Serology Is More Sensitive Than Urea Breath Test or Stool Antigen for the Initial Diagnosis of Helicobacter pylori Gastritis When Compared With Histopathology

Dustin E. Bosch, MD, PhD; Niklas Krumm, MD, PhD; Mark H. Wener, MD; Matthew M. Yeh, MD, PhD; Camtu D. Truong, MD; Deepti M. Reddi, MD; Yongjun Liu, MD; Paul E. Swanson, MD; Rodney A. Schmidt; Andrew Bryan, MD, PhD


Am J Clin Pathol. 2020;154(2):255-265. 

In This Article

Abstract and Introduction


Objectives: To assess the concordance and performance characteristics of Helicobacter pylori laboratory tests compared with histopathology and to propose algorithms for the diagnosis of H pylori that minimize diagnostic error.

Methods: H pylori diagnostics were reviewed from a 12-year period within a health system (2,560 cases). Analyses were performed to adjust diagnostic performance based on treatment and consensus histopathologic diagnoses among pathologists. Markers of access to care, including test cancellation frequency and turnaround time, were assessed. Costs and performance of candidate noninvasive testing algorithms were modeled as a function of disease prevalence.

Results: Serum H pylori IgG demonstrated a higher sensitivity (0.94) than urea breath and stool antigen tests (0.64 and 0.61, respectively). Evidence of an advantage in access to care for serology included a lower cancellation rate. Interobserver variability was higher (κ = 0.34) among pathologists for cases with a discordant laboratory test than concordant cases (κ = 0.56). A model testing algorithm utilizing serology for first-time diagnoses minimizes diagnostic error.

Conclusions: Although H pylori serology has modestly lower specificity than other noninvasive tests, the superior sensitivity and negative predictive value in our population support its use as a noninvasive test to rule out H pylori infection. Reflexive testing with positive serology followed by either stool antigen or urea breath test may optimize diagnostic accuracy in low-prevalence populations.


Helicobacter pylori infection is common, with serologic prevalence exceeding 50% worldwide.[1] However, there is considerable variation by location, for example, with prevalence of approximately 35% in the United States but as high as 88% in Nigeria.[1] Within the United States, the prevalence of H pylori is related to geographic region and ethnicity, among other factors.[1,2] Infection with H pylori is associated with gastric ulcers, adverse outcomes in bariatric surgery patients, and neoplasia including adenocarcinoma and gastric marginal zone lymphoma.[3] Eradication is effective in preventing malignancy and can reverse nonneoplastic lesions.[4–7]

Diagnostic tests for H pylori can be categorized as invasive/tissue-based or noninvasive. Invasive tests include mucosal biopsy with histopathologic examination and H pylori culture. Histopathologic evaluation with routine H&E stain has a reported sensitivity of 70% to 95%[8] that can be increased by special stains such as the silver-based Genta or H pylori immunohistochemistry (IHC).[8] The morphology of H pylori and thus the performance of histopathology is affected by treatment, including proton pump inhibitors (PPIs).[8]H pylori culture is highly specific and may be considered the gold standard for definitive active infection, but the organism is fastidious and the sensitivity of culture is low.[9,10]

Commonly used noninvasive tests include the stool antigen test, the urea breath test (UBT), and H pylori serum IgG.[10] Stool antigen testing is performed by ELISA or lateral flow chromatography.[11] The UBT involves administration of either 14C- or 13C-labeled urea.[12] After a waiting period, the breath specimen is captured in a bag and assessed by scintigraphy, spectrophotometry, or mass spectrometry. The stool antigen test and UBT perform similarly in direct comparison studies,[12,13] and both suffer from decreased sensitivity in the context of acid reduction therapy and recent antibiotic exposure.[14]H pylori IgG serology is a highly sensitive test unaffected by PPI or antibiotic therapy, but active infection cannot be distinguished from past exposure.[8,15] Multiple H pylori serology kits are available, and the performance of some are related to patient factors including age, sex, and ethnicity.[16,17] Thus, appropriate kit selection and local validation of performance are important. The limitations of H pylori serology have prompted recommendations to avoid its use (eg, Choosing Wisely Campaign).[18] The American College of Gastroenterology's 2017 guidelines similarly recommend tests that detect active infection for most presentations, except if the pretest probability is high (eg, peptic ulcer disease) and serology may be acceptable.[19]

There are clear clinical benefits of H pylori eradication. Guidelines have tended to expand recommendations for diagnostic testing to broader populations over time and have recommended routinely confirming successful H pylori eradication more than 4 weeks after therapy.[19] Multimodal testing creates complexity of interpretation but also presents an opportunity to retrospectively compare test performance and concordance in a real-world clinical population. To our knowledge, we report the largest data set comparing invasive and noninvasive H pylori diagnostic tests and model diagnostic errors and costs of noninvasive testing algorithms.