Helicobacter pylori infection is associated with an increased risk of chronic obstructive pulmonary disease and asthma

Helicobacter pylori is a well-established pathogen responsible for chronic gastritis and peptic ulcer disease. Its presence has been implicated in the development of gastric malignancies such as adenocarcinoma and mucosa-associated lymphoid tissue lymphoma [1]. Chronic H. pylori infection is associated with systemic inflammatory responses and various extragastric diseases, including cardiovascular, metabolic, and neurological disorders [1‐3]. Furthermore, H. pylori infection contributes to gastrointestinal dysbiosis by interacting with gastrointestinal microbiota, which may be involved in gastric carcinogenesis and other systemic disorders [4, 5]. Growing evidence highlights the role of dysbiosis in chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma [6, 7]. These airway diseases are driven by persistent inflammation and are increasingly linked to systemic influences, including gastrointestinal health. However, the association between H. pylori infections and chronic airway conditions remains unclear.

Previous studies investigating this association have yielded mixed results. Some case-control and retrospective studies have reported a significant association between H. pylori infection and COPD, suggesting a possible link [8‐10]. In contrast, no significant association was observed in a case-control study conducted in Korea [11]. Similarly, the relationship between H. pylori infection and asthma has been debated, with some studies suggesting a protective effect, in line with the hygiene hypothesis [12, 13], while others have reported no association [14, 15]. These studies were methodologically limited by (1) the accuracy of H. pylori infection [10], (2) accuracy of asthma diagnosis [12, 13], (3) lack of smoking history [10], and (4) limited sample size (Supplementary Table 1) [8, 9, 11‐14].

Given these uncertainties, further large-scale population-based studies that incorporate clinically verified H. pylori infections and control for major confounders, such as smoking, are needed. The current study addresses these gaps by evaluating the association between H. pylori infection and the risk of developing COPD and asthma in a nationwide cohort in Korea. The diagnosis of H. pylori infection was made based on the history of H. pylori eradication treatment rather than serological tests to address the clinically significant chronic inflammatory conditions associated with H. pylori infection. Owing to the Korean national insurance strategy, eradication treatment can only be prescribed when H. pylori infection and eradication indications are documented [16].

In this large-scale population-based cohort study, we demonstrated that individuals with clinically confirmed H. pylori infection had a significantly higher risk of developing both COPD and asthma, independent of established risk factors such as smoking, comorbidities, and socioeconomic status. The association between H. pylori infection and COPD was particularly pronounced in older adults and current smokers, whereas the increased risk of asthma was consistent across the age and smoking strata. To the best of our knowledge, this is the first study to investigate the association between H. pylori infection and chronic airway diseases based on the definition of H. pylori eradication treatment.

A significant association between H. pylori infection and COPD (13% increased risk) and asthma (17% increased risk) was observed in the present study. Given the higher prevalence of H. pylori seropositivity (51.0% in 2015–2016) in Korea [22], a considerable proportion of the control group may have H. pylori infection. However, individuals receiving eradication treatment are likely to have a higher inflammatory burden owing to symptomatic or severe gastrointestinal disease. Accordingly, while precise estimation of the effect size remains difficult, our findings support a meaningful association between H. pylori-associated chronic inflammation and the risk of chronic airway disease.

The observed associations are biologically plausible, given the known pro-inflammatory and immunomodulatory effects of H. pylori. First, H. pylori, which is typically acquired early in life and colonizes in the gastric mucosa [27], causes chronic inflammatory conditions and releases several systemic inflammatory mediators, such as tumor necrosis factor-α, interleukins (e.g., IL-1, IL-6, IL-12), and transforming growth factor-β, into the systemic circulation [28]. Furthermore, autoantibodies induced by H. pylori lipopolysaccharides (molecular mimicry) can induce extragastric inflammatory conditions [29]. These processes may create a systemic inflammatory milieu that predisposes individuals to airway disease. Epidemiological studies have reported that chronic systemic inflammatory diseases outside the lungs can be a risk factor for COPD and asthma. This correlation has previously been described in rheumatoid arthritis [23, 30] and psoriasis [31, 32].

Second, H. pylori colonization can lead to local dysbiosis and affect downstream gastrointestinal microbial composition [33, 34]. Furthermore, eradication therapy itself, often involving broad-spectrum antibiotics and proton pump inhibitors, can disrupt the microbiome equilibrium, potentially influencing immune tolerance and lung inflammation [33‐35]. Although these mechanisms remain to be directly confirmed in the context of COPD and asthma, the gut-lung axis provides a compelling framework for future investigations.

While the first two hypotheses address the risks associated with chronic inflammatory conditions attributable to H. pylori infection, the third hypothesis explores the potential adverse effects of eradication therapy, specifically, the increased risk of gastroesophageal reflux disease (GERD) following H. pylori eradication. Microaspiration of gastric contents can lead to direct injury to the lungs [36]; thus, GERD is an established risk factor for chronic airway conditions [37, 38]. H. pylori may protect against GERD (decreased gastric acid secretion), and its eradication may reduce acid suppression and impair esophageal motility, thereby exacerbating GERD and increasing the likelihood of microaspiration [39]. Potential aggravation of GERD after H. pylori eradication may partially contribute to the development of COPD and asthma.

Stratified analysis according to age revealed a more pronounced association between H. pylori infection and COPD among older adults. In contrast, the risk of asthma did not differ across the age groups. H. pylori infection is typically acquired in childhood [1, 27]; consequently, older individuals are exposed to H. pylori for a longer duration, which may contribute to the development of chronic inflammatory conditions associated with infection.

The heightened COPD risk observed in current smokers with H. pylori infection may reflect both immunological synergy and differential eradication efficacy. Smoking has been shown to impair antibiotic efficacy and increase gastric acidity, potentially reducing the success of H. pylori eradication therapy [40]. Thus, current smokers may experience prolonged exposure to chronic inflammation from persistent infection, amplifying pulmonary damage, given the 70–80% success rate of first-line eradication treatment regimens in Korea (mainly due to increasing resistance to clarithromycin) [16]. Thus, the effects of age and smoking on asthma in H. pylori infection warrant further investigation.

This study has several strengths that reinforce the credibility of our findings. First, our strict definition of H. pylori infection, based on eradication treatment records, likely captured clinically meaningful conditions, such as peptic ulcers or early gastric cancer, rather than incidental seropositivity (IgG antibody positivity does not necessarily indicate a current infection) [9‐14]. Furthermore, the possibility of meaningful H. pylori infection was likely low among individuals who did not receive eradication therapy after health examinations (including esophagogastroduodenoscopy). Second, the large sample size and use of nationwide insurance data provided robust statistical power and minimized selection bias. In addition, detailed demographic, behavioral, and clinical variables enabled a thorough multivariable adjustment.

However, some limitations of this study should be acknowledged. First, this study aimed to compare H. pylori-infected individuals who received eradication treatment due to significant gastrointestinal symptoms or diseases in the general population, which likely includes many asymptomatic H. pylori-infected and uninfected individuals. Thus, the observed association may be confounded by underlying gastrointestinal diseases that are also associated with systemic inflammation, which is a known driver of COPD and asthma. Unfortunately, key clinical data, such as specific indications for eradication therapy, endoscopic findings, and histopathological results, were not available in the source dataset, which limited our ability to perform further stratified analyses or propensity score matching. Because the source database did not contain information on the results (success or failure) of eradication therapy, the long-term effects of chronic H. pylori infection and the short-term impact of eradication therapy itself could not be distinguished. Second, although our definitions of COPD and asthma were based on diagnostic claims, objective confirmation via spirometry was not possible. However, repeated coding within the claims data likely reflects a clinically recognized disease. Third, as with any observational study, residual confounding factors cannot be entirely excluded. Furthermore, as this was a retrospective observational study, our findings may be correlative and inconclusive and should be interpreted with caution. Fourth, the generalizability of our findings may be limited to populations with similar H. pylori prevalence and healthcare systems, particularly given the relatively high infection rate [22]. Finally, this study aimed to explore the epidemiological relationship among H. pylori infection, associated chronic gastrointestinal conditions, and the risk of chronic airway diseases. We did not intend to determine the direct causal role of H. pylori infection in the development of chronic airway diseases.

In conclusion, H. pylori infection is associated with an elevated risk of developing COPD and asthma in adults, with the COPD risk being most pronounced among older individuals and current smokers. These findings highlight the potential systemic consequences of gastric infection and suggest that the gastrointestinal-respiratory axis warrants greater attention in both research and clinical care. Future studies should explore the mechanistic pathways linking H. pylori to airway inflammation and investigate whether timely diagnosis and treatment of the infection could mitigate long-term pulmonary outcomes.