Proton pump inhibitors and gastroenteritis

Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs worldwide, but seem to be associated with an increased risk of bacterial gastroenteritis [1‐9]. As a result warnings are introduced for people using PPIs, such as avoiding raw meat consumption and antibiotic treatment on demand for travels to the tropics, to prevent food borne infections. This cohort study was designed to asses if the magnitude of this risk, warrants preventive recommendations.

Common indications for PPIs are dyspepsia, peptic ulcer disease, reflux esophagitis, and Barrett’s oesophagus [10]. PPIs reduce gastric acid production by up to 99 % by irreversible blocking of H+/K+ ATPase of parietal cells in the stomach [11]. They have a maximal effect within 4 days and the effect may persist up to 3 days after stopping use [12]. Associations between PPIs and infectious adverse events such as pneumonia, Clostridium difficile-associated diarrhoea and bacterial gastroenteritis have often been described [1‐9, 13‐17]. An increased risk of gastroenteritis might be explained by the strong reduction in gastric acid resulting in increased susceptibility to bacterial infections. Exogenous bacteria are usually destroyed in the stomach when the pH is <3.0. For species such as Vibrio cholerae and Campylobacter jejuni it has been shown in vitro that they are very sensitive to pH [18]. However, Salmonella species have been found to respond to low pH by developing adaptive mechanisms that allow survival in acid environments [19]. Furthermore, PPIs change the gut flora, which provides a homeostatic protection against ingested pathogens [20, 21]. PPIs also reduce the antibacterial activity of neutrophils which may facilitate Salmonella and Campylobacter infections [22, 23]. Several case–control studies have shown an increased risk of acquiring gastrointestinal infections caused by Campylobacter or Salmonella species in patients using PPIs [1‐8]. In these case–control studies, a relatively high adjusted odds ratio (aOR) or relative risk was observed, ranging from 2.9 to 11.7. In one nested case–control study, in which participants with a gastroenteritis prior to first PPI prescription were excluded, a considerably lower effect was observed (aOR 1.6) [9]. It has even been stated that there is no evidence that PPIs are associated with gastrointestinal infections based on outcomes adjusted for pre-treatment susceptibility to bacterial gastrointestinal infections and time-dependent confounding factors [24], which observation suggests that previous case–control studies have suffered from selection or information bias. Therefore, we designed a nested case control study within The Rotterdam Cohort, a prospective cohort study, to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis. To minimize the risk of information bias we used participants with negative stool samples as a control group. To test the hypothesis that an incorrect control group will influence the study results we also analysed the association using the total cohort as a control group.

During the study period, 1329 stool cultures of participants of The Rotterdam Study were identified at Star-MDC. We excluded 30 stool samples because of isolation of a parasite, resulting in 1299 stool samples for the study. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In total 105 (84.0 %) Campylobacter species, 16 (12.8 %) Salmonella species, 3 (2.4 %) Yersinia species and 1 (0.8 %) Shigella sonnei were isolated. All 125 positive stool samples were collected from 118 different participants and all 1174 negative stool samples from 903 different participants. The percentage of missing data of BMI was 7.6 % and of dietary data 28.6 %. Characteristics of cases and controls are shown in Table 1.

PPIs have been associated with an increased risk of bacterial gastroenteritis in previous studies [1‐9]. In this population based cohort study we found that current PPI therapy was associated with a strongly increased risk of bacterial gastroenteritis, with an aOR of more than six. However, this risk decreased to 1.94 after restriction to the subgroup with stool samples. Therefore, we suspect that information bias inflated the risks in other population based studies which have shown an association between PPI therapy and an increased risk of Campylobacter and Salmonella infections before. Although, people using PPIs still should be careful consuming food which could be contaminated, such as beef, poultry or processed food, the risk of gastroenteritis is probably less than previously assumed.

One of the strengths of our study is that we tried to use a comparable control group by only using participants with negative stool samples. In most of the previous population based studies the magnitude of the effect may have been overestimated as a result of the use of incomparable control groups. Typically, case control studies regarding use of PPIs may suffer from a “healthy control” bias. We further tried to avoid healthy control bias by correcting for the use of chronic medication. Some of the previous studies used a random sample of population registries, or volunteering friends or relatives of the cases as control group [2, 4‐6]. These participants are probably healthier and will therefore differ considerably from the cases. But also commonly used strategies, such as using matched controls, obtained from general practitioner databases, will not prevent information bias [1]. Studies considering self-limiting diseases such as gastroenteritis, might select a “help seeking” and therefore biased population. As a consequence, people using a PPI will be more inclined to consult medical help in case of gastroenteritis compared to randomly selected controls, even if they are matched.

Residual confounding might also have influenced previous study results, because dietary pattern, which has been shown to be the most important risk factors for Campylobacter and Salmonella infections has not been included in these studies [29, 30]. An association with dietary data was not observed in our study. Unfortunately, the number of missing dietary data in our study was rather high with as a consequence a large number of imputed data.

Observational studies may always suffer from bias and residual confounding. We had no data on other important risk factors for bacterial gastroenteritis, such as foreign travelling, eating in a restaurant, or contact with animals [29, 30].

We believe we used a comparable control group using participants with negative stool samples. However, results from a test-negative study design may also underestimate the risk, since a number of the controls with negative stool cultures may be false-negatives. They can be false-negative either because of low diagnostic sensitivity against the four bacterial species (e.g., too little material received, long transportation time, stool collected many days after onset of gastroenteritis) or because the patient suffered from other causes of bacterial gastroenteritis (diarrheagenic Escherichia coli or Clostridium difficile).

Furthermore, in elderly gastric acid secretion is impaired compared to younger aged individuals [31]. If gastric acid secretion is already impaired, PPIs will have a smaller effect. Therefore, the smaller risk estimate in our study might be explained by the fact that our population mainly consisted of elderly, in which gastric acid secretion is already impaired.

Because Salmonella species are less susceptible to pH, the association between PPI therapy and gastroenteritis might be smaller for Salmonella species [19]. Unfortunately, however, the number of Salmonella infections in this study was too small to draw conclusions on this association.

During the study period the method of detection of enteric pathogens changed by the introduction of PCR, resulting in an increased sensitivity. To correct for an increased risk of false negative stool samples in the earlier years of the study, we included calendar date and cohort in the assessment of model design.

Although male gender has been shown to be an independent risk factor for bacterial gastroenteritis, it has not been shown before that the association between PPI therapy and bacterial gastroenteritis is much higher for males [32]. We were unable to explain this result by other covariables. Possibly there are unmeasured (hygiene related) behavioural aspects to explain this difference. In experimental studies a gender difference was observed between male and female neutrophils. Male neutrophils show higher responsiveness to stimulation with lipopolysaccharide and interferon-ϒ [33]. Neutrophils play an important role in Salmonella and Campylobacter infections [22, 23]. The harmful effect of PPIs may therefore be greater for male than for female subjects. Of course, studies are needed to test this rather speculative hypothesis.

In conclusion, current PPI therapy was associated with an increased risk of bacterial gastroenteritis. We demonstrated that the effect is lower than previously assumed, by reducing the risk of information bias in our study design.