Table of Contents

HK J Paediatr (New Series)
Vol 23. No. 4, 2018

HK J Paediatr (New Series) 2018;23:288-293

Update on Clinical Practice

Update on Helicobacter pylori Infection in Children

CO Sham


Abstract

Helicobacter pylori infection is a common worldwide infection. It is an important cause of gastric cancer, but an overwhelming majority of those get infected will not suffer any consequences during their lifetime. The indication of testing, diagnosis and management of this bacterial infection are also different in children and in adult. This article serves to highlight the important points included in the two guidelines, difference in management of adult and children patients, and discuss the applicability of the guidelines in the Hong Kong setting.

Keyword : Children; Diagnostic tests; Eradication; Helicobacter pylori; Triple therapy


Abstract in Chinese

Introduction

Helicobacter pylori (H. pylori) infection is a well-recognised aetiology for peptic ulcer disease and gastric cancer. The infection is often chronic and usually acquired in childhood, but it rarely causes complications in childhood and adolescence, in contrast to adults. Significant scientific advances have been made in this field throughout these years. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)/ the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the American College of Gastroenterology (ACG) have issued new guidelines in management of this disease in 2016 and 2017. 1,2 This article serves to highlight the important points included in the two guidelines, difference in management of adult and children patients, and discuss the applicability of the guidelines in the Hong Kong setting.

Who Should Be Tested and Treated?

All adult patients with an evidence of active H. pylori infection should be treated.2 However, this statement may not be true in children.1 In children with peptic ulcer disease, eradication of the infection may lower the risk of ulcer recurrence. For other situations, treatment is controversial. This is because there are no data showing that H. pylori cause symptoms or complications in children in the absence of peptic ulcer disease. H. pylori associated gastritis can be an incidental finding which is picked up during upper gastrointestinal endoscopy for work up of other conditions such as inflammatory bowel disease or coeliac disease, but this condition rarely gives rise to complications such as peptic ulcer disease and gastric cancer in childhood. Moreover, some young children can be re-infected with H. pylori after its successful eradication. A study in Bolivia has shown that the re-infection rate in 1 year can be up to 20% in young children.1 Furthermore, there is epidemiological evidence for an inverse association between H. pylori infection and allergic diseases in young children.1 Indeed, eradication of H. pylori in these children may not relieve the symptoms, but may also expose the child to potential risk of treatment such as treatment failure, cramps, diarrhoea and undesirable alteration of the gut microbiome. Of course, in discussion with parents and older patient, these problems should be addressed as well as the risk of complications related to infection, such as peptic ulcer disease and gastric cancer, later in life.

For iron deficiency anaemia, testing and treatment of H. pylori remains controversial. A recently published systematic review and meta-analysis showed that there was a significantly increased likelihood of iron deficiency anaemia in H. pylori infected individuals compared with un-infected ones.3 A study in Texas also found out that children with H. pylori infection eradicated had a significant 3-fold increase in ferritin over baseline level. However, such changes were not noted in a study conducted in Bangladesh.4 A review in Iran concluded that there was not enough evidence to conclude that there was association of H. pylori eradication therapy and refractory childhood iron deficiency anaemia.5

Table 1 listed the indications of H. pylori testing and its treatment in adults and children:1,2

Table 1 Indications of H. Pylori testing and its treatment
Adults Children

Testing indicated:

  • Active peptic ulcer disease
  • Past history of peptic ulcer disease without cure of
    H. pylori infection documented
  • Low grade gastric mucosa associated lymphoid tissue (MALT) lymphoma
  • History of endoscopic resection of early gastric cancer
  • Uninvestigated dyspepsia below the age of 60 without alarming
  • Patients taking long term low dose aspirin
  • Patients initiating chronic treatment with a non-steroidal anti-inflammatory drug (NSAID) (point 2)
  • Unexplained iron deficiency anaemia despite appropriate evaluation
  • Adults with idiopathic thrombocytopenic purpura

Testing NOT indicated:

  • Typical symptoms of gastro-oesophageal reflux disease without history of peptic ulcer disease (GERD) (point 3)
  • Asymptomatic individuals with family history of gastric cancer

Testing indicated:

  • Active peptic ulcer disease
  • Past history of peptic ulcer disease without cure of
    H. pylori infection documented
  • Refractory iron deficiency anaemia in which other causes have been ruled out (weak evidence)
  • Chronic immune thrombocytopenic purpura in features (point 1) childhood (weak evidence)

Testing NOT indicated:

  • Functional abdominal pain disorders (point 4)
  • Initial investigation of children with iron deficiency anaemia
  • Short stature

 

Note points:

  1. Number needed to treat to cure functional dyspepsia was 14.
  2. Benefit of testing and treating H. pylori in NSAID-treated patients remains unclear.
  3. In the author's opinion, treatment of GERD may involve prolonged use of proton pump inhibitors (PPI), and eradication of H. pylori infection before starting this treatment may prevent the progression to atrophic gastritis.
  4. Beware of warning signs, which include 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, coeliac disease or peptic ulcer disease.1

Test and Treat Strategy

The ACG Guideline endorsed this treatment strategy for H. pylori infection for patients under 60 years of age who have dyspeptic symptoms and without warning features.1 In areas that H. pylori is prevalent, non-invasive tests for this bacterium may be performed in this group of patients, and eradication therapy should be offered if test positive. Otherwise, the patient can be given a trial of proton pump inhibitors (PPI) and see if his or her symptoms will improve. In case of treatment failure in both situations, upper gastrointestinal endoscopy may then be arranged. The test and treat strategy was found to be more cost effective than proceeding with endoscopy right away or empirical acid suppression with PPI.1 In children, as there was no data showing that H. pylori causes symptoms in the absence of peptic ulcer disease, if organic cause of dyspepsia is suspected, upper gastrointestinal endoscopy should be arranged. The test and treat strategy is not recommended.2

Diagnosis

In adults, diagnosis of H. pylori can be made easily by non-invasive tests such as urea breath tests and stool antigen test. The sensitivity and specificity of both tests are above 90%.6 However, because of low prevalence of H. pylori infection in children, especially in Europe and North America, the positive predictive values of these tests are low. The ESPGHAN/NASPGHAN Guideline recommended that H. pylori infection in children should be diagnosed either by positive culture or by finding H. pylori gastritis on histopathology plus one more positive test such as rapid urease test (RUT). To achieve this diagnosis, the current standard is to obtain at least six gastric biopsies, including two from antrum and two from corpus for histopathological evaluation as well as one from antrum and one from corpus for H. pylori culture. One more gastric biopsy should be obtained for additional diagnostic test such as RUT. Urea breath test or stool antigen test may help to support the diagnosis of H. pylori infection.1

Note: The ACG Guideline recommends to collect biopsies of normal-appearing gastric mucosa for H. pylori detection during endoscopy in patients with dyspeptic symptoms; while the ESPGHAN/ NASPGHAN Guideline recommends that during endoscopy if antral nodularity without mucosal lesions (gastric/duodenal erosions or ulcers) is visualised, biopsies for RUT and culture to diagnose H. pylori infection and guide treatment should only be taken if treatment is likely to be offered upon confirmation of infection.

Treatment

Tables 2 and 3 summarised first line treatment options recommended by ESPGHAN/ NASPGHAN Guideline.1

For rescue therapy if first line treatment option fails, please refer to the original guidelines for details.

The ACG Guideline recommends enquiry of patients' previous antibiotic exposure, particularly macrolides and fluoroquinolones, when choosing a treatment regimen (Table 4). Previous macrolide therapy for longer than 2 weeks in 20 years is associated with higher risk of treatment failure with clarithromycin triple therapy.7,8 For those with reported penicillin allergy and failed first line H. pylori eradication therapy, the ACG Guideline recommends that these patients should be referred for allergy testing since the vast majority, who do not have true penicillin hypersensitivity, can ultimately be safely given amoxicillin-containing salvage regimens.2 Enquiry about previous antibiotic exposure and penicillin allergy testing are not mentioned in the paediatric guidelines but the author believes that these are good practice (and paediatricians should consider to follow).

The ESPGHAN/NASPGHAN Guideline mentioned that levofloxacin or tetracycline may be considered in the rescue regimen if an adolescent patient failed treatment with first line therapy options. Paediatricians may worry about the safety profile of these two groups of drugs. A study published in 2014 has shown that levofloxacin may be safe for use in children.9 Doxycycline has been used for treatment of macrolide resistant Mycoplasma pneumoniae in children and so-far no significant adverse events have been reported.10

Table 2 Treatment options recommended by ESPGHAN/ NASPGHAN
H. pylori antimicrobial susceptibility Suggested treatment

Known susceptibility to clarithromycin and to metronidazole

Known resistance to clarithromycin but susceptibility to metronidazole

Known resistance to metronidazole but susceptibility to clarithromycin

Resistance to both clarithromycin and metronidazole

Unknown

PPI + amoxicillin + clarithromycin for 14 days

PPI + amoxicillin + metronidazole for 14 days or bismuth based

PPI + amoxicillin + clarithromycin for 14 days or bismuth based

PPI + amoxicillin + metronidazole for 14 days with high dose amoxicillin or bismuth based

PPI + amoxicillin + metronidazole for 14 days with high dose amoxicillin or bismuth based, or concomitant therapy

(PPI + amoxicillin + clarithromycin + metronidazole) for 14 days

* PPI dose 1.5-2.5 mg/kg/day refer to esomeprazole and omeprazole and should be adapted if other PPIs are used


Table 3 Standard dosing regimen as recommended by ESPGHAN/NASPGHAN Guideline1
Drug Body weight range Morning dose, mg Evening dose, mg
PPI 15-24 kg 20 20

25-34 kg 30 30

35 kg or more 40 40
Amoxycillin 15-24 kg 500 500

25-34 kg 750 750

35 kg or more 1000 1000
Clarithromycin/metronidazole 15-24 kg 250 250

25-34 kg 500 250

35 kg or more 500 500

Table 4 First line treatment options recommended by ACG Guideline2
Name of regimen Drug
Clarithromycin triple PPI + clarithromycin + amoxicillin or metronidazole for 14 days
(The only regimen approved by US Food and Drug Administration)
Bismuth quadruple PPI + bismuth + tetracycline + metronidazole for 10-14 days
Concomitant PPI + clarithromycin + amoxicillin + nitroimidazole for 10-14 days
Sequential PPI + amoxicillin for 5-7 days then PPI + clarithromycin + nitroimidazole for 5-7 days
Hybrid PPI + amoxicillin for 7 days then PPI + amoxycillin + clarithromycin + nitroimidazole for 7 days
Levofloxacin triple PPI + levofloxacin + amoxicillin for 10-14 days
Levofloxacin sequential PPI + amoxicillin for 5-7 days then PPI + levofloxacin + nitroimidazole for 5-7 days
LOAD Levofloxacin + PPI double dose + nitazoxanide + doxycycline for 7-10 days

Outcome Assessment

The ACG and the ESPGHAN/ NASPGHAN Guidelines recommend testing to prove eradication of H. pylori at least 4 weeks after completion of antibiotic therapy, and after PPI therapy have been withheld for two weeks. This may be carried out by the urea breath test or stool antigen test.1,2

Probiotic

The ESPGHAN/NASPGHAN Guideline does not support the routine addition of probiotic to H. pylori eradication therapies due to the lack of evidence that this treatment can reduce the side effects.

Further Research Questions

A study published in 2008 involving 2480 Hong Kong children aged 6-19 years has shown that 13.1% of the population had positive urea breath test that suggested

H. pylori infection.11 A continuous surveillance of the situation is needed as disease prevalence will affect the positive predictive value and cost effectiveness of different diagnostic tests, as well as our recommendation in diagnosing H. pylori infection among local children.

Research should also be conducted on whether the test and treat strategy is suitable for management of Hong Kong adolescents with apparent dyspepsia. Dyspeptic symptoms are not uncommon in adolescents in Hong Kong, and H. pylori infection is much more prevalent in Hong Kong than in countries in Europe and North America.12,13 This may be a cost-effective strategy in the management of this group of patients.

Applicability

Although the prevalence of H. pylori infection in children is different, there are similarities between the situation in Hong Kong and that in Europe and North America

(Table 5). There are no data showing that H. pylori cause symptoms or complications in children in the absence of peptic ulcer disease in Hong Kong, Europe and North America. Due to the even higher prevalence of H. pylori infection in Hong Kong, the risk of re-infection after eradication may even be higher. There is so far no evidence that eradication of H. pylori infection in childhood can lower the risk of stomach cancer in adulthood in Hong Kong. Therefore the author believed that the Joint ESPGHAN/NASPGHAN Guideline can be applied in Hong Kong.

Summary

1. Management of H. pylori infection is different between adults and children because of different treatment aims, different risk of disease complications such as peptic ulcer disease and gastric cancer, and different re-infection rate.

2. H. pylori associated gastritis without peptic ulcer disease does not cause symptoms in most children. Therefore, treatment of such condition may not relieve the gastrointestinal symptoms of children. Children with functional abdominal pain should not undergo testing for H. pylori infection.

3. The traditional 7-day triple therapy regimen should not be used to eradicate H. pylori in view of its low efficacy. The ACG Guideline recommends that triple therapy should be given for 14 days in the North America.2

Competing Interest

None declared.

Acknowledgement

The author would like to thank the Hong Kong Society of Gastroenterology, Hepatology and Nutrition (HKSPGHAN) for reviewing the article.

Table 5 Prevalence of Helicobacter pylori infection in children
Area Prevalence estimates
Hong Kong 13.1%11
Iran 64.2%14
United Kingdom Less than 5%15

Turkey

23.6%16
United States Less than 5%16

References

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2. Chey WD, Leontiadis GL, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol 2017;112:212-39.

3. Hudak L, Jaraisy A, Haj S, Muhsen K. An updated systemic review and meta-analysis on the association between Helicobacter pylori infection and iron deficiency anaemia. Helicobacter 2017;22: e12330.

4. Cardenas VM, Prieto-Jimenez CA, Mulla ZD et al. Helicobacter pylori eradication and change in markers of iron stores among non-iron deficient children in El-Paso, Texas: an etiologic intervention study. J Paediatr Gastroentrol Nutr 2011;52:326-32.

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8. Lim SG, Park RW, Shin SJ, et al. The relationship between the failure to eradicate Helicobacter pylori and previous antibiotics use. Dig Liver Dis 2016;48:385-90.

9. Bradley SJ, Kauffman RE, Balis DA, et al. Assessment of musculoskeletal toxicity 5 years after therapy with levofloxacin. Pediatrics 2014;134:e146-53.

10. Lung DC. The fall of macrolide: Macrolide resistant Mycoplasma pneumoniae. J Paediatr Respirol Crit Care 2014;10:4-10. http://www.hkspra.org/product_image_pub/264_894267.pdf

11. Tam YH, Yeung CK, Lee KH, et al. A population-based study of Helicobacter pylori infection in Chinese children resident in Hong Kong: Prevalence and potential risk factors. Helicobacter 2008;13:219-24.

12. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology 2017; In press. http://dx.doi.org/10.1053/j.gastro.2017.04.022

13. Torres BZ, Lucero Y, Lagomarcino AJ, et al. Review: Prevalence and dynamics of Helicobacter pylori infection during childhood. Helicobacter 2017;22: e12399.

14. Jafar S, Jalil A, Soheila N, Sirous S. Prevalence of Helicobacter pylori infection in children, a population-based cross-sectional study in west Iran. Iran J Pediatr 2013;23:13-8.

15. Vyse AJ, Gay NJ, Hesketh LM, et al. The burden of Helicobacter pylori infection in England and Wales. Epidemiol Infect 2002;128:411-7.

16. Ceylan A, Kirimi E, Tuncer O, Türkdoan K, Ariyuca S, Ceylan N. Prevalence of Helicobacter pylori in Children and Their Family Members in a District in Turkey. J Health Popul Nutr 2007;25:422-7.

 
 

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