Helicobacter Pylori

Etiology

H pylori is primarily transmitted from person to person, with transmission more likely among individuals living in the same household or sharing a common environment. Fecal–oral transmission is considered the most likely route, particularly in settings with poor sanitation. Evidence for oral–oral transmission exists but remains less well defined, and the role of maternal-to-child transmission is not fully understood.[8] A major risk factor for increased infection prevalence is lower socioeconomic status.[1]

Epidemiology

Global prevalence of Helicobacter pylori infection varies widely, with findings from systematic reviews showing the highest rates in Africa and the Eastern Mediterranean region. In the Americas, prevalence is approximately 38%, while in the United States, it is about 5% among children younger than 10 years of age.[1][2]

Pathophysiology

In the host, bacterial factors trigger both innate and adaptive immune responses, leading to the recruitment and activation of neutrophils, eosinophils, mast cells, and dendritic cells. The resulting sustained inflammatory response reflects the ongoing interaction between bacterial persistence mechanisms and host immune-mediated tissue injury, ultimately leading to progressive gastric mucosal damage and the development of gastritis and peptic ulcer disease.[3][4]

Histopathology

Chronic active gastritis is a consistent histologic finding in H pylori infection. Organisms may be identified on hematoxylin and eosin staining, although special stains such as Giemsa or immunohistochemistry increase diagnostic sensitivity. Histologic evaluation is primarily used when endoscopy is indicated. Immunohistochemistry is useful in cases of suspected infection with negative routine stains but persistent inflammation. Invasive testing also enables culture and antimicrobial susceptibility assessment when clinically indicated.[5]

History and Physical

Clinical manifestations of H pylori infection vary widely, ranging from asymptomatic colonization to significant upper gastrointestinal tract disease. Most infected individuals remain asymptomatic. When symptoms occur, they are most commonly related to chronic gastritis or peptic ulcer disease. Symptoms may include epigastric pain or discomfort, dyspepsia, nausea, vomiting, bloating, early satiety, and, less commonly, gastrointestinal bleeding or anemia secondary to chronic blood loss. In more severe or chronic cases, H pylori–associated inflammation can lead to complications such as peptic ulcer disease (gastric or duodenal ulcers), gastric outlet obstruction, and upper gastrointestinal hemorrhage. Long-standing infection is also associated with an increased risk of gastric malignant neoplasms, including gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma.

The majority of children with H pylori infection are asymptomatic, which contributes to underdiagnosis in the pediatric population.[6] If symptoms are present, they are usually related to gastritis or peptic ulcer disease and may include abdominal pain, nausea, vomiting, or dyspepsia.[1] In particular, infected children may have reduced iron stores; therefore, testing for H pylori is considered in cases of refractory iron-deficiency anemia when no alternative cause is identified, as well as in selected patients with chronic immune thrombocytopenia. Evidence suggests a poor association with other extraintestinal manifestations such as otitis media, upper respiratory tract symptoms, periodontal disease, sudden infant death syndrome, or short stature; therefore, testing for H pylori is not recommended in these patients.[7]

Evaluation

H pylori infection is diagnosed by both invasive and noninvasive methods. Noninvasive tests include detection of H pylori antigens in stool, detection of H pylori antigen in serum, and a urea breath test. The stool antigen test and urea breath test have high sensitivity and specificity, similar to those of invasive methods.[8] In contrast, serologic antibody testing (typically IgG) has limited clinical utility due to poor sensitivity and inability to distinguish active from prior infection. Serologic antibody testing is therefore not recommended for routine clinical use.[7] Invasive tests require gastric tissue to detect the organism and include culture, rapid urease testing, histopathology, polymerase chain reaction, and fluorescence in situ hybridization. Culture is highly specific (approaching 100%) and allows for antimicrobial susceptibility testing; however, culture has lower sensitivity and is not routinely available in all clinical microbiology laboratories due to the organism’s fastidious growth requirements. Nevertheless, culture may be particularly useful in cases of suspected antibiotic resistance, treatment failure, or refractory infection, because it enables targeted antimicrobial therapy. When diagnostic testing for H pylori infection is indicated in children, current guidelines recommend upper gastrointestinal tract endoscopy with gastric biopsies from the antrum and corpus for histology and rapid urease testing, with culture performed in selected cases, such as treatment failure or when antimicrobial susceptibility testing is required. To confirm H pylori eradication, both the urea breath test and stool H pylori antigen detection by enzyme-linked immunosorbent assay are reliable noninvasive methods.[9] Testing should be performed at least 2 weeks after discontinuation of proton pump inhibitors and at least 4 weeks after completion of antibiotic therapy to avoid false-negative test results.[6]

Treatment / Management

In adult therapy, rising antibiotic resistance has led to a major shift away from empiric clarithromycin-based triple therapy. Current first-line treatment recommendations vary according to regional antibiotic resistance patterns. Commonly recommended regimens include 14-day bismuth quadruple therapy and concomitant (nonbismuth quadruple) therapy consisting of a proton pump inhibitor (PPI), amoxicillin, clarithromycin, and metronidazole. Clarithromycin-based triple therapy is now reserved only for regions with low clarithromycin resistance and in patients with no prior macrolide exposure. Salvage regimens following treatment failure may include levofloxacin-based therapy or rifabutin-based therapy, with selection ideally guided by antimicrobial susceptibility testing when available.

In children, European Society for Paediatric Gastroenterology, Hepatology and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines have been updated to improve eradication rates after H pylori infection in children and adolescents. Triple therapy including a PPI (1 to 2 mg/kg/d), amoxicillin (50 mg/kg/d), and clarithromycin (20 mg/kg/d) for 14 days is the treatment of choice if the strain is susceptible to clarithromycin and metronidazole. If this regimen is unsuccessful, clarithromycin can be replaced with metronidazole (20 mg/kg/d) without further antibiotic susceptibility testing.

Another treatment option is sequential therapy for 10 days (PPI with amoxicillin for 5 days followed by PPI with metronidazole and clarithromycin for 5 days) in pediatric patients infected with fully susceptible strains. Sequential therapy should not be given if the strain is resistant to metronidazole or clarithromycin; however, this treatment regimen exposes the child to 3 different antibiotics. Medication doses should be calculated based on the child's weight, and a higher PPI dose per kg of body weight is recommended to sufficiently suppress acid in younger children compared with adolescents and adults. PPIs should preferably be given at least 15 min before meals.

In cases of resistance to both clarithromycin and metronidazole, or when antimicrobial susceptibilities are unknown, bismuth quadruple therapy consisting of bismuth salts (8 mg/kg/d), a PPI, amoxicillin (in children younger than 8 years) or tetracycline (in children older than 8 years), and metronidazole is effective. Although evidence is limited, the other regimen recommended in this setting is the combination of high-dose amoxicillin triple therapy with metronidazole.[6][9] The development of antibiotic resistance is a serious problem that varies by region. Macrolide antibiotic use for respiratory tract infections has led to the emergence of H pylori clarithromycin resistance.[10] In the event of treatment failure, rescue therapy should be individualized based on antibiotic susceptibilities. Compared with Asian populations, White populations metabolize PPIs more rapidly because of CYP2C19 genetic polymorphism. Therefore, PPIs such as esomeprazole and rabeprazole, which are less prone to degradation by rapid metabolizers with CYP2C19 polymorphism, should be used when available. Additionally, results from current studies showed that probiotics do not improve eradication rates or reduce adverse effects.[6](A1)

Vonoprazan is a potassium-competitive acid blocker that provides faster, more potent, and more consistent acid suppression than traditional PPIs, independent of CYP2C19 metabolizer status. Vonoprazan is FDA-approved for H pylori eradication in both dual therapy (vonoprazan 20 mg twice daily + amoxicillin 1 g three times daily for 14 days) and triple therapy (vonoprazan 20 mg twice daily + amoxicillin 1 g twice daily + clarithromycin 500 mg twice daily for 14 days). In the pivotal US/European trial of 1046 patients, vonoprazan triple therapy (81%) and dual therapy (77%) both achieved significantly higher eradication rates than lansoprazole-based triple therapy (69%), with the most striking advantage seen in clarithromycin-resistant strains (66% to 70% vs 32%). However, all regimens fell below the 90% eradication threshold considered optimal, and the 2024 ACG guideline positions vonoprazan-based regimens as alternatives when bismuth quadruple therapy is not feasible.[11][12][11] Results from a 2024 meta-analysis found that vonoprazan-based quadruple therapy achieves the highest pooled efficacy at 94%, though data remain more limited for this regimen. Notably, vonoprazan-based regimens appear to maintain efficacy against clarithromycin-resistant strains better than PPI-based counterparts, making them a particularly valuable option in areas with high clarithromycin resistance.[13][14][13](A1)

Differential Diagnosis

The differential diagnosis includes the following:

• Celiac disease
• Upper gastrointestinal tract Crohn disease
• Peptic ulcer disease
• Nonsteroidal anti-inflammatory drug–induced gastritis
• Gastroesophageal reflux disease
• Eosinophilic esophagitis
• Lactose intolerance
• Constipation

Pertinent Studies and Ongoing Trials

A landmark phase 3, randomized, double-blind, placebo-controlled trial conducted in China evaluated an oral recombinant H pylori vaccine in children aged 6 to 15 years. Results from the study demonstrated a vaccine efficacy of approximately 71.8% in preventing infection within the first year following vaccination, with sustained but slightly reduced protection over a 3-year follow-up period. The vaccine was generally well tolerated, with adverse event rates comparable to placebo, and no vaccine-related serious adverse events reported.[15]

Medical Oncology

The bacterium H pylori is a group 1 carcinogen and can lead to gastric adenocarcinoma through a pathologic sequence progressing from gastritis to atrophy, intestinal metaplasia, dysplasia, and carcinoma. In patients with mucosa-associated lymphoid tissue lymphoma, H pylori has been identified in more than 75% of cases.[2] Testing for H pylori is recommended in children with first-degree relatives with gastric cancer, given the increased risk of infection-related malignant neoplasm in this high-risk group.[9]

Prognosis

The prognosis of Helicobacter pylori infection is generally favorable when appropriately diagnosed and treated. Most patients achieve successful eradication with guideline-directed antibiotic therapy, particularly when regimens are selected based on local resistance patterns and adherence is optimized. Untreated infection is typically chronic and may persist for life, leading to progressive gastric mucosal damage. Long-term complications include peptic ulcer disease, recurrent gastrointestinal bleeding, atrophic gastritis, intestinal metaplasia, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Eradication of H pylori significantly reduces the risk of peptic ulcer recurrence and may lead to regression of early-stage mucosa-associated lymphoid tissue lymphoma. However, risk reduction for gastric adenocarcinoma is variable and depends on the stage of preexisting mucosal damage at the time of treatment. Advanced precancerous changes such as extensive intestinal metaplasia may not be fully reversible. Overall, early detection and successful eradication are associated with excellent long-term outcomes and reduced gastrointestinal morbidity.