Improving the clinical utility of the Forced Oscillation Technique in preschool-aged children

Abstract

Introduction: The assessment of lung function in young children is crucial to the diagnosis, treatment and management of respiratory disease. Since measuring lung function in this age group can be challenging, specific lung function tests for this age group have been developed. Of these tests, the Forced Oscillation Technique (FOT) is a non-invasive method of measuring respiratory impedance (Zrs), requiring minimal cooperation from the patient. Whilst highly feasible in young children, conventional FOT measurements have inherent limits in both the clinical application and interpretation of the test. The conventional FOT has shown to be more useful at detecting differences in lung function between patient groups rather than following disease progression in individuals. This may, in part, be explained by the Zrs reference data that were developed using a commercial FOT device with a reported systematic bias in the estimation of Zrs. In addition to this, the calculation of Zrs as an average over several breathing cycles may account for the limited clinical utility of the conventional FOT. It can be hypothesised that accounting for the well-established intrabreath changes of Zrs during normal breathing in both health and disease will enhance the diagnostic value of the FOT. Aims: This thesis aims to improve the clinical utility of Zrs measurements in preschool-aged children through the development of a novel, custom-made FOT device tracking the intrabreath changes of Zrs. This will be achieved through three distinct studies; firstly the development of reference ranges for the conventional Zrs measurements using a gold-standard FOT device and examining the definition of “healthy” in preschool-aged children. Secondly, the feasibility of intrabreath Zrs measurements will be examined and e reference ranges developed for a preschool-aged population. Lastly, the diagnostic power of the intrabreath FOT measurements will be examined in preschool-aged children with airway obstruction. Methodology: Children 3-6 years of age were recruited. Children were classified into one of six health groups based on a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Custom-made FOT equipment consisting of a loudspeaker and a wave-tube were used to measure Zrs. Two distinct types of Zrs measurements were made; firstly, the conventional FOT employed a multi-frequency 4-36 Hz measurement from which the Zrs spectra were ensemble averaged. Secondly, single-frequency (10 Hz) measurements were obtained to track the intrabreath changes in Zrs at every 0.1 s. Summary statistics and FOT variables are presented as either mean ± SD or median (25th; 75th percentile). Reference ranges were developed using mixed-effect linear regression and z-scores were calculated. The diagnostic power of within-breath Zrs measurements were investigated using Receiver Operator Characteristic analysis. Results: A total of 494 children contributed 587 acceptable conventional FOT measurements, a feasibility of 85.5%. Comparison of z-scores between healthy children and the five health groups revealed no significant difference between healthy children, children with early-life wheeze and children born preterm. The lack of significant differences validated a more inclusive approach to defining healthy by combining the conventional Zrs data of children with early-life wheeze and born preterm with the healthy children, increasing the reference dataset by 22.3%.Intrabreath Zrs measurements were successfully obtained in 517 children (86.7% feasibility). The intrabreath FOT outcome variables were significantly associated with height, whereas the volume dependence of resistance (R) (∆R) and reactance (X) (∆X) were not associated with height, weight, sex and age. Normative intrabreath Zrs reference values and z-scores were developed based on 200 healthy children. An upper limit of normal of 1.96 hPa.s.L-1 for ΔR and the lower limit of normal of -0.54 hPa.s.L-1 were defined for ΔX.Having demonstrated the feasibility of intrabreath Zrs measurements, the diagnostic power of these measurements was investigated. FOT was employed in 26 children with acute wheeze and 75 healthy children. The conventional FOT outcome variables of resistance (Rrs) and reactance (Xrs) were not statistically significant between groups. In contrast, the intrabreath changes in Rrs and Xrs (ΔR and ΔX) were significantly different in the children with acute wheeze compared to healthy children. Furthermore, the largest area under the curve was observed for ΔR (0.95) and a cut-off value for ΔR of 1.42 hPa.s.L-1 detected airway obstruction with a sensitivity of 92% and specificity of 89% in children with acute wheeze. Conclusions: As the main result of this thesis, a novel lung function test was developed, tested and introduced into clinical practice. Measurements of Zrs using a novel FOT device are highly feasible in preschool-aged children 3-6 years of age. Whilst measurements of conventional FOT have limited clinical utility in children with acute wheeze, the intrabreath tracking of Zrs finding the zero-flow points significantly improves the diagnostic power of the FOT in preschool-aged children with acute wheeze. Development of normative reference data, z-scores and cut-off limits for detecting airway obstruction provide further improvement in the clinical application and interpretation of FOT measurements in preschool-aged children.