Allergy

REVIEW ARTICLE

Anti-acid medication as a risk factor for food allergy

I. Pali-Schöll & E. Jensen-Jarolim
IPA – Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University
Vienna, Vienna, Austria

To cite this article: Pali-Schöll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011; 66: 469–477.

Keywords Abstract
acid suppression; anti-ulcer drugs; food
allergy; gastric pH; oral sensitization.
An important feature for oral allergens is their digestion-resistance during gastroin-
testinal transit. For some oral allergens, digestion stability is an innate feature,
Correspondence whereas digestion-labile antigens may only persist in times of impairment of the
Prof. Erika Jensen-Jarolim, MD, IPA – digestive system. In this review, we collect evidence from mouse and human studies
Institute of Pathophysiology and Allergy that besides the inherent molecular characteristics of a food protein, the stomach
Research, Center of Pathophysiology, function is decisive for the allergenic potential. Gastric acid levels determine the
Infectiology and Immunology, Medical activation of gastric pepsin and also the release of pancreatic enzymes. When anti-
University Vienna, Waehringer Guertel ulcer drugs inhibit or neutralize gastric acid, they allow persistence of intact food
18-20, 1090 Vienna, Austria. allergens and protein-bound oral drugs with enhanced capacity to sensitize and elicit
Tel.: +43 (01) 40400 5110 allergic reactions via the oral route. Mouse studies further suggest that maternal
Fax: +43 (01) 40400 5130 food allergy arising from co-application of a food protein with anti-acid drugs
E-mail: erika.jensen-jarolim@ results in a Th2-biased immune response in the offspring. Especially, anti-ulcer
meduniwien.ac.at drugs containing aluminum compounds act as Th2 adjuvants. Proton pump inhibi-
tors act on proton secretion but also on expression of the morphogen Sonic hedge-
Accepted for publication 21 October 2010 hog, which has been related to the development of atrophic gastritis. On the other
hand, atrophic gastritis and resulting hypoacidity have previously been correlated
DOI:10.1111/j.1398-9995.2010.02511.x
with enhanced sensitization risk to food allergens in elderly patients. In summary,
impairment of gastric function is a documented risk factor for sensitization against
Edited by: Hans-Uwe Simon
oral proteins and drugs.

two possibilities of sensitization: (i) indirectly, when respira-

Food allergies and intolerances – the basics
tory allergens lead to induction of IgE that is cross-reactive
Approximately 1.8–3.3% of the young adult population with food proteins, or (ii) directly, when oral sensitization
(aged 18–39 years) in industrialized countries like Denmark and IgE induction occur via the gastrointestinal mucosa. As
(1), France (2), or Germany (3) suffer from immunologically a consequence, effector cells like mast cells and eosinophils
mediated adverse reactions to food, i.e. food allergies. How- get armed by IgE, thus ready to release mediators when the
ever, a recent study of the European Community Respiratory relevant food allergen is ingested subsequently. This may lead
Health Survey (ECRHS) found even higher numbers, with to mild up to severe immediate-type symptoms. For yet
positive allergen-specific IgE to any of 24 tested food aller- unknown reasons, the same patient may react toward food
gens in 7–24% of a young adult population aged from 20 to allergens to different extents at different time points of life.
39 years in different countries of Western Europe, the USA, Today, consequent avoidance of allergen exposure is the
and Australia (4). Furthermore, 6–8% of children younger only option for food-allergic patients because no causative
than 3 years are affected in the USA (5, 6). therapies are available yet. Therefore, much focus is given on
In these patients, sensitization occurs in a ‘silent way’, i.e. the development of methods to predict allergenicity of
without symptoms, and leads to IgE formation and specific proteins or to trace allergens in food. A multidisciplinary
hypersensitivity against the offending food. There are at least International Workshop held in May 2007 focused on risk
assessment and safety assessment for allergenic foods and
Abbreviations concluded that three possible approaches should be consid-
GERD, gastro-esophageal reflux disease; H2RA, H2-receptor ered to protect consumers from potentially hazardous
antagonist; HP, Helicobacter pylori; LOAEL, lowest observed reactions: (i) safety assessment using no observed adverse
adverse effect level; NOAEL, no observed adverse effect level; effect level (NOAEL)/lowest observed adverse effect level
PPI, proton pump inhibitor. (LOAEL) and uncertainty factors; (ii) safety assessment using

Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 469
Anti-acid medication as a risk factor for food allergy Pali-Schöll and Jensen-Jarolim

Benchmark Dose and Margin of Exposure (MoE); and (iii) Several important questions still remain open: Which are
risk assessment using probabilistic models (7). the first cells responsible for sensitization to oral allergens
Regarding the in vitro safety assessment, different food and turning on the IgE program? Why are some persons
processing methods have been recognized to result in differ- going to develop allergy, independent of atopic or nonatopic
ent impacts on stability and/or allergenicity of different foods genetic background, whereas others being exposed toward
[reviewed in (8)]. Some processes were shown to enhance the same type of food will not? Which factors determine the
either the IgE-binding capacity, the digestion stability, or the threshold of food allergens leading to symptoms in the same
skin prick test reactivity to food proteins, for instance roast- patient at different time points? Why are some proteins able
ing of peanuts (9); pasteurization of milk (10); or smoking of to sensitize via the oral route although they are obviously
fish (11). However, there are also studies showing that some easily digested by gastric proteases?
treatments of food can reduce its capacity to induce allergic
reactions, for instance the simple addition of vinegar to
Physiological fate of food proteins during digestion
extracts of boiled chicken meat, eggs, or lentils decreased
their capacity to induce positive reactions in skin prick test Resistance to gastrointestinal digestion has been proposed as
and oral provocation test, as well as IgE-binding in immuno- one dominant feature of food allergens (24). This cognition
blotting experiments, indicating that some allergens may led to the development of so-called in vitro digestion assays
already be disarmed by low pH (12). Also, technological using simulated gastric fluid as part of food safety tests (25).
treatment like homogenization of bovine or ovine meat can Some working groups have tried to come closer to the in vivo
reduce the skin prick test reactivity in allergic patients (13). situation by combining gastric and intestinal digestion in
Additionally, formation of aggregates or multimers may in vitro models (26, 27); by imitating and comparing the adult
influence the immunogenicity/allergenicity of antigens (14). vs the infant digestion situation in vitro (26); or by using
The occurrence of dimers and/or multimers was shown to so-called dynamic models of digestion (28), which mimic not
enhance immunogenicity as well as allergenicity of aeroaller- only the influence of digestive enzymes, but also the physical
gens (14) and food allergens (10). Multimers can also arise processes and temporal changes in conditions of the stomach
during cross-linking processes, accomplished for instance by and the lumen of the small intestine, like hydration, mixing,
the enzyme tissue transglutaminase in the gastrointestinal shear forces, transport, and delivery [reviewed in (27)].
tract, which gets activated under stress-like conditions like However, resistance to gastrointestinal digestion is not an
exercise, inflammation, etc. This cross-linking process involves innate characteristic to all food proteins, and some authors
glutamine residues, for instance present in gliadins of wheat, have even concluded that missing stability to digestion may
and leads to enhanced IgE-binding and skin prick test reac- speak for a minor importance of proteins as allergens. Exam-
tivity to the high-molecular weight complexes formed (15). ples are glycinin and Ara h 3 from soybean and peanut,
Furthermore, the food matrix might play a role in the determi- respectively, of which the authors concluded that due to their
nation of allergenicity, as for instance most allergic patients sensitivity to peptic digestion, they may not be such impor-
tolerate egg and milk, respectively, when heated/baked with tant food allergens (29), although these proteins were previ-
wheat (16, 17). Another factor determining the allergenicity ously described as major allergens in these legumes (30, 31).
outcome could be the fat content of the food stuff, as a higher The hindrance of normal digestion of these allergens because
fat content of the vehicle also led to tolerance of higher aller- of some external influence factors, however, has not been
gen amounts in peanut-provoked patients (18). Similarly, the implicated in their allergenicity.
presence of different plant polysaccharides used in food indus- From a physiological point of view, the gastric digestive
try, such as xylan, pectin, and gum arabicum, was shown to system uses pH shifts to control the activity state of proteases
change/reduce the IgE-binding capacity of digested peanut and as a means to protect the mucosa against autodigestion.
proteins (19) or heated milk-protein beta-lactoglobulin (20). Gastric propepsin is activated to become pepsin by cleavage
The search for common food allergen characteristics is, of a peptide, which is produced exclusively at low pH (32,
however, unsatisfactory yet, even if a limited number of 33). Hunger, appetite, or ingestion enhance gastric acid
proteins seem to be relevant for sensitization (21, 22): only production from parietal cells in the stomach and lead to
eight foods/food groups, namely crustacean, eggs, fish, milk, propepsin release from gastric chief cells, protease activation,
peanuts, soybeans, tree nuts, and wheat account for 90% of and finally peptic protein digestion. Further transit of the
food-allergic reactions (23). Accordingly, in the above-men- acidic chymus to the duodenum leads to stimulation of the
tioned ECRHS study of young adults, the most frequent pancreas to release alkaline secrets containing the classical
sensitizers were found to be hazelnut, peach, shrimp, and pancreas proteases trypsin, chymotrypsin, and carboxypeptid-
wheat (4). Importantly, this top list still remained true when ases. However, this releasing process is dependent on the acti-
birch pollen positive patients were excluded, which means vation of secretin, a hormone detected in 1902 by Bayliss and
that the high number of reactions to hazelnut and peach Starling (34). This substance is synthesized in cytoplasmic
(cross-reactive food allergens to birch pollen) cannot solely secretory granules of S-cells, especially present in the mucosa
present cross-reactive food intolerance. In contrast, no of the duodenum and less numerous in the first portion of
wheat-sensitized individuals remained when the group of rye the jejunum (35). Importantly, the release of secretin into
grass allergic patients was excluded in the Australian cohort plasma and/or the lumen of the intestine is dependent on low
of this study. duodenal pH (between 4 and 4.5) (36, 37). This low pH

470 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
Pali-Schöll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy

usually stems from the acidic chyme of the stomach (38), mucosal barrier function, are reached at an age of approxi-
although digested products of fat and protein, bile acids, and mately 2 years only [reviewed in (51)]. For example, the
some herbal extracts have also been shown to release secretin output of pepsin/kilogram body weight per hour was found to
(39). There has been some controversy on this dependency of be 1/15 of the adult levels on the first day of life (52) and
secretin release on low pH in early times after secretin detec- would only be roughly comparable to that of adults in the
tion (40); however, according to more recent work, actually second year of life (53). Similarly, the mean acid output in
the acid in the duodenum appears to be the major stimulant 21-month-old children after histamine stimulation was found
of secretin release (39, 41). to be only 50% of that observed in adults and is roughly
This means that low gastric acid pH is crucial for activa- similar to adult levels only by the end of the second year of
tion and liberation of gastric and pancreatic proteases. In life (54, 55). Therefore, peptic digestion may not be complete
concert, these enzymes degrade proteins to small nutritionally during early life, and protein remnants of the diet could act
valuable peptones and peptides, which optimally are ignored as allergens. Together, these facts may contribute to the
by the immune system or lead to tolerance. This implicates higher incidences of food allergies in children.
that the functional acidic stomach has a protective function Food allergies in adults have been observed at any age,
against many digestion-labile proteins, which otherwise could and thus novel sensitization principally may occur at any
present antigens or even allergens. point of time. There are different scenarios when the stom-
The low pH in the gastrointestinal tract is also important ach’s acid and pepsin production and thus protective func-
to minimize the risk of intestinal infections (42, 43). In line tion could be disturbed in adults. Hypochlorhydria or
with this, it has been observed that bactericidal activity in the achlorhydria can be due to chronic atrophic gastritis. Inter-
stomach is given when the pH is below 3.0, in contrast, bac- estingly, the other way round, it was shown that the loss of
terial overgrowth (e.g. Clostridium difficile, Campylobacter parietal cell function is preceding the development of gastric
jejuni, Salmonella spp.) occurs during hypochlorhydria at pH atrophy. Owing to parietal cell loss, hydrochloric acid is
above 4.0 (43–45). The consequence of this colonization due missing, and this results in the negative fate of other cell
to breakdown of the ‘gastric bactericidal barrier’ (42, 45) is lineages in the stomach leading to atrophic gastritis (56). In
diarrhea, and actually this symptom was found to be associ- parallel, the expression of the morphogen called Sonic hedge-
ated with the usage of proton pump inhibitor (PPI) as the hog (Shh) correlated with atrophic gastritis and metaplasia in
second-most important reason after the usage of antibiotics the intestine (57). It was further shown that Shh expression
(46). Vice versa, babies aged between 1–12 months with and signaling depends on gastrin levels and gastric acidity, as
chronic diarrhea presented with increased gastric pH (mean the omeprazole-induced hypoacidity inhibited the cleavage
pH above 4.0 in about 57%) (47). However, to complete the of the precursor protein of Shh. This cleavage is mediated by
picture, one has to mention that also breast-fed babies were the protease pepsin A, which is acid-dependent (58). Omepra-
shown to have an increased gastric pH (mean pH around zole furthermore reduced the expression of Shh mRNA
4.0), but there was no bacterial overgrowth of gram-negative (59). Loss of Shh expression, however, is not the outcome of
bacilli and no diarrhea, an observation that may be related loss of glandular cells but is preceding it, although not neces-
to the transfer of protective factors (e.g. lysozyme, lacto- sarily being causative for parietal cell loss. Nevertheless, loss
ferrin, IgA antibodies) by the mother’s milk. Underlining the of Shh may be involved in hypochlorhydria and hyperg-
bactericidal barrier function of the stomach, in young gastro- astrinemia with subsequent morphological changes and loss
esophageal reflux disease (GERD)-affected children, aged of sensitivity to histamine-regulated acid secretion (60). Sum-
4–36 months, who were treated either with ranitidine [H2- ming up these recent data, Shh is responsible for parietal cell
receptor antagonist (H2RA)] or omeprazole (PPI) for function, the loss of it leads to hypochlorhydria and hyperg-
8 weeks, an enhanced risk for acute gastroenteritis and astrinemia, resulting in atrophic gastritis (61). The circle
community-acquired pneumonia was detected, although chil- closes as Shh is acid-dependent and therefore could be
dren were healthy otherwise (42). These risks even sustained reduced/inhibited by acid-suppressing drugs. Based on these
after ending the therapy. facts, we hypothesize that the treatment for atrophic gastritis
with acid-suppressing drugs (see below) may in fact accelerate
the disease. Actually, studies have shown that all patients on
Physiological situations and pathophysiological events
long-term treatment with PPIs develop hypergastrinemia (as
leading to impaired digestion
is the case during any situation with lowered gastric acid
One population group who often presents with enhanced secretion) (62); however, other authors have attributed the
gastric pH (pH > 4.0 for 80–90% of time) are preterm born main reason for atrophic gastritis to Helicobacter pylori (HP)
infants, the acidity in these children only rising with age (48). infection and dismissed the contribution of PPIs (63).
In full-term infants, the acidity in the stomach changes Achlorhydria may be frequently found in older people
during the first hours and days of life: starting with a median (32.4% in subjects aged 74–80 years) (64); in context with
pH of about 6.1, it decreases to a median pH of 2.2 after 6 h chronic alcohol consumption (65); or during acute (66, 67);
of age (49). However, after this initial low pH, there occurs a or chronic gastric infection (68). In addition, low gastric acid-
loss of acidity for 10 day (pH increases), and thereafter pH ity, for instance due to atrophic gastritis, represents an
only slightly goes down again (50). Adult values of gastric enhanced risk for oral infection e.g. elderly people are more
pH, as well as the full digestive capacity and the complete likely to be infected with HP (69). Other diseases with

Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 471
Anti-acid medication as a risk factor for food allergy Pali-Schöll and Jensen-Jarolim

reduced acid production are chronic renal failure (70) and much higher (80), also digestion-labile food proteins might
gastric ulcer (in contrast to duodenal ulcer), where patients acquire allergenic potency (Fig. 1).
may present with decreased basal and stimulated acid pro-
duction (71). Also, resections and bypasses of the stomach,
From a case of caviar allergy to a novel mouse model
including bariatric surgery, cause achlorhydria (72).
of food allergy
More importantly, inhibition or neutralization of gastric
acid with so-called anti-ulcer drugs is performed when treat- Our work was originally triggered by a case of Beluga caviar
ing gastritis and peptic ulcers. The therapy goal is to reach allergy (81) occurring in a patient suffering from chronic
gastric pH levels above 4.5 (73), also for children (74), or ulcer and constantly taking PPIs during years. The patient
even above 6.0 for treating bleeding peptic ulcers (75). Avoid- noted specific sensitization several years after the first caviar
ance of acid is needed in these therapies to stop autodigestive consumption when experiencing anaphylactic episodes. As
processes and support mucosal healing in the extreme caviar consumption usually is a rare event, he remembered
environment of the gastric lumen. Long-term treatments with that the first time eating caviar happened during treatments
steroidal and nonsteroidal anti-inflammatory drugs are with PPIs.
associated with gastric mucosal damage for various pharma- We imitated this case in an animal study and fed mice with
cological reasons. Therefore, anti-ulcer drugs are also co-pre- caviar (82). Only those groups that were additionally treated
scribed during these treatments to protect the gastric mucosa. with sucralfate, H2 receptor blockers, or PPIs developed an
Several classes of medications are available for these pur- allergic phenotype consisting of specific IgE and positive
poses: PPIs already mentioned above; H2RA; sucralfate; and immediate-type skin tests. Subsequently, we repeated the
acid neutralizers like bismuth compounds. Our in vitro diges- experiments with other types of allergens, like parvalbumin
tion assays have indicated that already at pH 2.75–3.0 pepsin from fish (82), hazelnut (83), and recently ovalbumin (84)
is no longer fully activated (76, 77). The work of Tanaka and and peanut (unpublished). In these novel animal models of
colleagues also underlines this observation, as the activation food allergy, we also found dense infiltration with eosinophils
of pepsins optimally occurs at pH 1.0–3.5 and at higher pH in the gastric mucosa (85), which may support IgE produc-
drops significantly (78, 79). As a consequence, peptic diges- tion via IL-4 secretion. Furthermore, the morphology and
tion is significantly hampered. This implies that during immunologic setting of the gastrointestinal tract was altered
medications with anti-ulcer drugs, when pH values even get in animals that received sucralfate along with the allergen, as

A B C
Physiology Pathophysiology Pathophysiology
Digestion-susceptible antigens Digestion-susceptible antigens Digestion-resistant antigens
Prototype: Bet v 1-homologues in edible plants Prototype: parvalbumin from fish Prototype: Ara h 2 from peanut

Stomach: acidic pH Stomach: non-acidic pH Stomach: acidic pH

=> Pepsin activated => Pepsin not activated => Pepsin activated
=> Protein digestion I. => Protein persists I. => Protein resists I.

Duodenum: Duodenum: Duodenum:

=> Acidic chyme => Alkaline chyme => Acidic chyme
=> Secretin release => No secretin release => Secretin release
=> Release of pancreatic enzymes => No release of pancreatic enzymes => Release of pancreatic enzymes
=> Protein digestion II. => Protein persists II. => Protein resists II.

Immune response: Immune response: Immune response:

tolerance/ignorance *sensitization *sensitization
*allergic symptoms at *allergic symptoms at
low threshold levels low threshold levels

Figure 1 The fate of a food protein depends on its intrinsic stabil- ished activation of pepsin. The elevated pH of the chyme subse-
ity and/or the gastric acidity level at the time point of ingestion. (A) quently prevents the release of duodenal secretin resulting in
Proteins homologous to Bet v 1 from birch pollen are easily impaired pancreatic digestive function. Persisting protein remnants
degraded. They cause oral, but rarely systemic reactions because are then able to induce an (allergic) immune response. (C) Sensiti-
in degraded form they are ignored or tolerated by the immune sys- zation against digestion-stable food proteins/oral antigens like Ara h
tem. (B) Digestion-labile proteins, like parvalbumin from codfish, 2 occurs independently of the gastric acid condition because of
may become allergenic when digestion is inhibited. This may occur specific molecular features causing stable tertiary or quaternary
in conditions where the gastric pH is elevated, resulting in dimin- structures of these proteins.

472 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
Pali-Schöll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy

this treatment induced changes in the structure of epithelium response, as the addition of aluminum hydroxide to the
and villi, and an increase in eosinophils and mucus-producing model antigen keyhole limpet hemocyanin (KLH) resulted in
cells in the intestine (86). a clear Th2-response (96) compared with studies where KLH
was used without an adjuvant (97).
Anti-ulcer medications are relevant in human patients
Impaired digestion lowers threshold levels of food
To evaluate the impact of our observations for human
allergens
patients, we designed an observational study of 150 gastroen-
terological patients who were treated during 3 months with In the sensitization phase of allergy, IgE-antibodies are obvi-
anti-ulcer drugs. The data showed that anti-ulcer drugs ously formed against conformational epitopes but not against
indeed supported IgE induction and de novo sensitization smaller peptides, except in persistent allergy. Does this also
against food proteins from the average daily diet (87). The apply for the effector phase when IgE is already formed and
sensitization was clinically relevant and long lasting, as skin fixed to effector cells? We hypothesized that conformationally
prick tests toward specific food allergens remained mostly intact allergens would trigger mediator release much easier,
positive even 5 months after discontinuation of anti-ulcer whereas peptide leftovers should no longer be able to cross-
therapy. As the patients were around 65 years of age, the link IgE, which would have implications in clinics. Indeed,
results indicated that oral sensitization may occur also in when in a clinical study, fish allergic patients were orally
elderly persons. Moreover, we concluded that by the oral exposed to native or in vitro predigested fish, the native pro-
route also established tolerance toward previously well- tein expressed much higher capacity to elicit clinical reactivity
tolerated food can be broken. and positive type I skin test reactions (98). Moreover, in his-
Another important target group for anti-ulcer drugs are tamine release test, the dose of native allergen eliciting posi-
pregnant women. During pregnancy, anti-ulcer drugs are tive reactivity was 10 000 times lower than with predigested
consumed because of heartburn/gastro-esophageal reflux (88), allergen (77). This implies that in settings of impaired diges-
which is caused by hormonal changes leading to reduced tion, lower levels of allergens may be able to induce hyper-
esophageal sphincter pressure (89), and by increasing abdom- sensitivity reactions. These data might finally also explain
inal volume. Whereas in the past modifications of life-style why some food-allergic patients develop symptoms of differ-
and short-term treatments with acid neutralizers were pre- ent intensity at different time points: their actual symptom
ferred (88), also this patient group is treated with highly effi- intensity may depend on the current functional capacity of
cient PPIs today (90). We hypothesized that in this setting, the digestive system. We consider this observation being
sensitization of the mother could predispose the child for clinically important and suggest that a question clarifying
Th2 immune responses. When we fed pregnant mice with fish anti-ulcer drug consumption should be regularly included in
protein in context with anti-ulcer medication, we observed allergologic anamnesis.
not only allergy induced in the mother animal but also a Th2
bias in the offspring (91). This prompted us to suggest that
these treatments in pregnancy might contribute to the Table 1 Undesired effects of different acid-suppressing drugs*
increased numbers of atopic predisposition in babies (92).
Drug/mechanism of drug Side effects
Interestingly, when Dehlink et al. investigated three data sets
from a Swedish birth registry and correlated the allergy/ Antacids/neutralize Diarrhea
asthma incidences of babies with anti-ulcer drug consumption produced acid Constipation
of the mothers, they could confirm our prediction in the Interference with drug
human setting (93). absorption
Renal, metabolic, and
acid-base disturbances
Sucralfate with an aluminum compound acts as
immunostimulant H2-receptor antagonists/ Mental confusion
block histamine receptor 2 Interference with drug
In immunology, aluminum compounds such as Al(OH)3 are and therefore absorption
classically used as Th2 adjuvants. Sucralfate is a hydrous histamine-induced acid Gynecomastia
basic aluminum salt of sucrose octasulfate. Indeed, its adju- production Interstitial nephritis
vant effect could be recently demonstrated in a mouse model Cytochrome P450
(94, 95), where ovalbumin as a less degradable protein was interactions
used as a model allergen and applied together with sucralfate.
Proton pump inhibitors/block Hypergastrinemia
The induced allergen-specific IgE-antibodies as well as IL-4
H+K+-ATPase and Rebound acid
and IL-5 cytokines indicated a Th2 shift when sucralfate was
therefore complete acid hypersecretion
co-applied. Therefore, whereas other antacids and the dietary
production during their Malabsorption
supplement base powder bind and reduce acid only (76), presence Infections
sucralfate additionally acts as immune stimulant (94). It was Drug interactions
further confirmed in a recent study by another working
group that aluminum does also impact the human immune *Modified from (71) and (101).

Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 473
Anti-acid medication as a risk factor for food allergy Pali-Schöll and Jensen-Jarolim

Anti-ulcer drugs as co-medications: role in drug Synopsis

allergy?
Based on in vitro data as well as mouse and human studies, we
Anti-ulcer drugs are useful co-medications to protect propose that anti-ulcer drugs support clinically relevant sensiti-
the mucosa from damage due to steroidal and nonsteroi- zation against oral proteins like food allergens and drugs and
dal drugs. This is especially relevant during long-term possibly favor eosinophilic gastrointestinal inflammation (101).
pain- and anti-inflammatory therapies, for instance in The induced Th2 bias is long lasting, clinically relevant and
management of rheumatoid arthritis or inflammatory bowel transmitted to the offspring during pregnancy. Several immu-
disease. nological mechanisms may be causative: (i) anti-ulcer drugs
A number of these patients develop intolerances to these inhibit peptic digestion and turn harmless food proteins into
drugs. It is apparent that in some incidences, clinical symptoms allergenic molecules, which are able to perform sensitization
are of the immediate-type and mimic antibody-mediated and to elicit allergy at lower threshold levels and (ii) some anti-
hypersensitivity. However, serum tests often remain negative ulcer compounds such as sucralfate exhibit additional Th2
for specific IgE or IgG possibly due to methodological limita- adjuvant function. The patient groups affected are those trea-
tions. Moreover, these drugs are haptens and should act as ted or co-medicated with anti-ulcer drugs to heal or prevent
complete antigens only in context with other proteins. In stud- gastro-esophageal reflux, gastritis, or gastric ulcer. Moreover, a
ies of the pharmacokinetics of oral drugs, the adsorption to high number of patients use anti-acid substances, antacids, or
gastric proteins hindering regular distribution is a well-known dietary supplements – without a prescription of a physician –
phenomenon. Especially, albumin occurring at high levels in on a more or less daily basis to treat heartburn and stomach
gastric juice is a preferred binding partner for oral drugs, for ache. Acid-suppressing drugs are considered safe, with – admit-
instance for the pain killer diclofenac. Thereby, a complete tedly rare- side effects [reviewed in (71) and (102)] (Table 1).
antigen is formed as an intermediate product (99). However, However, to this list, we suggest that ‘Increased risk for sen-
this product is normally digested by pepsin, leading to the sitization against dietary proteins’ and ‘Lowering the food
release of the drug. It was tempting to speculate that a problem allergens levels needed to elicit hypersensitivity reactions in
might arise when anti-ulcer drugs are co-medicated. Exactly, in food-allergic patients’ should be added. Therefore, we question
this setting, the intermediate drug-carrier complexes would over-the-counter sale of anti-ulcer drugs and suggest prescrib-
possibly be able to persist the transit and sensitize the patient. ing them according to strict indications during a therapeuti-
Could this be an explanation for antibody-mediated drug cally useful period of time, especially during pregnancy.
allergy? The answer was found in a BALB/c mouse model
when a drug-albumin conjugate was fed with and without
Acknowledgments
co-medication of the anti-ulcer drugs sucralfate and PPI (100).
Only the group treated with anti-acid drugs developed IgE and Financial support has been obtained by the Hertha Firnberg
IgG1 against diclofenac. Clearly, more studies are needed to stipend T283-B13 and grant SFB1808-B13 of the Austrian
confirm this theory in the human setting. Science Fund (FWF).

References
1. Osterballe M, Mortz CG, Hansen TK, disorders. J Allergy Clin Immunol Pasteurization of milk proteins promotes
Andersen KE, Bindslev-Jensen C. The 1999;103:717–728. allergic sensitization by enhancing uptake
prevalence of food hypersensitivity in 6. Sampson HA, Burks AW. Mechanisms through Peyer’s patches. Allergy
young adults. Pediatr Allergy Immunol of food allergy. Annu Rev Nutr 1996;16: 2008;63:882–890.
2009; 20:686–692. 161–177. 11. Sletten G, Van Do T, Lindvik H, Egaas E,
2. Kanny G, Moneret-Vautrin DA, Flabbee 7. Madsen CB, Hattersley S, Buck J, Gendel Florvaag E. Effects of industrial process-
J, Beaudouin E, Morisset M, Thevenin F. SM, Houben GF, Hourihane JO et al. ing on the immunogenicity of commonly
Population study of food allergy in Approaches to risk assessment in food ingested fish species. Int Arch Allergy
France. J Allergy Clin Immunol allergy: report from a workshop ‘‘develop- Immunol 2010;151:223–236.
2001;108:133–140. ing a framework for assessing the risk 12. Armentia A, Duenas-Laita A, Pineda F,
3. Soost S, Leynaert B, Almqvist C, from allergenic foods’’. Food Chem Toxicol Herrero M, Martin B. Vinegar decreases
Edenharter G, Zuberbier T, Worm M. 2009;47:480–489. allergenic response in lentil and egg food
Risk factors of adverse reactions to 8. Besler M, Steinhart H, Paschke A. Stabil- allergy. Allergol Immunopathol (Madr)
food in German adults. Clin Exp ity of food allergens and allergenicity of 2010;38:74–77.
Allergy 2009;39:1036–1044. processed foods. J Chromatogr B Biomed 13. Fiocchi A, Restani P, Riva E, Restelli AR,
4. Burney P, Summers C, Chinn S, Hooper Sci Appl 2001;756:207–228. Biasucci G, Galli CL et al. Meat allergy:
R, van Ree R, Lidholm J. Prevalence and 9. Beyer K, Morrow E, Li XM, Bardina L, II–Effects of food processing and enzy-
distribution of sensitization to foods in the Bannon GA, Burks AW et al. Effects of matic digestion on the allergenicity of
European Community Respiratory Health cooking methods on peanut allergenicity. bovine and ovine meats. J Am Coll Nutr
Survey: a EuroPrevall analysis. Allergy J Allergy Clin Immunol 2001;107:1077– 1995;14:245–250.
2010; 65:1182–1188. 1081. 14. Schöll I, Kalkura N, Shedziankova Y,
5. Sampson HA. Food allergy. Part 1: 10. Roth-Walter F, Berin MC, Arnaboldi P, Bergmann A, Verdino P, Knittelfelder R et
immunopathogenesis and clinical Escalante CR, Dahan S, Rauch J et al. al. Dimerization of the major birch pollen

474 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
Pali-Schöll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy

allergen Bet v 1 is important for its in vivo of food structure on allergen breakdown. with gastric acidity inhibitors increases the
IgE-cross-linking potential in mice. J Mol Nutr Food Res 2009;53:952–958. risk of acute gastroenteritis and commu-
Immunol 2005;175:6645–6650. 28. Marciani L, Bush D, Wright P, Wickham nity-acquired pneumonia in children. Pedi-
15. Palosuo K, Varjonen E, Nurkkala J, M, Pick B, Wright J et al. Monitoring of atrics 2006;117:e817–e820.
Kalkkinen N, Harvima R, Reunala T gallbladder and gastric coordination by 43. Canani RB, Terrin G. Gastric acidity inhib-
et al. Transglutaminase-mediated cross- EPI. J Magn Reson Imaging 2005;21: itors and the risk of intestinal infections.
linking of a peptic fraction of omega-5 82–85. Curr Opin Gastroenterol 2010;26:31–35.
gliadin enhances IgE reactivity in wheat- 29. van Boxtel EL, van den Broek LA, Kopp- 44. Giannella RA, Broitman SA, Zamcheck
dependent, exercise-induced anaphylaxis. elman SJ, Gruppen H. Legumin allergens N. Gastric acid barrier to ingested micro-
J Allergy Clin Immunol 2003;111:1386– from peanuts and soybeans: effects of organisms in man: studies in vivo and in
1392. denaturation and aggregation on allergen- vitro. Gut 1972;13:251–256.
16. Nowak-Wegrzyn A, Fiocchi A. Rare, med- icity. Mol Nutr Food Res 2008;52:674–682. 45. Drasar BS, Shiner M, McLeod GM. Stud-
ium, or well done? The effect of heating 30. Helm RM, Cockrell G, Connaughton C, ies on the intestinal flora. I. The bacterial
and food matrix on food protein allergen- Sampson HA, Bannon GA, Beilinson V flora of the gastrointestinal tract in healthy
icity. Curr Opin Allergy Clin Immunol et al. A soybean G2 glycinin allergen. 1. and achlorhydric persons. Gastroenterology
2009;9:234–237. Identification and characterization. Int 1969;56:71–79.
17. Yoshino K, Sakai K, Mizuha Y, Shim- Arch Allergy Immunol 2000;123:205–212. 46. Dial MS. Proton pump inhibitor use and
izuike A, Yamamoto S. Peptic digestibility 31. Koppelman SJ, Knol EF, Vlooswijk RA, enteric infections. Am J Gastroenterol
of raw and heat-coagulated hen’s egg Wensing M, Knulst AC, Hefle SL et al. 2009;104(Suppl. 2):S10–S16.
white proteins at acidic pH range. Int J Peanut allergen Ara h 3: isolation from 47. Maffei HV, Nobrega FJ. Gastric pH and
Food Sci Nutr 2004;55:635–640. peanuts and biochemical characterization. microflora of normal and diarrhoeic infants.
18. Grimshaw KE, King RM, Nordlee JA, Allergy 2003;58:1144–1151. Gut 1975;16:719–726.
Hefle SL, Warner JO, Hourihane JO. 32. Samloff IM. Peptic ulcer: the many pro- 48. Sondheimer JM, Clark DA, Gervaise EP.
Presentation of allergen in different food teinases of aggression. Gastroenterology Continuous gastric pH measurement in
preparations affects the nature of the 1989;96:586–595. young and older healthy preterm infants
allergic reaction–a case series. Clin Exp 33. al-Janabi J, Hartsuck JA, Tang J. Kinetics receiving formula and clear liquid feedings.
Allergy 2003;33:1581–1585. and mechanism of pepsinogen activation. J Pediatr Gastroenterol Nutr 1985;4:352–
19. Mouecoucou J, Fremont S, Sanchez C, J Biol Chem 1972;247:4628–4632. 355.
Villaume C, Mejean L. In vitro allergen- 34. Bayliss WM, Starling EH. The mechanism 49. Ebers DW, Gibbs GE, Smith DI. Gastric
icity of peanut after hydrolysis in the of pancreatic secretion. J Physiol acidity on the first day of life. Pediatrics
presence of polysaccharides. Clin Exp 1902;28:325–353. 1956;18:800–802.
Allergy 2004;34:1429–1437. 35. Polak JM, Coulling I, Bloom S, Pearse 50. Miller RA. Observations on the gastric
20. Peyron S, Mouecoucou J, Fremont S, AG. Immunofluorescent localization of acidity during the first month of life. Arch
Sanchez C, Gontard N. Effects of heat secretin and enteroglucagon in human Dis Child 1941;16:22.
treatment and pectin addition on beta- intestinal mucosa. Scand J Gastroenterol 51. Deren JS. Development of structure and
lactoglobulin allergenicity. J Agric Food 1971;6:739–744. function in the fetal and newborn stom-
Chem 2006;54:5643–5650. 36. Rominger JM, Chey WY, Chang TM. ach. Am J Clin Nutr 1971;24:144–159.
21. Radauer C, Breiteneder H. Evolutionary Plasma secretin concentrations and gastric 52. Agunod M, Yamaguchi N, Lopez R,
biology of plant food allergens. J Allergy pH in healthy subjects and patients with Luhby AL, Glass GB. Correlative study of
Clin Immunol 2007;120:518–525. digestive diseases. Dig Dis Sci 1981;26: hydrochloric acid, pepsin, and intrinsic
22. Huby RD, Dearman RJ, Kimber I. Why 591–597. factor secretion in newborns and infants.
are some proteins allergens? Toxicol Sci 37. Frohman LA, Felig P. Gastrointestinal hor- Am J Dig Dis 1969;14:400–414.
2000;55:235–246. mones and carcinoid syndrome. In: Ghosh 53. Rodbro P, Krasilnikoff PA, Bitsch V.
23. Lehrer SB, Ayuso R, Reese G. Current PK, O’Dorisio TM, editors. Endocrinology Gastric secretion of pepsin in early child-
understanding of food allergens. Ann NY & metabolism. New York: McGraw-Hill, hood. Scand J Gastroenterol 1967;2:257–
Acad Sci 2002;964:69–85. Medical Pub. Div. 2001:1326. 260.
24. Astwood JD, Leach JN, Fuchs RL. 38. Bayliss WM, Starling EH. On the unifor- 54. Rodbro P, Krasilnikoff P, Christiansen
Stability of food allergens to digestion in mity of the pancreatic mechanism in PM, Bitsch V. Gastric secretion in early
vitro. Nat Biotechnol 1996;14:1269–1273. vertebrata. J Physiol 1903;29:174–180. childhood. Lancet 1966;2:730–731.
25. Evaluation of allergenicity of genetically 39. Chey WY, Chang TM. Neural control of 55. Rodbro P, Krasilnikoff PA, Christiansen
modified foods. Report of a Joint FAO/ the release and action of secretin. J Physiol PM. Parietal cell secretory function in
WHO Expert Consulation on Allergenicity Pharmacol 2003;54(Suppl. 4):105–112. early childhood. Scand J Gastroenterol
of Foods Derived from Biotechnology. 40. Mellanby J, Huggett AS. The relation of 1967;2:209–213.
Available at: http://www.who.int/foodsaf- secretin formation to the entrance of acid 56. Li Q, Karam SM, Gordon JI. Diphtheria
ety/publications/biotech/en/ec_jan2001.pdf. chyme into the small intestine-the proper- toxin-mediated ablation of parietal cells in
Accessed 22 September 2010. ties of secretin. J Physiol 1926;61:122–130. the stomach of transgenic mice. J Biol
26. Dupont D, Mandalari G, Molle D, Jardin 41. Li P, Lee KY, Chang TM, Chey WY. Chem 1996;271:3671–3676.
J, Leonil J, Faulks RM et al. Comparative Mechanism of acid-induced release of 57. Shiotani A, Iishi H, Uedo N, Ishiguro S,
resistance of food proteins to adult and secretin in rats. Presence of a secretin- Tatsuta M, Nakae Y et al. Evidence that
infant in vitro digestion models. Mol Nutr releasing peptide. J Clin Invest 1990;86: loss of sonic hedgehog is an indicator of
Food Res 2010;54:767–780. 1474–1479. Helicobater pylori-induced atrophic
27. Wickham M, Faulks R, Mills C. In vitro 42. Canani RB, Cirillo P, Roggero P, Romano gastritis progressing to gastric cancer. Am
digestion methods for assessing the effect C, Malamisura B, Terrin G et al. Therapy J Gastroenterol 2005;100:581–587.

Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 475
Anti-acid medication as a risk factor for food allergy Pali-Schöll and Jensen-Jarolim

58. Zavros Y, Waghray M, Tessier A, Bai 71. Schubert ML, Peura DA. Control of 84. Diesner SC, Knittelfelder R, Krishnamur-
L, Todisco A, D LG et al. Reduced gastric acid secretion in health and disease. thy D, Pali-Scholl I, Gajdzik L, Jensen-
pepsin A processing of sonic hedgehog in Gastroenterology 2008;134:1842–1860. Jarolim E et al. Dose-dependent food
parietal cells precedes gastric atrophy and 72. Sipponen P, Harkonen M. Hypochlorhy- allergy induction against ovalbumin under
transformation. J Biol Chem 2007;282: dric stomach: a risk condition for calcium acid-suppression: a murine food allergy
33265–33274. malabsorption and osteoporosis? Scand J model. Immunol Lett 2008;121:45–51.
59. Waghray M, Zavros Y, Saqui-Salces M, Gastroenterol 2010;45:133–138. 85. Untersmayr E, Ellinger A, Beil WJ, Jen-
El-Zaatari M, Alamelumangapuram CB, 73. Julapalli VR, Graham DY. Appropriate sen-Jarolim E. Eosinophils accumulate in
Todisco A et al. Interleukin-1beta pro- use of intravenous proton pump inhibitors the gastric mucosa of food-allergic mice.
motes gastric atrophy through suppression in the management of bleeding peptic Int Arch Allergy Immunol 2004;135:1–2.
of Sonic Hedgehog. Gastroenterology ulcer. Dig Dis Sci 2005;50:1185–1193. 86. Pali-Schöll I, Yildirim AO, Ackermann U,
2010;138:562–572. 74. Tofil NM, Benner KW, Fuller MP, Win- Knauer T, Becker C, Garn H et al. Anti-
60. Xiao C, Ogle SA, Schumacher MA, kler MK. Histamine 2 receptor antagonists acids lead to immunological and morpho-
Orr-Asman MA, Miller ML, Lertkowit N vs intravenous proton pump inhibitors in logical changes in the intestine of BALB/c
et al. Loss of parietal cell expression of a pediatric intensive care unit: a compari- mice similar to human food allergy. Exp
Sonic hedgehog induces hypergastrinemia son of gastric pH. J Crit Care Toxicol Pathol 2008;60:337–345.
and hyperproliferation of surface mucous 2008;23:416–421. 87. Untersmayr E, Bakos N, Scholl I, Kundi
cells. Gastroenterology 2010;138:550–561. 75. Vorder Bruegge WF, Peura DA. Stress- M, Roth-Walter F, Szalai K et al. Anti-
61. Van Dop WA, Van Den Brink GR. Sonic related mucosal damage: review of drug ulcer drugs promote IgE formation toward
hedgehog: a link between inflammation, therapy. J Clin Gastroenterol 1990;12(Sup- dietary antigens in adult patients. FASEB
gastric atrophy, and acid suppression? pl. 2):S35–S40. J 2005;19:656–658.
Gastroenterology 2010;138:426–429. 76. Pali-Schöll I, Herzog R, Wallmann J, 88. Richter JE. Review article: the manage-
62. Koop H, Klein M, Arnold R. Serum Szalai K, Brunner R, Lukschal A et al. ment of heartburn in pregnancy. Aliment
gastrin levels during long-term omeprazole Antacids and dietary supplements with an Pharmacol Ther 2005;22:749–757.
treatment. Aliment Pharmacol Ther 1990; influence on the gastric pH increase the 89. Van Thiel DH, Gavaler JS, Joshi SN, Sara
4:131–138. risk for food sensitization. Clin Exp RK, Stremple J. Heartburn of pregnancy.
63. Reilly JP. Safety profile of the proton- Allergy 2010;40:1091–1098. Gastroenterology 1977;72:666–668.
pump inhibitors. Am J Health Syst Pharm 77. Untersmayr E, Poulsen LK, Platzer MH, 90. Gill SK, O’Brien L, Einarson TR, Koren G.
1999;56:S11–S17. Pedersen MH, Boltz-Nitulescu G, Skov PS The safety of proton pump inhibitors
64. van Asselt DZ, de Groot LC, van Staveren et al. The effects of gastric digestion on (PPIs) in pregnancy: a meta-analysis. Am J
WA, Blom HJ, Wevers RA, Biemond I codfish allergenicity. J Allergy Clin Immu- Gastroenterol 2009;104:1541–1545; quiz
et al. Role of cobalamin intake and nol 2005;115:377–382. 1540, 1546.
atrophic gastritis in mild cobalamin 78. Yoshimasu MA, Ahn JK, Tanaka T, Yada 91. Schöll I, Ackermann U, Ozdemir C, Blu-
deficiency in older Dutch subjects. Am J RY. Soluble expression and purification of mer N, Dicke T, Sel S et al. Anti-ulcer
Clin Nutr 1998;68:328–334. porcine pepsinogen from Pichia pastoris. treatment during pregnancy induces food
65. Segawa K, Nakazawa S, Tsukamoto Y, Protein Expr Purif 2002;25:229–236. allergy in mouse mothers and a Th2-bias
Goto H, Yamao K, Hase S et al. Chronic 79. Tanaka T, Yada RY. Expression of in their offspring. FASEB J 2007;21:1264–
alcohol abuse leads to gastric atrophy and soluble cloned porcine pepsinogen A in 1270.
decreased gastric secretory capacity: a his- Escherichia coli. Biochem J 1996; 92. Pali-Schöll I, Renz H, Jensen-Jarolim E.
tological and physiological study. Am J 315(Pt 2):443–446. Update on allergies in pregnancy, lacta-
Gastroenterol 1988;83:373–379. 80. Prichard PJ, Yeomans ND, Mihaly GW, tion, and early childhood. J Allergy Clin
66. Morris A, Nicholson G. Ingestion of Jones DB, Buckle PJ, Smallwood RA Immunol 2009;123:1012–1021.
Campylobacter pyloridis causes gastritis et al. Omeprazole: a study of its inhibition 93. Dehlink E, Yen E, Leichtner AM, Hait
and raised fasting gastric pH. Am J of gastric pH and oral pharmacokinetics EJ, Fiebiger E. First evidence of a possible
Gastroenterol 1987;82:192–199. after morning or evening dosage. Gastroen- association between gastric acid suppres-
67. Graham DY, Alpert LC, Smith JL, terology 1985;88:64–69. sion during pregnancy and childhood
Yoshimura HH. Iatrogenic Campylobacter 81. Untersmayr E, Focke M, Kinaciyan T, asthma: a population-based register study.
pylori infection is a cause of epidemic Poulsen LK, Boltz-Nitulescu G, Scheiner Clin Exp Allergy 2009;39:246–253.
achlorhydria. Am J Gastroenterol 1988; O et al. Anaphylaxis to Russian Beluga 94. Brunner R, Wallmann J, Szalai K, Kara-
83:974–980. caviar. J Allergy Clin Immunol 2002; giannis P, Altmeppen H, Riemer AB et al.
68. Derakhshan MH, El-Omar E, Oien K, 109:1034–1035. Aluminium per se and in the anti-acid
Gillen D, Fyfe V, Crabtree JE et al. 82. Untersmayr E, Scholl I, Swoboda I, Beil drug sucralfate promotes sensitization
Gastric histology, serological markers and WJ, Forster-Waldl E, Walter F et al. Ant- via the oral route. Allergy 2009;64:
age as predictors of gastric acid secretion acid medication inhibits digestion of dietary 890–897.
in patients infected with Helicobacter proteins and causes food allergy: a fish 95. Brunner R, Wallmann J, Szalai K, Kara-
pylori. J Clin Pathol 2006;59:1293–1299. allergy model in BALB/c mice. J Allergy giannis P, Kopp T, Scheiner O et al. The
69. Green LK, Graham DY. Gastritis in the Clin Immunol 2003;112:616–623. impact of aluminium in acid-sup-
elderly. Gastroenterol Clin North Am 83. Schöll I, Untersmayr E, Bakos N, Roth- pressing drugs on the immune response of
1990;19:273–292. Walter F, Gleiss A, Boltz-Nitulescu G BALB/c mice. Clin Exp Allergy 2007;37:
70. Muto S, Murayama N, Asano Y, Hosoda et al. Antiulcer drugs promote oral sensiti- 1566–1573.
S, Miyata M. Hypergastrinemia and zation and hypersensitivity to hazelnut 96. Spazierer D, Skvara H, Dawid M, Fallahi
achlorhydria in chronic renal failure. allergens in BALB/c mice and humans. N, Gruber K, Rose K et al. T helper 2
Nephron 1985;40:143–148. Am J Clin Nutr 2005;81:154–160. biased de novo immune response to

476 Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S
Pali-Schöll and Jensen-Jarolim Anti-acid medication as a risk factor for food allergy

keyhole limpet hemocyanin in humans. laxis in patients with allergy. J Allergy sensitization model. Clin Exp Allergy
Clin Exp Allergy 2009;39:999–1008. Clin Immunol 2007;119:711–717. 2010;40:486–493.
97. Boelens PG, Fonk JC, Houdijk AP, Sche- 99. Chan KK, Vyas KH, Brandt KD. In vitro 101. Merwat SN, Spechler SJ. Might the use of
per RJ, Haarman HJ, Meijer S et al. Pri- protein binding of diclofenac sodium in acid-suppressive medications predispose to
mary immune response to keyhole limpet plasma and synovial fluid. J PharmSci the development of eosinophilic esophagi-
haemocyanin following trauma in relation 1987;76:105–108. tis? Am J Gastroenterol 2009;104:1897–
to low plasma glutamine. Clin Exp Immu- 100. Riemer AB, Gruber S, Pali-Scholl I, 1902.
nol 2004;136:356–364. Kinaciyan T, Untersmayr E, Jensen-Jaro- 102. Thomson AB, Sauve MD, Kassam N,
98. Untersmayr E, Vestergaard H, Malling lim E. Suppression of gastric acid increases Kamitakahara H. Safety of the long-term
HJ, Jensen LB, Platzer MH, Boltz-Nitule- the risk of developing Immunoglobulin use of proton pump inhibitors. World J
scu G et al. Incomplete digestion of E-mediated drug hypersensitivity: human Gastroenterol 2010;16:2323–2330.
codfish represents a risk factor for anaphy- diclofenac sensitization and a murine

Allergy 66 (2011) 469–477 ª 2010 John Wiley & Sons A/S 477