Wheeze monitoring in children for assessment of nocturnal asthma and response to therapy

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1 Eur Respir J 23; 21: DOI: / Prited i UK all rights reserved Copyright #ERS Jourals Ltd 23 Europea Respiratory Joural ISSN Wheeze moitorig i childre for assessmet of octural asthma ad respose to therapy L. Betur*,#, R. Beck*, M. Shiawi*, T. Naveh*, N. Gavriely # Wheeze moitorig i childre for assessmet of octural asthma ad respose to therapy. L. Betur, R. Beck, M. Shiawi, T. Naveh, N. Gavriely. #ERS Jourals Ltd 23. ABSTRACT: The utilisatio of octural wheeze moitorig ad quatificatio for assessmet of asthma activity was studied i symptomatic school-aged childre before ad durig treatmet. Twelve childre 6 14 yrs of age with mild or moderate utreated asthma were studied at home three times: before, 48 h ad 6 weeks ito treatmet with 5 mg motelukast daily. Lug souds were recorded overight by a automatic wheeze detectio device (PulmoTrack1). Per cet wheezig withi each respiratory cycle was calculated every 3 s throughout the ight ad a Noctural Wheeze Idex (NWI) was calculated for the total ight. The results were compared with spirometric idices (forced expiratory volume i oe secod (FEV1), forced vital capacity), brochial reactivity (provocative cocetratio causig a 2% fall i FEV1 by adeosie 59-moophosphate (PC2)) ad daily symptom scores, performed i parallel at each stage of the study. The pretreatmet NWI was (mea SD), which declied to days after oset, ad to after 6 weeks of treatmet. The NWI i seve healthy childre was The FEV1, PC2 ad symptom scores improved i parallel. Wheeze moitorig provides quatitative ad oivasive iformatio about the extet of octural wheezig i childre, correlates well with covetioal idices of asthma activity ad ca assist i assessig efficacy of treatmet. Eur Respir J 23; 21: *Divisio of Paediatric Pulmoology, Rambam Medical Cetre ad # Pulmoary Physiology Sectio, The Bruce Rappaport Faculty of Medicie at Techio - Israel Istitute of Techology, Haifa, Israel. Correspodece: N. Gavriely, Pulmoary Physiology Sectio, The Bruce Rappaport Faculty of Medicie, Techio - Israel Istitute of Techology, P.O. Box 9697, Haifa 3196, Israel. Fax: gavriely@tx.techio.ac.il Keywords: Asthma moitorig, automatic wheeze detectio, breath souds, leukotriee receptor atagoist, octural asthma, pulmoary acoustics Received: May 1 22 Accepted after revisio: November This study was fuded i part by grats from Merck, Sharp & Dohme (MSD), Israel ad by Karmel Medical Acoustic Techologies Ltd, Yokeam Illit, Israel. Worseig of asthma symptoms at ight is a commo, troublesome, yet poorly recogised compoet of the disease. Noctural asthma (NA) symptoms were reported i 47 75% of asthma patiets i a umber of large surveys from differet coutries [1, 2]. Patiets with NA ofte do ot wake up util their airways are severely obstructed. The eed to recogise ad treat NA is also based o the observatio that improvemet i sleep quality ad daytime psychological fuctio, icludig resolutio of learig ad behavioural difficulties, occurs whe patiets with NA (adults ad childre) are treated successfully [3, 4]. Objective measuremets of airflow obstructio durig sleep are difficult to obtai. A diural variatio of w15% i forced expiratory volume i oe secod (FEV1) or peak expiratory flow (the "morig dip") ad symptom diaries have bee used as a quatitative ad objective, yet idirect, method to detect the presece ad severity of NA. The FEV1 of NA patiets was 31% lower early i the morig tha i the previous afteroo [5], but o detectable chages i the respiratory rate or expiratory duratio were foud durig sleep. Direct measuremet of airway resistace durig sleep requires substatial patiet istrumetatio ad caot be used i routie cliical practice. Whe studies of NA patiets did iclude these measuremets, a patter of substatially icreased airflow obstructio durig sleep was foud [6]. The eed for a simple, objective ad quatitative method to assess NA severity is illustrated by the study of FALCONER et al. [7], who foud poor agreemet betwee subjective estimatio ad objective measuremets of cough, a commo symptom of NA. Wheezig is the acoustic maifestatio of airways obstructio [8] ad ca be recorded ad moitored oivasively with miimal patiet cooperatio durig sleep or wakefuless. A automatic wheeze detectio device was used by LENCLUD et al. [9] to compare tracheal wheezes with measuremets of airway resistace. A 79% positive predictive power ad 83% egative predictive power were reported with this system. I aother study, KIYOKAWA et al. [1] recorded tracheal souds i asthmatic patiets durig sleep, before ad after a chage i treatmet. Observers performed auditory review ad maually recorded the presece of wheezes. Although tedious, this method provided objective iformatio o the respose to therapy. The authors hypothesised that quatificatio of wheezes ca provide accurate iformatio o NA activity ad would correlate with other measures of asthma severity. The use of a ew automatic wheeze detectio device (PulmoTrack1 11; Karmel Medical Acoustic Techologies Ltd, Yokeam Illit, Israel) for all-ight moitorig of asthmatic childre ad healthy cotrols is described. Study desig Methods This was a prospective pilot study with each subject servig as their ow cotrol. Rambam Medical Cetre9s Istitutioal Review Board approved this study. All procedures were explaied to the childre ad the parets siged a detailed iformed coset form.

2 622 L. BENTUR ET AL. Patiets Utreated asthmatic childre referred to a paediatric pulmoary cliic were recruited. Iclusio criteria were as follows: 1) age 6 14 yrs; 2) diagosis of asthma by Global Iitiative for Asthma (GINA) criteria [11]; 3) ability to perform spirometry cosistetly; 4) FEV1 w6% predicted at iitial assessmet; ad 5) asthma severity "mild persistet" or "moderate persistet" by GINA classificatio [11]. Exclusio criteria were as follows: 1) other chroic coditios; 2) emergecy room visit i the previous 3 moths; 3) respiratory ifectio i the previous moth; ad 4) use of ati-iflammatory medicatio i the previous 3 moths, or ay asthma medicatio except short-actig brochodilators i the 2 weeks prior to erolmet. The healthy subjects were childre who were ever diagosed with ay respiratory disorder, had ormal spirometry ad a ormal physical exam. Wheezig was cotiuously measured at the five sesor positios simultaeously usig all data received from the sesors ad was quatified i real time as per cet of wheezig time to breathig time, wheeze rate (Wz%) [14]. Wheeze detectio was performed by a fast Fourier trasform-based algorithm that was previously verified ad foud to have sesitivity of 91% ad specificity of 89% whe compared with cosesus assessmet by a pael of experts [15]. Speech, cryig ad other vocal cord souds are idetified by the system ad discarded [15]. I additio, auditory audit of the data was also performed to verify the detectio accuracy. The detected wheezes are show cotiuously as a Wheezogram1, (Karmel Medical Acoustic Techologies Ltd) a plot of wheeze frequecy versus time (fig. 1), alog with the chest impedace sigal. I additio, a Acoustic Vector TM (Karmel Medical Acoustic Techologies Ltd) cotiuously shows the timig of wheezes Study procedure Utreated childre with symptomatic asthma were erolled ad treated with motelukast to cotrol their symptoms. Noctural wheezig, covetioal asthma idices ad symptom scores were measured durig therapy. At erolmet, iclusio/exclusio criteria were verified, baselie spirometry was performed, ad a 2-week ru-i period was started, durig which the subjects used short-actig ihaled brochodilators oly ad completed a daily symptom diary. At the ed of the 2-week ru-i period, overight acoustic respiratory moitorig (ARM) of wheezig activity was performed for wheeze quatificatio. Spirometry ad a adeosie 59-moophosphate (AMP) brochial provocatio test (BPT) were also performed, prior to which the childre were examied by stethoscope ad a 1-mi ARM performed to detect presece of wheezes. Five milligrams daily motelukast (Sigulair TM, Merck Sharp & Dome Ltd, Israel), a oral leukotriee receptor atagoist, was the started at bedtime. ARM, spirometry ad AMP BPT, as described above, were repeated 2 days later to assess the early effects of motelukast (oset), ad after 6 weeks to assess the delayed effects (durig). b) c) Descriptio of acoustic respiratory moitorig procedure d) Recordig ad aalysis of respiratory souds were coducted accordig to stadardised methods as described previously [12, 13]. Respiratory acoustic sigals were recorded from five phoopeumography piezoelectric cotact sesors (PPG Sesors; Karmel Medical Acoustic Techologies Ltd) applied over the trachea, right ad left axillae ad both posterior bases of the lugs. The sesors were coi-shaped piezoelectric elemets with liear 3dB frequecy respose of 75 2, Hz, a resoace at 2.7 khz, a useable rage that exteded beyod 4 khz ad a built-i passive ambiet oise rejectio capability. The sesors were attached to the chest with adhesive foam pads that further reduced ambiet oise iterferece ad elimiated cotact oise. All sesors were coected to the PulmoTrack1 where sigal coditioig (amplificatio 63,, bad pass filtratio 8 4, Hz at 24 db/oct) was performed prior to aalogue-to-digital coversio (11,25 samples?s -1?chael -1 ). Two other sigals were tracked; ambiet oise, with a air-coupled microphoe placed ear the patiet, ad chest impedace for measuremet of breathig activity (respiratory rate, phase ad amplitude). Prior to sleep, the sesors were placed by a techicia who moitored the procedure for the etire ight ad oted ay uusual evets. The sesors ad wires posed o restrictio o the childre, who moved freely durig sleep. e) Tot. Is. Exp. % Time s Fig. 1. Example of a 3-s data segmet from patiet Respiratory Moitorig Study umber 3. Soogram plot of frequecy of wheezes i Hz versus time with amplitude i grey scale show for the left axilla chael. b) Wheezogram1 plot showig the wheezes detected by the automatic wheeze detectio algorithm i all five chaels, which are displayed idividually as idicated o the left of e). c) Breathig activity by chest impedace. Respiratory rate: 14.1 breaths per mi; ispiratory duratio: 1.5 s; expiratory duratio: 2.7 s; ispiratio:expiratio:.6. d) Detectio of ispiratory (I; &), ad expiratory (E; &) phases. e) Acoustic vector plot, idicatig the timig of wheeze activity i the differet chaels (first row: tracheal whistles; secod row: tracheal wheezes; third row: right base; fourth row: left base; fifth row: right axilla; sixth row: left axill. Ambiet chael showed o evidece of wheezig (ot show). The total (Tot.), ispiratory (Is.) ad expiratory (Exp.) wheeze rates % are show.

3 WHEEZE MONITORING IN NOCTURNAL ASTHMA :23 :23 2:23 4:23 6:23 Time b) 6 Wheeze rate Wheeze rate :32 :32 2:32 4:32 6:32 Time Fig. 2. Wheeze activity durig a full ight9s sleep i a 9-yr-old asthmatic patiet (Respiratory Moitorig Study umber 2) before treatmet ad b) 2 days after startig treatmet. Each arrow bar represets the combied per cet time wheezig (wheeze rate) from all chaels i a 3-s soud segmet. Note periods of sigificat wheezig throughout the ight i ad their marked dimiutio i b). The patiet did ot wake up durig both ights. detected at the differet sesor sites. The automatic wheeze detectio algorithm idetifies cotiuous advetitious breath souds at 8 4,8 Hz i the tracheal chael ad 8 2,4 Hz i the chest wall chaels. These frequecy rages iclude low-frequecy wheezes ad rhochi as well as high-pitch tracheal "whistles" [16]. Durig octural ARM the PulmoTrack1 moitored wheezig activity throughout the ight (y8 h) ad logged the timig ad frequecy of all detected wheezes, as well as iformatio o ambiet oise ad breathig activity. I additio, the system automatically recorded 3-s segmets of raw data every 1 mi, for quality assurace ad possible further future aalyses. Data reductio ad statistical methods At the coclusio of the octural recordig, the wheeze rate (Wz%) was displayed for each chael i successive 3-s itervals. The full ight9s data were plotted as a tred report as show i figure 2. These data ca be plotted for ay oe of the five sesors or combiatio of sesors ad by respiratory phase. The tred report provides a temporal distributio of wheezig activity durig the ight. The system also provides a quatitative umeric output i the form of a distributio fuctio (histogram) of the Wz% as the rate of occurrece (i % of the total ight test) of wheeze activity i each of the followig Wz% rages:..75, , , , , , ad (fig. 3). Itegratig the total wheeze activity, aalogous to calculatio of the area uder the curve, reduced the data further. This was doe by multiplyig the "rate of occurrece" for each Wz% rage by the mea of that rage ad summig the total for all Occurrece rate % of ight b) Occurrece rate % of ight the rages. This calculated the octural wheeze idex (NWI). Accordigly, the maximal possible NWI score is 7,4. Establishig ormal rage This study coducted ARM i healthy childre that had ever bee diagosed with ay respiratory disorders ad had ormal physical examiatio ad ormal spirometry. The moitorig procedure was idetical to that of the study group ad was doe o two cosecutive ights to establish itrasubject variability. Adeosie brochial provocatio Rage of Wz% Fig. 3. Examples of wheeze activity histograms before ad b) durig treatmet with motelukast. Occurrece rate is the per cet of the total umber of 3-s segmets with wheeze rate (Wz%) that fall withi the predetermied rages show o the ordiate. Wz% values v1.5% (h) were cosidered withi ormal rage, Wz% w1.5% (p) above ormal rage. Total extet of wheezig 229, 678, 55, 14, 42, ad b) 88, 52, 48 from left to right, is calculated from the bar size ad the middle value of the Wz% rage. BPT was performed by ihalatio of AMP solutios i doublig doses [17]. Fresh solutios of AMP (SIGMA, St. Louis, MO, USA) were prepared, startig at.39 mg?ml -1 to a maximum of 4 mg?ml -1. Nebulised AMP solutio was ihaled for 2 mi, followed by spirometry (Microloop II portable spirometer; Micromedical Ltd, Rochester, Ket, Eglad).

4 624 L. BENTUR ET AL. Table 1. Patiet baselie data ad chages i forced expiratory volume i oe secod (FEV1), forced vital capacity (FVC) ad provocatio dose causig a 2% fall i FEV1 (PC2; expressed as the adeosie 59-moophosphate (AMP) doublig dose umber at which FEV1 dropped by 2%) durig the various study phases. Wilcoxo tests were used to compare the study phases Patiet Test age FEV1 % pred FVC % pred PC2 AMP doublig dose Combied symptom score Pre- Oset Durig Pre- Oset Durig Pre- Oset Durig Pre- Oset Durig Mea SD p-value NS #.5 } NS #.4 }.43 # NS }.1 #.1 }.3 #.3 #.1 #.1 # Statistical aalysis comparig the study phases (Wilcoxo) is show. % pred: % predicted; NS: osigificat. # : compared with the prestudy phase; } : compared with the oset study phase. The best of three efforts was recorded. The provocatio dose was doubled at 5-mi itervals util the FEV1 dropped 2% below baselie level (PC2), or a cocetratio of 4 mg?ml -1 was reached, producig a egative result. sesors. A Wheezogram1 from oe of the patiets Respiratory Moitiorig Study (RMS) umber 3) is show i figure 1. All childre where wheeze-free whe examied at Symptom scores 3 The subjects completed a daily asthma symptom diary that icluded day cough, ight cough, exercise tolerace ad the use of brochodilators. Each category was graded as oe (), mild (1) or sigificat (2). Combied scores of the four categories for 2-week periods (maximal possible score 112), correspodig to the "pre", "oset" ad "durig" stages, were tallied ad compared. NWI % 2 1 s Statistical aalysis Noparametric Wilcoxo rak-sum test was used to aalyse the chages of the various parameters i the differet stages of the study. A p-value v.5 was cosidered sigificat. b) 12 s s Results Sixtee asthmatic childre were erolled ito the study ad 12 (six males ad six females) completed it. Their ages raged from 6 14 yrs (mea 9.5). Four patiets dropped out, two due to itercurret illess (viral meigitis, peumoi ad two for persoal reasos. Seve healthy childre had octural ARM performed, five of them o two cosecutive ights. The results of the chages i the various parameters durig the three study phases are preseted i table 1 ad i figure 4. NWI % 8 4 Pre # Oset + Durig Acoustic respiratory moitorig data All ARM sessios were completed without icidet, the childre slept ormally ad were ot bothered by the attached Fig. 4. Idividual octural wheeze idex (NWI) values for all 12 study subjects at the three phases of treatmet. b) Average SEM values of NWI i the 12 study subjects ad the correspodig values SEM of the healthy group. q: ormal rage. # : p=.5; } :p=.28; z :p=.26.

5 WHEEZE MONITORING IN NOCTURNAL ASTHMA 625 daytime prior to their spirometry ad AMP BPT, both by stethoscope ad a 1-mi ARM. Noctural ARM data The Wz% values from a full ight of pretreatmet moitorig of a 9-yr-old asthma patiet (RMS umber 2) are show i figure 2a. Multiple substatial wheezig episodes lastig 3 6 mi each that subsided ad reappeared spotaeously without treatmet ad without wakig up are evidet. Wheezig activity dimiished markedly after 2 days of treatmet (oset), as show i figure 2b. Examples of the wheeze activity distributio curve (histogram) with calculatio of the NWI for patiet RMS umber 2 at the pre- ad durig stages are show i figure 3. The idividual ad mea SD of the values of the NWI from the 12 patiets who completed the protocol are show i figure 4. Note that i the six patiets with mild persistet asthma ad ormal spirometry (umbers 2, 4, 5, 6, 8, ad 12; table 1), four had a high degree of octural wheezig. I ie of the subjects (75%) the NWI dimiished substatially after 6 weeks of treatmet. I the other three subjects (25%), o chages i NWI were detected. The mea NWI fell six-fold betwee the pre- ad the durig stages (p=.28). This fall cosisted of 2.6-fold dimiutio after 48 h (p=.5) ad additioal 2.3-fold reductio after 6 weeks (p=.26). Auditory audit of the above data cofirmed the accuracy of the automatic aalysis performed by the PulmoTrack1. Establishig ormal rage ARM was coducted i seve healthy childre, five of whom had ARM o two cosecutive ights to establish itrasubject variability. The healthy group9s NWI was 47 43%, with a rage of Itra-subject variability was small ( 1% maximum). The "ormal" rage is show i figure 4b as the shaded area represetig the mea SD of the healthy group. Pre- to oset. Mea NWI fell from to (p=.5). By doublig doses, there was a statistically sigificat improvemet i PC2 by 1.3 (p=.43), but o statistical chage i FEV1 or FVC. I cotrast, the symptom scores showed a marked ad statistically sigificat improvemet i all categories (table 1). Pre- to durig. There was further improvemet from oset i all parameters after 6 weeks of treatmet (table 1). Mea NWI fell further to (p=.28), PC2 improved by oe additioal doublig dose to (p=.1), FEV1 improved from to % pred (p=.3) ad FVC rose from to % pred (p=.3). Symptom scores remaied at the same low levels of oset, sigificatly better tha prestudy (table 1). Discussio This study demostrates that computerised octural wheeze moitorig is a practical ad oivasive method for assessig asthma activity i childre ad that the results of octural wheeze quatificatio correlate well with stadard asthma idices such as spirometry results, PC2 ad symptom scores. Noctural wheezig as a maifestatio of ucotrolled asthma is a well-kow pheomeo. Previous studies have quatified octural wheeze activity usig automated or auscultatory methods to geerate a objective estimate of the extet of wheezig [9, 1, 14]. A importat fidig of the preset study was the large extet of octural wheezig i the paediatric asthma patiets. Based o their cliical symptoms ad spirometric data, all patiets who participated i this study were classified as havig either mild persistet or moderate persistet asthma [11]. The fact that they were utreated may accout for some icrease i symptoms. However, most of the patiets were uaware of octural symptoms ad they were categorised accordig to other symptoms ad pulmoary fuctios. Promiet octural wheezig was preset i eight of 12 childre who were uaware of it. Sice healthy childre do ot wheeze durig sleep, the authors iterpret the presece of octural wheezes i asthmatic childre as a maifestatio of their disease. I these childre, the degree of octural wheezig correlated well with other asthma idices durig treatmet. Some asthmatic patiets with severe airflow obstructio do ot ecessarily wheeze (silet lug) ad wheeze moitorig may ot be a adequate idicator of disease severity i these patiets. However, the majority of asthmatics do wheeze, ad octural wheeze moitorig ca be a practical oivasive tool of moitorig disease severity ad activity. I the patiets i this study, octural wheezig was a promiet fidig, whereas little or o wheezig occurred durig daytime. Therefore, octural ARM provides additioal practical iformatio that ca help i moitorig the patiet9s asthma ad the respose to therapy. May characteristics of wheezes, such as amplitude, frequecy rage, umber of simultaeous wheezes, duratio ad chest distributio, ca be recorded ad measured, but the parameter that best correlates with other cliical idices of asthma severity is wheeze duratio [14]. I the preset study, the authors used the total duratio of wheeze activity, irrespective of the respiratory phase or site, as the primary quatitative measure of wheeze activity. Compared with previous studies [18, 19], the authors used a wider frequecy rage to idetify wheezes so that low frequecy wheezes ad rhochi, as well as high frequecy tracheal whistles, were icluded i the wheeze rage calculatio. I the curret study, as i previous reports, the authors foud wheezes i both the ispiratory ad expiratory phases. What, if ay, correlatio exists betwee wheeze frequecy ad/or their predomiat timig to the severity ad aatomic distributio of airway costrictio requires further research. I order to provide a cliically meaigful output, the octural wheeze activity is reported as a tred plot of Wz% i 3-s segmets throughout the ight, as illustrated i figure 2. A more codesed view is provided by the histogram (fig. 3), from which a umeric score (NWI) is derived, which quatifies the total octural wheeze activity. The tred plot is also useful for idetifyig the timig ad distributio of wheeze activity durig the ight; i some patiets the wheezes were most promiet i the early morig hours, whereas i others, wheezes were preset throughout the ight. Some patiets had mild wheezig throughout the whole ight, while i others there were a few short episodes of high Wz%. It is clear that while both may have idetical NWI, the distributio durig the ight o the oe had ad the peak Wz% o the other, reflect differet temporal patters of airway costrictio that may have differet implicatios regardig aetiology, cliical course ad treatmet strategy. The dropout rate i the curret study (four of 16 origially erolled), though sigificat, is ot uusual for this type of study. It was a log ad time-cosumig study that required cosiderable commitmet o the part of the subjects ad their parets. Aother limitatio of this study is the small umber of subjects. This umber is adequate, however, for a pilot

6 626 L. BENTUR ET AL. study, ad to esure appropriate statistical validity, the authors used more striget oparametric statistics, which demostrated statistically sigificat chages. There was also o true cotrol group who received placebo ad followed logitudially. This study was ot desiged as a therapeutic trial, but was meat to assess the utility of octural wheeze moitorig i the assessmet of asthma. Motelukast was give to create chages i asthma activity that ca be followed ad moitored, both covetioally ad by ARM. The authors foud a substatial ad statistically sigificat declie i wheeze activity ad early symptom relief with motelukast treatmet: 75% of the patiets had a marked drop i octural wheezig, while the rest had o sigificat respose (fig. 4). A similar ratio of respoders to orespoders durig motelukast treatmet has bee reported i other studies [2]. The wheeze activity durig treatmet correlated sigificatly (pv.14) with baselie FEV1 ad with PC2 (pv.14) durig treatmet. The decrease i symptoms was associated with a parallel reductio i NWI. The preset study demostrates the usefuless of octural wheeze moitorig i the assessmet of asthma patiets. A ususpectedly high level of octural wheezig i the group of utreated asthmatic childre, icludig those with mild asthma ad ormal spirometry, was foud. Quatitative wheeze assessmets, expressed as Wheeze Rate ad Noctural Wheeze Idex, correspoded well with chages i forced expiratory volume i oe secod, provocatio dose where forced expiratory volume i oe secod dropped 2% below baselie level, ad symptom scores. Thus, octural wheeze moitorig ad quatificatio provides a simple ad oivasive method for assessmet of asthma severity ad respose to treatmet. While this study was carried out i older childre, it seems likely that moitorig of youger childre, ifats ad elderly patiets may be eve more cliically useful by providig cotiuous objective measuremets of asthma activity ad respose to treatmet i patiets who caot perform spirometry. Ackowledgemets. The authors wish to ackowledge the skilful techical assistace of KMAT cliical coordiators. They thak S. Godfrey, D.W. Cugell ad C.S. Irvig for discussig the data ad for their umerous, useful commets ad suggestios. Refereces 1. Turer-Warwick M. Epidemiology of octural asthma. Am J Med 1988; 85: Meijer GG, Postma DS, Wempe JB, Gerritse J, Kol K, va Aaldere WM. Frequecy of octural symptoms i asthmatic childre attedig a hospital outpatiet cliic. Eur Respir J 1995; 8: Stores G, Ellis AJ, Wiggs L, Crawford C, Thomso A. Sleep ad psychological disturbace i octural asthma. Arch Dis Child 1998; 78: Weersik EJ, va Zomere EH, Koeter GH, Postma DS. Treatmet of octural airway obstructio improves daytime cogitive performace i asthmatics. Am J Respir Crit Care Med 1997; 156: Morga AD, Rhid GB, Coaughto JJ, Catterall JR, Shapiro CM, Douglas NJ. Breathig patters durig sleep i patiets with octural asthma. Thorax 1987; 42: Ballard RD, Saathoff MC, Patel DK, Kelly PL, Marti RJ. Effect of sleep o octural brochocostrictio ad vetilatory patters i asthmatics. J Appl Physiol 1989; 67: Falcoer A, Oldma C, Helms P. Poor agreemet betwee reported ad recorded octural cough i asthma. Pediatr Pulmool 1993; 15: Kercsmar CM. Asthma. I: Cherick V, Boat TF, eds. Disorders of the Respiratory Tract i Childre. Philadelphia, Sauders Co., 1999; p Leclud C, Cuttitta G, Viscoti A, va Muylem A, Bellia V, Yerault JC. All ight o lie moitorig of wheezig: compariso with moitorig of airway resistace i octural asthma. Bull Eur Physiopathol Respir 1986; 22: Kiyokawa H, Yoemaru M, Horie S, Kasuga I, Ichiose Y, Toyama K. Detectio of octural wheezig i brochial asthma usig itermittet sleep tracheal souds recordig. Respirology 1999; 4: Natioal Istitute of Health. Global Iitiative for Asthma: (GINA) the ew GINA workshop report 22. Natioal Heart Lug ad Blood Istitute/World Health Orgaizatio Workshop Report. Bethesda, MD, Natioal Istitute of Health, Gavriely N. Breath Souds Methodology. Boca Rato, CRC Press, 1995; pp Earis JE, Sovijarvi ARA, Vederschoot J. Europea Respiratory Society Task Force Report: Computerized Respiratory soud aalysis (CORSA): recommeded stadards for terms ad techiques. Eur Respir Rev 2; 1: Baughma RP, Loudo RG. Lug soud aalysis for cotiuous evaluatio of airflow obstructio i asthma. Chest 1985; 88: Lim S, Gavriely N, Irvig CS, Chug KF, Bares PJ. Quatitative documetatio of wheezes i asthma cliics usig a automatic wheeze quatificatio device. Eur Respir J 1999; 14: Suppl. 3, Gavriely N, Irvig CS. Tracheal whistles a ew physical sig of airway costrictio. Eur Respir J 1999; 14: Suppl. 3, Avital A, Picard E, Uwyyed K, Spriger C. Compariso of adeosie 59-moophosphate ad methacholie for the differetiatio of asthma from chroic airway diseases with the use of the auscultative method i very youg childre. J Pediatr 1995; 127: Feto TR, Pasterkamp H, Tal A, Cherick V. Automated spectral characterizatio of wheezig i asthmatic childre. IEEE Tras Biomed Eg 1985; 32: Gavriely N, Palti Y, Alroy G, Grotberg JB. Measuremet ad theory of wheezig breath souds. J Appl Physiol 1984; 57: Korr B, Matz J, Berstei JA, et al. Motelukast for chroic asthma i 6 to 14 year old childre: a radomized, double-blid trial. JAMA 1998; 279: