CHILDHOOD ALLERGY LINKED WITH ADHD/ASD
WORD COUNT:
• Abstract – 218 words
• Main Text – 2912 words
NUMBER OF TABLES AND FIGURES:
• Tables – 4
• Figures - 3CONFLICT OF INTEREST: The Authors whose names are listed
below, declare that there is no conflict of interest in the subject
matter or materials discussed in this manuscript.
FINANCIAL SUPPORT: The work was partially funded by a grant from the
Israel Ambulatory Pediatric Association.
ABSTRACT:
Background: Previous studies reported controversial results regarding
the association between allergic disorders and ADHD/ASD. The aim of this
article is to investigate whether allergic disorders are associated with
ADHD/ASD in a large cohort of pediatric patients.
Methods: A retrospective study using the pediatric (0-18 year) database
(ICD-9-CM codes) of Clalit Health Services during the years (2000-2018).
Diagnosis of all disorders was made by specialist physicians.
Results: 117,022 consecutive non-selective allergic children diagnosed
with one or more allergic disorder (asthma, rhinitis. conjunctivitis,
skin, food, or drug allergy) and 116,968 non-allergic children were
enrolled to our study. The mean follow-up period was 11±6 years. The
presence of allergic disorders in early childhood (mean age of allergic
diagnosis 4.5± 4.3 years) in boys as well as in girls, significantly
increased the risk to develop ADHD (O.R 2.45, CI 2.39-2.51;
P<0.0001), ASD (O.R 1.17, CI 1.08-1.27; P<0.0001) or
both ADHD+ASD (O.R 1.5, CI 1.35-1.79; P<0.0001). Children with
more than one allergic comorbidity revealed a much higher risk. In a
multivariable analysis (adjusted for age at study entry, number of
yearly visits and gender) the risk of allergic children to develop ADHD
and ADHD+ASD, but not ASD alone, remained significantly higher.
Conclusion: Allergic disorder in early childhood significantly increased
the risk to develop ADHD, and to a less extend ASD, in later life.
KEYWORDS:
pediatric allergic disorders, risk factor, ADHD, ASD, gender.
INTRODUCTION
Allergic disorders including allergic dermatological diseases especially
atopic dermatitis (AD), rhino-conjunctivitis, asthma, food, and drug
allergies are common chronic morbidities in pediatric patients. The
prevalence of allergic diseases is constantly increasing in the last
decades especially in high developed countries.1Though the exact pathogenesis of allergic disorders is not yet defined,
it appears that genetic and environmental factors play a role in their
development.2 In addition to physical discomfort,
chronic allergic disorders in early childhood may cause mental and
behavioral problems.3 Attention deficit hyperactivity
disorder (ADHD) is a common neurobehavioral disorder characterized by
inattention and hyperactivity that appear before to age of
12.4 The prevalence of ADHD in American population
(<18 years) is about 9-12 %.5 A study from
Israel reported ADHD prevalence of 15.2%.6 Autism
spectrum disorder (ASD) is a complex neurodevelopmental disorder
characterized by deficits in social interaction, language communication
with repetitive problems.4 Its prevalence of in
children is about 2.47%, in the USA,7 whereas an
Israeli study reported a prevalence of 0.65%.8 ADHD
as well as ASD are more common in boys compering to
girls.5–7 In some pediatric patients the symptoms of
ADHD and ASD overlap, thus they have features of both
disorders.9
As was shown for allergic disorders,1 the prevalence
of ADHD and ASD is steadily increased over the past
decades.5–8 Furthermore, as was reported for allergic
disorders,2 genetic and environmental factors were
shown to play a role in the pathogenesis of ADHD and
ASD.10–13 Indeed, several studies did investigate the
association between allergic disorders and ADHD and/or ASD with
controversial results.14–26 Differences in size of
the studies, follow-up period and diagnostic criteria which were used in
the various studies as well as the specific types of allergic disorders
that were investigated are most probably the causes for the conflicting
reports.
We, therefore, conducted a very large cohort study (about 240,000
pediatric patients) with a long follow up period (from birth to 18 years
of age) of consecutive non-selective allergic (rhinitis, conjunctivitis,
asthma, food, drug, and skin allergy) and non-allergic patients in order
to define the relationship and the association between allergic
disorders (all allergic disorders and each one separately) and the
development of ADHD, ASD, or both neurological disorders.
PATIENTS AND METHODS
Data Sources
In the present retrospective study, we used the pediatric (0-18 years of
age) database of Clalit Health Services which is the largest health care
provider in Israel during the years 2000-2018. The database contains
comprehensive information of all insured subjects including demographic
characterizations, dates and details of all hospitalizations and all
clinical visits with diagnosis (for each clinical visit/hospitalization)
which were coded according to the International Classification of
Diseases, 9th revision, Clinical Modification
(ICD-9-CD). The follow up period was defined from the date of the first
to the date of the first to the date of last clinic visit reported for
each patient.
We intend to enroll to the present study a large number of consecutive
nonselective pediatric subjects - 120,000 subjects with a diagnosis of
allergic disease designated as ”allergic patients” and 120,000 control
subjects without any diagnosis of allergic disease - ”non-allergic
patients” from that database.
Allergic disease was defined in the present of one (or more) of the
following: asthma (ICD-9-CM code 493) diagnosed by pulmonologist,
allergist or pediatrician; allergic rhinitis (ICD-9-CM code 477)
diagnosed by allergist, pediatrician or otolaryngologist; allergic
conjunctivitis (ICD-9-CM code 372) diagnosed by ophthalmologist,
allergist or of pediatrician; skin allergy including atopic dermatitis
(ICD-9-CD code 691,692,708) diagnosed by dermatologist, allergist, or
pediatrician; food allergy (ICD-9 CM code 693) diagnosed by allergist;
drug allergy (ICD-9 CM code 995) diagnosed by allergist or pediatrician.
ADHD (ICD-9-CM code 314) and ASD (ICD-9-CM code 299) where diagnosed by
pediatric psychiatrics or pediatric neurologists according to the
current version of the diagnostic and statistical manual of mental
disorders (the DSM-5).27
ETHICAL APPROVAL:
The study was approved by the Clalit Health Services Ethics Committee in
Israel, and was conducted in accordance with all rules of the
Declaration of Helsinki.
Statistical analysis
Data is presented as mean \(\pm\) standard deviation (SD). For between
group comparisons the independent t-test was used for continuous
variables and the Pearson Chai-squared test for categorical variables.
We performed, first, univariable analysis to calculate the unadjusted
odds ratios (OR) and the 95% confidence intervals (CI) of allergic
patients to develop ADHD, ASD or both. (Tables 1, 2, 3; Figure 1). To
control for possible confabulations, a multivariate logistic regression
analysis adjusting for age at study entry, number of yearly visits per
patient and gender was performed (Model 1), (Table 4). A two-tailed
p-value equal or less than 0.05 was considered statistically
significant. All data processing and statistical analysis were performed
with Statistical Package for Social Science (SPSS 27).
RESULTS
234,170 pediatrics patients (119,874 males, 114,323 females) were
enrolled to our study. During the time of the study (2000-2018), a total
of 23,690,318 clinical visits (including hospitalizations) were
recorded. The mean (\(\pm SD)\) number of yearly visits per patient was
10.3\(\pm 10.7\ and\ the\ mean\ (\pm SD)\ \)follow-up period, for all
enrolled patients was 11 \(\pm\) 06 (range 2-18) years.
117,022 patients were diagnosed with at least one allergic disorder
during the time of the study (”allergic patients”) whereas the other
116,968 control patients were not diagnosed with any allergic disorder
(”non- allergic patients”). As can be seen in Table 1, allergic skin
diseases, conjunctivitis, and asthma, were the most prevalent allergic
disorders (49.6%, 41.5% and 32.8%, respectively). About 40% of our
allergic patients had two or more types of allergic disorders (Table 1).
During the years of the study, 33,008 of our patients (14%) where
diagnosed with ADHD, 2341 (0. 99%) with ASD and 816 (0.34%) with
both, ADHD and ASD (Table 1).
As can been seen in Table 1, significantly more pediatric patients with
a diagnosis of at least one allergic disorder, compared to the
non-allergic group of patients, were also diagnosed with ADHD (19.3%
Vs. 8.9%; P<0.0001), with ASD (1.1% Vs. 0.9%;
P<0.0001) or with both, ADHD and ASD (0.4% Vs. 0.3%;
P<0.0001). The vast majority of those patients (95% of ADHD
and 97% of ASD patients) were diagnosed with one or more allergic
disorders prior to their neurological diagnosis. Furthermore, the mean
age of the patients at the time of their first allergic disorder
diagnosis (4.5 ±4.3 years) was lower than the ages of ADHD (8.5±3.4
years), ASD (5.1±3.5 years) and both ADHD and ASD (5.0±2.9 years)
diagnosis. Therefore, we investigated whether allergic disorder in early
childhood is associated with the development of ADHD, ASD or both
disorders in later life. The presence of any (one or more) allergic
disorder significantly increased the risk of those pediatric patients to
develop ADHD (OR 2.25; 95% CI 2.39-2.51), ASD (OR 1.17; 95% CI
1.08-1.27) or both, ADHD and ASD (OR 1.56; 95% CI 1.35-1.79) (Table 1).
Interestingly, the mean age at the time of ADHD or ASD diagnosis was
similar in the allergic and non-allergic group of patients (Table 1).
Table 2 clearly demonstrates that any allergic disorder (evaluated
separately) significantly increased the risk of the develop ADHD as
compared to the risk observed in non-allergic patients. The early
diagnosis of rhinitis and conjunctivitis was associated with the highest
risk to develop ADHD (OR 3.958; 95% CI 3.801-4.122 for rhinitis and OR
3.36; 95% CI 3.53-3.74 for allergic conjunctivitis). Early diagnosis of
skin, drug and especially food allergy were associated with a
significant risk to develop ASD. All types of allergic disorders were
significantly associated with an increased risk to develop both, ADHD
and ASD, except for drug allergy that almost reached statistical
significance (Table 2).
We further investigated the association between early diagnosis of
allergic disorders and the development of ADHD, ASD or both neurological
disorders. To this end, we studied the effect of the number of allergic
disorders (for each patient) on the risk to develop ADHD or ASD. As can
be seen in Figure 1A, the risk to develop ADHD, significantly increased
in patients with several allergic comorbidities. Thus, a patient with
five or six allergic disorders demonstrated higher risk to develop ADHD
as compared to patients without any allergic disorder or with only one
allergic disease. Similar significant results were observed for allergic
patients that develop both disorders (ADHD+ASD) (Figure 1C). The
association between the number of allergic disorders and the development
of ASD was not significant except for patients with six allergic
comorbidities that demonstrated significant high OR as compared to the
other patients (Figure 1B)
More boys (53.4%) than girls were recruited to our study. Furthermore,
both ADHD and ASD are more common in boys.5–7Therefore, we further evaluated the impact of gender on the association
between allergic disorders and the development of ADHD and ASD. Indeed,
as can be seen in Table 3, more boys than girls in our study were
diagnosed with ADHD and ASD regardless to the presence of any allergic
disorder. Nevertheless, the OR to develop ADHD or ADHD with ASD were
similar in both genders. The OR to develop ASD alone was significant for
boys (1.13; CI 1.03-1.24) but it did not reach statistical significance
in allergic girls (Table 3).
To ensure that allergy in early childhood is an independent risk factor
for the development of ADHD, ASD or both disorders, we further preformed
a logistic regression multivariate analysis adjusted for gender, age at
study entry and the number of yearly visits per patient (Model 1). As
can be seen in Table 4, the presence of allergy was shown to be an
independent risk factor to develop ADHD (OR 2.08; 95% CI 2.03-2.15) or
the combination of both, ADHD and ASD (OR 1.19; 95% CI 1.02-1.38).
Although early childhood allergy was shown to be a significant risk
factor for ASD development univariable analysis (Tables 1, 4), in the
multivariable analysis (Model 1), it did not reach statistical
significance (Table 4).
DISCUSSION
The present study demonstrates significant association between various
allergic disorders (rhinitis, conjunctivitis, asthma, drug, and food
allergy) in early childhood and the development of ADHD. The association
with ASD was less significant. The presence of several allergic
comorbidities (in one patient) further increases the risk to develop
those neurobehavioral disorders.
In a very large (117,022) cohort of pediatric allergic (with one or more
of the following: asthma, rhinitis, conjunctivitis, skin, food, and drug
allergy) and non-allergic (116,968) patients from rural and urban
communities, we were able to demonstrate significant association between
allergic disorders (one or more) in early childhood and the development
of ADHD or ASD (Table 1). The OR for ADHD (2.45) and ADHD+ASD (1.56)
were higher than for ASD (1.17), but still the later was statistically
significant in a univariate analysis. A dose dependent relationship was
observed, thus as was previously reported,17,28 the
risk to develop ADHD or ASD increased in children with several (more
than one) allergic comorbidities (Figure 1). The latter, further support
the link between allergic disorders and ADHD/ASD. The large number of
enrolled patients, the long follow up period (from birth to 18 years of
age), the assessment of various allergic comorbidities which were
diagnosed by specialist physicians contribute to the strength and
validation of our study.
Most previous studies investigated the association of a single allergic
disorder,15–17,29–33 or up to three allergic
comorbidities,14,23,24,26,28,34,35 and ADHD/ASD. To
the best of our knowledge, the present study is the first study which
enrolled children with up to six allergic comorbidities (Table 1)
including drug allergy that was not previously studied. Moreover,
whereas most previous studies reported the association between allergic
disorders and ADHD or ASD,15,16,29,31 we investigated
the link to ADHD and ASD (or both ADHD+ASD) using our large pediatric
cohort, with the same methodological and statistical analysis that add
to the validity of our findings.
The presence of each allergic disorder (studied separately)
significantly increased the risk to develop ADHD or ADHD+ASD. The fact
the association between drug allergy and ADHD+ASD (OR 1.7; 95% CI
0.95-3.03) did not reached statistical significance is most probably due
to the relatively low number of patients with drug allergy that were
enrolled to our study. The highest OR was observed for children with
rhinitis and conjunctivitis (OR of 1.93; 95% CI 1.51-2.47 and 1.86;
95% CI 1.58-2.2; respectively) (Table 2). Although the presence of one
or more allergic disorder was significantly associated with the
development of ASD (Table 1), when studied separately only skin, food
and drug allergy were found to be significant with OR’s that were lower
compared to the risk (OR) to develop ADHD (Table 2).
The prevalence of ADHD and ASD, diagnosed by pediatric psychiatrics or
neurologists, in our study (Table 1, 3), is similar to previous
reports.5–8 Moreover, as was previously
demonstrated,5–7 more boys than girls were diagnosed
with ADHD or ASD (Table 3). Allergic boys and girls revealed similar
significant risk to developed ADHD or ADHD+ASD, whereas only boys
demonstrated significant risk to develop ASD alone (Table 3). Indeed,
after adjusting for age at study entry, number of yearly visits per
patient and gender (Model 1) (Table 4), the risk of allergic children to
develop ADHD or ASD +ADHD as compared to non-allergic children was
significantly higher (OR of 2,08 and 1.19; respectively) whereas their
risk to develop ASD alone was not significant in the multivariable
analysis (Table 4).
Several previous studies did not find significant association between
allergic disorders and the development of ADHD15,17 or
ASD,25,29 . However, most studies that were done in
different parts of the world provide evidence for high risk of pediatric
allergic patients to develop ADHD17,24,28,30–32 or
ASD14,17,23,28,32 regardless to the ethnicity of the
enrolled patients. A meta-analysis by Schans et al,26reported that asthma, rhinitis, and eczema were independent risk factors
for ADHD development which is similar to our observation. Interestingly,
in contrast to our observations (Tables 1, 2, 3, 4), two
studies17,28 reported that the risk of allergic
children to develop ASD was higher than their risk to develop ADHD.
Differences in methodology (e.g. cohort type and size, follow up period
and mode of diagnosis: self-report Vs. physician) and in the statistical
evaluation are most probably the reason for the conflicting results.
There are several possible mechanisms, not mutually exclusive, for the
association between allergic disorders (Table 1, 2, 3, and 4) and ADHD
or ASD. First, allergic disorders and ADHD and ASD may have common
genetic and environmental factors that increase the co-occurrence of
those disorders. The high rates of ASD in children of mothers with
allergic disorders36 and the increased risk for
allergic disorders in siblings of ASD patients,37 may
support the above mechanism. Indeed, genetic links between allergic
diseases and ASD36 or ADHD10,38 were
reported. In addition, dysregulation of tryptopan and serotonin
metabolism was reported to play a role in the pathogenesis of allergic
disorders as well and in ADHD39 and
ASD.40 The fact that we (Table 1), as well as
others17 had demonstrated that allergy preceded the
development of ADHD or ASD may point to other mechanism(s). Mast cell
activation, high levels of inflammatory cytokines (especially Th2
cytokines) and chemokines (CCXL8, CCL2) observed in patients with
allergic disorders can cause neuroimmune microglial and mammalian Target
of Rapamycin (mTOR) activation, brain inflammation and neurobehavioral
disorders.11,13,41,42 In addition, stress, fear
(especially in food and skin allergy) and sleep disturbances (observed
in allergic children) may also play a role in the pathogenesis of ADHD
or ASD. Schmitt el al suggested that the usage of antihistamine agents
that pass the brain blood barrier (in early childhood) may contribute to
the development of the neurobehavioral disorders.16
The main limitation of our present study is its retrospective nature
rather than a prospective controlled study that may give more valid
results. Our study does not provide genetic or environmental data which
may be potential confounders. In addition, the prevalence of allergic
disorders as well as ADHD or ASD in our study might be underestimated
since only those who sought medical services were recruited.
Nevertheless, our study presents a very large number of pediatrics
patients (237,170; Table 1) from urban and rural areas with a long
follow up period (11±0.6 years). Moreover, the diagnosis (allergic,
neurological) in our study, was made by specialist physicians, rather
than by self or parent reports, leading to a high diagnostic validity.
Interestingly, Sohn et al reported recently that individuals with
developmental disorders had higher odds of self-reported allergic
disease but not of allergic sensitization to foods or environmental
allergens.43 The fact that the diagnosis of all
diseases, allergic as well as ADHAD/ASD, in our study were made by
specialist physicians overcome such a confabulation. Finally, we
investigated the association between the presence of six allergic
disorders (together and each one separately), and the development of
ADHD or ASD (Tables 1, 2, 3, 4). Taken together, our study provides
solid evidence supporting the association between allergic disorders and
ADHD/ASD.
The results of our study have clinical applications for physicians who
take care of pediatrics patients. Treatment and reduction of sleep
disorders, stress, and all kind of physical discomforts in allergic
children, may (tough it is not proved) reduce the development of
neurobehavioral disorders such as ADHD and ASD. In addition, knowledge
of the link and the association between allergic disorders and the
development of ADHD or ASD will lead to early diagnosis and better
treatment of allergic children with neurobehavioral symptoms.
In conclusion, our study provides strong evidence for the association
between allergic disorders in early childhood and the development of
ADHD. The risk of those children to develop ASD was less significant.
ACKNOWLEDGMENTS:
The authors would like to express their appreciation to Ms. Ronit
Harris, Statistics Consultant, for her assistance in statistical
analysis of the data for this paper.
KEY MESSAGE:
Early and effective treatment of allergic disorders, including sleep
disorders, stress, and all types of physical discomforts found in
allergic children, may reduce the development of neurobehavioral
disorders such as ADHD and ASD.
REFERENCES
1. Gupta R, Sheikh A, Strachan DP, Anderson HR. Burden of allergic
disease in the UK: secondary analyses of national databases. Clin
Exp Allergy . 2004;34(4):520-526. doi:10.1111/j.1365-2222.2004.1935.x
2. Vickery BP, Chin S, Burks AW. Pathophysiology of food allergy.Pediatr Clin North Am . 2011;58(2):363-76, ix.
doi:10.1016/j.pcl.2011.02.012
3. Tzeng N-S, Chang H-A, Chung C-H, et al. Increased Risk of Psychiatric
Disorders in Allergic Diseases: A Nationwide, Population-Based, Cohort
Study. Front Psychiatry . 2018;9:133. doi:10.3389/fpsyt.2018.00133
4. Miyasaka M, Kajimura S, Nomura M. Biases in understanding attention
deficit hyperactivity disorder and autism spectrum disorder in japan.Front Psychol . 2018;9:244. doi:10.3389/fpsyg.2018.00244
5. Visser SN, Danielson ML, Bitsko RH, et al. Trends in the
parent-report of health care provider-diagnosed and medicated
attention-deficit/hyperactivity disorder: United States, 2003-2011.J Am Acad Child Adolesc Psychiatry . 2014;53(1):34-46.e2.
doi:10.1016/j.jaac.2013.09.001
6. Brook U, Boaz M. Attention deficit and learning disabilities
(ADHD/LD) among high school pupils in Holon (Israel). Patient Educ
Couns . 2005;58(2):164-167. doi:10.1016/j.pec.2004.07.012
7. Xu G, Strathearn L, Liu B, Bao W. Prevalence of Autism Spectrum
Disorder Among US Children and Adolescents, 2014-2016. JAMA .
2018;319(1):81-82. doi:10.1001/jama.2017.17812
8. Davidovitch M, Hemo B, Manning-Courtney P, Fombonne E. Prevalence and
incidence of autism spectrum disorder in an Israeli population. J
Autism Dev Disord . 2013;43(4):785-793. doi:10.1007/s10803-012-1611-z
9. Avni E, Ben-Itzchak E, Zachor DA. The presence of comorbid ADHD and
anxiety symptoms in autism spectrum disorder: clinical presentation and
predictors. Front Psychiatry . 2018;9:717.
doi:10.3389/fpsyt.2018.00717
10. Tylee DS, Sun J, Hess JL, et al. Genetic correlations among
psychiatric and immune-related phenotypes based on genome-wide
association data. Am J Med Genet B, Neuropsychiatr Genet .
2018;177(7):641-657. doi:10.1002/ajmg.b.32652
11. Marshall P. Attention deficit disorder and allergy: a neurochemical
model of the relation between the illnesses. Psychol Bull .
1989;106(3):434-446. doi:10.1037/0033-2909.106.3.434
12. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van
deaaa 1Water J. Elevated plasma cytokines in autism spectrum disorders
provide evidence of immune dysfunction and are associated with impaired
behavioral outcome. Brain Behav Immun . 2011;25(1):40-45.
doi:10.1016/j.bbi.2010.08.003
13. Theoharides TC, Tsilioni I, Patel AB, Doyle R. Atopic diseases and
inflammation of the brain in the pathogenesis of autism spectrum
disorders. Transl Psychiatry . 2016;6(6):e844.
doi:10.1038/tp.2016.77
14. Xu G, Snetselaar LG, Jing J, Liu B, Strathearn L, Bao W. Association
of food allergy and other allergic conditions with autism spectrum
disorder in children. JAMA Netw Open . 2018;1(2):e180279.
doi:10.1001/jamanetworkopen.2018.0279
15. Johansson EK, Ballardini N, Kull I, Bergström A, Wahlgren C-F.
Association between preschool eczema and medication for
attention-deficit/hyperactivity disorder in school age. Pediatr
Allergy Immunol . 2017;28(1):44-50. doi:10.1111/pai.12657
16. Schmitt J, Buske-Kirschbaum A, Tesch F, et al. Increased
attention-deficit/hyperactivity symptoms in atopic dermatitis are
associated with history of antihistamine use. Allergy .
2018;73(3):615-626. doi:10.1111/all.13326
17. Chen M-H, Su T-P, Chen Y-S, et al. Is atopy in early childhood a
risk factor for ADHD and ASD? a longitudinal study. J Psychosom
Res . 2014;77(4):316-321. doi:10.1016/j.jpsychores.2014.06.006
18. Bakkaloglu B, Anlar B, Anlar FY, et al. Atopic features in early
childhood autism. Eur J Paediatr Neurol . 2008;12(6):476-479.
doi:10.1016/j.ejpn.2007.12.008
19. Biederman J, Milberger S, Faraone SV, Guite J, Warburton R.
Associations between childhood asthma and ADHD: issues of psychiatric
comorbidity and familiality. J Am Acad Child Adolesc Psychiatry .
1994;33(6):842-848. doi:10.1097/00004583-199407000-00010
20. Mogensen N, Larsson H, Lundholm C, Almqvist C. Association between
childhood asthma and ADHD symptoms in adolescence–a prospective
population-based twin study. Allergy . 2011;66(9):1224-1230.
doi:10.1111/j.1398-9995.2011.02648.x
21. Schmitt J, Romanos M, Schmitt NM, Meurer M, Kirch W. Atopic eczema
and attention-deficit/hyperactivity disorder in a population-based
sample of children and adolescents. JAMA . 2009;301(7):724-726.
doi:10.1001/jama.2009.136
22. Chen M-H, Su T-P, Chen Y-S, et al. Comorbidity of allergic and
autoimmune diseases among patients with ADHD. J Atten Disord .
2017;21(3):219-227. doi:10.1177/1087054712474686
23. Hori D, Tsujiguchi H, Kambayashi Y, et al. The Association of Autism
Spectrum Disorders and Symptoms of Asthma, Allergic Rhinoconjunctivitis
and Eczema among Japanese Children Aged 3 - 6 Years. Health
(Irvine, Calif) . 2017;09(08):1235-1250. doi:10.4236/health.2017.98089
24. Tsai J-D, Chang S-N, Mou C-H, Sung F-C, Lue K-H. Association between
atopic diseases and attention-deficit/hyperactivity disorder in
childhood: a population-based case-control study. Ann Epidemiol .
2013;23(4):185-188. doi:10.1016/j.annepidem.2012.12.015
25. Akpınar F, Kutluk G, Özomay G, Yorbik Ö, Çetinkaya F. Frequencies of
Allergic Diseases Among Children with Autism Spectrum Disorders.Asthma Allergy Immunol . Published online January 5, 2019.
doi:10.21911/aai.170
26. Schans J van der, Çiçek R, de Vries TW, Hak E, Hoekstra PJ.
Association of atopic diseases and attention-deficit/hyperactivity
disorder: A systematic review and meta-analyses. Neurosci Biobehav
Rev . 2017;74(Pt A):139-148. doi:10.1016/j.neubiorev.2017.01.011
27. Doernberg E, Hollander E. Neurodevelopmental Disorders (ASD and
ADHD): DSM-5, ICD-10, and ICD-11. CNS Spectr . 2016;21(4):295-299.
doi:10.1017/S1092852916000262
28. Lee C-Y, Chen M-H, Jeng M-J, et al. Longitudinal association between
early atopic dermatitis and subsequent attention-deficit or autistic
disorder: A population-based case-control study. Medicine .
2016;95(39):e5005. doi:10.1097/MD.0000000000005005
29. Jónsdóttir U, Lang JE. How does autism spectrum disorder affect the
risk and severity of childhood asthma? Ann Allergy Asthma
Immunol . 2017;118(5):570-576. doi:10.1016/j.anai.2017.02.020
30. Genuneit J, Braig S, Brandt S, et al. Infant atopic eczema and
subsequent attention-deficit/hyperactivity disorder–a prospective
birth cohort study. Pediatr Allergy Immunol . 2014;25(1):51-56.
doi:10.1111/pai.12152
31. Atefi N, Rohaninasab M, Shooshtari M, et al. The Association between
Attention-Deficit/Hyperactivity Disorder and Atopic Dermatitis: A Study
among Iranian Children. Indian J Dermatol . 2019;64(6):451-455.
doi:10.4103/ijd.IJD_458_18
32. Liao T-C, Lien Y-T, Wang S, Huang S-L, Chen C-Y. Comorbidity of
Atopic Disorders with Autism Spectrum Disorder and Attention
Deficit/Hyperactivity Disorder. J Pediatr . 2016;171:248-255.
doi:10.1016/j.jpeds.2015.12.063
33. Nygaard U, Riis JL, Deleuran M, Vestergaard C.
Attention-Deficit/Hyperactivity Disorder in Atopic Dermatitis: An
Appraisal of the Current Literature. Pediatr Allergy Immunol
Pulmonol . 2016;29(4):181-188. doi:10.1089/ped.2016.0705
34. van der Schans J, Cao Q, Bos EH, et al. The temporal order of
fluctuations in atopic disease symptoms and
attention-deficit/hyperactivity disorder symptoms: a time-series study
in ADHD patients. Eur Child Adolesc Psychiatry .
2020;29(2):137-144. doi:10.1007/s00787-019-01336-2
35. Chang HY, Seo J-H, Kim HY, et al. Allergic diseases in preschoolers
are associated with psychological and behavioural problems.Allergy Asthma Immunol Res . 2013;5(5):315-321.
doi:10.4168/aair.2013.5.5.315
36. Croen LA, Qian Y, Ashwood P, et al. Family history of immune
conditions and autism spectrum and developmental disorders: Findings
from the study to explore early development. Autism Res .
2019;12(1):123-135. doi:10.1002/aur.1979
37. Dai Y-X, Tai Y-H, Chang Y-T, Chen T-J, Chen M-H. Increased Risk of
Atopic Diseases in the Siblings of Patients with Autism Spectrum
Disorder: A Nationwide Population-Based Cohort Study. J Autism Dev
Disord . 2019;49(11):4626-4633. doi:10.1007/s10803-019-04184-w
38. Solberg BS, Zayats T, Posserud M-B, et al. Patterns of Psychiatric
Comorbidity and Genetic Correlations Provide New Insights Into
Differences Between Attention-Deficit/Hyperactivity Disorder and Autism
Spectrum Disorder. Biol Psychiatry . 2019;86(8):587-598.
doi:10.1016/j.biopsych.2019.04.021
39. Banerjee E, Nandagopal K. Does serotonin deficit mediate
susceptibility to ADHD? Neurochem Int . 2015;82:52-68.
doi:10.1016/j.neuint.2015.02.001
40. Abdulamir HA, Abdul-Rasheed OF, Abdulghani EA. Serotonin and
serotonin transporter levels in autistic children. Saudi Med J .
2018;39(5):487-494. doi:10.15537/smj.2018.5.21751
41. Pelsser LMJ, Buitelaar JK, Savelkoul HFJ. ADHD as a (non) allergic
hypersensitivity disorder: a hypothesis. Pediatr Allergy Immunol .
2009;20(2):107-112. doi:10.1111/j.1399-3038.2008.00749.x
42. Kalkman HO, Feuerbach D. Microglia M2A Polarization as Potential
Link between Food Allergy and Autism Spectrum Disorders.Pharmaceuticals (Basel) . 2017;10(4). doi:10.3390/ph10040095
43. Sohn JK, Keet CA, McGowan EC. Association between allergic disease
and developmental disorders in the National Health and Nutrition
Examination Survey. J Allergy Clin Immunol Pract .
2019;7(7):2481-2483.e1. doi:10.1016/j.jaip.2019.04.013
LEGEND TO FIGURE 1
The risk to develop ADHD (A), ASD (B) or both ADHD and ASD (C) in
non-allergic patients (0 allergic comorbidities) was defined as 1.
Concomitantly with the number of allergic comorbidities per patient
(from 1 to 6), the OR to develop ADHD (A) or ADHD and ASD (C) also
increased significantly. The number of allergic comorbidities per
patient did not reveal significant effect on the risk to develop ASD
(B). Allergic comorbidities per Table 1 (Asthma, rhinitis,
conjunctivitis, skin, food and drug allergy).