Maternal and child immune disease and autism or other developmental disorder

The paper by Lisa Croen and colleagues [1] provides the brief blogging fodder today and some further results from the Study to Explore Early Development (SEED) initiative based in the United States. Whilst SEED has already produced quite a bit of peer-reviewed research data (see here), this time around the focus was on "the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD)." Yep, immune function yet again (see here).

Researchers mention how following their analysis of some 660 children with ASD, nearly a thousand children with DD and over 900 not-autism, not-DD population (POP) controls, they turned up some potentially important *associations* pertinent to immune system related conditions potentially elevating the risk of autism and/or DD. So: "Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD" and "children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls." Conversely, they did not detect any statistically significant associations between "paternal history or family history of these immune conditions for either ASD or DD."

I'm gonna leave things there for now on this topic. The immune system seems to be related to at least 'some' autism. There's nothing particularly new or novel about that sentiment but it does cover an awful lot of ground. A lot more research is required on the 'hows-and-whys' (see here for one example research route) and whether intervening on various immune system related conditions, one *might* also impact on the presentation of behaviour too...

And on the topic of intervention, may I also draw your attention to the mammoth paper by Marchezan and colleagues [2] reviewing the many and varied (evidence-based) intervention methods that are available as and when immune system issues crop up in the context of autism?

----------

[1] Croen LA. et al. Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development. Autism Res. 2018 Aug 10.

[2] Marchezan J. et al. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation. 2018. Sept 5.

----------

The ties that bind? Comorbidity and autism (again)

"It was found that 92.9% of participants presented with a family history of autoimmune disease."

That was one of the headline findings reported in the paper by Arlene Mannion & Geraldine Leader [1] who conducted a follow-up study to previous work [2] looking at the important issue of comorbidity and autism with a specific focus on whether "comorbid symptoms changed over time."

Fifty-six children and adolescents diagnosed with DSM-IV autism spectrum disorder (ASD) participated in their study, drawn from a previous cohort of 89 involved in previous research by these authors. A range of measures were included for study including a focus on sleep and functional bowel issues.

When it came to describing this smaller cohort two years after their original research participation, examination of current comorbid diagnoses alongside ASD showed a worrying trend insofar as rates of epilepsy, attention-deficit hyperactivity disorder (ADHD) and anxiety disorder. An additional 5 children/young adults presented with ADHD at this second time of study for example. Three participants also presented with an anxiety disorder this time around. These are perhaps not unexpected findings (see here and see here).

Drilling down further into the presented data, a few other trends are present:

• Sleep issues were prevalent. Nearly 80% of participants showed signs of a sleep problem "classified as a score of 41 or more on the CSHQ [Children's Sleep Habits Questionnaire]."
• Gastrointestinal (GI) symptoms, as measured on the Gastrointestinal Symptom Inventory from the ATN, were also notable in this cohort. Nearly three-quarters of participants presented with at least on GI symptom within the last 3 months. A smaller group (7%) presented with 5 GI symptoms recently. GI symptoms also persisted in over 80% of participants during the 2-year period before this follow-up study.
• GI and sleep issues also seemed to go hand-in-hand. Almost two-thirds of the cohort "presented with both sleep problems and gastrointestinal symptoms" as evidenced when specific GI symptoms were analysed (bloating, nausea, abdominal pains, diarrhoea and constipation).
• Researchers also questioned about family medical history as well as participants. Alongside the figure already presented about familial autoimmune disease, various other "psychological, developmental or medical disorder" were noted.
• Osteoarthritis, psoriasis and hypothyroidism (Hashimoto's thyroiditis) were the most common familial autoimmune conditions described in this cohort. Mention is however also made about Crohn's disease (n=9) and coeliac disease (n=4) too.

Obviously one has to keep in mind a few salient points before getting to carried away with this information. The participant numbers on the first occasion (N=89) and this time around (N=56) are quite small. The authors also note that the use of "parental report" might also be considered a limitation; balancing that however by making reference to the Phillip Gorrindo paper [3] covered in previous posts (see here) on how: "Parents were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]".

That all being said, the trends reported by Mannion & Leader are consistent with previous peer-reviewed data on the issue of comorbidity and autism. Sleep problems are pretty widespread (see here) as are functional bowel issues (see here). Indeed, even more pathological bowel issues seem to be 'over-represented' when it comes to a diagnosis of autism (see here). That the two issues might be somehow 'joined together' has also been previously raised in the research literature (see here).

The reports on certain familial health conditions being associated with cases of autism is also not new news. I've long speculated about the role of familial autoimmune conditions and autism on this blog (see here and see here) on the back of research spanning several decades (see here). Talk specifically of a connection between the skin condition psoriasis and autism is included (see here) as is the idea that both inflammatory bowel conditions (see here) and more food-related bowel states (see here) might in some families, show a connection to autism. Much more study is implied including a focus on the N=1 [4].

The idea that autoimmune disease specifically affecting the thyroid might also be a route of further scientific inquiry with autism in mind is something of real interest in light of quite a bit of other research in this area (see here and see here). As I've mentioned in previous posts, the idea that familial autoimmune disease affecting the thyroid might also be related to the onset of presentation of offspring autism [5] is a research topic crying out for further replication. The possibility of an association also opens up a number of other avenues for study based on the idea that autoimmune features might reflect one or more 'types' of autism (see here) or indeed, linked to one or more of the common comorbidities occurring alongside autism (see here and see here). Speculations are potentially aplenty in this area (see here) so we need more hard data.

----------

[1] Mannion A. & Leader G. An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder: A two year follow-up. Research in Autism Spectrum Disorders. 2016; 22: 20-33.

[2] Mannion A. et al. An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder: A two year follow-up. Research in Autism Spectrum Disorders. 2013; 7: 35-42.

[3] Gorrindo P. et al. Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, & Associated Factors. Autism Research. 2012;5(2):101-108.

[4] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

[5] Molloy CA. et al. Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):317-24.

----------

Mannion, A., & Leader, G. (2016). An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder: A two year follow-up Research in Autism Spectrum Disorders, 22, 20-33 DOI: 10.1016/j.rasd.2015.11.002

Familial autoimmune disease and offspring autism risk

"An overall increased risk of autism in children with family history of ADs [autoimmune diseases] was identified."

That was the bottom line of the "systematic review and meta-analysis" carried out by Shunquan Wu and colleagues [1] summarising the "current evidence on the relationship between family history of autoimmune diseases (ADs) and risk of autism in children." Autoimmune disorders by the way, are the various conditions that come about when the body fails to recognise self as 'self' and the immune system mounts an offensive against healthy tissue as if they were 'other' by mistake.

Regular readers of this blog might already know that I'm an avid follower of the idea that autoimmunity might show more than a passing connection to at least some cases of autism (see here) among other things (see here). Bearing in mind that autoimmunity might be just one immune system 'presentation' linked either directly or peripherally to autism (see here) I've read enough peer-reviewed evidence on the topic to be convinced that quite a bit more resource and research power should be dedicated to seeing just how deep the rabbit hole gets [2].

The Wu paper lists a number of specific ADs as showing something of an important 'correlation' to offspring autism risk including:

• "a statistically significant association with family history of hypothyroidism." Hypothyroidism - an underactive thyroid gland - is quite commonly due to the presence of autoimmune thyroiditis (a condition that has been mentioned once or twice on this blog). Hypothyroidism, maternal hypothyroidism, is potentially something important to offspring autism risk as per other research discussions (see here).
• A familial history of type 1 diabetes - where the pancreas doesn't produce insulin - is also mentioned as a risk factor. In amongst the research looking at the various types of diabetes and how they may have an important bearing on autism (see here), type 1 diabetes has previously cropped up on more than one occasion (see here).
• Psoriasis - a blanket term for various autoimmune mediated skin conditions - is also identified by Wu et al as a possible risk factor for offspring autism. Again, I've talked about this condition in relation to autism before on this blog (see here).

"More mechanistic studies are needed to further explain the association between family history of ADs and increased risk of autism in children." I'd very much agree with the parting sentiments discussed by the authors on this topic. Appreciating that genetics (see here) and environment (see here) seemingly combine when it comes to the appearance of autoimmune disease, such studies of potential mechanism might need to be rather broad in their remit. I'd also put forward the notion that some potentially important data may also be garnered by looking at other facets of our genes outside of just the HLA (human leukocyte antigen) region [3] as per the growing body of work talking at HERVs (human endogenous retroviruses) and autoimmunity potentially intersecting with the science of epigenetics [4]. Oh, and in case you'd like a little more background on HERVs, a small contribution from me on the subject (see here)...

Music: Ben E. King - Stand by me.

----------

[1] Wu S. et al. Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2015. May 15.

[2] Gesundheit B. et al. Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun. 2013 Aug;44:1-7. 

[3] Gough SC. & Simmonds MJ. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Curr Genomics. 2007 Nov;8(7):453-65.

[4] Lavie L. et al. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J Virol. 2005 Jan;79(2):876-83.

----------

Wu, S., Ding, Y., Wu, F., Li, R., Xie, G., Hou, J., & Mao, P. (2015). Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis Neuroscience & Biobehavioral Reviews DOI: 10.1016/j.neubiorev.2015.05.004

Asthma and autism: a spanner in the works?

As happens so many times in autism research, spanners are thrown in works. Take the paper from Ousseny Zerbo and colleagues [1] who concluded that: "children with autism have elevated prevalence of specific immune-related comorbidities". Nothing surprising about that finding based on the volumes of other research which seemed to have reached similar conclusions (see here).

Then the spanner: "asthma was diagnosed significantly less often" in autism cases compared with asymptomatic controls. Asthma diagnosed significantly LESS often? I was taken aback by this finding bearing in mind the small but significant difference in cases reported (13.7% vs. 15.9% respectively). Quite a few times on this blog I've talked about research which indicated something quite the opposite when it came to asthma and autism as per post such as this one and this one. One might quibble about what was correlating with what (autism rates elevated in cases of asthma or asthma rates elevated in cases of autism) but there did seem to be something of a relationship between the conditions noted.

OK, let's step back a little. The Zerbo paper (from a group who've appeared before on this blog) and a few details...

• A case-control study based on data derived from "among members of Kaiser Permanente Northern California (KPNC) born between 1980 and 2003". Further: "Cases were children and young adults with at least two autism diagnoses recorded in outpatient records (n=5,565)" who were matched 5:1 based on "birth year, sex, and length of KPNC membership (n=27,825)." Sample size was therefore pretty good.
• Databases were combed for outcomes - "asthma, allergies, and autoimmune diseases" - and differences were detailed complete with odds ratios (ORs).
• Results: as just described, there was something of a difference between the autism and not-autism groups in that: "Allergies and autoimmune diseases were diagnosed significantly more often among children with autism than among controls." Asthma diagnosis aside, psoriasis got a particular mention occurring "more than twice as often in cases than in controls." This is not the first time that the skin condition psoriasis has been mentioned with autism in mind (see here).
• Conclusion: "results support previous observations that children with autism have elevated prevalence of specific immune-related comorbidities."

I'm having a hard time with the 'asthma diagnosed less often in autism' sentiments of the Zerbo paper. I talked about the Kotey paper [2] last year (2014) and their headline: "Asthma is approximately 35 % more common in autistic children." That finding complemented the various data coming out of the fabulous Taiwanese database (see here) including asthma and other autism comorbidity being potentially related. Yes, one could highlight the differences between these studies in terms of geography and also the type of data collected (reports vs. medical records). One might also consider the impact of other variables such as mold exposure too [3] potentially linked to asthma. But could science have been that wrong?

Well, there have been other examples in the research literature where asthma does not seem to be over-represented when it comes to a diagnosis of autism. Take the paper from Mrozek-Budzyn and colleagues [4] as an example. The findings reported by Bakkaloglu and colleagues [5] are another case where there was very little reported (accepting the much lower participant number included for study). And then there is the recent report from Kristen Lyall and colleagues [6] to consider: "Prevalence of asthma and overall allergies did not differ between cases and controls" based on their cohort, albeit flanked by a finding that: "food allergies and sensitivities may be more common in children with ASD [autism spectrum disorder]."

That all being said, I'm not going to fall into the scientific trap that normally follows null findings over positive findings specifically with autism in mind. My recent musings on 'what have we learned about autism' (see here) kinda said it all - plurality, different trajectories and outcome and comorbidity clusters - in terms of the potential way forward for autism research. The idea that certain 'types' of autism might be preferentially more strongly related to certain types of comorbidity is perhaps a better way of approaching this issue. As per the growing evidence base on air pollution potentially 'correlated' with some autism, asthma might be something of an important variable to study (see here). Oh, and then there are certain pharmaceutics to potentially consider [7] too in light of other associations (see here).

Music to close: Pulp and er, don't do drugs kids!

----------

[1] Zerbo O. et al. Immune Mediated Conditions in Autism Spectrum Disorders. Brain Behav Immun. 2015 Feb 11. pii: S0889-1591(15)00019-7.

[2] Kotey S. et al. Co-occurrence of autism and asthma in a nationally-representative sample of children in the United States. J Autism Dev Disord. 2014 Dec;44(12):3083-8.

[3] Karvonen AM. et al. Moisture Damage and Asthma: A Birth Cohort Study. Pediatrics. 2015. Feb 16.

[4] Mrozek-Budzyn D. et al. The frequency and risk factors of allergy and asthma in children with autism--case-control study. Przegl Epidemiol. 2013;67(4):675-9, 761-4.

[5] Bakkaloglu B. et al. Atopic features in early childhood autism. Eur J Paediatr Neurol. 2008 Nov;12(6):476-9.

[6] Lyall K. et al. Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study. Autism Res. 2015. Feb 26.

[7] Becker KG. & Schultz ST. Similarities in features of autism and asthma and a possible link to acetaminophen use. Med Hypotheses. 2010 Jan;74(1):7-11.

----------

Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, & Croen LA (2015). Immune Mediated Conditions in Autism Spectrum Disorders. Brain, behavior, and immunity PMID: 25681541

Autism and psoriasis

Spring blossom has sprung @ Paul Whiteley

Trawling the web, as one does, looking at new research studies on this, that and t'other often provides a few 'memory lane' moments.

For example, some weeks back I stumbled upon some interesting discussions on whether okra might have the ability to induce male sterility. Strange you might think that lady's fingers might be a good male contraceptive, but there is some good science behind it specifically based on the actions of a compound called gossypol.

Why is gossypol part of my vocabulary? Well my better-half did some research on this compound a few years back, primarily derived from the cotton plant (Gossypium), with a view to its potential anti-psoriatic abilities. Real pharmacognosy in action. The anti-psoriatic abilities of gossypol got me thinking about psoriasis with autism spectrum conditions in mind.

Psoriasis is a topic which has cropped up before on this blog with regards to autoimmunity and how having one autoimmune-related condition might raise your risk of developing another (or others). Psoriasis is a bit of a blanket description for several manifested skin conditions. It is basically a fault in the production of skin cells; cells pile up on top of each other forming patches or plaques which can cause some quite serious physical discomfort, also having been linked to secondary bacterial infections. More recently is the suggestion that the disease might not just be skin related and not necessarily having just a physical effect. Prevalence and incidence studies are rife on psoriasis; this study suggested a prevalence of 2.5% among a European (German) population.

There is a limited body of literature which suggests that psoriasis might be more common in autism, and families of people of autism, than compared to control populations. The paper that struck me is this one from Lisa Croen and colleagues* looking at immune comorbidities in autism. I say paper but in this form it was actually a conference proceeding from IMFAR 2008. The findings however, based on quite an impressive sample size (autism; n=5565; controls; n=27,825) suggested some interesting differences when it came to the prevalence of autoimmune conditions. Psoriasis came top of the pops; being diagnosed twice as often in autism cases vs. controls.

Croen appears again with regards to the literature on familial psoriasis and 'risk' of autism. This paper** (open-access) suggested that within a 4-year period surrounding pregnancy, maternal psoriasis appeared with greater frequency in cases of autism vs. controls. That being said, their overall conclusions were that maternal autoimmune disorders were unlikely to be strongly related to risk of autism in offspring. I'm not too sure about this last statement in light of more recent findings. Bakkaloglu and colleagues also reported one case of psoriasis in one parent of a child with autism in their study of 30 children compared with none in 39 controls.

Appreciating that the absolute numbers of people with autism with comorbid psoriasis is likely to be quite small (that's what we found at least) I do wonder about the whole autoimmune effect. I would be hard-pressed to say that autism, all autism, is an autoimmune condition because the universal population data really don't bear this out. Having said that, the move towards biological phenotypes would perhaps be an ideal vehicle to see if autoimmune comorbidity reflects a sub-group of those on the autism spectrum. So those cases where coeliac disease, Crohns disease, ulcerative colitis, type-1 diabetes or psoriasis are mentioned: a phenotypic subgroup perhaps? Again not directly linked, but schizophrenia has also been tied into psoriasis albeit with the similar caveats to that of autism. I do also wonder whether the the phototherapy sometimes used for psoriasis might also have some relation to vitamin D status and onward links?

I finish with some Orange Crush from REM (they were great, weren't they).

* Croen LA. et al. Immune comorbidities in children with autism spectrum disorders. IMFAR 2008

** Croen LA. et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders. Archives of Pediatrics and Adolescent Medicine. 2005; 159: 151-157