Increased prevalence of urticarial diseases and antihistamine/corticosteroid consumption in patients with attention-deficit/hyperactivity disorder

Abstract

Objectives

This nationwide cohort study investigated the association between attention-deficit/hyperactivity disorder (ADHD) and various types of urticarial diseases.

Methods

We conducted a population-based cohort study using data from Leumit Health Services (LHS), a health maintenance organisation in Israel. The study population consisted of all members of LHS between 1 January 2002 and 30 November 2022 aged 5–18 years. Diagnoses of ADHD and urticarial diseases were based on International Classification of Diseases, 9th Edition codes. The study group consisted of subjects with ADHD, while matched controls were randomly selected non-ADHD subjects (2:1 ratio).

Findings

Demographic characteristics of ADHD (n=18 558) and control (n=37 116) groups were well-matched, with no significant socio-demographic differences. A significantly higher prevalence of various subtypes of urticarial diseases was found in the ADHD group compared with the control group. Specifically, urticaria (5.00% vs 4.22%, OR (95% CI) 1.19 (1.10 to 1.30), p<0.001), allergic urticaria (3.26% vs 2.73%, OR (95% CI) 1.20 (1.08 to 1.33), p<0.001). Inducible forms of urticaria did not show significant differences between the groups. The ADHD group had a higher use of systemic and topical antihistamines and systemic corticosteroids.

Conclusions

Various urticarial diseases are more prevalent in individuals with ADHD, possibly due to shared genetic factors, immune system dysfunction, or environmental triggers.

Clinical implications

This study suggests an association between ADHD and some urticaria subtypes. Physicians should be aware of this association and its public health implications.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Attention-deficit/hyperactivity disorder (ADHD) is associated with inflammatory and autoimmune disorders, with previous research suggesting a link to allergic conditions and immune dysregulation.

WHAT THIS STUDY ADDS

• Our research identifies a significant correlation between ADHD and various urticarial syndromes, highlighting the potential role of mast cell activation and autoimmunity in the pathophysiology of ADHD.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• The findings emphasise the need for further investigation into the role of mast cells and immune factors in ADHD. This may lead to novel therapeutic strategies that influence clinical management of ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a widespread neurodevelopmental disorder that has garnered significant attention due to its impact on both children’s and adults’ well-being.¹ An international consensus statement of the World Federation of ADHD suggested that ADHD is associated with somatic conditions.² We previously demonstrated that ADHD is associated with increased rates of infections and inflammatory diseases.³ A Swedish National Registry-based study has shown a significant link between ADHD and autoimmune disorders.4,6 This connection points to possible immune dysregulation in individuals with ADHD, as reflected by alterations in both the immunoglobulin levels⁷ and cytokine responses.⁸

A recent study, using the Taiwan National Health Insurance Research Database, identified 8201 individuals with ADHD and compared them to matched controls at a 1:4 ratio. The findings revealed a higher prevalence of urticaria (OR=1.39) in the ADHD group compared with the control group.⁹ Unfortunately, this study did not go into a detailed investigation of the various subtypes of urticaria.

Urticaria includes diverse inflammatory skin diseases affecting as many as 20% of the global population during their lifetime.¹⁰ These conditions arise when skin mast cells become activated and release histamine and various other substances, subsequently triggering sensory nerve activation, blood vessel dilatation, leakage of plasma and the recruitment of immune cells.¹¹ Urticaria is primarily categorised by duration into acute urticaria lasting up to 6 weeks, and chronic urticaria persisting for more than 6 weeks.¹² Urticaria can be further classified into inducible and spontaneous forms. Inducible urticaria is characterised by symptoms triggered by specific factors, such as low temperature in the case of cold urticaria. On the other hand, spontaneous urticaria (SU) involves symptoms that occur without identifiable triggers, although factors like stress or infections can exacerbate the condition in some individuals. SU is more prevalent than inducible urticaria, and both forms can coexist in the same patient.¹² Acute urticaria is typically spontaneous and often lacks a clear underlying cause, although some instances may be associated with infections or the consumption of specific medications or foods.¹³

The primary aim of our study was to further investigate the relationship between ADHD and various types of urticarial diseases in a nationwide controlled study.

Materials and methods

Study design

This was a population-based cohort study using data extracted from the Leumit Health Services (LHS) electronic medical database. LHS is one of four Israeli health maintenance organisations. It has a countrywide presence and its membership during the study period consisted of 724 129 individuals, which constitutes about 7.4% of the Israeli population. The members come from all ethnic, religious and socioeconomic groups. All LHS members have uniform health insurance coverage and equitable access to healthcare services. The LHS database is continuously updated with information on demographics, medical visits, diagnoses, laboratory tests, hospitalisations, and medication prescriptions. It includes prescription records dating back to 1998, consisting of both refills and purchases for each patient. The validity of diagnoses in the database has been previously found to be high.¹⁴

Study population and definitions

This observational historical cohort study encompassed all LHS members aged 5–18 years between 1 January 2002 and 30 November 2022. The study group consisted of individuals with a confirmed diagnosis based on International Classification of Diseases, 9th Edition (ICD-9) criteria of ADHD (314.00–314.9). The control group consisted of randomly selected LHS members without ADHD, at a 2:1 ratio, individually matched for age (to a precision of quarter years), gender, socioeconomic status (SES; see details below), major sector (Arabs, Secular Jews, Ultra-Orthodox Jews), residence, year of first membership and cumulative years of LHS membership up to the index date.

SES classification was based on the Israeli Central Bureau of Statistics criteria, ranked from 1 (lowest) to 20 (highest); categories 1–3 indicated very low SES, 4–6 indicated low SES, 7–9 indicated medium SES, and 10–20 denoted medium-high SES.

The study group consisted of individuals with a confirmed diagnosis of ADHD (ADHD group) as described above. Diagnosis was based on Israeli Ministry of Health criteria, which adhere to international standards. Namely, the diagnosing physician must be a senior physician specialising in ADHD, such as a child or adult psychiatrist, child or adult neurologist or a paediatrician or family physician certified for ADHD diagnosis. Diagnoses were established according to the DSM-4-TR or DSM 5 criteria, depending on the year of diagnosis.³

Each individual in the ADHD group was randomly matched with two individuals from a control pool of LHS members without an ADHD diagnosis, matched on key demographic characteristics: year and quarter of birth, gender, major religious sector, SES, geographical region and years of LHS membership. Control group individuals were assigned the same index date as their corresponding ADHD cases to minimise potential confounding factors.

For each individual in the cohort, demographic and body mass index (BMI) data were extracted as recorded at the index date or, if unavailable, from the first measurement taken after the index date.

Additional medical parameters, including laboratory results, medication usage and specialist visits, were queried for the cohort. These data were collected for the 7 years following the index date. For laboratory tests with multiple results during the follow-up period, the median value was used. Medication usage was defined as at least one purchase of a drug within the relevant Anatomical Therapeutic Classification (ATC) during the follow-up period. The analysed ATC categories included D04AA (topical antihistamines), H02 (systemic corticosteroids), N03 (antiepileptics), N05 (psycholeptics), N06AB (selective serotonin reuptake inhibitors (SSRIs)), N06BA (centrally acting sympathomimetics), and R06 (systemic antihistamines).

Urticaria diagnoses included all urticarial diseases, according to ICD-9 codes 708, 708.0, 708.1, 708.2, 708.3, 708.5, 708.8, 708.9, 698.22. To identify the patients with SU, we used the following algorithm: one or more of the ICD-9 diagnoses codes 708.1, 708.8, 708.9, and absence of inducible urticaria diagnoses 708.0, 708.2, 708.3, 708.5 or 698.22.¹⁵ All SU patients were diagnosed and managed according to the joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA (2) LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) (EAACI/GA(2)LEN /EDF/WAO) guidelines.¹²

Statistical analysis

We conducted all statistical analyses using R-statistics software, with two-sided tests and a significance level α<0.05. Comparisons between the ADHD and control groups were conducted using t-tests for continuous variables and Fisher’s exact test for categorical variables. Alongside values, we report standardised mean differences (SMD, Cohen’s d) for continuous variables and ORs with 95% CIs for categorical variables.

Written informed consent was waived due to the retrospective nature of the study.

Results

Figure 1 illustrates the flowchart of the cohort selection process. From a total of 23 631 LHS members aged 5–18 with ADHD, 18 558 were successfully matched in a 1:2 ratio with control individuals of the same age who did not have an ADHD diagnosis.

Figure 1. Flowchart of the cohort selection process. ADHD, attention-deficit/hyperactivity disorder; LHS, Leumit Health Services; SES, socioeconomic status.

Demographic characteristics

Table 1 summarises the demographic characteristics of the study participants. The ADHD and control groups were well-matched concerning gender, mean age, age categories, residence, major religious sector or SES (p>0.05 for all). The mean BMI was somewhat higher in the ADHD group compared with the control group (17.77 vs 17.37), with an SMD of 0.053. While this difference was statistically significant (p<0.001), its clinical significance remains uncertain.

Table 1. Participants’ demographics by groups.

		AHDH group	Control group	P value	Cohen’s D
Number		18 558	37 116
Gender, n (%)	Male	11 777 (63.5)	23 553 (63.5)	0.999
	Female	6781 (36.5)	13 563 (36.5)	0.999
Age, years, mean (SD)		8.38 (2.71)	8.38 (2.71)	0.979	0.000
Age category, years, n (%)	9	13 581 (73.2)	27 138 (73.1)	0.871
	10–18	4977 (26.8)	9978 (26.9)	0.879
Sector, n (%)	Arab	1640 (8.8)	3280 (8.8)	0.999
	General	10 267 (55.3)	20 534 (55.3)	0.999
	Jewish Ultra-orthodox	6651 (35.8)	13 302 (35.8)	0.999
Socio-economic status, mean (SD)		7.92 (3.94)	7.92 (3.98)	0.928	0.000
BMI, mean (SD)		17.77 (3.95)	17.37 (3.94)	<0.001	0.053

ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index.

Table 2 presents comparisons between laboratory results, medication purchases and physician specialist visit rates in both groups.

Table 2. Comparison of laboratory results, specialist visits and purchased medications in the ADHD and control groups.

	AHDH group	Control group	P value	SMD	OR (95% CI)
Number	18 558	37 116
Laboratory tests, median (IQR)
White blood cells, (109 cells/L)	6.80 (5.80–7.98)	6.73 (5.73–7.91)	<0.001	0.018
Haemoglobin, (g/L)	132 (126–138)	132 (126–138.6)	0.371	0.013
Basophils, (109 cells/L)	0.04 (0.03–0.05)	0.04 (0.03–0.05)	<0.001	0.041
Basophils %	0.60 (0.40–0.80)	0.60 (0.40–0.80)	0.022	0.023
Eosinophils, (109 cells/L)	0.24 (0.15–0.40)	0.23 (0.14–0.38)	<0.001	0.074
Eosinophils %	3.60 (2.30–5.90)	3.45 (2.10–5.55)	<0.001	0.069
TSH, (mIU/L)	1.98 (1.49–2.66)	2.01 (1.49–2.69)	0.145	0.012
Immunoglobulin E, (IU/mL)	137.0 (42.6–372.5)	145.0 (47.5–433.5)	0.256	0.093
C-reactive protein, (mg/L)	1.30 (0.50; 4.10)	1.25 (0.50; 4.10)	0.563	0.019
Purchased medications n (%)
Centrally acting sympathomimetics	14 252 (76.8)	1493 (4.0)	<0.001		79.1 (74.1 to 83.8)
Psycholeptics	2554 (13.8)	1099 (3.0)	<0.001		5.2 (4.9 to 5.6)
Selective serotonin reuptake inhibitors	935 (5.0)	514 (1.4)	<0.001		3.8 (3.4 to 4.2)
Antiepileptics	477 (2.8)	373 (1.0)	<0.001		2.6 (2.3 to 3.0)
Antihistamines, topical	1818 (9.8)	2059 (4.4)	<0.001		1.85 (1.73 to 1.98)
Antihistamines, systemic	8577 (46.2)	14 430 (38.9)	<0.001		1.35 (1.30 to 1.40)
Systemic corticosteroids	2026 (10.9)	3362 (9.1)	<0.001		1.23 (1.16 to 1.30)
Specialist visits, n (%)
Allergology specialist visits	825 (4.45)	1218 (3.28)	<0.001		1.37 (1.25 to 1.50)
Dermatology specialist visits	6066 (32.68)	11 605 (31.27)	<0.001		1.07 (1.03 to 1.11)

ADHD, attention-deficit/hyperactivity disorder; SMD, standardised mean differences.

Laboratory data

No significant differences were observed between the ADHD and control groups in blood haemoglobin, TSH, immunoglobulin E and C-reactive protein levels. However, patients with ADHD had a significantly higher eosinophil percentage (SMD 0.069, p<0.001), a borderline higher basophil percentage (SMD 0.022, p=0.023) and a higher total white blood cell count (SMD 0.018, p<0.001).

Medication usage

Centrally acting sympathomimetics were purchased by 76.8% of patients in the ADHD group compared with only 3.0% in the control group (OR=79.1, 95% CI (74.1 to 83.8)). The ADHD group demonstrated higher usage of psychoactive substances, including psycholeptics (OR=5.2, 95% CI (4.9 to 5.6)), SSRIs (OR=3.8, 95% CI (3.4 to 4.2)) and antiepileptics (OR=2.6, 95% CI (2.3 to 3.0)). Additionally, the ADHD group had significantly higher usage rates of topical antihistamines (OR=1.85, 95% CI (1.73 to 1.98)), systemic antihistamines (OR=1.35, 95% CI (1.30 to 1.40)) and systemic corticosteroids (OR=1.23, 95% CI (1.16 to 1.30)) compared with the control group.

Specialist visits

Compared with the control group, the ADHD group had significantly higher rates of visits to allergy specialists (OR=1.37, 95% CI (1.25 to 1.50)) and dermatology specialists (OR=1.07, 95% CI (1.03 to 1.11); table 2).

Figure 2 presents forest plots comparing the incidence of urticaria diagnoses during 7 years of follow-up between the ADHD and control groups. Higher rates were observed for urticaria overall (OR 1.19, 95% CI (1.10 to 1.30)) and allergic urticaria (OR=1.20, 95% CI (1.08 to 1.33)). The prevalence of SU was also significantly higher in the ADHD group (OR 1.17, 95% CI (1.01 to 1.36)). The associations with urticaria were statistically significant for both males and females.

Figure 2. Forest plot of the association between urticarial syndromes and ADHD during the 7-year follow-up period. ADHD, attention-deficit/hyperactivity disorder.

Subgroup analyses, stratified by gender and age category, are provided as supplementary material (online supplemental figure S1).

Discussion

The present comprehensive nationwide cohort study demonstrated that children with ADHD had significantly higher rates of various urticarial syndromes, higher use of systemic and topical antihistamines and systemic corticosteroids as well as more visits to allergology and dermatology clinics than matched controls. Children with ADHD also had a significantly greater absolute number and percentage of eosinophil leucocytes in their blood.

These findings support the notion of a significant association between ADHD and urticarial diseases in paediatric populations. There are several plausible explanations for this association. Those include the possibility of shared genetic or environmental factors, the possibility that one condition impacts the other or that pharmacological treatment of one condition affects the other. These hypotheses warrant further investigation in future studies but also indicate that more attention should be paid to this issue by clinical and public health authorities.

Our study also found that individuals with ADHD exhibited higher rates of urticaria, both allergic urticaria and spontaneous compared with the control group. This observation is in accordance with previous studies suggesting an association between urticaria and ADHD.⁹

The association between ADHD and urticarial diseases suggests the following intriguing possibilities for mechanisms. One possibility is that common genetic factors or immune dysregulation pathways may underlie both conditions.¹⁶ Alternatively, immune system over-activity may contribute to the development of both conditions, as enhanced immune responses and inflammation have been implicated in the pathogenesis of ADHD.¹⁷

A supportive clinical aspect of our findings is the higher usage of topical and systemic antihistamines in the ADHD group. Antihistamines are commonly prescribed to alleviate allergic symptoms, including those associated with urticaria. The increased use of these medications in the ADHD group probably reflects the higher prevalence of allergic conditions in this population.¹⁸

A case–control study found that children with a history of antihistamine prescriptions had a 50% higher risk of being diagnosed with ADHD later.¹⁹ We too have observed an association between higher consumption of antihistamines and ADHD. It is worth noting that the first-generation antihistamines crossing the blood-brain barrier can produce cognitive/behavioural adverse effects that are similar to some ADHD symptoms, and may thus aggravate the ADHD clinical presentation.²⁰

The association between ADHD and urticarial diseases, particularly allergic urticaria, may be influenced by environmental factors as well.²¹ Exposure to allergens or environmental triggers that induce urticaria may impact neurodevelopment and contribute to the manifestation of ADHD symptoms.²² Most of the individuals with ADHD were treated with stimulants; however, to the best of our knowledge, there are no solid data on the impact of these medications on the immune system.² Thus, it is unlikely that the increased rate of urticaria among individuals with ADHD is related to their treatment. Further research is needed to elucidate the complex interplay between genetic, immune and environmental factors in the relationship between ADHD and urticaria.

The observation of higher rates of SU in patients with ADHD raises interesting questions regarding the underlying mechanisms. One possibility may involve neuroinflammation and mast cell activation. Mast cells, known for their central role in the pathophysiology of chronic SU (CSU), are also involved in neuroinflammatory responses.²³ An abnormal neuroinflammatory state in individuals with ADHD may trigger mast cell activation, leading to the development of CSU.²⁴ Stress is a well-known trigger for both ADHD symptoms and mast cell activation.²⁵ Chronic stress, often seen in individuals with ADHD, can dysregulate the immune system and lead to mast cell hyperactivity.²⁶ Such immune dysregulation may contribute to the increased prevalence of CSU in patients with ADHD.²⁷ Neurotransmitter imbalances seen in ADHD, like dopamine and norepinephrine dysregulation, may have downstream effects on immune responses and mast cell function.²⁸

Emerging research suggests a strong connection between the gut microbiota, the brain and the immune system. Disruptions in the gut-brain axis may contribute to both ADHD, CSU and mast cells in the gastrointestinal tract, while microglial cell activation in the brain may be involved in the immune responses related to both ADHD and CSU.²⁹ These wide-ranging plausible mechanisms merit further investigation to shed light on the associations observed in the current study.

Study strengths

This study included a substantial nationwide cohort, thus enhancing the generalisability of the study’s findings. The study used LHS’ extensive electronic database, allowing for detailed analysis and minimising the risk of missing relevant information. Controls were individually matched to ADHD cases for various essential variables, including age (to a precision of quarter years), gender, SES, major religious sectors, region of residence and cumulative years of LHS membership. This matching strategy helps minimise potential confounding factors and strengthens the validity of the results. The study integrates clinical data, epidemiological analysis and theoretical hypotheses from both immunology and psychiatry, providing a comprehensive perspective on the association between ADHD and urticarial diseases.

Study limitations

As an observational study, this research is subject to inherent limitations. The associations observed between ADHD and urticarial diseases may be influenced by unmeasured confounders or the possibility of reverse causation. Diagnoses of both ADHD and urticarial diseases were based on ICD-9 codes recorded by treating physicians, and the accuracy of these documented diagnoses may vary. Additionally, the ICD-9 classification lacks a specific code for CSU and does not differentiate between chronic and acute inducible urticaria.

Additional limitations are as follows. The fact that the study population was strictly Israeli may limit generalisation of the findings. Details of medication used by the patients with ADHD and their comorbid conditions were not evaluated in this study. The study does not provide a definitive explanation for the observed associations between ADHD and urticarial diseases. Further research and experimental studies, including preclinical studies, are needed to establish causality, elucidate underlying mechanisms and lead to better understanding of this association.

Clinical implications

The findings suggest the existence of associations between ADHD and urticarial diseases, including SU. Clinical practitioners should be aware of this association and its public health implications.

Data availability statement

The data used in this study consist of deidentified participant data. They are available upon reasonable request from EMerzon (ORCID 0000-0001-5469-0236) or AI (ORCID 0000-0003-4389-8896).