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Seasonal distribution of febrile seizure and the relationship with respiratory and enteric viruses in Korean children based on nationwide registry data

Highlights • Febrile seizures were reported to be associated with seasonal viral epidemics.• The seasonal distribution of febrile seizures was high from late spring to summer.• Influenza virus and enterovirus was most frequently associated with febrile seizure.


Introduction
Febrile seizure is a benign convulsive disorder that affects 2-8% of children between the ages of 6 months and 5 years [1,2] This disease is preceded by or accompanied with fever in the absence of other causes, such as central nervous system infection or metabolic disease [3]. The etiology of febrile seizures remains unclear, although fever, age, and genetic predisposition have been identified as major factors. In addition, multifactorial models based on genetic and environmental causes have been proposed recently [4]. Pediatric infectious diseases are the most frequent environmental causes, of which viral infections are the most frequent entities in children. Recent studies have explored the connections between febrile seizures and respiratory and enteric viral infections [5,6].
Some studies have investigated the seasonal distribution of febrile seizures. In those studies, febrile seizures were reported to be associated with seasonal viral epidemics, and the two events exhibited similar trends [7][8][9][10][11]. However, those studies were mostly conducted at single institutions with small numbers of patients, and no studies have been based on data from an entire population. In South Korea, the National Health Insurance (NHI) covers approximately 98% of the national population. Moreover, the Korean Health Insurance Review and Assessment Service (HIRA) claims that their data includes 46 million patients each year. [12]. This study aimed to investigate seasonal trends in febrile seizures in a nationwide sample of South Korean children and to analyze the relationship between febrile seizures and commonly associated respiratory and enteral viral infections.

Materials and methods
2.1. Big data from the Korean Health Insurance Review and Assessment Service (HIRA) database South Korea [13]. This program covers almost 98% of the health insurance administered to South Koreans [12,14]. Big data from HIRA includes information for most of the population of South Korea and are provided to researchers for academic purposes, using a strict screening process. All data provided to researchers are anonymized. This study was approved by the Institutional Review Board of Chung-Ang University Hospital (IRB no.: 1710-005-16112). Informed consent from each patient was not required because of the anonymized nature of the information extracted from the HIRA database.

Study population
The study population included patients who were diagnosed with febrile seizure and included in the HIRA database from 2008 to 2016. Our initial request for data did not include children aged ≥6 years, according to the diagnostic criteria of febrile seizures. The diagnoses were coded using the 5th, 6th and 7th Korean Classifications of Diseases (KCD-5 from 2008 to 2010; KCD-6 from 2011 to 2015; and KCD-7 in 2016). KCD-5, KCD-6, and KCD-7 are classification systems modified from the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). We extracted medical records coded with a main or sub-diagnosis of febrile seizure (KCD-5, KCD-6, and KCD-7 code R560). A total of 666,136 records were selected from 2008 to 2016. Medical records in the HIRA database are classified by ages of < 1 month, 1 month to 1 year, and ≥1 year. We excluded records with ages of < 1 month according to the definition of febrile seizure [15]. We also excluded records from 2008, which was the first year in which the HIRA database was compiled. A total of 108,006 records were excluded. Finally, a total of 558,130 medical records with a diagnosis of febrile seizure were selected for this study.
Among the cases diagnosed with a febrile seizure, 472,482 included additional diagnostic codes along with febrile seizure, and 32,337 records were related to specific viral infections.

Data and statistical analysis
The data analysis was performed using SAS Enterprise version 9.2 (SAS Institute, Cary, NC, USA) and the HIRA database system via remote access. The statistical analysis was performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). The mean age and mean values in medical records were estimated using the t-test. We used a Pearson correlation analysis to determine the correlations of febrile seizure with viral infection. A two-tailed P value of < 0.05 was considered significant.

Characteristics of febrile seizure medical records
A total of 558,130 records with a diagnosis of febrile seizures were included in the HIRA database from 2009 to 2016. These records corresponded to physician billing data associated with hospital visits; accordingly, a single patient could have multiple records. We did not exclude these records because multiple febrile seizure events could occur in a single patient. The records included 315,774 (56.6%) male children and 242,356 (43.4%) female children with a ratio of 1.30: 1, indicating a male predominance. The mean age of the patients was 2.31 ± 1.31 years. The highest number of cases was recorded among patients aged 1 year (210,403, 37.7%), followed by 137,093 (24.5%) among those aged 2 years. Patients older than 2 years exhibited a gradually decreasing trend beginning at 3 years of age, and the lowest frequency was observed at 5 years (25,754, 4.6%) ( Table 1).
The average annual number of cases diagnosed with febrile seizures was 69,766 (95% confidence interval [CI]: 64,397-75,135). The highest annual number of febrile seizure records was recorded in 2012 (80,643, 14.4%), while the lowest frequency was recorded in 2011 (59,554, 10.7%) ( Table 1). Because the HIRA database covers the entire Korean population, we calculated the annual incidence of febrile seizure according to the average population of Korean children younger than 6 years. This number was 2,749,488 (1,414,696 for boys and 1,334,792 for girls). The annual incidence of febrile seizure was calculated as 25.4 per 1000 person-years (27.9 for boys and 22.7 for girls).

Monthly distribution of febrile seizure medical records
From 2009 to 2016, the monthly average number of febrile seizure records was 46,510 (95% CI: 40,420-52,601). The highest monthly number of febrile seizure records was recorded in May (64,969, 11.64%), followed by June (58,265, 10.44%). A peak in the number of febrile seizure records was observed from April to July. The lowest number of febrile seizure records was recorded in October (34,242, 6.17%) (Fig. 1).

Correlation of febrile seizure with other diagnoses associated with viral infection
Of the 558,130 included medical records, 472,482 (84.7%) included diagnoses of febrile seizures along with additional diagnoses. Of these records, we investigated 32,337 (6.8%) that included virus-related diagnoses. The influenza virus was the most common etiology of infection, according to these records (16,809, 52.0%), followed by enterovirus (12,571, 38.9%), and these two viruses accounted for the majority of cases (29,380, 90.9%). Rotavirus, RSV, and adenovirus cases were also included. However, the frequencies of these viral infections were much lower than those caused by influenza virus and enterovirus. Other viruses accounted for less than 1% of all viral infections (Table 2).
During the peak period of febrile seizure records (from April to July), enterovirus was the most frequent causative virus. Influenza virus infection was only most common in April, whereas enterovirus infection was most common from May to July (Fig. 1). Rotavirus was prevalent from January to April, and RSV was prevalent in November and December. Adenovirus exhibited a consistent monthly distributional pattern throughout the year (Table 3).
We further made a time series graph of febrile seizure, influenza virus and enterovirus during the study period (Fig. 2) and performed a correlation analysis using these data. We identified a significant correlation between febrile seizure and enterovirus infection. However, there was no significant correlation between febrile seizure and influenza virus infection (Table 4).

Discussion
Our study describes the monthly and seasonal distributions of febrile seizures and the relationship of this disorder with associated respiratory and gastrointestinal viral infections in South Korea, based on an analysis of HIRA data. Many studies have investigated the seasonal distribution of febrile seizure. Most studies reported frequent febrile seizures in winter, but differed with respect to events in summer. According to a study conducted in Japan, febrile seizure was predominant during both the winter (from November to January) and summer (from June to August). This result was attributed to the prevalence of respiratory virus infection in winter and gastrointestinal virus infection in summer [7]. Similar results were reported in Italy and Iran [9,20]. However, a study conducted in Finland reported that febrile seizure occurred most frequently in winter but was uncommon in summer [16]. The authors reported that this result was associated with febrile episodes, which were also frequent in winter and uncommon in summer [10]. In a study of febrile seizure distribution and associated viral infection in in Bosnia and Herzegovina, the distributions of febrile seizure from spring to winter were similar, and no statistically significant association with virus infection was observed [11]. Our study showed that febrile seizures occurred most frequently from late spring to summer. We believe that this result can be attributed to enterovirus infection, which occurs predominantly in the summer.
Influenza virus, enterovirus, rotavirus, RSV, and adenovirus were the most frequent types of viral infection among cases of febrile seizures in the HIRA database. Of these viruses, the pattern of enterovirus infection was most similar to that of febrile seizure, and these patterns exhibited a significant correlation. Previous studies internationally and in South Korea have reported the high prevalence of enterovirus infection in the summer [21][22][23][24]. As enterovirus infection frequently causes a high fever, this high summer prevalence might be the cause of febrile seizures shown in this study. Enterovirus has an affinity for neuronal cells and is a major cause of central nervous system infections, such as viral meningitis. These central nervous system infections may present with mild symptoms, or with severe infection and consequent encephalitis associated with disability and death [25,26]. In a study conducted in Japan, 13 of 21 children with febrile seizures in the summer yielded positive results in an enterovirus polymerase chain reaction examination of cerebrospinal fluid [27]. In our study, febrile seizures that occurred during summer might have been mild neurologic manifestations of enterovirus infections.
Influenza virus infection is a major viral infection associated with  febrile seizure during the winter season. In Australia, the number of pediatric patients who visited the emergency department for febrile seizures increased in during influenza pandemics [28]. In China, the incidence of febrile seizures associated with influenza A infection was higher than that associated other respiratory viruses in a study of hospitalized children [29]. The rate of recurrent febrile seizure was also associated with influenza A infection [30]. In accordance with previous studies, we identified influenza virus infection as the most common viral infection associated with febrile seizures in winter. This finding suggests that influenza virus infection is the major cause of febrile seizures in the winter season. After influenza virus and enterovirus, the next most frequent viruses in our study were rotavirus, RSV, and adenovirus. Rotavirus causes gastrointestinal infection and is prevalent in winter [31]. RSV, a respiratory virus, is prevalent in winter and is the most common cause of acute bronchiolitis in children younger than 2 years [32]. The incidence of adenovirus infection remains fairly consistent throughout the year [33]. In our study, the seasonal distribution patterns of rotavirus, RSV, and adenovirus infection were similar to those reported in previous studies. All these viruses appear to be associated with febrile seizures.

Conclusion
This is the first nationwide HIRA database study in South Korea concerning the seasonal distributions of febrile seizures and associated viral infections. According to our findings, the prevalence of febrile seizure was high from late spring to summer, and enterovirus was the most commonly associated virus.