JonesNASPGHAN Hp guidelines 2008 · Managing Helicobacter pylori infection in children- the updated European/ North American ... • Periodontal disease ... if the anemia is refractory

$Page 1: JonesNASPGHAN Hp guidelines 2008 · Managing Helicobacter pylori infection in children- the updated European/ North American ... • Periodontal disease ... if the anemia is refractory$
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Managing Helicobacter pylori

infection in children- the

updated European/ North American

guidelines

on behalf of theESPGHAN /

NASPGHAN Clinical Practice Guidelines

Committee on H. pylori Infection

ObjectivesObjectives

To develop recommendations for Helicobacter pylori infection in children and adolescents, particularly those living in Europe and North America, based on– the best available peer-reviewed evidence;– the use of validated consensus guideline

methodology;– a joint effort by experts in relevant fields and

from NASPGHAN and ESPGHAN

Consensus CommitteeConsensus CommitteeCo-Chairs ESPGHAN- Sybille Koletzko

NASPGHAN-Ben GoldGroup members1. Who should be tested?

Thomas Casswall, Marion Drumm-Rowland, Nicola Jones, Richard Peek, John Snyder

2. What tests should be used?Yoram Elitsur, Jeannette Guarner, Nicolas Kalach, SibylleKoletzko,

3. Who should be treated?Samy Cadranel, Sonny Chong, Karen Goodman, Armando Madrazo, Steve Czinn

4. What are the appropriate eradication strategies?Ben Gold, Giuseppina Oderda, Richard Colletti, Francis Mégraud, Frédéric Gottrand, Karen Goodman

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Outline of presentationOutline of presentation

Brief review of guideline developmentWho to test?How to test?Who to treat?What to treat with?

Who to test?Who to test?

NoAsymptomatic childrenYesFamily history of gastric CA

YesFollowing Rx of complicated PUDYesMALT lymphoma

YesUnexplained refractory iron deficiency anemia

NoFunctional abdominal pain

YesPeptic ulcer disease

H. pyloriH. pylori and gastric cancerand gastric cancerWHO type 1 carcinogen in 1994(WHO 1994; 61:177-201)

Epidemiologic studies support association(N Engl J Med 2001; 345:784-9)

Koch’s postulates fulfilled in animal model(Gastroenterology 1998; 115:642-8)

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Does Does H. pyloriH. pylori eradication modify eradication modify gastric CA risk?gastric CA risk?

JAMA 2004; 291: 187-94

Why shouldn’t we screen children to Why shouldn’t we screen children to reduce risk of gastric cancer?reduce risk of gastric cancer?

Children rarely exhibit precancerous lesions(J Pediatr Gastroenterol Nutr 2003;37:309-4)

Prevalence of H. pylori infection is decreasing(J Pediatr Gastroenterol Nutr 2003;37:360)

As prevalence decreases cost of treating children at age 10 soars ($869,000/yr of life saved!)

(Lancet 1996;348:150-4)Consider testing and treating if there is a family history of gastric CA

ExtradigestiveExtradigestive Disease associated with Disease associated with H. pyloriH. pylori infectioninfection

Vascular• Atheroschlerotic heart disease• RaynaudsAutoimmune• Henoch-Schonlein purpura• Sjogren’s syndrome• ITPSkin diseases• Rosacea• Alopecia areata

Others• Iron deficiency anemia• SIDS• Otitis media• Periodontal disease• Allergies• Diabetes melitis• Short stature

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H. pyloriH. pylori infection and refractory infection and refractory iron deficiency anemiairon deficiency anemia

Refractory iron deficiency can resolve post H. pylori eradicationH. pylori infected subjects have lower iron and ferritin in case control studies Ferritin improves post eradication

Reviewed in: Barabino, Helicobacter 2002;7:71

Helicobacter pyloriHelicobacter pylori and iron deficiency:and iron deficiency:Case control studiesCase control studies

Am J Gastroenterol 2001; 96: 1014–8Reduced ferritin1806German adults

Med J Austr 1998; 169: 188–90Reduced ferritin(comparable Fe intake)160Australian

women

Gastroenterology 1998; 115: 274–8Reduced ferritin(comparable hemoglobin)2794Danish adults

JAMA 1997; 277: 1135–9Iron deficiency(comparable Fe intake)140Yupik adults

CitationFindingNo.Subjects

Reviewed in: Barabino, Helicobacter 2002;7:71

H. pyloriH. pylori and iron deficiency and iron deficiency anemia: intervention studiesanemia: intervention studies

Choe et al. J Pediatr 2001;139:100

0

5

10

15

Baseline Post Rx

Hem

oglo

bin

(g/d

L)

H. pylorieradicationIron alone

*

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Occult GI blood loss(JAMA 1997; 277: 1135)

Decreased gastric acid and ascorbic acid secretion

(JPGN 2004;38:137)

Iron scavenging by the bacterium(Mol Microbiol 2000;37:274; Res Microbiol

1999;150:475; Clin Infect Dis. 2008 15;46:e31-3. )

Potential mechanisms forPotential mechanisms for H. pyloriH. pyloriin iron deficiency anemiain iron deficiency anemia

How to test ? How to test ? --initial diagnosisinitial diagnosis

RecommendationNonNon--invasive testsinvasive tests

NoUrea breath tests

No!Serologic assays

NoStool antigen tests

YesGI endoscopy and biopsyRecommendationInvasive Diagnostic testInvasive Diagnostic test

How to test ? How to test ? ––confirm eradicationconfirm eradication

RecommendationNonNon--invasive testsinvasive tests

YesUrea breath tests

No!Serologic assays

YesStool antigen tests

*confirmation testing should be performed at least 4-8 weeks after stopping therapy

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Who to treat?Who to treat?

YesMALT lymphoma

YesUnexplained refractory iron deficiency anemia

YesFamily history of gastric CAconsiderH. pylori without peptic ulcer disease

YesPeptic ulcer disease

How to treatHow to treat--11stst line?line?Proton pump inhibitor 7-14damoxicillin imidazole

Proton pump inhibitor 7-14damoxicillin clarithromycin

Bismuth salts 7-14damoxicillin imidazole

Sequential therapy 10d

Amoxicillin, PPI 5 daysPPI, clarithromycin, tinidazole 5 days

Sequential therapySequential therapy

How to treatHow to treat--11stst line?line?

Gastroenterology 2005; 129:1414-9Gut 2007; 56:1353-7

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Surveillance of antibiotic resistance rates is recommended from different geographic areasAntibiotic susceptibility testing is recommended prior to initial clarithromycin- based triple therapy in area with a known high resistance rate (>20%)

How to treatHow to treat--antibiotic resistance?antibiotic resistance?

Modify therapy-add/change antibiotic, bismuth, change dose/ durationCulture and susceptibility testing to guide therapyFISH on previous biopsy for clarithromycinsusceptibility testing

How to treatHow to treat--treatment failure?treatment failure?

SummarySummaryGoal of testing is to diagnose the cause of symptoms- not detect H. pylori infectionLimitations of guideline statements– few high quality evidence studies in

children– extrapolation from studies in adults

Recommendations may not be valid in developing countriesRecommendations need further validation in clinical trials to be adapted to variety of demographics and geographic locations

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Acknowledgements:Acknowledgements:

Thanks for your attention!

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ESPGHAN & NASPGHANHelicobacter pylori Infection in Children and Adolescents:

Evidence-based Recommendations for Diagnosis and Treatment

Presented bySibylle Koletzko, MD

Ludwig Maximillians University, Munich, GERMANY

and

Benjamin Gold, MDChildren’s Healthcare of Atlanta;

Emory University School of Medicine, Atlanta, Georgia, USA

on behalf of theESPGHAN Working Group on H. pylori

NASPGHAN Clinical Practice Guidelines Committee on H. pylori Infection in Children

ESPGHAN & NASPGHANRevised Management Guidelines for Helicobacter pyloriinfection in Children (Part 1)

Sibylle Koletzko, MDDr. v. Haunersches KinderspitalHead of the Division of Pediatric

Gastroenterology and HepatologyLudwig Maximillians University, Munich, GERMANY

Previously published guidelinesCANADA (CANADIAN HELICOBACTER PYLORI STUDY GROUP)

Sherman P, Hassall E, Hunt RH, Fallone CA, Veldhuyzen van Zanten S, Thomson ABR. Canadian Helicobacter Study Group Consensus Conference on the Approach to Helicobacter pylori infection in Children and Adolescents. Can J Gastroenterol 1999;13:553-559.Update/Revised Guidelines: Jones NL, Sherman P, Fallone CA et al. Update on the approach to Helicobacter pylori infection in children and adolescents - An evidence-based evaluation. Can J Gastroenterol2005; 19:399-408.

EUROPE (Pediatric task force on H. pylori, EHSG and ESPGHAN)Drumm B, Koletzko S, Oderda G et al. Helicobacter pylori infection in children : A consensus statement. J Pediatr Gastroenterol Nutr 2000; 30:207-213.

UNITED STATES (NASPGHAN)Gold BD, Colletti RB et al. Helicobacter pylori Infection in Children: Recommendations for Diagnosis and Treatment. J PediatrGastroenterol Nutr 2000;31:490-497.

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Objective

To develop recommendations for Helicobacter pylori infection in children and adolescents, particularly those living in Europe and North America, based on

the best available peer-reviewed evidence;the use of validated consensus guideline methodology;a joint effort by experts in relevant fields and from NASPGHAN and ESPGHAN

Consensus Group Selection

Two chairs of the committee and processESPGHAN: S. Koletzko NASPGHAN: B. Gold

4 Working groups with 2 members each from ESPGHAN and NASPGHANMembers were experts in the field of H. pyloriand other relevant disciplines

Pediatric GastroenterologyEpidemiologyGastrointestinal pathologyMicrobiology, Infectious Disease

Subgroup Members for Each Topic

1. Who should be tested?Thomas Casswall, Marion Drumm-Rowland, Nicola Jones, Richard Peek, John Snyder

2. What tests should be used?Yoram Elitsur, Jeannette Guarner, Nicolas Kalach, Sibylle Koletzko,

3. Who should be treated?Samy Cadranel, Sonny Chong, Karen Goodman, Armando Madrazo, Steve Czinn

4. What are the appropriate eradication strategies?Ben Gold, Giuseppina Oderda, Richard Colletti, Francis Mégraud, Frédéric Gottrand, Karen Goodman

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Systematic Literature Search andEvidence Grading

Primary searches performed by the epidemiologist (K Goodman) and her graduate studentsAdditional searches also performed by each sub-committeeRelevant English-language studies from Jan 2000 until Aug 2007 were identified via systematic searches of PubMed, Medline, EMBASE, Cochrance Library, Losis previews, EBM Reviews, ISI Web of Science and Scopus.Grading the quality of evidence

Classification system of the Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/index.asp)

Face-to-Face MeetingMunich, Germany December 2007

Face-to-Face MeetingMunich, Germany - December 2007

Grades of EvidenceThe strength of evidence for each statement was evaluated using the GRADE system

ProcessLiterature reviews performed and citations/references circulatedSubcommittees prepared Draft Guideline Statements via conference calls and e-mail exchangeA modified Delphi technique and Cochrane-based methodology was used to agree on a set of statements.

Initial electronic and anonymous votingDiscussions ensued after first voting

Wording changes made to statementsDecisions to delete statements or keep statements also took place

2nd electronic and anonymous voting

*Grade Working Group. BMJ 2004;328:1490–4

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Grades of EvidenceHigh: Further research is unlikely to change our confidence in the estimate of effect.Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Very low: Any estimate of effect is uncertain.

6-point scale

Agree strongly (A+), Agree with minor reservations (A), Agree with major reservations (A–)Disagree with major reservations (D–), Disagree with minor reservations (D), Disagree strongly (D+)

Agreement with a statement

(A+, A or A–) by ≥ 75% of the voting group members was defined a priori as consensus.

Consensus Agreement and Voting at Face-to-Face Meeting

Results

Initial vote43 statements presented for reviewagreement in 22 statements (>75%)

Discussionseveral statements omittedsome combined to oneothers reworded after discussion.

Final vote21 statementsconsensus reached for all statements

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Statement 1 (Who should be tested ?)

The primary goal of clinical investigation of gastrointestinal symptoms is to determine the underlying cause of the symptoms and not solely the presence of H. pylori infection.

Agreement: 100% A+ 92.3%; A 7.7%; Grade of evidence: not applicable

Diagnostic testing for H. pylori infection is not recommended in children with functional abdominal pain.

Agreement: 92.3% A+ 53.9%; A 23.1%; A- 15.4%, D- 7.7% Grade of evidence: moderate


H. pylori infection does not appear to cause specific gastrointestinal symptoms in children unless PUD is present.

At present, there is no evidence supporting a causal relationship between H. pylori-associated gastritis and abdominal symptoms in the absence of PUD.

Comment to Statement 2

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In children with first degree relatives with gastric cancer, testing for H. pylori can be considered.

Agreement: 92.9% A+ 28.6%; A 50.0%; A- 14.3%, D 7.1% Grade of evidence: low


In children with refractory iron deficiency anemia, where other causes have been ruled out, testing for H. pylori infection can be considered

Agree: 100% A+ 35.7%; A 35.7%; A- 28.6%, Grade of evidence: low



Iron deficiency anemia in children and adolescents has multiple etiologies. Upper endoscopy with gastric biopsies is indicated if

non-invasive diagnostic tests are not able to find the cause of anemia or iron deficiency and/or if the anemia is refractory to oral iron therapy

H. pylori infection may the only cause of iron deficiency or iron-deficiency anemia in

the absence of mucosal erosions or ulceration or the absence of gastrointestinal symptoms

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There is currently insufficient evidence that H. pylori infection is causally related to otitismedia, upper respiratory tract infections, periodontal disease, food allergy, sudden infant death syndrome (SIDS), idiopathic thrombocytopenic purpura (ITP), or short statureAgreement: 100% A+36.4%; A 27.3%; A- 36.4% Grade of evidence: very low


Of the tissue based (invasive) diagnostic tests for H. pylori infection the following tests have been validated and can be used for clinical decision making:

HistologyRapid urease testCultureFISHPCR and Real Time PCR

Diagnostic Testing for H. pylori Infection in Children

Note: primary culture, FISH and PCR may not be applicablein most clinical laboratories

For the diagnosis of H. pylori infection during EGD, it is recommended that gastric biopsies (antrum, incisura and corpus) are obtained for histopathology according to the updated Sydney classification.

Agreement: 93.3% A+ 33.3%; A 40.0%; A-20.0%, D- 6.7% Grade of evidence: moderate

Statement 6 (What tests should be used?)

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It is recommended that the initial diagnosis of H. pylori infection is based on positive histopathology, or a rapid urease test, or culture.

Agreement: 100% A+ 35.7%, A 50.0%, A- 14.3% Grade of evidence: moderate


The13C-urea breath test is a reliable non-invasive test to determine whether H. pylori has been eradicated.

Agreement: 93.3% A+ 66.7%; A 20.0%; A- 6.7%, D- 6.7% Grade of evidence: high


The ELISA for detection of H. pylori antigen in stool is a reliable non-invasive test to determine whether H. pylori has been eradicated.

Agreement: 85.8% A+ 21.4%; A 28.6%; A- 35.8%, D 7.1%, D+ 7.1% Grade of evidence: moderate


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Comments to Statements 8 & 9

0.96 [0.94-0.97]0.97 [0.96-0.98]Specificy monoclonal EIA

0.93 [0.89-0.96]0.94 [0.93-0.95]Sensitivity monoclonal EIA

Post therapy.Prior therapy

The monoclonal EIA for fecal H. pyloriantigen is as reliable as the UBT1

Meta-analysis of 22 studies, including 2,499 patients prior and 957 patients post therapy

No age dependency of the accuracy of the test results2

1 Gisbert et al Am J Gastroenterol 2006;101:1921-19302 Koletzko et al Gut 2003;52:804-806

Comments to Statements 8 & 9

0.96 [0.94-0.97] 0.95 [0.93-0.96]

0.96 [0.94-0.98] 0.95 [0.93-0.97]

Specificy prior tx.Specificy post tx

0.83 [0.80-0.85] 0.76 [0.69-0.81]

0.95 [0.93-0.96]0.91 [0.86-0.94]

Sensitivity prior tx.Sensitivity post tx.

Polyclonal EIA.Monoclonal EIA

Monoclonal EIA has a significant higher sensitivity than the polyclonal EIA

Meta-analysis of 8 “head to head” studies1

Quick tests for fecal H. pylori antigen are not reliable2,3

1 Gisbert et al Am J Gastroenterol 2006;101:1921-1930, 2 Antos et al J Clin Microbiol 2005;43:2598-26013. Schwarzer et al Eur J Clin Microbiol Infect Dis 2007;26:491-3

Tests based on the detection of antibodies (IgG, IgA) against H. pylori in serum, whole blood, urine and saliva are not reliable for use in the clinical setting.

Agreement: 86.6% A+ 53.3%; A 20.0%; A- 13.3%, D- 6.7%, D 6.7% Grade of evidence: high


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It is recommended not to perform biopsy based tests and non-invasive tests (UBT, stool test) within 2 weeks after stopping PPI therapy and within 4 weeks after stopping antibiotics.

Agreement: 100% A+ 46.7%; A 24.0%; A- 13.3% Grade of evidence: high


ESPGHAN & NASPGHANRevised Management Guidelines for H. pylori infection in Children (Part 2)

Benjamin D. Gold, MDChildren’s Healthcare of AtlantaMarcus Professor and Director

Division of Pediatric Gastroenterology, Hepatology and Nutrition; Department of Pediatrics

Emory University School of MedicineAtlanta, Georgia

Statement 12 (Who should be treated?)

In the presence of H. pylori-positive peptic ulcer disease, eradication of the organism is recommended.

Agreement: 100% A+ 78.6%; A 14.3%; A- 7.1%,Grade of evidence: high

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When H. pylori infection is detected by histopathology in the absence of peptic ulcer disease, H. pylori treatment can be considered.

Agree: 78.6% A+ 28.6%; A 50.0%; D- 21.4%Grade of evidence: low

Comments on Statement 13

This was the most debated statement. Some group members felt that H. p. in the absence of PUD should not even looked for. However, many pediatric gastroenterologists perform gastric biopsies during EGD regardless of the indication for EGD, and H. p. infection may be found on histopathologyIn this situation, treatment can be offered after informed consent on potential risks and benefits of therapy.


A ‘test and treat’ strategy is not recommended in children.

Agreement: 80.0% A+ 46.7%; A 20.0%; A- 13.3%, D- 13.3%, D 6.7%

Grade of evidence: moderate

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Abdominal complains like pain, nausea or other dyspeptic symptoms are non-specific and can be caused by a variety of etiologies within and outside the digestive tract. The etiologies to abdominal symptoms may be missed or their diagnosis and treatment delayed with a “test and treat”strategy for H. pylori.



In children who are infected with H. pyloriand who have a first degree relative with gastric cancer, treatment (eradication therapy) can be offered.

Agreement: 93.3% A+ 20.0%; A 46.7%; A- 26.7%, D+ 6.7% Grade of evidence: low

Surveillance of antibiotic resistance rates of H. pylori strains in children and adolescents is recommended in the different countries and geographic areas.

Agreement: 100% A+ 60.0%; A 20.0%; A- 20.0%

Grade of evidence: not applicable

Statement 16(What are the appropriate eradication strategies?)

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Antibiotic resistance to clarithromycin (CLA) is highly predictive of treatment failure when CLA is part of triple therapy. Primary antibiotic resistance rates to CLA

have increased over the last years1

are higher in children than adults1,2

vary in different populations and geographic regions2

reach >20% in some European and North American regions2,3


1 Cabrita et al J Antimicrob Chemother 2000;46:1029-31.2 Koletzko et al Gut 2006;55:1711-16 3. Tolia et al Pediatr Infect Dis J 2000;19:1167-71.

First line eradication regimen arePPI + Amoxicillin + Imidazole* orPPI + Amoxicillin + Clarithromycin orBismuth salts + Amoxicillin + Imidazole*

orSequential Therapy. *Imidazole = Metronidazole or Tinidazole

Agreement: 100% A+ 35.7%; A 40.0%; A- 14.3% Grade of evidence: moderate


PPI BID+

Amoxicillin BID X 5 days

PPI BID+

Clarithromycin BID+

Imidazole BID (Tinidazole; Metronidazole)

X 5 days

Comment to Statement 17Sequential Therapy

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It is recommended that the duration of triple therapy is 7 – 14 daysCosts, compliance and adverse effects should be taken into account when choosing the eradication regimen.

Agreement: 93.3% A+ 26.7%; A 40.0%; A-26.7%; D- 6.7%

Grade of evidence: high


A reliable non-invasive test for eradication is recommended at least 4-8 weeks following completion of therapy.

Agreement: 93.3% A+ 53.3%; A 26.7%; A-13.3%; D- 6.7%



Antibiotic susceptibility testing for clarithromycinis recommended prior to initial clarithromycin-based triple therapy in areas or populations with known high resistance rate (>20%) of H. pyloristrains in children.

Agreement: 93.3% A+ 33.3%; A 40.0%; A- 20.0%, D- 6.7%



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If the treatment has failed there are 3 options recommended

1) FISH on previous paraffin embedded biopsies if Clarithromycin susceptibility testing has not been performed before to guide therapy, 2) EGD, culture and susceptibility testing including alternate antibiotics if not performed before to guide therapy, 3) Modify therapy by adding an antibiotic, using different antibiotics, bismuth and/or increasing dose and/or duration of therapyAgreement 100% A+ 28.6%; A 42.9%; A- 28.6%;Grade of evidence: not applicable


Conclusions and Summary

Limitations of guideline statementsvery few high evidence studies in pediatricssome extrapolation from studies in adults

Recommendations may not be valid for developing countries.Recommendations need further validation in clinical trials to be adapted to a variety of demographic groups and geographic locations

prevalence of H. pylori infection in the populationavailability of and access to health care resources (testing and follow up)

Screening in the general population, at present, not recommended

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JonesNASPGHAN Hp guidelines 2008 · Managing Helicobacter pylori infection in children- the updated European/ North American ... • Periodontal disease ... if the anemia is refractory