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1、Sren PedersenUniversity of Southern DenmarkKolding HospitalRecurrent Wheezing and Asthma5 years and YoungerClinical presentationClinical presentationWheeze (50%), cough (80%) and breathlessness (20%)Wheeze (50%), cough (80%) and breathlessness (20%)TirednessTirednessReduced physical activityReduced
2、physical activityNocturnal wake-upsNocturnal wake-upsRecurrent bronchitis or pneumonia antibioticsRecurrent bronchitis or pneumonia antibioticsCold air or activity induced symptomsCold air or activity induced symptomsMostofthesymptomsarenotspecificforasthmaParentsdonotreportwheezeuntillungfunctionis
3、reducedbyaround50%GINA 2014 Children 5 years and Younger Outcome of Childhood AsthmaMildModerateSevereChildhoodChildhood70% symptom free as adultsAdulthoodAdulthood30%30% symptom free as adults70%Marked tracking of asthma severitybetween childhood and adult lifeSummary65% loose their symptoms before
4、 age 5.65% loose their symptoms before age 5.35% continue to have symptoms after 5.35% continue to have symptoms after 5.Viral infections are the most common trigger of Viral infections are the most common trigger of symptoms in both groupssymptoms in both groupsReduction of maternal smoking reduces
5、 Reduction of maternal smoking reduces occurrence of wheeze in both groupsoccurrence of wheeze in both groupsPreschool WheezeFor intervention strategies that include allergen avoidance: Strategiesdirectedatasingleallergenhavenotbeeneffective Multifacetedstrategiesmaybeeffective,buttheessentialcompon
6、entshavenotbeenidentifiedCurrent recommendations, based on high quality evidence or consensus, include: AvoidexposuretoenvironmentaltobaccosmokeduringpregnancyandthefirstyearoflifeEncouragevaginaldeliveryAdvisebreast-feedingforitsgeneralhealthbenefits(notnecessarilyforasthmaprevention) Wherepossible
7、,avoiduseofparacetamol(acetaminophen)andbroad-spectrumantibioticsduringthefirstyearoflifeThe development and persistence of asthma are driven by geneThe development and persistence of asthma are driven by geneenvironment interactions. For children, a window of opportunity exists in environment inter
8、actions. For children, a window of opportunity exists in utero and in early life, but intervention studies are limited. utero and in early life, but intervention studies are limited. Primary Prevention of Asthma0123456789101112-1.2-1.0-0.80.60.40.20.00.20.4NeverTranient earlyLate onsetPersistent*p0.
9、05 vs. neverp0.05 vs. latep0.05 vs. never, late and persistentMean (SE)*Lung Function and timeZ - ScoreAge (years)*Outcome of Childhood AsthmaUntreated asthmais associated withreduced growthof lung functionAdverse effecton lung functionseems more markedduring the beginningof the diseaseMartinez. J A
10、llergy Clin Immunol 1999;104:S169-S174.Asthma Predictive Index for ChildrenCastro-Rodriguez JA et al. AJRCCM 162:1403-1406, 2000.* by history of MD diagnosis Criteria:Criteria: Age 2 - 3 years old frequent wheeze 1 major or 2 minor criteria:Likelihood of Asthma 77% PPV97% SpecificityThis is a verysm
11、all proportionof the cohortThe majority withschool age asthma do not belong tothis group Managing Asthma in Pre-school ChildrenDuration of wheezeDuration of wheeze Transient early wheezingTransient early wheezingStarts during first two yearsDisappeared (retrospectively) by age 6Pattern: Episodic or
12、multiple trigger late onset wheezelate onset wheezeSymptoms starts after age 3Pattern: Episodic or multiple trigger Persistent wheezePersistent wheezeSymptoms beyond age 6 (retrospectively) Pattern: Episodic or multiple trigger Episodic (Viral) wheezeEpisodic (Viral) wheezeWheezing during discrete t
13、ime periodsNo symptoms between attacksNormally associated with a viral coldEach episode normally short (one week)The episodes can be mild, moderate or severe Multiple trigger wheezeMultiple trigger wheezeWheezing that shows discrete exacerbationsSymptoms between episodes Preschool wheeze Preschool w
14、heeze Temporal patternsTemporal patternsGINA 2014 Children 5 years and Younger (Brand PLP et al ERJ 2010;38:1096-1110)Martinez. J Allergy Clin Immunol 1999;104:S169-S174.Schultz A, Devadason SG, Savenije OE, Sly PD et al Acta Paediatr 2010;99:56-6000The distinction between EVW and MTW is not as clea
15、r-cut as the report suggested. Changes in symptom pattern over time is common there is a large overlap between the groupsWhen children with preschool wheeze are classified into episodic (viral) wheeze or multiple trigger wheeze based on retrospective questionnaire, the classification is likely to ch
16、ange significantly within a 1-year period.Phenotypic classification remained the same in 45.9% of children and altered in 54.1% of children within one yearBrand PL et al. Eur Respir J. 2014 Apr;43(4):1172-7.Asthma Management for Young ChildrenThere is little evidence that the EVW and MTW phenotypes
17、are related to the longitudinal patterns of wheeze, or to different underlying pathological processes. The temporal pattern of wheeze during preschool years (EVW or MTW) is a relatively poor predictor of long-term outcome (transient versus persistent wheeze). Frequency and severity of wheezing episo
18、des are stronger predictors of long-term outcome. Thus, the clinical usefulness of the EVW-MTW approach is doubtfulPescatore AM et al J Allergy Clin Immunol 2013 Epub ahead of print“The distinction between Episodic Viral Wheeze and Multiple Trigger Wheeze is more a marker of disease severity than of
19、 different clinical phenotypes” Garcia-Marcos L, Martinez FD:J Allergy Clin Immunol 2010;126:489-490Asthma Management for Young ChildrenEpisodic (Viral) wheeze and Multiple trigger wheezeEpisodic (Viral) wheeze and Multiple trigger wheezeNoIdeal situationReal life Episodic (Viral)Wheeze Multiple tri
20、ggerwheezeAsthma Management for Young ChildrenItisnotpossibletobreakthepatientsdownintomutuallyexclusivesubgroupsthatremainconsistentovertime.Oftenthevariousdifferencesarequantitativeratherthanqualitative.Whichsymptompatternmaysuggestasthma?Characteristic for asthmaCoughRecurrent or persistent non p
21、roductive cough that may be worse at night or accompanied by wheezing and breathing difficulties. Occurring with exercise, laughing, crying or exposure to tobacco smoke in the absence of an apparent URTIWheezingRecurrent wheezing, including during sleep or with triggers such as activity, laughing, c
22、rying or exposure to tobacco smoke or air pollutionDifficult or heavy breathing or shortness of breathOccurring with exercise, laughing, or cryingReduced activity Not running, playing or laughing at the same intensity as other children; tires earlier during walks (wants to be carried)Past or family
23、history Other allergic disease (atopic dermatitis or allergic rhinitis)Asthma in first degree relatives.Therapeutic trial with ICS and as needed beta-2 agonistClinical improvement during 2-3 months of controller treatment and worsening when treatment is stoppedAsthma Management for Young ChildrenAny
24、 of the following features suggest an alternative diagnosis and indicate the need for further investigations:Failure to thrive Neonatal or very early onset of symptoms (especially if associated with failure to thrive) Vomiting associated with respiratory symptoms Continuous wheezing Failure to respo
25、nd to asthma controller medications No association of symptoms with typical triggers, such as viral URTI Focal lung or cardiovascular signs, or finger clubbing Hypoxemia outside context of viral illness Keyindicationsforreferralofachild5yearsoryoungerforKeyindicationsforreferralofachild5yearsoryoung
26、erforfurtherdiagnosticinvestigationsfurtherdiagnosticinvestigationsGINA 2014 Children 5 years and Younger Recurrent wheezing occurs in a large proportion of children 5 years and younger, typically with viral upper respiratory tract infections. Deciding when this is the initial presentation of asthma
27、 is difficultPrevious classifications of wheezing phenotypes (episodic wheeze and multiple-trigger wheeze; or transient wheeze, persistent wheeze and late-onset wheeze) do not appear to represent stable phenotypes, and their clinical usefulness is uncertain A diagnosis of asthma in young children wi
28、th a history of wheezing is more likely if they have: Wheezing or coughing that occurs with exercise, laughing or crying in the absence of an apparent respiratory infection should be treatedA history of other allergic disease (eczema or allergic rhinitis) or asthma in first-degree relatives Clinical
29、 improvement during 23 months of controller treatment, and worsening after cessationSummary of studies in pre-school children:Asthma Management for Young ChildrenWhoshouldbetreated?Frequencyand/orintensityofintervalsymptomsIntensityand/orfrequencyofexacerbationsMildorrareFrequentorsevereFrequentorse
30、vereMildorrareGINA 2014 Children 5 years and YoungerTreatment should be decided on frequency and severity of symptoms and exacerbations rather than phenotypesTo achieve good control of symptoms and maintain normal activity levels To minimize the risk of future asthma flare-ups, impaired lung develop
31、ment and medication side-effects. Maintaining normal activity levels is particularly important in young children because engaging in play is important for their normal social and physical development. It is important to also elicit the goals of the parent/carer, as these may differ from conventional
32、 medical goals. GoalsofmanagementGINA 2014 Children 5 years and YoungerRiskfactorsforasthmaexacerbationswithinthenextfewmonthsUncontrolledasthmasymptomsOneormoresevereexacerbationinpreviousyearThestartofthechildsusualflare-upseason(especiallyifautumn/fall)Exposures:tobaccosmoke;indoororoutdoorairpol
33、lution;indoorallergens(e.g.Housedustmite,cockroach,pets,moldandviralinfection)Majorpsychologicalorsocio-economicproblemsforchildorfamilyPooradherencewithcontrollermedication,orincorrectinhalertechniqueRiskfactorsforfixedairflowlimitationSevereasthmawithseveralhospitalizationsHistoryofbronchiolitisRi
34、skfactorsformedicationside-effectsSystemic:FrequentcoursesofOCS;high-doseand/orpotentICSFutureRiskGINA 2014 Children 5 years and YoungerIn the past 4 weeks, has the child had:Well controlledPartly controlledUncontrolled Daytime asthma symptoms for more than a few minutes, more than once a week? Yes
35、No None of these12 of these34 of these Any activity limitation due to asthma? (Runs/plays less than other children, tires easily during walks/playing?) Yes No Reliever medication needed* more than once a week? Yes No Any night waking or night coughing due to asthma? Yes NoGINA 2014 Children 5 years
36、and YoungerAssesmentofcontrolWhich medications?(Castro-Rodriguez et al. Pediatrics 2009;123: 519-525)Significant reductions were seen in children with a diagnosis of wheeze as well as and asthma, but the magnitude was greater in asthma RR 0.76 (0.58-0.99) (P=0.04)ICS for Young ChildrenMeta-analysis
37、of the effect of ICS29 studies including a total of 3592 pre-school children 29 studies including a total of 3592 pre-school children with wheezewith wheezePrimary outcomePrimary outcome: Wheezing/asthma exacerbations: Wheezing/asthma exacerbationsSecondary outcomesSecondary outcomesWithdrawal due t
38、o Wheezing/asthma Withdrawal due to Wheezing/asthma exacerbationsexacerbationsAlbuterol useAlbuterol useChanges in symptomsChanges in symptomsChanges in lung functionsChanges in lung functions(Castro-Rodriguezetal.Pediatrics2009;123:519-525)45%48%37%7%P0.001TherewasnodifferenceineffectsTherewasnodif
39、ferenceineffectsbetweenbetween:InfantsandpreschoolersAtopicversusnon-atopic(Similarresult:Allergolimunopat2010;38(1):31-6)MDI(spacer)versusnebulizerAsthma Management for Young Children2.341.600123Montelukast4mg(n=265)Placebo(n=257)Wheezingepisodesrate/year32%p 0.001Bisgaard H et al Am J Respir Crit
40、Care Med 2003;171:315322.ExacerbationsNoeffectonPrednisoloneuseHospitalizationsDurationofexacerbationSeverityofexacerbationDayswithoutasthmaMontelukast in pre-school Children PatientDemographicsPatientDemographicsStudydurationStudyduration24weeks24weeksRandomized/CompletedRandomized/Completed979/745
41、979/745Males/FemalesMales/Females58/42%58/42%MeanageMeanage88monthsmonthsPrimaryendpointPrimaryendpoint PercentagesymptomfreedaysPercentagesymptomfreedaysSecondaryendpointSecondaryendpointPercentagebronchiolitisfreedaysPercentagebronchiolitisfreedays SymptomfreedaysSymptomfreedaysCoughfreedaysCoughf
42、reedaysSymptomscoresSymptomscoresRescuefreedaysRescuefreedaysSystemicsteroiduse,exacerbations,health-careusSystemicsteroiduse,exacerbations,health-careusBisgaard H et al.AmJRespirCritCareMed2008;(178)85486.Montelukast in pre-school Children Nostatisticallysignificanteffectsonanyoftheoutcomesmeasured
43、Post-bronchioliticwheezePost-bronchioliticwheezeChildrenTreatment of Preschool-Childen(Szefler et al JACI 2007:120:1043-50)OneyearcomparisonofMontelukastandBudesonideOneyearcomparisonofMontelukastandBudesonideNebulizerin395childrenaged25yearsNebulizerin395childrenaged25yearsBudesonideMontelukastBUDb
44、etterthanMontwithrespectto:Timetoadditionalmedicationsduringfirst3months(p0.05)Exacerbationsover1year(p0.05)NoofpatientstreatedwithOralsteroids(p0.05)Peakexpiratoryflow(p0.05)Physicianglobalassessment(p0.05)Caregiverglobalassessment(p0.05)*If symptom control is poor and/or exacerbations persist desp
45、ite 3 months of adequate controller therapy, check the following before any step up in treatment is considered. Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition. Refer for expert assessment if the diagnosis is in doubt.Check and correct inhaler technique
46、.Confirm good adherence with the prescribed dose.Enquire about risk factors such as allergen or tobacco smoke exposureBefore stepping-up of controller treatmentBefore stepping-up of controller treatmentGINA 2014 Children 5 years and YoungerIntermittenttreatmentduringexacerbationsOralsteroids:Conflic
47、tingevidencesomeeffects?Threecoursesoforalsteroids(ever)isassociatedwithincreasedriskoffractureandadverseeffectsonbonemineraldensityLeukotrieneModifiers:Conflictingevidencesmalleffects?Inhaledsteroids:Conflictingevidencesmalleffects?1500gFP/dayreducesexacerbationsby40%,butthisregimenisassociatedwith
48、adverseeffectsongrowthandbonesManagingAsthmainPre-schoolChildrenRatherdiscouraging!Growth during intermittent treatment Growth during intermittent treatment of ICS in pre-school childrenof ICS in pre-school children(Durcharme FM et al N Engl J Med 2009;360:339-53)Cm/yearPlaceboFP1500gintermittently6
49、.566.23P0.05kg/yearPlaceboFP1500gintermittently2.171.53P5m()MMAD5m()SedimentationSedimentation(MMAD3m)(MMAD3m)DiffusionDiffusion(MMAD1.5m)(MMAD1.5m)AdultChildAgeInhalation therapyDeposition pattern of Nebulized budesonideDeposition pattern of Nebulized budesonide020406080% of dose to the patientAdul
50、tsChildrenLungsOropharynx AUC per mg inhaled dose0510152025(nmol/lh)(Agertoft, Arch Dis Child 1999;80:241-247)The same dose of BUD resulted in the same degree of systemicexposure in adults and 3 - 5 years old childrenIV infusionAgertoft & Pedersen. Am J Respir Crit Care Med. 2003, 1;168(7):779-782.I
51、nhaled corticosteroidsBudesonide was eliminated significantly faster from the systemic circulationthan fluticasoneMeta-analysis: 21 studies Meta-analysis: 21 studies Dose of Corticosteroids, mg/dSuppression of Urinary Cortisol, %Lipworth. Arch Intern Med 1999;159:941-55.1008060402000.20.40.81.62.0Fl
52、uticasoneBeclomethasoneTriamcinoloneBudesonideComparison of Inhaled SteroidsBudesonide had low systemic effects even rather high daily dosesHealth Resource UtilizationHealth Resource Utilization01020304050EmergencyDepartment VisitsUrgent Care VisitsEmergency Department or Urgent Care VisitsPercent o
53、f Children *P= 0.06*P.05; *P.01 vs nebulized cromolyn sodium.Nebulized BUD Nebulized Cromolyn SodiumNebulized Budesonide(Leflein, Pediatrics 2002;109(5):866-872)SummaryCompared with cromolyn sodium, nebulized budesonide demonstrated:Significantly longer times to first exacerbation and first use of a
54、dditional chronic asthma therapySignificantly fewer days of breakthrough medication use Significantly greater improvements in nighttime and daytime asthma symptom scoresSignificantly less health resource utilizationNebulized Budesonide(Leflein, Pediatrics 2002;109(5):866-872)GC-receptorBudesonidelip
55、olysisNucleusCellMiller-Larsson et al. 1998 and Wieslander et al. 1997Esterification of BudesonideBudesonide esters INACTIVEesterifi-cation26241101001,00010,000Time (hrs)pmol/gBudesonideBudesonide oleate/palmitateFluticasone* p0.001 Nasal Biopsy Concentrations Single Doses of Bud and FP to 24 health
56、y subjectsSingle Doses of Bud and FP to 24 healthy subjects Petersen et al, Petersen et al, Br. J. PharmacolBr. J. Pharmacol 51:159-163, 2001 51:159-163, 2001Budesonide had was present in the biopsies after 24 hoursImportant for once daily dosingSzefler S and Eigen H J. Allergy Clin Immunol 2002;109
57、:730-42Nebulized BudesonideMean improvement in nighttime and daytime Mean improvement in nighttime and daytime asthma symptoms in 3 the double-blind studies.asthma symptoms in 3 the double-blind studies.Szefler S and Eigen H J. Allergy Clin Immunol 2002;109:730-42Nebulized BudesonideMean number of d
58、ays with rescue Mean number of days with rescue use per two week perioduse per two week periodBasal and ACTH-stimulated cortisol levels atBasal and ACTH-stimulated cortisol levels atfrom 3 the double-blind studies.from 3 the double-blind studies.Szefler S and Eigen H J. Allergy Clin Immunol 2002;109
59、:730-42Nebulized BudesonideAdvantages of Nebulized Delivery Minimal cooperation and coordination May use while sleeping Higher drug doses possible Allows child to breathe at own rhythm No propellantInhalation TherapyDisadvantages of Nebulized Delivery Requires power source More expensiveSome trainin
60、g necessaryMaintenance requiredMore time consuming Once daily dosing reduces daily timeInhalation TherapySummaryBudesonide is one of the most studied ICS in childrenNo other ICS has so many long-term safety data Most ages from 1 to 20 years have data on:Clinical efficacyPharmacokineticsLung deposition of drugPharmaco-economicsLifestyle on and off treatmentSafety (cataracts, cortisol excretion in urine, growth and bone mineral density)Budesonide studies in children
