Neuropsychiatric disorder onset "temporally related to prior vaccinations"?

"Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines."

The quote opening this post comes from the paper published by Douglas Leslie and colleagues [1] (open-access) and offers not a conclusion from their study looking at the possibility that "the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals" but a caution that cause-and-effect were not 'proven' in their study. Anyone with any knowledge about previous occasions where administration of vaccines have been correlated with specific psychiatric or behavioural outcomes (see here and see here for examples) will recognise how important such a caution is, bearing in mind that vaccines are medicines (albeit preventative) and are subject to similar monitoring for safety and the small possibility of adverse effects as other medicines.

Based on the examination of "the MarketScan® Commercial Claims and Encounters database", a US drug and medical insurance claims database, researchers looked at various diagnoses of interest including OCD (obsessive compulsive disorder), AN (anorexia nervosa), anxiety disorder, tic disorder, major depression, bipolar disorder and ADHD (attention-deficit hyperactivity disorder) in children/young adults aged 6-15 years old. This alongside several other classes of diagnosis including broken bones and 'open wounds'. Participants were matched one-to-one with controls without said neuropsychiatric diagnoses and exposure(s) to various vaccinations - "influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella" - were 'tracked'. Interestingly, this is not the lead authors' first foray into using the MarketScan database [2], where autism was the previous topic of analysis (specifically healthcare service use and costs).

Results: bearing in mind that samples sizes varied according to those diagnoses under investigation, the authors report: "Receipt of any vaccine in the previous 6 months was highest for children with AN (21.4%), followed by OCD (15.9%) and tic disorder (15.8%), and was lowest for children with open wounds (10.3%)." This information needs to be treated carefully because - again - it tells us nothing about any cause-and-effect relationship, just correlation and trend; trends that could be there for all-manner of different reasons outside of the variables looked at. Further: "HRs [hazard ratio] associated with receipt of any vaccine were highest for children with AN... followed by OCD."

The authors also looked at specific vaccinations in relation to those neuropsychiatric disorders included in their study. They report: "Influenza vaccinations during the prior 3, 6, and 12 months were... associated with incident diagnoses of AN, OCD, and an anxiety disorder." Conversely: "children with major depression were less likely to have received the influenza vaccine in the previous 3 months" and "children with bipolar disorder were also less likely to have received the influenza vaccine in the previous 3 or 6 months."

OK, it is worth reiterating - yet again - that this was a study looking at possible associations and not necessarily cause-and-effect. Indeed, judging by that last paragraph and the table of HRs produced by the authors (see here) one might easily claim that flu vaccination might potentially shield someone from developing major depression as much as 'cause' AN, OCD and/or anxiety disorder. Such is the nature of such studies and the findings being reported. And indeed someone has actually looked at depressive symptoms (symptoms that is, not depression as a clinical diagnosis) before and after an influenza vaccination and found very little...

I note that with specific regard to the influenza vaccine and the findings that "children with AN, OCD, or a tic disorder were more likely to have received the influenza vaccine in the preceding periods" the authors head into the research talking about narcolepsy and the "AS03-adjuvanted H1N1 vaccine" as a possible template for their findings. This despite not covering the diagnosis of narcolepsy in their study (they could have). I've touched upon this area of research before on this blog (see here) (something that continues to appear in media discussions) and whilst not disputing the findings, do for example, wonder why in the work of Szakács and colleagues [3] ADHD was picked up as a comorbidity present in their "post-H1N1 vaccination (PHV) narcolepsy group" but in the Leslie data the HRs showed little evidence of any relationship. Yes, H1N1 vaccination is not necessarily the same as influenza vaccination reported in the Leslie data (we don't actually know what specific influenza vaccines were administered), but surely if discussions turn to an 'autoimmune' element as a possible mechanistic feature potentially linking vaccination and [some] neuropsychiatric disorder(s), one would expect to see the same/similar pattern of conditions being represented and reported? For balance, I should also point out that other independent study has talked about eating disorders potentially having "immune-mediated mechanisms" connected, particularly those associated with autoimmunity [4] although I don't doubt such a connection is likely complicated and probably not universally applicable.

It's not difficult to find issues with the Leslie paper and no doubt these will be emphasised in any further discussions about the data reported even when the authors stress throughout that "findings do not demonstrate a causal role of vaccination in the pathoetiology of any of these conditions." The strengths of the data - e.g. the use of that administrative database for confirming diagnoses and vaccine exposure - are worth mentioning again in light of other debates on data sources from other 'disappearing' manuscripts in this area. I might also add that by focusing in on various diagnoses but not autism (which again, they could have done) and not a certain vaccine, the authors seem well aware of the history in this area - "the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven" - and probably either thought nothing more of it or chose to steer well clear of it (or perhaps a combination of both).

Is there a 'where next' when it comes to the Leslie data? To quote again from the paper: "findings require replication in a larger population-based sample, possibly including assessments of various potentially important host factors, e.g., the individual’s genomic and epigenomic background, the individual’s microbiome, their history of antecedent psychosocial stress, infections, as well as other potentially simultaneously administered vaccinations, the differences in vaccine types, and the route of administration (e.g., intramuscular or intranasal administration of influenza vaccine)." The scientific literature also provides some other avenues for further study in this area [5]. But science does not happen in a social vacuum; any further research needs to be done with care and focus. Mindful of both the important reliance on vaccination in protecting both the individual and population at large and mindful that sweeping generalisations (often emanating from scientific study) need to be minimised.

And on the topic of the research of Douglas Leslie, I'll be coming to another recent paper he published on the important issue of depression in parents of children diagnosed with autism [6] quite soon...

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[1] Leslie DL. et al. Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Front Psychiatry. 2017 Jan 19;8:3.

[2] Wang L. et al. Healthcare Service Use and Costs for Autism Spectrum Disorder: A Comparison Between Medicaid and Private Insurance. Journal of autism and developmental disorders. 2013;43(5):1057-1064.

[3] Szakács A. et al. Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination. Sleep. 2015 Apr 1;38(4):615-21.

[4] Raevuori A. et al. The increased risk for autoimmune diseases in patients with eating disorders. PLoS One. 2014 Aug 22;9(8):e104845.

[5] Sadarangani SP. et al. "Let there be light": the role of vitamin D in the immune response to vaccines. Expert Rev Vaccines. 2015;14(11):1427-40.

[6] Cohrs AC. & Leslie DL. Depression in Parents of Children Diagnosed with Autism Spectrum Disorder: A Claims-Based Analysis. J Autism Dev Disord. 2017 Feb 18.

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Leslie DL, Kobre RA, Richmand BJ, Aktan Guloksuz S, & Leckman JF (2017). Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case-Control Study. Frontiers in psychiatry, 8 PMID: 28154539