Guglielmo Scala

Napoli

Update sulla terapia dell’asma

bronchiale allergico in pediatria.

Focus sugli antiossidanti

Programma

• Morte per asma

• Aderenza

• Step-up

• Azitromicina

• Terapia intermittente

• Antiossidanti?

Di asma si muore

Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993–2012)

Ebmeier S, et al 2017, Lancet

Fatal asthma; is it still an epidemic?

Vianello A et al, 2016, WAOJ

Oggi in Italia ancora si muore per asma

Fatal asthma; is it still an epidemic?

Vianello A et al, 2016, WAOJ

Fatal asthma; is it still an epidemic?

Vianello a et al, 2016, WAOJ

Ozono (O3)

Fatal asthma; is it still an epidemic?

Vianello a et al, 2016, WAOJ

Alternaria

aderenza

Linee Guida e «Real life»

Eugenio, 12 anni

Allergico agli acari

In terapia con Fluticasone 100 mcg x 2 da due mesi

• Asma da sforzo

• Risvegli notturni non controllato

• Necessità di salbutamolo

© Global Initiative for Asthma © Global Initiative for Asthma

Stepwise approach to control asthma symptoms

and reduce risk

GINA 2017, Box 3-5 (1/8)

Symptoms

Exacerbations

Side-effects

Patient satisfaction

Lung function

Other

controller

options

RELIEVER

REMEMBER TO...

• Provide guided self-management education (self-monitoring + written action plan + regular review)

• Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety

• Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of sensitizers where appropriate

• Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler technique and adherence first

• Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite ICS treatment, provided FEV1 is >70% predicted

• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised.

STEP 1 STEP 2 STEP 3

STEP 4

STEP 5

Low dose ICS

Consider low dose ICS

Leukotriene receptor antagonists (LTRA) Low dose theophylline*

Med/high dose ICS Low dose ICS+LTRA

(or + theoph*)

As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol#

Low dose

ICS/LABA**

Med/high

ICS/LABA

Diagnosis

Symptom control & risk factors (including lung function)

Inhaler technique & adherence

Patient preference

Asthma medications

Non-pharmacological strategies

Treat modifiable risk factors

PREFERRED CONTROLLER

CHOICE

Add tiotropium* High dose ICS + LTRA (or + theoph*)

Add low dose OCS

Refer for add-on

treatment e.g.

tiotropium,* anti-IgE, anti-IL5*

UPDATED

2017

© Global Initiative for Asthma

Before considering step-up

Check inhaler technique and adherence, confirm diagnosis

Adults/adolescents: preferred options are either combination low dose

ICS/LABA maintenance with as-needed SABA, OR combination low dose

ICS/formoterol maintenance and reliever regimen*

Adding LABA reduces symptoms and exacerbations and increases FEV1, while

allowing lower dose of ICS

In at-risk patients, maintenance and reliever regimen significantly reduces

exacerbations with similar level of symptom control and lower ICS doses

compared with other regimens

Children 6-11 years: preferred option is medium dose ICS with

as-needed SABA

Step 3 – one or two controllers + as-needed

inhaled reliever

GINA 2017

UPDATED

2017

If asthma is uncontrolled in children and young people

(aged 5 to 16) on a paediatric low dose of ICS as

maintenance therapy, consider an LTRA1 in addition to

the ICS and review the response to treatment in 4 to 8

weeks.

Aumenta ICS

Aggiungi LABA

Aggiungi LTRA

NEW ZEALAND 1989

BTS 1990 EPR 1991

GINA 1995

BTS-SIGN 2003

NICE 2013

LE LINEE GUIDA PER L’ASMA

Two pathways, one patient; UK asthma guidelines

Fowler SJ, O’Byrne PM, 2018, Thorax

“It is not known whether these guidelines

have improved the care of people with

asthma; asthma prevalence has continued

to rise”

The biggest controversy

surrounds initial add-on therapy.

What is required is not varying and contradictory

guidance, but testing of both the evidence for and

implementation of current guidelines

Two pathways, one patient; UK asthma guidelines

Fowler SJ, O’Byrne PM, 2018, Thorax

“It is not known whether these guidelines

have improved the care of people with

asthma; asthma prevalence has continued

to rise”

The biggest controversy

surrounds initial add-on therapy.

What is required is not varying and contradictory

guidance, but testing of both the evidence for and

implementation of current guidelines

Two pathways, one patient; UK asthma guidelines

Fowler SJ, O’Byrne PM, 2018, Thorax

“It is not known whether these guidelines

have improved the care of people with

asthma; asthma prevalence has continued

to rise”

The biggest controversy

surrounds initial add-on therapy.

What is required is not varying and contradictory

guidance, but testing of both the evidence for and

implementation of current guidelines

ASMA

episodic Multiple trigger

“Perhaps guidelines were created without first

establishing whether the entity whose management we

are seeking to guide is useful and sufficiently

welldefined” (Lancet commission)

“Treatment decisions at different steps are

overgeneralised, resulting in illogical treatment in a

considerable number of patients”

“Perhaps guidelines were created without first

establishing whether the entity whose management we

are seeking to guide is useful and sufficiently

welldefined” (Lancet commission)

“Treatment decisions at different steps are

overgeneralised, resulting in illogical treatment in a

considerable number of patients”

After asthma: redefining airways diseases

Pavord ID and The Lancet Commission, 2017, Lancet

«Treatable traits»

1919

• III Internazionale Comunista

• Associazione Fasci Italiani

• D’Annunzio a Fiume

• Don Sturzo e il PPI

1974

• Nixon - Watergate

• Piazza della Loggia e Italicus

• Iva Zanicchi a Sanremo

• A Napoli…

“Intravenous salbutamol will probably become the standard beta-adrenergic stimulator for use in acute asthma.”

Sotto i 4 anni erano troppo

nervosi per l’aerosol

1977

• Anni di piombo

• TV a colori in Italia

• Stop a Carosello

• A Napoli…

RCT

20 pazienti con asma severo

Salbutamolo IM

(20 mcg/kg)

Therapy «as needed»

Risk of asthma attack x3

Lemanske 2011, JAMA

Physicians do not prescribe Adherence in mild asthma

= 20%

© Global Initiative for Asthma

Stepwise approach to control asthma symptoms and reduce risk

GINA 2017, Box 3-5 (1/8)

Symptoms

Exacerbations

Side-effects

Patient satisfaction

Lung function

Other

controller

options

RELIEVER

REMEMBER TO...

• Provide guided self-management education (self-monitoring + written action plan + regular review)

• Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety

• Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of sensitizers where appropriate

• Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler technique and adherence first

• Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite ICS treatment, provided FEV1 is >70% predicted

• Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised.

STEP 1 STEP 2 STEP 3

STEP 4

STEP 5

Low dose ICS

Consider low dose ICS

Leukotriene receptor antagonists (LTRA) Low dose theophylline*

Med/high dose ICS Low dose ICS+LTRA

(or + theoph*)

As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol#

Low dose

ICS/LABA**

Med/high

ICS/LABA

Diagnosis

Symptom control & risk factors (including lung function)

Inhaler technique & adherence

Patient preference

Asthma medications

Non-pharmacological strategies

Treat modifiable risk factors

PREFERRED CONTROLLER

CHOICE

Add tiotropium* High dose ICS + LTRA (or + theoph*)

Add low dose OCS

Refer for add-on

treatment e.g.

tiotropium,* anti-IgE, anti-IL5*

UPDATED

2017

Budesonide/Formoterol Combination Therapy as Both Maintenance and Reliever Medication in Asthma

O’Byrne P, Bisgaard H et al, 2005, Am J Resp Crit Care Med

342 children, 4 – 11 y, mild to moderate asthma

Main Outcome: Time to the first wheezing episode

Uso di steroidi inalatori

Regular vs prn nebulized treatment in wheeze preschool children

Papi A et al, 2009, Allergy

276 children with frequent wheeze, aged

1–4 years

(1) 400 mcg beclomethasone bid plus 2500 mcg salbutamol prn; (2) placebo bid plus 800 mcg beclomethasone/1600 mcg salbutamol combination prn; (3) placebo bid plus 2500 mcg salbutamol prn.

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind,

placebo-controlled trial.

Martinez FD et al, 2011, Lancet

• Twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group) • twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group) • twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); • twice daily placebo with placebo plus albuterol as rescue (placebo group)

Azitromicina

nel wheezing prescolare

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History

of Such Illnesses: A Randomized Clinical Trial

Bacharier L et al, 2015 JAMA

n. 607 pre-school children (1 – 5 yrs) with severe intermittent wheezing

Azitro 5 days (+ salbutamol)

Azitro riduce il rischio di

progressione verso wheezing

severo Not indicated at

present

Azithromycin for episodes with asthma-like symptoms in young children aged 1–3 years:

a randomised, double-blind, placebo-controlled trial.

Stokholm J et al 2015 Lancet Resp Med

N: 158, 3-day course of Azitro (10 mg/kg) in children with recurrent asthma-like symptoms

Episode: at least

three days

• The earlier the

better (< 6 days)

The role of macrolides in asthma: current evidence and future directions

Wong EHC et al, 2014, Lancet Resp Med

Treatment of preschool children presenting to the emergency department with wheeze with azithromycin:

A placebo-controlled randomized trial.

Mandhane PJ et al, 2017, Plos One

No differences Azitro - placebo

first wheezing episode

Previous wheezers

Time to symptoms resolution (days)

Treatment of preschool children presenting to the emergency department with wheeze with azithromycin:

A placebo-controlled randomized trial.

Mandhane PJ et al, 2017, Plos One

Time to respiratory exacerbation by wheeze

category

Again: not to be

prescribed yet,

but…

?

• Claudia Calabrò

• Anna Ciccarelli

• Clara Imperatore

S.M. di Loreto - Crispi

guglielmoscala@gmail.com

Empedocle

Joachim Becher 1635 - 1682

Terra lapidea tutti i corpi solidi

Terra mercurialis essenzialmente fluida

Terra pinguis elemento combustibile

George Ernst Stahl, 1660-1734

Teoria del FLOGISTO

La combustione è la perdita della terra pinguis in esso contenuta

• ogni materiale infiammabile

contiene flogisto;

• quando una di tali sostanze

brucia, perde la sua

componente flogistica;

• il fuoco individua il rapido

passaggio del flogisto

all'esterno della sostanza.

Antoine-Laurent de Lavoisier, 1743 - 94

Joseph Priestley

Scoperta dell’ossigeno definita “aria deflogisticata”

Dà il nome di ossigeno e confuta la teoria del flogisto

Cellular mechanisms and physiological consequences of redox-dependent signalling

Holmström KM et al, 2015, Nat Rev Molecular Cel Biol

Gli asmatici hanno una esagerata risposta infiammatoria

allo stress ossidativo indotto dall’inquinamento.

Endotossine (LPS) sul particolato diesel e

nel fumo di tabacco

Ozono e LPS attirano neutrofili

produttori di ROS

Ozono aumenta l'espressione del

TLR-4 solo negli asmatici

The effect of environmental oxidative stress on airway inflammation

Auerbach A et al, 2012 Curr Op Allergy Clin Immunol

Ac glucuronico + N-acetilglucosamina

The effect of environmental oxidative stress on airway inflammation

Auerbach A et al, 2012 Curr Op Allergy Clin Immunol

Ac. Ialuronico alto PM effetto protettivo Ac. Ialuronico basso PM effetto infiammatorio

ROS e ialuronidasi depolimerizzano ac ialuronico ad alto

peso molecolare formando frammenti a basso peso che sono

ligandi del TLR-4 (pro-infiammatori)

The effect of environmental oxidative stress on airway inflammation

Auerbach A et al, 2012 Curr Op Allergy Clin Immunol

House dust mite–induced asthma causes oxidative damage and DNA double-strand breaks in the lungs

Chan TK et al, J Allergy Clin Immunol, 2016

GLUTATIONE

Airway glutathione homeostasis is altered in children with severe asthma: Evidence for oxidant stress

Fitzpatrick AN et al, J Allergy Clin Immunol 2009

65 bambini (m 8 anni) con asma severo BAL

Controlli: 6 bambini con tosse psicogena e 35 adulti sani

Airway glutathione homeostasis is altered in children with severe asthma: Evidence for oxidant stress

Fitzpatrick AN et al, J Allergy Clin Immunol 2009

The Effects of asthma medications on reactive oxygen species production in human monocytes.

Ming-Kai T et al, 2017, J Asthma

Monociti umani incubati con H2O2

pretrattati con

Montelukast,

Salmeterolo / Fluticasone

Budesonide / Formoterolo,

Indacaterolo.

The Effects of asthma medications on reactive oxygen species production in human monocytes.

Ming-Kai T et al, 2017, J Asthma

Guallar E et al, 2013, Ann Int Med

2014

Cellular mechanisms and physiological consequences of redox-dependent signalling

Holmström KM et al, 2015, Nat Rev Molecular Cel Biol

• Oral supplementation with sulforaphane upregulates expression of NRF2-regulated Phase II enzymes (GSTM1, GSTP1, HO1, and NQO1).

• Phase II enzymes in nasal epithelial cells can be induced by 3 days of oral SFN supplementation.

• Application of sulforaphane induced phase II enzymes in B cells and effectively blocked diesel exhaust particle enhancement of IgE-production.

• In primary bronchial epithelial cells exposed to diesel extract, sulforaphane pre-treatment inhibited pro-inflammatory cytokine production by diesel.

The effect of environmental oxidative stress on airway inflammation

Auerbach A et al, 2012 Curr Op Allergy Clin Immunol

Wan J, et al . J Immunol, 2006 Ritz SA, et al. Am J Physiol Lung Cell Mol Physiol, 2007

Riedl MA et al. Clin Immunol, 2009

Il SULFORAFANO dei broccoli

Yale Image Finder

Predictive value of serum uric acid in hospitalized adolescents and adults with acute asthma

Abdulnaby NK et al, 2016, Ther Clin Risk Management

L’acido Urico è un potente antiossidante e un marker di presenza di ROS in eccesso

Predictive value of serum uric acid in hospitalized adolescents and adults with acute asthma

Abdulnaby NK et al, 2016, Ther Clin Risk Management

sUA: 6.3 mg/dl

120 asmatici, 13 – 56 anni

La curcuma

Antioxidant supplementation and exhaled nitric oxide in children with asthma

Tenero L et al, 2016, Allergy Asthma Proc

Misurina

47 bambini (m. 12 anni)

asma moderato – severo,

allergici ai Dermatofagoidi

Curcuma 100 mg Resveratrolo 20 mg Ac. Folico 90 mcg Magnesio 300 mg Zinco 7 mg Vit D 15 mcg

15 gruppo attivo

32 controlli

Antioxidant supplementation and exhaled nitric oxide in children with asthma

Tenero L et al, 2016, Allergy Asthma Proc

Misurina P = 0.003 P = 0.3

Natural antioxidant ice cream acutely reduces oxidative stress and improves vascular function and physical performance in healthy

individuals. Sanguigni V et al, 2016, Nutrition

CONCLUSIONE