What Is The Impact of Atopic Diseases On Symptoms Dimension of Attention-Deficit/Hyperactivity Disorder: A Systematic Review And Meta-Analysis

doi:10.21203/rs.3.rs-753342/v1

Studies in the field of neuroscience and psychology have hypothesized that a causal association exists between atopic diseases and attention-deficit/hyperactivity disorder (ADHD). Previous systematic reviews and meta-analyses have reported a higher risk of ADHD in children with atopic diseases; however, the relationship between ADHD symptoms and atopic diseases remains unclear. We systematically reviewed observational cross-sectional and longitudinal studies to investigate the relationship between atopic diseases and ADHD symptom severity (hyperactivity/impulsivity and inattention). The majority of studies showed a statistically significant association between atopic diseases and both ADHD symptoms, with substantial heterogeneity in the outcome of hyperactivity/impulsivity. Inconsistent results were observed in the subgroup analysis of different exclusion criteria for patients with ADHD. Our study indicated that atopic diseases not only increase the risk of ADHD but also are associated with ADHD symptom severity. This association was even observed in children with subthreshold ADHD, indicating that atopic diseases play a role in the spectrum of ADHD symptom severity.

Trial registration: This study was registered on PROSPERO (registration ID: CRD42020213219).

Immunology

Psychology

neuroscience

psychology

hypothesized

longitudinal

In the past decade, atopic diseases have been a cause of increased concern because of their substantially high prevalence(approximately 20–40%) worldwideThe International Study of Asthma and Allergies in Childhood Steering Committee, ¹, with more prominent increasing trend in developing countries². Atopic march, defined as the development of atopic dermatitis in infancy and subsequent allergic rhinitis and asthma in later childhood, can cause fatigue; attention, learning, and memory deficits; and depression. Moreover, atopic diseases have been reported to considerably affect children’s sleep, school performance, development, and quality of life ³; ⁴. In addition, recent studies have reported that the parents or main caregivers of children with atopic diseases, particularly those with multiple atopic diseases, experience considerable stress and psychosocial burden^4–8 Thus, increasing public attention has been focused on the management of atopic diseases⁸.

Attention-deficit/hyperactivity disorder (ADHD) is among the most common neuropsychiatric disorders in children and adolescents, with a prevalence of approximately 5%. ADHD is characterized by hyperactivity, impulsivity, and inattention that lead to not only functional impairment but also executive function impairment and emotional dysregulation ^9,10. ADHD can be caused by multiple factors (e.g., genetic, epigenetic, and environmental). Moreover, studies have indicated that ADHD occurs due to immature brain development, and it may also be accompanied by other neurobehavioral developmental delays and even intellectual disability ^10,11. Many studies have reported that ADHD symptoms were still observed in adulthood in a majority of patients with ADHD, even in those with adult ADHD who did not meet the criteria for ADHD in their childhood ^12–14. Adult patients with ADHD experience a financial burden and may even require considerable support ¹⁴. These findings indicate that ADHD is a matter of considerable concern in child and adolescent psychiatry.

A previous study investigated the relationship between atopic diseases and ADHD ¹⁵. A higher risk of ADHD was noted in patients with all three atopic diseases, namely atopic dermatitis, asthma, and atopic rhinitis (i.e., atopic march) ^16,17. In addition, children with both atopic diseases and ADHD had an increased risk of developing more severe ADHD symptoms compared with those with only ADHD ¹⁸. Although several meta-analyses and systematic reviews have strongly supported the relationship between atopic diseases and ADHD ^17,19−21, they still had many limitations. The heterogeneity observed in some systematic reviews might have affected their findings; for instance, some reviews did not include studies with standard inclusion and exclusion criteria, and whether the atopic and control groups included patients diagnosed as having ADHD remained unclear ^16,19. In addition, few studies have reported a relationship between atopic diseases and subthreshold ADHD. Moreover, no systematic review and meta-analysis has examined whether atopic diseases affect the severity of both hyperactivity/impulsivity and inattention—the two main symptoms and diagnostic criteria related to ADHD.

In this systematic review and meta-analysis, we reviewed studies examining the relationship between atopic diseases and the severity of ADHD symptoms including hyperactivity/impulsivity and inattention. In addition, we explored more precise value of this relationship by defining inclusion and exclusion criteria for groups. By doing so, we could exclude some confounding effects and provide additional information regarding the relationship between atopic diseases and subthreshold ADHD; this involved examining the data of children without a previous diagnosis of ADHD but who had a risk of developing more severe ADHD symptoms.

Search results

Through our literature search, we identified 2406 studies (753, 1620, and 33 from PubMed, Embase, and Cochrane Library, respectively). Five additional studies were identified through other sources. Using EndNote, we found that 405 studies were duplicates and we thus excluded them. Subsequently, we screened the titles and eligibility of the remaining 2006 studies. During title screening, we removed 727 studies because they were not relevant to our research. During abstract screening, from the remaining 1279 studies, we removed 673 because of their nonrelevance. Additionally, we excluded 70 studies because they were not original research. Moreover, 393 and seventeen studies were excluded because they did not include a relevant control group and were letters or replies, respectively. Subsequently, after reviewing the full texts of the remaining 126 studies, we excluded 100 studies, 23 of which had double or serial publications, 46 had missing data, and 32 were not case–control, cross-sectional, or cohort studies. Finally, we included the remaining 25 studies in this systematic review for qualitative synthesis, and 12 of them were included in the quantitative review and meta-analysis. The procedure for study inclusion is shown in Appendix A in the Supplementary Materials.

Qualitative systematic review

In 25 studies including 58,253,734 participants, the researchers examined the relationship between atopic diseases and ADHD symptom severity by displaying prevalence of ADHD in patients with atopy, odds ratios(OR) of ADD/ADHD in children with atopy, or calculating scores for hyperactivity/impulsivity, inattention, or total ADHD symptoms. Table 1 lists the characteristics of included studies. Most of the studies assessed atopic diseases by using parental questionnaires or based on their diagnosis by physicians or dermatologists according to specific diagnostic criteria, including the Global Initiative for Asthma guidelines, Allergic Rhinitis and its Impact on Asthma guidelines, and UK Working Party criteria. Seven study groups ²²; ^23,24 conducted an advanced additional test for atopy such as the skin-prick test and blood sampling for serum-specific IgE (MAST or Phadiatop tests). The included studies used different outcome scales including the Conners’ Parent Rating Scale; ADHD Rating Scale; Swanson, Nolan, and Pelham IV Scale; Child Behavior Checklist, Early Childhood Inventory-4, the German ADHD Rating scale (FBB-HKS), and the Strengths and Difficulties Questionnaire (SDQ). Despite the variability in outcome scales, most scales were designed on the basis of the DSM-IV criteria. Four studies ^25–28 adopted the SDQ, which is not derived from the DSM-IV criteria; however, the SDQ has been reported to be relevant to the DSM-IV ^29,30, He et al. 2013, ³¹. Most of the studies investigated the effect of confounding factors, including age, sex, multiple atopic diseases, the comorbidity with ADHD, severity of atopic diseases, persistent atopic diseases, and stressful parenting. Twelve of the thirteen studies examining the outcome of total ADHD symptoms reported a significant relationship between the severity of ADHD symptoms and atopic diseases. Furthermore, 8 of the 14 studies examining the outcome of hyperactivity and 11 of the 13 studies examining the outcome of inattention demonstrated a significant relationship between the severity of the examined ADHD symptoms and atopic diseases.

Two of the three studies reported a significant association between the comorbidity of ADHD and atopic diseases in patients with ADHD. Ten studies reported a significantly positive correlation among atopic diseases, sleep disturbance, and ADHD or an increased risk of ADHD in children with atopic diseases. One research group ³² performed structural equation modeling to determine interactions among eczema, asthma, rhinitis, sleep, and behavior disorders. In three studies, the computerized comprehensive attention test (CAT) was performed, a more objective and precise measurement tool, to assess attention deficit, and they obtained results similar to those of other studies, thus supporting our hypothesis that atopy increased ADHD symptoms severity. In addition, seven studies examined treatment modalities for atopic diseases; however, additional randomized controlled trials are required to obtain more consistent results and causal relationships. The included studies evaluated several confounding factors such as age, sex, and atopic disease severity. Additional detailed information is provided in Table S1 in the Supplementary Materials.

Quantitative review and meta-analysis of longitudinal studies

Twelve studies including 20,928 participants examined the relationship between at least one type of atopic disease and the severity of ADHD symptoms, either hyperactivity/impulsivity or inattention, by including control groups consisting of participants without atopic diseases. Table 2 lists the characteristics of included studies. Of the included studies, two were case–control studies and the remaining were cross-sectional studies.

Overview of total ADHD symptoms through a meta-analysis

In terms of the outcome of total ADHD symptoms, the overall effect exhibited a statistically significant association with a 95% CI of 0.26–0.53 (Fig. 1a). We observed considerable heterogeneity among subgroups with an I² value of 92.8%. The funnel plot displayed no asymmetry (p > 0.05; Fig. 1b).

Overview of hyperactivity/impulsivity through a meta-analysis

In terms of the outcome of hyperactivity/impulsivity, the overall effect showed a statistically significant association with atopic diseases (95% CI: 0.23–0.79; Fig. 1c). Substantial to considerable heterogeneity was noted (I² value: 86%). The funnel plot (Fig. 1d) and Egger’s test (Figure S1; p = 0.15) showed no significant publication bias.

Overview of inattention through a meta-analysis

The overall effect of the outcome of inattention showed a significant and positive correlation with atopic diseases (95% CI: 0.3–0.75; Fig. 1e). Different from the outcome of hyperactivity/impulsivity, substantial heterogeneity (I² = 68%) was observed for the outcome of inattention. The funnel plot (Fig. 1f) and Egger’s test (Figure S2; p = 0.79) showed no statistically significant publication bias.

Atopic group and a healthy control group

Two of the studies included an atopic group and a healthy control group to examine total ADHD symptoms, hyperactivity/impulsivity, and inattention. Both studies reported a significant and positive correlation between atopy and severity of total ADHD symptoms, hyperactivity/impulsivity, and inattention, with 95% CIs of 0.57–0.89 (Fig. 2a), 0.55–1.65 (Fig. 2b), and 0.23–1.14 (Fig. 2c), respectively.

Atopic group and a nonatopic control group

Six, three, and two studies included an atopic group and a nonatopic control group to examine the outcome of total ADHD symptoms, hyperactivity/impulsivity, and inattention, respectively. Six studies investigating ADHD symptoms showed a statistically significant association, with a 95% CI of 0.09–0.41 (Fig. 2a). Three and two studies focusing on hyperactivity/impulsivity and inattention demonstrated no statistically significant correlation with atopic diseases, with a 95% CI of − 0.3–0.84 (Fig. 2b) and − 4.53–5.56, respectively, with considerable heterogeneity (I² = 92%; Fig. 2c).

Pure atopic group with a healthy control group

Four studies included a pure atopic group and a healthy control group to examine the outcomes of total ADHD symptoms, hyperactivity/impulsivity, and inattention. Four studies investigating total ADHD symptoms, hyperactivity/impulsivity, and inattention exhibited a statistically significant association, with 95% CIs of 0.06–0.57 (Fig. 2a), 0.11–0.68 (Fig. 2b), and 0.13–0.73 (Fig. 2c).

Subgroup analysis of different types of atopic diseases

A total of six, five, and three studies examined the association between total ADHD symptoms and atopic dermatitis, allergic rhinitis, and asthma, respectively. Furthermore, four, five, and two studies evaluated the association between hyperactivity/impulsivity and dermatitis, allergic rhinitis, and asthma, respectively. Three, five, and two studies examined the association between inattention and atopic dermatitis, allergic rhinitis, and asthma, respectively.

A significant association was observed between atopic dermatitis and total ADHD symptoms and hyperactivity/impulsivity, with low to moderate heterogeneity (I² = 0–59%; Fig. 3a). A significant association was noted between allergic rhinitis and total ADHD symptoms, hyperactivity/impulsivity, and inattention, with moderate to substantial heterogeneity (I² = 59–91%; Fig. 3b). Furthermore, a significant association was observed between asthma and only total ADHD symptoms, with low to substantial heterogeneity (I² = 0–68%; Fig. 3c).

We observed decreased heterogeneity among subgroups categorized according to their exclusion criteria related to a previous ADHD diagnosis. However, in subgroups were categorized according to the types of atopic diseases, only the atopic dermatitis subgroup showed low to moderate heterogeneity for the outcome of hyperactivity/impulsivity and inattention (I² = 0–59%), whereas allergic rhinitis and asthma subgroups both showed low to considerable heterogeneity. In terms of the study design, low to substantial heterogeneity was observed in case–control studies (I² = 0%– 72%); however, higher heterogeneity than that in the overall meta-analysis was observed in cross-sectional studies (I² = 77%– 96%) for all outcomes (Appendices E–G).

The results of our study indicated that atopic diseases were related to not only increased odds of ADHD but also the severity of ADHD symptoms. Total ADHD symptoms, hyperactivity/impulsivity, and inattention were all significantly associated with atopic diseases. The results of the subgroup analysis indicated that children with subthreshold ADHD in the atopic disease groups had increased severity of ADHD symptoms, including total ADHD symptoms, hyperactivity/impulsivity, and inattention, and atopic dermatitis and allergic rhinitis were significantly associated with ADHD symptoms.

Although we included a small number of studies, these studies in total included more than 20,000 participants. In addition, this is the first systematic review and meta-analysis to investigate not only the association of atopic diseases with the severity of ADHD symptoms but also the presentation of ADHD symptoms in children with atopic diseases with normal development. The results of both the qualitative systematic review and meta-analysis tended to demonstrate higher severity of total ADHD symptoms and inattention in participants with atopic diseases, and the meta-analysis showed a significant association between atopic diseases and hyperactivity-impulsivity severity although qualitative synthesis showed relatively inconsistent outcome. Three studies that adopted the computerized CAT to assess attention deficits also demonstrated similar results, thus supporting our hypothesis. However, our qualitative systematic review and meta-analysis exhibited inconsistency in outcomes and considerable heterogeneity.

We divided studies into the following subgroups based on their inclusion and exclusion criteria: atopic group and a healthy control group, atopic group and a nonatopic control group, pure atopic group and a healthy control group. These three subgroups exhibited distinct results in terms of the association between atopic diseases and the severity of total ADHD symptoms, hyperactivity/impulsivity, and inattention. The subgroups of “atopic group and a healthy control group” and “pure atopic group and healthy control group” showed a significant association between atopic diseases and the severity of total ADHD symptoms, hyperactivity/impulsivity, and inattention. However, the subgroup “atopic group and a nonatopic control group” showed a significant association between atopic diseases and only total ADHD symptoms, with low to considerable heterogeneity, despite the inclusion of a small number of studies (I² = 45–92%). The subgroup analysis of different types of atopic diseases showed that atopic dermatitis was significantly and positively correlated with the severity of total ADHD symptoms and hyperactivity/impulsivity, with low to moderate heterogeneity (I² = 0–59%). Allergic rhinitis was significantly associated with the severity of total ADHD symptoms, hyperactivity/impulsivity, and inattention, with moderate to considerable heterogeneity (I² = 59–91%). Asthma was significantly associated only with the severity of total ADHD symptoms, with low to substantial heterogeneity (I² = 0–68%).

This inconsistency in heterogeneity can be attributed to differences in participants’ sex and mean age and the inclusion and exclusion criteria of related studies. A previous study reported a higher male to female ratio for hyperactivity but an equal male to female ratio for inattention ³³. This study also indicated that the distribution of sex differences within the severity of symptoms varied between children without ADHD and children with ADHD. The differences in the clinical course of participants can also result in these inconsistencies. Hyperactivity/impulsivity is usually observed from 4 years of age, peaks in severity at approximately 7 to 8 years, and then declines later, whereas inattention is not apparent until 8–9 years of age ³⁴. In this study, we observed a significantly decreased heterogeneity in the subgroups “atopic group and a healthy control group” and “pure atopic group and a healthy control group,” indicating that inconsistent inclusion and exclusion criteria for ADHD may have been the source of heterogeneity in our study. Moreover, the lack of standard inclusion and exclusion criteria for not only ADHD but also other neuropsychiatric disorders or developmental delays in studies from which the subgroup “atopic group and a nonatopic control group” were formed may be responsible for the high heterogeneity in our study (other subgroups had strictly defined exclusion criteria for confounding factors). Furthermore, our results suggested that children with atopic diseases but without developmental disorders had a higher risk of more severe ADHD symptoms than did control groups, indicating a more consistent result for inattention than hyperactivity/impulsivity. The subgroup “pure atopic group and a healthy control group,” which included both atopic and control groups and excluded patients with ADHD, showed a statistically significant association between atopic diseases and the severity of both hyperactivity/impulsivity and inattention. This result suggested that children with subthreshold ADHD and atopic diseases still had an increased severity of ADHD symptoms. The subgroup “atopic group and a healthy control group,” which consisted of an atopic group including patients with ADHD and a control group excluding patients with ADHD, had similar results to the aforementioned subgroup.

We also observed low to considerable heterogeneity in the subgroup analysis of different types of atopic diseases. Asthma had a significant association only with the severity of total ADHD symptoms. Considering that previous studies have reported that children with asthma had an increased risk of developing severe ADHD symptoms ^18,21,35, this result may be attributed to the small number of included studies (n = 3). The results of the subgroup analysis of different types of atopic diseases indicated that all atopic diseases were significantly associated with the severity of total ADHD symptoms; however, inconsistent heterogeneity was observed in the association between atopic diseases and the severity of hyperactivity/impulsivity and inattention. These findings suggest that different types of atopic diseases may have distinct interactions with ADHD symptoms, although our results demonstrated that any type of atopic disease was associated with the severity of ADHD symptoms.

Although the causal relationship and mechanism underlying the association between atopic diseases and ADHD remain unclear, many studies have provided several hypotheses ³⁶) (Figure S6). One of the more commonly accepted hypotheses is that atopic diseases induce inflammation, including Th1, Th2, and Th17 immune responses, which lead to the downstream hypersecretion of IgE ^37–39 (Figure S7). These inflammatory factors may affect the neuroactivity of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) that have been reported to be strongly associated with ADHD pathology ^40–42. This process affects the maturation of the PFC and ACC, which usually occurs in early life when the brain is undergoing profound changes and is important for the development of cognitive function ⁴³. In addition to the direct effect, cytokines may indirectly affect these brain areas by disturbing the hypothalamic–pituitary–adrenal axis (HPA) axis ⁴⁴, altering the central metabolism of neurotransmitters including norepinephrine and dopamine ^41,45 .

In addition to neuroimmunological pathways, psychological mechanisms should also be considered. Atopic diseases cause psychological stress in not only patients but also their main caregivers since early childhood when the onset of atopic diseases occurs ^46,47. An unsatisfactory parent–child relationship characterized by overprotection, anxiety, low support, and poor sleep quality can lead to a decline in psychosocial and cognitive performance due to tiredness; emotional problems were reported to be associated with negative outcomes in a previous study ⁴⁸. Although the relationship between these effects and brain development in early life has not yet been well studied, stress in early childhood is believed to affect the balance between neurotransmitters and neuroendocrine systems, including norepinephrine, dopamine, and the HPA axis ^44,49. This eventually resulted in increased vulnerability to psychological diseases, such as ADHD, because of altered neuropsychologic pathways leading to unsuccessful brain development and maturation ⁵⁰.

An increased risk of the development and progression of atopic diseases was observed in children with ADHD because atopic diseases are attributed to stress ⁵¹. Although these mechanisms were obscure, studies have found that stress may induce deficits in skin barriers, and a similar inflammatory cascade with atopy-associated immune responses was observed in patients with atopic diseases; some patients exhibited an increased tendency to exhibit Th1 responses ⁵². These findings indicate that stress can exacerbate atopic diseases. ADHD was reported to be related to psychosocial stress because poor family support, school performance, and peer relationships can all be the sources of stress ⁵³. Therefore, ADHD-related stress can exacerbate atopic diseases. Recently, genetic factors and prenatal stress have been indicated as common risk factors for atopic diseases and ADHD. Although few studies have evaluated genetic susceptibility and other associated interaction factors leading to epigenetic reactions ^54,55, a twin study supported the hypothesis that common genetic factors between atopy and ADHD exist ⁵⁶. Moreover, studies reporting a relationship between maternal stress and symptoms of atopic diseases and ADHD have indicated that dysregulation of the HPA axis results in delayed brain development and a shift in Th1/Th2 balance, resulting in an atopic disease–prone immune profile ^57,58.

Previous systematic reviews and meta-analyses had discussed about increased risk of diagnosed ADHD in atopic group; however, the evidence of whether atopic diseases associated with increased severity of ADHD symptoms in participants with subthreshold ADHD remained unclear. This association could be observed in the subgroup “pure atopic group and a healthy control group” in the present study, provided an evidence that atopic diseases are associated with “spectrum of ADHD symptom severity”, the term which we quoted following a previous study to explain how atopic diseases affect ADHD symptoms⁵⁹, and this association existed in subthreshold ADHD group in our result as well.

This study has several limitations that should be considered. First, although more than 20,000 participants were included, the outcome of inattention was examined in only 1593 participants, which may reduce the strength of evidence. Second, Atopic diseases were diagnosed based on physicians’ decisions or by using some questionnaires in the included studies; these might have caused heterogeneity. Third, we chose to combine scores of hyperactivity/impulsivity and inattention as the primary outcome, and this method has been used in several studies ⁶⁰. However, potential systematic errors may still occur. Finally, differences in exclusion criteria, including the exclusion of patients with ADHD and other neuropsychiatric disorders and development problems, caused significant heterogeneity in our study.

To minimize the effect of those limitations, we conducted subgroup analyses to assess the effects of potential confounding factors, namely different types of atopic diseases, exclusion criteria, and study design; this considerably reduced heterogeneity in most subgroup analyses, except in the subgroup analysis of different study designs. Therefore, standardized and more strictly defined exclusion and inclusion criteria should be included in future studies. Moreover, additional studies investigating the relationship between different types of atopic diseases and ADHD symptoms should be conducted because we could not conduct a complete subgroup analysis of different atopic diseases owing to the limited number of studies.

Our study results indicated that atopic diseases not only increased the odds of ADHD but also were associated with more severe ADHD symptoms. We observed increased severity of ADHD symptoms in children with atopic diseases with normal development after the exclusion of participants with previously diagnosed ADHD, indicating that atopic diseases may also associated with spectrum of ADHD symptom severity in participants with subthreshold ADHD, which was never been investigated in previous researches. According to the results of this study, while treating children with ADHD, clinicians should consider the possibility of comorbid atopic diseases. However, the comorbidity of ADHD should be considered when treating children with atopic diseases. Moreover, clinicians should be aware of the increased severity of ADHD symptoms in children with atopic diseases. Additional studies including more strictly defined criteria, studies investigating the mechanism underlying this association, and randomized controlled trials of related therapeutic strategies should be conducted.

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ⁶¹. Related checklists are provided in the Supplementary Materials. Two researchers searched for and pooled longitudinal studies examining atopic diseases and ADHD symptom severity to examine the association between them.

Eligibility criteria for study selection

To reduce selection bias, we defined eligibility criteria before the inclusion of studies. We included the following studies: (1) observational studies investigating the association between one of the three major types of atopic diseases (i.e., asthma, eczema, and allergic rhinitis) and the severity of ADHD symptoms, irrespective of whether they included patients with ADHD in the experimental group; (2) studies recruiting children and adolescents; (3) studies including any of the three atopic diseases as the exposure variable and ADHD symptom severity (scores of a behavior rating scale) as the outcome variable; (4) studies investigating the severity of ADHD symptoms in patients with at least one type of atopic disease by using any type of assessment method; (5) studies including a matched or an unmatched control group for comparison with the exposed group; and (6) cross-sectional, case–control, or cohort studies. The following studies were excluded: (1) studies that did not provide adequate information regarding the relationship between atopic diseases and ADHD symptom severity, including the crude data of exposed cases and the outcome of the association between at least one type of atopic disease and the severity of hyperactivity/impulsivity, inattention, and/or total ADHD symptoms (hyperactivity/impulsivity + inattention) determined on the basis of the scores of a behavior rating scale; (2) studies including only outcomes measured after interventions or those not including a separate outcome of total ADHD symptoms, hyperactivity/impulsivity, and inattention; (3) studies using the same database in different published articles (studies with longer follow-up periods and higher quality, which were classified as included(see ‘Table S2 in the Supplementary Materials’) were included); and (4) studies whose full texts were not available or those for which only abstracts or editorial materials (i.e., comments, responses, and letters without original data) were available.

Search strategy and study selection

Two authors performed a literature search on PubMed, Embase, and Cochrane Library for studies published up to January 27, 2021. The following search terms were combined and adjusted to fulfill the demand of the database.

“Atopic eczema” [MeSH] OR “atopic dermatitis” [MeSH] OR “asthma” [MeSH] OR “allergic rhinitis” [MeSH]
“Psychiatric disorder” [MeSH] OR “ADHD” [MeSH] OR “attention deficit and hyperactivity disorder” [MeSH] OR “hyperactivity” [MeSH] OR “inattention” [MeSH] OR “mental health” [MeSH] OR “behavior problem” [MeSH]
“Preschool children” OR “preschooler” OR “children” OR “adolescent” OR “toddler”

A three-step screening strategy was adopted. In the title screening step, studies that met the inclusion criteria and were not letters or replies were included. In the abstract screening step, studies that were original research and included relevant control groups were included. In the full-text screening step, studies for which full texts and data were available and those that did not meet the exclusion criteria were finally included. A third author resolved any disagreement between the two authors in terms of the eligibility and inclusion of studies through discussion.

Data extraction

By using a customized data form, the first author extracted the following information from eligible studies: study title, study design, study characteristics (country, composition of participants, and outcome assessment scales used), and assessment methods and criteria for diagnosing atopic diseases and ADHD. Subsequently, the second author reviewed the extracted data. Any disagreement regarding data extraction was resolved by the third author through discussion. If required, data were calculated from the available data of included studies (see ‘Data abstraction for the meta-analysis’). The main outcome variables were the scores of the behavior rating scales used to evaluate hyperactivity/impulsivity and inattention in the atopic disease and control groups. Although the included studies used different outcome scales, they were all based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria. In addition, to minimize the potential confounding effects, we analyzed standardized data. Because of the limited availability of studies, we combined the three types of atopic diseases in the meta-analysis and conducted a subgroup analysis. The authors individually recorded abstracted data in Microsoft Excel.

Data abstraction for the meta-analysis

The relationship between one of the three main types of atopic diseases with the severity of hyperactivity/impulsivity, inattention, or total ADHD symptoms was independently investigated. To exclude confounding factors, any study including outcomes measured after interventions were excluded. For each study, the relative weight of outcome data to the whole data set was calculated using the generic inverse variance method along with the 95% confidence interval (95% CI) by using Rstudio software, Version 1.2.5042Rstudio ⁶². The random effects model with the Hartung–Knapp–Sidik–Jonkman method was used to determine the estimated variance for pooling effect sizes in our meta-analysis. The I² value was calculated to assess statistical heterogeneity, and this value represents the total variance of pooled data explained by the heterogeneity. According to the Cochrane handbook for systematic reviews of interventions, the I² values of 0–40%, 30–60%, 50–90%, and 75–100% indicated low, moderate, substantial, and considerable heterogeneity ⁶³. We used a funnel plot to assess the potential publication bias.

For the outcome “severity of total ADHD symptoms,” we combined data on the “severity of hyperactivity/impulsivity” and “severity of inattention” from several studies to measure total ADHD symptoms and conducted a multistep calculation: we obtained the average of the mean scores of hyperactivity/impulsivity and inattention as a combined mean and divided it by the mean scores of hyperactivity/impulsivity or inattention reported in each study. Subsequently, we multiplied the data with the original standard deviation of the scores of hyperactivity/impulsivity or inattention to obtain the combined standard deviation.

For studies including a subgroup analysis, we pooled effect sizes two times. First, we combined subgroups within studies to pool effect sizes and calculated 95% CIs and standard errors. Subsequently, we included the calculated standard errors into our meta-analysis and pooled effect sizes a second time.

Sensitivity analysis

To assess the strength of the association between atopic diseases and ADHD in different scenarios, we performed a subgroup analysis by using a mixed-effects model. We divided included studies into groups based on their study design, exclusion criteria for previous ADHD diagnosis, and atopic disease types to perform the subgroup analysis. Detailed information on the risk of bias assessment could be found in Table S2 in the Supplementary Materials

Subgroup analysis of exclusion criteria for those with a previous ADHD diagnosis

We categorized studies into groups based on whether their experimental or control group included children with ADHD. Theoretically, this categorization would yield four groups: experimental and control groups both including children with ADHD, an experimental group excluding children with ADHD and a control group including children with ADHD, an experimental group including children with ADHD and a control group excluding children with ADHD, and experimental and control groups both excluding children with ADHD. However, none of the included studies had a design wherein the experimental group excluded children with ADHD and the control group included children with ADHD. Thus, we included only the remaining three subgroups. To easily explain the outcome, we named the experimental groups including and excluding children with ADHD as the atopic and pure atopic groups, respectively, and the control group including or excluding ADHD were named the nonatopic or healthy control groups, respectively.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they no conflicts of interest with respect to this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

We would like to acknowledge Yi-No Kang for his help and useful suggestions related to statistical measurements. This manuscript was edited by Wallace Academic Editing.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

Conceived and designed the experiments: Yu-chieh Chuang, Yu-Jui Huang, Yang-Ching Chen
Analyzed the data: Yu-Chieh Chuang, Liang-Jen Wang, Yang-Ching Chen
Wrote the paper: Yu-Chieh Chuang, Yu-Jui Huang, Wei-Lieh Huang
Data acquisition, analysis and interpretation; manuscript drafting, editing and submission: Wei-Lieh Huang, Ching-Yun, Wang, Ho-Chang Kuo
Abstracts review, evaluation of inclusion criteria and bias analysis: Wei-Lieh Huang, Ching-Yun, Wang, Ho-Chang Kuo

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Table 1 Studies examining the relationship between atopic diseases and hyperactivity in the qualitative analysis.

Study name	Outcome (95% CI)	Study design	Country/City	Ethnicity	Number of participants/ experimental group/control group	Age (mean of the experimental group)/sex (male, %)	Diagnostic criteria for ADHD	Atopic disease/method used for assessing atopic diseases	Adjustment for confounding factors
Yuksel et al., 2008⁶⁴	Continuous data for HI and IN*	Cross-sectional	Manisa, 45020 Turkey	Not reported	100/62/38	7–12 years (9.2)/57%	DSM-IV	Asthma/Physician’s diagnosis (GINA 2006)	No
Camfferman et al., 2010³²	Continuous data for HI* and total ADHD symptoms*	Cross-sectional	South Australia, Australia	Not reported	107/77/30	6–16 years (9.9)/46.72%	Conner’s Parent Rating Scale-Revised	Atopic dermatitis/ Physician’s diagnosis (Hanifin and Rajka criteria)	Yes
Chang et al., 2013⁶⁵	Continuous data for HI and IN	Cross-sectional	Seoul and Ilsan and Gwacheon in Gyeonggi-do province in Korea	Not reported	575	3–7 years (4.8)/ 51.3%	CBCL	Atopic dermatitis, allergic rhinitis, and asthma/Physician’s diagnosis and questionnaire (ISAAC questionnaire and SCORAD index)	No
Goodwin et al., 2013⁶⁶	OR of ADHD in children with asthma(different grades of severity [moderate]/persistent [remission* and late onset*])	Cohort	Perth, Western Australia	Not reported	2193/390/ 1803	5, 8, 10, 14, and 17 years/ 62.56%	CBCL	Asthma/Physician’s diagnosis (Australian Asthma Handbook)	Yes
Kim et al., 2014²⁴	Continuous data for impulsivity and inattention (divided attention task*)	Cohort	Korea	Not reported	1036/797/239	3–16 years (11.4)/ 69.88%	Computerized comprehensive attention test	Allergic rhinitis/skin prick test	Yes
Lee et al., 2014⁶⁷	Continuous data for HI and IN*	Cross-sectional	Seoul, Korea	Not reported	160/87/73	6–13 years (8.49)/39.4%	DSM-IV	Allergic rhinitis/physician’s diagnosis (ARIA guideline)	Yes
Yang et al., 2014⁶⁸	Continuous data for HI* and IN*	Cross-sectional	Taipei, Taiwan	Not reported	122/93/29	6–14 years (10.78)/52.2%	DSM-IV-TR	Allergic rhinitis/Physician’s diagnosis (ARIA 2008) + IgE test (MAST or Phadiatop tests)	Yes
Catal et al., 2016⁶⁹	Continuous data for total ADHD symptoms* and percentage of psychiatric disorders determined by ECI-4*	Cross-sectional	Malatya, Samsun, Aydın, Istanbul, Turkey	Not reported	154/80/74	3–5 years (4.03)/51.3%	ECI-4	Atopic dermatitis/Physician’s diagnosis (Hanifin and Rajka criteria)	No
Hammer-Helmich et al., 2016²⁵	Continuous data for total ADHD symptoms *©	Cross-sectional	Copenhagen, Denmark	Not reported	9036/2433/ 6603	3–15 years (NA)/49.5%	SDQ	Eczema, asthma, and hay fever/ Questionnaire (UK Working Party Criteria)	Yes
Strom et al., 2016⁷⁰	OR of ADD/ADHD in children with atopic dermatitis*	Cross-sectional	U.S. Bureau of Census	Not reported	180799/17277/163522	<18 years (NA)/49.94%	Questionnaire	Atopic dermatitis, asthma, and allergic rhinitis/ questionnaire	Yes
Yang et al., 2016²²	Continuous data for HI* and IN*	Case–control	Taipei, Taiwan	Not reported	99/68/31	6–14 years (9.25)/82.4%	DSM-IV	Allergic rhinitis/physician’s diagnosis + IgE test (MAST or Phadiatop tests)	Yes
Feng et al., 2017⁷¹	Continuous data for HI* and IN*	Cross-sectional	Wenzhou, China	Not reported	643/248/320	6–12 years (9.25)/51.9%	DSM-IV	Allergic rhinitis/physician’s diagnosis (ARIA 2008) + skin prick test	Yes
Lin et al., 2017⁵¹	OR of ADHD (inattentive/ Hyperactive impulsive/combined) in children with atopic dermatitis, asthma, allergic rhinitis (fever/active)*	Cross-sectional	Taiwan	Han Chinese	2896/2235/ 661	9–10 years (10)/50.5%	SNAP-IV	Atopic dermatitis, asthma, and allergic rhinitis/questionnaire (ISAAC questionnaire)	Yes
Abd El-Hamid et al., 2018⁷²	Prevalence of different grades of ADHD symptoms (mild, moderate, and severe) in children with or without atopic diseases*	Case–control	Cairo, Egypt	Not reported	160/100/60	6–12 years (8.54)/81.25%	DSM-IV	Allergic diseases/physician’s diagnosis, skin prick test, and total IgE enzyme immunoassay (ELISA)	No
Kuniyoshi et al., 2018²⁶	Continuous data for total ADHD symptoms©*	Cross-sectional	Miyagi Prefecture, Japan	Not reported	9954/1641/8313	7–14 years (10.42)/49.9%	SDQ	Eczema/ISAAC (Eczema symptom questionnaire)	Yes
Schmitt et al., 2018⁷³	Continuous data for HI and IN*	Case–control	Dresden, Germany	Not reported	89/35/45	6–12 years (9.9)/62.9%	ICD-10	Atopic dermatitis/dermatologist’s diagnosis (UK Working Party Criteria)	Yes
Cices et al., 2019⁷⁴	Continuous data for HI and IN*	Case–control	US, Chicago, Illinois	Caucasian (31.43%) African American (22.86%) Hispanic (20%) Asian (20%) Other(5.71%)	35/17/18	6–16 years (11.07)/65.7%	Standardized Vanderbilt questionnaires	Atopic dermatitis/ SCORAD	Yes
Tajdini et al., 2019²³	Prevalence of ADHD in patients with asthma and controls*	Case–control	Tehran, Iran	Not reported	171/79/92	5–11 years (7.54)/57%	Child Symptom Inventory-4 (CSI-4)	Asthma/respiratory function test	Yes
Zhou et al., 2019⁷⁵	Prevalence of ADHD in patients with asthma and controls*	Cross-sectional	Guiyang, China	Han(77.59%)	522/261/261	6–16 years (9.35)/61.69%	Mini-International Neuropsychiatric Interview for children and adolescents	Asthma/physician’s diagnosis (Bronchial Asthma Diagnostic and Prevention Guide for Children [2016 version])	Yes
Feng et al., 2020⁷⁶	Continuous data for HI* and IN*	Cross-sectional	Chongqing, China	Not reported	273/89/184	6–12 years (8.3)/62.63%	SNAP-IV	Atopic dermatitis/dermatologist’s diagnosis (UK criteria)	Yes
Guo et al., 2020⁷⁷	Continuous data for HI (AR, AD, and asthma) and IN (AR, AD, and asthma)	Cohort	Kaohsiung, Taiwan	Not reported	97	6 years/54.6%	SNAP-IV	Atopic dermatitis, asthma, and allergic rhinitis/ ISAAC questionnaire, physician’s diagnosis (Hanifin–Rajka criteria), and IgE test	Yes
Huang et al., 2020⁷⁸	OR of ADD/ADHD in children with atopic dermatitis*	Cross-sectional	US Northeast (17.96%) North Central (19.33%) South (45.83%) West (16.42%) Unknown (0.47%)	Not reported	203533/86969/116564	0-17 years(5.3) /51.74%	ICD-10-CM	Atopic dermatitis/ IBM MarketScan Commercial Claims database (ICD-10-CM code for AD: L20*)	Yes
Jackson-Cowan et al., 2020⁷⁹	OR of ADD/ADHD in children with atopic dermatitis*	Cross-sectional	US Northeast (15.73%) North Central (20.27%) South (36.21%) West (27.78%)	White (48.44%) Black (15.38%) Hispanic (27.86%) Asian (6.06%) Native American (0.97%) Other (1.29%)	109482/13398/96084	2-17 years/51.48%	Questionnaire	Atopic dermatitis/ questionnaire	Yes
Kuo et al., 2020⁴⁷	Continuous data for HI* and IN	Cross-sectional	Kaohsiung, Taiwan	Not reported	191/109/92	(6.59)/54.44%	SNAP-IV	Atopic dermatitis, asthma, and allergic rhinitis/physician’s diagnosis	Yes
Sollander et al., 2020⁸⁰	OR of ADD/ADHD in children with atopic dermatitis*	Cross-sectional	Uppsala, Sweden	Not reported	4451/397/4054	3-5 years (4.34)/50.42%	SDQ	Asthma/ questionnaire	Yes

Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; OR, Odds Ratio; HI, Hyperactivity/Impulsivity; IA, Inattention; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; GINA 2006, Global Initiative for Asthma, 2006; CBCL, Child Behavior Checklist; ARIA, Allergic Rhinitis and its Impact on Asthma; MAST, multiple-antigen simultaneous test; ECI-4, The Early Childhood Inventory-4; SDQ, Strengths and Difficulties Questionnaire; ICD-10, International Classification of Diseases, Tenth Revision; SCORAD, SCORing Atopic Dermatitis; ISAAC, International Study of Asthma and Allergies in Childhood

Table 2 Studies examining the relationship between atopic diseases and hyperactivity in the meta-analysis.

Study name	Country	Study design	Number of participants/ experimental group/control group	Age (mean of the experimental group)/sex (male, %)	Diagnostic criteria for ADHD	Atopic disease/method used for assessing atopic diseases	Outcome scale	Overall risk of bias
Yuksel et al., 2008⁶⁴	Turkey	Cross-sectional	100/62/38	7–12 years (9.2)/57%	DSM-IV	Asthma/physician’s diagnosis (GINA 2006)	Conner’s Parent Rating Scale	Included
Camfferman et al., 2010³²	Australia	Cross-sectional	107/77/30	6–16 years (9.9)/46.72%	Conner’s Parent Rating Scale-Revised	Atopic dermatitis/physician’s diagnosis (Hanifin and Rajka criteria)	Conner’s Parent Rating Scale	Included
Lee et al., 2014⁶⁷	Republic of Korea	Cross-sectional	160/87/73	6–13 years (8.49)/39.4%	DSM-IV	Allergic rhinitis/physician’s diagnosis (ARIA guideline)	ARS	Included
Yang et al., 2014⁶⁸	Taiwan	Cross-sectional	122/93/29	6–14 years (10.78)/52.2%	DSM-IV-TR	Allergic rhinitis/physician’s diagnosis (ARIA 2008) + IgE test (MAST or Phadiatop tests)	SNAP-IV (parent)	Included
Catal et al., 2016⁶⁹	Turkey	Cross-sectional	154/80/74	3–5 year	ECI-4	Atopic dermatitis/physician’s diagnosis (Hanifin and Rajka criteria)	ECI-4	Included
Hammer-Helmich et al., 2016²⁵	Denmark	Cross-sectional	9036/2433/6603	3–15 years (NA)/49.5%	SDQ	Eczema, asthma, and hay fever/Questionnaire	SDQ	Included
Yang et al., 2016²²	Taiwan	Case-control	99/68/31	6–14 years (9.25)/82.4%	DSM-IV	Allergic rhinitis/Physician’s diagnosis + IgE test (MAST or Phadiatop tests)	SNAP-IV (parent)	Included
Feng et al., 2017⁷¹	China	Cross-sectional	643/248/320	6–12 years (9.25)/51.9%	DSM-IV	Allergic rhinitis/Physician’s diagnosis (ARIA 2008) + skin prick test	SNAP-IV	Included
Kuniyoshi et al., 2018²⁶	Japan	Cross-sectional	9954/1641/8313	7–14 years (10.42)/49.9%	SDQ	Eczema/ISAAC Eczema Symptom questionnaire	SDQ	Included
Schmitt et al., 2018⁷³	Germany	Case-control	89/35/45	6–12 years (9.9)/62.9%	ICD-10	Atopic dermatitis/Dermatologist’s diagnosis (UK Working Party Criteria)	FBB-HKS	Included
Feng et al., 2020⁷⁶	China	Cross-sectional	273/89/184	6–12 years (8.3)/62.63%	SNAP-IV	Atopic dermatitis/Dermatologist’s diagnosis (UK criteria)	SNAP-IV	Included
Kuo et al., 2020⁴⁷	Taiwan	Cross-sectional	191/109/92	(6.59)/54.44%	SNAP-IV	Atopic dermatitis, asthma, and allergic rhinitis/Physician’s diagnosis	SNAP-IV	“Seek further information”

Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; GINA 2006, Global Initiative for Asthma, 2006; ARIA, Allergic Rhinitis and its Impact on Asthma; ARS, ADHD Rating Score; MAST, multiple-antigen simultaneous test; The Early Childhood Inventory-4; SNAP-IV, Swanson, Nolan, and Pelham Questionnaire; SDQ, Strengths and Difficulties Questionnaire; ICD-10, International Classification of Diseases, Tenth Revision; FBB-HKS, The German ADHD Rating Scale

No competing interests reported.

What Is The Impact of Atopic Diseases On Symptoms Dimension of Attention-Deficit/Hyperactivity Disorder: A Systematic Review And Meta-Analysis

Status:

Version 1

Abstract

Figures

Introduction

Results

Search results

Qualitative systematic review

Quantitative review and meta-analysis of longitudinal studies

Overview of total ADHD symptoms through a meta-analysis

Overview of hyperactivity/impulsivity through a meta-analysis

Overview of inattention through a meta-analysis

Atopic group and a healthy control group

Atopic group and a nonatopic control group

Pure atopic group with a healthy control group

Subgroup analysis of different types of atopic diseases

Discussion

Limitations

Conclusion

Methods

Eligibility criteria for study selection

Search strategy and study selection

Data extraction

Data abstraction for the meta-analysis

Sensitivity analysis

Subgroup analysis of exclusion criteria for those with a previous ADHD diagnosis

Declarations

Data Availability

Authors' contributions

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1