update sulla terapia dell’asma - fimpnapoli.it fimp 2018... · teoria del flogisto la combustione...
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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?
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
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.
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
“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
“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
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)
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…
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
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
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
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
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
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