Point-of-care testing for Heliobacter pylori infection

Importance:
Approximately 5% of uninvestigated dyspepsia is caused by HP infection (27). The British Society of Gastroenterology (BSG) defines dyspepsia as a group of symptoms of the upper GI tract lasting for 4 weeks or more, including upper abdominal pain or discomfort, heartburn, gastric reflux, nausea or vomiting (28). Eradication therapy using a test-and-treat strategy is thought to improve symptoms by a combination of the healing of undiagnosed peptic ulcer and small improvements in the symptoms in uninvestigated dyspepsia (4). In patients with functional dyspepsia (epigastric pain with normal endoscopy) a meta-analysis of RCTs comparing HP eradication to placebo showed the NNT to cure one case of dyspepsia with eradication therapy was 13 (95% CI 9 to 19) (3).

HP-positive patients have a 10 to 20% lifetime risk of developing peptic ulcer disease (29). Meta-analysis of RCTs comparing HP eradication therapy to placebo show eradication therapy to be cost effective leading to significantly lower rates of ulcer relapse compared with long term acid suppression (3). To prevent duodenal and gastric ulcer relapse, the numbers needed to treat (NNT) with HP eradication therapy are 2 and 3 respectively (3).

HP was the first infection to be classified as a grade 1 carcinogen by the World Health Organisation. 5.2% of the global cancer burden was attributable to HP infection in 2008 (more than any other infective agent including Human Papilloma Virus), totalling 46% of infection related cancers in the developed world and 29% in the less developed (30). HP is implicated in gastric cancer and gastric mucosa-associated lymphoid tissue (gMALT) lymphoma. A systematic review of nested case-control studies reported that HP infected cases were three to six times more likely to develop gastric cancer than controls (31). A systematic review of over 6000 patients from six RCTs showed that HP eradication resulted in a significant reduction in the incidence of gastric cancer compared to placebo (32). Nearly all cases of gastric MALT lymphoma are HP positive, which has seven times greater risk of developing in the presence of HP infection (1, 30).

Patient Group and Use:

Adults presenting to primary care in settings where HP prevalence is >10% (4):

-          with uninvestigated dyspepsia lasting for 4 weeks with no alarm symptoms.

-          with a past history of gastric ulcer or duodenal ulcer who have not previously been tested for HP, are starting or already taking NSAIDS.

-          with unexplained iron-deficiency anaemia, idiopathic thrombocytopenic purpura & vitamin B12 deficiency who have not previously been tested for HP.

-          to confirm HP eradication following treatment.

Previous Research:
Gisbert et al conducted a narrative review of studies published before May 2004 reporting the clinical application and accuracy of the ¹³C urea breath test for HP detection (12). Of 43 studies included, 12 reported the diagnostic accuracy of NDIRS method to detect HP infection. Sensitivity ranged from 91-100% and specificity from 74-100%. A range of HP thresholds (from 3.5-11 ‰) were used across studies, and a range of reference standards (rapid urease testing, histology, culture, ¹⁴C-urea breath test, and the stool antigen test). All 12 studies investigated the utility of NDIRS for the detection of active infection pre-eradication, and one (33) also the utility post eradication (Sn 100%, Sp 89%). A quality assessment of the included studies was not performed. Neither the NDIRS device models/manufacturers nor the location of the device were reported by the review authors.

In a systematic review, Ling extracted sensitivity and specificity values from 21 studies published between 2003 and 2012 to determine the diagnostic accuracy of the ¹³C urea breath test against a composite reference standard (most commonly culture followed by concordance on histology and the rapid urease test) (34). Pooled sensitivity was 98.1% (95% CI, 96.3%–99.0%) and specificity was 95.1% (95% CI, 90.3%–97.6%). The summary LR+ and LR− estimates were 19.9 (95% CI, 9.9–39.9) and 0.02 (95% CI, 0.01–0.04), respectively. The AUC was 98.8% (95% CI, 97.4%–100%). Neither the analysis technique nor the location of the device were reported.

Fewana et al, more recently conducted a meta-analysis of cross-sectional studies including consecutive adult patients with dyspeptic symptoms to assess the diagnostic accuracy of the ¹³C or ¹⁴C breath tests against a reference standard of HP culture and/or histological examination (not blood or stool antigen testing) (35). The pooled sensitivity for the five studies reporting the accuracy of “infrared assisted” ¹³C detection was 95% (95% CI, 93-96%) and the pooled specificity was 93% (91-95%) which were not significantly different from the 18 studies reporting “infrared not assisted” techniques (Sensitivity 97% [95% CI 96-98%]; Specificity 93% [95% CI 91-95%]). Although there were some ¹⁴C devices included in the “infrared not assisted” group, a separate subgroup analysis comparing ¹³C with ¹⁴C devices also showed no statistically significant subgroup effect (35). The authors concluded that more widespread breath testing should be adopted given the high accuracy, but the NDIRS device model/manufacturer and setting were not reported (35).

Accuracy compared to existing technology

Kibion

We retrieved five studies that reported on the accuracy of devices related to the technology in current Kibion NDIRS devices (IRIS).

1. A German study compared IRMS (Tracemass, Europa Scientific Ltd., Crewe, UK) and IRIS using breath samples from 538 asymptomatic volunteers attending the annual meeting of the German Society for Internal Medicine in 1995 (36). For the IRIS analysis breath was expired into 1200ml aluminized breath bags, eight of which could be connected to IRIS and analysed sequentially taking 90 seconds a sample. Using a threshold of 5‰, a highly linear correlation was found (r=0.945; p<0.001), the mean difference between the two methods was -1.96% ± 2.76‰. IRIS had a sensitivity of 98.3% and a specificity of 98.6% compared to IRMS (confidence intervals not reported).

1. A German prospective study of 145 patients undergoing endoscopy (indication unknown) reported the accuracy of IRIS 30 minutes after ingesting 75mg of urea and 200mls of apple juice against a composite reference standard of histology, culture, and rapid urease testing. The optimal threshold reported was 3.5‰: 52 out of 57 (87%) patients were correctly diagnosed by IRIS; sensitivity was 91.2%; specificity 90.2% (confidence intervals not reported) (37). Nine thresholds were reported in total (Table 3).

Table 3. Diagnostic accuracy of IRIS at nine thresholds in 145 patients undergoing endoscopy.

1. A Brazilian study compared IRIS (using a threshold of 4.0‰) with a combined reference standard of the ¹⁴C-urea breath test (using a threshold of 0.8% CO2/Kgs weight), rapid urease test and histology using samples from fifty-three patients with duodenal ulcers attending outpatients (38). Sample collection bags were sent by airmail to a central laboratory for analysis. There was 100% agreement between the results of the ¹³C-urea breath tests and the HP status determined by the combination of the urease test, histological examination and ¹⁴C-urea breath tests leading authors to state that IRIS is a low cost, easy to manage, highly sensitive and specific test for HP detection.

1. IRIS was compared with two mass spectrometers (ABCA, Europa Scientific, Crewe, UK, and Breath Mat, Finnigan, Bremen, Germany) in an Italian study of 134 fasted consecutively endoscoped dyspeptic patients suffering from non-ulcer dyspepsia (97 cases) or duodenal ulceration (37 cases) (39). Breath samples were collected in aluminumised bags 15 mins and 30 mins after ingestion of 75 mg of ¹³C-urea dissolved in 150 ml 0.033 mol/L citric acid. A highly linear correlation (r=0.963-0.987 at 15 min and 0.977-0.985 at 30 min; p<0.0001) was found in every two-by-two comparison using a threshold of 5.0‰. The sensitivity ranged from 97–100% at both times with all devices. Specificity was slightly inferior with NDRS than with the two IRMS machines (95% vs 98–100% at 30 min), but the difference was not significant (exact p-value not reported). The authors recommended that NDIRS was a valid alternative to IRMS in patients who had fasted.

1. A Belgian study including 223 fasted patients referred for endoscopy assessed IRIS against histological examination of 4 gastric biopsy specimens (40). The authors investigated four test lengths (10, 20, 25, 30 minutes) and five thresholds (3, 3.5, 4, 4.5, 5‰) (40). They suggested using a 10-minute test with a cut-off value lying between 4 and 5‰ after ingesting 75 mg of urea and 0.1N citric acid. Sensitivity at these thresholds was 100% and specificity was 95% for the 182 patients taking no acid suppression or antibiotic medication in the past three days. However, at the lower threshold of 3.5‰, sensitivity was 68% and specificity was 91% in the 41 patients taking acid suppression or antibiotic medication in the past three days.

Otsuka

We retrieved six studies that reported on the accuracy of devices related to the technology in current Otsuka NDIRS devices.

1. An American study included 178 fasted patients undergoing upper gastrointestinal endoscopy for “any reason” who had not received eradication therapy (acid suppression, bismuth preparations, or antibiotics) within 1 month (41). The Meretek ¹³C urea breath test was compared to gastric biopsy culture and stain as part of a larger study comparing the accuracy of serology, rapid urease testing, and breath testing. The breath samples were collected in a sampling device 30 and 40 minutes following ingestion of ¹³C urea and a pudding designed to delay gastric emptying. Samples were analysed by the manufacturer who reported the 30 minute result in all but one patient. Sensitivity of the Meretek ¹³C device was 97% (95% CI 94-100%) and specificity 94% (95% CI 87-100%) with an overall accuracy of 95% (95% CI 91-98%). The authors did not report the threshold used.

1. A Taiwanese study included 177 patients undergoing upper endoscopy for dyspepsia if they had taken no bismuth salts, proton pump inhibitors, or antibiotics within the previous 8 weeks. Patients with a past history of HP eradication therapy, gastric malignancy, penicillin allergy, or previous gastrointestinal surgery were excluded (42). Breath samples were collected in 20ml glass test tubes for IRMS analysis (ABCA, Europa Scientific, UK) and in 200ml gas storage bags for UBiT IR200 anaysis at baseline, and 10 and 15 min after the ingestion of 50 mg of urea and 100-mL of citric acid. Comparing a threshold of 3.5‰ to a reference standard of histology or culture from gastric biopsy, a close correlation of was found between UBiT IR200 and IRMS at 10 and 15 minutes (r=0.983 and 0.992, respectively). At 10 minutes sensitivity was 94% for both techniques, and specificity was 96.4% for IRMS and 94.6% for UBiT (confidence intervals not reported). At 15 minutes the same sensitivity (96.4%) and specificity (98.9%) were achieved.

1. A Spanish multicentre study including 41 patients, some with dyspepsia who had not undergone prior eradication therapy and some with gastric ulceration receiving eradication compared the UBiT IR200 NDIRS device to an IRMS device, using a reference standard of histology and the rapid urease test (33). No difference was found between the mean values obtained for the IRMS and NDIRS devices with identical AUROCs (0.96), however the NDIRS device was more sensitive (100% vs 90%) and less specific (89% vs 96%).    

1. A second Taiwanese study included 586 patients aged between 20 and 70 years who were undergoing upper endoscopy without receiving eradication therapy (43). Patients with ulcer complications, previous stomach surgery, gastric cancer, drug allergies, who had used benzimidazoles or bismuth preparations within the previous 7 days, were pregnant, had taken HP eradication therapy, or had a severe systemic disease were excluded . Culture, histology, and rapid urease test on biopsies from the antrum and corpus of the stomach were used as a reference standard for HP infection. Breath samples were collected before and 20 min after drinking 100 mg ¹³C-urea in 100 mL water. After 15 min a breath sample was collected into a collection bag and analysed using NDIRS (IR20) which printed the results in 5–6 minutes. The AUROC was 0.994. At a threshold of 3.5‰, a sensitivity of 97.8%, a specificity of 96.8% and an accuracy of 97.5% were reported. At a threshold of 5‰, a sensitivity of 97.0%, a specificity of 99.5% and an accuracy of 97.8% were reported (confidence intervals not reported).

1. A  third Taiwanese study assessed NDIRS in a population of 100 patients undergoing routine gastrointestinal endoscopy (44). HP was defined as the presence of a positive culture or positive results of both histology and rapid urease test following gastric biopsy. 100 mg of ¹³C-urea was dissolved in 50 ml sterile water and breath samples collected in a 200-ml gas storage bag before and 15 min after consumption. Using a threshold of 4.8‰ the sensitivity, specificity, positive predictive value and negative predictive value of NDIRS was 100% (95% CI, 100-100); 85.1% (95% CI, 74.8-95.2), 88.3 (95% CI, 80.2-96.4) and 100% (95% CI, 100-100), respectively.

1. A later Spanish prospective study included 199 patients undergoing endoscopy for dyspepsia who had stopped anti-secretory medication for 2 weeks and not received antibiotics in the previous 4 weeks (45). Breath samples were collected in a collection bag 20 mins after ingesting a 100mg urea solution. The NDIRS (POCone Infrared Spectrophotometer; Otsuka Pharmaceutical) and IRMS (Tau-Kit; ISOmed) methods showed high correlation (r = 0.992). The AUROC for IRMS was 0.948. However, at the manufacturers threshold of 2.5‰, NDIRS was highly sensitive (99.2%) but poorly specific (60%). At a threshold of 8.5% the sensitivity and specificity of NDIRS were 90% and 90% respectively.

Fischer ANalysen Instrumente (FAN)

We retrieved no studies specifically reporting the accuracy of the FAN devices.

Impact compared to existing technology

We retrieved no studies reporting on the impact of POC NDIRS use in primary care. However, a large study included 44,487 breath samples from patients >45yrs from a well-defined region of Denmark, who were judged to “meet criteria” for a test-and-treat strategy by their GPs. Patients were asked to conduct the breath test at home and mail the two breath collection bags to the laboratory for analysis using the IRIS infrared spectroscope (Wagner Analysen Tecknik, Bremen, Germany) (46). One in five patients tested positive for HP, although 726 samples (1.6%) were not included in the analysis because of bag errors. The authors concluded that a test-and-treat system was possible to implement that allowed patients to perform UBTs at their homes.

Health Economics:

Seven studies were identified in the review that evaluated cost-effectiveness of ¹³C UBT testing, although none said whether they were evaluating point of care tests. Two studies evaluated the costs and consequences of testing, but did not calculate a cost-effectiveness estimate, such as an incremental cost-effectiveness ratio (ICER). Two studies did report an ICER, but only for interim outcomes. Three studies conducted a full cost-utility analysis of incremental cost per quality-adjusted life year (QALY), which took into account the downstream health and cost impact of each strategy (Table 1).

Mahadeva (2008) reported the costs of testing with ¹³C UBT compared with endoscopy in uncomplicated dyspepsia in young adults in Malaysia, with the Leeds Dyspepsia Questionnaire (LDQ) score as the primary outcome. The LDQ was not significantly improved in the endoscopy group compared with ¹³C UBT, although patient satisfaction was higher, as were treatment costs (47). Cuddihy (2005) also compared 13C UBT to endoscopy, this time in a US population with dyspepsia, along with treatment based on empirical judgement alone, and ELISA serology. The primary outcome was symptom resolution, with a time horizon of 6 months. They found no statistically significant differences in costs, quality of life measured with SF-36, or symptom resolution between

 any of the groups (48).

The two cost-effectiveness studies both reported ICERs of cost per additional correct diagnosis. Elwyn (2007) compared serology, ¹³C UBT and SAT in a population with dyspepsia in the UK over a 12 month follow up. They found that ¹³C UBT was dominated by SAT, which was both less costly and more accurate (49). Masucci (2013) compared ¹³C UBT with serology and with a two-step process that confirmed the serology result with ¹³C UBT. Two step testing dominated ¹³C UBT alone, over the 1 month time horizon in a Canadian population (50).

Three cost-utility studies reported the value of testing in cost-per-QALY outcomes; the preferred outcome of many national decision makers, as it enables comparison across health conditions. Delaney (2008) conducted an economic evaluation alongside a trial in the UK, from the perspective of the NHS. Comparing ¹³C UBT against no testing, they reported an ICER of £1000/QALY, a highly cost-effective finding, but with very broad uncertainty, due to the uncertain impact of dyspepsia on quality of life (51). The time horizon was only 12 months, so potential benefits from cancer prevention were not included. Two studies by Xie and colleagues considered cost-effectiveness of testing and treating in an asymptomatic screening population, rather than in patients with dyspepsia. The outcome reported by both was gastric cancer prevention over the patient’s lifetime. Both studies developed decision analytic models to assess cost-effectiveness: one for a Canadian male population (52), the other for Singapore (53). Both reported that screening with ¹³C UBT would not be cost-effective compared with serology or SAT (ICER versus serology: US $390,000; ICER versus SAT: CAN $533,000).

No studies have evaluated whether ¹³C UBT testing is cost-effective in symptomatic patients over a lifetime horizon. Testing and treating dyspepsia is potentially cost-effective, by reducing the costs of treating future dyspepsia, but quality of life benefits appear to be minimal or non-existent. Further health and cost consequences with respect to gastric cancer cases avoided have not been evaluated in this setting.

Guidelines and Recommendations

Public Health England recommends that HP testing should be performed in the following four groups: (1) patients with uncomplicated dyspepsia unresponsive to lifestyle change, antacids, single course of PPI for 1 month and without alarm symptoms; (2) patients with a past history of gastric ulcer or duodenal ulcer who have not previously been tested; (3) patients before starting or taking NSAIDs, especially if a prior history of gastro-duodenal ulcers; (4) unexplained iron-deficiency anaemia, idiopathic thrombocytopenic purpura & vitamin B12 deficiency (54).

NICE make a number of recommendations in relation to HP. In relation to testing: (1) leave a 2-week washout period after proton pump inhibitor (PPI) use before testing; (2) test using a ¹³C-urea breath test, stool antigen test, or laboratory-based serology (where its performance has been locally validated); (3) offer a 'test and treat' strategy to people with dyspepsia; (4) offer HP retesting 6 to 8 weeks after beginning treatment using a ¹³C-urea breath test. Regarding treatment: (1) offer HP eradication therapy to people who have tested positive and who have peptic ulcer disease using first-line a 7-day, twice-daily course of acid suppression therapy, amoxicillin, and either clarithromycin or metronidazole; (2) stop NSAIDS in patients diagnosed with peptic ulcer full-dose acid suppression therapy for 8 weeks and then offer eradication therapy if HP is present; (3) treat patients with endoscopically determined functional dyspepsia with HP eradication followed by symptomatic management (55).

The European Maastricht V / Florence Consensus Report on the management of HP infection makes the following recommendations: (1) acid suppression should be discontinued at least 2 weeks before testing for HP, and antibiotics and bismuth compounds at least 4 weeks; (2) HP testing should be performed in aspirin and NSAIDs users with a history of peptic ulcer; (3) the UBT is the most investigated and best recommended non-invasive test in the context of a ‘test-and-treat strategy’, which is appropriate for uninvestigated dyspepsia without alarm symptoms; (4) HP should be sought and eradicated in unexplained iron deficiency anaemia (IDA), idiopathic thrombocytopenic purpura (ITP), and vitamin B12 deficiency; (5) HP eradication heals gastritis in long-term PPI users and HP gastritis has to be excluded before a reliable diagnosis of functional dyspepsia can be made, (6) HP eradication is the first-line treatment for localised stage gastric MALToma; (7) UBT is the best option for confirmation of HP eradication and should be performed at least 4 weeks after completion of therapy (4).

Research Questions:

1. Does using POC NDIRS ¹³C-UBT testing in primary care reduce referrals for endoscopy in patients with dyspepsia?
2. Does using POC NDIRS ¹³C-UBT testing in primary care reduce the prescription of HP eradication therapy?
3. Does using POC NDIRS ¹³C-UBT testing in primary care reduce GP appointments and reduce delay in gastric cancer diagnosis?
4. Does using POC NDIRS ¹³C-UBT testing in primary care lead to more rapid confirmation of HP eradication?
5. What is the diagnostic accuracy of POC NDIRS ¹³C-UBT testing in primary care for the confirmation of active HP and HP eradication?
6. What is the cost of  a test-and-treat approach for managing patients with suspected HP infection using POC NDIRS ¹³C-UBT testing in primary care relative to current practice using other non-invasive tests for HP?

Suggested next steps:

A diagnostic accuracy study comparing the accuracy of POC NDIRS ¹³C-UBT devices when used in primary care is needed before a prospective cohort study can be conducted to assess the introduction and cost-effectiveness of POC NDIRS ¹³C-UBT testing into routine primary care practice in relation to endoscopy referrals, specialist referrals, antibiotic prescription, patient attendances, and time to diagnosis compared to a region without POC NDIRS technology.

Acknowledgements:

The authors would like to thank Nia Roberts for performing literature searches, and Professor Barbara Braden for her expert advice on this topic. This work is supported by the National Institute for Health Research (NIHR) Diagnostic Evidence Co-operative Oxford at Oxford Health NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. 

This report was prepared by the Primary Care Diagnostic Horizon Scanning Centre Oxford

Authors: Brian D Nicholson, Elizabeth A Spencer, Lucy Abel, Christopher P. Price, Carl Heneghan, Gail Hayward, Annette Plüddemann

Contact details:  Dr. Annette Plüddemann; Email: dec@phc.ox.ac.uk

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