Pediatrics 2010 Spee e651 69

DOI: 10.1542/peds.2010-0941; originally published online February 15, 2010; 2010;125;e651PediatricsMarjolein Y. Berger

Leo A. A. Spee, Marieke B. Madderom, Maaike Pijpers, Yvonne van Leeuwen andChildren

and Gastrointestinal Symptoms inHelicobacter pyloriAssociation Between

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Association Between Helicobacter pylori andGastrointestinal Symptoms in Children

abstractOBJECTIVE: Recurrent abdominal pain (RAP) and other gastrointesti-nal (GI) symptoms are common complaints among children. The role ofHelicobacter pylori in the cause of these complaints remains contro-versial. Nevertheless, there is an increasing pressure on primary careclinicians to screen for H pylori infection in symptomatic children. Wesystematically reviewed the published evidence for an association be-tween H pylori infection and GI symptoms in children.

METHODS: Medline and Embase databases up to July 2009 weresearched to identify studies that evaluated the association betweenH pylori and GI symptoms in children aged up to 18 years. When studiesreported on abdominal pain without additional definition, thus notfulfilling Apley’s criteria, we grouped these outcomes as unspecifiedabdominal pain (UAP). Methodologic quality was scored by using astandardized list of criteria, and crude odds ratios (ORs) with 95%confidence intervals (CIs) were calculated and pooled.

RESULTS: Thirty-eight studies met our inclusion criteria: 23 case-control studies, 14 cross-sectional studies, and 1 prospective cohortstudy. The overall methodologic quality was low. Pooled ORs for theassociation between RAP and H pylori infection in children were 1.21(95% CI: 0.82–1.78) in 12 case-control studies and 1.00 (95% CI: 0.76–1.31) in 7 cross-sectional studies. Meta-analysis of the association be-tween UAP and H pylori infection in 6 hospital-based studies resulted ina pooled OR of 2.87 (95% CI: 1.62–5.09) compared with 0.99 (95% CI:0.46–2.11) in 5 population-based studies. Two of 3 studies concerningepigastric pain reported a statistically significant positive associationwith H pylori infection.

CONCLUSIONS: We found no association between RAP and H pyloriinfection in children and conflicting evidence for an association be-tween epigastric pain and H pylori infection. We found evidence for anassociation between UAP but could not confirm this finding in childrenseen in primary care. Pediatrics 2010;125:e651–e669

AUTHORS: Leo A. A. Spee, MD, Marieke B. Madderom,MSc, Maaike Pijpers, MD, Yvonne van Leeuwen, PhD, andMarjolein Y. Berger, MD, PhD

Department of General Practice, Erasmus MedicalCenter–University Medical Center, Rotterdam, Netherlands

KEY WORDSHelicobacter pylori, signs and symptoms, digestive, meta-analysis, review

ABBREVIATIONSGI—gastrointestinalRAP—recurrent abdominal painOR—odds ratioCI—confidence intervalUAP—unspecified abdominal painSRAP—short-term recurrent abdominal painGP—general practitioner

www.pediatrics.org/cgi/doi/10.1542/peds.2010-0941

doi:10.1542/peds.2010-0941

Accepted for publication Oct 21, 2009

Address correspondence to Marjolein Y. Berger, MD, PhD,Erasmus MC, Department of General Practice, PO Box 2040, 3000CA Rotterdam, Netherlands. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

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Helicobacter pylori is 1 of the mostcommon bacterial pathogens in hu-mans and affects�50% of the world’spopulation.1 The prevalence of H pyloriinfection varies greatly between devel-oping countries and developed coun-tries (respectively, 90% vs 40% at theage of 40),1 and infection is mainly ac-quired in early childhood.2 In adults,H pylori infection is associated withconditions such as chronic active gas-tritis and peptic ulcer disease,1 andH pylori has been confirmed as themost important risk factor for non-cardia gastric adenocarcinomas andgastric mucosa-associated lymphoidtissue lymphomas.3 Despite this knowl-edge, the natural history of H pyloriinfection in children, such as the modeof acquisition and signs of infection, ispoorly understood.

Guidelines on screening for H pyloriin children contradict. Recommenda-tions vary from no need to screen chil-dren with gastrointestinal (GI) symp-toms4 and no need to screen childrenwith recurrent abdominal pain (RAP)5

to all children with upper GI symptomsshould be tested for H pylori infection(Maastricht III).6 These recommenda-tions are based on the lack of proofthat infection with H pylori is a signifi-cant cause of GI symptoms.

In addition, nowadays, a lot of diagnos-tic tests for H pylori are available.Some of them, such as the 13C-ureabreath test, detection of H pylori anti-gen in stool, and detection of specificantibodies in serum,7 are suitable foruse in primary care. Thus, this in-creased availability is likely to result inincreased number of children to betested. This emphasizes the need forup-to-date guidelines with indicationsfor investigating and treating childrenfor H pylori infection.

Good-quality studies, preferably sum-marized in a systematic review, formthe basis for evidence-based screen-ing guidelines. Previous reviews8,9 re-

garding this topic were limited to theassociation between H pylori and spe-cific symptoms, such as RAP. Becauseof the limitations of previous system-atic reviews and the several studiespublished after the publication of theseanalyses, we performed a new system-atic literature review to review sys-tematically the extent and the qualityof the current published evidence for arelationship between GI symptoms andH pylori infection in children.

METHODS

To identify relevant publications, weperformed a Medline database searchfrom 1966 to July 27, 2009, by using thefollowing key words: “Helicobacter py-lori,” “Campylobacter pylori,” “abdo-minal pain,” and “dyspepsia.” A searchstrategy for follow-up studies recom-mended by Altman10 was added. TheEmbase database was searched from1980 to July 27, 2009; the search strat-egy for Medline was adapted for Em-base with the assistance of a librarian(Appendix 1). To identify additionalpotentially relevant publications, wehand searched the reference lists ofincluded studies, of published reviewarticles, and of articles written by ex-perts in the field. No language restric-tion was used.

Study Selection

We limited our search to studies thatcompared children who did havesymptoms with children who did nothave symptoms. All abstracts ofidentified articles were screened foreligibility, and decisions regarding in-clusion of studies were made indepen-dently by 2 reviewers (L.A.A.S. andM.B.M. or Y.vL.). We used 4 criteria toselect relevant studies: (1) the studyhad a case-control, cross-sectional, orprospective cohort design; (2) 1 of itsaims was to evaluate the associationbetweenH pylori infection and GI symp-toms; (3) the study group included chil-dren aged 0 to 18 years; and (4) at least

30 children were included and sepa-rately analyzed. Because of an in-creased risk for acquiring an H pyloriinfection, studies concerning exclu-sively childrenwith relevant comorbid-ity such as mental disabilities, immu-nodeficient disorders, and diabeteswere excluded.

Interobserver reliability of the eligibil-ity screening was calculated with Co-hen’s �.11 Any disagreements betweenboth reviewers were resolved throughconsensus or by arbitration of a thirdperson (M.B.M. or Y.vL.). Full-text arti-cles of all selected titles were re-trieved or in case the abstract gave in-sufficient information on the inclusioncriteria. When an included study or thedata of a study were not available, firstauthors were contacted.

Quality Assessment

To rate the risk for bias of the includedstudies, we scored 9 identical method-ologic criteria with 1 additional crite-rion for case-control/cross-sectionalstudies and 2 additional criteria forprospective cohort studies (Appendix2). The criteria were adapted from Alt-man,10 Lievense et al,12 Hayden et al,13

and the STROBE Statement14 and weremodified to cover the topic of this re-view. Criteria could be answered with“yes (�),” “no (�).” or “don’t know(?).” One point was given to a criterionanswered with “yes,” and no pointswere given when answered with “no”or “don’t know.” Equal weights wereapplied to all items, resulting in a max-imum score of 10 points for case-control/cross-sectional studies and 11points for prospective cohort studies.Low risk for bias was defined as ascore of �7 points. Two reviewersscored all included articles indepen-dently (L.A.A.S. and M.B.M.). Interob-server variability was calculated withCohen’s �. In case of disagreement be-tween both reviewers, a third reviewer(Y.vL.) made the final decision.

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Data Extraction and Analysis

Two reviewers performed data extrac-tion on a structured list independently.Extracted data included demograph-ics, description of the study popula-tion, inclusion and exclusion criteria,baseline characteristics, type of symp-toms analyzed, diagnostic tests used,and outcome data. As a measure forthe association between GI symptomsand H pylori, odds ratios (ORs) with95% confidence intervals (CIs) werecalculated for each symptom on thebasis of unadjusted data presented inindividual studies.

Data analysis was performed by usingReview Manager 5.0 (RevMan). Theweight given to each study was basedon the inverse of the variance. Hetero-geneity was quantified by Z2 and I2,which can be interpreted as the per-centage of the total variation betweenstudies that is attributable to hetero-geneity rather than to chance. A valueof 0% indicates no heterogeneity.When statistically significant heteroge-neity (P � .05) was observed, the re-sults of the random-effects model arepresented. When there was statisti-cally significant heterogeneity in out-comes across studies, subgroup anal-yses according to the level of risk forbias and different geographic loca-tions (ie, low-prevalence areas [West-ern countries, United States, Canada]versus high-prevalence areas [Medi-terranean, African, and Asian coun-tries]) were performed. In addition,the effect of outliers on the results wasevaluated.

When in studies the term RAP wasused, we considered it conform Apley’scriteria,15 when there was a referenceto Apley or the definition used by theauthors was almost similar in timespectrum to the definition proposed byApley (ie, at least 3 discrete episodesof abdominal pain of sufficient severityto interrupt normal daily activities orperformance over a period of not

less than 3 months). When studies re-ported on “unspecified abdominalpain,” “abdominal pain,” “symptomaticpatients,” or “GI-referral patients” inrelation to H pylori infection andthus not fulfilling Apley’s criteria, wegrouped these outcomes as unspeci-fied abdominal pain (UAP).

RESULTS

In total, 1120 potentially relevant ab-stracts were identified. After removingduplicates, we were left with 880unique abstracts. After screening allabstracts, 39 publications met our in-clusion criteria and none of the exclu-sion criteria.16–54 By searching the ref-erence lists of previous review articlesand included studies, we identified 1additional study.55 The interobserveragreement of the overall eligibility was� � 0.826.

One study could not be retrieved andthus could not be included in our anal-ysis.49 After reading full-text articles,we excluded another article becausethe study population did not includechildrenwhowere aged 0 to 18 years.50

Finally, 38 articles were reviewed: 23case-control studies,16–35,53,54 14 cross-sectional studies,36–47,51,52 and 1 pro-spective cohort study.48 Of 23 in-cluded case-control studies, 19 werehospital based16,17,19–21,23–35,55, 3 werepopulation-based,18,53,54 and 1 wasprimary care based.22 All cross-sectional studies were populationbased,36–42,44–47,51,55 except for 1 that in-cluded children in whom infection wassuccessfully eradicated previously.43

The only included prospective cohortstudy was population based.48

Results of the MethodologicQuality Assessment

The 2 reviewers (L.A.A.S. and M.B.M.)initially agreed on 89.5% of all qualityitems scored. The interobserveragreement of the assessment of riskfor bias was high (� � 0.789).

Mean score of risk for bias of all 38included studies was 6.03, rangingfrom 3.00 to 10.00. The mean qualityscore of case-control studies andcross-sectional studies separatelywas 5.35 (range: 3.00–10.00) vs 6.93(range: 5.00–9.00), respectively. Thisdifference was mainly caused by thelack of equal assessment of GI symp-toms for both case patients and con-trol subjects in 19 of 23 case-controlstudies, whereas all 14 cross-sectionalstudies used equal symptom assess-ment. Furthermore, 12 case-controlstudies did not draw case patients andcontrol subjects from a population atthe same risk for exposure, whereasthe studied populations of all cross-sectional studies did. The only prospec-tive cohort study scored 9 of 11 points.

In total 8 case-control stud-ies,17–19,22,28,29,30,53 7 cross-sectionalstudies,36,37,39,41,45,46,52 and the prospec-tive cohort study48 were categorized ashaving low risk for bias. Themost prev-alent shortcomings of case-controland cross-sectional studies were alack of blinded assessment of GI symp-toms and H pylori infection (n � 31),no use of multivariate analysis (n �27), and that prognostic factors werenot comparable at baseline and nocorrection for these factors was ap-plied in the analysis (n� 29).

Prevalence of H pylori

The prevalence of H pylori in population-based cross-sectional studies rangedfrom 9.4% to 56.6% with a mean prev-alence of 28.0% (SD: 16.2%). The prev-alence in high-prevalence areas (n �8) ranged from 15.8%47 to 56.6%36 witha mean prevalence of 37.0%. The prev-alence in low-prevalence areas (n� 6)ranged from 9.4%41 to 28.9%,42 with amean prevalence of 16.1%. The effectof different tests on the prevalence ofH pylori could not be evaluated be-cause a large diversity of (combina-tions of) diagnostic tests for H pylori

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with different cutoff points were used,although the vast majority of studiesincluded serology testing.

RAP and H pylori

Fourteen case-control studies, involv-ing 3253 participants, reported on therelationship between RAP and H pyloriinfection in children.* Six had low riskfor bias17,18,22,26,30,53 and 8 had high riskfor bias.23,25,31–34,54,55 Figure 1 presentsthe meta-analysis of the OR of an H py-lori infection given the presence ofRAP. Because of statistically significantheterogeneity (P � .00001), therandom-effects model is presented.The pooled OR for all case-control stud-ies was 1.69 (95% CI: 0.99–2.86).

When we excluded the 2 outlier stud-ies of Mendez Nieto et al32 andMukherjee et al.34 the pooled OR be-came 1.21 (95% CI: 0.82–1.78), butstatistical heterogeneity remainedsignificant. In all additional analyses, theaforementioned outliers remained ex-cluded. Evaluation of heterogeneity ex-plained some of it but did not alter theestimated effect size.

Ten cross-sectional studies, involving3980 participants, reported on the re-lation between RAP and H pylori. Four

had low risk for bias36,37,39,45 and 6 highrisk.38,42–44,47,51 However, the study ofErtem et al,44 reporting an OR of 1.33,could not be pooled due to missing thepooled OR for the remaining studieswas 1.69 (95% CI: 0.83–3.44; randomeffects-model; P � .00001; Fig 2). Thestudies of Leandro Liberato et al47 andTelmesani51 explained statistical heter-ogeneity; excluding these outliers re-sulted in a pooled OR of 1.00 (95% CI:0.76–1.31; fixed model; P� .60). In ad-ditional analyses, these outliers re-mained excluded.

The pooled OR for the 4 studies withlow risk for bias was 0.95 (95% CI:0.66–1.37; fixed model; P � .24). Therelationship between RAP and H pyloriinfection was not influenced by risk forbias, setting, or geographic location.Two case-control studies22,30 and 2cross-sectional studies37,46 concerningRAP reported ORs adjusted for con-founders (Tables 1 and 2) ; however, alladjusted ORs are comparable to thepooled unadjusted ORs presented andremained nonsignificant.

UAP and H pylori

Six hospital-based case-control stud-ies16,19,21,24,28,35 that included 3142 partici-pants reported on the association be-

tween UAP and H pylori infection. Twostudies with low risk for bias19,28 and 4with high risk16,21,24,35 had a pooled OR of2.87 (95% CI: 1.62–5.09; random-effectsmodel; P � .0001; Fig 3). In the studieswith low risk for bias only, the pooled ORwas 1.66 (95% CI: 1.21–2.28; fixed model;P � .23). Pooling the 4 studies with highrisk for bias resulted in apooledORof 4.69(95%CI: 3.35–6.57; fixedmodel; P� .36).

Five population-based cross-sectionalstudies36,37,39,41,52 that included 3251participants and reported on UAP inchildren who were seen in primarycare all had low risk for bias. Thepooled OR was 0.99 (95% CI: 0.46–2.11;random-effectsmodel; P� .00001; Fig 4).

Three studies, 1 hospital-based case-control study16 and 2 population-basedcross-sectional studies,37,52 adjustedfor confounders (Tables 1 and 2). Theadjusted ORs were comparable to thepooled ORs presented.

Epigastric Pain and H pylori

Epigastric pain was evaluated in 2case-control studies18,20 and 1 cross-sectional study.43 Because of the diver-sity of outcome definitions, we werenot able to pool data. The population-based case-control study of Yang etal18 had low risk for bias and included*Refs 17, 18, 22, 23, 25, 26, 30–34, and 53–55.

FIGURE 1Meta-analysis of case-control studies concerning RAP related to H pylori infection. Events indicates number children with H pylori infection.




253 participants. They reported onshort-term recurrent abdominal pain(SRAP): abdominal pain that met Ap-ley’s criteria15 but with a shorter dura-tion in a range from 2 weeks to 3months. The prevalence of H pyloriinfection was higher in children withSRAP than in healthy control subjects(OR: 3.4 [95% CI: 1.6–7.2]). They furtherassessed whether specific clinicalpresentations were associated withH pylori infection in the children withSRAP or RAP. Children who presentedwith abdominal pain in the epigastricarea had a significantly higher preva-lence of H pylori infection when theyhad SRAP but not when they had RAP;the OR could not be calculated with theavailable data.

The hospital-based case-control studyof Ng et al20 had high risk for bias.The study, which included 1088 par-ticipants, reported an OR of 2.03(95% CI: 1.35–3.06) given the pres-ence of epigastric pain. The OR ofthe 1 hospital-based cross-sectionalstudy with high risk for bias43 was 3.2(95% CI: 0.77–13.35).

Diarrhea and H pylori

Two case-control studies18,27 and 3population-based cross-sectional stud-ies36,39,40 reported outcomes on theassociation between diarrhea andH pylori infection in children. One case-

control study18 and 2 cross-sectionalstudies36,39 had low risk for bias. Allstudies that reported on diarrhea, ex-cept for the 1 by Bode et al,39 were per-formed in high-prevalence areas. Thepooled OR in case-control studies thatincluded 365 participants, 1 of whichwas population based18 and 1 of whichwas hospital based,27 was 0.95 (95% CI:0.47–1.90; fixed model; P� .32). In thecross-sectional studies that included999 participants, the pooled OR was0.70 (95% CI: 0.13–3.96; random-effectsmodel; P� .01).

Vomiting and H pylori

Three population-based cross-sectionalstudies, all of which were at low riskfor bias, included 2054 participantsand investigated the association be-tween vomiting and H pylori infec-tion36,39,52; the pooled OR was 1.05 (95%CI: 0.40–2.75; random-effects model;P � .0002). Two studies36,52 were per-formed in high-prevalence areas, and1 study39 was performed in low-prevalence areas.

Other Symptoms and H pylori

Several studies reported on variousother GI symptoms, such as perium-bilical pain,18 flatus,18 constipation,18,37

nausea,43 loose stools,37 postprandialfullness,18,43 halitosis,43 dyspepsia,29,36

and regurgitation,37 but none of these

symptoms was associated with H py-lori infection.

The only prospective cohort study witha follow-up period from 6months to 11years48 included 305 participants andhad low risk for bias. The authors con-cluded that UAP during childhood wasreported more often in children withH pylori seropositivity at some pointduring the study than for seronegativechildren (adjusted OR: 2.2 [95% CI: 1.0–4.4). Childrenwhowere seropositive atsome point during the study more of-ten reported RAP at 11 years of agethan did seronegative children, but thedifference was not statistically signifi-cant (OR adjusted for gender: 2.0 [95%CI: 0.8–4.6) (Table 3). Spontaneousclearance of H pylori infection was re-ported in 80% of previously infectedchildren at the end of the study.

DISCUSSION

We found evidence for an associationbetween UAP (ie, patients with abdom-inal pain, symptoms, or GI referral)and H pylori infection in referred chil-dren (pooled OR: 2.87 [95% CI: 1.62–5.09) but could not confirm this findingin children who were seen in primarycare (pooled OR: 0.99 [95% CI: 0.46–2.11). Two studies16,37 adjusted forknown risk factors for H pylori, but thisdid not change this results. In addition,we found conflicting evidence for an

FIGURE 2Meta-analysis of cross-sectional studies concerning RAP related to H pylori infection. Events indicates number children with H pylori infection.

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TABLE1StudyCharacteristicsofIncludedCase-ControlStudies

Source

Setting,Place,Country,Period

CasePatients

ControlSubjects

DiagnosticTestUsed

forDeterminationof

HpyloriInfection

(CutoffPoint)

OR(95%CI)

Quality

Score

Daugule

etal,162007DiagnosticCentreofRiga,Latvia,

1998–2000

40consecutivechildrenwithindicationforupper

GIendoscopy,agerange8–12y,39%male

55asymptomaticchildrenwhovisitedtheirdoctor

forgeneralcheckuporminorhealthproblems,

aged7–12,55%male

Cases:RUTand/or

culturepositive

Controls:13C-UBT

UAP:1.80(0.62–5.14)

(adjustedforage)

4

Malatyetal,17

2006

PediatricGastroenterologyClinic

TexasChildren’sHospitaland

6primarycarepediatric

clinics,Houston,TX,Jun

2001–Dec2002

243consecutivechildrenreferredwith

abdominalpain,agerange3–18y,40%male;

excluded:childrenwithchronicillness/other

medicalconditions

330asymptomaticchildrenattending13licensed

childcarecentersinHouston,TX,aged3–18y,

45%male

Cases:13C-UBT

Controls:13C-UBT

(increaseof13C

abundanceof10

�g

ofureahydrolyzed

permin)

RAP:0.61(9.37–1.00)

7

Yangetal,18

2005

Elementaryschooland

associatedpreschool

kindergarten,Tainan,Taiwan

178childrenwhofulfilledthecriteriaofRAPor

SRAP(RAPduring2wk–3mo);agerange4–12

y,mean:9.2y,52%male

212age-andgender-matched,asymptomatic

childrenfromthesameschool

Cases:ELISA

Controls:ELISA

(absorbanceindexof

�0.14)

RAP:0.54(0.21–1.40)

SRAP:3.39(1.60–

7.17)

7

Chongetal,19

2003

12children’shospitalsor

medicalcentersthroughout

theUnitedStates,Jun

1996–Dec1997

373symptomaticGIreferralchildrenevaluated

inaGIclinicforabdominalpainandvomiting,

agerange:1–18y,mean:10.1y,48%male;

excluded:childrenwithintakeofantibiotics,

histamine-2blockers,orprotonpump

inhibitors1mobeforeenteringthestudy

618childrenseeninaclinicalsetting,who

requiredblooddrawingaspartofstandard

clinicalmanagement,withoutGIcomplaintsage

range:2mo–18y,meanage:7.7y,56%male

Cases:EIA

Controls:EIA

Referred

(symptomatic):

1.77(1.27–2.47)

8

Ngetal,20

2003

NationalUniversityHospital,

Singapore,Republicof

Singapore

489consecutivepatientswithepigastricpain;

outpatientreferralstopediatricGIclinic,

meanage:8.5

�3.3y,46%male;excluded:

childrenwhousedantibioticswithin4wkof

thestudy

599schoolchildrenparticipatingina

seroepidemiologicsurveyofDengueinthe

easternpartofSingapore,meanage:9.0

�0.5

y

Cases:ELISA

Controls:ELISA(2SD

abovevaluefor

histology-confirmed

negativesera)

Epigastricpain

(spiral):2.03

(1.35–3.06)

5

Plebanietal,21

1999

PediatricDepartment,Padua

UniversityHospital,Italy

183consecutivesymptomaticchildrenwho

underwentupperGIendoscopy,agerange:

1–16y,43%male

921randomlyselectedfromthosepresentatthe

second-degreeschoolsofPadua,agerange:

11–14y,53%male

Cases:atleast

histologypositive

Controls:anti–Hp-IgG

UAP:4.98(3.03–8.16)

3

MacArthur

etal,2219996primarycarepediatricians,

Toronto,Canada

100childrenpresentingwithRAP,agerange:

5–15y,mean:9.0

�2.7y,37%male;excluded:

childrenwithconcurrentdisease,suspected

organicdisease,aged

�5y,orhadused

bismuthinthepreviousmonth

100healthychildrenundergoingaroutine

checkuporvaccination,meanage:10.0

�3.2y,

57%male

Cases:serologyand/or

13C-UBT

Controls:serology

and/or13C-UBT

RAP:0.65(0.08–2.56)

(adjustmentnot

mentioned)

10

Guneletal,23

1998

DepartmentsofPediatric

SurgeryandPediatrics,Konya,

Turkey,during12-moperiod

42childrenwithRAP,agerange9–15y,mean:

9.4

�3.2y;excluded:iforganiccauseforRAP

(eg,pepticdisease,IBD,enzymedeficiencies)

wasfound

50healthychildrenattendingroutinedaysurgery,

meanage:9.65

�3.15y

Cases:IgGantibodytest

Controls:IgG

antibodytest

RAP:1.41(0.58–3.40)

3

Blumeletal,24

1998

KinderspitalderStadtWien,

Austria

31childrenpresentingwithchronicabdominal

pain

�4wkwithnegativestoolculture,

normalbloodcounts,andnormalabdominal

echo,agerange:6–14y,mean:10.51y,52%

male

31age-andnationality-matchedasymptomatic

childrenwhowereundergoingelective/acute

surgeryoroutpatientchildrenwhoreceived

treatmentfornoninfectiousdiseases,mean

age:10.5y

Cases:HpIgG-AK(�3

SDabovethemean

ofallnegativetests)

Controls:HpIgG-AK

UAP:2.52(0.90–7.02)

5




TABLE1Continued

Source


CasePatients

ControlSubjects

DiagnosticTestUsed

forDeterminationof

HpyloriInfection

(CutoffPoint)

OR(95%CI)

Quality

Score

Bansaletal,25

1998

KalawatiChildrenHospital,

DivisionofPediatric

Gastroenterologyand

Nutrition,NewDelhi,India

72childrenreferredwithcomplaintsofRAP;no

organiccausewasfoundafterstoolandurine

examinationsandapsychologicalevaluation;

agerange:3–12y,55%male

26age-andgender-matchedchildrenwith

complaintsotherthanthoserelatedtotheGI

tract,agerange:3–14y

Cases:RUTand/or

histologypositive

Controls:serology

(Hp-IgG

�20U/mL)

RAP:1.23(0.34–4.44)

3

Weweretal,26

1998

HvidovreHospital,Universityof

Copenhagen,Denmark

450childrenwithRAPwithnootherobvious

causesofRAP,agerange3.1–17.0y,mean:

9.0y,40%male

93childrenadmittedforminorelectivesurgery,

otherwiseingoodhealthanddidnotsuffer

fromGIcomplaints,agerange:3–15y,mean

age:6.3y,82%male

Cases:ELISA(�200EU)

andWesternblot

positive

Controls:ELISAand

Westernblotpositive

RAP(Westernblot):

2.36(1.14–4.87)

RAP(ELISA):2.09

(1.16–3.78)

7

Kehrtetal,27

1997

HealthCenter,Tipitapa,

Nicaragua,Sep1993–Dec199359childrenwithpersistentdiarrhearecruited

fromtheUROofthehealthcenterwithno

historyofantibioticuseinthepreviousmonth,

agerange:2–56mo,53%male

64randomlyselectedage-matchedasymptomatic

childrenreferredfrompediatriciansofthe

center,agerange:1–65mo,41%male

Cases:13C-UBT(13C/

12Cratioat60min

�3‰overbaseline)

Controls:13C-UBT

Persistentdiarrhea:

0.75(0.32–1.74)

6

Ozturketal,28

1996

DaySurgeryClinic,Hacettepe

UniversityChildren’sHospital,

Ankara,Turkey,Mar1993–Jun

1993

29childrenwhohadGIsymptomsandreported

tothedaysurgeryclinic,thelatterforminor

outpatientsurgicalproceduresofnon-GI

origin,agerange:1–17,59%male;excluded:

childrenwhousedantibiotics,Bismuth-

containingcompounds,NSAIDs,orantacids

duringpreceding2mo

32childrenwithoutGIsymptomswhoreportedto

thedaysurgeryclinic,thelatterforminor

outpatientsurgicalofnon-GIorigin,agerange:

1–17y,81%male

Cases:atleast2of4

followingtests

positive:serology,

RUT,histology,

bacterialculture

Controls:atleast2of

4followingtests

positive:serology,

RUT,histology,

bacterialculture

UAP:0.93(0.34–2.55)

7

Gurakan

etal,291996PediatricGastroenterologyUnit,

Ankara,Turkey,Nov1993–May

1994

59childrenreferredforevaluationofepigastric

orperiumbilicalpainand/ornausea,vomiting,

orregurgitationforatleast1mo,agerange:

5–17y,mean:11.1

�3.4,53%male;excluded:

useofantibiotics,H2-antagonists,Bismuth-salt

1mobeforeserologicexamination

48childrenwhowereseenintheoutpatient

clinicsfornon-GIcomplaints,agerange:5–17y,

meanage:10.73

�3.63,50%male

Cases:serology(IgG

�2SDabovethe

meanofallnegative

titers:ODunitsat

450nm)

Controls:serology

Dyspepsia:1.55

(0.72–3.34)

6

Hardikar

etal,301996RAPClinicatRoyalChildren’s

Hospital,Melbourne,

Australia,Feb1990–Feb1991

111childrenbetween5and12ywhohadRAP

andhadnotbeenseenpreviouslybya

pediatricianorsubspecialist,meanage:

8.5

�2.1y,33%male

103consecutivechildrenbetween5and12y

attendingdaysurgeryunitforcommonsurgical

disorders,otherwiseingoodhealthand

withoutGIsymptoms,meanage:7.7

�2.1y,

74%male


(8Uofanti-HpIgG/

mL)Controls:IgG

antibodytest

RAP:0.21(0.05–0.85)

(adjustedfor

gender,age,and

parentalethnicity

andoccupation)

7

Chongetal,31

1995

GIDiseaseOutpatientClinic,J

Whitcomb,RileyHospitalfor

Children,IndianaUniversity,

IN,Jan1991–Dec1993

218childrenwhofulfilledcriteriaofRAPand

wereseenintheGIdiseaseoutpatientclinic

(RAPgroup),agerange:3–18y,meanage:

9.5y,49%male

238children,notfulfillingcriteriaofRAP,who

wereseenintheGIdiseaseoutpatientclinic

(non-RAPgroup)agerange:3–18y,meanage:

9.8y,55%male

Cases:serology

Controls:serology

RAP:1.80(1.05–3.10)

5

MendezNieto

etal,321994GastroenterologyDepartment,

NationalPediatricInstituteof

Mexico,Jan–Jun1993

40childrenreferredforrecurrentabdominal

pain,agerange5–18y,meanage:10.3y

40healthychildrenwithoutGIcomplaints

Cases:histologyand

rapidureasetest

Controls:ELISA(OD

of2SDofthemean

ofhealthychildren)

RAP:21.00

(4.45–99.08)

3

REVIEW ARTICLES




TABLE1Continued

Source


CasePatients

ControlSubjects

DiagnosticTestUsed

forDeterminationof

HpyloriInfection

(CutoffPoint)

OR(95%CI)

Quality

Score

vanderMeer

etal,331992AcademicHospitalMaastricht,

Netherlands,during6-mo

period

82childrenbetween5.5and12.0y,withatleast

a6-moperiodofRAPofunknownorigin,

attacksofpainvaryinginseverity,duration,

andfrequency,sometimesaccompaniedby

vegetativesymptomssuchaspaleness,

nausea,orvomiting,meanage:10.8y,34%

male

39preoperativechildrenorchildrenattendingthe

outpatientclinicsforotherthanGIdiseases,

meanage:6.6y,64%male

Cases:ELISA(1.40OD

units)Controls:

ELISA

RAP:1.70(0.34–8.73)

4

Mukherjee

etal,342005OutpatientDepartmentofa

teachinghospital,Punjab,

India

68children

�3yofageattendingtheoutpatient

departmentofateachinghospitalbecauseof

RAPwithnoobviouscauseofpain,agerange:

3–12y,52%male

90normalcontrolsubjects,agerange:3–12y,

74%male


Controls:IgG

antibodytest

RAP:13.67(5.88–

31.70)

5

Sedlackova

etal,352003HospitalinMorvia,Czech

Republic,1994–1999

829childrenbetween2and18y,whowere

referredforGIendoscopybecauseofRAPand/

ordyspepsia

205Age-,gender-,andSES-matchedchildren

attendingthehospitalinMorviaforother

reasonsthanGIcomplaints

Cases:serology

Controls:serology

Unspecified

(symptomatic):

6.20

4

Camorlinga

etal,551998NationalMedicalCenterofthe

InstitutoMexicanodelSeguro

Royal,MexicoCity,Mexico,Jan

1995–Sep1996

82consecutivechildrenseekingmedical

attentionbecauseofRAP,agerange:1–17y,

meanageinfectedcases:9.1

�3.9y,42%

male;excluded:childrenwhoreceived

antibiotics,H2blockers,orprotonpump

inhibitorsduringtheprevious30d

246age-andgender-matched,asymptomatic

patientsselectedusingamastersampling

framebasedongeneralpopulationcensus

data,agerange:2–17y,meanageinfected

controls:10.6

�3.7y,35%male

Cases:ELISA(mean

value

�3SDofthe

ODof30uninfected

patients)Controls:

ELISA

RAP:2.02(1.20–3.38)

3

Masoodpoor

etal,532008GuidanceschoolsinRafsanjan

City,Iran,Jan2006–Jan2007

40childrenfulfillingcriteriaofRAP,attendingthe

guidanceschool,meanage:12.7

�1.0y,50%

male;excluded:childrenwhoreceived

antibiotictreatment,H2blockers,orproton

pumpinhibitorsbeforeenteringstudy

60randomlyselected,age-,school-,andgender-

matchedhealthychildrenwhohadnoclinical

manifestationsofRAPandwerenormalon

physicalexamination,meanage:12.9

�1.1y,

50%male

Cases:HpSAELISAstool

antigentest(an

absorbanceat450/

630of

�0.120)

Controls:HpSAELISA

stoolantigentest

RAP:2.00(0.85–4.73)

7

Devanarayana

etal,542007SchoolinGampahaDistrictofSri

Lanka

55childrenidentifiedasfulfillingcriteriaofRAP

wererecruitedduringaschoolsurvey,mean

age:7.9

�3y,agerange:5–15y,41%male;

excluded:childrenwhoreceivedantibiotics,

acidsuppression,oranti–Hpyloritherapy

within3mobeforeinclusion

20healthychildrenrecruitedfromthesamearea,

meanage:9.0

�2.7y,agerange:5–15y,50%

male

Cases:Microwell-based

EIAthatdetectedH

pyloriantigensin

stool(absorbance

value

�190)Controls:

antigensinstool

RAP:1.03

(0.09–12.00)

4

RUTindicatesrapidureasetest;13C-UBT,13C-ureabreathtest;EIA,enzymeimmunoassay;ELISA,enzyme-linkedimmunosorbentassay;SES,socioeconomicstatus;IBD,irritablebowelsyndrome;URO,oralrehydrationunit;NSAID,nonsteroidal

anti-inflammatorydrug;OD,opticdensity.




TABLE2StudyCharacteristicsofIncludedCross-SectionalStudies

Source

Setting,Place,Country,

Period

StudyPopulation

DiagnosticTestUsedfor

DeterminationofHpyloriInfection

(CutoffPoint)

N(Prevalence)

OR(95%CI)

Quality

Score

Ozenetal,36

2006

Preschoolsandschools,

Turkey,2004

136childrenwhoparticipatedinaprevious

study(Ertemetal),meanage:

13.45

�1.90y,range:8–17y,47%male

13C-UBT(achangeinthe13Cvalue

overbaselineof

�5‰)

136(56.6%)

RAP:1.05(0.48–2.28)

UAP:0.49(0.17–1.38)

Vomiting/diarrhea:1.80(0.68–4.74)

Dyspepsia:1.06(0.44–2.51)

9

Tindbergetal,37

2005

11localpublicschoolsin

Stockholm,Sweden,

Jan1998

695children,between10and12y,

attending1oftheparticipatinglocal

publicschools,meanage:11.2

�1.0y,

range:9–13y,48%male

PositiveifELISA(�0.22ODvalue)

positiveandatleast1of2ofthe

followingtestswaspositive:

immunoblot(CagA

�116kDa,

VacA

�89kDa),13C-UBT

695(16.1%)

RAP:1.00(0.50–2.10)

UAP:0.50(0.30–0.80)

Regurgitation:0.50(0.30–0.90)

Constipation:0.70(0.40–1.50)

WeeklyAP:1.50(0.70–3.30)

Loosestools:0.90(0.50–1.60)

(adjustedforage,gender,SES,

familysize,andimmigrant

background)

8

Linetal,382005

1primaryschool,

Danshuei,Taipei,

Taiwan,2003

289randomlyselectedgrades1to6

primaryschoolstudentswho

volunteeredforblood-testsforHpylori

IgGandanti–hepatitisAantibody,mean

age:9.21,51%male

ELISA

289(21.5%)

RAP:0.89(0.47–1.67)

6

Bodeetal,39

1998

SchoolsinUlm,Southern

Germany,1996

945preschoolchildren,aged5–8,who

wereexaminedforschoolfitnessbythe

PublicHealthService,meanage:5.84y,

range:5–8y,50%male;excluded:

childrenwhoreceivedantibiotic

treatmentwithinthelast4wk

13C-UBT(differencebetween

baseline13CO2/12CO2ratioand

30minratio

�5‰)

945(13.7%)

UAP:0.48(0.33–0.72)

Vomiting:0.45(0.29–0.72)

Diarrhea:0.31(0.20–0.48)

8

Rahmanetal,40

1998

Periurbancommunity

adjacenttothecapital

cityofBangladesh,

Jan–Oct1993

151childrenwhowerefreefromsystemic

infectioncausingdiarrhea,respiratory

infection,andotherinfectionsattimeof

enrollment,meanageHppos:8.9

�7.0

mo,Hpneg:9.9

�6.7,range:1–23mo,

50%male

13C-UBT(theexcessoverbaseline

valueof13CO2wasexpressed

aspartsperthousand(�%);a

cutoffpointof5intheratiowas

regardedaspositive)

151(45.0%)

Diarrhea:(after1mo):0.91(0.20–4.22)

Diarrhea(after6mo):1.08

(0.56–2.09)

6

Grimmetal,41

2003

SchoolsinAschaffenburg

andsurroundings,

Germany,schoolyear

1997/1998

540schoolchildren,aged7–9,11–15,and

16–20,whovoluntarilytookpart,age

range:7–20y,46%male

13C-UBT(theDOBvalueswere

elevatedabove3.5‰)

540Prevalence

�9.4

UAP:5.43(2.64–11.13)

7

McCallion

etal,421995

RoyalBelfastHospitalfor

SickChildren,Ireland,

during6-moperiod

439childrenattendingforroutineday

surgery,meanage:7.3y,range:4–13y

ELISA

439(28.9%)

RAP:1.10(0.63–1.90)

6

Magistaetal,43

2005

DepartmentofPediatric

Gastroenterology,

UniversityofBari,

Italy,1998–2000

52childreninwhominfectionwas

successfullyeradicatedpreviously,mean

age:12y,range:4.9–19.0y,52%male

Positivewhenall3testswere

positive:13C-UBT(changeof3.5

perthousandormorerelated

tobaselinesignal),RUT,and

histology

52(28.8%)

Epigastricpain:3.20(0.77–13.35)

Nausea:4.38(0.65–29.40)

RAP:1.29(0.28–6.01)

Halitosis:(4.28(0.65–29.40)

Postprandialfullness:1.27

(0.21–7.79)

6

REVIEW ARTICLES




TABLE2Continued

Source

Setting,Place,Country,

Period

StudyPopulation

DiagnosticTestUsedfor

DeterminationofHpyloriInfection

(CutoffPoint)

N(Prevalence)

OR(95%CI)

Quality

Score

Ertemetal,44

2003

Preschoolsandschools,

Turkey

327preschoolandschool-agedhealthy

children,meanage:8.2

�2.1y,range:

3–12y,52%male;excluded:children

whoreceivedoralorparenteral

antibioticswithin4wkbeforethe

investigation

13C-UBT(achangeinthe13Cvalue

overbaselineof

�5‰)

327(49.5%)

RAP:1.33(95%CIcouldnotbe

calculated)

5

O’Donohoe

etal,451995

7schoolsin1central

LondonDistrict,

England

640stateschoolandprivateschool

childrenwhovoluntarilyparticipated,

meanage:9.15y,range:4–13y,60%

male

IgGELISA(10U/mL)

640(16.7%)

RAP:0.49(0.23–1.07)

7

Bodeetal,46

2003

SchoolsinUlm,Erbach,

andEhingen,south

Germany,Jan–Jul

1997

1143preschoolchildrenaged5–8ywho

weretoattendfirstgradeand

underwentanschoolfitnessexamination

bythePublicHealthService,meanage:

5.88y,range:5–8y,49%male;excluded:

childrenwhousedantibioticswithinthe

past4wk

13C-UBT(achangeofthe13Cvalue

overbaselineof

�5‰)

1143(11.3%)

RAP:1.60(0.50–5.55)(adjustedfor

nationality,single-parenthousehold,

historyofpepticulcersofparents,

andhistoryofGIdisordersof

parents)

8

Leandroetal,47

2005

Healthcarecenter,Foral

deNavarra,Spain,Jan

2003–Mar2004

Randomsampleofchildrenaged1–14y,

visitingaregularhealthcareprogram,

meanage:6.89

�4.25y,50.7%male;

excluded:antibioticsinpastmonth,

previouseradicationtherapyforH

pylori,chronicdisease

EIAforfecalHpyloriantigen;at

450nmpositiveatDO

�0.160,

negativeatDO

�0.140

284(15.8%overall)

1–3y:8.4%

4–9y:13.9%

10–14y:24%

(P�.05)

RAP:7.66(3.46–16.93)

6

Telmesani,51

2008

Boys’schoolinMakkah

City,MakkahRegion,

WesternSaudiArabia

314boys,103ofwhominintermediatelevel

and211ofwhominsecondarylevel,age

range:12–18y,100%male;excluded:

recentuseofantibioticsorallergy

towardthetestmaterial

14C-UBT(resultscalculatedusing

grades0,notinfected;1,

borderline;2,infected;

borderlineresultsrequireda

repeattest)

314(27.4%)

RAP:12.35(6.30–24.22)

6

Siaietal,52

2008

SchoolsintheCap-Bon

region,Nabeul

Governorship,Tunesia

1055randomlyselected(1st,10th,20th,

etc)first-gradeprimaryschoolchildren

belongingtotherecruitmentpopulations

of13healthcarecenters’databases,813

childrenof6y,242childrenof7y,49.9%

male

IgGELISA

1055(51.4%)

UAP:1.45(1.01–2.50)(adjustedfor

householdmembers

�5,bottle

weaning

�18moplate/bed-sharing,

SES,abdominalpain,vomiting)

Vomiting:1.63(1.04–2.54)

9

ELISAindicatesenzyme-linkedimmunosorbentassay;OD,opticdensity;DOB,deltaoverbaseline.




association between epigastric painand H pylori infection. In total, 2 of 3studies showed a statistically signifi-cant association between epigastricpain and H pylori infection. This findingwas independent of setting. Further-more, there is strong evidence thatRAP is not related to H pylori.

The European Pediatric Task Force4

concluded in their guidelines on man-agement of H pylori infection that, inchildren, H pylori infection is not re-lated to GI symptoms. Our findings con-tradict this assumption but are in

agreement with findings in adults, forwhom dyspepsia is thought to becaused by H pylori. Our findings par-tially support the Consensus Reportof The European Helicobacter StudyGroup; they reported that RAP is not anindication for a test-and-treat strategyfor H pylori infection in children; how-ever, children with upper GI symptomsshould be tested after exclusion ofother causes of the symptoms.6

The finding for an association betweenUAP and H pylori infection in referredchildren but not in children who were

seen in primary care is in agreementwith our finding of evidence that RAPandH pylori are not related. Abdominalpain in a child who sees a generalpractitioner (GP) has a different differ-ential diagnosis than abdominal painin a child who is seen in secondarycare. Abdominal pain in primary caremore often will be functional. In a set-ting where a symptom is dominantlyrelated to functional disease, an asso-ciation between the symptom and alow-prevalent disorder might be tooweak to detect. In addition, a GP will

FIGURE 3Meta-analysis of case-control studies concerning UAP related to H pylori infection. Events indicates number children with H pylori infection.

FIGURE 4Meta-analysis of cross-sectional studies concerning UAP related to H pylori infection. Events indicates number children with H pylori infection.

TABLE 3 Study Characteristics of Included Prospective Cohort Study

Source Setting, Place, Country,Period

Study Population Diagnostic Test Used forDetermination ofH pylori Infection(Cutoff Point)

Patients Lost to Follow-up,%

OR (95% CI) QualityScore

Tindberg et al,48

1999Vaccine trial, Southernpart of Sweden,Stockholm,1984–1995

305 children, born in 1984,who participated in apertussis vaccine trial,starting at 6 mo to 11 y;mean age at end offollow-up: 10.9 y (range:10.5–12.3 y)

ELISA (0.360 A405 nm),measured at 6 mo, 8mo, 10 mo, 18 mo, 2 y,4 y, and 11 y

Blood samples from 6 to 18mo of age and at least 1additional serum sampledrawn at 2, 4, or 11 y ofage were available from294 children; lost tofollow-up: 11 (3.6%)

RAP (during last 6 mo):2.0 (0.8–4.6) UAP(during childhood):1.4 (0.7–2.9) UAP(last 6 mo):2.2 (1.2–4.7)

9

ELISA indicates enzyme-linked immunosorbent assay.

REVIEW ARTICLES




refer only children in whom he sus-pects underlying disease; therefore, inreferred children, the same symptomis more likely to be related to a poten-tial pathogen such as H pylori.

RAP as defined by Apley and Naish15 isthought to be related to functionaldisease and should therefore theo-retically preclude H pylori. We foundno evidence for any relation betweenRAP by Apley and Naish and H pyloriinfection in children in both case-control studies (OR: 1.21 [95% CI:0.82–1.78) and cross-sectional stud-ies (OR: 1.00 [95% CI: 0.76 –1.31). Sub-group analyses of RAP in differentsettings, high-quality studies, anddifferent geographic locations didnot alter this finding. In low-qualitycase-control studies, the associationbetween RAP and H pylori was clini-cally and statistically significant (OR:2.68 [95% CI: 1.47– 4.89); however, webelieve that this OR is overestimatedbecause of a biased selection of con-trol subjects. Whereas in 4 of 5 high-quality studies case patients andcontrol subjects were drawn from apopulation at a comparable risk forexposure (ie, H pylori infection), thiswas not the case in all of the low-quality studies. The ORs suggest a se-lection of control subjects in whomnot only GI symptoms but also H py-lori infection was precluded. Thismight have seriously biased theseoutcomes.

After excluding the outlier studies ofLeandro Liberato et al47 and Telme-sani,51 the pooled OR of cross-sectionalstudies that evaluated the relation be-tween RAP and H pylori was 1.00 (95%CI: 0.76–1.31). This finding underlinesthe absence of a relation between RAPand H pylori infection in children asfound in the case-control studies. Onthe basis of the data presented, wecould not explain the outlying resultsof the study of Leandro Liberato et al47

and Telmesani.51

RAP is mainly defined by the durationof abdominal pain. We assume that se-lecting children with RAP is more thana selection that is based on duration ofabdominal pain alone. Selection ofchildren with RAP will implicitly com-prise the belief of the primary care cli-nician that RAP in the long-term doesnot affect growth and that develop-ment of the child will be functional andthat in referred children it will com-prise the (negative) results of previousinvestigations. Because of these im-plicit selection criteria, we assumethat the included childrenwith RAPwillbe at high risk for functional disease.None of these selection mechanisms,however, was described in the studieson RAP that were included in this re-view. That duration of pain may pre-clude underlying disorders as a resultof the aforementioned mechanisms isaffirmed by the findings of Yang et al.18

That population-based study reporteda statistically significant associationbetween SRAP (ie, abdominal pain thatmet the criteria of Apley and Naish15

but with a shorter duration in rangefrom 2 weeks to 3 months) in the epi-gastric region and H pylori infection.

To our knowledge, this is the first pub-lished review to investigate the associ-ation between GI symptoms in generaland H pylori infection in children. Theresults of our review concerning RAPare consistent with 2 previous system-atic reviews that reported no obviousassociation between RAP and H pyloriinfection in children.8,9

Although our literature search wascomprehensive, some published andunpublished studies may have beenmissed. Also, some information perti-nent to the review and collected by thereviewers may not have been providedin the journal article, although we con-tacted first authors to request missingdata with variable success.

Cautious interpretation of pooled ORsis necessary because we found a large

statistical and clinical heterogeneitybetween studies and an overall poormethodologic quality. Using a best evi-dence synthesis to summarize the datacould overcome these problems, butlimited data exist on best evidence syn-theses for observational studies, andthe possibility of misclassifying the re-sults of studies with a small samplesize is large.

We found that children who are re-ferred to a gastroenterologist withUAP or pain in the epigastric region ingeneral are at two- to threefold higherrisk for H pylori infection than childrenwithout these symptoms. Because weare not aware of the criteria on whicha GP decides to refer a child with ab-dominal pain to a pediatric gastroen-terologist, a more specific clinical pic-ture has yet to be established. Whetherto screen systematically referred chil-dren with abdominal (epigastric) paindepends on effectiveness and adverseeffects of eradication therapy. No opti-mal treatment has yet been defined.

To confirm, disclaim, or specify ourfindings on UAP and epigastric pain,additional research is necessary. Ifthere is an association between thesesymptoms and H pylori infection, thentreating and thus eradicating H pylorimust lead to improvement or disap-pearance of symptoms. Randomized,placebo-controlled, double-blind trialswith minimal loss to follow-up andstandardized and validated outcomemeasures are needed. To our knowl-edge, no such trial has been published.

CONCLUSIONS

There is no association betweenRAPandH pylori infection in children; therefore,screening children with this classicalsymptom is not warranted, regardlessof setting and geographic location. Fur-thermore, all other GI symptoms in-vestigated in primary care–based orpopulation-based studies, except for epi-gastric pain, were not associated with H




pylori infection in children; therefore, wepostulate that as long as no typical clini-cal picture of a child with H pylori infec-tion has been established and treatmenteffectiveness is not known, referral to a

subspecialist for this matter is notrecommended.

Furthermore we postulate that UAPin a hospital-based setting and epi-gastric pain in general might be as-

sociated with an (acute) H pylori in-fection. Data reporting on epigastricpain, however, were limited, so addi-tional research to investigate this as-sociation is needed.

APPENDIX 1: SEARCH STRATEGIES

Medline search, 27th of July 2009 608 results

(epidemiologic-studies OR case-control OR cohort OR follow-up OR longitudinal OR prospective OR retrospective OR cross-sectional) AND (helicobacter pylori OR campylobacter) AND (“Signs and Symptoms, Digestive”[mesh] OR abdominal pain ORdyspepsia) AND (infant OR infant* OR child OR child* OR adolescent OR adolescen*)

Embase search, 27th of July 2009 512 results

((‘epidemiologic studies’/exp OR ‘epidemiologic studies’) OR ‘cross-sectional study’ OR ‘case control study’ OR ‘cohort analysis’OR (‘follow up’/exp OR ‘follow up’) OR longitudinal OR prospective OR retrospective) AND ((‘helicobacter pylori’/exp OR ‘heli-cobacter pylori’) OR (‘campylobacter’/exp OR ‘campylobacter’)) AND ((‘gastrointestinal symptom’/exp OR ‘signs and symp-toms, digestive’) OR (‘abdominal pain’/exp OR ‘abdominal pain’) OR (‘dyspepsia’/exp OR ‘dyspepsia’)) AND ((‘infant’/exp OR‘infant’) OR infant* OR (‘child’/exp OR ‘child’) OR child* OR (‘adolescent’/exp OR ‘adolescent’) OR adolescen*)

REVIEW ARTICLES




APPENDIX 2: EXPLANATION OF CRITERIA

MB / YvL / LS / MM

General

Case control study / Cross-sectional study

Criteria Score

1.

2.

3.

4.

5.

6.

7.*

8.

9.

10.

Total Score (10 points maximum)

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

……*




Explanation of criteria: Case control study/Cross-sectional study

Study population1.

2.

3.

Helicobacter pylori4.

5.

6.

Study design7.

Analysis and data presentation8.

9.

10.

OR

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MB / YvL / LS / MM

General

Prospective cohort study

Criteria Score

1.

2.

3.

4.

5.

6.

7. *

8.

9.

10.

11.

Total Score (11 points maximum)

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

+ / - / ?

…….*




Explanation of criteria: Prospective cohort study

Study population1.

2.

3.

Helicobacter pylori4.

5.

Gastrointestinal symptoms6.

Study design7.

8.

Analysis and data presentation9.

10.

11

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DOI: 10.1542/peds.2010-0941; originally published online February 15, 2010; 2010;125;e651PediatricsMarjolein Y. Berger

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