Helicobacter Pylori Infection Testing

Number: 0177

Policy

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

    1. Evaluation of new onset dyspepsia in persons younger than 55 years of age without alarm symptoms (anemia, weight loss, vomiting, lymphadenopathy); or
    2. Evaluation of persons with persistent symptoms of dyspepsia despite 2 weeks of appropriate antibiotic therapy for Helicobacter pylori (H. pylori); or
    3. Before starting proton pump inhibitor therapy for dyspepsia; or
    4. Before bariatric surgery for obesity; or
    5. Recurrent dyspeptic symptoms suggesting re-infection with H. pylori; or
    6. 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. Aetna considers urea breath testing and stool antigen testing experimental and investigational for all other indications, including any of the following because their effectiveness for indications other than the ones listed above has not been established:

    1. Assessing risk of developing dementia; or
    2. 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
    3. Evaluating infantile colic; or
    4. Managing recurrent aphthous stomatitis; or
    5. New-onset dyspepsia in persons aged 55 years or older (upper GI endoscopy is indicated because of concern about gastric neoplasia); or 
    6. Screening of asymptomatic persons for H. pylori infection.
  3. Aetna considers H. pylori serology experimental and investigational because of its inadequate performance.

  4. 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.

  5. Aetna considers the TZAM H. pylori Multiplex PCR experimental and investigational because of insufficient evidence of its effectiveness.

  6. Aetna considers plasma pepsinogen II testing experimental and investigational for evaluation of the success of H. pylori eradication because of insufficient evidence of its effectiveness.

  7. Aetna considers testing of tonsillar H. pylori colonization for the management of chronic tonsillitis experimental and investigational because of insufficient evidence of its effectiveness.

  8. Aetna considers testing of H. pylori infection for the management of autoimmune gastritis experimental and investigational because of insufficient evidence of its effectiveness.

  9. Aetna considers IL1B -31C > T polymorphism testing for H. pylori experimental and investigational because of insufficient evidence of its effectiveness.

  10. Aetna considers tumor necrosis factor-alpha (TNFA) gene polymorphisms testing for H. pylori Infection experimental and investigational because of insufficient evidence of its effectiveness.

  11. Aetna considers AmHPR Helicobacter pylori antibiotic resistance next generation sequencing panel experimental and investigational because of insufficient evidence of its effectiveness.

  12. Aetna considers testing for anti-Helicobacter pylori IgG in urine for diagnosis of H. pylori infection experimental and investigational because of insufficient evidence of its effectiveness.

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 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), 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  revalence 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.

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.

IL1B -31C > T 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.

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

AmHPR H. pylori antibiotic resistance panel examines antibiotic resistance to 6 types of antibiotics that are currently used in Helicobacter pylori (H. pylori) treatment by means of next generation sequencing (NGS):
  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.

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.

This study had 2 main drawbacks:
  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.



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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

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:
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
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

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)
R10.83 Colic
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

The above policy is based on the following references:

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