DOI: https://doi.org/10.21203/rs.3.rs-2758990/v1
Objectives:This study sought to investigate the characteristics of febrile seizures in children infected with the Omicron variant in Chongqing province, west of China, and underscore the importance of monitoring for potential neurological complications associated with this variant.
Methods: This retrospective study enrolled a total of 84 pediatric patients with COVID-19 and FS who were admitted to Chongqing University Three Gorges Hospital between December 11th and December 26th, 2022. Demographic, clinical, laboratory, radiological and EEG data were retrospectively summarized.
Results: The study enrolled 84 children, with a median age of 21.5 (15-35.5) months and a range of 6-162 months. Among these, 11.9% were of atypical age (age > 5 years). The patient population comprised of 54 (64.29%) boys and 30 (35.71%) girls. 32.14% presented with complex FS. Generalized tonic-clonic seizures occurred in 51.19%, followed by generalized tonic seizures (43.43%). 86.9% occurred within 24h after fever onset and 80.95% continued for ≤ 5min.
Conclusions: Febrile seizures in children with Omicron VOC are common COVID-19 illness with a higher prevalence compared with other VOCs. They present with similar clinical manifestations and resolve spontaneously with a benign clinical outcome in line with other seasonal viruses.
Seizure is a commonly encountered critical condition during childhood, with febrile seizures (FS) representing the leading cause. The prevalence of FS is age-dependent, with the majority of cases occurring between 6 months and 5 years of age and ranging from 3–5% []. The etiology and pathogenesis of FS are complex, with both environmental and genetic factors thought to play a role. Among these factors, viral and bacterial infections are considered to be important triggers of FS, particularly viral infections. Several viruses such as rhinovirus, adenovirus, influenza virus, enterovirus, parainfluenza virus, human herpesvirus type 6 and 7 (HHV-6/7), and respiratory syncytial virus (RSV) have a strong correlation with the occurrence of FS [].
Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and rapidly spread worldwide. As of the end of 2022, the World Health Organization (WHO) has identified five variants of concern (VOC): Alpha, Beta, Gamma, Delta, and Omicron. The Omicron variant was first detected in November 2021 and is characterized by significantly enhanced transmissibility and immune evasion capabilities compared to other VOCs. In early 2022, the Omicron variant emerged as the dominant global epidemic strain, displacing the Delta variant. Previous studies have reported that COVID-19 can lead to neurological complications, particularly febrile seizures (FS), which are more prevalent in children infected with the Omicron variant [-]. Following the government's lifting of COVID-19 control measures on December 11th, 2022, there was a significant surge in the number of children attending fever clinic in Chongqing University Three Gorges Hospital, located in western China. During the Omicron pandemic, we observed a rapid increase in cases of febrile seizures (FS), within the ensuing 16 days up to December 26th, 2022, however SARS-CoV-2 testing no longer being routinely performed thereafter. While previous studies have reported neurological involvement in children and adults with COVID-19, there have been relatively few investigations on FS, with most of these studies limited by small sample sizes and incomplete information. Therefore, in the present study, we collected and summarized the clinical data of 84 hospitalized children with FS during the Omicron variant surge in our hospital, between December 11th and December 26th, 2022.
In this study, we selected a total of 84 children aged 0–18 years, who were admitted to Chongqing University Three Gorges Hospital between December 11th and December 26th, 2022, and had been diagnosed with both FS and COVID-19. All patients had tested positive for SARS-CoV-2 antigen by colloidal gold method or ORF1ab and N gene by real time fluorescent quantitative polymerase chain reaction (RT-qPCR), using a nasopharyngeal swab sample, and were characterized by family clusters. Patients with a history of epilepsy or neurodevelopmental delay were excluded. Demographic information, including age, sex, past medical and family history, clinical manifestations, laboratory data, and therapy, were collected for analysis. This study was approved by the Ethics Committee of Chongqing University Three Gorges Hospital (Approval number: 2023 NO.25). The continuous variables were expressed as median with interquartile range or range. The categorical variables were expressed as frequency (percentage).
During the study period, a total of 84 pediatric patients with confirmed COVID-19 infection and presenting with FS were enrolled. The demographic and clinical characteristics of the patients are presented in Table 1. The median age of the patients was 21.5 months, with a range of 6-162 months, and 10 (11.9%) patients were of atypical age (> 5 years). Among the enrolled patients, 63 (75%) were younger than 3 years and therefore ineligible for COVID-19 vaccination, while the remaining 21 patients (25%) did not have a documented COVID-19 vaccination status. Of the patients, 54 (64.29%) were male and 30 (35.71%) were female. A total of 31 (36.9%) patients had a prior history of FS, while 11 (13.1%) patients had a family history of FS. Two patients had a history of viral encephalitis or congenital adrenal hyperplasia, respectively. Additionally, three patients were born prematurely between 33 and 36 weeks of gestation, while the remaining 81 patients (96.43%) were born at term.
As shown in Table 1, all patients had a reported median maximum temperature of 39.5℃ (IQR 39.2–40). The median febrile days were only 2 days (IQR 2–3, range 1–6) and thus the patients had a fairly short duration of hospitalization with a median of 3 days (IQR 3–4, range 1–8). 73 patients (86.9%) experienced FS on the first day, with the remaining 11 patients (13.1%) experiencing FS on the second day following the onset of fever. Furthermore, 27 patients (32.14%) presented with complex provoked seizures, which were defined as exhibiting two or more seizures within 24h or the same febrile course, seizures with a duration over 15 min, or focal seizures. Of these, two patients showed focal features, including tonic movements of one extremity or gaze deviation. The proportion of generalized tonic-clonic seizures (n = 43, 51.19%) was found to be slightly higher than that of generalized tonic seizures (n = 39, 43.43%). Moreover, the majority of FS episodes (80.95%) continued for 5min or less, with only one patient (1.19%) presenting with status epilepticus, defined as either a single unremitting seizure lasting longer than 30min or frequent clinical episodes without an interictal return to the baseline clinical state. In terms of symptoms, cough was the most commonly reported, accompanied in 64 (76.19%) of FS episodes, followed by vomiting (n = 19, 22.62%).
Details of laboratory data are presented in Table 2. The SARS-CoV-2 omicron variant mainly affected lymphocyte in blood routine. Of all patients, 56 cases (66.67%) had lymphopenia defined as lymphocyte count < 1.5×109/L, and one case (1.19%) had thrombocytopenia defined as platelet count < 100×109/L accompanied with the lowest WBC, lymphocyte count and hemoglobin levels. Furthermore, 28 cases (34.57%) had elevated C-reactive protein (CRP) (> 8mg/L) and 13 cases (22.8%) had elevated procalcitonin (PCT) (༞0.5ng/mL). As a result, 25 patients (29.76%) received antibiotic treatment. IgM antibody tests and mPCR tests were performed in 33 and 21 episodes, respectively. Of these, 15 tested positive for mycoplasma pneumoniae and two were positive for adenovirus by the IgM antibody test, respectively. All 21 patients tested negative for RSV, adenovirus, influenza A virus, influenza B virus, parainfluenza virus type I and parainfluenza virus type III by the mPCR test. Six patients had cerebrospinal fluid analysis, all with normal findings.
Table 3 shows the results of EEG, neuroimaging, and chest imaging. A total of 17 patients underwent EEG, and none of them showed epileptic discharge. However, 12 patients showed generalized background slow-waves. Twenty patients underwent brain CT, and one of them showed widened extracerebral space. Five patients underwent brain MRI, and only one showed a few abnormal signals near the posterior horns of bilateral ventricles, which was mostly myelinated terminal area, but presented normal neuromotor development. To sum up, there were no remarkable findings in neuroimaging. Of all patients, 4 cases had chest CT images available, of whom one had increased lung markings, and one had uneven transmittance and bilateral pulmonary flocculent shadow; 13 cases had chest radiographs available, of whom eight had increased lung markings, and two had bilateral pulmonary flocculent or spotty high-density shadow, respectively.
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.
Febrile seizures in children with Omicron VOC are common COVID-19 illness with a higher prevalence compared with other VOCs. They present with similar clinical manifestations and resolve spontaneously with a benign clinical outcome in line with other seasonal viruses.
Acknowledgments
The authors would like to thank Chongqing University Three Gorges Hospital, SARS-CoV-2 laboratory and medical team that are fighting against the illness.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This project was supported by Natural Science Foundation of Chongqing (No.cstc2020jcyj-msxmX0969).
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Author Contributions
All authors participated in study design and conceptualization of the study. LL and RO collected data. LL performed the literature review for this article and was a major contributor in writing the manuscript. HC and NW reviewed and revised the manuscript. All authors read and approved the final manuscript.
Ethics Statement
The studies protocol was designed in accordance with the ethical guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Chongqing University Three Gorges Hospital (Approval number:2023 NO.25). Written informed consent of participants was waived with an approval by the Institutional Review Board.
Tables 1-3 is available in the Supplementary Files section.