Viral exposure and autism

A whole slew of articles published by Ivan Gentile and colleagues based at the University of Naples (Italy) brought me to writing this post looking at some of the literature on viral exposures and autism. Viruses, in case you didn't know, are some of nature's survivors, infecting host cells and reproducing, onwards hopeful of finding more (un)willing cells/organisms to infect. Humankind have developed various biological defence mechanisms against the viral (and bacterial) onslaught that we all face as part of daily life, part of which is the production of antibodies. Antibodies are all about identification, action and memory and form the basis for why we vaccinate against various disease causing viruses. Sometimes antibodies also take part in a process called neutralisation which is all about rendering a virus ineffective when it comes to infectivity.

A founder of virology @ Wikipedia 

I've talked previously on this blog about viruses and their possible connection to some cases of autism (see here for example). I've also discussed how traces of the viruses of yesteryear (many, many yesteryears) can still be found in our genome and how such fossil viruses may, in some cases, still impact on our health and wellbeing (see here and see here). But enough of all this idle chatter...

The specific papers under discussion today include:

• Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder [1]
• Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study [2]
• Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders [3]

Let's call them paper 1, paper 2 and paper 3 respectively for convenience.

All were published in the journal In Vivo and follow some history looking at viral infections and autism by this research group [4] including those most contentious of viral infections when it comes to autism: measles, mumps and rubella [5]. I might also add that some speculations from this group looking at linking genetic predisposition, vitamin D deficiency and infection potentially correlating with a "a deranged immune response" with some autism in mind [6] might not be as outlandish as once thought. Indeed, that review paper [6] is probably one of the best I've read in a long time drawing on the available data on immune function and autism bearing in mind the emerging vitamin D story (see here).

Anyhow:

• Papers 1-3 all relied on the same participant groups, that is: 54 children diagnosed with an autism spectrum disorder (ASD) and 46 asymptomatic controls. 
• Exposure (seropositivity) rates and antibody titer levels to Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) (paper 1), Varicella Zoster Virus (VZV) (paper 2) and Herpes Simplex Virus 1 (HSV1) and Herpes Simplex Virus 2 (HSV2) (paper 3) were measured and compared between groups.
• Paper 3 detailing the findings on HSV1 and HSV2 concluded: "Seropositivity rate and levels of anti-HSV1/2 were not dissimilar between cases and controls". In other words, nothing to see there in this cohort.
• Paper 1 looking at CMV and EBV came to a similar conclusion as that of paper 3, although the authors note: "considering only patients with ASD, those seropositive for CMV tended to test worse to the major severity scales than the seronegative ones". With my recent interest in CMV and autism (see here), I'm intrigued...
• Paper 2 provides something of a more 'positive' result with it's analysis of VZV, the virus linked to chickenpox and shingles, in connection to the autism grouping. Authors concluded: "The exposure rate and titer of anti-VZV antibodies were significantly higher in children with ASD compared to controls (59% vs. 39% and 694 mIU/ml vs. 94 mIU/ml, respectively)". Further: "exposure to VZV was found to be independently associated with ASD".

We do have to be a little bit careful when it comes to these studies on the basis of their small participant numbers and the applicability of results to other groups whether in age or geography. As per some previous chatter about the other Gentile paper on MMR antibodies and autism (see here) not every study agreed with their findings [7]. Likewise, these latest results say nothing about 'causation' in terms of autistic presentation outside what is already suspected with something like CMV and autism in mind [8]. Correlation is not the same as causation, as if you needed telling.

That all being said I do think there is more to do in this area. There is some research history when it comes viral infection and autism as per the review by Libbey and colleagues [9] and in amongst that literature is mention of varicella [10] including "cases of autism associated with postnatal varicella encephalitis" [11]. The quite stark disparity in mean antibody titers to VZV between autism and control groups suggests that something might be afoot outside of just some healthy immunity to something like chicken pox.

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[1] Gentile I. et al. Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder. In Vivo. 2014 07-08;28(4):621-626.

[2] Gentile I. et al. Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study.  In Vivo. 2014 07-08;28(4):627-631.

[3] Gentile I. et al. Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders. In Vivo. 2014 07-08;28(4):667-671.

[4] Gentile I. et al. Prevalence of HHV-6 and HHV-8 antibodies in patients with autism spectrum disorders. In Vivo. 2013 Nov-Dec;27(6):843-9.

[5] Gentile I. et al. Response to measles-mumps-rubella vaccine in children with autism spectrum disorders. In Vivo. 2013 May-Jun;27(3):377-82.

[6] Gentile I. et al. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013 Jul;81(1):26-35.

[7] Singh VK. et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64.

[8] Sakamoto A. et al. Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain Dev. 2014 Apr 22. pii: S0387-7604(14)00094-1.

[9] Libbey JE. et al. Autistic disorder and viral infections. J Neurovirol. 2005 Feb;11(1):1-10.

[10] Deykin EY. & MacMahon B. Viral exposure and autism. Am J Epidemiol. 1979 Jun;109(6):628-38

[11] Knobloch H. & Pasamanick B. Some etiologic and prognostic factors in early infantile autism and psychosis. Pediatrics. 1975 Feb;55(2):182-91.

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Gentile I, Zappulo E, Bonavolta R, Maresca R, Messana T, Buonomo AR, Portella G, Sorrentino R, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Prevalence and Titre of Antibodies to Cytomegalovirus and Epstein-Barr Virus in Patients with Autism Spectrum Disorder. In vivo (Athens, Greece), 28 (4), 621-626 PMID: 24982232


Gentile I, Zappulo E, Bonavolta R, Maresca R, Riccio MP, Buonomo AR, Portella G, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Exposure to Varicella Zoster Virus Is Higher in Children with Autism Spectrum Disorder than in Healthy Controls. Results from a Case-control Study. In vivo (Athens, Greece), 28 (4), 627-631 PMID: 24982233


Gentile I, Zappulo E, Bonavolta R, Maresca R, Riccio MP, Buonomo AR, Portella G, Vallefuoco L, Settimi A, Pascotto A, Borgia G, & Bravaccio C (2014). Prevalence of Herpes Simplex Virus 1 and 2 Antibodies in Patients with Autism Spectrum Disorders. In vivo (Athens, Greece), 28 (4), 667-671 PMID: 24982239