Giuseppe Di Mauro pdf

(1)

Le origini dell’atopia e dell’asma

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1. 1. Atopici si nasce Atopici si nasce 1. 1. Atopici si cresce Atopici si cresce 2. 2. Atopici si diventa Atopici si diventa

3. 3. Conclusioni? Conclusioni?

Le origini dell’atopia

(3)

CD14 CD14 IL-4 IL-4 IL-13

IL-13

TNF TNF LTA LTA HLA- HLA-

DRB DRB

IL-4RA IL-4RA

FCER1B FCER1B

TCR TCR α α / / δ δ

p40 p40

GPRA GPRA

TIM TIM

PHF11 PHF11

GATA-3 GATA-3

T-bet T-bet DPP10

DPP10

FOXP3 FOXP3 ADAM ADAM

33 33

Grammatikos AP. The genetic and environmental basis of atopic diseases. Ann Med. 2008;40:482-95

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Gene polymorphisms and individual's predisposition to allergic diseases.

DPP10 dipeptidyl peptidases (DPPs) cleave terminal dipeptides from cytokines and chemokines

T-bet, A tissue-specific transcription factor, controls Th1 differentiation and IFN-γ production, affects IgG class switching

GATA-3 A transcription factor crucial for the activation of Th2 gene expression

TNF, LTA

Lymphotoxin alpha - a member of the TNF cytokine superfamily FCER1B High-affinity IgE Receptor

GPRA G protein-coupled receptor for asthma susceptibility TIM, T-cell immunoglobulin and mucin

p40, subunit of IL-12

PHF11 lower levels associated with reduced Th1 T-cells activity

FOXP3 A transcriptional partners in regulatory T cells

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Contextual basis of asthmatic inflammation and remodelling

Holgate ST. Treatment strategies for allergy and asthma.

Nature Rev Immunol 2008, 8:218-30

CD14 CD14 IL-4 IL-4

IL-13

IL-13 LTA LTA TNF TNF

GATA-3 GATA-3

T-bet T-bet

ADAM ADAM

33 33

(6)

• DPP10 (Dipeptidyl protease 10) …..2q14

• PHF11 (B cell transcription factor) ……13q14

• SPINK5 (Serine protease inhibitor Kazal-type 5, LEKT1)…5q31

• GPRA-A (G-protein receptor 154, neuropeptide S receptor)……7p15

• HLA-G (Human lymphocyte antigen G)……6p21

• MUC8 (Mucin 8)……12q23-qter

• Filaggrin (filament-aggregating protein)……1q21

• ADAM33 (A disintegrin and metaloprotease 33)……20p13

• Chitinase 3-like-1 (YKL-40)

• PCDH-1 (Protocadherin-1)……5q31

• ORMDL3 (ORM1-like3)……7q24

• GSDLG (Gasdermin-like gene)…….7q24

Szczepankiewicz A, Holgate ST. Association analysis of brain-derived neurotrophic factor gene polymorphisms in asthmatic families. Int Arch Allergy Immunol. 2009;149:343-9

Novel asthma susceptibility genes identified by

positional cloning or genome-wide association

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ADAM33, an asthma susceptibility gene

• ADAM33, first asthma susceptibility gene discovered by positional cloning

• SNPs strongly associated with asthma and bronchial hyperresponsivess (BHR).

• Replication studies in different populations including a meta- analysis.

• Selectively expressed in mesenchymal cells.

BHR

Metanalysis

Chromosome 20

Van Eerdewegh. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature, 2002; 418:426-30

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The Domain Organisation of A Disintegrin And Metalloprotease (ADAM)33

Signal sequence

Pro- domain

Catalytic domain

Disintegrin domain

Cysteine rich domain

EGF- domain

Trans- membrane

domain

Cytoplasmic domain

V-I M-T A-V

T-A

Y-H Zn²⁺

site

3’ UTR

proteolysis adhesion fusion signalling activation

A B C D E F G H I J K L M N O P Q R S T U V

A-1 D-2

D-1D1 F1

F+1G-1 I1 KL+1KL+2L-1L-2L1

M+1 Q-1 S2S1

S+1 ST+6ST+7ST+4ST+5 T+2 V1 V3 V5 V7 T+1 V-1V2 V4 V5 T2 V-2

T1 V-4V-3

A B C D E F G H I J K L M N O P Q R S T U V

V-I M-T

P-S Q-H A-V

T-A Y-H

T/C A/G G/A C/T G/A T/C A/T C/T

C/T C/T

G/C

T/C G/C

G/C A/G

Exon size

Polymorphisms

Name of Polymorphism 1031

72 92 148 109 78 199 109 196 90 178 143 85 167 72 66 190 77 77 79 80 102

D1 D1 I1 L1 S1 S2 T1 T2 V1 V1 V3 V4 V5 V6 V7

Chromosome 20p13

Courtesy of Steve Holgate

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Lee JY. A disintegrin and metalloproteinase 33 protein in patients with asthma:

Relevance to airflow limitation. AJRCCM 173, 729-35.

Presence of ADAM33 in airways lining fluid

Is the effect of ADAM33 in asthma due to a gain of function?

(10)

Correlation between increased vascularity and decreased in FEV

₁

Correlation between increased vascularity and asthma severity

Angiogenesis and Asthma

Collagen IV staining in Asthma

Control Asthma

Hoshino M. Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma. J Allergy Clin Immunol. 2001;107:1034- 8

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sADAM33 promotes angiogenesis in vitro

wild type mutant buffer

Matrigel HUVEC + treatment

Image at 18hours

Puxeddu I. The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis:

implications for airway remodeling in asthma. J Allergy Clin Immunol. 2008;121:1400-6

(12)

ADAM33 promotes smooth muscle formation in human embryonic lung

Puxeddu I. The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis:

implications for airway remodeling in asthma. J Allergy Clin Immunol. 2008;121:1400-6

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Gene-environment interactions in the development of atopy

Environmental Influences

Prenatal maternal influences, allergens, respiratory infections,

tobacco smoke,

pollutants, prematurity, dietary factors

Genetics Susceptibility:

Asthma, atopy, bronchial hyperresponsiveness

Expression:

Disease severity, pharmacogenetics

Chronic (Persistent) Asthma (reversible and irreversible changes in airway structure

and function) Early

Atopic disease – early asthma

Courtesy of Steve Holgate

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Marenholz I et al. An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma.

J Allergy Clin Immunol 2009;123:911-6.

I

ll fenotipo con la mutazione della filaggrina

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Simple (Mendelian) versus Complex Traits

Mendelian Traits

• Example: CF

• Rare

• Single gene

• Severe mutations

• Large phenotypic effect

Complex Traits

• Example: asthma, allergy

• Common

• Many genes

• Mild mutations

• Small phenotypic effect (gene-environment

interaction)

(16)

1. 1. Atopici si nasce Atopici si nasce 2. 2. Atopici si diventa Atopici si diventa

1. 1. Atopici si cresce Atopici si cresce 2. 2. Conclusioni? Conclusioni?

Le origini dell’atopia

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Gern JE. Relationship of viral infections to wheezing illnesses and asthma.Nat Rev Immunol. 2002 Feb;2(2):132-8

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Weinmayr G. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med. 2007;176:565-74

Asthma by atopy status in ISAAC

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Weinmayr GAtopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med. 2007;176:565-74

Gross national product and ISAAC

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Weinmayr GAtopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med. 2007;176:565-74

Gross national product and ISAAC

(21)

Wills-Karp M. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol. 2001; 1:69-75

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Food for thought

Devereux G. Early life events in asthma--diet. Pediatr Pulmonol. 2007;42:663-73

No support for early intake of PUFAs.

⇓ maternal intake of vit E, zinc vit D?

Could early life dietary intervention be used as a public health measure to reduce the

prevalence of childhood asthma?

(23)

D'Amato G. Effects of cimate change on environmental factors in respiratory allergic diseases.

Clin Exp Allergy. 2008;38:1264-74

Climate change and respiratory allergic diseases

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The hygiene hypothesis

The hygiene hypothesis proposes that as a result of modern public health practices, individuals living in the

industrialized world experience a relative deficiency in immune stimulation by microbes, rendering them

vulnerable to the development of allergic

hypersensitivities and their associated diseases.

Horner AD. Toll-like receptor ligands and atopy: A coin with at least two sides.

J Allergy Clin Immunol 2006; 117: 1133 -40

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Adleberth I. J Allergy Clin Immunol 2007: 119;1019-21

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P ro p o rt io n o f 2 -y e ar -o ld ch ild re n w ith a to pi c ec ze m a ( % )

-

75 - -

50 - -

25^-

-

0

Lactobacillus GG

Placebo

I probiotici nella prevenzione primaria delle malattie allergiche

Kalliomaki M. Probiotics and prevention of atopic disease: a randomised placebo controlled trial. Lancet 2001; 357:1076-79

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Cosa succede a 4 anni ?

Kalliomaki M. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361:1869-71

RR=0,57

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Probiotic supplementation, eczema and allergic sensitization

• A double-blind, placebo-controlled randomized clinical

• 253 infants with a family history of allergic disease

• At least 60 mL of cow’s milk formula/day for the first 6 months, with or without

• Bifidobacterium longum & Lactobacillus rhamnosus (LPR)

• Clinical evaluation at 1, 3, 6 and 12 months of age

• total IgE measurement & skin prick tests at 12-months.

• Endpoints:

a. Eczema

b. Allergen sensitization

Soh SE. Probiotic supplementation in the first 6 months of life in at risk Asian infants - effects on eczema and atopic sensitization at the age of 1 year. Clin Exp Allergy. 2009;39:571-8

(30)

Probiotic

supplementation, eczema and allergic

sensitization

(31)

Probiotic supplementation and eczema

• Eczema: 22% vs. 25%; ORadj = 0.82; 95% CI= 0.44–1.52

• median SCORAD at 12 months: 17.10 vs. 11.60 (P = 0.17)

• Total IgE geometric mean (95% CI): 18.76 (12.54–24.98) kU/L vs. 23.13 (16.01–30.24) kU/L in the placebo group (P = 0.15)

• Atopic eczema (with sensitization): 7.3% vs. 5.8%; ORadj

=1.08; 95% CI = 0.44–2.65.

(32)

Probiotic supplementation and allergic sensitization

Early life administration of a cow’s milk formula supplemented with

probiotics showed no effect on prevention of eczema or allergen

sensitization in infants at risk of allergic disease.

(33)

Probiotic supplementation and allergic diseases

OBJECTIVE

To study the effect of probiotic and prebiotic supplementation in preventing allergies.

METHODS:

1223 mothers with infants at high risk for allergy randomized to receive a probiotic mixture (2 lactobacilli, bifidobacteria, and propionibacteria) or placebo during the last month of pregnancy

Their infants randomized to receive it from birth until age 6 months.

Infants also received a prebiotic galacto-oligosaccharide or placebo.

Kuitunen M. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol. 2009;123:335-41

(34)

Probiotic supplementation and allergic diseases

OUTCOMES

Cumulative incidence of allergic diseases (eczema, food allergy, allergic rhinitis, and asthma) at 5 years

IgE sensitization at 5 years STUDY POPULATION

1018 intent-to-treat infants,

891 (88%) attended the 5-year visit

(35)

Probiotic supplementation and allergic diseases

RESULTS:

Allergic disease 52.6% vs. 54.9%

IgE-associated allergic disease 29.5% vs. 26.6%

Eczema 39.3% vs. 43.3%

Atopic eczema 24.0% vs 25.1%

Allergic rhinitis 20.7% vs 19.1%

Asthma 13.0% vs 14.1%

(36)

Probiotic supplementation and allergic diseases

RESULTS in cesarean-delivered children:

IgE-associated allergic disease 24.3% vs 40.5%

OR 0.47; P = .035 CONCLUSIONS

No allergy-preventive effect that extended to age 5 years was achieved with perinatal supplementation of probiotic bacteria to high-risk mothers and children. It conferred protection only to cesarean-delivered children.

(37)

1. 1. Atopici si nasce Atopici si nasce 2. 2. Atopici si diventa Atopici si diventa

3. 3. Atopici si cresce Atopici si cresce 1. 1. Conclusioni? Conclusioni?

Le origini dell’atopia

(38)

Early onset sensitisation to food allergens

(in infancy)

Sensitisation to inhalant allergens

(in childhood) No sensitisation

time 0

The atopic march

Potential manifestation as atopic dermatitis

Potential manifestation as rhinitis and asthma

t₁ t₂

Progression Progression

(39)

Do children with atopic dermatitis progress to Do children with atopic dermatitis progress to

asthma?

• This concept formed the very basis of the Early Treatment of the Atopic Child study

• The study failed to show any benefit from the antihistamine cetirizine in preventing subse-quent asthma in children

with early eczema.

Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immuno 2006;118:209-13

(40)

0 1 2 3 4 5 6 7 8 9 10

EAD+EW EAD+EW+LPT EAD-EW+LPT EAD-EW

OR Wheezing at 7 yrs

EAD: Early Atopic Dermatitis

EW : Early Wheezing AFT: Any Frequent Type Of Sensitization at 2 yrs (milk, egg, grass)

LPT : Less Prevalent Type of sensitization at 2 yrs

(wheat, cat, mite, soy, birch)

The natural course of atopic dermatitis from birth to age 7 years

and the association with asthma

Illi S. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113:925- 31

“… rather than early AD being a risk factor for

subsequent asthma in a progressive atopic march, it seems more likely that a certain phenotype exists as a coexpression of asthma and AD characterized in early life by AD plus either wheezing or a specific pattern of atopic sensitization and a more severe course,

resulting in significant impairment of lung function”.

(41)

Defining childhood atopic phenotypes to investigate the association of atopic

sensitization with allergic disease

• Children were recruited at birth (n 1456) and reviewed at 1, 2, 4 and 10 years.

• Skin prick testing (SPT) to common allergens was done at 4 (n 980) and 10 years (n 1036)

• Lung function (n 981),

• Bronchial challenge (n 784)

• Serum IgE (n 953) testing at 10

• Atopic phenotypes were defined, by sensitization pattern, for children with SPT at both 4 and 10 years (n 823)

Kurukulaaratchy RJ. Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease. Allergy 2005:60: 1280–1286

(42)

*

Defining childhood atopic phenotypes to investigate the association of atopic

sensitization with allergic disease

R. J. Kurukulaaratchy. Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease.

Allergy 2005:60: 1280–1286

Chronic childhood atopics have high prevalence of early persistent wheeze and persistent asthma

It is plausible that aeroallergen sensitivity might manifest in

infancy amongst chronic childhood atopics (almost at the

same time of food sensitization).

(43)

MiCMAC cohort: survival curve

Months from diagnostic DBPCFC

P e rsi st en t C M A %

Fiocchi A. Factors associated with cow's milk allergy outcomes in infant referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol 2008;101:166-73

(44)

Terracciano L. Impact of dietary regimen on the duration of cow’s milk allergy. EAACI 2009

(45)

Cow’s milk substitutes and onset of tolerance in the MiCMAC study population

(46)

Duration model hazard ratios for cow’s milk

protein hydrolysate, soy formula and rice hydrolysate (Cox regression analysis) showing the contrast between being (red square) and not being

(blue rhombus) co-sensitised to soy.

The data of MiCMAC 1 and 2 are similarly consistent with the emergence of a specific phenotype characterized by the involvement of two or more organ systems and high intensity of atopic expression associated with longer duration of CMA.

These findings buttress the emerging concept that a

phenotype-dependent course of atopic disease may be

modifiable by the introduction/withdrawal of environmental

factors such as allergen exposure.

(47)

1. 1. Atopici si nasce Atopici si nasce 2. 2. Atopici si diventa Atopici si diventa

3. 3. Atopici si cresce Atopici si cresce 4. 4. Conclusioni Conclusioni

Le origini dell’atopia

(48)

Atopici si nasce – ma la predisposizione non è predestinazione Atopici si nasce – ma la predisposizione non è predestinazione

Atopici si diventa – e forse si può evitare Atopici si diventa – e forse si può evitare

Atopici si cresce – ma a volte non lo si può evitare Atopici si cresce – ma a volte non lo si può evitare

L’unica prevenzione primaria che può funzionare è quella L’unica prevenzione primaria che può funzionare è quella

proibizionistica proibizionistica

Conoscere le origini dell’atopia è basilare per la pratica pediatrica Conoscere le origini dell’atopia è basilare per la pratica pediatrica

Le origini dell’atopia - conclusioni

(49)

Adverse Reactions to Bovine Proteins – II.

Changing Patterns, Mechanisms and

Treatment.

The 5 ^th Milan Meeting Dal Mito alla realtà

Milan,

4-6 February 2010

(50)

Il GINA ed i problemi della gestione dell’asma in pediatria

(51)

Levels of Asthma Control

Characteristic Controlled

(All of the following)

Partly controlled

(Any present in any week)

Uncontrolled

Daytime symptoms None (2 or less/ week) More than twice / week

3 or more features of partly controlled asthma present in any week

Limitations of activities None Any

Nocturnal symptoms/

Awakening

None Any

Need for rescue/ “reliever”

treatment

None (2 or less/ wk) More than twice / week Lung function

(PEF or FEV₁)

Normal < 80% predicted or personal best (if known) on any day

Exacerbation None One or more / year 1 in any week

Class IV evidence (expert opinion) Measuring asthma control:

ACT (www.asthmacontrol.org)

ACQ (www.qoltech.co.uk/Asthma1.htm) Not validated for use in children

“their value in clinical use … has yet to be demonstrated”

It isn’t clear if this concept of asthma control is valid in children

Yawn, Pediatrics 2006;118:322-9

Childhood asthma can be episodic: long symptom-free intervals interspersed with short severe exacerbations

Wensley, AJRCCM 2004;170:606-12

Difference between daily asthma control and

exacerbations; different treatments have different effects on these end points.

Pedersen, Lancet 2006;368:707-8

(52)

controlled

partly controlled

uncontrolled

exacerbation

LEVEL OF CONTROL LEVEL OF CONTROL

maintain and find lowest controlling step

consider stepping up to gain control

step up until controlled

treat as exacerbation

TREATMENT OF ACTION TREATMENT OF ACTION

TREATMENT STEPS

REDUCE INCREASE

STEP

1 STEP

2 STEP

3 STEP

4 STEP

5 R E D UC E INCR E A S E

(53)

A general problem of GINA

• guidelines developed for “asthma” in general

• main focus on studies in adults

• no clear distinction between adults and children

• unclear if and how guideline recommendations apply to children

• there is no justification to extrapolate data from adults to children

Custovic & Simpson, Clin Exp Allergy Rev 2006;6:1-5

Rubin, Chest 2006;129:1118-21

(54)

Need for answers

(55)

Childhood asthma: not enough evidence Childhood asthma: not enough evidence

0 50 100 150 200 250

Adult Teenage School Preschool Infant

2004 2005 2006

Asthma + randomized control trial

Courtesy of Niklas Papadopulos

(56)

Changes to the definition of “asthma”

• Old definition

– Recurrent episodes of reversible airflow obstruction

• A more modern definition

– An airway inflammatory disease characterized by

– Recurrent episodes of reversible airflow obstruction, and

– Bronchial hyperreactivity

(57)

IFN gamma, feNO, IL4, IL6 , IL8, IL-13, IL-17 ^,

edema, local acidification, vascular permeability, increased blood flow, Th1 cells, Th2 cells, Tc1, Tc2, Treg cells, PAF, TNF, TGF, VEGF, neutrophils, eosinophils, basophils, mast cells, dendritic cells, macrophages, NO, endothelin, IL1beta, histamine, leukotriene B4, cys-Leukotrienes, major basic protein, chymase, tryptase, C1esterase, elastase, eosinophil peroxidase, myeloperoxidase,

glutathione-dependent formaldahyde dehydrogenase, glutaminase, CD4 cells, CD8 cells, Th1 cells, Th2 cells

,

Tc1, Tc2, Treg cells, neurokinin A, neurokinin B, substance P, C3a, C5a gobbledygook, plegm1alpha, stooge 3, ADAM ant, ringwraithe, flybynight,dogbert, dilbert, bert, ernie, gerbil, shawshank1 and 2, Parrot head, the weather is here, wish you were

beautiful;;;;;’;’;’;’;’>>>>>>>>>>>……….. . . . . . . . . . .

The current definition of inflammation?

(58)

Changes to the definition of “asthma”

• Old definition

– Recurrent episodes of reversible airflow obstruction

• A more modern definition

– An airway inflammatory disease characterized by

– Recurrent episodes of reversible airflow obstruction, and

– Bronchial hyperreactivity

(59)

Changes to the definition of “asthma”

• Old definition

– Recurrent episodes of reversible airflow obstruction

• A more modern definition

– An airway inflammatory disease characterized by

– Recurrent episodes of reversible airflow obstruction, and

– Bronchial hyperreactivity

(60)

Answers to paediatric needs

Bacharier LB, Boner A, Carlsen K-H, Eigenmann, PA, Frischer T, Gotz M, Helms PJ, Hunt J, Liu A, Papadopoulos N, Platts-Mills TAE, Pohunek P, Simons FER, Valovirta E, Wahn U, Wildhaber J. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report.

The European Pediatric Asthma Group. Allergy 2008; 63:5–34

British Thoracic Society Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. Thorax. 2008 May;63 Suppl 4:IV1-121

(61)

PRACTALL Recommendations:

Global Management

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

(62)

Case history

In all children, ask about:

• Wheezing, cough

• Specific triggers: e.g. passive smoke, pets, humidity, mold and

dampness, respiratory infections, cold air exposure, exercise/activity, cough after laughing/crying

• Altered sleep patterns: awakening, night cough, sleep apnea

• Exacerbations in the past year

• Nasal symptoms: running, itching, sneezing, blocking.

(63)

Importance of age

(64)

Case history - infants

• Noisy breathing, vomiting associated with cough

• Retractions (sucking in of the chest)

• Difficulty with feeding (grunting sounds, poor sucking)

• Changes in respiratory rate

(65)

Case history – children > 2 years

1. Shortness of breath (day or night)

2. Fatigue (decrease in playing compared to peer group, irritability) 3. Complaints about not feeling well

4. Poor school performance or school absence

5. Reduced frequency or intensity of physical activity, e.g. in sports, gym classes

6. Avoidance of other activities (e.g. sleepovers, visits to friends with pets) 7. Specific triggers: sports, gym classes, exercise/activity

(66)

Identification of Asthma Phenotypes Is Critical

Is the child completely well between symptomatic periods?

Yes No

Are colds the most common precipitating

factor?

Is exercise the most common or only precipitating factor?

Does the child have clinically relevant allergic sensitization?

Yes Yes Yes No

Virus-induced asthma^a

Exercise-induced asthma^a

Allergen-induced asthma

Unresolved asthma^a,b

No No

aChildren may also be atopic.

bDifferent etiologies, including irritant exposure and as-yet not evident allergies, may be included here.

Adapted from Bacharier LB, et al. Allergy. 2008;63(1):5–34.

Asthma Phenotypes in Children >2 Years of Age

(67)

Phenotypes according to trigger

(68)

PRACTALL Recommendations:

Global Management

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

(69)

In children with severe recurrent wheeze, or in infants with persistent nonresponsive wheeze, other diagnoses must be excluded as well as the presence of aggravating factors, such as gastroesophageal reflux, rhinitis, aspiration of a foreign body, cystic fibrosis, or structural

abnormalities of the upper and lower airways. These cases may require fiber optic bronchoscopy with bronchoalveolar lavage, chest computed tomography scan, or esophageal pH probing.

In addition, treatment response should be considered. If therapy with ICS, leukotriene receptor antagonists (LTRA) or bronchodilators fails, the asthma diagnosis should be reconsidered.

Co-morbidities

(70)

(71)

Figure 1 – Pulmonary function tests: spirometry before [blue] and after [red]

salbutamol 400 mcg (1a); airway resistance and Raw/VTG loop (1b). Spirometry indicates severe disventilation (FVC 90%, FEV1 38%, Tiffenau Index 35% and MEF50 17% of expected normal value). After salbutamol 400 mcg, FVC rises to 97%, FEV1 to 40% while Tiffenau and MEF50 remain unchanged. MIF50 is 0.79 L/

sec; FIV1/FIVC is reduced at 16 % and MEF50/MIF50 is 0.77. Normal lung volumes (TLC 109%, RV 124%, RV/TLC 26%) with airway resistance of 325% of

expected value and a reduction of specific airway conductance of 22% are obtained at body pletysmography.

1a 1b

Fiocchi A. A 16-year-old boy with delayed growth and moderate persistent asthma.

Ann Allergy Asthma Immunol. 2007 99:99-100

(72)

(73)

(74)

(75)

Fig. 4 – Pulmonary function tests: spirometry one (4a) and six (4b) months after surgery. Airway resistance and Raw/VTG loop one month after

surgery (4c)

4a 4b 4c

(76)

PRACTALL Recommendations:

Global Management

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

(77)

Allergen avoidance – GINA 2007

(78)

Allergen avoidance – ARIA 2007

Misura Effetto sui livelli

Di allergene Effetto clinico ACARI

Coprimaterassi/cuscini Ia Ib

Lavaggio lenzuola a caldo (55-60^oC) IIb IV

Rimozione tappeti Ib IV

Acaricidi III IV

Pulizia con aspirapolvere a filtri HEPA IIb IV

EPITELI ANIMALI

Allontanamento animale da casa IIb IV

Allontanamento dalla stanza da letto IIb IV

Filtri aria HEPA Ib Ib

Lavaggio dell’animale IIb IV

Rimozione tappeti IV IV

Pulizia con aspirapolvere a filtri HEPA IV IV

(79)

Avoidable environmental factors

(80)

Other triggers

• A balanced diet and avoidance of obesity are favorable

• Smoke avoidance

• Exercise should not be avoided; asthmatic children should

be encouraged to participate in sports, with efficient control

of asthma inflammation and symptoms

(81)

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

PRACTALL Recommendations:

Global Management

(82)

Education: School intervention

McCann DC, McWhirter J, Coleman H, Calvert M, Warner JO. A controlled trial of a school- based intervention to improve asthma management. Eur Respir J 2006; 27:921-8

Increases in self esteem measures

(83)

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

PRACTALL Recommendations:

Global Management

(84)

LTRA Steroids

Association

Options for children 0 to 2 Years

(85)

Options for children 0 to 2 Years

• Asthma ~ >3 episodes in the previous 6 months

• Start with β₂ agonists as first choice

• LTRA daily controller therapy for virus induced asthma symptoms

• Inhaled steroids for persistent asthma, especially if severe or requiring frequent oral corticosteroid therapy

• Oral steroids (e.g. 1–2 mg/kg prednisone) for 3–5 days during acute and frequently recurrent obstructive episodes

• Evidence of atopy lowers the threshold for use of ICS and they may be used as first- line treatment in such cases

(86)

Pharmacological treatment > 2 Years

* LTRA may be particularly useful if the patient has concomitant rhinitis ** Check compliance, allergen avoidance and re-evaluate diagnosis *** Check compliance and consider referring to specialist

(87)

de Blic J. Efficacy of nebulized budesonide in treatment of severe infantile asthma:

a double-blind study. J Allergy Clin Immunol. 1996; 98:14-20

Inhaled steroids in infants

(88)

ICS control but do not cure the disease

285 preschool kids with wheeze and high asthma risk Index

Guilbert, NEJM

2006; 354:1985-97

(89)

Does early inhaled steroids influence long term prognosis of asthma?

• ICS control asthma symptoms and lung function, but does ICS influence long term prognosis?

– Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al.

Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97

– Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN):

double-blind, randomised, controlled study. Lancet 2006;368:754-62.

– Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354:1998-

2005

The early use of inhaled fluticasone propionate for wheezing in preschool

children had no effect on the natural history of asthma or wheeze later in

childhood, and did not prevent lung function decline or reduce airway

reactivity.

Intermittent inhaled corticosteroid therapy had no effect on the progression from episodic to persistent wheezing and no short-

term benefit during episodes of wheezing in the first three years of

life.

(90)

Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, Fabbri LM; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356:2040-52

Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma

The BEST study:

-mild asthma

-symptom-driven beclomethasone/albuterol vs

- regular beclomethasone

(91)

BEST is not the best for children

1. The use of morning peak expiratory flow rate as primary outcome does not reliably reflect disease control among children with mild persistent asthma

2. In this adult population trial, lung growth, which affects treatment outcomes in children, could obviously not be accounted for

3. Inflammation, the major determinant of tissue thickening in children’s airways, could not be measured.

Terracciano L. Beclomethasone and albuterol in mild asthma (letter).

N Engl J Med 2007; 357:506-7

A word of caution for caregivers ready to apply this important

research in children under

eighteen years of age may not be

unnecessary!

(92)

• 61 children with intermittent wheeze

• Fluticasone or placebo for 16 weeks

• Measurement of airway resistance (Rint), bronchodilator responsiveness (BDR)

-20 -15 -10 -5 0

SPT(+) (14/60) SPT(-) (44/60)

Rint BDR

Pao CS, McKenzie SA. Randomized controlled trial of fluticasone in preschool children with intermittent wheeze. Am J Respir Crit Care Med. 2002; 166:945-9

Steroid improvement only in atopic children

(93)

PREventing Virus-Induced Asthma

• 549 children

• Aged 2 to 5 years

• Intermittent asthma symptoms from common cold

• 1-week screening period

• 2-week, single-blind, placebo run-in period

• 48-week, double-blind active treatment period

• Montelukast 4-mg chewable tablet or placebo

Bisgaard H. Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent Asthma. AJRCCM 2005; 171:315-22

(94)

2.34

1.60 0 1 2 3

Montelukast 4 mg (n=265)

Placebo (n=257) Exacerbation

episode rate / year

32%

p ≤ 0.001 Exacerbation rate

Bisgaard H. Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent Asthma. AJRCCM 2005; 171:315-22

(95)

Zeiger RS. Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol. 2006;117:45-52

Different response profiles

(96)

Zeiger RS. Response profiles to fluticasone and montelukast in mild-to-moderate

persistent childhood asthma. J Allergy Clin Immunol. 2006;117:45-52

(97)

(98)

Treatment according to phenotypes

(99)

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

PRACTALL Recommendations:

Global Management

(100)

Immunotherapy:

10-year follow-up of the PAT study

Jacobsen L. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62:943-8

(101)

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

PRACTALL Recommendations:

Global Management

(102)

Measuring asthma control

1. Asthma Quiz for Kidz - a short questionnaire that can be used by children and parents of infants.

1. The Asthma Control Test (ACT) (for children >12 years)

1. the Childhood ACT (for children 4–11 years), patient-based tools for identifying patients with inadequately controlled asthma

1. Patient diaries correlate with physiologic measures when used by older children, although their reliability has been questioned.

(103)

Measuring asthma control

GINA Global Strategy for Asthma Management and the Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma, 2006

Asthma is well controlled when all of the following are achieved and maintained:

• Daytime symptoms twice or less per week (not more than once on each day)

• No limitations of activities due to asthma

• Night-time symptoms 0-1 per month (0-2 per month if child is≥12 years)

• Reliever/rescue medication treatment twice or less per week

• Normal lung function (if able to measure)

• 0-1 exacerbations in the last year

(104)

• Importance of symptoms

• Importance of co-morbidities

• Avoidance of triggers

• Education

• Pharmacotherapy

• Immunotherapy

• Regular follow-up

In conclusion!

PRACTALL Recommendations:

Global Management

(105)

• GINA focus on asthma control instead of severity GINA focus on asthma control instead of severity

• Steroids and modification of natural history of asthma Steroids and modification of natural history of asthma

• Intermittent treatment for mild persistent asthma? Intermittent treatment for mild persistent asthma?

GINA & asthma

(106)

Does early inhaled steroids influence long term prognosis of asthma?

• ICS control asthma symptoms and lung function, but does ICS influence long term prognosis?

– Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97

– Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study.

Lancet 2006 Aug 26;368(9537):754-62.

– Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F.

Intermittent inhaled corticosteroids in infants with episodic wheezing. N

Engl J Med 2006 May 11;354(19):1998-2005.

(107)

ICS control but do not cure the disease

285 preschool kids with wheeze and high asthma risk index

Guilbert, NEJM

2006; 354:1985-97

(108)

Does early inhaled steroids influence long term prognosis of asthma?

ICS control asthma symptoms and lung function, but does ICS influence long term prognosis?

– Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985-97 – Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A.

Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 2006 Aug 26;368(9537):754-62.

– Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F.

Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354:1998-2005.

The early use of inhaled fluticasone propionate for wheezing in preschool

children had no effect on the natural history of asthma or wheeze later in

childhood, and did not prevent lung function decline or reduce airway

reactivity.

Intermittent inhaled corticosteroid therapy had no effect on the progression from episodic to persistent wheezing and no short-

term benefit during episodes of wheezing in the first three years of

life.

(109)

Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma

Symptom-driven rescue use of a short-acting β2-agonist in combination with

a relatively high-dose inhaled corticosteroid in control of mild persistent asthma

is as effective as

regular treatment with the same dose of the same inhaled corticosteroid twice daily

plus a short-acting β2-agonist as needed?

Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, Fabbri LM; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma.

N Engl J Med. 2007;356:2040-52

(110)

Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, Fabbri LM; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356:2040-52

Beclomethasone and Albuterol in a Single Inhaler for Mild Asthma

In patients with mild asthma, the symptom-driven use of inhaled

beclomethasone (250 μg) and albuterol (100 μg) in a single inhaler is as effective

as regular use of inhaled

beclomethasone (250 μg twice daily) and is associated with a lower 6-month

cumulative dose of the inhaled

corticosteroid.

(111)

BEST is not the best for children

1. the use of morning peak expiratory flow rate as primary outcome does not reliably reflect disease control among children with mild persistent asthma

2. In this adult population trial, lung growth, which affects treatment outcomes in children, could obviously not be accounted for

3. Inflammation, the major determinant of tissue thickening in children’s airways, could not be measured.

Terracciano L, Bouygue GR, Fiocchi A. N Engl J Med 2007;356:2040-52

A word of caution for caregivers ready to apply this important

research in children under

eighteen years of age may not be

unnecessary!

(112)

0 1 2 3 4 5 6 7 8 9

5 10 15 20 25 30 40 50 60 70 80 90 100 normali asmatici

Anni

Picco di Flusso

L/sec

Mod. da Irvin CG. JACI 2000; 105: S 540-6

(113)

Life expectancy by age group and sex, in years, 1900 to 1997

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 1997 LIFE EXPECTANCY AT BIRTH

TOT 49.2 51.5 56.4 59.2 63.6 68.1 69.9 70.8 73.9 75.4 76.5 M 47.9 49.9 55.5 57.7 61.6 65.5 66.8 67.0 70.1 71.8 73.6 F 50.7 53.2 57.4 60.9 65.9 71.0 73.2 74.6 77.6 78.8 79.4

National Vital Statistics System

(114)

Percorsi assistenziali per il bambino con Asma tra centro

specialistico e territorio: l’esperienza della Lombardia

(115)

(116)

Dimensioni

• Il progetto riguarda 7 Aziende

Ospedaliere, 169 Pediatri di famiglia ( e dal 2010 a 1141 MMG) per un

totale di 1.600.000 abitanti (0-15 anni 198.000, pari al 12 %).

• La spesa farmaceutica pediatrica totale si aggira in media annualmente sui 3.9 – 4 milioni di euro (quella per ATR intorno a 800.000 Euro). Quindi in media 19% Dato costante dal 2002.

(117)

0 10 20 30 40 50 60 70

Assenze scolastiche Attività fisica limitata USA Europa occ. Europa or.

3153 bambini asmatici

Worldwide severity and control of asthma in children and adults: the Global Asthma Insights

and Reality surveys

Rabe KF, Adachi M, Lai CKV. J Allergy Clin Immunol 2004;114:40-7.

(118)

Uso dei farmaci di fondo e broncodilatatori short acting in Europa

J Allergy Clin Immunol 2004;114:40-7.

26 76

20 26

81

18 30 75

16 18

44 10 0

10 20 30 40 50 60 70 80 90

Severo Moderato Lieve Intermittente

Fondo Short USA

(119)