what is new in asthma¸œศ_นพ_ธีระ... · diagnosis of asthma symptoms features are...

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


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)

Numeric data

MCID (Minimal Clinical Important Difference)

• Symptom score (Patient perceived improvement ) = -0.31 point(0-6 points baseline 3)

• Reliever use (Patient perceived improvement ) = -0.83 puffs/day (5.4 puffs/day baseline)

• PEF (Patient perceived improvement )= 18.8 L/min • ACQ score change =0.5

(0-6 point baseline 1.5)

• Clinically relevant MCID of morning PEF = 15-20 L/min

Helen K Raddel ATS/ERS task force et al. AJRCCM 2009

Risk factor of poor outcome (Future risk)

Risk factors of exacerbation

• Uncontrolled symptoms

• High SABA use (≥3 canisters/yr)

• ≥1 exacerbation in last 12 mo

• Low FEV1; high BD reversibility

• Incorrect inhaler technique and/or poor adherence

• Smoking

• Obesity, chronic rhinosinusitis,

• pregnancy

• Blood eosinophilia

• Elevated FeNO in adults with allergic asthma taking ICS

• Ever intubated for asthma

Risk factors for developing fixed AO

•No ICS treatment

•Smoking

•Occupational exposure

•Mucus hypersecretion

•Blood eosinophilia

•Pre-term birth, low BW

Risk factors of medication side effect

•Frequent oral steroids

•High dose/potent ICS

•P450 inhibitors

GINA 2018

Poor asthma outcome

Having 1 or more risk factors increase risk of exacerbation •even if symptoms are well controlled

Additional risk factors, even if the patient has few symptoms

L-Arginine

Arginase

L-Ornithine Polyamine

L–proline

Agonists

Ca2+Ep

ith

eliu

m

Epith

elium

in

flamm

atory cells

L citruline

cNOS

NO

Ca2+

NA

NC

ner

ve

iNOS

Reductase Oxygenase

O2 O2- NO O2 L citruline

nNOS

L citruline

ONOO-

ASM

cGMPAgonists Ca2+

NO

Airway contraction Airway relaxation

AHR

AHR Inflammation Cytotoxicities

Th2 cytokines Airway remodeling

Pro-inflammatory cytokineNF-kB

Factors affecting FeNO level

Elevated FeNO Reduced FeNO

Airway infection Spirometric maneuver

Allergic rhinitis Exercise

Nitrate-rich diet Alcohol consumption

Bronchodilator Bronchoconstriction

Ciliary dyskinesia

Pulmonary hypertension

Smoking

ICS therapy

FeNO modestly associated with levels of blood & sputum eosinophils

Am J of Respir Crit Care Med 2011; 184(5):602-15.

Parameters FENO < 25 ppb (<20 ppb in children)

FENO 25-50 ppb(20-35 in children)

FENO > 50 ppb (>35 in children )

Diagnosis

Symptoms present during past 6 wk

Eo inflammation unlikely Alternative DXUnlikely to benefit from ICS

Be cautiousEvaluate clinical context Monitor FeNO change over time

Eosinophilic inflammation likely

Likely to benefit from ICS

Monitoring in patient with diagnosed asthma

Symptomspresent

Probable alternative DXUnlikely to benefit from ICS

Persistent allergen exposure Inadequate ICS dose Poor adherence Steroid resistance

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


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)


STEP1

Consider low dose

ICS

STEP 2Low dose ICS


Add tiotropium High dose ICS


Add low dose OCS





Reliever




STEP 5



STEP 4

Med/ high ICS /LABA


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


Equivalent dose of inhaled corticosteroidAdult and adolescents (12 y and older)

Estimated equivalent daily dose inhaled corticosteroid (g)

Drug Low Medium High

Beclomethasone dipropionate (CFC) 200-500 >500-1000 >1000

Beclomethasone dipropionate (HFA) 100-200 >200-400 >400

Budesonide (DPI) 200-400 >400-800 >800

Ciclesonide (HFA) 80-160 160-320 >320

Fluticasone propionate (DPI) 100-250 250-500 >500

Fluticasone propionate (HFA) 100-250 250-500 >500

Mometasone fuorate 110-220 220-440 >440

Triamcinolone 400-1000 >1000-2000 >2000

STEP1

Consider low dose

ICS

STEP 2Low dose ICS




Add low dose OCS





Reliever




STEP 5



STEP 4

Med/ high ICS /LABA


Step 2

Preferred option: regular low dose ICS with as-needed SABAOther options

Leukotriene receptor antagonists (LTRA) with as-needed SABAIntermittent ICS with as-needed SABA for purely seasonal

allergic asthma with no interval symptoms


Stepwise approach for asthma treatmentBefore adjusting treatments by adding LABA or increasing ICS/LABA

Check …..

• Incorrect diagnosis

• Incorrect inhaler technique

• Poor adherence

• Persistent exposure at home/work to agents such as allergen, tobacco smoke, indoor or outdoor air pollution, or to medications (β-blocker or NSAIDs)

Global Strategies for Asthma Management and Prevention GINA report

Co-morbidities

Global airway disease conceptFrom noses and mouth to lungs

Peter W. Hellings et al Curr Allergy Asthma Rep (2010) 10:143–149

Oral candidiasis :local side effect

Malampatti score (OSAHS) :co-morbidities

Allergic Rhinitis : co-morbidities

Vasomotor rhinitis: co-morbidities

Allergic rhino-conjunctivitis Allergic shiners co-morbidities

รปนไดรบอนญาตจากผปวยในการถายเพอใชในการเรยนการสอนและการบรรยายทางวชาการ

Pulmonary drug deposition Highly variable from inhaler devices to devices

Rau JL Jr. Respiratory care pharmacology. 2002

10% As

benchmark

Exhaled

Device

Oropharynx

Lungs

100

90

80

70

60

50

40

30

20

10

0

Lun

g d

epo

siti

on

(%

do

se)

pMDI pMDISpacer

pMDIVHC

Electrostatic

pMDIVHC

Nonelectrostatic

SVNNB

DPI

Inhaler devices in asthma and COPD

Dry powder inhaler (Lactose carrier) Aerosol generator (w or w/o propellant)

Multiple dose DPI-blister

Single dose DPI capsule

Reservoirmulti-dose DPI

Metered dose inhaler

Breath actuate MDI

Soft mist inhaler

Acc

uh

aler

Bre

ezh

aler

Ellip

ta

Turb

uh

aler

Easy

hal

er

Han

dih

aler

Pre

ssu

rize

dM

DI

Res

pim

at

Au

toh

aler

Pre

ssai

r(G

enu

air)

NEX

Thal

er

Twis

thal

er

Optichamber

ACE spacer

Aerochamber

Inhale FAST and DEEP Inhale SLOW and STEADY

Propellant(HFA)

High speed aerosol MDI

Propellant free

Low speed aerosol SMI

Lactose Drug Sp

inh

aler

Physical and mental impairment Pressurized MDI Pressurized MDI with chamber

Dry Powderinhaler (DPI)

Decreased peakinspiratory flow rate

Impaired cognition

Impaired manual dexteritory

Impaired press and breath coordination

? ?? ??

P Gibson. Asthma in Elderly Lancet Respiratory 2009

4C for correct inhaler technique in asthma

Choose• Choose an appropriate device before prescribing. Consider medication options,

arthritis, patient skills and cost. For ICS by pMDI, prescribe a spacer

• Avoid multiple different inhaler types if possible

Check• Check technique at every opportunity – “Can you show me how you use your

inhaler at present?”

• Identify errors with a device-specific checklist

Correct• Give a physical demonstration to show how to use the inhaler correctly

• Check again (up to 2-3 times)

• Re-check inhaler technique frequently, as errors often recur within 4-6 weeks

Confirm• Can you demonstrate correct technique for the inhalers you prescribe?

• Brief inhaler technique training improves asthma control


Role of healthcare professional (nurses and pharmacists)in improving patient inhaler skill and technique

STEP1

Consider low dose

ICS

STEP 2Low dose ICS




Add low dose OCS





Reliever




STEP 5



STEP 4

Med/ high ICS /LABA


Step 3

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*


Approved only for beclometasone/formoterol and budesonide/formoterol

HN

OH

OH

Olodaterol

OH

NH O

OH

O

NH

Procaterol

OH

NH

OH

OH

OH

NH

HN

OH

OH

Indacaterol

OH

NH

HN

OH

OH

NHCHO

OMe

Formoterol

Catechol nucleus

Side chain (B2 selectivity)

Salbutamol OH

OH

OH

NH

Terbutaline

Β2 sympathomimetics basic structure

Pharmacology of β2 agonists(onset and duration)

Properties Salbutamol Formoterol Salmeterol Indacaterol

Selectivity for b2-adrenoceptors Moderate High High High

Affinity for b2-adrenoceptors (pKi) Low

(6.12 ± 0.09)

High

(7.84 ± 0.05)

High

(9.19 ± 0.12)

High

(7.36 ± 0.06)

Onset of bronchodilator action (min) Quick

(11.0 ± 4.0)

Quick

(5.8 ± 0.7)

Slow

(19.4 ± 4.3)

Quick

(7.8 ± 0.7)

Duration of bronchodilator action (hours) Short

(3–6)

Long

(12 )

Long

(12)

Longer

(24)

Efficacy (agonist) Partial Complete Partial Complete

Potency (EC50) High

(8.43 ± 0.22)

High

(9.84 ± 0.22)

High

(8.36 ± 0.16)

High

(8.82 ± 0.41)

Intrinsic efficacy

(Emax % of isoprenaline)

High

(47 ± 1)

High

(90 ± 1)

Low

(38 ± 1)

High

(73 ± 1)

Classes of β2 agonistsOnset of acting* (fast or slow) and #duration (short or long acting)

Inhaled Terbutaline

Inhaled Salbutamol

Fast onset long duration

Inhaled formoterol

Inhaled indacaterol

Oral Terbutaline

Oral Salbutamol

Oral Formoterol

Slow onset long duration

Inhaled Salmeterol

Oral Bambuterol

Fast

Slow

Short Long

Speed of action

Duration of action

Rescued medications for symptoms(Reliever)

Mai

nte

nan

ce fo

r p

reve

nti

on

(co

ntr

olle

rs)

GINA 2017Step 3-4: Fixed ICS/LABA combination

Controller option Reliever Maintenance and reliever therapy

GINA 2017Step 3-4: MART approach

Maintenance and Reliever Therapy

Optimised daily

maintenance dose

Symptom relief &

increase

anti-inflammatory

Optimised daily

maintenance doseSymptom relief

Conventional approach

ICS+LABA fixed combination

SABAICS+formoterol MART

Controller A.M. Controller P.M. Rescuer PRN Controller A.M. Controller P.M. Rescuer PRN

STEP1

Consider low dose

ICS

STEP 2Low dose ICS




Add low dose OCS





Reliever




STEP 5



STEP 4

Med/ high ICS /LABA


Step 3

Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less effective than ICS/LABA)

Adults: consider adding SLIT (see Non-pharmacological interventions)


Medication changes for WAAP

ICS/FORM : BUD/FORM or BDP/FORMMaintenance ICS/FOR 4 x Maintenance ICS/FORM (<72 µg FORM/d)Maintenance & reliever ICS/FORMContinue maintenance & Reliever ICS/FORM (<72 µg/d)

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


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




Add low dose OCS





Reliever




STEP 5



STEP 4

Med/ high ICS /LABA


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


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




Add low dose OCS

Sputum guidance

Step 5 ReferSTEP 3 Low dose ICS-LABA



Reliever




STEP 5



ReslizumabBenralizumab

STEP 4

Med/ high ICS /LABA


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)]


STEP1

Consider low dose

ICS

STEP 2Low dose ICS




Add low dose OCS

Sputum guidance

Step 5 ReferSTEP 3 Low dose ICS-LABA



Reliever




STEP 5



ReslizumabBenralizumab

STEP 4

Med/ high ICS /LABA


Step 5

Other add-on treatment options • Sputum-guided treatment: in specialized centers

(reduces exacerbations & corticosteroid dose• Add-on low dose oral corticosteroids

(≤7.5mg/day prednisone equivalent)


Difficult to control asthma vs. severe asthma

Watch patient using their

inhaler

Discuss adherence & barriers

Confirm the diagnosis

of asthma

Remove potential risk factors.

Assess & manage comorbidities

Consider treatment

step-up

Refer to a specialist or

severe asthma clinic

Compare inhaler technique with a device-specific checklist

AND correct errors; recheck frequently

Have an empathic discussion about barriers to adherence.

If PFT normal during symptoms

Consider halving ICS dose and repeating PFT after 2–3 weeks

Check risk factors or inducers(smoking, B-blockers, NSAIDs, allergen)

Check comorbidities (rhinitis, obesity, GERD, depression/anxiety)

Consider step up to next treatment level. Share decision-making, and balance potential benefits and risks

If asthma still uncontrolled after 3–6 months on Step 4 treatment, refer for expert advice

Refer earlier if symptoms severe or doubts about diagnosis

Dif

ficu

lt t

o c

on

tro

l ast

hm

a Se

vere

as

thm

a

Bronchial thermoplastyFDA approved indication and procedural detail

• Adult severe persistent asthma (age >18 years)

• Inadequate control despite combination ICS/LABA

• Able to safely undergo bronchoscopy

Patient stable for FOB

BRONC 1 RLL

BRONC 2 LLL 3 weeks

BRONC 3 LUL RUL

3 weeks

Electrode array is contact to airway wall and RF energy is activatedAlair® delivers RF energy (65 °C) to wall for 10 s per activation

Clinical trials of bronchial thermoplasty in asthma

Feasibility trial AIR (RCT) n=108

RISA (RCT) n=32

AIR 2 (RCT) n=297

A.M. PEFR AQLQ AQLQ AQLQ

P.M. PEFR Rescue Medications Rescue Medication Severe exacerbations

Symptom free days

Symptom free day FEV1 ER visit

Exacerbation Oral steroid (NS) Day lost from workand school or activities

AJRCCM 2006 NEJM 2007 AJRCCM 2007 AJRCCM 2010

Ext 5 year AIR 2

89% rate

No AENo RS AENo EXAFEV1 NS

BDR+

JACI 2013

X 3 procedure vs. sham control

Potential phenotypes Targeted therapies in severe asthma for clinical use

Characteristics Associations Specific target treatments

Severe allergic

asthma

Blood and sputum eosinophilsHighs serum IgEHigh FeNo

Anti-IgE (Adult and children) Anti-IL-4/IL-13Anti-IL-4 receptor

Esoniophilic

asthma

Blood and sputum eosinophilsRecurrent exacecerbationHigh FeNo

Anti-IL-5 Anti-IL-4/IL-13Anti-IL-4 receptor

Neutrophilic

asthma

Corticosteroid insensitivityBacterial infection

Anti-IL-8 CXCR2 antagonists Anti-LTB4 (Adult and children) Macrolide (Adult and children)

Chronic airflow

obstruction

Airway wall remodeling as increased airway wall thickness

Anti-IL-13 Tiotropium bromide Bronchial thermoplasty

Recurrent

exacerbation

Sputum eosinophiliaReduced response to ICS/OCS

Anti-IL-5 Anti-IgE (Adult and children)

Corticosteroid

insensitivity

Increased sputum neutrophilia P38 MAPK inhibitorTheophylline (adult & children) Macrolides (adult and children)

KF Chung et al, Eur Respir J 2014; 43: 343-373

Biomarkers to identify T2 phenotypesFor personalized treatment of asthma

• Sputum eosinophils (>2% or 3%)

• Exhaled nitric oxide (>30 ppb)

• Circulating eosinophils (150-400/µl)

• Serum periostin (> 50 ng/ml)

• Serum IgE

• Allergen skin testing

What is the impact of monoclonal Ab for Th2/eosinophilic phenotype asthma?

Am J of Respir and Crit Care Med, 2011; 184(5):602-15.

PG Gibson et al Lancet 2011; 378: 983-991

Guiquan Jia et al. J Aller Clin Immunol. 2012; 130(3): 647–654.

Green et al, Lancet 2002; 360: 1715-21

• Eosinophilic/Th2 phenotypes (IL-4, IL-5 and IL-13)

• Non eosinophilic (sputum eosinophils< 2% or blood Eo <200/µl)

Mechanisms of IL-5 targeted treatment

IL-5Rα

IL-5Rα

IL-5

IL-5

No signaltransduction

IL-5

Differentiation & maturationEosinophil migration Mediators releaseInhibition of apoptosis

Eosinophil Eosinophil

IL-5

Mepolizumab(Anti-IL-5)

Reslizumab(Anti-IL-5)

IL-5Rα

Benralizumab(Anti-IL-5Rα)

Neutralize circulating IL-5

IL-5R receptorblock

Tan LD. J Asthma Allergy. 2016; 4;9:71-81

Mechanism of Benralizumab(Anti-IL-5R, IgG1) deplete eosinophils in blood and airways

IL-5Rα

ADCC

IL-5

IL-5 mAbMepolizumab

Reslizumab

Passive removal ofactivating interleukin

Antibody Dependent Cell mediated Cytotoxicity(ADCC: Active mode of action)

IL-5

Eosinophil

Basophil

Macrophage NK cell

FcgRIIIα

BenralizumabIL-5Rα mAb

Summary of biologics and mAb in T2 asthma

Targettherapies

Drug name(antibody)

Route of administration

Markers Development phase

IgE OmalizaumabLigelizumabQuilizumab

Subcutaneous Subcutaneous Subcutaneous

Total serum IgE, FENO, periostin, and blood Eo

Marketed Phase 2Phase 2

IL-5

IL-5Rα

MepolizumabReslizumabBenralizumab

Subcutaneous Intravenous Subcutaneous

Blood Eo (> 150-300/µl)Blood Eo (> 400/µl)Blood Eo (> 200-300/µl)

Marketed (12 y+)Marketed (18 y+)Marketed (12 y+)

IL-4Rα Dupilumab

Pitrakinra(IL-4 varient)

Subcutaneous

SubcutaneousNebulizer

Blood Eo (> 300/µl)Sputum Eo (> 3%)

Phase 3 Phase 2

IL-13 Lebrikizumab

Tralokinumab

Subcutaneous

Subcutaneous

Blood Eo (> 300/µl)Serum periostin (> 50 ng/dl)High serum periostin

Phase 3

Phase 3

TSLP AMG-157 Intravenous NA Phase 3

Eotaxin(CCL11)

Bertilimumab(CCR3 block)

Oral NA Phase 3

Diagnosis criteria of severe eosinophilic asthma

Major criteria

• Late onset

• Involvement of upper airway (chronic sinusitis, nasal polyps)

• Other biomarker (FeNO)

• Fixed airflow obstruction

• Hyperinflation or mucus plug

• Severe asthma

• Blood eosinophil

(> 2 occasions)

• Frequent exacerbation (> 2 per year)

• Need for (chronic intermittent) oral steroid

Minor criteria

Buhl R et al Eur Resp J 2017

Murano et al J Allergy Clin Immunol 2016; 137;1347-58

2003 2015 2016

Total IgEand kg BWT

(75-375 mg SC)Q 2-4 weeksUS FDA EMA

≥ 6 years

Blood EO >150-300/mm3

(100 mg SC)Q 4 weeks

US FDA ≥ 12 years

Blood EO > 400/mm3

(3 mg/Kg IV)Q 4 weeks

US FDA, EMA ≥ 18 years

Benralizumab Dupilumab Lebrikizumab

Trivedi A. Lancet Respir Med 2016;4:585-592

Blood EO > 200-300/mm3

(30 mg SC)Q 4 weeks

US FDA>12 years

Blood EO > 300/mm3

(200 mg SC)Q 2-4 weeks

US FDANot approved

Blood EO > 300/mm3

PONST >50 (150-300 SC)

Q 4 weeksNot approved

Omalizumab Mepolizumab Reslizumab

2017

Biologics in severe asthmaWhen start, continue and discontinue?

Eosinophils (cell/µl)

30 1500

300

Serum IgE(IU/ml)

Eosinophilic asthma Anti-IL-5

MepolizumabReslizumabAnti-IL-5R

Benralizumab

Allergic asthma Anti-IgE

Allergic asthma Eosinophilic

asthma Anti-IL-5

Anti-IL-5RAnti-IgE

No-eosinophilic asthma

Anti-IL-17Anti-CXCR2Macrolide

4 months 12 months

Nonresponders

Intermediate responders

Superresponder

Continue treatment

Continue treatment for a year

to assess response ORConsider switching if response is low

Stop treatment

Severe asthmaInflammatory phenotypes and current therapies

Induced sputum, FeNO and peripheral blood eosinophils

‘’Th2 high’’

Eosinophilic

Steroids Anti-eosinophilic

Anti-IgEAnti IL-5/IL5RAnti IL4Rα/IL-13

Anti TSLPAnti IL-33

CRTH2 antagonist

‘’Th2 low’’

Neutrophilic

Steroid resistance Anti-neutrophilic

MacrolidesCXCR2 antagonist

Anti TNFAnti IL-1

Anti IL-17/IL-23P38 MAPK inhibitor

PDE4 inhibitors

Paucigranulocytic

Steroid resistance

LAMALAMA+LABA

LABA/LAMA/ICSBronchial

thermoplasty

Barnes PJ. J Allergy Clin Immunol 2015; 136:631-645

Roadmap & milestone for anti-eosinophilic in asthmaFrom corticosteroid to biologic agents

1950

Cortisone 1949

1960 1970

IgE(Reagin)

1968

ICS1973

1980 1990 2000

Omalizumab2003

IL-5 IL-13

IL-5Rα

IL-4R

2010 2020

Mepolizumab 2015

Reslizumab 2016

Benralizumab 2017

Dupilumab

Trakolinumab

Lebrikizumab

Bertilimumab

FevipiprantmAb

BA

C D

3

2

9

45

67

8

17

10

11

1213

1

14 15

1618

CH3

18CH3OH

C 18CH3

20 O

OH

O

Corticosteroid

GINA 2018 Revised asthma treatments

ICS should be considered for mild asthma (rather than prescribing SABA alone) is to reduce their risk of serious exacerbations

Adding LABA to ICS in a combination inhaler reduces exacerbation risk and improves symptoms and PFT, compared with the same dose of ICS alone

SC benralizumab(monoclonal anti-IL5R αAb) is another add-on treatment for patients with severe eosinophilic asthma

Step 1 Step 3-4Step 5

Severe asthma management

Reddel HK et al. START study. Lancet 2017;389:157-66

Peters SP et al. N Engl J Med 2016;375:850-60Stempel DA et al. N Engl J Med 2016;374:1822-30

Castro M et al. Lancet Respir Med2:879-890.Bleecker ER. Lancet;388:2115-2127FitzGerald JM. Lancet;388:2128-2141.

Stepwise asthma management Additional components (The 7 wonders of GINA 2018)

1. Provide guided self-management education

2. Treat modifiable risk factors and comorbidities

3. Advise about non-pharmacological therapies and strategies

4. Consider adding SLIT in HDM-sensitive adults with allergic rhinitis having exacerbation despite ICS (FEV1 > 70%)

5. Consider step up if uncontrolled symptom or exacerbationBUT check diagnosis, inhaler technique and adherence

6. Consider step down if symptom controlled for 3 m and low risk for exacerbations

7. Stopping ICS is not advised

Pregnancy drug safety(US FDA drug safety in pregnancy)

Drug Pregnancysafety

Lactation

ICS

Beclomethasone C Unknown

Budesonide B Unknown

Ciclesonide C Unknown

Fluticasone C Unknown

Mometasone C Unknown

LABA

Formoterol C Unknown

Salmeterol C Unknown

Systemic corticosteroids

Dexamethasone C Probably safe

Hydrocortisone C Probably safe

Methylprednisolone C Probably safe

Prednisone C Probably safe

Drug Pregnancysafety

Lactation

SABA

Albuterol C Probably safe

Levalbuterol C Unknown

Terbutaline C Probably safe

Theophylline C Probably safe

SAMA

Ipratropium bromide B Unknown

Leukotriene inhibitors

Montelukast B Unknown

Zafirlukast B Possibly unsafe

Zileuton C Probably safe

Prednisone C Probably safe

Mast-cell stabilizers

Nedocromil B Unknown

Cromolyn B Unknown

Omalizumab B Unknown

Asthma education, environmental control, influenza vaccine and pulmonary rehabilitation

As needed rapid- acting 2-agonist

Low dose steroid

ส ำหรบผปวยทม

High Risk

exacerbation

Select one Select one Add one or more Add one or both

Low-doseinhaled ICS

Low-dose ICS pluslong-acting 2 -agonist

Medium or high-dose ICS plus long-acting 2-agonist

Oral glucocorticosteroid

(lowest dose)Leukotriene

modifierMedium or high-dose ICS Leukotriene modifier Anti - IgE

Low-dose ICS plus leukotriene modifier

Sustained release theophylline

Low dose ICS plus sustained release

theophylline

Tiotropium bromide

Step 1 Step 2 Step 3 Step 4 Step 5

Decrease IncreaseTreatment steps

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