This systematic review and meta-analysis investigated the link between Allergic Rhinitis (AR) and Attention Deficit Hyperactivity Disorder (ADHD) across 12 studies involving a total of 530,360 participants. Our primary finding indicated a significant correlation between AR and ADHD. Furthermore, subgroup analyses, considering various demographic variables, revealed that female individuals with ADHD were more prone to developing AR compared to their male counterparts. Additionally, the risk of AR was higher among individuals with ADHD aged 9–15 years in various age groups. Interestingly, we observed no significant distinctions across different study types, but the relationship between ADHD and AR was notably more pronounced in studies of higher quality. Remarkably, when we examined the data by categorizing participants based on their geographical regions, it became evident that the association between ADHD and AR was notably stronger in Asia compared to other regions.
Moreover, various studies have concentrated on assessing the influence of AR on children's mental health and behavior, with particular attention to the connection between AR and ADHD as a pivotal area of interest. Multiple studies have already found a strong correlation between AR and ADHD[23, 26–27].Some studies suggest that treating AR can significantly reduce the severity of ADHD[28–29]. Conversely, ADHD has been examined for its impact on AR, such as ADHD treatment improving allergic symptom[30]. This suggests that the relationship between AR and ADHD is not a simple one-way influence but rather a mutual interaction. However, some studies indicate that there is no significant correlation between neurodevelopmental disorders and allergic reactions, suggesting that there may not be a clear link between ADHD and AR[31].
Subgroup Analysis
Subsequent subgroup analysis revealed variations in the strength of the association between these two conditions in different groups, such as gender, average age, study quality, diagnostic methods, and region. Given the disparities in the prevalence of ADHD and AR among different genders and the varying genetic factors influencing dopamine systems and endocrine factors like estrogen and thyroid in different genders[32–35], we conducted gender stratification. This revealed that the association between ADHD and AR was more pronounced in females (OR = 1.97; 95% CI: 1.52–2.56). Considering that ADHD and AR progress differently with age, it is essential to examine their relationship with age[36–37]. This study indicated a more pronounced association between ADHD and AR in the 9–15 years age group (OR = 2.24; 95% CI: 1.16–4.33). In all types of studies (cohort, case-control, and cross-sectional), there was evidence of an association between these two conditions. Both high-quality and moderate-quality studies demonstrated a relationship between ADHD and AR, with this relationship being more pronounced in high-quality studies (OR = 1.97; 95% CI: 1.58–2.45). Due to variations in disease prevalence resulting from different diagnostic methods, we stratified by AR diagnostic methods, with the SPT-based diagnosis group showing the highest OR. This suggests that the association between ADHD and AR is stronger when AR is diagnosed using the SPT method (OR = 2.49; 95% CI: 1.67–3.71), possibly because the Skin Prick Test (SPT) method is regarded as the gold standard for diagnosing AR[38], leading to higher diagnostic rates[39–40]. ADHD and AR both involve genetic-environment interactions in their pathogenesis, and they may share similar genetic mechanisms[15]. To explore the association between ADHD and AR in varying racial and environmental contexts, we stratified by region. The findings revealed a more robust connection between ADHD and AR in the Asian region (OR = 1.95; 95% CI: 1.61–2.37).
Pathophysiological Mechanism
From a biological perspective, both ADHD and AR are genetic diseases involving gene-environment interactions, and they have common genetic mechanisms. Signal transducer and activator of transcription 6 (STAT6) is involved in immune system regulation, cell proliferation, and apoptosis. It is also believed to play a role in the pathogenesis of ADHD. This further supports the correlation between allergic rhinitis (AR) and ADHD[41]. The mechanism by which AR leads to the occurrence of ADHD is primarily attributed to the activation of the immune system and in the initiation of inflammatory responses in allergic rhinitis, which can affect the neurochemistry, neuroendocrine system, autoimmunity, and behavioral changes in the brain, resulting in behavioral disturbances, including cognitive dysfunction, social withdrawal, and abnormal behavior[42]. When exposed to allergens, dendritic cells interact with T cells, leading to the activation of T cells that migrate to the bone marrow and release inflammatory cytokines. These cytokines indirectly affect the neuronal activity of brain structures by activating the hypothalamic-pituitary-adrenal axis, thereby influencing the neuroimmune pathway[40, 42–43]. At the same time, these cytokines can disrupt the metabolism of central neurotransmitters crucial for ADHD development, such as norepinephrine and dopamine[15].
On the other hand, the mechanism by which ADHD leads to AR may be related to increased stress levels in individuals with ADHD, which trigger neuroimmune mechanisms. Both physical and psychological stress stimulate the production of cytokines, which leads to a series of immune responses. Stress generation is sensed by the central nervous system (CNS) and transformed into biological responses by stimulating the hypothalamus and pituitary gland. This activation then stimulates the autonomic nervous system, leading to the release of neurotransmitters that act on other effector systems in the body, such as the immune system[44]. Comparable neuroimmune alterations have been identified in neurodevelopmental disorders, such as autism and panic disorder[45–46]. Additionally, a positive correlation between high levels of psychological stress and atopic dermatitis has been revealed[47–48]. The sensory and autonomic nervous systems, in conjunction with the adaptive/innate immune system, exhibit intricate interrelations in the pathophysiology of specific dermatitis conditions[49]. Our research results suggest that further exploration is needed in the future to understand the pathological and physiological changes that lead to AR in individuals with ADHD.
The mechanisms responsible for the mutual association between these two conditions remain unclear, possibly due in part to the interplay between the immune system and the nervous system. However, due to the complexity of the pathophysiological mechanisms, further research is needed[42]. Overall, this study adds to our comprehension of the intricate interplay between ADHD and AR. The results suggest that these two conditions are interconnected, with each influencing the risk of the other. This underscores the significance of taking into account both conditions in clinical practice, especially when evaluating and treating children with ADHD and AR. Further research is essential to delve deeper into the mechanisms underlying this relationship and explore potential therapeutic interventions that may benefit children with both conditions.
Strengths and Weaknesses
In this systematic review, we performed a meta-analysis based on systematic evaluation and combined previous research results, resulting in a relatively large sample size and confirming the link between AR and ADHD. This meta-analysis also explored more precise connections between ADHD and AR by considering gender disparities, variances in age, distinctions in study types and their quality, diverse diagnostic approaches for AR, and regional variations across the studies. The results of this investigation need further validation and exploration. Despite its limitations, the study results still provide preliminary clues about the potential connection between AR and ADHD. Further understanding of the etiology of ADHD/AR may reveal the underlying pathogenic mechanisms for preventing and/or treating these conditions in children. Our analysis offers important guidance and insights for future research.
This study also has certain limitations. Firstly, there were relatively few studies included in the analysis that considered AR as an exposure variable and ADHD as an outcome variable, potentially introducing selection bias and limiting the representativeness of the results. Secondly, observational studies can only reveal the association between AR and ADHD and cannot establish causality or the underlying pathophysiological mechanisms. Therefore, more experimental research is needed to further explore this relationship and investigate potential biological and neural mechanisms. Additionally, the limited diversity of the included study populations may restrict the generalizability of the results. Furthermore, in some of the incorporated studies used subjective questionnaires to collect information on AR and ADHD, which may carry a risk of recall bias. Therefore, future research can employ more objective diagnostic methods and assessment tools to obtain more accurate data. Finally, the diagnosis of ADHD may be accompanied by the presence of other psychiatric disorders, while the control group in the included studies may not have received the same level of attention, potentially introducing bias.