Respiratory Medicine (2012) 106, 1362e1368

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Inspiratory airflow limitation after exercisechallenge in cold air in asthmatic children

Jean M. Driessen a,*, Job van der Palen b,c, Wim M. van Aalderen d,Frans H. de Jongh b,d, Boony J. Thio a

aDepartment of Pediatrics Medisch Spectrum Twente, P.O. Box 50 000, 7500 KA Enschede, The NetherlandsbDepartment of Pulmonology, Medisch Spectrum Twente, Enschede, The NetherlandscDepartment of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, The NetherlandsdDepartment of Pediatric Respiratory Medicine and Allergy, Emma Children’s Hospital, AMC, Amsterdam, The Netherlands

Received 23 March 2012; accepted 25 June 2012Available online 11 July 2012

KEYWORDSAirwayhyperresponsiveness;Asthma in children;Extrathoracic airwayhyperreactivity;Exercise inducedasthma

Abbreviations: EIB, exercise inducedcontrol questionnaire; FEV1, forced exconfidence intervals; FVC, forced vcorticosteroid.* Corresponding author. Tel.: þ31 0E-mail addresses: jeandriessen@gm

w.m.vanaalderen@amc.uva.nl (W.M. v

0954-6111/$ - see front matter ª 201http://dx.doi.org/10.1016/j.rmed.20

Summary

Methacholine and histamine can lead to inspiratory flow limitation in asthmatic children andadults. This has not been analyzed after indirect airway stimuli, such as exercise. The aimof the study was to analyze airflow limitation after exercise in cold, dry air.

72 asthmatic children with mild to moderate asthma (mean age 13.2 � 2.2 yrs) performeda treadmill exercise challenge. A fall of >10% in FEV1 was the threshold for expiratory flowlimitation and a fall of >25% of MIF50 was the threshold for inspiratory flow limitation. Theoccurrence of wheeze, stridor and cough were quantified before and after exercise.

After exercise, the mean fall in FEV1 was 17.7 � 14.6%, while the mean fall in MIF50 was25.4 � 15.8%; no correlation was found between fall in FEV1 and MIF50 (R2: 0.04;p Z 0.717). 53 of the 72 children showed an inspiratory and/or expiratory airflow limitation.38% (20/53) of these children showed an isolated expiratory flow limitation, 45% (24/53)showed both expiratory and inspiratory flow limitation and 17% (9/53) showed an isolatedinspiratory flow limitation. The fall in FEV1 peaked 9 min after exercise and correlated to expi-ratory wheeze. The fall in MIF50 peaked 15 min after exercise and correlated to inspiratorystridor. The time difference in peak fall between FEV1 and MIF50 was statistically significant(5.9 min; p < 0.001, 99% CI: 2.3e9.5 min).

bronchoconstriction; VCD, vocal cord dysfunction; RAST, radioallergosorbent test; ACQ, asthmapiratory volume in the first second; MIF50, maximal mid inspiratory flow; SD, standard deviation; CI,ital capacity; ICS, inhaled corticosteroid; LABA, long acting bronchodilating agent; NCS, nasal

53 4872310; fax: þ31 053 4872326.ail.com, jean.driessen@tjongerschans.nl (J.M. Driessen), j.vanderpalen@mst.nl (J. van der Palen),an Aalderen), f.h.dejongh@amc.uva.nl (F.H. de Jongh), b.thio@mst.nl (B.J. Thio).

2 Elsevier Ltd. All rights reserved.12.06.017

Inspiratory flow limitation after exercise 1363

In conclusion, this study shows that an exercise challenge in asthmatic children can give riseto inspiratory airflow limitation, which may give rise to asthma like symptoms.ª 2012 Elsevier Ltd. All rights reserved.

Introduction

Asthma is a common, chronic disease in which indirectstimuli such as exercise may lead to transient narrowing ofthe lower airways resulting in an expiratory flow limitation(EIB).1 A direct stimulus such as methacholine may lead toinspiratory as well as expiratory flow limitation in asthmaticchildren and adults.2e4 It has been hypothesized that thisinspiratory flow limitation is the result of chronic inflam-mation of the upper airways, a frequent co-morbidity inchildhood asthma.5

In asthmatic children, exercise may also lead to symp-toms mimicking EIB.6,7 Vocal cord dysfunction (VCD) maylead to many exercise induced symptoms and can easily bemistaken for EIB.8 In most cases of VCD exercise inducedsymptoms, such as stridor and acute ‘choking’ occur duringexercise.9 In field observations however, inspiratory stridorand dyspnoea may be present in asthmatic children wellafter exercise. We propose that an indirect challenge suchas exercise may cause inspiratory airway obstruction likemethacholine and histamine, mimicking asthma likesymptoms.

The aim of the study was to analyze airflow limitationafter exercise in cold, dry air.

Materials and methods

Study design

Open, cross sectional design. All exercise challenge testswere performed between January 1st 2005 and April 1st2008.

Subjects

Seventy-two children (mean age 13.2 � 2.2 yrs) with mildto moderate paediatrician diagnosed asthma in accor-dance with GINA guidelines with exercise induced dysp-noea were selected from the paediatric outpatient clinicof Medisch Spectrum Twente Hospital.10 Most childrenused inhaled corticosteroids (79%) and had a history ofallergy and 65 completed a radioallergosorbent test(RAST). None of the children were hospitalized for anexacerbation of asthma for at least 6 months prior totesting. Subjects were required to withhold the use oflong acting bronchodilators for 24 h and the use of shortacting bronchodilators for 8 h prior to the tests. Novigorous exercise was permitted for 4 h prior to theexercise challenge. All testing commenced in the clinicalsetting and the internal review board (Medisch EthischeToetsings Commissie of the Medisch Spectrum Twente)filed no complaint to perform the study.

Exercise challenge

Exercise testing was performed on a treadmill (Reebok�, TR1premium run, Canton, MA, USA) according to ATS/ERS recom-mendations.11 The exercise challenges were performed in thelocal ice skating rink, to obtain cold air (2e5 �C, 1e5 mg l�1

H2O). Children ran, nose clipped, on a treadmill with a 10�

slope, for a 4 min period with a heart rate at 90 percent ofpredicted maximum (210-age) after an acclimatization periodof 2min.11,12 The total exercise timewas 6min.Heart ratewasmonitoredwithaPolar Sport tester (Polar Electro�, Finland).Asingle observer (JD) quantified respiratorywheeze, inspiratorystridor and cough using auscultation.13

The asthma control questionnaire (ACQ) developed byJuniper and colleagues is a reliable and validated instru-ment to measure asthma control.14 All children completedthe original Dutch version of the ACQ before exercise.Responses were given on a 7-point scale and the overallscore is the mean of 6 questions, with the question of theFEV1 omitted. Well-controlled asthma was defined by anACQ of less than 0.75 and uncontrolled asthma by an ACQ ofmore than 1.50; an ACQ between 0.75 and 1.49 was seen asan indifferent control of asthma.15

Pulmonary function measurements

A Masterscope� Jaeger�, (IBM PS 235X; Jaeger, Wurzburg,Germany) was used to measure lung volumes and flow-volume loops. This spirometer was calibrated on themorning of each study day. The flow-volume loop wasrecorded using ATS/ERS guidelines. After exercise flowvolume loop measurements were repeated in duplex at 1,3, 6, 9, 12, 15, 20 and 25 min. Pulmonary function wascalculated from the best curve.

The best forced expiratory volume in the first second(FEV1) value was used for analysis of the expiratory airflowlimitation and Zapletal reference values were used tocalculate the predicted value of the FEV1.

16 A fall of morethan 10% in FEV1 was considered positive for expiratory flowlimitation, as recommended by the ATS-ERS guidelineswhen evaluating EIB in a research setting.11

The best maximal mid inspiratory flows (MIF50), reachinga plateau and accompanied by a forced inspiratory vitalcapacity of more than 80% of baseline, were used to eval-uate inspiratory flow limitation. A fall of more than 25% ofMIF50 was considered positive for inspiratory flow limita-tion.4,5 Tomalek reference values were used to calculatethe predicted value of the MIF50.

17

Statistical analysis

Results were expressed as mean values � standard devia-tion (SD) for normally distributed data, as median (range)

1364 J.M. Driessen et al.

for non-normal data or as numbers with correspondingpercentages if nominal or ordinal. Because of the largenumber of tests, we chose to set the level of significance at0.01 (99% confidence intervals (CI)). To identify variablesthat were associated with inspiratory and expiratory flowlimitation, unpaired t-tests or ManneWhitney U tests wereperformed as appropriate. Between-group comparisons ofnominal or ordinal variables were performed by Chi-squaretests. SPSS� for Windows� version 15 (IBM, Chicago, IL,USA) was used to perform all analyses.

Figure 1 Expiratory flow limitation plotted against inspira-tory flow limitation for each individual patient; no correlationwas found (R2: 0.04; pZ 0.72). FEV1: Forced expiratory volumein 1 s; MIF50: Mid inspiratory flow.

Results

Seventy-two children with mild to moderate asthma per-formed an exercise challenge test in cold air. Baselinecharacteristics of the patients are shown in Table 1.

After exercise, the mean fall in FEV1 was 17.1 � 14.7%,while the mean fall in MIF50 was 25.8 � 16.1%. When plot-ting the fall in FEV1 against the fall in MIF50, no correlationwas found (R2: 0.04; p Z 0.717), as can be seen in Fig. 1.

Using the cut-off points as stated before (fall in FEV1 ofmore than 10% and fall in MIF50 of more than 25%) patientswere divided into 4 subgroups, after exercise 26% of thepatients did not show any flow limitation, while74% of thepatients showed a flow limitation (53/72). Of these, 38%(20/53) showed an isolated expiratory flow limitation, 45%(24/53) an expiratory and inspiratory flow limitation, and17% (9/53) showed an isolated inspiratory flow limitation. Itis remarkable that of the children without a significant fallin FEV1, almost half (9/19) showed a significant fall in MIF50;additionally, of the children without a significant fall inMIF50, almost half (20/39) showed a significant fall inFEV1.The mean time to maximum fall in FEV1 was9.2 � 7.6 min after exercise, while the mean time tomaximum fall in MIF50 was 15.1 � 7.9 min after exercise(Difference 5.9 min; p < 0.001, 99% CI: 2.3e9.5 min). The

Table 1 Baseline characteristics. Data are given inmean � SD or numbers (percentage) FEV1: Forced expira-tory volume in 1 s. FVC: Forced vital capacity, MIF50:Maximal mid inspiratory flow, ICS: Inhaled corticosteroid,LABA: Long acting bronchodilating agent, NCS: Nasal corti-costeroid, ACQ: Asthma control questionnaire.

Patient characteristics Value

Age (years) 13.2 � 2.2Male gender 48 (67)Height (cm) 168 � 9FEV1 (% of predicted) 101.4 � 9.5FEV1/FVC ratio 83.4 � 16.5MIF50 (% of predicted) 129.7 � 28.6ICS 57 (79)ICS þ LABA 44 (61)NCS 19 (26)ACQ � 0.75 38 (54)0.75 < ACQ < 1.50 20 (29)ACQ � 1,50 12 (17)House dustmite allergy 43 (60)Grass - tree pollen allergy 38 (53)Food allergy 14 (19)

inspiratory and expiratory airflow in time for each groupcan be seen in Fig. 2.

The use of inhaled corticosteroids was not related to theoccurrence of EIB (chi-square p Z 0.573) or inspiratory flowlimitation (chisquare p Z 0.367). Similarly, the use of nasalcorticosteroids was not related to the occurrence of EIB(chi-square p Z 0.528 or inspiratory flow limitation (chis-quare p Z 0.457), suggesting that the use of inhaled ornasal corticosteroids did not significantly effect the likeli-hood for EIB or inspiratory flow limitation in asthmaticchildren.

The correlation between the overall ACQ and fall in FEV1after exercise was 0.12 (p Z 0.864) and the correlationwith the fall in MIF50 was 0.18 (p Z 0.810). When dividingthe patients into groups by the asthma control cut-offsprovided by Juniper et al., there was no correlation withfall in FEV1 (p Z 0.077) nor with fall in MIF50 (p Z 0.126) ascan be seen in Table 2.

The occurrence of expiratory wheeze and cough werelinked with a fall in FEV1, while the occurrence of inspira-tory stridor was linked with a fall in MIF50, as can be seen inTable 3. The relation over time between spirometry andwheeze, stridor and cough can be seen in Figs. 3e5respectively.

Discussion

This study shows that exercise can induce inspiratory flowlimitation as well as expiratory flow limitation in asthmaticchildren. Inspiratory flow limitation was related to aninspiratory stridor but unrelated to the occurrence orseverity of expiratory flow limitation.

Exercise induced inspiratory stridor and flow limitation ismost commonly attributed to VCD. VCD is a heterogeneousentity and as such the inspiratory flow limitation weobserved could be attributed to VCD.8,9 Laryngoscopyduring and immediately after exercise and not lung-function is considered to be the gold standard to diagnoseVCD.18,19 However the inspiratory flow limitation weobserved peaked well after ceasing exercise and was notaccompanied by acute ‘choking’, both of which are not

Figure 2 Expiratory flow limitation and inspiratory flow limitation over time for each group of patients: 1) No flow limitation; 2)Isolated expiratory flow limitation; 3) Isolated inspiratory flow limitation and 4) Both expiratory and inspiratory flow limitation.FEV1: Forced expiratory volume in 1 s; MIF50: Mid inspiratory flow.

Inspiratory flow limitation after exercise 1365

compatible with a diagnosis of VCD and suggest anothercause.8,9,18,19

Methacholine and histamine have also been known tocause inspiratory flow limitation, mimicking asthma likesymptoms, in both children2 and adults.3,4 Rolla et al. foundinflammation of the laryngeal mucosa in patients withmethacholine induced inspiratory flow limitation andhypothesized that this was due to chronic mouth breathingas a result of chronic upper airway inflammation.20 Turktaset al. observed that the responsiveness to methacholinemeasured with the MIF50 subsided after appropriate treat-ment of upper airway co-morbidity.2 Although the majorityof asthmatic children have an upper airway inflammation,5

we did not find a lower prevalence of inspiratory airflowlimitation in children using nasal corticosteroids. Wepropose this is due to a limited medication adherence.

Several remarks should be made about this study. Anal-ysis of the inspiratory flow limb is difficult, especially inchildren. The MIF50 can be used to analyze inspiratory flowlimitation in children17,21 and Tomalak and co-workers havecalculated reference values for children.17 The observedmean pre-exercise MIF50 was approximately 1 standarddeviation above predicted, which indicates that the

Table 2 Subdivision of patients for control of asthma as measuexpiratory volume in 1 s; MIF50: Mid inspiratory Flow. ACQ: Asthm

Well-controlledACQ < 0.75 n Z 38

Fall in FEV1 greater than 10% 14 (37)Fall in FEV1 after exercise 17.2 � 15.8Fall in MIF50 greater than 25% 16 (42)Fall in MIF50 after exercise 22.1 � 17.7

children in our study were capable of performing techni-cally acceptable flow volume loops. To accurately analyzethe inspiratory limb, three repeated inspiratory limbs arerequired for analysis.22 Although feasible before exercise,the time schedule after exercise forced the use of duplexflow volume loops. The number of forced breathingmanoeuvres following exercise might have enhanced theobserved flow limitation although we did not see theinspiratory flow limitation in all children. Furthermore, thenumber of forced breathing manoeuvres in the usedprotocol is similar to the number of forced breathingmanoeuvres required for Methacholine testing reducing thelikelihood of a significant effect of fatigue.2,3,11 A reductionof the inspiratory vital capacity could be accompanied bya higher peak and mid inspiratory flow and a reduction ofthe plateau phase of the curve. To avoid artificially deviantMIF50 values, and to increase the accuracy of the analysis,the maximal MIF50 was chosen when accompanied bya forced inspiratory vital capacity of more than 80% ofbaseline and reaching a plateau phase.17

We choose to use the fall in MIF50 to analyze the inspi-ratory flow limitation similar to studies using direct chal-lenges. One cannot copy the rate of decline in flow

red with the ACQ versus fall in FEV1 and MIF50. FEV1: Forceda control questionnaire.

Indifferent ACQ0.75e1.49 n Z 20

UncontrolledACQ � 1.50 n Z 12

5 (25) 8 (67)12.2 � 5.9 24.4 � 19.910 (50) 5 (42)30.9 � 19.1 28.7 � 14.5

Table 3 The occurrence of wheeze, stridor and cough compared to the maximum fall in FEV1 and MIF50.

Fall in FEV1 (% of baseline) Fall in MIF50 (% of baseline)

Yes No p-value 99% CI Yes No p-value 99% CI

Wheeze 22.6 � 17.1 11.0 � 6.0 <0.001 2.8e18.4 26.9 � 16.6 22.6 � 15.3 0.080 �6,5e15.0Stridor 19.4 � 15.7 13.0 � 11.7 0.048 �3.0e15.7 28.8 � 16.2 17.0 � 12.8 <0.001 1.8e21.8Cough 19.0 � 15.8 10.4 � 4.7 0.001 1.9e15.3 26.2 � 16.6 20.6 � 13.5 0.158 �8.0e19.3

1366 J.M. Driessen et al.

limitation used in direct provocation to indirect provoca-tion. As the cut off for expiratory flow limitation used istypically higher in direct challenges than in indirect chal-lenges, we believe using the same cut-offs for inspiratoryflow-limitation in indirect challenges is sensible. We did notuse the fall in the MIF50/MEF50 ratio, as MEF50 fell consid-erably in most children.

We compared the changes in inspiratory airflow limita-tion in the different groups with the group of asthmaticchildren without exercise induced airflow limitation. Thepattern of inspiratory airflow limitation is unknown inhealthy children. However, in the group in which we did notobserve airflow limitation, airway inflammation wasapparently well controlled. Allowing comparison betweenthe groups with different flow patterns.

Clinical signs, i.e. cough, wheeze and stridor, wereanalyzed by a single observer (JD), which might have givenrise to observer bias. However the strong associationbetween wheezing and expiratory flow limitation andstridor and inspiratory flow limitation warrents the use ofthese symptoms for diagnosis.

Figure 3 FEV1 and MIF50 in % fall over time, for children withand without wheeze. FEV1: Forced expiratory volume in 1 s;MIF50: Mid inspiratory flow. * Marks significant differences(p � 0.01).

The ACQ can be used to assess control of asthma andexercise induced symptoms (question 3)14. We did not finda relation between either expiratory or inspiratory flowlimitation after exercise and the outcome of the ACQ.This is in line with previous studies that analyzed theoutcome of an exercise challenge of children with exer-cise induced symptoms.23 Seear et al. and Abu-Hassanet al. found that persistent exercise induced symptomscan be due to other causes than expiratory flow limita-tion.6,7 In these studies a definitive diagnosis for thecause of the exercise induced dyspnoea could not befound in a sizable group (21e63%).6,7 We speculate thatthese cases can be due to an inspiratory flow limitation.Inspiratory flow restriction is closely related to overallperceived dyspnea.24 Furthermore, inspiratory flow limi-tation can compromise effective inhalation of rescue drypowder beta-2-agonists.25 The inhalation of dry powder,commonly used by children for EIB in this age group, isdependent on peak inspiratory flow and the ability tosustain inspiratory flow, which are both reduced byinspiratory flow limitation.26

Figure 4 FEV1 and MIF50 in % fall in time, for children withand without stridor. FEV1: Forced expiratory volume in 1 s;MIF50: Mid inspiratory flow. * Marks significant differences(p � 0.01) Open marker indicates n < 10.

Figure 5 FEV1 and MIF50 in % fall in time, for children withand without cough. FEV1: Forced expiratory volume in 1 s;MIF50: Mid inspiratory flow. * Marks significant differences(p � 0.01).

Inspiratory flow limitation after exercise 1367

This study shows that an exercise challenge in asthmaticchildren can give rise to inspiratory as well as expiratoryairflow limitation in asthmatic children. Inspiratory airflowlimitation is not related to expiratory flow limitation andmay give rise to asthma like symptoms after exercise andhamper the effect of inhaled rescue medication. Moreresearch should be done to analyze the pathological basisof the observed inspiratory flow limitation.

Acknowledgements

The authors would like to thank Professor S. Anderson,J. Delong and Euregio� kunstijsbaan and its employees fortheir valuable assistance.

Funding

This work was supported by an unrestricted grant from theFoundation for pediatric research in Enschede (StichtingPediatrisch Onderzoek Enschede).

Conflict of interest statement

All authors have no conflict of interest.

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