Helicobacter pylori

Background

• Slow-growing Gram-negative microaerophilic bacillus with a curve, gull-wing, or spiral appearance
• Oxidase-positive and urease-positive
• Major cause of peptic ulcer disease and gastric cancer worldwide

Pathophysiology

• Urease neutrolizes acid and induces angiogenesis
• Strains with CagA, VacA, and BabA are associated with more cellular metaplasia

Epidemiology

• Present worldwide
• About half of the world's population is estimated to have chronic infection
• Usually acquired during infancy or childhood
• Transmission is likely fecal-oral or oral-oral

Prevalence of Helicobacter pylori infection across the world. From: Zamani et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther. 2018;47(7):868-876. doi: 10.1111/apt.14561.

Clinical Manifestations

• Mostly asymptomatic
• Complications include:
  • Peptic ulcer disease in 1 to 10%
  • Gastric cancer in 0.1 to 3%
  • MALT lymphoma in 0.01%

Diagnosis

• Gastroscopy with biopsy for histopathology is the gold standard
• Culture is challenging but necessary for phenotyping susceptibility testing

Urea Breath Test

• Patient is fed urea labelled with ¹³C or ¹⁴C isotopes, which is hydrolyzed into ammonia and isotope-labelled CO₂, which is detected in exhaled breath 30 minutes later and measured by mass spectrometry (or other method)
  • The delta over baseline (DOB) (i.e. increase in labelled CO₂) is compared to a threshold
  • Cutoff DOB is usually 5%
• False negatives may be seen with PPIs (which should be held for 7 days before test), recent antibiotics (should be off of them for 4 weeks before test), bleeding ulcers (should be resolved before test), and corpus-predominant gastritis
• False positives may be seen with Helicobacter heilmannii and rarely with other urease-producing organisms such as Proteus mirabilis, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Staphylococcus aureus, Staphylococcus capitis subsp. urealyticus

Stool Antigen Test

• Non-invasive testing, and preferred to pediatric patients
• Based on ELISA, immunochromatographic assay, and CLIA
• Affected by PPIs (should be held for 7-14 days), antibiotics, bismuth-containing medications, and N-acetylcysteine
• Sample is temperature sensitive: max 24 hours at room temperature, 72 hours at 4ºC, or long-term if frozen

Serology

• Includes IgM, IgA, and IgG antibodies
• More false positives with IgA and IgM
• Post-treatment IgG titres can take 6-12 months to fall below 50% compared to pre-treatment
• Not affected by concurrent medications, unlike other non-invasive tests
• Accuracy varies by strain, so ideally should use locally-validated tests

Test of Cure

• Urea breath test is preferred to stool antigen
• Serology not helpful

Management

• Treatment is with combination therapy for 14 days followed by confirmation of eradication
• First-line:
  • PBMT (BMT Quad): bismuth subsalicylate 524 mg p.o. four time daily, metronidazole 500 mg p.o. three to four times daily, tetracycline 500 mg p.o. four times daily for 14 days
  • PAMC (CLAMET Quad): PPI twice daily, amoxicillin 1 g p.o. twice daily, metronidazole 500 mg p.o. twice daily, and clarithromycin 500 mg p.o. twice daily for 14 days
  • PAC (PPI, amoxicillin, clarithromycin), PMC (PPI, metronidazole, clarithromycin), or PAM (PPI, amoxicillin, metronidazole) only in areas with clarithromycin resistance <15% or with proven high local eradication rates >85%
• Prior treatment failure:
  • PBMT: PPI twice daily, bismuth subsalicylate 524 mg p.o. four times daily, metronidazole 500 mg p.o. three to four times daily, tetracycline 500 mg p.o. four times daily
  • PAL: PPI twice daily, levofloxacin 500 mg p.o. once daily, and amoxicillin 750 mg p.o. three times daily for 14 days
  • PAR: PPI twice daily, amoxicillin 750 mg p.o. three times daily, and rifabutin 300 mg p.o. once daily for 10-14 days
• Duration generally 14 days
• Confirmation of eradication should be done 4 weeks following treatment
• Recommended order of treatment, if persistently positive:
  • PBMT (or PAMC)
  • PAMC (or PBMT)
  • PAL
  • PAR vs. repeat endoscopy for culture and susceptibility testing

Antibiotic Resistance

• Mechanisms:
  • Amoxicillin resistance is caused by modified PBPs (rather than β-lactamases)
  • Clarithromycin resistance is caused by point mutations in the 23S rRNA of 50S ribosomal subunit
  • Metronidazole resistance is caused by mutations in RdxA and FrxA enzymes
  • Levofloxacin resistance is caused by point mutations in DNA gyrase (gyrA or gyrB)
  • Tetracycline resistance is uncommon and not fully understood
  • Rifabutin resistance is uncommon and caused by mutations in DNA-dependent RNA polymerase
• The most important regional rates of resistance to pay attention to when choosing empiric treatment is to clarithromycin and metronidazole, since they are most frequent

Further Reading

• H. pylori Enhanced Primary Care Pathway: 2016 version, 2019 version, 2020 version
• The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterol. 2016;151:51–69. doi: 10.1053/j.gastro.2016.04.006
• Houston Consensus Conference on Testing for Helicobacter pylori Infection in the United States. Clin Gastroenterol Hepatol. 2018;16(7):992-1002.e6. doi: 10.1016/j.cgh.2018.03.013