Ann Allergy Asthma Immunol 119 (2017) 362e373

Contents lists available at ScienceDirect

Frequency of self-reported drug allergy

A systematic review and meta-analysis with meta-regression
Bernardo Sousa-Pinto, MD *, y, z; João Almeida Fonseca, PhD *, y; Eva Rebelo Gomes, MD x
* MEDCIDSeDepartment of Community Medicine, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Porto, Portugal
y
CINTESISeCenter for Health Technology and Services Research, Porto, Portugal
z
Laboratory of Immunology, Basic and Clinical Immunology Unit, Faculty of Medicine, University of Porto, Porto, Portugal
x
Immunoallergology Department, Centro Hospitalar do Porto EPE, Porto, Portugal

A R T I C L E I N F O A B S T R A C T

Article history:
Received for publication May 9, 2017.
Received in revised form July 3, 2017.
Accepted for publication July 5, 2017.
Background: Patients reporting drug allergy are treated with second-line therapies, with possible negative
clinical and health consequences.
Objective: To assess the prevalence of self-reported drug allergy.
Methods: We performed a systematic review of observational studies assessing the prevalence of
self-reported drug allergy. We searched 4 electronic databases. From selected studies, we extracted data on
self-reported drug allergy prevalence, study design, participants’ demographic characteristics, reported
clinical manifestations, and suspected culprit drugs. We performed a random-effects meta-analysis followed
by a meta-regression.
Results: Fifty-three studies were included in the systematic review, assessing a total of 126,306 participants,
of whom 8.3% (range across studies 0.7e38.5%) self-reported drug allergy. Cutaneous manifestations were
reported by 68.2% of participants, and anaphylactic or systemic reactions were reported by 10.8%. Antibiotics,
nonsteroidal anti-inflammatory drugs, and anesthetics were the most frequently reported culprit drug
classes. The frequency of self-reported drug allergy was higher in female (11.4%) than in male (7.2%) patients,
adults (10.0%) than in children (5.1%), and in studies in the medical setting (15.9% in inpatients, 11.4% in
outpatients) than in the general population (5.9%). The meta-analysis rendered a pooled prevalence of 7.9%
(95% confidence interval 6.4e9.6), and the meta-regression identified study region, participants’ age group,
and study setting as factors associated with significant heterogeneity. Confirmation tests (including skin,
in vitro, and drug provocation tests) were performed in only 3 studies.
Conclusion: The prevalence of self-reported drug allergy is highly variable and is higher in female patients,
adults, and inpatients. To overcome this variability, further studies using confirmation tests are needed.
Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction
Adverse drug reactions (ADRs) are unintended adverse drug
events that occur at doses normally used for prophylactic, diag-
nostic, or therapeutic purposes. Drug hypersensitivity reactions are
particular kinds of ADRs in which there are objectively reproducible
signs and/or symptoms that clinically resemble an allergic event,
whereas drug allergy corresponds to immunologically mediated
drug hypersensitivity reactions.1 These reactions are a concern for
prescribing physicians and patients, because having a label of drug
allergy can be an important limitation for future treatments. In fact,
patients reporting drug allergy are treated with second-line
Reprints: Eva Rebelo Gomes, MD, Immunoallergology Department, CHP-EPE, Largo
do Professor Abel Salazar, Porto, Portugal; E-mail: evamariasrg@yahoo.com.
Disclosures: Authors have nothing to disclose.
therapies that might be less effective, with more frequent compli-
cations, and more expensive than the first-line options.2e4 Unfor-
tunately, the term drug allergy is often incorrectly used by patients
and health professionals, being frequently mistaken for other ADRs,
infectious manifestations, or other conditions.5,6 The largest part of
drug allergy suspicions is not confirmed after a careful diagnostic
evaluation of patients.7 However, this evaluation is seldom done,
leading to overdiagnosis of drug allergy.8,9
The frequency of self-reported drug allergy varies widely in
different populations and settings and has been reported to be as
high as 39%.10 Several systematic reviews have been performed,
assessing the frequency of ADRs in different populations and, in
particular, providing estimates of ADRs resulting in hospitaliza-
tions and on the incidence of ADRs in hospitalized patients.11,12
However, the frequency of self-reported drug allergy has not
been systematically reviewed. Therefore, we performed a

http://dx.doi.org/10.1016/j.anai.2017.07.009
1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373
systematic review of prevalence studies aiming to assess the
frequency of self-reported drug allergy, taking into account
participants’ demographic characteristics, the reported clinical
manifestations, the drugs to which patients claimed allergic
reactions, and studies’ methodologic characteristics. Risk factors
identified by the investigators to be associated with
self-reported drug allergy also were assessed.
Methods
Data Sources and Searches
A comprehensive search was performed in November 2016,
in 4 electronic databases: MEDLINE, Scopus, Embase, and
Cochrane Library. We used the following query: (allerg* OR
hypersensitivity) AND (drug* OR antibiotic* OR penicillin* OR
beta-lactam* OR sulfonamide* OR cephalosporin* OR macrolide*
OR NSAID* OR anti-inflammator* OR anticonvulsant* OR anti-
neoplastic* OR chemotherap* OR anesthetic*) AND (prevalen*
OR epidemiolog* OR frequen* OR incidence) AND (consult* OR
outpatient* OR inpatient* OR admission* OR database* OR
health record* OR population*). No language or publication date
restrictions were applied. Efforts to contact the investigators
were made to obtain publications not accessible by other means.
Study Selection
After eliminating duplicate results, 2 researchers examined
article titles and abstracts for exclusion and inclusion criteria.
We included observational studies evaluating the prevalence of
self-reported drug allergy in the general population or in the
hospital (outpatient, inpatient, and emergency department)
setting. We excluded studies assessing the prevalence of allergy
to a single drug or drug class (because we were interested in
assessing the frequency of individuals claiming to be allergic to
any drug irrespective of class) and studies performed in patients
with a specific disease or in an occupational context. In addition,
we excluded case reports, reviews, pharmacovigilance and
administrative database studies, and studies not assessing drug
allergy by self-report.
Data Extraction
The full texts of studies meeting the inclusion criteria were
analyzed by 2 researchers who obtained information on the
number and demographic characteristics of participants,
particularly their country and sex and age distribution. Studies
were classified as performed in children, adults, or children and
adults. In addition, information was retrieved for the study
setting (general population, outpatients, inpatients, or emer-
gency department patients) and sampling and data collection
methods. We assessed the number of participants self-reporting
drug allergy and retrieved information regarding the presumed
drug classes, reported clinical manifestations (which were
further grouped into cutaneous, respiratory, gastrointestinal,
cardiovascular, ocular, systemic, and anaphylaxis), and whether a
confirmation test was subsequently performed. Any disagree-
ment between researchers was solved by consensus.
Quality Assessment
Study quality was assessed using an adaptation of a risk-of-
bias tool for prevalence studies developed by Hoy et al.13 The
original 10-item list consisted of 4 items assessing the external
validity of studies and 6 items concerning the internal validity.
From the original list, we removed 2 internal validity items
(“Was an acceptable case definition used in the study?” and
“Was the length of the shortest prevalence period for the
parameter of interest appropriate?”), because they were not
363
applicable to our context. A risk-of-bias graph and summary
were produced using Review Manager (RevMan) 5.3 (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark, 2014).
Quantitative Synthesis
The frequency of self-reported drug allergy was assessed using
absolute and relative frequencies. When absolute frequencies were
not provided, values were estimated based on the available
percentages.
A random-effects meta-analysis was performed using
logit-transformed proportions.14,15 Pooled logit prevalence
estimates were transformed to their original scale to simplify
their interpretation. Heterogeneity was evaluated using I2 and
Cochran Q statistics. An I2 more than 50% and a Cochran Q test P
value less than .10 were considered to represent substantial
heterogeneity. In the presence of substantial heterogeneity, a
meta-regression analysis was performed using mixed-effects
models.16 Covariates assessed included year of publication,
participants’ age group (children, adults, or children and adults),
sex distribution, study region (Western Europe, Eastern Europe,
Middle East, Far East and Southern Asia, Latin America, North
America, and Oceania), setting (patients vs general population),
sampling (random vs nonrandom), and data collection methods
(questionnaires vs interview). Covariates were individually
assessed in a univariate analysis, and covariates significantly
associated with heterogeneity of prevalence estimates (P < .10)
were entered into a multiple meta-regression model. Expo-
nentials of the coefficients and respective confidence interval
bounds were calculated and interpreted as odds ratios. All
analyses were performed using OpenMetaAnalyst software.17
The possibility of publication bias was assessed by funnel plots
for visual analysis. Funnel plots were performed based on
untransformed prevalences using MetaXL 5.3 (EpiGear
International, Sunrise Beach, Queensland, Australia).
Results
Search Results
The database search yielded 10,265 publications. We discarded
2,017 duplicate publications and removed 8,127 studies based on title
and abstract screening (Fig 1). In addition, we excluded 59 articles
based on full-text evaluation (Fig 1). We could not obtain the full text
of 10 articles despite efforts to contact the investigators18e27; 7 of
these articles had been published in languages other than Eng-
lish19e21,23e26 and 7 of them had been published before 2000.18e24
Thus, 53 articles were included in the systematic review,10,28e79 of
which 5 were congress abstracts.35,37,39,58,64 In 28 of the included
articles, the specific assessment of drug allergy was the main objec-
tive of the study.10,30e33,35e37,39e41,43,44,46,48,49,51,53,56e60,62,63,70,71,73,75
Description of Studies
The included studies were published from 1973 through 2016
and assessed a total of 126,306 participants (range 183e12,477
participants per study).10,28e79 Twenty-six studies included
exclusively adult participants,10,43e67 and 12 studies assessed only
children28,31e38,40e42 (Table 1). In 15 studies, children and adults
were assessed29,30,39,68e79; for 3 of these studies, results are
presented separately for children and adults.29,30,39 Five studies did
not provide information regarding participants’ sex distribu-
tion.33,35,37,53,61 In the remainder, 52.8% of participants were
female.10,28e32,34,36,38e52,54e60,62e79 The selected studies were per-
formed in 24 different countries; most studies were performed in
Western Europe, followed by the Middle East and Eastern Europe.
364 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram illustrating study selection process.

Thirty-two studies assessed participants sampled from the investigators assessed risk factors potentially associated with
general population,28e30,33e38,40e43,46,47,50,51,54e58,60,62e65,67,68,73,76,79 drug allergy,10,29,30,32,34,36,39e41,43,44,46,49e51,57,58,60,62,63,65,67,69,70,78,79
17 studies assessed outpatients,10,31,39,44,45,48,52,53,59,66,69e72,74,75,77 performing multivariate analyses in 10 of these
and 4 studies evaluated inpatients,32,49,61,78 one of which also studies.10,29,34,40,44,57,60,62,63,67 Twenty-three studies provided
assessed emergency department patients.32 Most studies used information on the reported clinical manifes-
nonrandom sampling methods, particularly convenience tations,10,30e33,35e37,39,40,43,44,46,51,53,56e58,60e63,71 and 33 studies
(n ¼ 9),42e44,54,55,57,60,66,75 consecutive (n ¼ 10),10,31,32,49,53,59,61,69,70,72 listed the patient-reported drugs and drug
quota (n ¼ 1),65 and volunteer (n ¼ 1)67 sampling. Eighteen studies classes.10,28,30e33,35e37,39e41,43,44,46,49,51,53e60,62,63,68e72,75
used other sampling methods, such as simple random sampling
(n ¼ 1),47 stratified random sampling (n ¼ 8),28e30,33,46,50,62,63 and
Frequency of Self-Reported Drug Allergy
cluster sampling (n ¼ 9).34,36e38,40,51,58,74,76 In 13 studies, the sampling
method used was not explicitly stated.35,39,41,45,48,52,56,68,71,73,77e79 The included studies assessed 126,306 participants, of whom
In most studies, data were collected by questionnaires 10,437 (8.3%; range across studies 0.7e38.5%) self-reported drug
(n ¼ 28),28,31e38,40e46,48,51,56,60,63,64,67,72,73,75,76,79 including school- allergy.10,28e79 Among studies that provided information regarding
given questionnaires (n ¼ 16)28,33e38,40,42,51,56,60,63,64,73,76 and participants’ sex, the frequency of self-reported drug allergy was
patient-completed questionnaires (n ¼ 7; questionnaires given to 11.4% (3,876 of 33,938) for female patients (range 4.4e33.7%) and
children were completed by their parents).31,32,44,45,48,72,75 In 21 7.2% (2,119 of 29,586) for male patients (range
studies, self-reported drug allergy was evaluated by face-to-face 3.1e27.1%).29e31,33,36,39,43e46,49e51,53,56e60,63,64,69e71,75,77 Only 2
(n ¼ 19)10,47,49,53,55,57e59,61,62,65,66,68e71,74,77,78 or telephone-based studies found the frequency of self-reported drug allergy to be
(n ¼ 2)29,50 interviews. In 3 studies, confirmation tests (including higher in male than in female patients.31,43 The frequency of self-
skin prick tests, intradermal tests, patch tests, assessment of specific reported drug allergy was lower in studies performed only in
immunoglobulin E, and drug provocation tests) were performed in children (5.1%; range 1.0e10.2%)28e42 than in studies performed
patients self-reporting drug allergy.31,35,36 In 26 studies, only in adults (10.0%; range 1.5e38.5%)10,29,30,39,43e67 or studies
Table 1
Description of Studies Included in Systematic Review by Country, Setting, Sampling Method, Method of Reporting, Number of Participants, and Number of Self-reported Allergy Cases

Study Country Setting Sampling Data collection method No. of participants, (%) Participants self-reporting drug allergy, n (%) Observations
of women [mean age]
Total Female

Studies performed in
children
Muñoz López et al, Spain General population Stratified random School-given 6,996 (43.5)a,b 230 (3.3) d
199428 sample questionnaires
Shahar and Lorber, Israel General population Stratified random Telephone-based 133b,c 7d (5.0) c

200129 sample interview

ska-Mi
skiewicz
Balin Poland General population Stratified random Not explicitly stated 334 (44.9) [10.4] 34 (10.2) 18 (12.0)
et al, 200630 sample
a
Rebelo Gomes et al, Portugal Outpatients Consecutive sample Patient-completed 1,426 (39.2) [7.3] 67 (4.8) 26 (4.8)
200731 questionnaires
Lange et al, 200832 Germany Inpatients and ED Consecutive sample Patient-completed 1,446 (50.1) [3] e
108 (7.5) d
patients questionnaires
Orhan et al, 200833 2,885b,f

B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373

Turkey General population Stratified random School-given 81 (2.8) 40 (d)
sample questionnaires
Al-Hammadi et al, United Arab General population Cluster sample School-given 397 (52.0) [7.2] 16 (4.0) d
201034 Emirates questionnaires
Karakas et al, 201135 Turkey General population Not explicitly stated School-given 3,914b,f
136 (3.5) d
questionnaires
lu et al,
Erkoçog Turkey General population Cluster sample School-given 10,059 (50.3) [12.9] 792 (7.9) 429 (8.5) Only immediate-type
201336 questionnaires reactions were
assessed
_
Ipek et al, 201337 Turkey General population Cluster sample School-given 3,944b,f 205d (5.2) d
questionnaires
Kim et al, 201338 South Korea General population Cluster sample School-given 615 (47.0) [5.0] 18 (2.9) d
questionnaires
e d
Nakrosyte et al, Lithuania Outpatients Not explicitly stated Not explicitly stated 3,222 (50.5) [8.3] 255 (7.9) d
201339
Martins et al, 201440 Portugal General population Cluster sample School-given 1,169 (47.5) [3.5] 48 (4.1) d
questionnaires
Porebski et al, 201541 Poland General population Not explicitly stated Questionnaires 4,080 (47.4)b 138 (3.4) d
Ontiveros et al, Mexico General population Convenience sample School-given 1,049 (51.6) [8.6] 10 (1.0) d
201642 questionnaires
Total 41,669 (44.9) [10.8] 2,145 (5.1) 513 (8.2)
Studies performed in
adults
Muranaka et al, Japan General population Convenience sample Company-completed 12,477 (51.9) [31.0] 578 (4.6) 326 (4.4) All participants were
197343 questionnaires white-collar workers
in Tokyo companies
Haddi et al, 199044 France Outpatients Convenience sample Patient-completed 2,067 (47.0) [39.4] 303 (14.7) 200d (20.6)
questionnaires
Peacock and Carson, United States Outpatients Not explicitly stated Patient-completed 590 (54.1) [45.7] 128 (21.7) 74 (23.2)
199545 questionnaires
b
Skúladóttir et al, Iceland General population Stratified random Mail-sent 545 (51.0) 77 (14.1) 53 (19.1)
199746 sample questionnaires
Çelik et al, 199947 Turkey General population Simple random sample Face-to-face interview 1,056 (47.8) [34.5] 41 (3.9) d
Porri et al, 199948 France Outpatients Not explicitly stated Patient-completed 258 (52.3) [32.1] 42 (16.3) d
questionnaires
Trinkle, 199949 Canada Inpatients Consecutive sample Face-to-face interview 183 (48.0) [62.0] 43 (23.5) 29 (33.0) This study particularly
assessed allergy to
antibiotics, opiates,
and NSAIDs
Shahar and Lorber, Israel General population Stratified random Telephone-based 1,504b,c 130d (8.6) c

200129 sample interview

(continued on next page)

365
Table 1 (continued )

366
Study Country Setting Sampling Data collection method No. of participants, (%) Participants self-reporting drug allergy, n (%) Observations
of women [mean age]
Total Female

50 b
Gaig et al, 2004 Spain General population Stratified random Telephone-based 4,949 (51.5) 288 (5.8) 190 (7.5)
sample interview
51
Gomes et al, 2004 Portugal General population Cluster sample School-given 2,309 (51.6) [36.9] 181 (7.8) 122 (10.2)
questionnaires
Sánchez Palacios Spain Outpatients Not explicitly stated Not explicitly stated 201 (56.2) [41.0] 3 (1.5) d
et al, 200452

ska-Mi
skiewicz
Balin Poland General population Stratified random Not explicitly stated 1,273 (54.7) [44.8] 106 (8.4) 88 (12.6)
et al, 200630 sample
MacPherson et al, Australia Outpatients Consecutive sample Face-to-face interview 1,260b,f 420 (33.3) 269 (d)
200653
Becerril Ángeles et al, Mexico General population Convenience sample Not explicitly stated 333 (84.4) [67.0] 78 (23.4) d All participants were
200854 >60 y old
e
Mossakowska et al, Poland General population Convenience sample Face-to-face interview 301 (85.7) [101] 9 (3.0) d All participants were
200855

B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373

centenarians
Ensina et al, 201056 Brazil General population Not explicitly stated School-given 1,015 (74.8) [23.1] 123 (12.1) 98 (12.9) All participants were
questionnaires university students
Kurt et al, 201057 Turkey General population Convenience sample Face-to-face interview 1,152 (0) [42.9] 41 (3.6) 0 All participants were
workers in a factory
58
Stoleski et al, 2010 Macedonia General population Cluster sample Face-to-face interview 722 (60.8) [39.6] 76 (10.5) 54 (12.4)
Tamayo et al, 201059 Spain Outpatients Consecutive sample Face-to-face interview 1,439 (40.8) [62.9] 119 (8.3) 63 (10.7)
Bavbek et al, 201160 Turkey General population Convenience sample School-given 1,267 (51.1) [21.7] 60 (4.7) 41d (6.3) All participants were
questionnaires university students
Becerril-Ángeles et al, Mexico Inpatients Consecutive sample Face-to-face interview 328b,f 49 (14.9) d
201161
Kurt et al, 201162 Turkey General population Stratified random Face-to-face interview 1,052 (58.8) [41.6] 124 (11.8) d
sample
63
Bavbek et al, 2012 Turkey General population Stratified random School-given 1,370 (51.8) [23.9] 183 (13.4) 117 (16.5)
sample questionnaires
64 b
Kozulina et al, 2013 Russia General population Random sample School-given 350 (39.4) 48 (13.7) 24 (17.4) All participants were
(unspecified) questionnaires university students
Nakrosyte et al, Lithuania Outpatients Not explicitly stated Not explicitly stated 2,148 (58.1) [48]e 296d (13.8) 218d (17.5)
201339
Bedolla-Barajas et al, Mexico General population Quota sample Face-to-face interview 1,126 (50.2)b 110 (9.8) d
201465
Veli
ckovi

c et al, Serbia Outpatients Consecutive sample Face-to-face interview 1,126 (44.3) [58.9] 434 (38.5) d
201510
Al-Azzam et al, Jordan Outpatients Convenience sample Face-to-face interview 2,898 (59.5) [56.6] 264 (9.1) d
201666
Hua et al, 201667 United States General population Volunteer sample Online questionnaires 1,879 (53.1) [45.5] 353d (18.8) d This study used public
data from the
American Gut Project
Total 47,178 (54.0) [38.5] 4,707 (10.0) 1,966 (9.4)
Studies performed in
adults and children
Wolfin and Denis, France General population Not explicitly stated Face-to-face interview 3,015 (40.0) [28.0] 22 (0.7) d
197468
Dundee et al, 197869 British Isles Outpatients Consecutive sample Face-to-face interview 10,000 (61.5) b
1,350 (13.5) 995 (16.2)
Hung et al, 199470 Canada Outpatients Consecutive sample Face-to-face interview 1,818 (50.3)b 511 (28.1) 308 (33.7)
Escolano et al, 199871 Spain Outpatients Not explicitly stated Face-to-face interview 1,218 (61.9) [58.5] 159 (13.1) 108 (14.3)
Chandler-Gutiérrez Spain Outpatients Consecutive sample Patient-completed 716 (60.0) [36.8] 60 (8.4) d
et al, 200472 questionnaires

ska and
Trzcin Poland General population Not explicitly stated School-given 1,360 (62.9) [17.3] 108 (7.9) d All participants were
Dziedziczko, questionnaires high school students
200573
Miller et al, 200674 Australia Outpatients Cluster sample Face-to-face interview 8,215 (58.8)b 91 (1.1) d
 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373 367

including children and adult participants (9.6%; range

Information on sex was available only for a limited number of participants: 6,609 subjects in the study by Muñoz López et al,28 1,396 subjects in the study by Rebelo Gomes et al,31 and 3,895 subjects in the study by Kongkaew
0.7e28.1%).68e79 Sex differences in the self-reported prevalence of
drug allergy were greater among adults (female 9.4%, male
6.2%)30,39,43e46,49e51,56e60,63,64 than among children (female 8.2%,
male 7.0%).30,31,36
The frequency of self-reported drug allergy was lower for studies
performed in the general population (5.9%; range
0.7e23.4%)28e30,33e38,40e43,46,47,50,51,54e58,60,62e65,67,68,73,76,79
compared with those performed in outpatients (11.4%; range
1.1e38.5%)10,31,39,44,45,48,52,53,59,66,69e72,74,75,77 and inpatients (15.9%;
range 7.5e23.5%).32,49,61,78 Among general population studies, the
130 (22.1)

165 (10.0)

1,706 (17.0)
4,185 (11.4)

frequency of self-reported drug allergy was 4.8% in children

(range 1.0e10.2%)28e30,33e38,40e42 compared with 7.5% in adults
(range 3.0e23.4%)29,30,43,46,47,50,51,54e58,60,62e65,67 and 7.8% in female
d

patients (range 4.4e19.1%) compared with 5.9% in male patients

(range 3.1e11.3%).29,30,36,43,46,50,51,56e58,60,63,64 Of studies performed in
the medical setting (outpatients and inpatients), the frequency of self-
reported allergy was 7.1% in children (range 4.7e7.9%)31,32,39 compared
186 (17.6)

734 (18.8)

80 (12.9)

with 16.8% in adults (range 1.5e38.5%)10,39,44,45,48,49,52,53,59,61,66 and

38 (2.2)

246 (6.5)

3,585 (9.6)
10,437 (8.3)

16.8% in female patients (range 4.8e33.7%) compared with 9.2% in

d

male patients (range 3.8e22.5%).31,39,44,45,49,59,69e71,75,77

A lower frequency of self-reported drug allergy also was found
in studies that selected their participants on a random basis
(5.5%; range 1.1e14.1%)28e30,33,34,36e38,40,46,47,50,51,58,62e64,74,76
37,459 (55.5) [41.4]
3,904 (53.1)a [65.4]
1,751 (54.0) [26.0]

compared with a nonrandom method (11.4%; range

619 (73.8) [22.7]

1.0e38.5%).10,31,32,42e44,49,53e55,57,59e61,65e67,69,70,72,75 When consid-

126,306 (52.8)
1,057 (55.6)b

b
3,786 (43.7)

ering only studies that selected their participants randomly, the

frequency of self-reported drug allergy was 5.4% in children
(range 2.8e10.2%)28e30,33,34,36e38,40 and 8.3% in adults (range
Sex distribution among children and adults (separately) not provided. Overall, 53.1% of participants in this study were female.

5.8e14.1%)29,30,46,47,50,51,58,62e64 and 9.8% in female patients

(range 7.5e19.1%) compared with 6.5% in male patients (range
Face-to-face interview

Face-to-face interview

3.1e11.3%).29,30,36,46,50,51,58,63,64 Studies in which questionnaires were

Patient-completed
questionnaires

questionnaires

used reported a lower frequency of self-reported drug allergy (6.5%;

Questionnaires

range 1.0e21.7%)28,31e38,40e46,48,51,56,60,63,64,67,72,73,75,76,79 compared

School-given

with those in which an interview was performed (10.3%; range

0.7e38.5%).10,29,47,49,50,53,55,57e59,61,62,65,66,68e71,74,77,78
A random-effects meta-analysis was performed, rendering a
pooled prevalence of 7.9% (95% confidence interval 6.4e9.6%;
P < .001). However, substantial heterogeneity was found
Convenience sample

Not explicitly stated

Not explicitly stated

Not explicitly stated

(Cochran Q P < .001; I2 ¼ 99.1%). To assess the potential causes of

Abbreviations: ED, emergency department; NSAIDs, nonsteroidal anti-inflammatory drugs.

heterogeneity, a meta-regression was performed. The univariate

Cluster sample

analysis found that study region (P ¼ .076), participants’ age

group (P ¼ .001), study setting (P ¼ .002), and sampling methods
(P ¼ .014) were associated with significant heterogeneity
Estimated absolute frequency calculated based on the provided percentage.

(Table 2). All these covariates, except for the sampling methods,
also were associated with significant heterogeneity in the
multivariate model (Table 2).
General population

General population

Clinical Manifestations and Drug Classes

Outpatients

Outpatients

Inpatients

Cutaneous manifestations were the most frequently reported, with

a frequency of 68.2% (3,187 of 4,673) in assessed participants
(range across studies 27.3e98.6%); these manifestations were
more frequent in children (72.0%) than in adults
United Kingdom

(66.9%).10,30,31,33,35e37,39,40,43,44,46,51,53,56e58,60,62,63,71 Anaphylactic and

systemic reactions were reported by 10.8% (296 of 2,732) of assessed
participants10,32,33,39,40,43,53,58,60,61,63,71 (systemic reactions were
Poland
France

India
Iran

Sex distribution not available.

generally defined as “reactions involving more than 1 organ system”

but also included “shock” and “collapse”); in studies specifically
Mean age not available.
Varasteh et al, 200876

assessing anaphylaxis, the frequency of the latter condition was 8.8%

Sztormowska et al,

(141 of 1,596),10,32,39,40,53,61 being less frequently reported in studies

Kongkaew et al,
Aggarwal et al,
Branellec et al,

performed in children (7.6%; range 2.1e10.0%)32,39,40 compared with

Median age.
Total studies

studies that included adult participants (9.3%; range

200775

201177

201378

201679

8.2e10%).10,39,53,61 In contrast, respiratory, gastrointestinal, and ocular

Total

et al.78

manifestations were more frequently reported by children than by

adults (Table 3).
d
b

e
a

f
368 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373

Table 2
Univariate and Multiple Meta-regression Models

Study characteristics Univariate meta-regression models Multiple meta-regression model

Studies, n OR (95% CI) P value Studies, n OR (95% CI) P value

Year of publication
Before 2000 (reference) 12 d d
After 2000 41 0.7 (0.4e1.4) .335
Female proportion
<50% (reference) 14 d d
50% 34 1.4 (0.8e2.5) .231
Age group
Children (reference) 12 d da 12 d d
Adults 26 3.1 (1.7e5.5) <.001 26 2.6 (1.5e4.6) <.001
Adults and children 15 2.1 (1.1e4.1) .019 15 1.3 (0.7e2.5) .496
Setting
General population 32 d d 32 d d
(reference)
Patients 21 2.2 (1.3e3.5) .002 21 2.8 (1.3e6.0) .006
Sampling
Random methods (reference) 19 d d 19 d d
Nonrandom methods 21 2.0 (1.1e3.4) .014 21 0.7 (0.4e1.4) .364
Region
Western Europe (reference) 18 d db 18 d d
Eastern Europe 9 1.2 (0.6e2.5) .557 9 1.4 (0.7e3.0) .329
Middle East 13 0.7 (0.4e1.2) .166 13 0.9 (0.5e1.7) .789
Far East and Southern Asia 3 0.5 (0.2e1.5) .245 3 0.7 (0.3e2.1) .557
Oceania 2 0.9 (0.3e3.0) .809 2 0.46 (0.2e1.3) .136
North America 3 3.3 (1.2e9.4) .024 3 3.6 (1.3e10.0) .016
Latin America 5 1.1 (0.5e2.7) .781 5 1.2 (0.5e3.0) .637
Data collection method
Questionnaires (reference) 28 d d
Interview 21 1.4 (0.8e2.3) .262

Abbreviations: CI, confidence interval; OR, odds ratio.

a
Omnibus P ¼ .001.
b
Omnibus P ¼ .076.

Antibiotics (especially b-lactams), nonsteroidal Publication Bias

anti-inflammatory drugs, and anesthetics were the drug
classes to which participants more often reported
allergy10,28,30e33,35e37,39e41,43,44,46,49,51,53e60,62,63,68e72,75 (Table 4).
Confirmation studies (including skin, in vitro, and drug
provocation tests) were performed in only 169 participants (from
3 different studies), of whom 13 (7.7%) had positive results.31,35,36
All 169 participants were children with a detailed clinical history
compatible with drug allergy. This means that, in those 3 studies,
drug allergy was initially reported by a total of 995 children, of
which only 169 (17.0%) had a consistent clinical history
suggesting a drug allergy, prompting them to be subjected to
confirmation tests. In 1 study, although confirmation tests were
not performed, patients with self-reported drug allergy were
referred for further allergy evaluation.10
Among the risk factors found by investigators to be associated
with self-reported drug allergy, the most commonly identified,
even after adjustment by multivariate models, included female
sex10,29,44,62 and a personal history of other atopic
conditions,34,40,44,57,60,62,63 particularly food allergy.
Assessment of Study Quality
A risk-of-bias graph is presented in Figure 2, and a risk-of-
bias analysis is presented in eFigure 1. Most studies had a high
risk of bias in their sample representation (particularly
with respect to the national population) and in the reliability
and validity of the instruments used for data collection. A higher
frequency of self-reported drug allergy was found in studies
with a high risk of biasdstudies with more than 3 items
classified as having a “high risk of bias”d(8.8%;
range 1.0e38.5%)31,32,35,39,41,43e45,48,49,52e56,58e61,63,66e68,71,75e79
compared with studies with a low risk of bias (7.1%; range
0.7e33.3%).10,28e30,33,34,36e38,40,42,46,47,50,51,57,62,64,65,69,70,72e74
There was potential for publication bias because the funnel
plots showed asymmetry for all age groups studied (eFigure 2).
Nevertheless, the significant heterogeneity found also might
account for the asymmetry of the funnel plots.
Discussion
This systematic review included 53 studies assessing the
frequency of self-reported drug allergy. The results suggest that
this is a frequent clinical problem, with 8.3% of participants
reporting drug allergy. Antibiotics and nonsteroidal
anti-inflammatory drugs were the most commonly involved
drug classes, perhaps mirroring their frequent use.10,31 Most
suspicions involved cutaneous reactions, which were reported
by at least 68% of assessed participants. Although this proportion
is possibly an underestimation (because some studies did not
present a combined frequency of all cutaneous reactions), it is
consistent with the 66% skin manifestations described by Rubio
et al80 in the largest published series of patients studied for
suspected drug allergy. In contrast, anaphylaxis was reported by
9% of participants, although this amount can be as high as 11% if
other systemic reactions are considered together. Compared
with studies assessing general data on ADRs, we found a larger
proportion of patients reporting cutaneous manifestations.81 In
addition, a more diverse amount of drugs was reported to be
implicated in general ADRs.81
We found a wide variation in the prevalences of self-reported
drug allergy across different studies (0.7e38.5%), because they
assessed different populations and settings, and used different
methods. Drug allergy was most commonly reported by adults,
by female patients, and in studies performed in medical settings
(outpatients or inpatients). Each of these factors might be
associated with an increased exposure to medications, thus
 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373 369

Table 3
Clinical Manifestations Among Participants With Self-reported Drug Allergy

Study Participants Cutaneous Respiratory Gastrointestinal Cardiovascular Ocular Anaphylaxis and

assessed, n manifestations, manifestations, manifestations, manifestations, manifestations, systemic
n (%) n (%) n (%) n (%) n (%) manifestations,
n (%)

Studies performed
in children
Balin
ska- 34 26 (76.5) d d d d d
Mi
skiewicz
30
et al, 2006
Rebelo Gomes 67 41 (61.2) 13 (19.4) 17 (25.4) d d d
et al, 200731
Lange et al, 108 d d d d d 3 (2.8)
200832
Orhan et al, 81 76 (93.8) 8 (9.9)a 17 (21.0) d d 19 (23.5)b
200833
Karakas et al, 45 39 (86.7) 6 (13.3) 12 (26.7) d d d
201135
Erkoçog lu et al, 792 507 (64.0) 279 (35.2) 309 (39.0) 92 (11.6) 166 (21.0) d
201336
_
Ipek et al, 201337 205c 193c (94.1) d d d d d
Nakrosyte et al, 255c 178c (69.8) 5c (2.0) 13c (5.1) d 8c (3.1) 26c (10.0)
201339
Martins et al, 34 29 (85.3) d 7 (20.6) d d 1 (2.1)
201440
Total 1,621 1,089 (72.0) 311 (25.1) 375 (29.4) 92 (11.6) 174 (16.6) 49 (10.3)
Studies performed
in adults
Muranaka et al, 578 570 (98.6) 15 (2.6) d d d 44 (7.8)d
197343
Haddi et al, 303 129 (42.6)e 55 (18.2) d d d d
199044
Skúladóttir et al, 77 50 (64.9) 10 (13.0) d d d d
199746
Gomes et al, 181 115 (63.5) 26 (14.4) 21 (11.6) 65 (35.9) 12 (6.6) d
200451
Balin
ska- 106 67 (62.9) d d d d d
Mi
skiewicz
et al, 200630
MacPherson et al, 420 254 (60.5)f d 124 (29.5) d d 41 (9.8)
200653
Ensina et al, 123 99 (80.5) 40 (32.5) 23 (18.7) d d d
201056
57
Kurt et al, 2010 41 34 (82.9) d d d d d
Stoleski et al, 76 49 (64.0) 14 (18.7) d d d 12 (15.6)g
201058
Bavbek et al, 60 26 (43.3) 5 (8.3) 2 (3.3) 5 (8.3) d 22 (36.7)b
201160
Becerril-Ángeles 49 d d d d d 4 (8.2)
et al, 201161
62 h
Kurt et al, 2011 124 53 (42.7) 32 (25.8) d d d d
Bavbek et al, 183 50 (27.3) 34 (18.6) 13 (7.1) 15 (8.2) d 32 (17.5)b
63
2012
Nakrosyte et al, 296c 176c (59.5) 40c (13.5) 39c (13.2) d 28c (9.5) 30c (10.0)
201339
Velickovi
c et al, 434 312 (71.9) 148 (34.1) 48 (11.1) 78 (18.0) d 36 (8.3)
201510
Total 3,051 1,984 (66.1) 419 (17.2) 270 (15.9) 163 (19.0) 40 (8.4) 221 (10.5)
Studies performed
in adults and
children
Escolano et al, 158 114 (72.1) 11 (6.9) d 7 (4.4) d 26 (16.4)b
199871
Total studies 4,830 3,187 (68.2) 741 (19.3) 645 (21.7) 262 (14.5) 214 (14.0) 296 (10.8)
a
Includes ocular manifestations.
b
“Systemic reactions” defined as reactions involving more than 1 organ system.
c
Estimated absolute frequency calculated based on the provided percentage.
d
Figures for patients identified as having “shock.”
e
Includes only the number of subjects reporting extensive urticaria. Ninety-nine participants (33%) reported angioedema, but the number of participants reporting urticaria
and angioedema was not provided.
f
Includes only the number of subjects reporting rash or pruritus. Sixty-one participants (15%) reported edema or swelling, but the number of participants reporting rash or
pruritus and edema or swelling was not provided.
g
Figures for patients identified as having “collapse.”
h
Includes only the number of subjects reporting urticaria. Fifty-five participants (44%) reported pruritus and 37 participants (30%) reported angioedema, but the number of
participants reporting more than 1 cutaneous condition was not known.
Table 4

370
Drug Classes Identified by Participants With Self-reported Drug Allergy

Drug class Total participants Children Adults

Participants Self-reported Cases of confirmed Participants Self-reported allergy, n (%) Cases of confirmed allergy/ Participants Self-reported Cases of confirmed allergy/
assessed, n allergy, n (%) allergy/participants assessed, n participants with assessed, n allergy, n (%) participants with
with confirmation confirmation tests confirmation tests
tests performed, performed, n/n (%) performed, n/n (%)
n/n (%)

Antibiotics
Penicillins 4,798 1,974 (41.1) d 463 202 (43.6) d 2,228 819 (36.8) d
Cephalosporins 1,760 124 (7.0) d 233 26 (11.2) d 1,016 90 (8.9) d
Unspecified b-lactams 1,214 513 (42.3) 7/119 (5.8)a 1,033 409 (39.6) 7/119 (5.8)a 181 104 (57.5) d
Macrolides 2,234 87 (3.9) 0/2 (0) 407 25 (6.1) 0/2 (0) 1,316 51 (3.9) d
Aminoglycosides 847 16 (1.9) d 34 3 (8.8) d 813 13 (1.6) d
Glycopeptides 119 4 (3.4) d d d d 119 4 (3.4) d
Tetracyclines 2,635 59 (2.2) d 34 3 (8.8) d 2,090 45 (2.2) d

B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373

Sulfa drugs 3,403 438 (12.9) d 483 64 (13.3) d 2,349 275 (11.7) d
Other antibiotics 1,328 39 (2.9) 1/32 (3.1) d d 1/32 (3.1) 817 20 (2.4) d
Unspecified antibiotics 6,086 1,000 (16.4) d 1,600 405 (25.3) d 2,444 340 (13.9) d
Anesthetics and drugs
acting on nervous
system
General anesthetics 183 29 (15.8) d d d d 183 29 (15.8) d
Local anesthetics 1,350 22 (1.6) 0/1 (0) d d 0/1 (0) 1,131 11 (1.0) d
Neuromuscular blockers 60 1 (1.7) d d d d 60 1 (1.7) d
Unspecified anesthetics 587 8 (1.4) d d d d 587 8 (1.4) d
Anticonvulsant and 539 19 (3.5) d d d d 539 19 (3.5) d
psychotropic drugs
Sedatives 692 30 (4.3) d d d d d d d
Autonomic nervous 679 13 (1.9) 1/7 (14.3) 126 8 (6.3) 1/7 (14.3) 553 5 (0.9) d
system agents
Analgesics and anti-
inflammatory drugs
Nonsteroidal anti- 4,961 871 (17.6) 3/24 (12.5) 1,496 264 (17.6) 3/24 (12.5) 2,713 506 (18.7) d
inflammatory drugs
Paracetamol 1,347 27 (2.0) 0/18 (0) 298 12 (4.0) 0/18 (0) 538 6 (1.1) d
Opioids 2,636 385 (14.6) d d d d 775 157 (20.3) d
Unspecified analgesics 870 120 (13.8) d d d d 359 110 (30.6) d
Corticosteroids 723 16 (2.2) 0/1 (0) d d 0/1 (0) 723 16 (2.2) d
Other drugs
Antidysrhythmic drugs 119 1 (0.8) d d d d 119 1 (0.8) d
Antihypertensive drugs 553 16 (2.9) d d d d 553 16 (2.9) d
Anticoagulants 119 1 (0.8) d d d d 119 1 (0.8) d
Agents primarily 116 1 (0.9) d d d d 116 1 (0.9) d
affecting endocrine
system
Agents primarily 41 1 (2.4) d d d d 41 1 (2.4) d
affecting
gastrointestinal system
Agents primarily 695 20 (2.9) d 143 12 (8.4) d 41 1 (2.4) d
affecting respiratory
system and antiallergic
drugs
 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373 371
d

d
d
d
d
(37.7)
(14.9)
1 (2.4)

(5.3)
(5.7)
39
73
310
320
d

Figure 2. Risk-of-bias graph. Review of authors’ judgments of each risk-of-bias item

presented as percentages across all included studies.
1,285

2,147
41

733

822

increasing the possibility of reactions.82,83 In addition, hormonal

d

factors might play a role in female patients.84 In contrast, the

increased frequency of self-reported drug allergy in studies
selecting their participants by nonrandom methods or in studies
collecting data by an interview might simply reflect the fact that
these studies were mostly performed in a medical setting. In
addition to these factors, several studies found that, even after
1/3 (33.3)

adjustment by multivariate analysis, a personal history of food

allergy was associated with increased frequency of self-reported
drug allergy. This can be due to an increased awareness of
d

d
d

patients with allergic diseases to other possible allergic

manifestations, although a real influence on the occurrence of
drug allergy or on ADR cannot be discarded.
Taking into account the clinical and methodologic differences
in the included studies, it is not surprising that the meta-analysis
found significant heterogeneity. The performed meta-regression
Includes 4 of 49 participants (8.2%) tested for penicillins and 0 of 28 participants (0%) tested for cephalosporins.
6 (9.8)

4 (3.1)

2 (3.3)

3 (6.3)
125 (9.5)

identified, in a multivariate model, that participants’ age group,

study setting, and study region were associated with significant
d

heterogeneity. Some other factors might account for the

observed heterogeneity, including differences in the adopted
definitions of drug allergy or variations in the questions posed to
identify drug allergy (it is noteworthy to mention that, although
61

129

61

48
1,322

most studies asked whether participants had “drug allergy,” a

d

more correct expression would be “drug hypersensitivity”

because “drug allergy” presupposes the existence of a specific
immune-mediated reaction mediated by cells or antibodies). In
fact, most studies used non-validated methods in data collection,
1/3 (33.3)

which represents an important threat to their internal validity.

Moreover, the lack of sample representation was the most
commonly observed problem affecting the external validity of
d

d
d

the studies. The assessment of the quality of some studies is

further hampered by lack of information on the methods of
(35.2)
(19.6)
7 (6.9)

4 (3.1)

(5.7)
(4.3)

participant selection or data collection. These serious limitations

in the quality of evidence stress the need for future studies to be
54
113
314
993

performed with rigorous study designs and validated methods.

The importance of a correct epidemiologic characterization of
self-reported drug allergy is becoming particularly evident,
because an increasing amount of evidence highlights the
102

129

953

892
2,635

5,060

problematic consequences of an overdiagnosis of drug allergy. As

an example, inpatients with a label of penicillin allergy are
frequently treated with less effective and more expensive
antibiotics, resulting in an increased risk of drug-resistant
infections.4,85 Although drug allergy is overdiagnosed, the
affecting the skin

affecting the eye

extent of such overdiagnosis appears to differ according to the

Agents primarily

Agents primarily

study setting and population; Rubio et al80 found that only 15.2%
Radiocontrast

Other drugs
Unspecified

of allergy suspicions (16.5% for adults and 10.6% for children)

could be confirmed, whereas a recent meta-analysis found that
Iodine

only 3% of patients (and <2% of children) with reported

penicillin allergy had a confirmed diagnosis of immediate
a
372 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373
reactions.86 Importantly, in this systematic review, we could not
estimate the prevalence of true allergic reactions, because only 3
studies performed confirmation tests. In addition, even in these
studies, not all participants with self-reported drug allergy were
subjected to these tests, but only those with a detailed clinical
history compatible with drug allergy (169 children). Because
only 13 (7.7%) of these selected children had positive results, it is
expected that, among all children with self-reported drug
allergy, the frequency of a confirmed diagnosis would be even
lower. Because anaphylaxis is the severest allergic reaction, self-
report of this condition could mirror more accurately the
frequency of actual drug allergy, which might be important in
clinical studies. However, even for a suspected anaphylactic
shock induced by a drug, the diagnostic confirmation was only
approximately 29%.80 Clearly, to obtain a more accurate estimate
of the real prevalence of drug allergy in the general population,
future studies would benefit from performing confirmation tests
in all or, if unfeasible, in a random unselected sample of
participants claiming to have a drug allergy, irrespective of
whether their clinical history is highly suspicious of drug allergy;
in addition, in participants not claiming any drug allergy, at least
a detailed clinical history should be performed. In fact, according
to the 2014 International Consensus on Drug Allergy, the
diagnosis of drug allergy should rely not only on a detailed
clinical history but also, whenever possible, on standardized skin
tests, reliable in vitro tests, and drug provocation tests.1
Otherwise, according to the same position paper, misclassifica-
tion can ensue, with more harmful consequences for patients
than a complete drug allergy workup.1
The main strengths of this systematic review concern the
study search methodology and the meta-regression performed.
We used a comprehensive search in several databases in the
absence of restrictions of language or publication date and with
efforts to contact the investigators whenever publications were
not accessible; as a consequence, a large number of studies
published in international and local journals, and encompassing
a total of 126,306 participants, were included in this systematic
review. In addition, we performed a meta-regression allowing for
the identification of some causes of heterogeneity across studies.
In conclusion, self-reported drug allergy is frequent,
particularly in female patients, adults and hospital patients. The
estimates on the prevalence of self-reported drug allergy vary
widely across studies, reflecting several methodologic
limitations. Across the included studies, the most commonly
identified risk factors for self-reported drug allergy were female
sex and personal history of atopy. Current available studies
based only on self-reporting cannot accurately ascertain the real
frequency of drug allergy. Therefore, and given the increasing
evidence on the repercussions of drug allergy overdiagnosis,
further studies using confirmation tests are certainly needed.
Supplementary Data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.anai.2017.07.009.
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eFigure 1. Risk-of-bias summary. Authors’ judgments of each item for each included study performed only in children (A), only in adults (B), and in children and adults (C).
 B. Sousa-Pinto et al. / Ann Allergy Asthma Immunol 119 (2017) 362e373 373.e2

eFigure 2. Funnel plots depicting the frequency of self-reported drug allergy among all studies (A) and studies performed in children (B), adults (C), and children and
adults (D).