Allergy and autism linked (again)

There was something rather timely about the publication of the result by Guifeng Xu and colleagues [1] observing that: "In a nationally representative sample of US children, a significant and positive association of common allergic conditions, in particular food allergy, with ASD [autism spectrum disorder] was found."

Timely, because earlier the same day I read a rather disparaging piece titled 'oversold diets' *trying* to condense down the findings reported by Gogou & Kolios [2]. This duo looked at the "current literature data about the effect of therapeutic diets on autism spectrum disorder", where certain diets are often put in place because of a perceived allergy or intolerance to certain foodstuffs and effects on behaviour and physiology. Gogou & Kolios concluded that: (a) "No serious adverse events have been reported" ('first, do no harm' and all that) and (b) the currently available peer-reviewed data on things like the use of a ketogenic diet and/or a gluten- and casein-free (GFCF) diet 'for' autism is promising but: "More research is needed to provide sounder scientific evidence." I agree that lots more resources and money need to be put into the scientific examination of such diets in the context of autism (see here and see here) including identifying potential best-responders [3]. I'd also like to see gastrointestinal (GI) issues included in the research agenda, in light of other promising peer-reviewed data too on a potential tie-up with said diets and autism (see here)...

Anyhow, back to the Xu findings, which have seemingly attracted some media attention (see here for example). The source of the data was the "National Health Interview Survey [NHIS] collected between 1997 and 2016", a US initiative designed to 'monitor the health of the United States population through the collection and analysis of data on a broad range of health topics'. Including parent or guardian responses on a questionnaire used as part of the NHIS, and specifically the questions: "during the past 12 months, has your child had (1) any kind of food or digestive allergy; (2) any kind of respiratory allergy; (3) eczema or any kind of skin allergy?", data was crunched for nearly 200,000 children.

Authors reported that as a total group (N=199,520), the weighted prevalence of food allergy being reported was about 4%. For a respiratory allergy, the prevalence came in at about 12% and 9% for a skin allergy.

Then to the autism vs. not-autism comparisons where: "A diagnosis of ASD was reported in 1868 children (weighted prevalence, 0.95%; 95% CI, 0.89%-1.01%)." Parents/guardians of those diagnosed with autism were significantly more likely to report all of those various allergies compared to the not-autism group. The figures were: food allergy (autism: 11.25% vs. not-autism: 4.25%), respiratory allergy (autism: 18.7% vs. not-autism: 12%) and skin allergy (autism: 16.8% vs. not-autism: 9.8%). Further: "After adjustment for age, sex, race/ethnicity, family highest education level, family income level, and geographical region, the OR [odds ratio] of ASD was more than doubled (OR, 2.72; 95% CI, 2.26-3.28; P < .001) among children with food allergy compared with those without food allergy." This last observation basically said that there was more chance of autism being reported among those with a food allergy than those without a food allergy.

Caveats? Well, a few to mention. First of all, you'll have noted the words 'parent or guardian responses on a questionnaire' being used, which need to be taken into consideration. No, I'm not casting any aspersions on reporting accuracy of anything like that (parents can be very sensitive to lots of things), but this was not a study of hospital records and tests or anything like that. Second is the use of the word 'allergy'. The medical definition of allergy (see here) is something like 'a biological response to a normally harmless substance'. Allergy is obviously immune-related and typically involves something called IgE (immunoglobulin E) among other things. Whilst some people might think they have an allergy to this, that or t'other, there is still some confusion about whether 'allergy' is the most suitable word in that context without for example, suitable allergy testing being undertaken. I might be being a bit pedantic, but words count...

That all being said, the Xu findings are not the first time that allergy and autism has been raised as being *associated* (see here and see here for examples). Indeed, allergic illness such as something like asthma, has quite a long association with autism (see here) and hints at a possible 'immune-related' connection to at least 'some' autism. That also one of the most common 'comorbid' conditions over-represented in relation to autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger connection with allergy (see here) is also important to mention, and further strengthens some immune system involvement where there is diagnostic intersection. It also *might* have intervention implications too (see here) (with no medical advice given or intended)...

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[1] Xu G. et al. Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA Network Open. 2018; 1: e180279.

[2] Gogou M. & Kolios G. Are therapeutic diets an emerging additional choice in autism spectrum disorder management? World Journal of Pediatrics. 2018. May 30.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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Cow's milk allergy and risk of psychiatric disorder

"Psychiatric disorders are frequent and severe in pre-school children with cow's milk allergy."

That research 'bottom line' reported by Topal and colleagues [1] looking at the possibility of behavioural correlations accompanying an immune response to milk caught my eye recently. Building on the idea that atopic or allergic disease might elevate the risk of various behavioural outcomes (see here) or vice-versa, researchers set about comparing rates of various behavioural conditions using the "Early Childhood Inventory-4 form" in cases of cow's milk allergy (n=40) vs asymptomatic (not cow's milk allergy) controls (n=41).

With little demographic difference between the groups in terms of gender and age, we are told that: "65% of the group with cow's milk allergy received at least one psychiatric diagnosis, while 36.6% of the control group received at least one psychiatric diagnosis." Specifically, attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were more likely reported in the cow's milk allergy group. Based also on "psychiatric symptom severity scores" researchers also reported that both ADHD and ODD severity were higher in the cow's milk allergy group.

It is a little ironic that I'm actually writing this post on World Milk Day (1 June) and certainly I don't want to dampen down any rejoicing about the virtues of milk (see here). It is however important to highlight how not everyone can enjoy a glass of the white stuff (for various reasons) and that, when it comes to how a particular type of immune system meets something like milk and its various constituents, there may be outcomes further than that of the typical somatic ones linked to classical milk allergy. Obviously, replication is the name of the research game following the Topal results and perhaps with a little more detailed inspection of behaviours pertinent to ADHD and ODD in what was a very young sample population (mean ages: 44-47 months).

In terms of the mechanism behind the Topal findings, well, there is still work to be done there. I could turn speculative and suggest that set within an emerging idea that food might, under certain circumstances, be able to affect behaviour for some (see here) one might entertain the idea that gut and brain might show a greater link than has perhaps been hitherto accepted. ADHD already falls into that category of food potentially affecting presentation as per older research in this area (see here). Indeed, if one wants to get really speculative, how about connecting early cow's milk allergy to ADHD and ADHD as raising the risk for something like schizophrenia (see here) as potentially accounting for other immune-related findings on milk and schizophrenia for example (see here)? Yes, I know that immunoglobulins are different across allergy and 'intolerance' and one has to be careful about using the singular definition of schizophrenia in modern times (see here) but one might forsee some kind of connection at least for some?

I might also at this point direct you to the findings reported by Wu and colleagues [2] and the suggestion that "mTOR [mammalian target of rapamycin] activation may be central to both the intestinal, immunological, and psychiatric ASD [autism spectrum disorder]-like symptoms seen in CMA [cow's milk allergic] mice." Whilst not trying to force clinical endpoints like autism into the Topal findings, the idea from Wu et al about looking at "whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms" seems very testable in the context of possible ADHD or ODD presentation also being linked to cow's milk allergy...

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[1] Topal E. et al. Psychiatric disorders and symptoms severity in pre-school children with cow's milk allergy. Allergol Immunopathol (Madr). 2016 May 27. pii: S0301-0546(16)30043-X.

[2] Wu J. et al. mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits. Neuropharmacology. 2015 Oct;97:220-32.

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Topal E, Catal F, Soylu N, Ozcan OO, Celiksoy MH, Babayiğit A, Erge D, Karakoç HT, & Sancak R (2016). Psychiatric disorders and symptoms severity in pre-school children with cow's milk allergy. Allergologia et immunopathologia PMID: 27240441

MoBa does bowel issues in autism

'MoBa' in the title of this post, refers to the Norwegian Mother and Child Cohort Study and a handy resource which has already impacted on autism research (see here for example).

Now MoBa has turned its epidemiological clout to an issue which less and less is encountering scientific resistance: are gastrointestinal (GI) symptoms over-represented when it comes to a diagnosis of autism? Further, when do such bowel issues start to present?

The answer, shown in the paper by Michaeline Bresnaha and colleagues [1] is yes, functional bowel symptoms are seemingly more frequently reported when it comes to autism as per the results of quite a few other studies. To quote from the authors: "maternally reported GI symptoms are more common and more often persistent during the first 3 years of life in children with ASD [autism spectrum disorder] than in children with TD [typical development] or DD [developmental delay]." Said symptoms also seemed to present pretty early on; quite a bit before many children are diagnosed with autism. Some further coverage of these findings can be seen here and here.

Including a couple of giants in research terms on the authorship list - Mady Hornig and Ian Lipkin - who also continue to push the research boundaries in relation to another diagnosis which crops up on this blog (CFS/ME or SEID as it may well be eventually known) - MoBa was put to use.

Authors "defined 3 groups of children: children with ASD (n = 195), children with DD and delayed language and/or motor development (n = 4636), and children with TD (n = 40 295)." Maternal reports garnered prospectively covering various GI symptoms including "constipation, diarrhea, and food allergy/intolerance" were analysed across the groups covering children at 6, 18 and 36 months of age.

The results suggested that constipation and food allergy/intolerance were more likely to be reported in children with autism during the 6-18 month old age range compared with typically developing controls. Diarrhoea and food allergy/intolerance were also more likely to be reported in children with autism in the 18-36 month age range again, compared with TD controls. Children with autism/ASD were also more likely to present with "1 or more GI symptom in either the 6- to 18-month or the 18- to 36-month-old age period and more than twice as likely to report at least 1 GI symptom in both age periods compared with mothers of children with TD or DD." Some might quibble about the use of maternal report in discussing the presentation of bowel issues in children but I'm not one of them (see here) as the Gorrindo findings [2] drift back into my consciousness.

The press release attached to this study also contains an intriguing quote from Mady Hornig: "Although the connection of GI disturbances to autism remains unclear, the presence of GI symptoms in early life may not only help to identify a subset of children with autism who require clinical input for their GI issues, it may also open new avenues for determining the underlying nature of the disorder in that subgroup." The implication being that (a) GI symptoms, early GI symptoms, are not a universal (or exclusive) feature of autism, but are present in quite a few infants, and (b) among the increasingly pluralised view of autism (see here), the idea that said GI symptoms might represent something quite fundamental to some cases of autism offers something of an opportunity to perhaps intervene and treat/manage both bowel symptoms and potentially impact on behavioural features linked to autism. On this point I'm drawn back to some of the research from Micah Mazurek and colleagues talking about sensory issues and anxiety completing a triad with bowel issues with autism in mind (see here).

I'm probably repeating myself here but quite a bit more research is required on the relationship between autism and the presentation of GI issues. I'd be inclined to suggest that a few research areas might be useful to explore: (a) the link between functional bowel issues and more pathological bowel states (see here), (b) the link between inflammation / inflammatory markers and bowel issues (see here) taking into account the work of people like Harumi Jyonouchi for example (see here), (c) the possibility that bowel issues might have some connection back to the gut microbiota as per other work by Hornig/Lipkin (see here), and (d) how said GI issues might impact on issues such as pharmacotherapy in terms of drug availability and absorption issues (see here). This isn't an exhaustive list, just a few ideas to play around with.

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[1] Bresnahan M. et al. Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism Evidence From a Prospective Birth Cohort. JAMA Psychiatry. 2015. March 25.

[2] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

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Bresnahan, M., Hornig, M., Schultz, A., Gunnes, N., Hirtz, D., Lie, K., Magnus, P., Reichborn-Kjennerud, T., Roth, C., Schjølberg, S., Stoltenberg, C., Surén, P., Susser, E., & Lipkin, W. (2015). Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.3034