1、Sren PedersenUniversity of Southern DenmarkKolding HospitalMost of the symptoms are not specific for asthmaParents do not report wheezeuntil lung function is reducedby around 50%GINA 2014 Children 5 years and Younger Outcome of Childhood AsthmaMildModerateSevere70%symptom free as adults30%30%symptom
2、 free as adults70%Marked tracking of asthma severitybetween childhood and adult lifeFor intervention strategies that include allergen avoidance:Strategies directed at a single allergen have not been effective Multifaceted strategies may be effective,but the essential components have not been identif
3、ied Current recommendations,based on high quality evidence or consensus,include:Avoid exposure to environmental tobacco smoke during pregnancy and the first year of life Encourage vaginal delivery Advise breast-feeding for its general health benefits(not necessarily for asthma prevention)Where possi
4、ble,avoid use of paracetamol(acetaminophen)and broad-spectrum antibiotics during the first year of life Primary Prevention of Asthma0123456789101112-1.2-1.0-0.80.60.40.20.00.20.4NeverTranient earlyLate onsetPersistent*p0.05 vs.neverp0.05 vs.latep 4%Sensitized toInhaled AllergensSensitized to FoodAll
5、ergens*by history of MD diagnosis Age 2-3 years old frequent wheeze 1 major or 2 minor criteria:Likelihood of Asthma77%PPV97%SpecificityThis is a verysmall proportionof the cohortThe majority withschool age asthma do not belong tothis group Managing Asthma in Pre-school Children Starts during first
6、two years Disappeared(retrospectively)by age 6 Pattern:Episodic or multiple trigger Symptoms starts after age 3 Pattern:Episodic or multiple trigger Symptoms beyond age 6(retrospectively)Pattern:Episodic or multiple trigger Wheezing during discrete time periods No symptoms between attacks Normally a
7、ssociated with a viral cold Each episode normally short(one week)The episodes can be mild,moderate or severe Wheezing that shows discrete exacerbations Symptoms between episodes GINA 2014 Children 5 years and Younger(Brand PLP et al ERJ 2010;38:1096-1110)Martinez.J Allergy Clin Immunol 1999;104:S169
8、-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 clear-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 classif
9、ied into episodic(viral)wheeze or multiple trigger wheeze based on retrospective questionnaire,the classification is likely to change 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
10、 Respir J.2014 Apr;43(4):1172-7.Asthma Management for Young ChildrenThere is little evidence that the EVW and MTW phenotypes 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 rela
11、tively poor predictor of long-term outcome(transient versus persistent wheeze).Frequency and severity of wheezing episodes 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“T
12、he distinction between Episodic Viral Wheeze and Multiple Trigger Wheeze is more a marker of disease severity than of different clinical phenotypes”Garcia-Marcos L,Martinez FD:J Allergy Clin Immunol 2010;126:489-490Asthma Management for Young ChildrenNoEpisodic(Viral)Wheeze Multiple triggerwheezeAst
13、hma Management for Young ChildrenIt is not possible to break the patients down into mutually exclusive subgroups that remain consistent over time.Often the various differences are quantitative rather than qualitative.Which symptom pattern may suggest asthma?Characteristic for asthmaCoughRecurrent or
14、 persistent non productive 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
15、,laughing,crying 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 f
16、amily 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 Childr
17、enAny 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 re
18、spond 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 GINA 2014 Children 5 years and Younger Recurrent wheezing occurs in a large proportion of childr
19、en 5 years and younger,typically with viral upper respiratory tract infections.Deciding when this is the initial presentation of asthma is difficultPrevious classifications of wheezing phenotypes(episodic wheeze and multiple-trigger wheeze;or transient wheeze,persistent wheeze and late-onset wheeze)
20、do not appear to represent stable phenotypes,and their clinical usefulness is uncertain A diagnosis of asthma in young children with 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
21、 should be treated A history of other allergic disease(eczema or allergic rhinitis)or asthma in first-degree relatives Clinical improvement during 23 months of controller treatment,and worsening after cessationAsthma Management for Young ChildrenWho should be treated?Frequency and/or intensity of in
22、terval symptoms Intensity and/or frequency of exacerbationsMild or rare Frequent or severe Frequent or severe Mild or rareGINA 2014 Children 5 years and YoungerTreatment should be decided on frequency and severity of symptoms and exacerbations rather than phenotypesTo achieve good control of symptom
23、s and maintain normal activity levels To minimize the risk of future asthma flare-ups,impaired lung development 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 develo
24、pment.It is important to also elicit the goals of the parent/carer,as these may differ from conventional medical goals.GINA 2014 Children 5 years and YoungerRisk factors for asthma exacerbations within the next few months Uncontrolled asthma symptoms One or more severe exacerbation in previous year
25、The start of the childs usual flare-up season(especially if autumn/fall)Exposures:tobacco smoke;indoor or outdoor air pollution;indoor allergens(e.g.House dust mite,cockroach,pets,mold and viral infection)Major psychological or socio-economic problems for child or family Poor adherence with controll
26、er medication,or incorrect inhaler technique Risk factors for fixed airflow limitation Severe asthma with several hospitalizations History of bronchiolitis Risk factors for medication side-effects Systemic:Frequent courses of OCS;high-dose and/or potent ICS GINA 2014 Children 5 years and YoungerIn t
27、he 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 No None of these12 of these34 of these Any activity limitation due to asthma?(Runs/plays less than other children,tires easily during walks/pla
28、ying?)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 and YoungerWhich medications?(Castro-Rodriguez et al.Pediatrics 2009;123:519-525)Significant reductions were seen in children with a diagnosis of whe
29、eze as well as and asthma,but the magnitude was greater in asthma RR 0.76(0.58-0.99)(P=0.04)(Castro-Rodriguez et al.Pediatrics 2009;123:519-525)45%48%37%7%P0.001:Infants and preschoolersAtopic versus non-atopic(Similar result:Allergol imunopat 2010;38(1):31-6)MDI(spacer)versus nebulizerAsthma Manage
30、ment for Young Children2.342.341.601.600 01 12 23 3Montelukast 4 mg Montelukast 4 mg(n=265)(n=265)Placebo Placebo(n=257)(n=257)WheezingWheezingepisodesepisodesrate/yearrate/year32%32%p p 0.0010.001Bisgaard H et al Am J Respir Crit Care Med 2003;171:315322.Prednisolone useHospitalizationsDuration of
31、exacerbationSeverity of exacerbationDays without asthmaMontelukast in pre-school Children Bisgaard H et al.Am J Respir Crit Care Med 2008;(178)85486.No statistically significant effects on any of the outcomes measured ChildrenTreatment of Preschool-Childen(Szefler et al JACI 2007:120:1043-50)Budeson
32、ideBudesonide MontelukastMontelukastBUD better than Montwith respect to:Time to additional medicationsduring first 3 months(p0.05)Exacerbations over 1 year(p0.05)No of patients treated withOral steroids(p0.05)Peak expiratory flow(p0.05)Physician global assessment(p0.05)Caregiver global assessment(p0
33、.05)*If symptom control is poor and/or exacerbations persist despite 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
34、 the diagnosis is in doubt.Check and correct inhaler technique.Confirm good adherence with the prescribed dose.Enquire about risk factors such as allergen or tobacco smoke exposureGINA 2014 Children 5 years and Younger Oral steroids:Conflicting evidence some effects?Three courses of oral steroids (e
35、ver)is associated with increased risk of fracture and adverse effects on bone mineral density Leukotriene Modifiers:Conflicting evidence small effects?Inhaled steroids:Conflicting evidence small effects?1500 g FP/day reduces exacerbations by 40%,but this regimen is associated with adverse effects on
36、 growth and bones Managing Asthma in Pre-school ChildrenManaging Asthma in Pre-school ChildrenRather discouraging!(Durcharme FM et al N Engl J Med 2009;360:339-53)Cm/yearPlaceboFP1500gintermittently6.566.23P0.05kg/yearPlaceboFP1500gintermittently2.171.53P0.05Changes in height correlated significantl
37、y with the cumulative ICS dose Adverse effectsMore studies are needed on the safety aspectsof intermittent high doses of ICS Although practiced in some parts of the world,the evidence to support the initiation of oral corticosteroid(OCS)or high doses of ICS by the family in the home management of as
38、thma exacerbations in children is weak.The treatments have a high potential for side-effects,especially if the treatment is continued inappropriately or is given frequently.Family-administered OCS or high dose ICS should be considered only where the health care provider is confident that the medicat
39、ions will be used appropriately,and the child is closely monitored for side-effects.GINA 2014 Children 5 years and Younger Inhaled steroids have been most extensively studied Significant effects have been demonstrated on several outcomes in several subgroups of children.The effect maybe around 25%sm
40、aller in children with episodic viral wheezeMontelukast is less well studied Significant effects have been demonstrated on uncontrolled,multiple trigger wheeze whereas there is no/little effect on other kinds of wheezeIntermittent early treatment of acute episodes of virally induced wheeze has littl
41、e or no effect Clinically in it not possible to reliably predict which patients will respond to regular treatment Treating one group only (High risk,multiple trigger)will lead to under-treatmentOften a short clinical trial with ICS has to be tried to help assessing who will benefitAsthma Treatment D
42、rug Deposition in the AirwaysAdultChildAgeInhalation therapy020406080%of dose to the patientAdultsChildrenLungsOropharynx 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 ol
43、d childrenAgertoft&Pedersen.Am J Respir Crit Care Med.2003,1;168(7):779-782.Inhaled corticosteroidsBudesonide was eliminated significantly faster from the systemic circulationthan fluticasoneDose of Corticosteroids,mg/dSuppression of Urinary Cortisol,%Lipworth.Arch Intern Med 1999;159:941-55.1008060
44、402000.20.40.81.62.0FluticasoneBeclomethasoneTriamcinoloneBudesonideComparison of Inhaled SteroidsBudesonide had low systemic effects even rather high daily doses01020304050EmergencyDepartment VisitsUrgent Care VisitsEmergency Department or Urgent Care VisitsPercent of Children*P=0.06*P.05;*P.01 vs
45、nebulized cromolyn sodium.Nebulized BUD Nebulized Cromolyn SodiumNebulized Budesonide(Leflein,Pediatrics 2002;109(5):866-872)Compared with cromolyn sodium,nebulized budesonide demonstrated:Significantly longer times to first exacerbation and first use of additional chronic asthma therapySignificantl
46、y 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-receptorBudesonidelipolysisNucleusCellMiller-Larsson et al.1998 an
47、d Wieslander et al.1997Esterification of BudesonideBudesonide esters INACTIVEesterifi-cation26241101001,00010,000Time(hrs)pmol/gBudesonideBudesonide oleate/palmitateFluticasone*p0.001Budesonide had was present in the biopsies after 24 hoursImportant for once daily dosingSzefler S and Eigen H J.Aller
48、gy Clin Immunol 2002;109:730-42Nebulized BudesonideSzefler S and Eigen H J.Allergy Clin Immunol 2002;109:730-42Nebulized BudesonideSzefler S and Eigen H J.Allergy Clin Immunol 2002;109:730-42Nebulized Budesonide Minimal cooperation and coordination May use while sleeping Higher drug doses possible A
49、llows child to breathe at own rhythm No propellantInhalation Therapy Requires power source More expensiveSome training necessaryMaintenance requiredMore time consuming Once daily dosing reduces daily timeInhalation TherapyBudesonide 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
