Inflammatory Indices in Predicting the Failure of Inhaled Corticosteroids Reduction in Young Participants With Asthma
Inflammatory Indices in Predicting the Failure of Inhaled Corticosteroids Reduction in Young Participants With Asthma
A prospective, observational, interventional, single-blind study (blinded for a clinician in
 the field of inflammatory parameters).

 The aim of the study is evaluation of the usefulness of induced sputum eosinophilia and other
 inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature, bronchial
 hyperresponsiveness] in predicting the failure of treatment reduction with inhaled
 corticosteroids (ICS) in stable asthma in children and adolescents.

 In participants with a stable course of the asthma (confirmed in the run -in period), every 3
 months the dose of ICS is halved (according to GINA guidelines) until the control is lost or
 the lowest daily ICS dose is reached (200 mcg, calculated as budesonide equivalent).
 Throughout the treatment reduction period, the participants run an observation card (clinical
 symptoms) and peak expiratory flow rate (PEFR) measurements. Clinical evaluation is performed
 every month, with spirometry, exhaled NO and exhaled breath temperature measurements. Before
 the reduction and then one month after the change of treatment, the hyperresponsiveness
 measurement is carried out with the sputum induction (combined method using hypertonic
 saline), and 2 months after the change of treatment with the exercise challenge test.

 In the case of loss of asthma control, beta-mimetic will be administered (temporarily) and
 return to dose of ICS before reduction or further increase of treatment is planned. In severe
 asthma exacerbations, oral steroids will be considered.

 The study is observational: treatment is modified according to GINA guidelines based on
 clinical data as part of routine medical care. Only difference compared do standard care is
 supplementary inflammation evaluation (exhaled NO, sputum eosinophilia, bronchial
 hyperreactivity).
Introduction Guidelines for the treatment of asthma recommend the use of the smallest dose of
 inhaled steroid (ICS), which allows to maintain control of the symptoms of the disease. The
 GINA 2006 guidelines proposed (and later editions it upheld) that in the case of symptom
 control by monotherapy with ICS, to reduce their dose every 3 months, up to the lowest dose
 administered once a day, which should be used for one year before taking possible decision to
 stop it.

 There are no clear of simple and sensitive indicators that would allow detection of a
 threatening loss of control before the clinical symptoms worsen.

 Aim of the study Evaluation of the usefulness of induced sputum eosinophilia and other
 inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature (EBT), bronchial
 hyperresponsiveness] in predicting the failure of treatment reduction with inhaled
 corticosteroids in stable asthma in children and adolescents.

 Subjects Participants aged 12-18 years with stable asthma (mild or moderate), treated in the
 Allergy Clinic of the Hospital in Lesko with medium doses in ICS. The severity of asthma was
 initially determined in accordance with the GINA criteria and verified during several years
 of observation by the assessment of clinical symptoms, functional examinations and the dose
 of inhaled steroids controlling the disease.

 Project description A prospective, observational, single-blind study (blinded for a clinician
 in the field of inflammatory parameters). Clinician takes decision about possible reduction
 of ICS dose basing on clinical data only - is not aware of the results of the inflammatory
 parameters measurement.

 The study is consisting of two periods:

 First period (run - in):

 A four-week run - in period in which clinical symptoms and the use of short acting beta2
 agonists (SABA) and PEFR are monitored. At the end of this period, in participants with
 stable disease the following parameters are measured: eNO, EBT, spirometry, and sputum
 induction with hyperosmolar saline in combination with the hyperresponsiveness. Before the
 reduction of treatment on another day, an exercise challenge test is also performed.

 The criteria for the stability of asthma in the run - in period are:

 -  symptoms no more than 3 times a week

 -  SABA use less than 3 times a week

 -  without night wake up

 -  PEFR variability below 20%

 -  FEV1 above 80% of predicted

 Second period of the study - reduction of anti-inflammatory therapy. In participants with
 previously stable course of the asthma (confirmed in the run -in period), the control of
 asthma is monitored regularly throughout the observation period. All participants run an
 observation card (clinical symptoms) and PEFR measurements. Monthly spirometry, exhaled NO
 and exhaled breath temperature measurements are performed. Every 3 months and one month after
 the change of treatment (i.e in months 0, 1, 3, 4, 6 and 7), the hyperresponsiveness
 measurement is carried out with the sputum induction (combined method, [7]). Two months after
 the dose change (months 2, 5, 8) the exercise challenge test is carried out.

 Every 3 months control of the asthma symptoms is evaluated taking account the clinical data,
 and possible change of ICS dose is considered. Results of bronchial reactivity measurements
 and sputum cytology are not known to clinician who decide on a possible ICS dose change - he
 is blinded to the results of tests and the therapeutic decision is based solely on clinical
 evaluation.

 In participants with a stable course of the disease over past 3 months, the dose of ICS is
 halved, in accordance with GINA guidelines. In the case of loss of asthma control,
 appropriate treatment modifications are administered and the patient is withdrawn from the
 study.

 Participation in the study is continued until asthma control is lost or the lowest daily dose
 is reached (200 mcg, calculated as budesonide equivalent) - without losing asthma control at
 next visit.

 Measurements

 1. Daily clinical evaluation by the patient:

 -  symptoms score according to the Santanello questionnaire

 -  PEFR measurement

 2. Every month

 -  Asthma Control Test

 -  spirometry [forced expiratory flow in 1st second (FEV1), forced vital capacity
 (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25-75)]

 -  eNO measurement

 -  exhaled breath temperature measurement (EBT)

 3. every 3 months

 -  quality of life test (QoL, Polish version of the questionnaire), i.e. months 3, 6,
 9

 -  cytological evaluation of induced sputum (i.e. months 0, 1, 3, 4, 6, 7)

 -  assessment of bronchial hyperresponsiveness:

 -  one month after the ICS dose reduction and then before each subsequent dose
 reduction in ICS ((i.e. months 0, 1, 3, 4, 6, 7) - during the sputum induction
 with hyperosmolar salt (combined method)

 -  2 months after each treatment reduction (i.e. months 2, 5, 8): exercise
 challenge test (6-minute free-running test monitored by pulse)

 Criteria for loss of control [1, 6] - any of the following:

 -  use of bronchodilators> 5 times a week

 -  the need for treatment with oral corticosteroids

 -  PEFR decrease above 20% for 2 consecutive days, compared to the average run-in period In
 the case of loss of asthma control, beta-mimetic will be administered (temporarily) and
 return to the chronic administration of the previous, twice higher dose of ICS is
 restored (or further increase of treatment). In severe exacerbations, inclusion of oral
 steroids will be considered.

 Criteria for discontinuation of participation in the study

 1. Loss of asthma control (treatment strategy: beta-mimetic temporarily, return to dose of
 ICS before reduction or further increase of treatment; in severe exacerbations,
 inclusion of oral steroids).

 2. Lack of adherence to the recommendations or failure to report.

 The staff of the center has experience in the production of sputum induction in participants
 with asthma [Ciółkowski J, Mazurek H, Stasiowska B. Evaluation of step - down therapy from an
 inhaled steroid to montelukast in childhood asthma. Allergologia et immunopathologia (Madr.),
 2014: Jul - Aug; 42 (4): 282 - 288].

 The test will be performed in conditions ensuring patient safety, with the availability of an
 anaesthesiologist and anti-shock kit.
Inclusion Criteria:

 -  mild or moderate asthma with a stable course of at least 3 months:

 -  symptoms less than 4x per week,

 -  use of SABA below 3x a week,

 -  night awakening below 1x per week,

 -  FEV1> 80% of predicted

 -  no dose change in ICS or use of systemic steroids from 3 months

 -  good adherence to treatment

 Exclusion Criteria:

 -  infection or exacerbation of asthma requiring the use of systemic steroids (or changes
 in the dose of inhaled steroids) in the last 3 months before the study

 -  other chronic lung diseases or general diseases affecting the respiratory system

 -  tobacco smoking

 -  FEV1 below 80% of the predicted value