Incidence of febrile seizures in children with COVID-19

doi:10.21203/rs.3.rs-2116645/v1

Purpose

This study aimed to investigate the incidence of febrile seizures (FS) associated with coronavirus disease 2019 (COVID-19) in children and examine the variation in these incidences after the Omicron surge.

Methods

The number of confirmed COVID-19 cases aged below 5 years residing in the Jeonbuk province from January 2020 to June 2022 was obtained from official data released by the Korean government. During the same period, data regarding FS patients with COVID-19 were obtained from all local hospitals capable of FS treatment in Jeonbuk. The data were analyzed retrospectively.

Results

The number of children under 5 years of age in Jeonbuk was 62,772, of which 33,457 (53.2%) were diagnosed with COVID-19 during the study period. Of these, 476 patients (1.4%) required hospitalization and 64 (0.19%, 44 boys: 20 girls) developed FS. Until 2021, before the Omicron surge, 23.4% of the patients (89 of 381) required hospitalization, but no children with COVID-19 were hospitalized for FS. However, after the Omicron surge in 2022, 16.5% of hospitalized children (64 of 387) experienced FS, despite the decline in hospitalization rates among COVID-19 patients (1.2%). Twenty-five patients (39.1%) had complex FS, and one (1.6%) presented with febrile status epilepticus. Forty-two patients (65.6%) experienced first-time FS, with an average of 1.5 convulsive events.

Conclusions

During the COVID-19 pandemic, the incidence of FS was approximately 0.19%; however, after the emergence of the Omicron variant, FS occurred more frequently and became more complex.

Children

Coronavirus 19

Febrile seizure

SARS-CoV-2

∙ Adenoviruses, influenza, human herpesvirus-6, and rhinoviruses have been reported to be the main culprits of febrile seizures.

∙ The prevalence of infection with the Omicron variant of COVID-19 increased with the number of definitive diagnoses, and the numbers of affected children and FS cases also increased

∙ Febrile seizures may occur in approximately 0.19% of all COVID-19 patients under the age of 5 years

∙ After the of the Omicron surge, febrile seizures occurred more frequently and became more complex especially in boys.

Febrile seizures (FS) are a common neurologic disorder in children aged 6–60 months. Approximately 2–5% of children reportedly experience FS.¹ Although the exact etiology of FS is unclear, it occurs frequently during fever episodes caused by various vaccinations and viral and bacterial infections.^2–4 The consensus on the most common viruses that cause FS varies depending on the published data; however, adenoviruses, influenza, human herpesvirus-6, and rhinoviruses are reported to be the main culprits.^5–7 Thus far, studies on these viruses have been focused on the incidence rate and clinical characteristics of FS among hospitalized patients for each virus. Reportedly, 15–20% of patients hospitalized for influenza A infection develop FS.⁸ However, since these studies have focused on hospitalized patients, which are relatively difficult to manage, the reported rates do not reflect the actual rate of FS in the general population with confirmed viral infections. Moreover, the novel coronavirus SARS-CoV-2 (coronavirus disease 2019; COVID-19), has an advantage when it comes to estimating the prevalence rate of FS over the total population of patients, as the overall incidence of COVID-19 is determined in the general population as a national statistic.

The COVID-19 pandemic, which began in 2020, changed the incidence rates of several diseases.^9–11 Owing to the valiant efforts of the Korean government during the COVID-19 pandemic, the COVID-19 infection rate in children was minimal during the early stages of the pandemic. However, many pediatric cases occurred after the SARS-CoV-2 Omicron variant infection began, and the number of FS increased concurrently.

As of July 1, 2022, the ratio of the cumulative number of confirmed cases of COVID-19 to the population of South Korea stood at 37.9%, ranking 8th worldwide.¹² The prevalence of infection with the Omicron variant of COVID-19 increased with the number of definitive diagnoses, and the numbers of affected children and FS cases also increased. Byeon et al. reported that the prevalence of other viral infections and the incidence of FS in South Korea were significantly reduced as mask-wearing and strict personal hygiene were implemented during the COVID-19 pandemic.¹³ However, the incidence of FS during COVID-19 has not yet been reported, except for a paper published in 2022 in the United States that reported that it was 0.5%.¹⁴ This study aimed to calculate the incidence of FS in general population under aged 5 years.

Jeonbuk is a province in South Korea with a population of 1.78 million and 62,772 children under 5 years of age. Five hospitals can provide medical care for FS: one in each of the three most densely populated cities in the province. As a province with a limited number of general and tertiary hospitals, Jeonbuk has favorable conditions for the study of the incidence rate of specific diseases, as most patients with FS receive their final treatment at these hospitals.

This study aimed to predict the incidence of FS compared to the general population with COVID-19 by calculating the ratio of the number of FS to COVID-19 cases among children under the age of 5 years, and to investigate the clinical characteristics of these children.

Patients

Retrospective data were collected from children diagnosed with COVID-19 under 60 months of age in Jeonbuk province from January 2020, when the first COVID-19 patient was reported in Korea, to June 2022, after the Omicron variant pandemic. Five hospitals in each of the three most populous cities dedicated to treatment of children with COVID-19 infection. The number of patients with confirmed COVID-19 and those with FS under 5 years of age were investigated. Most of the Korean can be performed COVID-19 polymerase chain reaction (PCR) with only minor symptoms or history of contact with a COVID-19 patients. Those who were confirmed COVID-19 were quarantined for 7 days and patients requiring medical treatment due to high fever, seizure or respiratory distress were admitted to the hospital. This recommendations were also applied for children. All participants tested positive on COVID-19 PCR after hospitalization. The International League against Epilepsy defines FS as seizures that occur as a result of a high-grade fever (over 38℃) with the absence of central nervous system infection, inflammation, or an acute systemic metabolic abnormality that may induce convulsions.¹⁵ According to the abovementioned criteria, among convulsive patients, patients who had underlying epilepsy disorder, had no fever, or had other causes of convulsions, such as electrolyte imbalances and structural anomalies in brain magnetic resonance imaging (MRI), were excluded from the FS group.

Data Collection

We investigated the number of children under the age of 5 years who were diagnosed with COVID-19 in Jeonbuk province during the study period. The number of confirmed COVID-19 cases was collected using public data related to the COVID-19 pandemic provided by the Ministry of Public Administration and Security. In the Republic of Korea, from April 7, 2021, all public health centers have provided a PCR test for COVID-19 diagnosis without suspicious symptoms or epidemiological associations.

To determine the incidence of FS associated with COVID-19, we divided the number of patients with FS due to COVID-19 by the total number of COVID-19 patients. Additionally, patient characteristics, including demographic characteristics, type of seizures, duration, electroencephalography, and length of hospitalization, were also evaluated.

Using SPSS 23.0, the mean and standard deviation were calculated for continuous variables such as age, number of seizures, and duration, and categorical variables such as sex and seizure type were summarized using frequencies and percentages.

Study population

During the study period, 53.2% (33,457 of 62,772) of children aged < 5 years in Jeonbuk were confirmed to have COVID-19. Of the 33,457 patients, the number of patients with COVID-19 was 19 (0.03%) in 2020, 381 (0.6%) in 2021, and 33,057 (52.6%) by June 2022 (Figure 1); of the confirmed patients, 476 (1.4%) were boys and 264 (girls, 212) required hospitalization (Table 1). Their mean age was 26.9 ± 18.3 months (1–60 months) (Table 1). Of the 476 hospitalized patients, 71 had convulsions with fever; however, seven of them had already been diagnosed with epilepsy and were prescribed anticonvulsant medications (ASMs). Finally, 64 patients (0.19%); (44 boys, 68.8%; 20 girls, 31.2%) were diagnosed with COVID-19-associated FS (Figure 2, Table 1). The ratio of FS to confirmed COVID-19 cases according to sex was 0.3% for male and 0.1% for female patients, respectively (Figure 2). FS cases were first observed in 2022 after the Omicron variant surge (Figure 1). The mean age of children with FS was 36.7 ± 15.0 months.

Clinical manifestations in children with COVID-19-associated FS

Twenty-five patients (39.1%) with FS had complex febrile seizures (CFS), and only one patient (1.6%) presented with febrile status epilepticus (FSE), which was defined as seizure activity lasting at least 30 minutes.¹⁶ Forty-two patients (65.6%) experienced first-time FS, and the remaining 22 patients (34.4%) had a prior history of FS (Table 2). Children with FS had an average of 1.5 ± 1.2 convulsive episodes, and patient with most of the convulsions experienced ten episodes over a course of three days. The average duration of FS was 5.0 ± 8.4 minutes, and the longest reported seizure in a patient lasted for 60 minutes and required ventilator care. Thirteen children (20.3%) had a familial history of FS in first-degree relatives, and the mean hospitalization period was 3.7 ± 2.7 days. Most patients did not need ASM after hospitalization; however, seven patients (10.9%) required primary ASM (intravenous [IV] lorazepam, 0.1 mg/kg). Furthermore, two of these patients required secondary ASM (IV fosphenytoin, 20 mg/kg) and one patient required a continuous intravenous infusion of midazolam (5 µg/kg/min). Most of the patients had normal leukocyte counts (7.49 ± 2.11 × 10³/µL) and lymphocyte counts (22.5% ± 13.2%), and the average serum C-reactive protein level was 4.85 ± 6.46 mg/L.

Neurologic manifestations of patients with prolonged FS during COVID-19

To determine the risk of prolonged convulsions, we studied the characteristics of six patients with prolonged febrile seizures (PFS) lasting more than 15 minutes.¹⁷ Table 3 shows that most of the patients with PFS were boys (n = 5, 83.3%). Four patients (66.7%) experienced their first seizures due to COVID-19. Electroencephalography (EEG) and brain MRI were performed in four patients (66.7%), while the other two children could not undergo additional examinations during quarantine. All four patients showed no abnormalities on brain MRI, and three out of four showed slow background activity on EEG; however, no electrical epileptiform discharge was observed. Despite the long seizure duration in all patients, the hospital stays lasted less than 8 days, and only two patients (33.3%) required ASM. The glucose levels of those who required ASM were 232 mg/dL and 291 mg/dL, and their lactate levels were 3 mmol/L and 26 mmol/L, respectively. The convulsive events in other patients were self-limiting.

We observed a significant increase in the number of patients with FS from December 2021, when the Omicron variant was first reported in Korea (Table 1).¹⁸ Until 2021, prior variants of COVID-19 were associated with severe disease and a 20.5% hospitalization rate among the infected patients; however, no FS was observed (Figure 1, Table 1). Conversely, after the Omicron surge, 16.5% of hospitalized patients (64 of 387, Figure 1) had FS, despite the hospitalization rate dropping to 1.2% (387 of 33,057). This result concurs with the findings of a study conducted in South Africa, which reported that 20% of hospitalized patients with the Omicron variant aged below 19 years experienced seizures.¹⁹ Human herpesvirus-6 or influenza A virus, which are common causes of FS, also led to a 10–20% incidence of FS in hospitalized patients.^20,21 Thus, this study provides more evidence that the Omicron variant can also be a common cause of FS.

The mean age of patients with FS due to COVID-19 was 36.7 ± 15.0 months, which was older than the peak age of FS, which is 18–20 months.^22,23 Furthermore, 39.1% of patients with FS had CFS, and 1.6% of them had FSE, which is also higher than the average 25%–30% incidence of CFS.^24,25 In 2022, Apirada et al. reported the characteristics of 16 pediatric patients with seizures due to COVID-19 after the Omicron surge.²⁶ Six patients (38%) presented with focal seizures and eight patients (50%) presented with status epilepticus. However, a higher rate of status epilepticus than that found in our study was reported per the criteria for status epilepticus (seizures lasting more than 5 minutes). Eleven children (17.2%) had seizures lasting more than 5 minutes in our study, which also indicated that neurological symptoms occurred more frequently than in the previous COVID-19 variants.

Overall, this study confirmed that the Omicron variant could also be a common cause of FS, and CFS and FSE were more frequent at an older age. The findings of this study may be due to the increase in the total number of confirmed COVID-19 cases; however, they suggest the possibility of the Omicron variant leading to poor neurologic clinical outcomes, even though the disease severity is less than that associated with the previous variants.

The biggest advantage of this study was that the incidence of FS among confirmed COVID-19 patients could be calculated based on government statistical records rather than inpatient population organizations. Only 0.19% of children with COVID-19 developed FS. This can be considered an advantage of previous COVID-19 research in which inpatients were the target population.^27,28 To the best of our knowledge, the existing reports on FS related to COVID-19 were also studies on hospitalized patients.^14,16 Our study may contribute to strengthening the basis for predicting the incidence of FS in the general COVID-19 population. It is thought that the number of FS cases among children under the age of 5 years can be predicted. Additionally, we found that the incidence of FS was more than doubled in 68.8% of boys compared to girls, and most of the patients who had PFS were boys, although there was no significant difference in the incidence of COVID-19 infection and hospitalization according to sex within 10%. Previous studies before the Omicron surge suggested lower incidences of FS among Korean children,¹³and the possibility that the incidence of FS may increase after the Omicron pandemic should not be neglected.

In this study, we investigated all hospitals where FS treatment was available in Jeonbuk province. However, one of the limitations is that the precise incidence may differ because of the loss of patients who received medical care at primary hospitals and those who did not receive treatment at all. Additionally, selection bias may have occurred because the studies were conducted in only one province in Korea. Nationwide research is needed to estimate the incidence rate of FS more accurately by comparing the number of patients diagnosed with FS and COVID-19 simultaneously in all hospitals across the country.

FS may occur in approximately 0.19% of all COVID-19 patients under the age of 5 years, and FS appears to occur more frequently with the Omicron variant in boys. Moreover, CFS and FSE were more likely to occur with this variant.

ASM: Anti-seizure medication

CFS: Complex febrile seizure

COVID-19: Coronavirus disease 2019

EEG: Electroencephalography

FS: Febrile seizure

FSE: Febrile status epilepticus

IV: Intravenous

MRI: Magnetic resonance imaging

PFS: Prolonged febrile seizure

RT-PCR: Reverse-transcriptase polymerase chain reaction

Ethics approval

This study was approved by the Institutional Review Board of our center (IRB No. 2022-06-001).

Consent to participate

The requirement for informed consent was waived.

Competing interests

The authors declare no competing interests.

Funding

No financial and no specific support to disclose.

Acknowledgments

The authors thank the Ministry of Public Administration and Security of the Republic of Korea for providing the public data on the COVID-19 pandemic.

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Table 1. Demographic factors of children with coronavirus 2019 in Jeonbuk

COVID-19 infection

Hospitalized COVID-19 (%*)

FS with COVID-19 (%**)

Number (n)

2020

2021

2022

Total

19

381

33,057

33,457

0

89 (23.4)

387 (1.2)

476 (1.4)

0

64 (0.19)

Sex distribution (M:F)

2020

2021

2022

Total

9:10

186:195

16706:16351

16,901:16,556

0

47:42

217:170

264:212

0

44:20

Age (months)

2021

2022

Total

31.2 ± 16.7

25.8 ± 18.6

26.9 ± 18.3

36.7 ± 15.0

COVID-19; coronavirus 2019, FS; Febrile seizure

*Ratio of hospitalized patients with COVID-19 compared to confirmed COVID-19 patients

** Ratio of febrile seizure patients with COVID-19 compared to confirmed COVID-19 patients

Table 2. Clinical manifestations of children with coronavirus 2019 associated febrile seizures

Gender n (%)	44 boys, 20 girls (68.8/31.2)
Type of FS, n (%) Simple Complex FSE	39 (60.9) 24 (37.5) 1 (1.6)
First FS, n (%)	42 (65.6)
Recurrent FS, n (%)	22 (34.4)
Average episode of seizure, n	1.5 ± 1.2 (range 1-10)
Duration of seizures, minutes	5.0 ± 8.4 (range 0.5-60)
Family history of FS, n (%)	13 (20.3)
Hospitalization, day	3.7 ± 2.7 (rage 0-9)
Ventilator care, n (%)	1 (1.6)
ASM, n (%) 1^st 2^nd 3^rd or more	7 (10.9) 2 (3.1) 1 (1.6)
WBC, x10³/㎕	7.49 ± 2.71 (range 2.68-17.39)
Differential lymphocyte, %	22.5 ± 13.2 (range 4.6-64.7)
CRP, mg/L	4.85 ± 6.46 (range 0.2-36)

FS; febrile seizure, FSE; Febrile status epilepticus, ASM; antiseizure medication, WBC; white blood cell, CRP; C-reactive protein

Table 3. Clinical characteristics of prolonged febrile seizures with coronavirus 19

	Sex	Age (months)	Previous FS	Epi	Duration (min)		EEG	bMRI	Admission (days)	ASM	Glucose (mg/dL)	Lactate (mmol/L)
Pt 1	M	13	0	1	60	Slow waves		n/s	5	2^nd	232	3
Pt 2	M	7	0	2	20	-		-	8	1^st	291	26
Pt 3	M	28	0	1	15	-		-	1	X	78	0.9
Pt 4	M	57	10	3	15	Slow waves		n/s	2	X	91	1
Pt 5	F	37	0	2	20	Slow waves		n/s	3	X	95	1.33
Pt 6	M	51	1	1	15	n/s		n/s	6	X	106	1.6

FS; febrile seizure, Epi; episode, EEG; electroencephalography, bMRI; brain magnetic resonance imaging, ASM; antiseizure medication, Pt; patient

No competing interests reported.

Incidence of febrile seizures in children with COVID-19

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Abstract

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What Is Known

What is new

Introduction

Methods

Patients

Data Collection

Results

Discussion

Conclusions

Abbreviations

Statements And Declarations

References

Tables

Additional Declarations

Status:

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