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Increasing trends of anaphylaxis-related events: an analysis of anaphylaxis using nationwide data in Taiwan, 2001–2013

Increasing trends of anaphylaxis-related events: an analysis of anaphylaxis using nationwide data... Background: Anaphylaxis is a severe, potentially fatal, and systemic allergic reaction. Previous studies document increasing trends in incidence rates of anaphylaxis-related events in Western countries, yet little is known about the incidence and trend of anaphylaxis in Asia. In this study, we aimed to determine time trends in incidence rates of anaphylaxis-related events in Taiwan from 2001 through 2013. Methods: We utilized medical claims data from the National Health Insurance Research Databases in Taiwan. We identified anaphylaxis-related events (ICD-9-CM-codes: 995.0, 995.60–995.69, 999.41–999.42, and 999.49) and calculated incidence rates. Poisson regression models were applied to examine trends and incidence rates. Results: A total of 2496 patients (mean age, 45.11 years; 56% male) with first-time anaphylaxis were identified during 34,430,000 person-years of observation time. The overall incidence of anaphylaxis was 7.25 (95% confidence interval (CI) = 6.97–7.53) per 100,000 person-years, increasing from 4.79 in 2001 to 8.20 in 2013, with an incidence rate ratio (IRR) of 1.05 (95%CI = 1.04–1.06). Over the 13-year period, the increasing trends were found in incident diagnosis of anaphylaxis-related outpatient or emergency department visits (IRR = 1.06, 95%CI = 1.05–1.08) and admissions to intensive care units (IRR = 1.06, 95%CI = 1.03–1.10), whereas the trends in incidence of anaphylaxis- related hospitalizations remained steady. The proportion of patients requiring hospitalizations among all patients with anaphylaxis (p = 0.01), as well as the proportion requiring intensive care treatment among patients who _trend were hospitalized (p = 0.01), both increased with age. _trend Conclusion: The incidence rate of anaphylaxis in Taiwan has increased at an average rate of 5% annually since 2001, paralleling the rising trends in several Western countries. Keywords: Anaphylaxis, Epidemiology, Incidence, Time trends, Asian Background [8]. In a U.K. study cohort, Gonzalez-Perez et al. docu- Anaphylaxis, a severe and potentially fatal systemic reaction mented that the incidence rate of anaphylaxis was 21 and that is triggeredsuddenlybyexposure tospecificallergen 50 per 100,000 person-years among subjects with asthma substance, has been referred to as “the latest allergy epi- and without asthma, respectively, from 1996 to 2005 [9]. demic” [1–3]. Previous studies have suggested an increase In recognizing its rapidly increasing incidence, anaphylaxis in the incidence of anaphylaxis, which may have reached has attracted substantial public health attention in devel- epidemic levels in developed countries [4–8]. oped countries during the past years. Due to its significant For example, Lee et al. reported an estimated annual economic and healthcare burden, the anaphylaxis epi- anaphylactic incidence rate of 42 per 100,000 person-years demic has led to increasing demand for specialty and from 2001 to 2010 in Olmsted County, Minnesota, U.S. medical services [10]. Nevertheless, the majority of epide- miologic studies on incidence of anaphylaxis have been from Western developed countries, and relatively few * Correspondence: tsaihj@nhri.org.tw studies assess the incidence of anaphylaxis in Asian coun- Division of Biostatistics and Bioinformatics, Institute of Population Health tries, including Taiwan [11]. Sciences, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yao et al. World Allergy Organization Journal (2018) 11:23 Page 2 of 8 In the present study, we aimed to investigate time trends in the incidence rate of anaphylaxis using a repre- sentative nationwide sample of an Asian population from Taiwan’s National Health Insurance Research Data- base (NHIRD) from 2001 to 2013, to examine the effect of age and gender on having an anaphylactic episode, and to evaluate the trends of severity of anaphylactic episodes in an Asian population. Methods Data source The study cohort was three million subjects obtained from three different Longitudinal Health Insurance Databases (LHID) composed of medical claims data from the National Health Insurance Research Database (NHIRD) in Taiwan. The National Health Insurance (NHI) program has provided mandatory medical care to residents in Taiwan since 1995. The NHIRD derived from the medical reimbursement of the NHI program provided medical claims data, including demographic Fig. 1 Flow chart showing the identification of patients with characteristics, disease diagnoses, ambulatory care and anaphylaxis. LHID: Longitudinal Health Insurance Database; OPD: inpatient claims data, and prescription records. Currently, outpatient department; ED: emergency department; ICU: intensive care unit. ICD-9-CM codes for anaphylaxis: 995.0, 995.60–995.69, the NHI program covers enrollees representing nearly 999.41–999.42, and 999.49) 98% of the total population in Taiwan [12]. Data used in this study were collected from three different LHID data- sets. In detail, each LHID dataset used in this study was person-years. Annual incidence rate was expressed as constructed by randomly selecting one million subjects the number of the first-time anaphylactic patients per from the NHI program in 2000, 2005, and 2010, individu- 100,000 person-years for each study year. We performed ally. We included medical claims data of approximately Poisson regression models to evaluate the relationships three million subjects from January 1, 2001 to December of incidence rates with various age groups, gender, 31, 2013 in this study. The Institutional Review Board of anaphylaxis-related OPD visits, ED visits, hospitaliza- the National Health Research Institutes, Taiwan, approved tions, and admissions to an ICU, respectively. We then this study protocol. applied linear regression analysis to examine time trends of anaphylaxis-related OPD visits, ED visits, hospitaliza- Study cohort tions, and admissions to an ICU, separately, across study During the 2001–2013 study period, we identified subjects years. All analyses were performed using SAS version 8.2 with first-time anaphylaxis according to the International (SAS institute, Cary, NC). P values less than 0.05 were Classification of Diseases, 9th Revision, Clinical Modifica- declared to be statistically significant. tion [ICD-9-CM] diagnosis codes: 995.0, 995.60–995.69, 999.41–999.42, and 999.49 from outpatient department Results (OPD) or emergency department (ED) visits, or inpatient Demographic characteristics of the 2496 incident cases of admissions, respectively, based on the World Allergy anaphylaxis are summarized in Table 1. The mean age of Organization anaphylaxis guidelines [13, 14]. The index patients with first-time anaphylaxis was 45.11 years (stand- date was defined as the first date of anaphylaxis diagnosis. ard deviation (SD), 20.64 years [range 3 months-100 years]), Figure 1 depicts the detailed flow chart in relation to the 56% (n = 1391) of patients were male. Nearly half of the identification of the study patients. cases (47%) were treated in the ED, while 21% (n =518) were evaluated and managed in the OPD. Twenty percent Data analysis were hospitalized, and 12% (n = 305) were further required The primary outcomes investigated in this study were admission to an ICU (Table 1). The distribution of anaphylaxis-related OPD visits, ED visits, hospitaliza- urbanization among study patients was suburban area tions, and admissions to an intensive care unit (ICU), (48%), followed by urban area (24%), and rural area (11%), separately. We calculated annual incidence rates of respectively (Table 1). A detailed flow chart related to iden- anaphylaxis-related events by dividing the number of tification of the study subjects is shown in Fig. 1. new cases of anaphylaxis by the number of observed Yao et al. World Allergy Organization Journal (2018) 11:23 Page 3 of 8 Table 1 Demographic characteristics of study patients with person-years in subjects ages 40–59 years; and 12.77 anaphylaxis (n = 2496) (95%CI = 11.78–13.75) per 100,000 person-years in sub- General characteristics Number Percent jects ages ≥ 60 years. When we evaluated the trends of incidence rates in each age group, the incidence rates of Age (years) anaphylaxis significantly increased in subjects ages ≤ ≤ 18 292 12 18 years (incidence rate ratio (IRR) = 1.09, 95%CI = 19–39 697 28 1.06–1.13; p < 0.01), 19–39 years (IRR = 1.03, _trend 40–59 858 34 95%CI = 1.01–1.06; p < 0.01), and 40–59 years (IRR _trend ≥ 60 649 26 = 1.04, 95%CI = 1.02–1.05; p < 0.01), respectively, _trend Gender but not in subjects ages ≥ 60 years (IRR = 1.02, 95%CI = 1.00–1.04; p = 0.05). Males 1391 56 _trend Figure 3 shows the time trends in anaphylaxis-related Females 1105 44 incidence rates of OPD or ED visits, hospitalizations, and Disposition admissions to an ICU, separately, across 2001–2013. The Outpatient department 518 21 time trends in the incidence of anaphylaxis-related OPD Emergency department 1178 47 or ED visits have increased (IRR = 1.06, 95%CI = 1.05– Hospitalizations 495 20 1.08; p < 0.01). The time trends in the incidence of _trend anaphylaxis-related admissions to an ICU have also in- Intensive care unit 305 12 creased (IRR = 1.06, 95%CI = 1.03–1.10; p <0.01), _trend Urbanization whereas hospitalizations have remained steady over time Urban 604 24 (IRR = 0.99, 95% CI = 0.97–1.02; p =0.66). In _trend Suburban 1205 48 addition, the proportion of patients requiring hospitaliza- Rural 262 11 tions including ICU among all patients (β =6.56; p = _trend Unknown 425 17 0.01), and the proportion requiring intensive care treat- ment among hospitalized patients (β =5.21; p =0.01) _trend The overall incidence of anaphylaxis was 7.25 (95%CI increased with age (Fig. 4 and Additional file 1: Table S1). = 6.97–7.53) per 100,000 person-years. There was signifi- cant difference in incidence rates between children aged Discussion less than 18 years and adults aged 18 years or older To date, limited studies related to incidence rate of ana- (4.06 per 100,000 person-years, 95%CI = 3.60–4.53 in phylaxis have been reported in Asian populations. This children; 8.1 per 100,000 person-years, 95% CI = 7.75– is one of the largest nationwide, population-based stud- 8.43 in adults; p < 0.01). The incidence rate of ies investigating long-term time trends in the incidence _difference anaphylaxis has increased from 4.79 per 100,000 rate of anaphylaxis in an Asian population. The overall person-years in 2001 to 8.20 per 100,000 person-years in incidence rate of anaphylaxis was 7.25 per 100,000 2013, with an incidence rate ratio (IRR) of 1.05 (95%CI person-years from 2001 to 2013, with the incidence rate = 1.04–1.06) (Fig. 2), indicating that there was a 5% being 8.1 and 4.06 per 100,000 person-years in adults annual increase. and children, respectively. The incidence rate increased As shown in Table 2, the incidence rate of anaphylaxis from 4.79 per 100,000 person-years in 2001 to 8.20 per was significantly greater in males than in females (8.17 100,000 person-years in 2013, with an incidence rate per 100,000 person-years, 95%CI = 7.74–8.60 in males; ratio of 1.05 (95% CI = 1.04–1.06), indicating that there 6.35 person-years, 95%CI = 5.98–6.73 in females; p < was a 5% annual increase in the incidence rate of ana- 0.01). The incidence rate of anaphylaxis (Table 2) also phylaxis. We identified a significant rise in incidence increased with age in both genders (both p < 0.01). Fig- rates of anaphylaxis in both genders over the 13-year ure 2a shows that the incidence rates of anaphylaxis in period, mainly in subjects aged less than 60 years, with both males and females (IRR = 1.06, 95%CI = 1.04–1.07; the most prominent increasing trend observed in chil- p < 0.01 in males; IRR = 1.04, 95%CI = 1.03–1.06; dren aged less than 18 years. The proportion of patients _trend p < 0.01 in females) increased significantly over time requiring hospitalizations or ICU among all patients _trend (2001–2013). with anaphylaxis increased with age. The incidence rates of anaphylaxis varied by age The steady increase (5% increase per year) in the groups as shown in Fig. 2b. The overall incidence rates anaphylaxis-related incidence rates in the current study of anaphylaxis were 4.06 (95%CI = 3.60–4.53) per is similar to those previously reported in the U.S., the 100,000 person-years in subjects ages ≤ 18 years; 5.87 U.K., Australia, and Spain [8, 15, 16]. In accordance with (95%CI = 5.44–6.31) per 100,000 person-years in subjects the national estimates in this study, Hsin et al. observed ages 19–39 years; 8.34 (95%CI = 7.78–8.90) per 100,000 an increase in incidence of anaphylaxis from 4.7 per Yao et al. World Allergy Organization Journal (2018) 11:23 Page 4 of 8 Fig. 2 a. Incidence rate of anaphylaxis across 2001–2013, stratified by gender. b. Incidence rate of anaphylaxis across 2001–2013, classified by various age groups Table 2 Incidence of anaphylaxis in Taiwan, 2001–2013, by gender and various age groups Male Female Total * * * n Rate n Rate n Rate Age at diagnosis (years) ≤ 18 155 4.17 137 3.95 292 4.06 19–39 412 7.19 285 4.64 697 5.87 40–59 495 9.69 363 7.01 858 8.34 ≥ 60 329 13.32 320 12.24 649 12.77 Total 1391 8.17 1105 6.35 2496 7.25 P-value P < 0.01 _gender P-value P < 0.01 P < 0.01 P < 0.01 _age_male _age_female _age_total Incidence per 100,000 person-years P-value for differences in incidence rates among gender (2001–2013) P-value for differences in incidence rates among age groups (2001–2013) Yao et al. World Allergy Organization Journal (2018) 11:23 Page 5 of 8 Fig. 3 Time trends in incidence rates of outpatient department or emergency department visits, admissions to an inpatient ward, and admissions to an intensive care unit, for anaphylaxis across 2001–2013. OPD: outpatient department; ED: emergency department; ICU: intensive care unit 100,000 patients in 2002 to 12.8 per 100,000 patients in observed in Western countries but also in Asia. The 2010 in a single hospital-based study in Taiwan [17]. cause of the recent increases in the incidence of ana- Similar to our observation in Taiwan, Yang et al. re- phylaxis around the world remains unclear. Potential ex- ported a 2-fold increase in the incidence of anaphylaxis planations may be lifestyle changes, differential exposure from 16.02 per 100,000 person-years in 2008 to 32.19 to environmental risk factors, and inherited epigenetic per 100,000 person-years in 2014 in Korea [18]. While changes activated or suppressed by genes pertinent to our results are consistent with the results of Hsin et al. immune regulation [20, 21]. Further studies are merited and Yang et al., our study includes a significantly larger in delineating the underlying responsible mechanisms. population. Previous epidemiological studies utilizing electronic Explanations for the increasing anaphylactic incidence databases to obtain the incidence rates of anaphylaxis are rates in Taiwan remain speculative but could be mirror- summarized in Additional file 1:Figure S1 [4, 6–9, 22– ing the increasing prevalence of other allergic diseases, 27]. The results show that anaphylaxis-related incidence such as allergic rhinitis and food allergy, or could be sec- varies across different countries, ranging from 6.7 to 112.2 ondary to increased diagnosis of anaphylactic episodes, per 100,000 person-years (Additional file 1:FigureS1). or both [19]. The time trend observed in this nationwide Despite consistent trend in elevated incidence of anaphyl- study in Taiwan is comparable with previous incidence axis, the estimated incidence in our study population is estimates in Western developed countries, suggesting relatively low compared to the estimated incidence in that the increasing incidence of anaphylaxis is not only Western developed countries [4, 5, 7–9, 26]. The Fig. 4 Proportions of patients with anaphylaxis admitted to the hospital (either inpatient ward or intensive care unit) or an intensive care unit across age groups. ICU: intensive care unit Yao et al. World Allergy Organization Journal (2018) 11:23 Page 6 of 8 observation may be partially explained by environmental Nevertheless, this study has some limitations. First, simi- variation and/or genetic difference. Previous studies have lar to most studies using medical claims data, our data indicated that food allergies trigger the majority of ana- lack detailed information regarding specific inciting phylactic episodes; among food specific allergens, peanuts triggers; however, such inaccuracies probably remained and tree nuts are the main sources responsible for ana- unchanged between 2001 and 2013. Nonetheless, we phylactic adverse events [28]. In parallel, hospitalizations found that the most common triggers among patients with due to food-induced anaphylaxis have elevated more than first-time anaphylaxis are foods, approximately 23.5%, in 3-time during the past years in the U.S. and U.K. [7, 29]. It this study. Second, this single-country study was con- has been noted that the prevalence of peanut allergy in ducted in Taiwan, which may or may not be generalizable Taiwan is lower than that reported in Western countries, to other Asian countries. Future efforts are needed to which may account for the observed relatively low ana- understand the time trends in the anaphylactic incidence phylaxis-related incidence in this study [30]. It is also in other Asian countries. Third, we cannot exclude the probably that the relatively low anaphylactic incidence potential bias caused by unmeasured confounding. may be due to difference in genetic background across dif- In summary, this study provides the national estimates ferent ethnicities. of the incidence of anaphylaxis in Taiwan’s general Few population-based studies have documented that the population over a 13-year period, 2001–2013. The steady occurrence of anaphylaxis varies by age and gender [31– increase in the incidence rate of anaphylaxis in both 34]. For example, Rudders et al. reported age-related differ- genders and most strikingly in children less than 18 years ences in food-induced anaphylaxis and underscored the of age in Taiwan is consistent with those previously necessity for improving awareness of food-induced ana- reported in Western countries. Our findings suggest that phylaxis in pediatric populations [33]. In addition, previous the increasing incidence of anaphylaxis is a public health reports indicate that common triggers of anaphylaxis are threat, not only affecting the Western populations, but different between children and adults [32]. Similarly, gen- also Asian populations. Our results highlight the neces- der differences in anaphylactic incidence have remained sity of disentangling the potential reasons responsible unclear [31]. Our study found that incidence of anaphyl- for the rising incidence of anaphylaxis in Taiwan and axis increased as age increased and had a male predomin- other countries. ance. To date, age and/or gender differences in incidence of anaphylaxis are largely unexplored. Therefore, the ob- Additional file served results should be interpreted with caution and is warranted for further investigation. Additional file 1: Table S1. Management of first-time anaphylaxis in Taiwan, 2001–2013. Figure S1. Incidence rate of anaphylaxis reported This study demonstrates a clear increase in the pro- from different countries. (DOCX 19 kb) portion of patients with anaphylaxis requiring hospitali- zations and/or an ICU as age increases. Likewise, the Abbreviations rising proportion of patients requiring intensive care CI: confidence interval; ED: emergency department; ICD-9-CM: International treatment among those hospitalized was also observed Classification of Diseases, 9th Revision, Clinical Modification; ICU: intensive as age increased. Our results are consistent with previ- care unit; IRR: incidence rate ratio; LHID: Longitudinal Health Insurance Database; NHI: National Health Insurance; NHIRD: National Health Insurance ous studies [35, 36]. For example, Jeppesen et al. have Research Database; OPD: outpatient department; SD: standard deviation found an increase in hospitalizations due to anaphylaxis in all ages in Denmark [35]. The observed rising rate of Acknowledgements anaphylaxis related hospitalization raises some concern This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, whether anaphylactic episodes have gotten more severe Department of Health and managed by the National Health Research over the past years. In addition, our results indicated an Institutes (Registered numbers: 99081, 99136, 99287, 101014, NHRID-101-548). increasing proportion of hospitalized patients requires The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health or National admission to the ICU, which is barely explored. It will be Health Research Institutes. of importance to further validate the findings in this study. The major strengths of this study are that we used na- Funding tional medical claims databases, which allow us to pro- HJT and TCY are supported in part by grants from the Ministry of Science and Technology, National Health Research Institutes, and Chang Gung vide a nationwide estimated incidence of anaphylaxis Memorial Hospital (PI: HJT, NSC 101–2314-B-400-009-MY2, MOST 103–2314-B- over a 13-year period in a Taiwanese population. In 400-004-MY3, MOST 107–2314-B-400-031 -MY3, PH-105-SP-05, PH-105-SP-04, addition, a large population-based sample from the and PH-106-PP-08; PI: TCY, MOST 103–2314-B-182-030, MOST 104–2314-B- 182-046-MY2, MOST 106–2314-B-182-051-MY3, CORPG3H0101, CORPG3F0361, NHIRD allows us to evaluate the trends of management CMRPG3F1711, CORPG3F0081 and CMRPG3E1201). administered in Taiwan’s medical facilities over the study period. Moreover, selection bias or information bias may Availability of data and materials not be a concern because of nationwide sampling. Not applicable. Yao et al. World Allergy Organization Journal (2018) 11:23 Page 7 of 8 Authors’ contributions 9. Gonzalez-Perez A, Aponte Z, Vidaurre CF, Rodriguez LA. Anaphylaxis Tsung-Chieh Yao and Hui-Ju Tsai conceptualized, designed and supervised epidemiology in patients with and patients without asthma: a United the study; raised funding for the study, assisted in data analysis, interpreted the Kingdom database review. J Allergy Clin Immunol. 2010;125:1098–104. e1 results and drafted the manuscript. Ya-Wen Huang performed data analysis, 10. Patel DA, Holdford DA, Edwards E, Carroll NV. Estimating the economic assisted in data collection, interpreted the results, and drafted the manuscript. burden of food-induced allergic reactions and anaphylaxis in the United Ann Chen Wu and Jiu-Yao Wang provided intellectual input and assisted States. J Allergy Clin Immunol. 2011;128:110–5. e5 in data analysis and interpretation. Hui-Ju Tsai coordinated the study, 11. Wang Y, Koplin JJ, Ho MHK, Wong WHS, Allen KJ. Increasing hospital raised funding for the study and staff working on the project, and provided presentations for anaphylaxis in the pediatric population in Hong Kong. J thoughtful input in interpretation of the results. All authors contributed to the Allergy Clin Immunol Pract. 2018;6:1050–2. e2 interpretation and discussion of the results; read and approved the final article. 12. 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Increasing trends of anaphylaxis-related events: an analysis of anaphylaxis using nationwide data in Taiwan, 2001–2013

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Medicine & Public Health; Allergology; Immunology
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Abstract

Background: Anaphylaxis is a severe, potentially fatal, and systemic allergic reaction. Previous studies document increasing trends in incidence rates of anaphylaxis-related events in Western countries, yet little is known about the incidence and trend of anaphylaxis in Asia. In this study, we aimed to determine time trends in incidence rates of anaphylaxis-related events in Taiwan from 2001 through 2013. Methods: We utilized medical claims data from the National Health Insurance Research Databases in Taiwan. We identified anaphylaxis-related events (ICD-9-CM-codes: 995.0, 995.60–995.69, 999.41–999.42, and 999.49) and calculated incidence rates. Poisson regression models were applied to examine trends and incidence rates. Results: A total of 2496 patients (mean age, 45.11 years; 56% male) with first-time anaphylaxis were identified during 34,430,000 person-years of observation time. The overall incidence of anaphylaxis was 7.25 (95% confidence interval (CI) = 6.97–7.53) per 100,000 person-years, increasing from 4.79 in 2001 to 8.20 in 2013, with an incidence rate ratio (IRR) of 1.05 (95%CI = 1.04–1.06). Over the 13-year period, the increasing trends were found in incident diagnosis of anaphylaxis-related outpatient or emergency department visits (IRR = 1.06, 95%CI = 1.05–1.08) and admissions to intensive care units (IRR = 1.06, 95%CI = 1.03–1.10), whereas the trends in incidence of anaphylaxis- related hospitalizations remained steady. The proportion of patients requiring hospitalizations among all patients with anaphylaxis (p = 0.01), as well as the proportion requiring intensive care treatment among patients who _trend were hospitalized (p = 0.01), both increased with age. _trend Conclusion: The incidence rate of anaphylaxis in Taiwan has increased at an average rate of 5% annually since 2001, paralleling the rising trends in several Western countries. Keywords: Anaphylaxis, Epidemiology, Incidence, Time trends, Asian Background [8]. In a U.K. study cohort, Gonzalez-Perez et al. docu- Anaphylaxis, a severe and potentially fatal systemic reaction mented that the incidence rate of anaphylaxis was 21 and that is triggeredsuddenlybyexposure tospecificallergen 50 per 100,000 person-years among subjects with asthma substance, has been referred to as “the latest allergy epi- and without asthma, respectively, from 1996 to 2005 [9]. demic” [1–3]. Previous studies have suggested an increase In recognizing its rapidly increasing incidence, anaphylaxis in the incidence of anaphylaxis, which may have reached has attracted substantial public health attention in devel- epidemic levels in developed countries [4–8]. oped countries during the past years. Due to its significant For example, Lee et al. reported an estimated annual economic and healthcare burden, the anaphylaxis epi- anaphylactic incidence rate of 42 per 100,000 person-years demic has led to increasing demand for specialty and from 2001 to 2010 in Olmsted County, Minnesota, U.S. medical services [10]. Nevertheless, the majority of epide- miologic studies on incidence of anaphylaxis have been from Western developed countries, and relatively few * Correspondence: tsaihj@nhri.org.tw studies assess the incidence of anaphylaxis in Asian coun- Division of Biostatistics and Bioinformatics, Institute of Population Health tries, including Taiwan [11]. Sciences, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yao et al. World Allergy Organization Journal (2018) 11:23 Page 2 of 8 In the present study, we aimed to investigate time trends in the incidence rate of anaphylaxis using a repre- sentative nationwide sample of an Asian population from Taiwan’s National Health Insurance Research Data- base (NHIRD) from 2001 to 2013, to examine the effect of age and gender on having an anaphylactic episode, and to evaluate the trends of severity of anaphylactic episodes in an Asian population. Methods Data source The study cohort was three million subjects obtained from three different Longitudinal Health Insurance Databases (LHID) composed of medical claims data from the National Health Insurance Research Database (NHIRD) in Taiwan. The National Health Insurance (NHI) program has provided mandatory medical care to residents in Taiwan since 1995. The NHIRD derived from the medical reimbursement of the NHI program provided medical claims data, including demographic Fig. 1 Flow chart showing the identification of patients with characteristics, disease diagnoses, ambulatory care and anaphylaxis. LHID: Longitudinal Health Insurance Database; OPD: inpatient claims data, and prescription records. Currently, outpatient department; ED: emergency department; ICU: intensive care unit. ICD-9-CM codes for anaphylaxis: 995.0, 995.60–995.69, the NHI program covers enrollees representing nearly 999.41–999.42, and 999.49) 98% of the total population in Taiwan [12]. Data used in this study were collected from three different LHID data- sets. In detail, each LHID dataset used in this study was person-years. Annual incidence rate was expressed as constructed by randomly selecting one million subjects the number of the first-time anaphylactic patients per from the NHI program in 2000, 2005, and 2010, individu- 100,000 person-years for each study year. We performed ally. We included medical claims data of approximately Poisson regression models to evaluate the relationships three million subjects from January 1, 2001 to December of incidence rates with various age groups, gender, 31, 2013 in this study. The Institutional Review Board of anaphylaxis-related OPD visits, ED visits, hospitaliza- the National Health Research Institutes, Taiwan, approved tions, and admissions to an ICU, respectively. We then this study protocol. applied linear regression analysis to examine time trends of anaphylaxis-related OPD visits, ED visits, hospitaliza- Study cohort tions, and admissions to an ICU, separately, across study During the 2001–2013 study period, we identified subjects years. All analyses were performed using SAS version 8.2 with first-time anaphylaxis according to the International (SAS institute, Cary, NC). P values less than 0.05 were Classification of Diseases, 9th Revision, Clinical Modifica- declared to be statistically significant. tion [ICD-9-CM] diagnosis codes: 995.0, 995.60–995.69, 999.41–999.42, and 999.49 from outpatient department Results (OPD) or emergency department (ED) visits, or inpatient Demographic characteristics of the 2496 incident cases of admissions, respectively, based on the World Allergy anaphylaxis are summarized in Table 1. The mean age of Organization anaphylaxis guidelines [13, 14]. The index patients with first-time anaphylaxis was 45.11 years (stand- date was defined as the first date of anaphylaxis diagnosis. ard deviation (SD), 20.64 years [range 3 months-100 years]), Figure 1 depicts the detailed flow chart in relation to the 56% (n = 1391) of patients were male. Nearly half of the identification of the study patients. cases (47%) were treated in the ED, while 21% (n =518) were evaluated and managed in the OPD. Twenty percent Data analysis were hospitalized, and 12% (n = 305) were further required The primary outcomes investigated in this study were admission to an ICU (Table 1). The distribution of anaphylaxis-related OPD visits, ED visits, hospitaliza- urbanization among study patients was suburban area tions, and admissions to an intensive care unit (ICU), (48%), followed by urban area (24%), and rural area (11%), separately. We calculated annual incidence rates of respectively (Table 1). A detailed flow chart related to iden- anaphylaxis-related events by dividing the number of tification of the study subjects is shown in Fig. 1. new cases of anaphylaxis by the number of observed Yao et al. World Allergy Organization Journal (2018) 11:23 Page 3 of 8 Table 1 Demographic characteristics of study patients with person-years in subjects ages 40–59 years; and 12.77 anaphylaxis (n = 2496) (95%CI = 11.78–13.75) per 100,000 person-years in sub- General characteristics Number Percent jects ages ≥ 60 years. When we evaluated the trends of incidence rates in each age group, the incidence rates of Age (years) anaphylaxis significantly increased in subjects ages ≤ ≤ 18 292 12 18 years (incidence rate ratio (IRR) = 1.09, 95%CI = 19–39 697 28 1.06–1.13; p < 0.01), 19–39 years (IRR = 1.03, _trend 40–59 858 34 95%CI = 1.01–1.06; p < 0.01), and 40–59 years (IRR _trend ≥ 60 649 26 = 1.04, 95%CI = 1.02–1.05; p < 0.01), respectively, _trend Gender but not in subjects ages ≥ 60 years (IRR = 1.02, 95%CI = 1.00–1.04; p = 0.05). Males 1391 56 _trend Figure 3 shows the time trends in anaphylaxis-related Females 1105 44 incidence rates of OPD or ED visits, hospitalizations, and Disposition admissions to an ICU, separately, across 2001–2013. The Outpatient department 518 21 time trends in the incidence of anaphylaxis-related OPD Emergency department 1178 47 or ED visits have increased (IRR = 1.06, 95%CI = 1.05– Hospitalizations 495 20 1.08; p < 0.01). The time trends in the incidence of _trend anaphylaxis-related admissions to an ICU have also in- Intensive care unit 305 12 creased (IRR = 1.06, 95%CI = 1.03–1.10; p <0.01), _trend Urbanization whereas hospitalizations have remained steady over time Urban 604 24 (IRR = 0.99, 95% CI = 0.97–1.02; p =0.66). In _trend Suburban 1205 48 addition, the proportion of patients requiring hospitaliza- Rural 262 11 tions including ICU among all patients (β =6.56; p = _trend Unknown 425 17 0.01), and the proportion requiring intensive care treat- ment among hospitalized patients (β =5.21; p =0.01) _trend The overall incidence of anaphylaxis was 7.25 (95%CI increased with age (Fig. 4 and Additional file 1: Table S1). = 6.97–7.53) per 100,000 person-years. There was signifi- cant difference in incidence rates between children aged Discussion less than 18 years and adults aged 18 years or older To date, limited studies related to incidence rate of ana- (4.06 per 100,000 person-years, 95%CI = 3.60–4.53 in phylaxis have been reported in Asian populations. This children; 8.1 per 100,000 person-years, 95% CI = 7.75– is one of the largest nationwide, population-based stud- 8.43 in adults; p < 0.01). The incidence rate of ies investigating long-term time trends in the incidence _difference anaphylaxis has increased from 4.79 per 100,000 rate of anaphylaxis in an Asian population. The overall person-years in 2001 to 8.20 per 100,000 person-years in incidence rate of anaphylaxis was 7.25 per 100,000 2013, with an incidence rate ratio (IRR) of 1.05 (95%CI person-years from 2001 to 2013, with the incidence rate = 1.04–1.06) (Fig. 2), indicating that there was a 5% being 8.1 and 4.06 per 100,000 person-years in adults annual increase. and children, respectively. The incidence rate increased As shown in Table 2, the incidence rate of anaphylaxis from 4.79 per 100,000 person-years in 2001 to 8.20 per was significantly greater in males than in females (8.17 100,000 person-years in 2013, with an incidence rate per 100,000 person-years, 95%CI = 7.74–8.60 in males; ratio of 1.05 (95% CI = 1.04–1.06), indicating that there 6.35 person-years, 95%CI = 5.98–6.73 in females; p < was a 5% annual increase in the incidence rate of ana- 0.01). The incidence rate of anaphylaxis (Table 2) also phylaxis. We identified a significant rise in incidence increased with age in both genders (both p < 0.01). Fig- rates of anaphylaxis in both genders over the 13-year ure 2a shows that the incidence rates of anaphylaxis in period, mainly in subjects aged less than 60 years, with both males and females (IRR = 1.06, 95%CI = 1.04–1.07; the most prominent increasing trend observed in chil- p < 0.01 in males; IRR = 1.04, 95%CI = 1.03–1.06; dren aged less than 18 years. The proportion of patients _trend p < 0.01 in females) increased significantly over time requiring hospitalizations or ICU among all patients _trend (2001–2013). with anaphylaxis increased with age. The incidence rates of anaphylaxis varied by age The steady increase (5% increase per year) in the groups as shown in Fig. 2b. The overall incidence rates anaphylaxis-related incidence rates in the current study of anaphylaxis were 4.06 (95%CI = 3.60–4.53) per is similar to those previously reported in the U.S., the 100,000 person-years in subjects ages ≤ 18 years; 5.87 U.K., Australia, and Spain [8, 15, 16]. In accordance with (95%CI = 5.44–6.31) per 100,000 person-years in subjects the national estimates in this study, Hsin et al. observed ages 19–39 years; 8.34 (95%CI = 7.78–8.90) per 100,000 an increase in incidence of anaphylaxis from 4.7 per Yao et al. World Allergy Organization Journal (2018) 11:23 Page 4 of 8 Fig. 2 a. Incidence rate of anaphylaxis across 2001–2013, stratified by gender. b. Incidence rate of anaphylaxis across 2001–2013, classified by various age groups Table 2 Incidence of anaphylaxis in Taiwan, 2001–2013, by gender and various age groups Male Female Total * * * n Rate n Rate n Rate Age at diagnosis (years) ≤ 18 155 4.17 137 3.95 292 4.06 19–39 412 7.19 285 4.64 697 5.87 40–59 495 9.69 363 7.01 858 8.34 ≥ 60 329 13.32 320 12.24 649 12.77 Total 1391 8.17 1105 6.35 2496 7.25 P-value P < 0.01 _gender P-value P < 0.01 P < 0.01 P < 0.01 _age_male _age_female _age_total Incidence per 100,000 person-years P-value for differences in incidence rates among gender (2001–2013) P-value for differences in incidence rates among age groups (2001–2013) Yao et al. World Allergy Organization Journal (2018) 11:23 Page 5 of 8 Fig. 3 Time trends in incidence rates of outpatient department or emergency department visits, admissions to an inpatient ward, and admissions to an intensive care unit, for anaphylaxis across 2001–2013. OPD: outpatient department; ED: emergency department; ICU: intensive care unit 100,000 patients in 2002 to 12.8 per 100,000 patients in observed in Western countries but also in Asia. The 2010 in a single hospital-based study in Taiwan [17]. cause of the recent increases in the incidence of ana- Similar to our observation in Taiwan, Yang et al. re- phylaxis around the world remains unclear. Potential ex- ported a 2-fold increase in the incidence of anaphylaxis planations may be lifestyle changes, differential exposure from 16.02 per 100,000 person-years in 2008 to 32.19 to environmental risk factors, and inherited epigenetic per 100,000 person-years in 2014 in Korea [18]. While changes activated or suppressed by genes pertinent to our results are consistent with the results of Hsin et al. immune regulation [20, 21]. Further studies are merited and Yang et al., our study includes a significantly larger in delineating the underlying responsible mechanisms. population. Previous epidemiological studies utilizing electronic Explanations for the increasing anaphylactic incidence databases to obtain the incidence rates of anaphylaxis are rates in Taiwan remain speculative but could be mirror- summarized in Additional file 1:Figure S1 [4, 6–9, 22– ing the increasing prevalence of other allergic diseases, 27]. The results show that anaphylaxis-related incidence such as allergic rhinitis and food allergy, or could be sec- varies across different countries, ranging from 6.7 to 112.2 ondary to increased diagnosis of anaphylactic episodes, per 100,000 person-years (Additional file 1:FigureS1). or both [19]. The time trend observed in this nationwide Despite consistent trend in elevated incidence of anaphyl- study in Taiwan is comparable with previous incidence axis, the estimated incidence in our study population is estimates in Western developed countries, suggesting relatively low compared to the estimated incidence in that the increasing incidence of anaphylaxis is not only Western developed countries [4, 5, 7–9, 26]. The Fig. 4 Proportions of patients with anaphylaxis admitted to the hospital (either inpatient ward or intensive care unit) or an intensive care unit across age groups. ICU: intensive care unit Yao et al. World Allergy Organization Journal (2018) 11:23 Page 6 of 8 observation may be partially explained by environmental Nevertheless, this study has some limitations. First, simi- variation and/or genetic difference. Previous studies have lar to most studies using medical claims data, our data indicated that food allergies trigger the majority of ana- lack detailed information regarding specific inciting phylactic episodes; among food specific allergens, peanuts triggers; however, such inaccuracies probably remained and tree nuts are the main sources responsible for ana- unchanged between 2001 and 2013. Nonetheless, we phylactic adverse events [28]. In parallel, hospitalizations found that the most common triggers among patients with due to food-induced anaphylaxis have elevated more than first-time anaphylaxis are foods, approximately 23.5%, in 3-time during the past years in the U.S. and U.K. [7, 29]. It this study. Second, this single-country study was con- has been noted that the prevalence of peanut allergy in ducted in Taiwan, which may or may not be generalizable Taiwan is lower than that reported in Western countries, to other Asian countries. Future efforts are needed to which may account for the observed relatively low ana- understand the time trends in the anaphylactic incidence phylaxis-related incidence in this study [30]. It is also in other Asian countries. Third, we cannot exclude the probably that the relatively low anaphylactic incidence potential bias caused by unmeasured confounding. may be due to difference in genetic background across dif- In summary, this study provides the national estimates ferent ethnicities. of the incidence of anaphylaxis in Taiwan’s general Few population-based studies have documented that the population over a 13-year period, 2001–2013. The steady occurrence of anaphylaxis varies by age and gender [31– increase in the incidence rate of anaphylaxis in both 34]. For example, Rudders et al. reported age-related differ- genders and most strikingly in children less than 18 years ences in food-induced anaphylaxis and underscored the of age in Taiwan is consistent with those previously necessity for improving awareness of food-induced ana- reported in Western countries. Our findings suggest that phylaxis in pediatric populations [33]. In addition, previous the increasing incidence of anaphylaxis is a public health reports indicate that common triggers of anaphylaxis are threat, not only affecting the Western populations, but different between children and adults [32]. Similarly, gen- also Asian populations. Our results highlight the neces- der differences in anaphylactic incidence have remained sity of disentangling the potential reasons responsible unclear [31]. Our study found that incidence of anaphyl- for the rising incidence of anaphylaxis in Taiwan and axis increased as age increased and had a male predomin- other countries. ance. To date, age and/or gender differences in incidence of anaphylaxis are largely unexplored. Therefore, the ob- Additional file served results should be interpreted with caution and is warranted for further investigation. Additional file 1: Table S1. Management of first-time anaphylaxis in Taiwan, 2001–2013. Figure S1. Incidence rate of anaphylaxis reported This study demonstrates a clear increase in the pro- from different countries. (DOCX 19 kb) portion of patients with anaphylaxis requiring hospitali- zations and/or an ICU as age increases. Likewise, the Abbreviations rising proportion of patients requiring intensive care CI: confidence interval; ED: emergency department; ICD-9-CM: International treatment among those hospitalized was also observed Classification of Diseases, 9th Revision, Clinical Modification; ICU: intensive as age increased. Our results are consistent with previ- care unit; IRR: incidence rate ratio; LHID: Longitudinal Health Insurance Database; NHI: National Health Insurance; NHIRD: National Health Insurance ous studies [35, 36]. For example, Jeppesen et al. have Research Database; OPD: outpatient department; SD: standard deviation found an increase in hospitalizations due to anaphylaxis in all ages in Denmark [35]. The observed rising rate of Acknowledgements anaphylaxis related hospitalization raises some concern This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, whether anaphylactic episodes have gotten more severe Department of Health and managed by the National Health Research over the past years. In addition, our results indicated an Institutes (Registered numbers: 99081, 99136, 99287, 101014, NHRID-101-548). increasing proportion of hospitalized patients requires The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health or National admission to the ICU, which is barely explored. It will be Health Research Institutes. of importance to further validate the findings in this study. The major strengths of this study are that we used na- Funding tional medical claims databases, which allow us to pro- HJT and TCY are supported in part by grants from the Ministry of Science and Technology, National Health Research Institutes, and Chang Gung vide a nationwide estimated incidence of anaphylaxis Memorial Hospital (PI: HJT, NSC 101–2314-B-400-009-MY2, MOST 103–2314-B- over a 13-year period in a Taiwanese population. In 400-004-MY3, MOST 107–2314-B-400-031 -MY3, PH-105-SP-05, PH-105-SP-04, addition, a large population-based sample from the and PH-106-PP-08; PI: TCY, MOST 103–2314-B-182-030, MOST 104–2314-B- 182-046-MY2, MOST 106–2314-B-182-051-MY3, CORPG3H0101, CORPG3F0361, NHIRD allows us to evaluate the trends of management CMRPG3F1711, CORPG3F0081 and CMRPG3E1201). administered in Taiwan’s medical facilities over the study period. Moreover, selection bias or information bias may Availability of data and materials not be a concern because of nationwide sampling. Not applicable. Yao et al. World Allergy Organization Journal (2018) 11:23 Page 7 of 8 Authors’ contributions 9. Gonzalez-Perez A, Aponte Z, Vidaurre CF, Rodriguez LA. Anaphylaxis Tsung-Chieh Yao and Hui-Ju Tsai conceptualized, designed and supervised epidemiology in patients with and patients without asthma: a United the study; raised funding for the study, assisted in data analysis, interpreted the Kingdom database review. J Allergy Clin Immunol. 2010;125:1098–104. e1 results and drafted the manuscript. Ya-Wen Huang performed data analysis, 10. Patel DA, Holdford DA, Edwards E, Carroll NV. Estimating the economic assisted in data collection, interpreted the results, and drafted the manuscript. burden of food-induced allergic reactions and anaphylaxis in the United Ann Chen Wu and Jiu-Yao Wang provided intellectual input and assisted States. J Allergy Clin Immunol. 2011;128:110–5. e5 in data analysis and interpretation. Hui-Ju Tsai coordinated the study, 11. Wang Y, Koplin JJ, Ho MHK, Wong WHS, Allen KJ. Increasing hospital raised funding for the study and staff working on the project, and provided presentations for anaphylaxis in the pediatric population in Hong Kong. J thoughtful input in interpretation of the results. All authors contributed to the Allergy Clin Immunol Pract. 2018;6:1050–2. e2 interpretation and discussion of the results; read and approved the final article. 12. 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World Allergy Organization JournalSpringer Journals

Published: Oct 10, 2018

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