Country-wide medical records infer increased allergy risk of gastric acid inhibition

Abstract

Gastric acid suppression promotes allergy in mechanistic animal experiments and observational human studies, but whether gastric acid inhibitors increase allergy incidence at a population level remains uncharacterized. Here we aim to assess the use of anti-allergic medication following prescription of gastric acid inhibitors. We analyze data from health insurance records covering 97% of Austrian population between 2009 and 2013 on prescriptions of gastric acid inhibitors, anti-allergic drugs, or other commonly prescribed (lipid-modifying and antihypertensive) drugs as controls. Here we show that rate ratios for anti-allergic following gastric acid-inhibiting drug prescriptions are 1.96 (95%CI:1.95-1.97) and 3.07 (95%-CI:2.89-3.27) in an overall and regional Austrian dataset. These findings are more prominent in women and occur for all assessed gastric acid-inhibiting substances. Rate ratios increase from 1.47 (95%CI:1.45-1.49) in subjects <20 years, to 5.20 (95%-CI:5.15-5.25) in > 60 year olds. We report an epidemiologic relationship between gastric acid-suppression and development of allergic symptoms.

Fig. 1

Overview of direct and indirect pro-allergenic immune responses to anti-ulcer drugs (AUD). a, f With regards to oral allergens, the gastric pH elevation by AUDs, most dominantly by proton-pump inhibitors (PPI) and H2 receptor antagonists (H2RA), leads to reduced pepsin activation and impaired food antigen degradation, enabling persistence of ingested epitopes and their uptake in the intestines^–,,. This leads to formation of antigen-specifc IgE and promotion of a Th2 type dominated immune milieu resulting in eosinophilic inflammation and allergic symptoms^,,. b–e With regards to directly AUD-associated innate and adjuvant immune effects, PPIs can (b) induce AhR-mediated mast cell activation synergizing with IgE-FcɛRI signaling and resulting in mediator release and enhanced CD63 expression via the S1P pathway; both mechanisms result in allergic symptoms manifestation; (c) H2RAs stimulate the release of Th2 cytokines from both monocyte and Th2 cells leading to a B-cell isotype switch resulting in IgG1 (mice) and IgE production (humans, mice); (d) Further, H2RAs promote an increase in Th2 cytokine releasing iNKT cells, particularly when co-exposed to lipid antigens, and increase in CD1d+ DCs via TLR2 activation; (e) Sucralfate, an aluminum compound, can induce IL-4 release from DCs along with IL-5^, and caspase-dependent IL-1β secretion from monocytes promoting an isotype switch in B-cells into IgE production; f The resulting disturbance of gut microbiota composition^,, additionally supports a pro-allergic Th2 milieu and enhances allergic symptoms

Fig. 2

Annual prevalence of anti-allergic drug prescriptions. Data presented by gender and age groups 2009–2013 in the Austrian county Burgenland with 977,488 person-years of follow-up

Fig. 3

Anti-allergic medication following treatment with acid-inhibiting drugs and controls. Kaplan–Meier plots of the cumulative proportion without subsequent first anti-allergic medication for those with an acid-inhibiting drug prescription and the contrast group of those with an anti-hypertensive or lipid-modifying drug (C09/C10) prescription