Gastric colonization with Helicobacter pylori in the human stomach persists in some individuals for a long time and is closely associated with the development of gastritis, gastric or duodenal ulcers, or extra‐gastrointestinal diseases such as iron deficiency anemia (IDA) in childhood. It is thought that long‐term persistent infection with the microorganisms leads to the development of gastric cancer – in particular, adenocarcinoma, especially the intestinal type – in a subset of the infected adults. In 1997, the Japan Pediatric H. pylori Study Group published the first practice guidelines for H. pylori infection in childhood.1 In 2005, the guidelines were revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN).2

In Japan, proton‐pump inhibitor‐based triple therapy with amoxicillin and clarithromycin (PAC regimen) is recommended as the first‐line therapy for H. pylori‐associated diseases in children.2 However, eradication rates of PAC regimen have decreased year by year, especially because H. pylori strains are increasingly resistant to clarithromycin. We are now forced to take prompt measures to address and account for the increasing antibiotic resistance of H. pylori, especially clarithromycin.

In the adult Japanese population, the so called “test‐and‐treat” strategy for H. pylori infection is now under consideration for gastric cancer prevention. On the other hand, the majority of children with H. pylori infection remain asymptomatic, although a percentage of the infected children do develop H. pylori‐associated diseases. The previous pediatric H. pylori guidelines in Japan2 did not recommend a “test‐and‐treat” strategy for H. pylori infection in asymptomatic children. Recently, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and European Societies for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) have updated the joint H. pylori guidelines.3 The joint guidelines have recommended against a “test‐and‐treat” strategy for H. pylori infection in children because, since the previously published joint transatlantic guidelines in 2011, there has been no evidence demonstrating improved outcomes in H. pylori‐infected children to support such strategy. However, because Japan is a country where there is a high risk of gastric cancer development, determining whether such a “test‐and‐treat” strategy can be recommended in asymptomatic children has become an urgent issue. Accordingly, the JSPGHAN has produced a second revision of the guidelines on the management of childhood H. pylori infection as of October 2018, mainly focusing on appropriateness of a “test‐and‐treat” strategy and measures to address the decreasing success rate of eradication therapies.4 The present guidelines are an English version of the revised guidelines.4 In the present English version, the introduction, the methods, and the comments for the statements have been shortened.

At present, JSPGHAN has provided the guidelines based upon the best available and most recently published evidence. However, responsibility for the management of H. pylori infection in children, including the choice of diagnostic tests, eradication therapy, and its clinical effects, rests with physicians who perform such practices but not with JSPGHAN.

Methods

Purpose and subjects

Based upon new evidence about childhood H. pylori infection, the JSPGHAN agreed to update the guidelines on the management of H. pylori‐related diseases in Japanese children,2 including an attempt to offer recommendations as to how asymptomatic children should be treated. The present guidelines comprise clinical questions and corresponding statements and comments. The most recent guidelines apply to children aged 15 years or younger, who include junior high school students in Japan. The H. pylori‐related disorders discussed in the guidelines include histological chronic gastritis, peptic ulcer disease, and extra‐gastrointestinal diseases such as IDA or idiopathic (immune) thrombocytopenic purpura (ITP).

Guideline Committee and Literature Review

In the Japanese version, the guideline committee consisted of 12 experts on childhood H. pylori infection, including pediatric gastroenterologists and microbiologists, who then voted on each of the statements. B. D. Gold, who has participated on the majority of the North American, Canadian and Joint NASPGHAN‐ESPGHAN guidelines, worked on writing the English version but did not vote in the Japanese version. The guidelines were revised based on the guideline development process proposed by the Medical Information Network Distribution Service (Minds).5 Twelve members of the committee were divided into three groups, namely (i) review of the H. pylori‐associated diseases including the management of asymptomatic children, (ii) diagnostic methods, and (iii) treatment, particularly paying attention to addressing the clinically important issue of antimicrobial resistance. Several committee members participated in more than one group. In each group, the members wrote the first draft of clinical questions and the corresponding statements and comments. The systematic review team (S.K., N.H., and T.I. in the acknowledgments) was organized in the guideline committee. The review team performed a systematic review of all peer‐reviewed academic manuscripts, including guidelines and systematic reviews, published until October 2016. With regard to English manuscripts, MEDLINE and the Cochrane Library were searched using key words and terms, including H. pylori, extracted from “clinical questions.” The review team also searched the International Guideline Library and National Guideline Clearinghouse (NGC) to pick up important overseas guidelines. Igaku Chuo Zasshi, Japan’s largest medical‐literature database, was used to search peer‐reviewed Japanese manuscripts. The present guidelines also included several important overseas guidelines or systematic reviews on childhood H. pylori infection, which have been published since November 2016.

Evidence Level

In each statement, the evidence levels were classified into A (high), B (moderate), C (low), and D (very low), based on quality of evidence. In principle, systematic review, meta‐analyses, and randomized controlled trials were placed in level A for quality of evidence, non‐randomized, cohort and case‐control studies were placed in level B or C, and case series in level D.

Consensus Process and Strength of Recommendation

A modified Delphi technique was used to develop a consensus statement based on critical evaluation of the evidence on each statement, anonymous votes, discussion and modification of the statement, and repeated anonymous votes. Votes for each statement were repeated a maximum of three times to arrive at an agreement. In each statement, a vote was conducted using a four‐point scale: agree strongly (A+), just agree (A), just disagree (D), and disagree strongly (D+). On each statement, consensus was defined as agreement (the sum of A+ and A) of 70% or higher of the voting members. If disagreement (the sum of D+ and D) was 70% or higher in the end, the statement was withdrawn. The sum of A+ and A was also described as “Agreement (%).” In the statement which was not applicable to consensus statement, “Not applicable” was mentioned on Agreement (%). According to the process of evidence evaluation and the quality of evidence for each statement, the committee’s recommendations were graded as either Strong or Weak. Voting on each statement was repeated a maximum of three times until either a rating of Strong or Weak had been reached by the Committee. Ratings of Strong or Weak were obtained when ≥70% of voting members reached agreement on the statement. When the strength of recommendation did not reach agreement with the final vote, the strength was described as Not determined. Overall discussion on the guidelines was done at a face‐to‐face meeting in Tokyo.

H. pylori‐associated diseases

[Clinical Question 1]

Are eradication therapies recommended for all children with H. pylori‐associated diseases?

Statement 1: Eradication therapy should be considered for children, 5 years of age or more, determined to be infected with H. pylori by a test for active infection, taking account possible re‐infection.

Strength of recommendation: Weak. Evidence level: C. Agreement: 92%.

Comments

In children aged 5 years or older, rates of H. pylori re‐infection are low at 2.0–2.4% per year.6, 7 It has therefore been suggested that eradication therapy should be recommended in children aged 5 years or older.8, 9 Konno et al. reported that mother‐to‐child transmission of H. pylori can occur in children under 5 years old in Japan.9 Considering these facts, in principle we recommend eradication therapy in children aged 5 years or older. However, eradication therapy should be considered in children under 5 years in whom the therapy is clinically indicated due to the disease or condition requiring a work up that results in the diagnosis of H. pylori infection including peptic ulcer diseases with stenotic lesion, perforation or recurrent hemorrhage, or MALT (mucosa‐associated lymphoid tissue lymphoma). It is important to note that it has also been reported that rates of re‐infection are low in children aged 7 years or older10 and that there does not appear to be an association between re‐infection rate and the age which eradication therapy is achieved.11, 12 Further investigation is therefore required about the specific age which is most valid for eradication therapy.

[Clinical Question 2]

Are eradication therapies recommended for H. pylori‐infected children with peptic ulcer disease?

Statement 2: We recommend eradication therapy for H. pylori‐infected children with gastric and/or duodenal ulcers.

Strength of recommendation: Strong. Evidence level: A. Agreement: 100%.

Comments

In meta‐analyses in adults with H. pylori‐associated gastric or duodenal ulcers,13, 14 patients with successful eradication significantly increased healing rates and decreased relapse rates compared with those with failed eradication or without eradication therapy.13, 14 In a randomized controlled trial,15 H. pylori eradication has accelerated rates of ulcer healing in children with H. pylori‐associated peptic ulcer disease. In a cohort study of children with duodenal ulcers,16 ulcer recurrence rates after H. pylori were successfully eradicated were low with rates of 9% per year at, on average, 2 years’ follow up.

In Japanese children, the H. pylori prevalence was 83% in duodenal ulcer and 44% in gastric ulcers, respectively.17 In a follow‐up study, seven out of 27 pediatric patients with peptic ulcer disease showed recurrence of the disease and all were more than 10 years old.18 In Taiwanese children with peptic ulcer disease, the first cause was H. pylori, which was involved in a half of the patients, and the second was non‐steroidal anti‐inflammatory drugs (NSAIDs).19 The joint ESPGHAN/NASPGHAN guidelines have recommended tests and treatment in children with gastric or duodenal ulcer disease.3

In acute gastric ulcers, which were clinically categorized as acute gastric mucosal lesion (AGML) in Japan, one out of six cases showed chronic persistent H. pylori infection.20 H. pylori was histologically found in gastric biopsy specimens of 75% of children with AGML.21 H. pylori testing should be considered in children with AGML, but eradication therapy should be undertaken when chronic persistent active infection is confirmed.

[Clinical Question 3]

What kinds of clinical conditions in which H. pyolri infection has been determined are appropriate for eradication therapies when upper gastrointestinal endoscopy was performed for abdominal symptoms?

Statement 3‐1: We recommend consideration of eradication therapy for H. pylori‐infected children who underwent diagnostic upper gastrointestinal endoscopy for abdominal symptoms.

Strength of recommendation: Weak. Evidence level: D. Agreement: 100%.

Comments

Eradication therapy is thought to be ineffective for the resolution of abdominal symptoms of pediatric patients without peptic ulcer disease.3, 22-24 A meta‐analysis22 suggests that prevalence of abdominal symptoms does not differ between H. pylori‐positive and ‐negative patients. Bode et al.23 demonstrated an association between prevalence of abdominal pain or vomiting and positivity of urea breath test, and Dore et al.24 showed that there was no association between nausea / vomiting or diarrhea and serum H. pylori antibody titer. The updated NASPGHAN/ESPGHAN guidelines recommended endoscopic examination as well as H. pylori testing for diagnosing pediatric patients with alarm signs or symptoms (“alarm features”) associated with abdominal symptoms.3 The guidelines also recommended against H. pylori testing for patients diagnosed with functional abdominal pain.

On recurrent abdominal pain (RAP), some studies suggest that there is no association between H. pylori infection and the symptoms.3, 23 Despite the weakness of antibody testing as a reflection of active infection, Bode et al.23 and Tindberg et al.25 reported no association with serum H. pylori antibody titers and RAP symptoms. A retrospective cohort study reported significant improvement of RAP symptoms in patients with successful eradication compared to those with failed eradication.26 However, prospective cohort studies27, 28 and a randomized controlled study29 have reported no significant differences in symptomatic improvement of RAP between both groups.

Based upon this evidence it appears that H. pylori eradication does not improve the abdominal symptoms of RAP in children with the infection. However, the Maastricht III consensus report recommended performing upper gastrointestinal endoscopy and H. pylori testing, as well as initiating eradication therapy for the infected individuals with symptoms on the upper abdomen, particularly if other causes are ruled out.30

Although eradication therapy is considered for patients in whom H. pylori infection is confirmed and evident endoscopic findings are shown, physicians should discuss with the patients and family the advantages and disadvantages of eradication therapy, taking into consideration the potential risk and benefits of treatment.

Statement 3‐2: We recommend consideration of eradication therapy for H. pylori‐infected children with histological evidence of chronic gastritis, in the absence of ulcers, to improve mucosal inflammation in the stomach.

Strength of recommendation: Weak. Evidence level: B. Agreement: 100%.

Statement 3‐3: We recommend eradication therapy for all H. pylori‐infected children in whom gastric atrophy (with or without intestinal metaplasia) is histologically shown.

Strength of recommendation: Not determined. Evidence level: D. Agreement: 100%.

Comments: common to Statements 3‐2 and ‐3.

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