No associations between type 1 diabetes and atopic dermatitis, allergic rhinitis, or asthma in childhood: a nationwide Danish case-cohort study

Studies examining the association between type 1 diabetes (T1D) and atopic diseases, i.e., atopic dermatitis, allergic rhinitis and asthma have yielded conflicting results due to different algorithms for classification, sample size issues and risk of referral bias of exposed cohorts with frequent contact to health care professionals. Using Danish national registries and well-established disease algorithms, we examined the bidirectional association between T1D and atopic diseases in childhood and adolescence using Cox Proportional Hazard regression compared to two different unexposed cohorts from a population of 1.5 million Danish children born from 1997 to 2018. We found no associations between T1D and atopic dermatitis, allergic rhinitis, or asthma (defined after age five). However, in multivariable analysis we found an increased risk of persistent wheezing (defined as asthma medication before age five) after T1D with an adjusted hazard ratio (aHR) of 1.70 [1.17–2.45]. We also identified an increased risk of developing T1D after persistent wheezing with aHR of 1.24 [1.13–1.36]. This study highlights similar risks of atopic diseases in children with T1D and of T1D in children with atopic disease after age of five years versus healthy controls. However, more research is needed to understand the possible early immunological effects of the link between persistent wheezing and T1D.


T1D
T1D was defined by using the Danish National Patient Registry and the ICD-10 code: DE10, all other DE10x and DE14 which had been validated in a pediatric age group using the Danish Registry of Childhood and Adolescent Diabetes 15 .Clinical onset of T1D was defined as the first hospital contact with the diagnosis-code.For T1D in parents only DE10, and all other DE10x was used.

Atopic dermatitis
Atopic dermatitis was defined by using the Danish National Patient Register and the ICD-10 code: DL20.The validity of the atopic dermatitis-diagnosis in Danish registries have been proven high 16 and most medication is not disease-specific explaining why algorithms with prescriptions are not included to get a more sensitive algorithm.Clinical onset or progression of atopic dermatitis was defined as the first hospital contact with the diagnosis-code.

Allergic rhinitis
Allergic rhinitis is defined based on three different algorithms: Dates for clinical onset for all models for allergic rhinitis was defined as the first hospital contact with the specific diagnosis or the first prescription and for model A, the first date of prescription of any antihistamine will be coded as the date of clinical onset.

Asthma
Asthma is defined based on three different models-all only for children after age of 5 years: -A: based on the Danish National Patient Register including ICD-10 codes: o J45, J450, J451, J458, J459, J469 which had been validated in both children 21

Other definitions
Cystic fibrosis (CF) is defined based on hospital diagnosis as any ICD-code DE84x.
Cerebral Palsy (CP) is defined based on hospital diagnosis as any ICD-code DG80x The atopic medication that are used for exclusion criteria for the secondary unexposed cohort to the atopic cohort is defined as dermatitis-drugs (D11AH), systemic steroids (H02), topical steroids (D07), inhalation steroids (R01AD, R03AK), nasal steroids (R03AL), or antihistamines (R06) with the first date of that medication included since criteria was no atopic medication prior to start of follow-up.
Delivery by caesarian section was based on mother's surgery diagnosis code KMCA from time of birth.
Prematurity was defined as gestational age less than 37 weeks and categorized from diagnosis code DP072 and DP073.
Season of birth was categorized based on birthdate in spring (March, April, and May), summer (June, July, and August), fall (September, October, and November) and winter (December, January, and February).
Family history of the outcome disease was for T1D based on parental T1D and for the atopic diseases based on full siblings since reliable parental atopic disease history was not available.
Definitions for the sensitivity methods: i. an atopic dermatitis-cohort exposed or unexposed to T1D investigated later onset of asthma or allergic rhinitis ii.
mild and severe atopic dermatitis (defined as use of corticosteroids from group three or group four (D07AC, D07AD) and subsequent risk of T1D iii.atopic dermatitis diagnosed by dermatologist or other specialties as exposure for T1D iv.
atopic dermatitis as both exposure and outcome for T1D with two new less strict or specific atopic dermatitis-algorithms defined as one prescription of D07 steroid lotion and based on Henriksen et al.'s algorithm 18 compared to the primary analysis v.
food allergy (defined as ICD-code DZ910x or DT780) alone or in a more severe type including prescription on adrenaline, C01CA24) as both exposure and outcome to T1D and as a sub analysis with combination of atopic dermatitis and food allergy vi.
asthma in a T2-high (defined as asthma + allergic rhinitis or food allergy) or T2-low (only asthma without any topical steroids used) as exposure for later T1D.

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A: based on a hospital diagnosis of allergic rhinitis (shown to yield high specificity (1.00) although low sensitivity (0.01) in adults 17 ) based on ICD-10-codes J30, H101 and H104A.-B: based on prescription data (showing specificity on 0.94 and sensitivity on 0.21 in adults 17 : o At least two prescriptions of oral/nasal/ophthalmic antihistamine or intranasal corticosteroids with the drug codes: S01GA51, S01GX02, S01GX06-09, R06AX13, R06AX18, R06AX22, R06AX26-29, R06AE07, R06AE09, R01AD.-C: based on Henriksen et al.'s algorithm 18 which by Stensballe et al. was shown a specificity in pediatric individuals on 0.80 and a sensitivity on 0.84 19 At least twice in 12 months ▪ Inhaled combination drugs of ICS and LABA (R03AK06, R03AK07) years of age was defined as persistent wheezing if criteria in model C for asthma is fulfilled, since asthma is not diagnosed in children in this age group.Clinical onset for all models for asthma or persistent wheezing was defined as the first hospital contact with the specific diagnosis in model A and the first prescription in model B and C.

Table S3 -
Effects of Type 1 Diabetes on later atopic disease compared to secondary unexposed cohorts Raw incidence rates (IR) shown per 1000 person-year for respectively T1D-exposed cohort (A) and the secondary unexposed cohort as control cohort (B), Hazard ratio (HR) from Cox regressions is based on exposed case cohort compared to the secondary unexposed cohort (individuals with cerebral palsy).The raw p-values are shown as Praw, where Pcorr are familywise corrected by Benjamini-Hochberg §Adjusted models are adjusted for age group, sex, born by Caesarian section, prematurity, season of birth and relevant family history (sibling with asthma for models of risk of asthma etcetera).
Abbreviations: SD, standard deviation, C-section, Caesarian section, T1D, Type 1 Diabetes *The number of random age-and sex-matched individuals per case were for allergic rhinitis in model B three and for allergic rhinitis in model C two.Supplementary