1 1.1. Update of Overview of Dutch cases of narcolepsy

1.1.
Update of Overview of Dutch cases of narcolepsy associated with
Pandemrix®.
Introduction
In August 2010, within a year after the vaccination campaign against H1N1, the
EMA acknowledged the existence of a possible association between vaccination
with Pandemrix® and the occurrence of cases of narcolepsy and studies were
initiated to confirm and quantify this association. Pandemrix® is an AS03adjuvanted monovalent, inactivated split virion influenza A/H1N1 vaccine. In the
Netherlands, Pandemrix® was used to immunize children from 6 months to 5
years old; 83% of them received 2 doses.
In 2011, Lareb presented 3 reports of patients with narcolepsy after administration
of Pandemrix® [1]. In May 2014 an update was presented with an overview of 7
reports [2]. Over the past months both spontaneous reporting and proactive
contacts of Lareb with a center specialized in treating patients with narcolepsy
revealed 13 additional cases. Because of the increase of the number of reports
an update is presented including all reports received till 7 November 2014.
Reports
Case definitions to classify patients with narcolepsy have been developed by the
Brighton Collaboration [3]. Where possible, reported cases have been classified
accordingly.
All but one of the reported cases here are children vaccinated up to the age of 5
years. The exception was an adolescent vaccinated with Pandemrix® in another
country. Compared to adults, narcolepsy may develop differently in young
children, both as to clinical symptoms and timing. Because of its rarity in young
children, it may remain undiagnosed for months or years. An analysis of cases in
Finland showed the importance of defining all stages in the process of
development of narcolepsy, from onset of disease (parental recall), first
documented contact with health care provider, referral to a sleep specialist, and
finally the diagnostic confirmation [4]. In cases reported to Lareb, we have tried to
define the time of onset of first complaints that could be associated with
narcolepsy as precise as possible, by relying on medical records. In most cases
the documented time of onset matched parental recall, but in a few it did not.
Lareb has now received 20 reports of narcolepsy after pandemic influenza
vaccination with Pandemrix® (Table 1). We included one report in which diagnosis
of narcolepsy was suspected by the parents, but Lareb did not receive medical
confirmation.
Nederlands Bijwerkingen Centrum Lareb
November 2014
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Table 1. Reports of narcolepsy associated with the use of Pandemrix ®
Patient,
Number,
Sex, Age at
vaccination,
Source
Drug
Indication for
use
Concomitant Suspected adverse
Medication
drug reaction
Brighton
Collaboration case
level
Time to onset,
Outcome,
Causality
111048
M, 3 years
RIVM/parents
Pandemrix®
2 doses
prophylaxis
DTaP-IPV
vaccination
narcolepsy
cataplexy
CSF hcrt test unknown
BC level unclassifiable
started before
Pandemrix®, and 4
months after DTaP-IPV
not recovered
unlikely
112011
M, 3 years
RIVM/specialist
Pandemrix®
1 dosis
prophylaxis
narcolepsy
CSF hcrt low
BC level 1
2 days
not recovered
unlikely
117581
F, 19 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
HLA+
CSF hcrt low
BC level 1
2 months
not recovered
possible
137759
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
BC level 3
>6 months
not recovered
unlikely
156002
F, 2 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
HLA+
CSF hcrt low
BC level 1
<1 month
not recovered
possible
156062
F, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
HLA+
CSF hcrt low
BC level 1
5-6 months
not recovered
possible
160436
F, 2 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
BC level 2 or 3
3 years
not recovered
unlikely
169846
F, 5 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
HLA not determined
CSF hcrt test not done,
BC level 2
3 months according to
parents; 1st HCP
contact after 18 months
not recovered
possible
173926
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
sleep attacks,
cataplexy,
nightmares,
CSF hcrt test not done,
HLA unknown
BC level 2
>3 years
not recovered
unlikely
174631
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
light cataplexy
CSF hcrt test not done,
HLA+
BC level 2-3
fatigue after 12 months
not recovered
unlikely
174632
F, 1 year
parents
Pandemrix®
2 doses
prophylaxis
extreme fatigue
parents suspect
narcolepsy
narcolepsy not
confirmed
fatigue after 1 month
not recovered
not assessable or
possible?
174709
M, 5 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
MSLT+,
CSF hcrt test not done
HLA test not done
BC level 2
16 months,
not recovered
unlikely
Nederlands Bijwerkingen Centrum Lareb
November 2014
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Patient,
Number,
Sex, Age at
vaccination,
Source
Drug
Indication for
use
Concomitant Suspected adverse
Medication
drug reaction
Brighton
Collaboration case
level
Time to onset,
Outcome,
Causality
175345
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
CSF hcrt negative
BC level 1
>1 year
not recovered
unlikely
179189
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
no test results available
started 6 months before
vaccination,
consultation neurologist
2 months after
vaccination
not recovered
unlikely
179192
M, 4 years
parents
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
CSF hrct low
BC level 1
started 11 months
before vaccination,
consultation neurologist
9 months before
vaccination
not recovered
unlikely
180902
M, 3 years
GP
Pandemrix®
2 doses
prophylaxis
narcolepsy without
cataplexy,
PS and MSLT positive
CSF hcrt test not done
BC level 2
4-5 months,
not recovered
possible
182491
F, 3 years
parents
Pandemrix®
1 dose
prophylaxis
narcolepsy
cataplexy
MSLT not conclusive
CSF hrct negative
BC level 1
<1 month
not recovered
possible
183019
M, 1 year
specialist
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
Sleep test not typical
CSF hcrt test not done
BC level 2
>3 years
not recovered
unlikely
183022
M, 4 years
specialist
Pandemrix®
2 doses
prophylaxis
narcolepsy
cataplexy
CSF hcrt negative
BC level 1
>15 months EDS
not recovered
unlikely
183024
M, 4 years
specialist
Pandemrix®
2 doses
prophylaxis
narcolepsy
>16 months EDS
no cataplexy
not recovered
sleep test doubtful
unlikely
CSF hcrt low
BC level 1
BC Brighton Collaboration case definition level; CSF cerebral spinal fluid; hcrt: hypocretin-1; EDS:
Excessive Daytime Sleepiness; HLA+: carrier of HLA-DQB1*0602; HCP: health care provider; MSLT
Multiple Sleep Latency Test; PS polysomnography.
Nederlands Bijwerkingen Centrum Lareb
November 2014
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Other sources of information
Literature
Since 2011 several studies have been published on narcolepsy in association
with pandemic influenza vaccination [4-10]. In the first signaling country Finland,
an excess of cases (with an age range 5 to 19 years) after vaccination were seen
compared to unvaccinated individuals, the majority of excess cases with an onset
of symptoms between a few weeks and 6 months after vaccination [4,7]. The
signal was confirmed in Sweden [5], Ireland [6] and the United Kingdom [10]. The
European VAESCO study linking hospital registrations with vaccination registers
gives a scattered pattern of countries with increased incidences and other
countries in which the signal is not confirmed [8,9]. Incidence rates were higher in
Finland and Sweden, and lower in The Netherlands. The VAESCO study includes
data from 21 patients (age 0-18 years) from the Netherlands, but only 4 below 5
years of age [8]. The VAESCO investigators concluded that the data from The
Netherlands did not confirm a higher risk for pandemic influenza vaccination and
narcolepsy [8,9]. However, now Lareb has identified more Dutch cases in young
children than the VAESCO study, probably because Lareb now has reports of
patients that were not diagnosed at the time of the VAESCO study.
In a recent review, it was concluded that the association between narcolepsy and
pandemic influenza A/H1N1 vaccination was based on epidemiological studies,
while investigations into a causative mechanism are not conclusive so far [11].
Prescription data
A total of 588.750 children received the first dosage and 490.584 children (83%)
received a second dosage of Pandemrix® [12].
Mechanism
A causative mechanism, on which an increased risk is based, is unknown.
Current theories favor a T-cell mediated autoimmune mechanism, possibly with
genetic factors that together lead to the development of narcolepsy [13,14].
Epitopes on the hemagglutinin protein of H1N1 virus closely resemble parts of the
hypocretin molecule. Immunization with H1N1 epitopes presented by a particular
HLA molecule (HLA-DQB1*0602), may lead to destruction of hypocretinproducing cells, mediated by T-lymphocytes [15]. The findings may point to a
unique combination of a genetic factor, epitopes on the influenza A/H1N1 virus
with specific cross-reaction with hypocretin-producing cells, possibly magnified by
the AS03 adjuvant. However, July 2014, the authors have retracted the
publication because they were not able to reproduce some of the immunological
tests. They nevertheless still strongly believe in the underlying immunological
hypothesis [15].
The role of circulating pandemic influenza A/H1N1 virus as an inducer of autoimmunity cannot be excluded either. Over a period of 12 years, an investigation in
China demonstrated that the onset of narcolepsy (629 patients; 86% children)
was seasonal, and increased after the H1N1 pandemic [14]. Of the new cases
identified after the pandemic started, 8 of 142 (6%) patients received a H1N1
vaccination [16], suggesting a minor contribution of the vaccination. In The
Netherlands, we may have a similar situation, because circulation of influenza
A/H1N1 virus was high in the months preceding the vaccination campaign in
2009.
Nederlands Bijwerkingen Centrum Lareb
November 2014
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Discussion and conclusion
Lareb received 20 reports of narcolepsy after pandemic influenza vaccination with
Pandemrix®, all but one in children below 5 years of age. Usually, narcolepsy
starts to occur in adolescence, and not at the young age at which 19 of our cases
occurred. The unexpected young age of our cases is remarkable.
If an auto-immune reaction induced by the vaccine is the cause of narcolepsy, a
compatible latency time would be in the order of weeks for the first symptoms to
start after vaccination (few weeks if the auto-immune destruction is mediated by
T-cells, later if mediated by IgG-antibodies). Dauvilliers et al report that acute
onset of cataplexy occurred between 2-8 weeks after vaccination [13], but also
suggest that a slower onset may occur later [13]. This pattern of onset resembles
the sudden rise in cases as found in Finland, within 6 months of vaccination [4].
Seven reports (117581, 156002, 156062, 169846, 174632, 180902, 182491),
including one suspected but not verified case) have a latency time that is
compatible with a possible auto-immune reaction.
We consider an onset of symptoms later than 6 months after vaccination less
compatible with a direct auto-immune cause of narcolepsy, as is the case in nine
reports (137759, 160436, 173926, 174631,174709, 175345, 183019, 183022,
183024. In theory the H1N1-vaccination in these nine cases may have induced
the immunological priming for an auto-immune reaction which then later may
have been boosted to a level that hypocretin-producing cells are affected. Thus,
in these cases, causality is not excluded.
In the three reports (111048, 179189, 179192) the time of onset was before
vaccination, which makes a causative role of the vaccine unlikely. In report
112011 the reported onset 2 days after vaccination is too early to induce an autoimmune reaction unless the patient had been primed before. However, it cannot
be excluded that vaccination has aggravated the disease in these cases.
Incidence data on narcolepsy in young children in The Netherlands before 2009
are missing. Further research into the causal association of Pandemrix® and
narcolepsy is recommended.
At present, Pandemrix® is no longer marketed. In November 2013, the US FDA
approved a potential future pandemic monovalent influenza A/H5N1 (Q-Pan)
vaccine, again with the AS03 adjuvant [17].
Nederlands Bijwerkingen Centrum Lareb
November 2014
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