Pediatric Neurology 51 (2014) 795e799
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Risk of Subsequent Asthma in Children With Febrile Seizures: A Nationwide Population-Based Retrospective Cohort Study Wen-Ya Lin MD a, Chih-Hsin Muo MSc b, c, Yi-Chia Ku MD a, Fung-Chang Sung PhD d, Chia-Hung Kao MD d, e, * a
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan c College of Medicine, China Medical University, Taichung, Taiwan d Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b
abstract BACKGROUND: No study has reported a relationship between febrile seizures and asthma; thus, we examined the association between these two disorders. METHODS: We identified 991 cases of children with febrile seizures as the case cohort, and the control group was matched according to age, sex, urbanization level, and their parents’ occupation at a 1:4 ratio. We applied the Cox proportional hazards regression model to estimate the hazard ratios and 95% confidence intervals for asthma among the children with febrile seizures. RESULTS: After 11 years of followup, the asthma incidence in the febrile seizure group was approximately 5% higher than that in the control group (log-rank test, P < 0.0001). The risk of asthma in the febrile seizure group was 1.41 times higher than that in the control group (95% confidence interval, 1.21-1.65; P < 0.001). Furthermore, the risk of asthma development increased (0.96 vs 3.62) in conjunction with the frequency of febrile seizure-related medical visits (one to two visits vs more than four visits; P < 0.0001). CONCLUSION: Febrile seizures may be associated with an increase in the risk of future asthma occurrence in children. We observed a significantly higher cumulative incidence of asthma occurrence in children with more febrile seizure-related medical visits. Keywords: febrile seizure, asthma, nationwide population-based, cohort study
Pediatr Neurol 2014; 51: 795-799 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Febrile seizures are the most common type of seizure in humans.1 Febrile seizures occur in 2-5% of children. They W.-Y.L., Y.-C.K., C.-H.K. are responsible for the study design, coordination, and drafted the article. C.-H.M., F.-C.S. collected data and performed analysis. W.-Y.L., C.H.M., C.-H.K. provided some intellectual recommendation and reviewed the article. All authors wrote and approved the final version of the article.
Article History: Received May 3, 2014; Accepted in final form June 26, 2014 * Communications should be addressed to: Dr. Kao; Graduate Institute of Clinical Medical Science and School of Medicine; College of Medicine; China Medical University; No 2; Yuh-Der Road; Taichung 404, Taiwan. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.06.017
typically affect children aged 2 months to 5 years, and the incidence is identical in boys and girls.2 Proinflammatory cytokines, including interleukin (IL)1b, IL-6, and tumor necrosis factor (TNF)-a, cause fever during infection. These cytokines not only play a role in activating an immune response after infection, but they also serve neuromodulatory functions and contribute to aberrant neuronal excitability underlying seizure disorders.3 Numerous previous studies have reported an increased level of proinflammatory cytokines (including IL-1b and IL6) in children with febrile seizures.2,4-10 Specific viral infections have also been associated with febrile seizures, including human herpes virus (HHV)-6, influenza, adenovirus, respiratory syncytial virus (RSV), herpes simplex virus
796
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
What is new in this subject (1) Febrile seizures are associated with an increased risk of future asthma in children. (2) Cumulative incidence of asthma is significantly higher in children with more febrile seizure-related medical visits.
(HSV)-1, and cytomegalovirus.11 These fever-related inflammatory cytokines and specific viral infections have been postulated to contribute to the pathogenesis of febrile seizures. Previous studies have reported an increasing incidence of atopic diseases such as asthma, particularly among children.12,13 Researchers have focused on identifying multiple risk factors that cause the development of atopic diseases. Certain studies have reported elevated IL-6 and IL-1b levels in patients with asthma,14-16 as well as increased expression of IL-1b on the asthmatic bronchial epithelium,17,18 indicating that these cytokines might be involved in mediating both the proinflammatory processes and airway hyperresponsiveness that underlie asthmatic diseases. Several studies have reported that RSV and HSV-1 infection have an increased association with subsequent asthma development.19-21 Both febrile seizures and asthma are common disorders among children, and they share a similar association with certain viral infections and proinflammatory cytokines. Thus, the objective of this study was to determine whether an increased risk of asthma exists among children with febrile seizures.
which were defined before the index date. Person-years were counted from the index date to asthma development, and the incidence of asthma per 1000 person-years was also calculated for both groups. The hazard ratio for asthma was assessed in comparison with the control group, and after controlling for comorbidity in the adjusted model, we observed statistically significant differences in comparison with the univariate model. We also estimated the association between asthma and the frequency of febrile seizure-related medical visits within the year after the index date. We used the Kaplan-Meier estimator to plot the proportion asthma free, and the log-rank test was used to test the differences between the two groups. All statistical analyses were performed using SAS 9.2 for Windows (SAS Institute, Cary, NC). All tests were two-tailed, and the level of statistical significance was set at 0.05.
Results
The febrile seizure and control groups comprised 991 and 3964 children, respectively. The mean age of the children with febrile seizures was 2.3 years (standard deviation, 1.20). Most of the children with febrile seizures were boys (56.8%), lived in urban areas (74.7% vs 25.3%), and had parents who worked in white collar positions (59.3% vs 40.7%). Compared with the control group, the children with febrile seizures exhibited a significantly higher frequency of comorbid conditions, including allergic conjunctivitis (P ¼ 0.002) and allergic rhinitis (P ¼ 0.0001; Table 1). The incidence of asthma for the febrile seizure and control groups was 28.62 and 19.56 per 1000 person-years, respectively (Table 2). After 11 years of follow-up, the proportion of asthma-free patients in the febrile seizure group was approximately 5% lower than that in the control group (log-rank, P < 0.0001, Figure). The incidence of asthma in the febrile seizure group was higher among children aged 0.5 to 2.0 years (compared with those >2 years), boys, and
Method and Materials The Taiwan National Health Insurance program is a unique program that was established by the Bureau of National Health Insurance on March 1, 1995. The program provides health insurance coverage for approximately 99% of the population of Taiwan.22 The National Health Research Institutes maintains the National Health Insurance Research Database (NHIRD) of medical claims data. We obtained data from the Longitudinal Health Insurance Database 2000, a subset of the NHIRD, comprising data on one million insurants who were randomly selected from the original registry of insurants in 2000. The Longitudinal Health Insurance Database 2000 contains all medical records from 1996-2010, and the diseases were defined based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We collected data on 1353 children (aged 1 month to 5 years) with newly diagnosed febrile seizures (ICD-9-CM 180.3) during the 20002005 period. We excluded data for 362 cases of children with epilepsy or recurrent seizures, myoclonus, seizures in newborn infants, or children with a history of asthma. The febrile seizure cohort comprised data on 991 children, and the date of febrile seizure diagnosis was set as the index date. Control patients were selected from children who were not diagnosed with febrile seizure before 5 years of age, and they were frequency matched at a 4:1 ratio based on age, sex, urbanization level, and their parents’ occupations. The urbanization levels were categorized from Level 1 (highest level of urbanization) to Level 5 (lowest level of urbanization).23 The follow-up period for all patients was from the index date to either the date of asthma diagnosis (ICD-9-CM 493) or the end of 2010. The differences in demographics and comorbidities between the 2 groups were analyzed using the chi-square test for categorical variables and the t test for continuous variables. The comorbidities analyzed were allergic conjunctivitis (ICD-9-CM 372.05, 372.10, and 372.14), allergic rhinitis (ICD-9-CM 477), and atopic dermatitis (ICD9-CM 691.8), all of
TABLE 1. Demographics of Children with and Without Febrile Seizures
Variable
Age 1 mo-2 years 2.1-5 years Mean (SD) Sex Boy Girl Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation White collar Blue collar Others Comorbidity Allergic conjunctivitis Allergic rhinitis Atopic dermatitis Abbreviation: SD ¼ Standard deviation Chi-square test and t test.
Febrile Seizures
P Value
Yes (N ¼ 991)
No (N ¼ 3964)
n
n
%
% >0.99
476 48.0 1904 48.0 515 52.0 2060 52.0 2.30 (1.20) 2.33 (1.19) 563 428
56.8 43.2
2252 1712
56.8 43.2
255 282 203 149 102
25.7 28.5 20.5 15.0 10.3
1020 1128 812 596 408
25.7 28.5 20.5 15.0 10.3
588 268 135
59.3 27.0 13.6
2352 1072 540
59.3 27.0 13.6
66 109 26
6.86 11.0 2.62
171 288 76
0.55 >0.99
>0.99
>0.99
4.31 7.27 1.92
0.002 0.0001 0.16
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
797
TABLE 2. The Risk of Asthma Compared With Children Without Febrile Seizures Stratified by Demographics in Cox Proportional Hazard Regression
Variable
Febrile Seizures
Control Patients
HR (95% CI)
Event Number
Person-years
IR
Event Number
Person-years
IR
All Age 1 mo-2 years 2.1-5 years Sex Boy Girl Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation White collar Blue collar Others
216
7548
28.62
623
31845
19.56
1.41 (1.21-1.65)z
120 96
3709 3839
32.35 25.01
363 260
15607 16238
23.26 16.01
1.34 (1.09-1.64)y 1.50 (1.18-1.89)z
128 88
4241 3307
30.18 26.61
379 244
17852 13993
21.23 17.44
1.40 (1.14-1.71)y 1.44 (1.12-1.84)y
58 60 47 33 18
1916 2154 1535 1113 830
30.27 27.86 30.62 29.66 21.69
169 187 115 91 61
8082 984 6546 4791 3342
20.91 20.59 17.57 19.00 18.25
1.39 1.30 1.67 1.46 1.19
134 55 27
4445 2048 1055
30.14 26.86 25.60
394 158 71
18673 8831 4341
21.10 17.89 16.36
1.37 (1.12-1.67)y 1.48 (1.09-2.02)* 1.49 (0.95-2.34)
(1.03-1.88)* (0.97-1.74) (1.19-2.35)y (0.98-2.18) (0.70-2.01)
Abbreviations: CI ¼ Confidence interval HR ¼ Hazard ratio IR ¼ Incidence rate per 1000 person-years Model adjusted for allergic rhinitis. * P < 0.05. y P < 0.01. z P < 0.001.
those with parents who worked in white collar occupations. The incidence of asthma increased in conjunction with the level of urbanization (Table 2). The overall risk of asthma in the febrile seizure group was 41% higher than that in the control group (95% confidence interval, 1.21-1.65). Moreover, the risk of asthma incidence in the febrile seizure
group was 40% higher than that in the control group, regardless of sex. In addition, the risk of asthma incidence was higher in the febrile seizure group, regardless of whether the children’s parents worked in white or blue collar occupations. Table 3 lists the association between asthma and the frequency of febrile seizure-related medical visits within the year following the index date. The frequency strata were divided according to the median and the highest 25% of frequency. In comparison with the control group, the risk of asthma in the febrile seizure group increased from 0.96 to 3.62, 1.19 to 2.41, and 0.82 to 4.72 when the frequency of febrile seizure-related medical visits increased from 1 to 2 visits to 4 visits in all groups, girls, and boys, respectively (trend P < 0.0001). Discussion
FIGURE. The Kaplan-Meier estimated cumulative incidence of asthma.
An increased association of asthma (1.41-fold risk) was observed among the children with febrile seizures, with a significantly higher risk among children who were 0.52.0 years old, boys, those living in areas with the highest level of urbanization, and those with parents working in white collar occupations. Regardless of sex, the risk of asthma increased exponentially with the frequency of febrile seizure-related medical visits (up to 3.62 in children with more than four febrile seizure-related visits). In addition, compared with the control group, the children with febrile seizures exhibited a stronger association with other atopic comorbidities, including allergic conjunctivitis (6.86% vs 4.31%, P ¼ 0.002) and allergic rhinitis (11.00% vs 7.27%, P ¼ 0.0001). Previous studies have reported increased levels of proinflammatory cytokines, with particular emphasis on an
798
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
TABLE 3. The Risk of Asthma Among Frequency for Medical Visits of Febrile Seizures in Cox Proportional Hazard Regression
Frequency of Medical Visit for Febrile Seizures Within 1 Year
All
Girl
Boy
Event Number
IR
HR (95% CI)
Event Number
IR
HR (95% CI)
Event Number
IR
HR (95% CI)
None 1-2 3 4 P for trend
623 112 35 69
19.56 19.19 43.12 76.59
1.00 0.96 (0.79-1.18) 1.99 (1.41-2.79)y 3.62 (2.82-4.65)y
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Risk of Subsequent Asthma in Children With Febrile Seizures: A Nationwide Population-Based Retrospective Cohort Study Wen-Ya Lin MD a, Chih-Hsin Muo MSc b, c, Yi-Chia Ku MD a, Fung-Chang Sung PhD d, Chia-Hung Kao MD d, e, * a
Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan c College of Medicine, China Medical University, Taichung, Taiwan d Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b
abstract BACKGROUND: No study has reported a relationship between febrile seizures and asthma; thus, we examined the association between these two disorders. METHODS: We identified 991 cases of children with febrile seizures as the case cohort, and the control group was matched according to age, sex, urbanization level, and their parents’ occupation at a 1:4 ratio. We applied the Cox proportional hazards regression model to estimate the hazard ratios and 95% confidence intervals for asthma among the children with febrile seizures. RESULTS: After 11 years of followup, the asthma incidence in the febrile seizure group was approximately 5% higher than that in the control group (log-rank test, P < 0.0001). The risk of asthma in the febrile seizure group was 1.41 times higher than that in the control group (95% confidence interval, 1.21-1.65; P < 0.001). Furthermore, the risk of asthma development increased (0.96 vs 3.62) in conjunction with the frequency of febrile seizure-related medical visits (one to two visits vs more than four visits; P < 0.0001). CONCLUSION: Febrile seizures may be associated with an increase in the risk of future asthma occurrence in children. We observed a significantly higher cumulative incidence of asthma occurrence in children with more febrile seizure-related medical visits. Keywords: febrile seizure, asthma, nationwide population-based, cohort study
Pediatr Neurol 2014; 51: 795-799 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Febrile seizures are the most common type of seizure in humans.1 Febrile seizures occur in 2-5% of children. They W.-Y.L., Y.-C.K., C.-H.K. are responsible for the study design, coordination, and drafted the article. C.-H.M., F.-C.S. collected data and performed analysis. W.-Y.L., C.H.M., C.-H.K. provided some intellectual recommendation and reviewed the article. All authors wrote and approved the final version of the article.
Article History: Received May 3, 2014; Accepted in final form June 26, 2014 * Communications should be addressed to: Dr. Kao; Graduate Institute of Clinical Medical Science and School of Medicine; College of Medicine; China Medical University; No 2; Yuh-Der Road; Taichung 404, Taiwan. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.06.017
typically affect children aged 2 months to 5 years, and the incidence is identical in boys and girls.2 Proinflammatory cytokines, including interleukin (IL)1b, IL-6, and tumor necrosis factor (TNF)-a, cause fever during infection. These cytokines not only play a role in activating an immune response after infection, but they also serve neuromodulatory functions and contribute to aberrant neuronal excitability underlying seizure disorders.3 Numerous previous studies have reported an increased level of proinflammatory cytokines (including IL-1b and IL6) in children with febrile seizures.2,4-10 Specific viral infections have also been associated with febrile seizures, including human herpes virus (HHV)-6, influenza, adenovirus, respiratory syncytial virus (RSV), herpes simplex virus
796
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
What is new in this subject (1) Febrile seizures are associated with an increased risk of future asthma in children. (2) Cumulative incidence of asthma is significantly higher in children with more febrile seizure-related medical visits.
(HSV)-1, and cytomegalovirus.11 These fever-related inflammatory cytokines and specific viral infections have been postulated to contribute to the pathogenesis of febrile seizures. Previous studies have reported an increasing incidence of atopic diseases such as asthma, particularly among children.12,13 Researchers have focused on identifying multiple risk factors that cause the development of atopic diseases. Certain studies have reported elevated IL-6 and IL-1b levels in patients with asthma,14-16 as well as increased expression of IL-1b on the asthmatic bronchial epithelium,17,18 indicating that these cytokines might be involved in mediating both the proinflammatory processes and airway hyperresponsiveness that underlie asthmatic diseases. Several studies have reported that RSV and HSV-1 infection have an increased association with subsequent asthma development.19-21 Both febrile seizures and asthma are common disorders among children, and they share a similar association with certain viral infections and proinflammatory cytokines. Thus, the objective of this study was to determine whether an increased risk of asthma exists among children with febrile seizures.
which were defined before the index date. Person-years were counted from the index date to asthma development, and the incidence of asthma per 1000 person-years was also calculated for both groups. The hazard ratio for asthma was assessed in comparison with the control group, and after controlling for comorbidity in the adjusted model, we observed statistically significant differences in comparison with the univariate model. We also estimated the association between asthma and the frequency of febrile seizure-related medical visits within the year after the index date. We used the Kaplan-Meier estimator to plot the proportion asthma free, and the log-rank test was used to test the differences between the two groups. All statistical analyses were performed using SAS 9.2 for Windows (SAS Institute, Cary, NC). All tests were two-tailed, and the level of statistical significance was set at 0.05.
Results
The febrile seizure and control groups comprised 991 and 3964 children, respectively. The mean age of the children with febrile seizures was 2.3 years (standard deviation, 1.20). Most of the children with febrile seizures were boys (56.8%), lived in urban areas (74.7% vs 25.3%), and had parents who worked in white collar positions (59.3% vs 40.7%). Compared with the control group, the children with febrile seizures exhibited a significantly higher frequency of comorbid conditions, including allergic conjunctivitis (P ¼ 0.002) and allergic rhinitis (P ¼ 0.0001; Table 1). The incidence of asthma for the febrile seizure and control groups was 28.62 and 19.56 per 1000 person-years, respectively (Table 2). After 11 years of follow-up, the proportion of asthma-free patients in the febrile seizure group was approximately 5% lower than that in the control group (log-rank, P < 0.0001, Figure). The incidence of asthma in the febrile seizure group was higher among children aged 0.5 to 2.0 years (compared with those >2 years), boys, and
Method and Materials The Taiwan National Health Insurance program is a unique program that was established by the Bureau of National Health Insurance on March 1, 1995. The program provides health insurance coverage for approximately 99% of the population of Taiwan.22 The National Health Research Institutes maintains the National Health Insurance Research Database (NHIRD) of medical claims data. We obtained data from the Longitudinal Health Insurance Database 2000, a subset of the NHIRD, comprising data on one million insurants who were randomly selected from the original registry of insurants in 2000. The Longitudinal Health Insurance Database 2000 contains all medical records from 1996-2010, and the diseases were defined based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We collected data on 1353 children (aged 1 month to 5 years) with newly diagnosed febrile seizures (ICD-9-CM 180.3) during the 20002005 period. We excluded data for 362 cases of children with epilepsy or recurrent seizures, myoclonus, seizures in newborn infants, or children with a history of asthma. The febrile seizure cohort comprised data on 991 children, and the date of febrile seizure diagnosis was set as the index date. Control patients were selected from children who were not diagnosed with febrile seizure before 5 years of age, and they were frequency matched at a 4:1 ratio based on age, sex, urbanization level, and their parents’ occupations. The urbanization levels were categorized from Level 1 (highest level of urbanization) to Level 5 (lowest level of urbanization).23 The follow-up period for all patients was from the index date to either the date of asthma diagnosis (ICD-9-CM 493) or the end of 2010. The differences in demographics and comorbidities between the 2 groups were analyzed using the chi-square test for categorical variables and the t test for continuous variables. The comorbidities analyzed were allergic conjunctivitis (ICD-9-CM 372.05, 372.10, and 372.14), allergic rhinitis (ICD-9-CM 477), and atopic dermatitis (ICD9-CM 691.8), all of
TABLE 1. Demographics of Children with and Without Febrile Seizures
Variable
Age 1 mo-2 years 2.1-5 years Mean (SD) Sex Boy Girl Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation White collar Blue collar Others Comorbidity Allergic conjunctivitis Allergic rhinitis Atopic dermatitis Abbreviation: SD ¼ Standard deviation Chi-square test and t test.
Febrile Seizures
P Value
Yes (N ¼ 991)
No (N ¼ 3964)
n
n
%
% >0.99
476 48.0 1904 48.0 515 52.0 2060 52.0 2.30 (1.20) 2.33 (1.19) 563 428
56.8 43.2
2252 1712
56.8 43.2
255 282 203 149 102
25.7 28.5 20.5 15.0 10.3
1020 1128 812 596 408
25.7 28.5 20.5 15.0 10.3
588 268 135
59.3 27.0 13.6
2352 1072 540
59.3 27.0 13.6
66 109 26
6.86 11.0 2.62
171 288 76
0.55 >0.99
>0.99
>0.99
4.31 7.27 1.92
0.002 0.0001 0.16
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
797
TABLE 2. The Risk of Asthma Compared With Children Without Febrile Seizures Stratified by Demographics in Cox Proportional Hazard Regression
Variable
Febrile Seizures
Control Patients
HR (95% CI)
Event Number
Person-years
IR
Event Number
Person-years
IR
All Age 1 mo-2 years 2.1-5 years Sex Boy Girl Urbanization 1 (highest) 2 3 4 5 (lowest) Occupation White collar Blue collar Others
216
7548
28.62
623
31845
19.56
1.41 (1.21-1.65)z
120 96
3709 3839
32.35 25.01
363 260
15607 16238
23.26 16.01
1.34 (1.09-1.64)y 1.50 (1.18-1.89)z
128 88
4241 3307
30.18 26.61
379 244
17852 13993
21.23 17.44
1.40 (1.14-1.71)y 1.44 (1.12-1.84)y
58 60 47 33 18
1916 2154 1535 1113 830
30.27 27.86 30.62 29.66 21.69
169 187 115 91 61
8082 984 6546 4791 3342
20.91 20.59 17.57 19.00 18.25
1.39 1.30 1.67 1.46 1.19
134 55 27
4445 2048 1055
30.14 26.86 25.60
394 158 71
18673 8831 4341
21.10 17.89 16.36
1.37 (1.12-1.67)y 1.48 (1.09-2.02)* 1.49 (0.95-2.34)
(1.03-1.88)* (0.97-1.74) (1.19-2.35)y (0.98-2.18) (0.70-2.01)
Abbreviations: CI ¼ Confidence interval HR ¼ Hazard ratio IR ¼ Incidence rate per 1000 person-years Model adjusted for allergic rhinitis. * P < 0.05. y P < 0.01. z P < 0.001.
those with parents who worked in white collar occupations. The incidence of asthma increased in conjunction with the level of urbanization (Table 2). The overall risk of asthma in the febrile seizure group was 41% higher than that in the control group (95% confidence interval, 1.21-1.65). Moreover, the risk of asthma incidence in the febrile seizure
group was 40% higher than that in the control group, regardless of sex. In addition, the risk of asthma incidence was higher in the febrile seizure group, regardless of whether the children’s parents worked in white or blue collar occupations. Table 3 lists the association between asthma and the frequency of febrile seizure-related medical visits within the year following the index date. The frequency strata were divided according to the median and the highest 25% of frequency. In comparison with the control group, the risk of asthma in the febrile seizure group increased from 0.96 to 3.62, 1.19 to 2.41, and 0.82 to 4.72 when the frequency of febrile seizure-related medical visits increased from 1 to 2 visits to 4 visits in all groups, girls, and boys, respectively (trend P < 0.0001). Discussion
FIGURE. The Kaplan-Meier estimated cumulative incidence of asthma.
An increased association of asthma (1.41-fold risk) was observed among the children with febrile seizures, with a significantly higher risk among children who were 0.52.0 years old, boys, those living in areas with the highest level of urbanization, and those with parents working in white collar occupations. Regardless of sex, the risk of asthma increased exponentially with the frequency of febrile seizure-related medical visits (up to 3.62 in children with more than four febrile seizure-related visits). In addition, compared with the control group, the children with febrile seizures exhibited a stronger association with other atopic comorbidities, including allergic conjunctivitis (6.86% vs 4.31%, P ¼ 0.002) and allergic rhinitis (11.00% vs 7.27%, P ¼ 0.0001). Previous studies have reported increased levels of proinflammatory cytokines, with particular emphasis on an
798
W.-Y. Lin et al. / Pediatric Neurology 51 (2014) 795e799
TABLE 3. The Risk of Asthma Among Frequency for Medical Visits of Febrile Seizures in Cox Proportional Hazard Regression
Frequency of Medical Visit for Febrile Seizures Within 1 Year
All
Girl
Boy
Event Number
IR
HR (95% CI)
Event Number
IR
HR (95% CI)
Event Number
IR
HR (95% CI)
None 1-2 3 4 P for trend
623 112 35 69
19.56 19.19 43.12 76.59
1.00 0.96 (0.79-1.18) 1.99 (1.41-2.79)y 3.62 (2.82-4.65)y
