Postvaccination Febrile Seizure

Severity and Outcome

Lucy Deng, MBBS,a,b Heather Gidding, PhD,a,c,d Kristine Macartney, MD,a,b Nigel Crawford, PhD,e,f Jim Buttery, MD,e,g
Michael Gold, MB, CHB,h,i Peter Richmond, MBBS,j,k Nicholas Wood, PhDa,b

BACKGROUND: Febrileseizures (FSs) are a common pediatric condition caused by a sudden rise in abstract
temperature, affecting 3% to 5% of children aged #6 years. Although vaccination can cause
FSs, little is known on whether FSs occurring in the time soon after vaccination (vaccine-
proximate febrile seizures [VP-FSs] differ clinically from non–vaccine-proximate febrile
seizures [NVP-FSs]). We compared the clinical profile and outcomes of VP-FS to NVP-FS.
METHODS: Prospectivecohort study of children aged #6 years presenting with their first FS at 1
of 5 Australian pediatric hospitals between May 2013 and June 2014. Clinical features,
management, and outcomes were compared between VP-FS and NVP-FS.
RESULTS: Of 1022 first FS cases (median age 19.8 months; interquartile range 13.6–27.6), 67
(6%) were VP-FSs. When comparing VP-FS to NVP-FS, there was no increased risk of
prolonged (.1 day) hospitalization (odds ratio [OR] 1.61; 95% confidence interval [95% CI]
0.84–3.10), ICU admission (OR 0.72; 95% CI 0.10–5.48), seizure duration .15 minutes (OR
1.47; 95% CI 0.73–2.98), repeat FS within 24 hours (OR 0.80; 95% CI 0.34–1.89), or
requirement for antiepileptic treatment on discharge (OR 1.81; 95% CI 0.41–8.02). VP-FS
patients with a laboratory-confirmed infection (12%) were more likely to have a prolonged
admission compared with those without.
CONCLUSIONS: VP-FSaccounted for a small proportion of all FS hospital presentations. There was
no difference in outcomes of VP-FS compared with NVP-FS. This is reassuring data for
clinicians and parents of children who experience FS after vaccination and can help guide
decisions on revaccination.

a
National Centre for Immunisation Research and Surveillance, Children’s Hospital at Westmead, Sydney, Australia; WHAT’S KNOWN ON THIS SUBJECT: Febrile seizures
b
Children’s Hospital Westmead Clinical School and cNorthern Clinical School, the University of Sydney, Sydney, are the most common childhood seizure disorder,
Australia; dClinical and Population Perinatal Health Research, Kolling Institute, Northern Sydney Local Health triggered by a sudden increase in temperature from
District, Sydney, Australia; eMurdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Australia;
f any cause, including vaccination. Previous studies
Department of Paediatrics, University of Melbourne, Melbourne, Australia; gDepartment of Infection and
Immunity, Monash Children’s Hospital and School of Population Health and Preventive Medicine, Monash revealed no difference in risk of hospitalization for
University, Clayton, Australia; hDepartment of Paediatrics, Women’s and Children’s Hospital, Adelaide, Australia; vaccine-proximate febrile seizures (VP-FSs) compared
i
Department of Paediatrics, University of Adelaide, Adelaide, Australia; jTelethon Kids Institute, Wesfarmers Centre to non–vaccine-proximate febrile seizures (NVP-FSs).
of Vaccines and Infectious Disease, West Perth, Australia; and kDivision of Paediatrics, School of Medicine,
University of Western Australia, Perth, Australia WHAT THIS STUDY ADDS: Comparing VP-FSs to NVP-
FSs, we identified no difference in ICU admission rates,
Dr Wood conceptualized and designed the study, coordinated, and supervised the project; Dr Deng
conducted the initial analyses and drafted the initial manuscript; Dr Gidding assisted in the
seizure duration, recurrent seizures during admission,
statistical analyses; Drs Macartney, Crawford, Buttery, Gold, and Richmond contributed to the or need for antiepileptics at discharge. VP-FS cases
interpretation of the results; and all authors reviewed and revised the manuscript, approved the with laboratory-confirmed coexisting infection had
final manuscript as submitted, and agree to be accountable for all aspects of the work. longer admissions compared with VP-FS cases without.
DOI: https://doi.org/10.1542/peds.2018-2120
To cite: Deng L, Gidding H, Macartney K, et al.
Accepted for publication Feb 21, 2019 Postvaccination Febrile Seizure Severity and Outcome.
Pediatrics. 2019;143(5):e20182120

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PEDIATRICS Volume 143, number 5, May 2019:e20182120 ARTICLE
Febrile seizures (FSs) are the most becoming increasingly available, only and reviewing all records with
common type of childhood seizures, 2 previous studies, within the same International Classification of
occurring in 3% to 5% of children cohort of US children aged 6 months Diseases, 10th Revision, Australian
between 6 months and 6 years of to 3 years, directly compared VP-FS Modification diagnosis code for FS
age, with peak incidence in the to non–vaccine-proximate febrile (R56.0).
second year of life. They are familial seizure (NVP-FS).16,17 In the first
in some cases and sporadic in others, study, children with a first VP-FS Children aged #6 years were
suggesting both genetic and were more likely to be girls, younger, included in the study if they
environmental factors play a role. A have a lower birth weight, a lower presented with their first seizure,
sudden rise in temperature is often Apgar score at 1 minute, and a higher where the seizure fulfilled the
described, and FSs are most chance of FS recurrence compared Brighton Collaboration case
commonly associated with a febrile with children with NVP-FS.16 The definition18 and was associated with
viral illness.1–4 They are frightening second study revealed no difference a fever, defined as a temperature of
to parents and often lead to medical in risk of hospitalization for first FS.17 .38°C, reported by their caregiver or
consultation. In addition, ∼30% of However, the authors of these documented by paramedics or health
children with a first FS will have retrospective studies did not examine care worker on presentation to the
a second episode,5 with risk factors other markers of seizure severity hospital. Per the International League
for recurrence being younger age at such as duration, recurrence within Against Epilepsy definition of FS,19
first FS and family history of FS.6 the same admission, or use of children were excluded if they had
Epidemiological studies reveal that antiepileptics. The effect of a previous seizure and/or existing
most children with a history of FS a laboratory-confirmed coexisting neurologic condition reported by
have normal behavior, intelligence infection on VP-FS has also never their caregiver or if they were found
and academic achievement, and do been examined. We conducted to have a central nervous system
not later develop epilepsy.7,8 a prospective cohort study of children infection by cerebrospinal fluid (CSF)
aged #6 years to examine differences analysis.
Whole-cell pertussis and measles-
in and contributors to first FS Clinical details were collected
containing vaccines9 as well as some
severity and FS recurrence in the through caregiver interviews and
influenza vaccines in combination
6 months after the initial FS included age at time of FS, aboriginal
with pneumococcal vaccines10 are
presentation in VP-FS and NVP- and Torres Strait Islander status,
associated with an increased rate of
FS cases. country of birth (Australia or other),
FSs within a defined period of time
after vaccination when fever birth weight, gestational age at birth,
peaks.11,12 FS associated with METHODS history of meningitis or encephalitis
a vaccination can decrease parent and or other chronic medical conditions,
provider confidence in vaccine safety Case Ascertainment and Study family history of FSs or epilepsy, and
and impact future vaccination of the Population clinical symptoms on seizure
child and other family members. Active prospective FS surveillance presentation. Investigations when
When 1 seasonal influenza brand in was conducted from May 1, 2013, to performed included blood, urine,
Australia was withdrawn in 2010 June 30, 2014, through the Pediatric CSF culture, nasopharyngeal
because of increased risk of FS,13 it Active Enhanced Disease Surveillance aspirate (NPA), EEG, and imaging
led to an overall reduction in (PAEDS) Network at 5 Australian (computed tomography [CT] or
influenza vaccine confidence and tertiary hospitals: the Children’s MRI), with these results being
coverage despite no further FS signal Hospital at Westmead Sydney, Royal obtained through medical record
being detected in subsequent Children’s Hospital Melbourne, review. Subsequent FS presentations
years.14,15 While that particular Princess Margaret Hospital for of the same child within the study
influenza vaccine was associated with Children Perth, Women’s and period were also recorded. Receipt
significant sequelae, it is unclear Children’s Hospital Adelaide, and of immunizations were verified for
whether other vaccine-proximate Lady Cilento Children’s Hospital all children by using data from the
febrile seizures (VP-FSs), occurring Brisbane, as previously described in Australian Immunization
within a time frame when the fever another study using the same study Register.11,20
may have been caused by vaccination, cohort.11
Participants recruited between May 1
are any different to FSs due to
Specialized surveillance nurses and December 31, 2013, were
another cause.
systemically identified potential FS contacted via phone to assess FS
Although data to define the cases by screening emergency recurrence 6 months after the initial
attributable risk of VP-FS are department and inpatient databases FS presentation. Because of study

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2 DENG et al
resource constraints, follow-up of TABLE 1 Baseline Profile of Patients Presenting With First FS (n = 1022)
cases recruited between January 1 Patient Characteristic All Cases NVP-FS VP-FS (n = 67) Pa
and June 30, 2014, was not (n = 1022) (n = 955)
performed. Male sex, n (%) 545 (53.3) 516 (54.0) 29 (43.3) .09
Age, median (IQR), mo 19.8 (13.6–27.6) 20.3 (14.2–28.1) 13.0 ,.001
Case Definitions and Outcome (12.4–17.6)
Measures ,12, n (%) 164 (16.0) 151 (15.8) 13 (19.4) —
12–24, n (%) 505 (49.4) 455 (47.6) 50 (74.6) —
On the basis of previous studies on 24–36, n (%) 214 (20.9) 213 (22.3) 1 (1.5) —
timing of fever onset after specific $36, n (%) 139 (13.6) 136 (14.2) 3 (4.5) —
vaccines, VP-FS was defined as an FS Indigenous, n (%) 25 (2.4) 25 (2.6) 0 (0.0) .40
that occurred from day 0 to 2 after Country of birth, n (%)
Australia 929 (90.9) 865 (90.6) 64 (95.5) .38
receipt of an inactivated vaccine, day
Other 40 (3.9) 39 (4.1) 1 (1.5) —
5 to 14 after a live-attenuated Unknown 53 (5.2) 51 (5.3) 2 (3.0) —
vaccine, or day 0 to 14 after Birth weight, n (%), g
a combination of inactivated and live- ,1500 10 (1.0) 10 (1.0) 0 (0.0) .11
attenuated vaccines.9,11,21,22 An FS 1500–2500 42 (4.1) 39 (4.1) 3 (4.5) —
2500–4000 737 (72.1) 683 (71.5) 54 (80.6) —
outside of this period was considered
.4000 98 (9.6) 90 (9.4) 8 (11.9) —
an NVP-FS. Unknown 135 (13.2) 133 (13.9) 2 (3.0) —
The primary outcome measures were Gestation, n (%), wk
,28 5 (0.5) 5 (0.5) 0 (0.0) .24
seizure severity defined as seizure 28–31 4 (0.4) 4 (0.4) 0 (0.0) —
duration .15 minutes, further 32–36 72 (7.0) 70 (7.3) 2 (3.0) —
seizures in the subsequent 24 hours, .36 880 (86.1) 816 (85.4) 64 (95.5) —
and antiepileptic drug (AED) use; Unknown 61 (6.0) 60 (6.3) 1 (1.5) —
secondary outcome measures were Past medical history, n (%)
Meningitis and/or encephalitis 10 (1.0) 10 (1.0) 0 (0.0) .99
length of stay (LOS) in hospital .1 (resolved)
day, transfer from a peripheral Chronic medical conditions 115 (11.3) 107 (11.2) 8 (11.9) .84
hospital, ICU admission, death, and Family history, n (%)
readmission for FS recurrence within FSs 382 (37.4) 353 (37.2) 29 (43.3) .30
48 hours of initial FS. Epilepsy 171 (16.7) 164 (17.2) 7 (10.4) .18
Indigenous represents aboriginal and/or Torres Strait Islanders. —, not applicable.
Cases were defined as having a x2 or Fisher’s exact test for categorical values and Mann-Whitney U test for nonparametric continuous values; unknown

a coexisting infection if $1 laboratory categories were not included in the statistical analyses.
investigations (blood, urine or CSF
culture, CSF polymerase chain the exposure of interest categorized neurologic condition, and 7 confirmed
reaction, or NPA polymerase chain as either VP-FS or NVP-FS and meningitis cases were excluded from
reaction) detected viral or bacterial adjusted for age categories (,12, the study. Of the 1662 FS cases
pathogens. Investigations performed 12–24, 24–36, $36 months) and sex. remaining, 640 were excluded
on readmission within 48 hours of VP-FS cases with coinfection were because they were not the first FS
initial presentation were considered compared with cases with no episode, leaving 1022 first FS cases of
as the same illness and were coinfection or not tested by using which 67 (6%) were VP-FSs and 955
combined with any initial Fisher’s exact test. Statistical analyses (94%) were NVP-FSs. A subset of 638
investigations in the analysis. were performed with SAS (SAS cases recruited between May 1 and
Investigations were performed at the Institute, Inc, Cary, NC) version 9.3. December 31, 2013, were
clinicians’ discretion. contacted for follow-up at 6 months,
and 398 responded (62% overall
Statistical Analysis RESULTS response rate, 62% [373 of 598]
Demographic data on and reported for NVP-FS; 63% [25 of 40] for
symptoms from patients with VP-FS Patient Characteristics
VP-FS).
and NVP-FS were compared by using There were 1735 potential FS
a x2 or Fisher’s exact test for episodes in 1504 children aged 0 to Children with their first VP-FS were
categorical values, as appropriate, 6 years identified through screening younger than children with their first
and the Mann-Whitney U test for between May 1, 2013, and June 30, NVP-FS (13 vs 20 months; P , .001)
nonparametric continuous values. 2014, across the 5 PAEDS sites. (Table 1). There was no difference in
Logistic regression was performed for Twenty-one patients with a previous family history of FS or epilepsy
each clinical outcome measure, with afebrile seizure, 45 with an existing between VP-FS and NVP-FS groups.

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PEDIATRICS Volume 143, number 5, May 2019 3
There were no differences in birth The peak incidence of FS was 9 days cases requiring transfer had
weight, gestational age at birth, postvaccination, of which 13 were a higher proportion of patients with
country of birth, Aboriginal and/or after vaccination with MMR and 1 prolonged seizures (44% vs 15%),
Torres Strait Islander background, after MMRV (Fig 1). repeat seizures within 24 hours of
or past medical history of meningitis initial (33% vs 9%), and AED use
or encephalitis or other chronic for initial management (56%
medical conditions between the Seizure Severity and Outcome vs 15%).
2 groups. Univariate and multivariate analyses
There was no FS recurrence within
revealed no increased risk of a severe
VP-FS 48 hours after all first VP-FS. There
seizure associated with a VP-FS
was also no increased risk of FS
Of the 67 VP-FS cases, 56 (84%) were compared to an NVP-FS (Table 2).
recurrence 6 months after the initial
after vaccination with measles- Most VP-FSs and NVP-FSs were short
VP-FS compared to NVP-FS (aOR
containing vaccines (of which 40 (#15 minutes) with a LOS of 1 day
1.17; 95% CI 0.46–2.94; P = .75) in
were measles-mumps-rubella [MMR] or less, and no differences in FS
the subset of 398 patients followed-
with Haemophilus influenzae type recurrence within the first 24 hours
up at 6 months (Table 2).
b and meningococcal C conjugate of the initial FS were observed.
[Hib-MenC] vaccine, 12 measles- There was an increased risk of AED Clinical Symptoms and Investigation
mumps-rubella-varicella [MMRV], 3 use for seizure termination for VP-FSs of Outcomes
MMR with diphtheria-tetanus- compared to NVP-FSs (adjusted Respiratory symptoms were the most
acellular pertussis and inactivated odds ratio [aOR] 2.24; 95% commonly reported symptom, with
polio combination vaccine [DTaP- confidence interval [CI] 1.07–4.67; similar proportions in each group
IPV], and 1 MMR only). The P = .03) but no difference at (62.7% VP-FS vs 62.8% NVP-FS).
remaining 11 VP-FSs occurred after discharge. An AED was used for There was also a similar proportion
diphtheria-tetanus-acellular seizure termination in all 10 cases of of patients in each group who had
pertussis, H influenzae type b, prolonged VP-FS compared to only 47 a rash (9.0% vs 6.6%) or irritability
hepatitis B, and inactivated polio cases (59%) of prolonged NVP-FS. and/or lethargy (11.1% vs 8.6%).
combination vaccine (DTaP-Hib- Children with VP-FS were more likely Vomiting and diarrhea were less
HepB-IPV) with 13-valent to be transferred from a peripheral frequently reported in VP-FS
pneumococcal conjugate vaccine hospital than children with NVP-FS than in NVP-FS cases (vomiting:
(PCV13) and rotavirus (n = 7), (aOR 2.36; 95% CI 1.09–5.11; 3.7% vs 22.0%; diarrhea: 7.5% vs
varicella (n = 2), DTaP-Hib-HepB-IPV P = .03). Compared to the VP-FS 11.6%).
(n = 1), and influenza (n = 1) vaccines. group overall, the 9 VP-FS
Laboratory investigations were
performed in a subset of patients at
the treating clinicians’ discretion
(24% of VP-FS versus 35% of NVP-FS
had 1 or more laboratory tests;
P = .3). A larger proportion of
children with prolonged seizures
(56% [61 of 108] vs 33% [285 of
880]; P , .001) or repeat seizures
within 24 hours of the initial FS (74%
[71 of 96] vs 31% [274 of 892]; P ,
.001) had investigations performed.
FS cases with respiratory symptoms
were less likely to have
investigations, although the
difference was not statistically
significant for VP-FS cases. There was
no difference in other reported
symptoms comparing VP-FS cases
that had laboratory investigation to
VP-FS cases that did not.
FIGURE 1 Laboratory-confirmed infection was
Timing of first FS after vaccination by type of vaccination received. found in similar proportions in those

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4 DENG et al
TABLE 2 Seizure Severity and Risk Estimates for Each Severity Indicator, Comparing VP-FS and NVP-FS Cases
All (n = 1022) NVP-FS VP-FS (n = 67) Univariate Multivariate
(n = 955)
n (%) n (%) n (%) OR (95% CI) P aORa (95% CI) P
Admission details
LOS .1 d 126 (12.3) 114 (11.9) 12 (17.9) 1.61 (0.84–3.10) .15 1.50 (0.76–2.94) .24
Transfer from peripheral hospital 61 (6.0) 52 (5.4) 9 (13.4) 2.70 (1.27–5.74) .01 2.36 (1.09–5.11) .03
ICU admission 20 (2.0) 19 (2.0) 1 (1.5) 0.72 (0.10–5.48) .75 0.67 (0.09–5.16) .70
Death 1 (0.1) 1 (0.1) 0 (0.0) NC — — —
Seizure details
Seizure duration .15 min 108 (10.6) 98 (10.3) 10 (14.9) 1.47 (0.73–2.98) .28 1.40 (0.70–2.79) .34
Repeat seizures 24 h after presentation 96 (9.4) 90 (9.4) 6 (9.0) 0.80 (0.34–1.89) .61 0.88 (0.59–1.31) .44
AED use
AED for termination of seizure 80 (7.8) 70 (7.3) 10 (14.9) 2.22 (1.09–4.53) .03 2.24 (1.07–4.67) .03
AED on discharge 18 (1.8) 6 (1.7) 2 (3.0) 1.81 (0.41–8.02) .44 1.68 (0.37–7.66) .50
Follow-up details
Readmission within 48 h with FS 8 (0.8) 8 (0.8) 0 (0.0) NC — — —
FS recurrenceb at 6 mo 88 of 398 (22.1) 81 of 373 (21.7) 7 of 25 (28.0%) 1.40 (0.57–3.47) .47 1.17 (0.46–2.94) .75
NC, not calculated; OR, odds ratio; —, not applicable.
a Multivariate analysis adjusted for age group (,12, 12–24, 24–36, $36 mo) and sex.
b Subset of 398 patients who were followed-up 6 mo after initial FS.

tested in both groups (30% VP-FS Patients with VP-FS with a coinfection had an EEG or imaging were either
versus 28% NVP-FS; P = .82) were younger compared with patients prolonged or recurrent FS cases.
(Table 3). Eight out of 27 VP-FS with VP-FS without coinfection and
cases tested had a laboratory- those not tested (9.8, 13.8, 13.2
confirmed infection (5 respiratory months, respectively; P = .02), and DISCUSSION
illnesses, 2 Escherichia coli urinary a larger proportion required an LOS We present a comprehensive
tract infections, and 1 enterovirus .1 day (75%, 26%, 2.5%, comparison of seizure severity
gastroenteritis). Four were after respectively; P , .001). between young children with VP-FS
the first dose of MMR and 4 after and NVP-FS that should be valuable
the combination of DTaP-Hib- Six (9%) VP-FS and 41 (5%) NVP-FS for counseling parents of children,
HepB-IPV, PCV13, and rotavirus cases had either EEG and/or CT or who, in Australia, will have received
vaccine. MRI on the brain. All VP-FS cases that 13 vaccinations by the time they reach

TABLE 3 Investigations and Diagnosis of Infection in NVP-FS and VP-FS Cases

NVP-FS (n = 921) VP-FS (n = 67) P
Tested (All Cases) Positive (All Tested) Tested (All Cases) Positive (All Tested)
n (%) 319 (34.6) 88 (27.6) 27 (40.3) 8 (29.6) .82
Laboratory investigations, n (%)
NPA 92 (10.0) 50 (54.3) 8 (11.9) 6 (75.0) .13
Stool culture 44 (4.8) 11 (25.0) 5 (7.5) 1 (20.0) .81
Urine culture 218 (23.7) 43 (19.7) 19 (28.4) 4 (21.1) .89
Blood culture 221 (24.0) 6 (2.7) 14 (20.9) 0 (0.0) .86
Neurologic investigations,a n (%) 41 (4.5) — 6 (9.0) — —
EEG 29 (3.1) 8 (27.6) 3 (4.5) 1 (33.3) .83
CT or MRI brain 28 (3.0) 4 (14.3) 4 (6.0) 0 (0.0) .70
Diagnosis of infection,b n
Bacteraemia and/or sepsis — 3 — 0 —
Gastroenteritis (viral) — 5 — 0 —
Gastroenteritis (bacterial) — 6 — 1 —
Respiratory infection — 49 — 5 —
Urinary tract infection — 25 — 2 —
P = x2 test comparing the proportion cases that tested with positive results in each FS group for each investigation. —, not applicable.
a Positive for neurologic investigations refers to an abnormality found on the investigation.
b Laboratory isolates in VP-FS group include 2 cases of E coli and 1 case of each of the following: rhinovirus; rhinovirus, respiratory syncytial virus, and adenovirus combination;

enterovirus; human metapneumovirus; parainfluenza virus; and parechovirus.

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PEDIATRICS Volume 143, number 5, May 2019 5
2 years of age as part of the National AED use on discharge between only the temporal relation
Immunization Program. Our study VP-FS and NVP-FS. with vaccination was considered.
reveals that VP-FSs are no different in
The majority of VP-FSs in our Although risk factors for FS
seizure severity to NVP-FSs, with the
study were after measles-containing such as family history, prematurity,
majority being brief (,15 minutes)
vaccines, in keeping with and fetal growth retardation
seizures with no recurrence in the acute
a known twofold risk in FS after have been well documented,27–30
period, no prolonged LOS (.1 day), measles vaccination.24–26 They we did not find any differences in
and not requiring AED use at discharge. were mostly after the first dose of sex, birth weight, or gestational
MMR, and because the first dose age between VP-FS and NVP-FS,
Our study supports the findings
of MMR is given at 12 months of which contrasts with Tartof et al17
of Tartof et al’s17 retrospective
cohort study, which also revealed
age in Australia, this has caused study findings. Study population
a left shift to a younger mean age differences may have contributed
no difference in LOS between
of first FS in VP-FS compared to to the difference in findings because
VP-FS and NVP-FS. Using detailed
individual clinical note review,
NVP-FS (mean age 13 vs 20 months; Tartof et al17 only included first FS
P , .0001). A similar age difference occurring at ,3 years of age and
we have better defined the severity
between groups was seen in the more broadly defined VP-FS as
of VP-FS with our study. We expand
Tartof et al study.17 an FS 0 to 15 days after any vaccine.
on the Tartof et al17 study to
To our knowledge, this is the The absence of differences in
demonstrate no difference in
first study used to examine the our study is reassuring given our
other clinical severity measures,
presence of clinical symptoms and more biologically plausible VP-FS
including rate of ICU admission,
the effect of coexisting infections definition and wider capture of all
seizure duration, recurrence within
on VP-FS. We identified a large FSs up to 6 years of age that is
the initial 24 hours, and requirement
proportion (63%) of VP-FS cases more in line with FS incidence.4
of AED use at discharge, which
has not been studied before. With with respiratory symptoms and In those followed up to 6 months,
our study, we are the first to some with vomiting, diarrhea, or the recurrence rate in both VP-FS
report no increased risk of prolonged abdominal pain, suggesting some (23.6%) and NVP-FS (28%) was
or recurrent FS after VP-FS compared may have an infective contributory slightly lower than the 30% recurrence
to NVP-FS even after adjusting for cause of the FS in addition to rate reported in previous FS
age and sex. We found the higher a vaccine. Authors of previous studies studies.5,30 The short follow-up period
examining the risk of vaccines and small sample size may account for
proportion of VP-FS cases transferred
and seizures have not reported on this difference. Although earlier onset
from peripheral hospitals compared
the presence of concomitant infection. of FS is a risk factor for recurrence,5,6
to NVP-FS cases was associated
It is not possible to determine there was no increased risk in the
with other markers of seizure
whether an infection or vaccine is younger VP-FS group compared
severity, with a higher proportion
the dominant cause of the FS; with the NVP-FS group. This was also
of children with prolonged seizures
however, it is reassuring that the reported by Tartof et al,17 whose study
or recurrence within the initial
presence of these infective symptoms had a longer mean follow-up
24 hours being transferred. We
did not impact seizure severity of duration of 2.2 years.
also found a higher proportion of VP-FS compared to NVP-FS. Of the
AED use for seizure termination in 12% of VP-FS cases with laboratory- The strength of this study lies
VP-FS cases. An AED was used for confirmed coinfection, the only in the prospective case
seizure termination in all prolonged clinical difference was a longer ascertainment through an
VP-FSs, in accordance to international LOS compared with those with no established robust active
acute seizure management laboratory-confirmed coinfection surveillance network in
guidelines,23 compared to only because of the need for treatment which comprehensive clinical
59% of prolonged NVP-FSs. It is of the underlying infection. Because data were collected for analysis.
unclear whether there was less than half of VP-FS cases were Our strict case definition for VP-FS
a difference in semiology or duration investigated for infection, it is accounted for differences in
of the prolonged seizures in either possible that the proportion of fever risk window of specific
group, which may account for VP-FS with a coinfection is vaccines allowing for more
the difference in AED use for seizure underestimated, and the proportion accurate delineation between VP-FS
cessation. Reassuringly, we found of FS that is solely attributable and NVP-FS. Our ability to collect
no difference in risk of prolonged to vaccination is lower than clinical symptoms and investigation
seizures or the requirement of previously reported17,24 where data allowed us to examine

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6 DENG et al
the impact of coinfections on VP-FS, studies with a longer follow-up
which was not examined in the period would be useful in
ABBREVIATIONS
comparative research studies. 16,17 confirming our findings AED: antiepileptic drug
and improving recurrence rate aOR: adjusted odds ratio
A limitation of case ascertainment
estimates. CSF: cerebrospinal fluid
from sentinel tertiary pediatric
CT: computed tomography
hospitals is that it may not
DTaP-Hib-
be representative of all FSs in CONCLUSIONS HepB-IPV: diphtheria-tetanus-
Australia. Differences in health
This study confirms that VP-FSs are acellular pertussis, H
care–seeking behavior could
clinically not any different from influenzae type b,
also contribute to bias. Patients
NVP-FSs and should be managed the hepatitis B, and
with existing medical conditions
same way. Our findings can be used inactivated polio
may be more likely to present
to counsel concerned parents that combination vaccine
for assessment, and families who
although some vaccines have DTaP-IPV: diphtheria-tetanus-
are familiar with FS may not.
a known associated risk of FSs, acellular pertussis and
However, as we examined first
clinical severity and outcomes of inactivated polio
FS only, we feel that this bias
these FSs are no different to an FS combination vaccine
is less likely than for subsequent FS.
from another cause. This FS: febrile seizure
Given the small proportion of information helps support the Hib-MenC: Haemophilus influenzae
VP-FS cases and limited cohort recommendation to these patients type b and
size, the study would have been and their families that meningococcal C
able to detect a true difference in additional required vaccinations conjugate vaccine
the proportion of prolonged seizure can be administered in the LOS: length of stay
in the VP-FS group if it was double future. MMR: measles-mumps-rubella
the 11.9% in the NVP-FS group, vaccine
with a power of 0.8. The 6.0% MMRV: measles-mumps-rubella-
difference between the groups, ACKNOWLEDGMENTS
varicella vaccine
however, would not be considered We thank all the PAEDS surveillance NPA: nasopharyngeal aspirate
clinically significant. Finally, our nurses involved in the data NVP-FS: non–vaccine-proximate
follow-up data are limited by the collection for this study: Karen febrile seizure
high proportion lost to follow-up Orr, Jenny Murphy, Helen Knight, PAEDS: Pediatric Active Enhanced
and short duration. Although it is Sharon Tan, Sue Low, Chris Disease Surveillance
unclear if there are any Heath, Mary Walker, Alissa McMinn, PCV13: 13-valent pneumococcal
differences between those who Donna Lee, Margaret Gibson, conjugate vaccine
responded and those who did not, the Chris Robins, Carolyn Finucane, VP-FS: vaccine-proximate febrile
response rates between NVP-FS and Carol Orr, Jacki Connell, and Sonia seizure
VP-FS were comparable. Larger Dougherty.

Address correspondence to Lucy Deng, MBBS, National Centre for Immunisation Research and Surveillance, Children’s Hospital at Westmead, Locked Bag 4001,
Westmead, NSW 2145, Australia. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2019 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Dr Deng is supported by the University of Sydney Research Training Program scholarship. Drs Gidding and Wood are supported by Australian National
Health and Medical Research Council Career Development Fellowships. Funding from the Australian Government Department of Health and the National Health and
Medical Research Council (project grant identification: APP1049557) supported the conduct of the study.
POTENTIAL CONFLICT OF INTEREST: Dr Richmond has served on advisory boards for Sanofi, Pfizer, and GlaxoSmithKline (from which he received no personal
remuneration) and has received grants from GlaxoSmithKline (that are unrelated to this study); the other authors have indicated they have no potential conflicts of
interest to disclose.

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PEDIATRICS Volume 143, number 5, May 2019 7
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PEDIATRICS Volume 143, number 5, May 2019 9
 Postvaccination Febrile Seizure Severity and Outcome
Lucy Deng, Heather Gidding, Kristine Macartney, Nigel Crawford, Jim Buttery,
Michael Gold, Peter Richmond and Nicholas Wood
Pediatrics 2019;143;
DOI: 10.1542/peds.2018-2120 originally published online April 19, 2019;

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 Postvaccination Febrile Seizure Severity and Outcome
Lucy Deng, Heather Gidding, Kristine Macartney, Nigel Crawford, Jim Buttery,
Michael Gold, Peter Richmond and Nicholas Wood
Pediatrics 2019;143;
DOI: 10.1542/peds.2018-2120 originally published online April 19, 2019;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/143/5/e20182120

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