Drugs for asthma Adrenaline Oral steroids Theophylline, 2011 PDE4i Short-acting B 2 Disodium Cromoglycate -Nedocromil Inhaled corticosteroids Anticholinergics Long – acting B 2 LTR antagonists Long- acting anticholinergic Anti IgE Ultra- long acting steroid and acting steroid and B 2

Definizione di asma bronchiale IERI Malattia caratterizzata da dispnea, ad insorgenza a crisi parossistiche, determinate da stenosi bronchiale per spasmo della muscolatura liscia, edema ed ipersecrezione, nella cui patogenesi può avere importanza il meccanismo allergico OGGI Patologia infiammatoria cronica delle vie aeree nella quale giocano un ruolo molte cellule, in particolare i mastociti, gli eosinofili, i linfociti T, e numerosi mediatori chimici, in grado di provocare alterazioni strutturali delle vie aeree e rimodellamento, a loro volta responsabili di una riduzione della funzione respiratoria

Source: Peter J. Barnes, MD Asthma Inflammation: Cells and Mediators

© Global Initiative for Asthma 3/04/2015 Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. Definition of asthma NEW! GINA 2014

A possible new definition of asthma: clinical syndrome or heterogeneous disease GINA 2014, draft

Il gomitolo dell’asma L. Allegra, tanti anni fa…

Asthma : defining of the persistent phenotypes S. Wenzel 2006; 368 : 804

Different asthma phenotypes Wenzel, Lancet 2007

Paucigranulocytic asthma Neutrophylic- eosinophylic asthma Neutrophylic asthma Eosinophylic asthma 8% 20% 31% 41% Inflammatory phenotypes

Boulet, ERJ 2009 Main comorbidities in asthma © 2010 PROGETTO LIBRA 24

Current smokers with asthma have greater rate of exacerbations, despite ICS or ICS/LABA treatment Pedersen et al, JACI 2007

Boulet, ERJ 2009 Main comorbidities in asthma © 2010 PROGETTO LIBRA 26

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Prevalence of comorbidities Novelli et al, ERS 2013

Predictors of poor control, lower lung function and eosinophilic phenotype Poor controlLower lung function (Post-BD FEV1<80%) Eosinophilic phenotype OR (CI 95%) Obesity5.3 ( ) *1.7 ( )0.6 ( ) Nasal polyps0.4 ( )3.6 (1,2-11.3) *5.5 ( ) * GERD1.8 ( )0.6 ( )0.4 ( ) Novelli et al, ERS 2013

Asthma: a heterogeneous disease Symptoms –Non specific –Blunted by bronchodilators or poor perception Risk factors –Atopic vs non atopic –Young vs older patients Mechanisms –Dfferent pattern of airway inflammation –Different mechanisms (non-inflammatory ?) Importance of functional assessment –Reversible obstruction –Bronchial hyperresponsiveness –Wide variability over time of pulmonary function

Primary role of lung function variability for diagnosis GINA 2014, draft

GINA guidelines Main points for clinical application Definition and assessment of asthma –Clinical and functional assessment –Severity vs control Main outcomes in asthma management –Reach and maintain asthma control –Consider future risk –The value of maintaining asthma control »Impact on natural history Strategies for maintaining asthma control –Role of ICS/LABA combination –Flexible dose according »Control: Step-up vs step-down »Phenotypes: high vs low airway inflammation

Classificazione di Gravità prima dell’inizio del trattamento Sintomi Sintomi notturni FEV 1 o PEF STEP 4 Grave Persistente STEP 3 Moderato Persistente STEP 2 Lieve Persistente STEP 1 Intermittente Continui Attività fisica limitata Quotidiani Attacchi che limitano L’attività > 1 volta/settimana ma < 1 volta / giorno < 1 volta/settimana Frequenti > 1 volta Alla settimana > 2 volte al mese  2 volte al mese FEV1  60% predetto Variabilità PEF> 30% FEV % predetto Variabilità PEF > 30% FEV1  80% predetto Variabilità PEF 20-30% FEV1  80% predetto Variabilita PEF < 20% CLASSIFICAZIONE DI GRAVITÀ Caratteristiche cliniche in assenza di terapia La presenza di almeno uno dei criteri di gravità è sufficiente per classificare un paziente in un determinato livello di gravità

Shaded green - preferred controller options TO STEP 3 TREATMENT, SELECT ONE OR MORE: TO STEP 4 TREATMENT, ADD EITHER

Levels of Asthma Control (Assess patient impairment) Characteristic Controlled (All of the following) Partly controlled (Any present in any week) Uncontrolled Daytime symptoms Twice or less per week More than twice per week 3 or more features of partly controlled asthma present in any week Limitations of activities NoneAny Nocturnal symptoms / awakening NoneAny Need for rescue / “reliever” treatment Twice or less per week More than twice per week Lung function (PEF or FEV 1 ) Normal < 80% predicted or personal best (if known) on any day Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side effects)

controlled partly controlled uncontrolled exacerbation 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 STEPS REDUCEINCREASE STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 REDUCE INCREASE

Main objectives in asthma treatment: control vs future risk ATS Statement, AJRCCM 2009

Main objectives in asthma treatment: control vs future risk ATS Statement, AJRCCM 2009

Future risk Expressed by –Low FEV1 –Persistent exposure to allergen or irritants (smoke) –Comorbidities –Persistent sputum or blood eosinophilia –Specific phenotypes (?) Consequences –Maintenance treatment vs step-down –Choise in the drugs/devices

Current level of control may predict the risk of future exacerbations Bateman et al, JACI 2010

Assessment of overall asthma control GINA 2014, draft

GINA guidelines Main points for clinical application Definition and assessment of asthma –Clinical and functional assessment –Severity vs control Main outcomes in asthma management –Reach and maintain asthma control –Consider future risk –The value of maintaining asthma control »Impact on natural history Strategies for maintaining asthma control –Role of ICS/LABA combination –Flexible dose according »Control: Step-up vs step-down »Phenotypes: high vs low airway inflammation

ICS/LABA combination therapy First choice in a large part of asthmatic patients »From step 3 »Sometimes associated with other drugs »Effective on all “outcomes” of the disease Simptoms, pulmonary function, exacerbations Complementary and/or synergic Safety demonstrated by several studies –Cochrane Database Syst Rev, apr & jul 2009, jan 2010 Effective also in step-down as single daily dose Effective also as rescue medication

CSI = corticosteroidi inalatori; LABA = long-acting β 2 -agonisti; LR = a lento rilascio * nei pazienti con asma e rinite rispondono bene agli anti-leucotrieni ** nei pazienti allergici ad allergeni perenni e con livelli di IgE totali sieriche compresi tra 30 e 700 U/ml APPROCCIO PROGRESSIVO ALLA TERAPIA DELL’ASMA NELL’ADULTO Controllo ambientale e Immunoterapia quando indicata Programma di educazione β 2 -agonisti a breve azione al bisogno aggiungere 1 o più: Anti-leucotrieni Anti-IgE (omalizumab) ** Teofilline-LR CS orali aggiungere 1 o più: Anti-leucotrieni Teofilline-LR CSI a bassa dose + anti-leucotrieni * CSI a bassa dose + teofilline-LR CSI a dose medio-alta Anti-leucotrieni * Cromoni Altre opzioni (in ordine decrescente di efficacia) Opzione principale CSI a alta dose + LABA CSI a media dose + LABA CSI a bassa dose + LABA CSI a bassa dose β 2 -agonisti a breve azione al bisogno STEP 5STEP 4STEP 3STEP 2STEP 1 Cicli di CSI o CSI+LABA? CSI+LABA a basso dosaggio ? Dose aggiuntiva di CSI+LABA

How to improve asthma control ? Frequent assessment of control –Regular use of ACT –Periodic assessment (APPs) «Tailoring» asthma treatment –In selected phenotypes »«heterogeneity» of asthma –Balance between ICS and LABA