Allergology International 67 (2018) 96e102

Contents lists available at ScienceDirect

Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Original Article

Different clinical features of anaphylaxis according to cause and risk

factors for severe reactions
Sang-Yoon Kim, Min-Hye Kim*, Young-Joo Cho
Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea

a r t i c l e i n f o a b s t r a c t

Article history: Background: Anaphylaxis is a life-threatening allergic reaction. Several studies reported different
Received 20 February 2017 anaphylactic reactions according to the causative substances. However, a comparison of anaphylaxis for
Received in revised form each cause has not been done. This study was conducted to identify common causes of anaphylaxis,
20 April 2017
characteristics of anaphylactic reaction for each cause and to analyze the factors related to the severity of
Accepted 6 May 2017
Available online 8 June 2017
the reaction.
Methods: Medical records of patients who visited the emergency room of Ewha Womans University
Mokdong Hospital from March 2003 to April 2016 and diagnosed with anaphylactic shock were
Keywords:
Anaphylactic shock
retrospectively reviewed. We compared the clinical features of anaphylaxis according to the cause. In
Anaphylaxis addition, the severity of anaphylaxis was analyzed and contributing factors for severe anaphylaxis were
Drug hypersensitivity reviewed.
Food hypersensitivity Results: A total of 199 patients with anaphylaxis were analyzed. Food was the most common cause
Risk factors (49.7%), followed by drug reaction (36.2%), bee venom (10.1%), and unknown cause (4.0%). Cardiovascular
symptoms of syncope and hypotension were more common in drug-induced anaphylaxis. The incidence
Abbreviations: of severe anaphylaxis was the highest in anaphylaxis due to drugs (54.2%). Urticaria and other skin
ED, emergency department; NOS, Not symptoms were significantly more common in food-induced anaphylaxis. Risk factors for severe
otherwise specified; KCD, Korean standard anaphylaxis included older age, male, and drug-induced one. Epinephrine treatment of anaphylaxis was
classification of disease; MAST, multiple done for 69.7% and 56.9% of patients with food-induced and drug-induced anaphylaxis, respectively.
allergosorbent test; WBC, white blood cell;
Conclusions: More severe anaphylaxis developed with drug treatment and in males. Low rate of
ECP, eosinophil cationic protein;
AST, aspartate transaminase; ALT, alanine
epinephrine prescription was also observed. Male patients with drug induced anaphylaxis should be paid
transaminase; NSAIDs, nonsteroidal anti- more attention.
inflammatory drugs; CT, computed Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
tomography article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
Anaphylaxis is a severe systemic allergic reaction in which
typical symptoms that include systemic urticaria, angioedema,
dyspnea, abdominal pain, and hypotension, develop immediately
or within minutes upon exposure to the allergen.1,2 Timely and
appropriate treatment is crucial, as the reaction progresses rapidly
and affects several organs. It can be fatal in some cases.3 The
prevalence of anaphylaxis in the general population in the United
States reportedly exceeds 1.6%.4 In Europe, the frequency is 1.5e7.9
* Corresponding author. Department of Internal Medicine, College of Medicine,
Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985,
South Korea.
E-mail address: mineyang81@ewha.ac.kr (M.-H. Kim).
Peer review under responsibility of Japanese Society of Allergology.
cases per 100,000 people.5 In South Korea, the precise prevalence
has not been reported, but data suggest that 7.2 patients per 10,000
patients visited the emergency department (ED) because of
anaphylaxis.6
Anaphylaxis is multifactorial, and its etiology varies according to
region and race.4,5,7 Moreover, clinical symptoms may vary from
patient to patient, even when the same allergen is involved. These
variations have complicated research on anaphylaxis.
It is important to identify the causes and risk factors for severe
and potentially fatal anaphylaxis, to prevent allergen re-exposure
and to manage subsequent anaphylactic episodes.8,9 Accordingly,
this study aimed to investigate the clinical manifestations among
anaphylactic patients. Particularly, this study sought to identify
different clinical features of anaphylaxis according to causes and
risk factors for severe anaphylaxis.

http://dx.doi.org/10.1016/j.alit.2017.05.005
1323-8930/Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
 S.-Y. Kim et al. / Allergology International 67 (2018) 96e102
Methods
Patients
We searched the electronic medical records of patients who
visited the ED at Ewha Womans University Mokdong Hospital, a
tertiary hospital in Seoul, South Korea, between March 2003 and
April 2016, and who were diagnosed with anaphylactic shock,
unspecified (T782), anaphylactic reaction Not Otherwise Specified
(NOS) (T78202), anaphylaxis NOS (T78203), anaphylactic shock due
to adverse effect of a correctly prescribed drug or medication that
was properly administered (T886) according to Korean standard
classification of disease (KCD). Electronic medical records were
reviewed by an allergist, and cases meeting the definition of
anaphylaxis were selected.10,11 The study was approved by the
Institutional Review Board at Ewha Womans University Mokdong
Hospital and it met the ethical principles of the Declaration of
Helsinki. IRB waived informed consents of patients because this
was a retrospective chart review study and patient anonymity was
preserved using methods approved by the Ethics Committee (Ewha
Womans University Mokdong Hospital IRB number: 2017-02-020-
001).
Anaphylaxis
As previously described, anaphylaxis was diagnosed when any
one of the following three criteria were fulfilled.10,11 First, symp-
toms occurred suddenly (within a few hours) in the skin and mu-
cous membranes (systemic urticaria, itching, flushing, lip-tongue-
uvula edema) plus either respiratory symptoms (dyspnea,
wheezing, stridor, hypoxemia) or cardiovascular symptoms (syn-
cope, hypotension, urinary incontinence, chest discomfort). Sec-
ond, two or more of the following occurred rapidly (within a few
hours) after exposure to a suspected allergen: (i) involvement of
skin-mucosal tissues, (ii) respiratory symptoms, (iii) reduced blood
pressure or associated symptoms, and (iv) persistent gastrointes-
tinal symptoms (crampy abdominal pain, vomiting, diarrhea).
Third, blood pressure reduction occurred suddenly (within a few
hours) after exposure to known allergen for the patient. Severity of
anaphylaxis was classified as mild, moderate, or severe.12 Mild
anaphylaxis was defined as cases those had limited skin or mucosal
symptoms, involving urticaria, erythema, and edema near the eyes
or angioedema and combined mild symptoms of other organs.
Moderate anaphylaxis was defined as reactions involving respira-
tory, cardiovascular, and gastrointestinal symptoms (such as dys-
pnea, wheezing, vertigo, nausea, vomiting, and abdominal pain);
the patient also had to be conscious with systolic blood pressure
>90 mmHg. Severe anaphylaxis was defined as reactions involving
cyanosis, hypotension, and neurological symptoms with oxygen
saturation <92% or systolic blood pressure <90 mmHg. With regard
to clinical course, cases involving one episode of symptoms were
classified as monophasic and cases involving a second episode of
symptoms 1e72 h after resolution of the initial symptoms were
classified as biphasic.13,14
Skin prick and laboratory tests
The electronic medical records were reviewed and obtained
demographic information including age, sex, history of underlying
disease, allergic diseases, suspected causes and clinical features of
the anaphylaxis, and laboratory tests. Skin prick test and serum
allergen specific IgE tests (multiple allergosorbent test, MAST) were
also performed. In some cases, MAST were performed at emergency
department at the time of patient's visit, or skin prick tests or MAST
were performed in Allergy outpatient clinic when the patients were
97
referred to the Allergy department after emergent treatment. The
skin prick test was performed using 55 common inhalant and food
allergens at least 2 weeks after the anaphylaxis for those patients
who agreed to undergo skin testing. Histamine and normal saline
were used as positive and negative control, respectively. After
15 min application of the allergens, a positive reaction was a wheal
diameter >3 mm. In the case of MAST, class 1 or more was defined
as positive. The presence of atopy in the patient was defined as a
positive skin prick test or when at least one allergen-specific IgE
test for common food and inhalation allergens was positive. The
probable causative agent was estimated based on clinical history.
Peripheral blood laboratory tests included white blood cell (WBC),
eosinophil counts, total IgE level, eosinophil cationic protein (ECP),
aspartate transaminase (AST), alanine transaminase (ALT), and
creatinine.
Statistical analyses
Variables with normal distribution were expressed as the
mean ± standard deviation or percentage (%). Variables with non-
normal distribution were expressed by median value. Continuous
variables were analyzed by t-test or ManneWhitney test. Cate-
gorical data were analyzed using the chi-square or Fisher's exact
test. To identify the risk factors related with severe anaphylaxis,
multiple logistic regression analysis was used. Variables that are
clinically important and those P value < 0.1 in the univariate
analysis were adjusted in the multiple variate analysis. Statistical
analyses were performed using SPSS version 20.0 (IBM, Armonk,
NY, USA). Statistical significance was considered for P-
values < 0.05.
Results
General characteristics of anaphylactic patients
During the study period, 199 patients visited the ED for
treatment of anaphylaxis. Of these, 103 were male (51.8%). The
overall mean age was 41.1 ± 23.4 years, and 45 patients were
under 18 years (22.6%). Atopy was present in 58 (29.1%) patients
and 55 (27.6%) had a history of allergic disease including asthma,
allergic dermatitis, allergic rhinitis, food allergies, and drug al-
lergies. Fifty five (27.6%) patients had a history of chronic disease
including hypertension (16.1%), malignant disease (4.5%),
ischemic heart disease (4.0%), diabetic mellitus (4.0%), neurologic
disease (2.5%), and renal disease (1.0%). Average values of labo-
ratory tests were: WBC 9287.9 ± 4131.2/uL, eosinophil count
154.2 ± 178.4/uL, total IgE 430.1 ± 762.6 IU/mL, ECP
18.1 ± 16.3 ug/L, AST 44.6 ± 152.0 IU/L, ALT 29.5 ± 74.0 IU/L, and
creatinine 1.03 ± 1.09 mg/dL (Table 1).
Causes of anaphylaxis
Food-induced anaphylaxis was the most frequent (n ¼ 99,
49.7%), followed by drug-induced (n ¼ 72, 36.2%), bee venom-
induced (n ¼ 20, 10.1%), and cause unknown anaphylaxis (n ¼ 8,
4.0%). The causes of food-induced anaphylaxis included seafood
(n ¼ 28, 28.3%), meat (n ¼ 18, 18.1%), grain/wheat flour (n ¼ 18,
18.1%), fruit (n ¼ 11, 11.1%), egg (n ¼ 7, 7.1%), milk/dairy product
(n ¼ 6, 6.1%), nuts (n ¼ 6, 6.1%), and pupa (n ¼ 3, 3.0%). Of the 72
patients with drug-induced anaphylaxis, antibiotics were the most
common culprit drugs (n ¼ 29, 40.2%), followed by nonsteroidal
anti-inflammatory drugs (NSAIDs; n ¼ 24, 33.3%), computed to-
mography (CT) radiocontrast agents (n ¼ 8, 11.1%), amino acids
solutions (n ¼ 6, 8.3%), lidocaine (n ¼ 3, 4.1%), ranitidine (n ¼ 1,
1.4%), and midazolam (n ¼ 1, 1.4%) (Table 2).
98 S.-Y. Kim et al. / Allergology International 67 (2018) 96e102

Table 1 (n ¼ 72) anaphylaxis revealed that the food-induced anaphylaxis

Characteristics of the anaphylactic patients. group was significantly younger with a significantly higher pro-
Number of patients (%) portion of patients aged <18 years (32.8 ± 23.8 years vs. 50.2 ± 19.7
Total number of patients 199
years, P < 0.001, 37.4% vs. 5.6%, P < 0.001, respectively). Fifty-five
Male 103 (51.8) (55.6%) patients in the food-induced anaphylactic group and 33
Age (years) 41.1 ± 23.4 (45.8%) patients in the drug-induced anaphylactic group were
Age <18 years 45 (22.6) male. The food-induced group comprised significantly more pa-
Atopy 58/71 (81.7)
tients with allergic disease (37.4% vs. 13.9%, P ¼ 0.001). Conversely,
History of allergic diseases 55 (27.6)
Asthma 12 (6.0) the food-induced anaphylactic group had lower prevalence of
Atopic dermatitis 8 (4.0) chronic diseases compared to the drug-induced anaphylactic group
Allergic rhinitis 8 (4.0) (20.2% vs. 36.1%, P ¼ 0.024; Table 3). Both groups showed different
Food allergy 33 (16.6)
clinical symptoms. The most common type was skin symptom in
Drug allergy 7 (3.5)
History of medical diseases 55 (27.6)
both groups, however 90.9% of 99 patients in the food-induced
Hypertension 32 (16.1)
Malignancy 9 (4.5)
Diabetes mellitus 8 (4.0) Table 3
Ischemic heart disease 4 (2.0) Comparison of food- and drug-induced anaphylaxis.
Renal disease 2 (1.0)
Neurologic disease 5 (2.5) Food (n, %) Drug (n, %) P
Anaphylaxis severity
Number 99 72
Mild/moderate 124 (62.4)
Male 55 (55.6) 33 (45.8) 0.219
Severe 75 (37.6)
Age (years) 32.8 ± 23.8 50.2 ± 19.7 <0.001
Laboratory results
Age <18 years 37 (37.4) 4 (5.6) <0.001
WBC (/uL) 9287.9 ± 4131.2
Atopy 40/47 (85.1) 12/16 (75.0) 0.448
Eosinophil count (/uL) 154.2 ± 178.4
History of allergic diseases 37 (37.4) 10 (13.9) 0.001
IgE (IU/ml) 262.0 (90.6e441.5)
Asthma 6 (6.1) 1 (1.4) 0.241
ECP (ug/L) 18.1 ± 16.3 (n ¼ 46)
Atopic dermatitis 4 (4.0) 2 (2.8) 1.000
AST (IU/L) 44.6 ± 152.0
Allergic rhinitis 8 (8.1) 2 (2.8) 0.194
ALT (IU/L) 29.5 ± 74.0
Food allergy 29 (29.3) 3 (4.2) <0.001
Creatinine (mg/dl) 1.03 ± 1.09
Drug allergy 3 (3.0) 4 (5.6) 0.456
The data are expressed as mean ± SD or median (25e75%). History of medical diseases 20 (20.2) 26 (36.1) 0.024
Hypertension 13 (13.1) 15 (20.8) 0.211
Diabetes mellitus 4 (4.0) 2 (2.8) 1.000
Comparison of clinical characteristics and laboratory findings Ischemic heart disease 2 (2.0) 2 (2.8) 1.000
between food- and drug-induced anaphylaxis Renal disease 1 (1.0) 1 (1.4) 1.000
Neurologic disease 2 (2.0) 3 (4.2) 0.651
A detailed analysis of the differences in clinical manifestations Malignancy 4 (4.0) 4 (5.6) 0.722
Symptoms of anaphylaxis
among 171 patients with food-induced (n ¼ 99) or drug-induced Cardiovascular 31 (31.3) 46 (63.9) <0.001
Hypotension 26 (26.3) 30 (41.7) 0.047
Syncope 3 (3.0) 14 (19.4) 0.001
Table 2 Chest discomfort 6 (6.1) 6 (8.3) 0.563
Suspected causes of anaphylaxis. Respiratory 49 (49.5) 33 (45.8) 0.646
Wheezing 2 (2.0) 1 (1.4) 1.000
Number of patients (%)
Dyspnea 47 (47.5) 33 (45.8) 0.877
Total number of patients 199 Gastrointestinal 24 (24.2) 18 (25.0) 1.000
Food 99 Abdominal pain 12 (12.1) 8 (11.1) 1.000
Seafood 28 (28.3) Vomiting 10 (10.1) 11 (15.3) 0.350
Shrimp 11 (11.1) Diarrhea 3 (3.0) 0 (0.0) 0.264
Fish 8 (8.1) Skin 90 (90.9) 50 (69.4) <0.001
Crab 6 (6.1) Urticaria 86 (86.9) 48 (66.7) 0.002
Shellfish 3 (3.0) Angioedema 23 (23.2) 13 (18.1) 0.452
Meat 18 (18.1) Generalized swelling 0 (0.0) 1 (1.4) 0.421
Pork 9 (9.1) Pruritus 27 (27.3) 17 (23.6) 0.723
Chicken 6 (6.1) Neurologic 20 (20.2) 19 (26.4) 0.361
Processed meat 2 (2.0) Anaphylaxis severity
Beef 1 (1.0) Mild/moderate 73 (73.7) 33 (45.8) <0.001
Grain/flour 18 (18.1) Severe 26 (26.3) 39 (54.2) <0.001
Fruit 11 (11.1) Treatment
Egg 7 (7.1) Epinephrine 69 (69.7) 41 (56.9) 0.106
Milk/dairy product 6 (6.1) Corticosteroids 94 (94.9) 64 (88.9) 0.155
Nuts 6 (6.1) Hospitalization 17 (17.2) 13 (18.1) 1.000
Pupa 3 (3.0) Clinical progression
Alcohol 2 (2.0) Monophasic 80 (80.8) 63 (87.5) 0.298
Drug 72 Biphasic 19 (19.2) 9 (12.5) 0.298
Antibiotics 29 (40.2) Laboratory tests
NSAID 24 (33.3) WBC (/uL) 9981.9 ± 4081.1 8504.6 ± 4336.3 0.034
CT radiocontrast 8 (11.1) Eosinophil count (/uL) 191.9 ± 207.5 108.1 ± 125.0 0.003
Amino acids solutions 6 (8.3) IgE (IU/ml) 462.3 ± 909.7 399.1 ± 468.5 0.765
Lidocaine 3 (4.1) ECP (ug/L) 19.3 ± 18.2 18.3 ± 15.6 0.860
Ranitidine 1 (1.4) (n ¼ 26) (n ¼ 14)
Midazolam 1 (1.4) AST (IU/L) 59.9 ± 214.9 29.6 ± 24.3 0.198
Bee venom 20 ALT (IU/L) 37.7 ± 104.4 108.1 ± 125.0 0.160
Exercise 5 Creatinine (mg/dl) 0.92 ± 0.32 1.20 ± 1.71 0.139
Unknown 3
The data are presented as mean ± SD.
 S.-Y. Kim et al. / Allergology International 67 (2018) 96e102 99

anaphylaxis showed skin manifestation, whereas only 69.4% of serum IgE, ECP, AST, and ALT between patients with mild/moderate
patients had skin reactions in drug-induced anaphylaxis and severe anaphylaxis. In the patients with severe reactions, drug-
(P ¼ 0.001). Among them, significantly higher proportion of pa- induced anaphylaxis was significantly more prevalent (Table 4).
tients experienced urticaria in the food-induced anaphylactic group The incidence of severe reactions was the highest among pa-
compared to those in the drug-induced anaphylactic group (86.9% tients with drug-induced anaphylaxis, with the proportion of se-
vs. 66.7%, P ¼ 0.002). Cardiovascular symptoms were less frequent vere reactions being 26.3% in the food-induced anaphylaxis, 54.2%
in food-induced anaphylactic patients than drug-induced anaphy- in the drug-induced anaphylaxis, 35.0% in the bee venom
lactic patients (31.3% vs. 63.9%, P < 0.001). Hypotension and syn- anaphylaxis, and 37.5% in the unknown cause anaphylaxis (Fig. 1).
cope were more common in the drug-induced anaphylactic group In the drug-induced anaphylaxis, the incidence of severe anaphy-
than in food-induced anaphylactic group. There was no significant laxis was the highest among patients whose culprit drug was a
difference in other clinical features including respiratory symp- radiocontrast agent (7 of 8, 87.5%), followed by NSAIDs (16 of 24,
toms, gastrointestinal symptoms, and neurological symptoms. 66.7%), antibiotics (13 of 29, 44.8%), amino acids solutions (2 of 6,
Regarding severity, a significantly higher number of patients had 33.3%), and lidocaine (1 of 3, 33.3%) (Fig. 2). In the food-induced
severe reactions in the drug-induced group (39/72, 54.2%) than in anaphylaxis, incidence of severe anaphylaxis was the highest
the food-induced group (26/99, 26.3%) (P < 0.001). Despite the among patients whose culprit food was meat (8 of 18, 44.4%), fol-
higher proportion of patients with severe anaphylactic reactions in lowed by milk/dairy products (2 of 6, 33.3%), seafood (8 of 28,
the drug-induced group, there was no significant difference in the 28.6%), egg (2 of 7, 28.6%), and grains/wheat flour (4 of 18, 22.2%)
proportion of patients hospitalized after emergency care between (Fig. 3).
the two groups. Further, there was no significant difference in the Multivariate logistic regression showed that old age (OR 1.020;
treatment with epinephrine or corticosteroids. Biphasic anaphy- 95% CI 1.002e1.039), male (OR 2.305; 95% CI 1.186e4.480), drug-
lactic reaction developed in 19.2% of the food-induced anaphylactic induced anaphylaxis (OR 2.244; 95% CI 1.059e4.753) were signifi-
patients and 12.5% of the drug-induced anaphylactic patients cant risk factors of severe anaphylaxis (Table 5).
(Table 3). Peripheral blood analyses revealed significantly higher
WBC and eosinophil counts in the food-induced anaphylactic pa-
tients compared to the drug-induced anaphylactic patients Discussion
(9981.9 ± 4048.1 vs. 8504.6 ± 4336.3/uL, P ¼ 0.034; 191.9 ± 207.5 vs.
108.1 ± 125.0, P ¼ 0.003, respectively). There was no significant This study investigated the causes of anaphylaxis and clinical
difference between the two groups in AST, ALT, creatinine, IgE, or features and differences according to cause and severity in 199
ECP (Table 3). patients who visited the ED of one tertiary hospital in Seoul, Korea
over a recent 13-year period.
Comparison of clinical characteristics according to the severity The most common causes of anaphylaxis were foods and drugs,
consistent with another study.15,16 The food-induced anaphylaxis
Among 199 anaphylactic patients, 75 (37.6%) had severe re- group was significantly younger and had a higher proportion of
actions including 26 food-induced patients, 39 drug-induced pa- allergic diseases than drug-induced anaphylactic patients.
tients, 7 bee venom patients, and 3 patients with unknown causes Conversely, drug-induced anaphylactic group had more chronic
(Fig. 1). The mean age of patients with severe anaphylaxis was diseases compared to food-induced anaphylactic group. Both
significantly higher than that of patients with mild-to-moderate groups also showed different clinical symptoms. Those with food-
anaphylaxis (50.2 ± 19.1 vs. 35.7 ± 24.2 years, P < 0.001). The induced anaphylaxis more commonly displayed skin manifesta-
proportion of male patients was also significantly higher in the tions than patients with drug-induced anaphylaxis. In contrast,
severe anaphylactic group than in the mild-to-moderate anaphy-
lactic group (47/75, 62.7% vs. 49/124, 39.5%, P ¼ 0.002). There were Table 4
no significant differences in the prevalence of atopy, allergic dis- Severity of anaphylaxis.
eases and medical diseases including cardiovascular comorbidities
Mild/moderate Severe (n, %) P
between patients with severe and mild/moderate anaphylaxis. (n, %)
There were no significant differences in the eosinophil count, total
Patients number 124 (62.4) 75 (37.6)
Age (years) 35.7 ± 24.2 50.2 ± 19.1 <0.001
Male 49 (39.5) 47 (62.7) 0.002
Atopy 43/50 (86.0) 15/21 (71.4) 0.184
History of allergic 37 (29.8) 18 (24.0) 0.416
diseases
History of medical 31 (25.0) 24 (32.0) 0.327
diseases
History of cardiovascular 21 (16.9) 13 (17.3) 1.000
disease
WBC (ug/L) 9795.7 ± 4034.9 8578.4 ± 4187.0 0.054
Eosinophil count (/uL) 182.4 ± 186.3 114.9 ± 159.7 0.054
IgE (IU/mL) 490.2 ± 898.9 307.5 ± 333.2 0.368
ECP (ug/L) 18.7 ± 17.3 16.7 ± 13.8 0.720
(n ¼ 34) (n ¼ 12)
AST (IU/L) 45.0 ± 165.7 44.1 ± 131.6 0.970
ALT (IU/L) 26.5 ± 43.5 33.6 ± 102.7 0.537
Suspected causes 0.003
Food 73 (58.9) 26 (34.7)
Drug 33 (26.6) 39 (52.0)
Bee venom 13 (10.5) 7 (9.3)
Exercise 3 (2.4) 2 (2.7)
Unknown 2 (1.6) 1 (1.3)

Fig. 1. Composition of severe anaphylaxis in each cause. The data presented as mean ± SD.
100 S.-Y. Kim et al. / Allergology International 67 (2018) 96e102

Fig. 2. Composition of severe anaphylaxis in each drug.

Fig. 3. Composition of severe anaphylaxis in each food.

cardiovascular symptoms including hypotension and syncope were
more frequent in drug-induced anaphylactic patients than in food-
induced anaphylactic patients. Severe anaphylactic patients were
also older and more male-predominant than patients with mild to
moderate reactions. In addition, drug medication was the most
common cause of severe anaphylaxis. Risk factors for the severe
anaphylaxis were old age, male sex, and drug-induced anaphylaxis.
Although there have been domestic reports on the characteristics of
Korean patients with anaphylaxis15,17,18 or those on a single cause of
anaphylaxis, such as foods,19 drugs,20 or bee venom,21 the differ-
ences in clinical features of anaphylaxis according to the cause is
not clear. In addition, the severity of anaphylaxis has been poorly
studied, owing to its low prevalence.
The key causes of anaphylaxis are drugs, foods, insects, and
exercise. Food is the most common cause of anaphylaxis in chil-
dren, while drugs are the most common cause in adults.4e6,17,22
Presently, 37.4% of patients with food-induced anaphylaxis were
pediatric patients (i.e., <18 years of age), whereas 5.6% of patients
with drug-induced anaphylaxis were pediatric. This is similar to
previous studies that reported that food-induced anaphylaxis more
commonly occurs in children <18 years of age. The causative foods
of anaphylaxis differ depending on dietary habits, geographic
conditions, and cultural differences. Nuts and seafood are the main
causes of anaphylaxis globally.22 In South Korea, seafood and wheat
flour or wheat flour and pupa are reported as the main causes of
food-induced anaphylaxis.19,23 In this study, seafood (28.3%), meat
(18.1%), and grain/wheat flour (18.1%) were the main causes of
food-induced anaphylaxis, similar to previous reports. While else-
where, the main cause of drug-induced anaphylaxis is antibi-
otics,4,5,16,24,25 CT radiocontrast agents have been reported as the
most common cause in South Korea.15,17,26e29 The present study
found that antibiotics were the most common cause of drug-
induced anaphylaxis, followed by NSAIDs and CT radiocontrast
agents. The incidence of CT radiocontrast-induced anaphylaxis in
the current study was lower than reported in previous domestic
studies. This is probably because mild anaphylactic cases caused by
 S.-Y. Kim et al. / Allergology International 67 (2018) 96e102
Table 5
Risk factors of severe anaphylaxis.
P OR (95% CI)
Age 0.033 1.020 (1.002e1.039)
Male 0.014 2.305 (1.186e4.480)
Drugs 0.035 2.244 (1.059e4.753)
History of allergic diseases 0.926 1.308 (0.468e2.303)
History of medical diseases 0.875 0.939 (0.429e2.056)
WBC (/uL) 0.503 1.000 (1.000e1.000)
Eosinophil count (/uL) 0.258 0.999 (0.997e1.001)
CT radiocontrast may be not included in the records because they
would not have been transferred to the ED if symptoms dissipated
with immediate treatment. Because usually there are many cases of
allergic or adverse reaction to CT contrast, CT room in our hospital is
ready to use antihistamines for acute allergic reactions. But it is
only special situation for CT room, not for other injection room or
other hospitals or clinics. In addition, there was no case of MRI
contrast-induced anaphylaxis during the study period. Because CT
contrast is iodinated and MRI contrast is gadolinium-based, they
are fundamentally different substances.30 MRI contrast is known
for less toxicity and superior safety compared to the CT contrast.31
Many studies have reported that the clinical manifestations of
anaphylaxis were most commonly accompanied by skin symp-
toms.6,7,15,17,32,33 The present study also found skin symptoms to be
the most common, followed by cardiovascular, respiratory, gastro-
intestinal, and neurologic symptoms. However, severe cardiovascular
events occurred more frequently in the drug-induced anaphylaxis.
With regard to the clinical course of anaphylaxis, a biphasic
course with concomitant late-phase reactions can develop in
1e20% of patients with anaphylaxis within 72 h after improving
from the initial symptoms and the recurrence rate of anaphylaxis is
over 60%.34,35 Based on this evidence, the second National Institute
of Allergy and Infectious Disease and the Food Allergy and
Anaphylaxis Network Symposium in 2006 recommended an
observation time for anaphylaxis patients of at least 4e6 h.11 In the
present study, a biphasic course occurred in 19.2% of patients with
food-induced and 12.5% of patients with drug-induced anaphylaxis.
Therefore, patients with anaphylaxis should be monitored for at
least 4e6 h before discharge.
The prevalence of severe anaphylaxis is a reported 12.2e42.3%
of all anaphylactic cases and 0.01e0.03% of the total popula-
tion.8,12,25 Studies conducted in South Korea have reported signif-
icantly increased severity of anaphylaxis caused by older age,
concomitant allergic diseases, medical diseases and their culprit
drugs, such as antibiotics, NSAIDs, and radiocontrast agents.15,18,27
In the present study, older age, male, and drug-induced anaphy-
laxis were significant predictors for severe anaphylaxis, but allergic
diseases, medical disease, and WBC and eosinophil counts were not
significantly associated with the severity of anaphylaxis.
The incidence of severe anaphylaxis in drug-induced patients
was 54.2% (39 of 72 patients), which is higher than that of food-
induced anaphylaxis patients (26.3%, 26 of 99 patients) and bee
venom-induced anaphylaxis patients (35.0%, 7 of 20 patients).
Among drug-induced causes, CT radiocontrast agents showed the
highest proportion of severe anaphylaxis (87.5%, 7 of 8 patients).
Thus, it is recommended to check for a history of anaphylaxis and
provide more caution when administering CT radiocontrast
agents.36e38 In addition, the present study observed incidence of
NSAIDs- and antibiotics-induced severe anaphylaxis were 66.7%
and 44.8%, respectively. As elderly patients are more likely to
develop severe anaphylaxis symptoms, it may be necessary to
check their history of drug allergy when prescribing NSAIDS or
antibiotics.
101
Emergent treatments for anaphylaxis include intramuscular
epinephrine, intravenous corticosteroids, antihistamine, and
normal saline.39,40 Epinephrine is the most important drug for the
treatment for anaphylaxis owing to its vasoconstriction and bron-
chodilation effects; rapid administration of epinephrine can lead to
a good prognosis and alleviate symptoms and stabilize mast cells to
prevent progression.39,41 Delayed administration of this drug can
lead to serious consequences. However, despite the importance of
epinephrine, the epinephrine prescribing rate was not high in
previous studies.22,40,42 In this study, the rate of treatment with
epinephrine was also not high (69.7% and 56.9% in patients with
food-induced and drug-induced anaphylaxis, respectively). The
prescription rate of epinephrine was even lower in patients with
drug-induced anaphylaxis who had more severe anaphylaxis
symptoms than those with food-induced anaphylaxis. Therefore,
doctors may consider rapid use epinephrine for anaphylaxis,
especially for patients with severe anaphylaxis symptoms. The use
of epinephrine is not contraindicated for patients with cardiovas-
cular disease and its use can increase myocardial contractility and
coronary circulation.11,40
The present retrospective study was conducted at a single
medical institution and has several limitations. First, because the
number of patients was small, it is not sufficient to represent the
overall anaphylactic cases. Nationwide multicenter studies are
necessary to accurately investigate the prevalence and clinical
features of anaphylaxis in South Korea. Second, there may be a
limitation in discriminating the precise causes of anaphylaxis, ac-
curate administration route, or dose because the cause of anaphy-
laxis was suspected based the patients' history. Thus, there is a
possibility that information about the patients' anaphylaxis and
medical histories might be not accurate or be missing. Many pa-
tients did not undergo test to identify the causes of anaphylaxis.
Precise skin tests or provocation tests are needed to more accu-
rately assess the cause of anaphylaxis. However, this study is sig-
nificant for its comparison and analysis of the clinical features and
characteristics according to the severity of anaphylaxis caused by
foods and drugs, which are the most common causes of anaphy-
laxis. Because there have been few studies on to the severity of
anaphylaxis in South Korea, the findings of this study are expected
to contribute to anaphylaxis-related studies and patient care.
In conclusion, this study revealed different clinical symptoms
and medical history according to the cause of anaphylaxis. Severe
symptoms were more frequent in the drug-induced anaphylaxis,
and risk factors for the severe anaphylaxis were found to be age, sex
and drug-induced anaphylaxis. Anaphylaxis can have varying de-
grees of severity for each cause, and more attention is needed for
patients who are older male and whose anaphylaxis is drug-
induced.
Conflict of interest
The authors have no conflict of interest to declare.
Authors' contributions
SYK: collection and assembly of data, analysis and interpretation of data, and
drafting and revision of manuscript. YJC: proving intellectual content of critical
importance to the work described. MHK: conception and design of the study, dis-
cussion of core ideas, and final approval of the manuscript.
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