Epstein-Barr Virus and Helicobacter pylori Co-Infection in Gastric Cancer: A Systematic Review and Meta-Analysis of Case-Control and Cross-Sectional Studies.

BACKGROUND

Gastric cancer (GC) is a multifactorial malignancy in which both Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV) have been implicated. Given the high prevalence of both pathogens, we performed a systematic review and meta-analysis to estimate the prevalence of H. pylori-EBV co-infection (HECo) in GC and to evaluate its association with GC.

METHODS

A systematic literature search was performed using a search strategy consisting of appropriate keywords in online databases including MEDLINE, Embase, and Web of Science from inception to July 2024. Eligible case-control and cross-sectional studies in English reported H. pylori and EBV status assessed using validated assays (e.g., PCR, serology, immunohistochemistry/in situ hybridization, rapid urease test), enabling ascertainment of HECo within the same participant. Study quality was assessed using the "Newcastle-Ottawa Quality Assessment Scale" (NOS) and the Appraisal Tool for Cross-Sectional Studies (AXIS tool). Random-effects meta-analyses were used to pool prevalence estimates and odds ratios (ORs) with 95% confidence intervals (CIs), and heterogeneity was quantified using I².

RESULTS

Eighteen studies (n = 4364; 1999-2023) were included. HECo prevalence among GC patients was 21.44% (95% CI: 9.46-33.42). HECo was associated with increased odds of GC (pooled OR = 3.09, 95% CI: 1.66-5.73; I² = 69.1%). Subgroup estimates by age (high vs low) were based on two studies per stratum and showed wide CIs (high age: OR = 9.61, 95% CI: 1.90-48.64; low age: OR = 9.52, 95% CI: 1.83-49.54) and should be interpreted cautiously. There was a significant association between the presence of metastasis, the high stage of GC, and HECo. Our results showed no significant association between moderately or poorly differentiated GC, diffuse-type GC, the presence of vessel invasion, and HECo.

CONCLUSION

HECo is associated with a higher risk of GC. Future primary studies should report mutually exclusive infection categories (HP only, EBV only, both, neither) and clarify the temporal relationship between infection and GC, to better disentangle independent versus joint effects and to inform prevention strategies.