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Infant lung function tests Its role in the management of wheezy disorders Department of Paediatrics Prince of Wales Hospital 15 November 2015 • Brief introduction of different lung function tests done in infants and toddlers. • What information did previous studies tell us on infant lung function and preschool wheeze • How infant and toddler lung function tests are applied in research and management of wheezy disorders. • Wheezing is one of the most common problems leading to medical consultation and hospitalization infants and preschool children. • Many of the children may grow out of it. • Others may have persistent wheezing symptoms and develop asthma. • Infants preschool age children are unable to cooperate and breathe voluntarily through respiratory apparatus. • Special technique and equipments are often required to assess their lung function. • ATS/ERS task force: Pulmonary function testing in preschool children Tidal breathing measurement • Tidal breathing through face mask or mouth piece, which is equipped with sensors and connected to a computer. • Volume and flow of each breath, respiratory rate and minute ventilation are recorded. Tidal breathing measurement • Time to reach peak tidal expiratory flow • Total expiratory time (tE) • Ratio of tPTEF/tE • Reduced tPTEF/tE in obstructive disease a: tPTEF a+b: tE tPTEF/tE = a/a+b Klin Phys 2002; 1: 18-20 Tidal breathing measurement • In infants, measurement can be made during • In preschool children measurement can be made during awake quiet breathing. • Stable breathing through a facemask or mouth piece for minimum 30 seconds of tidal breathing to obtain stable 10 tidal breaths (4-50 breaths used in published reports). Tidal rapid thoracoabdominal compression technique Thoraco-abdominal compression • "Squeeze technuqie" • In infants (sedation) • Measure the forced expiration Thoraco-abdominal compression • Infant breathes through the face mask and flow-measuring • When the computer senses that the infant has reached the end of a normal inspiration • The tap is rapidly turned to briefly connect squeeze bag to the pressure reservoir • Cause the infant to exhale Eur Respir Mon 2005:31 • Produce a partial forced
expiratory flow volume (PEFV)
Thoraco-abdominal compression • Maximal flow at functional residual capacity (V'maxFRC) is the most commonly reported parameter derived from RTC technique. • Equals to forced flows at low lung volumes. • Reflects intrapulmonary airway function that is relatively uninfluenced by the resistance of the upper airways. Partial flow-volume loops from a) health newborn maximal flow (at V'maxFRC= 92 ml.s -1) and b) a newborn with evidence of airway obstruction (V'maxFRC = 40 ml . s -1) P.J.F.M Merkus et al, Eur Respir Mon 2005, 31 Raised volume rapid thoraco- abdominal compression Raised volume rapid thoraco- abdominal compression • Modified thoraco-abdominal "squeeze" • Inflate the lungs to their maximum volume (total lung capacity) to standard pressure of 30 cmH2O through the face mask and then apply the thoraco-abdominal compression. • Resemble the forced expiration used in older children/adults. • Total amount of gas expelled forcibly (maximal expiratory flow volume) = Vital capacity Raised volume rapid thoraco- abdominal compression • Advantage compared with the simple thoraco- abdominal compression: • FVC, FEV 0.5, FEV 0.75, FEF at 25%, 75% and FEF between 25%-75% • Parameters derived from this test are more reliable and reproducible than those obtained from the partial expiratory flow-volume test. Measuring airway resistance • Interrupter technique • Forced oscillation technique • Whole body plethysmography

Interrupter technique • Interrupter resistance / Rint technique • Commercial devices are available. Schematic picture of the equipment used for the interruptor technique Am J Respir Crit Care Med Vol 175 p1320, 2007 Interrupter technique • Expiration is briefly interrupted by closing a shutter (stays closed for 100 milliseconds) • Based on the assumption that when there is sudden airflow interruption at the mouth, the alveolar pressure and the mouth pressure will rapidly equilibrate. • Rint is defined as pressure changes divided by the airflow measured during the brief interruption. • Resistance = pressure/flow Interrupter technique • Child in seated position. • Cheek supported reduce upper airway Forced oscillation technique • Use a "loudspeaker" to force small-amplitude oscillating signals of varying frequency into the airway during normal tidal breathing. Forced oscillation technique • Measures the respiratory impedance (Zrs). • Reflects pressure - flow relationship measured at the airway opening. • Data are reported as Rrs (respiratory resistance ) and respiratory reactance (Xrs). • Rrsf (respiratory resistance at a given frequency). Forced oscillation technique • Respiratory resistance (Rrs) • - in-phase component represents the sum of airway and tissue resistances, of which airway
resistance is the most significant component
above a few Hz.
Forced oscillation technique • Respiratory reactance (Xrs) • - Out-of phase component reflects energy storage capacity of the system. • - Determined jointly by the elastic properties (the
relationship between P and volume) dominant at
low oscillation frequencies and the inertive
(the relationship between P and
volume acceleration), which progressively more
important with increasing frequency.
Whole body plethysmography • Measure whole lung volume, plethysmographic functional residual capacity, (FRCpleth) and airway resistance (Raw). Whole body plethysmography • Airway resistance (Raw) can be calculated from the ratio of chamber pressure and flow rate during breathing. • Airway conductance (Gaw) is the reciprocal of Whole body plethysmography • Resistance to airflow varies at different volumes because airways are wider at high lung volume than at low lung volume, Raw is therefore normally measured at FRC to standardise the measurement. Whole body plethysmography • Specific resistance remain relatively independent of changes in body size. • Distinguish changes in airway function due to disease from those resulting from growth and development. Fractional concentration of exhaled Nitric Oxide ( FeNO ) • Marker of airway inflammation • On-line vs off-line measurement • For children >5 years, single breath on-line (SBOL) measurement can be used. • SBOL method requires child to inhale to near- TLC and immediate exhales at a constant flow for at least 4s. • May not be feasible in younger children. • Off-line measurement in pre-school children: • Exhaled air can be collected in Mylar or Tedlar balloon during tidal breathing via a mouth piece or facemask which are connected to a non-rebreathing valve. • Exhaled breath samples are collected into an NO-inert bag and analyzed later. • However, the result from off-line measurement cannot be directly compared with single-breath on-line assessment. What information did previous studies on infant lung function on wheezy children shown? Does functional impairment precedes the first episode of wheeze? • Tucson Children's Respiratory study (n=124) • - Infants whose total respiratory conductance (Crs) in the lowest tertile have 3.7 times higher risk of having a wheezing episode • - Reduced lung function is a predisposing factor for the development of a first wheezing illness in infants. N Eng J Med 1988, 319:1112-1117 Does functional impairment precedes the first episode of wheeze? • Subsequent cohort studies which use V'maxFRC to assess lung function also showed pre-morbid
lower lung function in wheezing infants.

Martinez FD 1998 (Tucson)
Martinez FD 1991 (Tucson)
Tager IB 1993
Dezateux C 1999
Young 2000
Murray CS 2002
Håland G (2007)
Pike KC (2001)
Does functional impairment precedes the first episode of wheeze? • The Southampton Women's Survey cohort (SWS study) showed that • - Decreased FEV0.4 measured before 14
weeks of age is a risk factor for later wheeze.
• - Association between impaired pre-morbid
lower infant lung function (V'maxFRC) and
preschool wheezing (both at 1 and at 3 years
of age).
Pediatr Pulmonol 2011, 46:75-82 Does functional impairment precedes the first episode of wheeze? • Some children are born with an obstructive airway pattern which poses them at risk of suffering wheezy disorders. Is the pre-morbid impaired infant lung function a risk factor for asthma later in life? • In Tucson Children's Respiratory Study: • - Transient wheezers had reduced V'maxFRC both in infancy and at 6 years. • - Persistent wheezers had normal early V'maxFRC, but significantly lower V'maxFRC at 6 years. Am Rev Respir Dis 1991, 143:312-316 Is the pre-morbid impaired infant lung function a risk factor for asthma later in life? • Copenhagen Prospective Study on Asthma in Childhood (COPSAC) • 411 infants from asthmatic mother
• Children who developed asthma by the age 7 had
reduced FEF50 and FEV0.5 in neonatal period.
• Neonates with increased bronchial
responsiveness were more prone to suffer from
asthma at 7 years of age.
Am J Respir Crit Care Med 2012, 185:1183-1189 Role of bronchial hyper- • Relationship of wheezy disorders and bronchial hyper-responsiveness. • Contradicting result. Relationship of atopy, inflammation • Hålan et al showed that in children less than 2 years with reurrent LRI and atopic eczema,
they had significantly lower tPTEF/tE at birth
and at 2 years, compared with those without
recurrent LRI or atopic eczema.
Pediatr Allergy Immunol 2007:18:528-534 Relationship of atopy, inflammation • In COPSAC cohort, increased neonatal FeNO levels
were significantly associated with the development of recurrent wheeze in the first year of life, but not
• In asymptomatic neonates born to mother with asthma, elevated FeNO level was found before the
development of transient early wheezing, but not
persistent wheezing during preschool age, and was unrelated to atopy. • Elevation of FeNO is unrelated to atopy. Am J Respir Crit Care Med 2010:182:138-142 Relationship of atopy, inflammation • Borrego et al showed children who wheeze and with risk factors of asthma has reduction
in FVC and FEF25-75
(Parental asthma,
personal history of allergic rhinitis, wheezing
without colds and/or eosinophil level >4%), as
compared with those without such risk factor.
Thorax 2009:64:203-209 • Complex relationship between early wheezing, atopy, and subsequent development of asthma. • Airway inflammation plays a role wheezy • ?Control of airway inflammation -> hopefully helps in symptoms control and prevention of recurrent of symptoms. How infant and toddler lung function tests are applied in research and management in wheezy disorders? • Bronchodilator is a common medication given to patient with wheezy disorders. • Patients are not always responsive. • Can we predict whether a patient will response to bronchodilator based on clinical features? Eur Respir J 2014 Aug; 44(2): 371-81
• First report concerning the influence of multiple early-life factors on baseline lung function and bronchodilator responsiveness in 4-year old. • Prospective birth cohort (n=535) • Collected information on symptoms and allergen exposures through half-yearly questionnaires. • At the age of 4 years, lung function tested by using forced oscillation technique at baseline
and after bronchodilation (n=498)
Larger baseline respiratory resistance in:
• - children with previous lower respiratory tract
infection and previous wheeze • - those with early-onset sensitization to inhalant allergens • - those who were shorter in height. Bronchodilator response • Several potential determinants were found to be associated with bronchodilator response (Rrs): • - lower gestation age at birth or lower birth • - children who are taller or heavier • - previous LRTIs or wheezing • - Early-onset sensitization to inhalant allergens an food allergens • However, only the baseline resistance (Rrs) was significantly associated with the bronchodilator-induced change in resistance (Rrs). • We cannot correctly predict the bronchodilator response in children just based on previous history of LRTIs, wheezing or history of atopy. Pediatr Pulmonol 2012 May; 47(5):421-8 • Multicenter study • 76 children • ≤36 months old • Mean (SD) age 16.8 (7.6) months • More than 3 episodes of physician-diagnosed wheezing treated with bronchodilators or corticosteroids. • Raised-volume rapid thoracic compression
method was used to measure the force
expiratory flows
in children<= 36 months old
before and after administration of albuterol.
• Definition of positive response: FEV0.5 ≥13% and/or FEF25-75 ≥24%. • 24% (n=18) children exhibit BDR. Assess which known risk factors of asthma were associated with greatest change in lung function after bronchodilator. Did not identify any factors that were statistically predictive of greater bronchodilator reversibility. • Patient who are clinically responsible to bronchodilator is not associated with asthma risk factors. • Aim to investigate the effectiveness of montelukast in recurrent wheezy infants (at least 1 wheezing episode). • Randomized control trial, 113 children, 6-24 month-old with recurrent wheezing • Received either placebo or montelukast daily for • Primary end-point: symptoms-free days • Secondary end point: lung function, airway responsiveness and exhaled nitric oxide fraction • FeNO
Infant whole body plethysmograph to
measure functional residual capacity (FRC)
and specific airway conductance (sGaw)
Thoraco-abdominal compression technique
to measure the maximal flow at functional
residual capacity (V'maxFRC).
• Dosimetric methacholine challenge test to
document airway responsiveness
• Primary end-point: • - Weekly symptoms-free days between the montelukast and the placebo group (3.1-3.7 days versus 2.7-3.1 days, p=0.965) - No significant • Secondary end-point: • - Use of rescue medication, FRC, sGaw, VmaxFRC, FeNO or airway responsiveness between groups - No significant difference. • Montelukast therapy did not influence the number of symptoms-free days, the use of rescue medication, lung function, airway responsiveness or airway inflammation in recurrently wheezy, very young children. • Prospective study • Children <=36 months • Wheezes started before the age of 24 months • Received inhaled corticosteroid for at least 3 • 40 infants with persistent wheezy respiratory symptoms, median age 14.5 (6-36) months. • 40 with optimal controlled infantile wheeze, median age 14 (6-29) months. • Two exhalation samples were collected in mylar balloon during quiet tidal breathing. • FeNO measurements were performed off-line by a NO analyzer. • The reproducibility of 2 samples was excellent (r = 0.95; p < 0.0001). • FeNO levels were significantly elevated in patients with persistent wheezy respiratory symptoms: 19.8 (2.5–99.3) ppb vs. 7.7 (0.6–29.5) ppb in controlled group (p < 0.0001). • At a FeNO level >15 ppb, the predictive values for uncontrolled disease were as follows: positive predictive value = 65%, negative predictive value = 90%. • FeN0 levels were not increased by atopy. • FeNO level was not affected by passive smoking, age, sex, weight and height. • FeNO is a non-invasive marker of bronchial inflammation in wheezy infants. • FeNO off-line measurement in these group of children is feasible, reproducible and well accepted. • Optimal clinical control is strongly associated with FeNO level in this age group. • Illustrate how infant lung function tests can be applied in research of preschool wheezy • Demonstrate the relationship of lung function in early life and wheezy disorders. • Infant lung function tests also help to quantify the effect of treatment. • More research and large scale studies are required to have better understanding in the trajectories and management of preschool wheezy disorders.



Alcohol studies in translational models: behavioural consequences of adolescent exposure and novel approaches to reduce the propensity to relapse. The research described in this thesis was conducted at the department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands and at the department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands. My research was supported by ZONMW Topgrant 912-06-148. Cover: artwork by Martijn C.L. Van Roovert. Layout by Esger Brunner. Printed by GVO drukkers & vormgevers B.V. P+L ISBN: 978-90-6464-703-1 Copyright © J.A. Wouda (, 2013. Al rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, transmitted in any form without prior permission from the author.