- Email: [email protected]
hyperactivity disorder: A cohort study
Letter to the Editor Childhood atopic dermatitis and risk of attention deficit/hyperactivity disorder: A cohort study To the Editor: Atopic dermatitis (AD) is a chronic, or chronically relapsing, inflammatory skin disease and it is the most common chronic disease of childhood.1 Inflammatory processes are known to play an important role in the development of psychiatric diseases.2 Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders.3 However, only 1 questionnaire-based follow-up study exists on the association between AD and ADHD and it does not report results related to sex.4 We conducted a nationwide population-based cohort study to determine the incidence of clinically verified ADHD among Danish patients with hospital-diagnosed AD, compared with the general population. The Danish National Health Service provides tax-supported health care, with free access to hospital-based and primary medical care, including care for AD and ADHD. We used the Danish National Registry of Patients (DNRP) to identify all individuals born between January 1, 1995, and January 1, 2010, who received a hospital discharge diagnosis of AD before the age of 15 years. The DNRP contains information on all hospital admissions and, since 1995, outpatient clinic visits in Denmark. Data on filled prescriptions on ADHD medication were available from the Danish National Prescription Database, established in 1995. For each patient with AD, we identified 10 individuals from the general population, matched for sex and birth year, based on the Civil Registration System. We used the personal identifiers of
the participants in both cohorts to search the Danish Psychiatric Central Registry (DPCR) for records from Danish psychiatric hospitals on inpatient admissions (maintained since 1970) and outpatient visits (maintained since 1995). The DPCR data were used to identify individuals in the study population with ADHD and also maternal or paternal psychiatric morbidity. A substantial part of ADHD treatment in Denmark is conducted by general practitioners and psychiatric specialists in private practice. Therefore, we tracked dates of any filled ADHD medication prescriptions as a separate outcome. We carried out a separate analysis for each outcome defined. Data on the educational level of parents were accessed from Statistics Denmark. The highest educational level achieved by the parents during the study period was classified as primary education, secondary education, or higher education. We used the DNRP to identify diagnoses of congenital defects and chromosomal abnormalities. We obtained data on gestational age at birth from the Danish Medical Birth Registry. The study was approved by the Danish Data Protection Agency. The role of this agency is to protect the privacy of individuals whose data are recorded in Danish registries. The informed consent of participants was not required for this study. We began follow-up of patients with AD and the comparison cohort on the date of AD diagnosis (index date for subjects in the comparison group). Follow-up continued until one of the following occurred: an ADHD diagnosis (or the date a prescription on ADHD medication was filled), emigration, death, or January 1, 2013. The computed risks of ADHD (Fig 1) were based on the Kaplan-Meier estimator because a competing risk of death was negligible in both cohorts. We used Cox proportional
FIG 1. Risk of filling 1 or more prescriptions for ADHD medication in patients with AD and in a sex- and age-matched comparison cohort. Risk of medication requirement is stratified according to sex (A and B), age at AD diagnosis (C-E), and parental educational level (F-H).
1
2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2016
TABLE I. Characteristics of 11,877 patients diagnosed with AD in Denmark between 1995 and 2011 and a general population comparison cohort matched for birth year and sex Characteristic
Patients with AD, n (%)
All 11,877 (100) Sex: male 6,881 (58) Year of birth 1995-1999 4,649 (39) 2000-2004 4,279 (36) 2005-2010 2,949 (25) Gestational age (y) <37 727 (6) 37-38 2,124 (18) 39-40 5,576 (47) > _41 3,009 (25) Missing data 441 (4) Congenital defects 902 (8) Maternal psychiatric diagnosis 1,518 (13) Paternal psychiatric diagnosis 961 (8) Highest parental educational level Primary education 1,500 (13) Secondary education 5,346 (45) Higher education 4,981 (42) Data missing 50 (0.4) Age at AD diagnosis (y) 0-1 6,250 (53) 2-4 3,525 (30) 5-14 2,102 (18) Asthma 1,798 (15) Inpatient AD admission 3,447 (29)
Comparison cohort, n (%)
118,751 (100) 68,834 (58) 46,446 (39) 42,815 (36) 29,490 (25) 7,365 21,152 56,775 29,683 3,776 6,186 11,966 8,261
(6) (18) (48) (25) (3) (5) (10) (7)
13,283 (11) 53,263 (45) 51,668 (44) 537 (0.5) — — — — — —
regression analyses to compute hazard ratios (HRs), presented with 95% CIs, of the time to an ADHD diagnosis or to filling a prescription for patients with AD compared with the general population cohort. The HRs were adjusted for sex, birth year, parental educational level, parental psychiatric history, gestational age at birth, and the presence of a congenital defect. Individuals with missing data on parental educational level were excluded from the analyses (;3%). We graphically verified the assumption of proportional hazards. Analyses were performed with Stata 13 (StataCorp LP, College Station, Tex). We identified 11,877 patients with AD. Their characteristics are presented in Table I. The overall HR comparing patients with AD with the general population cohort was 1.3 (1.2-1.5) for an ADHD medication requirement and it was 1.3 (1.1-1.6) for an ADHD-related admission or outpatient clinic visit. The HRs did not vary substantially according to sex, year of birth, length of follow-up, age at AD diagnosis, presence of asthma, highest parental educational level, and admission type. Our results have extended findings from earlier studies on ADHD in patients with AD. A few case-control5,6 and crosssectional7 studies also reported an association between AD and ADHD. A German questionnaire-based study, published in 2014, followed 770 children from birth to age 11 years (followup rate 71%).4 That study also found an increased risk of ADHD in children with AD, but only in the period just after the AD diagnosis. In contrast to that study, we found similar associations between AD and ADHD in various follow-up periods. Some possible mechanisms underlying the increased risk of ADHD among patients with AD include psychological stress (eg, from sleep deprivation) and prolonged release of inflammatory
mediators8; however, this study does not allow us to draw further conclusions with regard to causal mechanisms. The data in the DNRP were reported to have a high positive predictive value for several disease diagnoses. Moreover, any misclassification of AD would have been independent of future ADHD development. The Civil Registration System allowed a population-based design with complete long-term follow-up of vital status, emigration, prescriptions filled for ADHD medication, and ADHD hospital admissions. High validity was also expected for hospital ADHD diagnoses coded in the DPCR, based on validation studies on other psychiatric diagnoses, including schizophrenia, affective psychoses, and childhood autism.9 We considered several important factors known to be associated with ADHD in our analyses, that is, age, sex, parental psychiatric history, social status (in terms of parental educational level), gestational age at birth, and the presence of congenital defects or chromosomal anomalies. However, potential residual confounding may have been present, for example, subclinical parental psychiatric disorders or unknown risk factors for psychiatric disorders. The potential presence of 1 or more of these factors cannot be excluded. We identified increased ADHD risk in patients diagnosed with AD in a hospital setting compared with the risk in a general population cohort. Increased risk was also observed in patients with AD who only received outpatient treatment and were never admitted as inpatients. The results indicate that optimal medical follow-up of patients with AD may need to include mental health evaluation. Jette Lindorff Riis, MD, PhDa Christian Vestergaard, MD, PhD, DMSca Mette S. Deleuran, MD, DMSca Morten Olsen, MD, PhDb From athe Department of Dermatology and bthe Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors declare they have no relevant conflicts of interest. REFERENCES 1. Schmitt J, Schmitt NM, Kirch W, Meurer M. Outpatient care and medical treatment of children and adults with atopic eczema. J Dtsch Dermatol Ges 2009;7:345-51. 2. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56. 3. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007;164:942-8. 4. Genuneit J, Braig S, Brandt S, Wabitsch M, Florath I, Brenner H, et al. Infant atopic eczema and subsequent attention-deficit/hyperactivity disorder–a prospective birth cohort study. Pediatr Allergy Immunol 2014;25:51-6. 5. Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, et al. Comorbidity of allergic and autoimmune diseases among patients with ADHD: a nationwide population-based study. J Atten Disord February 11, 2013 [Epub ahead of print]. 6. Tsai JD, Chang SN, Mou CH, Sung FC, Lue KH. Association between atopic diseases and attention-deficit/hyperactivity disorder in childhood: a populationbased case-control study. Ann Epidemiol 2013;23:185-8. 7. 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;301:724-6. 8. Buske-Kirschbaum A, Schmitt J, Plessow F, Romanos M, Weidinger S, Roessner V. Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology 2013;38:12-23. 9. Lauritsen MB, Jørgensen M, Madsen KM, Lemcke S, Toft S, Grove J, et al. Validity of childhood autism in the Danish Psychiatric Central Register: findings from a cohort sample born 1990-1999. J Autism Dev Disord 2010;40:139-48. http://dx.doi.org/10.1016/j.jaci.2016.01.027
the participants in both cohorts to search the Danish Psychiatric Central Registry (DPCR) for records from Danish psychiatric hospitals on inpatient admissions (maintained since 1970) and outpatient visits (maintained since 1995). The DPCR data were used to identify individuals in the study population with ADHD and also maternal or paternal psychiatric morbidity. A substantial part of ADHD treatment in Denmark is conducted by general practitioners and psychiatric specialists in private practice. Therefore, we tracked dates of any filled ADHD medication prescriptions as a separate outcome. We carried out a separate analysis for each outcome defined. Data on the educational level of parents were accessed from Statistics Denmark. The highest educational level achieved by the parents during the study period was classified as primary education, secondary education, or higher education. We used the DNRP to identify diagnoses of congenital defects and chromosomal abnormalities. We obtained data on gestational age at birth from the Danish Medical Birth Registry. The study was approved by the Danish Data Protection Agency. The role of this agency is to protect the privacy of individuals whose data are recorded in Danish registries. The informed consent of participants was not required for this study. We began follow-up of patients with AD and the comparison cohort on the date of AD diagnosis (index date for subjects in the comparison group). Follow-up continued until one of the following occurred: an ADHD diagnosis (or the date a prescription on ADHD medication was filled), emigration, death, or January 1, 2013. The computed risks of ADHD (Fig 1) were based on the Kaplan-Meier estimator because a competing risk of death was negligible in both cohorts. We used Cox proportional
FIG 1. Risk of filling 1 or more prescriptions for ADHD medication in patients with AD and in a sex- and age-matched comparison cohort. Risk of medication requirement is stratified according to sex (A and B), age at AD diagnosis (C-E), and parental educational level (F-H).
1
2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2016
TABLE I. Characteristics of 11,877 patients diagnosed with AD in Denmark between 1995 and 2011 and a general population comparison cohort matched for birth year and sex Characteristic
Patients with AD, n (%)
All 11,877 (100) Sex: male 6,881 (58) Year of birth 1995-1999 4,649 (39) 2000-2004 4,279 (36) 2005-2010 2,949 (25) Gestational age (y) <37 727 (6) 37-38 2,124 (18) 39-40 5,576 (47) > _41 3,009 (25) Missing data 441 (4) Congenital defects 902 (8) Maternal psychiatric diagnosis 1,518 (13) Paternal psychiatric diagnosis 961 (8) Highest parental educational level Primary education 1,500 (13) Secondary education 5,346 (45) Higher education 4,981 (42) Data missing 50 (0.4) Age at AD diagnosis (y) 0-1 6,250 (53) 2-4 3,525 (30) 5-14 2,102 (18) Asthma 1,798 (15) Inpatient AD admission 3,447 (29)
Comparison cohort, n (%)
118,751 (100) 68,834 (58) 46,446 (39) 42,815 (36) 29,490 (25) 7,365 21,152 56,775 29,683 3,776 6,186 11,966 8,261
(6) (18) (48) (25) (3) (5) (10) (7)
13,283 (11) 53,263 (45) 51,668 (44) 537 (0.5) — — — — — —
regression analyses to compute hazard ratios (HRs), presented with 95% CIs, of the time to an ADHD diagnosis or to filling a prescription for patients with AD compared with the general population cohort. The HRs were adjusted for sex, birth year, parental educational level, parental psychiatric history, gestational age at birth, and the presence of a congenital defect. Individuals with missing data on parental educational level were excluded from the analyses (;3%). We graphically verified the assumption of proportional hazards. Analyses were performed with Stata 13 (StataCorp LP, College Station, Tex). We identified 11,877 patients with AD. Their characteristics are presented in Table I. The overall HR comparing patients with AD with the general population cohort was 1.3 (1.2-1.5) for an ADHD medication requirement and it was 1.3 (1.1-1.6) for an ADHD-related admission or outpatient clinic visit. The HRs did not vary substantially according to sex, year of birth, length of follow-up, age at AD diagnosis, presence of asthma, highest parental educational level, and admission type. Our results have extended findings from earlier studies on ADHD in patients with AD. A few case-control5,6 and crosssectional7 studies also reported an association between AD and ADHD. A German questionnaire-based study, published in 2014, followed 770 children from birth to age 11 years (followup rate 71%).4 That study also found an increased risk of ADHD in children with AD, but only in the period just after the AD diagnosis. In contrast to that study, we found similar associations between AD and ADHD in various follow-up periods. Some possible mechanisms underlying the increased risk of ADHD among patients with AD include psychological stress (eg, from sleep deprivation) and prolonged release of inflammatory
mediators8; however, this study does not allow us to draw further conclusions with regard to causal mechanisms. The data in the DNRP were reported to have a high positive predictive value for several disease diagnoses. Moreover, any misclassification of AD would have been independent of future ADHD development. The Civil Registration System allowed a population-based design with complete long-term follow-up of vital status, emigration, prescriptions filled for ADHD medication, and ADHD hospital admissions. High validity was also expected for hospital ADHD diagnoses coded in the DPCR, based on validation studies on other psychiatric diagnoses, including schizophrenia, affective psychoses, and childhood autism.9 We considered several important factors known to be associated with ADHD in our analyses, that is, age, sex, parental psychiatric history, social status (in terms of parental educational level), gestational age at birth, and the presence of congenital defects or chromosomal anomalies. However, potential residual confounding may have been present, for example, subclinical parental psychiatric disorders or unknown risk factors for psychiatric disorders. The potential presence of 1 or more of these factors cannot be excluded. We identified increased ADHD risk in patients diagnosed with AD in a hospital setting compared with the risk in a general population cohort. Increased risk was also observed in patients with AD who only received outpatient treatment and were never admitted as inpatients. The results indicate that optimal medical follow-up of patients with AD may need to include mental health evaluation. Jette Lindorff Riis, MD, PhDa Christian Vestergaard, MD, PhD, DMSca Mette S. Deleuran, MD, DMSca Morten Olsen, MD, PhDb From athe Department of Dermatology and bthe Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors declare they have no relevant conflicts of interest. REFERENCES 1. Schmitt J, Schmitt NM, Kirch W, Meurer M. Outpatient care and medical treatment of children and adults with atopic eczema. J Dtsch Dermatol Ges 2009;7:345-51. 2. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56. 3. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007;164:942-8. 4. Genuneit J, Braig S, Brandt S, Wabitsch M, Florath I, Brenner H, et al. Infant atopic eczema and subsequent attention-deficit/hyperactivity disorder–a prospective birth cohort study. Pediatr Allergy Immunol 2014;25:51-6. 5. Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, et al. Comorbidity of allergic and autoimmune diseases among patients with ADHD: a nationwide population-based study. J Atten Disord February 11, 2013 [Epub ahead of print]. 6. Tsai JD, Chang SN, Mou CH, Sung FC, Lue KH. Association between atopic diseases and attention-deficit/hyperactivity disorder in childhood: a populationbased case-control study. Ann Epidemiol 2013;23:185-8. 7. 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;301:724-6. 8. Buske-Kirschbaum A, Schmitt J, Plessow F, Romanos M, Weidinger S, Roessner V. Psychoendocrine and psychoneuroimmunological mechanisms in the comorbidity of atopic eczema and attention deficit/hyperactivity disorder. Psychoneuroendocrinology 2013;38:12-23. 9. Lauritsen MB, Jørgensen M, Madsen KM, Lemcke S, Toft S, Grove J, et al. Validity of childhood autism in the Danish Psychiatric Central Register: findings from a cohort sample born 1990-1999. J Autism Dev Disord 2010;40:139-48. http://dx.doi.org/10.1016/j.jaci.2016.01.027