diego peroni-pisa - fimp federazione italiana medici pediatri · gina 2015, box 6-5 (3/8) respiro...

Diego Peroni-Pisa

“Qualcosa è cambiato?? Steroidi Inalatori e Orali

Antistaminici - Antileucotrienici”

Definition, assessment and treatment of wheezing disorders

in preschool children: an evidence-based approach

Brand: Eur Respir J 2008; 32: 1096

Episodic

(viral)

wheeze

clinical evidence of a viral respiratory tract infection

Multiple-trigger

wheeze

Children who wheeze

intermittently and are

well between episodes

Triggers: viruses

Wheeze both during and

between exacerbations

Triggers: viruses, smoke,

allergenes, exercise

WHEEZING PHENOTYPES

based on “temporal pattern”

Episodic

Viral

Wheeze

Brand: Eur Respir J 2008; 32: 1096

Multiple Trigger Wheeze

http://images.google.it/imgres?imgurl=http://www.remcomp.fr/asmanet/school/images/logoers.gif&imgrefurl=http://www.remcomp.fr/asmanet/school/school99-sa.html&h=143&w=108&sz=2&hl=it&start=6&tbnid=3CxNnKpAKjYQxM:&tbnh=94&tbnw=71&prev=/images?q=european+respiratory+society&gbv=2&svnum=10&hl=it

FREQUENCY SEVERITY

Indications to MAINTENANCE THERAPY:

)

• frequent symptoms (on most days of the week)

• frequent or severe acute episodes

2014

Brand: ERJ 2014; 43: 1172

Classification and pharmacological treatment of preschool

wheezing: changes since 2008 Brand: Eur Respir J 2014; 43: 1172

The distinction between

EVW and MTW is not clear

in all patients

Symptom patterns change

over time in many patients

Severity and frequency

of episodes are stronger

predictors of long-term

outcome

Maintenance therapy:

ICS or Montelukast

Maintenance therapy:

INHALED STEROIDS (ICS

(up to 400 mcg Beclomethasone or equivalent)

Any treatment given should: • be viewed as a terapeutic trial (2-3-months) • discontinued if no benefit • and the child investigated further Brand: ERJ 2014; 43: 1172 GINA 2014

Episodic

Viral

Wheeze

Multiple Trigger Wheeze

Probabilità di diagnosi d’asma o risposta al

trattamento per asma nei bambini con ≤5 anni

GINA 2015, Box 6-1 (1/2)

Proporzione dei bambini con respiro sibilante indotto da infezioni virali che rispecchiano questo pattern di sintomi

Proporzione di bambini con respiro sibilante indotto da infezione virale che possono avere diagnosi di asma o rispondere a trattamenti di controllo, basati su questo pattern di sintomi

Pattern di sintomi Può cambiare nel tempo

Sintomi (tosse, respiro sibilante, respirazione pesante) per <10

giorni durante infezione delle alte vie respiratorie

________

2-3 episodi all’anno

________

Nessun sintomo nell’intervallo temporale tra un episodio e l’altro

Sintomi (tosse, respiro sibilante, respiro pesante) per <10 giorni durante infezione delle alte vie

respiratorie ________

>3 episodi all’anno, o episodi severi e/o peggioramenti notturni

________

Il bambino potrebbe avere tosse occasionale, respiro sibilante o

respirazione pesante nell’intervallo temporale tra un episodio e l’altro

Sintomi (tosse, respiro sibilante, respiro pesante) per <10 giorni durante infezione delle alte vie

respiratorie ________

>3 episodi all’anno, o episodi severi e/o peggioramenti notturni

________

Tra un espisodio e l’altro il bambino potrebbe avere tosse occasionale, respiro sibilante o

respirazione pesante durante il gioco o quando ride

________

Atopia, o storia familiare di asma

Features suggesting asthma in children ≤5 years

Feature Characteristics suggesting asthma

Cough Recurrent or persistent non-productive cough that may be worse at night or accompanied by some wheezing and breathing difficulties. Cough occurring with exercise, laughing, crying or exposure to tobacco smoke in the absence of an apparent respiratory infection

Wheezing Recurrent wheezing, including during sleep or with triggers such as activity, laughing, crying or exposure to tobacco smoke or air pollution

Difficult or heavy breathing or shortness of breath

Occurring with exercise, laughing, or crying

Reduced activity Not running, playing or laughing at the same intensity as other children; tires earlier during walks (wants to be carried)

Past or family history Other allergic disease (atopic dermatitis or allergic rhinitis) Asthma in first-degree relatives

Therapeutic trial with low dose ICS and as-needed SABA

Clinical improvement during 2–3 months of controller treatment and worsening when treatment is stopped

GINA 2014, Box 6-2

Ciclo di gestione dell’asma basato sul controllo nei bambini ≤5 anni

GINA 2015, Box 3-2

Diagnosi Controllo dei sintomi e fattori di rischio (incluso la funzionalità respiratoria)

Tecnica inalatoria e aderenza terapeutica

Preferenze dei genitori

Farmaci per asma

Strategie non farmacologiche

Trattamento dei fattori di rischio modificabili

Sintomi

Riacutizzazioni

Effetti collaterali

Soddisfazione dei genitori

Approccio terapeutico graduale (a step) per il controllo dei sintomi e la riduzione dei

rischi (bambini ≤5 anni)

GINA 2015, Box 6-5 (3/8)

Respiro sibilante

infrequente e

nessun periodo

sintomatico

Pattern sintomatologico corrispondente ad asma con sintomi non ben controllati, o più di 3 riacutizzazioni in un anno. Pattern sintomatologico non corrispondente ad asma ma ma respiro sibilante frequente, per esempio ogni 6-8 settimane. Trial diagnostico per 3 mesi.

Diagnosi di asma e asma

non controllata con basse

dosi di ICS

Asma non

controllata

con ICS

doppio

Controllare la diagnosi, la tecnica

inalatoria, l’aderenza terapeutica e

l’esposizione inquinanti o fumo

CONSIDERARE QUESTO STEP PER

BAMBINI CON

FARMACI AL BISOGNO

Altre opzioni

di controllo

FARMACI DI CONTROLLO DI PRIMA SCELTA

SABA secondo necessità (in tutti i bambini)

Antagonista del recettore dei leucotrieni (LTA)

ICS intermittente Bassa dose ICS+LTRA Aggiungere LTRA

Aggiungere ICS

intermittente

Bassa dose di ICS giornaliera

Bassa dose ICS

doppia

Continuare i

controlli e

rivolgersi ad

uno specialista

per la gestione

STEP 1 STEP 2 STEP 3

STEP 4

What Drives Prescribing of Asthma Medication to Preschool Wheezing Children? A Primary Care Study. Montella S, Pediatric Pulmonology 48:1160–1170 (2013)

A cross-sectional study at 32 PCPs sites in Campania, Italy. Medical, family, and environmental information of 376 preschool wheezy children, and characteristics of the enrolled PCPs were collected. Main outcome measures of multilevel multivariate logistic regression analyses were the prescribing of maintenance treatment, and the prescription of a combined therapy as opposed to monotherapy


Stepwise-Built, Multivariate, Multilevel, Logistic Regression Analysis of Anti-Inflammatory Therapy Prescription Taking Into Account Child, Family, Environmental, and PCP Characteristics


Stepwise-Built, Multivariate, Multilevel, Logistic Regression Analysis of Anti-Inflammatory combined Therapy versus monotherapy Taking Into Account Child, Family, Environmental, and PCP Characteristics

Diego Peroni-Pisa



45%

FP Placebo

60 - 50 – 40 – 30 – 20 – 10 – 0

25%

% increase in days without symptoms

305 ch (12-47 mo.)

Fluticasone 100 µg MDI x 2 with spacer vs placebo

4 week run-in 12 wks treatment

54%

FP

35%

in ch with frequent symptoms (>3 days/wk)

during run-in

in ch with a FH of asthma

Placebo

p = 0.005

p = 0.002

Response of preschool children with asthma symptoms to fluticasone propionate.

Roorda RJ, JACI 2001;108(4):540-6.

Long-Term Inhaled Corticosteroids in Preschool Children at High Risk for Asthma Guilbert: N Engl J Med 2006;354:1985-97.

Significantly increased proportion of episode-free days 93.2% vs. 88.4% ( P = 0.006).

No increase in proportion of episode-free days 86.8% vs. 85.9% ( P = 0.78)

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young Children

Ducharme NEJM 2009;360:339

• 129 children 1 to 6 ys

• to receive 750 μg of fluticasone propionate or placebo x2

• beginning at the onset of an upper respiratory tract infection

• Continuing for 10 days, over a period of 6 to 12 months Placebo

Treatment with rescue systemic corticosteroids in

% of upper respiratory infections

ICS

8%

18% OR 0.49

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young






Treatment with rescue systemic corticosteroids in

% of upper respiratory infections

Fluticasone

8%

18% OR 0.49

In ICS treated children:

-symptoms milder and of shorter duration;

-fewer days of albuterol

use

-less negative effect on their parents’ quality of

life.

Preemptive Use of High-Dose Fluticasone for Virus-Induced Wheezing in Young






gains from baseline in height

in cm

Fluticasone

6,23 6,59

Difference between groups in z score from baseline to end

point, −0.24 [95% CI, −0.40 to −0.08])

Relative Risk For Requirement of Oral

Steroids 5 randomized controlled trials in children with a hystory of mild episodic viral wheeze

most of the children had previously required no or infrequent oral corticosteroids and had very infrequent hospital admissions.

Inhaled steroids for episodic viral wheeze of childhood. McKean M, Cochrane Database Syst Rev. 2000

0.53

1.0 –

0.5 –

0.0 Episodic

high dose ICS (1.6-2.25 mg/day)

Maintenance low-dose ICS

(400 µg/day)

0.82

Markers of Differential Response to Inhaled Corticosteroid Treatment among Children with Mild Persistent Asthma. Gerald, JACI pract 2015 ; 3(4): 540

Children age 6-18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 mcg of beclomethasone twice daily. Rescue treatment consisted of 40 mcg beclomethasone accompanying each symptom-driven albuterol actuation

Mean Change in Asthma Control Days among Participants Treated with a Daily Inhaled Corticosteroid

Intermittent versus daily inhaled corticosteroids for

persistent asthma in children and adults

Chauhan: Cochrane Database of Systematic Reviews 2012, 12: CD009611

Paediatic studies:

Papi: Allergy 2009;64:1463–71

Turpeinen: Arch Dis Child

2008;93:654–9.

Zeiger: NEJM 2011;365:1990

Martinez: Lancet 2011;377:650–7

The duration of intervention

varied from 12 to 52 weeks




Intermittent ICS group vs Daily ICS group: significant differences

Improvement

from

baseline

PEFR (%)

symptom

-free

days

(n)

asthma

control

days

(n)

rescue

b2-agonists

(puffs/day)

FeNO

(ppb)

+

- -2.56% -0.15

0.12

-9%

16.8




Intermittent and daily ICS strategies did not significantly differ in:

use of rescue oral corticosteroids

rate of severe adverse health events

neither did

they reach

equivalence

Daily ICS was superior to intermittent ICS in:

lung function

airway inflammation

asthma control

reliever use

A modest growth suppression was associated with daily, compared

to intermittent, ICS (BUD & BDP)

Daily vs. intermittent inhaled corticosteroids for recurrent wheezing

and mild persistent asthma: A systematic review with meta-analysis

Rodrigo: Respir Med 2013; 107:1133

Systematic review of randomized,

placebo-controlled trials with:

a minimum of 8weeks of daily

(daily ICS with rescue SABA during

exacerbations)

vs.

intermittent ICS (ICS plus

SABA at the onset of symptoms

Primary outcome: asthma exacerbations;

Secondary outcomes: lung function,

symptoms, days without symptoms,

SABA use, corticosteroids use, days without

rescue medication use,

expired nitric oxide and serious adverse

events.

Rate of exacerbations








exacerbations)

vs.









events.

percent asthma free days

mean change in rescue medication








exacerbations)

vs.









events.

percent asthma free days

mean change in rescue medication

this study suggests not to change

daily for intermittent ICS use among

preschoolers, children with persistent

wheezing and adults with mild-to

moderate stable persistent asthma

This is not a table of equivalence

A low daily dose is defined as the dose that has not been associated with clinically adverse effects in trials that included measures of safety

‘Low dose’ inhaled corticosteroids (mcg/day) for children ≤5 years

GINA 2014, Box 6-6

Inhaled corticosteroid Low daily dose (mcg)

Beclometasone dipropionate (HFA) 100

Budesonide (pMDI + spacer) 200

Budesonide (nebulizer) 500

Fluticasone propionate (HFA) 100

Ciclesonide 160

Mometasone furoate Not studied below age 4 years

Triamcinolone acetonide Not studied in this age group

Low, medium and high dose inhaled corticosteroids Children 6–11 years

This is not a table of equivalence, but of estimated clinical comparability

Most of the clinical benefit from ICS is seen at low doses

High doses are arbitrary, but for most ICS are those that, with prolonged use, are associated with increased risk of systemic side-effects

Inhaled corticosteroid Total daily dose (mcg) Low Medium High

Beclometasone dipropionate (CFC) 100–200 >200–400 >400

Beclometasone dipropionate (HFA) 50–100 >100–200 >200

Budesonide (DPI) 100–200 >200–400 >400

Budesonide (nebules) 250–500 >500–1000 >1000

Ciclesonide (HFA) 80 >80–160 >160

Fluticasone propionate (DPI) 100–200 >200–400 >400

Fluticasone propionate (HFA) 100–200 >200–500 >500

Mometasone furoate 110 ≥220–<440 ≥440

Triamcinolone acetonide 400–800 >800–1200 >1200

GINA 2014, Box 3-6 (2/2)

Low, medium and high dose inhaled corticosteroids Adults and adolescents (≥12 years)

This is not a table of equivalence, but of estimated clinical comparability

Most of the clinical benefit from ICS is seen at low doses

High doses are arbitrary, but for most ICS are those that, with prolonged use, are associated with increased risk of systemic side-effects

Inhaled corticosteroid Total daily dose (mcg)

Low Medium High

Beclometasone dipropionate (CFC) 200–500 >500–1000 >1000

Beclometasone dipropionate (HFA) 100–200 >200–400 >400

Budesonide (DPI) 200–400 >400–800 >800

Ciclesonide (HFA) 80–160 >160–320 >320

Fluticasone propionate (DPI or HFA) 100–250 >250–500 >500

Mometasone furoate 110–220 >220–440 >440

Triamcinolone acetonide 400–1000 >1000–2000 >2000

GINA 2014, Box 3-6 (1/2)

Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled

randomized trial Busse W, Allergy 2014;69:1522

24-week placebo-controlled study

351 patients (aged ≥12 years; uncontrolled by non-ICS therapy) randomized to treatment (1 : 1 : 1) with once-daily Fluticasone Furoate* 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo

Repeated measures analysis of mean change from

baseline in trough FEV1

* Longer duration of action in vitro vs FP

* Longer duration of action in vitro vs FP

Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled

randomized trial Busse W, Allergy 2014;69:1522

24-week placebo-controlled study

351 patients (aged ≥12 years; uncontrolled by non-ICS therapy) randomized to treatment (1 : 1 : 1) with once-daily Fluticasone Furoate 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo

Repeated measures analysis of mean change from

baseline in trough FEV1 FP 100 mcg twice daily improved evening FEV1

in patients with mild-to-moderate

persistent asthma, but FF 50 mcg once daily did not

demonstrate a significant effect

Authors’ conclusions

Current evidence does not support increasing the dose of ICS as

part of a self initiated action plan to treat exacerbations in

adults and children with mild to moderate asthma. Increased ICS

dose is not associated with a statistically significant reduction in the

odds of requiring rescue oral corticosteroids for the exacerbation,

or of having adverse events, compared with a stable ICS dose.

Kew KM, Quinn M, Quon BS, Ducharme FM. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD007524

Targeting the small airways asthma phenotype: if we can reach it, should we treat it? B. Lipworth, Ann Allergy Asthma Immunol 2013;110: 233

There is an unmet need in current asthma guidelines for those individuals who exhibit the small airways asthma phenotype with a preserved FEV1 second but abnormal forced midexpiratory flow and peripheral airway resistance, which tends to be associated with poorer control.

Extrafine hydrofluoroalkane solution formulations of inhaled corticosteroid either alone or in combination with long-acting β-agonist may improve small airways outcomes and associated control.

It makes sense to try to deliver asthma treatment to more of the lung to improve clinical outcomes, especially in patients who exhibit the small airways asthma phenotype.

Real-life comparison of beclometasone dipropionate as an extrafine- or larger-particle formulation for asthma. D. Price, Respiratory Medicine (2013) 107, 987

Retrospective matched cohort study including primary care patients with asthma (ages 12-60 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n 11,289) or switched from another ICS without dose change

Real-life comparison of beclometasone dipropionate as an extrafine- or larger-particle formulation for asthma. D. Price, Respiratory Medicine (2013) 107, 987

Retrospective matched cohort study including primary care patients with asthma (ages 12e60 and non-smokers 61e80 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n Z 11,289) or switched from another ICS without dose change

The odds of no loss of asthma control (no asthma-related hospital

attendance, consultation for lower respiratory tract infection,

or oral corticosteroids) were significantly higher in

the extrafine beclometasone cohorts of both initiation population

Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study. Martin, Primary Care Respiratory Medicine (2014) 24, 14081

retrospective matched cohort analyses used large electronic databases to study asthma-related outcomes for patients in the UK (12–60 years old; n=1730) and US (12–80 years; n = 10,312) prescribed extrafine beclomethasone or fluticasone as their first ICS therapy for asthma. Patients were matched on demographic characteristics and asthma severity during 1 baseline year, and asthma control and asthma-related costs were compared during 1 outcome year

The odds of overall control (no hospitalisation or oral steroids for asthma, no antibiotics for lower respiratory infection, limited reliever use) were greater for extrafine ICS in both countries (UK odds ratio, 1.23; 95% confidence interval (CI), 1.01–1.50).

Asthma-related annual costs, adjusted for baseline, were significantly lower for extrafine-particle ICS cohorts in both countries (UK difference, − £66 (95% CI, − 93 to − 37)).

Cost-effectiveness analyses using the two measures of asthma control found 92 and 98% probabilities of extrafine-particle ICS being the preferred treatment strategy (less costly and more effective than standard size-particle ICS)

Cost-effectiveness of initiating extrafine- or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study. Martin, Primary Care Respiratory Medicine (2014) 24, 14081

Initiating ICS therapy for asthma as extrafine-particle ICS seems the dominant treatment option

(less costly and more effective) compared with

standard size-particle ICS in both the UK and the US.

Extra-fine particle inhaled corticosteroids with a median aerodynamic diameter < 2 um have been introduced in the treatment of asthma.

Systemic bioavailability of oral and pulmonary deposition of

extra-fine ciclesonide and beclomethasone dipropionate was 52% and 82%, the half-life in serum 3.2 and 1.5 h and first-pass hepatic metabolism >99% and 60%.

Ciclesonide pMDI 40, 80 and 160 ug/day caused no effects on

short-term lower leg growth rate as assessed by knemometry.

Extra-fine particle inhaled corticosteroids, pharma-cokinetics and systemic activity in children

with asthma. Wolthers OD. PAI 2016;27:13-21

Pharmacokinetics of extra-fine ciclesonide (CIC) and

beclomethasone dipropionate (BPD)

Des-CIC: des-isobutyrol-ciclesonide; 17-BMP: beclomethasone-17-

monopropionate. *The information is given in 2); no

specific data are available. **These are the only available data from studies in children (36, 37); see text for further references.



Effectiveness of Nebulized Beclomethasone in Preventing Viral Wheezing: An RCT Clavenna A., Pediatrics, 2014; 133:e505-12

521 children aged 1 to 5 yrs with at least 1 episode of viral wheezing in the last 12 months, presenting to any of 40 Italian pediatricians for an upper respiratory tract infection.

Randomly allocated to receive beclomethasone 400 mg or placebo twice daily for 10 days. Medications were administered through a nebulizer.

9.0%

% children with diagnosed wheezing

10 –

5 –

0




9.0%


10 –

5 –

0

With no statistically significant differences between

treatment groups.


Day-by-day overall

asthma-like symptom score

(mean and 95% CI)




9.0%


10 –

5 –

0

The findings from this study confirm that

inhaled steroids are not effective

in preventing recurrence

of viral wheezing.

Diego Peroni

“Qualcosa è cambiato?? Steroidi Inalatori e Effetti collaterali


In età prepubere, l’uso continuativo di dosi medio/alte di CSI

riduce la velocità di crescita in altezza durante i primi 1-2 anni di

terapia

Il decremento della velocità di crescita in altezza, sebbene non

progressivo né cumulativo, può persistere fino all’età adulta

Si raccomanda di usare la dose più bassa di CSI efficace per il

controllo dei sintomi, allo scopo di ridurne gli effetti sul

raggiungimento della altezza da adulti.

Effetti degli ICS sulla crescita in altezza del bambino

Kelly, N Engl J Med 2012 © 2013 PROGETTO LIBRA •

www.ginasma.it

Effect of Inhaled Glucocorticoids in Childhood on Adult Height. Kelly H, NEJM 2012, 367:904

adult height in 943 of 1041 participants (90.6%) in the CAMP study. adult height at age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive -400 μg of budesonide, -16 mg of nedocromil, or -placebo Daily for 4 to 6 years.

Effect of Inhaled Glucocorticoids in Childhood on Adult Height. Kelly H, NEJM 2012, 367:904

adult height in 943 of 1041 participants (90.6%) in the CAMP study. adult height at age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive -400 μg of budesonide, -16 mg of nedocromil, or -placebo Daily for 4 to 6 years.

In an intention-to-treat analysis of the growth suppressive

effect of long-term inhaled glucocorticoid therapy for asthma initiated in children between the ages of 5 and 13 years, we found that the height deficit observed at

1 to 2 years after treatment initiation persisted into adulthood, although the deficit was neither

progressive nor cumulative.

Height growth in children with asthma treated with guideline-recommended dosages of fluticasone and electronically assessed adherence. Wardenier, Arch Dis Child 2016;101:637

99 prepubertal children with asthma, 2–13 years of age, who had been using ICS in guideline-recommended dosages for ≥3 months, and continued to do so during 1-year follow-up. ICS adherence was assessed by electronic monitoring devices,

Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood

wheezing Sidoroff VH, Pediatr Pulmonol. 2015;50:1-7

Regular use of ICS for >6 months at age <6

years was associated with a lower BMD of the

lumbar spine.

In 89 children at 12.3

(median) yrs of age bone mineral density (BMD).

A prospective follow-up study after hospitalization for wheezing at <24 months of age.

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.derryimaging.com/body-map/bone-densitometry/&ei=kXsFVeWkN4i3PMeZgKgJ&psig=AFQjCNFSWYnMr5fstpTdcurVU6h1lUgTSQ&ust=1426509042018374

BMD values (g/cm2) in the lumbar spine

at the median age of 12.3 yrs in relation to the cumulative dose of inhaled corticosteroids (ICS)

used between 0-12.3 yrs of age. R2 Linear=0.030

In 89 children at 12.3 (median) yrs of age bone mineral density (BMD).

A prospective follow-up study after hospitalization for wheezing at <24 months of age.

Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood

wheezing Sidoroff VH, Pediatr Pulmonol. 2015;50:1-7

ICS use during childhood may be related to < BMD at late school age.

It is important to use the lowest possible

ICS dose that maintains adequate asthma control.

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.derryimaging.com/body-map/bone-densitometry/&ei=kXsFVeWkN4i3PMeZgKgJ&psig=AFQjCNFSWYnMr5fstpTdcurVU6h1lUgTSQ&ust=1426509042018374

Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use. Cavkaytar Eur J Pediatr (2015) 174:1421

Impact of Inhaled Corticosteroids on Growth in Children with Asthma: Systematic Review and Meta-Analysis. Locke, Plos One 2015

Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users.

Intranasal Triamcinolone and Growth Velocity. Skoner, Pediatrics 2015;135;e348 double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 mg) on the growth velocity (GV) of children aged 3–9 years with PAR by using stadiometry at baseline (4–6 months), during treatment (12 months), and at follow-up (2 months).

Intranasal Triamcinolone and Growth Velocity. Skoner, Pediatrics 2015;135;e348 double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 mg) on the growth velocity (GV) of children aged 3–9 years with PAR by using stadiometry at baseline (4–6 months), during treatment (12 months), and at follow-up (2 months).

By using rigorous Food and Drug Administration–recommended design

elements, this study detected a small, statistically significant

effect of TAA-AQ on the GV of children with PAR.

Inhaled corticosteroid and children’s growth Bush A, Arch Dis Child 2014;99:191-192

1) No one ever died because they fell 1 cm short of their potential final height, but many families understandably worry about the side effects of inhaled corticosteroids (ICS), and may stop ICS treatment in consequence.

2) Atopy per se may lead to delay in puberty and a more prolonged prepubertal growth deceleration; poorly controlled asthma, as with any chronic disease, may lead to growth failure; and coincidental disease such as growth hormone deficiency should be considered.

3) Accurate height measurement, with the results plotted on an appropriate centile chart is an essential part of the paediatric asthma clinic.

4) Children still do die of asthma attacks, which may result from nonadherence to treatment.

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=tojJ3RYN2ESwHM&tbnid=479n-aJW5c3C3M:&ved=&url=http://www.leidonnaweb.it/mamma/itemlist/tag/Bambino.html?start=10&ei=Ay4nU6H8IqSf0QX97oCgAw&psig=AFQjCNGRNkjNv-2nr3sLZRvHzHHQwWvX5Q&ust=1395163012116103

Is asthma overdiagnosed? A Bush Arch Dis Child 2016;101:688

Martin Luther likened human reason to a drunken man on horseback, alternately falling off to the left and then to the right. The same is true of diagnosing asthma; undoubtedly in the past it was underdiagnosed, but have we gone too far in the opposite direction? The evidence is that we have!

Overdiagnosis of asthma clearly matters. The fiscal cost of asthma medications is not trivial. Inhaled corticosteroids (ICS), when properly used, drastically improve quality of life and reduce the risk of asthma attacks and mortality. However they have side effects, including adrenal failure and growth suppression, with increasingly worrying evidence (mainly in adults) that they cause mucosal immunosuppression and an increased risk of respiratory infections. There is also evidence that systemic absorption of ICS depends not just on the prescribed dose, but is greater if the dose is inappropriately high

Diego Peroni



Median duration of hospitalization (hrs)

15 –

10 –

5 –

0

placebo prednisolone

13.9

11.0

ns

Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing

Panickar J, NEJM 2009;360:329

700 children (10-60 months) with an attack of wheezing associated with a viral infection 5-day course of oral prednisolone (10 mg once a day for children 10 to 24 months of age and 20 mg once a day for older children) compared with placebo

The implication of these two studies, involving more than 900 children, is that any preschool child with viral induced wheeze who is well enough to stay in the community should not be prescribed oral prednisolone, and many children admitted to hospital also should not be prescribed oral prednisolone. These studies, however, were undertaken in children with relatively mild symptoms and most were discharged from hospital in less than 24 hours, so what these studies do not tell us is whether prednisolone is indicated in really severe preschool viral wheeze. Bush A, BMJ 2014; February 4

2) Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing Panickar J, NEJM 2009;360:329

1) Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years:

randomised controlled trial. Oommen A, Lancet. 2003;362:1433.

Short- and long-term efficacy of prednisolone for first acute rhinovirus-induced wheezing episode

Jartti T, J Allergy Clin Immunol 2015; 135:691-98

Time to a new physician-confirmed wheezing episode in children randomized to receive prednisolone or placebo for their first rhinovirus-induced wheezing episode

According to rhinovirus load Total patients

*

*

*

*

No difference was found at the 2-month or 12-month time points

Children with a rhinovirus load of greater than 7000 copies/mL had significantly less recurrence at both time points in the prednisolone group compared with the placebo group.

Should a Preschool Child with Acute Episodic Wheeze be Treated with Oral Corticosteroids? A Pro/Con Debate

Beigelman A, JACI Pract 2016;4:27-35

Summary: How Do We End This Debate?

Most of the available data do not support the role of OCSs as a treatment for acute mild episodic wheeze.

However, we cannot recommend to completely abandon this traditional therapy.

OCSs should be given only to a subgroup of severely ill children in the inpatient setting.

We agree that clinicians may consider postponing OCS therapy, while providing supportive care and albuterol inhalations especially in the outpatient setting in otherwise healthy toddlers.

Should a Preschool Child with Acute Episodic Wheeze be Treated with Oral Corticosteroids? A Pro/Con Debate

Beigelman A, JACI Pract 2016;4:27-35

Summary: How Do We End This Debate? We cannot conclude that OCSs are not an effective therapy in

subgroup of hospitalized preschool children presenting with and/or progressing to severe exacerbation; therefore, these children with severe exacerbation based on clinical signs included in PRAM such as suprasternal retractions, scalene muscle contraction, chest air entry, wheezing, and oxygen saturation should be treated with OCSs.

Moreover, because it was never shown that OCSs are not effective in preschool children hospitalized in the intensive care unit or in children who have other chronic medical conditions, these children should be treated with OCSs.

Single-dose oral dexamethasone is effective in preventing

relapse after acute asthma exacerbations Watnick CS, Ann Allergy Asthma Immunol 2016;116:162

7.130 patients 3-17 yrs presenting to our tertiary care children’s hospital ED from January 2006 through December 2014 for acute asthma.

The institutional practice guideline transitioned from 2 mg/kg of prednisone or prednisolone for 3 to 5 days to single-dose dexamethasone (0.6 mg/kg, maximum 16 mg, SOLDESAM®) in the spring of 2014.

This dose of dexamethasone is approximately twice as potent as a 2 mg/kg dose of daily prednisone or prednisolone; however, as a long-acting corticosteroid, its effects last up to 3 days.



2.01%

% patients who returned ≤72 hours for continued asthma

symptoms 3.0 –

2.0 –

1.0 –

000

p=0.05

oral prednisone or

prednisolone

oral dexamethasone

1.28%





2.01%


symptoms 3.0 –

2.0 –

1.0 –

000

p=0.05

oral prednisone or

prednisolone

oral dexamethasone

1.28%



Soldesam® gocce 1 ml = 2 mg

di desametasone.



2.01%


symptoms 3.0 –

2.0 –

1.0 –

000

p=0.05

oral prednisone or

prednisolone

oral dexamethasone

1.28%



Single-dose oral dexamethasone

is associated with a decrease of ED relapse

for pediatric patients with acute asthma

exacerbations.

Comparative Effectiveness of Dexamethasone versus Prednisone in Children Hospitalized with Asthma

Parikh K, J Pediatr 2015;167:639-44

Prednisone and its metabolite prednisolone (1-2 mg/kg/day for 3-5 days) have traditionally been used to manage acute asthma exacerbations. Recently, dexamethasone administered in the emergency department (ED) setting has been found to be equally effective in treating mild to moderate exacerbations of asthma. Prednisone, or prednisolone, typically used as an oral tablet or syrup, is a relatively short-acting corticosteroid with a half-life of 12 to 36 hours, thereby requiring daily or 2 daily dosing.



Prolonged treatment course, vomiting, and bitter taste may reduce patient adherence to prednisone or prednisolone prescription. Alternatively, dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours, and therefore a single dose or 2 doses administered over 2 days are considered to be equivalent to a 5-day course of prednisone or prednisolone. Dexamethasone has a greater affinity for the glucocorticoid receptor compared with methylprednisolone, prednisolone, or prednisone, and is 5 times more potent when receptor affinity and pharmacokinetics are considered together.



Dexamethasone is also well-absorbed by both oral and intramuscular routes of administration.

In addition, dexamethasone is generally considered more palatable than prednisone or prednisolone, with less emesis and better adherence.

Therefore, dexamethasone may improve medication adherence due to less frequent dosing, a shorter duration of treatment and better taste (when administered orally) compared with prednisone or prednisolone.



Dexamethasone (n=1166) vs Prednisone/Prednisolone (n=39091) Children aged 4-17 years hospitalized with asthma (40 257 hospitalizations)

15 –

10 –

0 -

Proportion of subjects with a length of stay of ≥ 3 days

6.7%

12.0%

dexamethasone group

prednisone/prednisolone group

P=0.002




15 –

10 –

0 -

Proportion of subjects with a length of stay of ≥ 3 days

6.7%

12.0%

dexamethasone group

prednisone/prednisolone group

P=0.002

The dexamethasone group had lower costs

of index admission ($2621 vs $2838; p<0.001) and total episode of care (including readmissions)

($2624 vs $2856; p<0.001) compared with the

prednisone/prednisolone group.




1. Dexamethasone (Decadron, Soldesam) was given as: a single intramuscular

a single oral dose

2 oral doses with the most common dosage being 0.6 mg/kg (range 0.3-1.7 mg/kg). 2. Prednisone or prednisolone was given for 3-6 days and at a dosage of 1-2 mg/kg per day.

Ethnic Variation in Response to IM Triamcinolone in Children With Severe Therapy-Resistant Asthma

Koo S. CHEST 2016;149(1):98-105

79 Children with severe therapy-resistant asthma

Classified as white, black, Asian, or mixed white/black

Steroid responsiveness according to symptoms (Asthma Control Test), inflammation (sputum eosinophil count and exhaled nitric oxide), and FEV1 measured before and 4 weeks after IM triamcinolone

white

70 –

60 –

50 –

40 –

30 –

20 –

10 -

0-

68%

20% 6% 5% black asian Mixed

black/white

% children


Koo S. CHEST 2016;149(1):98-105

The dose of IM triamcinolone was 40 mg for children with weight < 30 kg and 80 mg for children with weight ≥ 30 kg,

white black

Drop in median FENO (ppb) after administration of triamcinolone

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 -

46.8

23.1

52.2

34.5


Koo S. CHEST 2016;149(1):98-105




white

86.7%

45.3%

black

% children FENO non responders 90 –

80 –

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 - p<0.05


Koo S. CHEST 2016;149(1):98-105




white

61%

17%

black

% children with exacerbations in the 4 weeks after triamcinolone injection

p<0.05

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 -


Koo S. CHEST 2016;149(1):98-105




white

61%

17%

black

% children with exacerbations in the 4 weeks after triamcinolone injection

p<0.05

70 –

60 –

50 –

40 –

30 –

20 –

10 –

0 -


Koo S. CHEST 2016;149(1):98-105




Black children with asthma were less likely to report an Feno response and had more exacerbations 4 weeks after

administration of triamcinolone than white children.

Further research is needed to understand the mechanisms of

these differences, but they cannot be due to

differences in adherence or access to care.

Systematic review of the toxicity of short-course oral corticosteroids in children. F. Aljebab, Arch Dis Child 2016;101:365

A literature search of EMBASE, MEDLINE, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions to identify studies in which oral corticosteroids were administered to patients


A literature search of EMBASE, MEDLINE, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions to identify studies in which oral corticosteroids were administered to patients

Diego Peroni



Nota 89 La prescrizione a carico del SSN è limitata alle seguenti condizioni: pazienti affetti da patologie su base allergica di grado medio e grave (rinocongiuntivite allergica stagionale, orticaria persistente non vasculitica) per trattamenti prolungati (superiori ai 60 giorni) Le malattie allergiche costituiscono un serio problema sanitario sia per il costante e continuo incremento epidemiologico in Italia (i dati ISTAT si attestano attualmente sul 20% dell’intera popolazione), sia per i risvolti farmaco-economici: i costi per il trattamento e le assenze lavorative e scolastiche. Le forme perenni alterano significativamente la qualità di vita, addirittura tanto quanto l’asma lieve o moderata. La rinite e la rinocongiuntivite allergica rappresentano il più importante fattore di rischio per lo sviluppo di asma bronchiale e spesso le due patologie sono associate. Un non adeguato trattamento delle vie aeree superiori comporta un insuccesso terapeutico nel paziente asmatico. Per questi motivi la rinite allergica deve essere considerata una patologia importante sia per le sue caratteristiche di cronicità, sia per il fatto di essere un fattore aggravante l’asma. A tale proposito deve essere sottolineato lo stretto legame esistente tra la rinite allergica e la patologia asmatica: questo nesso è talmente cruciale che l’Organizzazione Mondiale della Sanità ha stilato un documento che valuta appunto l’impatto della rinite allergica sull’asma (ARIA Document, “Allergic Rhinitis and its Impact on Asthma”). Da tale documento emerge il concetto che la rinite allergica è caratterizzata da un processo infiammatorio strettamente dipendente dall’esposizione all’allergene causale, anche in assenza di sintomi. Si evince inoltre che un trattamento ottimale della rinite allergica può prevenire l’insorgenza di asma o migliorare l’asma coesistente. Il documento ARIA ha anche rivisitato la classificazione e i protocolli terapeutici della rinite allergica. La nuova classificazione è basata sulla durata dei sintomi e prevede due forme: intermittente e persistente. La seconda è caratterizzata dalla presenza di sintomi rinitici per più di quattro giorni alla settimana e per più di quattro settimane consecutive. A seconda dell’impatto sulle attività del soggetto, del senso di fastidio e delle ripercussioni sul sonno, la rinocongiuntivite allergica è riclassificata in base all’intensità dei sintomi. Il trattamento pertanto deve essere differenziato a seconda della forma e della gravità. Tale trattamento deve essere indirizzato verso obiettivi prioritari: l’antagonismo degli effetti indotti dai mediatori sugli organi bersaglio e la riduzione dell’accumulo delle cellule infiammatorie attivate. In questa ottica, l’istamina costituisce il più importante mediatore patogenetico.

Nota 89 Evidenze disponibili Gli antistaminici sono farmaci che esplicano il loro ruolo con differenti meccanismi tra i quali il principale è il blocco del recettore H1 per l’istamina. I farmaci di seconda generazione possiedono proprietà farmacologiche aggiunte che differiscono tra le diverse molecole. Gli antistaminici sono in grado di bloccare il rilascio di mediatori da basofili e mastociti. Possono avere anche un effetto antinfiammatorio. Gli antistaminici di seconda generazione si sono dimostrati più efficaci e accompagnati da minori effetti collaterali di sedazione rispetto a quelli di prima generazione, nonché da migliore compliance (monosomministrazione). Nell’orticaria acuta e cronica sono efficaci sintomatici. Sono in grado di ridurre il numero, la dimensione e la durata delle lesioni cutanee negli episodi di orticaria. Nell’orticaria cronica si ottengono risultati migliori nella somministrazione continua rispetto a quella intermittente al bisogno. Nei casi di orticaria vasculitica la risposta agli antistaminici non è ottimale. Nella dermatite atopica gli antistaminici non hanno effetto sul decorso della malattia.

Moderata-grave uno o più dei seguenti

. Alterazioni del sonno

. Limitazioni delle attività quotidiane

. Riduzione prestazioni lavorative/scolastiche

. Sintomi gravi

Persistente . > 4 giorni/settimana

. e > 4 settimane

Lieve Tutte le seguenti

• Sonno conservato

• Nessuna limitazione nelle attività quotidiane

• Normale attività lavorativa o scolastica

• Non sintomi fastidiosi

Intermittente

. < 4 giorni/settimana

. o < 4 settimane

Classificazione ARIA

Nei pazienti non trattati

BSACI guideline for the management of chronic urticaria and angioedema Powell RJ, CEA 2015;45:547–565

Algorithm for diagnosis of chronic urticaria and/or angioedema


General management plan for chronic urticaria (adults and children)

4 X


Antihistamine (H1 antihistamines) for chronic urticaria

(CU)


Antihistamine (H1 antihistamines) for chronic urticaria

(CU)

The effectiveness of desloratadine and

levocetirizine in up to

4 times the conventional doses

has been demonstrated

in difficult to treat urticaria


Second-line pharmacotherapy

Adverse drug reactions of systemic antihistamines in children in the Netherlands. De Vries, Arch Dis Child 2016;101:968

We retrospectively studied all reported ADRs on systemic antihistamines (Anatomical and Therapeutic Chemical classification (ATC) code R06A) in children aged 0–18 years reported to the Netherlands Pharmacovigilance Centre Lareb in the years 1991– 2014. All these reports were assessed for causality by trained assessors.

Adverse drug reactions of systemic antihistamines in children in the Netherlands. De Vries, Arch Dis Child 2016;101:968

All medicines have side effects. K. Allegaert Arch Dis Child 2016;101:951

One needs to ask the following questions before prescribing either a new medicine or repeating a prescription for an existing treatment. ▸ Is a medicine required? ▸ Is the medicine to be prescribed likely to be effective, in this age group for this condition? ▸ What are the likely side effects? ▸ What is the risk/benefit to this individual patient? ▸ How long is treatment required for? It is only by asking such questions that one can ensure that patients will receive the optimal treatment.



The rational use of medicines is recognised as being a major

problem in low-income countries but there is increasing awareness

that it is also a problem in high-income countries.



The rational use of medicines is recognised as being a major

problem in low-income countries but there is increasing awareness

that it is also a problem in high-income countries.

Their findings do not suggest that

we should stop using antihistamines in

children. They do, however, highlight that medicines we consider

to be safe do have side effects.

Diego Peroni



Nota 82 La prescrizione a carico del SSN è limitata alle seguenti condizioni: trattamento di “seconda linea” dell’asma moderata persistente, in aggiunta agli steroidi per via inalatoria, quando questi non garantiscano un controllo adeguato della patologia, anche dopo associazione con β-2 agonisti profilassi dell’asma da sforzo Quando gli steroidi risultino insufficienti è preferibile, piuttosto che aumentarne il dosaggio, aggiungere un farmaco di “seconda linea”. Tra questi la prima scelta è rappresentata dai β-2 agonisti a lunga durata d’azione, seguiti, come seconda scelta, dagli antileucotrienici. Background Nei pazienti affetti da asma lieve-moderata persistente non controllata da steroidi inalatori, è preferibile aggiungere un farmaco di seconda linea (β -2 inalatori a lunga durata d’azione, teofillina o antagonisti dei leucotrieni) piuttosto che aumentare la dose di steroide inalatorio. Fra queste terapie di seconda linea, i β -2 inalatori a lunga durata d’azione rimangono i farmaci di prima scelta.

Nota 82 Evidenze disponibili Gli antagonisti dei leucotrieni costituiscono farmaci di seconda linea, da aggiungere quindi agli steroidi inalatori e ai β -2 stimolanti, quando tale associazione non sia sufficiente a controllare la sintomatologia o per mantenere il controllo con dosaggio ridotto di steroide inalatorio in pazienti con asma persistente di moderata entità. Gli steroidi per via inalatoria sono i farmaci di prima linea e di prima scelta nel trattamento dell’asma lieve persistente, ma, quando inefficaci o non tollerati, possono essere sostituiti, come seconda scelta, dagli antagonisti dei leucotrieni. Questi ultimi invece sono sconsigliati nell’asma grave persistente in quanto non efficaci e potenzialmente associati allo sviluppo di complicanze quali la sindrome di Churg-Strauss. L’uso di montelukast e lo sviluppo di disturbi comportamentali dell’umore, pensieri e comportamenti suicidiari e suicidi, hanno spinto la Food and Drug Administration ad una revisione dei dati di sicurezza di tale possibile associazione. Gli antagonisti dei leucotrieni sono consigliati come farmaci di prima scelta nella profilassi dell’asma da sforzo in alternativa ai b-2 stimolanti a breve o lunga durata d’azione o ai cromoni.

CHARACTERIZATION OF WITHIN-SUBJECT RESPONSES TO FLUTICASONE AND MONTELUKAST IN CHILDHOOD ASTHMA Szelfer JACI 2005; 115: 233

144 ch. 6 to 17 yrs

Mild-to-moderate persistent asthma (FEV1 >70%)

2 crossover sequences, including 8 weeks of fluticasone propionate (FP) (100 ug twice daily by Diskus), and 8 weeks of montelukast (M) (5-10 mg nightly depending on age)

Defining response as improvement in FEV1 of 7.5% or greater

Both Only FP Only M Neither

FP&M FP or M

% children with a (+) response i.e.improvement in FEV1 > 7.5%

60 –

50 –

40 –

30 –

20 –

10 –

0

17%

23%

5%

55%

144 ch. 6 to 17 yrs

Mild-to-moderate persistent asthma (FEV1 >70%)

2 crossover sequences, including 8 weeks of fluticasone propionate (FP) (100 ug twice daily by Diskus), and 8 weeks of montelukast (M) (5-10 mg nightly depending on age)

Defining response as improvement in FEV1 of 7.5% or greater

Both Only FP Only M Neither

FP&M FP or M

% children with a (+) response i.e. improvement in FEV1 > 7.5%

60 –

50 –

40 –

30 –

20 –

10 –

0

17% 23%

5%

55% Higher FeNO, Eosinophils, ECP IgE, lower PC20

* Younger age, * Shorter duration of disease

CHARACTERIZATION OF WITHIN-SUBJECT RESPONSES TO FLUTICASONE AND MONTELUKAST IN CHILDHOOD ASTHMA Szelfer JACI 2005; 115: 233

In Montelukast treated group compared to placebo

Emergency department visits

Overall acute health care utilization

Nights awakened per episode

Time off school

Time off works for parents

* p<0.05 ** p<0.01

0

-10 –

-20 –

-30 –

-40 –

-50 – -46.6%

-23.6%

-9.4%

-36.6% -33.5%

*

**

*

*** ***

*** p<0.0001

SHORT COURSE MONTELUKAST FOR INTERMITTENT ASTHMA IN CHILDREN: THE PRE-EMPT STUDY Robertson AJRCCM 2007; 175:323

194 asthmatic children

2 to 14 years

Montelukast or placebo in addition to usual asthma therapy between September 1 and

October 15, 2005.

% days with worse asthma symptoms

Placebo Montelukast

10 –

5 –

0

8.3%

3.9%

p<0.02

Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of

montelukast added to usual therapy. Johnston NW, Pediatrics. 2007;120(3):e702-12.

Before After

Time relative to treatment

300

200

100

Lung function before and after 4 weeks of treatment with

Montelukast () or placebo ()

FEV

0.5 m

L

p=0.038

Prospective randomised double-blind placebo-controlled study

24 ch. (10-26 mo.) with wheeze, allergy and a positive family history of asthma

Montelukast 4 mg or placebo

(FEV0.5) was measured using the raised volume rapid thoracic compression technique

Fractional exhaled nitric oxide (FeNO)

Symptoms scores

The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma.

Straub DA, Eur Respir J. 2005;25(2):289-94.

Weekly prevalence of a) symptom-free days

ns

ns

113 (6-24-mo-old-children) with recurrent wheezing.

Placebo or montelukast daily for an 8-week period.

Symptom-free days, rescue medication, lung function (squeeze technique), airway responsiveness (dosimetric methacholine challenge test), FeNO.

b) days without rescue medication.

The effect of montelukast on respiratory symptoms and lung function in wheezy infants. Pelkonen, ERJ 2013; 41: 664

Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised,

placebo-controlled trial Nwokoro C, Lancet Respir Med 2014;2:796

Between Oct 1, 2010, and Dec 20, 2013.

21 primary care sites and 41 secondary care sites in England and Scotland.

Children aged 10 months to 5 years with ≥ 2 wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) to intermittent montelukast (n=669) or placebo (n=677) given by parents at each wheeze episode over a 12 month period.

Montelukast Placebo

2.3 2.0

3.0 –

2.0 –

1.0 –

00 p =0.06

Mean unscheduled medical visits for wheezing episodes

over 12 months

Montelukast Placebo

2.4 2.0

3.0 –

2.0 –

1.0 –

00 p =0.01

Between Oct 1, 2010, and Dec 20, 2013.

21 primary care sites and 41 secondary care sites in England and Scotland.

Children aged 10 months to 5 years with ≥ 2 wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) to intermittent montelukast (n=669) or placebo (n=677) given by parents at each wheeze episode over a 12 month period.

62.5% of the children are in the 5/5 stratum which may identify a

montelukast responsive group.

In black children this allele is less frequent

(31%)

Mean unscheduled medical visits for wheezing episodes

of the children are in the 5/5 stratum for arachidonate

5-lipoxygenase in children (62.5%)

Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised,

placebo-controlled trial Nwokoro C, Lancet Respir Med 2014;2:796

Do children with stable asthma benefit from addition of montelukast to inhaled corticosteroids: Randomized, placebo controlled trial. I. Stelmach, Pulmonary Pharmacology & Therapeutics 31 (2015) 42

76 asthmatic children aged 6-14 years, allergic to HDM were randomized to a double-blinded trial comparing montelukast therapy to a matching placebo. End-points: the reduction in the ICS dose, the frequency of exacerbations, lung function, asthma control test score

Do children with stable asthma benefit from addition of montelukast to inhaled corticosteroids: Randomized, placebo controlled trial. I. Stelmach, Pulmonary Pharmacology & Therapeutics 31 (2015) 42

76 asthmatic children aged 6-14 years, allergic to HDM were randomized to a double-blinded trial comparing montelukast therapy to a matching placebo. End-points: the reduction in the ICS dose, the frequency of exacerbations, lung function, asthma control test score

The addition of montelukast to regular treatment with an ICS

for management of asthmatic children during the school season

resulted in a significant reduction in the frequency of exacerbations

and EIB protection, with no effect on asthma control, and lung

function.

Montelukast in paediatric asthma: where we are now and what still needs to be done? A. Bush, Paed Respir Rev 16 (2015) 97

Montelukast in large groups of school age children is inferior to ICS as a first line preventer and inferior to LABA as add on therapy. Clinical experience is that some individuals may benefit, but we do not know how to select them prospectively. Clinical experience is also that many children are left on leukotriene receptor antagonists long term with no evidence of benefit, and no deterioration on stopping treatment.

ROLE OF LTRAS IN SCHOOL AGE ASTHMA

Clearly it will not work for all children, but clinical experience is that there are a sub-group for whom this treatment is dramatically effective. Whereas ICS are first line preventive treatment for MTW, especially if the child is atopic, montelukast can be positioned as first line ‘preventive treatment’ in EVW in pre-school children, provided that preventive treatment is justified by the symptoms. I would trial montelukast intermittently with viral colds as first line therapy. If that does not work, I would next go to continuous therapy, especially in children who have a pattern of very rapid deterioration

ROLE OF LTRAS IN PRE-SCHOOL AGE WHEEZE

Montelukast in paediatric asthma: where we are now and what still needs to be done? A. Bush, Paed Respir Rev 16 (2015) 97

Authors’ conclusions

In pre-school children with EVW, there is no evidence of benefit associated

with maintenance or intermittent LTRA treatment, compared to placebo, for

reducing the number of children with one or more viral-induced episodes

requiring rescue oral corticosteroids, and little evidence of significant clinical

benefit for other secondary outcomes. Therefore until further data are

available, LTRA should be used with caution in individual children. When used,

we suggest a therapeutic trial is undertaken, during which efficacy should be

carefully monitored. It is likely that children with an apparent EVW phenotype

are not a homogeneous group and that subgroups may respond to LTRA

treatment depending on the exact patho-physiological mechanisms involved.

Cochrane Database of Systematic Reviews 2015, Issue 10.

diego peroni-pisa - fimp federazione italiana medici pediatri · gina 2015, box 6-5 (3/8) respiro...

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