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Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland

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Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002-2010. All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference. Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002-2009 giving an annual incidence of 0.79 per 100,000 inhabitants (95% confidence interval 0.62-0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12-0.51) per 100,000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100,000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100,000, which equals that in 2002-2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy. A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children.
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Increased Incidence and Clinical Picture of Childhood
Narcolepsy following the 2009 H1N1 Pandemic
Vaccination Campaign in Finland
Markku Partinen
1,2,15
*, Outi Saarenpa
¨a
¨-Heikkila
¨
3
, Ismo Ilveskoski
4
, Christer Hublin
5
, Miika Linna
6
,
Pa
¨ivi Olse
´n
7
, Pekka Nokelainen
8
, Reija Ale
´n
9
, Tiina Wallden
10
, Merimaaria Espo
10
, Harri Rusanen
11
,
Jan Olme
12
, Heli Sa
¨tila
¨
13
, Harri Arikka
14
, Pekka Kaipainen
15
, Ilkka Julkunen
16
, Turkka Kirjavainen
17
1Helsinki Sleep Clinic, Finnish Narcolepsy Research Centre, Vitalmed Research Centre, Helsinki, Finland, 2Department of Clinical Neurosciences, University of Helsinki,
Helsinki, Finland, 3Unit of Child Neurology, Department of Paediatrics, Tampere University Hospital, Tampere, Finland, 4Department of Child Neurology, Children’s
Hospital, Helsinki University Central Hospital, Helsinki, Finland, 5Finnish Institute of Occupational Health, Helsinki, Finland, 6Department of Statistics and Registers,
National Institute for Health and Welfare (THL), Helsinki, Finland, 7Department of Child Neurology, Oulu University Hospital, Oulu, Finland, 8Department of Child
Neurology, Kuopio University Hospital, Kuopio, Finland, 9Department of Child Neurology, Jyva
¨skyla
¨Central Hospital, Jyva
¨skyla
¨, Finland, 10 Department of Child
Neurology, Central Hospital of Kymenlaakso, Kotka, Finland, 11 Department of Neurology, Oulu University Hospital, Oulu, Finland, 12 Department of Child Neurology,
Vaasa Central Hospital, Vaasa, Finland, 13 Department of Child Neurology, Kanta-Ha
¨me Central Hospital, Ha
¨meenlinna, Finland, 14 Department of Child Neurology, Turku
University Hospital, Turku, Finland, 15 Rinnekoti Research Centre, Espoo, Finland, 16 Department of Vaccination and Immune Protection, National Institute for Health and
Welfare (THL), Helsinki, Finland, 17 Department of Paediatrics, Children’s Hospital, Helsinki University Central Hospital, Helsinki, Finland
Abstract
Background:
Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the
beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime
sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland
between the years 2002–2010.
Methods:
All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national
hospital discharge register from 2002 to 2009 was used as a reference.
Findings:
Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002–2009 giving an annual
incidence of 0.79 per 100 000 inhabitants (95% confidence interval 0.62–0.96). The average annual incidence among
subjects under 17 years of age was 0.31 (0.12–0.51) per 100 000 inhabitants. In 2010, 54 children under age 17 were
diagnosed with narcolepsy (5.3/100 000; 17-fold increase). Among adults $20 years of age the incidence rate in 2010 was
0.87/100 000, which equals that in 2002–2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for
narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42)
before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency ,8 min and $2 sleep onset REM
periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the
onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood
narcolepsy.
Interpretation:
A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We
consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this
increase in genetically susceptible children.
Citation: Partinen M, Saarenpa
¨a
¨-Heikkila
¨O, Ilveskoski I, Hublin C, Linna M, et al. (2012) Increased Incidence and Clinical Picture of Childhood Narcolepsy following
the 2009 H1N1 Pandemic Vaccination Campaign in Finland. PLoS ONE 7(3): e33723. doi:10.1371/journal.pone.0033723
Editor: Benjamin J. Cowling, University of Hong Kong, Hong Kong
Received November 9, 2011; Accepted February 15, 2012; Published March 28, 2012
Copyright: ß2012 Partinen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no external support or funding to report. The collection of data from the registries and from different hospitals was funded by THL.
The study group had freedom for the study design, data collection, data analysis, data interpretation, and writing of the report. The authors had access to all the
data, take responsibility for the integrity of the data and the accuracy of the analysis, and had final responsibility for the reporting of the data.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: markku.partinen@helsinki.fi
Introduction
The reported prevalence of narcolepsy-cataplexy among adults
in Finland is 26 cases/100 000 inhabitants (95% confidence
interval CI of 0 to 60) [1]. According to Silber et al. the incidence
is estimated to be 0.74 per 100 000 person-years for narcolepsy
with cataplexy and 1.37 per 100 000 person-years for narcolepsy
with or without cataplexy [2]. The most common symptoms
of narcolepsy are unintended sleep episodes, excessive daytime
sleepiness (EDS) and cataplexy [3,4]. Most often narcolepsy starts
between 12–25 years of age with the main peak of onset at 14–16
years. An onset before age of 10 years has been rare [2,5].
PLoS ONE | www.plosone.org 1 March 2012 | Volume 7 | Issue 3 | e33723
Typically narcolepsy-cataplexy is characterized by the lack of
hypothalamic hypocretin (orexin) production [3,6] and strong
association with HLA DR15 (DR2) and DQB1*0602 [3,6,7,8].
Among Caucasians over 90% of patients with narcolepsy-
cataplexy are HLA DQB1*0602 positive [3]. In a recent Danish
study including a meta-analysis of seven studies the CSF-
hypocretin-1 was low or undetectable in 69–100% (overall
approximately 80%; 218/274) of patients with narcolepsy-
cataplexy [9]. Similarly approximately 20% of patients with
narcolepsy without cataplexy had low CSF hypocretin. More than
97% of patients with low CSF-hypocretin-1 are HLA DQB1*0602
–positive [9].
Genetic associations [10,11,12,13,14,15,16], presence of anti-
tribbles 2 antibodies [17,18,19] and other recent observations
[20,21] suggest that autoimmune mechanisms are involved in the
etiopathogenesis of narcolepsy [22,23,24]. Seasonality of onset
[25] and reports of an association to preceding streptococcal
infections [26,27] have suggested a link with upper respiratory
tract infections.
At the end of December 2009, a 7-year old boy consulted
physicians because of a recent onset excessive daytime sleepiness.
The H1N1 epidemic was ongoing and he had been vaccinated
with Pandemrix. He had no history of recent upper respiratory
tract infection or influenza-like illness (ILI). In February 2010 he
was diagnosed with narcolepsy. A possible causal relationship with
influenza and/or Pandemrix vaccination was suspected. Several
new cases of recent onset childhood narcolepsy were observed in
Pandemrix-vaccinated children, without previous history of ILI. In
Finland up to fourteen diagnoses were confirmed before August
2010, bringing forward a possibility of a novel environmental
trigger for increased incidence of narcolepsy in children [28].
Similar findings were reported from Sweden, and there was
a time-related association observed with influenza A (H1N1)
pandemic and H1N1 vaccination [28,29,30]. Due to the time-
related association with influenza vaccination, the Finnish health
authorities decided to cease Pandemrix vaccinations in August
2010 [31]. A systematic study was started to recognize all
narcoleptic patients in Finland diagnosed in 2010, and to compare
incidence figures with the diagnoses made between 2002 and 2009
[32]. A parallel study was focused to study the role of the AS03-
adjuvanted vaccine (Pandemrix) based on register data [33]. Also
in Sweden, the government funded studies were initiated [29].
Parallel case reports were reported in France and Canada, where
Pandemrix or a similar AS03 adjuvanted vaccine Arepanrix was
used. A possible association with H1N1 vaccination and recent
onset narcolepsy was found in fourteen (9 children, 5 adults). In
eleven cases Arepanrix/Pandemrix had been used (6 children ,17
years and 5 adults). Two of the six children were from France, two
from Canada, one from Switzerland and one from UK [34]. In the
present study, we report our findings on the change in incidence of
childhood narcolepsy. We also describe the clinical picture of post-
Pandemrix narcolepsy in children, and compare that to previous
descriptions of childhood narcolepsy.
Methods
Ethics statement
This study has been approved by the Institutional Review Board
of the National Institute for Health and Welfare (THL). The
clinical part of the study is based on case history obtained by the
clinician authors. Most results are based on clinical examination of
patients that was part of normal diagnostic procedures. A written
informed consent was received from all patients for use of their
data, and for laboratory studies and examinations that were not
part of the diagnostic procedure or that were done after the
diagnosis of narcolepsy had been confirmed. Parents (legal carers)
signed the written informed consent on behalf of the minors/
children involved in the present study.
Collection of information of diagnosed cases of
narcolepsy
In Finland the patients with specific diagnoses can be identified
from the national hospital discharge registry (HILMO) kept by the
National Institute for Health and Welfare (THL). This register
includes comprehensively discharge abstracts from public and
private patient care in hospitals and institutions in Finland. The
unique personal identification code made it possible to obtain
incident first-ever patient cohorts in 2002–2009 with narcolepsy
with or without cataplexy (ICD-10 code G47.4) as the main
diagnosis. Patients with a previously diagnosed of narcolepsy were
retrospectively analysed until January 1
st
, 1997 and incident
cohorts from 2002 to 2009 were included. Since there is
approximately 18-month lag in the complete HILMO registry
data, G47.4 diagnoses set during 2010 were collected by
contacting the same sources that are used to collect data for the
national registry. The included databases are based on discharge
data of all hospitals and other health care organizations
responsible for specific diagnosis of narcolepsy.
To verify the onset of symptoms and to gather information of
the clinical picture of the diagnosed patients in 2009–2010 all
available patient information was collected nation widely from
hospitals and sleep centres. In addition, child neurologists in
different hospitals were contacted to ensure that all patients had
been recognized. The status and date of Pandemrix influenza
vaccination was verified from the vaccination certificates that were
filled by health care professionals. According to national guidelines
all vaccinated individuals had received only one dose of
Pandemrix vaccine. The presence of symptoms and their onset
were obtained from medical records. They were based on face-to-
face interviews with a child neurologist and the parents and
children. The date of first contact with health personnel due to
EDS was verified from school nurses and health care centres.
Calculation of narcolepsy incidence rates for different
years
The incidence rates for narcolepsy were calculated by dividing
the number of yearly-diagnosed narcolepsy patients by the total
number of people in Finland in each age group during the same
year. The incidence rates in different age groups (,11, 11–16, 17–
19 and people aged 20 years or more) were calculated. We used
the age at the time of diagnosis to allow comparison with the data
obtained from the hospital discharge registry (which includes age
at diagnosis). The demographics of Finnish population were
obtained from the Statistics Finland.
Diagnosis of narcolepsy
The diagnosis of narcolepsy was based on the criteria of the
International Classification of Sleep Disorders (version 2, ICSD-2)
[4]. Multiple sleep latency test (MSLT) was done for all children.
Analysis of cerebrospinal fluid (CSF) hypocretin-1 was done at the
Rinnekoti Research Centre (Orexin A RIA kit, Phoenix
Pharmaceuticals, San Mateo, CA). HLA-typing was done for
some patients although it is not an official ICSD-2 diagnostic
criterion. Other causes of EDS (e.g. sleep apnoea, delayed sleep
phase syndrome or sleep deprivation) as well as other neurological
disorders (encephalitis, encephalopathy, other neurological disor-
ders) were excluded by polysomnography, actigraphy, thorough
Incidence and Symptoms of H1N1-Related Narcolepsy
PLoS ONE | www.plosone.org 2 March 2012 | Volume 7 | Issue 3 | e33723
neurological examination, magnetic resonance imaging (MRI),
EEG, CSF examinations, blood tests, and other examinations
when necessary. A child neurologist always determined the
diagnosis of narcolepsy. Before the patient was considered to
suffer narcolepsy the diagnosis was verified by a panel of five
neurologists/sleep specialists (CH, MP, OSH, PO, TK).
Statistical analysis
Statistical analyses were performed with STATA 10.1 (Stata
Corporation, TX). The incidence ratios were calculated for each
year and the average incidence ratios from the period of 2002–
2009 were compared to those observed in 2010 (1
st
Jan 2010 until
31
st
Dec 2010). The 95% confidence intervals (95% CI) are given
for the average incidence rates for the years 2002–2009. Age is
given as years and decimals. For statistical comparisons of the
continuous variables parametric or non-parametric methods were
used according to the normality of the distributions.
Results
Incidence of narcolepsy in 2002–2009
Altogether 335 cases of narcolepsy were diagnosed in Finland
during 2002–2009 giving an annual incidence of 0.79 per 100 000
inhabitants (95% CI 0.62–0.96). Among adults $20 years of age, 281
new cases of narcolepsy (range 25 to 52 per year) were diagnosed
between 2002–2009 giving an average annual incidence of 0.87 (95%
CI 0.71–1.03) per 100 000. Twenty-eight (3 to 5 per year) cases of
narcolepsy were diagnosed among individuals aged 17 to 19 with an
average annual incidence of 1.79 (95% CI 1.49–2.09) per 100 000
(Figure 1, Figure 2, Figure 3, Figure S1, Figure S2). Twenty-six
patients were younger than 17. In that age group the average annual
incidence in 2002–2009 was 0.31 (95% CI 0.12–0.51) per 100 000
children. Only one child aged less than 11 years (a 9-year-old) was
diagnosed with narcolepsy prior to 2010 (Figure 1, Figure S1).
Incidence of narcolepsy in 2010
In 2010 altogether 101 persons were newly diagnosed for
narcolepsy giving an incidence of 1.88/100 000. Of these patients
65 were younger than 20 years of age (incidence rate 5.33/
100 000/year). Among adults $20 years of age (n = 36) the
incidence rate in 2010 was 0.87/100 000, which equals with the
average incidence figure in 2002–2009 (0.87). Among 17 to 19-year-
olds it was 5.46/100 000 (3-fold increase). In 2010 altogether 54
cases of childhood narcolepsy were diagnosed in children and
adolescents (,17 years; Appendix S1) giving an incidence rate of
5.30/100 000, which is 17 times higher than the average incidence
between 2002 and 2009. In children aged ,11, the incidence rate in
2010 was 3.39/100 000 (1.89 in children aged ,8and7.56in
children aged 8 to10). Even if the highest incidence figures were
seen in peripubertal and pubertal children aged 11 to 16 years (8.76
diagnoses per 100 000), the highest increase from previous figures
was seen in children aged less than 11 years of age (increase from an
average of 0.02 to 3.39 per 100 000 giving a 177-fold increase in
incidence; see Figure 3, Figure S2).
Figure 1. Number of new diagnoses of narcolepsy among children and adolescents aged under 20 years of age by year of
diagnosis.
doi:10.1371/journal.pone.0033723.g001
Incidence and Symptoms of H1N1-Related Narcolepsy
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Based on patient records 50 of the 54 children had received the
pandemic H1N1 vaccine (Pandemrix, GSK) 0–242 days (median
38 days; 95% CI 40 to 67) before the onset of EDS. In 4 of the 50
vaccinated children (Appendix S1) influenza-like illness (ILI) was
reported during the national H1N1 epidemic peak during the
weeks 43–48 in 2009 [35]. However, laboratory confirmation of
influenza infection of ILI cases had not been done. No other
microbiologically confirmed infections were found in any of the 54
patients.
Clinical picture of children (,17 years) with H1N1
vaccination-associated narcolepsy
Fifty children and adolescents, aged under 17 (age limit of
paediatric care in Finland), had an onset of EDS after Pandemrix
vaccination, and had a diagnosis of narcolepsy in 2010. All
children were of Caucasian origin. There were 28 (56%) girls and
22 boys (Table 1). There were no significant differences in the
clinical presentation of narcolepsy between boys and girls. The
mean (6SD) age at the time of vaccination was 10.863.0 years
Figure 2. Number of new diagnoses of narcolepsy among adults aged 20 years or more by year of diagnosis.
doi:10.1371/journal.pone.0033723.g002
Figure 3. Annual incidence of narcolepsy by age group and year of diagnosis.
doi:10.1371/journal.pone.0033723.g003
Incidence and Symptoms of H1N1-Related Narcolepsy
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(range 4.5 to 16.1 y). The mean age at onset was 11.063.1 years.
The mean age at onset was 10.262.8 years in boys and 11.663.1
years in girls (P = 0.055). Eighteen per cent of the children were
younger than 8 years, 24% were 8–10 years old, 38% were 11 to
13 years old and 20% were 14–16 years old at onset of symptoms.
None of the 50 children had a prior history of EDS, cataplexy, or
other symptoms of narcolepsy. The initial symptoms of narcolepsy
included EDS, reappearance of regular daytime naps, and
unintended sleep episodes (Table 1). Forty-seven of the 50 children
(94%) have developed cataplexy, which started 6 to 359 days after
the vaccination (median 77 days, i.e. 11 weeks). All children had
abnormal multiple sleep latency test (MSLT) with a mean sleep
latency of 1.861.4 minutes (95% CI 1.4 to 2.2) and with at least 2
(median 4; mean 3.860.9) sleep onset REM periods (SOREMPs).
Clinically significant sleep-related breathing disturbances were not
found. The mean apnea-hypopnea index was 0.4 (SD 0.4, range
0–1.4). In 11 out of 13 children CSF hypocretin-1 levels were
undetectable (below 10 pg/ml) and it was pathologically low in the
remaining two children (32 and 69 pg/ml; ICSD-2 criterion for
narcolepsy ,110 pg/ml). All three children without cataplexy had
undetectable CSF hypocretin levels. MRI was done in 34 subjects.
There was one arachnoidal cyst without clinical significance while
in other patients MRI was normal. One child had type 1 diabetes
and one had von Willebrand disease. They were both DQB1*0602
positive. Nine children (16.7%) had atopy and/or asthma and four
children (7.4%) had had problems with attention and hyperactivity
before onset of narcolepsy. Twenty-four (48%) children showed
behavioural changes or psychiatric problems (conduct disorders/
challenging and aggressive behaviour, self mutilation), which
needed psychiatric treatment after the onset of narcolepsy.
Table 1. Clinical findings.
Study
Country
Present study
Finland
Dauvilliers et al.
2010
34
Canada, France,
Switzerland, UK
Aran et al.
2010
40
Italy, Israel,
USA
Nevsimalova
et al. 2011
41
Czech
Han et al.
2001
42
North China
Number of subjects 50 6
1
51 30 29
Period of diagnoses (yr) 1 ,12101
Proportion of females 28/50 (56%) N/A 22/51 (43%) 18/30 (60%) 8/29 (28%)
Had Pandemrix or Arepanrix 50/50 (100%) 6/6 (100%) N/A N/A N/A
Age of onset (yr), mean (SD) 11.0 (3.0) Not given 10.3 (3.57) 14.0 (3.0)
***
9.2 (2.0)
Age at onset (yr) of cataplexy, mean (SD) 11.4 (2.8) Not given Not given Not given 9.2 (2.0)
Days from vaccination to onset, mean (SD);
median; 95% confidence interval (days)
53.8 (47.1); 38; 40 to 67 Not given N/A N/A N/A
Age (yr) at diagnosis, mean (SD) 11.6 (3.1) 11.4 (4.6) 11.8 (3.57) 15.6 (3.1)
***
10.7 (3.1)
Time (yr) from onset to diagnosis 0.1 to 0.9 , mean 0.7 (SEM
0.03); 45 to 345 days
,1 Mean 1.5 (SEM 0.3) Not given 1–2
Cataplexy 47/50 (94%) 6/6 (100%) 51/51 (100%) 18/30 (60%)
**
29/29 (100%)
Time (wk) from vaccination to cataplexy,
mean (SD); median; range
13.7 (10.6); 11;
0to51
6.5 (4.5)
*
; 4.5;
3to15
N/A N/A N/A
Months from onset of EDS to onset of
cataplexy, median; range
0;8; 0 to 10
In 70%
#
2 (N = 47)
29 to 2 In 82%#2 Not given Cataplexy
present at
onset in all?
Hypnagogic hallucinations 26/49 (53.1%) Not given 33/50 (66%) 15/30 (50%) 17/29 (59%)
Behavioral problems 24/50 (48%) Not given 26/39 (66%) 10/30 (33.3%) 27/29 (93%)
***
Sleep paralysis 9/49 (18.4%) Not given 28/51 (55%)
***
12/30 (40%)
**
12/29 (41%)
Disturbed nocturnal sleep 44/50 (88%) Not given 47/51 (92%) Not given Not given
Rapid weight gain in the beginning
#
26/41 (63.4%)
#
‘‘frequent’’ 32/38 (84%)
#
‘‘frequent’’ Not given
BMI in kgm
22
, mean (SD) 19.6 (4.1); (N = 42) Not given 25.2 (1.2)
**
;
(N = 40)
22.7 (7.2)
*
;
(N = 30)
20.4 (4.2);
(N = 29)
Sleep latency (min) in MSLT, mean (SD) 1.8 (1.4) Not given 2.5 (2.5) 4.0 (3.1)
***
2.0 (1.3)
SOREMPS 3.8 (0.9) Not given Not given 3.2 (1.4)
*
4.2 (0.9)
*
Short SL and
$
2 SOREMPs in MSLT 100% (N = 50) Not given 92% (N = 39) 90% (N = 30) 96.5% (N = 29)
CSF-hypocretin-1 Mean (SD) 8.6 (20.2); (N = 13)
Median (range) 0 (0–69)
Not given Mean (SD) 4.5 (7.9);
(N = 13)
,110 pg/ml ;
(N = 6)
Not given
1This table contains information of only those 6 subjects who were aged#17 years at diagnosis. The other 10 of the 16 subjects reported by Dauvilliers et al.2010
34
were
older. They were not included to enable comparisons.
#We defined weight gain as an increase of body mass index (BMI) .5%. Aran et al
40
defined it as .4 kg weight gain. NC: narcolepsy and cataplexy; NwC: narcolepsy
without cataplexy. N/A: Not applicable; SD: standard deviation; SEM: standard error of mean. Statistically significant differences between our study and other studies are
marked as.
***for P,0.001,
**for P,0.01 and,
*for P,0.05. The numbers (N = ) in parenthesis refer to number of subjects with data.
Comparison of the present study and published studies from literature for children aged#17 years.
doi:10.1371/journal.pone.0033723.t001
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Psychiatric hospitalisation was necessary in four cases, and one
patient needed temporarily benzodiazepine and antipsychotic
treatment. No signs of central nervous system infection were found
in CSF, MRI or EEG. During the spring 2010 three children
received intravenous gammaglobulin without any clinical im-
provement. All 32 of the 50 HLA-typed children were positive for
DQB1*0602/DRB1*15/DR15 – DQ6 genotype. Twenty patients
were typed also for narcolepsy protective [8] genotype
DQB1*0603, which was negative in all patients. At the first visit
the mean body mass index (BMI) was 19.6 (SD 4.1; 95% CI 18.3–
20.9; median 19.2; range 14.0–35.3) kgm
22
. It increased by more
than 5% in 26/41 (65.4%) of the children. The main clinical
parameters are given in Table 1 and the Appendix S1 table.
To compare the clinical data of the children with onset in 2009
or 2010 (defined as POST) to those with an earlier onset (PRE) we
analyzed the data of the 65 children and adolescents aged less than
20 years at diagnosis in 2010. Seven of the 65 children had an
onset before 2009. The mean age at diagnosis was 15.3 years (95%
CI 11.8 to 18.7) in PRE and 12.1 y (11.2 to 13.0) in POST group
(P = 0.0272). The time from onset of EDS to onset of cataplexy
was longer in the PRE (mean 546.2 days, 95% CI 48.7 to 1043.5)
group than in the POST (mean 35.9,days, 23.3 to 48.5;
P = 0.0038) group. The time from onset of symptoms to diagnosis
was much longer in PRE (mean 47.6 months, 95% CI 14.2 to
80.9, range 17 to 111 months) than in POST group (mean 7.9,
95% CI 7.2 to 8.6, range 1 to 11 months; P,0.0001). There were
no statistically significant differences between the groups regarding
age at onset, cataplexy, aggressive behavior, or other symptoms
and findings.
Discussion
In 2010 we observed a significant increase in childhood
narcolepsy in Finland. In 2002–2009, the average annual
incidence of narcolepsy in children aged less than 17 years was
0.31 per 100 000 children. In 2010, the incidence rose to 5.3 per
100 000 children being about 17-fold higher as compared to
previous years. In adolescents aged 17 to19, the increase was
moderate (3-fold), and no increase was seen in adults $20 years of
age. Based on registry data, a significant (6.6-fold) increase in
childhood narcolepsy after Pandemrix vaccination has been
reported also from Sweden [36,37]. In a study from the Stockholm
area the small number of cases of narcolepsy (six among
vaccinated and two in the unvaccinated cohort) did not allow to
make reliable conclusions whether clearly increased incidence of
narcolepsy was found in that area [38]. In the same study the
hazard ratio for Bell’s palsy among vaccinated against unvacci-
nated was 1.25 (1.06 to 1.48). Risk for Guillain-Barre´ syndrome,
multiple sclerosis, type 1 diabetes, and rheumatoid arthritis
remained unchanged [38]. There has been no evidence of
narcolepsy or other sleep-related adverse effects in recipients of
MF59-adjuvanted A(H1N1) pandemic or other MF59-adjuvanted
influenza vaccines [39].
In 2002 and 2009, narcolepsy was extremely rare in children
aged less than 11 years. Only one 9-year-old child had been
diagnosed in Finland in 2003. In 2010, twenty-two children aged
less than 11 years were diagnosed giving an annual incidence of
3.39/100 000 children in that age group. In the only previous
study of the incidence of narcolepsy, Silber and co-workers
presented the average annual incidence of narcolepsy to be 1.37/
100 000 and 0.74/100 000 for narcolepsy with cataplexy [2]. The
annual incidence of narcolepsy in 2002–2009 (for all ages) in our
study is 0.79 (95% CI 0.62 to 0.96) corresponding well with the
published incidence rates [2].
All diagnoses were based on international criteria [4]. The
symptoms were relatively severe (Table 1) but similar to those
described in Caucasian children in other recent publications
[34,40,41] and in the 1998–1999 series of 29 children from North
China [42]. Psychiatric symptoms were common in our patients
(48%) as it was in other studies as well (Table 1) [3,40,41,42,43]. In
the Chinese study psychosocial problems were reported in 27/29
(93%) of children and academic problems were reported in 88% of
the cases [42]. It is possible, however, that the psychiatric symptoms
are more severe in post-vaccination narcolepsy than in ‘‘normal
narcolepsy’’ prior to 2010. Four of our children have needed long-
term psychiatric hospitalisation and antipsychotic treatment was
needed in one. More studies are needed to study in more detail the
nature of psychiatric symptoms relative to type of narcolepsy. One
12-year-old boy had Type 1 diabetes. He was DQB1*0602 positive,
which is interesting since this HLA haplotype is regarded as
protective against type 1 diabetes. Knowing the strong genetic
association of narcolepsy with HLA type DQB1*0602 [3,7], it is
possible that all our narcoleptic children could be DQB1*0602
positive. Hypocretin-1 CSF levels were clearly below 110 pg/ml in
all 13 children who had their CSF specimen analysed.
Fatigue and sleepiness and also more severe neurological
complications have been associated with influenza [44,45].
Symptoms of the 1918 Spanish influenza consisted also of
excessive sleepiness having features similar to narcolepsy. The
present 2009 pandemic H1N1 virus is genetically and immuno-
logically more related with the Spanish influenza virus than recent
seasonal influenza viruses [35,46,47]. The present pandemic virus
has genes from avian, human and swine influenza viruses
[35,46,47,48] and the surface hemagglutinin (HA) and neuramin-
idase (NA) genes are more related to Spanish influenza genes than
to present seasonal influenza A virus genes [35]. Unlike in the
Spanish flu, the present pandemic 2009 H1N1 virus usually causes
a mild infection and so far, except in North China [25], no
narcoleptic symptoms or increased incidence of narcolepsy has
been reported after the two epidemic seasons (2009/2010 and
2010/2011) of the present pandemic virus. It is anyway tempting
to hypothesize that the present cases of narcolepsy could have
been caused by an H1N1 influenza infection [45]. However,
narcolepsy was not diagnosed in any of the nearly 8 000
laboratory confirmed H1N1 cases during the first pandemic wave
in 2009 [35]. Also, none of our children had abnormal MRIs or
any signs of focal encephalitis/encephalopathy that has been
suggested to be involved in the destruction of the hypocretin cells
of the hypothalamic area [49].
Could the increased incidence be explained by the increased
awareness of narcolepsy in 2010 compared to previous years -
triggered by the intensive public discussion in Finland in August
2010 of the possible association of narcolepsy with Pandemrix
vaccination? This is unlikely since in the majority of our patients
the symptoms of sleepiness or cataplexy started abruptly before
August 2010, and the parents had consulted health care personnel
already during the winter or early spring 2010. At that time there
had been no news or articles of the increase in narcolepsy
incidence or its possible association with the H1N1 pandemic.
Also, the symptoms of narcolepsy and cataplexy were so clear that
they impaired the daily life of the children. It is very unlikely that
similarly severe abrupt sleepiness with cataplexy and behavioural
problems would have remained unnoticed before 2009–2010. In
addition, the incidence of adult and childhood narcolepsy in
Finland in 2002–2009 has been similar to that seen in other
countries [2,5].
The strength of this study is that it is based on nationwide
registries and thus includes the whole Finnish population. We are
Incidence and Symptoms of H1N1-Related Narcolepsy
PLoS ONE | www.plosone.org 6 March 2012 | Volume 7 | Issue 3 | e33723
confident that practically all severe narcoleptic children with a fast
onset in late 2009–2010 have been identified. Symptomatic
narcolepsy due to brain diseases was excluded by careful
neurological examination, EEG, MRI and other examinations
[49].
There are, however, certain clinical aspects that have to be
considered. In this study, we are limiting our analysis to the years
2002 to 2010. Some cases have remained undetected, since after
2010 we have continued to diagnose new children who have had
their first symptoms during the first half of 2010 (data not
presented). In most cases their initial symptoms have been less
severe than in the present series, explaining why they have not
been sent to specialists earlier. Thus our figure of post-Pandemrix
narcolepsy cases is an underestimation. This is consistent with the
reports showing that the delay from onset of symptoms to
narcolepsy diagnosis may be several years [3,43]. The increased
awareness of narcolepsy in Finland, starting in the fall 2010, has
lead to a clearly faster diagnosis. The incidence figures in previous
years are based on nationwide hospital discharge registry data.
Although the diagnostic criteria and practice in Finland has not
changed, the general awareness of narcolepsy has increased, which
may explain the slightly increased incidence figures in recent years.
To avoid bias we compared the incidence figures from 2009 and
2010 also from the same registries in a similar fashion for all years.
As stated above, the symptoms of most patients started during the
spring (median 38 days after vaccination; see table 1) before any
media attention took place. This means that the possible bias is
limited to the speed of diagnosis and not to the disease onset itself.
The onset, and the nature of symptoms and other diseases is based
on information from the patients, parents, school health nurses
and general practitioners, and some inadequacies are possible. In
two children EDS started on the day of vaccination. They both
fulfilled the diagnostic criteria of narcolepsy with cataplexy. Three
children had no clear cataplexy at the moment of diagnosis, but in
all of them the diagnosis was confirmed by the lack of CSF
hypocretin-1. One of them has developed cataplexy during the
follow-up about 18 months after onset of sleepiness. Four of the 50
post-vaccination patients were reported to suffer from ILI.
However, microbiological verification of influenza or any other
microbial infection had not been done suggesting a lack of
clinically important microbial infections in our narcoleptic
patients. Systematic determination of CSF hypocretin-1 and
HLA typing were not done for all patients since they are not
obligatory in the diagnosis when cataplexy is present and also
MSLT is verifying narcolepsy [4]. Also some children/parents did
not give their consent for CSF specimen when it was suggested.
Narcolepsy is considered an immune-mediated, autoimmune
disease. In addition to a strong association especially with HLA
DQB1*0602/DRB1*15/DR15 – DQ6 HLA type, narcolepsy has
been associated with the presence of TRIB-2 antibodies [17],
specific T-cell receptor alpha [11], and purinergic receptor
P2RY11 [16] genotypes. The onset of symptoms in our children
has been very abrupt which contrasts with most other autoimmune
diseases [50] and with previous concepts of the natural course of
narcolepsy [5]. The incidence of many autoimmune diseases has
increased over the past decades [50], but the rise has never been as
abrupt and as strong as in the case of childhood narcolepsy in
Finland in 2010.
What could be the mechanism(s) of a sudden increase in
childhood narcolepsy in Finland and Sweden? Co-occurrence is
not synonymous to causation. We have therefore carefully
differentiated the effects of the pandemic and the effects of the
vaccination. What is remarkable in Finland is that only the
Pandemrix vaccine was used and that the vaccination coverage
was very high in children and adolescents (75%). In the age-group
5 to 14 years the vaccination coverage was more than 80% [33].
In children the vaccination coverage in Sweden was approxi-
mately 67% [37,51]. In the case Pandemrix vaccination
contributed to the onset of narcolepsy, the high vaccination
coverage in Finland and Sweden may explain the highly increased
narcolepsy incidence in these countries as compared to those
countries where the H1N1 vaccination coverage was much lower,
e.g. in France 10% were vaccinated, and in Italy 0.3% [51]. In the
Netherlands, where only few Pandemrix-related narcolepsy cases
were found, Pandemrix was used in healthy children aged 6
months to 5 years and in siblings and close relatives of children
aged less than 6 months, but not in older children [52]. In addition
to the mathematical explanation, the lack of an increase in
narcolepsy in other countries would suggest that there are other
genetic or environmental factors, in addition to the AS03
adjuvanted vaccination, contributing to the onset. Recent
microbial infections have been suggested as possible environmen-
tal triggers that initiate the symptoms of narcolepsy [53]. A likely
trigger in our patients could be influenza vaccination, which took
place in a close time-relation with the onset of narcolepsy.
Vaccination may have induced or accelerated already pre-existing
autoimmunity leading to a rapid destruction of the hypocretin cells
among genetically susceptible children and adolescents. All our
HLA typed patients (n = 32) were of HLA DQB1*0602 type,
which is the presently known major genetic susceptibility factor
[54]. We cannot formally rule out the contribution of other
infectious agents (H1N1, seasonal influenza, enterovirus, rhinovi-
rus, streptococcal infection [26], or some other microbial
infections) together with vaccination that could have lead to the
development of narcolepsy.
A recent Chinese study observed an epidemiological link with
pandemic influenza and narcolepsy, without significant relation to
vaccination, showing a 3-fold increased incidence of narcolepsy 5
to 7 months after the 2009 epidemics [25]. ILI, without
microbiological confirmation, was observed in only 4 of our
patients (10%). There was, thus, no evidence of simultaneous or
closely time-related microbial infections in most of our patients.
Unfortunately, serum or CSF specimens for detailed viral and
streptococcal antibody analyses were not available since there was
no suspicion of microbial etiology of the narcoleptic symptoms.
Almost a similar increase in the incidence of narcolepsy has been
reported in Sweden, where only Pandemrix was used, as in
Finland [36,37]. Although isolated cases of narcolepsy have been
diagnosed also after other vaccinations than Pandemrix, there is
no evidence of an increased risk of narcolepsy with any other
vaccine than the AS03 adjuvanted Pandemrix [34,39,55]. In order
to draw a link between an environmental effect one must show
that the incidence has increased significantly as compared to
previous years. This was the case in the Chinese study, where the
increase was not explained by Pandemrix [25]. Combining their
and our results, it seems that several different or multiple triggering
factors may exist for the narcolepsy to develop. Based on our study
and the study by Nohynek and co-workers [33] Pandemrix vaccine
was likely one of the triggers. The role of possible other closely
time-related triggers remains to be studied in future epidemiolog-
ical and experimental studies.
The adjuvant (AS03) in the Pandemrix vaccine is very potent,
since it frequently induces local inflammatory reactions and
occasional systemic side effects like fever. We can speculate that
the inflammatory response was so strong that it included central
nervous system affection. It is, however, difficult to say whether the
systemic response produced by the adjuvant could have caused
cellular damage. The hypocretin-1 levels were very low or
Incidence and Symptoms of H1N1-Related Narcolepsy
PLoS ONE | www.plosone.org 7 March 2012 | Volume 7 | Issue 3 | e33723
undetectable in our narcoleptic patients, which may indicate a
rapid destruction of hypocretin cells within weeks or a few months
after vaccination. This does not, however, mean that the adjuvant
would be causing hypocretin cell damage directly. Rather, there is
a possibility that already an ongoing autoimmune process was
accelerated by the nonspecific inflammatory responses induced by
the vaccine or its specific components leading to the destruction of
hypocretin producing cells. Thus, theoretically any inflammatory
process whether it is iatrogenic or infectious (such as influenza and
streptococcal infection) could non-specifically enhance the auto-
immune process leading to narcolepsy. There is also a possibility
that some other genetic factors, in addition to the commonly
accepted HLA-DAB1*0602 risk allele [8,11,16,23,56] are en-
riched in Finland and Sweden making Nordic children susceptible
to an acute inflammation/autoimmune-related narcolepsy.
Why were adult onset cases not increased? Theoretically it is
possible that the vaccine precipitated onset in people who would
have developed it later, anyway. In this case we should see a drop
in adult incidence later during the coming years. Another
possibility is that some children with multiple genetic predisposi-
tion factors are especially vulnerable to develop narcolepsy. In
some other autoimmune diseases, such as in type 1 diabetes, early
age onset is also often seen. It is also possible that the onset is more
insidious in older adolescents and adults and thus there may be a
delay in the diagnosis. In this case we would expect an increase in
the incidence in adults during the coming years. All this mandates
continued clinical and epidemiological surveillance in the future.
Conclusions
We observed a 17-fold increase in the annual incidence of
narcolepsy in 2010 as compared to previous years in children aged
under 17 years of age. A common feature in the history of our 54
newly diagnosed childhood narcoleptic patients was that 50
children had received an adjuvanted pandemic influenza vaccine
(Pandemrix) within 8 months before the onset of symptoms. In
most cases, the development of symptoms was fast. We consider it
likely that Pandemrix vaccination contributed to the increased
incidence of narcolepsy in Finland in 2010 in HLA DQB1*0602
positive children. Our observations warrant further studies on the
role of different environmental factors as well as pathogenetic
studies to understand how a vaccination/adjuvant and other
environmental triggers can cause narcolepsy.
Supporting Information
Appendix S1 Clinical characteristics of 54 children with
narcolepsy (
,
17 years of age) diagnosed in 2010 in
Finland.
(DOC)
Figure S1 Occurrence of childhood narcolepsy in 2002–
2010 in Finland in different age groups. The highest peak
was seen in children aged 11 to 13 years of age. No children aged
less than 8 years had been diagnosed in Finland before 2010.
(TIFF)
Figure S2 Incidence of narcolepsy by year in different
age-groups. The highest incidences were seen in children aged
from 11 to 16 years – especially in the age-group 11 to 13 years of
age.
(TIFF)
Acknowledgments
We thank all our colleagues and everybody else who have been involved in
the diagnosis and treatment of these children and adolescents.
Author Contributions
Conceived and designed the experiments: MP OSH CH TK IJ. Performed
the experiments: MP OSH TK IJ II ML PO PN RA TW ME HR JO HS
HA PK. Analyzed the data: MP OSH TK IJ II ML PO PN RA TW ME
HR JO HS HA PK. Contributed reagents/materials/analysis tools: MP IJ
ML PK. Wrote the paper: MP TK IJ OSH CH. Provided input on the
manuscript: II PO PN RA TW ME HR JO HS HA PK.
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PLoS ONE | www.plosone.org 9 March 2012 | Volume 7 | Issue 3 | e33723
... 1,4 Most NT1 patients have a delay up to several years or even decades between symptom onset and correct diagnosis, although few NT1 patients can sometimes have an acute course in which the symptoms develop within weeks after a trigger event like Pandemrix vaccination that may lead to shortening diagnosis delay. 1,5,6 The long diagnostic delay in narcolepsy may lead to a substantial medical and socioeconomic burden caused by misdiagnosis, inappropriate medication exposure, multiple clinical visits, reductions in patients' quality of life and productivity, poor school performance, increased unemployment, absenteeism, and adverse impact on patients' family, etc. 7,8 Shortening the delay of NT1 diagnosis is one of the major goals of awareness campaigns and efforts invested in narcolepsy medicine/research in the past decades. A shorter delay to NT1 diagnosis may improve future diagnostic procedures and disease management, and even impact decision makers in the healthcare system/industry. ...
... We stratified the raw data because: 1) it can yield a larger number of patients in each subgroup thus leading to higher statistical power; 2) significantly increased number of acute NT1 post 2009-2010 H1N1 influenza pandemic was widely reported including in European countries. 5,6,23 Those patients were characterized by quick disease deterioration and usually diagnosed soon after symptom onset. 25 Thus, we could expect that the diagnostic delay in subgroup 2010-2013 was likely to be shortened compared to the other subgroups. ...
... Therefore, we further showed the changes in stratified diagnostic delay in Figure 5C. There are no significant differences (Kruskal-Wallis rank sum test, P-value=0.263) in the stratified diagnostic delays among 1990s (median: 6 Figure 5C). ...
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Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.
... Reports suggested that the development of narcolepsy could have been triggered by the AS03-adjuvanted H1N1 vaccine in many countries such as Denmark, Finland, and Sweden, reporting an incidence rate ranging from a 1.9 to 14.2 per million p-y [29]. Pandemrix, an AS03-adjuvanted H1N1 vaccine, contributed to a spike in narcoleptic onset among children and young adults, with a 12.7-fold increased risk of narcolepsy diagnosis 8 months after the vaccine [30][31][32]. Adjuvants are helpful in many kinds of vaccines because some viral strains induce different levels of immunological responses. Adjuvants may stimulate the strongest sub-pathways of the immune system of interest to the immune responses [2]. ...
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Purpose of review Central nervous system (CNS) hypersomnias can be triggered by external factors, such as infection or as a response to vaccination. The 2019 coronavirus disease (COVID-19) pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to a worldwide effort to quickly develop a vaccine to contain the pandemic and reduce morbidity and mortality. This narrative review is focused on the literature published in the past 2 years and provides an update on current knowledge in respect of the triggering of CNS hypersomnias by infection per se, vaccination, and circadian rhythm alterations caused by social isolation, lockdown, and quarantine. Recent findings At present, there is no consensus on the association between hypersomnias and COVID-19 vaccination or infection per se; however, the data suggest that there has been an increase in excessive daytime sleepiness due to vaccination, but only for a short duration. Kleine Levin syndrome, hypersomnia, excessive daytime sleepiness, and narcolepsy were aggravated and exacerbated in some case reports in the literature. Both increased and decreased sleep duration and improved and worsened sleep quality were described. In all age groups, delayed sleep time was frequent in studies of patients with hypersomnolence. Summary The hypothesis that there is a pathophysiological mechanism by which the virus, vaccination, and the effects of quarantine aggravate hypersomnias is discussed in this review.
... Adjuvants enable dose-sparing, but adverse events have been associated with some adjuvanted influenza virus vaccinations. 24,25 We are developing an alternative approach to redress the low immunogenicity of H7N9 influenza that is linked to fewer CD4 + T cell epitopes in HA when compared with seasonal H1-HA and H3-HA, 13 and the presence of an epitope that induces functional regulatory T cells that may inhibit helper T cells needed to support a protective antibody response. 15 Our approach introduces seasonal HA-specific CD4 + T cell epitopes into H7N9 HA to produce a novel immunogen capable of priming protective responses by inducing CD4 + T cell memory. ...
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Strategies that improve influenza vaccine immunogenicity are critical for the development of vaccines for pandemic preparedness. Hemagglutinin (HA)-specific CD4+ T cell epitopes support protective B cell responses against seasonal influenza. However, in the case of avian H7N9, which poses a pandemic threat, HA elicits only weak neutralizing antibody responses in infection and vaccination without adjuvant. We hypothesized that an immune-engineered H7N9 HA incorporating a broadly reactive H3N2 HA-specific memory CD4+ T cell epitope that replaces a regulatory T cell-inducing epitope at the corresponding position in H7N9 HA could harness preexisting influenza T cell immunity to increase CD4+ T cells that are needed for protective antibody development. We designed and produced a virus-like particle (VLP) vaccine that carries the epitope augmented H7N9 HA (OPT1) and immunized HLA-DR3 transgenic mice with established H3N2 immunity. OPT1-VLPs stimulated higher stem cell, central, and effector memory CD4+ T cell levels over wild type VLP immunization. In addition, activated, IL-21-producing follicular helper T cell frequencies were enhanced. This novel immunogen design strategy illustrates that site-specific modifications aimed to augment T cell epitope content enhance CD4+ T cell responses among critical subpopulations capable of aiding protective immune responses upon antigen re-encounter and that mobilization of immune memory can be used to overcome the poor immunogenicity of avian influenza viruses.
... Notably, they found a 3-fold increase in narcolepsy incidence after the 2009 H1N1 influenza pandemic, which returned to pre-pandemic basal levels in later years [70,71]. Along this line, European countries experienced 6-fold to 9-fold increase in the incidence of narcolepsy, especially in children, following the 2009-2010 Pandemrix vaccination campaign that was carried out to prevent pandemic H1N1 influenza [72][73][74][75][76]. However, this evidence was not confirmed with any other influenza vaccines, which may be explained by the vaccine composition itself [77]. ...
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Narcolepsy is a rare chronic neurological disorder characterized by an irresistible excessive daytime sleepiness and cataplexy. The disease is considered to be the result of the selective disruption of neuronal cells in the lateral hypothalamus expressing the neuropeptide hypocretin, which controls the sleep-wake cycle. Diagnosis and management of narcolepsy represent still a substantial medical challenge due to the large heterogeneity in the clinical manifestation of the disease as well as to the lack of understanding of the underlying pathophysiological mechanisms. However, significant advances have been made in the last years, thus opening new perspective in the field. This review describes the current knowledge of clinical presentation and pathology of narcolepsy as well as the existing diagnostic criteria and therapeutic intervention for the disease management. Recent evidence on the potential immune-mediated mechanisms that may underpin the disease establishment and progression are also highlighted.
... When the 2009 influenza A (H1N1) pandemic was declared, the AS03-adjuvanted vaccine Pandemrix was used in several European countries. A significant association between the onset of narcolepsy type 1 and exposure to Pandemrix in children and adolescents was reported in Finland and Sweden 9 . A GWAS of Pandemrix-associated narcolepsy type 1 was performed, and GDNF-AS1 was identified as a novel genetic factor 10 . ...
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Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10−8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
Article
Narcolepsy type 1 (NT1), a disorder caused by hypocretin/orexin (HCRT) cell loss, is associated with human leukocyte antigen (HLA)-DQ0602 (98%) and T cell receptor (TCR) polymorphisms. Increased CD4 ⁺ T cell reactivity to HCRT, especially DQ0602-presented amidated C-terminal HCRT (HCRT NH2 ), has been reported, and homology with pHA 273–287 flu antigens from pandemic 2009 H1N1, an established trigger of the disease, suggests molecular mimicry. In this work, we extended DQ0602 tetramer and dextramer data to 77 cases and 44 controls, replicating our prior finding and testing 709 TCRs in Jurkat 76 T cells for functional activation. We found that fewer TCRs isolated with HCRT NH2 (∼11%) versus pHA 273–287 or NP 17–31 antigens (∼50%) were activated by their ligand. Single-cell characterization did not reveal phenotype differences in influenza versus HCRT NH2 -reactive T cells, and analysis of TCR CDR3αβ sequences showed TCR clustering by responses to antigens but no cross-peptide class reactivity. Our results do not support the existence of molecular mimicry between HCRT and pHA 273–287 or NP 17–31 .
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Background The heterologous prime-boost vaccination technique is not novel as it has a history of deployment in previous outbreaks. Aim Hence, this narrative review aims to provide critical insight for reviving the heterologous prime-boost immunization strategy for SARS-CoV-2 vaccination relative to a brief positive outlook on the mix-dose approach deployed in previous and existing outbreaks (ie, Ebola virus disease (EVD), malaria, tuberculosis, hepatitis B, HIV and influenza virus). Methodology and Materials A Boolean search was carried out to find the literature in MEDLINE-PubMed, Clinicaltrials, and Cochrane Central Register of Controlled Trials databases up till December 22, 2021, using the specific keywords that include “SARS-CoV2”, “COVID-19”, “Ebola,” “Malaria,” “Tuberculosis,” “Human Immunodeficiency Virus,” “Hepatitis B,” “Influenza,” “Mix and match,” “Heterologous prime-boost,” with interposition of “OR” and “AND.” Full text of all the related articles in English language with supplementary appendix was retrieved. In addition, the full text of relevant cross-references was also retrieved. Results Therefore, as generally evident by the primary outcomes, that is, safety, reactogenicity, and immunogenicity reported and updated by preclinical and clinical studies for addressing previous and existing outbreaks so far, including COVID-19, it is understood that heterologous prime-boost immunization has been proven successful for eliciting a more efficacious immune response as of yet in comparison to the traditional homologous prime-boost immunization regimen. Discussion Accordingly, with increasing cases of COVID-19, many countries such as Germany, Pakistan, Canada, Thailand, and the United Kingdom have started administering the heterologous vaccination as the technique aids to rationalize the usage of the available vaccines to aid in the global race to vaccinate majority to curb the spread of COVID-19 efficiently. However, the article emphasizes the need for more large controlled trials considering demographic details of vaccine recipients, which would play an essential role in clearing the mistrust about safety concerns to pace up the acceptance of the technique across the globe. Conclusion Consequently, by combatting the back-to-back waves of COVID-19 and other challenging variants of concerns, including Omicron, the discussed approach can also help in addressing the expected evolution of priority outbreaks as coined by WHO, that is, “Disease X” in 2018 with competency, which according to WHO can turn into the “next pandemic” or the “next public health emergency,” thus would eventually lead to eradicating the risk of “population crisis.”
Article
Study objectives: Previous estimated prevalence of narcolepsy in Europe was 47 patients per 100,000 persons, with a yearly incidence of 0.64-1.37 per 100,000. However, analyses of representative datasets from large cohorts are limited. This study aimed to estimate the population-based diagnostic prevalence and incidence of narcolepsy in Germany, and to describe these patients and their health care resource utilization. Methods: This study used the InGef research database, an anonymized representative dataset of 4 million persons covered by statutory health insurance in Germany. Patients with confirmed narcolepsy diagnoses in 2018 were included. Mid-p exact tests were used to calculate 95%-confidence intervals. Patients with narcolepsy diagnoses and narcolepsy-targeting therapy in 2014-2018 were included to describe health care resource utilization in the year prior to diagnosis. Results: In 2018 diagnostic prevalence was estimated as 17.88 (95%-CI 16.45-19.40), and 12-month incidence as 0.79 (0.52-1.15) per 100,000 persons. 46% patients were in psycho-behavioral therapeutic treatment and 61% of employees had sick-leave days. One in three patients was hospitalized for any cause. 28% received antibiotics. Conclusions: Diagnostic prevalence was lower, but incidence was consistent with previous reports, though previous estimates may diverge in terms of age/gender-distributions. Patients showed a substantial utilization of health care resources, including sick leave and hospitalization. Almost half the patients underwent psycho-behavioral treatment in the year prior to diagnosis, which might indicate high burden of psychiatric symptoms. The increased use of antibiotics could indicate more frequent infections than in the general population.
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Thrombosis has long been reported as a potentially deadly complication of respiratory viral infections and has recently received much attention during the global coronavirus disease 2019 pandemic. Increased risk of myocardial infarction has been reported during active infections with respiratory viruses, including influenza and severe acute respiratory syndrome coronavirus 2, which persists even after the virus has cleared. These clinical observations suggest an ongoing interaction between these respiratory viruses with the host’s coagulation and immune systems that is initiated at the time of infection but may continue long after the virus has been cleared. In this review, we discuss the epidemiology of viral-associated myocardial infarction, highlight recent clinical studies supporting a causal connection, and detail how the virus’ interaction with the host’s coagulation and immune systems can potentially mediate arterial thrombosis.
Article
Aim We assessed psychosocial burdens in children who developed narcolepsy after receiving the Pandemrix H1N1 vaccine during the 2009-2010 pandemic. Parental quality of life was also assessed. Methods This multicentre study covered four of the five Finnish University Hospital Districts, which dealt with about 90% of the paediatric narcolepsy cases after the Pandemrix vaccination. The medical records of children diagnosed from 2010-2014 were reviewed. The questionnaires included the Youth Self Report (YSR), Children´s Depression Inventory (CDI), the Child Behaviour Checklist (CBCL) and questions on parental resources, stress and quality of life. Results We obtained the medical records of 94 children who were aged 5-17 years at the time of their narcolepsy diagnosis and questionnaire data for 73 of those children. Most children had strong narcolepsy symptoms 25% had CDI scores that suggested depression. In addition, 41% had total CBCL problem scores above the clinically significant limit and 48% were anxious, withdrawn and had somatic complaints. Sleep latency was weakly associated with the CBCL total problem score. Half of the children needed psychiatric interventions and parental stress was common. Conclusion Depression and behavioural problems were common in children with narcolepsy after the Pandemrix vaccination and their parents frequently reported feeling stressed.
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Narcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups. Retrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started. Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1-30.8). The vaccine-attributable risk of developing narcolepsy was 1:16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1:13,000-1:21,000). Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009-2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.
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In August 2010 the Vaccine European New Integrated Collaboration Effort (VENICE) project conducted a survey to collect information on influenza A(H1N1)pdm09 vaccination policies and vaccination coverage in the European Union (EU), Norway and Iceland. Of 29 responding countries, 26 organised national pandemic influenza vaccination and one country had recommendations for vaccination but did not have a specific programme. Of the 27 countries with vaccine recommendations, all recommended it for healthcare workers and pregnant women. Twelve countries recommended vaccine for all ages. Six and three countries had recommendations for specific age groups in children and in adults, countries for specific adult age groups. Most countries recommended vaccine for those in new risk groups identified early in the pandemic such as morbid obese and people with neurologic diseases. Two thirds of countries started their vaccination campaigns within a four week period after week 40/2009. The reported vaccination coverage varied between countries from 0.4% to 59% for the entire population (22 countries); 3% to 68% for healthcare workers (13 countries); 0% to 58% for pregnant women (12 countries); 0.2% to 74% for children (12 countries). Most countries identified similar target groups for pandemic vaccine, but substantial variability in vaccination coverage was seen. The recommendations were in accordance with policy advice from the EU Health Security Committee and the World Health Organization.
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To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months. Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period. Stockholm county, Sweden. Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1,024,019 were vaccinated against H1N1 and 921,005 remained unvaccinated. Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell's palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status. Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell's palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0.94, 0.91 to 0.98), whereas those vaccinated in the late phase had an overall reduced mortality (0.68, 0.64 to 0.71). These associations could be real or explained, partly or entirely, by residual confounding. Results for the safety of Pandemrix over 8-10 months of follow-up were reassuring -notably, no change in the risk for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Relative risks were significantly increased for Bell's palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the vaccination campaign. Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions.
Article
Study Objectives The International Classification of Sleep Disorders (ICSD-2) criteria for low CSF hypocretin-1 levels (CSF hcrt-1) still need validation as a diagnostic tool for narcolepsy in different populations because inter-assay variability and different definitions of hypocretin deficiency complicate direct comparisons of study results. Design and Participants Interviews, polysomnography, multiple sleep latency test, HLA-typing, and CSF hcrt-1 measurements in Danish patients with narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwC), CSF hcrt-1 measurements in other hypersomnias, neurological and normal controls. Comparisons of hypocretin deficiency and frequency of HLA-DQB1*0602-positivity in the Danish and eligible NC and NwC populations (included via MEDLINE search), by (re)calculation of study results using the ICSD-2 criterion for low CSF hcrt-1 (<30% of normal mean). Measurements and Results In Danes, low CSF hcrt-1 was present in 40/46 NC, 3/14 NwC and 0/106 controls (P < 0.0001). Thirty-nine of 41 NC and 4/13 NwC patients were HLA-DQB1 *0602-positive (P < 0.01). Hypocretin-deficient NC patients had higher frequency of cataplexy, shorter mean sleep latency, more sleep onset REM periods (P < 0.05) and more awakenings (NS) than did NC patients with normal CSF hcrt-1. Across populations, low CSF hcrt-1 and HLA-DQB1*0602-positivity characterized the majority of NC (80% to 100%, P = 0.53; 80% to 100%, P = 0.11) but a minority of NwC patients (11% to 29%, P = 0.75; 29% to 89%, P = 0.043). Conclusion The study provides evidence that hypocretin deficiency causes a more severe NC phenotype. The ICSD-2 criterion for low CSF hcrt-1 (<30% of normal mean) is valid for diagnosing NC, but not NwC. HLA-typing should precede CSF hcrt-1 measurements because hypocretin deficiency is rare in HLA-DQB1*0602-negative patients.
Article
Polymorphisms in the TCRA and P2RY11, two immune related genes, are associated with narcolepsy in Caucasians and Asians. In contrast, CPT1B/CHKB polymorphisms have only been shown to be associated with narcolepsy in Japanese, with replication in a small group of Koreans. Our aim was to study whether these polymorphisms are associated with narcolepsy and its clinical characteristics in Chinese patients with narcolepsy. We collected clinical data on 510 Chinese patients presenting with narcolepsy/hypocretin deficiency. Patients were included either when hypocretin deficiency was documented (CSF hypocretin-1≤110 pg/ml, n=91) or on the basis of the presence of clear cataplexy and HLA-DQB1∗0602 positivity (n=419). Genetic data was compared to typing obtained in 452 controls matched for geographic origin within China. Clinical evaluations included demographics, the Stanford Sleep Inventory (presence and age of onset of each symptom), and Multiple Sleep Latency Test (MSLT) data. Chinese narcolepsy was strongly and dose dependently associated with TCRA (rs1154155C) and P2RY11 (rs2305795A) but not CPT1B/CHKB (rs5770917C) polymorphisms. CPT1B/CHKB polymorphisms were not associated with any specific clinical characteristics. TCRA rs1154155A homozygotes (58 subjects) had a later disease onset, but this was not significant when corrected for multiple comparisons, thus replication is needed. CPT1B/CHKB or P2RY11 polymorphisms were not associated with any specific clinical characteristics. The study extends on the observation of a strong multiethnic association of polymorphisms in the TCRA and P2RY11 with narcolepsy, but does not confirm the association of CPT1B/CHKB (rs5770917) in the Chinese population.
Article
The loss of hypothalamic hypocretin/orexin (hcrt) producing neurons causes narcolepsy with cataplexy. An autoimmune basis for the disease has long been suspected and recent results have greatly strengthened this hypothesis. Narcolepsy with hcrt deficiency is now known to be associated with a Human Leukocyte Antigen (HLA) and T-cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a single peptide unique to hcrt-cells via specific HLA-peptide-TCR interactions. Recent data have shown a robust seasonality of disease onset in children and associations with Streptococcus Pyogenes, and influenza A H1N1-infection and H1N1-vaccination, pointing towards processes such as molecular mimicry or bystander activation as crucial for disease development. We speculate that upper airway infections may be common precipitants of a whole host of CNS autoimmune complications including narcolepsy.
Article
Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of narcolepsy in northern Europe following H1N1 vaccination. The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998-2010). Self-reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi-square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history. The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7-fold increase from trough to peak. Studying year-to-year variation, we found a 3-fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross-correlation indicated a significant 5- to 7-month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences. In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample.
Article
During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally.
Article
Narcolepsy has been studied as a possible autoimmune disease for many years, and recent findings lend more credence to this belief. Although recent and important advances have been done, no study has analyzed the role of the CD40L in patients with narcolepsy. The purpose of this study was to assess CD40L levels, CD3, TCD4, TCD8, CD19, and CD56 lymphocytes, as well as levels of tumor necrosis factor-α and interleukin-6 in narcoleptic patients. We quantified the levels of CD40L, different types of lymphocytes, and levels of tumor necrosis factor-α and interleukin-6 in narcoleptic patients and control subjects. Narcoleptic patients had lower levels of CD40L. Total lymphocytes; CD3, and TCD4 were lower than in the control group. Our findings highlight the important role of CD40L in narcolepsy.