Evaluation of the Potential Risk Factors for Drug-Induced Anaphylaxis in Adult Patients

Abstract

Aim: To investigate the potential risk factors in patients who have experienced anaphylaxis from drugs. Method: The study included 281 adult patients (median age 40 years; 76.5% female) who experienced immediate types of hypersensitivity reaction to a drug. The patients were divided into an anaphylaxis group and a nonanaphylaxis group. The anaphylaxis group was diagnosed according to the criteria of the World Allergy Organization. Skin testing with culprit drugs was performed. In the nonanaphylaxis group, drug provocation tests were performed with culprit drugs, including aspirin or diclofenac, to determine nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. Atopy was determined by skin prick tests with the common inhalant allergens. Patients' demographics, clinical features, and baseline tryptase and total IgE levels were compared between the 2 groups. Results: The median interval between the last reaction in the patient's history and the study evaluation was 7 months (range 1-120 months). In 52.3% of the patients, reactions were defined as anaphylaxis. The most common culprit drugs were NSAIDs (56.9%) and β-lactams (34.7%). The culprit drugs were used parenterally in 13.2% of the patients. 34.9% of the patients had comorbid diseases and 24.6% used additional drugs, the most common being antihypertensives (10%). Atopy was determined in 28.8% and 28.1% of the patients were smokers. The median serum level of baseline tryptase and total IgE was 3.5 μg/L and 77 kU/L, respectively. In 46.3% of the patients, skin tests with culprit drugs were positive and the positivity ratio was higher in the anaphylaxis group (p = 0.002). Anapyhlaxis was more common in patients who were: hypertensive, atopic, using angio-tensin-converting enzyme inhibitors/angiotensin receptor blockers, and received the culprit drug parenterally (p = 0.034, p = 0.04, p = 0.03, p = 0.035, p = 0.013, and p < 0.001). In the multivariate analysis, it was observed that the parenteral usage of the drug and the presence of atopy were significantly higher in the anaphylaxis group (p < 0.001, odds ratio [OR] = 20.05, confidence interval [CI] 4.75-88.64; p = 0.012, OR = 2.1, CI 1.17-3.74). Age, smoking, family history, and serum levels of baseline tryptase and total IgE did not differ between groups. Conclusion: The parenteral route and atopy increase the risk of drug-induced anaphylaxis. IgE-mediated sensitivity to the culprit drug seems to facilitate anaphylaxis.

Full text

Clinical Allergy – Research Article
Int Arch Allergy Immunol 2019;178:167–176
Evaluation of the Potential Risk Factors
for Drug-Induced Anaphylaxis in Adult
Patients
Semra Demir
a Fusun Erdenen
a Asli Gelincik
b Derya Unal
b Muge Olgac
b
Raif Coskun
b Bahauddin Colakoglu
b Suna Buyukozturk
b
a Adult Allergy and Immunology Clinic, Istanbul Research and Training Hospital, Health Science University,
Istanbul, Turkey; b Division of Immunology and Allergic Diseases, Department of Internal Medicine, Faculty of
Medicine, Istanbul University, Istanbul, Turkey
Received: July 16, 2018
Accepted after revision: September 28, 2018
Published online: November 16, 2018
Semra Demir, MD
Adult Allergy and Immunology Clinic
Istanbul Research and Training Hospital, Health Science University
Nafiz Gurman Street, TR–34098 Fatih, Istanbul (Turkey)
E-Mail ertansemra @ yahoo.com
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/iaa
DOI: 10.1159/000494130
Keywords
Drug-induced anaphylaxis · Risk factors · Atopy · Tryptase ·
Total IgE
Abstract
Aim: To investigate the potential risk factors in patients who
have experienced anaphylaxis from drugs. Method: The
study included 281 adult patients (median age 40 years;
76.5% female) who experienced immediate types of hyper-
sensitivity reaction to a drug. The patients were divided into
an anaphylaxis group and a nonanaphylaxis group. The ana-
phylaxis group was diagnosed according to the criteria of
the World Allergy Organization. Skin testing with culprit
drugs was performed. In the nonanaphylaxis group, drug
provocation tests were performed with culprit drugs, includ-
ing aspirin or diclofenac, to determine nonsteroidal anti-in-
flammatory drug (NSAID) hypersensitivity. Atopy was deter-
mined by skin prick tests with the common inhalant aller-
gens. Patients’ demographics, clinical features, and baseline
tryptase and total IgE levels were compared between the 2
groups. Results: The median interval between the last reac-
tion in the patient’s history and the study evaluation was 7
months (range 1–120 months). In 52.3% of the patients, reac-
tions were defined as anaphylaxis. The most common culprit
drugs were NSAIDs (56.9%) and β-lactams (34.7%). The cul-
prit drugs were used parenterally in 13.2% of the patients.
34.9% of the patients had comorbid diseases and 24.6% used
additional drugs, the most common being antihyperten-
sives (10%). Atopy was determined in 28.8% and 28.1% of
the patients were smokers. The median serum level of base-
line tryptase and total IgE was 3.5 µg/L and 77 kU/L, respec-
tively. In 46.3% of the patients, skin tests with culprit drugs
were positive and the positivity ratio was higher in the ana-
phylaxis group (p = 0.002). Anapyhlaxis was more common
in patients who were: hypertensive, atopic, using angio-
tensin-converting enzyme inhibitors/angiotensin receptor
blockers, and received the culprit drug parenterally (p =
0.034, p = 0.04, p = 0.03, p = 0.035, p = 0.013, and p < 0.001).
In the multivariate analysis, it was observed that the paren-
teral usage of the drug and the presence of atopy were sig-
nificantly higher in the anaphylaxis group (p < 0.001, odds
ratio [OR] = 20.05, confidence interval [CI] 4.75–88.64; p =
Edited by: H.-U. Simon, Bern
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0.012, OR = 2.1, CI 1.17–3.74). Age, smoking, family history,
and serum levels of baseline tryptase and total IgE did not
differ between groups. Conclusion: The parenteral route
and atopy increase the risk of drug-induced anaphylaxis. IgE-
mediated sensitivity to the culprit drug seems to facilitate
anaphylaxis. © 2018 S. Karger AG, Basel
Introduction
Anaphylaxis is a serious systemic hypersensitivity re-
action (HR) with an acute onset and unpredictable
course which occurs due to the sudden release of media-
tors from mast cells and basophils [1]. The American
College of Allergy, Asthma and Immunology (ACAAI)
Epidemiology of Anaphylaxis Working Group reported
that a lifetime prevalence of anaphylaxis was between
0.05 and 2% [2]. Studies from the USA, Australia, and
the UK indicate that the incidence of anaphylaxis has
increased over the years [3–5]. The rate of mortality
from anaphylaxis ranges from 2 to 20% [6]. Anaphylax-
is can be induced by food, drugs, venom, or latex, or can
be idiopathic. The most common causes of anaphylaxis
in adult patients are medications and venom [7–10].
Amongst causative drugs, the most common triggering
ones are nonsteroidal anti-inflammatory drugs (NSAIDs)
and antibiotics [9–15]. It has been estimated that the in-
cidence of drug-induced anaphylaxis and biphasic or re-
sistant anaphylaxis are 0.04–3.1 and 10%, respectively
[16–19]. Furthermore, drug use leads to more severe re-
actions than other causative agents. The most common
reason for fatal anaphylaxis is medications, representing
58% of the cases [11, 20]. Several studies have investi-
gated the risk factors for drug-induced anaphylaxis.
Older age, intravenous administration, African-Ameri-
can ethnicity, and decreased platelet-activating factor
acetylhydrolase activity are the factors associated with
fatal drug-induced anaphylaxis [11, 21, 22]. Up to now,
the role of atopy [13–15, 23, 24] and the basal serum
tryptase level [25–29] in drug-induced anaphylaxis has
remained controversial. Moreover, in a study investigat-
ing the HR to quinolone, the authors observed that a
high total IgE level was associated with anaphylaxis [30].
It is important to try to decrease mortality and mor-
bidity rates caused by anaphylaxis, and recurrence can
be avoided by determining the triggers and risk factors.
The aim of this study was to evaluate the potential risk
factors in patients experiencing drug-induced anaphy-
laxis.
Methods
This cross-sectional study was conducted in the Adult Allergy
and Immunology Clinics, Istanbul Training and Research Hospi-
tal and Istanbul University Faculty of Medicine in 2017. The study
included patients > 17 years of age who had experienced immedi-
ate-type HRs with any drug. We excluded patients who had: expe-
rienced nonimmediate-type HRs (such as Stevens-Johnson syn-
drome, toxic epidermal necrolysis, and DRESS syndrome), reac-
tions that did not recover after discontinuation of the drug, a
negative provocation test with culprit drugs, comorbid diseases
involving uncontrolled hypertension, uncontrolled cardiac diseas-
es, uncontrolled diabetes, uncontrolled asthma, malignancy, and
those who did not give informed consent.
Drug HRs (DHRs) were classified as immediate DHRs which
occurred within 24 h after NSAID administration, within 1 h for
drugs other than NSAIDs after the last drug ingestion, and other-
wise as nonimmediate DHRs [31, 32].
The patients who experienced immediate DHRs were divided
into an anaphylaxis group and a nonanaphylaxis group. Anaphy-
laxis was diagnosed according to the World Allergy Organization
(WAO) criteria [33]. Nonanaphylactic immediate DHRs consisted
of itching, flashing, urticaria and/or angioedema, or acute rhinitis
with or without dyspnea.
Allergologic Work-Up
Allergologic work-up was performed according to the Consen-
sus Statement of the European Network of Drug Allergy [34]. De-
mographic data and clinical features were evaluated along with a
detailed history. Skin prick tests (SPTs; undiluted, 1: 100, or 1: 10
dilutions of the drug depending on the severity of the reaction) on
the volar side of forearm with the culprit drugs were performed on
all patients, with the exception of drugs that induce a non-IgE-
mediated mechanism involving a cross-reactive NSAID HR. The
SPT with drugs available only in oral tablet form was performed
by crushing the tablet and diluting the powder with saline to obtain
a drug concentration of 1 mg/mL. Tests were considered positive
if a wheal > 3 mm in diameter was present after 20 min. If the results
were negative, intradermal tests were performed with the culprit
drugs in 3 incremental dilutions (1: 1,000, 1: 100, and 1: 10) if they
had a parenteral form. The intradermal tests were interpreted 20
min after the injection, and wheals > 5 mm were considered posi-
tive [35, 36]. SPTs and intradermal testing with drugs were per-
formed with the commercial forms of the drugs as described in the
literature [31, 37].
In the nonanaphylaxis group, single-blind placebo-controlled
drug provocation tests (SBPCDPTs) with culprit drugs were done
if the SPT was negative. In NSAID-hypersensitive patients,
SBPCDPTs with aspirin were performed to differentiate cross-re-
active patients from selective responders. Patients with a history of
severe anaphylaxis and those who did not accept reexposure were
not provoked with the culprit drug.
Atopy was determined by SPTs with the most common inhal-
ant allergens. Basal tryptase and total IgE levels were measured.
Serum total IgE was determined using the ImmunoCAP system
and serum tryptase by an enzyme immunoassay method.
Statistical Analysis
Descriptive statistics were used to evaluate demographic and
clinical characteristics. They were described in percentages and
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mean ± standard deviation (SD) or median, and categorical data
were compared by χ2 tests or the Mann-Whitney U test according
to data distribution. For the associated factor which was obtained
from univariate analysis, multivariate analysis was performed by
binary logistic regression analysis. p < 0.05 was considered statisti-
cally significant. All data analyses were performed with SPSS v21.0.
Results
The study included 281 patients (Fig.1). Median age
was 40 years (range 16–90 years) and 76.5% were female.
The median interval between the last reaction in a pa-
tient’s history and the evaluation was 7 months (range
1–120 months). In 52.3% of the patients, reactions were
defined as anaphylaxis. The most common culprit drugs
described by patients were NSAIDs (56.9%) and β-lactams
(34.7%) (Fig. 2). However, in the anaphylaxis group,
β-lactams comprising penicillin (n = 30) and cephalospo-
rin (n = 37) replaced NSAIDs for the first rank (n = 70,
47.6% and n = 58, 39.5%, respectively). The culprit drugs
were used parenterally in 13.2% of the patients. 34.9% of
the patients had comorbid diseases and 24.6% were using
additional drugs, the most common being antihyperten-
sives (10%). Atopy was determined in 28.8% of patients.
Median serum level of baseline tryptase and total IgE was
3.5 µg/L and 77 kU/L, respectively. Demographic and
clinical features are detailed in Table 1. HR types are il-
lustrated in Figure 3.
Anaphylaxis developed very rapidly in most patients
after the ingestion or injection of the drug: within 10 min
in 90 patients, 10–30 min in 50 patients, and 30–60 min
in 7 patients. Immediate-type HRs other than anaphy-
laxis developed within 10–30 min in 60 patients, 30–60
min in 51 patients, 1–6 h in 21 patients, and within 10 min
in 2 patients.
In 147 patients (52.3%), skin testing with culprit drugs
were performed. The remaining patients did not undergo
skin testing since they had non-IgE-mediated HRs, their
suspected culprit drugs did not have a parenteral form, or
they did not wanted to be tested. In 46.3% (n = 68) of the
patients, skin tests with culprit drugs were positive. The
skin test positivity ratio was higher in the anaphylaxis
group (p = 0.002). SBPCDPT with culprit drugs was pos-
22 patients were excluded since the SBPCDPTs with
culprit drugs were negative
32 patients were excluded because their reactions
were nonimmediate-type HRs
13 patients were excluded due to comorbidities such
as malignancy, uncontrolled asthma, uncontrolled
diabetes mellitus, or uncontrolled hypertension
18 patients were excluded because the causative
drugs were not clarified
366 patients were evaluated for the study
281 patients were included in the study
69 patients who had cross-reactive
NSAID HRs were excluded
Subgroup analysis
Analysis of only
NSAID HRs: 160
patients were included
Analysis of HRs most
probably involving
immunogenic mechanisms:
212 patients were included
Analysis of only
β-lactam HRs: 97
patients were included
Fig. 1. Number of excluded patients, reasons for exclusion, and subgroup analysis. SBPCDPTs, single-blind pla-
cebo-controlled drug provocation tests; HRs, hypersensitivity reactions.
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itive in 66 patients. The results of skin and SBPCDPTs are
illustrated in Table 2.
In 4 patients, anaphylaxis developed during the SPT
with the culprit drug cefuroxime. In 3 of these patients,
the reaction in the history was anaphylaxis; in the remain-
ing patients, it was urticaria. Among 281 patients, 33 ex-
perienced HRs with cefuroxime in the history, 30 of
whom underwent skin testing. The rate of anaphylaxis
during skin testing with cefuroxime was 13%. In 118
NSAID-hypersensitive patients, 47 of whom were in the
anaphylaxis group, SBPCDPT with aspirin was per-
formed to distinguish cross-reactive patients from selec-
80
70
60
50
40
30
20
10
0
Number of patients
NSAID
(n = 160, 56.9%)
β-lactam antibiotics
(n = 97, 34.5%)
Non-β-lactam
(n = 10, 3.5%)
Proton pump inhibitors
(n = 10, 3.5%)
Feniramidol
(n = 3, 1%)
Para-aminophenol
Propionic acid
Acetic acid
Aspirin
Pyrazolones
Oxicam
Penicillin
Cephalosporins
Penicillin + cephalosporin
Quinolones
Imidazole
Clarithromycin
Trimethoprim sulfamethoxazole
Lansoprazole
Pantoprazole
29#
36#
70#
26#
26#
2#
20#
5#
2# 2# 1# 1#
7*
4*
10*
18*
18*
30*
37*
3*4*
2*1*1*
7*2*2*
Fig. 2. Culprit drugs in the history. *Number of patients in the anaphylaxis group. #Number of patients in the nonanaphylaxis group.
52.3% 47%
15.7%
2.2%
35.1%
47.7%
■ Anaphylaxis
■ Immediate-type HR other
than anaphylaxis
■ Urticaria
■ Urticaria + angioedema
■ Angioedema
■ Asthma/rhinitis
Type of reaction Immediate-type HR other than anaphylaxis
Fig. 3. Reaction types in the history.
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Table 1. Demographic and clinical features of patients and comparison of these features in the anaphylaxis and nonanaphylaxis groups
by univariate analysis
All patients Anaphylaxis
group
Nonanaphylaxis
group
p value OR (95% CI)
Female gender 215 (76.5) 120 (55.8) 95 (44.2) 0.034 0.54 (0.31–0.95)
Current smoker 79 (28.1) 42 (48.6) 37 (27.6) ns –
Comorbid diseases 98 (34.9) 48 (32.7) 50 (37.3) ns –
Asthma 8 (8.2) 4 (2.2) 4 (2.2) ns –
Allergic or nonallergic rhinitis/rhinosinusitis 43 (43.8) 15 (10.2) 28 (20.9) ns –
Chronic urticaria 10 (10.2) 2 (1.4) 8 (6.0) ns –
Hypertension 27 (27.5) 19 (70.4) 8 (29.6) 0.048 2.3 (0.98–5.5)
Diabetes mellitus 5 (5.1) 3 (2.0) 2 (1.5) ns –
Atherosclerotic cardiac diseases 4 (4.1) 4 (2.7) 0 ns –
Reflux/dyspepsia 9 (9.2) 5 (3.4) 4 (2.7) ns –
Thyroid disorders 13 (13.3) 8 (5.4) 5 (3.7) ns –
Rheumatologic diseases 6 (6.1) 2 (1.4) 4 (2.7) ns –
Psychiatric disorders 6 (6.1) 3 (2.2) 3 (2.2) ns –
Presence of atopy 81 (28.8) 48 (59.3) 33 (40.7) 0.013 0.51 (0.3–0.87)
Mites 66 (23.5) 24 (36.4) 42 (63.6) ns –
Pollen 22 (10) 9 (32.1) 16 (67.9) ns –
Mold 5 (1.8) 2 (1.4) 3 (2.2) ns –
Venom 6 (2.1) 5 (3.4) 1 (0.7) ns –
Food 2 (0.7) 1 (0.7) 1 (0.7) ns –
Latex 2 (0.7) 1 (0.7) 1 (0.7) ns –
Concomitant drug usage 69 (24.5) 41 (59.4) 28 (40.6) ns –
Antihypertensives 28 (40.5) 20 (71.4) 8 (28.6) 0.033 2.4 (1.05–5.8)
ACEIs/ARBs 20 (29) 15 (75) 5 (25) 0.035 2.93 (1.03–8.3)
Other antihypertensives 14 (20.3) 10 (6.8) 4 (3.0) ns –
Oral antidiabetics 5 (7.4) 3 (2.0) 2 (1.5) ns –
Antidepressants 5 (7.4) 2 (1.4) 3 (2.2) ns –
Aspirin 5 (7.4) 5 (3.4) 0 ns –
Proton pump inhibitors 21 (30.4) 15 (10.2) 6 (4.5) ns –
L-tyroxine 13 (18.8) 8 (5.4) 5 (3.7) ns –
İnhaler corticosteroids 8 (11.6) 3 (2.0) 5 (3.7) ns –
Antihistamines/montelukast 8 (11.6) 2 (1.4) 6 (4.5) ns –
Family history
Allergic diseases 34 (12.1) 18 (12.2) 16 (11.9) ns –
Drug hypersensitivity 15 (5.3) 10 (6.8) 5 (3.7) ns –
Culprit drug
β-Lactams 97 (34.7) 70 (72.2) 27 (27.8) <0.001 3.6 (2.12–6.13)
Cephalosporins 48 (17.1) 41 (85.4) 7 (14.6) <0.001 7.01 (3.02–16.29)
Non-β-lactam antibiotics 10 (3.6) 7 (4.8) 3 (2.2) ns –
NSAIDs 160 (56.9) 9 (90) 1 (10) 0.021 8.6 (1.08–69.4)
Proton pump inhibitors 10 (3.6) 58 (36.3) 102 (63.7) <0.001 0.2 (0.12–0.34)
Application route of culprit drug
Parenteral 37 (13.2) 35 (94.6) 2 (5.4) <0.001 20.6 (4.8–87.6)
Oral 244 (86.8) 112 (55.9) 132 (54.1)
Skin test positivity with the culprit drug 68 (24.2) 55 (80.9) 13 (19.1) 0.002 0.3 (0.14–0.66)
Interval between the last reaction in the patient’s
history and the evaluation, months 7 (1–120) 8 (1–120) 6.5 (1–120) ns –
Number of reactions in the history 1 (1–5) 1 (1–3) 2 (1–5) ns –
Basal tryptase level, µg/L 3.5 (0.1–17.20) 3.5 (1.1–17.2) 3.5 (1.1–9.39) ns –
Total IgE, IU/L 77 (1.71–1,960) 77.5 (3.8–924) 74.2 (1.7–1,960) ns –
Values express n (%) or median (range). ACEIs, angiotensin-converting enzyme inhibitor; ARBs, angiotensin receptor blocker; NSAIDs, nonsteroidal
anti-inflammatory drugs; ns, not significant.
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tive responders; it was positive in 44 patients, none of
whom were in the anaphylaxis group. As a result, 43.75%
(n = 70) of the NSAID-hypersensitive patients were cross-
reactive, and their HR involved multiple NSAID-induced
urticaria/angioedema (NIUA, n = 55), NSAID-exacerbat-
ed cutaneous diseases (NECD, n = 11), and NSAID-exac-
erbated respiratory disease (NERD, n = 4). The remaining
56.25% (n = 90) were cases of single NSAID-induced ur-
ticaria/angioedema/anaphylaxis (SNIUAA).
Anaphylaxis was more common in the patients who
were hypertensive, atopic, using angiotensin-converting
enzyme inhibitors (ACEIs)/angiotensin receptor block-
ers (ARBs), and in those who used the culprit drug par-
enterally (p = 0.034, p = 0.04, p = 0.03, p = 0.035, p = 0.013,
and p < 0.001, respectively).
While β-lactam antibiotics, especially cephalosporin
and proton pump inhibitors (PPIs), caused anaphylaxis
more commonly than other causative agents (p < 0.001,
p < 0.001, and p = 0.021), NSAIDs led to nonanaphylactic
immediate-type HRs more frequently (p < 0.001) (Table
1). Age, smoking, family history, serum level of baseline
tryptase and total IgE level did not differ between groups.
In the multivariate analysis, it was observed that paren-
teral use of the drug and the presence of atopy were sig-
nificantly higher in the anaphylaxis group than in the
nonanaphylaxis group (p < 0.001, odds ratio [OR] =
20.05, confidence interval [CI] 4.75–88.64; p = 0.012,
OR = 2.1, CI 1.17–3.74) (Table 3). Since these results var-
ied according to the type of drug, we performed an addi-
tional analysis. Further comparative analysis between
groups with these parameters was performed in β-lac-
tam- and NSAID-hypersensitive patients. In β-lactam-
hypersensitive patients, parenteral application of the
drug and concomitant drug use were higher in the ana-
phylaxis group than in the nonanaphylaxis group (p =
0.01, OR = 6.117, CI 1.33–28.08; p = 0.010, OR = 6.117,
CI 1.33–28.1), but there were no relations regarding spe-
cific drug subgroups such as antihypertensives, antide-
pressants, PPIs, etc. In both β-lactam- and NSAID-hyper-
sensitive patients, parenteral drug administration was as-
sociated with more severe anaphylaxis (p = 0.010, OR =
6.12, CI 1.33–28.1; p < 0.001, OR = 1.23, CI 1.09–1.39).
Other parameters involving atopy and the level of serum
total IgE and basal tryptase were not associated with ana-
phylaxis in either β-lactam- or NSAID-hypersensitive pa-
tients.
A subgroup of the study population that excluded 69
patients who had cross-reactive NSAID HRs (presumably
mediated by a non-IgE mechanism involving NERD,
NIUA, and NECD) was reanalyzed. Of 212 patients, 168
were female, mean age was 40.7 ± 17.7 years, and the me-
dian interval between the HR and the evaluation was 6.5
Table 2. Results of skin tests and drug provocation tests with the culprit drugs
Culprit drug Skin tests, nSBPCDPTs, nTotal
not performed positive negative not performed positive
NSAIDs 85 12 63 106 54 160
Para-aminophenol 15 3 18 19 17 36
Aspirin 37 0 3 15 25 40
Propionic acid 68 0 12 40 40 80
Acetic acid 18 3 23 32 12 44
Pyrazolones 21 5 18 35 9 44
Oxicam 1 1 0 1 1 2
β-Lactam antibiotics 37 52 8 89 8 97
Penicillin 28 20 7 48 7 55
Cephalosporins 9 32 1 41 1 42
Non-β-lactam antibiotics
Quinolones 2 1 3 4 2 6
Imidazole 0 1 1 2 0 2
Clarithromycin 0 0 1 1 0 1
Trimethoprim sulfamethoxazole 0 1 0 1 0 1
Proton pump inhibitors 7 0 3 9 1 10
Feniramidol 2 0 1 3 0 3
NSAID, nonsteroidal anti-inflammatory drug; SBPCDPTs, single-blind, placebo-controlled drug provocation tests.
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months. In 145 patients, the reactions were anaphylaxis
and the culprit drugs were NSAIDs, β-lactams, non-β-
lactam antibiotics, PPIs, and feniramidol in 91, 97, 10, 10,
and 3 patients, respectively. In 17% of the patients, the
culprit drugs were administered parenterally. In 34.4% of
the patients, the skin tests with culprit drugs were posi-
tive, 31.6% of the patients had comorbid diseases, 24.1%
were using other drugs concomitantly, and atopy was de-
tected in 22.2%. In the comparative analysis between
groups with the same parameters above, parenteral ad-
ministration of the culprit drug, concomitant drug usage,
and skin test positivity were higher in the anaphylaxis
group, and cephalosporins caused anaphylaxis more
commonly than the other symptoms (p < 0.001, OR = 9.9,
CI 2.31–42.8; p = 0.034, OR = 2.24, CI 1.04–4.82; p =
0.005, OR = 2.7, CI 1.33–5.52; p = 0.004, OR = 3.37, CI
1.42–8.01). Although the use of antihypertensives was
higher in the anaphylaxis group than in the nonanaphy-
laxis group, this had a marginal level of significance sta-
tistically (p = 0.043, OR = 3.42, CI 0.9–11.98). Serum bas-
al tryptase and total IgE level and the other parameters
were similar between groups.
Discussion
This study evaluated the risk factors for drug-induced
anaphylaxis by comparing anaphylaxis with nonanaphy-
lactic immediate-type drug reactions. Most studies indi-
cate that the most common cause of anaphylaxis in adult
patients is medications and can lead to more severe reac-
tions and fatalities [7–10, 20]. Accordingly, studying
drug-induced anaphylaxis to determine specific risk fac-
tors is of great importance. Previous studies have focused
on the general risk factors for severe anaphylaxis or com-
pared anaphylaxis according to the causative agents such
as foods or drugs [38–41]. Up to now, no study has com-
pared drug-induced anaphylaxis with nonanaphylactic
immediate-type drug reactions in terms of risk factors for
adult patients.
The main findings of our study were that the paren-
teral route of drug administration increased the risk of
anaphylaxis 20-fold and atopy increased this risk 2-fold.
In a separate analysis of β-lactam- and NSAID-hypersen-
sitive groups, parenteral drug usage was still a risk for
anaphylaxis, but atopy was not.
Parenteral administration, particularly via the intrave-
nous route, has already been defined as a risk factor for
drug-induced anaphylaxis [11, 42]. Another study ana-
lyzing cephalosporin-related adverse reactions retrospec-
tively found that physician-documented anaphylaxis ra-
tios due to oral or parenteral administration of cephalo-
sporins were similar; our study once more points out the
importance of the route of drug administration for the
development of anaphylaxis, independent of the type of
causative drug [43]. This matter should be taken care-
fully into account when treating patients with a history of
any drug hypersensitivity.
Regarding the association between atopy and DHRs,
whether atopy predisposes to a new allergen sensitization
or is a risk factor for severe reactions is not known. Al-
though there are some studies about this association, to
draw a conclusion from their results would not be accu-
rate due to the differences in methodology, selection of
patients, and reaction types as well as insufficient assess-
ments of atopy. In the late 1960s, atopy was reported for
the first time as a risk factor for penicillin allergy [23].
More recently, authors from southern Spain and the USA
observed that atopy was related to β-lactam allergy in
their patients [44, 45]. In France, another study group re-
ported that atopy is a personal risk factor for NSAID hy-
persensitivity [46]. However, Aun et al. [13] and Faria et
al. [14] reported that anaphylaxis did not differ among
different causative types of drugs such as NSAIDs,
β-lactams, non-β-lactam antibiotics, or general anesthet-
ics but they did not compare an anaphylaxis group with
nonanaphylaxis patients. In another study performed in
Latin America, the authors observed that drug-induced
anaphylaxis was less severe in atopic patients, but they
also did not compare anaphylaxis with nonanaphylaxis
[15]. Their study bears a resemblance to ours by compar-
ing anaphylaxis to nonanaphylactic immediate-type HRs
(less severe than anaphylaxis) in terms of severity [15].
We observed that atopy increased the anaphylaxis risk
Table 3. Multiple regression analysis of the factors associated with
anaphylaxis
Factor Anaphylaxis
OR (95% CI) p value
Female 0.6 (0.34–1.15) >0.05
Hypertension 0.7 (0.4–2.3) >0.05
Use of an antihypertensive 0.5 (0.1–2.6) >0.05
Use of an ACEI/ARB 0.4 (0.05–3.1) >0.05
Parenteral route 20.05 (4.75–88.64) <0.001
Atopy 2.1 (1.17–3.74) 0.012
ACEI, angiotensin-converting enzyme inhibitor; ARB, angio-
tensin receptor blocker.
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174
DOI: 10.1159/000494130
2-fold but was not associated with specific groups of
drugs such as β-lactams or NSAIDs; there was a different
association when we excluded non-IgE-mediated NSAID
HRs. Such variations can be caused by different study
methodologies as well as the geographical and racial dif-
ferences which affect atopy development. Therefore, to
identify the exact effect of atopy on DHRs, more compre-
hensive studies are needed.
While the most common causative drugs in our study
patients were NSAIDs, β-lactam antibiotics were found
to be the leading drugs in the anaphylaxis group, a finding
which concurs with those of other studies [34, 38, 47].
An important finding of our study was the high ratio
of anaphylaxis among cephalosporin-hypersensitive pa-
tients. In the early 2000s, Kelkar and Li [48] reported that
cephalosporins rarely caused anaphylaxis. A few years
later, other authors observed that cephalosporin-induced
anaphylaxis has increased over the years [49].
Anaphylaxis occurred during the SPT with cefuroxime
in 13% of our patients. Mota et al. [50] from Portugal re-
cently published the results of their 3-year follow-up
study which evaluated HRs to β-lactam antibiotics. They
did not observe any systemic reactions during skin test-
ing. Somech et al. [51] from Canada also did not observe
any systemic reactions during skin testing in their study
assessing immediate-type HRs (mostly nonanaphylaxis)
to cephalosporins. On the other hand, Riezzo et al. [52]
from Italy reported that fatal anaphylactic shock devel-
oped during intradermal testing with ceftriaxone in a pa-
tient. Variations in race and reaction types could be the
reason for this discrepancy.
Regarding our finding that cephalosporins are a com-
mon cause of anaphylaxis, especially when given paren-
terally (also with skin testing), we suggest that physicians
should be more careful when prescribing cephalosporins
for common infections such as upper and lower respira-
tory tract infections and cellulitis [50]. They should avoid
the parenteral route unless it is absolutely necessary, and
allergists should be cautious while skin testing the patient
with cefuroxime.
Previously, our group reported that the total IgE level
was higher in quinolone-induced anaphylaxis [30] and
Pastorello et al. [53] reported that higher total IgE level
was associated with severity in amoxicillin-induced ana-
phylaxis. However, in this study, serum total IgE levels
were not associated with anaphylaxis in the general study
population, and also not in β-lactam- or NSAID-hyper-
sensitive patients. Similarly, Kim et al. [40] reported that
total IgE level was not associated with drug-induced ana-
phylaxis.
Anaphylaxis is seen in 22–49% of adult patients with
systemic mastocytosis [54]. It can thus be assumed that a
high serum tryptase level, with no clonal disorder but re-
flecting a mast-cell burden, can be associated with ana-
phylaxis. Regarding this hypothesis, many authors have
investigated the role of basal serum tryptase levels in ana-
phylaxis. A high basal serum tryptase level has been re-
ported as a risk factor for food-induced anaphylaxis and
overall anaphylaxis by some authors [25, 26]. However,
the role of basal serum tryptase in drug-induced anaphy-
laxis is controversial. While some authors report that a
high level is related to both drug-induced anaphylaxis
and severe reactions, it is not associated with drug-in-
duced anaphylaxis in children or NSAID-induced HRs in
other studies and also indicated by our findings [27–29].
The role of comorbidities and concomitant drug usage
in drug-induced anaphylaxis has been somewhat debated.
Some studies which evaluated the risk factors for severe re-
actions in drug-induced anaphylaxis reported that comor-
bidities involving chronic lung diseases or cardiac diseases
and drugs used simultaneously such as β-blockers, ACEI/
ARBs, or PPIs increased the risk of severe anaphylaxis, but
others did not observe such a relationship [39, 55, 56]. We
observed that anaphylaxis was more common in hypersen-
sitive patients and the patients who used ACEI/ARBs in the
univariate analysis. However, based on the multivariate
analysis, we could not define these as risk factors.
Another finding was that immediate-type HRs due to
PPIs were mostly anaphylaxis. PPIs are widely used drugs
which are generally well-tolerated, causing side effects in
only 1–3% of patients and anaphylaxis in around 0.2–
0.7% [57, 58]. Özdemir et al. [59] from Turkey reported
that anaphylaxis was the most common HR type among
60 PPI hypersensitive patients (66.7%) and the most com-
mon culprit PPI was lansoprazole (68.3%), followed by
pantoprazole (20.0%). These findings are in agreement
with our results. The most common culprit PPI changes
from country to country depending on prescription hab-
its. In countries other than Turkey, the most frequent cul-
prit drugs are esomeprazol, omeprazol, and pantoprazol
[60, 61]. Although PPI-induced anaphylaxis seems to be
rare, physicians must be aware of the possibility, in order
to avoid severe reactions and recurrence.
To avoid recurrence of anaphylaxis and anaphylactic
shock, an accurate diagnosis involving determination of
the culprit drug is very crucial. Drug skin testing is not
helpful for non-IgE mechanisms and not reliable for most
drugs. The drug provocation test, which is the gold stan-
dard for the diagnosis of drug allergy, can be frightening
because of the possibility of a severe reaction [2, 62]. In
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Drug-Induced Anaphylaxis in Adult
Patients
175
Int Arch Allergy Immunol 2019;178:167–176
DOI: 10.1159/000494130
this study, skin test positivity was higher in the anaphy-
laxis group than in the group that had nonanaphylactic
immediate-type HRs, an observation reflecting the higher
IgE-related mechanism involved in anaphylaxis. There-
fore, we can recommend skin testing in drug-induced
anaphylaxis to identify the culprit drug.
In conclusion, this was a unique study which evaluated
the potential risk factors for drug-induced anaphylaxis by
comparing it with nonanaphylactic, immediate-type HRs
in a relatively homogenous group. The findings empha-
size that the parenteral route increases anaphylaxis risk
independent of the type of causative drug, while atopy has
a lesser, but nonetheless apparent, effect on this risk. It
was found that skin test positivity with culprit drugs, the
most common being β-lactam antibiotics, was higher in
patients who experienced anaphylaxis, suggesting that
those who have IgE-mediated sensitivity are indeed more
prone to anaphylaxis.
Statement of Ethics
The study was approved by the ethics committee of the Istanbul
Training and Research Hospital and informed consent was ob-
tained for all patients.
Disclosure Statement
We declare that we have no conflicts of interest.
Funding Sources
There was no funding.
Author Contributions
All authors listed contributed to the design of the study, the
acquisition and interpretation of data for the study, and the critical
revision of the manuscript.
References
1 Simons FE, Ardusso LR, Bilò MB, Cardona V,
Ebisawa M, El-Gamal YM, et al. International
consensus on (ICON) anaphylaxis. World Al-
lergy Organ J. 2014 May; 7(1): 9.
2 Lieberman P, Camargo CA Jr, Bohlke K, Jick
H, Miller RL, Sheikh A, et al. Epidemiology of
anaphylaxis: findings of the American College
of Allergy, Asthma and Immunology Epidemi-
ology of Anaphylaxis Working Group. Ann
Allergy Asthma Immunol. 2006 Nov; 97(5):
596–602.
3 Decker WW, Campbell RL, Manivannan V,
Luke A, St Sauver JL, Weaver A, et al. The etiol-
ogy and incidence of anaphylaxis in Rochester,
Minnesota: a report from the Rochester Epide-
miology Project. J Allergy Clin Immunol. 2008
Dec; 122(6): 1161–5.
4 Poulos LM, Waters AM, Correll PK, Loblay
RH, Marks GB. Trends in hospitalizations for
anaphylaxis, angioedema, and urticaria in
Australia, 1993-1994 to 2004-2005. J Allergy
Clin Immunol. 2007 Oct; 120(4): 878–84.
5 Gupta R, Sheikh A, Strachan DP, Anderson
HR. Time trends in allergic disorders in the
UK. Thorax. 2007 Jan; 62(1): 91–6.
6 Pumphrey R. Anaphylaxis: can we tell who is
at risk of a fatal reaction? Curr Opin Allergy
Clin Immunol. 2004 Aug; 4(4): 285–90.
7 Wood RA, Camargo CA Jr, Lieberman P,
Sampson HA, Schwartz LB, Zitt M, et al. Ana-
phylaxis in America: the prevalence and char-
acteristics of anaphylaxis in the United States.
J Allergy Clin Immunol. 2014 Feb; 133(2): 461–
7.
8 Sole D, Ivancevich JC, Borges MS, Coelho MA,
Rosario NA, Ardusso LR, et al; Latin American
Anaphylaxis Working Group. Anaphylaxis in
Latin America: a report of the online Latin
American Survey on anaphylaxis (OLASA).
Clinics (São Paulo). 2011; 66(6): 943–7.
9 Civelek E, Erkoçoğlu M, Akan A, Ozcan C,
Kaya A, Vezir E, et al. The etiology and clini-
cal features of anaphylaxis in a developing
country: a nationwide survey in Turkey.
Asian Pac J Allergy Immunol. 2017 Dec; 35(4):
212–9.
10 Gelincik A, Demirtürk M, Yılmaz E, Ertek B,
Erdogdu D, Çolakoğlu B, et al. Anaphylaxis in
a tertiary adult allergy clinic: a retrospective re-
view of 516patients. Ann Allergy Asthma Im-
munol. 2013 Feb; 110(2): 96–100.
11 Jerschow E, Lin RY, Scaperotti MM, McGinn
AP. Fatal anaphylaxis in the United States,
1999-2010: temporal patterns and demo-
graphic associations. J Allergy Clin Immunol.
2014 Dec; 134(6): 1318–1328.e7.
12 Patel TK, Patel PB, Barvaliya MJ, Tripathi CB.
Drug-induced anaphylactic reactions in Indi-
an population: A systematic review. Indian J
Crit Care Med. 2014 Dec; 18(12): 796–806.
13 Aun MV, Blanca M, Garro LS, Ribeiro MR, Ka-
lil J, Motta AA, et al. Nonsteroidal anti-inflam-
matory drugs are major causes of drug-in-
duced anaphylaxis. J Allergy Clin Immunol
Pract. 2014 Jul-Aug; 2(4): 414–20.
14 Faria E, Rodrigues-Cernadas J, Gaspar A,
Botelho C, Castro E, Lopes A, et al.; Portuguese
Society of Allergology and Clinical Immunol-
ogy; Drug Allergy Interest Group. Drug-in-
duced anaphylaxis survey in Portuguese Al-
lergy Departments. J Investig Allergol Clin Im-
munol. 2014; 24(1): 40–8.
15 Jares EJ, Baena-Cagnani CE, Sánchez-Borges
M, Ensina LF, Arias-Cruz A, Gómez M, et al.;
Latin America Drug Allergy Interest Group.
Drug-induced anaphylaxis in Latin american
countries. J Allergy Clin Immunol Pract. 2015
Sep-Oct; 3(5): 780–8.
16 Lee S, Bellolio MF, Hess EP, Campbell RL. Pre-
dictors of biphasic reactions in the emergency
department for patients with anaphylaxis. J Al-
lergy Clin Immunol Pract. 2014 May-Jun; 2(3):
281–7.
17 Amornmarn LB, Kumar N. Anaphylaxis ad-
missions to a university hospital. J Allergy Clin
Immunol. 1992; 89: 349.
18 Klein JS, Yocum MW. Underreporting of ana-
phylaxis in a community emergency room. J
Allergy Clin Immunol. 1995 Feb; 95(2): 637–8.
19 Kaufman DW; International Collaborative
Study of Severe Anaphylaxis. Risk of anaphy-
laxis in a hospital population in relation to the
use of various drugs: an international study.
Pharmacoepidemiol Drug Saf. 2003 Apr-May;
12(3): 195–202.
20 Liew WK, Williamson E, Tang ML. Anaphy-
laxis fatalities and admissions in Australia. J
Allergy Clin Immunol. 2009 Feb; 123(2): 434–
42.
21 Clark S, Wei W, Rudders SA, Camargo CA Jr.
Risk factors for severe anaphylaxis in patients
receiving anaphylaxis treatment in US emer-
gency departments and hospitals. J Allergy
Clin Immunol. 2014 Nov; 134(5): 1125–30.
22 Brown SG, Stone SF, Fatovich DM, Burrows
SA, Holdgate A, Celenza A, et al. Anaphylaxis:
clinical patterns, mediator release, and severi-
ty. J Allergy Clin Immunol. 2013 Nov; 132(5):
1141–1149.e5.
23 Idsoe O, Guthe T, Willcox RR, de Weck AL.
Nature and extent of penicillin side-reactions,
with particular reference to fatalities from ana-
phylactic shock. Bull World Health Organ.
1968; 38(2): 159–88.
Downloaded by:
Istanbul Universitesi
194.27.138.2 - 2/27/2019 7:22:19 AM

Demir/Erdenen/Gelincik/Unal/Olgac/
Coskun/Colakoglu/Buyukozturk
Int Arch Allergy Immunol 2019;178:167–176
176
DOI: 10.1159/000494130
24 Gonzalez-Estrada A, Pien LC, Zell K, Wang
XF, Lang DM. Antibiotics are an important
identifiable cause of perioperative anaphylaxis
in the United States. J Allergy Clin Immunol
Pract. 2015 Jan-Feb; 3(1): 101–5.e1.
25 Sahiner UM, Yavuz ST, Buyuktiryaki B,
Cavkaytar O, Yilmaz EA, Tuncer A, et al. Se-
rum basal tryptase may be a good marker for
predicting the risk of anaphylaxis in children
with food allergy. Allergy. 2014 Feb; 69(2): 265–
8.
26 Fellinger C, Hemmer W, Wöhrl S, Sesztak-
Greinecker G, Jarisch R, Wantke F. Clinical
characteristics and risk profile of patients with
elevated baseline serum tryptase. Allergol Im-
munopathol (Madr). 2014 Nov-Dec; 42(6):
544–52.
27 Cavkaytar O, Karaatmaca B, Arik Yilmaz E, Sa-
hiner UM, Sackesen C, Sekerel BE, et al. Basal
serum tryptase is not a risk factor for immedi-
ate-type drug hypersensitivity during child-
hood. Pediatr Allergy Immunol. 2016 Nov;
27(7): 736–42.
28 Seitz CS, Brockow K, Hain J, Trautmann A.
Non-steroidal anti-inflammatory drug hyper-
sensitivity: association with elevated basal se-
rum tryptase? Allergy Asthma Clin Immunol.
2014 Apr; 10(1): 19.
29 Sala-Cunill A, Cardona V, Labrador-Horrillo
M, Luengo O, Esteso O, Garriga T, et al. Use-
fulness and limitations of sequential serum
tryptase for the diagnosis of anaphylaxis in 102
patients. Int Arch Allergy Immunol. 2013;
160(2): 192–9.
30 Demir S, Gelincik A, Akdeniz N, Aktas-Cetin
E, Olgac M, Unal D, et al. Usefulness of In Vivo
and In Vitro Diagnostic Tests in the Diagnosis
of Hypersensitivity Reactions to Quinolones
and in the Evaluation of Cross-Reactivity: A
Comprehensive Study Including the Latest
Quinolone Gemifloxacin. Allergy Asthma Im-
munol Res. 2017 Jul; 9(4): 347–59.
31 Kowalski ML, Asero R, Bavbek S, Blanca M,
Blanca-Lopez N, Bochenek G, et al. Classifica-
tion and practical approach to the diagnosis
and management of hypersensitivity to non-
steroidal anti-inflammatory drugs. Allergy.
2013 Oct; 68(10): 1219–32.
32 Demoly P, Adkinson NF, Brockow K, Castells
M, Chiriac AM, Greenberger PA, et al. Inter-
national Consensus on drug allergy. Allergy.
2014 Apr; 69(4): 420–37.
33 Simons FE, Ardusso LR, Bilò MB, El-Gamal
YM, Ledford DK, Ring J, et al.; World Allergy
Organization. World allergy organization
guidelines for the assessment and management
of anaphylaxis. World Allergy Organ J. 2011
Feb; 4(2): 13–37.
34 Romano A, Torres MJ, Castells M, Sanz ML,
Blanca M. Diagnosis and management of drug
hypersensitivity reactions. J Allergy Clin Im-
munol. 2011 Mar; 127(3 Suppl):S67–73.
35 Malling HJ. Allergen standardization and skin
tests. Methods of skin testing. Position paper.
Allergy. 1993; 48 Suppl 14: 55–6.
36 Venturini Díaz M, Lobera Labairu T, del Pozo
Gil MD, Blasco Sarramián A, González Ma-
have I. In vivo diagnostic tests in adverse reac-
tions to quinolones. J Investig Allergol Clin
Immunol. 2007; 17(6): 393–8.
37 Brockow K, Garvey LH, Aberer W, Atanasko-
vic-Markovic M, Barbaud A, Bilo MB, et al.;
ENDA/EAACI Drug Allergy Interest Group.
Skin test concentrations for systemically ad-
ministered drugs— an ENDA/EAACI Drug
Allergy Interest Group position paper. Allergy.
2013 Jun; 68(6): 702–12.
38 Kim SY, Kim MH, Cho YJ. Different clinical
features of anaphylaxis according to cause and
risk factors for severe reactions. Allergol Int.
2018 Jan; 67(1): 96–102.
39 Park HK, Kang MG, Yang MS, Jung JW, Cho
SH, Kang HR. Epidemiology of drug-induced
anaphylaxis in a tertiary hospital in Korea. Al-
lergol Int. 2017 Oct; 66(4): 557–62.
40 Kim SM, Ko BS, Kim JY, Ha SO, Ahn S, Sohn
CH, et al. Clinical factors for developing shock
in radiocontrast media induced anaphylaxis.
Shock. 2016 Mar; 45(3): 315–9.
41 Mirone C, Preziosi D, Mascheri A, Micarelli G,
Farioli L, Balossi LG, et al. Identification of risk
factors of severe hypersensitivity reactions in
general anesthesia. Clin Mol Allergy. 2015 22;
13(1): 11.
42 Gabrielli S, Clarke AE, Eisman H, Morris J, Jo-
seph L, La Vieille S, et al. Disparities in rate,
triggers, and management in pediatric and
adult cases of suspected drug-induced anaphy-
laxis in Canada. Immun Inflamm Dis. 2018
Mar; 6(1): 3–12.
43 Macy E, Contreras R. Adverse reactions associ-
ated with oral and parenteral use of cephalo-
sporins: A retrospective population-based
analysis. J Allergy Clin Immunol. 2015 Mar;
135(3): 745–52.e5.
44 Cornejo-García JA, Guéant-Rodriguez RM,
Torres MJ, Blanca-Lopez N, Tramoy D, Roma-
no A, et al. Biological and genetic determinants
of atopy are predictors of immediate-type al-
lergy to betalactams, in Spain. Allergy. 2012
Sep; 67(9): 1181–5.
45 Apter AJ, Schelleman H, Walker A, Addya K,
Rebbeck T. Clinical and genetic risk factors of
self-reported penicillin allergy. J Allergy Clin
Immunol. 2008 Jul; 122(1): 152–8.
46 Ponvert C. [Allergic and non-allergic hyper-
sensitivity to non-opioid analgesics, antipyret-
ics and nonsteroidal anti-inflammatory drugs
in children: epidemiology, clinical aspects,
pathophysiology, diagnosis and prevention].
Arch Pediatr. 2012 May; 19(5): 556–60.
47 Cianferoni A, Novembre E, Mugnaini L, Lom-
bardi E, Bernardini R, Pucci N, et al. Clinical
features of acute anaphylaxis in patients admit-
ted to a university hospital: an 11-year retro-
spective review (1985-1996). Ann Allergy
Asthma Immunol. 2001 Jul; 87(1): 27–32.
48 Kelkar PS, Li JT. Cephalosporin allergy. N Engl
J Med. 2001 Sep; 345(11): 804–9.
49 Gomez MB, Torres MJ, Mayorga C, Perez-
Inestrosa E, Suau R, Montañez MI, et al. Im-
mediate allergic reactions to betalactams: facts
and controversies. Curr Opin Allergy Clin Im-
munol. 2004 Aug; 4(4): 261–6.
50 Mota I, Gaspar Â, Chambel M, Piedade S,
Morais-Almeida M. Hypersensitivity to beta-
lactam antibiotics: a three-year study. Eur
Ann Allergy Clin Immunol. 2016 Nov; 48(6):
212–9.
51 Somech R, Weber EA, Lavi S. Evaluation of im-
mediate allergic reactions to cephalosporins in
non-penicillin-allergic patients. Int Arch Al-
lergy Immunol. 2009; 150(3): 205–9.
52 Riezzo I, Bello S, Neri M, Turillazzi E, Fineschi
V. Ceftriaxone intradermal test-related fatal
anaphylactic shock: a medico-legal nightmare.
Allergy. 2010 Jan; 65(1): 130–1.
53 Pastorello EA, Stafylaraki C, Mirone C, Pre-
ziosi D, Aversano MG, Mascheri A, et al. Anti-
amoxicillin immunglobulin E, histamine-2 re-
ceptor antagonist therapy and mast cell activa-
tion syndrome are risk factors for amoxicillin
anaphylaxis. Int Arch Allergy Immunol. 2015;
166(4): 280–6.
54 Brockow K, Bonadonna P. Drug allergy in
mast cell disease. Curr Opin Allergy Clin Im-
munol. 2012 Aug; 12(4): 354–60.
55 Ramírez E, Cabañas R, Laserna LS, Fiandor A,
Tong H, Prior N, et al. Proton pump inhibitors
are associated with hypersensitivity reactions
to drugs in hospitalized patients: a nested case-
control in a retrospective cohort study. Clin
Exp Allergy. 2013 Mar; 43(3): 344–52.
56 Simons FE, Ardusso LR, Dimov V, Ebisawa M,
El-Gamal YM, Lockey RF, et al.; World Allergy
Organization. World Allergy Organization
Anaphylaxis Guidelines: 2013 update of the
evidence base. Int Arch Allergy Immunol.
2013; 162(3): 193–204.
57 Thomson AB, Sauve MD, Kassam N, Kamita-
kahara H. Safety of the long-term use of proton
pump inhibitors. World J Gastroenterol. 2010
May; 16(19): 2323–30.
58 Gupta PP, Bhandari R, Mishra DR, Agrawal
KK, Bhandari R, Jirel S, et al. Anaphylactic re-
actions due to pantoprazole: case report of two
cases. Int Med Case Rep J. 2018 May; 11: 125–7.
59 Kepil Özdemir S, Öner Erkekol F, Ünal D,
Büyüköztürk S, Gelincik A, Dursun AB, et al.
Management of hypersensitivity reactions to
proton pump inhibitors: A retrospective expe-
rience. Int Arch Allergy Immunol. 2016;
171(1): 54–60.
60 Bonadonna P, Lombardo C, Bortolami O,
Bircher A, Scherer K, Barbaud A, et al. Hyper-
sensitivity to proton pump inhibitors: diagnos-
tic accuracy of skin tests compared to oral
provocation test. J Allergy Clin Immunol. 2012
Aug; 130(2): 547–9.
61 Mota I, Gaspar Â, Chambel M, Morais-Almei-
da M. Anaphylaxis induced by proton pump
inhibitors. J Allergy Clin Immunol Pract. 2016
May-Jun; 4(3): 535–6.
62 Joint Task Force on Practice Parameters;
American Academy of Allergy, Asthma and
Immunology; American College of Allergy,
Asthma and Immunology; Joint Council of
Allergy, Asthma and Immunology. Drug al-
lergy: an updated practice parameter. Ann Al-
lergy Asthma Immunol. 2010 Oct; 105(4):
259–73.
Downloaded by:
Istanbul Universitesi
194.27.138.2 - 2/27/2019 7:22:19 AM