Traveler's diarrhea in children

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Traveler's diarrhea in children: New insights and existing gaps
Shai Ashkenazi, Eli Schwartz
PII: S1477-8939(19)30207-8
DOI: https://doi.org/10.1016/j.tmaid.2019.101503
Reference: TMAID 101503
To appear in: Travel Medicine and Infectious Disease
Received Date: 16 July 2019
Revised Date: 15 October 2019
Accepted Date: 21 October 2019
Please cite this article as: Ashkenazi S, Schwartz E, Traveler's diarrhea in children: New insights
and existing gaps, Travel Medicine and Infectious Disease (2019), doi: https://doi.org/10.1016/
j.tmaid.2019.101503.
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Traveler's diarrhea in children: New insights and existing gaps
Shai Ashkenazi1,2
, Eli Schwartz3,4
1
Adelson School of Medicine, Ariel University, Ariel, 2
Schneider Children’s Medical Center of Israel,
Petach Tikva, 3
Center for Geographic Medicine and Tropical Diseases, Sheba Medical Center, Tel
Hashomer, 4
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Key words: Travel, gastroenteritis, enteric infection, children, resource-poor countries
Correspondence: Shai Ashkenazi, MD, MSc
Adelson School of Medicine
Ariel University
Ariel 40700, Israel
Phone: +972-3-645 3139
E-mail: shaias@ariel.ac.il or ashai@post.tau.ac.il
There are no relevant conflicts of interests to declare

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Abstract
The number of children accompanying their parents in international travel is increasing steadily, and with
the rising global migration, children more frequently accompany their parents or caregivers for visiting
friends or relatives (VFR). As compared to travel for tourism, VFR children are at higher risk of acquiring
local diseases, as they more often stay in rural areas in resource-poor locations, have longer periods of visit,
are less likely to attend pre-travel consultations, and less frequently adhere to recommended precautions.
Travelers’s diarrhea (TD) is the most common travel-associated illnesses in children. This review
updates the existing knowledge on TD in children, regarding its distinctive epidemiology, risk factors,
preventive measures, clinical manifestations, complications, causative microorganisms and management.
Despite the limited focused research on pediatric TD, which challenges the formulation of children-oriented
evidence-based guidelines, practical recommendations are suggested.
1. Introduction
Although traveling children present distinct characteristics and in several aspects are a specifically
vulnerable travel group, they are still under-represented in the travel literature, with limited focused
epidemiologic and clinical data, leading to challenges in the formulation of children-oriented guidelines,
especially regarding their management [1]. Since diarrhea is one of the most common travel-associated
illnesses, this review intends to provide an update on existing knowledge on this topic in children, suggest
practical recommendations regarding its prevention and management, and in addition highlight areas
requiring further research and progress.
1.1. International travel
According to the recent report of the United Nations World Tourism Organization (UNWTO), an
annual increase of about 4% in international travel for the last consecutive eighth years resulted in about
1,323,000,000 persons crossing international borders in 2017, including to low-income locations in Asia,
Africa, Central America and other places [2]. Global tourism obviously presents enormous social and

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economic benefits, especially to low-income countries; it has been estimated that international travel
accounts for about 10% of the world gross domestic product, 7% of global trade and 10% of employment
[2].
Unfortunately, international travel presents also several negative impacts, of which one of the most
important is health-related conditions [3,4], with special risks among immune-compromised populations [5-
7]. Acute diarrhea is usually the most common medical condition reported among travelers [8-12]. It
presents in up to 65% of travelers, depending on the destination and travel characteristics, and is associated
with considerable inconvenience, expenses, morbidity, hospitalizations and complications.
1.2. Child travel
Based on national statistical data on international travel [13-15] and on attendance to pre-travel
consultation centers [16-18], children represent a wide range of 8% to 31% of all travelers. The rate at the
Center for geographic Medicine and Tropical Diseases in Tel Hashomer (Israel) during 2016 to 2019 was
11.4% of all travelers attending the center. The wide range relates to the specific location and its population,
reason for travel, type of pre-travel clinic and also to the precise age limitation of the pediatric group: ≤16
years [19,20], <18 years [16] or <19 years [21] . Anyhow, the number of children accompanying their
parents in international travel is increasing steadily; it was concluded by the Centers for Disease Control and
Prevention (CDC) that children are the fastest growing population of travelers in the United States [22].
The purpose of pediatric travel is changing, with resultant clinical implications. Although tourism is
still the major reason for travel, with the increasing global migration, children more frequently accompany
their parents or caregivers for visiting friends or relatives (VFR). Data from pre- and post-travel studies and
from diverse locations have shown that the proportion of children traveling internationally for VFR ranged
between 2% to 53% [11,16,19-21,23,24]. When compared with adults, VFR was usually more common
among traveling children [23,25-27]. The difference is of clinical relevance because, as compared to travel
for tourism, VFR children are at higher risk of acquiring local diseases, including traveler's diarrhea, as they
often stay in rural areas in resource-poor locations, have longer periods of visit, are less likely to attend pre-

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travel clinics, and less frequently adhere to recommended precautions [16,25,27,28]. The main destinations
of the traveling children are South Asia, sub-Saharan Africa and Central America [20,23,25], but also
Europe and the Middle East [21]. The relative representation of these destinations in the various reports on
traveling children differs significantly.
1.3. Source of data
For the purpose of this review, we searched online the PubMed, Embase, Google Scholar and
Cochrane Library with the key words [diarrhea or gastroenteritis] and [travel or traveler* or traveller*] for
the period 2001-2019. Data related to the various aspects of traveler’s diarrhea in children were extracted
from these publications and from those in the authors’ libraries and analyzed.
It should be noted first that a considerable portion of previous data on pediatric travel-related health
issues were based on single-center experiences. Although valuable, these data often included small study
numbers, were limited to a specific location and population, and sometimes reported only on certain aspects
of the topic, such as children attending emergency departments [17,19,20] or hospitalized after international
travel [29]. Examples of such centers include the Boston Area Travel Medicine Network in the US [4,11,26];
the University of Zurich Center for Travel Medicine in Switzerland, which is a World Health Organization
(WHO) Collaborative Center for Travelers Health [20]; the University of Munich Travel Clinic [30]; the
Spanish Tropical Medicine Network in Spain [28]; the Center for geographic Medicine and Tropical
Diseases in Tel Hashomer, Israel [21], the Travel Clinic of Aava Medical Center in Helsinki, Finland
[12,31], among others. In the past, most studies on travelers have been performed in adults, limiting the
ability to suggest pediatric-specific recommendations [8,32].
It is encouraging that large, multicenter-based, broader data are recently more often utilized to
elucidate health issues related to pediatric travel. Of these, the Global TravEpiNet (GTEN) consortium is one
of the most promising [16,23,26]. This consortium currently includes 27 travel nationwide clinics and
practices in the US providing pre-travel consultation and post-travel care to international travelers. The
consortium supplies analyses of travel demographic characteristics and health issues. A review of a large

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cohort of 3,332 children (<18 years) of this consortium , which were about 10% of the 32,099 travelers,
presented for pre-travel consultation at the participating sites revealed important insights on the traveling
child [16]. Of all traveling children, 1,097 (33%) were aged ≤ 5 years. As compared to adults, children more
often traveled for VFR (36% vs 6%), traveled for >28 days (40% vs 19%) and their destination was Africa
(41% vs 33%).
The GeoSentinel Surveillance Network is the important source of global information of post-travel
consultation [25,27]. This network of the International Society of Travel Medicine (ISTM) and the CDC is
based on travel clinics of 70 sites across six continents that systematically collect information on ill-
returning travelers. Analysis of data from 1591 children returning from 218 global destinations who
presented to the clinics during 1997-2007 documented that children more frequently travel for VFR and
were less likely than adults to attend pre-travel health advice and more likely to be hospitalized [25]. Travel-
associated diseases differed among the pediatric age groups [25]. However, as the data are based on post-
travel consultations, the denominator is missing. The Pediatric Interest Group within ISTM was established
to advance the science of pediatric travel medicine and facilitate the development of evidence-based data
regarding the broad aspects of children travel [1,33].
The Foodborne Disease Active Surveillance Network (FoodNet), which is operated by the CDC,
includes 10 clinical sites which report laboratory-confirmed infections, based on the study of pathogens
commonly transmitted through food products. Since 2004 data regarding international travel among US
residents with enteric infections upon return have been routinely collected. During 2004-2009, 13% of the
64,039 enteric infections studied were travel-associated, of which 24.2% were in traveling children [34]. It
should be mentioned that no denominator of the number of travelers is available in the two last-mentioned
networks.
2. Definition

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Traveler’s diarrhea (TD) is usually defined as passage of ≥3 unformed stools/24 hours, with or without
one or more of the accompanying symptoms of nausea, vomiting, abdominal pain or fever, that develops
during or within 14 days of returning from a travel, usually to a resource-limited location [10,35,36]. The
WHO defines diarrhea as stooling which is more frequent than is normal for the individual, or passage of ≥3
unformed stools/24 hours [37]; this definition might be more appropriate for young children whose stooling
varies considerably. The WHO definition includes therefore mild cases of TD that are not included in the
traditional definition. A study which evaluated the impact of the precise definition showed that the usual
definition detected only 57% of TD cases diagnosed according to the WHO definition [12]. The causative
enteric pathogens were similar in the two defined groups.
3. Epidemiology
3.1. Rate of TD
Most studies have shown that TD is the most common international-travel health problem of children
[20,21,25,30,38,39]. However, the rated of diarrhea among traveling children varies considerably, from
13.5% to 39% [17-21,25,28,30,40], (Table 1). The overall rate of pediatric TD in these 8 publications is
28.6% (1469 TD cases of 5,130 traveling children). The reported rates are influenced by the methodology
of identifying the children with TD, the age group included (≤16 years [17,19,20,28], <18 years [25], <19
years [21] and <20 years [30,40]), the special population studied, reason of travel (tourism or VFR), and
travel destination, which has the major impact (Table 1). VFR children had higher rates of TD than tourist
children [20,25,28]; in a prospective study of 606 traveling children rates of TD among VFR and tourist
children were 21.6% and 5.6%, respectively [28]. There are also occasionally differences in the precise
definition of TD, as some investigators used the broader term of gastrointestinal symptoms [28]. When
compared to adults, most studies observed higher rates of TD among children [25,26,31,35]. Post-travel
cases of chronic diarrhea are not included in this review.
3.2. Risk factors

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The incidence and severity of TD in children are age-dependent. When studied as a separate group,
infants and young children aged ≤2 years [28,40] or ≤4 years [30] had the highest incidence rates of TD,
40% and 32%, respectively, usually with greater severity and higher likelihood of requiring hospitalization.
High rates of TD were also noted in travelling adolescents aged 15-19 [30], 15-20 [40] or 13-18 years [21].
In several studies, girls had higher rates of TD than boys [21,25]. The type of pediatric travel has also an
impact on the rates of TD: children traveling for VFR present higher rates then tourist travelers
[16,24,27,28]. Travel destination has a major impact on the risk of TD, with highest rates usually associated
with children traveling to Africa [19,20,21,30], South Asia [19,21,30] and Latin America [20], although the
local burden changes with time, in accordance with changes in the local hygiene conditions[9].
4. Pre-travel preparations and prevention
4.1.Pre-travel consultation
Attending a clinic specialized in travel medicine is recommended before travel to low-income
locations, especially when traveling with children [11,16,26]. The goals of the pre-travel visit are to prevent
travel-related hazards, including health problems and TD, by discussing behavior and personal hygiene
rules, administering vaccines and suggesting prophylactic medications [16,23,41]. Caregivers should also
receive information on the manifestations of acute diarrhea, how to detect symptoms and signs of
dehydration, the appropriate feeding when TD occurs and the use of oral rehydration solutions (ORS) when
needed. Individualized assessment of the travel risks is performed during the visit, with identification of
travelers at increased risk (i.e. VFR, children with underlying medical conditions). A large study has shown
that children who became ill during or after international travel were less likely to have received pre-travel
consultation [25], similar to the findings in adults [42]. The discussion below focuses on TD; unfortunately,
many of the recommendations for traveling children are not based on randomized controlled trials (RCTs)
[32].
4.2.Hygiene measures

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Although not definitely confirmed by evidence-based studies, dietary precautions and appropriate
behavior, including hand washing with soap before handling food or eating, are recommended to prevent
TD. They should be thoroughly explored during the pre-travel visit, as their implementation is especially
difficult in young children, due to their natural curiosity and the common habit of exploring the environment
with their hands and mouth. It is important to adhere to basic hygiene measures, which are summarized in
Table 2. Most important when travelling to resource-limited countries are safe drinking water (e.g. bottled or
boiled water), consuming only cooked vegetables and peeled fruits, and eating well-cooked food. It is
advisable that adults traveling with children carry readily available foods, such as healthy snacks, to avoid
the pressure of buying food from street vendors. Bathing in swimming pools or lakes of unknown
microbiological quality is not recommended at least not for young children, as it poses a risk for ingestion of
contaminated water.
In an observational study it has been shown that adolescents who did not adhere to hygienic rules had a
higher incidence rate of TD than those who did (p<0.005); no significant difference was observed in the
younger age groups [40]. Although these risk-avoidance strategies were not actually studied in children and
have limited support in adult studies and observations in adolescents – they are still recommended as a key
preventive element since most cases of TD are caused by ingestion of contaminated food or water [9,12].
4.3.Preventive medications
Medications have a very limited role, if any, in preventing TD in children. Prophylactic
administration of bismuth subsalicylate in adults provided up to 65% protection against TD and is
sometimes recommended [9,12,41]. However, as its use in children has been associated with Reye syndrome
(because of its salicylate content) and with significant adverse effects and drug interactions, with no
confirmed efficacy in pediatric travel – its use in children is not recommended [10,32,39,41].
Routine antimicrobial prophylaxis is not recommended in traveling adults [12,35] or children [39].
Administration of systemic antibiotics – such as fluoroquinolones and azithromycin – has shown some
proven efficacy in preventing TD in adults, but the associated adverse effects, the selective pressure on the

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development of bacterial resistance, including the acquisition of multidrug resistant bacteria, and the long-
term detrimental effects on the human microbiome precludes their preventive use [9,10,39,41,43]. They can
be considered in special circumstances with a very high risk of bacterial TD, for example in travelers with
underlying diseases or under immunosuppressive medications, and for a limited duration [9,10]; (in the
United States and many other countries fluoroquinolones are registered for children >17 years). Rifaximin is
a non-absorbable antimicrobial agent that is locally active only against non-invasive enteropathogens [39,
44]. Several RCTs in adults have shown that rifaximin can provide up to 77% protection against TD, with
minimal systemic adverse effects [10,12,39]. According to adult guidelines, when antibiotic prophylaxis is
indicated, rifaximin is recommended [8]. However, it should be remembered that invasive enteropathogens
are relatively more common in children and cause a more severe disease [46] and that rifaximin can be used
in children older than 12 years [44,46].
4.4.Probiotics
Although examined for safety and efficacy in some studies, the use of probiotics to prevent TD is
controversial [10,12,44,47]. Many of the studies were not well-controlled and used diversity of probiotic
strains and doses. A recent systematic review screened 158 publications, of which 6 RCTs were included in
the meta-analysis; only administration of saccharomyces boulardii CNCM 1-745 showed a significant
reduction in the incidence of TD [47]. More data are needed in order to give recommendations on the use of
commercially available probiotics for the prevention of pediatric TD.
4.5.Vaccines
Pre-travel individual immunization review, with administration of vaccines that should have been
given according the local routine immunization schedule during childhood but were missed, is generally
recommended, including rotavirus and hepatitis A vaccines [16,38]. However, the ability to prevent TD by
vaccines is currently very limited [48,49]. An oral cholera (cholera-E.coli) vaccine is available and licensed
in certain locations for children ≥2 years of age [39,49]. The WHO no longer recommends administration of
cholera vaccine for travelers to or from areas with cholera infection [51]. A Spanish retrospective study

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showed that administration of the cholera vaccine reduced the overall incidence of TD from 40% to 23%
with shortening of the duration of diarrhea; some cross-protection against enterotoxigenic Escherichia coli
(ETEC) was suggested [50]. Although TD caused by rotavirus is uncommon, it can be a severe disease in
young infants [44]. Oral rotavirus vaccination is therefore highly desirable for young infants [39]; the two or
three-dose regimen – pending the type of the vaccine that is used – should be started before the age of 15
weeks and completed by the age of 32 weeks. In several countries vaccination against rotavirus is included
in the routine vaccine schedule during infancy [51].
The Report of the Committee on Infectious Diseases of the AAP ("Red Book") summarizes
preventive measures and the recommended immunizations for travelers to developing countries [51], and
suggests unique considerations related to planning travel with children [52]. A friendly, colorful and
informative "patient page" on TD, with emphasis on prevention, has been prepared [53]; it can be delivered
to the travelers during the pre-travel consultation.
5. Clinical manifestations and course
5.1. Clinical manifestations
The average time from departure to diarrhea onset in children is 8 days, with 90% of the cases
appearing in the first two weeks of travel [35,36,39,40]. Diarrhea, by the definition of TD, is present in all
cases and usually lasts for 3 to 5 days [40,54,55]. Depending on the causative pathogen, the diarrhea is
usually watery, but it can be bloody or mucous with high fever (presentation of clinical dysentery), which is
caused by invasive enteropathogens and is more common among pediatric TD [10,25,29,35]. Most of the
children with TD have 3 to 5 unformed bowel movements per day [40].
The diarrhea can be accompanied by additional symptoms such as nausea (15%-80%), vomiting (5%-
50%), abdominal pain (40%-80%), and sometimes extra-intestinal symptoms, including high fever, myalgia
and arthralgia [35]. A prospective study of pediatric TD showed that 66.9% of the affected children had
additional symptoms, including abdominal cramps (43%), vomiting (18.3%), and fever 14.1%; young

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children had higher rates of fever [40]. Fever and vomiting are more common among young children
suffering from TD [10,55]; a prospective study of 784 individuals with TD found that 46% of children <10
years vs 17% of the older individuals had vomiting [55]. A prospective multicenter study of children (<18
years) visiting the emergency department because of TD demonstrated that 69% had fever, 67% had
vomiting and 50% had abdominal pain [29]. The high rates of vomiting in children with TD, especially in
the very young, may explain in part their increased rates of dehydration [17,29].
TD is often graded in three severity levels according to its influence on the (adult) travelers, mainly for
suggested structured guidelines [12]:
- Mild TD: acute diarrhea that is tolerable, is not distressing, and does not interfere with planned
activities.
- Moderate TD: acute diarrhea that is distressing or interferes with planned activities.
- Severe TD: acute diarrhea that is incapacitating or completely prevents planned activities; all
dysenteric diarrhea is considered severe.
TD tends to be prolonged and more severe in infants and young children [25,28,30,40,55]. The average
duration of diarrhea was 29.5 days in infants aged 2 years or younger, 8.4 days in 3-6 years old children, 2.6
days in 7-14 years old and 5.3 days in 15-20 years old (p<0.05) [40]. Activities were more frequently altered
(46% vs 26%) in children <10 years than in older ones [55].
5.2.Course
In most cases TD, in both adults and children, it is a self-limited acute syndrome [9,25,28,40,55], but
some patients progress to persistent (>2 weeks) or chronic (>4 weeks) diarrhea [19,24,30,40,54,56]. The
precise rates depend in part on the methodology and the definitions used; 20% of the children with TD at the
GeoSentinel Surveillance Network had diarrhea for longer than 2 weeks [25], 14% retuning from the tropics
or subtropics had diarrhea for 14 days or longer [30] and 5% had diarrhea for more than 30 days [19]. In one
study, all three children 2 years or younger with TD had an illness for more than 30 days [40]. In 28.2% of

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the children, a second episode of TD occurred during travel [40]. Irritable bowel syndrome sometimes
develops after TD [9], but its occurrence in the pediatric age group needs further evaluation.
5.3.Complications
The most common complication of TD in children is dehydration [17,29,39,44], which was found in
40% of the children with TD attending the emergency department [29]. Children with diarrhea are more
susceptible to dehydration than adults due to often higher severity of diarrhea, increased rates of vomiting,
increased insensible fluid losses, often reduced intake, and infant dependence on milk with a relatively high
osmotic load [39,44,54,55]. A systematic review found the following risk factors for dehydration: age less
than 1 year, greater than 8 stools per day, greater than 2 emesis a day, discontinuation of breast feeding and
failure to administer oral dehydration solution (ORS) [44,57]. The higher total body water per body mass of
children results in more severe complications caused by the dehydration [54]. Symptoms and signs occurring
during dehydration [Table 3] include decreased urine output, reduced tearing, dry mucous membranes,
reduced skin turgor, sunken eyes, weakness, altered mental status, tachycardia and orthostatic hypotension
[44,58]. The dehydration may be accompanied by electrolyte imbalance [39,44].
Other complications of TD are uncommon and include intestinal perforation (mainly with infections
caused by invasive bacterial enteropathogens), bacteremia, sometimes with extra-intestinal focal infections,
reactive arthritis or Reiter syndrome, Guillain-Barre syndrome (mainly following Campylobater infection)
and hemolytic-uremic syndrome following infections with Shigella dysenteriae type 1and Shiga toxin-
producing Escherichia coli (STEC) [39,44,54]. Fifteen percent of children with TD required examination by
a physician [40]. Regarding hospitalization, of 264 children with TD, 18 (6.8%) were hospitalized [17] and
of those attending the emergency department because of TD – 35% were hospitalized [29]; the main cause of
hospitalization was dehydration [17,29]. In a prospective study, 59.3% of hospitalized children with TD
traveled for VFR [29]. Death due to TD is very uncommon, but occurs, for example in a child with TD who
developed a secondary septicemia with septic shock [29].
5.4.Differential diagnosis

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The presentation of diarrhea in a child during or after travel, especially if accompanied by high fever,
has a differential diagnosis. In particular, malaria in children can be accompanied by diarrhea and other
gastrointestinal symptoms. It should be certainly considered in children traveling to malaria-endemic
locations, especially for VFR [10,17,19,21,23,24]. Additional possible diagnoses include mainly dengue
fever, respiratory infections (especially childhood influenza) and inflammatory bowel disease [10,17,20,
23,24,56].
6. Causative pathogens
Traveler’s diarrhea is essentially an infectious disease, caused by bacterial, viral or protozoal
pathogens [10,25,35]. However, in 28% [25], 29% [31], 31% [28] and up to 50% [54] of children with TD
no causative pathogen could be identified by the standard microbiological methods of stool culturing and
antigen detection of viruses and parasites. The low yield is caused in part by a delay in stool sampling, often
unavailable sufficient laboratory capacity at the travel destination and inherent inconvenience and problems
in transporting conventional stool specimens to central laboratories, local or in the home country.
New assays using multiplex PCR have been developed, which can identify simultaneously bacteria,
viruses and parasites in a single run from a single stool specimen, thus improving significantly the
sensitivity and rapidity of the etiologic detection of infectious diarrhea [59]. Applying this approach to 59
children with TD attending emergency departments increased the detection rate of enteropathogens from
only 64% by the traditional microbiological methods to 98%, with the identification of 9 different bacteria, 5
viruses and 2 parasites [29]. The multiplex PCR enables rapid detection of pathogens that may require
initiation of antimicrobial therapy or stopping antibiotics that were started empirically. To overcome the
transportation challenge, stool specimens were placed on Hemoccult cards, which were stored at room
temperature for up to 42 days, and showed high recovery rates of 97% to 100% [60].
However, the highly sensitive multiplex PCR examination revealed high rates of coinfections:
bacteria and viruses in 34%, bacteria and parasites in 16%, bacteria and viruses and parasites in 10% [29];

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with these high rates of coinfection, it is difficult to decide what is the real etiologic cause of the TD.
Moreover, the lack of asymptomatic control groups in these studies [29,59,60] precludes a true evidence-
based conclusion on the cause of TD. In addition, these multiplex PCR assays are currently expensive.
Most data on the causes of TD are based on adult series with limited pediatric data
[19,21,25,28,29,30], which are summarized in Table 4. The etiology of TD varies by travel destination and
by season [31], with usual predominance of bacteria. Bacteria were detected in 29% of 357 children with
acute diarrhea reported over nearly 11 years (January 1997 to November 2007) to the GeoSentinel
Surveillance Network [25], in 12% of 82 children with TD in a Spanish networking [28], by multiplex PCR
in 66% of 59 children with TD attending the emergency department [29], and was the most common
causative group among 25 children with TD returning from the tropics [61]. Bacterial causes of TD include
enterotoxigenic Escherichia coli (ETEC; especially in Latin America and Africa), enteroaggregative E. coli
(EAEC, Latin America and Southeast Asia), Campylobacter spp. (South Asia), Shigella spp. (Africa and
Latin America) and Salmonella spp [20,21,25,29,30]. Less frequent causative bacteria are Aeromonas spp.,
Plesiomonas shigelloides and Vibrio spp. (including V. cholerae) [9,10]. Enteroinvasive E. coli (EIEC) and
STEC play only a minor role in the causes of TD; the later should be considered in traveling children with
bloody because of the potential consequence of hemolytic-uremic syndrome [29,44,58]. Arcobacter spp.
and enterotoxigenic Bacteroides fragilis, which are difficult to detect, may also occur [61], although this
study did not include an asymptomatic control arm.
Parasites are a well-recognized cause of prolonged or chronic TD, typically in travelers to Asia
[10,25,29,30,61]; they were detected in 12% [30], 23% [28] and 28% [25] of children with TD. Protozoa-
related diarrhea is more gradual in nature and is usually caused by Giardia lamblia and Entamoeba
histolytica [25,30], and sometimes by Cryptosporidium parvum [29], although Giardia can cause acute
diarrhea as well. Helminths usually do not play a significant role in TD because of their long infectious
cycle, but has been reported in some children with TD [30]. Viruses were often not tested for in the past in

15
patients with TD, but are likely important and more frequently detected when molecular studies are utilized
[29,60,61].
Virus-related TD in children includes norovirus, sapovirus, adenovirus, rotavirus and astrovirus
[29,62,63]. A small study detected norovirus in 4/21 (17%) children returning from the tropics with a recent
episode of acute diarrhea [64]. Since rotavirus remains the most common cause of diarrhea worldwide, it can
be travel-related in children under 3 years of age who are not vaccinated against the virus [19].
Acquisition of enteric pathogens resistant to antimicrobial agents during international travel is
currently recognized as an alarming concern, as travel itself and antibiotic use have been identified as risk
factors for acquisition of multi-resistant bacteria during travel. [12,43,65,66]. This may introduce the
multiply resistant bacteria by the patient with TD to the home country with a further spread and challenges
to antimicrobial therapy [43]. A systematic review found that healthy travelers presented multi-resistant
Enterobacteriaceae acquisition rates of 21% to 51% [67]. The human intestinal microbiome, whose role in
health and illness has become increasingly recognized, is also considered as a factor in the the risk of
acquiring traveler’s diarrhea, especially after visiting tropical regions [66,68].
7. Management
7.1.Fluid administration
Assessment of the hydration state of the child with TD, detecting symptoms and signs of dehydration
and replacement of fluid and electrolyte losses are the mainstay of management, irrespective of the cause of
diarrhea [39,44]. Symptoms and signs of dehydration levels are summarized in Table 3. Administration of
oral rehydration solutions (ORS) is preferred over IV fluids as it is more convenient and associated with less
complications, unless the child has significant vomiting or reduced mental status [44,46,69]. Frequent small-
amount administration of the ORS is the key and likely to be successful even in the child with nausea and
vomiting. The usual goal is to administer over 2 to 4 hours 50 mL/kg and 100 mL/kg in mild and moderate
dehydration, respectively. The current recommendation of the WHO is to use decreased osmolarity (about

16
250 mOsm/L), low sodium (50-60 mMol/L) ORS, unless infection with V. cholerae, which is an uncommon
cause for TD, is suspected. ORS has been shown as efficacious in reducing the need for IV fluid and
decreasing the morbidity and mortality associated with dehydration [44,54]. In the pretravel visit, caregivers
should be advised regarding the symptoms and signs of dehydration and the use of ORS. It is highly
recommended that appropriate approved ORS or sachets should be included in the routine health pack of
travelers, as they may not be readily available in local pharmacies at the travel destination. Only when a
commercial ORS is unavailable, a substitute solution can be prepared by adding one tea spoon of salt and 7
tea spoons of sugar to a liter of bottled water.
7.2.Nutrition
It is recommended that breastfeeding should not be discontinued during the episode of diarrhea, but
be continued ad libitum, if necessary, in addition to oral rehydration [44,58]. The infant formula or the
child's regular diet should be resumed within 4-6 hours of correcting dehydration, unless vomiting persists
[35,39,41]. Special formula, such as lactose-free or hypoallergenic formula, or special diets, are usually not
useful. It is important to make effort not to stop oral intake for more than few hours because of its long-term
consequences [44,46].
7.3.Pharmacological therapy
The efficacy and safety of symptomatic medications in children with TD were actually not evaluated
by randomized controlled studies [1,32,39]. However, as TD in children is usually self-limited, the use of
such medications is usually not recommended and might be harmful [9,32,39,41]. Bismuth subsalicylate has
been recommended for the treatment of TD in adults [9,12], but is not recommended in children because of
potential adverse effects [10,32,39,44]. Antimotility agents, such as loperamide, can be sometimes used in
children aged 3 years or older with watery diarrhea [39,44,46]. It should not be used in children with
bloody/mucous diarrhea (suggesting bacterial causes), TD accompanied by fever or in children <3 years, as
it can lead to serious adverse events, such as toxic megacolon and central nervous system depression
[9,32,39]. Regarding anti-emetic medications, ondansetron has shown efficacy in reducing vomiting in

17
controlled studies in children with acute gastroenteritis, but not specifically in TD; it is usually not
recommended but can be used occasionally with caution [44]. Zinc supplementation is not recommended
routinely in the treatment of diarrhea in children traveling from high-income locations, as zinc deficiency is
uncommon there [39,44].
7.4.Antimicrobial therapy
Antimicrobial therapy should not be used routinely in the otherwise healthy child with TD; it should
be considered in limited defined settings that will be discussed below [10,39,44]. A review of epidemiologic
and metagenomic studies confirmed that even a short antibiotic course, before or during travel, disrupts the
intestinal microbiome up to a year and longer and predisposes to acquisition of Enterobacteriaceae carrying
antibiotic resistance genes and multi-drug-resistant bacteria [9,67,70].
The recommendations for antimicrobial treatment for the major bacterial causes of TD is summarized
in Table 5. Randomized controlled studies, which were reviewed by a meta-analysis, documented that
appropriate antibiotic treatment of Shigella gastroenteritis shortened significantly the duration of fever,
diarrhea and fecal excretion of the pathogen [44,58]. The problem, however, is increasing antimicrobial
resistance of Shigella spp, in particular, among travelers [44,71]. The current treatment options (Table 5)
should be supplemented by continuous monitoring of antibiotic susceptibility profile of shigellae in the
travel destination. A meta-analysis of 11 double-blind, placebo-controlled trials showed that antibiotic
treatment of gastroenteritis caused by Campylobacter spp. reduces the duration of intestinal symptoms by
1.3 days, with a more pronounced effect in children with Campylobacter dysentery and when treatment
initiated within 3 days of illness onset; azithromycin is currently the drug of choice (Table 5), although
resistance has been reported mainly in East Asia [39,44]. A Cochrane systematic review documented that
antibiotic therapy of Salmonella gastroenteritis does not significantly affect the duration of fever or diarrhea
in otherwise healthy children; antibiotic therapy is recommended only for neonates or young infants and in
children with certain underlying immune or intestinal disorders to reduce the risk of secondary Salmonella
bacteremia (Table 5) [39,44,46]. Antimicrobial therapy is not recommended in most cases of pediatric TD

18
caused by diarrheagenic E. coli (Table 5). In fact, in STEC-caused diarrhea it might increase the risk of
developing hemolytic-uremic syndrome. Appropriate antibiotic treatment of cholera, which is hardly seen in
travelers, reduces the durations of diarrhea by about 50% and fecal shedding of V. cholerae by about a day.
It is recommended, based on epidemiologic data, with intense fluid administration [44,58].
Because the specific etiological diagnosis of TD is uncommonly available during the acute infection,
the use of empiric antibiotic therapy should be based on local epidemiologic data and on some clinical
characteristics. Moderate to severe bloody or mucous diarrhea with high fever suggests an infection caused
by Shigella and sometimes Campylobacter spp. Azithromycin is the empiric drug of choice for childhood
travelers' diarrhea, as it covers most relevant pathogens, is well-tolerated, is conveniently dosed once daily
(a dose of 10 mg/kg/day, maximum 500mg, for 3 days is typically recommended) and drug resistance is
overall uncommon (Table 5) [10,39]. Rifaximin can be used in children >12 years for non-invasive
enteropathogens [39,44].
Carrying antibiotics for self-treatment after a pre-travel visit with explanations of its use (“stand-by
therapy”) is relatively common and sometimes recommended for adults with severe TD [10], as a
randomized placebo-controlled study in adults showed that it reduced the duration of TD symptoms. It is
controversial for pediatric TD [32]. A non-randomized prospective study of 316 patients with TD
documented that carrying antibiotics for self-treatment increased antibiotic use as compared to non-carriers
(34% vs 22%), also for TD of mild to moderate severity (38% vs 4%) [72]. Antibiotic use was significantly
associated with stand-by antibiotic carriage (OR 7.2; 95% CI 2.8-18.8) and, interestingly, did not reduce
healthcare visits [72]. We therefor do not recommend antibiotic self-treatment; when children need
antibiotics, an evaluation by a healthcare professional is warranted. However, realizing the potential inherent
difficulties of seeking healthcare consultation in certain locations, our approach is that carrying antibiotics
for self-treatment of pediatric TD should be kept to a minimum, pending selected travel type and
destination, and only after giving detailed pretravel instructions on its use [39].

19
Antimicrobial treatment is also required for infections caused by Giardia lamblia and Entamoeba
histolytica. A prolonged diarrheal course of more than one or two weeks with weight loss may suggest G.
lamblia infection. In confirmed cases, tinidazole can be highly effective, although other alternatives such as
metronidazole or nitazoxanide are suitable alternatives [39,44,46].
7.5.Need for medical attention
It is recommended to seek medical attention for TD, especially for infants and young children, when
there are signs of moderate to severe dehydration, such as no urine output for several hours, somnolence,
rapid deep breathing and rapid weak pulse (Table 3), persistent vomiting, fever higher than 38.50
C, severe
abdominal distension, bloody diarrhea and diarrhea persisting for more than few days [10,44,58].
8. Travel of children with underlying diseases
With the achievements of modern pediatrics – including higher numbers of children after organ
transplantation, increased survival of children with primary immunodeficiencies and HIV infection and
widespread use of cytotoxic, immunosuppressive and biologic agents – the number of immunocompromised
children that travel internationally has increased considerably. It is unfortunate, however, that no focused
data exist on travelling immunocompromised children and their travel-related health problems, including
TD. Limited information is available for traveling adults who are immunocompromised or had significant
underlying morbidity [5-7,74], with suggestion of some recommendations [7,10,74].
From our experience, children with significant underlying immune-related diseases tend to have a
more severe infectious diarrhea, including TD [39], as reported in adults [74]. Besides the common
pathogens causing TD, in these children additional pathogens can cause moderate to very severe disease,
including Cryptosporidium parvum, Cystoisospora belli, Cyclospora spp. and others, including several
viruses [44,74]. This special population may also be at increased risk of complications of TD, such as
bacteremia associated with Salmonella or Campylobacter spp. [5,44]. As recommended in adults [7,74], it
is advised that these children have a comprehensive multi-disciplinary pre-travel evaluation, with individual

20
risk assessment and contact with the primary pediatrician. Detailed instructions should be given for extra
precautions on water, food and animal exposure that are mandatory during travel, including a
comprehensive guidance regarding special medications that should be carried during travel, pre-
identification of health centers in the travel destination and contingency plan in case of medical emergency.
Routine antimicrobial prophylaxis is not recommended [10]. If TD occurs, early medical advice, a
comprehensive evaluation – with the stool examined for bacteria, parasites and viruses, preferably by
sensitive molecular techniques – and giving an individual consideration for the need of early empiric
antibiotic and anti-parasitic therapy, are needed [29,39.74].
9. Gaps in pediatric TD
As actually reflected in the various aspects of pediatric TD discussed in this review, research focused
on traveling children is very limited. It is encouraging, though, that in recent years, large, multicenter-based,
data resources have been created and utilized to study health issues related to pediatric travel. Of these, the
Global TravEpiNet consortium, the GeoSentinel Surveillance Network and the Pediatric Interest Group of
the ISTM should be mentioned [16,23,25,33]. These resources provided invaluable information on pre-travel
consultations and post-travel medical care attendance of pediatric travelers, such as demographics, type and
destination of travel, attending pre-travel consultations, vaccinations and health-related illness, although the
denominator is sometimes missing [16,23,25].
The major gaps relate to interventions and specifically regarding randomized controlled studies on
measures to prevent and manage TD in children [32]. It is obvious that this type of studies is difficult to
conduct and requires a multicenter collaboration and considerable funding. As a consequence of these
existing gaps, specific evidence-based guidelines for children are generally lacking [32,39] and indeed,
significant differences in the approach to a variety of clinical scenarios related to health travel of children
were identified in a survey among health workers practicing pediatric travel medicine [1]. Strategies to

21
facilitate pediatric-focused controlled studies in travel medicine in general and TD in particular, are highly
recommended.
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1
Table 1. Rates of traveler’s diarrhea (TD) among children by type, location and period of study
______________________________________________________________________________________________
Reference Type of Number of Age range TD rate Comments
(years & location) of study Children studied
______________________________________________________________________________________________
17 (2008-2010) Prospective 801 ≤16 years 33.1% 8.8% hospitalized for TD
(Zurich, Switzerland)
19 (2014-2015) Retrospective 104 ≤16 years 17.3% Highest TD rates in travelers to
(Helsinki, Finland) N. Africa/Middle East
20 (2007-2008) Retrospective 328 ≤16 years 39% Highest TD rates in travelers to
(Zurich, Switzerland) N. Africa/Latin America
21 (1999-2015) Retrospective 314 <19 years 30.6% Highest TD rates in travelers to
(Tel Hashomer, Israel) South Asia/Africa; higher in girls
25 (1997-2007) Retrospective 1840 <18 years 28% 7% hospitalized; higher in girls
(GeoSentinel Network)
28 (2009-2013) Prospective 606 ≤16 years 13.5% Highest TD rates in <2 years
(Spanish Centers)
30 (1999-2009) Retrospective 774 <20 years 32.9% Highest TD rates in <4 years and in
(Munich, Germany) Travelers to N. Africa/Southeast Asia
40 (1987-1988) Retrospective 363 <20 years 30.9% Highest TD rates in <2 years and in
(Zurich, Switzerland) Travelers to N. Africa
______________________________________________________________________________________________

2
Table 2. The main rules to prevent TD in children*
_____________________________________________________________________________________________
1. Continue breast-feeding throughout the travel in breast-fed infants
2. Use only bottled or boiled water for drinking and tooth brushing; avoid use of tap water
3. Prepare all beverages and ice cubes with bottled or boiled water
4. Consume only pasteurized or irradiated milk and dairy products
5. Wash hands with soap or with alcohol-based detergents before eating or preparing foods
6. Eat only well-cooked food served hot
7. Consume only peeled vegetables or fruits and cooked vegetables
8. Avoid raw seafood or shellfish
9. Avoid food from street vendors
10. Carry readily available healthy snacks for children to avoid the temptation to buy food from street vendors
11. Get rotavirus vaccine (for infants <32 weeks)
__________________________________________________________________________________________
*Adapted from Ashkenazi et al. [39]. Most recommendations are not evidence-based, but they are widely
accepted.

3
Table 3. Symptoms and signs of dehydration in infants according to its level
Symptom/sign Mild Moderate Severe
Weight loss 4%-5% 6%-9% ≥10%
Urine output Normal Reduced, concentrated None for ≥8 hours
General condition Restless Irritable Somnolent/comatose
Pulse Normal Rapid Rapid and weak
Breathing Normal Mildly rapid Deep and rapid
Skin turgor Normal Decreased Severely decreased
Anterior fontanelle Normal Mildly sunken Very sunken
Tears Normal Absent Absent
Eyes Normal Mildly sunken Very sunken
Mucous membranes Mildly dry Dry Very dry
____________________________________________________________________________

4
Table 4. Enteric pathogens isolated in children with traveler’s diarrhea (TD)
__________________________________________________________________________________
Reference Number of Pathogens isolated
(years & location) Children with TD Bacteria Viruses Parasites
__________________________________________________________________________________
19, (2014-2015, (Helsinki, Finland) 18 0 6% 6%
21, (1999-2015, Tel Hashomer, Israel) 31 13% - 3%
25, (1997-2007, GeoSentinel Network) 357 29% - 25%
28, (2009-2013, Spanish Centers) a
82 12% - 25%
29, (2014-2015, France)b
59 89% 49% 28%
30, (1999-2009, Munich, Germany) 202 33% - 31%
_________________________________________________________________________________
a
A multicenter study within the Spanish Tropical Medicine Network on Imported Infections, which included 66%
immigrants (399/606) with diarrhea.
b
Multiplex PCR examination of stool specimens of children with TD attending Emergency Departments. Using this
highly sensitive method revealed high rates of coinfections: bacteria and viruses 34%, bacteria and parasites 16%,
bacteria and viruses and parasites 10%. Bacteria only were isolated in 29% and viruses only in 5%.

5
Table 5. Antibiotic therapy of major bacterial causes of TD in childrena
Pathogen Indication for antibiotics Treatment of choiceb
Alternative agentsb
Shigella spp. Confirmed or suspected Oral: azithromycin (10mg/kg) cefixime (8mg/kg)
Parenteral: ceftriaxone (50 mg/kg) ciprofloxacinc
(20-30mg/kg)
for known susceptibility:
TMP/SMXd
or ampicillin
-----------------------------------------------------------------------------------------------------------------------------
Campylobacter spp. Dysenteric disease azithromycin (10mg/kg) doxycycline (>8 years)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Escherichia coli:
- ETECe
Severe disease azithromycin (10mg/kg) cefixime, TMP/SMXd
rifaximinf
- EAECe
Antibiotics not recommended
- STECe
Antibiotics not recommended
------------------------------------------------------------------------------------------------------------------------------
Salmonella spp. High-risk children ceftriaxone (50-100mg/kg) azithromycin, TMP/SMXd
(nontyphoidal)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Vibrio cholerae Confirmed or suspected azithromycin (10mg/kg) doxycycline (>8 years)
___________________________________________________________________________________
a
Depends on the antimicrobial susceptibility profile in the travel destination. Duration of antibiotics therapy is
usually 5 days; azithromycin can be given for 3 days
b
Daily doses
c
Ciprofloxacin is registered in most countries for individuals >17 years
d
TMP/SMX, trimethoprim-sulfamethoxazole
e
ETEC, enterotoxigenic E. coli; EAEC, enteroaggregative E. coli; STEC, Shiga toxin-producing E. coli
f
Rifaximin is registered in certain locations for children >12 years

There are no relevant conflicts of interests to declare

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