Continuing Education Activity

H. pylori is a gram-negative, microaerophilic bacterium that can infect humans. It is often found in the stomach of affected individuals and causes inflammation and ulceration. Patients harboring the bacteria are asymptomatic with abdominal pain, nausea, vomiting, and dyspepsia developing only after gastritis and peptic ulcer disease have set in. This activity describes the evaluation and treatment of H. pylori and explains the role of the interprofessional team in managing patients with these conditions.

Objectives:

• Identify the pathophysiology of Helicobacter pylori infection.
• Summarize the use of a urea breath test in the evaluation of Helicobacter pylori infection.
• Describe the triple therapy used in the eradication of Helicobacter pylori infection.
• Outline the importance of collaboration and communication among the interprofessional team members to enhance the delivery of care for patients affected by Helicobacter pylori infections.

Introduction

Helicobacter pylori (H. pylori) is a gram-negative spiral-shaped bacterium that affects up to 50% of the population worldwide, with a higher prevalence in developing countries.[1][2][3] H. pylori is the most important cause for chronic or atrophic gastritis, peptic ulcer, gastric lymphoma, and gastric carcinoma[4]; however, these complications are less often seen in children and adolescents compared to adults.[5] H. pylori infection is usually acquired in early childhood and persists in the absence of treatment.[6] A phase 3 clinical trial in children in China documented the efficacy and safety of an oral recombinant H. pylori vaccine, a future option to reduce the incidence of H. pylori infection.[7]

Etiology

Transmission of H. pylori can occur via the fecal-oral, gastric-oral, oral-oral, or sexual routes.[8] A major risk factor for a higher prevalence of infection is lower socioeconomic status.[1]

Epidemiology

Prevalence of H. pylori varies across the world, with the United States having 5% prevalence in children less than 10 years.[1] The Hispanic and African American populations have a higher prevalence compared to White Americans.[9]

Pathophysiology

There are four important components that lead to the formation of clinical diseases such as gastritis and ulcer in H. pylori infection. First, the urease activity of H. pylori plays an important role in countering the acidic environment of the stomach. Second, the flagella-mediated motility helps H. pylori bacterium move towards the host gastric epithelial cells. This is followed by the bacterial adhesins interacting with the host cell receptors, leading to successful colonization and persistent infection. Finally, there are many effector proteins/toxins that include cytotoxin-associated gene A (Cag A) and vacuolating cytotoxin A (VacA) released by H. pylori that lead to host tissue damage. Both acute and chronic inflammation is seen in H. pylori gastritis as eosinophils, neutrophils, mast cells, and dendritic cells are stimulated.[9] The gastric epithelial layer also secretes chemokines to initiate innate immunity and activates neutrophils that further damages the host tissue leading to the formation of gastritis and ulcer.[10]

Histopathology

Microscopic gastric inflammation is always seen in H. pylori infection.[5] Hematoxylin and eosin (H&E) staining for visualizing the bacteria has a sensitivity and specificity up to 90%. Special stains like modified Giemsa stain, Warthin-Starry silver stain, Genta stain, and immunohistochemical (IHC) stain have shown to improve the specificity up to 100%.[11] H&E staining is normally sufficient for visualizing H. pylori while Giemsa stain is more beneficial compared to other stains as it is simple and consistent. In the presence of inflammation on histology and absence of bacteria on H&E or Giemsa staining, specialized IHC stains may be more useful. [12]

History and Physical

The majority of children with H. pylori infection are asymptomatic.[5] Symptoms, if present, are usually of gastritis or peptic ulcer disease such as abdominal pain, nausea, vomiting or dyspepsia. Children with these gastrointestinal symptoms should be investigated to identify the underlying etiology of the symptoms.[1] There are various extra-intestinal manifestations that are associated with H. pylori infection such as iron deficiency anemia and chronic immune thrombocytopenia (cITP). Therefore, guidelines recommend that non-invasive testing for H. pylori can be considered in children with cITP or with refractory iron deficiency anemia without an identifiable cause. Children may also be anemic as it has been documented that those infected with H. pylori have lower iron stores. There seems to be a poor association with other extra-intestinal manifestations such as otitis media, upper respiratory symptoms, periodontal disease, sudden infant death syndrome (SIDS), or short stature; therefore H. pylori testing is not recommended in such cases.[13]

Evaluation

H. pylori infection is diagnosed by both invasive and non-invasive methods. Noninvasive tests include the detection of H. pylori antigens in the stool, detection of antibodies against H. pylori in serum, urine and oral samples, and a urea breath test (UBT). The stool antigen test and UBT have high sensitivity and specificity similar to the invasive methods.[14] Serological assays detecting the presence of antibodies (IgG is used in clinical laboratory practice) to H. pylori have poor sensitivity and are not reliable for use in the clinical setting.[13] Invasive tests require gastric tissue for detecting the organism and include culture, rapid urease tests (RUT), histopathology, polymerase chain reaction, and fluorescent in situ hybridization (FISH). Culture is the only method with 100% specificity, and a positive culture is sufficient to diagnose H. pylori infection, but it has a lower sensitivity. For this reason, concordant results of at least two tests are needed to define the H. pylori status. It is recommended that the initial diagnosis of H pylori infection should be based on either positive histopathology and positive RUT or a positive culture from gastric biopsies. The current guidelines to diagnose H. pylori infection in children is an upper gastrointestinal endoscopy with gastric biopsies (antrum and corpus) for histology, culture, and RUT. To determine H. pylori eradication, both UBT and stool H. pylori antigen detection by ELISA are reliable non-invasive tests.[15] Before a patient is tested for H. pylori eradication, it is recommended to wait at least 2 weeks after stopping proton pump inhibitors (PPIs) and 4 weeks after stopping antibiotics.[5]

Treatment / Management

To achieve a higher eradication rate following H. pylori infection, the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) have updated the treatment guidelines for children and adolescents. Triple therapy including PPI (1-2 mg/kg/day), amoxicillin (AMO) (50 mg/kg/day), and clarithromycin (CLA) (20 mg/kg/day) for 14 days is the treatment of choice if the strain is susceptible to CLA and metronidazole (MET). If this regimen fails, CLA can be replaced with MET (20 mg/kg/day) without further antibiotic susceptibility testing. Another treatment option is sequential therapy for 10 days (PPI with AMO for 5 days followed by PPI with MET and CLA for 5 days) in pediatric patients infected with fully susceptible strains. Sequential therapy should not be given if the strain is resistant to MET or CLA; however, this treatment regimen exposes the child to three different antibiotics. Medication doses should be calculated based on the weight of the child, and a higher dose of PPI per kg body weight is recommended to suppress acid in younger children sufficiently compared to adolescents and adults. PPIs are preferred to be given at least 15 minutes before meals. In the case of resistance to both CLA and MET or when antimicrobial susceptibility is not known, bismuth quadruple therapy consisting of bismuth salts (8 mg/kg/day), PPI, AMO (in children younger than 8 years) or tetracycline (in children older than 8 years) and MET is effective. Although there is limited evidence, the other regimen recommended, in this case, is the combination of high dose AMO triple therapy with MET.[5][15] Development of resistance to antibiotics is a serious problem that varies from region to region. Using the macrolide group of antibiotics for respiratory tract infection has led to the emergence of H. pylori CLA resistance.[16] With treatment failure, rescue therapy should be individualized based on antibiotic susceptibility. In comparison to Asians, Caucasian populations metabolize PPI more rapidly due to CYP2C19 genetic polymorphism. Therefore PPIs like esomeprazole and rabeprazole that are less prone to degradation by rapid metabolizers with CYP2C19 polymorphism, should be used when available. Also, probiotics have not shown to improve eradication rates or reduce side effects from current evidence.[5]

Differential Diagnosis

• Celiac disease
• Upper gastrointestinal Crohn disease
• Peptic ulcer disease
• NSAID-induced gastritis
• Gastroesophageal reflux disease
• Eosinophilic esophagitis
• Lactose intolerance
• Constipation

Medical Oncology

H. pylori, a group 1 carcinogen can lead to gastric adenocarcinoma through a sequence of pathology starting from gastritis => atrophy => intestinal metaplasia => dysplasia => carcinoma. In patients with mucosa-associated lymphoid tissue (MALT) lymphoma, H. pylori has been seen in more than 75% of cases.[9] H. pylori testing is recommended in children having first-degree relatives with gastric cancer.[15]

Enhancing Healthcare Team Outcomes

A phase 3 clinical trial in children in China documented the efficacy and safety of an oral recombinant H. pylori vaccine. This could be considered as a future option to reduce the incidence of H. pylori infection, especially in the developing countries. The vaccine offered protection against H. pylori infection up to 3 years; however, longer follow-up is needed in the vaccinated cohort along with a study to identify the timing for booster doses for long-term protection against H. pylori infection.[7]