Theerasuk Kawamatawong MD, FCCP Assistant Professor of Medicine Division of Pulmonary and Critical Care Medicine Department of Medicine Ramathibodi Hospital Mahidol University Lecture Asthma Foundation of Thailand Saturday July 19 th , 2018 Miracle Grand Hotel 09.00-09.45 What is New in Asthma Lecture Asthma and COPD for HCW 2018
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What is New in Asthma¸œศ_นพ_ธีระ... · Diagnosis of asthma symptoms Features are increase the possibility that patient has asthma More than one symptom (wheeze, shortness
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Theerasuk Kawamatawong MD, FCCP
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Ramathibodi Hospital Mahidol University
Lecture Asthma Foundation of Thailand Saturday July 19th, 2018 Miracle Grand Hotel 09.00-09.45
What is New in AsthmaLecture Asthma and COPD for HCW 2018
Conflict of Interests Disclosures
Theerasuk Kawamatwong MD, FCCP
Department of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
Position: Assistant Professor of Medicine Consultant Chest Physician
Medical Advisory Board: Pfizer, Boehringer Ingelheim, Novartis, Astra Zeneca , MSD and Oxford Immunotech
Speaker Bureau: Glaxo Smith Kline, Astra Zeneca, MSD, Novartis, Pfizer, Takeda, OtsukaTravel grant : Astra Zeneca and Novartis Research funding : Novartis and Otsuka
There is no discussion in off labelled use of medications in my talk
Outline of presentation
• Asthma diagnosis (lung function)
• Asthma assessment (ACT, ACQ)
• Asthma biomarker (FeNo)
• GINA treatment steps
• Treatment for mild asthma (ICS vs ICS/FABA)
• Management of severe asthma
(drugs and non drug treatments: SLIT and BT)
• Biologics and FDA approval
Diagnosis of asthma symptoms
Features are increase the possibility that patient has asthma
More than one symptom (wheeze, shortness of breath, cough , chest tightness)
Symptoms worse at night or in the early morning
Symptoms vary over time and in intensity
Symptoms are triggered by viral infection (cold), exercise, allergen exposure,change in weather, irritant such as care exhaust fume, smoke, strong smell
Global Strategies for Asthma Management and Prevention GINA report 2018
Features decrease the possibility that the patient has asthma
Isolated cough without other respiratory symptoms
Chronic production of sputum
Shortness of breath associated with dizziness, light-headedness, peripheral tingling
Chest pain
Exercise induced dyspnea with noisy inspiration
Diagnosis of asthma Variable airflow limitation
• Confirm presence of airflow limitationDocument that FEV1/FVC is reduced (at least once when FEV1 is low)
(Normal FEV1/ FVC >0.75- 0.80 in healthy adults)
• Confirm variation in lung function is greater than in healthy individualsThe greater the variation, or the more times variation is seen, the greater probability that diagnosis is asthma
• Excessive bronchodilator reversibility (adults: ↑ in FEV1 >12% and >200 mL
• Excessive diurnal variability from 1-2 weeks’ twice-daily PEF monitoring (daily amplitude x 100/daily mean, averaged)
• Significant increase in FEV1 (12%) or PEF (20%) after 4 wks of controller
Summary: role of lung function in asthma
Diagnosis• Demonstrate variable expiratory airflow limitation• Reconsider diagnosis if symptoms and lung function are discordant
Frequent symptoms but normal FEV1: cardiac disease; lack of fitness? Few symptoms but low FEV1: poor perception; restriction of lifestyle?
Risk assessment• Low FEV1 is an independent predictor of exacerbation risk
Adjusting treatment?Utility for adjusting treatment is limited by between-visit variability of FEV1
Measure lung function to monitor progress• At diagnosis and 3-6 m after starting treatment (to identify personal best)
• Periodically (every 1-2 y for most adults (High risk patients)
• Consider long-term PEF monitor for severe asthma/impaired perception
Global Strategies for Asthma Management and Prevention GINA report 2018
Method of measuring asthma controlEfficacy of asthma clinical trials interventions
• Diary data Diary questionsAmbulatory lung function Peak flow variability
• Lung function and AHRSpirometryPeak expiratory flow Lung volume and airway resistance Airway hyper-responsiveness
• Composite score Categorical measure ;WC,PC,UC
(Asthma free days, well control weeks) Continuous measure (numeric)
(ACT, ATAQ, ACSS, ACQ)
• Biomarkers of T2 phenotypeInduces sputum FENO and EBC Serum ECP
• Health related QOL Generic HRQOL questionnaire (SF-36)Specific asthma related questionnaire (AQLQ, mini-AQLQ, LWAQ, AQ-20)
• Worsening of asthma or exacerbation
Primary care consultation Un-scheduled of secondary healthcare utilization ER visit or hospitalization Systemic corticosteroid usage
Helen K Raddel ATS/ERS task force et al. AJRCCM 2009
Cu
rren
t co
ntr
ol
Futu
re r
isk
Question topics ACT(4 weeks)
ACQ (1 week)
Limits daily activities
Shortness of breath
Disrupts sleep
SABA use
Effect of global control
Frequency of wheeze
Pre-bronchodilator FEV1
Asthma composite scores (ACT and ACQ)
Asthma Control Test (ACT) Asthma Control Questionnaire (ACQ)-7 (With FEV1)
Short form ACQ-5 or ACQ-6 (Without FEV1)
ACQ (Juniper et al., 1999)
ACT (Nathan et al., 2004) Schatz M. J Allergy Clin Immunol 2006
r = - 0.89(p<0.001)
ACQ score at baseline
ACTscore at baseline
5
10
15
20
25
0 1 2 3 4 5 6
Good control
Poor controlGood control
Poor control
0.75 1.5
ACT ≥ 20
Correlation between ACT and Asthma Control Questionnaire (ACQ-6)
Persistent allergen exposure Poor adherence or device technique Inadequate ICS dose Risk for exacerbation Steroid resistance
Symptomabsent
Adequate ICS dose Good adherence ICS taper
Adequate ICS doseGood adherenceMonitoring in FENO
ICS withdrawal or dose reduction may result in relapse Poor adherence or device technique
FeNO guidance diagnosis & treatmentAm J of Respir Crit Care Med 2011; 184(5):602-15.
• In steroid-naïve adult with non-specific respiratory symptom, FeNO >50ppb was associated with good short-term response to ICS
• No long-term studies examining the safety of withholding ICS if FENO is low• FeNO cannot be recommended for deciding against treatment with ICS
FeNO guidance in management of Asthma
Study design Dose ICS based on Main results
Smith et al 2005 FeNO > 15 vs.Asthma control
NS reduction exacerbation Sig reduction cumulative dose
ICS
Pijnenburg et al 2005
FeNO >30 plus symptom vs.Symptom only
AHR improve FeNO groupNS reduction exacerbation
Fritsch et al 2005 FeNO> 20 plus symptom vs. FEV1 vs.Symptom plus FEV1
NS outcomeImprove MEF in FeNO group
Shaw et al 2007 FeNO >26 ppb plus ACQ vs.ACQ
NS outcomeReduced ICS dose FeNO group
Szefler et al 2008 FeNO + AC vs. AC NS exacerbationIncreased dose in FeNO group
No significant difference in exacerbation with FENO-guided treatment compared with treatment based on current guidelinesFeNO-guided therapy is not recommended for general asthma population at present
Controller medications
Inhaled glucocorticosteroids
Leukotriene modifiers
Long-acting inhaled β2-agonists
Theophylline
Cromones
Long-acting oral β2-agonists
Anti-IgE, Anti-IL-5, Anti-IL-5R
Systemic glucocorticosteroids
Rapid-acting inhaled β2-agonist
Inhaled anticholinergics
Short-acting oral β2-agonists
Theophylline
Systemic glucocorticosteroids(for exacerbation)
Reliever medications
STEP1
Consider low dose
ICS
As needed short-acting β2 agonist (SABA)
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add titropiumHigh dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Recommendation for starting ICS in asthma
Presenting symptoms Preferred initial controller
Asthma symptoms or SABA less than twice a monthNo waking up due to asthma in the last month No risk factor for exacerbation & exacerbation in last year
No controller (Evidence D)
Infrequent asthma symptoms, but 1 or more risk factor for exacerbation
Low dose ICS (Evidence D)
Asthma symptoms or SABA between 2/m and 2 /w, or patients wake due to asthma 1 or more /mo
Low dose ICS (Evidence B)
Asthma symptoms or need for SABA more than 2/week Low dose ICS (Evidence A)
Troublesome asthma symptoms most day: or waking due to asthma 1/wk or more, especially if any risk factor exist
Medium ICS (Evidence A) or Low ICS/LABA (Evidence A)
Initial presentation is with severely uncontrolled asthma or with an acute exacerbation
Short course oral CS High dose ICS (Evidence A) or Mod ICS/LABA (Evidence D)
Global Strategies for Asthma Management and Prevention GINA report 2018
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 1
As-needed inhaled short-acting beta2-agonist (SABA) (very few patients)
Consider adding regular low dose ICS to reduce the risk of serious exacerbations
As needed short-acting β2 agonist (SABA)
Equivalent dose of inhaled corticosteroidAdult and adolescents (12 y and older)
ICS/SALMMaintenance ICS/SAML dose to highestConsider adding separate ICS inhaler for higher ICS
Oral prednisolone 1 mg/kg up to 50 mg/d 5-7 d
Increase frequency of SABA or low dose ICS/FORM
Increase ICS component 2 x dose to high dose (2000 mg BDP equivalent)
WAAP
Global Strategies for Asthma Management and Prevention GINA report 2015
4 puff BID
16 puff PRN
ICS/LABA in single inhaler as reliever therapy (ICS/FABA) in intermittent and mild asthma:
Proof concept study and meta-analysis (6 RCTs)
Pro
po
rtio
n o
f Ex
acer
bat
ion
1.0
0.9
0.8
0.7
0.6
0 100 200 300
FABA
ICS/FABA
ICS
Day after randomization
G Wang et al. Respiratory Research 2017, 18:203
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Step 5 Refer to add-on
RX STEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 4
Tiotropium SMI add-on (age ≥12 y) with a history of exacerbations Adults: consider adding SLIT for HDM (Non-pharmacological therapy)Trial of high dose combination ICS/LABAIncrease dosing frequency (for budesonide-containing inhalers)Add-on LTRA or low dose theophylline
As needed short-acting β2 agonist (SABA)
Step 4.5 Tiotropium bromide
Tiotropium Respimat in asthma clinical trial development program
Adult Pediatric
Kerstjens et al JACI 2011Phase II POC Add-on to ICS/LABA
Prima TinA-asthma Kerstjens et al NEJM 2012
Twin Phase III Add-on to ICS
Bateman et al JACI 2011Phase II POC Add-on to ICS
Grazia TinA-asthma Pagalaro et al AAAAI 2014
Twin Phase III Add-on to low ICS
Mezza TinA-asthma Kerstjens et al NEJM 2012
Twin Phase III Add-on to ICS
Coden TinA –asthma Japanese local registration
Add on to ICS+/-LABA
205, 424Phase II safety/ 12-17 YAdd-on to at lease ICS
205, 425Phase II safety/ 6-11 YAdd-on to at lease ICS
205, 443Phase II/III safety/ 1-5Y
Ruba Tin A-asthma Phase III in 12-17 y
Add-on to at least ICS
Pensie TinA-asthma Phase III in 12-17 y
Add-on to ICS +≥1 controller
205, 411Phase II posology
Add-on to ICS
18 trails in over 6,000 patients
Age groups 1-5 years
6-11 years 12-17 years ≥18 years
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Sputum guidance
Step 5 ReferSTEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
ReslizumabBenralizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 5 Preferred option: refer specialist investigation & consider add-on RxAdd-on tiotropium (age ≥12 y) with history of exacerbationsAdd-on anti-IgE for severe allergic asthma (omalizumab) Add-on biologics for severe eosinophilic asthma• Anti-IL5 [mepolizumab (SC, ≥12 y) or reslizumab (IV, ≥18 y)]• Anti-IL5R [benralizumab (SC, ≥12 y)]
As needed short-acting β2 agonist (SABA)
STEP1
Consider low dose
ICS
STEP 2Low dose ICS
Leukotriene receptor antagonist Intermittent ICS
Add tiotropium High dose ICS
+LTRA (or + Theophylline)
Add low dose OCS
Sputum guidance
Step 5 ReferSTEP 3 Low dose ICS-LABA
Preferred controller choice
Other controller choice
Reliever
Mod/high dose ICS Low dose ICS
+LTRA(or + Theophylline)
As needed SABA or low dose ICS/fomoterol
STEP 5
Refer to add-on treatment Tiotropium
OmalizumabMepolizumab
ReslizumabBenralizumab
STEP 4
Med/ high ICS /LABA
Global Strategies for Asthma Management and Prevention GINA report 2018
Step 5
Other add-on treatment options • Sputum-guided treatment: in specialized centers