Prevalence and Characteristics of Febrile Seizures in COVID-19 Pandemic in Thailand: A Tertiary Medical-Center Retrospective Study

Abstract

Background

Febrile seizures (FS) are often associated with viral infections. COVID-19 infection may be related to FS. The objective is to evaluate the prevalence and characteristics of FS during COVID-19 period.

Methods

This retrospective study of children aged 6-60 months with FS or COVID-19 infection was conducted at a tertiary hospital from January 2020 to November 2023, categorized by pre-Omicron, transition, and Omicron periods. Data from all FS and COVID-19 cases were descriptively analyzed using mean or median, and compared across three periods using ANOVA. The characteristics of FS with and without COVID-19 patients, as well as COVID-19 with and without FS patients, were compared by using t-test or Wilcoxon rank-sum test.

Results

The FS prevalence in COVID-19 patients was 0.36%, with age-specific prevalence of 1.31% in COVID-19 cases aged 6-60 months. Males were more prevalent in all FS groups. Generalized seizures and simple FS were the most common presentations. Thirty-three percent of FS with COVID-19 were complex febrile seizures, compared to 20% in non-COVID-19 cases. Cough was a significant symptom in COVID-19 without FS (p=0.03), while male, higher body temperature, pulse and respiratory rate were more prevalent in COVID-19 cases with FS (p <0.05).

Conclusions

COVID-19 does not increase the risk of FS compared to other causes. Male gender, higher body temperature, pulse and respiratory rate in COVID-19 children are associated with FS. Cough was a less relevant symptom for FS in COVID-19 children. Well-designed, large-scale research is needed to better understand FS in pediatric COVID-19 patients.

Keywords

febrile seizures characteristics COVID-19 prevalence children

Introduction

Febrile seizures (FS) are common in children, with an estimated 2-5% in the US and Western countries, but higher rates are reported elsewhere, such as 9-10% in Japan, 5-10% in India.^1,2 FS occurs in children aged 6-60 months, associated with a febrile illness, without CNS infection, neurological disease, or metabolic disturbance.³ FS are classified as simple (generalized, no recurrence in 24 hours, less than 15 minutes) and complex (focal onset, recurrence in 24 hours, or lasting over 15 minutes).^1,3 There is a genetic predisposition involving FEB 1-9, SCN1A/1B, SCN2A, and GABA-A receptor genes.⁴ The exact cause is unclear, but it is often related to viral infections like herpesviruses, influenza, adenovirus, parainfluenza, RSV, rotavirus, bacterial infections, or post-vaccination.⁵ Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, first identified in Wuhan in December 2019, with symptoms including fever, cough, rhinorrhea, sore throat, fatigue, diarrhea, and vomiting.^6-8 Neurological symptoms range from mild to severe, such as headache, encephalitis, seizures, and stroke.^9,10 Data on FS prevalence with COVID-19 and related risk factors in children are limited, especially in Thailand. The overall FS prevalence in COVID-19 varies from 0.19% to 4.5%,^11-14 with higher rates up to 13% during the omicron period.¹¹ Younger age, family history, and fewer symptoms increase FS risk.¹¹; older age and higher temperature may also be factors associated with an increased prevalence of FS during the Omicron period.¹⁵ This study aims to evaluate the prevalence of FS during the COVID-19 pandemic and identify characteristics in children with and without COVID-19.

Materials and Methods

Study Design and Setting

This was a retrospective review of medical charts for children aged 6 to 60 months diagnosed with FS or COVID-19 at HRH Princess Maha Chakri Sirindhorn Medical Center, Nakorn-Nayok, Thailand, a 500-bed tertiary university medical center and referral regional hub from nearby hospitals, including the primary, secondary, and general hospitals, from January 2020 to November 2023. Patients were identified using ICD-10 diagnostic codes for FS (R56.0) and COVID-19 (U07.1, U07.2, and B972). This study was conducted from March 2024 to March 2025. Data collection was performed over eight months from March 2024 to October 2024, following Ethics Committee approval, and subsequent analysis was conducted from November 2024 to March 2025.

Diagnosis of FS

Seizures in young children, typically aged 6-60 months, that occur with fever and are not associated with central nervous system infection, or acute symptomatic seizures, such as metabolic disturbances or a history of unprovoked seizures. We classified FS into two types: simple FS, defined as generalized seizures lasting less than 15 minutes without recurring within 24 hours, and complex FS, characterized by focal seizures, seizures lasting longer than 15 minutes, or recurrent seizures within 24 hours.

Diagnosis of COVID-19 Infection

COVID-19 infection was confirmed using polymerase chain reaction (PCR), antigen test kits (ATK), or both to detect SARS-CoV-2.

The Inclusion and Exclusion Criteria

All patients aged 6-60 months diagnosed with FS or COVID-19 at our hospital were included. Children younger than 6 months or older than 60 months were excluded from the FS and the COVID-19 groups. Patients with underlying epilepsy, structural brain anomalies, seizures without fever, or other causes of seizures, such as hypoglycemia or hyponatremia, were excluded from the FS group.

Study Periods

The study periods (January 2020–November 2023) were divided into three periods: pre-Omicron (January 2020- October 2021), transition phase (November 2021–January 2022), and Omicron phase (February 2022–November 2023). The pre-Omicron period began with the first reported COVID-19 case in Thailand in January 2020. The Omicron variant was first reported by the WHO in November 2021, and the first case in Thailand was identified in December 2021. As cases diagnosed with COVID-19 between November 2021 and January 2022 may have involved mixed circulating variants, this interval was defined as a transition period. The subsequent period, from February 2022 to November 2023, was therefore classified as the Omicron period.

Data Collection

Data for FS covered sex, age, clinical signs, fever duration before seizures, seizure type, FS type, history of FS, family history of FS and epilepsy, body temperature (BT), pulse (PR) and respiratory rate (RR), laboratory results (CBC, serum sodium), seizure treatment, FS cause—compared across periods and between patients with and without COVID-19. COVID-19 data included sex, age, symptoms, vital signs, SpO2, ICD-10 diagnosis, and antiviral treatment, also compared among periods and between those with and without FS.

Statistical Analysis

Categorical variables were summarized as counts and percentages and compared using the Chi-square or Fisher’s exact test. Continuous variables were reported as mean with standard deviation (SD) for data that were normally distributed, and as median with interquartile range (IQR) for non-normally distributed data. For comparison between two groups, the t-test was used for normally distributed data, and the Wilcoxon rank-sum test for non-normal data. When comparing more than two groups, one-way ANOVA was used for normally distributed data, whereas the Kruskal-Wallis test was used for non-normal data. A p-value less than 0.05 was considered statistically significant. All statistical analyses were conducted using Stata software, version 14 (StataCorp LP, College Station, TX, USA).

Results

From January 1, 2020, to November 30, 2023, our hospital treated a total of 144,695 pediatric patients. Of these, 36.33% (52,564 patients) were between 6 and 60 months old. The pediatric cases of 2,532 have been reported positive for COVID-19, including 686 in the 6-60 months age group. A total of 124 FS cases in the age group of 6-60 months were recorded, with 9 of these diagnosed with both FS and COVID-19 infection (Figure 1).

Figure 1.

Flow chart for selection of febrile seizure and COVID-19 study population. ICD-10: The 10th revision of the international classification of diseases; TSC: tuberous sclerosis complex; IEM: inborn error metabolisms; AFI: acute febrile illness; FS: febrile seizures

Prevalence of Febrile Seizure Patients in the COVID-19 Era

The overall FS prevalence among COVID-19-positive patients was 0.36% (9 of 2,532), with an age-specific prevalence of 1.31% (9 of 686) in the COVID-19-positive cases aged 6 to 60 months. Furthermore, the prevalence of FS with COVID-19 cases in all FS was 7.25% (9 of 124).

The Characteristics of All Febrile Seizure Patients

In FS cases, 72 (58.06%) were males and 52 (41.94%) females, with a median age of 20 months (IQR 13-29 months). Among these patients, 98 experienced simple FS, while 26 had complex FS; 22 had recurrent seizures within 24 hours, 2 had focal seizures, and 2 had seizures lasting over 15 minutes. A total of 25 individuals (20.16%) had a history of prior FS, which in 15, 7, 1, and 2 cases had 1, 2, 3, and 4 episodes of previous FS, respectively. Additionally, 41 participants (33.06%) reported a family history of FS. Only 2 (1.61%) reported a family history of epilepsy. Nine participants (7.25%) had prior COVID-19 infections. Of these, one experienced FS during the initial infection and subsequently developed a recurrent FS without COVID-19. Another did not experience FS during the initial infection but later developed FS during a subsequent COVID-19 infection. The remaining participants had no FS during their initial COVID-19 infection; however, they later experienced FS without COVID-19. All were classified into the FS group or the COVID-19 group, according to the prevalence of FS and/or COVID-19 infection during the study period.

Among these patients, 43 (34.68%) had fever alone, while others had fever with respiratory symptoms (40.32%), including rhinorrhea, cough, sputum production, sore throat, and nasal congestion; gastrointestinal symptoms (30.65%), such as diarrhea, vomiting, abdominal pain; poor intake (14.52%); and skin lesions (2.42%). The most common diagnosis/cause of FS was upper respiratory infections (19.36%), followed by unspecified viral infections (14.52%), influenza (9.68%), gastroenteritis (9.68%), COVID- 19 (7.26%), and fever with rash (7.26%) including herpangina, hand- foot- and- mouth disease (HFMD), varicella zoster, viral exanthems, and roseola infantum; unspecified fever (5.65%), RSV infections (4.03%), and other causes such as diarrhea, septicemia, urinary tract infections (UTI), and other respiratory infections like parainfluenza, rhino/enterovirus, human metapneumovirus, bronchitis, and croup, as shown in Table 1. The median duration of fever before seizure onset was 24 hours (IQR 6.5-24), with an average BT of 38.64 °C (SD 0.89).

Table 1.

Clinical Manifestations and Diagnosis/Causes of All FS Patients Classified by the Study Periods

Variables	Total of FS	Pre-omicron n=53 (%)	Transition n=3 (%)	Omicron n=68 (%)	P-value
Variables	N (%)	Pre-omicron n=53 (%)	Transition n=3 (%)	Omicron n=68 (%)	P-value
Clinical manifestations
Fever alone	43 (34.68)	20 (37.74)	2 (66.67)	21 (30.88)	0.320
Fever with other symptoms*
Respiratory System (RS)	50 (40.32)	21 (39.62)	1 (33.33)	28 (41.18)	1.000
Rhinorrhea	40 (32.26)	19 (35.85)	1 (33.33)	20 (29.41)	0.801
Cough	36 (29.03)	17 (32.08)	0 (0)	19 (27.94)	0.633
Sputum production	2 (1.61)	2 (3.77)	0 (0)	0 (0)	0.229
Sore-throat	1 (0.81)	1 (1.89)	0 (0)	0 (0)	0.452
Nasal congestion	1 (0.81)	0 (0)	0 (0)	1 (1.47)	1.000
Gastrointestinal tract (GI)	38 (30.65)	16 (30.19)	1 (33.33)	21 (30.88)	1.000
Diarrhea	24 (19.35)	12 (22.64)	0 (0)	12 (17.65)	0.740
Vomiting	24 (19.35)	9 (16.98)	1 (33.33)	14 (20.59)	0.531
Abdominal pain	1 (0.81)	1 (1.89)	0 (0)	0 (0)	0.452
Poor intake	18 (14.52)	8 (15.09)	0 (0)	10 (14.71)	1.000
Skin Lesion	2 (2.42)	1 (1.89)	0 (0)	2 (2.94)	1.000
Diagnosis/causes
Upper respiratory tract infection	24 (19.36)	3 (24.53)	1 (33.33)	10 (14.71)	0.276
Bronchitis	2 (1.61)	0	0	2 (2.94)	0.527
Croup	1 (0.81)	1 (1.89)	0	0	0.452
Influenza infection	12 (9.68)	3 (5.66)	0	9 (13.24)	0.431
RSV infection	5 (4.03)	3 (5.66)	0	2 (2.94)	0.693
Parainfluenza infection	1 (0.81)	0	0	1 (1.47)	1.000
Rhino/Enterovirus infection	1 (0.18)	0	0	1 (1.47)	1.000
Human metapneumovirus infection	1 (0.18)	0	0	1 (1.47)	1.000
COVID-19 infection	9 (7.26)	1 (1.89)	0	8 (11.76)	0.100
Gastroenteritis	12 (9.68)	8 (15.09)	0	4 (5.88)	0.246
Gastritis	3 (2.42)	2 (3.77)	0	1 (1.47)	0.611
Diarrhea	5 (4.03)	2 (3.77)	0	3 (4.41)	1.000
Fever with rash	9 (7.26)	2 (2.77)	0	7 (10.29)	0.439
Herpangina	4 (3.23)	1 (1.89)	0	3 (4.41)	0.665
Hand-Foot-Mouth Disease	2 (1.61)	0	0	2 (2.94)	0.527
Varicella zoster infection	1 (0.81)	1 (1.89)	0	0	0.452
Viral exanthem	1 (0.81)	0	0	1 (1.47)	1.000
Roseola infantum	1 (0.81)	0	0	1 (1.47)	1.000
Viral infection, unspecified	18 (14.52)	6 (11.32)	0	12 (12.65)	0.653
Occult bacteremia	6 (4.84)	2 (3.77)	1 (33.33)	3 (4.41)	0.213
Septicemia
Streptococcal pneumoniae	1 (0.81)	1 (1.89)	0	0	0.452
Septicemia
Klebsiella pneumoniae septicemia	2 (1.61)	1 (1.89)	0	1 (1.47)	1.000
Urinary tract infection (UTI)	2 (1.61)	1 (1.89)	0	1 (1.47)	1.000
Fever, unspecified	7 (5.65)	4 (7.55)	1 (33.33)	2 (2.94)	0.105
Fever post-vaccination	3 (2.42)	3 (5.66)	0	0	0.147

*A patient may have more than one clinical symptom.

Febrile Seizure Patients in the Pre-Omicron, Transition, and Omicron Periods

For FS patients in three periods, there were 53 cases in the pre-Omicron period, 3 during the transition period, and 68 in the Omicron period, with male-to-female ratios of 1.03:1, 2:1, and 1.72:1, respectively. Table 2 shows that the fever duration before seizure onset in the transition group was notably shorter than in the pre-Omicron and Omicron groups (p=0.019). Serum sodium levels were significantly lower in the pre-Omicron and Omicron groups than in the transition group (p=0.000). Generalized seizures were the most common seizure type across all periods, with fewer focal, atonic, and unknown types. One patient in the Omicron period had a seizure of unknown origin with loss of consciousness and foaming. Simple FS was the predominant diagnosis, with 19 cases of complex FS during the Omicron period, and 7 during the pre-Omicron period. Recurrent seizures within 24 hours were the most common symptoms of complex FS.

Table 2.

The Characteristics of FS Patients in the Pre-Omicron, Transition, and Omicron Periods

Characteristics	Totalcases	Pre-omicron n=53	Transition n=3	Omicron n=68	P-value
Age in months, median (IQR)	124	18 (14-26)	14 (9-21)	22 (13-30.5)	0.120
Sex, n (%)	124				0.350
Male		27 (50.94)	2 (66.67)	43 (63.24)
Female		26 (49.06)	1 (33.33)	25 (36.76)
Duration of fever preceding seizure onset (hours), median (IQR)	124	24 (10- 24)	4 (0-4)	22 (6.5-24)	0.019
Seizure types, n (%)	124				0.783
GTC/GT/GC		52 (98.11)	3 (100)	64 (94.12)
Atonic		1 (1.89)	0	1 (1.47)
Focal		0	0	2 (2.94)
Unknown/other		0	0	1 (1.47)
Body temperature (°C), mean (SD)	124	38.53 (0.95)	39.17 (0.35)	38.70 (0.85)	0.338
Pulse rate (BPM), mean (SD)	124	156.64 (25.36)	153.33 (30.55)	161.36 (25.40)	0.565
Respiratory rate (/min), mean (SD)	124	33.55 (8.09)	31.33 (7.57)	31.68 (7.63)	0.506
Hemoglobin (g/dL)^a, mean (SD)	123	11.85 (0.99)	12.8 (0.70)	11.74 (1.22)	0.191
Hematocrit (%)^a, mean (SD)	123	34.66 (2.76)	37.63 (3.76)	34.96 (2.95)	0.219
WBC (x10³cells/mm³)^a, mean (SD)	123	14.38 (7.23)	15.1(7.27)	14.25 (6.73)	0.965
Neutrophil (%)^a, mean (SD)	123	60.76 (15.59)	57.33 (20.66)	62.44 (12.42)	0.703
Lymphocyte (%)^a, mean (SD)	123	31.14 (14.37)	28.4 (10.74)	34.1 (19.15)	0.521
Serum Na (mEq/L)^b, mean (SD)	122	135.59 (2.24)	139.87 (3.36)	134.70 (1.81)	0.000
Diagnosis, n (%)	124				0.097
Simple FS		46 (86.79)	3 (100)	49 (72.06)
Complex FS		7 (13.21)	0	19 (27.94)
Complex FS types, n (%)	26
Recurrent seizures within 24 hours		5 (9.43)	0	17 (25)	0.068
Focal seizures		0	0	2 (1.61)	0.527
Prolonged seizure > 15 minutes		2 (3.77)	0	0	0.229
Treatment for seizures, n (%)	124				0.622
No treatment		48 (90.57)	3 (100)	65 (95.59)
Diazepam		3 (5.66)	0	2 (2.94)
Anti-seizure medication		2 (3.77)	0	1 (1.47)

GTC: generalized tonic clonic seizures, GT: generalized tonic seizures, GC: generalized clonic seizures, FS: febrile seizures, BPM: beats per minute, WBC: white blood cells, p-value < 0.05= significance.

^aThe number of FS cases in the pre-omicron era was 52.

^bThe number of FS cases in the pre-omicron era was 51.

Febrile Seizure Patients With and Without COVID-19 Infections

In FS cases with and without COVID-19, males were more common in both groups. A total of 53 cases were identified during the pre-Omicron period, of which one case (1.89%) involved FS with COVID-19. During the transition period, three cases were recorded, with FS without COVID-19. During the Omicron period, 68 cases were identified, including 8 (11.76%) of FS with COVID-19 (Table 2). Overall, nine cases of FS with COVID-19 were observed across all periods. Of these, the majority (88.89%) occurred during the Omicron period, while only one case (1.11%) was reported during the pre-Omicron period. The most common seizure type across both groups was generalized tonic-clonic/generalized tonic/generalized clonic seizures. Among COVID-19-positive FS patients, 33.33% had complex FS, compared to 20% in the COVID-19-negative group, as shown in Table 3. A comparison of FS cases with and without COVID-19 revealed no significant differences in the history of FS, family history of FS, or epilepsy. The FS without COVID-19 group reported cough more significantly as a clinical symptom than those with COVID-19 (p=0.040). There were no significant differences in other symptoms between the groups.

Table 3.

The Characteristics, Clinical Features, Laboratory Values, and Treatment of FS With and Without COVID-19

Characteristics	FS with COVID-19 (n=9)	FS without COVID-19 (n= 115)	P-value
Age in months, median (IQR)	27 (16-31)	20 (13-29)	0.438
Sex, n (%)			0.050
Male	8 (88.89)	64 (55.65)
Female	1 (11.11)	51 (44.35)
Period, n (%)			0.100
Pre-omicron	1 (11.11)	52 (45.22)
Transition	0	3 (2.61)
Omicron	8 (88.89)	60 (52.17)
Duration of fever preceding seizure onset (hours), median (IQR)	10 (0.5-13)	24 (7-24)	0.056
Clinical symptoms, n (%)
Respiratory system,	1 (11.11)	49 (42.61)	0.061
Rhinorrhea	2 (2.22)	38 (33.04)	0.398
Sore-throat	0	1 (0.87)	0.927
Cough	0	36 (31.31)	0.040
Sputum production	0	2 (1.74)	0.860
Nasal congestion	0	1 (0.87)	0.927
Gastrointestinal tract	3 (33.33)	35 (30.43)	0.559
Diarrhea	3 (33.33)	21 (18.26)	0.240
Vomiting	2 (22.22)	22 (19.13)	0.551
Abdominal pain	0	1 (0.87)	0.927
Poor intake	1 (11.11)	17 (14.78)	0.614
Skin lesion	0	3 (2.61)	0.796
Seizure types, n (%)			1.000
GTC/GT/GC	9 (100)	110 (95.65)
Atonic	0	2 (1.74)
Focal	0	2 (1.74)
Other/unknown	0	1 (0.87)
Body temperature (°C), mean (SD)	39.13 (0.64)	38.6 (0.89)	0.086
Pulse rate (BPM), mean (SD)	169.44 (17.5)	158.36 (25.8)	0.209
Respiratory rate (/min), mean (SD)	32.21 (7.92)	36.28 (5.22)	0.065
Hemoglobin (g/dL)^a, mean (SD)	12.21 (0.82)	11.78 (1.15)	0.305
Hematocrit (%)^a, mean (SD)	35.62 (1.52)	34.84 (2.98)	0.305
WBC (x10³cells/mm³)^a, mean (SD)	10.49 (3.36)	14.63 (7.03)	0.067
Neutrophil (%)^a, mean (SD)	64.9 (8.52)	61.35 (14.28)	0.464
Lymphocyte (%)^a, mean (SD)	24.33 (6.60)	30.12 (12.85)	0.185
Febrile seizure types, n (%)			0.284
Simple FS	6 (66.67)	92 (80)
Complex FS	3 (33.33)	23 (20)
Complex FS types, n (%)			0.531
Recurrent seizures within 24 hours	3 (33.33)	19 (16.52)
Focal seizures	0	2 (1.74)
Prolonged seizure > 15 minutes	0	2 (1.74)
Serum sodium (mEq/L)^b, n (%)			0.214
<135	6 (66.67)	53 (46.90)
135 -145	3 (33.63)	60 (53.10)
Serum sodium (mEq/L)^b, mean (SD)	134.44 (1.90)	135.26 (2.21)	0.284
Treatment for seizures, n (%)			0.055
No treatment	7 (77.78)	109 (94.78)
Diazepam	2 (22.22)	3 (2.61)
Antiseizure medication	0	3 (2.61)

^aTotal number of FS with COVID-19 negative was 114.

^bTotal number of FS with COVID-19 negative was 113.

COVID-19-Positive Pediatric Patients

Among COVID-19 patients, 686 were aged 6-60 months, with 23 cases having two separate infections at different times. Of these, 351 (51.17%) were males and 335 (48.83%) were females. The median age (IQR) was 24 months (13-39), with average BT (°C) at 37.39 (SD 1.09), PR (BPM) at 128.74 (SD 31.89), RR (per min) at 28.24 (SD 6.00), and SpO2 (%) at 98.21 (SD 1.11). During the three periods of COVID-19 infection, 92 cases (13.41%) were in the pre-Omicron period, 6 (0.87%) in the transition period, and 588 (85.71%) in the Omicron period, with male-to-female ratios of 1.04:1, 2:1, and 1.04:1, respectively. The median age of patients was notably lower in the Omicron period compared to the pre-Omicron and transition periods (p=0.044). A significant increase in symptomatic cases was observed during the Omicron period (p=0.000), including fever (p=0.000), respiratory symptoms (p=0.003) such as cough (p=0.006), gastrointestinal symptoms like vomiting (p=0.000), and malaise (p=0.049). Other clinical features did not vary significantly across periods. During the Omicron period, the BT, PR, and RR were significantly higher than in the other periods (p=0.0001), while SpO2 levels were lower. Treatment with antiviral agent regimens did not differ among COVID-19 cases across periods, as shown in Table 4. The most common diagnosis was symptomatic COVID-19 infection, with rates of 82.31% in Omicron period, 50% in the transition period, and 51.09% in pre-Omicron period. During Omicron period, 16 cases (2.72%) involved COVID-19 pneumonia, 5 (0.85%) had COVID-19 with croup and bronchitis, 2 (0.34%) presented with COVID-19 encephalopathy, and 2 (0.34%) experienced fever-provoked seizures (one with epilepsy, another with spastic cerebral palsy and developmental delay). Additionally, 3 (0.51%) cases involved co-infections (one with hand-foot-mouth disease and two with RSV), and there was one case of COVID-19 diagnosed alongside acute lymphoblastic leukemia, as shown in Table 4.

Table 4.

The Characteristics, Clinical Signs and Symptoms, Diagnosis, and Treatment in COVID-19 Patients in Each Period

Characteristics	Total cases	Pre-omicron (n= 92)	Transition (n=6)	Omicron (n= 588)	P-value
Age in months, median (IQR)	686	30 (17-44)	27 (19-54)	23 (13-38)	0.044
Sex, n (%)	686				0.822
Male		47 (51.09)	4 (66.67)	300 (51.02)
Female		45 (48.91)	2 (33.33)	288 (48.98)
Clinical symptoms, n (%)	686				0.000
Asymptomatic		33 (35.87)	3 (50)	64 (10/88)
Symptomatic*		59 (64.13)	3 (50)	524 (89.12)
Symptomatic symptoms
Fever		43 (46.74)	2 (33.33)	432 (73.47)	0.000

Respiratory symptoms		40 (43.38)	1 (16.67)	343 (58.33)	0.003
Cough		31 (33.70)	1 (16.67)	288 (48.98)	0.006
Rhinorrhea		17 (18.48)	0	163 (27.72)	0.059
Sore-throat		4 (4.35)	0	29 (4.93)	1.000
Sputum production		14 (15.22)	1 (16.67)	151 (25.68)	0.080
Dyspnea/short of breath		1 (1.09)	0	16 (2.72)	0.756
Snuffed nose		0	0	7 (1.19)	0.626
Hoarseness		1 (1.09)	0	1 (0.17)	0.265
Barking cough		0	0	2 (0.34)	1.000
Anopsia		0	0	2 (0.34)	1.000

Gastrointestinal symptoms		7 (7.61)	1 (16.67)	107 (18.20)	0.024
Diarrhea		6 (6.52)	0 (0)	42 (7.14)	1.000
Vomiting		1 (1.09)	1 (1.67)	76 (12.93)	0.000
Abdominal pain		0	0	4 (0.68)	1.000

Low appetite		3 (3.26)	1 (16.67)	31 (5.27)	0.267
Malaise		0	1 (16.67)	15 (2.55)	0.049
Headache		1 (1.09)	0	3 (0.51)	0.461
Seizures		1 (1.09)	0	12 (2.04)	1.000
Rash		1 (1.09)	0	5 (0.85)	0.605
Conjunctivitis		1 (1.09)	0	1 (0.17)	0.265
Oral ulcer		0	0	2 (0.34)	1.000
Eyelid swelling		0	0	1 (0.17)	1.000
Body Temperature (°C)^a, mean (SD)	637	36.82 (0.71)	36.48 (0.13)	37.49 (1.11)	0.0001
Pulse rate (BPM)^b, mean (SD)	566	111.87 (19.24)	96.4 (21.23)	130.86 (32.37)	0.0001
Respiratory rate (/min)^c, mean (SD)	545	24.94 (6.22)	20 (0)	28.61 (5.88)	0.0001
SpO2 (%)^d, mean (SD)	565	98.41 (1.11)	99.4 (0.55)	98.16 (1.11)	0.0042
Diagnosis, n (%)	686
Asymptomatic COVID -19 infection		28 (30.43)	3 (50)	62 (10.56)	0.000
Symptomatic COVID -19 infection		47 (51.09)	3 (50)	484 (82.31)
COVID-19 infection with
- Pneumonia		12 (13.04)	0	16 (2.72)	0.000
- Bronchitis		3 (3.26)	0	5 (0.85)	0.143
- Bronchiolitis		1 (1.09)	0	0 (0)	0.143
- Croup		0	0	5 (0.85)	1.000
- Covid encephalopathy		0	0	2 (0.34)	1.000
- Fever provoked seizures		0	0	2 (0.34)	1.000
- Febrile seizures		1 (1.09)	0	8 (1.36)	1.000
- HFMD		0	0	1 (0.17)	1.000
- RSV infection		0	0	1 (0.17)	1.000
- First diagnosis of ALL		0	0	1 (0.17)	1.000
- RSV bronchiolitis		0	0	1 (0.17)	1.000
Treatment with antiviral agent^e, n (%)	204				0.785
Favipiravir		29 (32.22)	1 (16.67)	172 (29.40)
Remdesivir		0	0	2 (0.34)

BPM: beats per minute, HFMD: Hand-Foot-Mouth-Disease, RSV: respiratory syncytial virus, ALL: acute lymphoblastic leukemia, p-value < 0.05 = significance.

*A patient can have more than one clinical symptom.

^aThe total number of patients in the pre-omicron period = 83, transition period = 5, and omicron period = 549.

^bThe total number of patients in the pre-omicron period = 54, transition period = 5, and omicron period = 507.

^cThe total number of patients in the pre-omicron period = 49, transition period = 2, and omicron period = 494.

^dThe total number of patients in the pre-omicron period = 81, transition period = 5, and omicron period = 479.

^eThe total number of patients in the pre-omicron period = 90, transition period = 6, and omicron period =585.

COVID-19 Patients With and Without Febrile Seizures

Comparison of the COVID-19 cases with and without FS, males were significantly more prevalent in the COVID-19 group with FS (p=0.022). No differences were noted in age, period, or history of previous COVID-19 infection, although the age was higher in the COVID-19 patients with FS (median age 27 months, IQR 16-31) compared with the COVID-19 patients without FS (median age 24 months, IQR 13-39). The respiratory symptoms, including cough, were significantly more pronounced in the COVID-19 cases without FS when compared to those with FS. BT, PR, and RR were significantly elevated in the COVID-19 group with FS (p<0.05). Moreover, the administration of antiviral agents was more common in the COVID-19 group with FS compared to those without FS, as shown in Table 5.

Table 5.

The Characteristics, Clinical Symptoms, and Treatment of COVID-19 With and Without FS

Characteristic	Total cases	COVID-19 with FS (n= 9)	COVID-19 without FS (n= 677)	P-value
Age in months, median (IQR)	686	27 (16-31)	24 (13-39)	0.941
Sex, n (%)	686			0.022
Male		8 (88.89)	343 (50.66)
Female		1 (11.11)	334 (49.34)
Period, n (%)	686			1.000
Pre-omicron		1 (11.11)	91 (13.44)
Transition		0	6 (0.89)
Omicron		8 (88.89)	580 (85.67)
Clinical symptoms, n (%)*	686			0.240
Symptomatic		9 (100)	577 (85.23)	0.162
Fever alone		0	125 (18.46)	0.007
Fever with other symptoms: -				0.270
Respiratory system		1 (11.11)	383 (56.57)
Rhinorrhea		1 (11.11)	179 (26.44)	0.640
Sore-throat		0	33 (4.87)	0.030
Cough		1(11.11)	319 (47.12)	0.081
Sputum production		0	166 (24.52)	0.797
Short of breath/dyspnea		0	17 (2.51)	0.911
Nasal congestion		0	7 (1.03)	0.974
Hoarseness		0	2 (0.30)	0.974
Barking cough		0	2 (0.30)	0.974
Anopsia		0	2 (0.30)	0.461
Gastrointestinal tract		2 (22.22)	113 (16.69)	0.126
Diarrhea		2 (22.22)	46 (6.79)	0.335
Vomiting		0	78 (11.52)	0.948
Abdominal pain		0	4 (0.59)	0.622
Poor intake		0	35 (5.17)	0.808
Malaise/fatigue		0	16 (2.36)	0.948
Headache		0	4 (0.49)	0.924
Skin lesion		0	6 (0.89)	0.974
Conjunctivitis		0	2 (0.30)	0.974
Oral ulcer		0	2 (0.30)	0.987
Mild eyelid swelling		0	1 (0.15)	2
History of previous COVID-19 infection, n (%)	686	1 (1.11)	30 (4.43)	0.342
Body temperature (°C)^a, mean (SD)	637	39.13 (0.64)	37.37 (1.07)	0.000
Pulse rate (BPM)^b, mean (SD)	566	178.11 (21.56)	127.95 (31.41)	0.000
Respiratory rate (/min)^c, mean (SD)	545	36.33 (5.99)	28.16 (5.95)	0.021
Treatment with antiviral agent, n (%)	686			0.024
No		3 (33.33)	474 (70.54)
Yes		6 (66.66)	198 (29.46)

BPM: beats per minute, p-value < 0.05 = significance.

*A patient may have more than one clinical symptom.

^aThe total number of COVID-19 patients without FS was 628.

^bThe total number of COVID-19 patients without FS was 557.

^cThe total number of COVID-19 patients with and without FS was 6 and 559, respectively.

Discussion

The prevalence of FS in pediatric COVID-19 patients varies across studies and regions, ranging from 0.19% to 4.5%,^11-14 with rates during the Omicron wave reaching 5.74-13.0%.^11,13,16 In Jeonbuk, South Korea, a study reported that 0.19% of children under five experienced FS following the Omicron surge.¹⁴ In Brunei, 4.5% of COVID-19-positive children under 12 years had FS, with occurrences solely during the Omicron wave.¹¹ A multicenter US cohort reported that 0.5% of COVID-19-positive patients aged 0-5 had FS,¹³ while another study noted a 2.7% prevalence in children aged 6-60 months.¹² There are limited studies on FS prevalence in COVID-19 cases in Thailand. Our research found an overall prevalence of 0.36% among pediatric COVID-19 patients and 1.31% in those aged 6-60 months, mainly during Omicron period. Similarly, other studies reported an increase in FS during the Omicron period, suggesting that this variant may trigger FS more than earlier strains.^11,14,16 However, our study did not include virological confirmation of specific SARS-CoV-2 variants. Consequently, we were unable to determine whether FS associated with COVID-19 during the Omicron period was directly attributable to the Omicron variant or whether this variant confers a higher risk of FS compared with other variants.

Most FS cases across all groups (including by period or COVID-19 status) were simple, although complex FS was more common among COVID-19 cases than without COVID-19 (33.33% vs. 20%). Literature indicates that around 70% of FS are simple, 25% are complex, and 5% are febrile status epilepticus.¹⁷ Multiple studies confirm an increased incidence of FS, including complex cases, in pediatric COVID-19 patients, in which complex seizures comprise 20–40% of COVID-19-related FS.^11,14,18-20 The Omicron variant is associated with higher rates of both febrile and complex FS than earlier strains, with children experiencing longer seizures and a later onset of FS compared to other infections.^{14,16,18,20,21}

FS incidence peaks between 12 and 18 months, with 90% occurring at age 36 months.^22,23 Our median ages in months (IQR) for FS during the pre-Omicron and transition periods were 18 (14-26) and 14 (9-21), respectively. The median ages in months (median, IQR) for FS during the Omicron period (22,13-30.5) and for FS with COVID-19 (27,16-31) were older than the overall FS and those without COVID-19 (20,13-29), aligning with the predominant age range of 12-30 months.^11,23 However, no significant age differences were found across periods or between those with and without COVID-19.

There was a male predominance in FS overall, consistent across groups and periods, like pre-COVID-19 data.^22,24,25 Notably, we observed a significant male predominance in COVID-19 patients experiencing FS compared to those without FS. Similarly, a study from China reported that the proportion of males in FS with COVID-19 was significantly higher than that of females,¹⁹ suggesting heightened awareness of FS risks in male patients aged 6-60 months. Research also suggests males tend to experience more severe COVID-19 outcomes, including ICU admissions and length of hospital stays.²⁶ Possible reasons include higher levels of inflammatory cytokines like IL-6 and TNF-α in males associated with poorer COVID-19 outcomes, while females often demonstrate stronger T cell responses, potentially leading to better outcomes.^27-29 However, no significant sex differences in severity, mortality, or FS incidence have been reported in children.¹⁹

The leading causes of FS during the pandemic were upper respiratory and unspecified viral infections, consistent with previous findings.^5,24,25 Several studies show the risk of FS with COVID-19 is similar to other viral infections, indicating COVID-19 does not increase FS risk beyond typical patterns.^12,13,30,31

Our study found a shorter duration of fever before seizure and higher serum sodium in the transition period, possibly due to the longer duration of fever attributed to the lower serum sodium level in the pre-Omicron and Omicron periods. Moreover, the most common causes of FS in the pre-Omicron and Omicron periods were respiratory infections, viral infections, and gastroenteritis. Previous research has associated hyponatremia with FS related to viral infections, including respiratory viruses and SARS-CoV-2 (COVID-19), implicating infection-induced inflammation and dysregulation of antidiuretic hormone (ADH).^32-36 Gastrointestinal losses from vomiting or diarrhea during viral illnesses may also contribute to hypovolemia and sodium loss.^37,38 However, the underlying mechanisms remain poorly understood.

Our study found that cough was a more prominent symptom in FS cases without COVID-19 compared to those with COVID-19. In contrast, a recent study comparing hospitalized children with FS, regardless of COVID-19 status, reported very similar clinical presentations in both groups, with no significant differences in the frequency of cough or rhinorrhea. This suggests that cough does not occur more often in COVID-19-negative FS cases than in positive ones.³¹

In addition, our results showed that COVID-19-positive patients without FS exhibited more pronounced respiratory symptoms (p = 0.007), including cough (p = 0.030), compared to those with FS. Similarly, a Wuhan study, on FS risk in children during the Omicron surge, found that cough was inversely related to FS in COVID-19-positive cases.³⁹ Similarly, a study from Brunei indicated that children who had COVID-19 with FS had fewer additional symptoms at presentation compared to those without FS.¹¹

Additionally, our findings showed that patients with COVID-19 infection and FS had significantly elevated BT (39.13°C vs 37.37°C, p=0.000), PR (178.11 bpm vs 127.95 bpm, p=0.000), and RR (36.33/min vs 28.16/min, p=0.021) compared to those without FS. These findings may help raise awareness of the FS risk associated with COVID-19 infection. As highlighted in the Brunei study, higher fever, younger age, and family history of FS were identified as risk factors for FS in children with COVID-19 infection.¹¹

There are some limitations to our study. First, this is a single-center, retrospective, observational study; some information was unavailable, including CBC, electrolytes, LFT, inflammatory markers (CRP/ESR), and viral panels. Second, our study’s small sample size, especially in the transition period, may not represent the exact prevalence and risk factors of FS in COVID-19 cases. Third, the semiology of seizures and the time of fever before seizure onset, which were collected from the guardian’s statement and medical record, might be inaccurate. Fourth, we did not know the exact COVID-19 strain of cases in all periods because we could not identify the viral strain. Further large-scale, prospective studies with well-designed methods, including the testing of laboratory and inflammatory markers, as well as viral panels, are essential.

Conclusions

Footnotes

Acknowledgements

We thank all patients and the Faculty of Medicine, Srinakharinwirot University, Thailand, for their support.

ORCID iD

Acharaporn Maksikharin

Ethical Considerations

This Study Was Conducted in Accordance with the Principles of the Declaration of Helsinki and Was Expedited and Approved by the Institutional Ethics Committee for Human Research. This study was performed in line with the principles of the Declaration of Helsinki, with expedited review and approval by Srinakharinwirot University Ethics Committee (SWUEC-673004).

Author Contributions

Acharaporn Maksikharin and Olarn Prommalikit substantially contributed to the project by participating in the conception and design, aiding in data acquisition, analysis, and interpretation, drafting and revising the manuscripts, and giving final approval.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Srinakharinwirot University funding (NO 401/2567). The authors declare no relevant financial or non-financial interests.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The complete datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.*

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