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,*Introduction
Febrile seizures are the most common type of seizure in humans.
1Febrile seizures occur in 2-5% of children. They typically affect children aged 2 months to 5 years, and the incidence is identical in boys and girls.
2Proinfammatory cytokines, including interleukin (IL)- 1 b , 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.
3Numerous previous studies have reported an increased level of proinfammatory cytokines (including IL-1 b and IL- 6) in children with febrile seizures.
2,4-10Specifc viral infections have also been associated with febrile seizures,
including human herpes virus (HHV)-6, infuenza, adenovirus,
respiratory syncytial virus (RSV), herpes simplex virus (HSV)-1, and cytomegalovirus.
11These fever-related infammatory
cytokines and specifc 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-1 b levels in patients with asthma,
14-16as well as increased expression of IL-1 b on the asthmatic bronchial epithelium,
17,18indicating that these cytokines might be involved in mediating
both the proinfammatory 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 proinfammatory
cytokines. Thus, the objective of this study was to determine whether an increased risk of asthma exists among
children with febrile seizures.
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 defned based on the International Classifcation of Diseases, Ninth Revision, Clinical Modifcation (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 2000- 2005 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 which were defned 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 signifcant 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 signifcance 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 seizureswas 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 signifcantly higher frequency of comorbid conditions, including allergic conjunctivitis
(P ? 0.002) and allergic rhinitis (P ? 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 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% confdence 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
An increased association of asthma (1.41-fold risk) was observed among the children with febrile seizures, with a signifcantly higher risk among children who were 0.5- 2.0 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 ? 0.002) and allergic rhinitis (11.00% vs 7.27%, P ? 0.0001).
Previous studies have reported increased levels of
proinfammatory cytokines, with particular emphasis on an enhanced IL-1 b response, in children with febrile seizures.
2This polypeptide is produced by peripheral blood monocytes,
central nervous system astrocytes, and glial cells.
7IL-
1 b is thought to contribute to febrile seizures by increasing glutamatergic neurotransmission and lowering the peak magnitude of gamma aminobutyric acid mediated currents.
4
Increased IL-1 b levels have been characterized to be related to the occurrence and increased duration of febrile seizures.
4,9Several studies have revealed elevated levels of other proinfammatory cytokines, such as IL-6 and TNF- a , in patients with febrile seizures.
4-9Similar cytokine profles have also been observed in patients with asthma.
An allergic reaction consists of early and late phases.
During the late phase, newly synthesized mast cell mediators are produced and infammatory cells, such as T-helper cells, eosinophils, and basophils, are activated. This is accompanied by the release of multiple cytokines, including IL-1 b , IL-5, IL-6, IL-8, TNF- a , and macrophage infammatory protein-1 a .
24,25A previous study revealed an increased expression of IL-1 b in the asthmatic bronchial epithelium (P < 0.0002).
18This exerts a proinfammatory effect, and researchers have asserted that it contributes to the airway hyper-responsiveness that underlies asthmatic bronchitis.
17IL-6 expression was also determined to be signifcantly higher in asthmatic patients (P < 0.01).
14Cytokine levels are particularly elevated following allergen inhalation, which has been associated with clinical asthma exacerbation.
16The similar cytokine profles of febrile seizures and
asthma can explain the increased risk association between the two disorders that was observed in this study.
Specifc viral infections have also been implicated in both febrile seizures and asthma. In a series of studies on Italian children with febrile seizures (mean age, 18 months), Bertolani et al.
11reported that febrile seizures coincided with
HHV-6 (35%), adenovirus (13.8%), RSV (10.7%), HSV-1 (9.2%),
cytomegalovirus (3%), and HHV-7 (2.3%) infections. The
contribution of viral infection to the febrile seizure etiology
can be explained by the fever, the height of the threshold
temperature for febrile seizures, and the elevated cytokine
response to infection.
26Viral infection has been associated
with an increased rate of sensitization to aeroallergens and
subsequent atopic disease development. Moreover, lower respiratory tract infection coinciding with RSV or other viruses can alter normal lung development, thereby causing a predisposition to asthma development in later life.
27Several studies have associated RSV bronchiolitis infection during infancy with a high risk of subsequent asthma development and sensitization for common allergens up to 7.5 years of age.
19,20The prevalence of HSV-1 IgG seropositivity is also signifcantly higher in atopic children (56.8%)
with allergic rhinitis and asthma than in age-matched nonatopic children (30.4%; P < 0.001).
21Research limitations
A strength of our study is the analysis of populationbased data that are highly representative of the general
population. However, certain limitations require consideration.
First, the NHIRD does not contain detailed information on the socioeconomic status and family history of
patients with systemic diseases, all of which might be risk factors for febrile seizures or asthma. Second, compared with randomized trials, the evidence derived from a retrospective cohort study is generally lower in statistical quality because of potential biases related to adjustments for confounding variables. In spite of our meticulous study design and control measures for confounding factors, bias resulting from unknown confounders might have affected our results. Third, all data in the NHIRD are anonymous.
Thus, relevant clinical variables, such as blood pressure, imaging results, pathology fndings, and serum laboratory data were unavailable. However, the data on the diagnosis of febrile seizures or allergic rhinitis were nonetheless reliable.
Conclusion
