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Allergology International 64 (2015) 35e40
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Allergology International
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Original article
The prevalence of Hymenoptera venom allergy in adults: The resultsof a very crowded city in Euroasia
Aslı Gelincik a, *, Halim _Issever b, Derya Unal a, Erol Isık b, Mustafa Demirturk a,Hülya Gül b, Raim _Iliaz a, Erdal Kara a, Belkıs Ertek a, Ferhan €Ozseker a,Bahattin Çolako�glu a, Suna Büyük€oztürk a
a Division of Allergy, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkeyb Department of Public Health, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
a r t i c l e i n f o
Article history:Received 22 May 2014Received in revised form16 June 2014Accepted 22 June 2014Available online 13 October 2014
Keywords:AnaphylaxisEpidemiologyAdrenalineHymenoptera venom allergyPrevalence
* Corresponding author. Division of Allergy, DepaIstanbul Faculty of Medicine, Istanbul University, MilleTurkey.
E-mail address: gelincikasli@hotmail.com (A. GelinPeer review under responsibility of Japanese Soci
http://dx.doi.org/10.1016/j.alit.2014.10.0011323-8930/Copyright © 2014, Japanese Society of Alle
a b s t r a c t
Background: There are scarce data about the prevalence of Hymenoptera venom allergy in the generalpopulation. The aim of this study was to determine the prevalence of Hymenoptera venom allergy in thegeneral adult population of Istanbul.Methods: A total of 17,064 randomly selected telephone numbers were contacted and 11,816 (69.25%)individuals who agreed to participate completed a questionnaire. Those who disclosed hypersensitivityreactions due to Hymenoptera stings in this initial survey were called again and given another ques-tionnaire. Those who were suspected of experiencing hypersensitivity reactions to Hymenoptera stingswere invited for a clinical investigation with in vivo and in vitro diagnostic tests.Results: According to the first questionnaire, a total of 1171 (9.9%; 95% CI: 9.38e10.47%) were suspectedof having a hypersensitivity to Hymenoptera stings. 51.75% (n: 606) answered the second questionnaireand 21% (n: 128) of these were still suspected of having a hypersensitivity to Hymenoptera stings (1.1%;95% CI: 0.9e1.29%). The confirmed prevalence of hypersensitivity to Hymenoptera stings according toskin tests and in vitro sIgE levels was 0.2% (95% CI: 0.14e0.30%). Nearly all of the participants withsystemic reactions were admitted to the emergency department, although only one tenth of themreceived adrenaline in the emergency room. 2.3% carried an adrenaline injector, whereas none of thepatients received venom immunotherapy.Conclusions: The prevalence of Hymenoptera sting reactions in our geographical region is comparablewith other European studies. There is a need to increase the awareness of adrenaline in the emergencymanagement of insect sting anaphylaxis and venom immunotherapy in the prophylaxis.Copyright © 2014, Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
Introduction
The prevalence of self-reported systemic Hymenoptera stingreactions among adults ranges from 0.5% to 3.3% in the US whileEuropean epidemiological studies report the prevalence of sys-temic reactions between 0.3% and 7.5%.1,2 Similarly, the prevalenceof large local reactions in the general population ranges from 2.4%to 26.4% in many studies.2 This wide variation may depend on the
rtment of Internal Medicine,t Street, Capa, Fatih, Istanbul,
cik).ety of Allergology.
rgology. Production and hosting by Els
different definitions of the large local reactions, the degree ofexposure and the study population.3,4
The prevalence of Hymenoptera venom allergy in adults wasevaluated in a number of studies conducted in Turkey.5e7 In each ofthese studies, a selected population such as factory workers, bee-keepers or hospital patients was used to determine the prevalenceof insect allergies in Turkey. However, in developing countries likeTurkey there is a need for large population-based studies whichreport both the results of a questionnaire as well as skin andserological tests that can confirm case histories and evaluate thegeneral prevalence of Hymenoptera allergy.
The aim of this study was to determine the prevalence of Hy-menoptera venom allergy in the general adult population ofIstanbul, the biggest city in Turkey with approximately 14 millioninhabitants.
evier B.V. All rights reserved.
A. Gelincik et al. / Allergology International 64 (2015) 35e4036
Methods
Study design
In the previous study of our group which evaluated the preva-lence of allergies including hypersensitivity reactions to Hyme-noptera stings, randomly selected telephone numbers from boththe European and Asian sides of Istanbul were contacted in2005e2006.8 A total of 17,064 telephone numbers were called, ofwhich 11,816 (69.25%) individuals completed a questionnaireincluding hypersensitivity reactions to Hymenoptera stings as wellas 8 questions relating to general allergic diseases. Those whodisclosed hypersensitivity reactions due to Hymenoptera stings inthis survey were called again in 2010e2011 and given anotherquestionnaire that focused on the details of these reactions. Thosewho were suspected of experiencing large local and systemic hy-persensitivity reactions to Hymenoptera stings were invited for apersonal investigation at the clinic.
Questionnaires
The first questionnaire inquired about hypersensitivity re-actions due to Hymenoptera stings in addition to other atopicdiseases. The reliability of the questions, as well as the sensitivityand specificity of the questionnaire were controlled.8 The exactquestion related to Hymenoptera reactions in the first call was‘Have you ever experienced an allergic reaction due to a Hyme-noptera sting?’ Participants who replied ‘YES’ to this question werealso asked the following two questions: If yes, was/were this/thesereaction/s local or systemic? If yes, was the culprit insect a bee or awasp?
The second questionnaire was conducted again with telephonecontacts with participants who had answered ‘YES’ to the firstquestion related to Hymenoptera stings. This questionnaire wasgiven by allergy specialists who were capable of providing detailedinformation about the questions when necessary, therebyincreasing the quality of the interviews (Table 1). The systemicreactions were classified according to Ring and Messmer and thedefinition of systemic and large local reactions were made ac-cording to the recent EAACI position paper.2,9 According to thisdetailed questionnaire, those who had experienced hypersensitiv-ity reactions and wanted to participate were invited to the clinic.
Table 1The second questionnaire conducted with 1171 particquestionnaire.
Investigations at the clinic
During the investigations at the clinic, a detailed personal his-tory was taken; additionally, skin prick tests were applied withstandard extracts of Apis mellifera, Vespula spp., Polistes spp. (100 mg/ml; Alk-Abello, Spain), positive (10 mg/ml histamine), and negative(saline) controls on the volar surface of the forearm. Tests wereconducted at least 3 weeks after a sting reaction to avoid false-negative results during the refractory period. Prick tests wereregarded as positive when the wheal diameter was at least 3 mmand were equal to 60% of that induced by histamine without re-action of the negative control after 15 min. Intradermal tests withthe standard extracts of the same venom allergens (Alk-Abello)were applied in tenfold increasing concentrations from 0.00001 mg/ml to a maximum of 1 mg/ml of 0.02 ml of venom respectively inpatients whose skin prick tests revealed negative results. An in-tradermal test was considered positive at a meanwheal diameter ofat least 5 mmwith erythema.10 Additionally, sIgE concentrations ofA. mellifera, Vespula spp., Polistes spp., and tryptase levels weredetected using UNICAP (Phadia, Uppsala, Sweden) in the sera of thesubjects. sIgE levels below 0.35 kU/L were regarded as negative.Values in the ranges of 0.35e0.69 kU/L, 0.70e3.49 kU/L,3.50e17.4 kU/L, 17.5e52.4 kU/L, 52.5e99.9 kU/L and >100 kU/Lwere considered as class I to class VI respectively. The normaltryptase level was below 11.4 ng/ml. Patients were not stingchallenged.
All the stages of the study were approved by the InstitutionalEthical Committee (2012/444-1002). Informed consent forms werecollected from patients who were investigated in the clinic.
Statistical analyses
The sample size of the study population was calculated in ourprevious study.8 Univariate analyses of categorical variables (age,familial atopy, household pets, nasal allergy, itching dermatitis/urticaria, doctor-diagnosed asthma, smoking habits) were con-ducted using Pearson's X2 test. Multivariate logistic regression(forward LR) models were performed to examine the associationbetween the suspicion of hypersensitivity to Hymenoptera stingsand the categorical variables found significant in the univariateanalyses. These included age, familial atopy, symptoms of nasalallergy and itching dermatitis/urticaria. Odds ratios (OR) were
ipants who were gathered according to the first
Table
2Th
ecalculatedself-rep
ortedpreva
lence
ofhy
persensitivity
toHym
enop
tera
stings
dep
endingon
agean
dsexacco
rdingto
thefirstqu
estion
naire.
Prev
alen
ceof
hyp
ersensitivity
System
icreaction
sLo
calreaction
sHon
eybe
eW
asp
Hon
eybe
e&
wasp
%(n)
CI(95%
)%(n)
CI(95%
)%(n)
CI(95%
)%/(n)
CI(95%
)%/(n)
CI(95%
)%(n)
CI(95%
)
Female
10(853
/861
4)9.3e
10.5
16.4
(140
/853
)14
e19
83.6
(713
/853
)80
.9e85
.972
.7(620
/853
)69
.6e75
.523
.3(199
/853
)20
.6e26
.22.3(20/85
3)1.5e
3.6
Male
10(318
/320
2)8.9e
10.9
14.8
(47/31
8)11
e19
85.2
(271
/318
)80
.9e88
.768
.6(218
/318
)63
.2e73
.423
.6(75/31
8)19
.2e28
.56(19/31
8)3.9e
9.1
18e39
years
8.7(563
/653
4)8.0e
9.4
15.1
(85/56
3)12
e18
84.9
(478
/563
)81
e87
74.8
(421
/563
)71
e78
21.8
(123
/563
)18
.6e25
.41.8(10/56
3)0.9e
3.2
40e59
years
11.4
(449
/394
7)10
.4e12
.417
.1(77/44
9)13
e20
82.9
(372
/449
)79
e86
71(319
/449
)66
.6e75
.022
.7(102
/449
)19
.0e26
.84.2(19/44
9)2.7e
6.5
60e79
years
12(146
/121
7)10
e13
16.4
(24/14
6)11
e23
83.6
(122
/146
)76
e88
60.3
(88/14
6)52
.1e67
.832
.2(47/14
6)25
.1e40
.16.8(10/14
6)3.7e
12.1
>80
years
11(13/11
8)6.6e
17.9
7.6(1/13)
1e33
92.3
(12/13
)66
e98
76.9
(10/13
)49
.7e91
.815
.4(2/13)
4.3 e
42.2
ee
A. Gelincik et al. / Allergology International 64 (2015) 35e40 37
given together with the 95% confidence interval (CI). The two-tailed p-value of <0.05 was considered significant.
Results
According to the first questionnaire, a total of 1171 (9.9%; 95%CI: 9.38e10.47%) persons had answered ‘YES’ to the first questionrelated to Hymenoptera stings. The self-reported lifetime preva-lence of hypersensitivity to Hymenoptera stings calculated for allage groups and gender is shown in Table 2. It was found as 10% forboth men (95% CI: 8.9e10.9) and women (95% CI: 9.3e10.5). Theprevalence of systemic and large local reactions and the culpritinsects are also shown in Table 3. There was no significant dif-ference between the prevalence of these reactions and the re-ported culprit insects between the age groups and the twogenders.
In the present study, people without nasal allergies, itchingdermatitis/urticaria or familial atopy were found to experiencemore hypersensitivity reactions to Hymenoptera stings. Peopleaged 40 years old and older were also found to be more affected(Table 4). Doctor-diagnosed asthma, food hypersensitivity, expo-sure to cigarette smoke or household pets did not seem to beinfluencing factors on hypersensitivity to Hymenoptera stings.
All 1171 participants with a suspected hypersensitivity to Hy-menoptera stings were called again and 51.75% (n: 606) answeredthe second questionnaire. This second contact was performed 4years after the first contact, which resulted in a reduced answerrate. 21% (n: 128) of these were suspected of having a hypersen-sitivity to Hymenoptera stings and were invited for an investiga-tion at the clinic. 84 subjects did not accept to be investigated inthe clinic. Detailed histories were taken and skin tests were per-formed on the 44 subjects who agreed to participate.
All the stages of the study are demonstrated in Fig. 1.
Sensitization evaluated by skin prick and/or intradermal tests andin vitro specific immunoglobulin E results
Skin tests or sIgE levels revealed that 24 participants weresensitized to a Hymenoptera compatible with the culprit insectin their history. The confirmed prevalence of hypersensitivity toHymenoptera stings was 0.2% (95% CI: 0.14e0.30%). 16 subjectsdescribed systemic reactions (0.14%; 95% CI: 0.08e0.22%),whereas 8 reported large local reactions (0.07%; 95% CI:0.03e0.13%).
The remaining 20 participants revealed negative results onboth skin tests and an in vitro sIgE test. 8 of these subjects hadexperienced systemic reactions with 5 of them experiencing theirreactions at least 5 or 6 years previously. As 2 subjects reportedvarious systemic symptoms after multiple simultaneous stingsand revealed negative diagnostic test results, they were regardedas having experienced toxic reactions. 10 subjects described largelocal reactions.
Skin tests and sIgE levels
Skin tests were conducted with 42 of 44 participants. The twoparticipants who rejected the skin tests were evaluated within vitro sIgE tests. Six, 3 and 1 participants were found sensitizedto solely A. mellifera, Vespula spp. and Polistes spp., respectivelywhereas 7 participants were sensitized to both A. mellifera andVespula spp., 1 participant was sensitized to both Vespula spp. andPolistes spp., and finally 4 partipants were sensitized to allextracts.
In vitro sIgE tests were carried out with 31 out of 44 partici-pants. Eight, 3 and 1 participants revealed high sIgE levels to solely
Table 3Data from the second questionnaire.
The second questionnaire Number (n) Prevalence (%)
Hymenoptera hypersensitivitysuspected
128 1.1 (95% CI: 0.9e1.29%)
Type of reactionSystemic reactions 61 0.52 (95% CI: 0.40e0.66%)Grade I 24 39.3Grade II 15 24.6Grade III 18 29.5Grade IV 4 6.6
Large local reaction 63 0.53 (95 %CI: 0.42e0.68%)Toxic reaction 4 0.03 (95% CI: 0.01e0.09%)Insect typeHoney bee 64 50Wasp 21 16.4Unknown 43 33.6
Subjects who experienced areaction within one hour ofexposure
115 89.8
Subjects who experienced morethan 1 reaction
72 56.3
Subjects who were admitted to anemergency department
56 43.8
Subjects who received adrenalinein the emergency department
12 9.4
Subjects carrying adrenaline auto-injectors
3 2.3
Subjects involved in beekeeping 11 8.6
A. Gelincik et al. / Allergology International 64 (2015) 35e4038
A. mellifera, Vespula spp and Polistes spp, respectively. Four partici-pants were sensitized to both A. mellifera and Vespula spp, 1participant had high sIgE levels to both Vespula spp and Polistes spp.
Serum tryptase levels
3 of 44 participants revealed high levels of serum tryptase(13.90, 16.60, 17.20 ng/ml, respectively). 2 of these patients hadlarge local reactions and one experienced a Grade 3 systemicreaction.
Evaluation of the data from the second questionnaire in patientswho were found sensitive to hymenoptera venom with diagnostictests
Data determined from the second questionnaire is shown inTable 3.
16 of 24 subjects who described systemic reactions weredetermined to be sensitized by skin prick and/or in vitro sIgE tests,and 8 out of 18 subjects (44%) who had experienced large local
Table 4The relationship between age, familial atopy, atopic diseases and the self reportedHymenoptera venom hypersensitivity.
Hypersensitivity to Hymenoptera stings
Independent variable Crudeodds ratio
Confidenceinterval(95%)
Adjustedodds ratio
Confidenceinterval(95%)
Lower Upper Lower Upper
Non-existence of familialatopy
1.64 1.43 1.84 1.33 1.14 1.57
Non existence of nasalallergy
1.58 1.38 1.82 1.31 1.12 1.54
Non-existence of itchingdermatitis/urticaria
1.68 1.43 1.99 1.31 1.08 1.58
Ages � 40 y. o. 1.26 1.12 1.42 1.16 1.09 1.24
reactions revealed positive test results. Skin test or in vitro testpositivity was correlated with more than one sting frequency(p ¼ 0.009).
A total of 22 subjects had experienced severe (Grade III/IV)systemic reactions. Among these, 13 subjects were over 40 years ofage, 16 were female, 11 had been stung by a honey bee and 11 hadexperienced the reaction only once.
According to the second questionnaire 64% of the subjects whohad experienced systemic reactions (39/61) had been admitted tothe emergency department and 18 described severe systemic re-actions. There was a significant correlation between the reactionseverity and admission to the emergency department (p ¼ 0.017).On the other hand, only 24% of the subjects who had experiencedlarge local reactions had been admitted to the emergencydepartment. The difference between those who described sys-temic reactions and others who had experienced large local re-actions was significant in terms of emergency room admissions(p < 0.001).
Discussion
This cross-sectional study is the first representative studyevaluating hypersensitivity reactions due to Hymenoptera stings inthe general adult population in Turkey. The number of non-respondents and dropouts, especially during the second tele-phone contact, may result in an underestimation of the actualprevalence, however, the large sample size and diagnostic work upused in addition to the questionnaires strengthen the reliability ofthe data.
In our study, the prevalence of Hymenoptera sting reactions,systemic and large local reactions in adults was found as 9.9%,1.58%and 8.32%, respectively, according to the first questionnaire. Whenwe consider the prevalence of sting reactions, systemic and largelocal reactions according to the second questionnaire, the preva-lence rates were found as 1.1%, 0.52% and 0.53%, respectively. Theseresults may reflect the reduced answer rate in the second ques-tionnaire; however we can assume that the application of thequestionnaire by allergy specialists may increase the reliability ofthis detailed questionnaire. Also in this second questionnaire largelocal reactions were identifiedmore accurately by the interviewers.This may have reduced the percentage of reported large local re-actions. According to the skin and in vitro sIgE tests, the confirmedprevalence of sting reactions, systemic and large local reactionsreduced to 0.2%, 0.14%, and 0.07%. This result again seems to dependon the small number of patients evaluated in the allergydepartment.
In other studies either the skin testing or the specific IgE wasfound positive in 50e100% of adult patients with systemic reactionsand in up to 80% of patients with large local reactions.3,11 In ourstudy nearly half of the subjects who reported systemic reactionsand 44% of people who had experienced large local reactionsrevealed positive diagnostic test results.
A recent study indicates that 65% of the hymenoptera venomallergic patients with an elevated serum tryptase level and a historyof systemic sting reaction have an underlying mast cell disorder.12
In our study the diagnostic evaluation for mastocytosis in 3 pa-tients with high basal serum tryptase levels, 2 of whom hadexperienced only large local reactions, did not reveal mastocytosis.A bone marrow biopsy was conducted in 1 patient who hadexperienced a systemic reaction and found normal. Recently inhymenoptera venom allergic patients without diagnosed masto-cytosis, elevated baseline serum tryptase levels were found to beassociated with severe anaphylactic reactions to stings.13,14 As ex-pected, among these 3 patients, the systemic reaction of the onepatient was a grade 3 reaction. Biphasic anaphylaxis due to insect
Fig. 1. Flow chart of the study and investigations performed.
A. Gelincik et al. / Allergology International 64 (2015) 35e40 39
stings is uncommon.15 None of the patients we investigated re-ported a biphasic anaphylaxis.
In our study nearly half of the patients were admitted to anemergency department, with approximately one-tenth of themreceiving adrenaline in the emergency department and with only2.3% carrying an adrenaline auto-injector. None of the patients werereferred to an allergist and had a prescription of specific immuno-therapy. In a nation-wide study in Spain, 64.4% of the Hymenopteraallergic patients visited the emergency department, which is ahigher percentage than that reported in our study.16 However, nearlyall the subjects who experienced systemic reactions were admittedto an emergency department in our study. Also the admission ratewas higher than the data presented in a previous Turkish study,indicating an emergency room visit for 9.3% of the patients.5
According to our findings none of the patients investigated inour clinic had received venom specific immunotherapy before. Thismay be due to the fact that they had not attended an allergy clinicbefore. Besides allergy clinics are very rare when compared to thehigh population of Istanbul. In fact there are few allergy clinics inIstanbul This finding was in parallel with the only epidemiologicalstudy of adult hymenoptera venom allergic patients conducted inTurkey previously.5
In the literature one-third of patients were reported as having aprescription for self-injectable adrenaline.11 In a recent multicenterstudy of emergency department visits for insect sting allergies,13% ofpatients with insect sting anaphylaxis received epinephrine in theemergencydepartment, 27%of theSRpatients received aprescriptionfor self-injectable epinephrine and 20% were officially referred to anallergist.17 Since our results revealed lower usage and prescriptionpercentages of epinephrine, it shows the importanceofpost-graduateeducation for emergency department doctors regarding epinephrineusage in the acute treatment of anaphylaxis due to insect stings.
In our investigations at the clinic we did not use sting challengetests as an initial diagnostic tool since they are not indicated forpatients who have not been treated with immunotherapy.11 Onelimitation of our study is that for people who had experienced
anaphylaxis with negative sensitivity, further diagnostic pro-cedures such as basophil activation tests or recombinant venomallergen extracts could have been tried.
In conclusion, the prevalence of Hymenoptera sting reactions inour geographical region is comparable with other Europeanstudies. Gender and atopic diseases do not seem to affect theprevalence of sting reactions whereas people aged 40 years andolder are more affected. The most frequent culprit insect is thehoney bee. Nearly all of the participants with systemic reactionswere admitted to the emergency department, although only onetenth of them received adrenaline in the emergency room and 2.3%carry adrenaline injector, whereas none of the patients receivedvenom immunotherapy. Therefore there is a need to increase theawareness of adrenaline in the emergency management of insectsting anaphylaxis and venom immunotherapy in the prophylaxis.
Acknowledgments
We thank Prof. Dr. Hanneke J.N.G. Oude Elberink for peerreviewing the manuscript before submission. This investigationwas supported by the Research Fund of Istanbul University, projectnumber 311/05012005.
Authors' contributionsEach author has contributed to the conception and design of the study, gener-
ation, analysis and interpretation of the data and preparation or critical revision ofthe manuscript.
Conflict of interestsThe authors have no conflicts of interest to declare.
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