Helicobacter pylori Infections

Introduction

Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans, with an estimated 4.4 billion people infected worldwide.¹ H. pylori is a small, motile, microaerophilic gram-negative curved bacillus that colonizes the mucin layer of the gastric mucosal epithelium. Urease production enables the bacteria to adapt to the acidic gastric environment.² Some hosts clear the bacteria, while others become chronically infected. H. pylori can induce a local inflammatory response, which may lead to gastritis, peptic ulcer disease, or neoplasia.

Epidemiology

Humans appear to be a natural reservoir for H. pylori. H. pylori is mainly transmitted by oral–oral and fecal–oral routes, and in low-resource settings it can be water borne.² Major risk factors for H. pylori infection are environmental exposures related to low socioeconomic status (e.g., living in crowded conditions, substandard sanitation, or a sharing a bed with siblings). Host genetic predisposition and bacterial virulence factors likely also affect rates of infection and complications.³

H. pylori prevalence varies globally. Africa, Western Asia, and South America are estimated to have the highest rates (60-70% of population infected), while prevalence in North America and Western Europe is approximately 35%.¹

In Canada, H. pylori infection is associated with immigration from high prevalence areas. A cross-sectional study of older adults in Ontario found a seroprevalence of 23.1%, and relative risk of 2.9 for foreign-born individuals who immigrated after 20 years of age.⁴ H. pylori prevalence is high in some Indigenous communities in Canada.^5-7

There are limited data on H. pylori in children in Canada. A multi-center study in the early 2000s of children referred for suspected H. pylori identified 5.8% with biopsy-proven H. pylori gastritis (age range 5-14 years).⁸ Infection rates as high as 30-50% have been detected in children in Indigenous communities.^5,9 There are no Canadian series of H. pylori in newcomer children, but in Australia, H. pylori stool antigen testing was positive in 21-82% of newly arrived refugees, with the highest prevalence in children from Africa.^10,11

Clinical Manifestations

H. pylori infection is usually asymptomatic. Lifetime risk of peptic ulcer disease is 10-15%. In children, chronic gastritis is not associated with symptoms.¹² Peptic ulcer disease (erosions or ulcerations in stomach or duodenum) can present with epigastric pain, hematemesis, and/or melena or bloody stools. Other non-specific GI and constitutional symptoms may be present (e.g., bloating, nausea/vomiting, anorexia, weight loss) but these, on their own, should not prompt H. pylori testing, and other etiologies should be explored. The differential diagnosis in newcomer children with such symptoms includes tuberculosis, intestinal helminths, schistosomiasis; gastrointestinal disorders such as inflammatory bowel disease, celiac disease, eosinophilic gastroenteritis; or somatic manifestations of post-traumatic stress disorder.

H. pylori has been postulated to contribute to iron-deficiency anemia via blood loss from ulcerative disease; however, this association is not well-supported in the literature.¹² There is a possible association with chronic immune thrombocytopenia (ITP), with small pediatric trials showing some benefit of H. pylori eradication therapy on platelet counts.¹³

Gastric cancer is a late sequelae of H. pylori. The lifetime risk is 1-3% for gastric adenocarcinoma and 0.1% for mucosa associated lymphoid tissue lymphoma.² These very rarely affect children, though H. pylori infections acquired in childhood may predispose to these cancers later in life.

Diagnostic tests

The gold standard for diagnosing H. pylori disease in symptomatic children and youth is upper endoscopy with biopsy samples for culture and histology. Current pediatric H. pylori guidelines by NASPGHAN/ESPGHAN¹² outline limited indications for testing and treatment to ensure net benefit for children, given: i) the invasive nature of endoscopy, ii) low prevalence of H. pylori clinical disease in children, iii) treatment benefit in children limited to peptic ulcer disease, and iv) rising rates of antimicrobial resistance and treatment failure. Summary of recommendations is as follows:

• Endoscopy is indicated for children with symptoms suggestive of peptic ulcer disease.
• Biopsies for H. pylori testing should be taken during endoscopy if peptic lesions are seen, and/or if treatment will be offered if biopsies positive.
• Consider endoscopy for refractory iron-deficiency anemia with no other cause identified.
• Consider non-invasive H. pylori testing for chronic ITP.
• No testing recommended for functional abdominal pain or short stature.

Multiple biopsies are sent for culture and susceptibility, histology, and rapid urease testing.

Non-invasive tests for H. pylori are commercially available but are not recommended for initial diagnosis, as the presence of H. pylori infection is not synonymous with clinical disease requiring therapy. Non-invasive tests are primarily used to confirm eradication of infection. Urea breath tests detect labeled carbon dioxide released by H. pylori in expired air after oral administration of isotopically labeled urea. This test is technically difficult for young children (FDA approved for children 3 and older) and has limited availability. Stool antigen testing uses enzyme-linked immunosorbent assays to detect H. pylori antigens in fecal specimens. It can be used for children of any age. Both tests have high sensitivity and specificity.³

Tests based on the detection of antibodies (IgG, IgA) against H. pylori in serum, whole blood and saliva are not considered reliable in the clinical setting.¹² IgG can persist for years after resolution of infection and thus does not provide information about active infection.

Treatment

Children with confirmed H. pylori infection and peptic ulcer disease should receive eradication therapy. Treatment should be considered for children with refractory iron-deficiency anemia or chronic ITP with evidence of H. pylori infection. If H. pylori is incidentally diagnosed on endoscopy biopsies in the absence of peptic ulcer disease, there should be a risk-benefit discussion with the patient and family regarding therapy.¹²

Eradication therapy consists of antibiotics combined with a proton pump inhibitor (PPI) to enhance antimicrobial effect. Treatment duration should be 14 days as longer courses have greater efficacy.

Selecting an appropriate regimen is critical. Eradication success rates have declined over time and often do not reach the desired 90% threshold.¹⁴ Treatment failure can occur due to poor compliance, but increasing antibiotic resistance (particularly to clarithromycin) is a major driving force. In one Canadian study, 30-40% of H. pylori isolates were resistant to each of metronidazole and clarithromycin.¹⁵ Susceptibility testing of H. pylori isolates -- by traditional or molecular methods – should be performed, though is not always possible if cultures do not grow the organism.

ESPGHAN/NASPGHAN guidelines recommend the following (please see guidelines for details):¹²

• When susceptibilities are not known:
  • First line is bismuth-based quadruple therapy.
  • Alternative is high dose amoxicillin, metronidazole, and PPI.
• When susceptibilities are known:
  • For fully sensitive strain, standard dose amoxicillin, clarithromycin and PPI
  • Otherwise according to susceptibilities, or alternatively bismuth-based therapy

Drug selection, dosing, and formulation may be tailored based on age and other factors.  Consulting with a specialist in infectious diseases and/or a gastroenterologist is recommended.

Patients and families should be counselled regarding the importance of strict adherence to optimize chances of eradication and prevent development of resistance.

Follow-up is recommended to assess for resolution of symptoms and successful eradication of H. pylori.  A non-invasive (i.e., urea breath test or stool antigen testing) is recommended at least 4 to 8 weeks after completing therapy. The stool antigen may test positive for up to 90 days after treatment.² Eradication is associated with long-term cure, though re-infection rates in the pediatric population range from 2-20% depending on local prevalence.¹²

Prevention

Screening for H Pylori in high-risk populations

Theoretically, screening and treating H. pylori in asymptomatic individuals could prevent peptic ulcer disease and gastric cancer. However, it is unclear who will progress to these complications, and treatment carries both individual and community (antibiotic resistance) risks. The Asia-Pacific Gastric Cancer Consensus group recommended screening for H. pylori infection in high-risk populations (incidence of gastric cancer >20/100,000).¹⁶ Screening in children was not recommended because of the low risk of clinically relevant disease and the increased risk of re-infection.^{16, 17} A recent meta-analysis of randomized controlled trials in Asia provided moderate evidence for screening and treating healthy adults: eradication therapy reduced gastric cancer incidence by ~50% compared to placebo, with signal for decreased mortality.¹⁸ It remains unclear if there is similar benefit in children in these regions, or in populations with lower rates of gastric cancer.

Current North American guidelines do not make specific recommendations regarding routine screening of asymptomatic immigrants and refugees for H. pylori infection.^12,19

Vaccination

There is currently no licensed vaccine to prevent H. pylori infection. An oral recombinant vaccine showed 71% efficacy in reducing H. pylori infection in children²⁰ but is not in clinical use.

Conclusion

Clinicians should be aware of the higher risk of H. pylori infection in new immigrants and refugees, and understand the indications for H. pylori testing and treatment as per current pediatric guidelines.

References

1. Hooi JKY et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology. 2017 Aug;153(2):420-429.
2. Maspons A, Gilger MA. Helicobacter pylori. In: Cherry J, Demmler-Harrison GJ, et al (eds.) Feigin and Cherry’s Textbook of Paediatric Infectious Diseases, 7th edn. Elsevier/Saunders, 2014:1691-9.2.
3. Korotkaya Y, et al. Helicobacter pylori in Pediatric Patients Pediatr Rev 2020 Nov;41(11):585-592.
4. Naja F et al. Helicobacter pylori infection in Ontario: prevalence and risk factors. Can J Gastroenterol. 2007 Aug;21(8):501-6.
5. Fagan-Garcia K, et al. Burden of disease from Helicobacter pylori infection in western Canadian Arctic communities. BMC Public Health. 2019 Jun 11;19(1):730.
6. Sethi A et al. Prevalence of Helicobacter pylori in a First Nations population in northwestern Ontario. Can Fam Physician. 2013 Apr;59(4):e182-7.
7. Jones N, Chiba N, Fallone C, et al. Helicobacter pylori in First Nations and recent immigrant populations in Canada. Can J Gastroenterol 2012; 26(2): 97-103.
8. Segal I et al. Low prevalence of Helicobacter pylori infection in Canadian children: a cross-sectional analysis. Can J Gastroenterol. 2008 May;22(5):485-9.
9. Sinha S et al. Age at acquisition of Helicobacter pylori in a pediatric Canadian First Nations population. Helicobacter. 2002 Apr;7(2):76-85.
10. Cherian S, et al. The epidemiology of Helicobacter pylori infection in African refugee children resettled in Australia. Med J Aust. 2008 Oct 20;189(8):438-41. 
11. Abdul Rahim NR, et al. Prevalence of Helicobacter pylori infection in newly arrived refugees attending the Migrant Health Service, South Australia. Helicobacter. 2017 Apr;22(2).
12. Jones NL, et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). .J Pediatr Gastroenterol Nutr. 2017 Jun;64(6):991-1003. 
13. Brito HS et al. Helicobacter pylori infection & immune thrombocytopenic purpura in children and adolescents: A randomized controlled trial. Platelets. 2015;26(4):336-41.
14. Kori M, et al. Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016. J Pediatr Gastroenterol Nutr. 2020 Oct;71(4):476-483.
15. Eng NF, et al. Antimicrobial susceptibility of Canadian isolates of Helicobacter pylori in Northeastern Ontario. Can J Infect Dis Med Microbiol. May-Jun 2015;26(3):137-44.
16. Talley NJ, Fock KM, Moayyedi P. Gastric Cancer Consensus conference recommends Helicobacter pylori screening and treatment in asymptomatic persons from high-risk populations to prevent gastric cancer. Am J Gastroenterol 2008 103(5):510-14.
17. K.M. Fock et al, Asia-Pacific Consensus Guidelines on Gastric Cancer Prevention, Journal of Gastroenterology and Hepatology 23 (2008) 351-36518.
18. Ford AC, et al. Helicobacter pylori eradication therapy to prevent gastric cancer: systematic review and meta-analysis. Gut. 2020 Dec;69(12):2113-2121.
19. Pottie K, et al. Evidence-based clinical guidelines for immigrants and refugees. CMAJ. 2011 Sep 6;183(12):E824-925.
20. Zeng M et al. Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015 Oct 10;386(10002):1457-64.