ΒΡΟΓΧΙΚΟ ΑΣΘΜΑ. ΠΕΤΡΟΣ ΜΠΑΚΑΚΟΣ Αναπλ. Καθηγητής Πνευμονολογίας ΕΚΠΑ

ΒΡΟΓΧΙΚΟ ΑΣΘΜΑ ΠΕΤΡΟΣ ΜΠΑΚΑΚΟΣ Αναπλ. Καθηγητής Πνευμονολογίας ΕΚΠΑ

GINA 2017

GINA 2015 GINA Global Strategy for Asthma Management and Prevention Not a guideline, but a practical approach to managing asthma in clinical practice A global strategy, relevant to both low and high resource countries Evidence-based and clinically-oriented Provides clinical tools and measurable outcomes

GINA 2015 Key changes in GINA 2015 update Add-on tiotropium by soft-mist inhaler is a new other controller option for Steps 4 and 5, in patients 18 years with history of exacerbations Management of asthma in pregnancy Monitor for and manage respiratory infections During labor/delivery, give usual controller, and SABA if needed Watch for neonatal hyperglycaemia (especially in preterm babies) if high doses of SABA used in previous 48 hours Breathing exercises Evidence level down-graded from A to B following review of quality of evidence and a new meta-analysis The term breathing exercises (not techniques ) is used, to avoid any perception that a specific technique is recommended

GINA 2015 Other changes for clarification in GINA 2015 update Assessment of risk factors: over-usage of SABA High usage of SABA is a risk factor for exacerbations (Patel et al, CEA 2013) Very high usage (e.g. >200 doses/month) is a risk factor for asthma-related death (Haselkom, JACI 2009) Beta-blockers and acute coronary events If cardioselective beta-blockers are indicated for acute coronary events, asthma is not an absolute contra-indication. These medications should only be used under close medical supervision by a specialist, with consideration of the risks for and against their use Asthma-COPD Overlap Syndrome (ACOS) The aims of the chapter are mainly to assist clinicians in primary care and nonpulmonary specialties in diagnosing asthma and COPD as well as ACOS, and to assist in choosing initial treatment for efficacy and safety A specific definition cannot be provided for ACOS at present, because of the limited populations in which it has been studied ACOS is not considered to represent a single disease; it is expected that further research will identify several different underlying mechanisms

Key changes in GINA 2016 stepwise treatment Step 3 Low-dose fluticasone furoate/vilanterol an option for Step 3 Step 4 Tiotropium now an add-on option for adolescents (age 12 years) as well as adults, with a history of exacerbations Step 5: refer for expert investigation and add-on treatment, such as: Add-on tiotropium by mist inhaler for patients age 12 years with a history of exacerbations Add-on omalizumab (anti-ige) for severe allergic asthma Add-on mepolizumab (anti-il5) for severe eosinophilic asthma ( 12 years) Sputum-guided treatment, if available Low, medium and high ICS doses Fluticasone furoate: 100mcg (low dose); 200mcg (high dose) Stepping down ICS when asthma well-controlled now Evidence A (Hagan et al, Allergy 2014) What s new in GINA 2016

Key changes in GINA 2016 - Maternal diet in pregnancy primary prevention No firm evidence that ingestion of any specific foods in pregnancy increases risk for asthma Instead, maternal intake of foods commonly considered allergenic (peanut, milk) is associated with a decrease in allergy and asthma in offspring (Bunyavanich et al, JACI 2014; Maslova et al, JACI 2012, 2013) Therefore, no dietary changes are recommended during pregnancy for prevention of allergies or asthma Maternal obesity in pregnancy Maternal obesity and maternal weight gain in pregnancy are associated with an increased risk for asthma in children (Forno et al, Pediatrics 2014) However, no recommendations can be made at present, as unguided weight loss in pregnancy should not be encouraged Dampness and mold For children at risk of asthma, dampness, visible mold and mold odor in the home are associated with increased risk of developing asthma (Quansah et al, PLoS ONE 2012)

What s new in GINA 2017? KEY CHANGES IN GINA 2017 Measurement of lung function - changes Frequency of measurement of lung function Lung function should be assessed at diagnosis or start of treatment; after 3 6 months of controller treatment to assess the patient s personal best FEV 1 ; and periodically thereafter Periodically has been clarified Most adults: lung function should be recorded at least every 1-2 yrs More frequently in higher risk patients More frequently in children based on severity and clinical course Lung function trajectories Children with persistent asthma may have reduced growth in lung function, and some are at risk of accelerated decline in lung function in early adult life [McGeachie, NEJMed 2016] Low resource areas Poverty is commonly associated with spirometric restriction, so where possible, both FEV 1 and FVC should be recorded

GINA 2015 Το φορτίο του άσθματος Συχνό χρόνιο νόσημα 300 εκατομμύρια πάσχοντες παγκοσμίως Ο επιπολασμός αυξάνεται σε πολλές χώρες, ιδιαίτερα στα παιδιά Κύρια αιτία αποχής από το σχολείο ή την εργασία Το κόστος του άσθματος είναι πολύ υψηλό Οι αναπτυγμένες χώρες ξοδεύουν 1-2% του συνολικού κόστους για την υγεία στο άσθμα Οι αναπτυσσόμενες χώρες αναμένεται να αντιμετωπίσουν αύξηση λόγω του αυξανόμενου επιπολασμού του άσθματος Το πτωχά ελεγχόμενο άσθμα είναι «ακριβό» Η επένδυση σε μέτρα πρόληψης αναμένεται να αποφέρει μείωση του κόστους στην επείγουσα αντιμετώπιση

NEW DEFINITION

Definition of asthma Το άσθμα είναι μια ετερογενής νόσος, που συνήθως χαρακτηρίζεται από χρόνια φλεγμονή των αεραγωγών. Ορίζεται ως ιστορικό αναπνευστικών συμπτωμάτων, όπως βήχας, συριγμός, δύσπνοια και σφίξιμο στο στήθος που μεταβάλλονται στο χρόνο και σε ένταση, σε συνδυασμό με μεταβλητό περιορισμό της εκπνευστικής ροής του αέρα. GINA 2015

GINA 2015 Diagnosis of asthma The diagnosis of asthma should be based on: A history of characteristic symptom patterns Evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests Document evidence for the diagnosis in the patient s notes, preferably before starting controller treatment It is often more difficult to confirm the diagnosis after treatment has been started Asthma is usually characterized by airway inflammation and airway hyperresponsiveness, but these are not necessary or sufficient to make the diagnosis of asthma.

ΔΙΑΓΝΩΣΗ ΑΣΘΜΑΤΟΣ - ΣΥΜΠΤΩΜΑΤΑ Αυξημένη πιθανότητα ότι τα συμπτώματα οφείλονται σε άσθμα εάν: - Περισσότερο από ένα είδος συμπτωμάτων (συριγμό, δύσπνοια, βήχας, σφίξιμο στο στήθος) - Τα συμπτώματα συχνά χειρότερα κατά τη νύχτα ή νωρίς το πρωί - Τα συμπτώματα ποικίλλουν στη διάρκεια του χρόνου και σε ένταση - Τα συμπτώματα προκαλούνται από ιογενείς λοιμώξεις, άσκηση, έκθεση σε αλλεργιογόνα, αλλαγές στον καιρό, γέλιο, ερεθιστικές ουσίες (όπως τα καυσαέρια των αυτοκινήτων, ο καπνός, ή έντονες μυρωδιές) Μειωμένη πιθανότητα ότι τα συμπτώματα οφείλονται σε άσθμα εάν: - Μεμονωμένες βήχα χωρίς άλλα συμπτώματα από το αναπνευστικό - Χρόνια παραγωγή πτυέλων - Δύσπνοια που σχετίζεται με ζάλη ή μούδιασμα των άκρων - Κυριαρχεί ο πόνος στο στήθος - Δύσπνοια στην άσκηση που συνοδεύεται από εισπνευστικό συριγμό (stridor) GINA 2015

ΦΥΣΙΚΗ ΕΞΕΤΑΣΗ ΕΚΠΝΕΥΣΤΙΚΟΙ ΜΟΥΣΙΚΟΙ ΡΟΓΧΟΙ Η ΦΥΣΙΟΛΟΓΙΚΗ ΕΞΕΤΑΣΗ ΤΟΥ ΘΩΡΑΚΑ ΔΕΝ ΑΠΟΚΛΕΙΕΙ ΤΟ ΑΣΘΜΑ

ΠΝΕΥΜΟΝΙΚΗ ΛΕΙΤΟΥΡΓΙΑ

Typical spirometric tracings Volume Normal Flow FEV 1 Asthma (after BD) Asthma (before BD) Normal Asthma (after BD) Asthma (before BD) 1 2 3 4 5 Time (seconds) Volume Note: Each FEV 1 represents the highest of three reproducible measurements GINA 2016 Global Initiative for Asthma

BRONCHODILATION TEST Baseline FEV 1 (<80% προβλ.) Inhalation 400 μg salbutamol (4 puffs) Increase FEV 1 12% AND 200 ml Reversibility (compatible with asthma)

GINA 2015, Box 1-2 ΔΙΑΓΝΩΣΗ ΑΣΘΜΑΤΟΣ ΠΕΡΙΟΡΙΣΜΟΣ ΡΟΗΣ ΑΕΡΑ Επιβεβαιώστε την παρουσία περιορισμού της ροής αέρα (airflow limitation): - Επιβεβαιώστε ότι FEV1 / FVC είναι μειωμένος (τουλάχιστον μία φορά, όταν ο FEV1 είναι χαμηλός) - O λόγος FEV1 / FVC είναι κανονικά> 0,75-0,80 σε υγιείς ενήλικες Επιβεβαιώστε ότι η μεταβλητότητα των αναπνευστικών λειτουργιών είναι μεγαλύτερη από ό,τι στα υγιή άτομα: - Αυξημένη αναστρεψιμότητα μετά βρογχοδιαστολή (Ενήλικες: Αύξηση του FEV1> 12% και> 200 ml, Παιδιά: αύξηση >12% predicted)) - Αυξημένη μεταβλητότητα της PEFR μετά από δύο φορές καθημερινή μέτρηση για1-2 εβδομάδες (daily amplitude x 100/daily mean, averaged) - Σημαντική αύξηση FEV1 ή PEF μετά από 4 εβδομάδες θεραπείας με ρυθμιστικό φάρμακο (increase in FEV1 by >12% and >200 ml (or PEFR by >20%)) - Εάν οι αρχικές δοκιμασίες είναι αρνητικές - Επανέλαβε όταν ο ασθενής είναι συμπτωματικός ή μετά τη διακοπή των βρογχοδιασταλτικών - Άλλες δοκιμασίες (Θετική δοκιμασία βρογχικής πρόκλησης (a negative test in a patient not taking ICS can help to exclude asthma, but a positive test does not always mean that a patient has asthma)

REVERSIBILITY The term reversibility is generally applied to rapid improvements in FEV 1 (or PEF) measured within minutes after inhalation of a rapid-acting bronchodilator e.g 200-400μg salbutamol) or more sustained improvement over days or weeks after the introduction of effective controller treatment such as inhaled corticosteroids.

COMMENTS REGARDING REVERSIBILITY Reversibility is higher when baseline VC or FEV 1 are lower regardless of whether the response is calculated as numerical difference or % of baseline value Thus, reversibility is greater in patient-based studies compared to studies in the general population. The lack of reversibility in a test does not preclude clinical response to bronchodilator treatment. Pellegrino R et al, Interpretative strategies for lung function tests, Eur Respir J 2005

VARIABILITY The term variability refers to changes (improvement or deterioration) in symptoms accompanied by changes in lung function occurring over time. Variability may be experienced over the course of one day (diurnal variability) from day-to-day, from month to month or seasonally.

Peak Flow Meter

Peak Flow Meter Peak Expiratory Flow Rate (PEFR) Easy to use, inexpensive, portable, plastic Adults and children > 5y.o Asthma diagnosis Diurnal variation >10% TOO WIDE RANGE OF PREDICTED VALUES (ideally compared to patient s previous personal best) Follow up Assessment of night symptoms

PEFR (%Predicted) Diurnal variation of PEFR Variation <20% Variation >20% 100% 100% 50% 50% Night peak flow Morning peak flow Maximum Minimum PEFR Variation PEFR = (X100) Mean PEFR

Patient with respiratory symptoms Are the symptoms typical of asthma? YES NO Clinical urgency, and other diagnoses unlikely Detailed history/examination for asthma History/examination supports asthma diagnosis? YES NO Further history and tests for alternative diagnoses Alternative diagnosis confirmed? Perform spirometry/pef with reversibility test Results support asthma diagnosis? NO YES Repeat on another occasion or arrange other tests Confirms asthma diagnosis? NO Empiric treatment with ICS and prn SABA YES NO YES Review response Diagnostic testing within 1-3 months Consider trial of treatment for most likely diagnosis, or refer for further investigations Treat for ASTHMA Treat for alternative diagnosis GINA 2015, Box 1-1 (4/4) Global Initiative for Asthma

ΒΡΟΓΧΙΚΗ ΥΠΕΡΑΝΤΙΔΡΑΣΤΙΚΟΤΗΤΑ ΑΜΕΣΗ Ισταμίνη Μεταχολίνη ΕΜΜΕΣΗ Άσκηση Μανιτόλη

ΔΟΚΙΜΑΣΙΕΣ ΠΡΟΚΛΗΣΗΣ Ισταμίνη, μεταχολίνη Συνήθως FEV 1 >80% προβλ. FEV 1 > 20% baseline PC 20 4 mg/ml, PD 20 0.8 mg Άσκηση FEV 1 10% baseline μετά από άσκηση (8-min running protocol)

ΔΟΚΙΜΑΣΙΑ ΠΡΟΚΛΗΣΗΣ ΜΕ ΜΕΤΑΧΟΛΙΝΗ FEV 1 (L) Baseline (100%) Metacholine Concentration/Dose PC20 (PD20) -20% Metacholine administration Bronchodilation step HIGH SENSITIVITY LOW SPECIFICITY

ΑΞΙΟΛΟΓΗΣΗ ΑΛΛΕΡΓΙΚΟΥ STATUS - ΑΤΟΠΙΑ Ιστορικό Αναγνώριση παραγόντων κινδύνου Skin prick tests Δεν συμβάλλουν στη διάγνωση του άσθματος Specific serum IgE (RAST) Δεν υπερτερούν σε αξιοπιστία από τα skin prick tests Πιο ακριβά Total IgE Δεν έχει αξία στη διάγνωση της ατοπίας

ΑΛΛΕΡΓΙΚΟ STATUS Η παρουσία αλλεργίας αυξάνει την πιθανότητα διάγνωσης του άσθματος σε ασθενείς με αναπνευστικά συμπτώματα και βοηθά στην αναγνώριση παραγόντων κινδύνου που προκαλούν ασθματικά συμπτώματα σε ορισμένους ασθενείς Θετική δερματική δοκιμασία δεν σημαίνει απαραίτητα αλλεργία γιατί μερικοί έχουν ειδικά αντισώματα χωρίς συμπτώματα

ΠΡΟΚΛΗΤΑ ΠΤΥΕΛΑ Ηωσινόφιλα πτυέλων σε υγιείς μη καπνιστές 0.4% (με 90th percentile 1.1%). Ποσοστό >3% θεωρείται μη φυσιολογικό. 1 Το εύρος των ηωσινόφιλων στα πτύελα σε ασθματικούς ποικίλει από 0-90 %. 1 Μέχρι το 70% ασθματικών που δεν λαμβάνουν ICS 2 και 40-50% αυτών που λαμβάνουν ICS 3,4 με συμπτωματικό άσθμα παρουσιάζουν αυξημένο ποσοστό ηωσινόφιλων στα πτύελα. 1. Louis, R.et al, Am J Respir Crit Care Med, 2000 2 Louis, R et al, Allergy, 2002 3 Gibson, P.G. et al, Chest, 2001 4 Green, R.H. et al, Thorax, 2002

FeNO Το FeNO δεν πρέπει να αξιολογείται διαγνωστικά σε ασθενείς με οξέα συμπτώματα εκ του αναπνευστικού με διάρκεια < 4-8 εβδομάδες για να αποφεύγεται η επίδραση λομώξεων του ανώτερου αναπνευστικού 1 Χαμηλή διαγνωστική αξία του FeNO σε ενεργούς καπνιστές 2 Το FeNO μπορεί να μην είναι εφικτό να διακρίνει μεταξύ άσθματος και αλλεργικής ρινίτιδας 3,4 1 Kharitonov, S.A. et al, Eur. Respir. J., 1995 2 Horvath, I. et al, Respiration, 2004 3 Kostikas, K. et al, Chest, 2008 4 Gratziou et al, Eur Respir J 1999

What s new in GINA 2017? Fraction of exhaled nitric oxide (FENO) changes - UPDATED 2017 Diagnosis of asthma Additional factors that increase or decrease FENO are listed FENO is not helpful in ruling in or ruling out asthma as defined by GINA Assessment of future risk Elevated FENO in allergic patients has been added to the list of independent predictors of exacerbations [Zeiger JACI 2011] Single measurements Results of FENO measurement at a single point in time should be interpreted with caution Controller treatment Given the lack of long-term safety studies, FENO cannot be recommended at present for deciding against treatment with ICS in patients with a diagnosis or suspected diagnosis of asthma. Based on current evidence, GINA recommends treatment with lowdose ICS for most patients with asthma, even those with infrequent symptoms, to reduce the risk of serious exacerbations.

Δ/Δ ΑΣΘΜΑΤΟΣ Localised pathology Inhaled foreign body Endobronchial tumour Vocal cord dysfunction Diffuse airway pathology Chronic obstructive pulmonary disease Eosinophilic bronchitis Post-infectious airway hyperresponsiveness Cystic fibrosis Bronchiectasis Left ventricular failure Other pathologies Gastro-oesophageal reflux Pulmonary embolism Pulmonary eosinophilia syndromes Drug-induced airway hyperresponsiveness

1. Έλεγχος άσθματος 2 domains Εκτίμησε τον έλεγχο των συμπτωμάτων τις 4 τελευταίες εβδομάδες Εκτίμησε παράγοντες κινδύνου για φτωχές εκβάσεις, συμπεριλαμβανομένης της χαμηλής πνευμονικής λειτουργίας 2. Ζητήματα θεραπείας Έλεγξε την τεχνική εισπνοών και τη συμμόρφωση Ρώτησε για ανεπιθύμητες ενέργειες Έχει ο ασθενής ένα γραπτό πλάνο δράσης? Ποιά είναι η στάση του ασθενούς και οι στόχοι της θεραπείας για το άσθμα του? 3. Συνοσηρότητες GINA 2015, BoxΠ 2-1 Εκτίμηση του άσθματος Σκέψου για ρινίτιδα/παραρινοκολπίτιδα, παχυσαρκία, ΓΟΠ, ΣΑΥ, κατάθλιψη, αγχώδεις διαταραχές Οι συνοσηρότητες συμβάλουν στα συμπτώματα και την φτωχή ποιότητα ζωής των ασθματικών

GINA assessment of symptom control A. Symptom control In the past 4 weeks, has the patient had: Daytime asthma symptoms more than twice a week? Any night waking due to asthma? Reliever needed for symptoms* more than twice a week? Yes No Yes No Yes No Any activity limitation due to asthma? Yes No Level of asthma symptom control Wellcontrolled None of these Partly controlled 1-2 of these Uncontrolled 3-4 of these B. Risk factors for poor asthma outcomes Assess risk factors at diagnosis and periodically Measure FEV 1 at start of treatment, after 3 to 6 months of treatment to record the patient s personal best, then periodically for ongoing risk assessment ASSESS PATIENT S RISKS FOR: Exacerbations Fixed airflow limitation Medication side-effects GINA 2016 Box 2-2B (1/4) Global Initiative for Asthma

Assessment of risk factors for poor asthma outcomes Risk factors for exacerbations include: Ever intubated for asthma Uncontrolled asthma symptoms Having 1 exacerbation in last 12 months Low FEV 1 (measure lung function at start of treatment, at 3-6 months to assess personal best, and periodically thereafter) Incorrect inhaler technique and/or poor adherence Smoking Obesity, pregnancy, blood eosinophilia Risk factors for fixed airflow limitation include: No ICS treatment, smoking, occupational exposure, mucus hypersecretion, blood eosinophilia Risk factors for medication side-effects include: Frequent oral steroids, high dose/potent ICS, P450 inhibitors GINA 2016, Box 2-2B (4/4) Global Initiative for Asthma

Assessment of risk factors for poor asthma outcomes Risk Independent* factors for risk exacerbations factors for exacerbations include: include: Ever intubated for asthma Uncontrolled asthma symptoms Having 1 exacerbation in last 12 months Low FEV 1 (measure lung function at start of treatment, at 3-6 months to assess personal best, and periodically thereafter) Incorrect inhaler technique and/or poor adherence UPDATED Smoking 2017 Obesity, Elevated pregnancy, FeNO in adults blood with eosinophilia allergic asthma Obesity, pregnancy, blood eosinophilia * Independent of the level of symptom control GINA 2017, Box 2-2B (2/4) Global Initiative for Asthma

GINA 2015 ΒΑΡΥΤΗΤΑ ΑΣΘΜΑΤΟΣ Πώς? Η βαρύτητα εκτιμάται αναδρομικά από το επίπεδο θεραπείας που απαιτείται για να ελέγχονται τα συμπτώματα και να αποφεύγονται οι παροξύνσεις Πότε? Μετά από αρκετούς μήνες θεραπείας με ρυθμιστικά φάρμακα Η βαρύτητα δεν είναι στατική μεταβάλλεται στο χρόνο ή καθώς διαφορετικές θεραπείες γίνονται διαθέσιμες Κατηγορίες βαρύτητας άσθματος Mild asthma: well-controlled with Steps 1 or 2 (as-needed SABA or low dose ICS) Moderate asthma: well-controlled with Step 3 (low-dose ICS/LABA) Severe asthma: requires Step 4/5 (moderate or high dose ICS/LABA ± add-on), or remains uncontrolled despite this treatment

GINA 2015 Treating to control symptoms and minimize risk Establish a patient-doctor partnership Manage asthma in a continuous cycle: Assess Adjust treatment (pharmacological and non-pharmacological) Review the response Teach and reinforce essential skills Inhaler skills Adherence Guided self-management education Written asthma action plan Self-monitoring Regular medical review

Εκπαίδευση στην τεχνική εισπνοών Εκπαίδευσε τον ασθενή Επανέλαβε και έλεγξε σε κάθε επίσκεψη

Example Of Contents Of An Action Plan To Maintain Asthma Control Your Regular Treatment: 1. Each day take 2. Before exercise, take WHEN TO INCREASE TREATMENT Assess your level of Asthma Control In the past week have you had: Daytime asthma symptoms more than 2 times? No Yes Activity or exercise limited by asthma? No Yes Waking at night because of asthma? No Yes The need to use your [rescue medication] more than 2 times? No Yes If you are monitoring peak flow, peak flow less than? No Yes If you answered YES to three or more of these questions, your asthma is uncontrolled and you may need to step up your treatment. HOW TO INCREASE TREATMENT STEP-UP your treatment as follows and assess improvement every day: [Write in next treatment step here] Maintain this treatment for days [specify number] WHEN TO CALL THE DOCTOR/CLINIC. Call your doctor/clinic: [provide phone numbers] If you don t respond in days [specify number] [optional lines for additional instruction] EMERGENCY/SEVERE LOSS OF CONTROL If you have severe shortness of breath, and can only speak in short sentences, If you are having a severe attack of asthma and are frightened, If you need your reliever medication more than every 4 hours and are not improving. 1. Take 2 to 4 puffs [reliever medication] 2. Take mg of [oral glucocorticosteroid] 3. Seek medical help: Go to ; Address Phone: 4. Continue to use your [reliever medication] until you are able to get medical help.

Stepwise approach to control asthma symptoms and reduce risk Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* anti-ige, anti-il5* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol# Add low dose OCS 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 SLIT added as an option 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. GINA 2017, Box 3-5 (1/8) Global Initiative for Asthma

Stepwise management, SLIT as an add-on option for some patients REMEMBER TO... Provide guided self-management education Treat modifiable risk factors and comorbidities Advise about non-pharmacological therapies and strategies 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 FEV 1 is 70% predicted Consider stepping down if symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised. SLIT: sublingual immunotherapy GINA 2017, Box 3-5 (3/8) (lower part) Global Initiative for Asthma

Treatment other changes in 2017 Step 5 treatment for severe asthma Anti-IL5: reslizumab (IV) added to mepolizumab (SC) for 18 years Step-down from low-dose ICS (Box 3-7) Add-on LTRA may help Insufficient evidence for step-down to as-needed ICS with SABA Side-effects of oral corticosteroids When prescribing short-term OCS, remember to advise patients about common side-effects (sleep disturbance, increased appetite, reflux, mood changes); references added Vitamin D To date, no good quality evidence that Vitamin D supplementation leads to improved asthma control or fewer exacerbations Chronic sinonasal disease Treatment with nasal corticosteroids improves sinonasal symptoms but not asthma outcomes What s new in GINA 2017? Global Initiative for Asthma

Step 1 as-needed inhaled short-acting beta 2 -agonist (SABA) STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 1 (4/8) Global Initiative for Asthma

GINA 2015 Step 1 as-needed reliever inhaler Preferred option: as-needed inhaled short-acting beta 2 - agonist (SABA) SABAs are highly effective for relief of asthma symptoms However. there is insufficient evidence about the safety of treating asthma with SABA alone This option should be reserved for patients with infrequent symptoms (less than twice a month) of short duration, and with no risk factors for exacerbations Other options Consider adding regular low dose inhaled corticosteroid (ICS) for patients at risk of exacerbations

Rate Ratio for Death from Asthma Effects of ICS on asthma mortality: Saskatchewan Health data 2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 ICS Canisters/year (N) Suissa S, N Engl J Med 2000

GINA 2016, Box 3-6 (1/2) Low, medium and high dose inhaled corticosteroids Adults and adolescents Total daily ( 12 dose (mcg) years) Inhaled corticosteroid This is not a table of equivalence, but of estimated clinical comparability Most of the clinical benefit from ICS is seen at low doses 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 furoate (DPI) 100 n.a. 200 Fluticasone propionate (DPI or HFA) 100 250 >250 500 >500 Mometasone furoate 110 220 >220 440 >440 Triamcinolone acetonide 400 1000 >1000 2000 >2000 UPDATED! High doses are arbitrary, but for most ICS are those that, with prolonged use, are associated with increased risk of systemic side-effects

Step 2 low-dose controller + as-needed inhaled SABA STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 2 (5/8) Global Initiative for Asthma

Step 2 Low dose controller + as-needed SABA Preferred option: regular low dose ICS with as-needed inhaled SABA Low dose ICS reduces symptoms and reduces risk of exacerbations and asthma-related hospitalization and death Other options Leukotriene receptor antagonists (LTRA) with as-needed SABA Less effective than low dose ICS May be used for some patients with both asthma and allergic rhinitis, or if patient will not use ICS Combination low dose ICS/long-acting beta2-agonist (LABA) with as-needed SABA Reduces symptoms and increases lung function compared with ICS More expensive, and does not further reduce exacerbations Intermittent ICS with as-needed SABA for purely seasonal allergic asthma with no interval symptoms Start ICS immediately symptoms commence, and continue for 4 weeks after pollen season ends GINA 2016 Global Initiative for Asthma

As monotherapy, ICS display superior efficacy to LTRA in adults and children with persistent asthma ; the superiority is particularly marked in patients with moderate airway obstruction. On the basis of efficacy, the results support the current guidelines recommendation that inhaled corticosteroids are the preferred monotherapy. Chauhan BF, et al. Cochrane Database Syst Rev 2012

Step 3 one or two controllers + as-needed inhaled reliever STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 3 (6/8) Global Initiative for Asthma

Step 3 one or two controllers + as-needed inhaled reliever 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 FEV 1, 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 Other options Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less effective than ICS/LABA) Adults: consider adding SLIT (see Non-pharmacological interventions) Children 6-11 years add LABA (similar effect as increasing ICS) *Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol GINA 2017 UPDATED 2017 Global Initiative for Asthma

«In asthmatic adults inadequately controlled on low doses of inhaled steroids, the addition of LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest.» Ducharme FM, et al. Cochrane Database Syst Rev 2011

LABAs are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV 1. There is evidence of decreased SABA requirement with salmeterol. Fewer adverse events occurred with LABAs (salmeterol and formoterol) compared to theophylline. Tee AK, et al. Cochrane Database Syst Rev 2007

Adding Salmeterol vs. >2x Dose of ICS FLTA4022 VanNoord Vermetten Kalberg Condemi Bloom FLTA4021 Kelsen Johansson Murray Greening Moderate or Severe Exacerbations Busse Pool 0.30 (0.10 to 0.50) -5-4 -3-2 -1 0 1 2 3 4 5 Log odds ratio Favours ICS Favours LABA PLUS: less withdrawals due to asthma, greater FEV 1, morning and evening PEF, and less use of reliever in the SALM group Masoli M, Thorax 2005

ICS + LABA : Better control of inflammation (Sputum eosinophils) % 12 10 BUD 800 µg / day BUD 200 µg / day + FORM 24 µg / day 8 6 4 2 0 Baseline 3 months 1 year Kips et al. AJRCCM 2000

SMART strategy for an ICS/LABA combination including formoterol «If a combination inhaler containing formoterol and budesonide or formoterol and beclomethasone is selected, it may be used for both rescue and maintenance. This approach has been shown to result in reductions in exacerbations and improvements in asthma control in adults and adolescents at relatively low doses of treatment (Evidence A)»

MART2 study: time to first severe exacerbation BECLOMETHASONE/FORMOTEROL PATIENTS WITH EVENTS (251) FOSTER + FOSTER N=852 FOSTER + SALBUTAMOL N=849 LOG RANK CHI SQUARE P- VALUE HAZARD RATIO (95% CI) 99 152 13.002 <0.001 0.64 ( 0.49-0.82) Papi A et al, Lancet Respir Med 2013

Step 4 two or more controllers + as-needed inhaled reliever STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* omalizumab, mepolizumab* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2016, Box 3-5, Step 4 (7/8) Global Initiative for Asthma

Step 4 two or more controllers + as-needed inhaled reliever Before considering step-up Check inhaler technique and adherence Adults or adolescents: preferred option is combination low dose ICS/formoterol as maintenance and reliever regimen*, OR combination medium dose ICS/LABA with as-needed SABA Children 6 11 years: preferred option is to refer for expert advice Other options (adults or adolescents) Tiotropium by mist inhaler may be used as add-on therapy for patients aged 12 years with a history of exacerbations Adults: consider adding SLIT (see Non-pharmacological therapy) Trial of high dose combination ICS/LABA, but little extra benefit and increased risk of side-effects Increase dosing frequency (for budesonide-containing inhalers) Add-on LTRA or low dose theophylline *Approved only for low dose beclometasone/formoterol and low dose budesonide/formoterol UPDATED 2017 GINA 2017 Global Initiative for Asthma

Step 5 higher level care and/or add-on treatment UPDATED 2017 STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS STEP 3 Low dose ICS/LABA** Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium,* anti-ige, anti-il5* Other controller options RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta 2 -agonist (SABA) Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol # Add low dose OCS *Not for children <12 years **For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations GINA 2017, Box 3-5, Step 5 (8/8) Global Initiative for Asthma

Step 5 higher level care and/or add-on treatment Preferred option is referral for specialist investigation and consideration of add-on treatment If symptoms uncontrolled or exacerbations persist despite Step 4 treatment, check inhaler technique and adherence before referring Add-on tiotropium for patients 12 years with history of exacerbations Add-on anti-ige (omalizumab) for patients with severe allergic asthma Add-on anti-il5 (mepolizumab (SC) or reslizumab (IV)) for severe eosinophilic asthma ( 12 yrs) Other add-on treatment options at Step 5 include: Sputum-guided treatment: this is available in specialized centers; reduces exacerbations and/or corticosteroid dose UPDATED 2017 Add-on low dose oral corticosteroids ( 7.5mg/day prednisone equivalent): this may benefit some patients, but has significant systemic side-effects. Assess and monitor for osteoporosis See ERS/ATS Severe Asthma Guidelines (Chung et al, ERJ 2014) for more detail GINA 2017 Global Initiative for Asthma

ΑΝΟΣΟΘΕΡΑΠΕΙΑ Μεγαλύτερο όφελος σε αλλεργική ρινίτιδα Περιορισμένος ρόλος στο άσθμα Πιο επιτυχής σε ασθενείς με ευαισθησία σε 1 αλλεργιογόνο GINA: Specific immunotherapy should be considered only after strict environmental avoidance and pharmacologic intervention, including inhaled glucocorticosteroids, have failed to control a patient s asthma

Anti-IgE στο άσθμα ΜΟΝΟ σε σοβαρό αλλεργικό άσθμα που δεν ελέγχεται με high-dose ICS και/ή απαιτεί per os στεροειδή (+) SPT σε 1 τουλάχιστον ολοετήσιο αεροαλλεργιογόνο Υποδόρια χορήγηση 1 ή 2 φορές / μήνα Πόσο καιρό?

ALLERGIC ASTHMA IS THE MOST FREQUENT PHENOTYPE OF SEVERE ASTHMA Percentage of patients (%) with allergic asthma in severe asthma studies 2 3 4 1. ENFUMOSA. Eur Respir J 2003; 2. Moore WC, et al. J Allergy Clin Immunol 2007; 3. Haselkorn T, et al. J Asthma 2006; 4. U-BIOPRED Study Group ERJ 2015

Mean number of exacerbations REDUCTION OF EXACERBATIONS Evidence from RCTs Evidence from Real-Life studies Clinically significant exacerbations Severe clinically significant exacerbations n=847 n=842 n=686 n=691 n=620 n=625 Rodrigo GJ, et,al. Chest 2011 Braunstahl G-J, et al. Respir Med 2013

% change in mean maintenance OCS dose Patients on OCS (%) REDUCED OCS USE Evidence from RCTs Evidence from Real-Life studies (n=916) (n=734) (n=643) *OAT = optimized asthma therapy (i.e. high-dose inhaled corticosteroids plus long-acting b 2 - agonist ± controller). Mean (SD) total daily OCS dose, mg 15.5 (14.0) 7.7 (10.9) 5.8 (8.9) Siergiejko Z, et al. Cur. Med. Research & Opinion 2011 Braunstahl G-J, et al. Respir Med 2013

Annualized rates Mean (SD) number REDUCED HCU SOURCE Evidence from RCTs Evidence from Real-Life studies RR 47% RR: 47% p=0.003 p<0.0001 9 8 7 Hospitalizations Emergency visits 6 5 Unscheduled doctor visits RR: 52% 4 p=0.041 RR: 61% 3 p=0.013 2 1 0 0.7 1.8 3.8 0.2 0.1 0.7 0.1 0.1 0.4 Baseline Month 12 Month 24 Pre-treatment (n=916) Month 12 (n=734) Month 24 (n=643) Bousquet J, et al. Allergy 2005 Braunstahl G-J, et al. Respir Med 2013

Mean (SD) change from baseline QOL IMPROVEMENT Evidence from RCTs Evidence from Real-Life studies n=419 n=294 n=364 n=523 n=537 n=315 n=2452 AQLQ Mini-AQLQ Chipps B, et al. Curr Med Res Opin 2006 Braunstahl G-J, et al. Respir Med 2013