Helicobacter Pylori Infection Testing

Number: 0177

Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses helicobacter pylori infection testing.

1. Medical Necessity

   Aetna considers FDA cleared carbon isotope (13C or 14C) urea breath testing or stool antigen testing (HpSA) medically necessary for testing for active Helicobacter pylori infection in selected persons who meet any of the following criteria:

   1. Adults with idiopathic thrombocytopenic purpura; or
   2. Before bariatric surgery for obesity as part of the pre-operative preparation; or
   3. Before starting proton pump inhibitor therapy for dyspepsia; or
   4. Evaluation of new onset dyspepsia in persons younger than 60 years of age with no more than one nonprogressive alarm symptom (anemia, weight loss, vomiting); or
   5. Evaluation of persons with persistent symptoms of dyspepsia despite 2 weeks of appropriate antibiotic therapy for Helicobacter pylori (H. pylori); or
   6. Persons taking long term, low-dose aspirin; or
   7. Persons initiating chronic treatment with a nonsteroidal anti-inflammatory drug (NSAID); or
   8. Persons with active peptic ulcer disease or past history of peptic ulcer if cure of H. pylori infection has not been documented; or
   9. Persons with early gastric cancer; or
   10. Persons with gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma); or
   11. Persons with iron deficiency anemia despite an appropriate evaluation; or
   12. Recurrent dyspeptic symptoms suggesting re-infection with H. pylori; or
   13. Re-evaluation to assess success of eradication of H. pylori infection. Note: Testing to ensure eradication should occur no sooner than 4 weeks post-treatment.

   This policy is consistent with guidelines of the American Gastroenterological Association and the American College of Gastroenterology.

2. Experimental, Investigational, or Unproven

   1. The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

      1. AmHPR Helicobacter pylori antibiotic resistance next generation sequencing panel
      2. H. pylori serology
      3. Interleukin (IL)-1B gene polymorphism testing (IL-1B-511C/T, IL-1B-31C/T, IL-1B+3954C/T) for H. pylori
      4. Plasma pepsinogen II testing for evaluation of the success of H. pylori eradication
      5. Testing for anti-Helicobacter pylori IgG in urine for diagnosis of H. pylori infection
      6. Testing of H. pylori infection for the management of autoimmune gastritis, or preeclampsia
      7. Testing of H. pylori infection for the prediction of risk of gastric cancer
      8. Testing of H. pylori infection for the prediction of risk of irritable bowel syndrome
      9. Testing of tonsillar H. pylori colonization for the management of chronic tonsillitis
      10. Tumor necrosis factor-alpha (TNFA) gene polymorphisms testing for H. pylori Infection
      11. TZAM H. pylori Multiplex PCR
      12. Urea breath testing and stool antigen testing for active Helicobacter pylori infection for all other indications, including any of the following:
          • Assessing risk of developing dementia; or
          • Assessing the risk of stroke; or
          • Dyspepsia associated with “alarm” markers, e.g., anemia, gastrointestinal bleeding, obstruction, perforation, anorexia, early satiety, or weight loss (upper gastrointestinal [GI] endoscopy is indicated); or
          • Evaluating infantile colic; or
          • Managing recurrent aphthous stomatitis; or
          • New-onset dyspepsia in persons aged 60 years or older (upper GI endoscopy is indicated because of concern about gastric neoplasia); or
          • Screening of asymptomatic persons for H. pylori infection.

   2. Aetna considers simultaneous urea breath testing and stool antigen testing for H. pylori not medically necessary because concurrent testing with both methods is not necessary.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met:

78267 Urea breath test, C-14 (isotopic); acquisition for analysis 78268 analysis 83013 Helicobacter pylori; breath test analysis for urease activity, non-radioactive isotope (eg, C-13) 83014 drug administration 87338 Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative, multiple-step method; Helicobacter pylori, stool

CPT codes not covered for indications listed in the CPB:

Interleukin (IL)-1B gene polymorphism testing, H. pylori (including IL-1B-511C/T, IL-1B+3954C/T) – no specific code 0008U Helicobacter pylori detection and antibiotic resistance, DNA, 16S and 23S rRNA, gyrA, pbp1, rdxA and rpoB, next generation sequencing, formalin-fixed paraffin embedded or fresh tissue, predictive, reported as positive or negative for resistance to clarithromycin, fluoroquinolones, metronidazole, amoxicillin, tetracycline and rifabutin 83009 Helicobacter pylori, blood test analysis for urease activity, non-radioactive isotope (eg, C-13) 83519 Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, by radioimmunoassay (eg, RIA) [plasma pepsinogen II testing] 86318 Immunoassay for infectious agent antibody, qualitative or semiquantitative, single step method (eg, reagent strip) [office-based serology] 86677 Antibody; Helicobacter pylori [laboratory-based] 87632 Infectious agent detection by nucleic acid (DNA or RNA); respiratory virus (eg, adenovirus, influenza virus, coronavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus, rhinovirus), includes multiplex reverse transcription, when performed, and multiplex amplified probe technique, multiple types or subtypes, 6-11 targets

ICD-10 codes covered if selection criteria are met:

A04.5 Campylobacter enteritis B96.81 Helicobacter pylori (H. pylori) as the cause of diseases classified elsewhere C16.0 – C16.9 Malignant neoplasm of stomach C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma] D69.3 Immune thrombocytopenic purpura E66.01 – E66.9 Overweight and obesity K25.0 – K25.9 Gastric ulcer K26.0 – K26.9 Duodenal ulcer K27.0 – K27.9 Peptic ulcer, site unspecified K28.0 – K28.9 Gastrojejunal ulcer K30 Functional dyspepsia K31.89 Other diseases of stomach and duodenum R10.13 Epigastric pain R12 Heartburn [new onset dyspepsia] Z79.82 Long term (current) use of aspirin Z87.11 Personal history of peptic ulcer disease

ICD-10 codes not covered for indications listed in the CPB:

D50 – D64.9 Anemias F01.x – F03.91 Dementias J35.01 Chronic tonsillitis K12.0 Recurrent oral aphthae K29.00 – K29.71 Gastritis [autoimmune gastritis] K56.0 – K56.7 Paralytic ileus and intestinal obstruction without hernia K63.1 Perforation of intestine (nontraumatic) O14.00 – O14.15 Pre-eclampsia R10.83 Colic R11.10 – R11.14 Vomiting R63.0 Anorexia R63.4 Abnormal weight loss R68.81 Early satiety T49.0x5+ Adverse effects of local antifungal, anti-infectives and anti-inflammatory drugs Z11.2 Encounter for screening for other bacterial diseases Z12.0 Encounter for screening for malignant neoplasm of stomach Z13.810 – Z13.818 Encounter for screening for digestive system disorders [the prediction of risk of irritable bowel syndrome]

Background

More than 90% of gastroduodenal ulcers are associated with Helicobacter pylori (H. pylori, formerly known as Campylobacter pylori) infection, whether on first presentation or on recurrence. Since cure of H. pylori infection facilitates healing and decreases recurrence rates, antibiotic therapy is indicated for all H. pylori -infected ulcer patients. Simultaneous conventional ulcer therapy using acid-suppressing drugs is recommended to facilitate symptom relief and healing.

Confirmation of the presence of the H. pylori bacterium can be determined non-invasively using an FDA-cleared urea breath test or a stool antigen test or invasively on endoscopic biopsy followed by rapid urease testing (CLOtest™, PyloriTek™, Hpfast™), histology with special stains, or culture.

The stool antigen test (HpSA, Meridian Bioscience, Cincinnati, OH) and the urea breath tests (UBT (Meretek Diagnostics, Lafayette, CO), PYtest (Halyard Health, Alpharetta, GA)) determine the presence of active H. pylori infection. The HpSA stool antigen test is cleared by the U.S. Food and Drug Administration (FDA) for use in the initial diagnosis, therapeutic monitoring and eradication confirmation in adults and children. The test does not require fasting and may be performed even while patients are on a proton pump inhibitor (PPI), bismuth or H2 blockers. The stool antigen test is based on the passage of H. pylori bacteria and H. pylori antigens in the gastrointestinal tract, and their detection by immunoassay.

Urea breath tests are cleared by the FDA for the initial diagnosis, and eradication confirmation in adults, and are based on the fact that H. pylori bacteria produce a urease that breaks down labeled carbon-13 (13C) or carbon-14 (14C) urea to ammonia and carbon dioxide, which can be detected in an exhaled sample from the lungs. The test should be performed while fasting.

According to guidelines from the American Gastroenterological Association (2005) and the American College of Gastroenterology (2007, 2017), urea breath testing or stool antigen testing are the non-invasive methods of choice for detecting new infection in younger patients without alarm symptoms. Patients older than 55 years of age and younger patients with alarm symptoms (e.g., weight loss, progressive dysphagia, recurrent vomiting, evidence of gastrointestinal bleeding, or family history of upper gastrointestinal cancer) should be evaluated by endoscopy with biopsy (AGA, 2005; ICSI, 2003). The stool antigen test and the urea breath test are also the tests of choice in those situations where post-treatment testing is required. Serology is not useful in this situation as antibody levels commonly remain elevated for months to years after successful treatment.

Stool antigen testing is the preferred method of testing for H. pylori infection in pediatric patients, as it has been cleared by the FDA for use in both adults and children. The urea breath test is cleared by the FDA only for use in adults (18 years of age and older).

H. pylori serology is no longer recommended by the American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG) as it is not a test of active infection. Based on H. pylori prevalence of 30% – 40% in the United States, serology is not recommended for use as it is a test of past exposure to H. pylori, and approximately half the positive tests are falsely positive, which may lead to unnecessary treatment.

The American College of Gastroenterology no longer recommends serology for detection of H. pylori infection. A negative serology for H. pylori antibody can be used to rule out infection. However, a positive serology only determines that a patient has been exposed to H. pylori at some time in the past, but not whether the patient is currently infected. Studies indicate that about 50 % of persons with a positive H. pylori serology do not have active infection (ACG, 2007). Moreover, serology cannot be used to show that H. pylori have been successfully eradicated after treatment, as antibody levels commonly remain elevated for months to years after treatment.

Guidance from the National Institute for Health and Care Excellence (NICE, 2014) recommends testing for H pylori using a carbon-13 urea breath test or a stool antigen test, or laboratory-based srology where its performance has been locally validated. (However, as local validation of serologic tests is typically not performed, the use of serology for the detection of H. pylori is not practical in the United States.) The guidelines recommend against using office-based serological tests for H. pylori because of their inadequate performance. The guidelines state that serology has been widely used in clinical practice and two metaanalyses indicate that sensitivity and specificity are usually greater than 85% (citing Loy, et al., 1996 Roberts, et al., 2000). The sensitivity and specificity of serology varies in different populations. The reason for this is uncertain but may relate to different strains of H pylori or genetic differences in the population causing diverse immune responses. The appropriate cut-off for a commercial kit being used should therefore be locally validated. The guidelines state that near patient serology tests have been developed, where the result is obtained in situ rather than from a laboratory, but the accuracy of these kits varies widely in different communities (NICE, 2014).

Guidelines from the American College of Gastroenterology indicate post-treatment testing in all patients treated for H. pylori infection (ACG, 2007). Previously published guidelines recommended post-treatment testing only in individuals with refractory symptoms or those with complicated ulcer disease, including low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma and resected gastric cancer (ICSI, 2003; Howden and Hunt, 1998). Stool antigen testing and urea breath test are the recommended modalities for confirming eradication of H. pylori after treatment.

According to ACG guidelines, all persons suspected of having peptic ulcer disease should be tested for H. pylori regardless of whether they are on non-steroidal anti-inflammatory drugs (NSAIDS). The guidelines note that H. pylori and NSAIDs are independent risk factors for the development of peptic ulcer disease.

According to guidelines from the American Society for Gastrointestinal Endoscopy (ASGE, 2008), 30-40% of patients undergoing bariatric surgery are infected with H. pylori. As H. pylori infection may increase the risk of postoperative marginal ulcers, testing for H. pylori with a noninvasive test is recommended as part of the routine pre-operative evaluation before bariatric surgery.

Updated guidelines from the American College of Gastroenterology (Chey, et. al. 2017) add the following conditions to the list of indications for H. pylori testing:

“In patients taking long-term, low-dose aspirin, testing for H. pylori infection could be considered to reduce the risk of ulcer bleeding. Those who test positive should be offered eradication therapy to reduce the risk of ulcer bleeding (conditional recommendation; moderate quality of evidence).

Patients initiating chronic treatment with a non-steroidal anti-inflammatory drug (NSAID) should be tested for H. pylori infection. Those who test positive should be offered eradication therapy (Strong recommendation; Moderate quality of evidence). The benefit of testing and treating H. pylori in a patient already taking an NSAID remains unclear (conditional recommendation; low quality of evidence).

Patients with unexplained iron deficiency anemia despite an appropriate evaluation should be tested for H. pylori infection. Those who test positive should be offered eradication therapy (conditional recommendation; low quality of evidence).

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Adults with idiopathic thrombocytopenic purpura (ITP) should be tested for H. pylori infection. Those who test positive should be offered eradication therapy (conditional recommendation; very low quality of evidence).”

The ACG guidelines (Chey 2017) have also updated the treatment regimens for H. pylori. While clarithromycin-based triple therapy remains a first line of therapy, the guidelines acknowledge the high rates of clarithromycin resistance by recommending the use of this regimen in regions with clarithromycin resistance lower than 15%, and in patients without prior macrolide exposure. While detailed data on regional prevalence is unavailable, the data that is currently present suggests that prevalence of clarithromycin resistance exceeds 15% in many parts of North America. The guidelines acknowledge that better data on regional antibiotic resistance is needed, and that the lack of tests to determine antibiotic sensitivity “remains an unfortunate barrier to making evidence-based treatment recommendations.” Given the concern for clarithromycin resistance, multiple additional therapies have been designated to be first-line options:

“Bismuth quadruple therapy consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10-14 days is a recommended first-line treatment option.

Bismuth quadruple therapy is particularly attractive in patients with any previous macrolide exposure or who are allergic to penicillin (strong recommendation; low quality of evidence).

Concomitant therapy consisting of a PPI, clarithromycin, amoxicillin and a nitroimidazole for 10-14 days is a recommended first-line treatment option (strong recommendation; low quality of evidence (for duration: very low quality of evidence)).

Sequential therapy consisting of a PPI and amoxicillin for 5-7 days followed by a PPI, clarithromycin, and a nitroimidazole for 5-7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (for duration: very low quality of evidence)).

Hybrid therapy consisting of a PPI and amoxicillin for 7 days followed by a PPI, amoxicillin, clarithromycin and a nitroimidazole for 7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (For duration: very low quality of evidence)).

Levofloxacin triple therapy consisting of a PPI, levofloxacin, and amoxicillin for 10-14 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (For duration: very low quality of evidence)).

Fluoroquinolone sequential therapy consisting of a PPI and amoxicillin for 5-7 days followed by a PPI, fluoroquinolone, and nitroimidazole for 5-7 days is a suggested first-line treatment option (conditional recommendation; low quality of evidence (for duration: very low quality of evidence)).”

In a case-control study, Ali (2012) examined if H. pylori is associated with infantile colic. A total of 55 patients with infantile colic who were 2 weeks to 4 months of age and who fulfilled modified Wessel criteria (i.e., crying and fussy behavior) and a total of 30 healthy controls with no history of colic who were matched by country of origin, age, sex, and ethnicity to the 55 colicky infants were included in this study. Main outcome measure was H. pylori infection determined by stool antigen testing. Of the 55 patients presenting with infantile colic, 45 (81.8 %) tested positive for H pylori; of the 30 healthy controls, 7 (23.3 %) tested positive for H pylori (odds ratio, 15.3 [95 % confidence interval: 17.9 to 29.8]). The author concluded that H pylori infection is associated with infantile colic and may be a causative factor.

Kheir (2012) stated that infantile colic is defined as paroxysms of crying lasting more than 3 hours a day, occurring more than 3 days in any week for 3 weeks in a healthy baby aged 2 weeks to 4 months. Colic is a poorly understood phenomenon affecting up to 30 % of babies, underlying organic causes of excessive crying account for less than 5 %. Laboratory tests and radiological examinations are unnecessary if the infant is gaining weight normally and has a normal physical examination. Treatment is limited and drug treatment has no role in management. Probiotics are now emerging as promising agents in the treatment of infantile colic. Alternative medicine (herbal tea, fennel, glucose, and massage therapy) have not proved to be consistently helpful and some might even be dangerous. The author concluded that infantile colic is a common cause of maternal distress and family disturbance, the cornerstone of management remains reassurance of parents regarding the benign and self-limiting nature of the illness. There is a critical need for more evidence based treatment protocols.

UpToDate reviews on “Evaluation and management of colic” (Turner and Palamountain, 2012a) and “Clinical features and etiology of colic” (Turner and Palamountain, 2012b) do not mention H. pylori testing in the evaluation of infantile colic.

Roubaud Baudron et al (2013) examined if H. pylori infection was associated with dementia and risk of developing dementia in a longitudinal population-based cohort of elderly adults living in the community. A total of 603 non-institutionalized individuals aged 65 and older living in the southwest of France followed from 1989 to 2008 were included in this study. A descriptive and comparative analysis including dementia prevalence, according to H. pylori status (serology), was made at baseline. Cox proportional hazard models were used to study the risk of developing dementia according to H. pylori status assessed on sera samples from elderly adults initially free of dementia and followed for 20 years. A neurologist diagnosed dementia according to Diagnostic and Statistical Manual of Mental Disorders Third Edition criteria. At baseline, 391 (64.8 %) subjects (348 women, mean age of 73.9 ± 6.5 years) were sero-positive for H. pylori. Dementia prevalence was higher in the infected group (5.4 % versus 1.4 %, p = 0.02). After 20 years of follow-up, 148 incident cases of dementia were diagnosed. After controlling for age, sex, educational level, apolipoprotein E4 status, cardiovascular risk factors, and Mini-Mental State Examination score, H. pylori infection was determined to be a risk factor for developing dementia (hazard ratio = 1.46, p = 0.04). The authors concluded that this longitudinal population-based study provided additional epidemiological support to the hypothesis of an association between dementia and H. pylori infection, which may enhance neurodegeneration. More research is needed to test this hypothesis.

Lopes and colleagues (2014) stated that considering the recommended indications for H. pylori eradication therapy and the broad spectrum of available diagnostic methods, a reliable diagnosis is mandatory both before and after eradication therapy. Only highly accurate tests should be used in clinical practice, and the sensitivity and specificity of an adequate test should exceed 90 %. The choice of tests should take into account clinical circumstances, the likelihood ratio of positive and negative tests, the cost-effectiveness of the testing strategy and the availability of the tests. This review concerned some of the most recent developments in diagnostic methods of H. pylori infection, namely the contribution of novel endoscopic evaluation methodologies for the diagnosis of H. pylori infection, such as magnifying endoscopy techniques and chromoendoscopy. In addition, the diagnostic contribution of histology and the urea breath test was explored recently in specific clinical settings and patient groups. Recent studies recommended enhancing the number of biopsy fragments for the rapid urease test. Bacterial culture from the gastric biopsy is the gold standard technique, and is recommended for antibiotic susceptibility test. Serology is used for initial screening and the stool antigen test is particularly used when the urea breath test is not available, while molecular methods have gained attention mostly for detecting antibiotic resistance.

An UpToDate review on “Indications and diagnostic tests for Helicobacter pylori infection” (Crow, 2014) states that “Polymerase chain reaction (PCR) is not practical for the routine diagnosis of H. pylori. It may, however, be useful in detecting the organism when ordinary culture is difficult, as with testing stool or drinking water”.

Leja et al (2014) noted that pepsinogen levels in plasma are increased by inflammation in the gastric mucosa, including inflammation resulting from H. pylori infection. A decrease in pepsinogen II level has been suggested as a reliable marker to confirm the successful eradication of infection. These researchers evaluated the potential role of pepsinogens I and II, gastrin-17 and H. pylori antibodies in confirming successful eradication. A total of 42 patients (25 women, 17 men), mean age of 45 years (range of 23 to 74), were enrolled. Pepsinogens I and II, gastrin-17 and H. pylori IgG antibodies were measured in plasma samples using an ELISA test (Biohit, Oyj., Finland) before the eradication and 4 weeks after completing the treatment. The success of eradication was determined by a urea breath test. Eradication was successful in 31 patients (74 %) and unsuccessful in 11 patients (26 %). Pepsinogen II decreased significantly in both the successful (p = 0.029) and unsuccessful (p = 0.042) eradication groups. Pepsinogen I decreased significantly in the successful (p = 0.025) but not the unsuccessful (p = 0.29) eradication group. The pepsinogen I/II ratio increased in the successful eradication group (p = 0.0018) but not in the group in which treatment failed (p = 0.12). There were no differences in gastrin-17 or H. pylori antibody values. The authors concluded that a decrease in pepsinogen II levels cannot be used as a reliable marker for the successful eradication of H. pylori 4 weeks after the completion of treatment. The increase in pepsinogen I/II ratio reflects differences in pepsinogen production following the eradication irrespective of improvement in atrophy.

Autoimmune Gastritis

Venerito et al (2015) stated that autoimmune gastritis leads to oxyntic gastric atrophy, a condition at increased risk for gastric cancer. Autoimmune gastritis in conjunction with autoimmune thyroid disease has been reported previously. In a case-control study in patients with autoimmune thyroid disease, these researchers evaluated the usefulness of serum pepsinogens for the identification of oxyntic gastric atrophy, and determined the relationship of H. pylori with oxyntic gastric atrophy. Patients with autoimmune thyroid disease (cases) and goiter (controls) were prospectively enrolled in the study. Pepsinogen (PG) I levels less than or equal to 25 μg/ml and PG I/II ratio less than or equal to 3 were indicative for oxyntic gastric atrophy. Antibodies against H. pylori, CagA and parietal cells were also determined. Esophagogastroduodenoscopy with biopsies was offered to patients with serological oxyntic gastric atrophy. In total, 34 autoimmune thyroid disease patients and 30 controls were enrolled. Serological oxyntic gastric atrophy was present only in autoimmune thyroid disease patients (8/34, 23.5 %, odds ratio [OR] 8.3, 95 % confidence interval [CI]: 1.9 to 36.2). In all 8 patients oxyntic gastric atrophy was confirmed by histology. OLGA stage I, II, III and IV was described in 0 %, 33 %, 50 % and 17 % of the cases, respectively. About, 89 % and 11 % of oxyntic gastric atrophy patients were sero-positive for antibodies against parietal cells or H. pylori infection, respectively. Gastric atrophy involved the angulus/antrum in 50 % of patients with autoimmune gastritis. The authors concluded that the sero-prevalence of oxyntic gastric atrophy is high in patients with autoimmune thyroid disease, and testing of serum pepsinogens should be included in the clinical assessment of these patients. They stated that H. pylori infection is unlikely to be a principal factor in the pathogenesis of oxyntic gastric atrophy in patients with autoimmune thyroid disease. In autoimmune gastritis, gastric atrophy can spread from the oxyntic towards the antral mucosa.

Furthermore, an UpToDate review on “Indications and diagnostic tests for Helicobacter pylori infection” (Crowe, 2015) does not mention autoimmune gastritis as an indication for H. pylori testing.

Chronic Tonsillitis

Hwang et al (2015) noted that H. pylori colonization contributes significantly to multiple disease states, but its role in the development of tonsillar infection is unclear. In a systematic review and meta-analysis, these investigators evaluated the correlation between H pylori colonization of tonsillar tissue in chronic tonsillitis and in non-infectious hyperplastic tonsils. They searched PubMed, MEDLINE, the Cochrane Trial Registry (through June 2014) and relevant article bibliographies. Systematic review and meta-analysis of studies assessing the correlation between H pylori colonization in tonsillar tissues of patients undergoing tonsillectomy for either chronic tonsillitis or non-infectious causes were included in the analysis. Included studies hypothesized that H pylori played a role in the development of chronic tonsillitis. All included studies examined the presence of H pylori in tonsillar tissue removed for various indications. Included studies must have used an accepted method of testing for H pylori. Studies were systematically reviewed by 2 independent reviewers for inclusion. Reported results of H pylori testing between tissues removed for infectious or non-infectious causes were systematically reviewed. The OR of H. pylori colonization in tissue removed for chronic tonsillitis compared with tissue removed for non-infectious causes was calculated using a random-effects model. A total of 6 studies met inclusion criteria and had suitable data for pooling (n = 436). Of these, 2 studies measured H pylori colonization of tonsillar tissue in pediatric populations. One study analyzed tissue in both adult and pediatric populations. Non-infectious indications for tonsillectomy included sleep apnea or sleep-related breathing disorder, obstruction, carcinoma, and tonsillar hypertrophy. Overall, tonsillar H pylori colonization was found not to be significantly present more often in tissue samples removed secondary to recurrent infection rather than to non-infectious indications. The OR of H pylori colonization in the tonsils of patients with chronic tonsillitis was 1.993 (95 % CI: 0.909 to 4.371) (p = 0.09). The authors concluded that H pylori colonization was not found to be more prevalent on tonsillar tissue with chronic or recurrent infections. They stated that the reviewed studies provided no evidence that H pylori infection plays a role in the pathogenesis or development of chronic tonsillitis.

Furthermore, an UpToDate review on “Indications and diagnostic tests for Helicobacter pylori infection” (Crowe, 2015) does not mention chronic tonsillitis as an indication for H. pylori testing.

Recurrent Aphthous Stomatitis

Gomes and colleagues (2016) stated that recurrent aphthous stomatitis (RAS) is a recurrent painful ulcerative disorder that commonly affects the oral mucosa. Local and systemic factors such as trauma, food sensitivity, nutritional deficiencies, systemic conditions, immunological disorders and genetic polymorphisms are associated with the development of the disease. Helicobacter pylori is a gram-negative, microaerophilic bacteria, that colonizes the gastric mucosa and it was previously suggested to be involved in RAS development. These investigators reviewed all previous studies that investigated the association between RAS and H. pylori. A search in PubMed (Medline) databases was made of articles published up until July 2015 using the following keywords: Helicobacter pylori or H. pylori and RAS or recurrent aphthous stomatitis. A total of 15 experimental studies that addressed the relationship between infection with H. pylori and the presence of RAS and 3 reviews, including a systematic review and a meta-analysis were included in this review. The studies reviewed used different methods to assess this relationship, including PCR, nested PCR, culture, ELISA and urea breath test (UBT). A large variation in the number of patients included in each study, as well as inclusion criteria and laboratorial methods was observed; H. pylori can be detected in the oral mucosa or ulcerated lesion of some patients with RAS. The quality of the all studies included in this review was assessed using levels of evidence based on the University of Oxford’s Center for Evidence Based Medicine Criteria. The authors concluded that although the eradication of the infection may affect the clinical course of the oral lesions by undetermined mechanisms, RAS ulcers are not associated with the presence of the bacteria in the oral cavity and there is no evidence that H. pylori infection drives RAS development.

Interleukin (IL)-1B Gene Polymorphism Testing

Sun and associates (2015) stated that host genetic factors that control the production of cytokines, including interleukin-1β (IL-1β), possibly affect susceptibility to many H. pylori-related diseases. There is a complex interplay between H. pylori infection, the subsequent production of certain cytokines, and H. pylori-related diseases. These investigators conducted a meta-analysis to clarify the association between the IL1B -31C > T polymorphism and H. pylori infection, and possible subsequent pathogenic mechanisms. Published literature contained within PubMed, Embase, and the Cochrane Library was used in this meta-analysis. Data were analyzed with the STATA 13.1 software package using pooled ORs with 95 % CI. Egger’s regression test, Begg’s rank correlation test, and Begg’s funnel plot were used to test publication bias. A total of 12 case-control studies comprising 5,827 subjects (3,335 cases and 2,492 controls) were available for this meta-analysis. The IL1B -31C > T polymorphism was associated with an increased risk of H. pylori infection in Asian and Latin American population (TT + CT versus CC, OR = 1.29, 95 % CI: 1.14 to 1.46; TT versus CT + CC, OR = 1.23, 95 % CI: 1.09 to 1.39; TT versus CC, OR = 1.43, 95 % CI: 1.22 to 1.67; T allele versus C allele, OR = 1.19, 95 % CI: 1.10 to 1.29). A significant association was also found for all genetic models in various subgroups (cancer and no-cancer, hospital- and population-based). The authors concluded that the findings of this meta-analysis showed that IL1B -31C > T polymorphism might increase H. pylori infection risk in Asian and Latin American population. Moreover, they stated that further studies with different ethnicities and larger sample size are needed to validate these findings.

In a meta-analysis, Ren and colleagues (2019) examined the impact of interleukin (IL)-1B gene polymorphisms (IL-1B-511C/T, IL-1B-31C/T, IL-1B+3954C/T) in H. pylori infection. The relevant studies were retrieved from PubMed, Web of Science, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases until September 9, 2018; OR and its 95 % CIs were used to evaluate the associations. Statistical analyses of this meta-analysis were conducted by using STATA 12 software. A total of 45 articles including 9,606 cases and 5,654 controls were enrolled in this meta-analysis. The results indicated that IL-1B-511C/T polymorphism was significantly related to an increased the risk of H. pylori infection under recessive model (OR = 1.13, 95 % CI: 1.00 to 1.27, p = 0.048). However, no significant associations were obtained between H. pylori infection and IL-1B-31C/T as well as IL-1B+3954C/T polymorphisms under all models. In addition, subgroup analyses were also performed by country, study design, and detection methods of H. pylori. The authors concluded that the findings of this meta-analysis suggested that IL-1B-511C/T polymorphism was related to the risk of H. pylori infection. Moreover, these researchers stated that further larger studies with high quality are needed to confirm these findings.

Tumor Necrosis Factor-Alpha (TNFA) Gene Polymorphisms Testing

Sun and colleagues (2016) noted that several host genetic factors are thought to affect susceptibility to H. pylori infection-related diseases, including tumor necrosis factor (TNF)-alpha (TNFA). Previous studies have evaluated the association between TNFA gene polymorphisms and H. pylori infection, but the results were inconclusive. These researchers conducted a meta-analysis to clarify the association between TNFA polymorphisms and H. pylori infection. Published literature within PubMed, Embase, and the Cochrane Library were used in this meta-analysis. Data were analyzed with the Stata13.1 software package using pooled ORs with 95 % CI. A total of 24 studies were included in this meta-analysis. The TNFA -308G>A polymorphism was associated with decreasing H. pylori infection (AA versus AG+GG, OR = 0.64, 95 % CI: 0.43 to 0.97; AA versus GG, OR = 0.64, 95 % CI: 0.43 to 0.97). A significantly decreased risk was also found for -1031T>C polymorphism (CC versus CT+TT, OR = 0.61, 95 % CI: 0.44 to 0.84); -863C>A polymorphism was associated with increasing risk of H. pylori infection (AA+AC versus CC, OR = 1.47, 95 % CI: 1.16 to 1.86; A allele versus C allele, OR = 1.40, 95 % CI: 1.14 to 1.72). There was no significant association between -857C>T polymorphism and H. pylori infection. When stratified analysis was conducted on H. pylori infection detection methods, -857C>T and -863C>A polymorphisms were associated with H. pylori infection for the non-ELISA subgroup. When stratified for ethnicity or study design, -863C>A significantly increased the risk and -1031T>C decreased the risk for the Asian subgroup and hospital-based subgroup. The authors concluded that the findings of this meta-analysis showed that TNFA -308G>A and -1031 T>C polymorphisms may be protective factors against H. pylori infection, and -863C>A may be a risk factor, especially in Asian populations. Moreover, they stated that further studies with larger sample sizes are needed to validate these results.

AmHPR Helicobacter Pylori Antibiotic Resistance Next Generation Sequencing Panel

1. 23S rRNA for clarithromycin,
2. gyrA for fluoroquinolones,
3. rdxA for metronidazole,
4. pbp1 for amoxicillin,
5. 16S rRNA for tetracycline, and
6. rpoB for rifabutin.

Binh and associates (2015) stated that metronidazole resistance is a key factor associated with H. pylori treatment failure. Although this resistance is mainly associated with mutations in the rdxA and frxA genes, the question of whether metronidazole resistance is caused by the inactivation of frxA alone is still debated. Furthermore, it is unclear whether there are other mutations involved in addition to the 2 genes that are associated with resistance. A metronidazole-resistant strain was cultured from the metronidazole-susceptible H. pylori strain 26695-1 by exposure to low concentrations of metronidazole. The genome sequences of both susceptible and resistant H. pylori strains were determined by Illumina next-generation sequencing (NGS), from which putative candidate resistance mutations were identified. Natural transformation was used to introduce PCR products containing candidate mutations into the susceptible parent strain 26695-1, and the metronidazole MIC was determined for each strain. Mutations in frxA (hp0642), rdxA (hp0954), and rpsU (hp0562) were confirmed by the Sanger method. The mutated sequence in rdxA was successfully transformed into strain 26695-1, and the transformants showed resistance to metronidazole. The transformants containing a single mutation in rdxA showed a low MIC (16 mg/L), while those containing mutations in both rdxA and frxA showed a higher MIC (48 mg/L). No transformants containing a single mutation in frxA or rpsU were obtained; NGS was used to identify mutations related to drug resistance. The authors confirmed that the mutations in rdxA were mainly associated with metronidazole resistance, and mutations in frxA were able to enhance H. pylori resistance only in the presence of rdxA mutations. Moreover, they stated that mutations in rpsU may play a role in metronidazole resistance.

The authors stated that this study had several drawbacks. They did not obtain metronidazole-resistant strains without mutations in the frxA and rdxA genes in order to confirm the presence of other mutations outside these 2 genes that are associated with metronidazole resistance; therefore, further work is needed to identify the role of mutations in addition to those known in the frxA and rdxA genes. On the other hand, it is well known that NGS alone cannot read the whole genome, as one contig and some sequences of the genome may not be read completely, especially in the repeated regions of the DNA sequences. Thus, these researchers may have missed some other mutations in other genes that may be related to metronidazole resistance.

Miftahussurur and colleagues (2016) noted that information regarding H. pylori antibiotic resistance in Indonesia was previously inadequate. In a pilot study, these investigators evaluated antibiotic susceptibility for H. pylori in Indonesia, and determined the association between virulence genes or genetic mutations and antibiotic resistance. They recruited 849 dyspeptic patients who underwent endoscopy in 11 cities in Indonesia; E-test was used to determine the minimum inhibitory concentration of 5 antibiotics; PCR-based sequencing assessed mutations in 23S rRNA, rdxA, gyrA, gyrB, and virulence genes. Next generation sequencing was used to obtain full-length sequences of 23S rRNA, infB, and rpl22. These researchers cultured 77 strains and identified 9.1 % with clarithromycin resistance. Low prevalence was also found for amoxicillin and tetracycline resistance (5.2 % and 2.6 %, respectively). In contrast, high resistance rates to metronidazole (46.7 %) and levofloxacin (31.2 %) were demonstrated. Strains isolated from Sumatera Island had significantly higher metronidazole resistance than those from other locations. Metronidazole resistant strains had highly distributed rdxA amino acid substitutions and the 23S rRNA A2143G mutation was associated with clarithromycin resistance (42.9 %). However, 1 strain with the highest MIC value had a novel mutation in rpl22 without an A2143G mutation. Mutation at Asn-87 and/or Asp-91 of gyrA was associated with levofloxacin-resistance and was related to gyrB mutations. The u=authors concluded that although this was a pilot study for a larger survey, available data showed that Indonesian strains had the high prevalence of metronidazole and levofloxacin resistance with low prevalence of clarithromycin, amoxicillin, and tetracycline resistance. Nevertheless, clarithromycin- or metronidazole-based triple therapy should be administered with caution in some regions of Indonesia.

The authors stated that the number of samples in this study was relatively low, which was the main drawback of this study. They stated that a larger sample size among region is needed to examine the prevalence of H. pylori antibiotic resistance in Indonesia. This was a pilot study for a larger survey and these investigators are now continuing the similar surveys to that performed in this study, to increase sample numbers and expand geographically to other islands. In addition, these researchers only determined the presence of well-known genetic mutations associated with antibiotic resistance. H. pylori contains approximately 1,600 genes, and it is likely that only a fraction of genomic changes that are related to drug resistance have been identified; NGS is beneficial in that it can yield enormous numbers of DNA sequences in less time and at lower cost, which could be used to clarify the evolution and pathogenicity of H. pylori. To guide antibiotic regimens in Indonesia, the locations were perhaps more important than the ethnicities of the patients. Most antibiotic resistance is related to local antibiotic consumption. Moreover, such resistance is primarily due to the H. pylori genotype, rather than the human genotype.

Furthermore, an UpToDate review on “Treatment regimens for Helicobacter pylori” (Crowe, 2017) does not mention next generation sequencing as a management tool.

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Rolon et al (2021) stated that Helicobacter pylori (H. pylori) infection is mainly diagnosed non-invasively, with susceptibility testing traditionally requiring endoscopy. Treatment is empirical, with clarithromycin-based triple therapy recommended where resistance rates are below 15 %. Rising rates of clarithromycin resistance, resulting in high clarithromycin-based therapy failure rates, are seen worldwide; however, U.S. data are limited. These researchers developed a real-time PCR assay for simultaneous detection of H. pylori and genotypic markers of clarithromycin resistance directly from stool specimens. The assay was validated by testing 524 stool samples using an H. pylori stool antigen test as the reference method for detection accuracy and Sanger sequencing to confirm genotypic susceptibility results. A separate set of 223 antigen-positive stool samples was tested and retrospective medical record review carried out to define clinical utility. PCR resulted in 88.6 % and 92.8 % sensitivity in the validation and clinical study sets, respectively. Sequencing confirmed correct detection of clarithromycin resistance-associated mutations in all positive validation samples. The PCR-predicted clarithromycin resistance rate was 39 % in the clinical data set overall and 31 % in treatment-naive patients; the clarithromycin-based triple therapy eradication rate in treatment-naive patients was 62 %. The clarithromycin-based triple therapy success was lower when resistance was predicted by PCR (41 %) than when no resistance was predicted (70 %; p = 0.03). PCR results were positive in 98 % of antigen-positive stools from patients tested for eradication. The authors concluded that the described PCR assay could accurately and non-invasively diagnose H. pylori, provide genotypic susceptibility, and test for eradication. They stated that these findings support the need for susceptibility-guided therapy in their region if a clarithromycin-based regimen is considered.

The authors stated that a limitation of this study, as with many H. pylori diagnostic studies, was an imperfect reference standard. These investigators used stool antigen; in a perfect study, a composite reference standard that includes stomach biopsy sample, culture, and possibly breath tests in addition to stool antigen testing might be a consideration. These researchers stated that this was one of few U.S. studies to evaluate regional clarithromycin resistance rates, to examine therapy outcome based on genotypic clarithromycin resistance prediction, and to assess the performance of a PCR assay as a test of cure. This trial highlighted the need for susceptibility-guided therapy and, in cases where empirical therapy is considered, demonstrated that clarithromycin-based regimens are not appropriate in their region. The described assay is, to the authors’ knowledge, the 1st to be developed and clinically implemented for molecular detection and susceptibility testing of H. pylori from stool specimens in the U.S. At the authors’ institution, based on these findings, the testing algorithm for H. pylori lists the described PCR assay as the preferred assay when endoscopy is not required. In addition to its utility as a diagnostic tool, the assay can be used to gather information on regional clarithromycin resistance rates that can then be used to inform future patient management.

Pichon et al (2022) noted that H. pylori infects 50 % of the world population and is responsible for gastric and duodenal ulcers as well as gastric cancer. The eradication of H. pylori cures ulcers and prevents ulcer recurrences and gastric cancer. Antibiotic resistance of H. pylori, and especially clarithromycin resistance, is the primary cause of treatment failure and is a major concern identified by the WHO as a high priority requiring research into new strategies. Treatments guided by the detection of antibiotic resistance have proven their medical and economical superiority; however, this approach is hampered by the invasive nature of the fibroscopy, since antibiotic resistance detection requires gastric biopsies. The eradication of H. pylori entails primary care physicians (PCPs). These researchers stated that the objective of this trial will be to examine the feasibility of a strategy for the management of H. pylori infection in primary care by a recently developed non-invasive procedure and its non-inferiority in eradication rates compared with the strategy recommended by the French National Authority of Health. The non-invasive procedure is a PCR on stool to detect H. pylori infection and mutations conferring resistance to clarithromycin allowing a treatment guided by the results of the PCR. The authors presented the protocol of a prospective, randomized-controlled, multi-center study in 2 arms. Moreover, these investigators stated that this study may allow evaluation of the performance of PCR in stools in comparison with the combination of serology/pathology/bacteriology for the initial diagnosis, evaluation of the performance of PCR in stools in comparison to the respiratory test for the control of eradication. Furthermore, it may lead to the constitution of a biobank of stools of infected patients, in view of further study of the development of in-vitro diagnosis.

Testing for H. Pylori in Laryngopharyngeal Reflux

In a meta-analysis, Campbell and colleagues (2017) determined the prevalence of H. pylori among patients with laryngopharyngeal reflux. The secondary objective was determining if H pylori eradication leads to greater symptom improvement in patients with laryngopharyngeal reflux as compared with standard PPI therapy alone. Data sources included Embase, Cumulative Index to Nursing and Allied Health Literature, Medline, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union Clinical Trials Register, Cochrane Library databases of clinical trials, and ClinicalTrials.gov. A systematic review was performed of studies assessing the diagnosis or treatment of H pylori among patients with laryngopharyngeal reflux. Randomized controlled trials (RCTs), cohort studies, case-control studies, and case series were included. A meta-analysis of prevalence data and assessment of heterogeneity was performed on relevant studies. A total of 14 studies were analyzed in the review, with 13 eligible for the meta-analysis. These investigators determined that the prevalence of H pylori among patients with laryngopharyngeal reflux was 43.9 % (95 % CI: 32.1 to 56.5). The heterogeneity of studies was high, with an overall I2 value of 92.3 %. These researchers were unable to quantitatively assess findings for secondary outcome, since H pylori identification and treatment were not the primary focus of the majority of studies. The authors concluded that there was a high rate of H pylori infection among patients with laryngopharyngeal reflux. The infection rate in North America and Western Europe has not been adequately studied. They stated that there is insufficient evidence to make a recommendation regarding the testing and treatment of H pylori infection among patients with laryngopharyngeal reflux.

Testing for Anti-H. Pylori IgG in Urine for H. Pylori Infection Diagnosis

In a meta-analysis, Gong and colleagues (2017) measured the potential diagnostic value of anti-H. pylori IgG in urine for infection diagnosis, using all eligible studies published in English and Chinese languages. The random effect model was used to analyze the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative LR (NLR), diagnostic OR (DOR), together with the summary receiver operator characteristic curve. Literature searches of databases including PubMed, Embase, Medline, Web of Science, Chinese National Knowledge Infrastructure and Wanfang databases were performed to retrieve studies evaluating the diagnostic value of urine IgG antibody for H. pylori infection. A total of 23 studies with 4,963 subjects were included in the current meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR and area under the curve (AUC) were 0.83 (95 % CI: 0.82 to 0.85), 0.89 (95 % CI: 0.88 to 0.90), 8.81 (95 % CI: 6.37 to 12.2), 0.13 (95 % CI: 0.09 to 0.2), 73 (95 % CI: 46.45 to 114.74) and 0.9551, respectively. Subgroup analyses showed that diagnostic accuracy of the urine IgG assay was no different in age, region, study population and assay method. The authors concluded that testing for anti-H. pylori antibodies in urine appeared to have an important function and represented a good marker for the diagnosis of H. pylori infection. Sources of heterogeneity were found to come from the quality of the studies included, and from the study population. They stated that further large-scale, well-designed studies examining different study populations are needed to confirm the results of this meta-analysis.

1. the studies included are not an exhaustive list because the search range was limited to published studies. Unpublished research, such as conference papers, cannot be obtained so it is possible that some relevant literature has been missed. Additionally, only studies published in English or Chinese were included, and
2. for articles that contained different cut-off values within the same study, these investigators selected cut-off values according to the manufacturers’ recommendations.

However, these may not be the most appropriate values for specific areas.

Testing of H. Pylori for Prediction of Risk of Gastric Cancer

Sheikh and associates (2018) identified the diversity of the virulence genes in patients with gastric cancer (GC). Gastric biopsy specimens from 301 patients suspected to gastro-intestinal (GI) disorders were analyzed for H. pylori using molecular and phenotypical methods (culture, and biochemical test (catalase, oxidase and urease tests)). Among 201 PCR positive for H. pylori, using histopathological methods, 22 (10.9 %) patients had GC. Presence of vacA gene in the H. pylori strains was 100 % (201/201), while the most virulent vacA s1 allele was detected in 82.6 % isolates, and the mid region vacA m1 was found in 39.8 % isolates. The vacA s1/m1 genotype was the most virulent allelic combination in GC and peptic ulcer disease (PUD) in 68.2 % and 50 %, respectively. The cagA gene was detected in 66.7 % isolates. Among the cagA positive isolates, EPIYA-ABC motif was the most common motif in the GC (66.7 %), PUD (55.6 %) and erosive gastroduodenitis (EG) samples (55.2 %), while EPIYA-ABCC was the most common motif (58.7 %) in the non-ulcer dyspepsia (NUD) samples. The vacA s1m1/cagA+ combination was detected in GC (73.3 %) and PUD (51.9 %), while vacA s1m2/cagA+ presented in the NUD and EG samples in 77.8 % and 62.1 %, respectively. The authors concluded that Western type (EPIYA-ABC and ABCC motifs) cagA, vacA s1m1 combinations have been demonstrated as the dominant genotype in the tested Ahvazian H. Pylori strains. Also the participation of cagA gene and vacA s1m1 genotype in development and severity of gastric disorder was well evident. Thus, infection with H. pylori strain containing the cagA gene or the vacA s1m1 genotypes could be associated with increased risk of GC. These researchers noted that this was the first study in their region that reported the high incidence and diversity of allelic combination of cagA and vacA genes in gastroduodenitis patients.

Pormohammad and colleagues (2018) stated that it has been proposed that specific analysis of H. pylori virulence factors can be suitable for predicting post H. pylori infection disorders such as GC. These researchers examined the association between different virulence factors of H. pylori and GC. Studies investigating the association between virulence factors of H. pylori and GC were collected from the several databases. All analysis was performed by Comprehensive Meta-Analysis V2.2 software (Biostat, Englewood, NJ). Based on a comprehensive literature search, a total of 25 eligible studies were included for meta-analyses. Infection with cagA- and vacA s1m1-positive H. pylori strains were significantly associated with increased risk of GC (OR of [2.82 (95 % CI: 1.96 to 4.06), p < 0.001]) and ([1.75 (95 % CI: 1.04 to 2.96), p < 0.034)], respectively. The authors concluded that infection by H. pylori strains with positive vacA s1m1 and the cagA genes could significantly increase the risk of GC. The association between the vacA s1m1 and the cagA and GC suggested that screening of these genes may be helpful for identifying populations at higher risk for GC.

An UpToDate review on “Clinical features, diagnosis, and staging of gastric cancer” (Mansfield, 2018) does not mention H. pylori testing.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Gastric cancer” (Version 2.2018) states that “H. pylori infection , smoking, and high salt intake are the risk factors for gastric cancer”. However, the guideline does not does not mention H. pylori testing.

Hamashima and colleagues (2020) noted that the Japanese government has recommended a 2-year endoscopic screening interval for GC; however, insufficient resources have constrained participation in endoscopic screening for GC. One way to avoid endoscopic screening harms and provide equal access is to define the appropriate screening interval. These investigators described a study protocol for expanding the screening interval of endoscopic screening for GC based on individual risks. To expand screening interval from more than 2 years for low-risk group, a single-arm cohort of endoscopic screening started. At the baseline screening, the participants underwent endoscopic screening for GC, H. pylori antibody test, and serum pepsinogen test (first year), and followed after 2 and 4 years (within the first 5 years). These researchers also evaluated H. pylori infection and atrophy status on images of upper GI endoscopy at the baseline. A new screening model will be developed by dividing the participants into high-risk and low-risk groups based on demographics, history of H. pylori eradication, serological testing, and endoscopic diagnosis. The cumulative GC incidence after negative results at baseline are compared between the low-risk group on the third screening round after 4 years from baseline and the total screening group on the second screening round after 2 years. If the cumulative GC incidence in the low-risk group on the third screening round is lower than that in the total screening group on the second screening round, the screening interval can be expanded to 4 years in the low-risk group. The authors concluded that to reduce mortality from GC, a high participation rate of the target population is needed. The screening interval of endoscopic screening can be changed if the individual risks for H. pylori infection are clarified. The authors stated that the objective of this study is to obtain relevant data that can be used to improve the efficient use of endoscopic screening for GC by referring to individual risks in Japan.

Urgessa et al (2023) noted that H. pylori is a gram-negative aerobic pathogen that primarily colonizes the gastric mucosa. Peptic ulcer disease, atrophic gastritis, gastric cancer, and mucosal-associated lymphoid tissue (MALT) lymphoma have all been linked to chronic H. pylori infection; therefore, it is important to diagnose and treat it as early as possible. There are both invasive as well as non-invasive tests available to detect it. In a systematic review, these investigators compared the diagnostic abilities of 2 invasive tests – histology and the rapid urease test (RUT) – in a variety of clinical situations. This systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 check-list. They carried out a literature search using the PubMed and Google Scholar databases in accordance with the eligibility criteria and ultimately selected 8 studies for final analysis. The Newcastle-Ottawa scale adapted for cross-sectional studies, the Scale for the Assessment of Narrative Review Articles (SANRA), and the PRISMA 2020 check-list were employed to evaluate the quality of selected articles for cross-sectional studies, traditional literature reviews, and systematic reviews, respectively. According to the findings of the review, both histology and the RUT have high sensitivity and specificity in diagnosing H. pylori although this varied depending on the clinical situation, making one test superior to the other. The authors concluded that both histopathologic tests and RUT have a high and comparable sensitivity and specificity in dyspeptic patients. However, they vary in different clinical situations, making one test a better choice than the other. They both have limitations and neither of them can be used as a single gold standard test. These investigators stated that in patients with peptic ulcer bleeding (PUB), atrophic gastritis (AG), and intestinal metaplasia (IM), histology with modified Giemsa stain is a better choice. It is also superior to RUT in patients taking PPI. These researchers noted that although non-invasive tests such as stool antigen and breath tests are used to ensure eradication, among invasive tests, histology is a better choice in the follow-up of eradication therapy. RUT, on the other hand, is a better choice compared to histology in a resource-limited setting, and if the results are needed faster.

Testing of H. Pylori for Preeclampsia

Di Simone and co-workers (2017) noted that preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality. Epidemiological association between H. pylori infection and PE onset has been widely shown. These investigators analyzed a possible correlation between H. pylori infection and the severity of clinical presentation of PE and identified an immunologic mechanism triggered by H. pylori infection potentially contributing to the pathogenesis of PE. Sera from 93 preeclamptic women and 87 healthy pregnant women were tested for H. pylori infection by immunoassay and for anti-CagA antibodies by Western blot assay. The serologic results were correlated with the clinical features of PE. The functional effect of serum IgG fractions, positive or negative for H. pylori, from preeclamptic women or controls were tested on trophoblast and endothelial cell cultures and in a murine model of angiogenesis. Preeclamptic women showed higher sero-prevalence of H. pylori infection (57.0 %) compared to controls (33.3 %) (p < 0.001). The sero-positivity for CagA-positive strains of H. pylori was 45.2 % in preeclamptic women versus 13.7 % in controls (p < 0.001). In PE women, H. pylori infection was associated with abnormality of uterine arteries Doppler (p < 0.001). H. pylori+ IgG fractions from preeclamptic women bound to trophoblast and endometrial endothelial cell cultures, reducing in-vitro invasiveness and angiogenesis, respectively, and inhibited angiogenesis in mice. The authors concluded that these findings showed, for the first time, an association between H. pylori infection and PE with abnormal uterine arteries Doppler velocimetry, suggesting a role for H. pylori infection in impairing placental development and increasing the risk to develop PE. This study opened the new perspective of a potential screening and treatment for H. pylori infection in pregnancy.

Nourollahpour Shiadeh and colleagues (2018) noted that H. pylori is associated with many pregnancy adverse effects such as PE. These researchers performed a systematic review and meta-analysis study to evaluate the possible association between H. pylori infection and PE and this was the first meta-analysis to clarify this issue. PubMed, ISI (Web of Science), SCOPUS, and Google Scholar databases were searched (up to April 2017) to identify the relevant studies. The Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines were used to do this study. Pooled OR and 95 % CI were estimated using a random-effects meta-analysis model; heterogeneity was assessed with the χ2-based Q-test and I2 statistic. A total of 8 studies including 889 participants (460 preeclamptic women and 429 controls) met the eligibility criteria. A positive association was found between H. pylori infection and PE (OR: 3.35; 95 % CI: 2.21 to 5.10). Heterogeneity was acceptable (χ2 = 13.39; I2 = 47.7, 95 % CI: 0 to 77). In subgroup analysis, cytotoxin-associated antigen A sero-positivity was a substantial risk factor for PE when immunoblotting methods (OR: 11.12; 95 % CI: 5.34 to 23.16; χ2 = 6.42; I2 = 53.3, 95 % CI: 0 to 85) were used, whereas it was not potential risk factor for PE when ELISA was used as a detecting method (OR: 1.11; 95 % CI: 0.6 to 2.06; χ2 = 1.83; I2 = 0, 95 % CI: 0 to 90). The authors concluded that this study indicated that women with H. pylori infection, especially those infected with Cag A-positive strains were more likely to have PE compared with the uninfected women.

In a meta-analysis, Bellos and associates (2018) summarized current evidence concerning the correlation of H. pylori infection and the risk of developing PE. These investigators searched the Medline (1966 to 2017), Scopus (2004 to 2017), Clinicaltrials.gov (2008 to 2017) Embase (1980 to 2017), and Cochrane Central Register of Controlled Trials CENTRAL (1999 to 2017) databases. They selected all observational studies (both prospective and retrospective) that reported the incidence of PE among women with H. Pylori infection; statistical meta-analysis was performed with the RevMan 5.3 software. A total of 14 studies were finally included in this review, which included a total number of 9,787 women; 9 % of these had PE (879 women). The evaluation of studies with the ROBINS-I tool revealed low-to-moderate risk of bias. H. pylori IgG sero-positivity was significantly more prevalent in preeclamptic than in healthy pregnant women (9,391 women, OR: 2.32, 95 % CI: 1.55 to 3.46). The frequency of anti-CagA antibodies was also higher in pregnancies complicated with PE (3,275 women, OR: 3.97, 95 % CI: 1.55 to 10.19). The authors concluded that the findings of this study support that H. pylori infection doubled the risk of developing PE. Moreover, they stated that to-date, it remains unclear if the odds differentiate among women with mild and severe forms of the disease. These investigators stated that larger epidemiological studies are needed to reach firm conclusions as well as to evaluate the impact of H. pylori eradication on the risk of developing the disease. Moreover, while the pathophysiological rationale has been partially investigated, further experimental studies are needed to thoroughly identify the implicated pathways.

The authors noted that this study had several drawbacks. The findings of the present meta‐analysis were based on data from studies with heterogeneous methodological characteristics. These researchers managed to overcome these limitations by using the random effects model meta‐analysis, which helped overcome the differences in studies by limiting the effect of studies that were over‐weighted in the statistical algorithm. The implementation of the sensitivity and meta‐regression analysis did not reveal potential confounders, with the exception of study size that appeared to influence the results of anti‐CagA antibodies. Moreover, given the lack of stratification of cases as early- or late‐onset PE, it was not possible to draw safe conclusions regarding the influence of H. pylori infection in each group. Finally, data were also limited concerning the sero-positivity of specific H. pylori antigens, such as vacuolating cytotoxin A (vacA), ureases, heat shock protein B and flagellin A. Specifically, the presence of these antibodies was only taken into consideration in one study, which reported that PE was significantly associated with higher anti‐vacA and anti‐urease E sero-prevalence.

Furthermore, UpToDate reviews on “Preeclampsia: Clinical features and diagnosis” (August and Sibai, 2018) and “Preeclampsia: Management and prognosis” (Norwitz, 2018) do not mention H. pylori testing as a management tool.

Anti-H. Pylori Antibodies Serum Assay Chronic Atrophic Gastritis

Sugano and co-workers (2015) presented results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on classification of chronic gastritis and duodenitis, clinical distinction of dyspepsia caused by H pylori from functional dyspepsia, appropriate diagnostic assessment of gastritis, as well as when, whom and how to treat H. pylori gastritis. A total of 23 clinical questions addressing the afore-mentioned 4 domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was pre-defined as greater than or equal to 80 %. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto. All 24 statements for 22 clinical questions after extensive modifications and omission of 1 clinical question were achieved with a consensus level of greater than 80 %. To better organize classification of gastritis and duodenitis based on etiology, a new classification of gastritis and duodenitis was recommended for the 11th international classification. A new category of H. pylori-associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before pre-neoplastic changes develop, if feasible, was recommended to minimize the risk of more serious complications of the infection. The Expert panel stated that serological tests (pepsinogen I and II and H. pylori antibody) are useful for identifying individuals at increased risk for gastric cancer (Grade of Recommendation: Strong)

In a position paper by the Italian Society of Hospital Gastroenterologists and Digestive Endoscopists [AIGO], the Italian Society of Digestive Endoscopy [SIED], the Italian Society of Gastroenterology [SIGE], and the Italian Society of Internal Medicine [SIMI], Lahner and colleagues (2019) stated that chronic atrophic gastritis (CAG) is an under-diagnosed condition characterized by translational features going beyond the strict field of gastroenterology as it may manifest itself by a variable spectrum of gastric and extra-gastric symptoms and signs. It is relatively common among the elderly in different parts of the world, but large variations exist. Helicobacter pylori-related CAG (multi-focal) and autoimmune CAG (corpus-restricted) are apparently 2 different diseases; however, they display overlapping features. Patients with cobalamin and/or iron deficiency anemia or autoimmune disorders, including autoimmune thyroiditis and type 1 diabetes mellitus (T1DM), should be offered screening for CAG. Pepsinogens, gastrin-17, and anti-H. pylori antibodies serum assays appeared to be reliable non-invasive screening tools for the presence of CAG, helpful to identify individuals to refer to gastroscopy with 5 standard gastric biopsies in order to obtain histological confirmation of diagnosis. Patients with CAG are at increased risk of developing gastric cancer, and they should be estimated with histological staging systems (OLGA or OLGIM). H. pylori eradication may be beneficial by modifying the natural history of atrophy, but not that of intestinal metaplasia. Patients with advanced stages of CAG (Stage III/IV OLGA or OLGIM) should undergo endoscopic surveillance every 3 years, those with autoimmune CAG every 3 to 5 years. In patients with CAG, a screening for autoimmune thyroid disease and micro-nutrient deficiencies, including iron and vitamin B12, should be carried out. The optimal treatment for dyspeptic symptoms in patients with CAG remains to be defined; and PPIs are not indicated in hypochlorhydric CAG patients.

In a Clinical Practice Update Expert Review, Shah and associates (2021) provided clinicians with guidance on the diagnosis and management of AG, a common pre-neoplastic condition of the stomach, with a primary focus on AG due to chronic H. pylori infection – the most common etiology – or due to autoimmunity. To-date, clinical guidance for best practices related to the diagnosis and management of AG remains very limited in the U.S., which results in poor recognition of this pre-neoplastic condition and suboptimal risk stratification. Furthermore, there is heterogeneity in the definitions of AG, autoimmune gastritis, pernicious anemia, and gastric neoplasia in the literature, which has led to confusion in clinical practice and research. Accordingly, the primary objective of this Clinical Practice Update was to provide clinicians with a framework for the diagnosis and management of AG. By focusing on AG, this Clinical Practice Update was intended to complement the 2020 AGA Institute guidelines on the management of gastric intestinal metaplasia. These recent guidelines did not specifically discuss the diagnosis and management of AG. Providers should recognize, however, that a diagnosis of intestinal metaplasia on gastric histopathology implies the diagnosis of AG because intestinal metaplasia occurs in underlying atrophic mucosa, although this is often not distinctly noted on histopathologic reports. Nevertheless, AG represents an important stage with distinct histopathologic alterations in the multi-step cascade of gastric cancer pathogenesis. These investigators provided the following “Best Practice Advices”:

• Atrophic gastritis is defined as the loss of gastric glands, with or without metaplasia, in the setting of chronic inflammation mainly due to H pylori infection or autoimmunity.
• All individuals with atrophic gastritis should be assessed for H. pylori infection. If positive, treatment of H pylori should be administered; and successful eradication should be confirmed using non-serological testing modalities.

Furthermore, an UpToDate review on “Acute and chronic gastritis due to Helicobacter pylori” (Jensen and Feldman, 2021) states that “H. pylori gastritis has been associated with iron deficiency anemia. The most plausible mechanism is decreased iron absorption due to H. pylori-associated gastric atrophy and hypochlorhydria”.

Testing for H Pylori Infection for Assessing the Risk of Stroke

Doheim and colleagues (2021) noted that stroke is one of the most leading causes of mortality worldwide. Although modifiable risk factors for stroke have been identified, current risk factors do not sufficiently explain the risk in young patients. Previous studies have postulated an association between infection by H. pylori (HP) and stroke. In a systematic review and meta-analysis, these investigators examined the association between HP infection and stroke. A total of 4 electronic search engines/libraries were systematically searched for relevant observational studies. Studies were screened for eligibility and data were extracted. The OR and 95 % CI were combined under the random-effect model. Among the included studies, 25 studies were analyzed for anti-HP IgG, 9 studies were for anti-Cag A, and 6 studies were for the C-urea breath test. The results showed that positive anti-HP IgG was significantly associated with an increased risk of stroke (OR 1.43, 95 % CI: 1.25 to 1.46). Similarly, both anti-Cag A and C-urea breath test were significantly associated with an increased risk of stroke with (OR 1.77, 95 % CI: 11.25 to 2.49), and (OR 2.21, 95 % CI: 21.33 to 3.66), respectively. Furthermore, these findings indicated that positive anti-HP IgG was associated with stroke caused by atherothrombosis and small artery disease. The authors concluded that the findings of this study suggested that HP infection was significantly associated with increased risk of stroke; however, these researchers stated that more well-designed studies are needed to examine if early HP eradication might decrease the incidence of stroke.

Helicobacter Pylori Infection – A Risk Factor for Irritable Bowel Syndrome

Li et al (2020) stated that in recent years, the incidence of IBS has gradually increased, and it is considered as one of the most common functional GI diseases. However, the etiology of IBS is still unclear, and expectations are rising for more targeted treatments. Many clinical trials have examined the link between Helicobacter pylori (H. pylori) and IBS, with different conclusions; thus, these investigators carried out a meta-analysis to examine if there is an association between H. pylori and IBS, which is of great significance for targeted treatment of IBS. They conducted a systematic review and meta-analysis of the association between H. pylori and IBS. They searched PubMed, Embase, Medline and the Cochrane Library to collect related studies; OR was used to describe the ratio of the probability of the H. pylori infection occurring in IBS patients versus the controls. Heterogeneity was assessed by subgroup and meta-regression analysis. A total of 8 studies (1,861 patients) assessed the association between H. pylori infection and IBS. The OR of H. pylori in IBS patients compared to controls was 1.32 (95 % CI: 0.94 to 1.87; p = 0.11). Subgroup analyses showed a difference between IBS patients diagnosed with Roman III criteria and those diagnosed with non-Roman III criteria. The authors concluded that the findings of this study suggested that H. pylori may have a positive effect on the development of IBS. Although the differences were not statistically significant, there were significant differences among subgroups of patients. Considering the limitations and heterogeneity, high quality studies are needed to further examine the effect of H. pylori on the development of IBS.

Fujimori (2021) noted that H. pylori infection causes changes to the intestinal flora, such as small intestinal bacterial overgrowth, and increases gastric acid secretion-stimulating GI hormones, mainly gastrin, due to a decrease in gastric acid caused by atrophic gastritis. Furthermore, the cellular components of H. pylori travel through the intestinal tract, so the bacterial infection affects the immune system; thus, the effects of H. pylori infection are observed not only in the stomach and the proximal duodenum but also in the small and large intestines. Meta-analyses reported that H. pylori-infected individuals had an increased risk of colorectal adenoma and colorectal cancer. Moreover, a recent study reported that the risk of developing colorectal cancer (CRC) was increased in subjects carrying H. pylori vacuolating cytotoxin A antibody. Additionally, it has been reported that H. pylori infection exacerbates the symptoms of Fabry’s disease and familial Mediterranean fever (FMF) attack and is involved in irritable bowel syndrome (IBS) and small intestinal ulcers. On the other hand, some studies have reported that the frequency of ulcerative colitis (UC), CD, and celiac disease was low in H. pylori-infected individuals; therefore, H. pylori infection is considered to have various effects on the small and large intestines. However, few studies have reported on these issues, and the details of their effects have not been well elucidated; thus, additional studies are needed.

Wang et al (2022) stated that the relationship between H. pylori infection (HPI) and IBS remains controversial. In a systematic review and meta-analysis, these investigators examined the relationship between HPI and IBS based on the current evidence. They carried out a systematic literature search in electronic databases (PubMed, Embase, and the Cochrane library) by computer to identify all reports published before August 8, 2021. The OR and CI were calculated to evaluate the association between HPI and IBS. Subgroup analyses were carried out for further assessment and exploration of heterogeneity sources. Furthermore, these researchers evaluated publication bias via funnel plots, Egger’s test, and Begg’s test. Finally, they performed a sensitivity analysis to examine the robustness of the results. A total of 13 studies with 13,173 subjects were included in the meta-analysis. The pooled OR of the association between HPI and IBS was 1.03 (95 % CI: 0.80 to 1.31; p = 0.84). The adjusted OR of the association between HPI and IBS after excluding the studies with confounding factors defined by the authors was 1.29 (95 % CI: 1.03 to 1.62; p = 0.03). These investigators found a positive association between HPI and IBS-D (diarrhea subtype) (OR: 1.54; 95 % CI: 1.22 to 1.95; p = 0.0003). The OR of the relationship between cytotoxin-associated gene A (Cag A) positive HPI and IBS was 4.3 (95 % CI: 0.51 to 36.17; p = 0.18). The authors concluded that the likelihood of HPI in IBS patients was relatively higher than that of non-IBS participants; but not statistically significant, implying that HPI was not significantly associated with IBS, albeit these researchers may have under-estimated this association. Moreover, these investigators found a positive association between HPI and IBS-D. They also observed an increased likelihood of Cag-A positive HPI in IBS patients than that of non-IBS participants but not statistically significant. These researchers stated that additional high-quality prospective studies are needed to examine the relationship between HPI and IBS. Moreover, the specific role of Cag A in the pathogenic mechanism of IBS remains unclear, and relevant experimental studies are suggested to study this issue.

The authors stated that this meta-analysis had several drawbacks. First, potential confounding bias still exists. These investigators did not consider the impacts of age, sex, or medical history. Second, various kinds of IBS diagnostic criteria and HP detection methods were used in the included studies. Due to the various sensitivities and specificities of IBS diagnostic criteria and HP detection methods, potential observation bias may be present. For instance, HP serological test may cause a pseudo-positive result because of the past-infection patients. Third, there was markable heterogeneity that should be treated with caution. The heterogeneity of the overall association between HPI and IBS was noteworthy, although these researchers examined its sources considering 5 factors via subgroup analysis and identified the primary source of the heterogeneity as study design; the high heterogeneity existed in the relationship between Cag A-positive HPI and IBS. Fourth, the relationship between HPI and different subtypes of IBS was different, which meant the overall relationship between HPI and IBS may be impacted by this difference. It is suggested to investigate the relationship between HPI and different subtypes of IBS separately instead of simply studying the overall relationship between HPI and IBS.

Additional Indications for Helicobacter Pylori infection Testing

An UpToDate review on “Indications and diagnostic tests for Helicobacter pylori infection in adults” (Lamont, 2024) provides the following information:

Testing for Helicobacter pylori should be performed only if the clinician plans to offer treatment for positive results. Indications include:

• Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
• Active peptic ulcer disease or past history of peptic ulcer if cure of H. pylori infection has not been documented
• Early gastric cancer.

Appendix

The American Gastroenterological Association algorithm for testing and treatment of H. pylori infection is available from the following website: The American Gastroenterological Association algorithm for testing and treatment of H. pylori infection.

References

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