diagnosis and treatment of H pylori related diseases in children and adolescent

Helicobacter pylori (H. pylori) is one of the most common bacterial infections worldwide. ⁽¹⁾ It is a Gram-negative microaerophilic bacterium colonizes the gastric mucosa, ⁽²⁾ the infections are usually acquired during early childhood and generally passes asymptomatically in most patients, in which it will remain in the gastric cavity throughout life in the absence of eradication therapy. ⁽³⁾

The prevalence of infection in pediatric age is high and varies from country to country.  In Egypt, a population-based cross-sectional study performed among asymptomatic school children used urea breath test (UBT) to show that the overall H. pylori prevalence was 72.38%. Its main risk factor is residing in an overcrowded home and socially deprived area ⁽⁴⁾ In a rural area, relatives with low socioeconomic level generally showed the highest seroprevalence (82.5% and 78.1%, respectively). ⁽⁵⁾

Another cross-sectional study showed that seroprevalence of H. pylori was significantly age-dependent: 60.6% of patients aged more than 5 years and 25.9% of patients aged less than 5 years. One of the main factors associated with seroprevalence was crowding in beds. The seroprevalence among children was 59.7% in the case of more than 3 persons sharing a bed and 26.9% in the case of fewer than 3 persons sharing a bed.

Moreover, the duration of breastfeeding also played a role in H. pylori acquisition. The seroprevalence was 64.7% among children who were breastfed for <1 year and only 42.4% among those breastfed for more than 1 year. ⁽⁶⁾ A cross-sectional study showed prevalence of about 70%, indicating that the burden of H. pylori infection is high in rural areas than in urban areas. ⁽⁷⁾

Several diagnostic tests for detection of H. pylori have been widely used in clinical practice  either invasive which require endoscopy to obtain biopsies of gastric tissues,  or non-invasive methods with different levels of sensitivity and specificity.⁽⁸⁾ However, each of these tests has certain disadvantages ⁽⁹⁾ The invasive methods include histological examination, culture, urease test and molecular methods, while the non-invasive methods include urea breath testing, serology and stool antigen testing. There is no single method that can meet, on its own, the criteria for acceptable sensitivity and specificity in identification of the bacterium. In the last few years, more interest has been paid for the non-invasive methods. ⁽¹⁰⁾ Molecular testing assays can be also a rapid and accurate methods for the diagnosis of H. pylori infection. ⁽¹¹⁾

Spontaneous eradication is described mainly in infants and young children but unfortunately the eradication decreases with age. Without a treatment scheme, eradication is highly improbable. ⁽¹²⁾

Although H. pylori infection is mainly acquired in childhood, complications generally arise much later. H. pylori infection is implicated in the pathogenesis of gastritis, gastric and duodenal ulcers, gastric cancer, and gastric mucosa‑associated lymphoid tissue (MALT) lymphoma ^{(13- 16)} In 2018, H. pylori was responsible for an estimated 810,000 new cases of non-cardia gastric adenocarcinoma worldwide, making it the leading cause of infection-attributable cancer ahead of high-risk human papillomavirus and hepatitis B and C viruses. ⁽¹⁷⁾

 It is now established that chronic H. pylori infection is the most important etiological factor for the occurrence of gastric cancer, ^(18-21) which is considered as the third leading cause of cancer death globally. ⁽²²⁾ Importantly, its eradication is recommended in the treatment and/or prevention of these conditions.

There is a strong association between H. pylori infection and diseases like; lymphoma, cardiovascular disease, dermatological disease, liver and gallbladder diseases, anemia, diabetes mellitus, autoimmune disease, atopy, asthma, neurological disease, bone disease, micronutrient deficiency , iron deficiency anemia, growth restriction, and idiopathic thrombocytopenic purpura (ITP) ^(1,2,23) H. pylori infection can lead to these diseases apart from the gastro-intestinal system by a series of hormonal, immunological, cytokine and chemokine mediators.

Indications for treatment of this infection and optimal regimens have been proposed by a recent consensus guideline as well as optimal diagnostic tests. 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 workup 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). Eradication therapy should also be considered in children who have recurrent or refractory IDA to iron supplementation and in whom an active H. pylori infection has been determined.

 All treatment guidelines agree that the best approach to the treatment of H. pylori infection is to succeed on the first attempt, thereby avoiding re-treatment and reducing cost, anxiety, and the further promotion of resistant strains. ⁽²⁴⁾

Treatment to eliminate H pylori infection is not expected to improve symptoms in children, except in cases of peptic ulcer disease (Gastric and duodenal ulcers) (PUD). Therefore, in children fulfilling the Rome criteria for functional abdominal pain, diagnostic testing (noninvasive or invasive) for H pylori infection should not be undertaken. (25-30) In the absence of alarm signs or symptoms (persistent right upper or right lower quadrant pain, dysphagia, odynophagia, persistent vomiting, gastrointestinal blood loss, involuntary weight loss, deceleration of linear growth, delayed puberty, unexplained fever, and a family history of inflammatory bowel disease, celiac disease, or PUD), recent updated recommendations from the committee for ROME IV did not identify compelling evidence to support upper endoscopy as part of the diagnostic work up. ⁽³¹⁾

Treatments targeting H. pylori infection consist of combinations of a PPI and several antimicrobial agents. ^(32,33) There are limited well-designed studies in children and adolescents with respect to the optimal duration of anti H pylori therapy. Meta-analyses of optimal duration of H pylori eradication therapy in adults have been performed and show that increasing the duration of therapy enhances eradication rates .⁽³⁴⁾ With respect to triple therapy, a recent systematic review and network analysis of studies in adults showed that 14-day duration of treatment improves eradication rates compared to 10-day, and both are superior to 7-day treatment. ⁽³⁵⁾

 The recommended goal for H pylori treatment is an eradication rate of at least 90% to avoid further investigations and antibiotic use. However, the latest clinical studies published have shown that the target of 90% eradication with first-line treatment may not be achieved by these regimens especially if treatment is not tailored to antimicrobial susceptibility tests and if compliance is not optimal (> 90%). ⁽³⁶⁾

This guideline was implemented for optimal diagnosis and treatment of H pylori related diseases in Egyptian children.

 

 

 

Guideline development process and methods

 

After revising inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guideline (CPG):

 

1.   The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood. Pediatrics International (2020) 62, 1315–1331

 

2.     Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016)

 

We conducted an adolopment for this guideline (Adoption, Adaptation, and Development)

• Adoption for most of the guideline recommendations.
• Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)
• Development of Good Practice Statements

 

We can summarize the guidelines’ recommendations for H. Pylori related diseases in children and adolescent

in the following:

 

We recommend that testing for H. pylori be performed in children with gastric or duodenal peptic ulcer disease (PUD). If H. pylori infection is identified then treatment should be administered and eradication confirmed. (Strong)

 

We recommend against diagnostic testing for H. pylori infection in children with functional abdominal pain disorders. (Strong)

 

We recommend against diagnostic testing for H. pylori infection as part of the initial investigation in children with iron deficiency anemia (IDA). (Strong)

 

We suggest that in children with refractory IDA in which other causes have been ruled out, testing for H. pylori during upper endoscopy may be considered. (Conditional)

 

We suggest that noninvasive diagnostic testing for H. pylori infection may be considered when investigating causes of chronic immune thrombocytopenic purpura (ITP). (Conditional)

 

We recommend against diagnostic testing for H. pylori infection when investigating causes of short stature. (Strong)

 

We recommend that one of the following tests be used to determine whether H. pylori treatment was successful: (1) The 13C‑UBT. (2) A 2‑step monoclonal stool H. pylori antigen test. (Strong)

 

To confirm eradication, we recommend that before testing for H. pylori, wait at least 2 weeks after stopping PPIs and 4 weeks after stopping antibiotics. (Strong)

 

We recommend against tests to detect anti‑H. pylori antibodies as single diagnostic tests in clinical settings to diagnose active H. pylori infection. (Strong)

 

We recommend more than two H. pylori tests such as two non‑invasive tests (breath test and stool test), or a biopsy‑based and non‑invasive test (breath test) for more accurate diagnosis of active infection. (Strong)

 

We recommend considering the performance of a rapid urease test directly on gastric biopsies to determine presence/absence of H. pylori as a diagnostic test for active infection. (Conditional)

 

We recommend histological examination of gastric biopsies as a biopsy‑based diagnostic test for active H. pylori infection. (Conditional)

 

We recommend H. pylori culture because the culture method is the gold standard biopsy‑based test for active infection and it can also be used for antimicrobial susceptibility testing for optimization of eradication therapy. (GPS)

 

Diagnostic accuracy: pre‑eradication H&E staining sensitivity is 92%–98.8% and specificity is 89%–100%. (GPS)

 

We recommend that at least 6 gastric biopsies should be obtained for the diagnosis of H. pylori infection during upper endoscopy. (Strong)

 

Diagnostic accuracy: sensitivity of 68%–98% and specificity of 100%. (GPS)

 

Diagnostic accuracy: Pre‑eradication sensitivity is 91.0%–98.5% and specificity is 90.9%–100%. Post‑eradication sensitivity is 58.8%–86% and specificity is 97.8%–99.2%. (GPS)

 

We recommend H. pylori tests when the following endoscopic findings are observed: antrum‑predominant nodularity, ulcerations or erosions in the stomach or duodenum, disappearance of regular arrangement of collecting venules (RAC) in the gastric body. (Strong)

 

We recommend eradication therapy for H. pylori‑infected children with gastric and/or duodenal ulcers. (Strong)

 

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. (Conditional)

 

We recommend consideration of eradication therapy for H. pylori‑infected children who underwent diagnostic upper gastrointestinal endoscopy for abdominal symptoms. (Weak)

 

We recommend eradication therapy for H. pylori‑infected children with gastric MALT lymphoma. (Strong)

 

We recommend eradication therapy for H. pylori‑infected children with IDA when the iron deficiency is recurrent or refractory to iron supplement therapy. (Strong)

 

We recommend eradication therapy for H. pylori‑infected children with chronic ITP as the first‑line therapy. (Strong)

 

We do not recommend eradication therapies for H. pylori‑infected children with chronic idiopathic urticaria. (Conditional)

 

We recommend against a “test‑and‑treat” strategy for H. pylori infection for asymptomatic children to protect against gastric cancer development. (Conditional)

 

If H. pylori is an incidental finding at endoscopy, treatment may be considered following careful discussion of the risks and benefits of H. pylori treatment with the patient/parents. When H. pylori is detected by biopsy‑based methods in absence of PUD, treatment may be considered. (GPS)

 

We recommend consideration of eradication therapies for children who have a family history of gastric cancer in their first‑ or second‑degree relatives and in whom active H. pylori infection has been found. (Weak)

 

We recommend against a “test‑and‑treat” strategy for asymptomatic children living in the household of an H. pylori‑infected adult who received eradication therapy to prevent re‑infection in that adult. (Weak)

 

A proton pump inhibitor‑based triple regimen with amoxicillin and clarithromycin is recommended as first‑line therapy if strains are susceptible or susceptibility is unknown. A proton pump inhibitor‑based triple regimen with amoxicillin and metronidazole is recommended if strains are resistant to clarithromycin. (Strong)

 

Regarding the duration of eradication regimen in children, a 7‑day course is basically recommended. However, if clinicians judge that there is a therapeutic need according to individual risk of eradication failure, then the regimen may be extended up to 14 days. (Strong)

 

Second‑line therapies in children in whom first‑line therapy failed: a proton pump inhibitor‑based triple regimen with amoxicillin and metronidazole was shown to be successful in children who failed clarithromycin‑containing triple therapy. In patients with second‑line eradication failure, antimicrobial susceptibility should be obtained and salvage therapy tailored accordingly. (Strong)

 

Improvement of eradication rate by a combination of probiotics is not clear. However, probiotics have been shown to be effective for prevention of side effects including diarrhea. Side effects such as diarrhea, nausea, vomiting, dyspepsia or dysphagia significantly decreased when combined with probiotics. (Conditional)

 

We recommend that the outcome of anti‑H. pylori therapy be assessed at least 4 weeks after completion of therapy. (Strong)

 

We recommend that one of the following tests be used to determine whether H. pylori treatment was successful: (1) The 13C‑UBT. (2) A 2‑step monoclonal stool H. pylori antigen test. (Strong)

 

We recommend H. pylori testing for active infection four weeks or more after completion of eradication therapy to avoid false negative results. (Strong)

 

We recommend that the 13C‑urea breath test or stool antigen ELISA test using a monoclonal antibody be employed to confirm eradication. (Strong)

 

We recommend against H. pylori tests using endoscopic biopsy specimens (rapid urease test, histological examination, and culture method) to confirm eradication. (Conditional)

 

We recommend against serological tests to detect anti‑H. pylori antibodies as a single test to confirm eradication. (Strong)

 

Guideline Registration

 

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/