On transparency in science: lessons from the Pandemrix vaccine and 'partial' evidence-based practice

Minus any hype or sweeping generalisation, I want to draw your attention to a feature article recently published by Peter Doshi [1] titled: "Pandemrix vaccine: why was the public not told of early warning signs?" complete with some media interest (see here).

The feature is based around the vaccines developed to counter the 2009 flu pandemic that starred the H1N1 influenza virus which was sweeping across the globe at the time. The 2009 flu pandemic was potentially serious insofar as its infection pattern and fatalities linked to infection although in reality did not turn out to be quite the 'global killer' that was prophesied. The rush to bring to market a vaccine to protect lives and counter the rise of H1N1 also brought with it controversy from several perspectives [2]; some later talking points seemingly stemming from the inclusion of a specific adjuvant - AS03 - in some vaccine preparations, and data suggestive of a possible correlation between onset of narcolepsy and use of certain flu vaccines containing the AS03 adjuvant (see here). Narcolepsy - a sleep disorder - was one potential adverse side-effect talked about, but other labels/conditions were also the source of some inquiry too (see here). On the basis of the emerging published data, court cases ensued, some of which have apparently unearthed some "internal reports" suggesting that some manufacturers "were aware of other serious adverse events logged" in relation to certain H1N1 vaccines...

The Doshi feature goes through some of these 'revelations' that did not seem to have been made public at the time. He talks about an 'undisclosed problem' whereby one vaccine in particular, Pandemrix, seemed to have a greater frequency of various adverse events reported according to those internal company reports. Most worrying are the reports of 'fatal outcome' across different vaccine preparations, particularly Pandemrix. He also writes: "And the raw numbers of adverse events were not small" highlighting how in one of the latest internal reports dated March 2010 seen by himself (or at least, the British Medical Journal) over 5000 reports of "serious adverse events for Pandemrix" had been received by the company behind the vaccine.

It's timely that the Doshi feature appears now at the time of writing this post, just days after the Peter Gøtzsche - Cochrane drama (see here) and at the same time as other relevant pieces have been published (see here and see here [3]). The similarities around questions of transparency in science (particularly industry-derived science that has a public health aspect attached to it) are very noticeable. As is also the question of 'how much detail should the public be provided with?' when it comes to science in general and then specifically, science and science communication linked to the potential cost-benefit ratio of particular medicines or medical preparations. It's interesting too that Doshi also references some past debate in Germany [4] about the 2009 flu pandemic where it was apparently reported that "the German interior ministry rejected accusations that the ministry had ordered a less risky vaccine for top officials" in light of some newspaper headlines published at the time. 'All animals are equal, but some animals are more equal than others' perhaps springs to mind...

I don't think the issue of less than full transparency in science and the question 'how much detail should the public be provided with' are going to go away any time soon. Such issues strike to the heart of the matter of how peer-reviewed published science is seemingly only one part of a much bigger picture when it comes to the search for a complete truth. One wonders for example, how many other 'internal reports' lie in [research] file cabinets around the world that could conceivably influence evidence-based decisions on the effectiveness and safety of various medicines and other interventions indicated for various conditions? Without such documents ever seeing the cold light of day, how can science ever truly be said to be complete, transparent or indeed settled?

Such a 'transparency' situation also makes initiatives like OpenTrials - calling for all research to be more 'discover-able' and 'traceable' - all the more vital and important. Issues such as the requirement for pre-registration of all studies via databases such as ClinicalTrials.gov and importantly, the timely release and publication of results (see here) are pressing features. Study pre-registration (especially prospective registration) in particular, should perhaps be pushed a lot more than it currently is, and shouldn't just be reserved for big studies of drugs and medicines either.

Science is great and is getting better all the time. But it still has lots of issues and problems to overcome. A lack of research transparency seems to be a particularly important issue that, whilst starting to receive some much required attention, will if present, always mean that evidence-based practice really should be re-branded as 'partial evidence-based practice'. And that has lots of implications...

To close, given the subject matter included in the Doshi paper, I want to end with a reminder about not making sweeping generalisations. At the same time I'd also champion the words included in another recent article by Jørgensen and colleagues [5] (yes, also including Peter Gøtzsche as an author) responding to the idea that public confidence in public health initiatives such as vaccination may be "undermined" by even having such discussions in public. To quote: "Debates over sources of evidence must take place in public, especially when public health interventions are at stake." This is again, with the idea that science needs transparency - even better in the peer-reviewed domain - and closed door discussions rarely aid such transparency.

----------

[1] Doshi P. Pandemrix vaccine: why was the public not told of early warning signs? BMJ 2018;362:k3948

[2] Doshi P. Influenza: marketing vaccine by marketing disease. BMJ 2013;346:f3037.

[3] Jørgensen L. et al. Challenges of independent assessment of potential harms of HPV vaccines. BMJ 2018;362:k3694

[4] Stafford N. Only 12% of Germans say they will have H1N1 vaccine after row blows up over safety of adjuvants. BMJ 2009;339:b4335.

[5] Jørgensen L. et al. Response to Cochrane editors: Jørgensen, Gøtzsche and Jefferson. BMJ EBM Spotlight. 2018. Sept 23.

----------

Vitamin D halting colds and flu?

"Overall, the study said one person would be spared infection for every 33 taking vitamin D supplements. That is more effective than flu vaccination, which needs to treat 40 to prevent one case, although flu is far more serious than the common cold."

That was some of the media interpretation of the paper - "systematic review and meta-analysis of individual participant data" - published by Adrian Martineau and colleagues [1] looking at the collected data on vitamin D supplementation "on risk of acute respiratory tract infection." Including data on approximately 11,000 'randomised' participants reported in 25 studies, authors assessed whether the quite messy data on vitamin d supplementation potentially decreasing the risk of acute respiratory tract infection showed any semi-definitive trends.

Results: "Vitamin D supplementation resulted in a statistically significant reduction in the proportion of participants experiencing at least one acute respiratory tract infection." Further: "Use of vitamin D did not influence risk of serious adverse events of any cause... or death due to any cause. Instances of potential adverse reactions to vitamin D were rare." And finally: "Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not."

I note that in the BBC news report on the Martineau paper we are told: "Public Health England (PHE) says the infections data is not conclusive, although it does recommend supplements." This slightly counter-intuitive position follows more general advice from the powers-that-be that perhaps we should all be taking a little more vitamin D (see here) given what is emerging when it comes to the varied functions of the sunshine vitamin/hormone. But bear in mind that supplementation comes with potential risks too (see here) particularly when people forget to treat their vitamins and minerals as what they are: biologically active pharmaceutics. Neither is everyone completely sold on the idea that vitamin D 'could stop colds or flu' as an accompanying editorial to the Martineau paper makes clear [2]: "The results are heterogeneous and not sufficiently applicable to the general population."

What such research does advance however, is that vitamin D is a potentially important nutrient (more so for some groups) and one that we should be [cautiously] dedicating a lot more investigation to for all-manner of possible reasons (see here and see here) outside of just bone health and the English disease. And within that scheme of research, don't forget a few things: (a) there's more to vitamin D metabolism than just 'getting enough' and (b) even today, science is still finding out new things about the chemistry of vitamin D [3]. In short, the scheme of science around vitamin D needs to be broad...

----------

[1] Martineau AR. et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583.

[2] Bolland MJ. & Avenell A. Do vitamin D supplements help prevent respiratory tract infections? BMJ 2017; 356: j456.

[3] Pauwels S. et al. 1β,25-Dihydroxyvitamin D3: A new vitamin D metabolite in human serum. J Steroid Biochem Mol Biol. 2017 Feb 10. pii: S0960-0760(17)30040-7.

----------

Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, & et al (2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ : 10.1136/bmj.i6583

Pregnancy influenza infection not linked to offspring autism

"There was no association between maternal influenza [flu] infection anytime during pregnancy and increased ASD [autism spectrum disorder] risk."

So said the findings reported by Ousseny Zerbo and colleagues [1] continuing a research theme from this author (see here for example) looking at how various infections 'encountered' during critical periods of pregnancy may / may not impact on offspring autism risk. This time around the focus was on viral infections and in particular "maternal influenza infection and vaccination from conception date to delivery date" as derived from either diagnosis using ICD-9 criteria or "a positive laboratory result for influenza based on the Prodesse ProFlu+ Assay (Hologic), a multiplex real-time polymerase chain reaction in vitro diagnostic test." Said participants numbering nearly 200,000 children were all born "at Kaiser Permanente Northern California from January 1, 2000 to December 31, 2010, at a gestational age of at least 24 weeks." The press release accompanying the publication can be seen here.

"Maternal influenza infection during pregnancy was not associated with increased ASD risk in this study, and the association did not vary by the timing of influenza infection." Importantly, authors also looked at whether maternal influenza vaccination during pregnancy was also related to offspring ASD risk based on the data contained in their patient databases. The results pertinent to pregnancy flu vaccination and offspring risk were not exactly cut-and-dried as "in an initial analysis unadjusted for multiple comparisons" the authors reported seeing a 'slightly increased' risk for offspring autism associated with maternal vaccination during the first few months of pregnancy. This was set against data indicating no significant association between maternal influenza vaccination covering 'anytime' during pregnancy. Indeed, after "adjusting for the multiplicity of hypotheses tested" they concluded that the first trimester vaccination - offspring autism risk was potentially a 'chance finding'. Minus any scaremongering and to be on the safe side the authors suggested that "additional studies are warranted to further evaluate any potential associations between first-trimester maternal influenza vaccination and autism."

Aside from a few potential 'weakness' attached to the Zerbo results including the fact that "subclinical infections or illnesses for which women did not seek medical attention" were not counted in the data, these are interesting results. Quite a few times on this blog I've covered the so-called maternal immune activation (MIA) hypothesis - where mum's reprogrammed pregnancy immune system is 'challenged' and potentially has implications for offspring development - and this work kinda falls into that category of autism science. Indeed, I've talked about the possibility quite recently (see here). Drawing also on data looking at season of conception/birth as potentially being important to pregnancy viral/bacterial exposure and onward offspring outcomes (see here) there has been a steady stream of peer-reviewed publications hinting at a potentially important 'association' between infection exposure in-utero and developmental outcomes for the child. The current Zerbo data however put a bit of a research spanner in the works when it comes specifically to any pregnancy flu and offspring autism risk suggestion albeit with the continued requirement for further investigations in this area covering other infections.

----------

[1] Zerbo O. et al. Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder. JAMA Pediatr. 2016 Nov 28.

----------

Zerbo O, Qian Y, Yoshida C, Fireman BH, Klein NP, & Croen LA (2016). Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder. JAMA pediatrics PMID: 27893896

Establishing environmental exposures as risk factors for bipolar disorder: Difficult.

The findings reported by Ciro Marangoni and colleagues [1] made for some interesting reading recently and their systematic review of longitudinal studies looking at the various environmental exposures put forward as possible risk factors pertinent to the development of bipolar disorder (BD).

Trawling through the peer-reviewed material on this topic, the authors were able to 'clump' the various proposed risk factors into one of three categories: "neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs - opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury)."

They did not however, report the presence of any specific 'smoking gun' on the basis of their investigations, concluding that: "Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD." That also the various risk categories seemed to be 'correlated' with various other psychiatric and/or behavioural labels is also an important point to make in these days of overlap and RDoC.

I personally am not surprised by these results. Appreciating that diagnostic labels do not equal homogeneous groups, and that just as when defining the genetics of something like BD, so defining the non-genetic correlates is an equally difficult task, studies of this type remind us just how complicated and individual the paths are bringing someone to such a clinically-relevant label. I say this with the understanding that just because an specific environmental (or non-environmental) risk factor might not be generalisable to all BD does not mean it can't exert a more pronounced effect in smaller groups or individuals. Lessons from other labels teach us this (see here).

Whilst important to understand whether there may be specific environmental exposures that might be more generally linked to an enhanced risk of developing BD, I do believe that the [research] future lies in a couple of other areas looking at: (a) how many different types of BD are there and what are the 'other' conditions/labels potentially related? (b) what does the biology of BD look like and does it include some common targets with other labels? and (c) outside of the array of interventions put forward for managing symptoms (see here), are there other intervention strategies that might fit with the findings of (a) and (b)?

To close, LEGO do it best...

----------

[1] Marangoni C. et al. The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. J Affect Disord. 2016 Jan 1;193:165-174.

----------

Marangoni C, Hernandez M, & Faedda GL (2016). The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. Journal of affective disorders, 193, 165-174 PMID: 26773919

CFS/ME associated with pandemic influenza infection

"Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME [Chronic fatigue syndrome/myalgic encephalomyelitis]."

That was the headline finding from the study by Per Magnus and colleagues [1] looking at whether large population data might provide some clues about 'associated' variables when it comes to the various debilitating conditions headed under the terms CFS/ME.

I'm blogging at a slight disadvantage with regards to the Magnus study because I don't yet have the full-text paper. Looking at the source data - "Using the unique personal identification number assigned to everybody who is registered as resident in Norway" - and observing some notable names on the authorship list, I'm inclined to suspect that this study might have some MoBa undertones (see here) bearing in mind the focus on the "complete Norwegian population" not just pregnant women and their offspring. Indeed, other research from this authorship group provides some further clues about data derivation [2].

Focusing on those specifically diagnosed with CFS/ME - "diagnostic code G93.3 in the International Classification of Diseases, Version 10" researchers calculated hazard ratios (HRs) for CFS/ME "after influenza infection and/or vaccination." A few details emerged including:

• "The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk." At this point I might direct you towards some details on the difference between incidence and prevalence.
• Influenza infection seemed to confer something of an enhanced risk for CFS/ME as per the finding of an adjusted HR of 2.04 (95% CI: 1.78-2.33). 
• That being said, the authors report "no indication of increased risk of CFS/ME after [pandemic] vaccination." This has potentially important public health implications (see here).
• They conclude by suggesting that such natural infection = increased risk of CFS/ME vs. antigenic stimulation (vaccination) = no increased risk of CFS/ME might indicate "a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME."

The first thing that struck me about these findings was the 'overlap' noted with a familiar concept to this blog: maternal immune stimulation and offspring outcomes. This is the idea that immune 'stimulation' during critical periods of pregnancy might have the propensity to affect offspring developmental outcomes in a behavioural fashion (see here for example). Two of the big names in this area (Alan Brown and the late Paul Patterson) wrote rather a good review of this area focused on how some of the tools of public health such as vaccination might already be affecting the risk of development/onset of schizophrenia in relation to the maternal immune activation (MIA) model [3] with viruses such as influenza in mind. More detailed work is of course indicated.

Without trying to equate CFS/ME with schizophrenia or any other related label, I do find it interesting that infection and the associated biological response associated with it, might show some 'connection' to CFS/ME in the same/similar way that such biology might also be involved in priming a person for later-life schizophrenia. If we've learned anything about CFS/ME this year aside from it being 'a real illness' (see here if you really needed telling) it is that in amongst the multitude of findings on the condition, there is some really interesting 'immune-related' features coming through (see here). I know the term 'immune-related features' covers a lot of ground but alongside the already tantalising idea that infection is linked to CFS/ME onset (see here) (why else would it be also referred to as post-viral fatigue syndrome), I'm talking about how infection and response to infection might so severely impact on a person and what could be done to potentially prevent it.

Further work is indicated on the basis of the Magnus findings including a focus not just on influenza and CFS/ME but other biological agents such as the really, really interesting prospect of a connection between cases of CFS/ME and acute enterovirus infection [4] for example. Assuming that genetic make-up probably plays an important role in the handling of such viruses in relation to labels like CFS/ME, I'd like to think that research is heading in the right direction to offer viable prevention / treatment options for such devastating disorders bearing in mind the heterogeneity present [5]...

Music: Therapy? - Nowhere.

----------

[1] Magnus P. et al. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine. 2015 Oct 13. pii: S0264-410X(15)01433-4.

[2] Bakken IJ. et al. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167.

[3] Brown AS. & Patterson PH. Maternal Infection and Schizophrenia: Implications for Prevention. Schizophrenia Bulletin. 2011;37(2):284-290.

[4] Chia J. et al. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb;63(2):165-8.

[5] Zdunek M. et al. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107.

----------

Magnus P, Gunnes N, Tveito K, Bakken IJ, Ghaderi S, Stoltenberg C, Hornig M, Lipkin WI, Trogstad L, & Håberg SE (2015). Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine PMID: 26475444

Paediatric congenital heart disease and autism risk?

"Children aged 2-17 with CHD [congenital heart disease] were more likely than those without CHD to have had a diagnosis of autism spectrum disorder (crude OR, 4.6; 95% CI, 1.9-11.0) or intellectual disability (Crude OR, 9.1; 95% CI, 5.4-15.4)".

The traveller @ Wikipedia 

That was a key conclusion reported in the study by Hilda Razzaghi and colleagues [1] based on their analysis of data from "the 1997-2011 National Health Interview Survey", a US initiative which aims to provide "information on the health of the U.S. civilian noninstitutionalized population through confidential interviews conducted in households" (see here).

I have to say that I was pretty interested in these findings (even though this is not the first time that neurodevelopmental outcomes have been tied to CHD); a view it seems, that was shared by the authors of the paper, bearing in mind the very wide confidence intervals (CIs) detailed for both conditions and the reliance on second-hand reporting over actual independent screening results. I can't readily offer any one 'smoking gun' explanation for the findings specifically in relation to the autism spectrum but will draw your attention to some discussion about the potential causes of congenital heart disease provided by the NHS Choices websites and how they might tie in.

So: various genetic conditions including Down's syndrome are linked to CHD [2] and the net seems to be closing in on some of the underlying genetics around the association [3]. Although still in need of quite a bit more study, there is a growing appreciation that a diagnosis of autism / autistic traits can coexist alongside a diagnosis of Down's syndrome (see here). As per a recent conversation (thanks Marilyn), one also wonders how this autism - Down's syndrome link might also play out with regards to other areas of the autism research landscape such as dietary effects for example...

Next up is maternal diabetes. As per the NHS Choices entry: "It is estimated that 3 to 6% of women with diabetes who become pregnant will give birth to a baby with a heart defect". Autism and maternal diabetes is an interesting topic which has again cropped up in the autism research literature [4]. If you want my take on the Xu meta-analysis paper and related literature, look no further...

After that is a role for alcohol consumption during pregnancy and mention of the condition called foetal alcohol syndrome (FAS). I have talked about FAS and foetal alcohol spectrum disorder (FASD) before on this blog in the context of autism (see here) but can't readily conclude that the links are overly strong between FAS/FASD and autism presentation.

"A rubella infection can cause multiple birth defects, including congenital heart disease". An interesting association given the history of rubella and autism based to quite a large extent on the work from Stella Chess [5]. I don't know enough about the rate of rubella infection in pregnant women to make any informed statement about how this risk factor might tie into both CHD and autism but the numbers of non-immune women do seem to be quite alarming here in the UK [6].

Influenza during pregnancy? "Women who get flu during the first trimester (three months) of pregnancy are twice as likely to give birth to a baby with congenital heart disease than the general population" according to the NHS Choices website. Regular readers of this blog might already know that I tend to talk quite a bit about how infection - immune system response to infection - during pregnancy seems to have some link to subsequent offspring psychology and development (see here). The link is not altogether straight forward with autism in mind and potentially better related to concepts like fever or fever control [7] but still, there might be more to do here.

The final links - certain medications taken during pregnancy, phenylketonuria (PKU) and exposure to organic solvents during pregnancy - have also, to various extents, been linked to autism (see here and see here for example).

I may very well just be plucking at straws trying to link the causes of CHD with some of the suspected 'causes' of autism (some autism at least) but it strikes me that if one was to further pursue the findings reported by Razzaghi et al those would be the places to start (assuming some shared effect). As per the reports of other physiological findings potentially manifesting alongside a diagnosis of autism (see here), some additional screening of children on the autism spectrum where one or more of the correlates of CHD are suspected might be indicated.

Peter Gabriel and Kate Bush with a beautiful song to close: Don't Give Up.

----------

[1] Razzaghi H. et al. Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. J Pediatr. 2014 Oct 8. pii: S0022-3476(14)00820-8.

[2] Laursen HB. Congenital heart disease in Down's syndrome. Br Heart J. Jan 1976; 38(1): 32–38.

[3] Ramachandran D. et al. Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med. 2014 Oct 23. doi: 10.1038/gim.2014.144.

[4] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[5] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

[6] Skidmore S. et al. Is the MMR vaccination programme failing to protect women against rubella infection? Epidemiol Infect. 2014 May;142(5):1114-7.

[7] Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. J Autism Dev Disord. 2013 Jan;43(1):25-33.

----------

Razzaghi H, Oster M, & Reefhuis J (2014). Long Term Outcomes in Children with Congenital Heart Disease: National Health Interview Survey. The Journal of pediatrics PMID: 25304924

Psychiatric comorbidity in post H1N1 vaccination narcolespy?

I can imagine that the paper by Atilla Szakács and colleagues [1] is likely to draw some rather differing opinions about potential importance based on their subject matter and methods/participant numbers looking at the frequency of psychiatric comorbidity among those with narcolepsy including narcolepsy post H1N1 vaccination. The fact that autism - "pervasive developmental disorder not otherwise specified (i.e., atypical autism)" - is mentioned as one of the comorbidity in the post-vaccination narcolepsy group, albeit only present in some 3% of the 31 participants (one person by my reckoning), potentially moves us into some contentious territory.

I can't go back to yesterday because
I was a different person then.

That being said, the finding that nearly half of the post-vaccination narcolepsy cases presented with some kind of psychiatric comorbidity and the lion's share of that comorbidity was represented by a diagnosis of attention-deficit hyperactivity disorder (ADHD) (~30%) is perhaps the bigger headline from this study. Or is it?

OK, it might be worthwhile taking this one step at a time. The report by the European Centre for Disease Prevention and Control (ECDC) [2] provides a good overview on the correlation between the use of the Pandemrix influenza vaccine and risk of narcolepsy in children and adolescents based on European data. The paper by Miller and colleagues [3] put a UK perspective on this, concluding that: "The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland". These findings and others suggested that there may be quite a bit more to see when it came to any relationship and, as a result, the door was opened to possible compensation as a vaccine-damage case (see the BBC report on this here). But, and it is an important point, other studies in other parts of the world have not reported a similar connection [4] and indeed, whether influenza infection (including 2009 H1N1 infection) itself could have been a risk factor for narcolepsy [5] has been discussed in the peer-reviewed literature.

The hows and whys of any relationship between the H1N1 influenza vaccine and [some] narcolepsy are still under discussion. The hypocretins have been the source of quite a bit of speculation [6] although the research road linking processes related to these compounds and the possible effects of vaccination has not run so smoothly (see here). Autoimmunity, or rather some of the genetics of autoimmunity, has also been highlighted as being a potentially revealing mechanism of involvement [7] perhaps shadowing some recent work in an unrelated area (see here). Indeed, another publication from Szakács and colleagues [8] hinted as much: "All patients in the postvaccination group were positive for human leukocyte antigen (HLA)-DQB1*0602".

Insofar as narcolepsy not related to vaccine administration, there is already a body of work to suggest quite a few comorbidities might already be elevated in risk following a diagnosis. The paper by Ohayon [9] detailed various somatic and psychiatric/behavioural issues to be over-represented alongside a diagnosis of narcolepsy. Of particular note to the psychiatric side of things were reports that: "major depressive disorder (MDD)... and social anxiety disorder" affected around 20% of people with the diagnosis. Both these conditions were noted in the Szakács study. Modestino & Winchester [10], based on the use of "a retrospective self-report questionnaire indicating the presence of childhood ADHD symptomatology in adults" suggested that "childhood ADHD symptomatology history among adult narcoleptics is common". Ideas about mis-diagnosis of ADHD covering for a condition like narcolepsy have also been suggested elsewhere (see here).

I will reiterate that the Szakács study only looked at 38 children and adolescents, and 31 of those participants fitted that post-vaccination narcolepsy criteria. This is a very small study where even the authors highlight that this means little can be conclusively taken from their findings. Insofar as that autism - atypical autism - finding, it is not beyond the realms of statistical possibility that such detection of a single case is entirely a fluke finding or indeed, something that might be expected given the increasing prevalence rate/estimates (see here). Indeed, I'll draw your attention to an earlier report on this matter [11].

The ADHD findings ("29% had attention deficit hyperactivity disorder (ADHD) inattentive type") are a little more difficult to explain away taking account of my previous chatter on the sample size of the Szakács paper. I've talked before on this blog about the paediatric ADHD prevalence figures/estimates (see here) and their hovering between 5-8% in the general population based on the collected work so far published in this area. Diagnoses like autism do seem to carry a greater risk of ADHD (see here) but given that only one case of autism was detected in the Szakács sample, I don't think we can say that this factor accounts for the results reported.

I draw back from suggesting that ADHD (in any or all its forms) is definitely related to narcolepsy post 2009 H1N1 vaccination or indeed natural infection on the strength of the current data and small (unevenly distributed) participant groups. What however the Szakács findings do perhaps impress, is the need for greater scrutiny of this possible variable; if anything else, to potentially highlight any possible mechanisms of response and possibly offer some further insights into the underlying genetics and biochemistry of [at least some] ADHD.

I close with the official (UK) advice on flu vaccination (see here).

Music: Wild Honey by Hugh Laurie (House).

----------

[1] Szakács A. et al. Psychiatric Comorbidity and Cognitive Profile in Children With Narcolepsy With or Without Association to the H1N1 Influenza Vaccination. Sleep. 2014 Oct 17. pii: sp-00241-14.

[2] European Centre for Disease Prevention and Control. Narcolepsy in association with pandemic
influenza vaccination (a multi-country European epidemiological investigation) Stockholm: ECDC; September 2012.

[3] Miller E. et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013 Feb 26;346:f794.

[4] Duffy J. et al. Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States. Neurology. 2014 Oct 15. pii: 10.1212/WNL.0000000000000987.

[5] Han F. et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011; 70: 410–417.

[6] Hungs M. & Mignot E. Hypocretin/orexin, sleep and narcolepsy. BioEssays. 2001; 23: 397-408.

[7] Mahlios J. et al. The autoimmune basis of narcolepsy. Curr Opin Neurobiol. 2013 Oct;23(5):767-73.

[8] Szakács A. et al. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology. 2013 Apr 2;80(14):1315-21.

[9] Ohayon MM. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013 Jun;14(6):488-92.

[10] Modestino EJ. & Winchester J. A retrospective survey of childhood ADHD symptomatology among adult narcoleptics. J Atten Disord. 2013 Oct;17(7):574-82.

[11] Cohen BI. Possible connection between autism, narcolepsy and multiple sclerosis. Autism. 1998; 2: 425-427.

----------

Szakács A, Hallböök T, Tideman P, Darin N, & Wentz E (2014). Psychiatric Comorbidity and Cognitive Profile in Children With Narcolepsy With or Without Association to the H1N1 Influenza Vaccination. Sleep PMID: 25325473