Associations of attention-deficit/hyperactivity disorder with inflammatory diseases. Results from the nationwide German Health Interview and Examination Survey for Children and Adolescents (KiGGS)

For this post hoc study, the subsample of 11- to 17-year-old children and adolescents was selected from the German KiGGS study, because both self- and parent-reported data for this age group were available. The survey, conducted by the Robert Koch Institute from May 2003 to May 2006, involved 17,641 children (8985 boys and 8656 girls) aged 0 to 17 years. The study design has been described in detail elsewhere [13]. The recruitment of participants was accomplished in two steps. First, 167 communities were selected as sampling points all over Germany and, in a second step, participants were randomly chosen from official local registers and invited to participate in the survey. The study included questionnaires completed by parents and adolescents, physical examinations and a computer-assisted personal interview [14]. The study was funded by the German Federal Ministry of Health (BMG) and the German Federal Ministry of Education and Research (BMBF) [15]. All study participants and their legal guardians gave written informed consent. Ethical approval for this study was obtained from the Ethics Committee of the Charité Universitätsmedizin Berlin and additionally from the German Federal Office for Data Protection.

The dataset used for the present analysis included information on sex, age, body mass index (BMI), socioeconomic status, migration status, systolic blood pressure, serum 25-hydroxyvitamin D [25(OH)VitD] concentration, and lifetime prevalences of atopic dermatitis, otitis media, and herpes simplex infection. Following a standardized protocol, body height was measured by trained personnel with an accuracy of 0.1 cm. Participants’ body weight was determined in underwear on a calibrated scale with an accuracy of 0.1 kg. Body mass index was calculated by dividing body weight in kilograms by the square of measured height in meters [16]. Socioeconomic status (SES) was determined based on parental information about participants’ schooling, professional qualifications, net income, and job-related positions for all household members, as recommended by the German Society of Epidemiology [17]. A participant was defined as having a migration background if one or both parents were not born in Germany and/or did not have German citizenship [18]. Blood pressure was measured noninvasively using the Datascope Accuratorr Plus blood pressure monitor and a portable monitor (SOMA Technology, Bloomfield, CT, USA) [19]. Two independent measurements were taken 5 min apart for each subject. For the measurement of 25(OH)VitD, peripheral venous blood was drawn by a pediatrician. Serum was obtained by allowing the blood sample to stand at room temperature for 45 min to clot. Subsequently, the samples were centrifuged and the serum was stored at −50 °C [20]. The determination of 25(OH)VitD concentrations was performed in a special laboratory of the Robert Koch Institute [21]. A change of method for the quantitative determination of 25(OH)VitD was necessary due to stability problems of the analyte, and the fully automated LIAISON chemiluminescence immunoassay (CLIA, DiaSorin, Dietzenbach, Germany) was used [22, 23]. To determine the lifetime prevalence of ADHD, parents were required to answer the question, “Has your child ever been diagnosed with attention-deficit/hyperactivity disorder?” Responses were rated ‘yes’, ‘no’, or ‘I don’t know’ on a three-point scale. If the answer was ‘yes’, the question was expanded to include the additional question, ‘If yes, how was the disorder diagnosed?’; possible responses were ‘medical doctor’, ‘psychologist’, or ‘other’ [24].

Lifetime prevalence of atopic dermatitis, otitis media, and herpes simplex was also assessed using the self-administered questionnaire in which parents reported diseases diagnosed by physicians [25].

From the total KiGGS study population of 17,641 children and adolescents, n = 6922 participants with available data on ADHD diagnosis were at least 11 years old, and all of these subjects were included in the present post hoc analysis. According to parents’ ratings, 430 of these children and adolescents had been diagnosed with ADHD. The mean age of the participants in the total study population was 14.6 ± 2.0 years, and because of the sampling procedure used in the KiGGS survey, male (49.9%) and female participants were almost equally represented, with a slightly higher proportion of girls. Mean systolic blood pressure and 25(OH)VitD levels were 114.8 ± 10.8 mm Hg and 44.5 ± 27.6 nmol/l, respectively. A lifetime diagnosis of ADHD was reported more frequently in patients with atopic dermatitis (8.1% vs. 5.7%, p = 0.002), otitis media (7.1% vs. 5.2%, p = 0.001), and herpes simplex (7.3% vs. 5.9%, p = 0.032) than in participants without these diseases. Demographic and biochemical characteristics, including participants with and without these conditions, are summarized in detail in Table 1.

Atopic dermatitis was diagnosed in n = 1164 study participants aged 11 years or older, with more probands being female than in the control group (53.8% vs. 49.3%, p = 0.005). Further differences between participants with and without atopic dermatitis were found in the socioeconomic status, as participants affected by atopic dermatitis tended to be of higher socioeconomic status (12.2 ± 4.3 vs. 11.6 ± 4.3, p < 0.001). Similarly, participants with an immigrant background were less likely to be affected by atopic dermatitis (6.4% vs. 12.8%, p < 0.001). In addition, mean arterial blood pressure was lower in the group of participants with atopic dermatitis (114.1 ± 10.5 mm Hg versus 115.0 ± 10.9, p = 0.012). A logistic regression model was constructed with atopic dermatitis as the dependent variable and ADHD diagnosis as the independent variable, adjusted for age, sex, BMI, socioeconomic status, migration status, mean systolic blood pressure, and 25(OH)VitD. In the multivariate model, the positive association between atopic dermatitis and ADHD was confirmed (Exp(β) = 1.692, 95% CI = 1.253–2.285, R² = 0.010, p = 0.001; Table 2).

Subsequently, the cohort was examined with regard to otitis media. In total, n = 3714 participants had been diagnosed with otitis media during their lifetime. No significant sex differences were found between participants with and without otitis media (Table 1). However, significant differences were found in socioeconomic status, whereby participants with otitis media more often belonged to a higher socioeconomic status (11.9 ± 4.3 vs. 11.4 ± 4.4, p < 0.001). Participants with an immigrant background were less likely to have otitis media, as previously observed for atopic dermatitis (7.8% vs. 16.7%, p < 0.001). The results also showed that there was a significant difference in the lifelong prevalence of otitis media in the comparison of the affected group with the unaffected group with regard to ADHD (7.1% vs. 5.2%, p = 0.001). A significant positive association between otitis media and the diagnosis of ADHD was confirmed in the corresponding adjusted logistic regression model (Exp(β) = 1.576, 95% CI = 1.213–2.048, R² = 0.029, p = 0.001; Table 2).

A total of n = 1895 subjects had a history of a herpes simplex infection, as self-reported by study participants and/or their parents. Compared with the control group, participants diagnosed with herpes simplex were significantly more likely to be female (54.6% vs 48.4%, p < 0.001) and less likely to have an immigrant background (10.0% vs 11.8%, p = 0.004). Whereas mean arterial blood pressure was lower than in the control group (114.3 ± 10.5 mm Hg vs 115.1 ± 11.0, p = 0.006), ADHD was significantly more common in the group of participants with herpes simplex (7.3% vs 5.9%, p = 0.032). The results from a correspondingly adjusted logistic regression model confirmed a significant and positive association between a lifelong herpes simplex virus infection and ADHD diagnosis (Exp(β) = 1.471, 95% CI = 1.129–1.918, R² = 0.016, p = 0.004). Furthermore, 25(OH)VitD levels were elevated in all three inflammatory diseases, but only in herpes simplex to a significant extent (47.1 ± 26.6 nmol/l vs 43.4 ± 28.1, p < 0.001). As expected, this association was also confirmed in the adjusted logistic regression model (Exp(β) = 1.781, 95% CI = 1.375–2.306, p < 0.001; Table 2).