Aims
- Describe disease characteristics, including comorbidities, exacerbation history, lung function and airway responsiveness among elderly adults with a history of severe childhood asthma.
- Investigate long-term outcome of severe childhood asthma with regard to remission in late adulthood.
- Assess socioeconomic status factors among elderly adults with a history of childhood asthma compared to age-matched individuals with no previous diagnosis of obstructive airways disease.
- Determine factors associated with airflow limitation in elderly adults with a history of childhood asthma.
- Assess all-cause and disease-specific mortality in individuals with a history of severe childhood asthma.
- Examine genetic variations (SNPs) that may increase the risk of developing asthma and COPD during adult life.
Study design
The Kongsberg cohort population
The Kongsberg cohort comprises children with asthma that were referred to the Kongsberg asthma care facility, Norway, for a 4-month stay between 1950 and 1979 by physicians, primarily from the former Queen Louise’s Children’s Hospital in Copenhagen, Denmark. The Danish Red Cross managed the asthma care facility and organized the stays in Kongsberg. There are index cards and registration lists for all groups of children with a stay at Kongsberg, and by that the individuals comprising the Kongsberg cohort.
The available data from the children’s index cards and registration lists will be linked to each individual’s unique civil personal registration (CPR) number, a ten-digit number provided permanent residents in Denmark, in three steps. Firstly, we will digitalize data by entering lists with individuals’ data, that is name and date of birth, obtained from the index cards and registration lists for each group of children that was sent to Kongsberg, Norway. Secondly, from the unique civil personal registration database (in Danish called the CPR register), all CPR numbers of all individuals with the same name and date of birth of individuals appearing on index cards and registration list for the Kongsberg cohort will be extracted. Finally, the Danish Health Data Authority will match the CPR numbers extracted from the CPR register individual names and birth dates of the Kongsberg cohort. The Danish Health Data Authority will afterwards deliver CPR number of every individual of the Kongsberg cohort currently alive and residing in Denmark.
The eligible individuals with a previous stay at the Kongsberg asthma facility in childhood will be contacted by the research group for a follow-up examination program to assess current health status. In addition, the research group will apply for approval of access to data from national registries to investigate current socioeconomic status and mortality of individuals in the Kongsberg cohort.
Setting
This study comprises a follow-up examination program for individuals, who attended the Kongsberg asthma care facility in childhood due to severe asthma, as described in the ‘Examination program at study visit’, together with data obtained from nationwide registries, as described under ‘Registries’. The examination program will take place at The Respiratory Research Unit at Copenhagen University Hospital - Hvidovre.
Registries
All hospital contacts, including primary and secondary diagnoses for each hospital contact, in Denmark are reported according to the International Classification of Diseases, 8th revision (ICD-8) from 1977 to 1993 and from 1994 the 10th revision (ICD-10) to the Danish National Patient Registry (DNPR), a part of Statistics Denmark. The DNPR has registered these data since 1977. The DNPR holds data on demographics, comorbidities, diagnoses, dates of admission and discharge from hospitals, and data for the registry data analyses will be provided from Statistics Denmark.
Data on filled prescriptions for each individual will be obtained from the Danish National Prescription Registry. The Danish National Prescription Registry comprises information on all prescriptions filled at national pharmacies since 1995. The available data includes information on date of dispensing, number of doses, strength, and the Anatomical Therapeutic Chemical (ATC) code. Statistics Denmark will also deliver data from the Danish National Prescription Registry for the analyses.
From Statistics Denmark, we will also obtain data from registries based on income, occupation (IND and LON) and education (UDDA). The data includes salaries, pensions (early retirement, which is granted to persons with a significant and permanently reduced ability to work, or voluntary early retirement), and levels of education. Registries on income and education comprise information on Danish residents since 1980.
Data on mortality of the Kongsberg cohort will be delivered from the Danish registry on cause of death (DAR), a part of the Danish Health Data Authority, which collects information from death certificates on all deaths in Denmark since 1970. The DAR holds data on causes of death, date of death, and age at time of death.
Examination program at study visit
The following examinations and procedures will be carried out at the day of study visit. All procedures will be explained and demonstrated in detail to the participant prior to data being obtained:
- Questionnaires
- ACT (Asthma Control Test) (26, 27).
- ACQ-7 (Asthma Control Questionnaire) (28).
- CAT (COPD Assessment Test) (29).
- CCQ (Clinical COPD Questionnaire) (30).
- MRC (Medical Research Council) dyspnea scale (31).
- Information will also be obtained for participants with regard to age, occupational history, marital status, lifestyle (including smoking habits, physical activity, alcohol use), comorbidities, including asthma, COPD, diabetes, cardio-vascular disease, osteoporosis, eczema, rhinitis, sleep-apnea, cataract, depression, and anxiety, and height and weight measurements, exacerbations in the past 12 months, prescribed medication for obstructive lung disease at the time of follow-up, unscheduled contacts with their GP for their chronic airways disease within the past 12 months, visits to the emergency room or hospital admission for chronic airway disease within the past 12 months.
- Blood samples: C-Reactive Protein (CRP), alpha1-antitrypsin, white cell count and differential, red cell count, hemoglobin, vitamin D, and serum total IgE. Approximately 200 ml of blood will be collected from each participant for analysis. Blood samples will either be analyzed when collected or stored as a research biobank throughout the project period and destroyed according to Danish legislation.
- Fractional exhaled nitric oxide: fractional exhaled nitric oxide (FENO) will be measured with EcoMedics CLD 88sp analyzer and DENOX 88 at a controlled flow rate of 50 ml/s according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines, and the mean value of two measurements in parts per billion (ppb) will be recorded (32).
- Skin prick test: the skin prick test (SPT) will be performed according to the European Academy of Allergy and Clinical Immunology (33, 34). The test will be carried out with 9 different aeroallergens: birch, grass, mugwort, dog, cat, dust mites (Dermatophagoides pteronyssinus and D. farinae), and moulds (Alternaria alternata and Cladosporium herbarum). The SPT will be positive if the wheal diameter is ≥ 3 mm after 15 minutes to at least one of the aeroallergens, and atopy is defined as a positive SPT (35).
- Spirometry: measurement of forced expiratory volume in the first second (FEV1) from a maximum inspiration, forced vital capacity (FVC) and calculation of the FEV1/FVC ratio (Vitalograph 6800 pneumotrac) according to ERS/ATS guidelines (36, 37). The participant will have three consecutive spirometry measurements. The reproducibility requirements must be met by the two best measurements. The best FEV1 and FVC values should be no more than 5% or 150 mL apart. Predicted FEV1 will be calculated based on height, age and sex (38).
- Bronchodilator reversibility test: the bronchodilator reversibility test will be a measurement of FEV1 before and after administration of 0.4 mg of salbutamol. A positive reversibility test will be defined as an improvement of 12% and ≥200 ml in FEV1 from the pre-bronchodilator value.
- Body Plethysmography: measurement of vital capacity (VC), and static lung volumes, including residual volume (RV), and total lung capacity (TLC) using a whole-body plethysmograph (Vitalograph 6800 pneumotrac) and according to ERS/ATS guidelines (36, 37).
- Diffusion capacity (DLCO): diffusion capacity will be measured by the single-breath carbon monoxide gas transfer method together with the diffusion constant KCO. The participant inhales a gas mixture containing 0.3% carbon monoxide (CO), 9.3% helium, 21% oxygen and nitrogen. All results will be presented as percent predicted (39).
- Bronchial challenge test: the mannitol bronchial provocation test will be performed using the commercial mannitol kit Osmohale© Pharmaxis (Pharmaxis Ltd, Australia) (40). The kit provided for the bronchial challenge test includes filled capsules of mannitol in increasing doses and a dry powder inhaler. The challenge is carried out as previously described (41). An evaluation of the safety of mannitol as a bronchial challenge test has previously been published (42). If needed, rescue bronchodilator (0.2 mg salbutamol) will be provided at the end of the challenge test for aided recovery.
- A genome-wide scan will be performed on EDTA blood samples in order to investigate genetic variants (SNPs) expected to influence airway development with a focus on SNPs related to asthma or COPD. This will be done using a modified version of the Infinium Global Screening Array. The method applied is, therefore, not considered extensive genetic mapping according to the genome guidelines. The analyses will be performed at the national State Serum Institute (SSI) department for neonatal screening.
Definitions
- Remission of asthma
Childhood asthma remission is defined as no use of asthma medications and no reported asthma symptoms within the previous 12 months (43).
- Severe asthma
Severe asthma is defined as asthma that is treated with high-dose inhaled corticosteroids plus a second controller (or systemic corticosteroids for more than 50% of the last 12 months) or which remains ‘uncontrolled’ despite this therapy (44).
Study endpoints
The primary endpoint will be to determine prevalence of childhood asthma remission in adult participants with previous severe childhood asthma in a follow-up examination.
The secondary endpoint is to quantify prevalence of airflow limitation and characteristics, including socioeconomical status in included population of adults with a history of childhood asthma.
The last endpoint is to determine mortality and genetic susceptibility associated with obstructive lung disease development in included study cohort.
Statistical Analyses
Data will be reported as mean values ± one standard deviation (SD). Clinical variables are compared using independent sample t-test for continuous variables and chi-square for binary variables. The comparison between variables of interest and characteristics will be conducted using a logistic regression model and reported as odds ratio (OR) and 95% confidence intervals (CI). A p-value < 0.05 will be considered statistically significant. Genetic effect modification will be analyzed based on candidate variants as well as combined polygenic risk scores for asthma and COPD. Data will be analyzed using the statistical program R Statistics 3.61 software (R Foundation for Statistical Computing, Vienna, Austria).