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Birch allergy and oral allergy syndrome: The practical
relevance of serum immunoglobulin E to Bet v 1
Giorgio Ciprandi, M.D.,
1
Paola Comite, M.D.,
2
Francesca Ferrero, B.S.,
2
Donatella Bignardi, M.D.,
1
Paola Minale, M.D.,
1
Susanna Voltolini, M.D.,
1
Costantino Troise, M.D.,
1
and Michele Mussap, M.D.
2
ABSTRACT
Background: Birch allergy (BA) may frequently be associated with fruit-vegetables oral allergy syndrome (OAS). Bet v 1
is the major birch allergen. Previously, it was reported that serum-specific immunoglobulin E (IgE) level could differentiate
allergy from sensitization. Thus, this study aimed to investigate the practical role of Bet v 1 IgE.
Methods: A total of 245 subjects (128 women, 117 men; mean age, 41 years) with suspected allergic rhinitis and
sensitization to Bet v 1 were evaluated. Serum IgE to Bet v 1 was assessed by using immuno-enzymatic. BA and OAS were
diagnosed according to validated criteria. Symptom severity perception was measured by the visual analog scale.
Results: A total of 158 patients (64.5%) had BA. Patients with BA had higher serum Bet v 1 IgE levels than subjects who
were sensitized (p ⬍0.0001). A cutoff value of 8.94 kUA/L predicted BA (area under the curve, 0.76; odds ratio, 6.18).
Fifty-three patients with BA (33.5%) had OAS. Patients positive for OAS had higher Bet v 1 levels (p ⬍0.0001) and
more-severe symptoms (p ⬍0.0001) than patients with BA and negative for OAS. A cutoff value of 17.4 kUA/L predicted OAS
(area under the curve, 0.59; odds ratio, 3.19).
Conclusions: The present study demonstrated that serum IgE levels to Bet v 1 could be a useful marker for differentiating
between different birch pollen sensitization phenotypes.
(Allergy Asthma Proc 37:43–49, 2016; doi: 10.2500/aap.2016.37.3914)
Allergic rhinitis (AR) is the most common allergic
disorder; the prevalence may be up to 40%.
1
AR
is characterized by an immunoglobulin E (IgE) medi-
ated inflammation induced by allergen exposure.
2
Al-
lergic inflammation represents the conditio sine qua non
for symptom appearance. Thus, IgE may be a conceiv-
able biomarker of allergy. The most common allergens
that cause AR are mites and pollens. In this regard,
there is a relatively restricted number of weeds and
plants able to elicit an allergic response.
The order Fagales accounts for eight families, includ-
ing Betulaceae, which can be divided into Betuloideae
(mainly the genera birch and alder) and Coryloideae
(mainly the genera hazel, hornbeam, hop-hornbeam,
and Ostryopsis). The pollens of the Betulaceae family
are a frequent cause of AR, mainly in northern and
central Europe.
3
The major birch pollen allergen is Bet
v 1, which is a pathogenesis-related molecule (PR-10);
Bet v 1 shares a molecular homology with many plants
of the Betulaceae family.
4
So, generally speaking, birch
allergy (BA) may define a series of allergies to different
Betulaceae pollen allergens, having homology with Bet
v 1 molecule. In our geographic area, BA is frequent;
⬃50% of patients with AR are sensitized to Betulaceae
pollens.
5
However, oral allergy syndrome (OAS) is a common
allergic disorder sustained by a pollen-fruit cross-reac-
tion. OAS is defined by the occurrence of itching and
tingling of the lips, mouth, and throat immediately
after eating some fruits and vegetables.
6
The most fre-
quent OAS is when patients with BA eat fruits from the
Rosaceae family, including, essentially, stone fruits
(mainly apple) and hazelnut.
6,7
The prevalence of OAS
in patients with allergies to Betulaceae pollen has var-
ied from 25% to 90%, even though it generally is
agreed that ⬎70% of patients with BA also have
OAS.
6–10
It is noted that pollen-related symptoms are
typically seasonal, such as after pollen allergen expo-
sure, whereas OAS-related symptoms usually persist
throughout the year. From a pathophysiologic point of
view, the BA-associated OAS depends on the molecu-
lar homology between the Betv1ofBetulaceae pollens
and the Bet v 1 homologs of hazelnut (Cor a 1) or of
Rosaceae fruits, which include apple, peach, pear, apri-
cot, and cherry. In effect, it has been demonstrated that
Mal d 1, the major allergen of apple, shares sequence
homology with Bet v 1.
11
In addition, Mal d 1 may be
considered a reliable diagnostic tool for birch pollen
allergen–associated apple allergy.
12
Recently, it was
reported that patients with AR due to BA and with
OAS had higher serum IgE levels to Bet v 1 than
patients with BA rhinitis but without OAS.
13
However,
From the
1
Allergy Department and
2
Laboratory Medicine Department, Istituto di
Ricovero e Cura a Carattere Scientifico-Azienda Ospedaliera-Universitaria San Mar-
tino, Genoa, Italy
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence to Giorgio Ciprandi, M.D., Allergy Department, IRCCS-
AOU San Martino, Largo R. Benzi 10, 16132 Genoa, Italy
E-mail address: gio.cip@libero.it
Copyright ©2016, OceanSide Publications, Inc., U.S.A.
Allergy and Asthma Proceedings 43
DO NOT COPY
further conflicting results were obtained as measure-
ments of IgE, IgG4, and IgA specific to Bet v 1–associ-
ated food allergens of the Rosaceae family did not
predict OAS.
14
From a clinical point of view, the BA workup is
based on a step-by-step pathway that starts from dif-
ferentiating between simple sensitization and true al-
lergy up to diagnosing OAS. In this regard, it is impor-
tant to clearly define the terms of sensitization and
allergy. Sensitization means the production of allergen-
specific IgE. Allergy is the presence of clinical symp-
toms that occur after exposure to the sensitizing aller-
gen. Thus, the two terms are not synonymous. In other
words, a subject may be sensitized to an allergen but
not necessarily allergic, whereas subjects with allergy
should be necessarily sensitized.
Previously, it was reported that serum IgE levels to
allergen extracts might be able to define allergy better
than a skin testing score.
15
We hypothesized that as-
sessment of serum IgE to Bet v 1 could be able to define
true BA and OAS. Therefore, this study aimed to test
this hypothesis in a group of adult patients with sen-
sitization to Bet v 1.
MATERIALS AND METHODS
This retrospective study consisted of 245 subjects
(128 women, 117 men; mean age, 41 years) who, during
2014, were referred to the allergy department for sus-
pected AR. Inclusion criteria were serum IgE positivity
to Bet v 1, e.g., ⬎0.35 kUA/L, and reported nasal
symptoms. The study was performed according to the
Review Board rules of the hospital. The Institutional
Review Board protocol was approved by Istituto di
Ricovero e Cura a Carattere Scientifico-Azienda Os-
pedaliera-Universitaria San Martino of Genoa Institu-
tion, according to the guidelines set forth by the Italian
Ministry of Health.
The first step was the differentiation between simple
sensitization and true allergy to Betulaceae pollen. Sen-
sitization is defined by IgE positivity without symp-
toms after exposure to Betulaceae pollen. BA is defined
by consistency between IgE positivity and symptoms
that occur after Betulaceae pollen inhalation. The sec-
ond step was the identification of patients with BA and
also with OAS. The presence of OAS was clinically
assessed by the patient’s history positive for experienc-
ing oropharyngeal itching immediately after eating
any type of fresh fruits or vegetables related to Bet v 1
allergens according to previous reports.
13,14,16
More-
over, the presence of comorbidities, including conjunc-
tivitis and asthma, was investigated. AR symptom se-
verity perception was assessed by using the visual
analog scale (VAS) in patients with BA.
Serum IgE Assay
Serum levels of specific IgE for Bet v 1 were detected
by the immunofluorimetric assay procedure (Immuno-
CAP Thermo Fisher Scientific, Uppsala, Sweden) in
peripheral blood samples from patients. Serum was
collected into gel-separator tubes, centrifuged, and
stored at ⫺20°C until analysis. Measurement of circu-
lating specific IgE antibodies was performed according
to manufacturer’s instructions.
17
Specific IgE levels
were expressed in kUA/L according to the traceable
calibration to the second International Reference Prep-
aration World Health Organization for Human IgE and
0.35 kUA/L has been considered as a cutoff.
18
VAS
The VAS was a 10-cm vertical line on which 0 im-
plied no respiratory symptom, while 10 corresponded
to the most severe respiratory symptoms.
19
Initially,
patients were instructed to make a mark on the line
indicating their symptom perception at that moment.
Thus, the lower was the numerical score marked by the
patient, the greater was the perceived symptom sever-
ity. With a movable marker, the subject could mark any
point on the 10-cm segment that best described his or
her perception. No interval marker was visible on the
line.
Statistical Analysis
Medians and percentiles (25th and 75th interquartile
range) were used as descriptive statistics. The Wil-
coxon, Friedman, and Mann-Whitney tests were used
to compare samples. In addition, a receiver operating
characteristic curve analysis was performed to deter-
mine a cutoff for specific IgE, which could optimize the
sensitivity and specificity of the test, to identify re-
sponder subjects. A pvalue of ⱕ0.05 was considered
statistically significant. All the data were analyzed by
using the Stata statistical package, Release 13.1 Statis-
tical Software. (StataCorp, College Station, TX).
RESULTS
Differentiation between Bet v 1 Sensitization and BA
In this group, 245 patients with sensitization to Bet v
1 were evaluated. When considering the appearance of
AR symptoms during the Betulaceae pollen season,
such as between February and April in our geographic
area, the diagnosis of BA was found in 158 patients
(64.5%) (Fig. 1). Patients with allergy had significantly
(p⬍0.0001) higher serum IgE levels (median [standard
deviation {SD}], 18.4 ⫾19.4 kUA/L), with a positive
predictive value of 85.2, negative predictive value of
51.8, likelihood ratio positive of 3.17, and likelihood
ratio negative of 0.51 than sensitized subjects (median
[SD], 7.0 ⫾12.4), as shown in Fig. 1. In addition,
44 January–February 2016, Vol. 37, No. 1
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receiver operating characteristic methodology pointed
out a high overall accuracy for defining BA (area under
the curve 0.76 [95% confidence interval], 0.69, 0.81)
(Fig. 1). Based on the Youden Index, the following
cutoff value was estimated: 8.94 kUA/L (sensitivity,
58.3%; specificity, 81.61%). Given that patients with
allergy had a higher geometric mean value for Bet v 1
IgE, BA could be defined when Bet v 1 IgE was ⱖ8.94
kUA/L. The odds ratio was 6.18 kUA/L.
Differentiation between Patients Positive for OAS
and Patients Negative for OAS
In this group, 158 patients (79 men; mean age, 43
years) with BA were analyzed. When considering the
appearance of oropharyngeal symptoms after eating
Rosaceae fruits, the diagnosis for OAS was performed,
on a clinical basis, in 53 patients (33.5%), as shown in
Fig. 2. In this group, 35 patients (66%) had a mono-fruit
OAS. In particular, the most frequently reported fruits
that caused a symptom were apple (44 patients), peach
(22), hazelnut (13), apricot (9), and cherry (8).
There were some significant differences among the
three subgroups regarding Bet v 1 serum IgE levels
(p⬍0.001), frequency of polysensitization (p⫽0.016),
conjunctivitis (p⫽0.007), asthma (p⫽0.003), rhinitis
(p⫽0.001), and VAS score (p⬍0.001), as reported in
Table 1. Particularly, there were differences between
subjects with allergy alone and patients with allergy
and with OAS of Bet v 1 IgE (p⬍0.001), conjunctivitis
(p⫽0.038), and VAS score (p⬍0.0001).
VAS values for AR symptoms were significantly (p⬍
0.0001) higher in patients positive for OAS (median
[SD], 7.2 ⫾1.1) than in patients negative for OAS
(median [SD], 4.8 ⫾0.9). In addition, patients with
OAS had significantly (p⬍0.001) higher serum IgE
levels (median [SD], 21.3 ⫾20.0 kUA/L) than patients
negative for OAS negative (median [SD], 9.7 ⫾19.6)
with positive predictive value of 49.2, negative predic-
tive value of 75.8, likelihood ratio positive of 1.92,
likelihood ratio negative of 0.63. Based on the Youden
Index, the following cutoff value was estimated: 17.4
kUA/L. The cutoff was able to differentiate patients
Figure 1. Upper left quadrant, percentages of patients sensitized and patients allergic to Bet v 1. Upper right quadrant, serum immuno-
globulin (IgE) levels to Betv1inpatients sensitized and patients with allergy. Data are expressed as median and interquartile range. Lower
quadrant, receiver operating characteristic curve to define the cutoff level for Bet v 1 IgE able to differentiate allergy from sensitization.
Allergy and Asthma Proceedings 45
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positive for OAS and patients negative for OAS with a
fair reliability (AUC 0.59 [95% confidence interval,
0.51–0.67]; sensitivity, 54.72; specificity, 71.4, with an
odds ratio of 3.19.
DISCUSSION
Allergy to Betulaceae pollen allergens is common in
our geographic area.
20
Betv1isthemajor birch pollen
allergen because 95% of patients with BA are Bet v 1
sensitized. Several homologous pollen allergens have
been characterized from Fagales-related species, in-
cluding alder (Aln g 1), hornbeam (Car b 1), hop-
hornbeam (Ost c 1), chestnut (Cas s 1), hazel (Cor a 1),
and oak (Que a 1).
21
Therefore, Bet v 1 assessment is
useful in the common practice,
22
and the term BA
commonly includes patients with allergy to any Betu-
laceae species. It is also noted that Bet v 1 sensitization
may occur in the absence of the Bet v 1 natural source,
e.g., a birch-free area.
23
Bet v 1 may co-react to the order
Fagales (such as birch, hazel, hornbeam, hop-horn-
beam, and oak).
24
So, molecular diagnostics may be
fruitful in defining Bet v 1–associated sensitizations.
25
However, the management of OAS is still debated,
26,27
mainly regarding the role of molecular diagnosis,
28,29
even though measuring PR-10 proteins was a reliable
tool for diagnosing apple-mediated OAS in birch
pollen allergy.
30
BA-related OAS might depend on
cross-reactivity between Bet v 1 and structurally ho-
mologous food proteins contained in some Rosaceae
fruits, such as apple (Mal d 1), hazelnut (Cor a 1),
peach (Pru p 1), pear (Pyr c 1), apricot (Pru ar 1), and
cherry (Pru av 1).
31
Because patients with BA and OAS have a more-
intense Bet v 1–induced T-cell proliferation than pa-
tients with BA and without OAS,
32
the present study
tested two main hypotheses concerning the role of IgE
to Bet v 1 as a tool able to differentiate sensitization
from BA and to verify whether OAS may characterize
a particular BA phenotype.
The first part of the study showed that not all sub-
jects sensitized to Bet v 1 were apparently truly aller-
gic. Actually, approximately two-thirds of the patients
had BA. This finding confirmed the paradigm that
sensitization does not correspond with real allergy.
In addition, these findings were also consistent with
a previous report, viz. patients with allergy have
Figure 2. Upper left quadrant, percentages of patients with birch allergy without oral allergy syndrome (OAS) or those with OAS. Upper
right quadrant, visual analog scale (VAS) values in patients without OAS and patients with OAS. Lower left quadrant, receiver operating
characteristic curve to define the cutoff level for Bet v 1 immunoglobulin E (IgE) able to define OAS. Lower right quadrant, serum IgE levels
toBetv1inpatients without OAS and patients with OAS. Data are expressed as median and interquartile range.
46 January–February 2016, Vol. 37, No. 1
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Table 1 Demographic and clinical characteristics of subjects when considering sensitization (A), allergy
alone (B), and allergy plus OAS (C)
A(nⴝ87) B (nⴝ105) C (nⴝ53) ABC BC Post Hoc, Mann-
WhitneyBirch
Sensitized
Alone
Birch
Allergy
Alone
Birch
Allergy ⴙ
OAS
p Value,
Friedman
p Value,
Friedman
Age, y 39 43 41 0.204 Sensitized vs allergy
alone, p⫽0.0680;
sensitized
vs allergy ⫹OAS
allergy, p⫽0.2011;
allergy alone
vs allergy ⫹OAS,
p⫽0.5781
Men, no. (%) 38 (44) 58 (41) 21 (40) 0.491 Sensitized vs allergy
alone, p⫽0.1135;
sensitized
vs allergy ⫹OAS
allergy, p⫽0.6411;
allergy alone
vs allergy ⫹OAS,
p⫽0.0663
Bet v 1 IgE level,
mean (SD)
7⫾12.4 9.7 ⫾19.6 21.3 ⫾20 ⬍0.001 Sensitized vs allergy
alone, p⫽⬍0.0001;
sensitized vs
allergy ⫹OAS
allergy, p⫽
⬍0.0001; allergy
alone vs allergy ⫹
OAS, p⫽⬍0.001
Polysensitization,
no. (%)
72 (82) 97 (92) 47 (89) 0.016 Sensitized vs allergy
alone, p⫽0.0455;
sensitized vs
allergy ⫹OAS
allergy, p⫽
⬍0.3528; allergy
alone vs allergy ⫹
OAS, p⫽0.4553
Conjunctivitis,
no. (%)
0 (0) 66 (63) 42 (79) 0.007 Allergy alone vs
allergy ⫹OAS,
p⫽0.0387
Asthma, no. (%) 0 (0) 45 (43) 16 (30) 0.003 Allergy alone vs
allergy ⫹OAS,
p⫽0.1945
Rhinitis, no. (%) 0 (0) 93 (89) 51 (96) 0.001 Allergy alone vs
allergy ⫹OAS,
p⫽0.1226
VAS, mean (SD) 0 4.8 ⫾0.9 7.2 ⫾1.1 ⬍0.001 Allergy alone vs
allergy ⫹OAS,
p⫽⬍0.0001
OAS ⫽oral allergy syndrome; IgE ⫽immunoglobulin E; SD ⫽standard deviation; VAS ⫽visual analog scale.
Allergy and Asthma Proceedings 47
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higher allergen-specific serum IgE than subjects who
are sensitized.
15
More interesting from a clinical
point of view, this study provided a cutoff value for
Bet v 1–specific IgE able to distinguish between sen-
sitization and allergy, e.g., 8.94 kUA/L. Patients with
Bet v 1 IgE levels of ⬎9 had a probability approxi-
mately six times (odds ratio, 6.2) higher of having BA
than patients with lower IgE levels. This outcome
was relevant because this value may be useful in
some doubtful situations, for instance, concerning
patients who are polysensitized when it is difficult to
recognize the exact pollen season. Therefore, the first
step of the present study could indicate the assess-
ment of serum Bet v 1 IgE as a useful tool for patients
with suspected pollen allergy.
The second part of the study focused on OAS in
patients with BA. In our area, only one-third of patients
with BA (33.5%) had OAS. This finding conflicted with
previous reports conducted in northern Italy
16
but was
consistent with a pediatric survey.
33
Asero et al.
16
found that patients positive for OAS were ⬃60% of the
recruited BA cohort. This result could be explained
when considering the particular characteristic of the
flora in the Genoa territory. Actually, Genoa may be
considered a birch-free area, whereas there is a wide
distribution of hop-hornbeam (Ostrya carpinifolia),
which belongs to the Betulaceae family. The allergen of
hop-hornbeam has been identified and characterized
as Ost c 1, such as a Bet v 1 homologous.
34
In particular,
based on IgE-binding experiments, it has been specu-
lated that the allergy to Fagales allergens is initiated by
an independent sensitization against a specific member
of the Betuloideae or the Coryloideae family.
35
Further,
a cross-reactivity could progress to Bet v 1-homologues
proteins. Therefore, the allergenic characteristic of Ost
c 1 could explain the low percentage of patients posi-
tive for OAS in our area, even though we did not
document it. This concept is consistent with a previous
study that demonstrated a different pattern of sensiti-
zation that compared Italian patients living in a birch-
free area with Austrian patients exposed to Bet v 1.
36
These outcomes, therefore, could indicate that Bet v 1
could be one of the allergenic proteins present in the
Ostrya pollen, possibly being responsible for a later
potential cross-reactivity with other members of taxo-
nomically related families, including pollens and fruits.
However, Ost c 1 should be responsible for the primary
sensitization that accounts for respiratory symptoms.
In addition, Fagales tree pollens show sequence iden-
tities with Bet v 1 ⬎70% among them but much lower
similarities to homologues from typical birch pollino-
sis–related fruits and vegetables.
37
Cross-reactive Bet v
1 homologues indeed share only 37–67% of their se-
quences with Bet v 1.
38
Another interesting finding was the identification of
a cutoff for Bet v 1 IgE was able to characterize patients
with OAS. This cutoff was higher than that able to
differentiate true BA. This finding might indicate the
concept that patients positive for OAS tend to have a
more strengthened IgE production than patients nega-
tive for OAS. This hypothesis might be supported by
the demonstration that patients positive for OAS per-
ceived more-severe AR symptoms than patients nega-
tive for OAS. Thus, the presence of OAS in patients
with BA might represent a characteristic able to define
two different BA phenotypes. Patients with BA and
also with OAS could correspond to a more-severe BA
phenotype. A convincing proof of this concept was the
evidence that patients with OAS have a more-intense
in vitro T-cell response to Bet v 1 than patients negative
for OAS.
32
However, this study had some limitations: it is ret-
rospective, the number of patients was relatively re-
stricted, only Bet v 1 was assessed (for economic rea-
sons because it was a real-life experience), nasal
challenge to birch was not performed as well as the IgE
assessment to offending fruits, and mediators were not
measured. In addition, the mode of diagnosis based on
patients’ report of symptoms was not always credible
or reliable, and the absence of allergy symptoms re-
ported by individuals in the sensitization-only group
could be because they were not living in an area where
there is significant exposure to birch pollens. Thus,
further studies should address these issues.
CONCLUSION
The present study demonstrated that the serum IgE
level to Bet v 1 could be a useful marker for differen-
tiating among different birch pollen sensitization phe-
notypes.
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