Increased Association Between Febrile Convulsion and
Allergic
Rhinitis in Children: A Nationwide Population-Based
Retrospective Cohort Study
Wen-Ya Lin MD
a, Chih-Hsin Muo MS
b, Yi-Chia Ku MD
a, Fung-Chang Sung PhD
c,
Chia-Hung Kao MD
c,d,*Introduction
Febrile convulsions (FC) are caused by fever and considered to be the most common form of seizures in humans.1 FC are exclusively limited to children, occurring in
2% to 5% of children, ages between 2 months and 5 years, and with equal incidence between boys and girls.2
Fever is induced by proinfammatory cytokines including interleukin (IL)-1
b
, IL-6, and tumor necrosis factor (TNF)-a
during infections. In addition to their involvement in activating an immune response after infection, these
proinfammatory cytokines also serve neuromodulatory functions and contribute to aberrant neuronal excitability underlying seizures.3 Various articles have also reported an
increased level of proinfammatory cytokines, including IL-1
b
and IL-6 in children with FC.2,4-10 Specifc viralinfections have also been associated with FC including those of human herpesvirus (HHV)-6, infuenza, adenovirus, respiratory syncytial virus, herpes simplex virus-1 (HSV-1) and cytomegalovirus.11 Thus, the generation of feverrelated
infammatory cytokines and association with specifc viral infections have been postulated to contribute to FC pathogenesis.
Increasing incidence of atopic diseases including allergic rhinitis has been reported over the past several decades, particularly among children, for largely unknown
reasons.12,13 Particular focus has been on identifying multiple
risk factors for development and progression of atopic diseases. Certain studies have demonstrated increased production of IL-1, TNF-
a
, and IL-6 in allergic rhinitis, with these proinfammatory cytokines contributing to the acutephase response of infammatory and immune diseases.14-17With specifc regard to allergic rhinitis and atopy, increased association with specifc viral infections including HSV-I, rhinovirus, hepatitis B, and cytomegalovirus have also been reported.18-21 FC and allergic rhinitis are both common
disorders among children, and according to previous literature, seem to share similar association with certain viral
infections and proinfammatory cytokines. Thus this study seeks to determine if there is indeed an association between children with FC and allergic rhinitis.
Materials and Methods
Data source
The Taiwan National Health Insurance program was established on March 1,1995, by the Bureau ofNationalHealth Insurance.More than 99% of the Taiwanese population is enrolled into this program at this time. The NationalHealthResearch Instituteswas commissioned to constructNational Health Insurance Research Databases (NHIRDs) for research proposals. The identifcation codes of benefciaries were scrambled by a computer. In this study, we used the Longitudinal Health Insurance Database, which is a subdataset of NHIRDs and contains 1 million benefciaries randomly selected from those enrolled in the insurance program in 2000. The Longitudinal Health Insurance Database contained insurant information, outpatient and inpatient visits, and medical treatment records
between January 1, 1996, and December 31, 2010. To defne disease in the Longitudinal Health Insurance Database, the International Classifcation of Disease, 9th Revision, Clinical Modifcation (ICD-9-CM), codes were used. Based on the Personal Information Protection Act, this studywas approved by the Institutional Review Board of the China Medical University. Study subjects
A total of 1304 children with FC (ICD-9-CM 780.3) at 0.5 to 5 years old were collected in this study and the date of diagnosed seizures was set as entry date. We excluded 388 children with epilepsy and recurrent seizures (ICD-9-CM 209), myoclonus (ICD-9 code 333.2), convulsions in newborns (ICD-9 code 779.0), or allergic rhinitis (ICD-9-CM 477) history before the entry date. To minimize the infuence of possible “reverse causation” owing to the allergic rhinitis before FC, we excluded those children with diagnosis of allergic rhinitis before the diagnosis of FC. Controlswere selected from 0.5- to 5-year-old children without FC history in a 4 to 1 ratio. The control group was frequency-matched with age, sex,
urbanization level, parent’s occupation, and entry-year as the case group. The exclusion criteria in control group were the same as with the case group. All study subjects were followed from the entry date to the frst event, which was occurrence of allergic rhinitis up to the end of 2010. Statistical analysis
All statistical analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC) and the signifcance level was set at a two-sided P value of less than 0.05. To test the differences of categorical and continuous variables between the two groups, chi-square and t tests were used. The categorical variables included sex, urbanization level, parents’ occupation, and comorbidities. The urbanization levels were grouped into seven levels based on Liu’s report.22 Because there were few people at urbanization levels 6 and 7, these were combined into level 5. Level 1 was the highest urbanized and the level 5 was the lowest. Parents’ occupations were grouped into white, blue collar, and others. “Others” included retained, low income, clergy, and so forth. Comorbidities included diseases such as allergic conjunctivitis (ICD-9-CM 372.05, 372.10 and 372.14), asthma (ICD-9-(ICD-9-CM 493), and atopic dermatitis (ICD-9-CM 691.8) and were defned before the entry date. The incidence of allergic rhinitis was calculated as occurrence of allergic rhinitis divided by 1000 person-years during the study period. Cox proportional hazard regression was used to estimate the risk of FC-associated allergic rhinitis after controlling allergic conjunctivitis and asthma, which showed signifcant difference between the two groups. We also assessed the association between the frequency for FC-related medical visits per year and allergic rhinitis incidence. The frequency of medical visits was stratifed by frst quartile. Kaplan-Meier analysis was used to plot the cumulative incidence and log-rank analysis was used to test the difference of cumulative incidence between two groups. Results
A total of 4580 children were selected in this cohort study: 916 and 3664 children as the FC case and control groups, respectively. The mean age in FC case group was 2.35 years of age (standard deviation ? 1.13). Children in the FC case group were predominantly girls, lived in higher
urbanized areas, and the parents’ occupation was predominantly white collar. Compared with controls, FC patients
allergic conjunctivitis and asthma (P < 0.05, Table 1). During the average 6.7 year follow-upperiod, the incidence of allergic rhinitis in the FC case group was higher (65.16 vs 51.45 per 1000 person-years, Table 2). After 11 years of followup, the allergic rhinitis incidence in patientswas approximate
4% higher than in controls (log-rank test P < 0.0001, Figure). The risk was 1.21-fold in the case group compared with the control group in the adjusted Cox proportional hazardmodel. The risk of younger children (0.5 to 2 years old) of developing allergic rhinitiswashigher thanthosewhowere older (2.1 to 5 years old) (57.08 vs 51.25 per 1000 person-years). Age-specifc risk in patients was approximately 20% signifcantly higher than controls. Boys were more prone to developing allergic rhinitis than girls (60.59 vs 45.55 per 1000 person-years). Children who lived in urbanized areas and children of parents with a white collar occupation had the highest allergic
rhinitis incidence. In addition, compared with controls, patientswith FS had a signifcantly higher risk of allergic rhinitis
if they had parents with white collar jobs.
Table 3 shows the association between the frequency for
annual medical visits for FC and allergic rhinitis. Compared with controls, the risk increased by frequency from 0.94 (one to three FC-related visits) to 18.9 (more than three FC-related visits) (P < 0.0001). The risk trend for both female and male is identical. Discussion
This study found an increased association of allergic rhinitis (1.21-fold risk) among children with FC, with the risk to be signifcantly higher in children from 0.5 to 2 years of age, of male sex, in the highest urbanization, and with parents with a white collar occupation. Irrespective of sex, risk of allergic rhinitis was found to increase exponentially with frequency of FC-related medical visits, with risk reaching as high as 18.9 in children with more than three medical visits. In addition, children with FC had a higher association with other atopic comorbidities, including
asthma (8.08% vs 5.62%, P ? 0.006) and allergic conjunctivitis (6.99% vs 4.39%, P ? 0.001).
accuracy of the data collected, only children with diagnostic codes (including allergic rhinitis) appearing on at least three medical visits were recruited.
Mechanisms of viral infections in FS are multifaceted including fever itself, height of fever exceeding individual threshold of convulsive temperature, elevated cytokine response to infection, and the neurotropic nature of specifc viruses.23 Infection and fever cause increased levels of
proinfammatory cytokines in the periphery and the brain, thus precipitating seizure events.3 The study by Choi et al. has
demonstrated higher serum levels of high mobility group box-1, IL-6, and IL-1
b
in FS patients thaninfever-onlycontrols (P<0.05), thus suggesting causative role of proinfammatory cytokine network in FC generation.4 In another study ofdouble-stranded RNA-stimulated leukocytes in FS by Matsuo et al.,5 greater numbers of IL-6 and IL-10 were found in
FC patients than in control after 24 hours of lipopolysaccharide stimulation. In addition, increased IL-1
b
production from double-stranded RNA-stimulated leukocytes in childrenwithFC was also found.5 Potential mechanisms of these proinfammatory
cytokines, especially IL-1
b
, involve both excitatory (glutamatergic) and inhibitory (GABAergic) systems.IL-1
b
has been shownto alter N-methyl-D-aspartate receptor phosphorylation, thus increasing excitatory neurotransmissionwith resultant seizure.2,24,25 There is also evidence that
IL-1
b
can affect GABAergic inhibition.2,26,27 Similar proinfammatorycytokineprofles have also beenfound inpatients
with allergic rhinitis.15-18 Allergic response is composed of
both early and late reactions. The early reaction is mediated by mast cells and the release of preformed biochemical mediators (histamine, tryptase) and other rapidly generated
mediators of infammation (leukotrienes, prostaglandins).
The late reaction involves the production of newly synthesizedmast cellmediators and activation of infammatorycells
such as T-helper cells, eosinophils, basophils, and others. Accompanying this late reaction is the release of multiple cytokines including IL-1
b
, IL-5, IL-6, IL-8, TNF-a
, andin the study by Bensch et al. inwhich signifcantly increased peak levels of TNF-
a
, IL4, IL-10, and macrophageinfammatory protein-1
a
have been found after allergen challenge.16 This similarity in the cytokine profle between FCand allergic rhinitis could explain increased risk association between the two disorders found in this study.
Both FC and allergic rhinitis have also been reported with specifc viral infections. In an Italian series by Bertolani et al. in children with mean age of 18 months, the incidence of viral infection in FS was HHV-6 (35%), adenovirus (13.8%),
respiratory syncytial virus (10.7%), HSV-1 (9.2%), cytomegalovirus (3%), and HHV-7 (2.3%).11 Review of HHV-6 infection
and febrile seizures has shown varied results, with
literature review demonstrating variability from 8% to 100% occurrence of seizure in HHV-6einfected children.23 This
demonstrates that the virus is not the only etiological factor. Fever associated with HHV-6 was found to be higher in those with seizures (39.93_C vs 39.68_C, P ? 0.048) in study
by Jee et al.,28 and because fevers are regulated by proinfammatory
cytokines released during viral infection, this
again emphasizes the link between viral infection, fever, and FC. Viral disease during childhood and adolescence contributes to the development of allergic rhinitis, with increased rates of sensitization to aeroallergens (odds ratio 1.394, 95% confdence interval 1.128-1.723, P ? 0.0021).29
Studies have also demonstrated association between HSV-1 infection and atopy,30,31 with signifcantly higher
HSV-1 IgG seropositivity found in atopic children (56.8%) with allergic rhinitis and asthma than in age-matched nonatopic children (30.4%) (P < 0.001).18
Limitations
The strengths of our study include its use of populationbased data that are highly representative of the general
population. However, certain limitations to our fndings should be considered. First, the NHIRD does not contain detailed information regarding socioeconomic status and family history of systemic diseases, all of which may be risk factors for FC or allergic rhinitis. Second, the evidence
derived froma retrospective cohort study is generally lower in statistical quality than that from randomized trials
because of potential biases related to adjustments for confounding variables. Despite our meticulous study design
and control measures for confounding factors, bias resulting
from unknown confounders may 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 regarding our study patients. However, the data
regarding the diagnoses of febrile convulsion or allergic rhinitis were nonetheless reliable.
Conclusion
Findings in this study included increased association of allergic rhinitis in children with FC, with exponentially
increasing allergic rhinitis risk in children with multiple FCrelated medical visits. The seizure pathogenesis in FC and
immune mechanisms in allergic rhinitis is extremely
complicated, and etiology of both disorders is multifactorial, but there may be a yet-unidentifed common link. This study has demonstrated a signifcant association in children with FC and allergic rhinitis; possible mechanisms postulated include exposure to specifc viral infections and the
sharing of similar proinfammatory cytokine profles. Yet
much work is still needed to fully explain the exact mechanisms and associations between these two disorders.
