Lung Function Variability in Children and Adolescents
Lung Function Variability in Children and Adolescents
Long-term variability analysis of peak expiratory flow (PEF) and forced expiratory volume in
 1 s (FEV1) has been successfully used in research to predict the exacerbation of the disease
 in adult individuals with asthma. However, there is a paucity of data regarding PEF and FEV1
 variability in asthmatic children and adolescents. Such a task requires at least daily PEF
 and FEV1 measurements, recording in diaries, and periodic evaluation of the data. The process
 may be proven both complicated and time consuming, thus reducing patients' adherence. Recent
 advances in biosensor technology have permitted the development of reliable, low-cost,
 portable spirometers, able to connect with smartphones and monitor lung function parameters
 in real time and from a distance.

 The objectives of the present study is the assessment of PEF and FEV1 variability: a) in
 healthy children and adolescents, in order to define the normal daily fluctuation of PEF and
 FEV1 and the parameters that may influence it, and b) in children and adolescents with
 asthma, in order to explore the differences from healthy subjects and reveal any specific
 variability changes prior to exacerbation. Such data would improve our understanding
 regarding the disease and permit the development of integrated tools for assessing the level
 of asthma control and the risk of future exacerbations.

 The study will include 100 healthy children and adolescents aged 6 to 18 years for the
 assessment of normal PEF and FEV1 variability, and 100 children and adolescents of the same
 age with diagnosed asthma for the assessment of PEF and FEV1 variability in asthmatics. PEF
 and FEV1 measurements will be performed using an FDA-approved portable spirometer (MIR
 Spirobank Smart) capable to connect to smartphone. Each participant will receive his personal
 spirometer. Measurements will be performed twice a day between 07:00-09:00 and 19:00-21:00
 hours and dispatched via email to a central database for a period of 3 months. PEF and FEV1
 variability will be assessed by detrended fluctuation analysis, aiming to define the normal
 pattern (healthy controls) and to detect and quantify the deviations (asthmatics). The
 anticipated duration of the study is 24 months.
Background

 Asthma represents the most common chronic disease of childhood and adolescence and an
 important cause of morbidity worldwide. The disease is characterized by episodes of
 reversible airway obstruction (exacerbations), associated with specific symptoms (wheeze,
 dyspnea, cough, chest tightness) and decrease in peak expiratory flow (PEF) and forced
 expiratory volume at 1 sec (FEV1). However, these spirometric changes occur in parallel with
 clinical deterioration, thus presenting limited ability to predict the exacerbation of the
 disease.

 Both PEF and FEV1 demonstrate significant daily variability, i.e., circadian and/or
 day-by-day fluctuation of the measured values. In healthy individuals the pattern of these
 fluctuations remains constant over long time periods (weeks, months), as opposed to asthmatic
 patients where PEF and FEV1 variability is increased, especially prior to exacerbations when
 the control of the disease is lost. Thus, the analysis of PEF and FEV1 variability has been
 used in research to evaluate the effectiveness of treatment, recognize high-risk patients and
 predict asthma exacerbations.

 In clinical practice, however, the evaluation of PEF and FEV1 variability requires at least
 daily measurements with special devices, recording in diaries, and periodic evaluation of the
 data by the attending physicians. The process may be proven both complicated and time
 consuming, thus reducing patients' adherence especially in the case of asthmatic children and
 adolescents. In addition, the periodic review of measurements may hamper the prediction of
 exacerbation, as the time of evaluation may not coincide with changes in the variability of
 lung function that characterize the loss of asthma control.

 Over the last years, technological advancements in the field of biosensors and
 microprocessors have permitted the development of reliable, low-cost, portable spirometers,
 able to connect with cutting-edge mobile phones (smartphones) and monitor lung function
 parameters in real time and from a distance. The use of such devices may overcome most of the
 aforementioned barriers in following-up lung function parameters in the long term.

 Currently, there is a paucity of data regarding PEF and FEV1 variability in children and
 adolescents with asthma. Such data would improve our understanding regarding the disease and
 permit the development of integrated tools for assessing the level of asthma control and the
 risk of future exacerbations

 Objectives

 The objectives of the study are:

 1. Assessment of PEF and FEV1 variability in healthy children and adolescents: definition
 of the normal range of daily PEF and FEV1 fluctuation and the parameters that may
 influence it

 2. Assessment of PEF and FEV1 variability in children and adolescents with asthma:
 differences from healthy subjects and definition of specific changes prior to
 exacerbation

 Methods

 A. Study population

 The study will include two cohorts:

 1. Healthy children and adolescents aged 6 to 18 years (N=100) for the assessment of
 normal PEF and FEV1 variability (objective #1).

 2. Children and adolescents aged 6 to 18 years with diagnosed asthma [2] (N=100) for
 the assessment of PEF and FEV1 variability in asthmatics (objective #2).

 B. Lung function measurements

 a. Device: PEF and FEV1 measurements will be performed using an FDA-approved portable
 spirometer (Spirobank Smart, MIR, Rome, Italy), with a disposable bi-directional digital
 turbine (flow range ±16L/s, volume accuracy ±3% or 50 mL, flow accuracy: ±5% or 200
 mL/s, dynamic resistance <0.5 cm H2O/L/s), capable to connect to smartphone via
 Bluetooth® using a dedicated freeware application (iSpirometry, MIR, Rome, Italy). Each
 participant will receive his personal spirometer. Detailed information regarding the use
 and maintenance of the device will be provided (brochure & online resources).

 b. Measurements: The correct technique for PEF and FEV1 measurements (ERS/ATS standards)
 will be demonstrated by one of the investigators at enrollment. Detailed information
 regarding the technique (brochure & online resources) will be also provided.
 Measurements will be performed twice a day between 07:00-09:00 and 19:00-21:00 hours,
 for a period of 3 months.

 c. Completed measurements (encrypted pdf format) will be dispatched via email to a
 central database by the participants or their parents.

 d. Monitoring: Participants' adherence will be monitored continuously. The investigators
 will notify the participants in case of lost measurements or inappropriate technique.

 C. Variability analysis

 PEF and FEV1 variability will be assessed by:

 a. The coefficient of variation b. Detrended Fluctuation Analysis (DFA), a method that
 has been widely used for the investigation of intrinsic correlation within time
 series.14 Initially, the square root of the time series [F(n)] is calculated for
 segments of different (time) length n. A linear relationship in the logarithmic graph F
 (n) - log (n) indicates the existence of fractal architecture in the scaling of the
 specific data, while the slope a of the line describes the pattern of long-term
 fluctuations.14 A change in daily variability of PEF or FEV1 results in a simultaneous
 deviation from the predetermined a value.6 This deviation can easily be detected and
 quantified. It has been shown that the magnitude of a deviation reflects the likelihood
 of asthma exacerbation within the next month.6 c. Variability analysis will be performed
 in MatLab (MathWorks, Inc., Natick, MA, USA) environment.

 D. Additional data Patients' characteristics (age, sex, baseline lung function, allergy,
 comorbidities, medication, etc) will be also recorded. These parameters will be included
 in regression models to explore their effect on the pattern of PEF and FEV1 variability.

 E. Statistics All analyses will be performed with the IBM SPSS software version 25.0
 (IBM Corp., Armonk, NY).

 F. Timeframes The expected duration of the study is 24 months. • Part I: Assessment of
 PEF and FEV1 variability in healthy children and adolescents Duration: 9 months (January
 - September 2020).

 PEF and FEV1 measurements from 100 participants (3 months each)

 • Part II: Assessment of PEF and FEV1 variability in asthmatic children and adolescents
 Duration: 15 months (October 2020 - December 2021). PEF and FEV1 measurements from 100
 participants (3 months each)

 G. Ethics The study will comply to the regulations and standards of good medical
 practice. Participants will receive a unique study number and no personal data will be
 recorded. Measurements will be dispatched via email in encrypted pdf format. Informed
 written parental consent will be obtained prior to enrollment. Children aged >12 years
 will also provide a written consent. The study has been approved by the Ethics Committee
 of the University Hospital of Patras, Greece (decision # 329/02-04-2019).
Cohort A. Healthy children and adolescents

 Inclusion Criteria:

 -  Age 6 - 18 years

 -  No asthma or asthma medication in the last 2 years

 -  Normal baseline spirometry

 -  Smartphone possession (parents or participants) with ability of internet connection
 (Wi-Fi or mobile data)

 -  Informed written consent (parents, parents & children >12 years old)

 Exclusion Criteria:

 -  Inability to perform 3 consecutive measurements within the 3-month period of
 observation

 -  Inability to perform 6 measurements in total (3.3% of the anticipated 180
 measurements) within the 3-month period of observation

 -  Major respiratory events (e.g., asthma attack, severe respiratory infection, chest
 trauma) or other health-related events that may hamper the performance of lung
 function measurements (e.g., surgery, trauma) within the 3-month period of
 observation.

 Cohort B. Children and adolescents with asthma

 Inclusion Criteria:

 -  Age 6 - 18 years

 -  Doctor-diagnosed asthma under treatment

 -  Smartphone possession (parents or participants) with ability of internet connection
 (Wi-Fi or mobile data)

 -  Informed written consent (parents, parents & children >12 years old)

 Exclusion Criteria:

 -  Inability to perform 3 consecutive measurements within the 3-month period of
 observation

 -  Inability to perform 6 measurements in total (3.3% of the anticipated 180
 measurements) within the 3-month period of observation

 -  Major respiratory events (e.g., severe respiratory infection, chest trauma) or other
 health-related events that may hamper the performance of lung function measurements
 (e.g., surgery, trauma) within the 3-month period of observation