Helicobacter pylori (H. pylori) is a gram negative spiral bacterium (NCBI 2014). Approximately 13% to 81% of people have H. pylori infection (Peleteiro 2014). Prevalence of the bacterium varies according to age (generally increasing with age, although infection rates tend to fall among older age groups in some Latin American and Northeast Asian countries), region (lower infection rates are seen in Australia and the United Kingdom, while higher rates are reported in Chile, China, Japan, Korea and Latvia), race (more prevalent amongst Afrocarribeans compared to Caucasians), and socioeconomic class (more common in poorer settings) (Graham 1991; Laszewicz 2014; Muhsen 2012; Peleteiro 2014).
Based on observational studies, H. pylori infection has been implicated in a number of malignancies including gastric cancer, premalignant lesions of the stomach (atrophic gastritis and intestinal metaplasia), gastric lymphoma, pancreatic cancer, colorectal cancer, and laryngeal cancer (Huang 1998; Huang 2003; Wu 2013; Xiao 2013; Xue 2001; Zhuo 2008). However, H. pylori is associated with a lower incidence of oesophageal adenocarcinomas (Islami 2008). H. pylori is also associated with a number of non-malignant conditions including peptic ulcers, non-ulcer dyspepsia, recurrent peptic ulcer bleeding, unexplained iron deficiency anaemia, idiopathic thrombocytopaenia purpura, and colorectal adenomas (DuBois 2005; Franchini 2007; Gisbert 2004; Huang 2002; Jaakkimainen 1999; Wu 2013).
Although a number of pathogenic factors such as cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and blood group antigen binding adhesin (BabA) are associated with increased virulence of H. pylori (Huang 2003; Malfertheiner 2012), detection of these pathogenic factors has no role in the management of H. pylori infection currently (Malfertheiner 2012). The recommended initial treatment for H. pylori infection is with a combination of proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole (triple therapy) in regions with low resistance to clarithromycin (< 20% resistance rate in the area), and the triple therapy along with bismuth (quadruple therapy) in regions with high resistance to clarithromycin (> 20% resistance rate in the area) (Malfertheiner 2012). If this results in failure of eradication, bismuth-quadruple therapy or levofloxacin-triple therapy (replacement of clarithromycin with levofloxacin in the classical triple therapy) when triple therapy was used as the initial treatment and levofloxacin-triple therapy when bismuth quadruple therapy was used as the initial treatment is recommended (Malfertheiner 2012). If even this treatment fails to eradicate H. pylori, then further treatment should be based on antibiotic susceptibility (Malfertheiner 2012). Eradication of H. pylori might lead to a decrease in malignant and non-malignant conditions associated with H. pylori infection. Adverse events related to H. pylori treatment include taste disturbance, diarrhoea, nausea, headache, skin rash, abdominal pain, dizziness, bloating, myalgias (muscle pain), and constipation (Ye 2014).
A glossary of terms in included in Appendix 1.
Target condition being diagnosed
Helicobacter pylori (H. pylori ) infection.
Urea breath test
The urea breath test is based on the presence of urease enzyme in live Helicobacter pylori (H. pylori) which breaks down urea into ammonia and carbon dioxide (McNulty 2005; Ricci 2007). After ingestion of urea labelled with either 13C or 14C, breath samples are collected for up to 20 minutes by exhaling into a carbon dioxide trapping agent (Ricci 2007). The urea breath test is performed by the clinician or the clinician's assistant. The thresholds used include the percentage of carbon recovered during the collection time or counts per minute (Ferwana 2015). Threshold levels above 4% or 5% are commonly used to diagnose H. pylori infection (Ferwana 2015). A wide range of threshold counts per minute, ranging from more than 25 counts per minute to 1000 counts per minute, have been used for diagnosis of (H. pylori) infection (Ferwana 2015).
These tests are based on circulating antibodies to H. pylori. There are three main methods for these tests: the enzyme-linked immunosorbent assay (ELISA) test, latex agglutination tests, and Western blotting (Ricci 2007). Of these ELISA is the most common method used. The total immunoglobulin, immunoglobulin subtypes, and antibody response to specific antigens can all be tested. Since they do not require any special equipment, they can be performed easily (Ricci 2007). However, the serology may be positive because of the presence of active infection at the time of the test, previous infection, or because of non-specific cross-reacting antibodies (McNulty 2005). Tests that use whole blood (rather than serum) and other bedside tests (that involves using a bedside centrifuge), are also available, although these whole blood tests and bedside serum tests are generally considered unreliable (Ricci 2007). Routine serum tests are performed by the laboratory technician and interpreted by the clinician. The bedside serum tests and whole blood tests are performed by the clinician or the clinician's assistant. Different threshold levels have been used by different researchers, for example, a titre ≥ 300 was interpreted as a positive serology by Lindsetmo 2008 et al while a titre ≥ 500 was interpreted as a positive serology by Granberg 1993 et al evaluating the prevalence of H. pylori.
Stool antigen tests
These tests use monoclonal and polyclonal antibodies to detect the presence of H. pylori antigen in stools and active H. pylori infection can be diagnosed (McNulty 2005; Ricci 2007). Serum tests are performed by the laboratory technician and interpreted by the clinician. As for other tests, several threshold levels have been used by different researchers, for example, an optical density of ≥ 0.15, ≥ 0.16, and ≥ 0.19 have all been used as the thresholds for the diagnosis of H. pylori using monoclonal antibodies for stool antigen tests.
Evidence from randomised controlled trials showed that screening and eradication programmes for H. pylori in populations at high risk of gastric cancer (e.g. East Asians), lowered the incidence of gastric cancer (Ford 2014). The Asia-Pacific Gastric Cancer Consensus conference recommended that screening and eradication of H. pylori is recommended in populations in countries at high risk of gastric cancer (i.e. Japan and Korea) (Talley 2008). The updated European Helicobacter Study Group (EHSG) Fourth Maastricht/Florence Consensus Conference guidelines suggest that people should be tested for H. pylori, and eradication of H. pylori (when present) has been recommended for the following conditions (Malfertheiner 2012).
People at high risk of gastric cancer.
Adults with dyspepsia with a locally determined age cut-off point (depending on local incidence of gastric cancer in different age groups), and without ‘alarm’ symptoms or signs associated with an increased risk of gastric cancer such as weight loss, dysphagia, upper gastrointestinal bleeding, abdominal mass, or iron deficient anaemia.
Unexplained iron deficiency anaemia.
Idiopathic thrombocytopenic purpura.
Uninvestigated young patients with dyspepsia should also be considered for testing for H. pylori when the prevalence of H. pylori is high (≥ 20%).
The clinical pathway is shown in Figure 1.
The index tests can be performed without any prior test.
Role of index test(s)
The index tests are used for the screening and diagnosis of H. pylori.
Other tests used in the screening and diagnosis of H. pylori infection include non-invasive saliva and urine antigen-based tests (Ricci 2007), and invasive gastric biopsy followed by Campylobacter-like organism (CLO) test, culture, histology, and polymerase chain reaction (PCR) (van Doorn 2000). We have not included the non-invasive saliva and urine antigen-based tests, since these are not commonly used (Ricci 2007).
Testing for Helicobacter pylori (H. pylori ) and eradication of H. pylori has been recommended for a number of population groups (Clinical pathway). These tests have to be non-invasive so that testing can be carried out for a large number of people. Undetected patients with H. pylori continue to be at high risk of gastric cancer or continue to have dyspepsia, anaemia, or purpura. Overdiagnosis (false positive tests) of H. pylori means that patients are subject to unnecessary adverse events related to eradication therapy (approximately 27% of patients receiving eradication therapy develop mild adverse events such as, bitter taste, nausea, diarrhoea, etc). Comparing the diagnostic accuracy of different index tests will highlight the best test for the diagnosis of H. pylori infection. There has been no Cochrane review on the diagnostic accuracy of the different non-invasive tests for the diagnosis of H. pylori infection.