On December 7, 2022, China abruptly amended its COVID-19 containment policy, ending the almost three-year-long zero Covid policy. This sudden shift in approach led to a surge in COVID-19 outbreaks countrywide, with the mutated Omicron variant as the dominant variant (1). Unlike its predecessor, the delta variant, Omicron was particularly associated with significantly increased pediatric admissions in China (2–4) and abroad (5–9). It further impacted other pediatric illnesses; for instance, several US investigators noticed a sharp rise in the incidence of Croup, a clinically diagnosed pediatric disease caused by virus-induced subglottic airway inflammation or laryngotracheobronchitis (10–13). Recent publications from Korea (14), Japan (15), and the USA (16) have all demonstrated an association between the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant and increased incidence of febrile seizures among children compared to the pre-Omicron stage. While emerging evidence clarifies this association, the clinical characteristics of these children and other associated factors are still largely undescribed.

Febrile seizure (FS) is a common neurological disorder affecting 2%–4% of children <5 years old who do not have any intracranial infections (17). Although its exact etiology is still unclear, it's strongly associated with the elevation of body temperature, certain vaccinations, previous history and family history of FS, maternal alcohol exposure, iron deficiency, and viral infections (18–20). Among the published viral causes of FS, adenoviruses, human herpesvirus-6, influenza, and rhinoviruses are the standout culprits (21, 22); for instance, evidence suggests that 15%–20% of children hospitalized with influenza A virus develop FS (23). In Wuhan City, the Omicron strains BA.1, BA.2, BA.5, and BF.7 were the dominant strains that significantly drove up pediatric admissions at our hospital in February 2023.

Given the reported association between the Omicron variant and increased incidence of FS, coupled with the paucity of studies on the risk factors associated with febrile seizures among children infected with the SARS-CoV-2 Omicron variant, we sought to evaluate SARS-CoV-2-Omicron infected children to ascertain their risks for developing febrile seizures and related treatment modalities.

In this case-control study, we examined the incidence of febrile seizure among SARS-CoV-2-Omicron-infected children, their admission rate, risk factors associated with febrile seizures among the infected children, and their treatment modalities. Our findings revealed that 5.74% of the children had febrile seizures, and approximately 60.8% were hospitalized. These findings suggest that both COVID-19 associated OPD visits and the incidence of febrile seizures among the COVID-19-infected children rapidly increased during the Omicron period. Our results are consistent with those of Cloete et al., who reported a rapid rise in pediatric COVID-19 hospitalizations in the early stages of the Omicron wave in South Africa (25). Furthermore, a Korean study by Joung et al. demonstrated that 7.0% of COVID-19 infected Korean children developed COVID-19-associated febrile seizures during the Omicron period (26).

In August 2021, during the highly transmissible “delta variant” wave, the Chinese government adopted the “Dynamic zero-COVID” policy to stem the spread of the disease (27). During that period, pediatric seizure-related hospitalizations dropped drastically. For instance, a study in Hong Kong demonstrated a significant reduction in seizure-related emergency department visits in 2020 [RR 0.39 (95% CI: 0.174–0.526), p = 0.001]. Furthermore, the rate of febrile seizure-related admissions for children aged 0–6 decreased by more than 20% from the previous year (28). However, on December 7, 2022, China abruptly abandoned its zero-COVID policy, leading to a surge in COVID-19 outbreaks nationwide, with the mutated Omicron variant as the predominant strain (1). Since then, there has been a significant increase in pediatric infections with the SARS-CoV-2 Omicron variant and subsequently increased incidence of febrile seizures (2).

This study had no statistical difference in the ages of cases and controls (p > 0.05). However, children with febrile seizures had a slightly higher median (IQR) age than the controls, 24.0 (15.5–41.0) vs. 22.5 (3.0–68.3) months, respectively. Our findings are supported by Juong et al., who also found that children with COVID-19 and febrile seizures were generally older than those without febrile seizures; median (IQR) age 33.0 (22.0–60.0) and 23.0 (14.5–31.5) months, although their control group was COVID-19 negative children (26). In addition, evidence suggests that sex can influence the differentiation and maintenance of virus-driven T cells and antiviral immune response in tissues (29). This study had no statistical difference between the groups regarding sex distribution. Similarly, the underlying disease, number of days of hospitalization, and poor sanity of both groups did not statistically differ.

Published literature alludes to genetic predispositions for FS. For instance, Veisani et al.'s meta-analysis concluded that family history is strongly associated with febrile seizure (30). In this study, we observed a previous history of FS and a family history of FS in 20.0% and 11.1% of the cases and only 2.9% and 0% of the controls, respectively. Based on these findings, genetic factors and shared environmental exposures may play an essential role in the development of FS.

According to Taytard and colleagues, children infected with the Omicron variant have significantly higher body temperatures than those infected with the Delta variant (30). The higher peak body temperature caused by SARS-CoV-2 infection during the Omicron period may have contributed to increased febrile seizures. Despite both cases and controls in our study being positive for the Omicron variant, the cases had significantly higher body temperatures than the controls; mean (±SD) body temperature, 39.5 ± 0.7°C and 38.8 ± 1.1°C, respectively. These findings are consistent with those of Margaretha et al. (31), who found mean temperatures of 39.01 ± 0.56°C and 38.64 ± 0.45°C for children with and without FS, respectively (31). Meanwhile, Leung et al. observed that FS tended to occur when body temperatures exceeded 39°C (32).

Other clinical symptoms associated with COVID-19 were not significantly different between cases and controls, except for cough, expectoration, dry rales, wet rales, and respiration rate, which were significantly higher in controls. In most cases, COVID-19 affects children in a mild form. Fever, dry cough, and fatigue are some of the common symptoms experienced by children (33). In previous studies, the cough has been associated with high intrathoracic pressure, which can result in cough-induced syncope and fainting (34). However, our study found that cough was associated with a lower risk of febrile seizures [RR 0.473 (95% CI: 0.252–0.890), p = 0.020]. Children with COVID-19 and cough were less likely to experience febrile seizures than controls, whereas those who had a high fever were more likely to experience febrile seizures. This suggests that fever is more closely associated with FS than respiratory symptoms.

Regarding the laboratory results, bacterial infection rates were higher in cases than in controls. Bacterial infection was observed in 33.3% of children with FS and 16.2% of controls. Our findings are consistent with Jarrett et al. (35), who found a higher prevalence of bacterial infection in cases than thin e control. Similarly, procalcitonin levels (PCT) were higher in cases than in controls, with median PCT levels of 0.29 ng/ml in cases ag/ml in controls. A similar finding was found by Murakami et al. (36) who found increased levels of PCT in convulsion patients. Increased levels of procalcitonin were first observed in 1993 in patients with sepsis, and today it is a widely used biomarker for serious bacterial infections (37). PCT is a natural prohormone of calcitonin synthesized by C-cells of the thyroid glands (38). Its production increases in patients with septicemia and infections caused by gram-negative bacteria due to inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 (IL-6) (39). This study observed gram-negative mycoplasma pneumonia co-infections in 23.3% of cases compared to 20% of controls. Furthermore, the erythrocyte sedimentation rate was significantly lower in cases than in controls, which corresponds with the findings of Abbasi et al. (40).

According to a study by Pisacane et al., children with FS had significantly higher rates of iron deficiency anaemia than their non-FS counterparts (41). Interestingly, Talebian et al. revealed that anaemic children had a reduced incidence of febrile seizure compared to children without anaemia (42). In support of this finding, Yousefichaijan and colleagues found that iron deficiency prevents febrile convulsions in children and likely increases the threshold of neuronal excitation during fevers (43). In line with these studies, our findings revealed that cases had lower haemoglobin levels than controls and had a lower risk of developing FS [RR, (0.979; 95% CI: 0.959–0.999), p = 0.044]. Similarly, children with low eosinophil counts had a lower risk of developing FS [RR 0.494; (95% CI: 0.311–0.783), p = 0.003] than the controls. Eosinophils play an essential role in allergic inflammation, but no evidence has been found linking them to FS (44).

Moreover, in a recent study by Romanowska et al., the platelet and lymphocyte count of children with FS were significantly lower than those of controls. In contrast, the neutrophil counts were significantly higher (45). In line with the study, our study found that the platelet and lymphocyte counts were significantly lower in cases than in controls. Meanwhile, neutrophil counts were significantly higher in cases than in controls. It has been determined that neutrophil-lymphocyte ratio and mean platelet volume are novel inflammatory biomarkers associated with the development of FS in children (44).

Regarding liver and renal function tests and serum electrolytes, there was no significant difference between cases and controls, other than blood urea nitrogen level, which was significantly higher in cases than in controls. This finding is supported by Abbasi et al., who also found that patients with febrile seizures had substantially higher levels of BUN and creatinine than those without febrile seizures (40). It has been shown that patients with a history of illnesses, such as vomiting and diarrhea or signs of dehydration, may affect their renal function tests (46). In this study, 24.4% of the cases and 11.8% of the controls reported vomiting during admission. While it has been shown that hyponatremia is associated with febrile seizures (47), another study by Yousefichaija et al. has found that children with febrile seizures have normal electrolyte levels. And therefore, it is not necessary to routinely test the electrolyte levels of all patients with simple febrile seizures (48). This study found no differences between cases and controls in electrolyte levels.

The prescription of antibiotics and antivirals was not significantly different between the two groups, except for the antiflu medications, where cases got more than the controls. In contrast, fewer children in the case group were given corticosteroids and expectorants than controls. The increasing use of antiflu medications could be attributed to SARS-CoV-2 co-infection with influenza A and B viruses. A meta-analysis by Masoud Dadashi et al. showed that influenza infection was 0.8% in patients with confirmed COVID-19, while the frequency of influenza virus co-infection among patients with COVID-19 was 4.5% in Asia and 0.4% in North America (49). In line with these findings, we observed a higher incidence of influenza A; 23.3% vs. 13.8%, and influenza B; 41.9% vs. 27.7% among cases than controls, respectively.

Strengths and limitations: This study had a few distinct advantages worth highlighting: (1) It was the first study to examine the incidence of febrile seizures in children infected with the SARS-CoV-2-Omicron variant in Hubei, China. (2) It further examined detailed clinical presentations and risk factors associated with febrile seizures in children infected with the SARS-CoV-2-Omicron variant. However, the following limitations existed: (1) Sample size was rather small and this could limit the study's power. (2) The study was retrospectively conducted thus it carried the inevitable disadvantages of retrospective studies such as recall bias and missing information. (3) The study was a single-center study, so the findings cannot be generalized to make inferences on the incidence of FS among children infected with COVID-19 across the country.

In summary, a significant increase in febrile seizures was observed in children with SARS-CoV-2-Omicron infection. Approximately 5.74% of participants with COVID-19 suffered febrile seizures. A higher body temperature, a history of FS, a higher procalcitonin level and a higher neutrophil count were all associated with an increased risk of FS in children with COVID-19. The risk of developing FS was lower in children with COVID-19 who had low eosinophil counts, and low hemoglobin levels. More children in the case were prescribed antiflu medications than those in the control group. In contrast, fewer children in the case group were given corticosteroids and expectorants than those in the control group.