Asthma phenotypes

Asthma Phenotypes
28th February 2020
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit
King Chulalongkorn Memorial Hospital

Asthma
• Asthma : Heterogeneous disease, usually characterized by
- Chronic airway inflammation (history of respiratory symptom :
wheeze shortness of breath, chest tightness, cough)
- Variable expiratory airflow limitation
• Diagnosis : based on history of characteristic symptom pattern
and evidence of variable airflow limitation
Phenotype: The observable characteristics of a disease, such as morphology,
development, biochemical or physiological properties, or behaviour. Some
phenotype guided treatment
Examples: allergic asthma, non-allergic asthma, adult onset asthma, asthma
with obesity, asthma with persistent airflow limitation
© Global Initiative for Asthma, www.ginasthma.org

• Endotype: subtype of disease, defined functionally and pathologically by
distinct molecular mechanism or distinct treatment responses (Anderson, Lancet 2008)
– Among patients with obstructive lung disease, likely to be several specific
endotypes associated with divergent underlying molecular causes, and distinct
treatment responses. These endotypes may or may not align with clinical or infl
ammatory phenotypes identified from studies limited to asthma or to COPD
– Examples: emphysema due to alpha1-antitrypsin deficiency
• Biomarker: defined characteristic measured an indicator of normal biologic
processes, pathogenic processes or response to an intervention
– Potential examples: FeNO, blood eosinophils – but these may not meet
quality criteria for biomarkers
Asthma

Other
controller options
RELIEVER
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Box 3-5B
Children 6-11 years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for i
ndividual child’s needs
Leukotriene receptor antagonist (LTRA), or
low dose ICS taken whenever SABA taken*
Low dose ICS+L
TRA
High dose ICS-
LABA, or add-
on tiotropium,
or add-on LTRA
Add-on anti-IL5,
or add-on low d
ose OCS,
but consider
side-effects
Low dose ICS tak
en whenever SAB
A taken*; or daily l
ow dose ICS
* Off-label; separate ICS and SABA inhalers; only one study in children
STEP 1
STEP 2
Daily low dose inhaled corticosteroid (ICS)
(see table of ICS dose ranges for children)
STEP 3
Low dose
ICS-LABA, or m
edium dose ICS
STEP 5
Refer for p
henotypic a
ssessment
± add-on
therapy,
e.g. anti-IgE
STEP 4
Medium dose
ICS-LABA
Refer for exp
ert advice
Symptoms Exa
cerbations Side
-effects Lung fu
nction
Child and parent
satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Child and parent goals
Treatment of modifiable risk factors
& comorbidities
Non-pharmacological strategies
Education & skills training
Asthma medications
As-needed short-acting β2 -agonist (SABA)
Phenotypic assessment and
consideration add-on
treatment
GINA Guideline 2019

* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
STEP 2
Daily low dose inhaled corticosteroid (ICS),
or as-needed low dose ICS-formoterol *
STEP 3
Low dose
ICS-LABA
STEP 4
Medium dose
ICS-LABA
Leukotriene receptor antagonist (LTRA), or l
ow dose ICS taken whenever SABA taken †
As-needed low dose ICS-formoterol *
As-needed short-acting β2 -agonist (SABA)
Medium dose I
CS, or low dose
ICS+LTRA #
High dose ICS
, add-on tiotro
pium, or add-o
n LTRA #
Add low dose
OCS, but con
sider
side-effects
As-needed low dose ICS-formoterol ‡
STEP 5
High dose
ICS-LABA
Refer for p
henotypic a
ssessment
± add-on ther
apy, e.g.tiotro
pium, anti-IgE
,
anti-IL5/5R,
anti-IL4R
Symptoms Ex
acerbations Si
de-effects Lun
g function
Patient satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Patient goals
Treatment of modifiable risk
factors & comorbidities
Non-pharmacological strategies
Education & skills training Asth
ma medications
1
STEP 1
As-needed
low dose
ICS-formoterol *
Low dose ICS t
aken whenever
SABA is taken†
‡ Low-dose ICS-form is the reliever for patients prescribed bu
d-form or BDP-form maintenance and reliever therapy
# Consider adding HDM SLIT for sensitized patients with aller
gic rhinitis and FEV >70%predicted
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other
controller options
Other
reliever option
PREFERRED
RELIEVER
Box 3-5A
Adults & adolescents 12+ years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for i
ndividual patient needs
Step 4 treatment is medium
dose ICS-LABA; high dose now
in Step 5
Phenotypic assessment and
consideration add-on
treatment
GINA Guideline 2019

ERS/ATS GUIDELINES ON SEVERE ASTHMA | K.F. CHUNG ET AL.Eur Respir J 2014;43:343-373
International ERS/ATS guidelines
definition, evaluation and treatment of severe asthma
Asthma which requires Rx for GINA step4-5 (high dose ICS-LABA or LTRA/
Theophylline) for previous year or systemic steroid for >50% of previous year
to prevent asthma from becoming uncontrolled or remains uncontrolled
despite therapy.
Uncontrolled asthma defined as at least one of the following:
1.Poor symptom control : ACQ>1.5,ACT<20, not well controlled by GINA
2.Frequent severe exacerbation : ≥2 bursts of OCS (>3days) in previous year
3.Serious exacerbation : at least one hospitalization ,ICU stay in previous year
4.Airflow limitation: after appropriate bronchodilator withhold, FEV1<80% predicted
Controlled asthma that worsens on tapering of these High dose of ICS or
systemic CS (or additional biologics)

▪ Uncontrolled asthma
▪ Frequent symptoms and/or flare-ups (exacerbations)
▪ Many of these patients may potentially have mild asthma, i.e. their asthma
could be well-controlled with low dose ICS, if taken regularly
▪ Difficult-to-treat asthma
▪ (not difficult patients!)
▪ Asthma uncontrolled despite prescribing high dose preventer treatment
▪ Contributory factors may include incorrect diagnosis, incorrect inhaler techni
que, poor adherence, comorbidities
▪ Severe asthma
▪ “Severe asthma”has had many different meanings (Taylor, ERJ 2008; Reddel AJRCCM 2009)
▪ Now defined as asthma that is uncontrolled despite maximal optimised thera
py and treatment of contributory factors, or that worsens when high dose tre
atment is decreased (Chung, ERJ 2014)
▪ i.e. relatively refractory to corticosteroids (rarely completely refractory)
▪ A retrospective definition, dependent on how thoroughly contributory factors
are excluded
Terminology

Severe Asthma
high daily dose of
various inhaled
corticosteroids
Copyright © 2020 · All Rights Reserved
· Global Initiative for Asthma – GINAFront. Pediatr., 23 August 2018

Goals of asthma treatment
• Few asthma symptoms
• No sleep disturbance
• No exercise limitation
• Maintain normal lung function
• Prevent flare-ups (exacerbations)
• Prevent asthma deaths
• Avoid medication side-effects
• The patient’s goals may be different from these
• Symptoms and risk may be discordant – need to assess both
Symptom control
Risk reduction

Severe Asthma
P. Santus, et al. Pharmacological Research 146 (2019) 104296
Tara F. Carr,Eosinophilic and Noneosinophilic Asthma : AJRCCM jan 2018

Cluster Analysis
AKAR-GHIBRIL ET AL. J ALLERGY CLIN IMMUNOL PRACT.2020.VOLUME 8, NUMBER 2
Several endotypes drive the phenotypes present in each cluster
Allergic asthma : atopy, early onset , Eo↑
2011
2015

Cluster Analysis
2013
2014
2014

Less atopy

Wenzel S. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012
Asthma phenotypes:
Early onset
allergic asthma

Asthma phenotypes:
- Less likely to
respond to
Corticosteroids
-ILC gr 1,3 :
produce IFN-Ɣ,
IL-17, and IL-22
-Respond to
Antibodies: block
TNF-a, IL-17, IL-23
Tabatabaian et al. Biologicand New Therapies in Asthma, Immunol AllergyClinN Am 37 (2017) 329–343
-respond to
corticosteroids
-antagonists of
IgE, IL-5, IL-13,
CRTH2

Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Asthma phenotypes:

• Eosinophilic asthma
- Sputum Eo levels > 2 to 3% (of total cells in a whole expectorate)
- BAL Eo > 2%
- No actual cut-off Eo in bronchial wall Bx
*Wenzel, et al.2012: ≥20 cells/mm2 of tissue (16-31)
- ↑Serum periostin (correlated to airway & sputum eosinophilia, IL-13 pathway)
- ↑ DPP-4: IL-13 pathway
- ↑ Fraction exhaled nitric oxide
- Respiratory epithelium under control of IL-13
- Often but not always correlated with sputum/blood Eosinophil
(marker of TH2 phenotype)
- Predicts responsiveness to inhaled corticosteroids
Eosinophilic vs Non-eosinophilic Asthma
Blood Eo: indirect, fluctuating, may not reflect sputum Eo (but if extreme(<90, >400) : ↑ reflective)
Absolute eosinophil count > 300-400

• Extracellular matrix protein induced by IL-4 and IL-13 from Eo, Mo, fibroblasts,
bronchial epithelial cells
• Eosinophil recruitment
• airway remodeling (TGF-B inducing protein homologue)
• Th2 endotype of asthma
• Predictor eosinophilic airway inflammation : ↑Inflammatory mediators
Periostin
Wei Li, et al. Periostin: its role in asthma and its potential as a diagnostictarget. Respir Res. 2015

• May be responsive to ICS
• If unresponsive to high dose ICS/need systemic steroid
• May be responsive some biologic Treatment
• Several endotypes -> EA
• IL-4/13: early onset atopic asthma
• IL-5: late onset, less atopic
• Allergic or atopic: Ag specific Th2
• Nonallergic or nonatopic: obesity
Eosinophilic Asthma (EA)

Allergic eosinophilic asthma
Figure 2 TH2 immune processes in the airways of people with asthma.
Asthma phenotypes: the evolution from clinical to molecular approaches.
Sally E Wenzel.nature medicine.may 2012
T2-high cytokines
: IL-4,IL-5,IL-13
IL-4 : activated B cell to IgE class switching
IL-5 : Eo development,
survival ,chemotaxis

Peter J. Barnes. Middleton 9th edition.2020.
1
2
Thymic stromal lymphopoietin (TSLP)
-Direct mast cell activation → release
proinflammatory cytokine
-Bind to receptor on DC → upregulated
enhancing Th2 polarization

• Non-atopic: less IL-4 for sIgE production
• Innate immune pathway: ILC-2 -> IL-5, IL-13
• Late onset, severe, relatively steroid insensitive
• Irritants/pollutants and microbes (protease)
airway epithelial injury
(IL-25, IL-33, and TSLP)
stimulate ILC-2, Th2, TSLP-primed DCs, mast cell
Non-allergic Eosinophilic Asthma

Guy G Brusselle et al. NATURE MEDICINE.AUGUST 2013
Heterogeneity of eosinophilic asthma
Allergen-
specific IgE
Polyclonal IgE
Tabatabaian et al. Biologicand New Therapies in Asthma, Immunol AllergyClinN Am 37 (2017) 329–343
IL-4 : activated B cell to
IgE class switching IL-5 : Eo development,survival ,chemotaxis

Microbial mechanism : staphylococcal enterotoxin
-Staphylococcal superantigens production(Sag)
→ Polyglonal IgE production in airway
→ non Ag specific mast cell activation
-Inhibits function of Treg
- Staphylococcal infection >>
damage epithelial cell by cytotoxic Ab
Cytokeratin-18
-Reduce corticosteroid
responsiveness in T cells

biomarkers & clinical features to identify asthma phenotype
Pierachille Santus. Current and future targeted therapies for severe asthma,2019

Mechanisms of eosinophilic asthma
express of 15-LOX-1
in airway > exacerbation
Periostin,TGF-B >
airway remodeling

Biomarkers to identify T2 phenotype
For personalized treatment of asthma
What is the impact of monoclonal Ab for Th2/Eosinophilic phenotype asthma
• Sputum eosinophils (≥ 2-3%)
• Fraction exhaled nitric oxide (FeNO)
• circulating eosinophils (150-400 /microliter)
• Serum periostin (≥ 50 ng/ml)
• Serum IgE
• Allergen skin testing

Treatment of allergic asthma
- Environmental control measure
- Immunotherapy
- Glucocorticoid
- Biologics

oral corticosteroid
sparing effects.

oral corticosteroid
sparing effects.
oral corticosteroid
sparing effects.

Lebrikizumab
- Dosage 250 mg sc every 4 weeks for 6 months
- Improved lung function (%change of FEV1 from BL)
• Not ↓severe exacerbation rates, ACQ5 score
- Higher pretreatment periostin: greater improve FEV1 with lebrikizumab
- Musculoskeletal side effects (13.2% vs. 5.4%, P = 0.045)
Tralokinumab
- Dosage 300mg sc every 2 or 4 weeks for 52 weeks
- Not ↓exacerbation rates in severe uncontrolled asthma compared with placebo,
• Improve FEV1 in Tralokinumab 300 mg sc every 2 weeks
• Post-hoc subgroup analysis (Tralokinumab 300mg sc every 2 weeks)
: DPP-4 = improvements in pre-BD FEV1, ACQ-6, and AQLQ(S)
: Periostin = pre-BD FEV1, ACQ-6, exacerbation rate
Anti IL-13: Lebrikizumab,Tralokinumab
1. Corren et al. Lebrikizumab Treatment in Adults with Asthma. N Eng J Med 2011;365:1088-98.
2. Brightling et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomized, dou
ble-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015;3:692–701.
FDA not approved

Pathophysiological mechanisms of T2-hi and T2-lo
asthma and the current biologics that target them
Zhu et al. Potentialnew targets for drug development in severe asthma World AllergyOrganizationJournal 2018 Activationtype
2-high and type 2-low inflammatorypathways

Agache I et al, Efficacy and safety of treatment with biologicals for severe eosinophilic asthma, Allergy. 2020 Feb 8.

-subjects 12 to 75 years old , ranging from 12 to 56 weeks were evaluated.
All biologicals reduce exacerbation rates with high certainty of evidence:
Benralizumab RR 0.53 (95% CI 0.39 to 0.72),
Dupilumab RR 0.43 (95% CI 0.32 to 0.59),
Mepolizumab RR 0.49 (95% CI 0.38 to 0.66),
Omalizumab RR 0.56 (95% CI 0.40 to 0.77),
Reslizumab RR 0.46(95% CI 0.37 to 0.58).
-Benralizumab, Dupilumab and Mepolizumab reduce the daily dose of oral
corticosteroids (OCS) with high certainty of evidence.

Agache I et al, Efficacy and safety of treatment with biologicals for severe eosinophilic asthma,
Allergy. 2020 Feb 8.
- All evaluated biologicals probably improve asthma control, QoL and
FEV1, without reaching the minimal important difference (moderate
certainty).
-Benralizumab, Mepolizumab and Reslizumab slightly increase drug-
related adverse events (AE) and drug-related serious AE (low to very
low certainty of evidence).

Benralizumab

Dupilumab

Mepolizumab

Reslizumab

• Non-eosinophilic
- Dominant cell: neutrophils,
mixed inflammatory granulocytes
Or very few inflammatory cells
“Paucigranulocytic”
Eosinophilic vs Non-eosinophilic Asthma
Unravelling the complexity of tissue inflammation .Erjefalt. 2019 Jan;25:79-86

• Sputum Eosinophil < 2%
• Paucigranulocytic : sputum neutrophils < 61%
• Mixed granulocytic, or neutrophilic: sputum neutrophilia >40%
or ≥76%
- Neutrophilic asthma
- Obesity-induced asthma
- Paucigranulocytic asthma
- Asthma related to environmental exposures
Non-eosinophilic Asthma

• Older age
• Impaired lung function
• Less bronchodilator reversibility
• Less atopy
- Associated smoke
• Trigger factors activate TLR4 and CD14 on epithelial cells, MØ
→NF-kB activation
→↑IL-8 (recruit activated neutrophils into the airways)
• Impaired Macrophage efferocytosis (phagocytosis of apoptotic cells)
• The p38 kinases(MAPK): induced by environmental triggers
• ↑IFN , TNF and inflammasome associated gene activity
• NK, NKT-like cells: corticosteroid insensitivity
Neutrophilic asthma

• MAPK: dephosphorylation enzyme →
generally halt protein
activation, signal amplification
(exc. Tyrosine kinase Src)
“p38 kinase”: control cell cycle,
gene transcription, stress response
• Relevant to asthma and in particular to NEA.
• Inhibition of p38/mitogen-activated protein kinase mitigates neutrophilic in
ﬂammation
MAPK Family: p38 Kinase
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 Middleton 8th edition
Peter J. Barnes. Middleton 9th edition.2020.

Th17
• Induced by chronic infection,
inhale exposure
• Neutrophilic, mixed granulocytic
• Severe, frequent exacerbation,
steroid resistance
• Mucus hypersecretion
• smooth muscle hypertrophy ,
airway remodeling
Non-eosinophilic Asthma: Th2/T2 Low
Neutrophilic asthma: clue for chronic subclinical infection
Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
1.Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018

• Smoking: alter histone deacetylase activity → corticosteroid
insensitivity
• HDACs: deacetylate AA of glucocorticoid receptor
(activate GR)
• Direct toxic effect from environment pollutants
Tara F. Carr, Eosinophilic and Non-eosinophilic Asthma: AJRCCM Jan 2018
Middleton 8th edition
Air Pollutant, Smoking, Occupational Asthma

Neutrophilic Asthma
biomarkers & clinical features to identify asthma phenotype
Pierachille Santus. Current and future targeted therapies for severe asthma,2019

• 40% NEA
• Well controlled, mild intermittent in SARP cohort
• Some: severe, may not response to ICS
• Dysfunction of airway smooth muscle, nerve, vascular tissues
• airway smooth muscle: secrete cytokines, chemokines
• ↑Bronchospasm: muscarinic, adrenergic pathways
• Tx by muscarinic(LAMA), B2 antagonist(↓bronchospasm),
bronchial thermoplasty (↓exacerbation )
• Aberrant repair mechanism: Airway remodeling
Paucigranulocytic Asthma

• Eosinophilic (Early onset eosinophilic)
• Metabolic: ↓CD4 effector cell function
• High fat diet: ↑ Eo
• TNF-α: ↑Airway hyperresponsiveness
• Surfactant protein A lipid: ↑ type 2 inflammation
• Adipokines ex leptin:
↑Airway hyperresponsiveness, serum IgE
(Adiponectin: ↓ Airway hyperresponsiveness)
Obesity Related Asthma : EA, NEA

• Non-eosinophilic (late onset, female predominant)
• Neutrophilic, paucigranulocytic
• ↑Airway Resistance, easy to closure
• Reverse with weight reduction
• Activated Macrophage → inflammation adipose tissue → ↑IL-6, TNFα, leptin
• Airway hyperresponsiveness:
• pollutant and irritant > O3 : ↓lung function, ↑IL-6, ↑airway PMN
Obesity Related Asthma (EA, NEA)
Wood LG, et al.A high fat challenge increase airway inflammation.J Allergy clin Immunol 2011;127:11333-1140
• Fat, antioxidants, lycopene-rich supplement
Obese asthma mouse model: high-fat diet
→ Airway hyperreactive from IL-17A(ILC3) ,macrophage derived IL-1B
• Modifying dietary fat intake: important in asthma Management

Viral infection
Eo, PMN trafficking,
Toxic degranulation

Recommendations for management
of severe asthma
Recommendation strength Quality of
evidence
Suggest anti-IL5 as add-on therapy for adult severe uncontrolled asthma
with an eosinophilic phenotype and severe corticosteroid-dependent asthma
Conditional Varied by
treatment
Suggest blood eosinophil ≥ 150/μl can be used to guide anti-IL5 initiation in
adult severe asthma and prior exacerbations.
Conditional Low
Suggest blood eosinophil ≥ 260 /μl to identify adolescents (>12 years) and
adults severe allergic asthma more likely to benefit from anti-IgE treatment
Conditional Low
Suggest FeNO ≥ 19.5 ppb to identify adolescents (>12 years) and adults
severe allergic asthma more likely to benefit from anti-IgE treatment
Conditional Low
Holguin F, Cardet JC, Chung KF, et al. Management of Severe Asthma: a European Respiratory Society/American Thoracic Society
Guideline. Eur Respir J 2019.

Recommendations for management
of severe asthma
Recommendation strength Quality of
evidence
For children, adolescents, and adults with severe asthma uncontrolled
despite GINA step 4-5 or NAEPP step 5 therapies, we recommend the
addition of Tiotropium
Strong Moderate
Suggest trial of macrolide treatment to reduce asthma exacerbations in
adult asthmatics on GINA/NAEPP step 5 therapy remain persistently
symptomatic or uncontrolled. against chronic macrolide treatment in children
and adolescents
Conditional Low
Suggest Dupilumab for adult severe eosinophilic asthma, and severe
corticosteroid-dependent asthma regardless of eosinophil levels
Conditional Low
Holguin F, Cardet JC, Chung KF, et al. Management of Severe Asthma: a European Respiratory Society/American Thoracic Society
Guideline. Eur Respir J 2019.

Treatment of Non-eosinophilic Asthma

Treatment of Non-eosinophilic Asthma : Non-Pharmacological
• Smoking cessation
• Avoidance environmental triggers/pollutants
• Treatment comorbid: weight reduction
• Look for chronic subclinical infection
• Dietary modification
• Low fat, low trans fat
• Adequate antioxidants
• Lycopene rich supplements
• Bronchial thermoplasty :Paucigranulocytic asthma
Wood LG, et al. A high-fat challenge increases airway inﬂammation and impairs bronchodilator recovery in ast
hma. J Allergy Clin Immunol 2011;127:1133–1140.

Heterogeneity of asthma phenotype
AnnalsATS Volume 11 Supplement 5|December 2014

Asthma phenotypes

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