The changes in incidence rates at different age intervals for those diagnostic codes that showed significant correlation with vaccination are summarized in Table, Supplemental Digital Content 1, http://links.lww.com/INF/C113.
The annual hospitalization rate for any kind of CS in children <5 years is negatively correlated with the vaccination coverage (r = −0.673; P = 0.033) (Table 1, Fig. 1) and positively correlated with the admission due to RAGE (ρ = 0.506; P = 0.001; Table 2). These decrease rates (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C113) ranged from 16.2% [95% confidence interval: 8.3–23.5%] in 2007 to 34.0% (27.3–40.1%) in 2010, as compared with the median rate of the pre-vaccination period (2003–2006). In children 1–2 years of age, there was also a significant decrease in hospitalization rates ranging from 28.5% (16.2–39.0%) in 2008 to 48.4% (38.2–56.9%) in 2012, significantly correlated with rotavirus vaccination (r = −0.798; P = 0.006) and RAGE hospitalization rate (ρ = 0.366; P = 0.020). There was a positive and significant correlation for children 2–3 years of age (ρ = 0.421; P = 0.007) but without evidence of concomitant reduction in seizures admission rates, which could be explained by the lack of power for a low number of cases in this age group. In the remaining age groups, changes were either not statistically significant or not related to vaccination changes and/or RAGE admission.
The hospitalization rate for convulsions (780.3* ICD-9-CM code) is also correlated with rotavirus vaccination coverage (Table 1, Fig. 1) and RAGE hospitalization rate (Table 2) and a significant decrease was found (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C113) in: (1) infants 1–2 years of age (coverage r = −0.813, P = 0.004; RAGE rate ρ = 0.395, P = 0.012) with decrease rates from 26.6% (12.9–38.1%) in 2007 to 51.8% (41.1–60.6%) in 2009; (2) children <5 years (coverage r = −0.747, P = 0.013; RAGE rate ρ = 0.543, P < 0.001) with decrease rates from 18.7 % (9.6–26.8%) in 2007 to 42.5% (35.3–48.9%) in 2012. Once again a significant and positive correlation for the children of 3 years of age was found (ρ = 0.249; P = 0.006), but no change was observed in seizure hospitalizations rate for this age group. The decrease rates obtained for the remaining age groups cannot be explained as a result of rotavirus vaccination and/or RAGE admission rates. Note that for these 2 pathologies there are other significant values in Table 2, however only those significant in both tables have been commented. For epilepsy (345* ICD-9-CM codes), there were no significant correlations (Tables 1 and 2) for any age group. For convulsions in newborns (779.0* ICD-9-CM codes), there was no significant correlation with RAGE hospitalization rate (ρ = −0.010; P = 0.950) and correlation with vaccination coverage was r = −0.175 (P-value was not computed because lack of homoscedasticity of the data). Therefore, variations obtained for both epilepsy and convulsions in newborns cannot be related to rotavirus vaccination.
To corroborate our findings an additional comparison was performed taking into account the lowest rate of the analyzed seizure code in pre-vaccination period instead of the average rate. These rates were selected according the age group and the corresponding pathology. Our positive findings for children <1 year of age and younger than 5 were maintained (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C113). Of note, as in the previous analysis, we have considered that the post-vaccination period started in the same year for all age groups, because there could be a herd effect from the vaccinated infants in non-vaccinated children. According to Table, Supplemental Digital Content 2, http://links.lww.com/INF/C114, there is a significant reduction in hospitalization rates only in children who actually received the vaccine.
Finally, an alternative analysis was performed comparing the vaccination coverage estimated in the whole population with the real coverage observed among “seizures” patients, obtained through the individual electronic vaccination record. (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C115). The coverage in cases were significantly lower than global coverage for all the pathologies (“any kind of CS” and “convulsions”) for all the years except 2010—the year when rotavirus vaccines were temporarily withdrawn from the Spanish market.12
This study shows for the first time that rotavirus vaccination even with moderate coverage may have a significant impact in seizure-related hospitalizations in childhood. This additional benefit of rotavirus vaccination appears more marked in the youngest infants, namely during the first 2 years of age. This reduction may mean not only additional prevention of rotavirus disease burden but also further cost saving and avoidance of infant and family suffering.
Our results are aligned with the recent Centers for Disease Control and Prevention report on the benefits of rotavirus vaccines in terms of effectiveness against CS.7 Payne et al7 found that a full course of rotavirus vaccination significantly reduced the risk of CS at least during the year following the last rotavirus vaccination, with a 18–21% decrease in risk seizures requiring emergency care attendance or hospitalization, as compared with children not receiving the vaccine. This study confirms the findings of Payne et al using a different analytical method in a different country, focusing on the more severe forms of CS, that is, those that require hospitalization. Interestingly, in our series no displacement of cases to later ages is found, which might suggest a longer duration of this protective effect of vaccination and/or the cumulative effect of vaccinated cohorts and increasing coverage.
The rotavirus vaccine impact found is driven mainly through its effect over hospitalizations due to convulsions (ICD-9-CM code) but not to other seizure-related conditions. This agrees well with the rationale behind its beneficial effect: the vaccination prevents the stimulus (ie, rotavirus infection) in infants otherwise susceptible to either febrile seizures or neurological tropism of rotavirus. This impact on CS hospitalizations is more obvious in the first 2 years of age, which may simply reflect that protection is provided soon after vaccination and that both febrile and non-febrile seizures have their maximum incidence around that age. Our design cannot distinguish whether the contribution is mainly driven by the decrease of non-febrile or febrile seizures. Non-febrile seizures incidence usually peaks before 1 year of age and is more frequently linked to rotavirus etiology. However, we consider that the benefit exerted by rotavirus vaccines is mainly due to the prevention of febrile seizure-related hospitalizations. Febrile seizures are the most frequent cause of seizure hospitalization in childhood and their incidence peaks also in this age range—around 1.5 years of age—when the magnitude of the hospitalization decrease found is larger.13,14
Rotavirus can act as a seizures trigger in susceptible children or get directly involved in the pathogenesis.1–5,15 Antigenemia is frequently found in children with rotavirus gastroenteritis, showing that the infection is not locally restricted to the intestine and that systemic illness can be produced.16 The specific relation between rotavirus infection and seizures has been described in the literature.1–5,15 Rotavirus-associated seizures are more frequently reported in clusters and in afebrile children.15,17 Whatever the case, rotavirus assessment is not part of the routine work-up of infants with febrile or afebrile convulsions, and thus, its actual burden is probably underestimated.18 Several mechanisms have been suggested to explain the relation between rotavirus infection and seizures, from direct neurotoxicity to specific neurotransmitter interferences at calcium channel levels.19,20
Our findings need to be carefully interpreted. Other uncontrolled factors (prematurity, any other infectious trigger…), the variability in management and admission policy in children with seizures or changes in the coding practices, may have also influenced our findings. The strengths and weakness of the national administrative database for hospital admissions used as data source in our study have been previously discussed.8 Even though the ICD-9-CM code combination applied in our study has been previously shown to have a high positive predictive value for seizures,11 it is also true that the positive predictive value was lower for inpatient admissions—the population in our study—than for emergency department visits. The sustained global reduction in CS hospitalization of “any cause” and specifically of “convulsions” observed is strongly correlated with the use of rotavirus vaccines and rotavirus gastroenteritis but this is not the case for other kind of childhood convulsions classified under the myoclonus, epilepsy or neonatal seizures codes. Further differentiation in other more specific clinical subgroups of seizures was not possible with the current design. In addition, although estimation of vaccination coverage using sales is a usual practice, the percentage obtained may be overestimated, as the distributed doses may not necessarily reflect the actual number of doses that have been administered. However, the strong correlation of our findings with rotavirus vaccine coverage and patient age reinforces our interpretation of the data. The impact increases with vaccine coverage and with the accumulation of vaccinated children in the cohort, suggesting also that this protective effect of rotavirus vaccines persist over time: there seems to be no displacement of cases to later ages. Also, the vaccine impact is driven mainly through its effect in infant convulsions (nonfebrile and febrile seizures) but not in other seizure-related conditions, which agrees well with the rationale behind its beneficial effect: the vaccination prevents the stimulus (ie, rotavirus infection) in otherwise susceptible infants. For all these reasons, continued surveillance and further population-based studies are needed to corroborate and follow-up our findings.
Rotavirus vaccine may reduce the risk of hospitalization due to CS, mainly in infants. These benefits can arise with just moderate rotavirus vaccination coverage. Additional studies are required, but rotavirus vaccination benefits seem to be broader than just prevention of severe forms of acute gastroenteritis.
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Gastroenteritis/epidemiology; seizures; febrile seizures; rotavirus infections/prevention & control; rotavirus vaccines
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