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expert reaction to study looking at prescription acid-reducing medicines (proton-pump inhibitors, PPIs) and allergies

Research, published in Nature Communications, reports that the taking of prescribed acid-reducing medications is linked to an increased risk of developing allergies.

 

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This paper, based on the health records of a large number of patients in Austria finds an ‘epidemiological’ association between prescription of drugs called proton-pump inhibitors (PPIs), which reduce gastric irritation, and the subsequent prescription of anti-allergic drugs.  The design of this study means it cannot show that PPIs cause allergies themselves.  There are many possible explanations for the observed association, so the title of the paper when it says ‘infer’, which suggests a causal relation, is at the very least misleading.

“In fact, the data make other explanations more than likely to be the cause of allergies.

“The authors note that PPIs are very often co-prescribed with aspirin or similar drugs known as Non-steroidal anti-inflammatory drugs (NSAIDs).  Aspirin and NSAIDs are among the drugs that are very well known to increase the risk of an allergic reaction.  It would seem that the authors might not have made adequate allowance for this co-prescription, so the conclusions they draw may not be correct.  Their data show that anti-allergic medicines are prescribed at a relatively similar rate at all ages, while PPI medications show a sharp rise in the elderly.  They show that some drugs for heart disease also have a similar age pattern with PPIs without having an association with anti-allergic medicines, but they do not do the same for NSAIDs.  If the rate of prescription of PPIs shows a steep rise with age and they are a significant cause of allergies, then the anti-allergy medicines (AAMs) should also show a steep rise with age.  The fact that they don’t, either means they show no relation or that any relation has a minimal effect on allergies.

“Nearly all drugs can have very rare allergic reactions, including PPIs, but this paper does not help to show what the true rate is of these very rare reactions, or whether they are caused by PPIs alone.  The design and analysis methods in the paper are likely to exaggerate their apparent occurrence.”

 

Prof Sir Munir Pirmohamed, David Weatherall Chair of Medicine and NHS Chair of Pharmacogenetics, and Director of the MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, University of Liverpool, said:

“Jordakieva and colleagues have used a claims database in Austria to show that the prescription of anti-ulcer medications was associated with an increased likelihood of having a subsequent prescription for anti-allergy medication.  The strengths of the study include the use of a large population database, inclusion of different drugs known to inhibit gastric acid suppression, a possible association with doses used per year, and biological plausibility.

“However, the conclusion is based on using the prescription of anti-allergy medications in patients taking anti-ulcer drugs as a proxy for allergic disease.  This is a limitation, and it would have been better to have the actual diagnosis of the types of allergies in patients given the anti-allergy drugs.

“The authors were not able to control for all confounding factors (which is a major problem for epidemiological studies such as this), and in particular, the authors did not have any information on the other diseases and conditions patients had, or on other drugs which were given to the patients.  It is also surprising that the potency of the anti-ulcer drug did not have a major impact on the incidence of allergic disease.

“Therefore, the finding of this study shows an association but does not prove causation.  Further work in other databases, where there are data on the patients’ other conditions, is required to validate this finding.

“Despite the limitations, there is an important message here: commonly used drugs such as anti-ulcer medicines can have unforeseen adverse effects, and these drugs should only be used where there is a clinical need, and for the shortest duration possible, and at the lowest dose necessary to control symptoms.  It is known that many drugs that are prescribed are never stopped even though the patient’s symptoms may have improved, or the disease cured.”

 

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This is an observational study – that is, the researchers did not allocate people to be treated with the drugs involved, but instead observed the patterns of prescriptions that had occurred without any research interventions.  With all observational studies, one has to be careful about concluding what might cause what effect, and this is no exception.

“The underlying problem is that there are likely to be many differences between people who were prescribed drugs to reduce stomach acid, and people who did not have such a prescription, apart from whether they were prescribed these drugs.  And any of these other differences might be the real reason for differences in prescription of anti-allergy drugs later, rather than the prescription of acid-reducing drugs.  The researchers were able to account for any differences in the participants’ patterns of age and gender, and they found associations between prescriptions of acid-reducing drugs and later prescriptions of anti-allergy drugs in both genders and all ages (though the strength of these associations differed between the genders and age groups).  But they did not have the data to make much investigation of other differences.

“One aspect of the research findings does indicate how important these other differences might be.  The researchers report results for the whole of Austria, and also, separately, for just one single region of the country, Burgenland.  The strengths of association between prescriptions of the two types of drug, overall and separately by gender and age group, are quite a lot different for Burgenland than for the whole of Austria.  For example, overall, in the whole of the country taken together, people who had been prescribed gastric acid inhibitors were twice as like to be prescribed an anti-allergy medication later, compared to those who had not had the acid inhibitors.  But in Burgenland, the association was much stronger – there, those prescribed acid inhibitors were three times as likely to be prescribed the anti-allergy drugs as those in Burgenland who had not had the acid inhibitors.  Three times compared to twice is a pretty substantial difference in strength of association.  In contrast, the association for older people (60 and over) was only half as strong in Burgenland as in the country overall.  I can’t see any good reason for these differences unless there are fairly substantial differences between Burgenland and the rest of the country in other factors related to prescription of gastric acid inhibitors and/or anti-allergy drugs.  And if such factors exist and adjustments could not be made for them, this make it very difficult to establish what causes what.

“One possibility that the researchers do mention is that there might be some long-term underlying diseases that produce both symptoms related to stomach acid and to allergies, so that it might be the presence of such a disease that makes anti-allergy prescriptions more likely in people who previously took a gastric acid inhibitor, and not any direct effect of the acid inhibitor itself.  But they also say that they could not investigate this possibility in much detail, because they did not have access to the relevant data.  Perhaps more light could have been thrown on this possibility if they had been able to look at the association in the other direction, that is, to see how rates of prescription of gastric acid inhibitors were associated with previous prescription of anti-allergy drugs.”

 

Prof Saad Shakir, Director, Drug Safety Research Unit (DSRU), said:

“This study is a hypothesis testing study.  The acid produced by the stomach for digestion provides a defence barrier for the body against a range of ingested exogenous substances.  Medications that suppress acid production by the stomach are very widely used for clear or unclear reasons.  They weaken this defence mechanism so that many substances can go beyond the stomach.  Some of these can cause infection and possibly allergy.  It is important to note this study is looking at prescribed medicines – not over-the-counter antacids, which are different.

“This study is a large observational drug utilisation study from Austria, which used the prescribing of anti-allergy medications after the intake of acid suppressing drugs as a surrogate marker for the development of allergic symptoms – so it didn’t measure allergies themselves.  But this is a reasonable approximation.

“The study found that the use of prescription anti-allergy medications compared to other groups of drugs was higher after patients have taken acid suppressing drugs.

“Given that this study used only prescribing patterns to examine the question, it has limitations acknowledged by the authors, e.g. they don’t know what other medical conditions the patients had.

“Considering its strengths and weaknesses this study does not provide a definitive answer to the question, however, it strengthens the hypothesis regarding the association between taking acid suppressants and the development of allergic symptoms.  Therefore, it raises the need for a more definitive study to answer the question.  A study producing a definitive answer will lead to clear and specific guidance for clinic decisions regarding the use of acid suppressing drugs.  Such a study will be important because of the very wide use of these prescription acid suppressing drugs.

“In the meantime, this study is not definitive but adds to the body of evidence that supports less indiscriminate use of prescribed acid suppressants, and that healthcare professionals should ensure that the indication, strength of acid suppressants used and the duration of their usage are appropriate for the patients’ clinical needs.”

 

* ‘Country-wide medical records infer increased allergy risk of gastric acid inhibition’ by Galateja Jordakieva et al. was published in Nature Communications at 16:00 UK time on Tuesday 30 July 2019. 

DOI: 10.1038/s41467-019-10914-6

 

Declared interests

Prof Stephen Evans: “No conflicts of interest.”

Prof Sir Munir Pirmohamed: “I have no conflicts of interest to declare.”

Prof Kevin McConway: “Prof McConway is a member of the SMC Advisory Committee, but his quote above is in his capacity as a professional statistician.”

Prof Saad Shakir: “I have no specific conflict of interest.”

 

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