CME / ABIM MOC / CE

Does Gastric Inhibition Increase Allergy Risk?

Authors: News Author: Nicola M. Parry, DVM; CME Author: Laurie Barclay, MD Faculty
and Disclosures
CME / ABIM MOC / CE Released: 9/13/2019
Valid for credit through: 9/13/2020

Clinical Context

In mechanistic animal experiments and observational human studies, gastric acid suppression
appears to promote allergy. Proton-pump inhibitor (PPI) medications that suppress gastric
acid can impair pH-dependent pepsin activation for protein digestion, allowing the persisting
allergenic epitopes to trigger de novo sensitization via the intestinal mucosa, and lead to
specific immunoglobulin E responses toward oral antigens, including nutritional proteins and
medications.

At a population level, however, it is still undetermined whether use of gastric acid inhibitors
is associated with increased allergy incidence. The goal of this study, using data from health
insurance records covering 97% of the Austrian population, was to examine the use of
antiallergic medication after prescription of gastric acid inhibitors.

Study Synopsis and Perspective

Patients receiving gastric acid-inhibiting drugs may be at an increased risk of developing

allergies, a study published online July 30 in Nature Communications has suggested.

"[W]e observed a highly significant increase in prescription of drugs relieving allergic

symptoms in patients who were on treatment with gastric acid inhibitors of any class," write
Galateja Jordakieva, PhD, from the Medical University of Vienna, Austria, and colleagues.

Because of their efficacy and seemingly favorable safety profile, physicians commonly
overprescribe PPIs, and patients commonly overuse them as a result of the over-the-counter
availability of these drugs.

Because of this, an increasing number of studies have demonstrated serious adverse events
associated with long-term use and overuse of these drugs. These include increased risk for
osteoporotic fractures, Clostridium difficile or other gastrointestinal infections, and
pneumonia.

Studies have also begun to suggest that use of gastric acid inhibitors may trigger development
of allergies.

Dr Jordakieva and colleagues conducted a population-based study to investigate patients' use

of antiallergic medication after prescription of gastric acid inhibitors.
They examined health insurance claims information for between 8.1 million and 8.3 million
people (approximately 97% of the population) in Austria between 2009 and 2013. This
included more comprehensive regional data from a single Austrian county for which
information was also available for a control group of individuals who had received
prescriptions for antihypertensive and/or lipid-modifying drugs.

The researchers included any prescription for a gastric acid-inhibiting drug (eg, PPIs,
sucralfate, H2-receptor antagonists, or prostaglandin E2) and/or any prescription for an
antiallergic medication (eg, antihistamines or specific allergen immunotherapy).

Patients in the general population who were prescribed gastric acid inhibitors were almost
twice as likely to later receive prescriptions for an antiallergic medication than were nonusers
of gastric acid inhibitors (prescription rate ratio [RR], 1.96; 95% confidence interval [CI],
1.95-1.97).

This rate was even higher among patients in the regional Austrian data set, who were at least
3 times as likely to receive prescriptions for an antiallergic medication after receiving gastric
acid inhibitors (prescription RR, 3.07; 95% CI, 2.89-3.27).

Overall, the prescription RR was increased for all classes of gastric acid inhibitors analyzed,
except for prostaglandin E2, which was too infrequently prescribed for data to be conclusive.

However, the RR was higher among women than men (2.10 vs 1.70; P<.001).

There was also an age trend among all patients, with RRs rising from 1.47 (95% CI, 1.45-
1.49) in individuals up to 20 years of age to 5.20 (95% CI, 5.15-5.25) for those older than 60
years.

As few as 6 doses of gastric acid inhibitors each year were associated with a greater chance
of being prescribed an antiallergic medication.

In addition, when patients were grouped into quartiles based on daily doses per year of gastric
acid inhibitors, analysis showed that cumulative exposure to these inhibitors also increased
the risk of receiving antiallergic medications.

For example, for patients receiving up to 20 daily doses per year (first quartile), the hazard
rate was 1.28 (95% CI, 1.18-1.39). This rose to 2.67 (95% CI, 2.47-2.88) for those receiving
68 to 213 daily doses per year (third quartile). The effect seemed to plateau at this level, with
a hazard ratio of 2.57 (95% CI, 2.38-2.78) for patients receiving more than 213 daily doses
per year (fourth quartile).

Because the link to prescribing of antiallergic medication was found with most of the classes
of gastric acid inhibitors analyzed in the study, the authors conclude the underlying
mechanism may relate to regulation of gastric pH, rather than to the specific mode of action
of a particular drug.

These results add to the growing body of evidence that links use of gastric acid inhibitors to
allergy risk.
 "Our findings confirm an epidemiological association between gastric acid suppression and
development of allergic symptoms, in line with previous mechanistic animal trials and human
observational studies," Dr Jordakieva and colleagues conclude.

This study was supported by the Burgenländische Gebietskrankenkasse and the Austrian
Science Fund. The authors have disclosed no relevant financial relationships.

Nat Commun. Published online July 30, 2019.

Study Highlights

 The source of data for this analysis was health insurance records covering 97% of the
Austrian population between 2009 and 2013.
 The investigators studied prescriptions of gastric acid inhibitors and antiallergy drugs,
as well as other commonly prescribed lipid-modifying and antihypertensive drugs as controls.
 Gastric acid-inhibiting drug prescriptions were associated with 2 to 3 times the risk
for subsequently receiving antiallergy prescriptions.
 RRs were 1.96 (95% CI, 1.95-1.97) in the overall Austrian population and 3.07 (95%
CI, 2.89-3.27) in a regional Austrian data set, comparing the prescription frequency of
antiallergic medication in patients previously treated with acid-inhibiting drugs with those
who had received commonly used antihypertensive or lipid-modifying medications.
 The association occurred across all measured gastric acid-inhibiting drugs of any class
(PPI, sucralfate, H2-receptor antagonists, prostaglandin E2), but prevalence of antiallergic
drug use was significantly higher after prescription of sucralfate, which is a sucrose sulfate
aluminum salt.
 The association was also stronger in women than in men (RR, 2.10 vs 1.70; P<.001),
and was age-dependent, with RRs increasing from 1.47 (95% CI, 1.45-1.49) in subjects 
younger than 20 years to 5.20 (95% CI, 5.15-5.25) in those older than 60 years.
 Daily acid inhibitor drug doses per year were associated with a clear increase in
hazard ratios, plateauing above the third quartile.
 However, risk for subsequent use of antiallergy medication was increased with as few
as 6 daily doses per year.
 Hazard ratios were 1.28 (95% CI, 1.18-1.39) for <20 daily doses per year (first
quartile), 2.67 (95% CI, 2.47-2.88) for 68 to 213 daily doses per year (third quartile), and
2.57 (95% CI, 2.38-2.78) in the fourth quartile (>213 daily doses per year).
 On the basis of their findings, the investigators concluded that there was an
epidemiologic relationship between gastric acid suppression and development of allergy
symptoms, consistent with previous mechanistic animal trials and human observational
studies.
 These database findings support the emerging concerns regarding use of antacid drugs
in adults, and especially in pregnant women.
 Clinicians may overprescribe PPIs because of their efficacy and relative safety, and
patients may overuse them because of their over-the-counter availability.
 However, long-term use and overuse of these medications may result in serious
adverse events including increased risk for osteoporotic fractures, C difficile or other
gastrointestinal infections, and/or pneumonia.
 The greater likelihood that women vs men will receive antiallergic medication, overall
as well as after the use of acid inhibitors, may reflect the female dominance in
immunoglobulin E-mediated allergies.
 The association between acid-suppressing and antiallergy medications showed a
steady risk elevation with increasing age, despite the typically higher prescription rates of
antiallergy medication in younger patients.
 In a geriatric cohort, use of acid inhibitors was shown to be linked to elevated
immunoglobulin E and ST2 levels, which may reflect Th2 helper T-cell responses.
 Because all analyzed acid inhibitor drug classes were associated with increased
prescription rates for antiallergy medication, the underlying mechanism appears to be gastric
pH modulation in general, rather than any particular drug-specific mode of action.
 The significantly higher prevalence of antiallergy medication use after sucralfate
prescription may be related to this drug's action as aTh2 adjuvant, similar to that of other
aluminum compounds.
 A partial explanation for the association may include antihistamine prescriptions for
allergic responses to the antiulcer or hypertensive/lipid-modifying drugs themselves, although
such reactions are uncommon.
 Because as few as 6 daily doses per year increased risk for subsequent antiallergy
medication use, the underlying effect occurs early on after first use of acid inhibitors, despite
the cumulative dose-response relationship of antiallergy prescription with acid-inhibitor
prescription.
 An observational study in human adults showed that antiulcer drugs can boost
preexisting specificities and induce new immunoglobulin E specificities.
 Elevation of gastric pH hinders protein degradation, so that otherwise labile and
harmless nutritional proteins persist during gastrointestinal transit, increasing their allergenic
potential.
 Antiulcer drugs may also directly promote allergic symptoms via immune bias of
adaptive cellular responses to oral antigens, but also via innate and adjuvant effects of the
drugs themselves, and by changes in gut microbiome skewing Th2 cell activity into a pro-
allergenic state.
 Study limitations include exclusion of corticosteroids and other related drug classes as
antiallergy medication; inability to monitor actual medication intake frequency and duration;
lack of access to individual data such as comorbidities, diagnoses, and other prescriptions;
and specific adverse effects and absolute contraindications for the control medications that
could introduce bias.
 An additional source of bias could be that people with acid inhibitor prescriptions are
generally more likely to receive any medication.

Clinical Implications

 An Austrian population database study showed an epidemiologic relationship between

gastric acid suppression and development of allergy symptoms, consistent with previous
mechanistic animal trials and human observational studies.
 These database findings support the emerging concerns regarding use of antacid drugs
in adults, and especially in pregnant women.
 Implications for the Healthcare Team: Clinicians may overprescribe PPIs because of
their efficacy and safety, and patients may overuse them because of their over-the-counter
availability, but long-term use and overuse of these medications may result in serious adverse
events.