Helicobacter pylori Chronic Gastritis in Children: To Eradicateor Not to Eradicate?

Roberta Buonavolont�a, MD, Erasmo Miele, MD, PhD, Daniela Russo, MD, Raffaella Vecchione, MD,

and Annamaria Staiano, MD

Objective To evaluate the efficacy of triple eradication therapy versus symptomatic therapy in children with Hel-icobacter pylori–associated chronic active gastritis (H pylori-ACAG).Study design Symptomatic patients with H pylori-ACAG (n = 31) were randomly assigned into two groups: (1)patients infected with H pylori who were treated with triple eradication therapy (n = 16); and (2) patients infectedwith H pylori who were treated with symptomatic therapy (n = 15).Results After 1 year of follow-up, macroscopic appearance was significantly different in group B (P = .023), andchronic inflammation, H Pylori density, and activity were significantly higher in group B than in group A (P = .022,.007, and .002, respectively); however, we did not find a significant difference in the symptoms comparing bothgroups (P = .287). After 1 year of follow-up, we observed the persistence of the H pylori infection in all childrenwho had not received eradication treatment.Conclusions There is no correlation between eradication of H pylori infection and improvement of dyspepticsymptoms. Self-eradication does not occur within 1 year of follow-up. A trend toward a higher rate of chronicinflammation in noneradicated children at 1 year limited the time of our study. (J Pediatr 2011;159:50-6).

See related article, p 45

elicobacter pylori infection is generally believed to be acquired in childhood and, if left untreated, is a lifelong illness.1

HPerson-to-person transmission within the family appears to be the predominant mode of transmission.2 However, theprimary source of the infection within the family is still unclear.3 Most individuals infected with H pylori do not have

symptoms or recognizable signs of disease. In most children, the presence of H pylori infection does not lead to clinically ap-parent disease, even when the organism colonizing the gastric mucosa causes chronic active gastritis.4

It is well known that childhood is an important period for the acquisition of H pylori infection. Studies have reported that thelonger the time interval betweenHpylori detection, the higher the risk of developing cancer.5,6 Eradication should be performed atthis time because after the gastric mucosa is irreversibly harmed, treatment does not prevent carcinogenesis.7 Nevertheless, theNorth American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)8 suggests that children shouldbe investigated forHpylori infection onlywhen they present with symptoms or signs suggestive of organic disease severe enough tojustify the risks of therapy. Eradication therapy of H pylori infection is recommended only in the case of gastric/duodenal ulcer,MALT lymphoma, and atrophic gastritis with intestinal metaplasia.9 In symptomatic H pylori–associated chronic active gastritis(H pylori-ACAG), eradication therapy has yet to be validated, and the decision to treat should bemade by the physician in consul-tationwith the patient and the patient’s family. In addition, nodata exist regarding self-eradicationofHpylori infection in children.

The primary aim of our study was to compare the efficacy of triple eradication therapy versus a symptomatic therapy ongastrointestinal symptoms and on endoscopic and histological findings; the secondary aim was to evaluate the rate of theself-eradication of H pylori infection in children with H pylori-ACAG.

H pylori-ACAG Helicobacter pylori–as

NASGHAN North American Societ

T0 Evaluated at enrollmen

T1 6 weeks after complet

T2 Revaluated at 1 year a

UBT Urea breath test

UGE Upper gastrointestinal

50

Methods

Children between 3 years and 17 years, 11 months, were consecutively recruited from patients with H pylori gastritis who un-derwent upper gastrointestinal endoscopy (UGE) from January 2007 to June 2008 at the Endoscopy and DigestiveMotility Unitof the Department of Pediatrics, University of Naples ‘‘Federico II.’’

From the Department of Pediatrics (R.B., E.M., A.S.) andthe Department of Biomorphological Science (D.R.,R.V.), University ‘‘Federico II,’’ Naples, Italy

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2011.01.033

sociated chronic active gastritis

y for Pediatric Gastroenterology, Hepatology, and Nutrition

t

ion of eradication or symptomatic treatment

fter enrollment

endoscopy

Vol. 159, No. 1 � July 2011

Exclusion criteria included history of antibiotics (amoxi-cillin, tetracycline, metronidazole, clarithromycin, azithro-mycin, or other), antacids, H2-blockers, proton pumpinhibitors, bismuth compound, and nonsteroidal anti-inflammatory drugs in the 4 weeks before endoscopy. Otherexclusion criteria were endoscopic evidence of gastroesopha-geal reflux, gastric or duodenal ulcer, inflammatory boweldisease, eosinophilic gastroenteritis, bleeding disorders, asso-ciated severe chronic disease, low compliance, and/or impos-sibility of follow-up.

A full medical history along with sociodemographic datawas collected, and a complete physical examination was per-formed on all index cases at diagnosis. Gastrointestinal symp-toms, recorded using a standardized questionnaire,10 and Curea breath tests (UBTs) were evaluated at enrollment(T0). H pylori infection was confirmed by histology.

Assignment of the children affected byH pylori infection toeradication therapy (group A) or symptomatic therapy(group B) was determined according to a computer-generated randomization scheme. Random assignment wasperformed by one blinded clinical trial investigator whokept the codes until completion of the study. None of the staffor patients had access to the randomization codes during thestudy.

Patients in group A were treated with a triple eradicationtherapy with omeprazole (at dose of 1 mg/kg/d), amoxicillin(at dose of 50 mg/kg/d), and clarithromycin (at dose of 15mg/kg/d), according to NASPGHAN guidelines8; those ingroup B were treated with symptomatic therapy (bufferingagents: aluminum hydroxide/magnesium hydroxide at doseof 112.5 mg/kg/d). The duration of treatment was 2 weeksfor both groups. Second-line therapy, used in cases of treat-ment failure, included omeprazole (at dose of 1 mg/kg/d),amoxicillin (at dose of 50 mg/kg/d), and metronidazole (atdose of 20 mg/kg/d).8 The compliance with therapy was as-sessed by asking the mothers directly about their degree ofadherence to instructions. The mothers were also instructedto record daily in a journal the child’s activities. The numberof days of treatment recorded in the journal was used as a sec-ond measure of compliance. The third measurement of com-pliance was a count of the number of treatment suppliesremaining after the month’s home program.

The standardized questionnaire of gastrointestinal symp-toms and UBT were revaluated 6 weeks after completion oferadication or symptomatic therapy (T1). UGE with histol-ogy and gastrointestinal symptoms were revaluated at 1year after enrollment (T2). All children with positiveH pylorihistology at T2 were treated with a triple eradication therapyconsisting of omeprazole, amoxicillin, and clarithromycin.

Informed consent for participation in the study was ob-tained from the parents of each patient. The experimental de-sign was approved by the Independent Ethics Committee ofUniversity of Naples, ‘‘Federico II.’’

Assessment of SymptomsA questionnaire was used to assess the presence of heartburn,pain, and regurgitation. The symptomatic questionnaire was

administered by the same investigator during the visits to theclinic at T0, T1, and T2.The severity of symptoms was classified as follows: grade 0,

no symptoms; grade 1, mild symptoms with spontaneous re-mission and no interference with normal activity or sleep;grade 2, moderate symptoms with spontaneous but slow re-mission and mild interference with normal activity or sleep;and grade 3, severe symptoms without spontaneous remis-sion and marked interference with normal activity or sleep.The frequency of symptoms was classified as follows: grade0, absent; grade 1, occasional (symptoms present less than2 days per week); grade 2, frequent (symptoms present 2 to4 days per week); and grade 3, very frequent (symptoms pres-ent more than 4 days per week). A score for each symptomand a total symptom score were calculated. The score foreach symptom was calculated by multiplying the severitygrade by the frequency grade, with a possible range for eachscore of 0 to 9. The total symptom score (range, 0 to 27)was calculated by adding up the scores for each symptom(mild, 0 to 9; moderate, 10 to 18, severe, 19 to 27).11 Symp-toms were defined as mild if the score was from 0 to 9, mod-erate from 10 to 18, and severe from 19 to 27.

C Urea Breath TestThe UBT (The Breathtek UBT Test, Otsuka America Phar-maceutical, Inc, Rockville, Maryland) was performed on allindex cases after overnight fasting. Triplicate breath sampleswere collected at baseline and 30 minutes after ingestion ofcitric acid (1.5 g) as a test meal and 50 mg of 13C urea as watersolution (75mg in children who weighed >50 kg). The breathsamples were analysed by a gas isotope ratio mass spectrom-eter. A cutoff value of 5 d over baseline was chosen, accordingto the manufacturer’s recommendations.12

Endoscopy and Histologic AssessmentAll UGEs were performed by an experienced endoscopistwho was unaware of the assessment of symptoms. Two bi-opsy samples were taken from each of the following anatomiclocations when possible: greater curvature (mid-fundus,mid-body, or mid-antrum) and lesser curvature (mid-body, incisura-angularis, or mid-antrum). In addition, oneantral specimen and one corpus gastric biopsy specimenwere taken for the rapid urease testing (CLO test) (total,six biopsies).All histologic specimens were reviewed under code by a sin-

gle pathologist experienced in analysing pediatric intestinalbiopsies, blinded to the patients’ clinical details. The degreeof inflammation and the presence of H pylori organismswere assessed by hematoxylin and eosin and Giemsa staining,respectively. Mucosal inflammation was graded according tothe revised Sydney System.13 Inflammation and H pylori or-ganism density were graded as mild, 0 to 1; moderate, 2; ormarked-severe, 3. A biopsy sample was considered positivewhen H pylori organisms were found histologically. H pyloriinfection was defined using theMarch 1995 addendum to theDAIDP of the FDA guidance points.14

51

Table I. Subjects’ specific symptoms at presentation and during followup

Symptoms at T0 symptoms at T1 symptoms at T2

PatientNo. Group

Age(year) Sex

HeartburnT0

PainT0

RegurgitationT0

HeartburnT1

PainT1

RegurgitationT1

HeartburnT2

PainT2

RegurgitationT2

1 A 8 M Not YES YES Not YES Not Not YES YES2 A 14 F YES YES Not YES YES Not Not YES Not3 A 10 F Not YES Not Not Not Not Not Not Not4 A 5 M Not YES YES Not YES Not Not YES Not5 A 14 F Not YES Not Not Not Not Not Not Not6 A 14 M YES YES Not YES YES Not Not YES YES7 A 13 F YES YES Not YES YES Not Not Not Not8 A 4 M YES YES Not YES YES Not YES YES Not9 A 9 M Not YES Not Not Not Not Not Not Not10 A 10 F Not YES Not Not YES Not Not YES Not11 A 6 M Not YES Not Not Not Not Not YES Not12 A 8 F YES YES Not Not YES Not Not YES Not13 A 8 M YES YES Not Not YES Not YES YES Not14 A 12 F YES YES YES Not Not Not Not YES Yes15 A 10 F YES YES Not Not Not Not Not Not Not16 B 10 F Not YES Not Not YES Not Not YES YES17 B 8 F Not YES YES Not YES YES Not YES Not18 B 9 F Not YES Not Not YES Not Not YES Not19 B 12 M Not YES Not Not YES Not Not YES YES20 B 3 M YES YES YES Not YES YES YES YES Not21 B 8 M Not YES Not YES YES Not Not YES YES22 B 10 F YES Not YES Not YES Not YES Not Not23 B 7 F Not YES Not Not Not Not Not YES Not24 B 12 M YES YES Not Not YES Not YES YES Not25 B 11 M Not YES Not YES YES Not Not YES Not26 B 7 F Not YES Not Not YES Not Not YES YES27 B 6 M Not YES YES Not YES YES Not YES Not28 B 15 F YES YES Not Not YES Not Not YES YES29 B 10 F YES YES YES YES YES Not YES YES Not30 B 11 M Not YES Not Not YES Not Not YES Not

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 159, No. 1

Statistical AnalysisAll data were stored in a common database and statisticallyanalyzed using the SPSS version 14.0 program (SPSS Inc,Chicago, Illinois). Comparisons between proportions weremade using the c2 or a Fisher test, as appropriate. A P value<.05 was considered to be statistically significant. The powerof the study was computed by the Schlessmann formula, ac-cording to the following variables: estimated population rate:24%; smallest difference: to be evaluated 30%; power (1-b) =80%, P = .05, one control per case. The estimated sample sizewas 20 couples.

Results

Forty-two patients were infected with H pylori, based on thepresence of H pylori in the gastric mucosa biopsies. Elevensubjects were excluded from the study because the parentsof seven refused consent and four had received antibioticswithin the previous 4 weeks. One patient was excluded be-cause he showed gastric ulcer. Thirty children were eligibleand participated in the study.

Fifteen patients infected withH pylori (group A) (M/F: 7/8;mean age: 121.25 � 42.27 months; range, 48 to 174) weretreated with triple eradication therapy. Fifteen patients in-fected with H pylori (group B) (M/F: 7/8; mean age: 113.85� 36.3 months; range, 41 to 180) were treated with symptom-atic therapy.

52

At baseline, UBT was evaluated in 17 of 30 children(56.6%) (group A/group B: 7/10 patients), and positive re-sults were found in all of them.At T0, we did not find statistically significant differences in

symptoms between those patients of group A and those ofgroup B (Table I).At the follow-up (T1), 6 weeks after UGE, all patients in

group A underwent UBT: 10 of 15 (66.7%) were negative,and the other five (33.3%) were positive. All patients(100%) from group B were positive. The subset of nonre-sponders (5/15) from group A underwent second-line ther-apy and 4 weeks after the termination of eradicationtherapy, 2 of them (40%) were UBT negative. At T2 (1-year follow up), we observed the persistence of the H pyloriinfection in all those children (100%) who had not receivederadication therapy (group B), whereas recurrence ofHpyloriinfection occurred in one of the 11 (9%) subjects who hadbeen successfully treated.At T1, 6 weeks after UGE, in group A we observed a signif-

icant partial improvement of the symptoms; group B, in con-trast, did not show any improvement of symptoms. Inaddition, there was no statistically significant difference be-tween group A and group B (Figure 1).At T2, 12 months from enrollment, 10 of 15 (66.7%) pa-

tients of group A had mild symptoms, five of 15 (33.3%)had moderate symptoms, and none of the patients had severesymptoms, compared with T0 (P = .044), whereas nine of 15

Buonavolont�a et al

Figure 1. Clinical symptoms of children with H pylori infec-tion. At T0, we did not find statistically significant differencesin symptoms between those patients of group A and those ofgroup B At T1, 6 weeks after UGE, in group A we observeda significant partial improvement of the symptoms; group B, incontrast, did not show any improvement of symptoms. At T2,we did not find a significant difference in the symptomscomparing both groups.

July 2011 ORIGINAL ARTICLES

(60%) patients from group B showedmild symptoms, four of15 (26.6%) showed moderate symptoms, and two of 15(13.3%) showed severe symptoms (P = .001) (Figure 1).

At enrollment, there were no statistically significant differ-ences between groups A and B, in terms of endoscopic or his-tological features (according to Sydney Score System)(Table II).

After 1 year of follow-up (T2), macroscopic appearancewas statistically significant different in group B (P = .023),and chronic inflammation, H Pylori density, and activitywere significant higher in group B than in group A(P = .022, .007, and .002, respectively) (Table II andFigure 2); however, we did not find a significant differencein the symptoms comparing both groups (P = .287).

Discussion

In this prospective, longitudinal study, we found that after 1year of follow-up, macroscopic appearance in children in-fected and uninfected with H pylori was not statistically sig-nificant different, and a trend toward a higher rate ofchronic inflammation was present in noneradicated children.

Ganga-Zandzou et al15 demonstrated in the 2-year follow-up study a deterioration in the histologic features of the gastricmucosa of 18 infected children despite stableHpylori coloniza-tion and the absence of symptoms. These patients had receivedno eradication therapy because they were asymptomatic andthe authors showed a progressive inflammatory change inthis cohort, particularly between the first and second years.

However, we did not observe precancerous lesions such asatrophy and intestinal metaplasia in patients infected and un-infected with H pylori. Given the hypothesis that the H pyloriinfection causes precancerous lesions over time and due to

Helicobacter pylori Chronic Gastritis in Children: To Eradicate or

the lack data on the age at which atrophy occurs, a limit ofour perspective study might be that the duration of follow-up was insufficient and the relatively small number ofpatients. Because the distribution of intestinal metaplasia isfrequently patchy in the gastric mucosa, there is also a possi-bility that incidence of such metaplasic change could beunderestimated.16 Considering that infection with CagA-positive strains has been found to increase the risk of noncar-dia gastric cancer,17 another possibility might be that ourpopulation was CagA-negative, but we cannot confirm thesedata because our patients did not undergo the immunoblotanalysis.Despite a clear causal link between H pylori and gastric

cancer in animal experiments, the results of clinical studiesare conflicting. However, in a recent meta-analysis, H pyloriinfection was found to be strongly associated with early gas-tric cancer.18 It is necessary that timing of eradication therapyis optimal if it is to have a protective effect against gastric can-cer. H pylori eradication before the development of precan-cerous lesions is ideal.19 In terms of age, the Asia PacificConsensus Guidelines report that H pylori eradication ther-apy appears to offer some protection even in older patients.20

Leung et al21 reported that persistent H pylori infection is anindependent risk factor associated with intestinal metaplasiaprogression, after adjusting for age.At present, only a small number of children with well-

defined clinical syndromes have benefited from testing andtreatment,8 but there are still large gaps in our knowledgeof the clinical significance of H pylori infection in childhood.Therefore, understanding the impact of testing and treatinginfants, children, and adolescents is critical and deserves at-tention.At 1-year follow-up, we did not find statistically significant

differences in terms of symptoms among children infectedand uninfected with H pylori according to the medical posi-tional statement of the NASPGHAN.8 However, at 6 weeksfollow-up, in the treated children, we observed a partial im-provement of the symptom. These data could be explained bythe fact that the omeprazole may relieve acid-related symp-toms in patients with dyspepsia. Here, the course with theproton pump inhibitor was 2 weeks and the symptom reduc-tion was most evident at 6 weeks of the follow-up period.Therefore, the initial effect of the acid suppression for the fi-nal outcome remains questionable.Our results could suggest that bacterial eradication per se

had no effect on gastrointestinal symptoms. Comparable re-sults were obtained in several studies in which identicalsymptoms scores were observed after a follow-up periodof a 4 weeks, irrespective of the treatment results.22,23 Con-sidering that validated questionnaires for assessment ofsymptoms in children infected by H pylori are not available,a limit of our study could be related the symptoms scaleused.10

At 1 year of follow-up, we observed the persistence of theH pylori infection in all children who had not received erad-ication treatment, suggesting that H pylori self-eradication isless likely than previously hypothesized.

Not to Eradicate? 53

Table II. Histological characteristics of the enrolled children according to Sydney classification

PatientNo.

Histologic parameter T0 (grade)*Histologic parameter T2 (grade)*

GroupAge(year) Sex Disease

Chronicinflammation Activity

HPdensity IM Disease

Chronicinflammation Activity

HPdensity IM

1 A 8 M Antral hyperemia 2 3 3 0 Normal 1 0 0 02 A 14 F Gastritis 2 1 2 0 Normal 0 0 0 03 A 10 F Gastritis 1 1 2 0 Gastritis 2 2 2 04 A 5 M Gastritis 2 1 3 0 Gastritis 2 1 2 05 A 14 F Gastritis 1 1 3 0 Gastritis 1 0 0 06 A 14 M Antral hyperemia 3 3 3 0 Hiatal hernia 0 0 0 07 A 13 F Gastritis 1 1 3 0 Normal 0 0 0 08 A 4 M Gastritis 1 1 2 0 Gastritis 0 0 0 09 A 9 M Gastritis 2 3 3 0 Antral hyperemia 0 0 0 010 A 10 F Gastritis 2 1 3 0 Gastritis 2 1 2 011 A 6 M Gastritis 2 2 3 0 Gastritis 2 2 2 012 A 8 F Antral hyperemia 1 1 3 0 Normal 0 0 0 013 A 8 M Antral hyperemia 2 1 3 0 Normal 1 0 0 014 A 12 F Antral hyperemia 1 2 2 0 Normal 1 0 0 015 A 10 F Gastritis 2 3 3 0 Gastritis 1 1 0 016 B 10 F Gastritis 1 1 1 0 Gastritis 2 1 2 017 B 8 F Gastritis 1 1 2 0 Gastritis 1 1 2 018 B 9 F Gastritis 2 1 2 0 Gastritis 2 1 2 019 B 12 M Gastritis 2 1 1 0 Esophageal hyperemia 2 1 2 020 B 3 M Gastritis 1 1 3 0 Gastritis 1 1 3 021 B 8 M Gastritis 2 1 2 0 Gastritis 2 1 2 022 B 10 F Gastritis 2 1 2 0 Gastritis 2 2 2 023 B 7 F Gastritis 1 0 1 0 Antral hyperemia 1 1 2 024 B 12 M Normal 1 1 2 0 Gastritis 1 1 2 025 B 11 M Gastritis 2 1 2 0 Gastritis 1 1 2 026 B 7 F Gastritis 2 1 1 0 Gastritis 1 1 2 027 B 6 M Normal 1 1 3 0 Gastritis 1 1 3 028 B 15 F Esophageal hyperemia 1 1 2 0 Esophageal hyperemia 2 2 2 029 B 10 F Gastritis 2 1 1 0 Gastritis 2 2 1 030 B 11 M Antral hyperemia 1 1 1 0 Gastritis 1 1 1 0

IM, intestinal metaplasia; HP, Helicobacter pylori.*The updated Sydney system.

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In contrast, our trial showed an eradication rate of 66.7%in children using omeprazole, amoxicillin, and clarithromy-cin–based triple therapy, according to previous paediatricstudies. Furthermore, in the subset of nonresponders, a sec-ond-line triple therapy consisting of omeprazole, amoxicillin,andmetronidazole obtained a 75% eradication rate, confirm-ing the contribution of a high background resistance to clar-ithromycin and metronidazole to the low global eradicationrate observed.

Dehghani et al24 showed that eradication rate was 91.9% inthose who received omeprazole, amoxicillin, metronidazole,and bismuth subcitrate; 82.1% in those who received ome-prazole, amoxicillin, and clarithromicin; and 80.5% in thosewho received the omeprazole, amoxicillin-clavulanic, andmetronidazole. Considering these data, the authors suggestedquadruple therapy as the first line of therapy for eradicationof H pylori infection in children in their geographic area(Iran).24

All guidelines onH pylori infection in children issued so farsuggest that the antibiotic susceptibility test should be per-formed whenever available.25 Koletzko et al26 reported thatthe primary resistance rate of H pylori strains obtainedfrom unselected children in Europe is high and that the useof antibiotics for other indications seems to be the majorrisk factor for development of primary resistance.

54

In our study, we observed a recurrence of H pylori infec-tion in 9% of successfully treated subjects. Recurrence of Hpylori infection is the result of either recrudescence or re-infection. True reinfection is defined as the situationwhere the tests for H pylori infection, which were negativefor 12 months after eradication treatment become positiveagain at a later stage, based on both the clinical and mo-lecular evidence previously reported.27 At present, thereare only four studies that were able to produce ‘‘true’’ re-infection rates in children, which range from 1.9% to9.6%. These rates were within the range of previously re-ported recurrence rates within the first year in chil-dren.28-32 On the basis of this definition, in our children,we could hypothesize that recrudescence rather than rein-fection probably was responsible for most recurrent casesbecause recurrences decrease over time and decline sharplyafter the first year.27

In conclusion, we demonstrated a trend toward a higherrate of chronic inflammation in children in whom infectionis not eradicated at 1-year follow-up. In addition, we did notfind any evidence of self-eradication. However, we do notsuggest the ‘‘test and treat approach’’ to limit the rate ofdrug resistance that would influence the treatment of otherinfections in childhood. Our results could provide evidenceto support the view that H pylori eradication should be

Buonavolont�a et al

Figure 2. Histologic chronicity scores in group A and group Bat T0 and at T2. At enrollment, there were no statisticallysignificant differences between groups A and B, in terms ofendoscopic or histological features After 1 year of follow-up(T2), macroscopic appearance was statistically significantdifferent in group B, and chronic inflammation, H pylori den-sity and activity were significant higher in group B than ingroup A.

July 2011 ORIGINAL ARTICLES

indicated in all symptomatic children for the prevention ofinflammation that could trigger precancerous lesions. In par-ticular, we would suggest treating all children who are foundto have H pylori-ACAG, and not only those with ulcers,MALT lymphoma, and gastric atrophy, as suggested by thelatest guidelines.8,32 n

Submitted for publication May 18, 2010; last revision received Nov 11, 2010;

accepted Jan 18, 2011.

Reprint requests: Dr Annamaria Staiano, MD, Department of Pediatrics,

University ‘‘Federico II,’’ Via S Pansini, 5, 80131 Naples, Italy. E-mail: staiano@

unina.it

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27. Zhang YY, Xia HHX, Zhuang ZH, Zhong J. Review article: ‘‘true’’

re-infection ofHelicobacter pylori after successful eradication: worldwide

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annual rates, risk factors and clinical implications. Aliment Pharmacol

Ther 2008;29:145-60.

28. Gisbert JP. The recurrence ofHelicobacter pylori infection: incidence and

variables influencing it: a critical review. Am J Gastroenterol 2005;100:

2083-99.

29. Leal-Herrera Y, Torres J, Monath TP, Ramos I, Gomez A, Madrazo-de la

Garza A, et al. High rates of recurrence and of transient reinfections of

Helicobacter pylori in a population with high prevalence of infection.

Am J Gastroenterol 2003;98:2395-402.

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30. Kato S, Abukawa D, Furuyama N, Iinuma K. Helicobacter pylori reinfec-

tion rates in children after eradication therapy. J Pediatr Gastroenterol

Nutr 1998;27:543-6.

31. Farrell S, Milliken I, Doherty GM, Murphy JL, Wootton SA,

McCallionWA. Total family unitHelicobacter pylori eradication and pe-

diatric re-infection rates. Helicobacter 2004;9:285-8.

32. Halitim F, Vincent P, Michaud L, Kalach N, Guimber D, Boman F, et al.

High rate of Helicobacter pylori reinfection in children and adolescents.

Helicobacter 2006;11:168-72.

The Protein Allowance in Infancy and ChildhoodJohnston JA, Sweeney MJ, Brown RC, Maroney JW, Manson G. J Pediatr 1961;59:47-55

This study by Johnston et al1 heralded an era of nitrogen balance work to determine human protein requirements.The authors reported 3-day nitrogen balance in neonates adapted to one or more formulas of varying protein

content. Over the subsequent 2 decades, more similar investigations were undertaken, forming the basis of our currentdietary reference intake.2 However, given methodological limitations, few further studies were done in neonates;under age 6 months, the protein content of breast milk determines the protein requirement.

Nitrogen balance represents the difference between intake and all losses. As in the study of Johnston et al, in practiceonly stool and urine losses were measured. Furthermore, these early studies failed to investigate low levels of proteinintake, provided excess nonprotein energy, and did not ensure optimal vitamin intake for protein metabolism.

In the ensuing 50 years, we have come so far as to be able to measure individual amino acid requirements in neo-nates using noninvasive techniques.3 The use of stable isotopes represents a considerable advance, combined with newknowledge that protein synthesis is suboptimal unless each indispensable amino acid is provided at or above therequired level. Today, accurate provision of nonprotein energy during metabolic studies is not the barrier that itwas to Johnston et al. Improved biostatistical methods enable the reanalysis of nitrogen balance data to more accu-rately account for all nitrogen losses.

In the next 50 years, these new methodologies, with advantages of short-term and minimally invasive techniques,have the potential to better define protein requirements across all stages of human development. Most noteworthy isthe potential to enable studies in disease states, where protein needs continue to be the most loosely defined.

Justine M. Turner, MD, PhDDivision of Pediatric Gastroenterology

University of AlbertaEdmonton, Alberta, Canada

10.1016/j.jpeds.2011.02.007

References

1. Garza JJ, Shew SB, Keshen TH, Dzakovic A, Jahoor F, Jaksic T, et al. Energy expenditure in ill premature neonates. J Pediatr Surg 2002;37:289-93.

2. Institute of Medicine. Dietary Reference Intakes for Protein and Amino Acids. Washington, DC: National Academies Press; 2005.

3. Chapman KP, Courtney-Martin G, Moore AM, Langer JC, Tomlinson C, Ball RO, et al. Lysine requirement in parenterally fed postsurgical hu-

man neonates. Am J Clin Nutr 2010;91:958-65.

Buonavolont�a et al