Feb 03 2011

Follow up on Pandemrix and Narcolepsy

Last year it was reported that there was a possible increase in narcolepsy, a sleep disorder characterized by excessive sleepiness, in children who had received the Pandemrix brand of H1N1 flu vaccine in Sweden, Finland, and Iceland. However a review of the data did not find a convincing connection, although concluded there was insufficient data at present and recommended further surveillance. A narcolepsy task force was formed in Finland, and now we have their preliminary report.

They conclude that the evidence suggests there is a connection:

Based on the preliminary analyses, the risk of falling ill with narcolepsy among those vaccinated in the 4-19 years age group was 9-fold in comparison to those unvaccinated in the same age group. This increase was most pronounced among those 5–15 years of age. No cases were observed among those under 4 years of age. Also, no increase in cases of narcolepsy or signs of vaccination impacting risk of falling ill with narcolepsy was observed among those above 19 years of age.

These results are intriguing, but should be considered preliminary. Epidemiology is a complex endeavor, and there are lots of wrinkles to this data. The increased risk of narcolepsy was only seen within a certain age range. In Iceland (but not Sweden or Finland) the increase in narcolepsy was also seen in those who were not vaccinated. And further, other countries that also used the Pandemrix vaccine have seen no increase narcolepsy, including Norway, the UK, Germany, and Canada.

Overall we have a very inconsistent pattern. The vaccine does not appear to be a consistent or unique risk factor for narcolepsy in these populations. The task force concludes from this that there must be another factor that is combining with the vaccine to increase the risk. This is logically possible, but until this factor X is identified it remains speculation.

One possibility is that the vaccine only increases risk within certain genetic populations. If a gene variant can be localized that renders individuals susceptible to some component in this brand of vaccine that could explain this data. Perhaps something else is also triggering the increase in Iceland, but not Finland and Sweden, to explain the rise in narcolepsy there in the unvaccinated.

Another possibility is that there is one or more confounding factors leading to the increase in narcolepsy, and the vaccines are a correlating but not causative factor.

Such is the nature of epidemiology, or observational studies. Variables are not controlled for and confounding factors are always a possibility. That does not mean that observational data is not useful or cannot be definitive – but it requires careful, thoughtful, and thorough collection and analysis of data from multiple different angles. The data we have so far from Finland is very preliminary, and generates more questions than answers. There is certainly sufficient cause for caution and further analysis. But at this point I would not be surprised by any particular outcome, since the data can be interpreted in many ways.

It will be interesting to see what the final outcome of this story is. These cases are always like mystery investigations, and the outcomes are often very interesting and can differ greatly from initial impressions. I would not be surprised if it turns out to be a real effect of the Pandemrix vaccine. Vaccines are not without risk, although over the decades the risks have proven to be very small and vastly outweighed by the benefits. Obviously it would be hugely useful to identify which ingredient was the culprit and exactly how it triggered narcolepsy in this population.

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17 responses so far

17 Responses to “Follow up on Pandemrix and Narcolepsy”

  1. passionlessDroneon 03 Feb 2011 at 8:50 am

    Hello friends –

    Of potential relevance here is the data that indicates narcolepsy is an autoimmune disorder.

    http://www.ncbi.nlm.nih.gov/pubmed/20614847
    http://www.ncbi.nlm.nih.gov/pubmed/20160349

    The regionally specific effects are curious.

    - pD

  2. Karl Withakayon 03 Feb 2011 at 10:57 am

    Of course, if any particular vaccine, say a hypothetical Widgitrex, were found to increase risk of some particular condition, that would be no more a slam dunk against vaccines in general that the Toyota recalls of last year are a slam dunk against transportation by automobile.

  3. daedalus2uon 03 Feb 2011 at 11:23 am

    Even if this narcolepsy is absolutely caused by the vaccination, the question to ask is what would getting the actual infection do? Unfortunately that isn’t a question that can be answered experimentally in a prospective manner.

    The papers pD linked to might suggest a genetic propensity based on HLA genotype. That could explain a geographic propensity. Involvement of autoimmunity could also depend on prior exposure to similar antigens, what is called “immunological original sin” (where the first antigen of a type the immune system is exposed to affects future responses to similar antigens).

    This type of interaction may occur more frequently in diseases of high mortality (which the H1N1 flu seemed to be). Presumably high lethality infections are highly lethal because the immune system can’t deal with them as readily. One mechanism might be due to cross reactivity with self-antigens causing autoimmune disorders.

    Vaccine side effects due to autoimmune sensitization may well correlate to strain lethality. If so, using side-effect profiles derived from vaccine use in low lethality strains of flu may under estimate the level of side effects acceptable in highly lethal strains. If the flu has a 1/100,000 chance of killing you, a vaccine to reduce that to 1/million needs to be much safer than 1/100,000. If this particular strain of flu has a 1/100 chance of killing you, a much higher levels of vaccine side effects (i.e. 1/10,000) is still a wise choice.

  4. Enzoon 03 Feb 2011 at 11:33 am

    It’s difficult to get a real feel for this without the full data.

    There were only 60 cases in the relevant age group as the report states and that represents a 9-fold risk increase when the total vaccine coverage is 70% in that age group. Hard numbers to work with for something like this. And I imagine the issue of non-vaccinated with non-reported narcolepsy is significant in this case.

    Look forward to the full report.

  5. desireeon 03 Feb 2011 at 12:34 pm

    i’m confused about where the authors are getting a 9-fold increase in narcolepsy among vaccinated kids. the press release on their website states that 8 of the 60 cases were among unvaccinated kids and 52 were found in vaccinated kids. they also state that 70% of kids were vaccinated.

    so, suppose that there are 100,000 kids aged 4 – 19 in finland. that means the rate of narcolepsy among the unvaccinated was 8/30,000 = 0.0267%. among the vaccinated it’s 52/70,000 = 0.074%. that’s almost tripe the rate, but not a 9-fold increase. (the denominators are fictional here of course, so so are my percentages, but since i’m using the same 100,000 for both groups, it cancels out when i compare the rates.)

    is my math wrong? i can’t figure out where it’s wrong. do you think they might be using last year’s rate of narcolepsy to calculate the 9-fold risk (on the grounds that the numbers among the unvaccinated were too small to use as a comparison)? if that’s the case, their numbers start to look a lot more like iceland’s, which would support the idea that the increase is unrelated to the vaccine.

    i am really stuck on this one!

  6. Woodyon 03 Feb 2011 at 4:07 pm

    I find this very interesting. There is a literature on antibody-mediated mechanisms for narcolepsy in the citations linked to by pd above, amongst others.

    The regional specificity wouldn’t be that surprising – the hypocretin neurons implicated in narcolepsy are very localized within the brain. If the proposed autoimmune mechanism is specific to that neuronal subpopulation, there probably wouldn’t be more widespread neurological manifestations.

    It is also interesting that the study comes from northern latitudes, mirroring what has been described for decades in another autoimmune central nervous system disorder, multiple sclerosis. Maybe those northern genetic populations are more susceptible autoimmune processes in general, including those provoked by an exogenous agent such as a vaccine? I wonder if those populations have been found to be more susceptible to other autoimmune disorders following immune challenges, like acute disseminated encephalomyelitis (ADEM) and Guillain-Barre syndrome?

    Finally, the neuronal populations that regulate sleep may be more susceptible to autoimmune processes in general, as sleep disturbances have also been reported in other antibody-mediated disorders of the central nervous system.

    If they confirm this, it may become a useful tool to study these questions in animal models of narcolepsy.

  7. eeanon 04 Feb 2011 at 1:10 pm

    so that 9x stat is of a subset of a subset of the vaccinated population. Couldn’t it be just statistical noise?

    If its an autoimmune disorder then certainly the basic science is solid. will be interesting to see what happens. My money is on reversion to the mean though.

  8. ccbowerson 04 Feb 2011 at 8:25 pm

    desiree – I agree that there appears to be something amiss with the 9 fold figure. I don’t see a mjor flaw with your logic there. It appears to me that a group of children who did not get a vaccine in countries in which 70% of children get the vaccine are likely a very different group of people in many ways. For one, they may be unlikely to seek healthcare for a sleep disorder if they don’t seek healthcare for vaccination.

  9. BillyJoe7on 05 Feb 2011 at 2:08 am

    eean,

    “so that 9x stat is of a subset of a subset of the vaccinated population. Couldn’t it be just statistical noise?”

    My thought exactly, except that I think you meant a statistical outlier extracted by data mining.

    (Like the the early studies of the EMRcancer link. With a long list of multiple comparisons to mine, one study extracts a link to leukaemia, whilst another extracts a link to brain cancer.)

  10. desireeon 06 Feb 2011 at 8:39 am

    oh, i see. when they write that “this increase was most pronounced among those 5-15 years of age,” maybe they mean that’s the group with a 9-fold increase? that’s a bit sloppy on their part, to word it like that, but maybe english isn’t their first language.

    it really does start to look like data mining when they cut up their group like that. but then again, 5-15 still encompasses more than half of the children. i still don’t think the word “probable” was justified. has anyone seen the full report, or was the press release all they released?

  11. Ufoon 06 Feb 2011 at 2:53 pm

    desiree, the full report is available, but (afaik) only in Finnish, here:

    http://www.thl.fi/thl-client/pdfs/f890b9f3-9922-4efe-889b-157fe2e03aa4

    The increase has happened only in the 4-19 age group.

    In 2006 there were 5 narcolepsy cases in this age group (ncitag).

    In 2007 there were 6 ncitag.

    In 2008 there were 14 ncitag.

    In 2009 there were 9 ncitag.

    In 2010 there were 62 ncitag.

    I’m a bit busy at the moment, but if you have any specific questions in mind I can take a look at the report and try to give you an answer.

    Best,

    Ufo from Finland

  12. daedalus2uon 06 Feb 2011 at 10:30 pm

    If you look at the report as html from the google cache, google will machine translate it for you (as a pdf it is too big).

    The tables don’t come through, but if you look at the original it is pretty clear what they mean.

    It does seem like the narcolepsy is associated with only a few batches of vaccine.

    I wonder if those batches were contaminated with streptococcal antigens (it is streptococcal antigens that causes the autoimmune sensitization associated with streptococcal infection, rheumatic fever and PANDAS and is also associated with narcolepsy) and with the adjuvants used (vitamin E, squalene, and aluminum sulfate), maybe there was enough of the antigen to cause sensitization in susceptible individuals?

    Flu virus for injection is grown in fertile chicken eggs. They used to use thimerosal to prevent bacterial growth during the growth and incubation. The bacteria would be easy to kill during vaccine preparation, but their antigens might persist in the final product (which is why they used thimerosal). They probably test for LPS, but they can’t test for everything.

  13. desireeon 07 Feb 2011 at 10:47 pm

    thanks Ufo!
    my first question is how they come up with a 9-fold increase in narcolepsy among vaccinated kids.

    and i glanced at the report you linked to (for the graphs, i don’t understand a bit of finnish), and what’s going on with taulu 4 (table 4?) are those the finnish names for iceland, sweden, norway, england, canada, and 2 other countries?

    thanks!

  14. Sherringtonon 10 Feb 2011 at 11:02 pm

    Narcolepsy has been shown to involve a loss of neurons that produce the chemical orexin. There are animal models of narcolepsy; it would be interesting to know if this vaccination causes a loss of orexin cells in rats. A lack of such a finding would not be that helpful, but if such a loss was found, it could be useful in isolating the relevant factors. Of course, I do realize the limitations of such models (and there was a great discussion of that on the most recent episode of Skeptic’s Guide to the Universe).

  15. Grim Redeemeron 10 Mar 2011 at 12:37 pm

    @desiree:

    In case you were still wondering, those are indeed Finnish names for countries in Table 4. From top to bottom: Iceland, Finland, Sweden, Norway, Great Britain, Germany and Canada. (They might be referring to the UK, not just Great Britain, Finns are often unclear about that.)

    The columns show reported cases of narcolepsy in 4-19-year-olds, the number of 4-19-year-olds vaccinated, and the number of cases per 100,000.

    As for the “9-fold” increase, the explanation is a tad complex. I have no understanding of epidemiology and have only done basic courses in statistics, but here goes…

    They did a retrospective cohort study. Incidence of narcolepsy was calculated for the unvaccinated and vaccinated groups from January 1st 2009 to August 16th 2010 — this latter date was chosen so as not to allow the potentially increased rate of diagnosis caused by publicity of the possible vaccine-narcolepsy-link to skew the data.

    For the unvaccinated, the number of diagnoses was divided by the whole period. For the vaccinated the divisor was only the time after getting the vaccination. By this method, the incidence for vaccinated 4-19-year-olds was 9.2 times greater (95% CI: 4.5-21.4) than for the unvaccinated cohort.

    They warn that these results are only preliminary, particularly because of the difficulty of determining the time at which symptoms first started and when narcolepsy can, in retrospect, be diagnosed.

    According to the latest news ( http://yle.fi/uutiset/kotimaa/2011/03/narkolepsiaepailyjen_maara_kasvoi_2425029.html , in Finnish) the number of suspected narcolepsy cases currently stands at 69, with 62 confirmed diagnoses.

    I guess it’s just a question of time when us Finns too begin dying of measles again…

  16. BerloD1on 11 Mar 2011 at 7:53 am

    Several cases of Narcolepsy/Cataplexy subsequent to vaccination with pandermrix are beginning to emerge in Ireland — documented recently in Irish Daily Mail newspaper …. these cases appeared as “mystery ilness symptoms” that the medical profession was unable to diagnose …. now it looks like Pandemrix was implicated …. watch this space …

  17. BerloD1on 21 Jul 2011 at 6:26 pm

    I just noticed that the European Medicines Agency has updated its advice on Pandemrix vaccine, taking into account the latest available data on the possible link to increased cases of Narcolepsy, and is recommending restricted use.

    http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001312.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1&jsenabled=true

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