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Different clinical features of anaphylaxis according to cause and risk factors for severe reactions
Allergology International xxx (2017) 1e7
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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: Received 20 February 2017 Received in revised form 20 April 2017 Accepted 6 May 2017 Available online xxx
Background: Anaphylaxis is a life-threatening allergic reaction. Several studies reported different anaphylactic reactions according to the causative substances. However, a comparison of anaphylaxis for each cause has not been done. This study was conducted to identify common causes of anaphylaxis, characteristics of anaphylactic reaction for each cause and to analyze the factors related to the severity of 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 retrospectively reviewed. We compared the clinical features of anaphylaxis according to the cause. In addition, the severity of anaphylaxis was analyzed and contributing factors for severe anaphylaxis were reviewed. Results: A total of 199 patients with anaphylaxis were analyzed. Food was the most common cause (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 of severe anaphylaxis was the highest in anaphylaxis due to drugs (54.2%). Urticaria and other skin symptoms were significantly more common in food-induced anaphylaxis. Risk factors for severe anaphylaxis included older age, male, and drug-induced one. Epinephrine treatment of anaphylaxis was done for 69.7% and 56.9% of patients with food-induced and drug-induced anaphylaxis, respectively. Conclusions: More severe anaphylaxis developed with drug treatment and in males. Low rate of epinephrine prescription was also observed. Male patients with drug induced anaphylaxis should be paid more attention. Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
Keywords: Anaphylactic shock Anaphylaxis Drug hypersensitivity Food hypersensitivity Risk factors Abbreviations: ED, emergency department; NOS, Not otherwise specified; KCD, Korean standard classification of disease; MAST, multiple allergosorbent test; WBC, white blood cell; ECP, eosinophil cationic protein; AST, aspartate transaminase; ALT, alanine transaminase; NSAIDs, nonsteroidal antiinflammatory drugs; CT, computed 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: [email protected] (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/).
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
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: 2017-02-020001). Anaphylaxis As previously described, anaphylaxis was diagnosed when any one of the following three criteria were fulfilled.10,11 First, symptoms occurred suddenly (within a few hours) in the skin and mucous membranes (systemic urticaria, itching, flushing, lip-tongueuvula edema) plus either respiratory symptoms (dyspnea, wheezing, stridor, hypoxemia) or cardiovascular symptoms (syncope, hypotension, urinary incontinence, chest discomfort). Second, 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 gastrointestinal 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 respiratory, cardiovascular, and gastrointestinal symptoms (such as dyspnea, 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
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 nonnormal distribution were expressed by median value. Continuous variables were analyzed by t-test or ManneWhitney test. Categorical 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 Pvalues < 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 allergies. 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 laboratory 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 venominduced (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 tomography (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).
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
S.-Y. Kim et al. / Allergology International xxx (2017) 1e7 Table 1 Characteristics of the anaphylactic patients. Number of patients (%) Total number of patients Male Age (years) Age <18 years Atopy History of allergic diseases Asthma Atopic dermatitis Allergic rhinitis Food allergy Drug allergy History of medical diseases Hypertension Malignancy Diabetes mellitus Ischemic heart disease Renal disease Neurologic disease Anaphylaxis severity Mild/moderate Severe Laboratory results WBC (/uL) Eosinophil count (/uL) IgE (IU/ml) ECP (ug/L) AST (IU/L) ALT (IU/L) Creatinine (mg/dl)
199 103 (51.8) 41.1 ± 23.4 45 (22.6) 58/71 (81.7) 55 (27.6) 12 (6.0) 8 (4.0) 8 (4.0) 33 (16.6) 7 (3.5) 55 (27.6) 32 (16.1) 9 (4.5) 8 (4.0) 4 (2.0) 2 (1.0) 5 (2.5) 124 (62.4) 75 (37.6) 9287.9 ± 4131.2 154.2 ± 178.4 262.0 (90.6e441.5) 18.1 ± 16.3 (n ¼ 46) 44.6 ± 152.0 29.5 ± 74.0 1.03 ± 1.09
The data are expressed as mean ± SD or median (25e75%).
Comparison of clinical characteristics and laboratory findings between food- and drug-induced anaphylaxis A detailed analysis of the differences in clinical manifestations among 171 patients with food-induced (n ¼ 99) or drug-induced
Table 2 Suspected causes of anaphylaxis. Number of patients (%) Total number of patients Food Seafood Shrimp Fish Crab Shellfish Meat Pork Chicken Processed meat Beef Grain/flour Fruit Egg Milk/dairy product Nuts Pupa Alcohol Drug Antibiotics NSAID CT radiocontrast Amino acids solutions Lidocaine Ranitidine Midazolam Bee venom Exercise Unknown
199 99 28 (28.3) 11 (11.1) 8 (8.1) 6 (6.1) 3 (3.0) 18 (18.1) 9 (9.1) 6 (6.1) 2 (2.0) 1 (1.0) 18 (18.1) 11 (11.1) 7 (7.1) 6 (6.1) 6 (6.1) 3 (3.0) 2 (2.0) 72 29 (40.2) 24 (33.3) 8 (11.1) 6 (8.3) 3 (4.1) 1 (1.4) 1 (1.4) 20 5 3
3
(n ¼ 72) anaphylaxis revealed that the food-induced anaphylaxis group was significantly younger with a significantly higher proportion of patients aged <18 years (32.8 ± 23.8 years vs. 50.2 ± 19.7 years, P < 0.001, 37.4% vs. 5.6%, P < 0.001, respectively). Fifty-five (55.6%) patients in the food-induced anaphylactic group and 33 (45.8%) patients in the drug-induced anaphylactic group were male. The food-induced group comprised significantly more patients with allergic disease (37.4% vs. 13.9%, P ¼ 0.001). Conversely, the food-induced anaphylactic group had lower prevalence of chronic diseases compared to the drug-induced anaphylactic group (20.2% vs. 36.1%, P ¼ 0.024; Table 3). Both groups showed different clinical symptoms. The most common type was skin symptom in both groups, however 90.9% of 99 patients in the food-induced
Table 3 Comparison of food- and drug-induced anaphylaxis.
Number Male Age (years) Age <18 years Atopy History of allergic diseases Asthma Atopic dermatitis Allergic rhinitis Food allergy Drug allergy History of medical diseases Hypertension Diabetes mellitus Ischemic heart disease Renal disease Neurologic disease Malignancy Symptoms of anaphylaxis Cardiovascular Hypotension Syncope Chest discomfort Respiratory Wheezing Dyspnea Gastrointestinal Abdominal pain Vomiting Diarrhea Skin Urticaria Angioedema Generalized swelling Pruritus Neurologic Anaphylaxis severity Mild/moderate Severe Treatment Epinephrine Corticosteroids Hospitalization Clinical progression Monophasic Biphasic Laboratory tests WBC (/uL) Eosinophil count (/uL) IgE (IU/ml) ECP (ug/L) AST (IU/L) ALT (IU/L) Creatinine (mg/dl)
Food (n, %)
Drug (n, %)
P
99 55 (55.6) 32.8 ± 23.8 37 (37.4) 40/47 (85.1) 37 (37.4) 6 (6.1) 4 (4.0) 8 (8.1) 29 (29.3) 3 (3.0) 20 (20.2) 13 (13.1) 4 (4.0) 2 (2.0) 1 (1.0) 2 (2.0) 4 (4.0)
72 33 (45.8) 50.2 ± 19.7 4 (5.6) 12/16 (75.0) 10 (13.9) 1 (1.4) 2 (2.8) 2 (2.8) 3 (4.2) 4 (5.6) 26 (36.1) 15 (20.8) 2 (2.8) 2 (2.8) 1 (1.4) 3 (4.2) 4 (5.6)
0.219 <0.001 <0.001 0.448 0.001 0.241 1.000 0.194 <0.001 0.456 0.024 0.211 1.000 1.000 1.000 0.651 0.722
31 (31.3) 26 (26.3) 3 (3.0) 6 (6.1) 49 (49.5) 2 (2.0) 47 (47.5) 24 (24.2) 12 (12.1) 10 (10.1) 3 (3.0) 90 (90.9) 86 (86.9) 23 (23.2) 0 (0.0) 27 (27.3) 20 (20.2)
46 (63.9) 30 (41.7) 14 (19.4) 6 (8.3) 33 (45.8) 1 (1.4) 33 (45.8) 18 (25.0) 8 (11.1) 11 (15.3) 0 (0.0) 50 (69.4) 48 (66.7) 13 (18.1) 1 (1.4) 17 (23.6) 19 (26.4)
<0.001 0.047 0.001 0.563 0.646 1.000 0.877 1.000 1.000 0.350 0.264 <0.001 0.002 0.452 0.421 0.723 0.361
73 (73.7) 26 (26.3)
33 (45.8) 39 (54.2)
<0.001 <0.001
69 (69.7) 94 (94.9) 17 (17.2)
41 (56.9) 64 (88.9) 13 (18.1)
0.106 0.155 1.000
80 (80.8) 19 (19.2)
63 (87.5) 9 (12.5)
0.298 0.298
9981.9 ± 4081.1 191.9 ± 207.5 462.3 ± 909.7 19.3 ± 18.2 (n ¼ 26) 59.9 ± 214.9 37.7 ± 104.4 0.92 ± 0.32
8504.6 ± 4336.3 108.1 ± 125.0 399.1 ± 468.5 18.3 ± 15.6 (n ¼ 14) 29.6 ± 24.3 108.1 ± 125.0 1.20 ± 1.71
0.034 0.003 0.765 0.860 0.198 0.160 0.139
The data are presented as mean ± SD.
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
anaphylaxis showed skin manifestation, whereas only 69.4% of patients had skin reactions in drug-induced anaphylaxis (P ¼ 0.001). Among them, significantly higher proportion of patients experienced urticaria in the food-induced anaphylactic group compared to those in the drug-induced anaphylactic group (86.9% vs. 66.7%, P ¼ 0.002). Cardiovascular symptoms were less frequent in food-induced anaphylactic patients than drug-induced anaphylactic patients (31.3% vs. 63.9%, P < 0.001). Hypotension and syncope were more common in the drug-induced anaphylactic group than in food-induced anaphylactic group. There was no significant difference in other clinical features including respiratory symptoms, gastrointestinal symptoms, and neurological symptoms. Regarding severity, a significantly higher number of patients had severe reactions in the drug-induced group (39/72, 54.2%) than in the food-induced group (26/99, 26.3%) (P < 0.001). Despite the higher proportion of patients with severe anaphylactic reactions in the drug-induced group, there was no significant difference in the proportion of patients hospitalized after emergency care between the two groups. Further, there was no significant difference in the treatment with epinephrine or corticosteroids. Biphasic anaphylactic reaction developed in 19.2% of the food-induced anaphylactic patients and 12.5% of the drug-induced anaphylactic patients (Table 3). Peripheral blood analyses revealed significantly higher WBC and eosinophil counts in the food-induced anaphylactic patients compared to the drug-induced anaphylactic patients (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 difference between the two groups in AST, ALT, creatinine, IgE, or ECP (Table 3). Comparison of clinical characteristics according to the severity Among 199 anaphylactic patients, 75 (37.6%) had severe reactions including 26 food-induced patients, 39 drug-induced patients, 7 bee venom patients, and 3 patients with unknown causes (Fig. 1). The mean age of patients with severe anaphylaxis was significantly higher than that of patients with mild-to-moderate anaphylaxis (50.2 ± 19.1 vs. 35.7 ± 24.2 years, P < 0.001). The proportion of male patients was also significantly higher in the severe anaphylactic group than in the mild-to-moderate anaphylactic group (47/75, 62.7% vs. 49/124, 39.5%, P ¼ 0.002). There were no significant differences in the prevalence of atopy, allergic diseases and medical diseases including cardiovascular comorbidities between patients with severe and mild/moderate anaphylaxis. There were no significant differences in the eosinophil count, total
serum IgE, ECP, AST, and ALT between patients with mild/moderate and severe anaphylaxis. In the patients with severe reactions, druginduced anaphylaxis was significantly more prevalent (Table 4). The incidence of severe reactions was the highest among patients with drug-induced anaphylaxis, with the proportion of severe reactions being 26.3% in the food-induced anaphylaxis, 54.2% in the drug-induced anaphylaxis, 35.0% in the bee venom anaphylaxis, and 37.5% in the unknown cause anaphylaxis (Fig. 1). In the drug-induced anaphylaxis, the incidence of severe anaphylaxis was the highest among patients whose culprit drug was a radiocontrast agent (7 of 8, 87.5%), followed by NSAIDs (16 of 24, 66.7%), antibiotics (13 of 29, 44.8%), amino acids solutions (2 of 6, 33.3%), and lidocaine (1 of 3, 33.3%) (Fig. 2). In the food-induced anaphylaxis, incidence of severe anaphylaxis was the highest among patients whose culprit food was meat (8 of 18, 44.4%), followed by milk/dairy products (2 of 6, 33.3%), seafood (8 of 28, 28.6%), egg (2 of 7, 28.6%), and grains/wheat flour (4 of 18, 22.2%) (Fig. 3). Multivariate logistic regression showed that old age (OR 1.020; 95% CI 1.002e1.039), male (OR 2.305; 95% CI 1.186e4.480), druginduced anaphylaxis (OR 2.244; 95% CI 1.059e4.753) were significant risk factors of severe anaphylaxis (Table 5).
Discussion This study investigated the causes of anaphylaxis and clinical features and differences according to cause and severity in 199 patients who visited the ED of one tertiary hospital in Seoul, Korea over a recent 13-year period. The most common causes of anaphylaxis were foods and drugs, consistent with another study.15,16 The food-induced anaphylaxis group was significantly younger and had a higher proportion of allergic diseases than drug-induced anaphylactic patients. Conversely, drug-induced anaphylactic group had more chronic diseases compared to food-induced anaphylactic group. Both groups also showed different clinical symptoms. Those with foodinduced anaphylaxis more commonly displayed skin manifestations than patients with drug-induced anaphylaxis. In contrast,
Table 4 Severity of anaphylaxis.
Patients number Age (years) Male Atopy History of allergic diseases History of medical diseases History of cardiovascular disease WBC (ug/L) Eosinophil count (/uL) IgE (IU/mL) ECP (ug/L) AST (IU/L) ALT (IU/L) Suspected causes Food Drug Bee venom Exercise Unknown
Fig. 1. Composition of severe anaphylaxis in each cause.
Mild/moderate (n, %)
Severe (n, %)
P
124 (62.4) 35.7 ± 24.2 49 (39.5) 43/50 (86.0) 37 (29.8)
75 (37.6) 50.2 ± 19.1 47 (62.7) 15/21 (71.4) 18 (24.0)
<0.001 0.002 0.184 0.416
31 (25.0)
24 (32.0)
0.327
21 (16.9)
13 (17.3)
1.000
9795.7 ± 4034.9 182.4 ± 186.3 490.2 ± 898.9 18.7 ± 17.3 (n ¼ 34) 45.0 ± 165.7 26.5 ± 43.5
8578.4 ± 4187.0 114.9 ± 159.7 307.5 ± 333.2 16.7 ± 13.8 (n ¼ 12) 44.1 ± 131.6 33.6 ± 102.7
0.054 0.054 0.368 0.720
73 (58.9) 33 (26.6) 13 (10.5) 3 (2.4) 2 (1.6)
26 (34.7) 39 (52.0) 7 (9.3) 2 (2.7) 1 (1.3)
0.970 0.537 0.003
The data presented as mean ± SD.
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
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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 foodinduced 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 differences 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 children, 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 elsewhere, the main cause of drug-induced anaphylaxis is antibiotics,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 druginduced 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
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
Table 5 Risk factors of severe anaphylaxis.
Age Male Drugs History of allergic diseases History of medical diseases WBC (/uL) Eosinophil count (/uL)
P
OR (95% CI)
0.033 0.014 0.035 0.926 0.875 0.503 0.258
1.020 2.305 2.244 1.308 0.939 1.000 0.999
(1.002e1.039) (1.186e4.480) (1.059e4.753) (0.468e2.303) (0.429e2.056) (1.000e1.000) (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 symptoms.6,7,15,17,32,33 The present study also found skin symptoms to be the most common, followed by cardiovascular, respiratory, gastrointestinal, 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 population.8,12,25 Studies conducted in South Korea have reported significantly 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 anaphylaxis 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 foodinduced 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.
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 bronchodilation 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 cardiovascular 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, accurate administration route, or dose because the cause of anaphylaxis 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 patients did not undergo test to identify the causes of anaphylaxis. Precise skin tests or provocation tests are needed to more accurately assess the cause of anaphylaxis. However, this study is significant 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 anaphylaxis. 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 degrees of severity for each cause, and more attention is needed for patients who are older male and whose anaphylaxis is druginduced. 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, discussion of core ideas, and final approval of the manuscript.
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7 5. Panesar SS, Javad S, de Silva D, Nwaru BI, Hickstein L, Muraro A, et al. The epidemiology of anaphylaxis in Europe: a systematic review. Allergy 2013;68: 1353e61. 6. Lee SY, Kim KW, Lee HH, Lim DH, Chung HL, Kim SW, et al. [Incidence and clinical characteristics of pediatric emergency department visits of children with severe food allergy]. [Korean J Asthma Allergy Clin Immunol] 2012;32: 169e75 (in Korean). 7. Lee YK, Kim MK, Kang HR, Kim TB, Sohn SW, Park HK, et al. [Seasonal and regional variations in the causes of anaphylaxis in Korean adults]. [Allergy Asthma Respir Dis] 2015;3:187e93 (in Korean). 8. Moneret-Vautrin D, Morisset M, Flabbee J, Beaudouin E, Kanny G. Epidemiology of life-threatening and lethal anaphylaxis: a review. Allergy 2005;60:443e51. 9. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:477e80. e42. 10. Simons FER, Ardusso LR, Bilo MB, Dimov V, Ebisawa M, El-Gamal YM, et al. 2012 update: World allergy organization guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol 2012;12:389e99. ~ oz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, 11. Sampson HA, Mun et al. Second symposium on the definition and management of anaphylaxis: summary reportdsecond national institute of allergy and infectious disease/ food allergy and anaphylaxis network symposium. Ann Emerg Med 2006;47: 373e80. 12. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371e6. 13. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217e26. 14. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762e6. 15. Ye Y, Kim M, Kang H, Kim T, Sohn S, Koh Y, et al. [Anaphylaxis in Korean adults: a multicenter retrospective case study]. [Korean J Asthma Allergy Clin Immunol] 2012;32:S226 (in Korean). 16. Lee S-Y, Ahn K, Kim J, Jang GC, Min TK, Yang H-J, et al. A multicenter retrospective case study of anaphylaxis triggers by age in Korean children. Allergy Asthma Immunol Res 2016;8:535e40. 17. Yang MS, Lee SH, Kim TW, Kwon JW, Lee SM, Kim SH, et al. Epidemiologic and clinical features of anaphylaxis in korea. Ann Allergy Asthma Immunol 2008;100:31e6. 18. Ye YM, Kim MK, Kang HR, Kim TB, Sohn SW, Koh YI, et al. Predictors of the severity and serious outcomes of anaphylaxis in Korean adults: a multicenter retrospective case study. Allergy Asthma Immunol Res 2015;7:22e9. 19. Koh YI, Choi IS, Chung SU, Cho S. [Clinical features of adult patients with anaphylaxis associated with food in Gwangju and Chonnam area]. [Korean J Asthma Allergy Clin Immunol] 2004;24:217e23 (in Korean). 20. Han SG, Ahn R, Kim SH, Choe SW, Hong ES. [Drug-induced anaphylactic shock at the emergency department]. [J Korean Soc Clin Toxicol] 2009;7:137e42 (in Korean). 21. Kim JC, Kim SC, Kim YS, Kim CH, Do HH, Lee BS, et al. [Clinical study of anaphylactic patients with bee stings who visited the emergency department]. [J Korean Soc Emerg Med] 2005;16:403e9 (in Korean). 22. Jirapongsananuruk O, Bunsawansong W, Piyaphanee N, Visitsunthorn N, Thongngarm T, Vichyanond P. Features of patients with anaphylaxis admitted to a university hospital. Ann Allergy Asthma Immunol 2007;98:157e62.
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23. Seo MH, Kim SH, Hong JS, Kim WY, Choe SW. [Clinical features of food-induced anaphylaxis in the southeastern coasted area of Korea]. [Korean J Asthma Allergy Clin Immunol] 2010;30:110e5 (in Korean). 24. Shimamoto SR, Bock SA. Update on the clinical features of food-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2002;2:211e6. 25. Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142 patients in a single year. J Allergy Clin Immunol 2001;108:861e6. 26. Banerji A, Rudders S, Clark S, Wei W, Long AA, Camargo CA. Retrospective study of drug-induced anaphylaxis treated in the emergency department or hospital: patient characteristics, management, and 1-year follow-up. J Allergy Clin Immunol Pract 2014;2:46e51. 27. Kim MJ, Choi GS, Um SJ, Sung JM, Shin YS, Park HJ, et al. [Anaphylaxis; 10 years' experience at a university hospital in suwon]. [Korean J Asthma Allergy Clin Immunol] 2008;28:298e304 (in Korean). 28. Hong SJ, Wong JT, Bloch KJ. Reactions to radiocontrast media. Allergy Asthma Proc 2002;23:347e51. 29. Kim HB, Kim DK. [Clinical features and treatment patterns of radiocontrast media induced anaphylaxis in the emergency department]. [J Korean Soc Emerg Med] 2009;20:709e14 (in Korean). 30. Hasebroock KM, Serkova NJ. Toxicity of MRI and CT contrast agents. Expert Opin Drug Metab Toxicol 2009;5:403e16. 31. Jung JW, Kang HR, Kim MH, Lee W, Min KU, Han MH, et al. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 2012;264:414e22. 32. Park JS, Park HS, Lee SY, Jung YS, Cho JP. [Anaphylactic shock patients admitted in the emergency department of a tertiary hospital]. [J Korean Soc Emerg Med] 2001;12:84e90 (in Korean). lu B, et al. 33. Gelincik A, Demirtürk M, Yılmaz E, Ertek B, Erdogdu D, Çolakog Anaphylaxis in a tertiary adult allergy clinic: a retrospective review of 516 patients. Ann Allergy Asthma Immunol 2013;110:96e100. 34. Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28:381e8. 35. Tole JW, Lieberman P. Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin North Am 2007;27:309e26. 36. Morcos S, Thomsen H. Adverse reactions to iodinated contrast media. Eur Radiol 2001;11:1267e75. 37. Greenberger PA. Contrast media reactions. J Allergy Clin Immunol 1984;74: 600e5. 38. Kim MH, Lee SY, Lee SE, Yang MS, Jung JW, Park CM, et al. Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock. PLoS One 2014;9:e100154. 39. Hare ND, Ballas ZK. Effectiveness of delayed epinephrine in anaphylaxis. J Allergy Clin Immunol 2007;120:716e7. 40. Choo KJL, Simons F, Sheikh A. Glucocorticoids for the treatment of anaphylaxis. Evid Based Child Health 2013;8:1276e94. 41. Simons FER, Gu X, Simons KJ. Outdated EpiPen and EpiPen Jr autoinjectors: past their prime? J Allergy Clin Immunol 2000;105:1025e30. 42. Seo DH, Ye YM, Kim SC, Ban GY, Kim JH, Shin YS, et al. [A single hospital survey of anaphylaxis awareness among health care providers and medical students]. [Allergy Asthma Respir Dis] 2016;4:133e9 (in Korean).
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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: Received 20 February 2017 Received in revised form 20 April 2017 Accepted 6 May 2017 Available online xxx
Background: Anaphylaxis is a life-threatening allergic reaction. Several studies reported different anaphylactic reactions according to the causative substances. However, a comparison of anaphylaxis for each cause has not been done. This study was conducted to identify common causes of anaphylaxis, characteristics of anaphylactic reaction for each cause and to analyze the factors related to the severity of 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 retrospectively reviewed. We compared the clinical features of anaphylaxis according to the cause. In addition, the severity of anaphylaxis was analyzed and contributing factors for severe anaphylaxis were reviewed. Results: A total of 199 patients with anaphylaxis were analyzed. Food was the most common cause (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 of severe anaphylaxis was the highest in anaphylaxis due to drugs (54.2%). Urticaria and other skin symptoms were significantly more common in food-induced anaphylaxis. Risk factors for severe anaphylaxis included older age, male, and drug-induced one. Epinephrine treatment of anaphylaxis was done for 69.7% and 56.9% of patients with food-induced and drug-induced anaphylaxis, respectively. Conclusions: More severe anaphylaxis developed with drug treatment and in males. Low rate of epinephrine prescription was also observed. Male patients with drug induced anaphylaxis should be paid more attention. Copyright © 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
Keywords: Anaphylactic shock Anaphylaxis Drug hypersensitivity Food hypersensitivity Risk factors Abbreviations: ED, emergency department; NOS, Not otherwise specified; KCD, Korean standard classification of disease; MAST, multiple allergosorbent test; WBC, white blood cell; ECP, eosinophil cationic protein; AST, aspartate transaminase; ALT, alanine transaminase; NSAIDs, nonsteroidal antiinflammatory drugs; CT, computed 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: [email protected] (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/).
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
2
S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
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: 2017-02-020001). Anaphylaxis As previously described, anaphylaxis was diagnosed when any one of the following three criteria were fulfilled.10,11 First, symptoms occurred suddenly (within a few hours) in the skin and mucous membranes (systemic urticaria, itching, flushing, lip-tongueuvula edema) plus either respiratory symptoms (dyspnea, wheezing, stridor, hypoxemia) or cardiovascular symptoms (syncope, hypotension, urinary incontinence, chest discomfort). Second, 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 gastrointestinal 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 respiratory, cardiovascular, and gastrointestinal symptoms (such as dyspnea, 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
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 nonnormal distribution were expressed by median value. Continuous variables were analyzed by t-test or ManneWhitney test. Categorical 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 Pvalues < 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 allergies. 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 laboratory 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 venominduced (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 tomography (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).
Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005
S.-Y. Kim et al. / Allergology International xxx (2017) 1e7 Table 1 Characteristics of the anaphylactic patients. Number of patients (%) Total number of patients Male Age (years) Age <18 years Atopy History of allergic diseases Asthma Atopic dermatitis Allergic rhinitis Food allergy Drug allergy History of medical diseases Hypertension Malignancy Diabetes mellitus Ischemic heart disease Renal disease Neurologic disease Anaphylaxis severity Mild/moderate Severe Laboratory results WBC (/uL) Eosinophil count (/uL) IgE (IU/ml) ECP (ug/L) AST (IU/L) ALT (IU/L) Creatinine (mg/dl)
199 103 (51.8) 41.1 ± 23.4 45 (22.6) 58/71 (81.7) 55 (27.6) 12 (6.0) 8 (4.0) 8 (4.0) 33 (16.6) 7 (3.5) 55 (27.6) 32 (16.1) 9 (4.5) 8 (4.0) 4 (2.0) 2 (1.0) 5 (2.5) 124 (62.4) 75 (37.6) 9287.9 ± 4131.2 154.2 ± 178.4 262.0 (90.6e441.5) 18.1 ± 16.3 (n ¼ 46) 44.6 ± 152.0 29.5 ± 74.0 1.03 ± 1.09
The data are expressed as mean ± SD or median (25e75%).
Comparison of clinical characteristics and laboratory findings between food- and drug-induced anaphylaxis A detailed analysis of the differences in clinical manifestations among 171 patients with food-induced (n ¼ 99) or drug-induced
Table 2 Suspected causes of anaphylaxis. Number of patients (%) Total number of patients Food Seafood Shrimp Fish Crab Shellfish Meat Pork Chicken Processed meat Beef Grain/flour Fruit Egg Milk/dairy product Nuts Pupa Alcohol Drug Antibiotics NSAID CT radiocontrast Amino acids solutions Lidocaine Ranitidine Midazolam Bee venom Exercise Unknown
199 99 28 (28.3) 11 (11.1) 8 (8.1) 6 (6.1) 3 (3.0) 18 (18.1) 9 (9.1) 6 (6.1) 2 (2.0) 1 (1.0) 18 (18.1) 11 (11.1) 7 (7.1) 6 (6.1) 6 (6.1) 3 (3.0) 2 (2.0) 72 29 (40.2) 24 (33.3) 8 (11.1) 6 (8.3) 3 (4.1) 1 (1.4) 1 (1.4) 20 5 3
3
(n ¼ 72) anaphylaxis revealed that the food-induced anaphylaxis group was significantly younger with a significantly higher proportion of patients aged <18 years (32.8 ± 23.8 years vs. 50.2 ± 19.7 years, P < 0.001, 37.4% vs. 5.6%, P < 0.001, respectively). Fifty-five (55.6%) patients in the food-induced anaphylactic group and 33 (45.8%) patients in the drug-induced anaphylactic group were male. The food-induced group comprised significantly more patients with allergic disease (37.4% vs. 13.9%, P ¼ 0.001). Conversely, the food-induced anaphylactic group had lower prevalence of chronic diseases compared to the drug-induced anaphylactic group (20.2% vs. 36.1%, P ¼ 0.024; Table 3). Both groups showed different clinical symptoms. The most common type was skin symptom in both groups, however 90.9% of 99 patients in the food-induced
Table 3 Comparison of food- and drug-induced anaphylaxis.
Number Male Age (years) Age <18 years Atopy History of allergic diseases Asthma Atopic dermatitis Allergic rhinitis Food allergy Drug allergy History of medical diseases Hypertension Diabetes mellitus Ischemic heart disease Renal disease Neurologic disease Malignancy Symptoms of anaphylaxis Cardiovascular Hypotension Syncope Chest discomfort Respiratory Wheezing Dyspnea Gastrointestinal Abdominal pain Vomiting Diarrhea Skin Urticaria Angioedema Generalized swelling Pruritus Neurologic Anaphylaxis severity Mild/moderate Severe Treatment Epinephrine Corticosteroids Hospitalization Clinical progression Monophasic Biphasic Laboratory tests WBC (/uL) Eosinophil count (/uL) IgE (IU/ml) ECP (ug/L) AST (IU/L) ALT (IU/L) Creatinine (mg/dl)
Food (n, %)
Drug (n, %)
P
99 55 (55.6) 32.8 ± 23.8 37 (37.4) 40/47 (85.1) 37 (37.4) 6 (6.1) 4 (4.0) 8 (8.1) 29 (29.3) 3 (3.0) 20 (20.2) 13 (13.1) 4 (4.0) 2 (2.0) 1 (1.0) 2 (2.0) 4 (4.0)
72 33 (45.8) 50.2 ± 19.7 4 (5.6) 12/16 (75.0) 10 (13.9) 1 (1.4) 2 (2.8) 2 (2.8) 3 (4.2) 4 (5.6) 26 (36.1) 15 (20.8) 2 (2.8) 2 (2.8) 1 (1.4) 3 (4.2) 4 (5.6)
0.219 <0.001 <0.001 0.448 0.001 0.241 1.000 0.194 <0.001 0.456 0.024 0.211 1.000 1.000 1.000 0.651 0.722
31 (31.3) 26 (26.3) 3 (3.0) 6 (6.1) 49 (49.5) 2 (2.0) 47 (47.5) 24 (24.2) 12 (12.1) 10 (10.1) 3 (3.0) 90 (90.9) 86 (86.9) 23 (23.2) 0 (0.0) 27 (27.3) 20 (20.2)
46 (63.9) 30 (41.7) 14 (19.4) 6 (8.3) 33 (45.8) 1 (1.4) 33 (45.8) 18 (25.0) 8 (11.1) 11 (15.3) 0 (0.0) 50 (69.4) 48 (66.7) 13 (18.1) 1 (1.4) 17 (23.6) 19 (26.4)
<0.001 0.047 0.001 0.563 0.646 1.000 0.877 1.000 1.000 0.350 0.264 <0.001 0.002 0.452 0.421 0.723 0.361
73 (73.7) 26 (26.3)
33 (45.8) 39 (54.2)
<0.001 <0.001
69 (69.7) 94 (94.9) 17 (17.2)
41 (56.9) 64 (88.9) 13 (18.1)
0.106 0.155 1.000
80 (80.8) 19 (19.2)
63 (87.5) 9 (12.5)
0.298 0.298
9981.9 ± 4081.1 191.9 ± 207.5 462.3 ± 909.7 19.3 ± 18.2 (n ¼ 26) 59.9 ± 214.9 37.7 ± 104.4 0.92 ± 0.32
8504.6 ± 4336.3 108.1 ± 125.0 399.1 ± 468.5 18.3 ± 15.6 (n ¼ 14) 29.6 ± 24.3 108.1 ± 125.0 1.20 ± 1.71
0.034 0.003 0.765 0.860 0.198 0.160 0.139
The data are presented as mean ± SD.
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
anaphylaxis showed skin manifestation, whereas only 69.4% of patients had skin reactions in drug-induced anaphylaxis (P ¼ 0.001). Among them, significantly higher proportion of patients experienced urticaria in the food-induced anaphylactic group compared to those in the drug-induced anaphylactic group (86.9% vs. 66.7%, P ¼ 0.002). Cardiovascular symptoms were less frequent in food-induced anaphylactic patients than drug-induced anaphylactic patients (31.3% vs. 63.9%, P < 0.001). Hypotension and syncope were more common in the drug-induced anaphylactic group than in food-induced anaphylactic group. There was no significant difference in other clinical features including respiratory symptoms, gastrointestinal symptoms, and neurological symptoms. Regarding severity, a significantly higher number of patients had severe reactions in the drug-induced group (39/72, 54.2%) than in the food-induced group (26/99, 26.3%) (P < 0.001). Despite the higher proportion of patients with severe anaphylactic reactions in the drug-induced group, there was no significant difference in the proportion of patients hospitalized after emergency care between the two groups. Further, there was no significant difference in the treatment with epinephrine or corticosteroids. Biphasic anaphylactic reaction developed in 19.2% of the food-induced anaphylactic patients and 12.5% of the drug-induced anaphylactic patients (Table 3). Peripheral blood analyses revealed significantly higher WBC and eosinophil counts in the food-induced anaphylactic patients compared to the drug-induced anaphylactic patients (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 difference between the two groups in AST, ALT, creatinine, IgE, or ECP (Table 3). Comparison of clinical characteristics according to the severity Among 199 anaphylactic patients, 75 (37.6%) had severe reactions including 26 food-induced patients, 39 drug-induced patients, 7 bee venom patients, and 3 patients with unknown causes (Fig. 1). The mean age of patients with severe anaphylaxis was significantly higher than that of patients with mild-to-moderate anaphylaxis (50.2 ± 19.1 vs. 35.7 ± 24.2 years, P < 0.001). The proportion of male patients was also significantly higher in the severe anaphylactic group than in the mild-to-moderate anaphylactic group (47/75, 62.7% vs. 49/124, 39.5%, P ¼ 0.002). There were no significant differences in the prevalence of atopy, allergic diseases and medical diseases including cardiovascular comorbidities between patients with severe and mild/moderate anaphylaxis. There were no significant differences in the eosinophil count, total
serum IgE, ECP, AST, and ALT between patients with mild/moderate and severe anaphylaxis. In the patients with severe reactions, druginduced anaphylaxis was significantly more prevalent (Table 4). The incidence of severe reactions was the highest among patients with drug-induced anaphylaxis, with the proportion of severe reactions being 26.3% in the food-induced anaphylaxis, 54.2% in the drug-induced anaphylaxis, 35.0% in the bee venom anaphylaxis, and 37.5% in the unknown cause anaphylaxis (Fig. 1). In the drug-induced anaphylaxis, the incidence of severe anaphylaxis was the highest among patients whose culprit drug was a radiocontrast agent (7 of 8, 87.5%), followed by NSAIDs (16 of 24, 66.7%), antibiotics (13 of 29, 44.8%), amino acids solutions (2 of 6, 33.3%), and lidocaine (1 of 3, 33.3%) (Fig. 2). In the food-induced anaphylaxis, incidence of severe anaphylaxis was the highest among patients whose culprit food was meat (8 of 18, 44.4%), followed by milk/dairy products (2 of 6, 33.3%), seafood (8 of 28, 28.6%), egg (2 of 7, 28.6%), and grains/wheat flour (4 of 18, 22.2%) (Fig. 3). Multivariate logistic regression showed that old age (OR 1.020; 95% CI 1.002e1.039), male (OR 2.305; 95% CI 1.186e4.480), druginduced anaphylaxis (OR 2.244; 95% CI 1.059e4.753) were significant risk factors of severe anaphylaxis (Table 5).
Discussion This study investigated the causes of anaphylaxis and clinical features and differences according to cause and severity in 199 patients who visited the ED of one tertiary hospital in Seoul, Korea over a recent 13-year period. The most common causes of anaphylaxis were foods and drugs, consistent with another study.15,16 The food-induced anaphylaxis group was significantly younger and had a higher proportion of allergic diseases than drug-induced anaphylactic patients. Conversely, drug-induced anaphylactic group had more chronic diseases compared to food-induced anaphylactic group. Both groups also showed different clinical symptoms. Those with foodinduced anaphylaxis more commonly displayed skin manifestations than patients with drug-induced anaphylaxis. In contrast,
Table 4 Severity of anaphylaxis.
Patients number Age (years) Male Atopy History of allergic diseases History of medical diseases History of cardiovascular disease WBC (ug/L) Eosinophil count (/uL) IgE (IU/mL) ECP (ug/L) AST (IU/L) ALT (IU/L) Suspected causes Food Drug Bee venom Exercise Unknown
Fig. 1. Composition of severe anaphylaxis in each cause.
Mild/moderate (n, %)
Severe (n, %)
P
124 (62.4) 35.7 ± 24.2 49 (39.5) 43/50 (86.0) 37 (29.8)
75 (37.6) 50.2 ± 19.1 47 (62.7) 15/21 (71.4) 18 (24.0)
<0.001 0.002 0.184 0.416
31 (25.0)
24 (32.0)
0.327
21 (16.9)
13 (17.3)
1.000
9795.7 ± 4034.9 182.4 ± 186.3 490.2 ± 898.9 18.7 ± 17.3 (n ¼ 34) 45.0 ± 165.7 26.5 ± 43.5
8578.4 ± 4187.0 114.9 ± 159.7 307.5 ± 333.2 16.7 ± 13.8 (n ¼ 12) 44.1 ± 131.6 33.6 ± 102.7
0.054 0.054 0.368 0.720
73 (58.9) 33 (26.6) 13 (10.5) 3 (2.4) 2 (1.6)
26 (34.7) 39 (52.0) 7 (9.3) 2 (2.7) 1 (1.3)
0.970 0.537 0.003
The data presented as mean ± SD.
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
5
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 foodinduced 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 differences 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 children, 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 elsewhere, the main cause of drug-induced anaphylaxis is antibiotics,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 druginduced 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
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S.-Y. Kim et al. / Allergology International xxx (2017) 1e7
Table 5 Risk factors of severe anaphylaxis.
Age Male Drugs History of allergic diseases History of medical diseases WBC (/uL) Eosinophil count (/uL)
P
OR (95% CI)
0.033 0.014 0.035 0.926 0.875 0.503 0.258
1.020 2.305 2.244 1.308 0.939 1.000 0.999
(1.002e1.039) (1.186e4.480) (1.059e4.753) (0.468e2.303) (0.429e2.056) (1.000e1.000) (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 symptoms.6,7,15,17,32,33 The present study also found skin symptoms to be the most common, followed by cardiovascular, respiratory, gastrointestinal, 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 population.8,12,25 Studies conducted in South Korea have reported significantly 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 anaphylaxis 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 foodinduced 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.
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 bronchodilation 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 cardiovascular 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, accurate administration route, or dose because the cause of anaphylaxis 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 patients did not undergo test to identify the causes of anaphylaxis. Precise skin tests or provocation tests are needed to more accurately assess the cause of anaphylaxis. However, this study is significant 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 anaphylaxis. 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 degrees of severity for each cause, and more attention is needed for patients who are older male and whose anaphylaxis is druginduced. 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, discussion of core ideas, and final approval of the manuscript.
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Please cite this article in press as: Kim S-Y, et al., Different clinical features of anaphylaxis according to cause and risk factors for severe reactions, Allergology International (2017), http://dx.doi.org/10.1016/j.alit.2017.05.005