Description:
The recognition of the role of the bacterium Helicobacter pylori (H. pylori) in the pathogenesis of peptic ulcer disease has revolutionized the therapy of peptic ulcer. Specifically, 80% to 95% of patients with duodenal ulcers and 70% to 90% of patients with gastric ulcers have coexisting H. pylori gastritis; eradication of H. pylori infection using a variety of combinations of antibiotics, bismuth compounds, and acid suppression therapy has emerged as a basic treatment strategy for these ulcers. However, it is important to realize that the majority of patients positive for H. pylori do not develop ulcer symptoms. In addition, the role of H. pylori therapy in non-ulcer dyspepsia alone is uncertain. Dyspepsia refers to a symptom complex of epigastric pain or discomfort. While some dyspepsia symptoms, such as a postprandial gnawing or burning relieved by foods or antacids are suggestive of ulcer, others, such as belching, bloating, and fullness are referred to as non-ulcer dyspepsia. Nevertheless, there is considerable overlap between ulcer and non-ulcer dyspepsia.

Coincident with the increased understanding of the pathophysiology of H. pylori has been the development of non-invasive methods of detection of H. pylori. Invasive detection of H. pylori involves endoscopy followed by culture and either direct histologic identification of the organism, or detection of the organism using the CLO (campylobacter-like organism) test. Non-invasive methods include serologic identification of anti-H. pylori antibodies, detection of H. pylori antigens in the feces, or the urea breath test (UBT). While serologic tests indicate either past or present infection, either fecal antigens or a UBT indicates active disease.

Urea breath testing is based on the high urease activity of H. pylori, which hydrolyzes urea to carbon dioxide and ammonia. In the urea breath test, the patient ingests urea labeled with a carbon isotope, either ¹³C or ¹⁴C, and then the concentration of the isotope is measured in the expired CO₂. Analysis of the concentration of ¹³C requires the use of mass spectrometry, and the sample must be submitted to the manufacturer’s reference laboratory for analysis. In contrast, ¹⁴C is radioactive, and while its use exposes the patient to a small dose of radiation, its presence can be measured using scintillation counting, a more readily available and economical technique. H. pylori antigens can be detected in the stool by applying antibodies to a diluted stool sample complexed to a detection molecule.

The advent of noninvasive technologies to test for past or present infection of H. pylori has prompted reconsideration of the treatment algorithms for patients presenting with dyspepsia. H. pylori testing has been investigated in the following clinical situations.

1. The Initial Workup of Patients with Simple Dyspepsia Symptoms

Patients presenting with uncomplicated dyspepsia have commonly been treated with an empiric trial of antisecretory therapy, followed by endoscopy only if symptoms persisted. Initial endoscopy was reserved for those patients with "alarm symptoms" suggestive of possible malignancy, e.g., anemia, gastrointestinal bleeding, early satiety, or weight loss. In addition, due to the increasing incidence of gastric malignancy as people age, endoscopy as part of the initial workup has been performed in patients over the age of 50 with new onset of dyspepsia. In new treatment algorithms, H. pylori testing has been used as a predictor of underlying peptic ulcer such that patients positive for H. pylori would then undergo either:

• Endoscopy followed by anti-H. pylori therapy only when peptic ulcer is confirmed.
• Initial empiric therapy with anti-H. pylori therapy followed by endoscopy only in those patients with persistent symptoms after treatment ("test and treat" strategy). In this setting, the H. pylori test is used to determine which type of empiric therapy to use, i.e., antisecretory therapy alone or antisecretory therapy plus anti-H. pylori therapy for those patients testing positive.

Cost-effective analyses of these 2 treatment strategies have compared the potential decreased costs associated with reducing the number of endoscopies in those treated initially with anti-H. pylori therapy versus the increased costs of unnecessarily treating some patients with antibiotics. As noted above, anti-H. pylori therapy has not been definitively shown to benefit dyspepsia symptoms in the absence of ulcer. Additional concerns regarding the empiric use of anti-H. pylori therapy are the complications of anti-H. pylori therapy and the possible emergence of resistant strains of H. pylori.

In patients with newly diagnosed H. pylori infection without prior treatment, the differentiation between past or present infection is not relevant. Therefore, serologic tests are appropriate in the initial workup of the patient. In a patient with a prior history of treated H. pylori with recurrent symptoms, a serologic test will not be informative. Therefore either UBT or fecal antigen testing may be performed to diagnose a recurrence of H. pylori infection.

2. UBT or Fecal Antigen Testing to Confirm Eradication of H. pylori at the Conclusion of Therapy

Eradication rates of H. pylori after antibiotic therapy vary from 80% to 90%. Since the purpose of this therapy is to eliminate H. pylori to decrease the ulcer recurrence rate, there has been interest in documenting eradication. In this setting, the breath testing or fecal antigen testing is appropriate to determine active infection. Prior to these technologies, confirmation of organism eradication required repeat endoscopic evaluation to obtain gastric antral biopsy specimens for histology of the CLO test. In most cases, it is unnecessary to document bacterial eradication with follow-up testing; monitoring of clinical symptoms is sufficient. However, patients with persistent symptoms after therapy and those at high risk for recurrence, such as patients with ulcers complicated by bleeding or perforation, may benefit from this testing to determine the necessity for additional anti-H. pylori therapy.

Policy:
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. For individuals 18 years of age and older, urea breath testing or stool antigen testing to diagnose an H. pylori infection is considered MEDICALLY NECESSARY in any of the following situations:
   1. For individuals with dyspeptic symptoms
   2. For individuals with active peptic ulcer disease (PUD)
   3. For individuals with past PUD without H. Pylori history
   4. For individuals with low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma
   5. For individuals with a history of endoscopic resection of early gastric cancer (EGC)
   6. For individuals with gastric intestinal metaplasia (GIM)
   7. For individuals with uninvestigated dyspepsia who are under the age of 60 years and without alarm features
   8. For individuals initiating chronic treatment with a non-steroidal anti-inflammatory drug (NSAID)
   1. For individuals with unexplained iron deficiency anemia
   10. For the evaluation of individuals with chronic immune thrombocytopenic purpura (ITP) and suspected H. pylori infection
   11. For individuals with a family history of gastric cancer
   12. For individuals who are first-generation immigrants from a high prevalence area
2. For individuals 18 years of age and older, urea breath testing or stool antigen testing to measure the success of eradication of H. pylori infection (follow-up measurement at least 4 weeks post-treatment) is considered MEDICALLY NECESSARY in any of the following situations:
   1. For individuals with an H. pylori-associated ulcer
   2. As part of the follow-up for individuals with persistent symptoms of dyspepsia following appropriate antibiotic treatment for H. pylori
   3. For individuals with Gastric MALT Lymphoma
   4. For individuals who have undergone resection of early gastric cancer
3. For individuals 18 years of age and older undergoing endoscopic examination or who have alarm symptoms, a biopsy-based endoscopic histology test and either a rapid urease test or a culture with susceptibility testing to diagnose an H. pylori infection is considered MEDICALLY NECESSARY.
4. For individuals less than 18 years of age, urea breath testing or stool antigen testing to diagnose an H. pylori infection is considered MEDICALLY NECESSARY in any of the following situations:
   1. For individuals with chronic ITP and suspected H. pylori infection
   2. To measure the success of eradication of H. pylori infection (follow-up measurement at least 4 weeks post-treatment)
5. For individuals less than 18 years of age, a biopsy-based endoscopic histology test and either a rapid urease test or a culture with susceptibility testing to diagnose an H. pylori infection is considered MEDICALLY NECESSARY in any of the following situations:
   1. For individuals with gastric or duodenal ulcers
   2. For individuals with refractory iron deficiency anemia (when other causes have been ruled out)
6. Urea breath testing or stool antigen testing to diagnose an H. pylori infection is considered NOT MEDICALLY NECESSARY for any of the following situations:
   1. For asymptomatic individuals of all ages
   2. For individuals 18 years and older with typical symptoms of gastroesophageal reflux disease (GERD) who do not have a history of peptic ulcer disease (PUD)
7. For individuals of all ages, serologic testing for H. pylori infection is considered NOT MEDICALLY NECESSARY.
8. For individuals less than 18 years of age, a biopsy-based endoscopic histology test and a rapid urease test or a culture with susceptibility testing to diagnose an H. pylori infection is considered NOT MEDICALLY NECESSARY in any of the following situations:
   1. For children with functional abdominal pain
   2. As part of an initial investigation in children with iron deficiency anemia
   3. When investigating causes of short stature
9. For individuals with recent use of antibiotics, proton pump inhibitors (PPIs), or bismuth, the urea breath test, stool antigen, or biopsy-based testing to diagnose an H. pylori infection is considered NOT MEDICALLY NECESSARY.
10. To diagnose an H. pylori infection, concurrent testing with any combination of the urea breath test, stool antigen testing, and/or biopsy-based testing is considered NOT MEDICALLY NECESSARY.
11. Nucleic acid testing for H. pylori is considered NOT MEDICALLY NECESSARY.

Rationale
Infection with H. pylori is common, with conservative estimates at 50% of the world’s population affected. Prevalence in the United States is significant, estimated to be 30 – 40% in the general population (Siao & Somsouk, 2014). H. pylori is associated with many conditions, such as peptic ulcer disease, chronic gastritis, and gastric mucosa associated lymphoid tissue (MALT) lymphoma. Other conditions such as dyspepsia have been attributed to H. pylori as well (Lamont, 2022). Common symptoms of these conditions include gastritis, dyspepsia, heartburn, and stomach pain (Jensen, 2022; Longstreth, 2022).

Identification of H. pylori infection is accomplished with one or more of the several tests available. The choice of test is guided by the reason for the test, cost and availability of the test, the patient’s age and clinical presentation, prevalence in a population, and the patient’s use of certain medications. Testing for H. pylori infection is done for two main reasons; to detect an active infection that will be treated and to confirm eradication of the infection post-treatment. Invasive and non-invasive approaches have been used. Endoscopy and collection of biopsy specimens for evaluation of H. pylori infection and early gastric cancer detection typically is done in older individuals and those with “alarm” symptoms, including bleeding, unexplained anemia, unexplained weight loss, progressing dysphagia, recurrent vomiting, a family history of gastrointestinal cancer, or a personal history of esophagogastric malignancy. Tissue samples can be tested for H. pylori via methods such as a rapid urease test, culture, or staining. Molecular methods include PCR and next-generation sequencing, and serological methods include ELISA, immunoassays, and dried blood spots. Other non-invasive methods include urea breath test and stool antigen test. Testing for eradication of infection may be performed with the same tests used for diagnosis (Lamont, 2022).

Analytical Validity
Non-invasive options for detection of active H. pylori infection include urea breath tests and stool antigen testing. The stool antigen test is an immunoassay that detects the presence of H. pylori in a stool sample. The test is reported to have greater than 90% sensitivity and specificity for detection of active H. pylori infection, and its use has been FDA cleared for all ages. This test may be used for initial diagnostic purposes and for post-treatment testing. Urea breath tests, which take advantage of the bacteria’s urease activity, may also be used to detect active H. pylori infection. The patient ingests a solution containing either 13C or 14C labeled urea, after a set amount of time, the patient’s breath is collected and analyzed for the presence of 13C or 14C labeled CO2. If H. pylori is present, it will have metabolized the labeled urea and labeled CO2 will be detected, thus indicating infection with H. pylori. This test takes approximately 15 – 20 minutes (Lamont, 2022).

ELISA-based serological tests are also available for detection of H. pylori. However, serological tests often need validation at the local level, which may not be practical in routine practice. Furthermore, serological tests do not distinguish between past and present infections. Serological tests also have a very low positive predictive value in populations with low or average prevalence, as the antibodies will be detected even after an infection has been treated or naturally resolved. In these low-prevalence areas, a positive serological test is more likely to be a false positive (Lamont, 2022).

Other tests such as PCR-based tests are infrequently used. The PCR test, despite its high accuracy, is often too expensive for routine use. In fact, nested PCR tests have approached 100% sensitivity and 100% specificity for detection of H. pylori (Singh et al., 2008), but the test may not be widely available and may be of limited use due to high cost (Lamont, 2022; Patel et al., 2014). PCR tests have been used for diagnostic purposes as well as identifying genetic variants of the bacteria and pathogenic genes present in a patient. A variety of body fluids, such as stool and saliva, have been used in PCR tests for this bacterial species (Patel et al., 2014).

Some medications are known to inhibit the growth or urease activity of H. pylori and can cause a false negative H. pylori test result. Proton pump inhibitors, antibiotics, and bismuth-containing medications may decrease sensitivity of tests, thereby increasing rates of a false negative. Eradication testing is often done weeks after treatment is completed (Lamont, 2022).

Dechant et al. (2020) evaluated the accuracy of various rapid urease tests (RUTs) and compared it with histopathology results. No differences were detected in the sensitivity or specificity of the various RUTs and RUTs had comparable results to histology; however, in patients treated with proton pump inhibitors and antibiotics. RUTs seemed to be more sensitive compared to histology. Pohl et al. (2019) discuss the drawbacks of RUTs, including false negative test results if the bacterial load is less than 104 in the gastric biopsy and false positive test results with some urease positive bacteria, affecting the sensitivity and specificity of RUTs. Commercially available RUTs, such as HpFast, CLOTest, and HpOne, have reported specificities ranging from 95% to 100%, but their sensitivity is moderate (85% to 95%) (Pohl et al., 2019). 

Hussein et al. (2021) compared the sensitivity, specificity, positive, and negative predictive values of invasive tests (RUT and gastric tissue culture) and noninvasive tests (14C-Urea breath test (14C-UBT), stool antigen test, and CagA-IgG serology) to the gold standard quantitative PCR (qPCR) tests for H. pylori in Iraq. One hundred and fifteen participants strongly suspected of H. pylori infection were tested. Overall, the prevalence rates ranged from 47.8% to 70.4% depending on the test method. “The 14C-UBT showed the highest overall performance with 97.5% sensitivity, 97% specificity, and total accuracy of 97.3% followed by SAT, RUT, Cag-IgG, and culture method.” SAT had a sensitivity of 95.0% and a specificity of 91.2%. RUT had a sensitivity of 93.8% and a specificity of 94.1%. CagA-IgG had a sensitivity of 75.3% and a specificity of 85.3%. Gastric tissue culture had a sensitivity of 67.9% and a specificity of 79.4%. The authors conclude that 14C-UBT “may be recommended as first choice due to its higher performance compared to other methods” (Hussein et al., 2021). Hassan et al. (2021) compared the accuracy, specificity, and sensitivity of the stool antigen test and the urea breath test in 45 children who underwent osophagogastroduodenoscopy between 2013 and 2019 in Sulaymaniyah City, Iraq. Histopathological findings from biopsies were used as a confirmatory diagnosis tool. The authors found that “UBT has a statistical significant correlation with result of biopsy, also it is more accurate and more sensitive than SAT, but they share same positive predictive value and same specificity.” The authors conclude that UBT is preferred over SAT in children above six years (Hassan et al., 2021).

Abdelmalek et al. (2022) evaluated the accuracy and utility assurance of H. pylori stool antigen lateral flow immunochromatography assay (HpSA-LFIA) in Egypt. The study used stool samples from 200 gastric patients and compared HpSA-LFIA results to the monoclonal antibody-based ELISA kit. The authors report that HpSA-LFIA achieved sensitivity of 93.75%, specificity of 59.76%, a negative predictive value of 98.00%, positive predictive value of 31.25%, and accuracy of 65.31%. The authors conclude that “HpSA-LFIA was not accurate enough to be the sole test for diagnosis and needs other confirmatory tests in case of positive conditions” (Abdelmalek et al., 2022).

Clinical Utility and Validity
The stool antigen test has been shown to have strong accuracy. A meta-analysis by Gisbert et al. (2006) focusing on 2499 patients of 22 studies found the diagnostic test to have a sensitivity of 0.94 and a specificity of 0.97. The monoclonal version of the test was shown to be more sensitive than the polyclonal one (0.95 vs 0.83). The authors also evaluated the diagnostic test after eradication of the bacteria in 957 patients of 12 studies. The authors evaluated the antigen test at 0.93 sensitivity and 0.96 specificity post-eradication (Gisbert et al., 2006). 

A new automated LIAISON® Meridian H. pylori SA assay, a chemiluminescent immunoassay that uses novel monoclonal antibodies for capture and detection of the H. pylori stool antigen, was evaluated for its clinical performance. Opekun et al. (2020) studied the utility of this assay on 277 patients who tested positive for H. pylori infection from an endoscopy. Comparing histology, culture, and rapid urease test results, the assay delivered a sensitivity of 95.5% and specificity of 97.6%. The authors conclude that LIAISON® “brings reliable noninvasive testing for H. pylori to the laboratory that is in very good agreement with the current, more invasive biopsy-based methods such as histology, culture, or rapid urease test” (Opekun et al., 2020).

The rapid in-office, monoclonal test is widely used and provides significant benefit in terms of availability and speed. However, a study using the test as a reference to compare against a new test found the in-office test to only have a 0.50 sensitivity and 0.96 specificity out of 162 patients (Korkmaz et al., 2015).

The UBT has also been well-validated. A meta-analysis by Ferwana et al. (2015) including 3999 patients of 23 studies found the diagnostic test to have a pooled sensitivity of 0.96 and a pooled specificity of 0.93. The authors noted that their populations had significant heterogeneity but concluded that the UBT had high diagnostic accuracy for detecting an H. pylori infection (Ferwana et al., 2015). This test is often considered the gold standard for diagnosing an H. pylori infection (Patel et al., 2014).

Serological tests to assess infection have also been used. A meta-analysis by Loy et al. (1996) focused on commercial serological kits assessing H. pylori. Loy et al. (1996) found these kits to have a pooled sensitivity of 0.85 and specificity of 0.79. The authors concluded that there was no major difference in accuracy between any of the kits tested (Loy et al., 1996). 

As costs of sequencing decreases, use of Next Generation Sequencing (NGS) to detect H. pylori infection and its antibiotic resistance has increased. In a study by Nezami et al. (2019), 133 H. pylori positive specimens from histological evaluation were analyzed by NGS to detect mutations in gyrA, 23S rRNA, and 16s rRNA genes. NGS detected H. pylori in 126/133 cases (95% sensitivity). NGS also detected multiple mutations associated with resistance in 92 cases (73%), one mutation in 63 cases (50%), and mutations in several genes in 29 cases (23%). In the 58 cases where treatment history was available, therapy failure was observed in cases where the number of mutated genes was high. Therapy failed in 11/16 cases with multiple gene mutations and 5/27 cases with one gene mutation (Nezami et al., 2019). 

Yang et al. (2019) performed a meta-analysis investigating the association between H. pylori and colorectal cancer. Twenty-seven studies encompassing 14357 cases were included. The authors found an increased rate of colorectal cancer with H. pylori infection (odds ratio [OR] = 1.27). The authors also identified odds ratios for certain subgroups, such as Western countries (OR = 1.34), serological testing (OR = 1.20), multiple methods of testing (OR = 2.63), and cross-sectional studies (OR = 1.92) (Yang et al., 2019).

Wang et al. (2019) performed a meta-analysis assessing the association between H. pylori and osteoporosis. Twenty-one studies totaling 9655 patients were analyzed. The authors found that H. pylori infection was associated with an increased risk of osteoporosis with an odds ratio of 1.39. However, the decrease of bone mineral density in H. pylori positive patients was not found to be significant compared to H. pylori negative patients (Wang et al., 2019).

Zhou et al. (2019) investigated the association between H. pylori infection and non-alcoholic fatty liver disease (NAFLD). Fifteen studies including 97228 patients were evaluated. The authors identified an increased risk of NAFLD in H. pylori positive patients compared to H. pylori negative patients by an odds ratio of 1.19. Similar results were found despite differing subgroups, such as geographical locations. Testing method did not significantly change the results, and there was no significant difference when using multiple detection methods (Zhou et al., 2019).

Halland et al. (2021) assessed two novel enzyme assays (EIA), H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™, for the detection of H. pylori antigen in stool from 271 patients in America, Germany, and Bangladesh. The EIA results were compared to clinical diagnosis, which included histological analysis and rapid urease test. H. PYLORI QUIK CHEK™ had a sensitivity of 92% and a specificity of 91%. H. PYLORI CHEK™ had a sensitivity of 91% and a specificity of 100%. The authors concluded that “the H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™ assays demonstrate excellent clinical performance compared the composite reference method” (Halland et al., 2021). Marrero Rolon et al. (2022) have developed and tested a real-time PCR assay to simultaneously detect H. pylori infection and genotypic markers of clarithromycin resistance. H. pylori infection can be treated with clarithromycin-based therapy; The American College of Gastroenterology (ACG) recommends clarithromycin-based triple therapy as first-line treatment in regions where clarithromycin resistance is known to be below 15% in patients with no history of macrolide exposure. “Clarithromycin resistance is most commonly caused by point mutations in the 23S rRNA (rRNA) gene, including A2143G, A2142G, and A2142C, which result in decreased macrolide binding to the 23S rRNA ribosomal subunit; clarithromycin resistance is considered the main cause of clarithromycin therapy failure.” The authors tested 524 stool samples. H. pylori stool antigen tests were used as a control test for H. pylori detection. Sanger sequencing was used as control tests for genetic susceptibility. PCR results were positive for 98% of positive antigen stool tests. “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).” The authors conclude that the PCR assay can diagnose H. pylori infection and provide genetic susceptibility information. The authors suggest the need for susceptibility-guided therapy when clarithromycin-based therapy is considered (Marrero Rolon et al., 2022).  

American Gastroenterological Association (AGA)  
The AGA recommends that “patients 55 years or younger without alarm features should receive H. pylori test and treat followed by acid suppression if symptoms remain” and note that “H. pylori testing is optimally performed by a 13C-urea breath test or stool antigen test.” Alarm features include symptoms such as recurrent vomiting and weight loss. Additionally, the AGA indicates that “although the yield of endoscopy is low, it is recommended for patients older than 55 years of age and for younger patients…presenting with new-onset dyspepsia.” They reason that endoscopy with biopsy is the preferred test for this age group because upper gastrointestinal malignancy becomes more common after age 55 years (Talley, 2005).

In 2015 the AGA published a technical review on Upper Gastrointestinal biopsy to evaluate dyspepsia in the absence of visible mucosal lesions and found that:

• In the defined population, biopsy of normal-appearing gastric mucosa can detect HP [H. pylori] infection that would be missed on the exam without biopsies. The quality of evidence is very low, and there are noninvasive methods to detect HP infection.
• “Detection of HP infection with tissue biopsy and its eradication in patients with dyspepsia is associated with symptom improvement and reduction of risk for HP-related comorbidities, including gastric cancer compared with no biopsy (or no eradication). The quality of evidence is moderate. The effect on symptom resolution is not universal and it does not appear to improve well-being. Quality of evidence for this statement is low” (Allen et al., 2015).
• The AGA also released guidelines focusing on gastric intestinal metaplasia. In it, they recommend testing for H. pylori (followed by eradication) over no testing and eradication (Gupta et al., 2020).

The AGA released guidelines on gastrointestinal evaluation of iron deficiency anemia. AGA recommends that patients with iron deficiency anemia, without other identifiable etiology after bidirectional endoscopy, should undergo noninvasive testing for H. pylori over no testing at all to reduce the incidence of gastric cancer (Ko et al., 2020).).

American College of Gastroenterology/Canadian Association of Gastroenterology  
The ACG and CAG have released guidelines on testing for H. pylori:

• All patients with active peptic ulcer disease (PUD), a past history of PUD (unless previous cure of H. pylori infection has been documented), low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, or a history of endoscopic resection of early gastric cancer (EGC) should be tested for H. pylori infection. Those who test positive should be offered treatment for the infection.
• In patients with uninvestigated dyspepsia who are under the age of 60 years and without alarm features, non-endoscopic testing for H. pylori infection is a consideration. Those who test positive should be offered eradication therapy.
• When upper endoscopy is undertaken in patients with dyspepsia, gastric biopsies should be taken to evaluate for H. pylori infection. Infected patients should be offered eradication therapy.
• Patients with typical symptoms of gastroesophageal reflux disease (GERD) without history of PUD need not be tested for H. pylori infection. For those who are found to be infected, treatment should be offered, acknowledging that effects on GERD symptoms are unpredictable.
• In patients taking long-term low-dose aspirin, testing for H. pylori infection could be considered.
• 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.
• Patients with unexplained iron deficiency (ID) anemia despite an appropriate evaluation or idiopathic thrombocytopenic purpura should be tested for H. pylori infection.
• There is insufficient evidence to support routine testing and treating of H. pylori in asymptomatic individuals with a family history of “gastric cancer or patients with lymphocytic gastritis, hyperplastic gastric polyps and hyperemesis gravidarum."
• The ACG recommends the breath test and fecal stool antigen test as eradication tests, supported by moderate evidence (Chey et al., 2017).

Another set of joint guidelines from the ACG and Canadian Association of Gastroenterology (CAG) noted that dyspepsia patients under 60 should be tested for H. pylori (Moayyedi et al., 2017).).

National Institute for Health and Care Excellence 
NICE recommends testing for H. pylori with a carbon-13 urea breath test or a stool antigen test. A re-test should be with a breath test. Office-based serological tests are not recommended. NICE recommends a “2-week washout period after proton pump inhibitor (PPI) use before testing for Helicobacter pylori.” NICE recommends that individuals with positive H. pylori tests be offered therapy to eradicate the bacteria; however, they note that re-testing to confirm eradication should not be routinely offered. NICE limits the recommendation for post-treatment testing to “people with peptic ulcer (gastric or duodenal) … 6 to 8 weeks after beginning treatment, depending on the size of the lesion" (NICE, 2019).

NICE released further guidelines in 2015 reaffirming the carbon-13 urea breath test and the stool antigen test to test for H. pylori. A locally validated lab-based serology test may also be used to assess H. pylori. NICE reaffirms the two week washout period before testing for H. pylori if the patient is on PPIs as well as the four week washout period if the patient is on antibiotics (NICE, 2015).  

American College of Cardiology  
The American College of Cardiology recommends testing for and eradicating H. pylori in patients with a history of ulcer disease before starting chronic antiplatelet therapy (Bhatt et al., 2008).

World Gastroenterology Organization  
The World Gastroenterology Organization Global Guidelines on Helicobacter pylori recommends testing for H. pylori based on evidence-based indications, noting that these indications may differ in different regions of the world based on prevalence, resources, competing needs, and individual patient factors. The guidelines state that “peptic ulcer disease is the prime indication in most of the world.” The guidelines list other indications for the treatment of H. pylori as: past or present duodenal and/or gastric ulcer, gastric MALT lymphoma, gastric mucosal atrophy and/or intestinal metaplasia, resection of gastric cancer, first-degree relatives with gastric cancer, functional dyspepsia, NSAID use, before long-term aspirin therapy in patients at high risk of ulcers and ulcer-related complications, during long-term low-dose aspirin therapy in patients with a history of upper gastrointestinal bleeding and perforation, patients with gastroesophageal reflux disease who require long-term proton-pump inhibitors, as a strategy for gastric cancer prevention in communities with a high incidence, unexplained iron-deficiency anemia or idiopathic thrombocytopenic purpura, and patients’ wishes after a full consultation with their physician (Katelaris et al., 2021). 

European Association for Gastroenterology, Endoscopy and Nutrition (EAGEN), European Society of Neurogastroenterology and Motility (ESNM), and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) 
The pan-European guideline recommends the use of 13C -urea breath tests as a noninvasive alternative for testing for “all indications of Helicobacter pylori testing if endoscopy is not required or if biopsies are contraindicated” and as “a preferred option for conformation of Helicobacter pylori eradication in adults and children.” Alternatively, when there is indication for endoscopy and no contraindication for biopsy, the guidelines recommend RUT as the first-line diagnostic tests (Keller et al., 2021). 

ESPGHAN and The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN)

The ESPGHAN and NASPGHAN have issued updated guidelines for management of H. pylori in children and adolescents. They have proposed recommendations for diagnosis and management of H. pylori infection in pediatric patients. They have defined pediatric patients as children and adolescents below 18 years of age. The following recommendations were stated:

The guidelines recommend biopsies for rapid urease test and other cultures should only be taken if treatment is likely to be offered in the case of a confirmed infection. Treatment may be considered if H. pylori is an incidental finding at endoscopy.

The guidelines recommend against a “test and treat” strategy for H. pylori infection in children. The panelists explained that performing a noninvasive test to detect infection and treat is not needed because H. pylori infection usually does not cause any symptoms in the absence of peptic ulcer disease (PUD).

The guidelines recommend that “testing for H. pylori be performed in children with gastric or duodenal PUD.”

The guidelines recommend against diagnostic testing for H. pylori infection in children with functional abdominal pain, iron deficiency anemia, and when investigating causes of short stature. Serology-based testing was also not recommended.

Proton pump inhibitors (PPIs) should be stopped two weeks before H. pylori testing, and antibiotics should be stopped four weeks before H. pylori testing. Diagnosis should be based on either: “positive culture or H. pylori gastritis on histopathology with at least 1 other positive biopsy-based test."

The non-invasive diagnostic testing was indicated in children when investigating causes of chronic immune thrombocytopenic purpura or for the assessment of anti-H. pylori therapy at least after four weeks of therapy (L. Jones et al., 2017). 

Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN)
The JSPGHAN have updated their guidelines for H. pylori testing in pediatrics, including recommendations for diagnostic methods in children.

For diagnosis using endoscopic biopsy specimens, the guidelines recommend considering the performance and accuracy of the rapid urease test, recommending an additional urea breath test or stool antigen test when there is inconsistency between histopathology and the rapid urease test. The guidelines further recommend histological examination of gastric biopsies, and culture diagnostic tests to diagnose active H. pylori infection (Kato et al., 2020). 

For diagnosis without endoscopic biopsy specimens, the guidelines recommend 13C-urea breath test and stool antigen tests. To increase the diagnosis accuracy, the guidelines recommend more than two tests (two noninvasive tests or a biopsy-based and a noninvasive test) be completed. The guidelines recommend urea breath test or stool antigen test four or more weeks after treatment to confirm eradication of H. pylori and recommend against using endoscopic biopsy methods and single serological tests to confirm eradication. The guidelines also recommend against anti-H. pylori antibody tests as a single test to diagnose H. pylori in a clinical setting (Kato et al., 2020).  

Maastricht V/Florence Consensus Report 
This report was published in 2017 on behalf of the European Helicobacter and Microbiota Study Group and Consensus panel. The panel reports that UBT is “the most investigated and best recommended non-invasive test in the context of a ‘test-and-treat strategy." The panel also notes that monoclonal tests can be used and that serological tests can be used only after validation. However, rapid “office” serology tests are not recommended and “should be avoided." The guidelines recommend the rapid urease test (RUT) as a first line diagnostic test if there is an indication for endoscopy and no contraindication for biopsy. The guideline state that H. pylori is linked to “unexplained iron deficiency anaemia (IDA), idiopathic thrombocytopenic purpura , and vitamin B12 deficiency”, and in these disorders, an H. pylori infection should be “sought and eradicated." The guidelines state that PPIs should be stopped two weeks and antibiotics and other bismuth compounds should be stopped 4 weeks before testing for H. pylori. In cases of chronic (active) gastritis in which H. pylori is not detected by histochemistry, immunohistochemical testing of H. pylori can be used as an ancillary test. If histology is normal, no immunohistochemical staining should be performed. It is recommended to perform clarithromycin susceptibility testing when a standard clarithromycin-based treatment is considered as the first-line therapy, except in populations or regions with well documented low clarithromycin resistance (< 15%). Pepsinogen (Pg) serology is considered the most useful non-invasive test to explore gastric mucosa status (non-atrophic vs atrophic). The PgI/PgII ratio can never be assumed as a biomarker of gastric neoplasia. UBT is the best option for confirmation of H. pylori eradication and monoclonal SAT is an alternative. It should be performed at least four weeks after completion of therapy (Malfertheiner et al., 2017).

The Maastricht IV from 2012 also addressed testing for the cagA and vacA variants, stating that no specific genetic or virulence markers can be recommended at this time (Malfertheiner et al., 2012).

American Society for Clinical Pathology (ASCP)
The ASCP recommends against using the serological tests for H. pylori and recommends the stool antigen and breath tests instead. The ASCP states that serological evaluation is no longer clinically useful and the stool and breath tests have superior statistical power (ASCP, 2016). 

American Society of Hematology (ASH) 
American Society of Hematology (ASH) published an update to the immune thrombocytopenic purpura guidelines in 2019. In it, they “suggest” that “Screening for H pylori be considered for patients with ITP in whom eradication therapy would be used if testing is positive." However, ASH still recommends against “routine testing for H pylori in children with chronic ITP” (Neunert et al., 2020).

Houston Consensus Conference 
This conference included 11 experts on “management of adult and pediatric patients with H. pylori, from different geographic regions of the United States” and was convened to “discuss key factors in diagnosis of H. pylori infection, including identification of appropriate patients for testing, effects of antibiotic susceptibility on testing and treatment, appropriate methods for confirmation of infection and eradication, and relevant health system considerations." Two cohorts of approval were present: one of the 11 experts, and another consisting of a selected group of United States-based gastroenterologists. These recommendations were intended to provide practical advice for US practitioners, and guidelines to be adopted by US health care systems

Recommendations approved by both groups are listed below:  

• “Statement 1: We recommend that all patients with active H pylori infection be treated (100% agree/strongly agree, Grade 1A).
• Statement 2: All patients with current or past gastric or duodenal ulcers should be tested for H pylori infection (100% agree/strongly agree; Grade 1A).
• Statement 3: We recommend that all patients with uninvestigated dyspepsia be tested for H pylori infection (100% agree/strongly agree, Grade 1A).
• Statement 4: We recommend routine testing for H pylori infection in patients with reflux symptoms only if they are at high risk for H pylori-related disease (91% agree/strongly agree, Grade 1C).
• Statement 5: We recommend that patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma be tested for H pylori infection (100% agree/strongly agree, Grade 1B).
• Statement 6: We recommend that individuals with family history of gastric cancer be tested for H pylori infection (100% agree/strongly agree, Grade 1B).
• Statement 7: We recommend that patients who are first-generation immigrants from high prevalence areas be tested for H pylori infection (82% agree/strongly agree, Grade 1B).
• Statement 8: We suggest that patients of Latino and African American racial or ethnic groups may be considered for H pylori testing due to their high risk of infection (91% agree/strongly agree, Grade 2C).
• Statement 17: We recommend that validated diagnostic testing of stool or gastric mucosal biopsy by culture and susceptibility, or molecular analysis be universally available (100% agree/strongly agree, Grade 1)
• Statement 18: We suggest that antibiotics that may be routinely evaluated for susceptibility include amoxicillin, clarithromycin, levofloxacin, metronidazole, and tetracycline (100% agree/strongly agree, Grade 2C).
• Statement 20: We recommend the use of tests for active H pylori infection (i.e., UBT, HpSAg testing) for the initial diagnosis (100% agree/strongly agree, Grade 1A).
• Statement 22: We recommend that serology not be utilized for detection of active H pylori infection (100% agree/strongly agree, Grade 1A).
• Statement 23: We recommend that bismuth and antibiotics be stopped at least 4 weeks before H pylori testing with tests for active infection (i.e., UBT, and HpSAg testing and histology; 100% agree/strongly agree, Grade 1C).
• Statement 27: We recommend that all patients receiving treatment for H pylori receive posttreatment confirmation of eradication. We recommend that only tests that evaluate for active infection, such as UBT, HpSAg test, or histology (if endoscopy is required for other reasons), are utilized for this purpose (100% agree/strongly agree, Grade 1A).
• Statement 28: Once appropriate testing has confirmed eradication, we recommend against further H pylori testing, (100% agree/strongly agree, Grade 1C)”

The following recommendations reached a consensus by the expert panel, but not the external group: 

• “Statement 9: We recommend that patients with idiopathic thrombocytopenia be tested for H pylori infection (experts vs survey: 100% vs 68% agree/strongly agree, Expert Grade 1B)
• Statement 10: We suggest that patients receiving long-term PPIs (> 1 month) be tested for H pylori infection (experts vs survey: 82% vs 68% agree/strongly agree, Expert Grade 2C)
• Statement 11: We recommend that family members residing in the same household of patients with proven active H pylori infections undergo H pylori testing (experts vs survey: 91% vs 78% agree/strongly agree, Expert Grade 1B)
• Statement 12: We recommend that individuals with a family history of peptic ulcer disease be tested for H pylori infection (experts vs survey: 91% vs (73% agree/strongly agree, Expert Grade 1B)” (El-Serag et al., 2018).

Table of Terminology

References:

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21. Ko, C. W., Siddique, S. M., Patel, A., Harris, A., Sultan, S., Altayar, O., & Falck-Ytter, Y. (2020). AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology, 159(3), 1085-1094. https://doi.org/10.1053/j.gastro.2020.06.046 
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Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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