This is the first ecologic study assessing febrile seizures with reference to contemporaneously collected multiplex viral respiratory samples from the same catchment population. We found that there was an increase in febrile seizures from May to October of each year compared to the risk of febrile seizure incidence in April, with the greatest risk in August. In Victoria, with a temperate climate, this correlates with late fall and winter seasons. These findings have been previously described and likely relate to the increased viral activity in these months, particularly Influenza, RSV and hMPV (Figs. 2 and 3) [10, 11, 13, 14]. This hypothesis is supported by the decreased risk observed in January, when fewer respiratory viruses are in circulation [34]. Notably, febrile seizures in children less than 1 year old were not significantly associated with any month of the year. One potential explanation for the absence of a trend in this age group is that febrile seizures occurring in this age group may be caused by non-seasonal viruses, such as HHV-6 [22].
There were four viruses in our model which were found to be positively associated with febrile seizure presentations. These were human metapneumovirus, influenza A and B, and RSV. Human metapneumovirus was positively associated with febrile seizures, with a RR of 1.19 (99% CI 1.07–1.33) in peak seasons, a strong and novel association. Human metapneumovirus infection has not been commonly described in association with febrile seizures and makes up a relatively small proportion of viral identifications in febrile seizure cohorts [10, 11]. However, hMPV has been associated with CNS illnesses ranging from seizures to encephalitis [35]. Further research is required to ascertain if a causal relationship exists between hMPV and febrile seizures, potentially focusing on the age distribution of children experiencing febrile seizures associated with hMPV infection.
Influenza viruses are recognised as an important cause of febrile seizures [19, 23, 29]. Our study has confirmed this with a 48% increase in febrile seizure incidence during peak Influenza A seasons and a 31% increase during peak Influenza B seasons, supporting previous findings that Influenza A is more strongly associated with febrile seizures [14, 29]. The strength of association between influenza and febrile seizures fluctuated in analysis of different subgroups. Influenza B was associated with a 1.37RR (99% CI 1.08–1.73) for severe febrile seizures, stronger than its association with mild febrile seizure occurrence. In general, Influenza viruses are associated with a greater proportion of complex febrile seizure presentations, though few studies have differentiated between Influenza A and B with regard to febrile seizure severity [10]. Nevertheless, given the small febrile seizure sample size in the subgroup analyses, the clinical significance of this association cannot be determined.
RSV had a distinct peak in May–July of each year, coinciding with the beginning of peak febrile seizure season. RSV is the most common cause of lower respiratory tract infections in children < 5 years old [36]. Moreover, it accounts for a significant proportion of respiratory viruses detected in children with febrile seizures [10]. RSV had a significant association with febrile seizures, with a 52% increase in risk in its peak seasons. This increase was consistent with previous findings [11, 25].
Ultimately, the goal of our study is to create a framework that depicts accurate risk of community health outcomes based on virus circulation. While the risk ratios of febrile seizures attributable to influenza viruses were approximately consistent with existing findings [20, 23], our risk ratios for RSV and hMPV were higher than those found in cohort studies of viral infections in febrile seizures [10, 11, 25]. One potential explanation for this is the abnormal influenza season observed in 2018, which had a delayed peak in October 2018–January 2019. Despite this, the peak of febrile seizures in winter 2018 was consistent with that of previous years. Our model likely attributed this to RSV and hMPV circulation which similarly maintained their trend of a winter peak. Thus, our findings highlight that there are multiple key viruses which may play a role in the occurrence of febrile seizures.
To our knowledge, this is the largest ecologic study relating febrile seizure incidence to circulating community viruses over such an extensive timeframe. The breadth of our inclusion criteria provided a sizeable dataset of both febrile seizure presentations and respiratory results. Respiratory PCR results were not restricted by age as the purpose was to estimate the local circulating community virus epidemiology for children presenting with febrile seizures. The 10-year time frame permitted sufficient data to confirm true seasonal patterns between viruses and febrile seizure presentations.
Additionally, the widespread use of multiplex PCR allowed collection of a large volume of concurrent sensitive data about numerous viruses [37, 38]. The interplay between the circulation of multiple viruses allowed realistic models for predicting febrile seizure incidence and the proportion attributable to specific viruses. We also determined our significance level at a low p-value (p < 0.01) to increase certainty in our findings.
The key limitation of the ecologic study design is that all associations are indirect links of febrile seizures incidence with key viruses. That is, although Influenza A and B, hMPV, and RSV circulation in the community may correlate temporally with febrile seizure presentations, our study cannot confirm that these are the causative agents associated with febrile illnesses leading to febrile seizures. In most febrile seizures presenting to emergency departments a respiratory PCR is rarely performed, and the assessment of the child usually only involves a clinical assessment to determine the cause of the seizure and rule out more sinister aetiologies [39].
The multiplex respiratory PCR performed at Monash Health sites had limitations. This PCR test does not detect HHV-6, a virus historically associated with febrile seizures. This may have been an explanatory variable for febrile seizure presentations in children less than 1 year old, which did not demonstrate a seasonal trend (Fig. 5). Additionally, our PCR assay did not differentiate between picornaviruses (i.e. enteroviruses and rhinoviruses). This made it difficult to determine the association of enterovirus and rhinovirus circulation with febrile seizures, which have been reported in previous studies [10, 11], and may have confounded our findings by leading to overestimation of the relationship between febrile seizures and the other viruses included in our model.
There was as gradual increase in the number of PCR tests performed throughout each year of our study due to the changes in the clinical use of PCR testing. Therefore, we calculated positive virus results as a proportion of the total number of PCR tests performed each month to ensure the values remained relatively consistent throughout the 10-year period. While this may have masked some seasonal variation in virus circulation, this was the simplest way to create uniformity in our virus variables for the sake of analysis.
It is also important to consider that our risk ratio values were obtained based on a comparison of peak viral circulation and median viral circulation. While this allows the findings of our study to be contextualised for clinicians and public health physicians, it is difficult to relate these values to previous cohort studies. Thus, our model requires further adjustments to increase the interpretability of our findings, and future research will focus on different definitions of peak viral seasons.
Although Monash Health is the major health network providing care to children from southern and eastern Melbourne, it does not capture all emergency presentations or PCR tests from that region. As such, our datasets represented a subset from that region.
Our study has established a method for studying temporal relationships of viruses to an illness of interest using independent datasets. This methodology has implications for future studies of illnesses with undefined viral pathogenesis. The ability to estimate “attributable proportion” for specific viruses for conditions such as febrile seizures, offers the potential to inform organism specific disease burden and resultant health technology assessments for viral vaccines and therapeutics. These studies can inform healthcare practices and resource allocation and increase public awareness of the implications of specific viral infections, as has been done in Utah with GermWatch [40].
