Helicobacter pylori Infection

Overview

Microbiology

• Curved gram-negative rod, urease-positive
• Produces urease at very high levels - a hallmark exploited by multiple diagnostic tests
• Key virulence factors:
  • CagA (cytotoxin-associated gene A) and VacA (vacuolating cytotoxin A): these proteins drive greater mucosal inflammation and are strongly associated with peptic ulceration and gastric cancer risk
  • The cag pathogenicity island induces high cytokine production
  • Outer membrane proteins BabA and OipA mediate enhanced epithelial adhesion
  • The s1m1 VacA genotype correlates with higher pathogenicity

Pathophysiology

1. Disrupts the gastric mucous barrier
2. Acts on antral G cells to cause gastrin release via disrupted negative feedback → modest hypergastrinaemia → inappropriate acid hypersecretion

• Chronic type B (antral) gastritis: the near-universal result of infection
• Duodenal ulceration: H. pylori cannot colonize normal duodenum, but excess acid causes duodenal gastric metaplasia, which can be colonized, producing duodenitis and eventual ulceration
• Gastric ulceration: direct mucosal breakdown by enzymatic disruption
• Hypochlorhydria and gastric cancer: corpus-dominant gastritis (more common in developing countries) leads to gland atrophy → intestinal metaplasia → dysplasia → adenocarcinoma

Epidemiology

• Affects up to 50% of the world's population; prevalence is up to 80-90% in some developing nations
• Infection is predominantly acquired in childhood; inversely related to socioeconomic status
• Fecal-oral spread is the most likely route; organism found in feces, not saliva/dental plaque
• Humans are the primary reservoir; no seasonal incidence
• Risk for developing ulcer disease during persistent colonization: 5-15% (3-8x higher than uninfected individuals)

Associated Diseases

Diagnosis

• ¹³C or ¹⁴C urea breath test (UBT): exploits urease activity; highly sensitive and specific; recommended for both pretreatment diagnosis and post-treatment confirmation
• Stool antigen test (SAT): sensitive and specific; useful for diagnosis and confirming eradication
• Serology (IgG ELISA): demonstrates exposure, not necessarily active infection; cannot confirm eradication; role is limited to non-invasive test-and-treat strategies

• Rapid urease test (CLO test): performed on gastric biopsy; rapid, relatively sensitive, highly specific
• Histology: modified Giemsa or Warthin-Starry silver stain; sensitive and specific
• Culture: microaerophilic conditions required; slow growth; relatively insensitive unless multiple biopsies taken; important for susceptibility testing

Note: PPIs, bismuth, and antibiotics suppress H. pylori and cause false-negative non-invasive tests; stop PPIs ≥2 weeks and antibiotics ≥4 weeks before testing.

Treatment - Eradication Regimens

First-line: Choice Based on Local Clarithromycin Resistance

• Low resistance (<15% clarithromycin resistance): triple therapy remains acceptable
• High resistance (>15%): quadruple therapy preferred

Standard Triple Therapy (14 days, low-resistance areas)

• Double-dose PPI (omeprazole 40mg BD equivalent) raises eradication rates by ~10%
• Vonoprazan 20mg BD is an emerging alternative to PPI with strong acid suppression
• Clarithromycin resistance is rising globally; cure rates in many countries have fallen to <80% (some <50%)

Bismuth-based Quadruple Therapy (14 days, high-resistance areas or first-line)

• Achieves eradication in ~85-90% of patients
• First-line preference when clarithromycin resistance is high

Non-bismuth Quadruple Therapies

Rescue/Second-line Therapy

• Levofloxacin-based quadruple (PPI + levofloxacin + amoxicillin ± bismuth) - if first-line fails
• Susceptibility-guided therapy: increasingly recommended in regions with high resistance; culture with antibiogram determines optimal regimen
• Reinfection post-successful eradication is rare (<0.5%), but incomplete eradication is a common clinical problem

Indications for Eradication

• All peptic ulcers (gastric and duodenal) - mandatory
• Gastric MALT lymphoma (can achieve complete remission in early-stage disease)
• Functional dyspepsia (modest benefit in a subset)
• Early gastric cancer post-resection (reduces metachronous cancer risk)
• Before long-term NSAID or aspirin therapy
• First-degree relatives of gastric cancer patients
• H. pylori-positive patients requesting treatment (test-and-treat strategy)

Recent Evidence (2024-2026)

• A 2025 systematic review and meta-analysis in Gastroenterology (Ford et al., PMID 39824392) confirms that H. pylori eradication significantly reduces gastric cancer risk in positive individuals, reinforcing current guidelines for universal treatment of confirmed infection.
• Globally, clarithromycin resistance continues to rise, supporting the shift toward bismuth quadruple or concomitant regimens as preferred first-line therapy in most regions.

Key Points Summary

1. H. pylori is the most common human infection worldwide and the primary cause of peptic ulcer disease
2. Urease production is its defining biochemical feature and the basis of the urea breath test and CLO test
3. Virulence factors (CagA, VacA, cag PAI) determine disease severity; most infections are asymptomatic
4. Diagnosis: UBT or stool antigen for non-invasive; CLO test or histology if endoscopy is performed
5. Treatment requires combination therapy (PPI + ≥2 antibiotics); choice depends on local resistance patterns
6. Clarithromycin resistance is rising globally, making bismuth quadruple or concomitant therapy increasingly preferred
7. Post-eradication testing (≥4 weeks post-therapy) by UBT or SAT is mandatory to confirm success