Infection with Helicobacter pylori (HP) is common, with an estimated 50% of the world affected, and can lead to a variety of gastrointestinal pathologies, from ulcer disease to malignancy (1–3). As such, consensus guidelines recommend treating all known HP infections and subsequently testing for the confirmation of eradication (4–6). Treatment comprises a multidrug regimen for 1–2 weeks and can include multiple antibiotics. Given the increasing awareness regarding untoward effects of antibiotics, such as increasing rates of resistance and side effects, there are those that caution against HP eradication (7–13). They argue that eradication of HP can be associated with antibiotic resistance, antibiotic associated diseases, and changes in the microbiome that could have downstream consequences. A particularly concerning, yet uninvestigated, area is the association of HP treatment with Clostridium difficile infection (CDI).
CDI is one of the most common healthcare-associated infections and results in significant morbidity and mortality in the US population (14,15). Antibiotic stewardship has been shown to decrease the impact of CDI and is an important public health initiative (16). Accordingly, the potentially deleterious effects of HP must be carefully balanced with untoward effects of antibiotics, including CDI. Previous literature regarding the development of CDI after HP eradication therapy has generally been limited to case reports, limiting the ability to draw conclusions (17–19). To our knowledge, no study has comprehensively studied CDI after HP, accounting for patient factors, risk factors for CDI (previous infection and recent hospitalization), antibiotic therapy, and the presence of confirmed eradication. Here, we utilize the largest North American cohort of patients with HP to identify the risk factors for future CDI and the impact of HP treatment on future CDI.
This retrospective cohort study was conducted within the Veterans Health Administration (VHA) Corporate Data Warehouse, which includes data from the unified electronic medical record of all VHA facilities (i.e., hospitals and outpatient).
We identified patients with HP infection, and this cohort has been extensively described elsewhere (20). Briefly, patients with HP infection (January 1, 1994–December 31, 2018) were included based on the following: (i) endoscopic pathology by natural language processing, (ii) positive stool antigen test, or (iii) positive urea breath test. For patients with multiple criteria, the criterion with the earliest date was used. (Unique identifiers assured no duplications.)
The primary outcome was a positive laboratory test for C. difficile toxin or polymerase chain reaction within the VHA within the 3 months after HP detection.
Logistic regression was performed, and a multivariable analysis was conducted evaluating the following covariates: age, ethnicity, race, gender, smoking history (21), poverty level of zip code where the patient resided at HP diagnosis, history of previous CDI, recent hospitalization (within 4 weeks or 12 weeks) (22,23), and whether the patient received prescription for an eradication regimen for HP (subcategorized by the regimen received). The zip code-level poverty was based on the 2010 census data and categorized based on the percentage of people within a zip code below the federal poverty line. Receipt of HP treatment was defined as receiving a recommended antibiotic regimen after HP diagnosis at the VHA using the prescription-filling data at any inpatient or outpatient VHA facility (20). Exploratory analyses were conducted, evaluating the receipt of HP treatment (yes/no), by antibiotic class and by antibiotic regimens. Similarly, for proton pump inhibitor (PPI) therapy, we evaluated PPI choice, dose (high-dose vs not, as per the United Kingdom National Institute for Health and Care Excellence classifications), duration, and whether the patient had been prescribed a PPI outside of the HP eradication period.
A secondary analysis evaluated whether the confirmation of HP eradication among those who received prescription therapy for their HP diagnosis was associated with CDI, given the varying rates of retesting and successful HP treatment, as well as the potential for HP eradication to change the microbiome, leading to subsequent CDI (3,4,24). This analysis was restricted to those who received treatment for HP. Eradication was based on having either a negative stool antigen, urea breath test, and/or pathology (gastric biopsy on endoscopy) on repeat testing. Failed eradication was defined as a positive stool antigen, urea breath test, and/or pathology, or a positive HP test after a previous negative test, given that true reinfection is exceedingly rare. Patients without any eradication testing were considered as “unknown” eradication status. HP status on pathology was determined by repeat natural language processing, which has been described elsewhere (20).
Stata/IC 15.1 (College Station, TX) was used to perform backward selection, with the inclusion of all clinically significant subhazard ratios, where P < 0.10. The Institutional Review Boards of the Corporal Michael J. Crescenz VA Medical Center and the University of Pennsylvania approved this study.
We identified 38,535 patients with detected HP infection on endoscopic pathology, urea breath testing, or stool antigen. Of these 38,535 patients, 284 (0.74%) had subsequent CDI. Among the 38,535, 28,818 (74.8%) were treated for HP. Table 1 compares those patients who developed CDI vs those who did not. Patients who developed CDI were older (median age 64 vs 62 years, P = 0.001) and more likely to be of non-Hispanic or Latino ethnicity (70.1% vs 66.3%, P = 0.01) without significant differences in gender, race, smoking history, or poverty level. They were more likely to have a history of CDI (58.1% vs 4.1%, P < 0.001) and a recent hospitalization, either within 4 weeks (15.5% vs 0.5%) or 12 weeks (17.3% vs 0.7%) of CDI, P < 0.001. There was no significant difference in the method of HP diagnosis. Those who developed CDI were less likely to have received treatment for HP within the VHA (66.2% vs 74.8%, P < 0.001). When evaluating antibiotics, those who developed CDI were less likely to have been prescribed a regimen that included amoxicillin (44.4% vs 56.8%, P < 0.001) or clarithromycin (45.4% vs 57.1%, P < 0.001), without significant difference in metronidazole prescription (20.1% vs 17.4%, P = 0.23) or levofloxacin (1.4% vs 1.2%. P = 0.70). There was no difference between the PPI used during HP eradication among those who go on to develop CDI and those who do not. Patients who developed CDI were not significantly more likely to have been prescribed a high dose PPI (11.4% vs 10.7%, P = 0.77) or been prescribed PPI therapy outside the HP eradication period (9.6% vs 11.7%, P = 0.57).
Figure 1 demonstrates the most commonly prescribed regimens (if any) for HP eradication. The most frequently prescribed regimen included amoxicillin- and clarithromycin-based triple therapy in 19,871 (51.6%) patients, followed by bismuth-based quadruple therapy in 3,196 (8.3%). Of the 38,535 patients, 9,717 (25.2%) had no eradication regimen prescribed in the VHA.
In multivariable analysis, there were multiple factors associated with increased future risk of CDI (Table 2). Recent hospitalization was strongly associated with future CDI, both within 12 weeks (odds ratio [OR] 2.15; 95% confidence interval [CI]: 1.22–3.77) and 4 weeks (OR 3.46; 95% CI: 2.18–5.48), P < 0.001. A history of CDI was also strongly associated with future CDI (OR 12.5; 95% CI: 9.21–17.0). Treatment of HP was not associated with increased future CDI in multivariable analysis, either as a whole or when analyzed by HP eradication regimen or which antibiotic the patient was prescribed. Neither long-term PPI use or PPI use during HP eradication (evaluated by PPI choice, dose, and duration, with and without specific antibiotic regimen) was significantly associated with CDI. Patient demographics demonstrated that women were more likely to have future CDI (OR 1.74; 95% CI: 1.20–2.52, P = 0.003) and those of white race were more likely to develop future CDI (see Table 2).
A subanalysis of those 28,818 patients who were prescribed treatment was performed, accounting for eradication status. Of these 28,818 patients, 933 (3.2%) had positive HP on repeat testing, whereas 7,541 (26.2%) were confirmed eradicated. There were 20,344 (70.6%) patients on whom we could not ascertain the eradication status. Table 3 demonstrates the results of the multivariable analysis regarding the risk factors for CDI after treatment of HP among these 28,818 patients. As compared to the larger cohort, patient demographics remained similar, and both previous CDI (OR 13.3; 95% CI: 9.38–18.9, P < 0.001) and recent hospitalization (within 12 weeks OR 2.10; 95% CI 1.08–4.08 and 4 weeks (OR 3.18; 95% CI: 1.86–5.43, P < 0.001) are striking for their strength of association. Eradication status did not demonstrate that the confirmation of eradication was significantly associated with future CDI (OR 1.49; 95% CI: 0.67–3.29). Figure 2 graphically displays the results of Table 3.
In the largest cohort of US patients with detected HP, we demonstrate that CDI after HP is rare, but not negligible at 0.74% within 3 months. Among those without recent hospitalization or previous CDI, the rate was lower, 0.37%, within 3 months. The most important finding from our study was that neither treatment of HP nor its eradication is associated with future CDI. In multivariable analysis, we identify the risk factors for CDI after HP treatment, history of CDI and recent hospitalization, both of which are well known and previously established in other studies (25–27). That younger age, white race, and female gender were associated with future CDI is interesting. Women are more likely to receive antibiotics than men, and although we controlled for HP antibiotic regimen, perhaps women have alterations in microbiota from previous (non-HP) antibiotic use, predisposing them to CDI (28). There is much recent evidence for a changing epidemiology of CDI, and these trends may be reflective of that, particularly given that older age was previously considered a strong risk factor (25). Despite quinolones being a known risk factor for CDI, we did not find that any particular antibiotic regimen was associated with future CDI (29). PPI choice, dose, and duration were not associated with CDI.
CDI after HP has been a reasonable, but theoretical, cause for concern, with previous studies limited by sample size and the lack of granular data. As we note above, previous literature has generally been limited to case reports (17–19). The largest series that we identified included 260 patients with ICD code diagnoses of HP with 12 subsequent cases of CDI (30). This series demonstrated that 4.6% of patients developed CDI, although 2 had additional antibiotic therapy before infection and 4 had hospitalization before infection. There was also a 3-year study period in which infection was captured, although previous literature has established that CDI is most frequent in the 1 to 3 month period after antibiotic use (31). These factors likely explain the differences between our findings.
The theoretical concern of CDI after HP could be microbiota change from the antibiotic regimen, microbiome change from HP eradication, or an otherwise undelineated protective effect of HP against CDI. As such, we evaluated both the receipt of HP treatment and subsequent eradication status, and future studies should attempt to identify the mechanism by which patients are predisposed to CDI. Because we show that previous CDI and recent hospitalization are the biggest risk factors for CDI after HP, these factors should be considered before prescribing HP therapy. For example, if a patient is hospitalized and found to have HP, in the right setting with ensured follow-up, HP eradication therapy could be delayed for a period, although future studies and guidelines should comment on the appropriateness of this strategy. It is possible that clinicians are already taking CDI into account during HP therapy. For example, we demonstrate that although patients with future CDI were more likely be prescribed an HP eradication regimen that contained metronidazole, metronidazole was not associated with future CDI. We hypothesize that this is due to clinical judgment, where a clinician may elect for a metronidazole containing HP regimen because of a patient's history of CDI or recent hospitalization.
Limitations of this study include its retrospective nature and the inherent limitations of retrospective studies in determining causality. There are measurement issues, including patients receiving care outside the VHA, and incomplete information. Although the VHA is among the largest comprehensive electronic medical records in the United States, it is not complete and is not linked with outside electronic medical records. As such, if a patient was diagnosed with CDI outside of the VHA or received treatment or eradication testing outside the VHA, we would not capture this. These limitations could decrease the apparent incidence of CDI or its association with HP treatment/eradication. When compared with those with persistent eradication, the point estimate among patients with confirmed eradication suggested a possible increased risk (OR 1.49, 95% CI: 0.67–3.29), but the CI crossed 1. This may be an issue related to sample size and a limitation in power or may simply reflect a lack of an association. However, the VHA is a longitudinal and comprehensive system, previously validated among many diseases and used widely in epidemiologic studies, and that we detect significant differences between those who develop CDI and those who do not (including reproducing previously established risk factors), lends validity to our cohort. Our success rate, although high, has been previously noted in the cohort and is similar to the published trial data on HP eradication therapy, further lending validity to our cohort (32,33). Another limitation is that we did not have complete and long-term PPI information. Although we were able to identify patients with prescription of PPI therapy outside of the HP eradication period, we were unable to analyze the duration of use of long-term PPI (which is outside the scope of this manuscript), and because PPIs are a commonly available over the counter medication, we cannot reliably conclude there is no association between PPI therapy and CDI, a question that has been previously raised (34). Similarly, we do not have information on other antacids, such as pepto-bismol or other acid suppressing agents. As such, although we can conclude that PPI choice as part of HP therapy does not seem to be associated with CDI, our suggestion that long-term PPI is not associated with CDI should only be considered hypothesis generating.
Our strengths include the size of our cohort, which is the largest cohort of patients with detected HP in the United States, and our ability to identify the granular data. For example, we did not need to rely on the administrative codes for CDI but were able to confirm true positivity by evaluating the testing for CDI. We were able to identify the regimens of HP eradication therapy to identify whether particular regimens or antibiotics were associated with CDI. Previous literature has been limited to case reports or series. Our study, with longitudinal and granular data of high fidelity among almost 40,000 patients in the VHA provides a more complete picture of CDI after HP. It suggests that HP treatment does not increase the risk of CDI on its own and reaffirms what is known: that history of CDI and recent hospitalization are the most important factors for future CDI. Although this should be confirmed in prospective studies, our findings suggest that HP should be continued to be treated when detected, given that it likely modifies future gastrointestinal disease risks, including peptic ulcer disease, gastric lymphoma, and adenocarcinoma.
CONFLICTS OF INTEREST
Guarantor of the article: Shria Kumar, MD.
Specific author contributions: S.K.: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and statistical analysis. D.C.M.: study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; and study supervision. D.E.K.: study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision. D.S.G.: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and study supervision.
Financial support: S. Kumar, MD, is supported by an NIH training grant (5 T32 DK 7740-22).
Potential competing interests: S.K: Travel (Boston Scientific Corporation and Olympus Corporation). D.C.M.: Consulting (Takeda, Lexicon, AAA, and Novartis), Grant Support (Lexicon, Wren Laboratories, Ipsen, and AAA). D.E.K.: Research grant support (Gilead, Bayer). D.S.G.: Research grant support (Gilead, Merck, AbbVie, and Zydus).
WHAT IS KNOWN
- ✓ H. pylori treatment involves a multidrug antibiotic regimen.
- ✓ There is a theoretical risk of antibiotic associated disease, including C. difficile infection, but studies on this have so far been limited.
WHAT IS NEW HERE
- ✓ The rates of C. difficile infection after H. pylori is low.
- ✓ The biggest risk factors include previous C. difficile infection and recent hospitalization.
- ✓ Neither treatment nor eradication of H. pylori is associated with future C. difficile.
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