Allergic disease and ADHD yet again...

Although words like 'first' and 'largest' were used in the paper by Chia-Feng Yang and colleagues [1] (open-access available here) observing that "AD [atopic dermatitis] and asthma with allergic sensitization are associated with ADHD [attention-deficit hyperactivity disorder] in children", I'm minded to be a little cautious with such 'we're the first/best' assertions.

Cautious because, on quite a few peer-reviewed research occasions (see here for example), a possible *link* between various allergic disease and ADHD has already been noted; even potentially extending to studies talking about how treatment for allergic disease might on some occasions also impact on presented ADHD symptoms (see here) (with no medical advice given or intended).

Yang et al relied on data from a research favourite country, Taiwan, derived from an initiative called the Childhood Environment and Allergic diseases Study (CEAS). The clue is in the name of the initiative in terms of what they were looking for/at, as per other publications derived from the initiative [2]. From the 3200-odd participants eligible for participation, researchers relied on data from over 2700 children. Questions about allergic disease history were asked to parents of said participants, alongside other 'environmental' factors such as family income, tobacco exposure and breastfeeding history. I note also a question about 'incensing at home' is also included relating to the use of burning incense typically linked to religious practices in certain cultures.

When it came to a diagnosis of ADHD, it's not entirely clear about how this was ascertained but it looks like diagnosis was given by a clinician: "The conditions of disease in children were confirmed by board-certified child psychiatrists or pediatric neurologists, according to the clinical evaluation." I should also mention that participants also received skin prick tests (SPTs) covering a range of potential allergens: "house dust mites (HDMs mix, including Der p, Der f, Der m, and Blot allergens), cockroaches, dog dander, milk, egg, and crab allergens" as way of defining allergic sensitisation.

Results: there was a "strong positive association between ADHD and allergic sensitization as diagnosed by positive SPTs." In other words, despite finding a fairly low level of ADHD in their sample (1%), those who 'reacted' to one or more of the allergens tested for via the skin prick test seemed to be at some increased risk of ADHD. Such an enhanced risk spanned both those presenting with "AD with allergic sensitization and asthma with allergic sensitization."

The authors provide some further results and details on the possible hows-and-whys of their results. Obviously the immune system figures quite strongly given what for example, they were testing for with the SPT and their focus on AD and asthma. The word 'inflammation' also figures quite heavily. I note too that the authors reiterate previous suggestions that: "Control of allergens exposure might be a critical factor influencing the development of ADHD."

There is a further scheme of work to follow in this area, not just dealing with mechanisms but also in relation to 'treating' allergies also potentially 'treating' [some] ADHD. I say this on the basis that other independent research has observed that before reaching for the antihistamine as a potential ADHD-modifier, there may actually be a connection between early antihistamine exposure and the development of ADHD [3] (albeit with potential confounders) to keep in mind. Other work also supporting a link between ADHD and atopic disease [4] provides some other 'clues' that may require further investigation; not least "cow's milk intolerance", which ties into similar findings (see here) and could also be one route from which ADHD heightens the risk of subsequent future psychiatric disorder (see here) in light of other 'milk' associations (see here).

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[1] Yang CF. et al. Association between allergic diseases, allergic sensitization and attention-deficit/hyperactivity disorder in children: A large-scale, population-based study. J Chin Med Assoc. 2017 Nov 24. pii: S1726-4901(17)30304-0.

[2] Wang IJ. et al. Allergens, air pollutants, and childhood allergic diseases. Int J Hyg Environ Health. 2016 Jan;219(1):66-71.

[3] Schmitt J. et al. Increased attention-deficit/hyperactivity symptoms in atopic dermatitis are associated with history of antihistamine use. Allergy. 2017 Oct 4.

[4] Hak E. et al. Association of childhood attention-deficit/hyperactivity disorder with atopic diseases and skin infections? A matched case-control study using the General Practice Research Database. Ann Allergy Asthma Immunol. 2013 Aug;111(2):102-106.e2.

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Atopic dermatitis and the "increased risk of developing ADHD and ASD later in life"

I'm not gonna dwell too much on the findings reported by Lee and colleagues [1] talking about how "toddlers who suffer from AD [atopic dermatitis] at the age younger than 3 years are at a higher risk of developing ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] during later childhood" because science already seems to understand that there may be an important connection between early allergic disease and later offspring behavioural/developmental outcomes (see here for example).

That the Lee data is derived once again from the 'big data' powerhouse that is Taiwan - specifically the National Health Insurance Research Database (NHIRD) - makes the findings that little bit more 'believable' given the numbers and processes involved in collecting said information.

"Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD." Within statements like that it is getting progressively more difficult to downplay the impact that immune function (or immune response?) might have to quite a few people diagnosed as on the autism spectrum or with ADHD (or both). Further, that for some the 'treatment' of certain allergic symptoms might also impact on behaviour/development (see here and see here for examples) provides an important roadmap for further investigations in this area and the identification of who might be 'best responders' for such intervention (with no medical advice given or intended).

"Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma." Who would disagree, bearing in mind that the spectrum of potential correlates linked to early life allergy may be pretty wide?

To close, some words of wisdom: "there is no good reason for self-conscious farters to avoid fibre."

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[1] Lee CY. et al. Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine (Baltimore). 2016 Sep;95(39):e5005.

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Lee CY, Chen MH, Jeng MJ, Hsu JW, Tsai SJ, Bai YM, Hung GY, Yen HJ, Chen TJ, & Su TP (2016). Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine, 95 (39) PMID: 27684861

Chronic Fatigue Syndrome following atopy?

Regular readers might already know that I'm a bit of a fan of the various data coming out of Taiwan based on interrogation of the National Health Insurance Research Database (NHIRD). If it's not the possibility of a connection between asthma and various behavioural outcomes (see here) confirmed by other independent research (see here), it's the idea that something like enterovirus encephalitis in its most severe form might link into something like attention-deficit hyperactivity disorder (ADHD) (see here). Yes siree, Taiwan is leading the way in quite a few research sectors.

We can now add chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) to the topics covered by NHIRD investigators as the study published by Tse-Yen Yang and colleagues [1] (open-access available here) suggests that there may be more to see when it comes to atopy and CFS.

The paper is open-access so no need for any grand discussions by me on the topic. Looking at nearly 43,000 people diagnosed with "with newly diagnosed atopic syndromes" including atopic dermatitis, asthma and allergic conjunctivitis according to ICD-9-CM diagnostic codes, and comparing them with over 170,000 patients without atopy, researchers reported some interesting trends. Taking into account various confounding conditions: "The overall incidence rate for CFS in the atopy cohort (1.37 per 1000 person-year) was higher than in the nonatopy cohort (0.87 per 1000 person-year)." This enhanced risk for CFS in cases of atopic disease crossed genders. Further: "patients with atopy and renal disease... and chronic hepatitis... exhibited a higher risk of CFS than did patients with renal disease in the nonatopy cohort." In short, there may be much more to see when it comes to atopic disease and risk of CFS.

Obviously, one has to take into account the limitations of this type of study despite the impressive participant numbers. To quote: "the data lacked certain information such as laboratory examination and exposure factor data" as one possible drawback. As I've discussed in other posts, CFS/ME is also complicated by the various ways and means that it is clinically defined (for the purposes of this study the authors used the CDC criteria), so again be careful with that one.

That all being said, there are some impressive strengths to this study and the data do merit further investigations. The idea that immune function and CFS/ME might be related is gaining some significant momentum in recent times (see here). The Yang results contribute to that growing peer-reviewed evidence base. Insofar as the idea that atopic disease might specifically show some connection to CFS, well, the previous research in this area is a bit of a mixed bag by all accounts. The paper by Straus and colleagues [2] reported that atopy exists in about half of people with CFS. Borish et al [3] reported that most of their small participant group with CFS were atopic but were not able to disentangle psychological symptoms as also showing some effect. Other research has not been so supportive of any link.

Yang et al conclude by suggesting that the idea of atopic-associated CFS is a potentially credible concept "but the evidence was insufficient for improving the symptom-based diagnostic criteria of CFS." They do however suggest that "physicians note that patients with amounts of atopic syndromes face a higher risk of CFS, regardless of diagnostic criteria."  We'll see how this eventually pans out...

To close: marvel at Quicksilver and wonder 'what if'...

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[1] Yang TY. et al. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211.

[2] Straus SE. et al. Allergy and the chronic fatigue syndrome. J Allergy Clin Immunol. 1988 May;81(5 Pt 1):791-5.

[3] Borish L. et al. Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables. J Allergy Clin Immunol. 1998 Aug;102(2):222-30.


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Yang TY, Kuo HT, Chen HJ, Chen CS, Lin WM, Tsai SY, Kuo CN, & Kao CH (2015). Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine, 94 (29) PMID: 26200644

Early childhood atopy and autism risk

De profundis clamo ad te, domine

Regular readers will probably have heard something like this before so I'm sorry if I'm repeating myself: "The presence of any atopic disease in early childhood increased the risk of developing ADHD [attention deficit hyperactivity disorder]... and ASD [autism spectrum disorder]... in later life".

So said Mu-Hong Chen and colleagues [1] with yet another 'big data' paper coming out of Taiwan.

There is little point in me turning this research into some sort of mega-post given that this topic has featured so heavily on this blog. In case you missed them, here are some of the relevant posts:

• Allergic and autoimmune diseases and autism (2012) (see here)
• Asthma increases risk of ADHD? (2013) (see here)
• Asthma as a risk factor for autism? (2014) (see here)
• Autism, ADHD and allergy: Taiwan and big data (again) (2014) (see here)

Lazy? Yes, I am being a bit lazy in this post by just supplying older links but what more can I say apart from that there seems to be a complicated relationship between immune function and behaviour. Oh, and other research from this group might also be worthwhile looking at as per studies linking epilepsy and atopic dermatitis [2] and major depression and/or bipolar disorder and asthma [3] knowing about the various comorbidity relationships with autism (see here and see here).

And here is some lazy music to accompany my lazy post...

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[1] Chen MH. et al. Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. J Psychosom Res. 2014 Oct;77(4):316-21.

[2] Chen MH. et al. Risk of epilepsy among patients with atopic dermatitis: a nationwide longitudinal study. Epilepsia. 2014 Aug;55(8):1307-12.

[3] Chen MH. et al. Higher risk of developing major depression and bipolar disorder in later life among adolescents with asthma: a nationwide prospective study. J Psychiatr Res. 2014 Feb;49:25-30.

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Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Pan TL, & Bai YM (2014). Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. Journal of psychosomatic research, 77 (4), 316-21 PMID: 25280829

The skin-brain axis and autism?

I'm sure that many people with an eye on the autism research scene will have come across the term 'gut-brain axis' at some point in their reading. Denoting the suggestion of a possible relationship between what goes on in our deepest, darkest recesses and brain function (and onwards observed behaviour), the gut-brain axis has seemingly found a home particularly when looking at autism spectrum disorders.

Be it when it comes to describing the potential hows and whys of things like a gluten- and casein-free diet (potentially) showing some effects, or those quite consistent findings of elevated rates of gastrointestinal (GI) issues reported in at least a proportion of cases of autism(s), the gut-brain axis seems to be quite an enduring concept as it might also be in other conditions such as schizophrenia.

Axis not axes @ Wikipedia  

The specifics of the gut-brain axis have not however yet been fully elucidated; although quite a lot of speculation has focused on things like gut bacteria and intestinal permeability as showing some involvement; concepts which have cropped up on this blog quite regularly.

In this post I want to talk about another axis potentially relevant to autism and quite a few other developmentally defined or mental health related conditions: the skin-brain axis following the appearance of a rather interesting paper by Yaghmaie and colleagues* on mental health comorbidity in patients with atopic dermatitis.

A few points are worth noting given that I'm not able to post a link to the full-text paper:

• This was a survey paper based on the US 2007 National Survey of Children's Health dataset (N=91,642). 
• In short, the parents of children aged 0-17 years (0 years denoting those under 1 year old) were contacted and asked quite a few questions about the health of their children. 
• For the purposes of this study, children with a history of atopic dermatitis (AD) as per the question: "during the past 12 months, have you been told by a doctor or other healthcare provider that XXX had eczema or any kind of skin allergy?" were asked about "provider-diagnosed mental health conditions" covering various diagnoses "previously been reported as associated with AD" and their results were compared with those without AD. Odds ratios (ORs) were calculated based on the risk derived from AD for various conditions.
• The 12-month prevalence of AD for 2007 was 12.9%; a rise from previous estimates from data in 2003 (10.6%). Interestingly when comparing AD estimates state-by-state, California turned out to have the lowest AD prevalence (8.5%). Regular readers will know that in autism research terms, California has always been a bit of a focus (see here for example).
• A diagnosis of AD was associated with an elevated risk of quite a few conditions: autism (OR: 3.04 CI: 2.13-4.34), ADHD (OR: 1.87 CI: 1.54-2.27) and conduct disorder (OR 1.87 CI: 1.46-2.39) among other things. All relationships were statistically significant when comparing AD and non-AD samples.
• The authors also report that the severity of AD was also related to the likelihood of a developmental/mental health condition, in that the more severe the AD, the more likely a diagnosis was to be received.

Bearing in mind the nature and sampling methods of the Yaghmaie study, I have to say that I was taken aback by the findings of this paper and the potential implications. It's not that skin conditions have not been talked about with autism for example in mind before, as per the research base on things like psoriasis for example (see this post) and the whole autoimmunity side of things. Indeed, the atopy and allergy field has been mentioned quite a few times in autism research; alongside issues such as mast cell activation also being a source of speculation. But the implication that a skin condition like AD might actually raise the risk of developing autism or ADHD or a conduct disorder is a whole new ballgame on the mind-body relationship stakes bearing in mind the question of correlation-and-causation.

The authors also go as far as to suggest: "Strategies to prevent AD or to aggressively treat early skin inflammation might modify the risk of mental health disorders in at-risk children". This sentence really got me thinking. Thinking about inflammation and how this topic has been looked at on more than one occasion in autism research circles. Thinking about how skin and brain/behaviour might be linked, bearing in mind the source embryological material. Thinking also about the genetic - environmental factors which are linked to AD, and indeed going back to that gut-brain axis, how food might also play a role as per the link between gluten and dermatitis herpetiformis for example. Lots of thinking indeed.

The final words about the paper by Yaghmaie and colleagues should I suppose be ones of caution insofar as science needs to (a) replicate these findings, both in the US (home to participants) and outside the US, and (b) start looking in more details as to what the shared biological mechanisms and pathways could be (at least one authorship group have asked similar questions recently**).

That being said, this is yet more potential evidence for the whole-body nature of quite a few developmental and mental health conditions - remember the airways and autism research - and how autism research needs to keep expanding its scientific boundaries outside of the view that the grey (or rather pinkish) matter floating inside our skull is working completely in isolation.

Oh and perhaps I should also mention the meta-analysis by Schmitt and colleagues*** as adding more fuel to the correlation fire? And while we are on the topic of atopy, how about the paper by Chou and colleagues**** on allergic rhinitis and ADHD?

Stop now... and I will.

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* Yaghmaie P. et al. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. December 2012.

** Denda M. et al. How does epidermal pathology interact with mental state? Medical Hypotheses. 2013; 80: 194-196.

*** Schmitt J. et al. Association of atopic eczema and attention-deficit/hyperactivity disorder - meta-analysis of epidemiologic studies. Z Kinder Jugendpsychiatr Psychother. 2013; 41: 35-44.

**** Chou PH. et al. Prevalence of allergic rhinitis in patients with attention-deficit/hyperactivity disorder: a population-based study. Eur Child Adolesc Psychiatry. December 2012.

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Yaghmaie P, Koudelka CW, & Simpson EL (2012). Mental health comorbidity in patients with atopic dermatitis. The Journal of allergy and clinical immunology PMID: 23245818