After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.
A growing body of studies suggests a link between inflammation and autoimmune diseases on the one hand and ADHD on the other. It has been hypothesized that excessive release of cytokines (small signaling proteins that regulate immune response and inflammation and repair) and keratinocytes (skin cells) under allergic conditions may cause structural and functional changes to the nervous system and brain, which can contribute to psychiatric disorders, including ADHD.
Noting that previous studies have focused primarily on associations between ADHD and respiratory allergies(asthma) and skin allergies, a joint Chinese and American study team set out to see what, if any, association there might be with food allergies.
To this end, they turned to the national health Interview Survey (NHIS), conducted annually by the National Center for Health Statistics at the Centers for Disease Control and Prevention. This survey relies on a very large, nationally representative sample of the U.S. population.
The study encompassed 192,573 youths aged 4 through 17 years old. Of these, 15,376 had an ADHD diagnosis, 8,603 had food allergies, 24,218 had respiratory allergies, and 18,703 had skin allergies.
After adjusting for age, sex, race/ethnicity, education level, family income to poverty ratio, and geographic region, youths with food allergies were found to be over 70% more likely to be diagnosed with ADHD than those without food allergies. After further mutual adjustment for other allergic conditions, they were still well over 40% more likely to be diagnosed with ADHD than their non-allergic peers.
How did that compare with respiratory and skin allergies? In the same study population, making identical adjustments for potential confounders, youths with respiratory allergies were 50% more likely to be diagnosed with ADHD than those without such allergies. Those with skin allergies were 65% more likely to be diagnosed with ADHD. After further mutual adjustment for other allergic conditions, those with respiratory allergies were still over a third more likely to be diagnosed with ADHD, and those with skin allergies were 50% more likely to be diagnosed with ADHD.
The authors concluded, “The current study found a significant and positive association between common allergic conditions, including food allergy, respiratory allergy, skin allergy, and ADHD in children. Although the detailed mechanisms linking food allergy and other allergic conditions to ADHD remain to be understood, physicians should be aware of the increased risk of ADHD as a comorbidity of children with allergic conditions.â€
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Taiwan has a single-payer healthcare system that covers virtually every inhabitant (99.5%). That makes it relatively easy to track healthcare issues using its comprehensive National Health Insurance Research Database.
This database maintains a subset, the Longitudinal Health Insurance Database (LHID), consisting of a million persons, with no significant differences in sex, age, or healthcare use from the parent database.
A Taiwanese research team used the LHID to identify 114,486 individuals diagnosed with ADHD from 1997 to 2013. It then compared their motor vehicle (including motorcycles, which are extremely common in Taiwan) crash patterns with 338,261 normally developing controls from the same database.
Adjusting for sex, age, and psychiatric comorbidities, persons with ADHD were about a fifth (19%)more likely to be in traffic crashes. Breaking it down further by sex, women with ADHD were no more likely to be in crashes, but men with ADHD were about a quarter (24%) more likely than their healthy counterparts.
Since the database also tracks pharmaceutical prescriptions, the team also looked into the effect of methylphenidate (MPH), the medication that is the first-line treatment for ADHD under Taiwanese guidelines, and the only approved stimulant. Atomoxetine, a non-stimulant, is used where MPH is either ineffective or not indicated for any other reason and is only used in 4% of all cases.
Of the 114,486 persons diagnosed with ADHD, 89,826 used MPH, and 24,660 did not.
Compared with persons with ADHD who were not on methylphenidate, those with ADHD who were on MPH for 180 days (roughly half a year) or less had 77% fewer accidents, and those on MPH for over 180 days had 93% fewer accidents. This strong dose-response relationship is suggestive of a causal relationship, with MPH perhaps reducing impulsive behavior, particularly among young men with ADHD.
The team also conducted within-person analyses, comparing times when persons with ADHD were taking MPH with periods when they were not. These showed no effect within 30 days of use, rising to a 65%reduction in crashes within 60 to 90 days of use, which was barely outside the 95% confidence interval (p = .07), very likely because of “the extremely low incidence of transport accidence (i.e. 0.6%)enlarged the confidence interval.â€
The authors concluded, “All registration medical claim data came from the nationally-representative sample of NHI, minimizing the selection and recall bias. By excluding transport accidents before ADHD diagnosis, we have precluded the reverse association between ADHD and road traffic accidents as much as possible. The advantage of the between-subjects comparison was that we were able to examine the MPH effect in different dose groups. However, confounding by indication cannot be eliminated. For example, those with a severe degree of ADHD symptoms, an exhibition of risky behaviors, or comorbid with other psychiatric illnesses were more likely to be prescribed medication. Hence, we also performed within-subject comparisons to adjust for time-invariant factors.â€
Transport safety thus offers another compelling reason to treat ADHD symptoms. Methylphenidate in particular seems to be especially effective in reducing traffic fatalities and injuries.
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Montelukast is a leukotriene receptor antagonist that binds to the cysteinyl leukotriene type 1 receptor. It thereby blocks the action of leukotriene, an inflammatory mediator produced by white blood cells. By binding with the receptors, montelukast decreases the inflammation associated with asthma, relaxing smooth muscles and dilating air passages. Though used as an alternative to inhaled corticosteroids for mild persistent asthma, it is not suitable for acute attacks.
Previous smaller studies have produced inconsistent results on whether montelukast treatment is a risk factor for ADHD. That led a Taiwanese research team to conduct a nationwide cohort study. They used the Nationwide Health Insurance Research Database (NHIRD), consisting of a million randomly selected participants drawn from the Taiwan’s universal single-payer health insurance system.
The team identified a total of 53,645 children 12 years old and under-diagnosed with asthma. Of these, 17,773 were treated with montelukast, and 35,912 were not. The two groups were then matched on a 1:1 ratio for age, sex, geographic region of residence, comorbidities including allergic rhinitis and atopic dermatitis, admission or emergency department visits due to an asthma attack, and index date. That yielded a montelukast group of 12,806 and an identically sized control group.
Both in the crude and adjusted results, children treated with montelukast were found to be no more likely to develop ADHD than those not treated with montelukast (p = .5). Longer treatment with montelukast (over 90 days) had no effect, with an adjusted hazard ratio of exactly 1.00 (p = .95).
The authors concluded, “Our current findings indicate that exposure to montelukast among pediatric asthma patients poses no increased risk of attention-deficit/hyperactivity disorder. Montelukast therapy, which may be necessary for pediatric patients with asthma, is a safe therapy for such patients.â€
Both Taiwan and Sweden have universal single-payer health insurance systems that in effect track their entire national populations. With detailed health and other records on millions of individuals, with no significant exclusions, one can essentially eliminate sampling error, and also explore how associations vary by degree of familial/genetic relationship.
A Taiwanese research team used the Taiwan National Health Insurance Research Database to follow 708,517 family triads (father–mother-child) from 2001 through 2011. That’s a total of over 2.1 million persons. The database covers over 99% of Taiwan’s population.
Noting that previous studies had found links between maternal autoimmune diseases and ADHD in their offspring and that research on associations with paternal autoimmune diseases had been inconclusive, they were particularly interested in exploring the latter.
Children born from 2001 through 2008 were enrolled in the study. The investigators then noted the presence or absence of any autoimmune disease in their parents from 1996 through childbirth.
In Taiwan, expert panels review diagnostic information of severe systemic autoimmune diseases to confirm the diagnosis. Once confirmed, patient co-payments are waived. ADHD diagnoses are by board-certified psychiatrists.
To reduce the effect of confounding variables, adjustments were made for family demographic data (income level and residence), parental ages, parental mental disorders, and sex of children.
The presence of any maternal autoimmune diseases was associated with a 60% greater risk of ADHD in offspring. The risk was especially elevated for inflammatory bowel diseases (2.4 times the risk) and ankylosing spondylitis (twice the risk).
The presence of any paternal autoimmune diseases was also associated with an elevated risk of ADHD in offspring, although only about half as much as for maternal autoimmune diseases, with a 33% greater risk overall. The association was especially pronounced for psoriasis and ankylosing spondylitis, both doubling the risk of ADHD in offspring.
Meanwhile, half a world away, a joint Swedish, Norwegian, and U.S. team used the Swedish national registries to dig further into these associations. They did this by examining data not only from mothers and fathers, but from full siblings, aunts, uncles, and cousins as well, to probe genetic links.
The team used the Swedish registers to identify 5,178,225 individuals born in Sweden between 1960 and 2010 for whom the identity of the biological mother was known, excluding all who died or emigrated before age 10. They then used the registers to identify the aforementioned relatives.
The researchers only included autoimmune diseases with at least two thousand diagnosed individuals in the cohort, to avoid small sample effects.
They adjusted for sex and year of birth, but not “for another covariate that is often adjusted for (e.g. maternal education, family income, parental psychiatric disorder, parental AD [autoimmune disease] as these are likely not true confounders of the association between ADHD and ADD, but may rather represent either mediator between ADHD and AD's, or proxies of ADHD and/or AD risk or alternatively proxies for the associations we aim to measure.â€
The team found statistically significant associations between ADHD and autoimmune diseases in all categories of relatives. Mothers of children with ADHD were 29% more likely to have an autoimmune disease than those of typically developing children; fathers were 14% more likely to have an autoimmune disease; full siblings 19% more likely; aunts 12% more likely; uncles 7% more likely; and cousins 4% more likely.
Quantitative genetic modeling produced a significant genetic correlation, but no significant environmental correlation. Genetic correlation explained most, if not all, the covariance between ADHD and any autoimmune disease.
The authors concluded, “ADHD was to some degree more strongly associated with maternal than paternal AD's, but by using aunts and uncles in a genetically informative study design, we demonstrate that this difference cannot be readily explained by AD-mediated maternal effects. Quantitative genetic modeling further indicates that the familial co-aggregation of ADHD and ADs is partly due to shared genetic factors. … In addition, biological aunts, uncles, and cousins must be assumed to share the little environment with the index individuals, in further support of shared genetic factors underlying the familial co-aggregation. Moreover, both epidemiological and molecular genetics studies have demonstrated positive genetic correlations between ADHD and ADs, in agreement with our findings.â€
The authors emphasize that these results do not warrant screening for autoimmune diseases among asymptomatic individuals with ADHD.
A Norwegian team based at the University of Bergen recently performed a population study using the country’s detailed national health registries. With records from more than two and a half million Norwegians, the team examined what, if any, associations could be found between ADHD and nine autoimmune diseases: ankylosing spondylitis, Crohn’s disease, iridocyclitis, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis.
After adjusting for age and maternal education, the team found no association between ADHD and five of the nine autoimmune disorders: type 1 diabetes, rheumatoid arthritis, iridocyclitis, systemic lupus erythematosus, and multiple sclerosis. In the case of ankylosing spondylitis, it found no association with males with ADHD, but a negative association with females. Females with ADHD were less likely to have ankylosing spondylitis. The adjusted odds ratio (AOR) was0.56 (95% CI 0.32-0.96).
Positive associations were found for only three autoimmune diseases. The strongest was for psoriasis, with adjusted odds ratios of 1.6(95% CI 1.5-1.7) for females and 1.3 (95% CI 1.2-1.4) for males. When further adjusted for education, smoking, and body mass index (BMI), however, the adjusted odds ratio for females with ADHD dropped to 1.3 (95% CI 1.0-1.6).
The second-strongest association was with Crohn’s disease. But here it was only among women. The odds ratio, in this case, was 1.4 (95% CI 1.2-1.8). Males with ADHD were less likely to have Crohn’s disease, with an odds ratio of 0.71 (95% CI 0.54-0.92).
Finally, females with ADHD were slightly more likely to have ulcerative colitis, with a barely significant odds ratio of 1.3 (95% CI 1.1-1.5), while no such association was found for males with ADHD, whose odds ratio was a statistically non-significant 0.9.
Given the large sample size of over two and a half million, this is no underpowered study. It found no association between ADHD and the generic category of autoimmune disorders. Furthermore, it is a stretch to argue that there are any clear and clinically meaningful links between ADHD and any of the specific disorders that were analyzed in this study. The small and often opposite effect sizes may simply reflect limitations with the data (presumed autoimmune disorders were identified based on drugs prescribed), or other unidentified confounding factors.
An international team of researchers has carefully examined the best current evidence and found strong evidence for an association between asthma and ADHD by combining a meta-analysis of prior data with a new analysis of the Swedish population.
The meta-analysis identified 46 datasets with a total of more than 3.3 million persons. It computed an unadjusted (odds)'s ratio (OR) of 1.7, which indicates that ADHD patients have about twice the risk of developing asthma compared with people without ADHD. Limiting the meta-analysis to studies that adjusted for confounding factors, 30 datasets with more than a third of a million participants still led to an adjusted (odds)' ratio of 1.5 (95% CI 1.4 – 1.7). The likelihood of obtaining this result by chance in such a large sample would be less than one in ten thousand.
When the team further checked this result against the results for the Swedish population of more than one and a half million persons, the (odds) ratio was almost identical to 1.6. Adjusting for confounding factors reduced it to 1.5 (95% CI 1.41 – 1.48). That means the findings are very robust: asthma and ADHD are associated, with an (odds)'ratio of 1.5, after adjusting for confounding factors.
What does this small but statistically very reliable association between asthma and ADHD mean? For researchers, it suggests that the two disorders may have common risk factors and that the search for these shared risk factors might lead to improved treatments. These risk factors might also be shared with two other somatic conditions for which ADHD patients are at increased risk: obesity and eczema. Common inflammatory processes may account for this overlap among disorders. Clinicians should be aware that children with asthma have an increased risk for ADHD, although, given the small association, systematic screening may not be warranted. But given that ADHD might interfere with asthma medication compliance, the disorder should be considered among noncompliant youth, especially among those who show other evidence of inattention, poor memory, or disorganization.
