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Hazelnut allergy across Europe dissected molecularly:
A EuroPrevall outpatient clinic survey
Mareen R. Datema, MSc,
a
Laurian Zuidmeer-Jongejan, PhD,
a
Riccardo Asero, MD,
b
Laura Barreales, MD,
c
Simona Belohlavkova, MD,
d
Fr
ed
eric de Blay, MD,
e
Peter Bures, MD,
f
Michael Clausen, MD,
g
Ruta Dubakiene, MD,
h
David Gislason, MD,
g
Monika Jedrzejczak-Czechowicz, MD, PhD,
i
Marek L. Kowalski, MD, PhD,
i
Andr
e C. Knulst, MD, PhD,
j
Tanya Kralimarkova, MD,
k
Thuy-My Le, MD, PhD,
j
Alison Lovegrove, MD,
l
Justin Marsh, PhD,
m
Nikolaos G. Papadopoulos, MD,
n,o
Todor Popov, MD,
p
N
ayade del Prado, BSc,
c
Ashok Purohit, MD,
e
Gerald Reese, PhD,
p
Isabel Reig, MD,
q
Suranjith L. Seneviratne, MD, PhD,
r
Athanasios Sinaniotis, MD,
n
Serge A. Versteeg, BSc,
a
Stefan Vieths, PhD,
p
Aeilko H. Zwinderman, PhD,
s
Clare Mills, PhD,
m
Jonas Lidholm, PhD,
t
Karin Hoffmann-Sommergruber, PhD,
u
Montserrat Fern
andez-Rivas, MD, PhD,
q
* Barbara Ballmer-Weber, MD,
f
* and
Ronald van Ree, PhD
a,v
Amsterdam and Utrecht, The Netherlands, Paderno Dugnano, Italy, Madrid, Spain, Prague, Czech
Republic, Strasbourg, France, Z€
urich, Switzerland, Reykjavik, Iceland, Vilnius, Lithuania, Lodz, Poland, Sofia, Bulgaria, Harpenden,
Manchester, and London, United Kingdom, Athens, Greece, Langen, Germany, Uppsala, Sweden, and Vienna, Austria
Background: Hazelnut allergy is birch pollen–driven in
Northern/Western Europe and lipid transfer protein–driven in
Spain and Italy. Little is known about other regions and other
allergens.
Objective: Establishing a molecular map of hazelnut allergy
across Europe.
Methods: In 12 European cities, subjects reporting reactions to
hazelnut (n 5731) were evaluated and sensitization to 24 foods,
From
a
the Department of Experimental Immunology, Academic Medical Center, Am-
sterdam;
b
Ambulatorio di Allergologia, Clinica San Carlo, Paderno Dugnano;
c
the
Clinical Epidemiology Unit, Preventive Medicine Department, Hospital Clinico San
Carlos, IdISSC, Madrid;
d
the Pediatric Department, Faculty Hospital Bulovka, Prague;
e
the Allergy Division, Chest Disease Department, University Hospital of Strasbourg,
Strasbourg;
f
the Allergy Unit, Department of Dermatology, University Hospital
Z€
urich, Z€
urich;
g
the Faculty of Medicine, University of Iceland, Landspitali University
Hospital, Reykjavik;
h
Medical Faculty, VilniusUniversity, Vilnius;
i
the Department of
Immunology, Rheumatology and Allergy, Faculty of Medicine, Medical University of
Lodz, Lodz;
j
the Department of Dermatology and Allergology, University Medical
Center Utrecht, Utrecht;
k
the Clinic of Allergy and Asthma, Medical University of So-
fia, Sofia;
l
the Department of Plant Biology and Crop Science, Rothamsted Research,
Harpenden;
m
the Institute of Inflammation and Repair, Manchester Institute of
Biotechnology, University of Manchester, Manchester;
n
the Allergy Department,
2nd Pediatric Clinic, University of Athens, Athens;
o
the Centre for Paediatrics and
Child Health, Institute of Human Development, University of Manchester, Manches-
ter;
p
the Division of Allergology, Paul-Ehrlich-Insitut, Federal Institute for Vaccines
and Biomedicines, Langen;
q
the Allergy Department, Hospital Clinico San Carlos,
IdISSC, Madrid;
r
the Department of Clinical Immunology, St Mary’s Hospital, and
Imperial College London, London;
s
the Department of Clinical Epidemiology, Biosta-
tistics and Bioinformatics, Academic Medical Centre, Amsterdam;
t
Phadia AB, Up-
psala;
u
the Department of Pathophysiology and Allergy Research, Medical
University of Vienna, Vienna; and
v
the Department of Otorhinolaryngology, Aca-
demic Medical Center, Amsterdam.
*These authors contributed equally to this work.
This work was funded by the European Union through EuroPrevall (grant no.
FP6-FOOD-CT-2005-514000). M.R.D., C.M., R.v.R., M.F.-R., and S.V. also received
support from the EU 7th framework programme under grant agreement no. 312147.
Disclosure of potential conflict of interest: M. R. Datema has received research support
from the European Commission (EC). L. Zuidmeer-Jongejan has received research
support and travel support from the European Union (EU). L. Barreales has received
research support and travel support from Fundaci
on para la Investigaci
on Biom
edica
del Hospital Cl
ınico San Carlos. F. de Blay has received research support from
Stallerg
enes and Chiesi; has received consultancy fees from and is a board member
for Stallerg
enes, ALK, Mundipharma, and Novartis; and has received participation
fees from Stallerg
enes and ALK. M. Clausen has received lecture fees from AstraZe-
neca and has received travel support from GlaxoSmithkline. M. L. Kowalski has
received research support from the EC (6Framwork Programme Grant). A. C. Knulst
has received research support and travel support from the EC. T.-M. Le has received
research support from the EU. N. G. Papadopoulos reports grants from GSK, Nestl
e,
and Merck and personal fees from Abbvie, Sanofi, Novartis, Menarini, Meda, ALK-
Abell
o, Allergopharma, Uriach, GSK, Stallergens, and MSD. G. Reese is employed
by Allergopharma GmbH Co. KG. S. L. Seneviratne is employed by the Royal Free
Hospital. S. Vieths has consultant arrangements with the Food Allergy Resource
and Research Program; has provided expert testimony for the Medical University of
Vienna; has received research support from the Monsanto Company; has received pay-
ment for lectures from the American Academy of Allergy, Asthma & Immunology,
Deutsche Dermatologische Gesellschaft, the Spanish Society of Allergy and Clinical
Immunology, Westdeutsche Arbeitsgemeinschaft f€
ur p€
adiatrische Pneumologie and
Allergologie e.V., Gesellschaft f€
ur p€
adiatrische Allergologie und Umweltmedizin,
and
€
Arzteverband Deutscher Allergologen; has received royalties from Schattauer Al-
lergologie Handbuch and Elsevier Nahrungsmittelallergien und Intoleranzen; and has
received travel support from the German Research Foundation, the Federal Institute
for Risk Assessment, the Austrian Society for Allergology and Immunology, the
French Society of Allergology, the European Directorate for the Quality of Medicines
and Health Care, the European Academy of Allergy and Clinical Immunology, the
World Allergy Organization, Deutscher Allergie und Asthmabund, Association Mon-
egasque pour le Perfectionnement des Connaissances des M
edicins, the German
Chemical Society, the Austrian Society for Dermatology and Venerology, and AKM
Allergiekongress. C. Mills has received research support from the EU and Biological
and Biotechnological Sciences Research Council; is a board member for Reacta
Biotech Ltd; is employed by the University of Manchester and the Institute of Food
Research; has received research support from the Biological and Biotechn ological Sci-
ences Research Council, the EU, the UK Food Standards Agency, the European Food
Safety Authority, the UK Technology Strategy Board, DBV Technologies, and Novar-
tis; has stock/stock options in Reacta Biotech Ltd; has received travel support from the
International Life Sciences Institute, the European Academy of Allergy and Clinical
Immunology (EAACI), Europa Bio, the Iceland Allergy Society, Fresenius, EuroFood
Tox 2013, and the International Union of Nutritional Sciences Annual Meeting (Gran-
ada, Spain, September 2013); and is a lecturer in Allergy at Imperial College. J. Lid-
holm is employed by Thermo Fisher Scientific. K. Hoffmann-Sommergruber has
received research support from the EC (PRoject EUROPREVALLand the Marie Curie
Project); is employed by the Medical University of Vienna; and has received lecture
fees from Thermofisher, Milupa, and Meda. M. Fern
andez-Rivas has received research
support and travel support from the EC, has received consultancy fees from DBV, and
has received lecture fees from ALK and GSK. B. Ballmer-Weberhas received research
support and travel support from the EU and has received consultancy fees and lecture
fees from Thermo Fisher Scientific. R. van Ree has received research support from the
EC, is a member of the EAACI Board, and has received consultancy fees from HAL
Allergy. The rest of the authors declare that they have no relevant conflicts of interest.
Received for publication August 4, 2014; revised November 25, 2014; accepted for pub-
lication December 4, 2014.
Corresponding author: Ronald van Ree, PhD, Departments of Experimental Immunology
and Otorhinolaryngology, Academic Medical Center, Meibergdreef 9, 1105 AZ Am-
sterdam, The Netherlands. E-mail: r.vanree@amc.uva.nl.
0091-6749/$36.00
Ó2015 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2014.12.1949
1
12 respiratory allergen sources, and latex was tested by using
skin prick test and ImmunoCAP. A subset (124 of 731)
underwent a double-blind placebo-controlled food challenge to
hazelnut. Sera of 423 of 731 subjects were analyzed for IgE
against 7 hazelnut allergens and cross-reactive carbohydrate
determinants by ImmunoCAP.
Results: Hazelnut allergy was confirmed in 70% of those
undergoing double-blind placebo-controlled food challenges.
Birch pollen–driven hazelnut sensitization (Cor a 1) dominated
in most cities, except in Reykjavik, Sofia, Athens, and Madrid,
where reporting of hazelnut allergy was less frequent anyhow.
In Athens, IgE against Cor a 8 dominated and strongly
correlated with IgE against walnut, peach, and apple and
against Chenopodium, plane tree, and mugwort pollen.
Sensitization to seed storage proteins was observed in less than
10%, mainly in children, and correlated with IgE to nuts, seeds,
and legumes. IgE to Cor a 12, observed in all cities (10% to
25%), correlated with IgE to nuts, seeds, and pollen.
Conclusions: In adulthood, the importance of hazelnut sensitization
to storage proteins, oleosin (Cor a 12), and Cor a 8 is diluted by the
increased role of birch pollen cross-reactivity with Cor a 1. Cor a 8
sensitization in the Mediterranean is probably driven by diet in
combination with pollen exposure. Hazelnut oleosin sensitization is
prevalent across Europe; however, the clinical relevance remains to
be established. (J Allergy Clin Immunol 2015;nnn:nnn-nnn.)
Key words: EuroPrevall, hazelnut allergy, component-resolved
diagnosis, outpatient clinic
From 2005 to 2010, the multicenter and multidisciplinary
EuroPrevall project was conducted, aiming to investigate the
prevalence, cost, and basis of food allergy across Europe.
1
Several
large-scale multicenter epidemiological surveys were performed,
including birth cohort surveys,
2
cross-sectional community
surveys in school-aged children and adults,
3
and an outpatient
clinic survey in 12 cities across Europe.
4
The project studied 24
foods, but its most detailed investigations were directed toward
9 foods, that is, egg, milk, fish, shrimp, peanut, hazelnut, celery,
peach, and apple.
1,3
In the present article, we describe the main
characteristics of hazelnut allergy across Europe.
Hazelnut allergy is one of the more common food allergies in
Europe, but most studies so far have been limited to European
countries such as Sweden, Germany, The Netherlands,
Switzerland (North-western and Alpine), and Spain and Italy
(Western Mediterranean).
5-10
These studies have established that
hazelnut allergy in the former countries is dominated by
cross-reactivity between birch pollen Bet v 1 and hazelnut Cor
a1
7,8
and in the latter by cross-reactivity between peach Pru p 3
and hazelnut Cor a 8.
11
Little is known about hazelnut
allergy in Central and Eastern European countries and in
North-Western (Iceland) and South-Eastern extremes of Europe
(Greece). The EuroPrevall consortium set out to fill these gaps.
In addition, very little has been reported about the importance
of hazelnut allergens other than Cor a 1 and Cor a 8 across Europe.
Besides profilin (Cor a 2), first described around 2 decades ago,
7
several allergens not related to pollen have now been identified
and characterized. These include the seed storage proteins Cor
a 9 (11S globulin),
12
Cor a 11 (7S vicilin-like),
13
and Cor a 14
(2S albumin).
14
More recently, oil-body–associated oleosins
have also been identified as hazelnut allergens, that is, Cor a 12
and Cor a 13.
15,16
Here, we investigate the full spectrum of
hazelnut allergens as is known to date (Cor a 1, Cor a 2, Cor a 8,
Cor a 9, Cor a 11, Cor a 12, and Cor a 14). The origin of
sensitization to hazelnut Cor a 1 is generally accepted to be
Fagales tree pollen, in particular birch pollen, but it is less well
established for the other hazelnut allergens. Sensitization to
profilin is thought to be closely linked to grass pollen
sensitization, but a role for other pollens cannot be excluded.
17
The concept of peach lipid transfer protein (LTP) Pru p 3 inducing
sensitization to fruit, vegetable, nut, and seed LTPs is quite firmly
established, but involvement of other foods or pollens as the
primary sensitizer cannot be ruled out.
18
In Northern China,
mugwort pollen was recently shown to induce LTP-reactive
IgE, resulting in cross-reactivity to peach.
19
Some studies demonstrated that IgE responses to storage
proteins are more common in children than in adults
5,20
and
pollen-related cross-sensitization first occurs at a later age. The
age composition in the EuroPrevall population with around
17% children allowed us to verify this.
In 12 EuroPrevall outpatient clinic surveys, all enrolled sub-
jects were tested by using skin prick test (SPT) and ImmunoCAP
on 24 foods, 12 respiratory allergen sources, and latex. We aimed
to identify differences in hazelnut sensitization patterns between
European cities and possible associations between IgE against
hazelnut components and IgE against pollen, latex, and/or other
foods, providing insight into possible primary sensitizers. To our
knowledge, this is the first detailed clinical and serological study
of hazelnut allergy with such a broad geographic, socioeconomic,
cultural, and lifestyle spectrum across Europe.
METHODS
Study design
This survey is part of the EuroPrevall project.
1
Subjects were prospectively
recruited from 2006 toward the end of 2009 in outpatient clinics from 12
European cities: Madrid (Spain), Sofia, (Bulgaria), Reykjavik (Iceland),
Athens (Greece), Prague (Czech Republic), q
od
z (Poland), Utrecht (The
Netherlands), Strasbourg (France), Manchester (United Kingdom), Milan
(Italy), Z€
urich (Switzerland), and Vilnius (Lithuania). Participating subjects
reported immediate adverse reactions occurring within 2 hours or less after
the ingestion of any food. The population was further complemented with
subjects enrolled in the EuroPrevall community surveys in adults and
children.
3,4,21
In the end, 2273 subjects were enrolled in the survey (see Fig
1; also see this article’s Methods section in the Online Repository at www.
jacionline.org). In the present study, we included 731 subjects reporting reac-
tions to hazelnut. Local ethical committees approved all studies, and written
informed consent was obtained from all subjects or their legal representatives.
Clinical evaluation and double-blind placebo-
controlled food challenge
Allergy specialists in the outpatient clinics applied standardized
case-report forms to collect a detailed medical history.
4
All subjects under-
went SPT and serum IgE testing to detect sensitization to 24 foods, latex,
Abbreviations used
CRD: Component-resolved diagnosis
DBPCFC: Double-blind placebo-controlled food challenge
LTP: Lipid transfer protein
sIgE: Specific IgE
SPT: Skin prick test
J ALLERGY CLIN IMMUNOL
nnn 2015
2DATEMA ET AL
and 12 inhalant allergen sources (see Table E1 in this article’s Online
Repository at www.jacionline.org). We asked all subjects to undergo a
double-blind placebo-controlled food challenge (DBPCFC) to hazelnut and
124 consented (see also this article’s Methods section in the Online Reposi-
tory). Those with a history of severe anaphylaxis
22
to hazelnut were excluded
from the challenge (n 522). Both a positive challenge and a history of severe
anaphylaxis to hazelnut were considered as confirmed hazelnut allergy.
Skin prick testing
SPT reagents were kindly provided by ALK-Abell
o (Madrid, Spain).
Details of the procedure are described in this article’s Methods section in the
Online Repository. SPT results were expressed as allergen/histamine wheal
ratios, with a ratio of 0.5 or more designated as positive.
Specific IgE measurements
Specific IgE (sIgE) antibodies to foods and respiratory allergen sources and
latex were tested by ImmunoCAP following the manufacturer’s instructions
(Thermo Fisher Scientific, Uppsala, Sweden). For component-resolved
diagnosis (CRD), we tested the following hazelnut components: rCor a 1
(Bet v 1 homologue), rCor a 2 (profilin), rCor a 8 (LTP), nCor a 9 (11S
globulin), nCor a 11 (7S globulin), nCor a 12 (oleosin), and rCor a 14 (2S
albumin). In addition, IgE against bromelain was used as a measure for sIgE
against cross-reactive carbohydrate determinants (CCDs).
Reported adverse reactions (≤2hrs) to hazelnut (n=731)
652 Outpatient clinics
79 Community survey
Anaphylaxis
22 Outpatient clinics
Serum available
(n=110)
Serum available
(n=361)
Random:
Centre >
50
patients
All:
Centre <
50
patients
Component Resolved Diagnosis: N=423
Community survey
Outpatient clinic survey
Willing to participate in full clinical
evaluation (n=152)
Screening self-reported food allergy
and IgE for same food (n=719)
Patients reporting adverse reactions to foods
(n=2121)
Cross-sectional food survey (n=2273)
DBPCFC
83 Outpatient clinics
41 Community survey
Serum available
(n=20)
CRD priority 2
290 Outpatient clinics
3 Community survey
CRD priority 1
95 Outpatient clinics
35 Community survey
No DBPCFC
547 Outpatient clinics
38 Community survey
87 Reactive
20 Tolerant
17 Placebo
responders
FIG 1. Flowchart showing the selection of subjects in the outpatient and community survey. The number of
included subjects with reported adverse reactions (>_2 hours) to hazelnut. The full clinical evaluation
included SPT and serum IgE testing for 24 foods, 12 inhalant sources, and latex. A subset also underwent a
DBPCFC to the food to which they reported symptoms.
J ALLERGY CLIN IMMUNOL
VOLUME nnn, NUMBER nn
DATEMA ET AL 3
Details of serology measurements are presented in this article’s Methods
section in the Online Repository. IgE levels of 0.35kU
A
/L or more were
considered as positive.
Serum selection for CRD
Because of restricted availability of experimental custom-made
ImmunoCAP tests, not all 731 sera were tested with CRD. Sera with sufficient
volumes from subjects who had undergone a DBPCFC (110 of 124) and
anaphylactic subjects (20 of 22) were tested with priority. Remaining
ImmunoCAP tests were used for analysis of samples (n 5293) selected so
as to achieve a more balanced representation of the 12 cities. In those with low
numbers (<50) of subjects with sufficient serum volume (Sofia, Madrid,
Reykjavik, Athens, Prague, Utrecht, Strasbourg, Manchester, and Milan), all
sera were tested. A random sample from subjects of the remaining cities
(q
od
z, Z€
urich, and Vilnius) was drawn.
Allergens
Hazelnut allergens were produced and purified as described else-
where.
14,16,23,24
Statistical analysis
Differences between cities in characteristics and proportions of positive
and negative test results were tested using the Pearson chi-square test and
ANOVA (age). We calculated medians and interquartile ranges and used the
Kruskal-Wallis test to compare differences in IgE levels to hazelnut between
cities. Correlations between IgE levels to hazelnut and pollen of 9 species, 23
foods, and latex (see Table E1 in this article’s Online Repository) were
analyzed using the Spearman correlation coefficient. To accommodate
possible differences between cities affecting the overall results, we also
assessed the correlations using random effects models. Because no significant
differences between the 2 methods were observed, the Spearman rho (r)
correlations are reported. Pvalues of .05 or less were considered significant.
For analyses including multiple comparisons, Pvalues adjusted according
to the Bonferroni method were calculated. We used R software (version
3.1.0 for all statistical analyses).
RESULTS
Population characteristics and hazelnut
sensitization
Hazelnut was the most reported food allergy in the EuroPrevall
outpatient clinic survey (32%). Differences in frequencies
between European cities were however considerable, ranging
from 68.4% in Vilnius to 5.7% in Madrid (see Fig E1 in this
article’s Online Repository at www.jacionline.org). The
population included more females (63.1%) than males (36.9%)
(Table I). Most were adults (83.6%) and among the 120 children
(<18 years), 22 were younger than 7 years (3-6 years).
Patients most commonly reported symptoms of the oral
mucosa (84.4%), of which around half were without other
symptoms. Upper airway (rhinitis, rhinoconjunctivitis), skin,
TABLE I. Characteristics of the EuroPrevall hazelnut study population stratified by city
Characteristic
European city
All
(N 5731)
Madrid
(n 515)
Sofia
(n 512)
Reykjavik
(n 513)
Athens
(n 523)
Prague
(n 529)
q
od
z
(n 570)
Type of clinic/department Allergy Allergy Pulmonology
& Allergy
Allergy Pediatrics Immunology,
Rheumatology,
and Allergy
Age (y), mean 6SD 32.3 614.8 24.7 614.0 21.5 615.0 32.7 617.1 27.8 612.7 17 610.8 32.2 618.1
<18 y, n/N (%) 120/731 (16.4) 5/15 (33.3) 6/12 (50.0) 3/13 (23.1) 5/23 (21.7) 16/29 (55.2) 18/70 (25.7)
Sex: female, n/N (%) 461/731 (63.1) 9/15 (60.0) 8/12 (66.7) 8/13 (61.5) 12/23 (52.2) 19/29 (65.5) 52/70 (74.3)
Hazelnut sensitization
SPT, n/N (%) 556/718 (77.4) 11/15 (73.3) 3/12 (25.0) 10/13 (76.9) 20/23 (87) 20/29 (69.0) 37/70 (52.9)
sIgE, n/N (%) 585/669 (83.7) 10/15 (66.7) 3/11 (27.3) 10/12 (83.3) 14/21 (66.7) 23/28 (82.1) 41/69 (59.4)
DBPCFCs hazelnut
Completed, n/N (%) 124/731 (16.9) 8/15 (53.3) 1/12 (8.3) 6/13 (46.2) 3/23 (13.0) 5/29 (17.2) 17/70 (25.0)
Reactive, n/N (%) 87/124 (70.2) 5/8 (62.5) 0/1 (0.0) 4/6 (66.7) 1/3 (33.3) 3/5 (60.0) 8/17 (47.1)
Anaphylaxis, n/N (%) 22/713 (3.0) — 1/12 (8.3) — 3/23 (13.0) 2/29 (6.9) 2/70 (2.9)
Characteristic
European city
P
value*
Utrecht
(n 580)
Strasbourg
(n 570)
Manchester
(n 551)
Milan
(n 550)
Z€
urich
(n 5177)
Vilnius
(n 5141)
Type of clinic/department Dermatology Pulmonology Allergy & Clinical
Immunology
Allergy Allergy/
Dermatology
Allergy
Age (y), mean 6SD 32 610.9 34.2 613 31.2 615.8 40.5 614.2 36 614.3 29.9 613.7 <.001
<18 y, n/N (%) 5/80 (6.2) 7/70 (10.0) 11/51 (21.6) 1/50 (2.0) 14/177 (7.9) 30.141 (21.3) <.001
Sex: female, n/N (%) 54/80 (67.5) 54/70 (77.1) 33/51 (64.7) 34/50 (68.0) 105/177 (59.3) 73/141 (51.8) <.001
Hazelnut sensitization
SPT, n/N (%) 62/73 (84.9) 60/69 (87.0) 38/51 (74.5) 48/50 (96.0) 129/173 (74.6) 118/140 (84.3) <.001
sIgE, n/N (%) 75/80 (93.8) 63/68 (92.6) 40/48 (83.3) 47/50 (94.0) 149/176 (84.7) 110/121 (90.9) <.001
DBPCFCs hazelnut
Completed, n/N (%) 20/80 (25.0) 9/70 (12.9) 0/51 (0.0) 13/50 (26.0) 41/177 (23.2) 1/1441 (0.7) <.001
Reactive, n/N (%) 15/20 (75.0) 8/9 (88.9) — 8/13 (61.5) 34/41 (82.9) 1/1 (100)
Anaphylaxis, n/N (%) 2/78 (2.6) 1/69 (1.4) 7/51 (13.7) 2/50 (4.0) 2/177 (1.1) — <.001
sIgE, Specific IgE >_ 0.35kU
A
/L.
*Pvalues were calculated by using ANOVA and Pearson x
2
test and show an overall difference in characteristics between the cities.
J ALLERGY CLIN IMMUNOL
nnn 2015
4DATEMA ET AL
and digestive symptoms were reported by 20.7% to 35.4%. More
severe symptoms were less often reported, with 13.5% reporting
asthma and 3% reporting cardiovascular or neurological
symptoms.
Symptoms to hazelnut were supported by sensitization for the
vast majority (88.2%), as detected in 566 of 718 (77.4%) by SPT
and 585 of 699 (83.7%) by ImmunoCAP (test results were
positive in 496 subjects). In 11.8% of all tested subjects, we did
not find evidence for hazelnut sensitization. On assessing
sensitization by CRD in 423 patients (excluding CCD), 86.5%
were positive. CRD detected IgE to individual hazelnut compo-
nents in 15 of 68 (22%) with a negative hazelnut ImmunoCAP and
49 of 91 (54%) with a negative SPT result (see more details in this
article’s Tables E2 and E3 in the Online Repository at www.
jacionline.org). Because only 3 of 11 patients from Sofia had
detectable IgE against hazelnut, they were excluded from further
statistical analysis of serological data.
To confirm hazelnut allergy, 124 of 731 subjects underwent a
DBPCFC (see Table E4 in this article’s Online Repository at
www.jacionline.org). Hazelnut DBPCFC was positive for 87 of
124 patients (70.2%). After including the 22 anaphylactic
subjects, we confirmed hazelnut allergy in 109 patients, of
which 95% had evidence for hazelnut sensitization by SPT
(87.0%), ImmunoCAP (89.9%), or CRD (93.8%). Sensitivity of
CRD was significantly higher than that of both other
tests, but specificity was significantly lower (see details
in Tables E5 and E6 in this article’s Online Repository at www.
jacionline.org).
Patterns of recognition of individual hazelnut
allergens in European cities
Hazelnut sIgE showed a clear variation across European cities
(Fig 2). The pattern closely followed that of sensitization to
birch pollen, and IgE levels significantly correlated (r50.88;
P< .001). IgE levels to hazelnut were significantly lower in
Athens and Madrid and, although not significantly, also in
Reykjavik than in the other cities.
A
B
FIG 2. IgE levels of all subjects with sIgE to hazelnut (A) and birch (B) (>_0.35 kU
A
/L). The black lines indicate
the median IgE values and the interquartile range. For each city, the number of positive responders (n), total
tested (N), and the proportion positives of the total (%) are shown. *Significantly different from q
od
z,
Utrecht, Strasbourg, Manchester, Milan, Z€
urich, and Vilnius. **Significantly different from Prague, q
od
z,
Utrecht, Strasbourg, Milan, Z€
urich, and Vilnius.
J ALLERGY CLIN IMMUNOL
VOLUME nnn, NUMBER nn
DATEMA ET AL 5
Fig 3 shows the frequency and level of sensitization to
individual hazelnut allergens and CCD. Sensitization to Cor a 1
was most prevalent (74.3%), followed at distance by both other
pollen-related allergens Cor a 2 (19.6%) and CCD (10.2%). IgE
levels against Cor a 1 were 5 to 10 times higher than those against
other hazelnut allergens. Cor a 1 was dominant (>_60%) in all
cities except Athens and Madrid (<10%) (Fig 4). In contrast,
sensitization to Cor a 8 dominated in Athens (15 of 18; 83%)
and to a lesser extent Madrid (4 of 11; 36%), while this was
rare in other cities (<15%). Almost all patients sensitized to Cor
a 14 were sensitized to Cor a 9 (20 of 22) and IgE levels closely
correlated (r50.74; P< .001). Cor a 9 and/or Cor a 14
sensitization was more common in Prague, Reykjavik, Utrecht,
Manchester, and Madrid (18.2% to 27.3%) than in other cities
(<7%). Sensitization to Cor a 11 reached a frequency of more
than 10% only in Prague. Finally, sensitization to Cor a 12 was
observed all over Europe in around 10% to 25% of the patients,
except in q
od
z and Strasbourg (<8%).
Age differences in hazelnut sensitization
Details of age-related sensitization are given in Table E7 in this
article’s Online Repository at www.jacionline.org. Sensitization
to Cor a 1 was less common in children (<18 years) than in adults
(61.5% vs 76.2%; P< .02). Children (<18 years) were
significantly more often sensitized to Cor a 9 and/or Cor a 14
than were adults (42.0% vs 5.8%; P< .001), with the exception
of Utrecht, where 9 of 10 sensitized to Cor a 9/Cor a 14 were older
than 18 years. In addition, children were more often sensitized to
Cor a 12 than were adults (34% vs 11.4%; P< .001).
Correlations between IgE to pollens and hazelnut
allergens
Sensitization to all pollen extracts was observed in all centers
(see Table E8 in this article’s Online Repository at www.
jacionline.org). Birch pollen sensitization was the most frequent
among the 9 pollen species tested (80.3%) followed by grass
pollen sensitization, ranging from just under 50% to over 80%.
To evaluate which of the 9 tested pollen species may be implicated
in cross-reactivity to hazelnut allergens, IgE correlations were
investigated. Fig 5,A, shows the strength of each correlation
between a hazelnut allergen and a pollen extract (for exact
correlation coefficients, see Table E9 in this article’s Online
Repository at www.jacionline.org).
IgE against Cor a 1 correlated with IgE against birch pollen
only (r50.92; P< .001), but such correlation was lacking in
Athens and Madrid. Almost all birch-hazelnut cosensitized
patients (301 of 318) were sensitized to Cor a 1 (median IgE,
14.60 kU/L; interquartile range, 6.08-31.20). However, 5 of 30
(16.1%) subjects sensitized to hazelnut but not birch pollen had
IgE against Cor a 1 (median, 4.07 kU/L; interquartile range,
0.85-6.48).
IgE to Cor a 8 correlated weakly (r< 0.55) with that to
Chenopodium, plane tree, mugwort, and Parietaria pollen.
Sensitization to these pollen was frequent in Athens, Madrid,
and Milan (see Table E8; also see Fig E2 in this article’s Online
Repository at www.jacionline.org), but only in Athens were
these correlations stronger compared with the total population
(r50.78, 0.71, 0.71, and 0.66, respectively; P5.001).
Patients sensitized to profilin (Cor a 2) and to CCD were
sensitized to virtually all pollen species (92%-100%). Surpris-
ingly, correlations between IgE against Cor a 12 and pollens
followed a very similar pattern. IgE to Cor a 9, Cor a 11, and Cor a
14 showed only very weak correlations to those against pollen.
Sensitization to other foods in a molecular
perspective
IgE to other foods was observed in almost all subjects
sensitized to hazelnut (92.9%), but the pattern of food sensitiza-
tions varied with the spectrum of hazelnut allergens recognized
(Fig 5,B; see Table E10 in this article’s Online Repository at
www.jacionline.org). Peach and apple IgE correlated with Cor a
1 and Cor a 2, although not in Athens, Madrid, and Milan. In these
cities, IgE against peach and apple correlated with that against
Cor a 8 in Athens (r50.95 and 0.94; P< .001) and Milan
(r50.68 and 0.66; P< .001). In Madrid, IgE only to peach
correlated with Cor a 8 (r50.63; P< .04).
Overall, however, IgE to Cor a 8 most closely correlated with
IgE to walnut, corn, and lentil. Walnut sensitization was very
common in Athens (92.8%) and Madrid (100.0%) than in other
cities (14.3% to 38%). IgE to walnut and Cor a 8 correlated highly
in Athens (r50.94; P< .001), but no significant correlation was
FIG 3. sIgE to hazelnut allergens in a subset of the population with hazelnut allergy (n 5423). Median sIgE
values and interquartile range are indicated with black lines. The dotted lines indicate the cutoff IgE level at
0.35 kU
A
/L. The number with positive IgE (>_0.35 kU
A
/L) is indicated for each hazelnut allergen.
J ALLERGY CLIN IMMUNOL
nnn 2015
6DATEMA ET AL
found in Madrid (see Fig E3 in this article’s Online Repository at
www.jacionline.org).
IgE responses to Cor a 9 and 14 showed weak correlations with
those to tree nuts (r<_ 0.57), seeds, and legumes. IgE correlations
between walnut and Cor a 9 were stronger in Utrecht and Prague
(r50.70 and 0.78) than in the total population (r50.57). No
such correlations were observed in Athens and Madrid.
IgE to Cor a 12 correlated moderately with IgE to oil-rich foods
such as tree nuts, seeds, and legumes, and surprisingly also to
melon and banana. No city-specific differences were observed for
these correlations. Fig E4 in this article’s Online Repository
shows correlations between IgE to walnut and soybean and Cor
a 9 and Cor a 12.
Finally, latex IgE correlated with all hazelnut allergens except
Cor a 1 and was strongest for Cor a 12, Cor a 2, and CCD.
DISCUSSION
In the present study, the largest case series on hazelnut allergy
ever performed was analyzed across Europe. Although the study
was not a general population-based survey, the inclusion of
consecutive patients coming into the clinic over a longer period of
time gives an indication of the magnitude of the problem of
hazelnut allergy across Europe. This study indicates that hazelnut
allergy is far less common in cities such as Athens, Madrid,
Reykjavik, and Sofia than in other European cities, similar to what
has been reported in population-based surveys.
21,25
One probable
explanation is the low exposure to birch pollen in these 4 cities
26
because IgE levels against hazelnut and birch are much lower than
in other cities (median IgE, <4 vs 8-30 kU
A
/L).
Birch pollen exposure has a dominant role in the occurrence of
hazelnut allergy.
21,25
The high frequency and magnitude of IgE
responses against Cor a 1 clearly support that, in most of our cit-
ies, birch pollen sensitization (ie, Bet v 1-Cor a 1 cross-reactivity)
is the driving force. In a small group, Cor a 1 sensitization was
observed in the absence of birch sensitization. This has also
been reported in hazelnut-sensitized children from the
Netherlands.
27
Although we cannot exclude direct food-driven
sensitization to hazelnut Cor a 1, it is perhaps more likely that
sensitization to pollen of other Fagales species, such as hazel,
oak, alder, or beech, might induce IgE antibodies cross-reactive
with Cor a 1.
FIG 4. Sensitization to hazelnut allergens stratified by city. Sensitization to single hazelnut allergens was
measured in a subpopulation (Sofia excluded) of the patients with allergy to hazelnut. The bars show the
percentage of patients with positive test results for each allergen.
J ALLERGY CLIN IMMUNOL
VOLUME nnn, NUMBER nn
DATEMA ET AL 7
Although the role of birch pollen as a dominant source of
sensitization for Cor a 1 is not disputed, the situation is more
complex for Cor a 8. A long-standing assumption is that
sensitization to LTP is a Mediterranean phenomenon.
6
The
dominant Cor a 8 profile in Athens and Madrid confirms this.
The currently prevailing opinion is that peach Pru p 3 induces
sensitization to other food LTPs. In Athens and Madrid, IgE to
Cor a 8 correlates strongly with that to peach (r50.68 and
0.95, respectively). However, the high frequency of walnut
sensitization (93%) and the strong correlation between Cor a 8
and walnut IgE (r50.94) in Athens suggest that a walnut-rich
diet could also be relevant for hazelnut sensitization. However,
several studies have demonstrated that sensitization to
mugwort and plane tree pollen LTP also plays a role in the
‘‘LTP-syndrome.’’
19,28-30
We found correlations between IgE to
Cor a 8 and IgE to weed and tree pollen, although weaker than
those to peach, apple, and walnut. Whether the associated foods
or pollens act as the primary cause of sensitization to Cor a 8
cannot easily be inferred from available data. Mediterranean
patients are perhaps geographically not likely to develop
LTP-driven food allergies, but less prone to develop birch
pollen–associated food allergies. Future studies, in particular
IgE inhibition assays, are needed to unravel the possible primary
source of sensitization to LTPs.
The geographical distribution of sensitization to seed storage
proteins (Cor a 9, Cor a 11, and Cor a 14) is less clear. Although
relatively more subjects from Prague, Reykjavik, Utrecht,
Manchester, and Madrid were sensitized to these allergens, the
total numbers are low (n 52-9). Other studies have shown
sensitization for Cor a 9 and Cor a 14 to occur preferentially in
FIG 5. Heat plots. A, Correlation between IgE to individual hazelnut allergens and 9 pollens. B, Correlation
between single hazelnut allergens and 23 foods and latex. Each color indicates the strength in correlation
of IgE levels to hazelnut allergens with pollen, foods, and latex. White: Spearman r< 0.4; red: Spearman
r0.4-0.92.
J ALLERGY CLIN IMMUNOL
nnn 2015
8DATEMA ET AL
younger children,
5,20,31
and we also observed significant
differences between children and adults (42% vs 5.8%).
These proportional differences can be explained by more Bet
v-1–related sensitization later in life (adults showed a
significantly higher proportion of Cor a 1 sensitization) causing
a diluting effect of hazelnut storage protein sensitization in adults.
Storage protein IgE correlates relatively weakly with other foods.
This may indicate that sensitization to these proteins is driven by
hazelnut consumption and sensitization to other foods are
independent cosensitizations.
Of interest are the sensitization patterns observed for hazelnut
oleosin (Cor a 12). To date, very little is known about allergic
reactions to oleosin in foods and have so far been reported only for
peanut,
32
sesame seed,
33
and buckwheat.
34
Hazelnut oleosin was
first described by Akkerdaas et al
15
and has recently been
associated with severe symptoms.
16
Our data show that hazelnut
oleosin sensitization is not uncommon in Europe. IgE against Cor
a 12 correlated with sensitization to many foods, in particular
oil-rich tree nuts, seeds, and legumes. Interestingly, the pattern
of associations to pollen sensitization was very similar to that
observed for Cor a 2 and CCD. Oleosins have been identified in
pollen as well,
35
so it cannot be excluded that pollens play a
role in sensitization to oleosins.
IgE against both Cor a 2 and CCD were associated with all
pollen species as true panallergenic structures. Surprisingly, the
closest correlation was with olive and cypress pollen and not with
grass pollen. Foods that have previously been linked to profilin
sensitization were closely associated in the present study as well:
carrot, celery, peach, tomato, and melon.
36-41
Some limitations of the present study have to be considered.
Although we performed the largest series of DBPCFCs for
hazelnut, still 83% of those reporting hazelnut allergy were not
challenged. Moreover, the number of challenges carried out was
unbalanced between cities. However, this is the most
comprehensive standardized study so far with respect to
sensitization and allergy to hazelnut. What can we say about
the place of the 3 tests for sensitization in an outpatient clinic
setting? Sensitivity of CRD with 7 allergens together is higher
than that of conventional hazelnut ImmunoCAP or SPT, but
probably too costly for routine application. A more realistic
approach, with a minimal loss of sensitivity (93.8% vs 91.2%),
would be to test IgE against Cor a 1, Cor a 8, and Cor a 14. For
simply assessing whether reported hazelnut allergy is supported
by sensitization, SPT or hazelnut ImmunoCAP is most likely
appropriate and more feasible. None of the 3 tests has a useful
specificity (10% to 30%), maintaining that the DBPCFC still
remains an important diagnostic procedure in cases in which
clinical relevance needs to be established. Having said that, CRD
has revealed associations between the outcome of a DBPCFC
including severity and specific allergens.
20
This certainly is an
added value of CRD, allowing better assessment of the risk of
severe reactions. Currently, we are analyzing the patients’
sensitization pattern reported here for associations of reported
symptoms in real life and during DBPCFC with sIgE against in-
dividual allergens.
In conclusion, our study has mapped hazelnut allergy across
Europe. Major differences in the number of cases were observed
across Europe, which are largely explained by differences in
exposure to birch pollen. This dominant cross-reactive phenom-
enon explains the lower sensitization rates to storage proteins,
oleosins, and LTPs. A dominance of Cor a 8 (LTP) was confirmed
for the Mediterranean basin, in particular for Athens, but the
source of primary sensitization is still not completely certain.
Finally, oleosin sensitization is observed across the whole of
Europe but whether pollen plays a role in sensitization to oleosins
needs to be established.
We thank ALK-Abello for providing the SPT reagents for this study. We
also thank Lothar Vogel for his involvement in the serum screening and
selection and thank all the patients who volunteered to participate in the
EuroPrevall studies.
Key messages
dSimilar to what has been described for North-Western
Europe, birch pollen exposure drives hazelnut allergy in
Central and North-Eastern Europe.
dSensitization to hazelnut storage proteins is observed
across Europe, with its relative importance decreasing
with age because of the increasing role of pollen cross-
reactivity.
dAs reported for Spain and Italy, hazelnut allergy in
Greece is an LTP-driven phenomenon, closely associated
not only with peach but also with walnut, and to a lesser
extent with pollen sensitizations.
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