Reference equations for parameters of impulse oscillometry in Egyptian children and adolescents

Impulse oscillometry (IOS) is important in diagnosing respiratory functions in non-cooperative children. Studies are rising nowadays to establish reliable reference values of IOS for children of different ethnicities. No available data about the regression equations for parameters of IOS for Egyptian children and adolescents. So, our study aimed to develop regression equations for parameters of IOS in Egyptian children and adolescents in relation to their age, weight, height, and body mass index. Height and age affected the regression equation of impedance at 5 Hz (Z5 Hz) and resistance at 5 Hz (R5 Hz) in both males and females, resistance at 20 Hz (R20 Hz) in males and reactance at 5 Hz (X5 Hz) in females. Height affected the regression equation of R20 Hz in females, resonant frequency (Fres) in males, and the area of reactance (AX) in both males and females. While age affected the equation of X5 Hz in males and Fres in males. Height and age were the most predictive values affecting the regression equation of IOS in Egyptian children and adolescents.


Background
Pulmonary function tests are important tools in the diagnosis and follow-up of different respiratory diseases especially chronic lung diseases [1]. The impulse oscillometry system (IOS) is important in the diagnosis of respiratory functions in non-cooperative children [2]. It does not depend on the effort of the patients as it needs only tidal breathing, then the sound waves emitted by the apparatus are superimposed on normal tidal breathing, and the disturbances in the flow and pressure (caused by the external waves done by the patients) are used to calculate the resistance to airflow and the reactive parameters over a wide range of frequencies (usually from 5 to 20 Hz). Both the airway resistance and reactance determines the impedance [3,4].
The best results of IOS done by the patients are usually compared to the predictive reference value of the same sex, age, weight, height, body mass index (BMI) of the patients. These reference values are different for children of different ethnicities; therefore, studies aim to develop local reference values [5]. Studies are increasing nowadays in different populations to increase the use of IOS and its reliability especially in non-cooperative children because till now spirometry is used more reliably as it is more studied [6].
No available predicted values of IOS for Egyptian children and adolescents. The purpose of this study was to get a reliable regression equation for Z5 Hz, R5 Hz, R20 Hz, X5 Hz, Fres, and AX according to age, sex, weight, and height for Egyptian children and adolescents.

Methods
One hundred thirteen children were able to perform the maneuver properly to get reliable results. They were 65 males and 48 females, their age ranging from 3 to 18 years with a mean of 9.97 ± 4.21 years.
Exclusion criteria: any patient with acute or chronic chest disease, on recent or previous respiratory medication, allergic rhinitis or acute and chronic rhinosinusitis, obese children; or children with neurological or muscular diseases.

Sample size justification
Using G power software for sample size calculation, using the F test for linear multiple regression, fixed model, R 2 deviation from zero.
Setting alpha error at 0.05, power at 0.95, medium effect size (0.15) for regression equation with two predictors, a sample size of at least 110 persons are needed.
Data of the patients were collected as age, sex, weight, height, and body mass index (BMI).    The impulse oscillometry procedure was done by all children using VIASYS Healthcare GmbH. Leibnizstrasse 7, Jaeggar, Germany ( Fig. 1 Steps were explained to the child for the best performance of the test. 4. The child was asked to sit down in a comfortable chair. 5. A nasal clip was applied to the patient who was asked to mouth breath through a sterile mouthpiece that was grasped tightly by his/her lips and the tongue did not occlude it. 6. On switching on IOS, a small loudspeaker creates a pulse-shaped pressure wave in front of the mouth, with alternate pulses (at different cycles per second [i.e., 5 Hz, 10 Hz, 20 Hz, 25 Hz]). 7. The patient was asked to take tidal breathing with his cheeks supported by the hands of the investigator or the caregiver. 8. Z5 Hz, R5 Hz, R20 Hz, X5 Hz, Fres, and AX were calculated by the software of the apparatus.
Each patient performed 3 trials with less than 10% variabilities. The time of the regular breathing pattern was 90 s. The impedance-time curve was monitored during the measurement to detect possible signs of artifacts.
Accepted patients did the technique properly, with coherence at least 0.8 at 5 Hz and 0.9 at 20 Hz The study was approved by the local ethics committee of Children's Hospital, Faculty of Medicine, Ain Shams University.
Written consent was taken from the caregiver of the children and adolescents who participated in the study.

Statistical analysis
Analysis of data was done using SPSS program version 23. Quantitative variables are presented as mean and SD, qualitative variables presented as count and percentage. The Student t test was used to compare different quantitative variables between boys and girls. Pearson's correlation was used to measure the correlation between IOS parameters and other variables.
Multivariate models were developed by multiple linear regression, incorporating predictor variables correlated to the dependent variable. To choose the best model, the coefficient of determination (adjusted R 2 ) was used. The significance level was set at 5% (P value < 0.05); and highly significant at 1% (P value < 0.01).

Results
From a total of 113 children who participated in the study, 65 were boys (57.5%) and 48 were girls (42.5%). Their age ranged from 3 to 18 years with a mean of 9.97 ± 4.21 years. Table 1 shows the description of their anthropometric measures and IOS parameters. No significant difference was found between boys and girls regarding age, anthropometric measures, and IOS parameters except for R20 Hz, X5 Hz, and Z5 Hz (P value < 0.05) ( Table 2). Table 3 and Fig. 2 shows a correlation between different IOS parameters and both age and anthropometric measures among studied boys. There was a statistically significant negative correlation between all IOS parameters and both age and weight except for X5Hz where the correlation was positive (P value < 0.05). There was also a statistically significant negative correlation between IOS parameters (AX, R5 Hz, R20 Hz, and Z5 Hz) and height and a significant positive correlation between X5 Hz and height (P value < 0.05).
Regarding the correlation between different IOS parameters and both age and anthropometric measures among girls, (Table 4 and Fig. 3) shows that there was a statistically significant negative correlation between all IOS parameters and both age and weight except for X5 Hz where the correlation was positive (P value < 0.05). There was also a statistically significant negative correlation between all IOS parameters and height and a significant positive correlation between X5 Hz and height (P value < 0.05). A significant negative correlation was found also between R20 Hz and BMI (P value < 0.05).   Table 5 shows the results of multiple linear regression equations for all IOS parameters in boys and girls with their coefficients of determination (R 2 ) adjusted R 2 and standard error of the estimate (SEE). Height was the variable with the most predictive power for models of all IOS parameters in girls and most of the parameters in boys.

Discussion
In our study, we found that in Z5 Hz and R5 Hz, height and age affected the prediction equation for both males and females, while in R20 Hz, height and age affected the equation of males; but only the height affected that for females. Concerning the prediction equation for X5 Hz, age was the variable most affecting the equation in males, while height and age affected the equation in females. Height was the variable that has been shown to influence Fres in females and AX in both males and females, but the age was the variable that affected the equation of Fres in males.
So most of the predictive equations for impulse oscillometry were affected by height or age or both of them but none of the equations were affected by weight or BMI, possibly because of the association of height and age with a linear increase in lung volumes.
Comparing these with the study done on Brazilian children, height was found to be the highest predictive variable in the equations for boys in all parameters of IOS, while age had a greater influence on Fres and AX for girls [8]. Also, in a study on Mexican children and adolescents, height was the most variable influencing the equation but age also influenced the regression equation of many IOS variables, whereas body weight did not influence any regression equation; thus, reference values were made considering age and height [9]. Also, Amra et al. 2018 concluded that both height and age influenced the equation of the Iranian population [10]. While in a study on North American children, height was the only significant predictor for all variables [11].
In Poland and Swedish children, the height −3 was the most variable affecting the different oscillometric variables. But the introduction of weight helped to improve the coefficient of determination of some IOS parameters, while, factors as gender, age, and body surface area did not influence the IOS variables. Therefore, height −3 and weight were used in the regression equations done for both sex [12].
Also, studies from different ethnicities as Anglo and Hispania [13], Brazil [14], northeast Poland [15], and Taiwan [2], all showed reliability of the regression equations on the height of the children. (Table 6) Nevertheless, both height and age affected the prediction equations of Korean and Mexican patients, although that for the Korean girls were affected by the height only [5,9]. Meraz et al. 2007, de Assumpção et al. 2016, Frei et al. 2005, and Dencker et al. 2006 showed no statistically significant difference between both genders in the predictive equations [11][12][13]8]. While Amra et al. 2007 found a statistically significant difference between genders [10]. But in our study, no significant difference was found between boys and girls regarding IOS parameters except for R20 Hz, X5 Hz, and Z5 Hz.
Comparing our study on the pediatric age group with other studies in adults, Kalchiem-Dekel and Stella E. Hines studied forty years of reference values for respiratory system impedance in adults from the years 1977-2017 and concluded that most of the prediction equations were from Europe (n = 20) and  Asia (n = 12) while studies in Africa are limited; and across publications, height and sex were major contributors to prediction equations. The contribution of weight was more pronounced in obese patients only. The contribution of age was less clear, and the elderly were largely under-represented. Ethnicity likely plays a role but was under-reported in currently available publications [3,16].
The study on adults done by Schulz et al. showed that R5 Hz was higher in females than males while X5 Hz was higher in males than females. Some of the IOS equations were age-dependent. Also, studies by Aarli et al. and Newbury et al. found that airway resistance is greater in women than in men during adulthood [17,18].
By comparing R 2 of our study to that in the studies done on different ethnicities, we found that our R 2 is higher than that in the equations of Korean, Angelo, Hispanic, and North American studies. While it was lower than R 2 of the Brazilian study except for the predictive equation for X5 Hz for boys where our R 2 was higher (Tables 5 and 6).
This study has a potential limitation that it did not include the population from different cities in Egypt. Further studies are needed to develop reference equations for parameters of IOS on a wider scale and larger sample sizes that can be applied to all Egyptian children and adolescents in different cities.

Conclusion
Both height and age affected the regression equation for parameters of impulse oscillometry in Egyptian children.