 but the association of the rhesus RV vaccine with
intussusception resulted in withdrawal of this vaccine from
the U.S. market in October 1999, following licensure in August of 1998. This vaccine has not been licensed in any other
country of the world. A vaccine of lamb origin has been used
in China for years, but its safety and efficacy profile are unknown. Phase III studies evaluating two new vaccines to prevent infection with RV are nearing completion or have been
finalized. The efficacy of these vaccines against severe RV
gastroenteritis surpasses 80 percent and against any RV gastroenteritis, regardless of severity, is approximately 70 percent. One vaccine is a G1 human attenuated monovalent
vaccine that has been tested in Latin America and Finland.
The other vaccine is a G1, G2, G3, G4, and P1A[8] bovinehuman reassortant pentavalent vaccine tested in the United
States, Europe, and in a few Latin American countries. The
monovalent RV vaccine has been licensed in Mexico for infants and should be available in early 2005 (Vaccine Enteric
Disease Meeting, Jamaica 2004). There are no licensed vaccines against parasitic enteric infection. Vaccines against
other enteric pathogens and improved vaccines against
pathogens for which immunizations are available are undergoing study.121
Nonspecific agents that may interfere with microbial adherence or with the virulence mechanisms of toxins are being
developed and evaluated, as are compounds that will serve as
competitors for binding of organisms or toxins to receptors in
the intestine. The use of glycoconjugates and probiotics in
prevention and treatment of diarrheal disease may be beneficial and is undergoing investigation.126
Breastfeeding provides young infants with significant protection against morbidity and mortality due to diarrheal disease.127-129 In part, breastfeeding protects against diarrhea
through decreased exposure of breastfed infants to organisms
present on or in contaminated bottles, food, or water. In
addition, immunologic components in human milk protect
infants against disease after exposure to an infectious agent.

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