management of the wheezing toddler

Management of the Wheezing Toddler

Diagnostic Practices, Therapy, andPredictors of Symptom Persistence

A c t a U n i v e r s i t a t i s T a m p e r e n s i s 814

U n i v e r s i t y o f T a m p e r eT a m p e r e 2 0 0 1

ACADEMIC DISSERTATIONTo be presented, with the permission of

the Faculty of Medicine of the University of Tampere,

for public discussion in the small auditorium of Building K,

Medical School of the University of Tampere,

Teiskontie 35, Tampere, on May 4th, 2001, at 12 o’clock.

PÉTER CSONKA

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University of TampereSales OfficeP.O. Box 61733101 TampereFinland

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Printed dissertationActa Universitatis Tamperensis 814ISBN 951-44-5087-6ISSN 1455-1616

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Electronic dissertationActa Electronica Universitatis Tamperensis 105ISBN 951-44-5088-4ISSN 1456-954Xhttp://acta.uta.fi

ACADEMIC DISSERTATION

University of Tampere, Medical School,Department of PaediatricsTampere University Hospital, Department of PaediatricsFinland

Supervised byDocent Per AshornUniversity of Tampere

Reviewed byDocent Mika MäkeläUniversity of TurkuDocent Harri SaxénUniversity of Helsinki

Through cigar smoke, throughnight’s fogged cloak, throughwreaths of the winter moon, through shawls of rain,in the opening dream’s light and uncertaingolden-dreampurple and ebonystage scenerybetween reckoning and translation,in brief relaxation,when tired brains like spider weave their screenit’s always you I’ve seen,the impossible, the brilliant green flyI catch as it flits by.You’re every picture, all the thoughts that riseunder the lids, behind the eyes.1

To Päivi

1Through the Smoke by István Vas, translated by György Szirtes

HENGENAHDISTUKSESTA KÄRSIVIEN LEIKKI-IKÄISTEN LASTEN HOITO – PÉTER CSONKA

TIIVISTELMÄUloshengityksen vaikeutuminen ja siihenliittyvä vinkuna on hyvin yleistä leikki-ikäisten lasten keskuudessa. Se vaivaa noinjoka viidettä lasta ensimmäisen elinvuodenaikana ja joka kolmatta kolmen vuoden ikäänmennessä. Vinkunan patomekanismi vaihteleeeri yksilöiden välillä ja suurella osalla lapsistaoireet vähenevät tai loppuvat iän myötä. Sitä,kenellä oireilu jatkuu ja kehittyy myö-hemmällä iällä astmaksi, on yksittäisen lapsenkohdalla vaikea ennustaa. Nämä seikatyhdessä vaikeuttavat näyttöön pohjautuviendiag-nostisten kriteereiden ja hoitosuositustenkehittämistä hengenahdistuksesta kärsivilleleikki-ikäisille lapsille.

Tavoitteemme oli neljän tutkimuksenavulla 1) tarkastella hengenahdistuksestakärsivien pienten lasten diagnostiikkaa jahoitokäytäntöjä, 2) arvioida suun kauttaannettavan (per os) prednisolonin tehoaakuutin hoidon yhteydessä, 3) sekä määritelläsellaisia tekijöitä, jotka auttaisivat niidenlasten tunnistamisessa, jotka jatkavat oireiluaja kehittävät astman kouluikään mennessä.

Retrospektiivisen aineistomme mukaanTurussa 6 kk - 7 v lasten keskuudessa astma-diagnoosin todennäköisyys oli kahdeksan-kertainen Tampereeseen verrattuna. Sekäaiempi hengenahdistuskertojen määrä ettälapsen vanhempi ikä lisäsivät poliklinikallatehdyn astmadiagnoosin todennäköisyyttä.Tampereeseen verrattuna per os kortiko-steroidia käytettiin Turussa suuremmalla osallalapsista sekä poliklinikalla (2,5% vs. 24,2%)että osastolla (10,6% vs. 89,7%). Osastollejoutumisen todennäköisyys oli suurempiTampereella. Ne lapset, jotka käyttivätinhaloitavia kortikosteroideja, tarvitsivatosastohoitoa vähemmän molemmissa klini-koissa. Osastohoidon pituuden mediaani oli3,0 vrk Tampereella ja 1,0 vrk Turussa.Väestötasolla aktiivinen kortikosteroidilääkitysassosioitui siis vähäisempään sairaalahoidontarpeeseen.

Prospektiivinen, satunnaistettu kaksoissok-kotutkimus varmisti yllä mainitun yhteyden.Tässä tutkimuksessa oli mukana 230obstruktiivista bronkiittia sairastavaa, 6-35 kkikäistä lasta. Osastohoitoon otettujen lastenjoukossa kolmen päivän mittaisen per osprednisoloni -kuurin saaneiden lasten oireetolivat lievempiä ja osastohoidon pituuslyhyempi lumelääkettä saaneisiin verrattuna.Per os prednisoloni -lääkitys ei vaikuttanutavohoidossa olevien lasten osastolle joutumi-sen todennäköisyyteen, oireiden kestoon taiuusintakäyntien määrään.

Tunnistaaksemme ne, joilla oli suurin riskisairastua myöhemmällä iällä astmaan,suoritimme 2027:n satunnaisesti valitun 6-13 -vuotiaan lapsen keskuudessa kysely-lomaketutkimuksen. Vastausprosentti oli 90%.Kolmen ensimmäisen ikävuoden aikana 10%lapsista tarvitsi hoitoa äkillisen hengen-ahdistuskohtauksen takia. Näistä 17,2% saivastaavanlaista hoitoa myös viimeisten 12 kkaikana kyselyä edeltävästi. Monimuuttuja-analyysi osoitti, että kaikista 6-35 kk ikäisistä,hengenahdistuksesta kärsivistä lapsista suurintodennäköisyys sairastua astmaan kouluikäänmennessä oli niillä, joilla oli ruoka-aineallergiaa, atooppista ihottumaa, perheessäastmaa tai he olivat altistuneet tupakansavulleensimmäisten ikävuosiensa aikana.

Yhteenvetona voimme todeta, että onperusteltua hoitaa kaikki yli 6 kk ikäiset,hengenahdistuksesta kärsivät ja osastohoitoavaativat lapset kolmen päivän per osprednisoloni -kuurilla (2 mg/kg/vrk). Niillä 6-35 kk ikäisillä toistuvasti vinkuvilla taiosastohoitoa tarvitsevilla lapsilla, joilla onruoka-aineallergiaa, atooppista ihottumaa,perheessä astmaa tai tupakansavualtistusta, onsuurin riski jatkaa oireilua. Lisäksi onpanostettava yhtenäisten diagnostistenkriteereiden sekä hoitosuositusten kehittämi-seen, erityisesti leikki-ikäisten heterogeeni-sessä ryhmässä.

MANAGEMENT OF THE WHEEZING TODDLER – ACADEMIC DISSERTATION – PÉTER CSONKA

SUMMARYWheezing is a very common entity amongtoddlers, exerting a substantial burden on thechild, family, and health care services. Duringthe first 3 years of life, one third of thechildren will have at least one episode ofrespiratory distress and 25% will developasthma later in life. The underlyingpathomechanisms for wheezing vary betweenindividuals. In addition, the high spontaneousrecovery rate and the lack of firm predictorsfor wheezing persistence complicate thedevelopment of evidence-based guidelines forthe diagnosis and comprehensive managementof wheezy infants and toddlers.

We carried out four studies in order to 1)evaluate the diagnostic and therapeuticpractices of wheezy toddlers; 2) to assess thevalue of oral prednisolone in the acute setting;and 3) to define predictor variables that couldfacilitate the identification of those wheezingunder-3-year-old individuals who continue tobe symptomatic and develop asthma at schoolage.

Retrospective data indicated that place oftreatment, was a strong independent predictorof asthma diagnosis among 6-months-to-7-year-old children with acute symptoms (Turkuvs. Tampere, adjusted OR 8.3). A high numberof earlier wheezing episodes, and older age ofthe child were also associated with asthmadiagnosis in the emergency room (ER). Oralcorticosteroids were given to 2.5% vs. 24.2%of children in the ER and 10.6% vs. 89.7% onthe hospital ward in Tampere and Turku,respectively. Hospitalisation rates were higherin Tampere. In both regions children with priorinhaled corticosteroid treatment needed lessinpatient care. The median length of hospitalstay was 3.0 days in Tampere and 1.0 inTurku. Thus, on a population level, activecorticosteroid use was associated withdecreased need for inpatient care.

This association was confirmed by thedouble-blind, placebo-controlled, randomised

trial of 230 children, aged 6-35 months, withwheezy bronchitis. Those hospitalised childrenwho received a 3-day course of oralprednisolone were less likely to have severerespiratory distress and more likely to bedischarged earlier. The medication had noeffect on the hospitalisation rate, on theduration of symptoms, or number ofsubsequent ER visits among the non-hospitalised subjects.

To identify those at high-risk for symptompersistence we performed a questionnaire-based cross-sectional survey of 2027 randomlychosen, 6-13 years old children. Altogether1829 (90%) questionnaires were returned.Around 10% of children had soughtemergency medical care for wheezing duringthe first 3 years of life, and 17.2% of these hadreceived similar ER treatment during the 12months preceding the survey. A logisticregression analysis indicated that among allunder-3-year-old children with wheezing,those who have a history of food allergy,atopic eczema, asthma occurrence in a siblingor parent, or are exposed to tobacco smokeduring the first years of life are at highest riskfor symptom persistence until school age.

In conclusion, if a child older than 6months has respiratory distress severe enoughto need hospitalisation, a 3-day course of oralprednisolone treatment (2 mg/kg/day) isjustified. A child aged 6-35 months withrecurrent expiratory wheezing or severewheezing requiring hospitalisation and withparental history of asthma or allergy; atopiceczema or food allergy; or exposure to tobaccosmoke during first years of life should beconsidered at very high risk for persistentwheezing. In addition, special attention shouldbe paid to the development andimplementation of diagnostic and therapeuticevidence based guidelines among theheterogeneous group of wheezing preschoolchildren.

CONTENTS

List of Original Publications.................................................................................. 9Abbreviations....................................................................................................... 111. Introduction...................................................................................................... 132. Review of the Literature .................................................................................. 14

2.1 Focus Points ............................................................................................................... 142.2 Definitions of Diagnostic Labels.................................................................................. 142.3 Prevalence of Wheezing in Toddlers .......................................................................... 172.4 Outcome of Wheezing in Toddlers............................................................................. 182.5 Risk Factors for Symptom Persistence ...................................................................... 192.6 Symptomatic Treatment of Toddlers with Wheezing .................................................. 252.7 Corticosteroids ............................................................................................................ 252.8 Oral Corticosteroids in Acute Wheezy Bronchitis ....................................................... 282.9 Parenteral Corticosteroids in Acute Wheezy Bronchitis ............................................. 342.10 Inhaled Corticosteroids in Acute Wheezy Bronchitis ................................................ 342.11 Other Drugs in Wheezy Bronchitis............................................................................ 34

3. Justification of the Study ................................................................................ 354. Aims of the Study............................................................................................. 365. Materials and Methods .................................................................................... 37

5.1 Regional Variation in the Management, Outcome, and Diagnosis of PreschoolChildren with Wheezing .................................................................................................... 375.2 Oral Prednisolone in the Acute Management of Children with Wheezy Bronchitis .... 385.3 Predictors of Wheezing Persistence........................................................................... 39

6. Results.............................................................................................................. 416.1 Regional Variation in the Management and Outcome of Preschool Children withWheezing .......................................................................................................................... 416.2 Regional Variation in the Diagnosis of Asthma Among Preschool Children .............. 416.3 Oral Prednisolone in the Acute Management of Children with Wheezy Bronchitis .... 426.4 Predictors of Wheezing Persistence........................................................................... 43

7. Key Findings .................................................................................................... 458. Discussion and Conclusions .......................................................................... 46

8.1 Defining and Identifying Study Groups ....................................................................... 468.2 Precision and Validity of the Results .......................................................................... 478.3 Management of the Wheezing Toddler....................................................................... 49

9. Clinical Implications ........................................................................................ 5610. Future Perspectives....................................................................................... 5711. Acknowledgements ....................................................................................... 5812. References ..................................................................................................... 60

APPENDIX A: Data Collection Form (I & II) .........................................................71APPENDIX B: Diary Card (III)................................................................................75APPENDIX C: Case Report Form (III)...................................................................81APPENDIX D: Questionnaire (IV) .......................................................................101

ORIGINAL PUBLICATIONS.................................................................................115

LIST OF ORIGINAL PUBLICATIONS

This work is based on the following four original publications, referred to in the textby their Roman numerals:

I. Csonka P, Mertsola J, Klaukka T, Kaila M, Ståhlberg M-R, Ashorn P.Corticosteroid therapy and need for hospital care in wheezing preschool children.Eur J Clin Pharmacol 2000;56:591-596.

II. Csonka P, Mertsola J, Kaila M, Ashorn P. Regional variation in the diagnosis ofasthma among preschool-age children. Pediatr Allergy Immunol 2000;11:189-192.

III. Csonka P, Kaila M, Laippala P, Iso-Mustajärvi M, Vesikari T, Ashorn P. Oralprednisolone in the acute management of children with wheezy bronchitis: arandomised placebo-controlled trial. Submitted.

IV. Csonka P, Kaila M, Laippala P, Kuusela A-L, Ashorn P. Wheezing in early lifeand asthma at school age: predictors of symptom persistence. Pediatr AllergyImmunol 2000;11:225-229.

ABBREVIATIONS

BHR Bronchial hyperresponsivenessCI Confidence intervalCIdiff Confidence interval for the

differenceDDD Defined daily doseDO2 Duration of oxygen therapyDOS Duration of symptomsDXM DexamethasoneER Emergency roomERV Emergency room visitsFEV1 Forced expiratory volume in 1

secondFVC Forced vital capacityHoR Hospitalisation rateHPA Hypothalamic-pituitary-adrenal axisHR Heart rateICD International Classification of

DiseasesIM IntramuscularISAAC International Study on Asthma and

Allergy in ChildhoodIV IntravenousLFT Lung function testLOS Length of hospital stayNNT Number needed to treatOR Odds ratioPF Pulmonary functionPO Per oralReR Respiratory rateRR Relative riskRSV Respiratory syncytial virusSD Standard deviationSII Social Insurance Institution in

Finland (Kansaneläkelaitos)SS Symptom scoreURTI Upper respiratory tract infectionV’maxFRC

Maximal forced expiratory flow atfunctional residual capacity

INTRODUCTION 13

1. INTRODUCTION

Wheezing is a very common entity amongtoddlers, exerting a substantial burden on thechild, family, and health care services. Duringthe first 3 years of life, roughly 1/3 of thechildren will have respiratory distress(Martinez et al 1995), many with recurrentepisodes (Korppi et al 1993). However,approximately 2/3 of toddlers will outgrowtheir symptoms before the age of 3 years(Foucard and Sjöberg 1984, Martinez et al1995).

Toddlers with expiratory wheezing representa heterogeneous group of children with aspectrum of clinically similar symptoms butwith several different underlying diseasemechanisms and outcome. Some childrenwheeze only during the first few years of lifeand become symptom-free as they grow older,others go on wheezing from infancy till schoolage, and there are those who start wheezinglater in childhood without prior symptoms(Martinez et al 1995, Stein et al 1997). Thosewith diminishing symptoms are thought tohave small airways that are narrowed below acritical diameter as a result of virally inducedoedema and mucous collection (Martinez et al1995, Taussig 1992). Many children withsymptoms persisting till school age suffer fromasthma characterised by eosinophilicinflammation of the airway mucosa andvariable bronchial muscle spasm (Phelan et al1995, Stevenson et al 1997).

The three most widely used diagnostic labelsamong toddlers are bronchiolitis, wheezybronchitis, and asthma (Cherry 1987).Nonetheless, since the boundaries betweenthese conditions are obscure there are nouniversally accepted diagnostic criteria.Consequently, there are no comprehensivemanagement guidelines, either. Many apply

empirical therapeutic approaches based ondata obtained from older children and adults(Twarog 1987).

One of the most controversial issues in themanagement has been the role of systemic andinhaled corticosteroids. The majority ofevidence suggests that corticosteroids,although effective for older children withasthma (Barnes and Pedersen 1993, Scarfoneet al 1995, Reijonen et al 1996) offer nobenefit for the younger ones having virallyinduced wheezing (Springer et al 1990,Roosevelt et al 1996, Bülow et al 1999). Otherstudies, however, have found that eventoddlers receiving oral or parenteralcorticosteroid medication recover faster fromtheir respiratory symptoms than untreatedcontrols (Daugbjerg et al 1993, Garrison et al2000).

Despite the generally favourable outcome,there is an association between wheezingbefore the age of 3 years and asthma at schoolage (Rooney and Williams 1971, Dodge et al1996). Thus, there is significant number ofyoung wheezers that might benefit from earlyanti-inflammatory medication to effectivelycontrol acute symptoms and to prevent chronicairway obstruction (Agertoft and Pedersen1994, Scarfone 1995). The identification ofthose at risk for symptom persistence remains,however, problematic.

The present study was designed to evaluatethe current diagnostic activity and treatmentpractice for preschool children with wheezingand to improve the overall managementstrategy of these children. Of special interestwas to assess the value of corticosteroids in thetreatment of children with wheezy bronchitisand to identify especially those who mightbenefit from early anti-inflammatory therapy.

14 REVIEW OF THE LITERATURE

2. REVIEW OF THE LITERATURE

2.1 Focus Points

Areas that have a central role in the studies (I-IV) are dealt with more detail. These includethe definitions of diagnostic labels of toddlerswith expiratory distress; background ofsystemic corticosteroids, their therapeutic rolein acute wheezy bronchitis, and possibleadverse effects; and risk factors of wheezing.Epidemiology and outcome of wheezing isshortly summarised. Apart from oralcorticosteroid medication, other specifictherapies for acute wheezing as well as long-term management strategies are mentionedonly briefly. Bronchiolitis – defined as adisease of early infancy primarily involvingthe small airways obstructing them byinflammatory exudate – is out of the scope ofthis study. It is discussed only to the extent towhich it is essential to pinpoint its similaritiesand differences to wheezy bronchitis andasthma.

2.2 Definitions of Diagnost ic Labels

The name of the disease refers to the sum ofthe abnormal phenomena displayed by patientsin association with a specified commoncharacteristic by which they differ from thenorm in a biologically disadvantageous way(Campbell et al 1979). It has been suggested inthe past that all wheezing illness in children,regardless of the aetiology, should be labelledasthma (Williams and McNicol 1969, Speightet al 1983). This concept has graduallychanged due to increasing evidence fromepidemiological and lung function studiessuggesting that the underlying aetiology,pathophysiology, and prognosis vary greatly

between different individuals (Martinez et al1988, Wilson 1989, Halonen et al 1992,Godden et al 1994, Martinez et al 1995,Stevenson et al 1997). Presently, preschool-aged children with expiratory wheezing aregenerally classified as having bronchiolitis,wheezy bronchitis, or asthma (Cherry 1987).These definitions are also adopted in Finland.Notwithstanding, these labels are problematicsince they refer to a heterogeneous group ofchildren with a spectrum of similar clinicalsymptoms but with several differentimmunopathological and physiologicalmechanisms.

Oversimplifying, three main componentscan be thought to govern wheezing: viralresponsiveness, bronchial responsiveness, andatopic responsiveness (Wilson 1989) (Figure2-1). In young infants with viralresponsiveness the main problem may be thesmall airways that are narrowed below acritical diameter as a result of virally inducedoedema and mucous collection (Martinez et al1988, Taussig 1992, Martinez et al 1995). Intoddlers, wheezy bronchitis is provoked byviral infections, however with increasingproportions of bronchial components. Others,particularly atopic children, have symptomssuggestive of asthma, characterised byeosinophilic inflammation of the airwaymucosa and variable bronchial muscle spasm(Phelan et al 1995, Stevenson et al 1997). Theuncertainty of definitions might have led to theincoherent nomenclature used in the literature.

The definitions below are largely clinical.Although wheezing is one of the commonhallmarks of these conditions, not all wheezingchildren have asthma and not all asthmaticchildren wheeze. In addition, there is no cleardefinition of asthma and viral infectionsusually exacerbate asthma at any age.

REVIEW OF THE LITERATURE 15

Establishing the correct – or most probable –diagnosis requires an overall evaluation of thepatient’s clinical and family history, additionalsymptoms, and other relevant information.

2.2.1 Bronchiolitis

Bronchiolitis is a disease of infancy primarilyinvolving the small airways obstructing themby inflammatory exudate. It is characterised byacute expiratory distress; with signs of viralrespiratory track illness, in the form of coryza,otitis media, or fever; with or withoutindications of lower respiratory tractinvolvement, such as tachypnoea, subcostalretractions, and hyperinflation; with or withoutindications of pneumonia or atopy; and firstsuch episode (Rooney and Williams 1971,McConnochie 1983, Lowell et al 1987,Klassen et al 1991, Sanchez et al 1993,Welliver and Welliver 1993, Gadomski et al1994, Roosevelt et al 1996).

The majority of typical cases are caused by

respiratory syncytial virus (RSV) (Rooney andWilliams 1971, Rakes et al 1999, Simoes EA1999). However, also rhino-, adeno-, andparainfluenza virus – and occasionallyclamydia trachomatis and mycoplasmapneumoniae – can produce similar symptoms(Korppi et al 1986, Carlsen et al 1987, Kellneret al 1988, Rakes et al 1999, Pichler et al2000). The requirement for identification ofviral aetiology varies between clinical trials.Some authors entail a proof of RSV infection(Rooney and Williams 1971, de Boeck et al1997, van Woensel et al 1997, Bülow et al1999). Others feel that its identification is notessential for the diagnosis (Lowell et al 1987,Klassen et al 1991, Turpeinen and Peltola1992, Daugbjerg et al 1993, Roosevelt et al1996).

The most controversial issue is thearbitrarily chosen upper age limit forbronchiolitis. It varies from 6 to 12 months(Turpeinen and Peltola 1992, Roosevelt et al1996, Korvenranta and Ruuskanen 2000) andeven to 2 years (Rooney and Williams 1971,de Boeck et al 1997, van Woensel et al 1997),or lies somewhere between i.e. 18 months(Klassen et al 1991, Daugbjerg et al 1993). Wedefined bronchiolitis to be a condition ofchildren younger than 6 months.

2.2.2 Asthma

In infancy where the information aboutimmunopathology in the airways is stilllimited the best available pragmatic definitionstates that: Asthma is a condition in whichrecurrent wheezing or persistent cough occursin a clinical setting where asthma is likely andother conditions have been excluded(Anonymous 1992). Wheeze can beprecipitated by viral infections but – unlikewheezy bronchitis (see chapter 2.2.3) – also bya number of other factors.

Viral responsiveness

A

AABronchial

responsivenessAtopic

responsiveness

WB

B

Figure 2-1. Simplified representation of thehypothetical interaction of three factors involved inwheezing among preschool children (B, bronchiolitis;WB, wheezy bronchitis; A, asthma; AA, atopic asthma).(Modified and extended from Wilson 1989)


It is generally recommended that below theage of 3 years, three or more wheezingepisodes should be diagnosed asthma(Tabachnik and Levison 1981, Horwood et al1985, Fisher et al 1993, Barnett et al 1997,Trindade 1998). Among children older than 3years, the diagnosis of asthma becomesprogressively more explicit and beyond 6years of age the definition of the NationalHeart, Lung, and Blood Institute is valid:Asthma is primarily a disease of airwayinflammation in which eosinophils and mastcells are prominent, producing recurrentepisodes of cough and wheeze, oftenassociated with increased bronchialhyperresponsiveness and reversible airflowlimitation (Anonymous 1998).

Despite the above-mentioned definitionsasthma in preschool children can be difficult todiagnose. The severity and presentation ofchildhood asthma varies in the population withno definitive pathognomonic findings(Silverman and Wilson 1997, Martinez andHelms 1998). In addition, the availableguidelines (Global Initiative for Asthma 1995,Joint Council of Allergy, Asthma, andImmunology 1995, National AsthmaEducation and Prevention Program 1997) lackclinical utility, since, they do not suggestdiagnostic algorithms nor do they weighfactors based on their relative importance. Inthis age group no absolute tests, questions, orphysical signs are available to provide aprecise cut off point for diagnosis (Warner etal 1989). The combination of clinical history,physical signs, and specific features can eithersupport or discourage the diagnosis of asthma.Thus, the diagnosis of asthma depends oninterpretations. Periodic, nocturnal or seasonalsymptoms, or symptoms provoked by allergenexposure or exercise are suggestive of asthma.Atopy of the child or atopy and asthma in thefamily can support, and a trial of appropriate

asthma therapy can strengthen the diagnosis(Warner et al 1989).

2.2.3 Wheezy bronchitis

Wheezy bronchitis, also called obstructivebronchitis, is characterised by acute cough,rhonchi or wheezing, and expiratory distressoccurring only in the presence of infection(Christie et al 1999) without indications ofpneumonia and without evidence of present orpreviously diagnosed asthma. Typically,wheezy bronchitis is provoked by rhino, RSV,and corona viruses (Kopppi et al 1986,Mertsola et al 1991, Rylander et al 1996). RSVinfection can also predispose to secondarybacterial infection (such as streptococcuspneumoniae, Haemophilus influenzae, andClamydia species) in the airways (Korppi et al1989 and 1991).

If bronchiolitis and asthma are consideredto represent the two far ends of the spectrumof conditions with expiratory distress, wheezybronchitis lays in between. The transition pointfrom one condition to the other is supplewithout a clear demarcation line resulting insome obvious overlapping between clinical

PathomechanismsBron

chioli

tis

WB Asthma

3 y

Figure 2-2. Schematic representation of therelationships between bronchiolitis, wheezy bronchitis(WB), and asthma. The white-to-black bar representsthe spectrum of underlying pathomechanisms thatrange from viral responsiveness and mucuscollection (white) to bronchial responsiveness,eosinophilic inflammation, and smooth musclecontraction (black). Wheezy bronchitis appears to bein a grey area with both bronchiolitic and asthmaticcomponents. Y, child’s age in years.


and pathophysiological features (Figure 2-2).Clinically, an important factor

distinguishing wheezy bronchitis frombronchiolitis is the age of the child. At thesame time, this is the most confusing part ofthe definition, frequently overlapping with thatof bronchiolitis. Several age limits have beenused ranging form 0-24 months (Wennergrenet al 1992), 2-66 months (Foucard and Sjöberg1984), 4-48 months (Rylander et al 1996), or12-72 months (Mertsola et al 1991). In Finlandthe most widely accepted age range forwheezy bronchitis is 6-35 months (Korppi et al2000).

The number of diagnosed wheezingepisodes is another designating factor. Mostauthors consider only the first such episode tobe true wheezy bronchitis (Mertsola et al 1991,Wennergren et al 1992, Rylander et al 1996)while others accept some degree of recurrence(Foucard and Sjöberg 1984). In general,frequent wheezing episodes – especially, whenadditional risk factors are present – aresuggestive of asthma and should be diagnosedas such when alternative diagnoses ofcongenital and acquired conditions associatedwith wheeze are excluded (Tabachnik andLevison 1981, Horwood et al 1985, Fisher et al1993, Trindade 1998).

In our studies, wheezy bronchitis wasdiagnosed if a child, aged 6-35 months, hadacute tachypnoea, rhonchi, wheezing ordecreased breath sounds, or use of accessoryrespiratory muscles, in the presence of anapparent viral respiratory infection (rhinorrheaor temperature >37.5° C).

2.3 Prevalence of Wheezing inToddlers

Many epidemiological studies identify thetarget population on the basis of symptoms,

others on diagnoses. Consequently, some ofthe data below refer to the prevalence ofwheezing itself and other deal withdocumented or assumed diagnoses.

The incidences of wheezing episodes varyworldwide from 3 to 12 per 1000, dependingon the age and disease severity (Infante-Rivardet al 1987, Rylander et al 1996, To et al 1996).Among preschool children, boys wheeze morecommonly than girls with a frequentlyobserved ratio of 2:1 (Wennergren et al 1992,Rylander et al 1996). In a large prospectivestudy conducted in Tucson, Arizona, (Figure2-3), during the first year of life roughly 20%of the children experienced wheezing (Wrightet al 1989) and by the age of 6 years everysecond child had at least one episode ofrespiratory distress (Martinez et al 1995).Unfortunately, there is no publishedcomparative follow-up data from otherpopulations.

During the past decades there has been asubstantial increase in the prevalence of

0

20

40

60

80

100

1 3 6

Age (year)

% o

f chi

ldre

n

Figure 2-3. Cumulative prevalence of wheezing in thefirst 6 years of life (data from the Children’sRespiratory Study, Tucson, Arizona [Wright et al 1989,Martinez et al 1995])


wheezing and hospital admissions forrespiratory distress and asthma inindustrialised societies, especially amongpreschool children (Anderson 1989, Gergenand Weiss 1990, Strachan and Anderson 1991,Weitzman et al 1992, Anderson et al 1994,Nystad et al 1997, Russo et al 1999, Shay et al1999). Concomitantly, the severity thresholdfor admission has increased (Russo et al 1999).

A recent study from Finland observed anaverage 10% annual increase in hospitaladmissions between 1976-1995 amongpreschool children younger that 4 years(Malmström et al 2000). In other countries theincrease was found to be around 4-5% (Gergenand Weiss 1990, Goodman et al 1998). In theUnited States, during 1980-1996 annualhospitalisation rates increased from 12.9 to31.2 per 1000 among children younger than 1year and from 1.3 to 2.3 per 1000 amongchildren aged 1 to 4 years (Shay et al 1999).During 1991-1995, hospitalisation rates forsevere asthma episodes among childrenyounger than 5 years have risen from 0.7 to2.9 per 1000 (Russo et al 1999). On the otherhand, the intensive care unit admissions in theFinnish study did not increase, suggesting thatthe occurrence of severe asthma has remainedstable in this country (Malmström et al 2000).

Although there is evidence for an increasein the incidence and prevalence of wheezingthe true magnitude is hard to evaluate due topossible systematic errors (Magnus andJaakkola 1997). The awareness of wheezingsymptoms might have resulted in more activeand earlier asthma diagnosis and earlierinitiation of anti-inflammatory treatment. Inaddition, there might be some degree ofdiagnostic substitution (between bronchiolitis,wheezy bronchitis, and asthma), change inadmission criteria, difference in the supply ofmedical care, or change in the nature of thedisease (Nystad et al 1997, Goodman et al1998, Shay et al 1999).

2.4 Outcome of Wheezing inToddlers

According to the current concept there are atleast three subset of wheezing children amongtoddlers: 1) those who wheeze only during thefirst years of life and become symptom-free asthey grow older; 2) others go on wheeze frominfancy till school age, and finally; 3) thosewho start wheezing later in childhood withoutprior episodes of wheezing (Martinez et al1995, Stein et al 1997).

Approximately 54% to 59% of toddlerswho experience wheezing during the firstyears of life will eventually be withoutsymptoms before the age of 3 years (Foucardand Sjöberg 1984, Martinez et al 1995). In aprospective study of 826 children, Martinez etal (1995) found that 19.9% of children had atleast one lower respiratory tract illness withwheezing during the first 3 years of life but nowheezing at 6 years of age. In the samepopulation 13.7% of children wheezed both atage 3 and 6 years. Others have reported that asmany as 80% of children with wheezingbefore the age of 5 did not wheeze at age 10and that 50% of the children with the diagnosisof asthma at the age of 5 no longer had adiagnosis of asthma at age 10 years (Park et al1986). Wennergren and co-workers (1992)followed prospectively 101 children youngerthan 2 years hospitalised for asthmaticsymptoms. At reinvestigation after 3-4.5 years,47% had asthma. Another follow-up study,from Finland, found that 25% of those childrenhospitalised during the first 2 years of life hadsubsequent wheezing up to 4.5-6 years of age(Kuikka et al 1994).

The prognosis depends also on the age atthe first wheeze. Namely, the later it’s onsetthe more likely to have asthma later in life


(Foucard and Sjöberg 1984, Sporik et al 1991,Reijonen and Korppi 1998, Clough et al 1999).In addition, although a high proportion of earlywheezers become symptom-free in laterchildhood, 10% to 27% will relapse again inadult life – the risk being highest amongsmokers and atopic subjects (Strachan et al1996).

2.5 Risk Factors for SymptomPersistence

As described earlier, wheezing in mosttoddlers has a rather benign course. Being acommon entity, however, a substantial amountof children do continue to wheeze.Unfortunately, it is still not possible to predictwho will have further symptoms. In theory,these children might: 1) have risk factors forboth wheezy bronchitis and asthma; 2) carryrisk factors only for asthma but in acombination that predispose them for earlysymptoms; 3) change from one phenotype toanother as they grow older; or 4) bearcharacteristics that are not discovered yet.

Mainly those studies are summarised herethat were particularly designed to examinehost-specific characteristics and environmentalfactors that could increase the risk forsymptom persistence. For comparison theindependent risk factors for wheezy bronchitisand asthma are also listed in Table 2-1.

2.5.1 Familial factors

Wheezing toddles with a family history ofasthma (Rooney and Williams 1971, Foucardand Sjöberg 1984, Martinez et al 1995, Sigurset al 1995) or atopy (Eisen and Bacal 1963,Foucard and Sjöberg 1984, Sigurs et al 1995,Clough et al 1999) are more predisposed to

develop persistent wheezing compared tothose without such heredity. Asthma andwheezing in the family increases the risk ofdeveloping persistent asthma two- to fourfold(Foucard and Sjöberg 1984, Martinez et al1995). Familial bronchial hyperresponsivenesscan also determine the severity of futuresymptoms in children with severe wheeze inthe first 2 years of life (Wilson et al 1997).

2.5.2 Atopy

Child’s own atopic eczema (Kuikka et al 1994,Martinez et al 1995, Rusconi et al 1999,Gustafsson et al 2000), positive skin prick testfor reactivity to specific allergens (Martinez etal 1995, Clough et al 1999, Reijonen et al2000), or allergic rhinitis (Martinez et al 1995,Rusconi et al 1999) increase significantly therisk of later asthma. Children with persistentwheezing tend to have elevated serumimmunoglobulin E (IgE) levels during firstyears of life (Korppi et al 1994, Kuikka et al1994, Martinez et al 1995). However,Wennergren and colleagues (1992) found noassociation between high total IgE at the timeof the first admission and the persistence ofasthma 3-4.5 years later. Cord IgE levels donot correlate well with the outcome ofwheezing (Martinez et al 1995). In general, theexpression of atopy increases with age (Sporiket al 1991, Kuikka et al 1994) and the degreeof atopic sensitisation is related to the severityof wheezing (Zimmerman et al 1988).


2.5.3 Food allergy

Most food allergies are transient (Bock 1982)but they are often followed by sensitisation toinhaled allergens and respiratory tractsymptoms. Studies in selected populations –children with genetic predisposition to atopy –have showed that sensitisation to foodallergens in infancy increases the risk ofrespiratory allergic diseases during laterchildhood (Burr et al 1997).

In a birth cohort of 508 children those whowere persistently (>1 year) sensitised to foodhad a 5.5 fold risk of developing asthma thaninfants who were only transiently foodsensitised. Sixty seven per cent of childrenwith persistent food sensitisation incombination with a positive atopic familyhistory developed asthma at 5 years of age(Kulig et al 1998).

Hill and co-workers (1994) found that 60 to70% of children with cow’s milk allergy

Table 2-1. Published risk factors that predict symptom persistence among early wheezers. Risk factors forwheezy bronchitis and asthma are listed for comparison. All data were derived from articles referred in thisthesis.

Risk Factors SymptomPersistence

WheezyBronchitis

Asthma

EndogenousFamily history of asthma + +/- +Family history of atopy + +/- +Atopic eczema + (+) +Allergic rhinitis + ? +Eosinophilia + - +Elevated IgE antibodies + +/- +Elevated serum ECP + ? +Food allergy +/- (+) +Male sex +/- + +Reduced initial lung function +/- + +/-Airway responsiveness + ? +Prematurity ? + +Increased fetal growth ? ? +

ExogenousMaternal smoking in pregnancy + + +Passive cigarette smoke exposure + + +Viral respiratory infections +/- + +Outdoor pollution ? ? +/-Indoor pollution ? +/- +/-Maternal infections in pregnancy ? ? +/-Small number of siblings ? ? +Short exclusive breast feeding ? + +

Allergy is defined as known allergy or positive skin prick tests to specific allergens. Atopy is defined as atopiceczema, raised IgE antibodies in the serum, or positive skin prick tests to specific allergens. IgE,immunoglobulin E; ECP, eosinophilic cationic protein.

+ Positive association(+) Weak association- No association

+/- Conflicting results? Not known


developed sensitisation to inhaled allergensduring a two-year follow-up period. At the endof their study the incidence of asthma was ashigh as 70%. Interestingly, there was nosignificant difference in the incidence ofasthma irrespective of whether the childrenshowed persistent cow’s milk allergy or thedisease remitted (Hill et al 1994).

Also egg sensitivity in infancy has beenshown to be strongly associated with thesubsequent diagnosis of asthma (at the age of 7years) (Burr et al 1997). In the study by Tariqand colleagues (2000) symptomatic eggallergy in infancy together with eczema had apositive predictive value of 80% for thedevelopment of asthma at 4 years of age.

Despite these associations, food allergyavoidance studies have failed in preventing thedevelopment of respiratory allergic disease(Arshad et al 1992, Pöysä et al 1992, Zeiger etal 1992).

2.5.4 Male sex

Male toddlers seem to be more prone todevelop severe lower respiratory tract illness(Bisgaard et al 1987, Ehlenfield et al 2000).Some have found a positive correlationbetween recurrent wheezing and male sex(Halken et al 1991, Martinez et al 1995),others failed to confirm this connection(Ehlenfield et al 2000, Reijonen et al 2000).The gender difference might be explained byfindings that suggest that girls have largerairways relative to their lung size (Tepper et al1986) and smaller resting airway tone (Landauet al 1993) than do boys.

2.5.5 Initial lung function and a irwayresponsiveness

The relationship of lung function andwheezing is complex and possibly age-related.Initial lung function level measured soon afterbirth correlates with clinical outcome duringtoddler years, but not with the development ofasthma in later childhood. The most widelyused parameter measured reflecting lungfunction is maximal forced expiratory flow atfunctional residual capacity (V’maxFRC).Infants with diminished V’maxFRC have 3 to6 times greater risk of wheezing in the first 3years of life (Martinez et al 1995). On theother hand, persistent wheezers seem to havenormal initial lung function in the first year oflife (Martinez et al 1995). Later in childhood(>5 years), lower lung function levels areassociated with more severe bronchialresponsiveness in adulthood (Grol et al 1999).

Young and colleagues (1991) found thatthe initial airway responsiveness was related tothe history of parental asthma, but not to theinitial level of lung function. Findings from thesame follow-up cohort indicated that the levelof airway responsiveness measured in infancypredicted well the development of asthma atthe age of 6 years. In addition, airwayresponsiveness during childhood tends topredict airway hyperresponsiveness inadulthood and is greater in asthmatics withpersistent symptoms (Godden et al 1994).

2.5.6 Tobacco smoke

Exposure to intrauterine and environmentaltobacco smoke is a major and avoidable riskfactor for the development of earlysensitisation to allergens (Magnuson 1986)and it is a leading risk factor for recurrentwheezing and asthma (Halken et al 1993,Arshad et al 1993, Holberg et al 1993).


Maternal smoking during pregnancy mayimpair airway maturation, alter lung elasticproperties, and is associated with persistentdeficits in lung function (Hanrahan et al 1992,Stick et al 1996, Li et al 2000). Environmentaltobacco smoke exposure contributes toelevated levels of airway responsiveness at anearly age (Young et al 1991) and has shown tobe independently associated with persistenceof wheezing (Martinez et al 1995, Infante-Rivard et al 1999).

2.5.7 Viral respiratory infections

Viral infections are involved in thedevelopment of individual wheezing episodes.A number of mechanisms have been proposedto explain this connection. These include:production of virus-specific IgE antibodies,induced cytokine production, enhancedleukocyte inflammatory function, beta-adrenergic blockade, and damage to the airwayepithelium (Busse 1993). However, therelation of these virally induced responses torecurrent wheezing is largely unknown.

Stein and co-workers (1999) found thatlower respiratory tract infections caused byRSV in early childhood is an independent riskfactor for the subsequent development ofwheezing up to age 11 years but not thereafter.Sigurs and colleagues (1995 and 2000)confirmed this association and observed thatthe risk for subsequent development of asthmais even higher if the child has coexistingasthma heredity. On the other hand, Reijonenand co-workers (2000) found that wheezingchildren, younger than 12 months, with RSVinfections had better prognosis than thosewithout confirmed RSV infection. The authorshypothesised that this is not because RSVwould be protective per se but that earlywheezing with other than RSV aetiology mightcarry a higher risk of asthma (Reijonen et al

2000). Rhinovirus could be a candidate as itcan cause mild and severe wheezing illness inchildren of all age groups – though more oftenamong children over 1 year of age (Kellner etal 1988, Mertsola et al 1991, Johnston 1999,Rakes et al 1999). In addition, recent resultsimply that rhinovirus infection may inciteeosinophil responses in both atopic and non-atopic children with acute wheezing illnesses(Rakes et al 1999).

Elevated eosinophil counts at the time ofbronchiolitis could predict the development ofasthma. In a study by Ehlenfield and co-workers (2000) the sensitivity and specificityof eosinophilia for the detection of subjectswho would have persistent wheezing through 7years of age was 60% and 75%, respectively.Clinical data also suggest that eosinophildegranulation in the respiratory tract occursduring RSV bronchiolitis and may play asignificant role in the development of virus-induced airway obstruction (Garafalo et al1992).

High concentrations of serum ornasopharyngeal eosinophilic cationic protein(ECP) during a wheezing episode is predictiveof recurrent bronchial obstructions and is alsoassociated with the occurrence of severewheezing episodes (Koller et al 1997,Reijonen et al 1997a, Reijonen et al 1997b).

RSV can induce an IgE antivirus responseand in addition, the formation of RSV-specificIgE and release of histamine may adverselyaffect the outcome of RSV infection (Welliveret al 1981). Moreover, RSV-specific IgEresponses in infancy are associated with laterrecurrence of wheezing (Welliver et al 1986,Welliver and Duffy 1993).

There is some evidence that RSV infectioncould be a Th2 predominant disease –similarto asthma – and that a Th2 cytokine profileduring RSV infection is associated withpersistent wheezing (Robinson et al 1992,Román et al 1997, Renzi et al 1997).


Recently, Bont and colleagues (2000)reported an increase in monocyte IL-10production during the course of RSVbronchiolitis. The increased IL-10 productionwas also associated with the development ofrecurrent wheezing and physician-diagnosedasthma. This would indicate that not onlyallergen-driven Th2 cytokine responses canresult in asthmatic symptoms but also virus-induced changes in monocyte cytokineresponses can lead to asthmatic symptoms(Bont et al 2000).

Finally, there is some data suggesting thatin contrast to lower respiratory tract infections,other infections (particularly runny nose andviral infections of the herpes type and measles)in the first year of life may stimulate theimmune response towards the Th1 phenotype,thereby reducing the risk for the developmentof asthma up to school age (Illi et al 2001).

2.5.8 Allergen exposure

A number of authors have argued that earlylife allergen exposure may producesensitisation and continued exposure may leadto clinical asthma through the development ofairway responsiveness, inflammation, andremodelling (Peat et al 1996, Barbee andMurphy 1998, Custovic et al 1998, Lundbäck1998, Warner et al 2000). Unfortunately, thereare relatively few longitudinal studiesfollowing infants from birth to later childhoodthat have evaluated the primary causation ofallergen levels early in life and the subsequentdevelopment of asthma. Two studies havebeen carried out in selected populations chosenon the basis of a family history of asthma orallergy. One study showed a non-significantassociation (Sporik et al 1990) whereas theother study found no association (Burr et al1993) between early allergen exposure andactive wheezing or doctor diagnosed asthma.

A recent birth-cohort study of 1314 childrenselected from the general population failed toshow an association between environmentalallergens and the prevalence of asthma andwheeze at age 7 years (Lau et al 2000).Indirect evidence from population-basedstudies shows similar controversy providinglittle evidence that allergen exposure early inlife is associated with the prevalence of asthmaat a population level (von Mutius et al 1994,Leung et al 1997, Krämer et al 2000, Pearce etal 2000a).

On the other hand, factors related toenvironmental influences on a farm such asincreased exposure to bacterial compoundsmay prevent the development of allergicdisorders and asthma in children (vonEhrenstein et al 2000, Riedler et al 2000).These results have also been supported byothers demonstrating a lower prevalence ratesof self-reported rhinitis in young adults whohave been raised on a farm as compared withthose from urban environment (Aberg 1989,Kilpeläinen et al 2000).

2.5.9 History of wheezing

History of wheezing is a strong predictor forwheezing persistence (Korppi et al 1994,Sigurs et al 1995, Reijonen et al 2000). Thereis a direct relationship between the number ofattacks during toddler years and later asthma(Park et al 1986, Kuikka et al 1994, Martinezet al 1995). As noted earlier, the age of firstwheezing episode can also predict symptompersistence. Wheezing below the age of 1 yearhas generally more favourable prognosis(Reijonen et al 2000).


2.5.10 Predictive algorithms

There is a strong demand for workingguidelines or models to predict which infantswill continue wheezing and develop asthmaduring later childhood. There are only fewpublished data concerning this issue.

Recently Martinez (1999a) suggested analgorithm for the identification of asthma riskamong young children who have neededhospitalisation or at least 3 outpatient contactsfor wheezing (Table 2-2). Over two thirds ofchildren who met these combinations of riskfactors during the first 3 years of life still hadreports of persistent wheezing at the age of 3.Castro-Rodríguez and colleagues (2000) haveslightly modified this algorithm into twoclinical indexes and tested their value in alongitudinal study (Table 2-3). The looseindex included children with any wheezingduring the first 3 years of life and with eitherone major risk factor (parental history ofasthma or child’s own atopic eczema) or twoof three minor risk factors (allergic rhinitis,wheezing apart from colds, and eosinophilia).The criteria for the stringent index werefrequent (3 or more) wheezing during the first3 years of life and the same combination ofrisk factors described previously. Childrenwith a positive stringent index were 4.3 to 9.8times more likely to have active asthmabetween ages 6 and 13 than children withoutthese risk factors. The positive predictivevalue of the loose and stringent criteria was59.1% and 76.6%, respectively. Thespecificity of the stringent index was morethan 95%, however, its sensitivity was only15% (Castro-Rodrígez et al 2000).

Clough and colleagues (1999) evaluatedprospectively the role of various combinationsof risk factors. They found that wheeze wasmore likely to persist in older, atopic childrenwhen both parents have atopy. Increasing ageat presentation together with raised soluble

interleukine-2 receptor levels were bestpredictors of wheezing with least risk ofincluding asymptomatic individuals.

Table 2-2. Algorithm to define asthma risk amongchildren with recurrent (more than 2 wheezing episodesduring previous 6 months) or severe wheezing thatrequire hospitalisation. Children who meet any majorcriteria and two minor criteria should be considered atvery high risk of persistent wheezing. (Modified fromMartinez 1999a).

Major criteria Minor criteria

Parent history of asthmaAtopic eczema

Allergic rhinitisWheezing apart from coldsEosinophilia (≥5%)Male sex

Table 2-3. A clinical index to define asthma risk amongchildren with wheezing before the age of 3 years. Looseindex for the prediction of asthma: Wheezing ever plusat least one of two major or two of three minor criteria.Stringent index: Recurrent wheezing (≥≥≥≥3 or morewheezing episodes) plus at least one of two major ortwo of three minor criteria. (Modified from Castro-Rodríguez et al 2000).


Parental history of asthmaAtopic eczema

Allergic rhinitisWheezing apart from coldsEosinophilia (≥4%)


2.6 Symptomatic Treatmen t ofToddlers with Wheezing

Respiratory distress in wheezy bronchitisresults from β-sympathetically mediatedbronchoconstriction and α-sympatheticallymediated bronchial oedema and mucusproduction (Wohl and Chernick 1978,Prendiville et al 1987, Martinez et al 1988,Phelan et al 1995). Drugs that counteract thesepathomechanisms have a central role in themanagement of wheezing. Salbutamol has β-mimetic and adrenaline has both α and β-mimetic activity.

2.6.1 Salbutamol

Salbutamol is routinely used in themanagement of acute asthma. Its role inwheezy bronchitis and bronchiolitis is lessclear. Among children younger that 12 monthsand especially among those with bronchiolitis,salbutamol has not been proven effective(Lenney and Milner 1978, Tal et al 1983, Hoet al 1991, Gadomski et al 1994). The positiveeffect of inhaled salbutamol among toddlersseems to increase with age (Lenney andMilner 1978). Studies that have recruitedchildren up to the age of 24 months (Bentur etal 1992, Schweich et al 1992) or toddlers withasthma (Avital et al 1994, Rachelefsky et al1981) have yielded positive results with onlyfew exceptions (Orlowski et al 1991, Wang etal 1992). There is some evidence that alsoorally administered salbutamol has a positiveeffect in acute wheezy bronchitis (Fox et al1996).

2.6.2 Adrenaline

Clinical trials indicate that racemic adrenalineis superior to placebo in improving

oxygenation and clinical symptoms amongchildren under the age of 18 months(Wennergren et al 1991, Kristjánsson et al1993). Lowell and co-workers (1987) showedthat also intramuscularly administeredadrenaline was superior to placebo.

Inhaled adrenaline was more effective inreducing hospitalisation rate, had more rapidonset, and provided greater degree of symptomrelief among children younger then 2 yearscompared to inhaled salbutamol (Sanchez et al1993, Menon et al 1995, Reijonen et al 1995).

2.7 Corticosteroids

2.7.1 Mechanism of action

The precise mechanisms by whichcorticosteroids improve respiratory distress areunknown. Those potentially importantbiological actions include, attenuation of 1) thenumber of circulating inflammatory cells, 2)eosinophil proliferation and response, and 3)airway inflammation (Booij-Noord et al 1971,Kaliner 1985, Schleimer 1990, Kita et al 1991,Lamas et al 1991, Burke et al 1992,Djukanovic et al 1992). Glucocorticoidsreduce the production of many inflammatorymediators, such as prostaglandins,leukotrienes, cytokines, and platelet activatingfactor (Flower 1988, Guyre and Munck 1988).Thus, corticosteroids may hinder the cell-to-cell communication essential for thepropagation of the inflammatory process.

Corticosteroids are involved in the up-regulation of β2-adrenergic receptors, mucosalvasoconstriction, and in the reduction ofairway oedema and mucus gland production(Duval et al 1983, Marom et al 1984, Miller-Larsson and Brattsand 1990, Svedmyr 1990).Both oral and inhaled corticosteroids decreasebronchial hyperresponsiveness to histamine or


methacholine, although, the topical formseems to be more effective (Jenkins andWoolcock 1988, Barnes 1990). Corticosteroidscan also prevent the late bronchoconstrictorresponse to allergens (Fabbri et al 1985,Cockcroft and Murdoch 1987).

In addition, corticosteroids increase thelevel and duration of hyperglycaemia withlipolytic as well as ketogenic actions. In theperipheral tissues – i.e. bone, muscles,connective tissue, and skin – this involves theconversion of protein to glycogen.Glucocorticoids are involved in themaintenance of blood pressure and in theregulation of glomerular filtration.Corticosteroids also inhibit bone formation byreducing the synthesis of bone matrixcomponents, decreasing the availability ofcalcium for bone mineralisation, and increasesbone resorption. Hampering collagen synthesisproduces thinning of the skin and of the wallsof capillaries. (Berne and Levy 1988).

2.7.2 Pharmacokinetics of oralcorticosteroids

There are several synthetic analogues ofcortisol available for oral administration. Theyall have increased anti-inflammatoryproperties and reduced mineralocorticoidactivity.

Dexamethasone is a very potentcorticosteroid having a 20-30 times anti-inflammatory potency of cortisol with aprolonged biological half-life (36-54 hours)(Chung and Clark 1992). The disadvantage ofits enhanced pharmacological potency lies inthe increased risk for unwanted effects.Methylprednisolone is rapidly absorbed afteroral administration but its absolutebioavailability can vary greatly betweenindividuals ranging from 50-100% (Patel et al1993, Varis 2000). Prednisone is biologically

inactive until hydroxylated into prednisolonein the liver. This conversion may be hamperedin the presence of liver dysfunction (Madsbadet al 1980).

Prednisolone is the best choice fortherapeutic purposes as it is independent ofliver function and has the samepharmacokinetic characteristics as prednisonewith 80-100% bioavailability (Varis 2000).Prednisolone taken by mouth is rapidlyabsorbed (Morrison et al 1977), reaches itspeak concentration within 1-3 hours (Figure2-4), has a plasma half-life of 2-3 hours, and abiological half-life of 18-36 hours (Frey andFrey 1990). It has 5 times anti-inflammatorypotency of cortisol (Chung and Clark 1992)and its clinical effect on airway functionbegins within 3-4 hours and peaks at 9 hoursafter oral administration (Ellul-Micallef et al1974, Storr et al 1987, Rubin et al 1990, Tal etal 1990, Scarfone et al 1993) (Figure 2-4).This delay might reflect the time needed tomanufacture new effector molecules via generegulation.

2.7.3 Administration and dosing of oralcorticosteroids

Unfortunately, the currently applied practiceregarding the administration of oralcorticosteroids in respiratory distress is largelybased on empirical observations (BritishThoracic Society et al 1997). There is no solidinformation on the ideal dosage or duration oftherapy. It has been shown by McAllister andcolleagues (1981) that increasing the dose ofprednisolone is not in proportion with theincrease in tissue concentration. Furthermore,as the actions of corticosteroids are conveyedby a secondary messenger system there is nocorrelation between blood levels and thetherapeutic response.


The most widely adopted dose of oralprednisolone ranges from 1 mg/kg/day(Brunette et al 1988, Ho et al 1994, vanWoensel et al 1997) to 2 mg/kg/day (Scarfoneet al 1993, Connett et al 1994, Grant et al1995, Fox et al 1996, Bülow et al 1999, Grieset al 2000, Schuh et al 2000). However, somestudies have used doses up to 4 mg/kg/day(Becker et al 1999). Whereas, others give themedication only once a day (Daugbjerg et al1993, Fox et al 1996) there are those whoprefer two divided daily doses (van Woensel etal 1997, Gries et al 2000). In addition, somefeel that an initial higher dose is moreappropriate with subsequent lower doses(Deshpande and McKenzie 1986, Daugbjerg etal 1993) (see also Table 2-4 and Table 2-5).

There is great variation in the duration ofmedication, as well (Table 2-4 and Table 2-5).Clinical trials have examined the effectivenessof oral corticosteroids from a single dose

(Storr et al 1987, Tal et al 1990, Scarfone et al1993, Singh and Kumar 1993, Connett et al1994, Ho et al 1994, Horowitz et al 1994,Grant et al 1995, Barnett et al 1997) to varyinglengths up to 7-8 days (Shapiro et al 1983,Harris et al 1987, Springer et al 1990, vanWoensel et al 1997). The results areinconsistent, leaving no suggestions of theoptimal regimen.

2.7.4 Safety of oral corticosteroids

Unwanted effects of synthetic corticosteroidscan be viewed as their amplifiedpharmacodynamic and physiologic actions. Inaddition, due to the sensitive regulatoryfeedback mechanism, exogenous cortico-steroids can suppress the secretion ofendogenous glucocorticoids. However, shortcourses (< 7 days) of oral corticosteroids are

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Figure 2-4. Plasma prednisolone concentration curve in one asthmatic patient (–�–)and effect of a single dose of prednisolone on peak expiratory flow rate in six asthmaticpatients (–ρ–) after a single dose of 40 mg oral prednisolone. (Modified from McAllisteret al 1981 and Ellul-Micallef et al 1974).


generally well tolerated, even in high doses(Sebire et al 1997). This finding is supportedby the fact that none of the studies described inTable 2-4 and Table 2-5, reported anyclinically relevant adverse effects. The mostworrisome complications are discussed below.

Growth suppression is thought to be asignificant risk particularly of long-term oralcorticosteroid treatment (Oberger et al 1990,Allen et al 1994). Wolthers and co-workersfound that even small daily doses (2.5-5.0 mgof prednisolone per day) can suppress short-term linear growth (Wolthers and Pedersen,1990) and may cause changes in bone turnover(Wolthers et al 1993). Since short-term growthkinetics is not a good predictor of long-termgrowth velocity (Wales and Milner 1987,Hermanussen and Burmeister 1989) theclinical relevance of these findings is not clear.In addition, long-term follow up studiesindicate that inhaled or short-term oralcorticosteroids have only a transient effect ongrowth velocity and do not influence the finalattained adult height (Silverstein et al 1997,van Bever et al 1999, Agertoft and Pedersen2000, The Childhood Asthma ManagementProgram Research Group 2000).

There is some degree of short-term adrenalsuppression during corticosteroid therapy(Zora et al 1986, Dolan et al 1987, Kannisto etal 2000). On the other hand, wheezing attackitself increases plasma cortisol levels with asubsequent decline in cortisol response tostimulation, independent of the administrationof exogenous glucocorticoids (Shapiro et al1983). Regardless of the cause – whetherendogenous or exogenous – of the transitoryadrenal suppression the hypothalamic-pituitary-adrenal axis (HPA) promptlyrecovers after acute short-term corticosteroidtherapy (Spiegel et al 1979, Shapiro et al1983). The frequency with which HPAsuppression occurs and its clinical significanceare not clear.

Sporadic cases of infection complicationsin children receiving oral corticosteroidsinclude Aspergillus lung abscess in amalnourished child (Morton et al 1980), andsevere or fatal varicella infections (Silk et al1988, Kasper and Howe 1990). In thesesituations the complications were related toimmunosuppression, and long or high doses ofcorticosteroids. There are no reports ofrecognised infectious complications that couldbe attributed to short-course oral corticosteroidtherapy. They can be administered safely –even concomitantly with influenza vaccination(Park et al 1996) – without increasing the riskof acute infections (Grant et al 1996, Davis etal 1998).

Cataract formation as a complication ofcontinuous treatment with oral corticosteroidsis limited to the posterior subcapsular type(Bhagat and Chai 1984). At present, there areno publications that would link few days longlow dose oral corticosteroid therapy with suchocular complications.

2.8 Oral Corticosteroids in AcuteWheezy Bronchitis

Although, glucocorticoids are now widelyrecognised to be particularly effective andpotent drugs for the treatment of asthma bothin adults and in school-children (Littenbergand Gluck 1986, Chapman et al 1991, Barnesand Pedersen 1993, Scarfone et al 1993), theeffectiveness of corticosteroids among toddlersis not well established. The study groups inthis population have been rather heterogeneous– within and between studies – yielding resultsthat are difficult to interpret unanimously. Dueto the lack of uniform guidelines, authors haverecruited children from different age-groupswith miscellaneous diagnostic labels (Table2-4). Diverse randomisation techniques and


settings have been used. Study preparationsand the duration of medication vary and thereare differences in the follow-up and outcomemeasures, as well.

Table 2-4 and Table 2-5 summarise thosestudies that approximate the target group ofinterest of this thesis, i.e. toddlers with wheezybronchitis. Clinical trials that compared thetherapeutic effect of oral corticosteroids toplacebo, to symptomatic treatment, or to othermeans of administration were evaluated. Thetables are arranged according to the age-groups of recruited children.

Most trials dealing with infants andtoddlers under the age of 24 months havefailed to show a positive effect of oralcorticosteroids (Webb et al 1986, Storr et al1987, Springer et al 1990, Fox et al 1996,Klassen et al 1997, Bülow et al 1999). Thereare only two studies with positive results inthis age-group. One concluded that alsochildren younger than 12 months weredischarged earlier when treated with oral orinhaled corticosteroids compared to placebo(Daugbjerg et al 1993). The other reportedfaster clinical improvement and shorterduration of mechanical ventilation of RSVpositive infants (van Woensel et al 1997).

Wider study populations that included alsoolder children with asthma have producedmore favourable results. Oral corticosteroidsreduced hospitalisation rate (Scarfone et al1993, Horowitz et al 1994), shortened thelength of hospital stay (Storr et al 1987),improved pulmonary function (Deshpande andMcKenzie 1986, Singh and Kumar 1993,Connett et al 1994), hastened the rate ofclinical improvement (Horowitz et al 1994),and reduced the need for further therapy (Storret al 1987). Some studies were unable toreproduce these findings (Ho et al 1994).

Oral corticosteroids administered at homedecreased the number of wheezing days(Brunette et al 1988), exacerbations (Shapiro

et al 1983, Deshpande and McKenzie 1986,Brunette et al 1988), ER visits (Brunette et al1988), and hospitalisations (Brunette et al1988). On the other hand Grant and co-workers (1995) found that a single dose ofprednisolone available for use at home early inasthma attack was associated with an increasein outpatient visits made for acute asthma.When prednisolone was given for an attack,there was no reduction in outpatient visits.

The therapeutic value of oralcorticosteroids has also been compared toother routes of administration (Table 2-5). Intreating acute respiratory distress, oralprednisolone was as effective as intramusculardexamethasone (Klig et al 1997, Gries et al2000) or intravenous methylprednisolone(Barnett et al 1997, Becker et al 1999).Scarfone and colleagues (1995) found thatnebulised dexamethasone was as effective asoral prednisolone in the ER treatment ofmoderately ill children with acute asthma andthat it was associated with more rapid clinicalimprovement, more reliable drug delivery, andfewer relapses. However, nebuliseddexamethasone has systemic effects that mayhave contributed to its efficacy (Scarfone et al1995). When compared to inhaled fluticasonewith minimal systemic properties oralprednisolone was more effective in childrenwith severe acute asthma (Schuh et al 2000).

Tabl

e 2-

4. C

linic

al tr

ials

that

com

pare

d th

e th

erap

eutic

effe

ct o

f ora

l cor

ticos

tero

ids

(ora

l CS)

to p

lace

bo o

r sym

ptom

atic

trea

tmen

t in

youn

g ch

ildre

n. T

he s

tudi

es a

reso

rted

by a

ge-g

roup

s of

recr

uite

d ch

ildre

n.

Pa

tient

s‡

M

edic

atio

n

Stud

yAg

eO

ral C

S(n

)C

ontr

ol(n

)D

esig

nSe

tting

Dru

g(R

oute

)D

ose

of o

ral C

SO

utco

mes

mea

sure

dD

gEf

fect

Sprin

ger e

t al 1

990

1.5

- 11

mo

2525

db/p

cw

ard

HC

(iv) +

P(p

o)2

mg/

kg/d

, unt

ildi

scha

rge

LOS,

SS,

LFT

W=

Klas

sen

et a

l 199

71.

5 - 1

5 m

o35

32db

/pc

war

dD

XM(p

o)0.

5 m

g/kg

, the

n 0.

3m

g/kg

x 1

, 2 d

LOS,

SS,

O2,

RR

, HR

, ReR

,m

edic

.W

=

Dau

gbje

rg e

t al 1

993

1.5

- 18

mo

3127

db/p

cw

ard

P(po

)*4-

6 m

g/kg

, the

n 1.

6-2.

6m

g/kg

x 1

, 2 d

SS, L

OS

W++

Berg

er e

t al 1

998

1 –

18 m

o20

18db

/pc

war

dP(

po)

2 m

g/kg

/d, 3

dSS

, O2,

ReR

, med

ic.

W=

Fox

et a

l 199

63

- 15

mo

2121

db/p

cER

P(po

)2

mg/

kg x

1, 5

dSS

, med

ic.,

LOS

W(+

)

Web

b et

al 1

986

3 - 1

8 m

o29

27db

/pc

cros

sov

erER

P(po

)1m

g/kg

x 2

, 5 d

SS, H

oRW

=

Bülo

w e

t al 1

999

<24

mo

7374

db/p

cw

ard

P(po

) or M

P(iv

)2

mg/

kg x

1, 5

dLO

S, D

OS,

med

ic.

RSV

=

van

Woe

nsel

et a

l 199

7<2

4 m

o20

19db

/pc

war

dP(

po)

0.5

mg/

kg x

2, 7

dLO

S, S

S, d

urat

ion

of m

echa

nica

lve

ntila

tion

RSV

+++

Stor

r et a

l 198

7<6

0 m

o67

73db

/pc

ERP(

po)

30 m

g x

1SS

, LFT

, HoR

, LO

S, m

edic

.A

- / +

+†

Brun

ette

et a

l 198

8<7

2 m

o16

16op

enho

me

P(po

)1

mg/

kg/d

, dur

ing

ever

yU

RTI

DO

S, S

S, R

eR, H

oRA

+++

Scar

fone

et a

l 199

312

mo

- 17

y41

40db

/pc

ERP(

po)

2 m

g/kg

x 1

HoR

, LFT

A++

Con

nett

et a

l 199

418

mo

- 14

y37

33db

/pc

war

dP(

po)

2 m

g/kg

x 1

SS, L

FT, R

RA

(+)

Gle

eson

et a

l 199

024

mo

- 11

y19

20db

/pc

war

dH

C(iv

) + P

(po)

1 m

g/kg

x 1

, 5 d

SS, L

FT, L

OS,

ReR

A(+

)

Ho

et a

l 199

424

mo

- 14

y31

27db

/pc

war

dP(

po)

1 m

g/kg

x 1

LOS,

DO

S, S

S, L

FT, O

2A

=

Gra

nt e

t al 1

995

24 m

o - 1

4 y

7878

db/p

ccr

oss

over

hom

eP(

po)

2 m

g/kg

x 1

, whe

nne

eded

ReR

, HoR

A-

Sing

h an

d Ku

mar

199

3>3

6 m

o12

12op

enw

ard

P(po

) + s

albu

t.1.

5 m

g/kg

/dSS

, O2,

LFT,

LO

SA

+

Hor

owitz

et a

l 199

448

mo

- 16

y38

29db

ERP(

po)

20-

40 m

g x

1H

oR, S

SA

++

Des

hpan

de a

nd M

cKen

zie

1986

60 m

o - 1

5 y

2321

db/p

cho

me

P(po

)2

mg/

kg x

1, th

en 1

mg/

kg x

1, 2

dR

eR, S

S, L

FTA

++

Shap

iro e

t al 1

983

5 - 1

5 y

1315

db/p

cho

me

MP(

po)

18 m

g x

1, th

ende

crea

sing

in 8

dR

eR, S

S, L

FTA

++

A, a

sthm

a; d

b/pc

, dou

ble

blin

d an

d pl

aceb

o-co

ntro

lled

trial

; Dg,

dia

gnos

is; D

OS,

dur

atio

n of

sym

ptom

s; H

C, h

ydro

corti

sone

; HoR

, hos

pita

lisat

ion

rate

; HR

, hea

rt ra

te;

im, i

ntra

mus

cula

r; iv

, int

rave

nous

; LFT

, lun

g fu

nctio

n te

stin

g de

fined

as

mea

sure

men

t of a

ny o

f the

follo

win

g: fo

rced

exp

irato

ry v

olum

e in

1 s

econ

d, p

eak

expi

rato

ryflo

w, f

orce

d vi

tal c

apac

ity, t

hora

cic

gas

volu

me,

spe

cific

airw

ay (

TGV)

con

duct

ance

(SG

aw),

max

imal

flow

at r

estin

g lu

ng v

olum

e (V

max

FRC);

LOS,

leng

th o

f hos

pita

lst

ay; m

edic

., ne

ed fo

r ad

ditio

nal m

edic

atio

n; M

P, m

ethy

lpre

dnis

olon

e; O

2, ox

ygen

sat

urat

ion;

P, p

redn

isol

one;

po,

per

ora

l med

icat

ion;

ReR

, rea

dmis

sion

rat

e; R

R,

resp

irato

ry r

ate;

RSV

, br

onch

iolit

is w

ith c

onfir

med

res

pira

tory

syn

cytia

l vi

rus

dete

ctio

n; s

albu

t., s

albu

tam

ol;

SS,

any

kind

of

sym

ptom

sco

re o

r co

mbi

natio

n of

sym

ptom

s;

UR

TI,

uppe

r re

spira

tory

tra

ct

infe

ctio

n;

W,

whe

ezin

g*S

ever

al

diffe

rent

co

mbi

natio

ns

of

med

icat

ion

wer

e us

ed.

†Ora

l pr

edni

solo

ne

had

no

bene

ficia

l ef

fect

am

ong

child

ren

youn

ger

than

2

year

s.‡ N

umbe

r of c

ases

and

con

trols

invo

lved

in th

e as

sess

men

t of p

redn

isol

one

vers

us p

lace

bo(+

)St

atis

tical

ly in

sign

ifica

nt p

ositi

ve tr

end

favo

urin

g or

al p

redn

isol

one

+St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

one

out

com

e fa

vour

ing

oral

pre

dnis

olon

e++

Stat

istic

ally

sig

nific

ant p

ositi

ve e

ffect

in tw

o ou

tcom

es fa

vour

ing

oral

pre

dnis

olon

e++

+St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

thre

e or

mor

e ou

tcom

es fa

vour

ing

oral

pre

dnis

olon

e=

No

diffe

renc

e be

twee

n th

e or

al p

redn

isol

one

and

plac

ebo

in a

ny o

f the

out

com

es-

Stat

istic

ally

sig

nific

ant e

ffect

favo

urin

g pl

aceb

o

Tabl

e 2-

5. C

linic

al tr

ials

that

com

pare

d th

e th

erap

eutic

effe

ct o

f ora

l cor

ticos

tero

ids

(ora

l CS)

to o

ther

mea

ns o

f adm

inis

tratio

n. T

he s

tudi

es a

re s

orte

d by

age

-gro

ups

of re

crui

ted

child

ren.

Patie

nts

Med

icat

ion

Stud

yAg

eO

ral C

S(n

)C

ontr

ol(n

)D

esig

nSe

tting

Dru

g(R

oute

)D

ose

of o

ral C

SO

utco

mes

mea

sure

dD

gEf

fect

Grie

s et

al 2

000

6 m

o - 7

y17

15op

enER

P(po

) vs.

DXM

(im)

2 m

g/kg

x1,

5 d

SS, m

edic

.A

=Sc

arfo

ne e

t al 1

995

12 m

o - 1

7 y

5556

db/p

cER

P(po

) vs.

DXM

(inh)

2 m

g/kg

x 1

SS, H

oR, t

ime

in E

RA

=Ba

rnet

t et a

l 199

718

mo

- 18

y23

26db

/pc

ERM

P(po

) vs.

MP(

iv)

2 m

g/kg

x 1

HoR

, DO

S, L

FT, O

2A

=Be

cker

et a

l 199

924

mo

- 18

y33

33db

/pc

war

dP(

po) v

s. M

P(iv

)2

mg/

kg x

2, v

ario

usle

ngth

sSS

, LO

SA

=

Klig

et a

l 199

736

mo

- 16

y21

21db

ERP(

po) v

s. D

XM(im

)2

mg/

kg x

1, 3

dSS

, ReR

A=

Schu

h et

al 2

000

60 m

o - 1

7 y

4951

db/p

cER

P(po

) vs.

flu(

inh)

2 m

g/kg

x 1

HoR

, LFT

A++

+D

evid

ayal

et a

l 199

92

- 12

y39

41db

/pc

ERP(

po) v

s. b

ud(in

h)2

mg/

kg x

1SS

, LFT

, RR

, HR

, O2,

A++

Mat

thew

s et

al 1

999

5 - 1

6 y

46 c

hild

ren*

dbw

ard

P(po

) vs.

bud

(inh)

2 m

g/kg

x 2

SS, L

FT, R

R, H

R, m

edic

.A

=Vo

lovi

tz e

t al 1

998

6 - 1

6 y

1111

dbER

P(po

) vs.

bud

(inh)

2 m

g/kg

x 1

SS, L

FTA

=

A, a

sthm

a; b

ud, b

udes

onid

e; d

b, d

oubl

e bl

ind

trial

with

out p

lace

bo; d

b/pc

, dou

ble

blin

d an

d pl

aceb

o-co

ntro

lled

trial

; Dg,

dia

gnos

is; D

OS,

dur

atio

n of

sym

ptom

s; D

XM,

dexa

met

haso

ne;

flu,

flutic

ason

e; H

C,

hydr

ocor

tison

e; H

oR,

hosp

italis

atio

n ra

te;

HR

, he

art

rate

; im

, in

tram

uscu

lar;

inh,

inha

led;

iv,

intra

veno

us;

LFT,

lung

fun

ctio

nte

stin

g de

fined

as

mea

sure

men

t of a

ny o

f the

follo

win

g: fo

rced

exp

irato

ry v

olum

e in

1 s

econ

d, p

eak

expi

rato

ry fl

ow, f

orce

d vi

tal c

apac

ity, t

hora

cic

gas

volu

me,

spe

cific

airw

ay (

TGV)

con

duct

ance

(SG

aw),

max

imal

flo

w a

t re

stin

g lu

ng v

olum

e (V

max

FRC);

LOS,

len

gth

of h

ospi

tal

stay

; m

edic

., ne

ed f

or a

dditi

onal

med

icat

ion;

MP,

met

hylp

redn

isol

one;

O2,

oxyg

en s

atur

atio

n; P

, pr

edni

solo

ne;

po,

per

oral

med

icat

ion;

RR

, re

spira

tory

rat

e; s

albu

t., s

albu

tam

ol;

SS,

any

kind

of

sym

ptom

sco

re o

rco

mbi

natio

n of

sy

mpt

oms.

*Num

ber o

f cas

es a

nd c

ontro

ls a

re n

ot a

vaila

ble

sepa

rate

ly.

(+)

Stat

istic

ally

insi

gnifi

cant

pos

itive

tren

d fa

vour

ing

oral

pre

dnis

olon

e+

Stat

istic

ally

sig

nific

ant p

ositi

ve e

ffect

in o

ne o

utco

me

favo

urin

g or

al p

redn

isol

one

++St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

two

outc

omes

favo

urin

g or

al p

redn

isol

one

+++

Stat

istic

ally

sig

nific

ant p

ositi

ve e

ffect

in th

ree

or m

ore

outc

omes

favo

urin

g or

al p

redn

isol

one

=N

o di

ffere

nce

betw

een

the

oral

pre

dnis

olon

e an

d pl

aceb

o in

any

of t

he o

utco

mes

-St

atis

tical

ly s

igni

fican

t effe

ct fa

vour

ing

plac

ebo

Tabl

e 2-

6. C

linic

al tr

ials

that

com

pare

d th

e th

erap

eutic

effe

ct o

f int

rave

nous

(iv)

or i

ntra

mus

cula

r (im

) cor

ticos

tero

id th

erap

y to

pla

cebo

in y

oung

chi

ldre

n. T

he s

tudi

esar

e so

rted

by a

ge-g

roup

s of

recr

uite

d ch

ildre

n.

Patie

nts

Med

icat

ion

Stud

yAg

eC

ase

(n)

Con

trol

(n)

Des

ign

Setti

ngD

rug(

Rou

te)

Dos

eO

utco

me

mea

sure

dD

gEf

fect

Roo

seve

lt et

al 1

996

1-12

mo

6553

db/p

cw

ard

DXM

(im)

1mg/

kg x

1, 3

dLO

S, S

S, O

2, C

O2

W=

Dab

bous

et a

l 196

61.

5 - 1

8 m

o22

22db

/pc

war

dM

P(im

)5

mg/

kg +

2.5

mg/

kgLO

S, S

S, C

O2

W=

de B

oeck

et a

l 199

7<2

4 m

o14

15db

/pc

war

dD

XM(iv

)0.

6 m

g/kg

x 1

, the

n0.

15 m

g/kg

x 1

, 2 d

LOS,

SS,

O2,

LFT

RSV

=

Tal e

t al 1

990

7-54

mo

3935

db/p

cER

P(im

)4

mg/

kg x

1SS

, HoR

A++

+

A, a

sthm

a; d

b/pc

, dou

ble

blin

d an

d pl

aceb

o-co

ntro

lled

trial

; CO

2, ca

rbon

dio

xide

rete

ntio

n; D

g, d

iagn

osis

; DXM

, dex

amet

haso

ne; H

oR, h

ospi

talis

atio

n ra

te; L

FT, l

ung

func

tion

test

ing

defin

ed a

s m

easu

rem

ent o

f any

of t

he fo

llow

ing:

forc

ed e

xpira

tory

vol

ume

in 1

sec

ond,

pea

k ex

pira

tory

flow

, for

ced

vita

l cap

acity

, tho

raci

c ga

s vo

lum

e,sp

ecifi

c ai

rway

(TG

V) c

ondu

ctan

ce (

SGaw

), m

axim

al f

low

at

rest

ing

lung

vol

ume

(Vm

axFR

C);

LOS,

len

gth

of h

ospi

tal

stay

; M

P, m

ethy

lpre

dnis

olon

e; O

2, ox

ygen

satu

ratio

n; R

SV, b

ronc

hiol

itis

with

con

firm

ed re

spira

tory

syn

cytia

l viru

s de

tect

ion;

SS,

any

kin

d of

sym

ptom

sco

re o

r com

bina

tion

of s

ympt

oms;

W, w

heez

ing.

(+)

Stat

istic

ally

insi

gnifi

cant

pos

itive

tren

d fa

vour

ing

pare

nter

al c

ortic

oste

roid

+St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

one

out

com

e fa

vour

ing

pare

nter

al c

ortic

oste

roid

++St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

two

outc

omes

favo

urin

g pa

rent

eral

cor

ticos

tero

id++

+St

atis

tical

ly s

igni

fican

t pos

itive

effe

ct in

thre

e or

mor

e ou

tcom

es fa

vour

ing

pare

nter

al c

ortic

oste

roid

=N

o di

ffere

nce

betw

een

pare

nter

al c

ortic

oste

roid

and

pla

cebo

in a

ny o

f the

out

com

es-

Stat

istic

ally

sig

nific

ant e

ffect

favo

urin

g pl

aceb

o


2.9 Parenteral Corticostero ids inAcute Wheezy Bronchitis

There are only few placebo-controlled data onthe therapeutic value of parenteralcorticosteroids among children below 3 years(Table 2-6). Some authors have concluded thatintramuscular prednisolone in the ER settingcan reduce hospitalisation rate especiallyamong children aged 7-24 months (Tal et al1983 and 1990). Others have found nobeneficial effect of intramuscular (Roosevelt etal 1996) or intravenous (de Boeck et al 1997)administration. Among older children, theeffect of parenteral corticosteroids wascomparable to oral prednisolone (Barnett et al1997, Klig et al 1997, Becker et al 1999, Grieset al 2000).

2.10 Inhaled Corticosteroids inAcute Wheezy Bronchitis

So far, there is only one published placebo-controlled clinical trial assessing the effect ofinhaled corticosteroids in young children withacute wheezing (Singhi et al 1999). This studyincluded 60 children between 3 and 12 yearsof age with acute moderate exacerbation ofasthma. Children receiving budesonide (400µg delivered by metered dose inhaler andspacer) showed greater improvement in peakexpiratory flow rate and were less frequentlyhospitalised compared to the placebo group.The value of inhaled corticosteroids inyounger children with acute wheezing remains

unclear. Long-term prophylactic asthmatreatment is out of the scope of this thesis.

2.11 Other Drugs in WheezyBronchitis

As long-term therapy, nebulised sodiumcromoglycate can reduce the number ofwheezing episodes and hospital admissionsafter an initial attack among children youngerthan 24 months (Reijonen et al 1996).Compared to inhaled corticosteroids they seemto be less effective (Reijonen et al 1996, deBaets et al 1998) and their role in acute settingis not determined.

There are no studies demonstrating anybeneficial effect of anticholinergics drugs inwheezy bronchitis (Naspitz and Sole 1992,Schuh et al 1992).

Leukotriene receptor antagonists areemerging as new line of drugs in themanagement of asthma with some promisingresults also among young asthmatics (Knorr etal 2000). There is no data available yet fortoddlers with mild respiratory distress.

Wheezy bronchitis is a virally induceddisease, although, there is a predisposition forsecondary bacterial infections (Korppi et al1989, Korppi et al 1992). Thus, routineantibiotic use is unwarranted without evidenceof bacterial involvement (Friis et al 1984, Hallet al 1988).

JUSTIFICATION OF THE STUDY 35

3. JUSTIFICATION OF THE STUDY

The successful management of preschoolchildren with wheezing is based on satisfyingthe following fundamental criteria:

1. Knowledge of the developmental anatomy,physiology, and immunopathology of theairways.

2. Identification of the risk factors forwheezing and symptom persistence.

3. Standardised and precise definitions toidentify subjects with different wheezingsyndromes.

4. Targeted acute and long-term therapy.

5. Understanding the effect therapy has on thecourse of disease and its outcome.

Reviewing the literature has revealed thatnone of the above criteria is fully met, so far.Hence, it is of paramount importance thatalgorithms, to identify subgroups of wheezingtoddlers, are further developed and additionalhost and environmental factors looked for.Undoubtedly, the current therapeutic anddiagnostic practices need to be re-assessed andimproved. In addition, there is a great demandfor clinical trials that evaluate the effect ofvarious therapeutic approaches on differentpatterns of symptoms separately in morehomogeneous populations.

36 AIMS OF THE STUDY

4. AIMS OF THE STUDY

The main goals of this study were to evaluatethe current diagnostic activity and therapeuticapproaches of preschool children withwheezing, to define subgroups of wheezytoddlers, and to improve the overallmanagement strategy of these children. Thespecific aims addressing these issues were:

1. To compare the management strategiesused in two Finnish university hospitals forpreschool children with wheezing. Toassess if the use of corticosteroids wereassociated with a more favourableoutcome.

2. To evaluate whether the regional differencein the prevalence of nationally reportedasthma and managing wheezing amongpreschool children is associated with the useof different diagnostic criteria.

3. To determine the effect of a 3-day courseoral prednisolone therapy in themanagement of acutely wheezing 6-35months old children without prior asthmadiagnosis.

4. To identify, among 6-35 months oldwheezers, those risk factors that would beassociated with the development of asthmatill school age, and hence to identify asubgroup of wheezing toddlers who mightespecially benefit from early anti-inflammatory medication.

MATERIALS AND METHODS 37

5. MATERIALS AND METHODS

The settings, target populations, outcomemeasures, and statistical methods differbetween the four studies included in this thesis(Figure 5-1). For clarity, studies are describedseparately where appropriate. All projectswere approved by the Ethics Committee ofTampere University Hospital.

5.1 Regional Variation in theManagement, Outcome, andDiagnosis of Preschool Childrenwith Wheezing (I & II)

In studies I and II, data was collectedretrospectively. Data on refundable anti-inflammatory medicine prescriptions(corticosteroids and cromones) were extractedfrom national Social Insurance Institution (SII)databases. Hospital discharge records wereexplored for individual patient files in twoFinnish university hospitals.

Two regions in Finland (Pirkanmaa in mid-west Finland and Varsinais-Suomi in south-west Finland) were chosen to comparetherapeutic activity, outcome of wheezing, anddiagnostic practices. We identified the 0.5-6.9years old children treated for wheezybronchitis or asthma during 1995-1996 in thepaediatric ER through computer-baseddischarge records. A representative samplewas randomly chosen from each hospital.Appropriate data was extracted fromindividual patient files into a structured form(Appendix A) by two research assistantsblinded to the research hypothesis.

Study groups were designated: age 0.5-2.9years (younger children), and 3.0-6.9 years(older children). The 14 days following theindex visit were included as the samewheezing episode, and 15 days to 6 months asrecurrences. Follow-up was discontinued at 6months after the index episode (Study I).Previous wheezing history was defined as thenumber of all physician-diagnosed episodes of

To comparemanagement

strategies

To evaluate thetherapeutic effect of

oral prednisolone

To identifyrisk factors for

symptom persistence

To evaluatediagnostic activity

Retrospective analysis of patient records intwo Finnish university hospitals (n=800)

&Computerised database of the Finnish

Social Insurance Institution (national data)

Study I Study II Study III Study IV

Prospective,randomised,

placebo-controlledclinical trial

(n=230)

Cross-sectional,questionnaire-based survey

(n=1816)

Aims

Design

Figure 5-1. Overall design of the thesis consisting of four individual studies.

38 MATERIALS AND METHODS

respiratory distress. Previous asthma wasdefined as earlier physician-made diagnosisdocumented in the patient file prior to or in theadmission text for the index episode. The childwas considered as having been given anasthma diagnosis in the ER if the attendingphysician had recorded it either in themanagement plan or as a diagnostic code forthe index episode.

We calculated (based on prior data) that asample of 270 children/hospital would give a90% power and 95% confidence to documenta 50% inter-hospital difference in the averageLOS both among the younger as well as theolder children. Expecting a maximum of 50%variation in the hospitalisation rates, we choseto include 400 children per hospital in theanalysis. In univariate analysis fordichotomous or categorical variables, wecalculated relative risks and used the Pearsonχ2 test to assess the statistical significance ofthe findings. For multivariate modelling of theprobability of receiving asthma diagnosis, weused logistic regression analysis.

5.2 Oral Prednisolone in the AcuteManagement of Children withWheezy Bronchitis (III)

Study III was carried out as a randomised,double-blind, placebo-controlled clinical trialof 6-35 months old acutely wheezing toddlers,without prior asthma diagnosis, presented inthe paediatric ER of Tampere UniversityHospital.

Children received either oral prednisolone(2 mg/kg) or an equivalent amount of placebo.The first dose of prednisolone wasadministered at enrolment in the ER. Thefollowing doses were 2 mg/kg/day for threedays in two divided daily doses. The ERphysicians were asked to make a decision

regarding hospital admission no sooner thanfour hours after the first drug administration.The standard treatment of hospitalised patientswas repeated doses of inhaled salbutamol.More symptomatic children received inhaledcorticosteroids and the most severely illindividuals were treated with intravenouscorticosteroids and theophylline.

All parents were given a diary card(Appendix B) with instructions to record,twice daily for 14 days, the time of studymedication taken, possible side effects, use ofadditional medication, and symptoms ofrespiratory distress. After a 14-21-day follow-up period children were examined by the studyphysician (PC) and all diary entries and patientfiles were reviewed. Data relevant to the studywere transferred to individual case reportforms (Appendix C).

The outcome measures were: 1) immediatehospitalisation from the ER; 2) development ofsevere respiratory symptoms as indicated bythe need for additional inhaled (corticosteroid)or intravenous (corticosteroids andtheophylline) asthma medication; 3) medianlength of hospital stay (LOS); 4) long (≥3days) hospitalisation; 5) duration of symptoms(median duration and proportion of childrenwith ≥3 symptomatic days); and 6) revisitsafter hospitalisation.

The trial's design was based on a priorpower calculation for the primary outcomeswith α of 5%, a discriminating power of 80%,and an estimated 45% hospitalisation rate inthe placebo group. The required number ofchildren in each treatment arm was thefollowing: 180 to demonstrate a minimumdifference of 33% in the immediatehospitalisation rate; 110 to demonstrate aminimum difference of 33% in the medianLOS; 106 to demonstrate a minimumdifference of 75% in the need for additionalintravenous asthma medication. Estimating a

MATERIALS AND METHODS 39

15% non-compliance with the study protocol,a sample size of 210 children per group waschosen at the beginning of the enrolment. Anexternal review board was formed to overseethe progress of the study and suggested a non-scheduled, external interim analysis. Thisanalysis indicated that the attending physiciansat ER seldom waited for the required fourhours before their decision abouthospitalisation or discharge of the studychildren. Due to this frequent deviation fromthe study protocol, the influence of oralprednisolone treatment on the hospitalisationrate could not be determined. Hence, thereview board suggested termination of thestudy on ethical basis. At that moment slightlyover half (230) of the intended sample size of360 children (to determine the rate ofhospitalisation) was reached. The targetsample size for other main outcome variableswas adequate (see above). The blinding fordoctors, parents, and investigators wasmaintained until data review for all patientswas complete.

The data were analysed with SPSS/Win 9.0software. Continuous variables were analysedusing Student’s t test and Mann-Whitney Utest for normally distributed and skewed data,respectively. For quantitative variables such asthe LOS and duration of symptoms, that didnot meet the assumption of normality, we usedmedians – in contrast to the mean, which canbe affected by a few extremely high or lowvalues – as the appropriate statistical method.Dichotomous variables were analysed byPearson χ2 test, or by Fisher’s exact test whereappropriate (expected cell value less than 5).Subgroup analysis was performed on featuresthat might influence disease severity andresponse to corticosteroids. All statistical testswere two-sided. Data on all children eligible tothe study were analysed as randomised, i.e. onan intention to treat basis.

5.3 Predictors of WheezingPersistence (IV)

The study was carried out as a cross-sectional,questionnaire-based survey in Tampere, aFinnish city with 190 000 inhabitants. From 40primary schools in the area, 96 classes wererandomly selected to form the target group forthe study (16 classes for each of the grades 1-6).

A 12-page questionnaire (Appendix D) wasmodified from that used in the InternationalStudy on Asthma and Allergy in Childhood[ISAAC questionnaire for 6-7 years oldchildren (Asher et al 1995)]. Themodifications included additional questionssoliciting information on a number of riskfactors for wheezing, previous respiratorysymptoms, and ER or hospital treatments foracute asthma symptoms in early childhood.Schoolteachers distributed the questionnaires.

During the 12 months preceding thesurvey, the children who reported having hadone or more of the following conditions wereconsidered to have current asthma: wheezybreathing, ER or hospital treatment for acuteasthma, or regular anti-inflammatory therapyfor chronic asthma. Children with a biologicalparent or sibling with known asthma wereconsidered to have a family history of asthma.Home exposure for tobacco smoke wasdefined as residence in a household where aparent or another permanent resident regularlysmoked indoors.

When testing associations between variousindividual exposures and the probability ofhaving current asthma, the Yates’-correctedMantel-Haenszel test was used to examine thesignificance of differences betweenproportions. To control for confounding and toidentify predictors of current asthma from dataavailable when the child was 3 years old, alogistic regression analysis was performed.Variables, showing a statistically significant

40 MATERIALS AND METHODS

association with current asthma in a univariateanalysis, or those potentially confounding thecurrent asthma symptoms, were stepwiseentered into the model. If two or more

variables explained the same exposure, themost relevant one was selected to eliminateinteractions between variables.

RESULTS 41

6. RESULTS

6.1 Regional Variation in theManagement and Outcome ofPreschool Children with Wheezing

At the end of 1996, the point prevalence ofunder-10-year-old children receivingpreferentially refundable anti-inflammatoryasthma medication from the SII ranged from1.12% to 2.70% (Figure I/1). A region with alow (Tampere, 1.24%) and another with a high(Turku, 2.41%) prevalence of beneficiarieswere chosen for further analysis. There wereno major differences between the age, sex orweight distributions, or the previous wheezinghistories of the children from the two clinics(Table II/1). In both Tampere and Turku, theincidence of first ER visits during 1995-1996was 11.0/1000/year.

Prior to referral to the ER, a higherproportion of children had received oral orinhaled corticosteroids in Turku compared toTampere. In the ER, around 90% of thepatients were treated with inhaled salbutamolin both clinics. Some received additionalmedication, usually either oral prednisolone orintramuscular adrenaline. The latter wasfavoured in Tampere, whereas prednisoloneuse was significantly more common in Turku(Figure I/3). Of the admitted children, one inten was given oral prednisolone in Tampere,whereas nine in ten received it in Turku (95%CIdiff 72.4 to 85.8%). In Tampere, childrenwith the most severe symptoms were treatedwith inhaled or intravenous corticosteroids, thelatter usually with intravenous theophylline. InTurku, these drugs were rarely used (FigureI/3).

Of all patients treated for wheezing in theER, 44.8% in Tampere and 36.8% in Turkuwere admitted (95% CIdiff 1.2 to 14.8%). Thedifference in hospitalisation rate was more

marked among the older children (Figure I/4).On analysis of the whole study population,46.6% of those not on corticosteroids wereadmitted, versus 21.0% of the patients onregular corticosteroid treatment (95% CIdiff

15.6 to 35.7%). Once admitted, the children inTampere remained hospitalised for an average[median] of 3.4 [3.0] days compared with 1.4[1.0] days in Turku (95% CIdiff 1.67 to 2.34,p<0.001, Student’s t-test [p<0.001, Mann-Whitney U test]) (Figure I/4). The averagelength of inpatient care for other conditionswas practically identical in the two hospitals.

Initial outpatient treatment was morecommonly followed by revisits (within 14days) in Tampere, whereas ward treatment wasmore commonly followed by revisits in Turku(Table I/1). During the 6-month period afterthe index ER contact, revisits with newepisodes were clearly more common inTampere than in Turku except for the youngerchildren initially treated in hospital (Table I/1).

6.2 Regional Variation in theDiagnosis of Asthma AmongPreschool Children

To analyse whether the marked regionaldifferences in the management of preschoolchildren was associated with the use ofdifferent diagnostic criteria, we compared, inTampere and Turku, the probability of anacutely wheezing child to receive an asthmadiagnosis.

As noted earlier, there were no majordifferences in baseline characteristics orprevious wheezing histories among thechildren treated in the two university hospitals(Table II/1). However, in Turku, asthma was

42 RESULTS

diagnosed significantly more often than inTampere (44.2% versus 15.8% of children,relative risk 2.78, 95% confidence interval2.16 to 3.58, p<0.001). The proportion ofasthma diagnosis increased with age andnumber of previous wheezing episodes andreached nearly 100% in Turku, among olderchildren with 3 or more previous attack(Figure 6-1).

Multivariate modelling indicated that placeof treatment (Turku versus Tampere) was astrong independent predictor of asthmadiagnosis in the ER (adjusted odds ratio 8.30,Table II/2). Previous asthma diagnosis, a highnumber of earlier wheezing episodes, andolder age of the child were also independentlyassociated with the probability of receiving anasthma diagnosis in the ER. In contrast,concomitant infections or sex of the patienthad no statistically significant association withasthma diagnosis.

6.3 Oral Prednisolone in the AcuteManagement of Children withWheezy Bronchitis

The results of the previous two studies (I andII) suggested that active corticosteroid therapymight be beneficial in the acute managementof toddlers with respiratory distress. Toinvestigate the direct effect of a 3-day courseof oral prednisolone we carried out aprospective, randomised, double-blind,placebo-controlled clinical trial.

Of the 603 acutely wheezing 6-35-month-old children, who had no prior asthmadiagnosis, 230 children were randomised toreceive either prednisolone or placebo (FigureIII/1). Both hospitalised and not hospitalisedchildren were similar in respect to theirbaseline characteristics in the two interventionarms (Table III/1). The decision about hospitaladmission or discharge was made on average1.6 (SD+1.2) hours later, for children in both

-100 -80 -60 -40 -20 0

TampereTurku

0 20 40 60 80 100

Under 3 years old* 3-6 years old†

Proportion (%) of children who received asthma diagnosis

>2

2

1

0‡

-100 -80 -60 -40 -20 0

TampereTurku

0 20 40 60 80 100

Under 3 years old* 3-6 years old†

Proportion (%) of children who received asthma diagnosis

>2

2

1

0‡

>2

2

1

0‡

Figure 6-1. Proportion of children who received asthma diagnosis in the ER of Tampere and Turku UniversityHospital. *Number of children in Tampere, 221 and in Turku, 222; †Number of children in Tampere, 128 and inTurku, 124; ‡Number of previous wheezing episodes.

RESULTS 43

groups. Before enrolment to the study, mostindividuals (100/117 placebo, 105/113prednisolone) had received at least one dose ofinhaled β2-agonist (salbutamol) medication.

Table III/2 summarises the impact of theintervention on different outcomes. There wasno difference in the hospitalisation rate amongchildren receiving either prednisolone orplacebo. In hospitalised patients oralprednisolone markedly reduced the amount ofsevere respiratory distress symptoms, asindicated by a difference in the need of inhaled(p=0.029) or intravenous (p=0.062) rescuetherapy. Additionally, prednisolone treatmentreduced the number of long (≥3 days)hospitalisations (Figure III/2) and decreasedthe median LOS by 1 day (p=0.060). Amongchildren not hospitalised, there was nodifference in duration of symptoms or revisitsbetween groups (Table III/2).

History of allergy or atopy stronglypredicted the need for inhaled or intravenousrescue therapy with asthma medication (TableIII/3). In addition, male sex seemed to be arisk factor for long hospitalisations. Familyhistory of asthma or passive smoking had noinfluence on any of the outcomes (Table III/3).

Prednisolone reduced the need of inhaledrescue therapy both in allergic and non-allergicchildren (Figure III/3). Similarly, it reducedthe need for intravenous rescue therapy in theallergic children. Finally, prednisolonetreatment decreased the number of longhospitalisations among the non-allergic, butnot among the allergic children (Figure III/3).

Fifteen children (4 in placebo and 11 inprednisolone group, p=0.12) discontinued thestudy medication due to perceived side-effects.These and other reported unwanted reactionswere mild and resolved without specialinterventions (Table III/4).

6.4 Predictors of WheezingPersistence

Of the 2027 questionnaires that weredistributed, 1829 (90%) were returned. Afterthe exclusion of 13 children falsely included1816 children (915 boys and 901 girls) wereleft in the final analysis. The ages of thechildren ranged from 6.1 to 12.9 years and themean(+SD) age was 9.7(+1.8) years for boysand girls, alike. Pertinent backgroundcharacteristics are shown in Table IV/1.

The proportion of children who hadrequired emergency medical care for acutewheezing during the first 3 years of life,between the ages 3 and 6 years, and in the 12months preceding the survey, were 10.2%,9.1%, and 4.6%, respectively (Table IV/2). Ofthose 186 children, who had been treated foracute wheezing when younger than 3 years,102 (54.8%) had required at least oneemergency treatment when aged between 3and 6 years, and 32 (17.2%) had required atleast one emergency treatment in the 12months preceding the survey.

Rhinitis was slightly more common amongboys than girls (36.5% versus 29.1%), butotherwise there were no gender differences inthe allergic symptom prevalence (Table IV/3).The proportion of children, who during thisperiod had used anti-inflammatory asthmamedication, had experienced wheezing, orneeded emergency care for asthma symptoms,was 11.4% (95% CI 10.0 to 13.0). Of these207 children considered to have currentasthma, 62 (30.0%) had required hospitaltreatment for wheezing when younger than 3years of age.

To identify factors that would facilitate therecognition of wheezy children less than 3years of age who would continue to haveasthma-like symptoms at school age,univariate (Table IV/4) and logistic regression(Table IV/5) analyses were performed. Both

44 RESULTS

indicated that, exposure to tobacco smoke athome before the age of 3 years, a history ofatopic eczema or food allergy, and a familyhistory of asthma were all significantlyassociated with current asthma. A history of

ER or hospital treatment for wheezing beforethe age of 3 years predicted current asthma,but not as strongly as similar treatment at theage of 3-6 years (Table IV/4).

KEY FINDINGS 45

7. KEY FINDINGS

1. There were marked regional differencesbetween Tampere and Turku UniversityHospital in the management of wheezingpreschool children. The data suggest thatthe majority of these children can bemanaged with short or no inpatient care, atleast if anti-inflammatory drugs areincluded in the overall managementstrategy.

2. Despite the similar incidences inrespiratory distress episodes in Tampereand Turku area there was marked regionalvariation (favouring Turku) in diagnosticactivity for early childhood asthma.

3. The clinical effectiveness of oralcorticosteroids in the acute management ofwheezing 6-35 months old children wasconfirmed by the double-blind placebocontrolled trial. Among the hospitalisedchildren a 3-day course of oralprednisolone successfully reduced diseaseseverity and length of hospital stay. Thosetreated on outpatient bases did not benefitfrom oral prednisolone.

4. The prognosis of 6-35 months old childrenwho need emergency treatment forwheezing is generally favourable. Thosewho have a history of food allergy oratopic eczema; asthma occurrence in asibling or parent; or are exposed to tobaccosmoke at home are at highest risk fordeveloping asthma till school age.

46 DISCUSSION AND CONCLUSIONS

8. DISCUSSION AND CONCLUSIONS

8.1 Defining and Identifying StudyGroups

Defining and identifying the precise targetgroup of interest is especially difficult amongpreschool children with wheezing (see chapter2.2, page 14). When attempting to differentiatebetween bronchiolitis, wheezy bronchitis, andasthma both the clinical response to thetriggering stimulus as well as the age and sizeof the child has to be taken into account. Byusing the following definitions, our aim was toidentify homogeneous groups of children, asprecisely as possible, using clinically readilyapplicable criteria.

We considered a child having wheezybronchitis if he or she was 6-35 months of agewith acute cough, rhonchi, or wheezing andhad expiratory distress occurring in thepresence of infection without indications ofpneumonia and without evidence of present orpreviously diagnosed asthma. Childrenyounger than 6 months were considered tohave bronchiolitis. All children older than 6months with more than two previous wheezingepisodes and any child older that 3 years withrespiratory distress were diagnosed as havingasthma. These variables are often included inthe criteria for asthma because of theirsuggested association to the development ofchronic pulmonary symptoms (Dodge et al1996, Remes et al 1998a). Among school-agedchildren those who reported having had atleast one of the following conditions during 12months preceding the retrospective survey(Study IV) were considered to have asthma:wheezy breathing, ER or hospital treatment foracute asthma, or regular anti-inflammatorytherapy for asthma.

By setting the age limit of wheezybronchitis to 6 months there is a possibility

that we have included also children withbronchiolitis. Similarly, by setting the upperage limit to 3 years, we might have missedsome of those children – between 3-6 years –who in fact would have never wheezed againafter their first episode. Nevertheless, theabove criteria were used coherently throughoutour studies. In addition, these are the generallyaccepted definitions adopted in Finland(Haahtela and Laitinen 1996, Korppi et al2000). Thus, the results are comparablebetween the studies and can be readily appliedin practice.

Information on underlying pathophysio-logical mechanisms such as lung function orairflow obstruction was not obtained. This isbecause measuring such parameters amongyoung toddlers is not commonly feasiblewithout special techniques such as rapidthoracic compression or oscillometry. Amongschool-children (Study IV) bronchialhyperresponsiveness (BHR) could have beenevaluated. However, current evidence suggeststhat symptom questionnaires have greatervalidity, sensitivity, and precision in asthmaprevalence studies than BHR testing (Jenkinset al 1996, Pearce et al 2000b). The ISAACstudy showed that surveys soliciting symptomsin the past 12 months can have high sensitivity(85%) and specificity (81%) with respect torespiratory physician diagnosis of asthma(Jenkins et al 1996).

Exclusion criteria in each study were set tocontrol for systematic errors. These includedclinical conditions that would have adverselyaffected the measured outcomes. The samplesize of all studies was based on prior powercalculations to detect statistically significanteffects.

DISCUSSION AND CONCLUSIONS 47

8.2 Precision and Validity o f theResults

8.2.1 Retrospective analysis o fhospital records

Retrospective cohort studies (I and II) haveseveral characteristics that could weaken thestrength of the results. The first potentialproblem, confounding, could arise if thecohorts were different in any other importantways, besides exposure to the predictorvariable. The second, inclusion bias, can occurif there is significant proportion of unidentifiedsubjects not included in the study.

In studies I and II, we identified patientsusing computerised ICD-codes. The codingand classification of diseases in universityclinics is uniform throughout the country andnational registers on hospital discharges aswell as on reimbursed drug sales have beenshown to be reliable sources of data forresearch (National Agency for Medicines andSocial Insurance Institution 1998, Gissler1999). The fact that there were no majordifferences in base-line characteristics orprevious wheezing histories of children inTampere and Turku would imply that thesamples were comparable (Table II/1).

The numbers and proportions of childrenseen at the university hospital ER in the tworegions were almost identical (11.0episodes/1000 children/year) and comparableto figures obtained in other countries (Infante-Rivard et al 1987, Rylander et al 1996, To et al1996, Goodman et al 1998), supporting therepresentativeness of our samples. In addition,the hospitalisation rate of children aged 6-35months was very similar to that seen in theprospective study (III) of this thesis.Concomitantly, no regional differences in thefrequency of asthma symptoms or hospitalcontacts due to acute wheezing have beenreported in Finland (Pekkanen et al 1997).

Another potential limitation of thisinvestigation is the use of data that wasprimarily collected for administrativepurposes. For this reason, we designed thestudy hypotheses in a way that all necessaryinformation could be obtained from hospitalrecords. Similarly, this setting did not allow usto control the nature and quality of themeasurements. On the other hand, because thedata were recorded into the patient files beforethe outcomes were known, the predictorvariables were not biased by knowledge ofwhich subjects had the outcome of interest.Moreover, the two research assistantsextracting data from the individual patient fileswere blinded to the research hypothesis.

The data from SII registers reflect theamount of inhaled asthma medicationdispensed on a population level. On anindividual level it is not possible to assesscompliance using pharmacy claims data. Thus,it is most likely that the actual use of asthmamedication was less – throughout the country– than reported in the study.

8.2.2 Prospective, double-blind ,placebo-controlled clinical trial

The generalisability of the results in Study IIIdepends on 1) the representativeness of thetarget population, 2) good randomisationtechniques, 3) proper blinding, 4) high degreeof compliance, 5) adherence to the studyprotocol, 6) use of practical outcome variables,and 7) adequate sample size.

As noted earlier, one of the mainpathogens provoking wheezing in toddlers isRSV (Rylander et al 1996). Due to theubiquitous and highly contagious nature ofRSV almost all children have been infected by2 years of age (Glezen et al 1986). RSV occursin annual epidemics between October andMay. In Finland, the timing and magnitude of


the peaks vary biannually with a larger peakevery other year (Waris 1991). For this reasonthe recruitment period was designed to lastthrough two winter seasons. To eliminate biasdue to other pre-randomisation confoundingvariables we used consecutive sampling bycomputer generated random list.

We did not attempt to determine viralaetiology of the illness episodes. This decisionwas mainly due to the insensitivity of thecurrently available direct antigen detectiontests (Korppi et al 1986) and the poorfeasibility of polymerase chain reaction andantibody tests for clinical practice.Furthermore, our aim was to study the effectof oral prednisolone in a clinical entity that canbe provoked by a wide variety of viruses(Korppi et al 1986, Rakes et al 1999).

Eventually, only 40% of children attendingthe ER were recruited to the study. This mightproduce a selection bias. However, the age andsex distribution as well as the hospitalisationrate of the recruited children were comparableto the non-recruited ones.

The randomisation in our study (III) wasdone in the ER prior to hospitalisation. Thismight have led to non-random distribution ofhospitalised patients. However, due to theproblem of timing in the ER the hospitalisationrates of both treatment arms were equal. Thus,it likely that the distribution of hospitalisedchildren ended up random.

Another potential problem is posed bythose individuals (8%) who discontinued thetreatment because of perceived side-effects orother reasons. To eliminate the influence ofbaseline confounding variables (i.e. compliantpatients may be inherently different from thosewho did not receive the active treatment), weanalysed the data on intention-to-treat basis.That is to say, all correctly enrolled childrenwere analysed in the groups they wererandomised to, even if they did not completethe treatment. This approach shows the true

effect of the intervention and makes the resultsapplicable to real practice. When the analysiswas restricted only to those individuals whocompleted the 3-day treatment course, allresults remained essentially the same (data notshown).

8.2.3 Population-based survey

The precision and validity of a population-based survey can be improved by minimisingrandom and systematic errors. Precision can beincreased by expanding the volume of thesurvey and by assessing random populationsamples, rather than selected populations.Systematic error includes selection bias (suchas poor response rate), information bias (suchas misclassification of disease), andconfounding (such as psychological andsociological factors) (Toelle et al 1992,Rothman and Greenland 1998).

In Study IV, we utilised the ISAACquestionnaire (Asher et al 1995) with a fewnecessary modifications. Such standardisedand validated symptom questionnaires havegenerally good sensitivity and specificity ascompared to bronchial hyperresponsivenesstesting and they can be administered to largenumbers of participants with high responserates (Shaw et al 1995, Pearce et al 2000b).The additional questions – solicitinginformation on risk factors for wheezing,previous respiratory symptoms, and ER orhospital treatments for acute asthma symptomsin early childhood – were tested but notvalidated. Data was analysed by logisticregression analysis controlling for all variablesand possible confounders included in themodel.

At 6-12 years of age, the prevalence ofwheezy breathing (10%), itchy rash (17%),allergic rhinitis (33%) and conjunctivitis(18%) were similar to those reported earlier in


Finland (Pekkanen et al 1997, Remes et al1998b) and in other parts of Europe (Lau et al2000). The ratio of boys to girls amongchildren who had needed emergency treatmentfor wheezing was 2/1. This is a proportionfound also in studies I-III and by others(Wennergren et al 1992, Korppi et al 1993,Rylander et al 1996). These, together with thelarge sample size (2027) and high responserate (90%) gives credibility to the results.

A few cautionary notes are needed,however, since the assessment of risk factorswas done retrospectively. This may leaveroom for recall bias. Parents of children withasthma may have been more inclined to recallprevious wheezing-related events that parentsof children without asthma. The accuracy ofthese figures was not ascertained fromindividual patient files.

8.3 Management of the WheezingToddler

8.3.1 Practice variation

We found marked regional differences in thetreatment of wheezing preschool children(Study I). This could be detected both in acuteand long-term therapy. Two distinct strategiescould be discerned. One (in Tampere) wascharacterised by infrequent use of anti-inflammatory therapy, the other (in Turku)included active treatment of symptomaticchildren with corticosteroids.

We were unable to identify similar reportsassessing the magnitude of inter-hospitalvariability using data from individual patientfiles. There are few studies examiningcomputerised hospital statistics and pharmacyrecords. Roberts and Bateman (1994) foundsignificant inconsistency in prescribing, othersin dispensing (Stempel et al 1997, Donahue et

al 2000) inhaled corticosteroids. The scarcityof such data is surprising, since the successfulimplementation of national guidelines requirescontinuous evaluation (Flores et al 2000). Anydetected heterogeneity between health careproviders implies divergence from theguidelines.

The management of patients withrespiratory distress and the use of anti-inflammatory medication can be influenced byasthma diagnostic rates (Roberts and Bateman1994). Our data (Study II) indicated that,although guidelines were followed by theattending physicians in both hospitals,adherence to the national recommendationswas much more common in Turku than inTampere. As a result, the probability ofchildren receiving an asthma diagnosis wasmarkedly higher in this centre. The differenceremained significant even after adjustment forchild’s age, number of previous wheezingepisodes, and other potential confounders.

We were unable to measure intrinsicdisease severity retrospectively. The twoclinics were, however, similar in relation totheir coverage area, patient numbers, staffing,and use of ICD codes. Furthermore, theincidence of ER contacts and previouswheezing histories of children werecomparable in the two centres. Thus, theobserved difference in pharmacotherapy anddiagnostic activity was not likely to be due to avariation in the clinical presentation of patientswith acute wheezing.

Variability in the adherence to diagnosticcriteria probably explains a part of the regionaldifferences in the reported prevalence ofchildhood asthma and use of anti-inflammatory medication in Finland. However,the present data offer no explanation why suchregional variation exists. Horowitz andcolleagues (1995) have showed, for example,that physician’s experience can significantlyinfluence the overall approach to care. Hence


it is possible, that the opinion of a smallnumber of paediatric allergists have guided thediagnostic practises and development ofdifferent local habits in the two study areas.Because anti-inflammatory therapy is inFinland preferably refundable for childrenwith asthma but not for those withbronchiolitis or wheezy bronchitis, drugmarketing may also have indirectly influencedasthma diagnostics.

Whatever the cause, the failure of attendingphysicians to follow national guidelines islikely to result in under-diagnosis of earlychildhood asthma. Since the lack of asthmadiagnosis will delay the institution ofappropriate anti-inflammatory therapy, manychildren may be at risk of developing chronicsymptoms and possibly irreversible airwayimpairment (Hogg 1981, Laitinen et al 1985,Pool et al 1989, Agertoft and Pedersen 1994).Therefore, the use of nationally recommendeduniform guidelines for asthma diagnosisamong preschool-age children should be morestrongly enforced.

8.3.2 Corticosteroid therapy and theneed for hospital care in wheezingpreschool children

The difference in therapeutic approaches wasreflected also in the outcome of wheezingchildren in the two university clinics (Study I).In Turku, children were less inclined to behospitalised, the length of hospital stay wasshorter and re-hospitalisation rates within thefollowing six months lower than in Tampere.Thus, on a population level, active prescriptionof anti-inflammatory therapy was associatedwith reduced need for hospital care for wheezypreschool children.

Theoretically, this could be connected withpositive influence of either inhaled or oralcorticosteroids. Alternatively, physicians in

Turku may be more prone to prescribe anti-inflammatory therapy, to use more stringentadmission criteria, or to discharge moresymptomatic children, without these featuresnecessarily being causally associated.

The LOS for acute conditions other thanrespiratory distress (such as gastroenteritis andother infectious diseases) was similar in thetwo hospitals. Although these data do notdirectly apply to the care of wheezy children,they indicate that there was no principaldifference in hospitalisation policy betweenthe two centres.

The stratified subgroup analysis indicatedthat in both regions those children, who werealready on inhaled corticosteroids, were lesslikely to be hospitalised than those with nosuch medication. In accordance with previousstudies (Storr et al 1987, Carlsen et al 1988,Bisgaard et al 1990, Noble et al 1992,Ilangovan et al 1993, Reijonen et al 1996), ourpopulation level effectiveness study suggests,that the use of inhaled corticosteroidsdecreased the need for inpatient care. Theimpact of inhaled steroids on hospitalisationmay have been underestimated in our study,since the children who had been prescribedanti-inflammatory treatment had probablymore often true asthma than the ones withoutsuch therapy. Thus, if the steroid-treated anduntreated children would have initially beencomparable in relation to their diseaseseverity, the difference in hospital use mighthave been even greater than now observed.Indeed, the effect of inhaled steroid treatmenton hospitalisation was more evident inTampere, where the infrequent use of anti-inflammatory therapy probably led to a largersimilarity between the treated and non-treatedgroups. The effect was greater among olderchildren, probably because inhaledcorticosteroids have limited effect on virallyinduced oedema and mucous collection, oftencausing problems in the under-3-year-old


toddlers (Martinez et al 1988, Taussig 1992,Martinez et al 1995).

Also oral corticosteroids have been shownto be beneficial for older (Storr et al 1987,Scarfone et al 1993, Horowitz et al 1994) butnot for younger (Webb et al 1986, Fox et al1996, Klassen et al 1997) children with acutewheezing. The results of Study I showed thathospital use was significantly lower in Turkuwhere oral corticosteroids were commonlyprescribed, even after adjustment for inhaledcorticosteroid therapy. Indirectly, this wouldsuggest a positive effect of oralcorticosteroids, both for younger (6-35months) as well as older (3-7 years) children.We performed the prospective study (III) ofthis thesis, to determine the role of oralcorticosteroids among children with wheezybronchitis.

8.3.3 Oral prednisolone in the acutemanagement of children with wheezybronchitis

The randomised, double-blind, placebo-controlled, clinical trial (Study III)demonstrated that 6-35 month old childrenhospitalised for wheezy bronchitis benefitedfrom a 3-day course of oral prednisolonetreatment. Those given the active preparationwere less likely to have severe respiratorydistress and more likely to be dischargedearlier. The medication had, however, nopositive effects on hospitalisation rate or onthe duration of symptoms or number ofsubsequent ER visits among the non-hospitalised subjects.

To identify those who might especiallybenefit from oral prednisolone, we performeda pre-defined subgroup analysis fromhospitalised children conditioned on child’spast history of allergy. As expected, theincidence of very severe respiratory distress

was higher among the allergic children and theeffect of prednisolone was most evident in thisgroup (Martinez et al 1995, Stein et al 1997,Garrison et al 2000). Nevertheless, oralprednisolone also reduced symptom severityamong the non-allergic individuals. The LOSwas, on the other hand, reduced only amongthe non-allergic patients. Theoretically, thiscould be due to a bias caused by the clinicians’awareness of the children’s allergy status. It ispossible that those without known allergy weredischarged immediately after their respiratorysymptoms had resolved whereas those withallergy were kept longer under observation,even when already asymptomatic. Otherexplanations are also possible but the mainconclusion is that oral prednisolone therapy isuseful for wheezy, 6-35 month old hospitalisedchildren, regardless of their allergy status.

There was no difference in hospitalisationrate between the two treatment arms. It isimportant to note, however, that due to itspharmacokinetic characteristics prednisoloneneeds at least 3-4 hours to exert its clinicaleffect on airway function (Figure 2-4, page27). In our study (III), the attending physiciansmade their decisions regarding discharge orhospitalisation on average already at 1.6 hours.Thus, if the observation period had beenlonger, prednisolone would have had moretime to exert its effect on the hospitalisationrate (Storr et al 1987, Tal et al 1990, Scarfoneet al 1993). In addition, we could notdemonstrate a beneficial effect of oralprednisolone on children not hospitalised. Thisgroup may contain more individuals whoserespiratory distress is caused by virallyinduced oedema and mucous collection, ratherthan true eosinophilic inflammation andsmooth muscle constriction. Like under-6-months old infants with bronchiolitis suchtoddlers would be less likely to respond tocorticosteroid therapy (Martinez et al 1988,Taussig et al 1992, Martinez et al 1995).


Together, these results question the value oforal prednisolone in the ER and suggest thatoral prednisolone treatment is best reserved forthose wheezy toddlers who needhospitalisation, especially in conditions wherelong ER observation periods are not feasible. Among the many alternative systemiccorticosteroid preparations, we chose oralprednisolone. It has excellent pharmacokineticcharacteristics suitable for therapeuticpurposes (see chapter 2.7.2, page 26) and hasbeen proven safe and effective in treatingasthma in children (Storr et al 1987, Scarfoneet al 1993, Grant et al 1996). The advantagesof oral therapy over parenteral therapy includepotential for pre-hospital administration,relative ease of administration, reduced cost,and decreased frequency of minorcomplications (e.g. pain and phlebitis). Although there were no major side effectsattributable to the study preparation, vomitingafter drug administration was reasonablycommon. Whereas the vomiting may havebeen caused by prednisolone itself, it is alsopossible that the solvent’s high sugarconcentration had a vomitogenic effect. Thesolvent was chosen because its sweet taste wasone of the few that could even partially maskthe bitterness of oral prednisolone. Othercarriers should be tested to identify the bestpossible drug preparation. The potential long-term benefits of moreaggressive treatment of wheezy toddlers areunknown. If wheezing among young toddlersis causally related to asthma, successfultreatment of acute attacks – as well as long-term therapy – with corticosteroids mightdecrease the prevalence of asthma.Alternatively, it may be that wheezy bronchitisis more common or severe among toddlerswho have a predisposition to develop asthmaand that this tendency is responsible for thepositive effect of corticosteroids in wheezybronchitis.

In conclusion, data from Studies I and IIIshowed the clinical effectiveness of a shortcourse oral prednisolone therapy in reducingdisease severity and length of hospital stayamong toddlers hospitalised for wheezybronchitis. For children with milder symptoms– namely those who could be treated on anoutpatient basis – similar positive effects couldnot be demonstrated.

8.3.4 Other factors effecting the lengthof hospital stay

The marked difference in LOS between theuniversity clinics (Study I) could not bereproduced with equal magnitude in theprospective clinical trial (III). This wouldsuggest that in addition to anti-inflammatorytherapy, discharge criteria and other complexfactors might play a central role in determiningthe overall LOS.

In order to clarify this issue we haverecently conducted a prospective, descriptivestudy in Tampere University Hospital. Ouraim was to identify clinical symptoms thatguide the clinicians when deciding whether todischarge the patient or not. In addition, we

100

80

60

40

20

0-1-2-3Days before discharge from the ward

% ofsym

ptomatic

children

Wheezing (stet.)

Wheezing (no stet.)

Retractions

Rhonchi (stet.)

Rhonchi (no stet.)

Figure 8-1. Proportion of children on the ward withspecific symptoms before discharge. Stet., heard onlyby stethoscope; ear, heard without stethoscope;retractions, subcostal retractions.


wanted to find out what are the prevailingattitudes of parents and health careprofessionals towards shortening the LOS.

Altogether, 116 (of 173 eligible) children,aged 6-35 months, with wheezy bronchitis orasthma were recruited to the study. Themedian LOS (2.5 versus 2.0 days) and otherbaseline characteristics were similar betweenrecruited and not-recruited children,respectively (data not shown). The responserates for the questionnaires were 85% (99/116)for parents, 52% (26/50) for physicians, and96% (24/25) for nurses.

As seen in Figure 8-1 wheezing was stillheard by stethoscope in more than half of thechildren (52.5%) one day before discharge. By

that time, wheezing heard without stethoscopeand subcostal retractions have disappeared inmore than 80% of the children. Thus in theory,if wheezing heard by stethoscope would nothave been included in the decision makingprocess, a large proportion of toddlers couldhave been discharged at least one day earlier.Wheezing is an important sign of airwaynarrowing, however, it is not known what isthe true value of identifying wheezing bystethoscope in a child who does not haveotherwise clinically distinguishable respiratorydistress.

Supposing, the discharge criteria could bechanged safely and the LOS could beshortened by at least one day. The parents and

0 20 40 60 80 100

No symptoms

Rhinitis & cough, no rhonchi

Rhinitis, cough, rhonchi heard only withstetoscope

Rhinitis, cough, no respiratory distress, nowheezing, some rhonchi

Rhinitis, cough, no respiratory distress,wheezing heard only with stetoscope, rhonchi

Rhinitis, cough, lesser degree of respiratorydistress, no retractions, wheezing & rhonchi

Rhinitis, cough, tachypnea, respiratorydistress, retractions, wheezing & rhonchi

% of opinion

Parents Doctors Nurses

Figure 8-2. Personal preference regarding the discharge of children treated on the ward for wheezing. The barsrepresent the proportion of parents and health care personnel who chose a specific level of disease severity as theideal stage for discharge.


heath care professionals were asked whether ornot such modifications would be desirable.Only 17.2% of the parents felt that shorteningthe LOS is necessary. In contrast, the majorityof the physicians (87.5%) and less than half ofthe nurses (43.5%) felt that shorter LOS wouldbe desirable.

Personal preference regarding the timingand clinical discharge criteria was alsoevaluated (Figure 8-2). A significant numberof parents considered rhonchi as an indicatorfor hospital treatment. As many as 46.2% ofthe physicians would have been ready todischarge a child even if there was somewheezing heard by stethoscope. Thus, theopinion of the physicians were in conflict withthe actual symptom pattern seen in Figure 8-1and reflected the situation seen approximatelyone day before discharge.

In summary, these preliminary resultssuggest that modifying the discharge criteriamight further reduce the LOS of wheezytoddlers. A significant number of physicianswould prefer such changes, whereas, parentsseem to be more concerned. It remains to bedetermined whether this approach is safe orfeasible.

8.3.5 Predictors of WheezingPersistence

There is increasing evidence that in a largeproportion of asthma cases, asthma-likesymptoms begin during the first years of life(Martinez 1999a). In keeping with results fromearlier studies, we found in Study IV a directassociation between early wheezing and laterasthma symptoms (Rooney and Williams1971, Busse 1990, Martinez et al 1995, Dodgeet al 1996). From those children who neededemergency treatment for wheezy breathingbefore the age of 3 years, only half continued

to need such treatment at 3-6 years of age andless than 20% at school age. This confirmsearlier findings that the majority of earlywheezers outgrow their problem duringchildhood (Foucard and Sjöberg 1984, Korppiet al 1994, Martinez et al 1995). However, theproportion of symptomatic individuals perage-group does not decrease accordinglysuggesting that other children start wheezingafter the age of 3 years (Martinez et al 1995).In fact, in our study (IV), only 30% of thosewith current asthma at school-age had neededemergency treatment for wheezing during thefirst 3 years of life.

The association between early childhoodwheezing and later asthma, together with thehigh spontaneous recovery rate complicatesthe development of evidence-based guidelinesfor the management of wheezy infants andtoddlers. With the present evidence, universalanti-inflammatory medication can hardly bejustified for all early wheezers. Infants andyoung toddlers, who go on wheezing, havesignificantly lower levels of lung function atage 6 compared with children who startwheezing after the age of 3 years (Martinez etal 1995). In addition, it seems that the earliersymptoms begin the more substantial is thefunctional deterioration and persistence ofsymptoms into adult life (Carlsen 1997,Berhane et al 2000). For this reason, it hasbeen suggested that these children mightrepresent an important group for earlyintervention aimed at changing the naturalcourse of the disease (Reijonen et al 1996,Martinez 1999b). It is therefore important todefine characteristics that help in theidentification of children at highest risk forsymptom continuation.

In our study, independent predictors ofsymptom persistence among under-3-year-oldwheezy children were a history of foodallergy, itchy rash, family history of asthma,and exposure to tobacco smoke at home before


the age of 3 years. Previous studies have alsoassociated continuing symptoms to child’sown atopy or family history of asthma (Eisenand Bacal 1963, Rooney and Williams 1971,Foucard and Sjöberg 1984, Martinez et al1995, Sporik et al 1991, Wennergren et al1992). Recently Martinez (1999a) suggestedan algorithm for the identification of asthmarisk among young children who have neededhospitalisation or at least three outpatientcontacts for wheezing (Table 2-2, page 24).According to this model, those with atopiceczema or parental history of asthma, have asignificantly increased asthma risk. Later thiswas slightly modified by the same group

(Castro-Rodríguez et al 2000, Table 2-3, page24). Our results strongly support thesealgorithms and add known food allergy to thechild's risk characteristics.

Taken together, our results confirm thegenerally favourable prognosis of under-3-year-old children who need emergencytreatment for wheezing. Those who have ahistory of food allergy, itchy rash, or asthmaoccurrence in a sibling or parent are at highestrisk for symptom persistence and might benefitfrom early anti-inflammatory therapy.Cessation of parental smoking should be alsoencouraged to minimise the risk of chronicasthma.

56 CLINICAL IMPLICATIONS

9. CLINICAL IMPLICATIONS

Based on the above findings and on publishedliterature the following recommendations havebeen reached:

1. If a child older than 6 months hasrespiratory distress severe enough to needhospitalisation, a 3-day course of oralprednisolone treatment (2 mg/kg/day) isjustified. Both, children with and withoutpersonal atopy or atopic heredity (parentalhistory of atopy or asthma) are likely tobenefit from such therapy. In the ER, oralcorticosteroids have proven to be effectiveonly among asthmatic children with acuteexacerbations.

2. A child aged 6 months to 3 years with morethan two episodes of expiratory wheezingor severe wheezing requiringhospitalisation and with any major criteria(parental history of asthma or allergy,atopic eczema, or food allergy) and twominor criteria (rhinorrhea or wheezingapart from colds, eosinophilia, or exposureto tobacco smoke during first years of life)should be considered at very high risk forpersistent wheezing (Table 9-1). After thethird year of life wheezing is alwaysstrongly suggestive of asthma irrespectiveof previous wheezing or atopic history.

3. Special attention should be paid to thedevelopment and implementation ofdiagnostic and therapeutic guidelinesamong the heterogeneous group ofwheezing preschool children. Dischargecriteria and other complex conditions onthe ward need to be taken into accountwhen developing the overall managementstrategy. Practice guidelines are most likelyto be followed if they are simple, flexible,rigorously tested, not used punitively, andare motivated by desires to improvequality, not reduce costs (Flores et al2000).

Table 9-1. Algorithm to define asthma risk among 6months to 3 years old children with more than 2episodes of expiratory wheezing or severe wheezingthat require hospitalisation. Children who meet anymajor criteria and two minor criteria should beconsidered at very high risk of persistent wheezing(modified and extended from Castro-Rodríguez et al2000).


Parental history ofasthma or allergy

Atopic eczemaFood allergy

Allergic rhinitisWheezing apart from coldsEosinophilia (≥4%)Exposure to tobacco

smoke during first years of life

FUTURE PERSPECTIVES 57

10. FUTURE PERSPECTIVES

Further prospective cohort studies andrandomised placebo-controlled clinical trialsare needed to enhance the diagnosis,comprehensive evidence based management,and outcome of wheezing preschool children.These studies should be large, including broadrange of patients with narrow (age- and other)subgroups, involving high and low risk

children, with and without symptoms. Inaddition, patient education should be improvedto increase compliance (Cerveri et al 1999)and international guidelines strongly enforced.For their successful implementation theseissues need regular testing on local, national,and international level.

58 ACKNOWLEDGEMENTS

11. ACKNOWLEDGEMENTS

This study was carried out at the Departmentof Paediatrics, Medical School, University ofTampere and at the Department of Paediatricsof Tampere University Hospital during 1996-2000.

I wish to express my deepest gratitude tomy supervisor Docent Per Ashorn, MD forintroducing me to the fascinating world ofscience. He offered me the opportunity to learnand develop in the field of medical research.His close guidance, broad vision, precision,and profound experience have been essentialfor my scientific work. Amazingly, Per alwaysfound time to answer my countless questions,to encourage and support me throughout theseyears. By working together from the verybeginning, planning and executing theprojects, our co-operation evolved intofriendship.

I am grateful to Professor Matti Salo, MD,Professor Mikael Knip, MD, and ProfessorMatti Koivikko, MD heads of the Departmentof Paediatrics, for providing me with theworking facilities and for creating an inspiringatmosphere for the research work. My specialthanks are due to Professor Timo Vesikari,MD and Docent Jussi Mertsola, MD for theirconstructive criticisms and contributions tothis thesis. I also thank Emeritus ProfessorJarmo Visakorpi, MD for his continuoussupport for the study.

I express my gratitude to Docent MikaMäkelä, MD and Docent Harri Saxén MD, theofficial referees, for their extremely quick andcareful review, valuable criticism, and adviceduring the preparation of the final manuscriptof this thesis.

I was privileged to work closely withDocent Minna Kaila, MD, whose friendshipand experience in the field of paediatricasthma and allergology I value greatly. She

helped so many times to straighten myintricate thoughts. I owe many thanks toDocent Timo Klaukka from the Finnish SocialInsurance Institution for his expertise andpositive attitude as a co-author. I would like tothank my collaborators Professor PekkaLaippala, Marja Iso-Mustajärvi, MSc(Pharm),Anna-Leena Kuusela, MD, and Marja-RiittaStåhlberg, MD for their input in the individualstudies.

I would like to thank Johanna Halkilahti,Ulla Hemmilä, Kirsi Jokinen, Raija Lietzén,and Anna Sivunen for their careful datacollection. Special thanks are due to AnnaMaija Koivisto, BSc for her statistical advice. Iwarmly thank my friend and colleague TeijaKulmala, MD, DMSc whose practical attitudetowards life has been of great help on the upsand downs of the road of research.

All parents and children participating in thestudies are warmly acknowledged. Withouttheir positive attitude towards research, thiswork could never have been accomplished.My heartfelt thanks are due to the entire staffof the Emergency Room and the LO4-ward ofthe Department of Paediatrics for their friendlyattitude and co-operation during these years. Iespecially want to thank Helena Ruusila forher cheerful assistance.

I wish to thank the personnel of theMedical Library, the Department ofInformation Service, and the Department ofMedical Records of Tampere UniversityHospital for their help on every occasion.

My deepest thanks and love goes to myparents Emilia Krassói and László Csonka foralways supporting and encouraging me. Myfather’s skilful, logical, and imaginativeknowledge on computer programming helpedtremendously the data collection andrecording.

ACKNOWLEDGEMENTS 59

No words can express my gratitude I feelfor my wife Päivi Junttila-Csonka for fillingmy life with love, joy, and precious moments.Päivi shared all these years with me, neverfailing in encouraging and understanding. Herlove and care is the greatest support to all theaspects of my life.

Tampere, April 2001Péter Csonka

This study was supported by grants from EmilAaltonen Foundation Finnish AllergyResearch Foundation, Foundation forPaediatric Research in Finland, MedicalResearch Fund of Tampere UniversityHospital, Research Foundation of theUniversity of Tampere, Scientific Foundationof the City of Tampere, Support Fund for theDepartment of Paediatrics, TuberculosisFoundation of Tampere, and Väinö and LainaKivi Foundation.

60 REFERENCES

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