Asthma Diagnosis Verified by Lung Function
Asthma Diagnosis Verified by Lung Function
Guidelines suggests that asthma should not be treated prior to a reversibility test and/or an
 assessment with peak expiratory flow (PEF) unless there is a clinical urgency for the patient
 to be treated. Approximately one third of patients with diagnosed asthma can safely step-wise
 withdraw their asthma medication and diagnosis based on repeated objective lung function
 measurements. AsthmaTuner is CE-marked and provides doctors and nurses with information on
 patient spirometry incl. reversibility test and diurnal or weekly variability of PEF in
 relation perceived symptoms. Thereby, digital supported asthma care with AsthmaTuner can
 improve objective diagnosis of asthma. The objectives of this study are to evaluate the
 sensitivity and specificity to establish objective asthma diagnosis with spirometry including
 reversibility test and PEF-monitoring with AsthmaTuner, and secondary, assess the number of
 asthma patients with objective verified asthma diagnosis with use of spirometry including
 reversibility test and/or periodic variability with PEF/FEV1 between traditional trial
 treatment and treatment with AsthmaTuner. At least 146 patients will be included who are at
 least six years old, with respiratory symptoms that can be signed to asthma last month or
 with physician-diagnosed asthma last five years without intake of anti-inflammatory treatment
 in the last three months. This is a randomised controlled trial evaluating a diagnostic two
 step algorithm that firstly includes dynamic spirometry with a reversibility test and
 PEF/FEV1 monitoring with AsthmaTuner during 2-4 weeks, and secondly randomization to
 traditional trial treatment with dynamic spirometry with a reversibility test, or AsthmaTuner
 incl. PEF/FEV1 monitoring during trial treatment. We plan to include in total 146 patients in
 primary care with either undiagnosed asthma having respiratory symptoms that can be signed to
 asthma last month, or patients with a asthma diagnosis last 5 years but no intake of regular
 anti-inflammatory asthma medication last 3 months. The study start in early 2021 and finish
 in 2023.
The Global Initiative for Asthma (GINA) guidelines suggests that asthma should not be treated
 prior to a reversibility test and/or an assessment of peak expiratory flow (PEF) variability
 over time unless there is a clinical urgency for the patient to be treated. If lung function
 measurements do not verify an asthma diagnosis, GINA suggests repeating these tests at a
 later time or applying alternative tests such as bronchial challenges. In spite of clear
 diagnostic guidelines, current clinical practice relies mostly on evidence of symptoms and
 assessments of the effect of trial treatments instead of frequently use objective lung
 function measurements to verify obstructive airway disease. Trial treatments including
 testing responses to anti-inflammatory medications have lead to increasing numbers of normal
 spirometry tests and fewer patients with an objective verified asthma diagnosis. Aaron et al.
 (JAMA 2017) showed that a current diagnosis of asthma could not be established in 33% of
 patients with a physician-diagnosed asthma within the last five years. Further, Aaron et al.
 gradually tapered off patients' asthma medication and defined them as mis-diagnosed if they
 were still symptom-free after 12 months of observation. Altogether, to solve the problem of
 mis-diagnosed asthma, it is necessary to secure objective evidence of airway obstruction, and
 if trial treatment is needed due to the clinical urgency of the patient's respiratory
 condition, reassessment with lung function test is mandatory.

 The CE-marked AsthmaTuner provides doctors and nurses with daily automated percentage
 calculations of diurnal and weekly variability of PEF or forced expiratory volume in one
 second (FEV1) in close relation with the patient's symptoms, thereby supporting asthma care
 with information if the patient has variable expiratory airflow limitation and a history of
 typical asthma symptoms. These collected data contain unexpected amounts of information for
 correct diagnosis of individuals with asthma and different phenotypes. Hence, AsthmaTuner may
 improve the quality of asthma care and support more precise diagnosis according to objective
 diagnostic criteria based on lung function, and if correctly validated and applied, reduce
 the problem with over- and under-diagnosis in asthma care.

 The objectives of this study are to evaluate the sensitivity and specificity to establish
 objective asthma diagnosis with spirometry including reversibility test and PEF-monitoring
 with AsthmaTuner, and secondary, assess the number of asthma patients with objective verified
 asthma diagnosis with use of spirometry including reversibility test and/or periodic
 variability with PEF/FEV1 between traditional trial treatment and treatment with AsthmaTuner.

 Study population At least 146 participants will be included who are at least six years old,
 with respiratory symptoms that can be signed to asthma last month or with diagnosed asthma
 last five years, but no regular intake of anti-inflammatory treatment in the last three
 months. Exclusion criteria are daily intake of asthma control medication, use of oral
 corticosteroids, pregnancy, breast feeding, inability to perform spirometry, or a
 contraindication of a severe a medical condition, i.e. heart failure or aorta or cerebral
 aneurysm or history of myocardial infarction or stroke within three months or a smoking
 history greater than ten pack-years (possible COPD). Patients will be included at Liljeholmen
 Healthcare Centre, Ekerö Healthcare Centre in the region of Stockholm County Council, and
 Närhälsan Färgelanda Healthcare Centre, Västra Götaland County Council in Sweden.

 Design This is a randomised controlled trial evaluating a diagnostic algorithm that includes
 dynamic spirometry with a reversibility test, PEF/FEV1 monitoring with AsthmaTuner and
 traditional trial treatment with dynamic spirometry with a reversibility test, PEF/FEV1
 monitoring with AsthmaTuner and trial treatment with AsthmaTuner in a primary care setting.
 In the first stage, each patient will perform spirometry with a reversibility test and two
 weeks of daily monitoring with AsthmaTuner. Patients will be prescribed an inhaler with
 beta-2 agonist to prevent respiratory symptoms during daily lung function measurements in
 morning (after awaking) and evening. If any test is positive, the patient will fulfil the
 study definition of current asthma. If both tests are negative, a trial treatment of at least
 three months will be performed that is either traditional or with AsthmaTuner. The allocation
 to either AsthmaTuner or trial treatment will be 1:1 and masked to investigator. After the
 three months trial treatment, participants will at final clinical visit perform spirometry
 with reversibility test. If current asthma is still unverified, physician may rule out asthma
 medication and diagnosis or initiate further investigations including measures in the regular
 clinical work-up or let patient continue with trial treatment up to 12 months after
 inclusion.

 AsthmaTuner (Medituner AB, Stockholm, Sweden) is a CE-marked cloud computing-based system
 with a healthcare interface and a downloadable patient app (Android or iOS). Patients
 download the app from the AppStore or Google Play and create a user account. The app consists
 of two features: 1) diagnosis based on serial measurements of PEF/FEV1, and 2)
 self-management with a physician-prescribed treatment recommendation.

 The intended use is to improve diagnosis and management of asthma with an automated clinical
 decision support system called AsthmaTuner by letting patients register symptoms and measure
 FEV1. The self-management feature consists of a treatment-adjusting algorithm that gives
 patient immediate feedback on the status of symptom control (i.e. controlled, partly
 controlled or uncontrolled) and a treatment recommendation with an image of the correct
 inhaler or other type of medication and the dose. Symptom control is quantified based on lung
 function, i.e. liter to percentage of personalized best FEV1 using a cut-off of ≤80% and
 symptoms during the last week based on answers to four questions about the following: 1) the
 need for rescue medication more than twice due to asthma symptoms, 2) any daytime symptoms,
 3) nocturnal symptoms/awakenings, and 4) limitations in physical activities. AsthmaTuner
 offers patients and health care providers longitudinal data views of assessed symptom
 control, prescribed treatments and lung function measurements. The back-end data storage of
 the cloud-based system provides information about participant adherence with AsthmaTuner use.

 Dynamic spirometry with reversibility test Lung function will be measured at study enrolment,
 including analysis of FEV1, forced vital capacity (FVC), FEV1/FVC and forced expiratory flow
 after 25-75% of vital capacity (FEF 25-75). A reversibility test will be performed after
 intake of at least four standard doses of salbutamol or terbutaline. During trial treatment,
 dynamic spirometry will be performed using AsthmaTuner online.

 Questionnaires Participants will complete an electronic questionnaire concerning demographic
 background factors, respiratory symptoms, treatment, and healthcare utilization at study
 enrollment and again about respiratory symptoms at study end, as well as answer questions
 about the usability and feasibility of using AsthmaTuner at study end.

 Statistical analyses The statistical power analysis is based on Aaron et al., who reported a
 proportion of positive reversibility tests of 14 percentage points among 613 randomised
 selected individuals with doctor-diagnosed asthma. An estimated proportion of 28% of
 participants with asthma will have positive diurnal or weekly PEF/FEV1 variability of at
 least 10% or more, including 146 participants who would provide a power of 80% at a 5%
 significance level with adjustment for a 10% drop out rate. A receiver-operating
 characteristic (ROC) curve will be plotted for spirometry and reversibility tests, and
 PEF/FEV1 percentage variability given by AsthmaTuner with Spearmen's rank correlations to
 estimate the predictive values. The optimal cut-off level for sensitivity and specificity
 will be estimated based on the area under the curve.
Inclusion Criteria:

 -  Presence of respiratory symptoms that can be signed to asthma last month or

 -  Only doctor diagnosed asthma last five years

 Exclusion Criteria:

 -  Daily intake of asthma control medication

 -  Use of oral corticosteroids

 -  Pregnancy, breast feeding

 -  Inability to perform spirometry

 -  A contraindication of a severe a medical condition, i.e. heart failure or aorta or
 cerebral aneurysm or history of myocardial infarction or stroke within three months

 -  Smoking history greater than ten pack-years (possible COPD).