During the sixteen-day study period, our team observed a total of 3536 children attending the children's fever clinic, among whom 343 were diagnosed with pediatric COVID-19 and subsequently hospitalized. Notably, 84 of the hospitalized children (24.49%) presented with FS. A prior report from South Africa documented a prevalence of FS in 16.8% of hospitalized children with COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave []. Thongsing et al., recently reported that 1.8% of pediatric patients with COVID-19 presented with FS during the Omicron surge [4]. This observation was in contrast to the rare occurrence of FS reported in the pre-Omicron era. Cadet et al., reported that only 0.5% of COVID-19 cases in children aged 0–5 years were diagnosed with FS [], while Duman et al., reported a slightly lower incidence of 0.3% of children with COVID-19 exhibiting seizures in the pre-Omicron era []. However, it is worth noting that a significant proportion of children with COVID-19 may not have sought medical attention at the fever clinic but instead opted for online consultations or home observation. Therefore, the incidence of FS in children with COVID-19 may be significantly lower than the observed rate of 2.38% (84/3536) in our study, and the assessment of this incidence in the Omicron era may prove challenging.
During the Omicron surge, a higher incidence of FS in children with COVID-19 was observed compared with COVID-19 negative patients or prior VOCs in several countries, including the United States, Japan, and South Korea [4,5,]. These findings indicate that FS is a common symptom in children infected with Omicron distinguished from other variants. Omicron differs from the other SARS-CoV-2 variants. For example, Omicron primarily affects the upper respiratory tract, whereas the other SARS-CoV-2 variants affect the lower respiratory tract []. As we know, upper respiratory tract infection is the most common cause of FS. Therefore, the Omicron VOC should be considered a strong potential contributor to FS in children with COVID-19.
In the present study, we observed that 11.9% of pediatric patients diagnosed with COVID-19 exhibited atypical age (age > 5 years), which was comparable to the rate seen in patients without COVID-19 [2,]. Additionally, we found no instances of FS reported in children aged < 6 months. In contrast, Seo et al., reported that patients with COVID-19 were more likely to present at atypical age (age < 6 months, or > 5 years) than those without COVID-19 (26.8% versus 9.5%, P = 0.006), with a particularly significant association noted in patients older than 5 years (22% versus 4.8%, P = 0.003) during the same time period [11]. Another study conducted in South Korea found that 24.59% of patients (15/61) were over 6 years of age [9].
However, male predominance was observed in previous study, which was in accordance with our research, especially in simple FS [11]. It is noteworthy that male predominance has been documented in other COVID-19-related complications in children, such as myocarditis and multisystem inflammatory syndrome (MIS-C) [8,]. Based on two studies, the number of children diagnosed with both febrile seizures (FS) and COVID-19 was either 18 or 44, with an even gender distribution noted in both groups. However, due to the small sample sizes and the lack of a control group, statistical comparisons between the sexes could not be made [4,7]. It is well-established that male gender is a strong predictor of severe COVID-19 in adults []. Conversely, no significant differences have been observed in the diagnosis of COVID-19 between males and females, regardless of children or adults [8]. Despite this, a comprehensive understanding of the molecular and biochemical mechanisms revealing the correlation between male gender and severe COVID-19 remains lacking. One possible explanation for this link is related to sex hormones, specifically testosterone, which can promote the expression of angiotensin converting enzyme (ACE) 2 and transmembrane protease serines (TMPRSS) 2 that are necessary for the entry of the SARS-CoV virus into target cells. Moreover, females generally possess a greater number of innate immune cells and demonstrate more robust adaptive, cell and humoral-mediated immune responses to antigenic stimulation compared to males [].
In line with typical viral infections, generalized tonic-clonic and generalized tonic seizures with a duration of 5 min or less were the most prevalent in individuals with FS, and simple FS remained the most frequently encountered form [7,9,11]. Nonetheless, in another investigation, complex FS was found to be more prevalent, accounting for 88% of all cases [4]. This can be attributed to the utilization of a distinct definition of complex FS with a duration exceeding 5min. Even if FS were classified using the same criterion, only six additional patients would be categorized as having complex FS, which was still a lower proportion. Due to the small sample size, the findings of their report may not fully and accurately represent the characteristics of FS. Although FS induced by SARS-CoV-2 were not that serious and did not require intensive care in most cases similar to other viral infections. However, it is important to note that multiple seizure episodes were observed in 25% of cases, and approximately 14.27% of patients experienced seizures lasting longer than 5min. These observations highlighted the importance of emphasizing management strategies for emergency seizures and seizure recurrence in the home setting.
Literature indicates that respiratory and gastrointestinal symptoms are the most prevalent in children with COVID-19 [6,], which is in consistent with the findings of our study. Specifically, vomiting occurred in 22.62% of patients, while diarrhea was present in 4.76%. Given these observations, possible causes of seizures in patients with fever could be associated with encephalitis or encephalopathy. However, due to concerns regarding potential contamination and sedation, only a small proportion of cases (7.14%) underwent cerebrospinal fluid (CSF) analysis, and a slightly larger proportion (29.76%) underwent neuroimaging, which revealed unremarkable findings. Furthermore, SARS-CoV-2 testing was not performed on CSF in our hospital. In this study, abnormal neurological signs were not observed, and none of the patient’s required intubation or died from seizures. All patients were quickly discharged with a median stay of 3 days and did not experience any readmissions or neurological sequelae during the two-month follow-up period. Therefore, routine CSF and neuroimaging examinations may not be necessary, except in cases of complex FS, suspected encephalitis, or abnormal neurological physical examinations.
The pathogenicity of the Omicron variant has been extensively reported to be significantly reduced compared to other VOCs [,]. In our study, only three patients were diagnosed with pneumonia by chest radiograph or CT and one was infected with enterococcus faecium validated by urine culture. All the patients with FS infected with Omicron showed mild symptoms and no serious organ damage or metabolic disorders. The researchers found that Omicron variant replicated poorly and displayed weaker cell-cell fusion activity when compared with the Delta variant in VeroE6/TMPRSS2 cells, which may explain the lower disease severity []. The exact pathophysiology of FS in pediatric COVID-19 patients is not yet fully understood, but it is speculated to involve inflammatory injury triggered by SARS-Cov-2. COVID-19 induces systemic inflammation, leading to the release of high levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17. This inflammatory response can damage the blood-brain barrier (BBB), activate microglia, and lead to increased glutamate levels, upregulation of N-methyl-D-aspartate (NMDA) receptors, and neurotransmitter depletion, ultimately inducing excitotoxicity and seizures. Additionally, vascular endothelial injury, which leads to the activation of the coagulation cascade and thrombotic events, and direct viral injury to the nervous system have been proposed as potential etiologies of other neurological complications such as encephalitis, neuropsychiatric symptoms, encephalopathy, or long-term brain sequelae [,].
This study had several limitations. Firstly, the retrospective nature and single-center design may limit the generalizability of the findings to a broader population. Secondly, not all patients underwent CSF, EEG, and neuroimaging examinations due to concerns about potential contamination and sedation. Additionally, the lack of long-term follow-up may raise concerns regarding the accuracy of the diagnosis of FS and the potential tendency to epilepsy. Thirdly, the identification of the Omicron strain was not available, but given the Chinese Center for Disease Control and Prevention report of Omicron VOC as the only variant present in the country during the study period [], all COVID-19 patients in our study were highly speculated to have Omicron. Finally, the possibility of unrecognized co-pathogens causing FS cannot be ruled out as only a small number of patients underwent multiple virus tests. Further studies are warranted to elucidate the mechanism behind the higher prevalence of FS during the Omicron surge.