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Asthma Phenotypes
Thitima Kantachatvanich, M.D.
Asthma
• Character: “Heterogeneity”
• Cluster analysis  asthma phenotypes
(statistically, molecularly, genetically)
• Link biology to phenotype
• Targeted and personalized approaches to therapy
Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
Phenotypes
• The visible characteristics of an organism resulting from the interaction
between its genetic makeup and the environment.1
1.The Encarta World Dictionary, 1st edn. New York: St Martin’s Press; 1999.
Endotypes
• A specific biological pathway is identified that explains the
observable properties of a phenotype
Lötvall, J. et al. Asthma endotypes: a new approach to classification of disease
entities within the asthma syndrome. J. Allergy Clin. Immunol. 127, 355–360 (2011).
Severe Asthma
• International Innovative Medicines Initiative criteria
• Asthma (R/O alternative Dx, compliance, trigger factors, Tx error)
• Poor asthma control or frequent (≥2) severe exacerbations per year
• Despite high-intensity treatment or can only maintain adequate control when taking
systemic corticosteroids and are thereby at risk of serious adverse effects of treatment.
• High intensity asthma Tx:
• 1000 mcg/day fluticasone equivalent combined + LABA or other controllers (adults)
• 500 mcg/day fluticasone equivalent (school-aged children)
• 400 mcg/day budesonide equivalent + oral leukotriene receptor antagonists (pre-school
children)
Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international
consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917.
GINA Guideline 2018
Asthma that requires GINA
steps 4 to 5 Tx
(high-dose ICS and LABA or LT
modifier/theophylline) for
the previous year or systemic
corticosteroids for ≥50% of
the previous year
“uncontrolled“
despite this therapy
M. Amelink, et al., Severe adult-onset asthma: A distinct phenotype; J Allergy Clin Immunol 2013
Old Asthma Phenotypes Approaches
• Extrinsic (Allergic)
• Atopy
• sIgE to trigger
• Intrinsic (Nonallergic)
• Develop later in life (> 40 years old)
• AERD, etc.
The Umbrella Term ‘Asthma’
Asthma phenotypes: the evolution from clinical to
molecular approaches: nature medicine MAY 2012
Eosinophilic and Noneosinophilic Asthma:
AJRCCM Jan 2018
Cluster Analysis
• SARP: Severe Asthma Research Program (by the National Heart, Lung,
and Blood Institute )
• Clinical characteristics of age of asthma onset, lung function, bronchodilator
reversibility, and demographics
• UBIOPRED: Unbiased Biomarkers for the Prediction of Respiratory
Disease Outcome Consortium
• ADEPT: Airways Disease Endotyping for Personalized Therapeutics
Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international
consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917.
Cluster Analysis
Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international
consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917.
Eo↑
Several endotypes drive the phenotypes present in each cluster.
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Eosinophilic vs Non-eosinophilic Asthma
• Eosinophilic
 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.: ≥20 cells/mm2 of tissue (16-31)
 ↑Serum periostin (correlated to AW & sputum
eosinophilia, IL-13 pathway)1
 DPP-4: IL-13 pathway
Exhaled nitric oxide
 Respiratory epithelium under control of IL-13
 Often but not always correlated with sputum/blood
Eo (marker of TH2 phenotype)
 Predicts responsiveness to inhaled corticosteroids
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
• Non-eosinophilic
 Dominant cell: neutrophils,
mixed inflammatory
granulocytes
 Or very few inflammatory cells
“paucigranulocytic”
1.Jia G et al.; Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group.
Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. JACl 2012;130:647–654.e10.
Blood Eo: indirect, fluctuating,
may not reflect sputum Eo
(but if extreme(<90, >400)
: ↑ reflective)
AEC > 300-400
Periostin
Wei Li, et al. Periostin: its role in asthma and its potential as a diagnostic or therapeutic target. Respir Res. 2015; 16(1): 57.
• Matricellular protein from Eo, MØ,
fibroblasts, epithelial cells
• Eo recruitment
• AW remodeling (TGF-B inducing
protein homoloque)
• Th2 phenotype
• ↑Inflammatory mediators
Eosinophilic Asthma (EA)
• May be responsive to ICS
• If unresponse to high dose ICS/need systemic steroid
• May be responsive some biologic Tx
• 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
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Allergic EA: childhood
Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
Non-allergic Eosinophilic Asthma
• 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) AW epithelial injury
IL-25, IL-33, and TSLP  stimulate ILC-2, Th2, TSLP-primed DCs, mast
cell
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Middleton 8th edition
TSLP (thymic stromal lymphopoietin)
• Direct mast cell activation  release of proinflammatory cytokines
and lipid mediators
• Bind to receptor on DC  upregulating CD40, OX40, and CD80
Enhancing Th2 polarization
IL-25, IL-33: directly on the naïve T cells to promote
Th2 immune deviation
Not predominant IL-4 production: minimizes B cell
class switching to IgE(Ag specific IgE is not prominent)
Non-allergic Eosinophilic Asthma
• Th2, Th17: Dual positive in
some patients
• “Late onset EA”
• IL-6, IL-1b, IL-23
• MEK(MAP-ERK kinase 1)
• IL-1b–mediated inflammation
• Corticosteroid insensitive
• Type 2 cytokine: inh IL-8
(Eo>PMN)
Middleton 8th edition
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Staphylococcal Enterotoxin: Non-allergic EA
• Superantigen production
• Polyclonal IgE production in the airways
 non-Ag-specific mast cell activation
• Suppression of Treg
• Production of cytotoxic Ab
to epithelial proteins (i.e., cytokeratin-18)
• corticosteroid insensitivity
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Middleton 8th edition
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Periostin, TGF-B: AW remodeling
Aspergillus protein: processed by DC (HLA-
DR2/DR5) potent T2 inflammation, directly
epithelial cell damage.
Genetic risk: IL-4 receptor, IL-10 promotor,
TLR, surfactant protein A polymorphisms
↑expressed levels of 15-LOX-1 in
airways of severe asthma patients
Exacerbation-prone asthma
PGD2 Receptor Type
Middleton 8th edition
• PGD2: Major mast cell–derived prostanoid, also from
eosinophils
• DP2 also is known as CRTH2 (chemoattractant receptor–like
molecule expressed on Th2, ILC2 cells)
• DP2 is preferentially expressed by IL-4+/IL-13+ T cells more
than by interferon (IFN)-γ+ T cells, ↑in severe asthma
Allergic inflammation(↑PDE)
Delays Th2 apoptosis,
Stimulates Th2 to produce IL-4, 5, 13
Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
Anti IL-5: Mepolizumab
• Steroid Reduction with Mepolizumab Study (SIRIUS)1
• Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma
(MENSA)2
• Severe asthma
• AEC ≥ 150 cells/mcL at screening or 300 cells/mcL in last year
1. Bel EH,et al.; Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. NEJM 2014;371:1189–1197.
2. Ortega HG,et al.; Mepolizumab treatment in patients with severe eosinophilic asthma. NEJM 2014;371:1198–1207.
Bel EH,et al.; Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. NEJM 2014;371:1189–1197.
• Steroid sparing
• ↓Exacerbation: 1.44/2.12
• ↑QoL, Improve ACQ-5
• (FEV1: nonsignificant diff)
Mepolizumab 100mg sc or placebo was administered subcutaneously once every 4 weeks until week 20
Ortega HG,et al.; Mepolizumab treatment in patients with severe eosinophilic asthma. NEJM 2014;371:1198–1207.
75mg IV dose or 100mg sc, or placebo every 4 weeks for 32 weeks
• ↓Exacerbation: 0.83/0.93/1.74 per patient per year
• ↑pre BD FEV1 from BL: 100 ml /98 ml compared to placebo
• ↑QoL, improve ACQ-5
IL-5 Receptor Antagonist: Benralizumab
Bleecker ER, et al.; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with highdosage inhaled
corticosteroids and long-acting b2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;388:2115–2127.
17 countries, 347 centers
Age 12–75 years
48 weeks add-on Tx
1ry outcome: Annual AE
Exacerbations, FEV1 in the benralizumab-treated and placebo cohorts diverged at 4 week
Benralizumab q 8 wk in Eo≥300: improve ACQ-6
Anti IL-13: Tralokinumab1, Lebrikizumab2
Tralokinumab 300mg sc every 2 or 4 weeks for 52 weeks1
• Not ↓exacerbation rates in severe uncontrolled asthma compared with
placebo,
• Improve FEV1 in Tralokinumab 300mg sc every 2 weeks
• Post-hoc subgroup analysis (Tralokinumab 300mg sc every 2 weeks)
: DPP-4 = improvements in preBD FEV1, ACQ-6, and AQLQ(S)
Periostin = preBD FEV1, ACQ-6, exacerbation rate
Lebrikizumab 250 mg sc every 4 weeks for 6 months2
• 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)
1. Brightling CE, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma:
a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015;3:692–701.
2. Corren J, et al. Lebrikizumab Treatment in Adults with Asthma. N Engl J Med 2011;365:1088-98.
Anti IL-4/13 : Dupilumab
• Fully human anti-interleukin-4 receptor α monoclonal antibody
• Dupilumab 200 mg or 300 mg sc every 2 weeks or every 4 weeks, or
placebo, over a 24-week period
• Dupilumab 300 mg q 2 weeks: the greatest ↑lung function in the
overall population (also ↑lung function in AEC ≥ 300 ,< 300 subgroup)
• Dupilumab q 2 weeks: the greatest ↓annualised rates of exacerbation
in the overall population (70–70.5%)
• AEC ≥ 300 : 71.2–80.7%
• AEC < 300 : 59.9–67.6%
Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled
corticosteroids plus a long-acting b2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31–44.
174 study sites across 16 countries or regions
Adults (aged ≥18 years)
1ry outcome: FEV1 in L change from baseline at 12th week
In patients with uncontrolled persistent asthma
• ↑lung function in AEC ≥ 300
• ↓severe exacerbations irrespective of baseline AEC
• Favourable safety profile
PGD2 Receptor 2 Antagonist: Fevipiprant
• Persistent, moderate-to-severe asthma and ↑sputum eosinophil
count (≥2%)
• Fevipiprant (225 mg twice per day orally) or placebo for 12 week
• Mean %sputum Eo was reduced by 4.5 times (1.3 times in the
placebo group)
• Difference between groups 3.5 times, 95% CI 1·7–7·0; p=0·0014).
• Favourable safety profile
Gonem S, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a
single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2016;4:699–707.
Single-centre
1ry outcome: change in
sputum Eo% from
baseline to 12 weeks
Biologics for EA
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
For non IL-5 specific EA endotypes (also benefit in NEA)
Non-eosinophilic Asthma
• Sputum Eo < 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
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Neutrophilic asthma
• Older age
• Impaired lung function
• Less bronchodilator reversibility
• Less atopy
• Trigger factors activate TLR4 and CD14 on epithelial cells, MØ
NF-kB activation
↑IL-8 (recruit activated neutrophils into the airways)
• Impaired MØ efferocytosis (phagocytosis of apoptotic cells)
• The p38 kinases(MAPK): induced by environmental triggers
• ↑inflammasome activity
• NK, NKT-like cells: corticosteroid insensitivity
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
MAPK Family: p38 Kinase
• MAPK: dephosphorylation enz  generally halt prot. 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 inflammation
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Middleton 8th edition
Non-eosinophilic Asthma: Th2/T2 Low
Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
Th171
• Induced by chr.infection, inhale
exposure
• Neutrophilic, mixed granulocytic
• Severe, frequent exacerbation,
steroid resistance
• Mucus hypersecretion
• SM hypertrophy, AW remodeling
Neutrophilic asthma: clue for chr.subclinical infection1
1.Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Air Pollutant, Smoking, Occupational Asthma
• 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 Noneosinophilic Asthma: AJRCCM Jan 2018
Middleton 8th edition
Paucigranulocytic Asthma
• 40% NEA
• Well controlled, mild intermittent in SARP cohort
• Some: severe, may not response to ICS
• Dysfunction of AW SM, n., vascular tissues
• AW SM: secrete cytokines, chemokines
• ↑Bronchospasm: muscarinic, adrenergic pathways
• Tx by muscarinic(LAMA), B2 antagonist(↓bronchospasm), bronchial
thermoplasty(↓exacerbation in severe paucigranulocytic asthma)
• Aberrant repair mechanism: AW remodeling
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Obesity Related Asthma (EA, NEA)
• Eosinophilic (Early onset eosinophilic)
• Metabolic: ↓CD4 effector cell function
• High fat diet: ↑BM Eo
• TNF-α: ↑AW hyperresponsiveness
• Surfactant protein A lipid: ↑type 2
inflammation
• Adipokines ex leptin: ↑AW
hyperresponsiveness, serum IgE
(Adiponectin: ↓AW hyperresponsiveness)
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
• Non-eosinophilic (late onset, female
predominant)
• Neutrophilic, paucigranulocytic
• ↑AW Resistance, easy to closure
• Reverse with weight reduction
• Activated MØ  inflammation in
adipose tissue  ↑IL-6, TNFα, leptin
• AW hyperresponsiveness:
• O3  ↓lung function, ↑IL-6,
↑AW PMN
• Fat, antioxidants, lycopene consumption
Obese asthma mouse model: hi-fat diet
AW hyperreactive from IL-17A(ILC3)
• Modifying dietary fat intake: important in asthma Mx
Wood LG, et al. A high-fat challenge increases airway inflammation and impairs
bronchodilator recovery in asthma. J Allergy Clin Immunol 2011;127:1133–1140.
• Nonobese (BMI < 30 kg/m2) and obese (BMI ≥30 kg/m2)
• Age > 18 years with stable asthma, nonsmokers
• AHF: Asthma high-fat
• AHF-NonO: Asthma high-fat/high energy—nonobese
• AHF-O:Asthma high-fat/high energy—obese ALF
• ALF: Asthma low-fat/low-energy
• HCHF: Healthy controls high-fat
• 4 hours postmeal, AHF-NonO 
• ↑sputum % PMN
• ↑TLR4 mRNA expression
• ↑FEV1/FVC were lower in the high-fat versus low-fat groups.
• After the high-trans fatty acid meal, sputum % neutrophils
were significantly higher than after the non-trans meal
• Activation of the innate immune response by fatty acids in the
airways
• Modifying dietary fat intake: important in asthma Mx
Lipoxin = endo. Arachidonate
↓Eo,PMN trafficking,toxic degranulation
EH: Epoxide hydrolase
Metabolize lipoxin
Viral infection
Chronic infection
Tx in NEA(1)
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
No proven targeted biologic, lacking clinical studies
Tx in NEA(2)
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
No proven targeted biologic, lacking clinical studies
Non-pharmacologic Mx in NEA
• Smoking cessation
• Avoidance environmental triggers/pollutants
• Tx comorbid: weight reduction
• Look for chronic subclinical infection
• Dietary modification
• Low fat, low trans fat1
• Adequate antioxidants2
• Lycopene rich supplements2
• Bronchial thermoplasty: paucigranulocytic asthma
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
1. Wood LG, et al. A high-fat challenge increases airway inflammation and impairs bronchodilator recovery in asthma. J Allergy Clin Immunol 2011;127:1133–1140.
2. Wood LG, Garg ML, Powell H, Gibson PG. Lycopene-rich treatments modify noneosinophilic airway inflammation in asthma: proof of concept. Free Radic Res
2008;42:94–102.
Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for (Omics) Technology, BioMed Research International, 2018
Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
Severe Asthma Evaluation
• Age of onset
• Symptom
• Comorbidity: AR, obesity, chronic rhinosinusitis
• Acute exacerbation
• Lung function: fixed/reversible airflow obstruction
• Cellular inflammation
• Treatment response: corticosteroid insensitivity

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Más de Chulalongkorn Allergy and Clinical Immunology Research Group

Más de Chulalongkorn Allergy and Clinical Immunology Research Group (20)

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Asthma phenotypes

  • 2. Asthma • Character: “Heterogeneity” • Cluster analysis  asthma phenotypes (statistically, molecularly, genetically) • Link biology to phenotype • Targeted and personalized approaches to therapy Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
  • 3. Phenotypes • The visible characteristics of an organism resulting from the interaction between its genetic makeup and the environment.1 1.The Encarta World Dictionary, 1st edn. New York: St Martin’s Press; 1999.
  • 4. Endotypes • A specific biological pathway is identified that explains the observable properties of a phenotype Lötvall, J. et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 127, 355–360 (2011).
  • 5. Severe Asthma • International Innovative Medicines Initiative criteria • Asthma (R/O alternative Dx, compliance, trigger factors, Tx error) • Poor asthma control or frequent (≥2) severe exacerbations per year • Despite high-intensity treatment or can only maintain adequate control when taking systemic corticosteroids and are thereby at risk of serious adverse effects of treatment. • High intensity asthma Tx: • 1000 mcg/day fluticasone equivalent combined + LABA or other controllers (adults) • 500 mcg/day fluticasone equivalent (school-aged children) • 400 mcg/day budesonide equivalent + oral leukotriene receptor antagonists (pre-school children) Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917.
  • 6. GINA Guideline 2018 Asthma that requires GINA steps 4 to 5 Tx (high-dose ICS and LABA or LT modifier/theophylline) for the previous year or systemic corticosteroids for ≥50% of the previous year “uncontrolled“ despite this therapy M. Amelink, et al., Severe adult-onset asthma: A distinct phenotype; J Allergy Clin Immunol 2013
  • 7. Old Asthma Phenotypes Approaches • Extrinsic (Allergic) • Atopy • sIgE to trigger • Intrinsic (Nonallergic) • Develop later in life (> 40 years old) • AERD, etc.
  • 8. The Umbrella Term ‘Asthma’ Asthma phenotypes: the evolution from clinical to molecular approaches: nature medicine MAY 2012 Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 9. Cluster Analysis • SARP: Severe Asthma Research Program (by the National Heart, Lung, and Blood Institute ) • Clinical characteristics of age of asthma onset, lung function, bronchodilator reversibility, and demographics • UBIOPRED: Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium • ADEPT: Airways Disease Endotyping for Personalized Therapeutics Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917.
  • 10. Cluster Analysis Elisabeth H Bel, et al.Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI); Thorax 2011;66:910e917. Eo↑ Several endotypes drive the phenotypes present in each cluster.
  • 11. Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 12. Eosinophilic vs Non-eosinophilic Asthma • Eosinophilic  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.: ≥20 cells/mm2 of tissue (16-31)  ↑Serum periostin (correlated to AW & sputum eosinophilia, IL-13 pathway)1  DPP-4: IL-13 pathway Exhaled nitric oxide  Respiratory epithelium under control of IL-13  Often but not always correlated with sputum/blood Eo (marker of TH2 phenotype)  Predicts responsiveness to inhaled corticosteroids Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 • Non-eosinophilic  Dominant cell: neutrophils, mixed inflammatory granulocytes  Or very few inflammatory cells “paucigranulocytic” 1.Jia G et al.; Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. JACl 2012;130:647–654.e10. Blood Eo: indirect, fluctuating, may not reflect sputum Eo (but if extreme(<90, >400) : ↑ reflective) AEC > 300-400
  • 13. Periostin Wei Li, et al. Periostin: its role in asthma and its potential as a diagnostic or therapeutic target. Respir Res. 2015; 16(1): 57. • Matricellular protein from Eo, MØ, fibroblasts, epithelial cells • Eo recruitment • AW remodeling (TGF-B inducing protein homoloque) • Th2 phenotype • ↑Inflammatory mediators
  • 14. Eosinophilic Asthma (EA) • May be responsive to ICS • If unresponse to high dose ICS/need systemic steroid • May be responsive some biologic Tx • 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 Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 15. Allergic EA: childhood Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
  • 16. Non-allergic Eosinophilic Asthma • 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) AW epithelial injury IL-25, IL-33, and TSLP  stimulate ILC-2, Th2, TSLP-primed DCs, mast cell Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 17. Middleton 8th edition TSLP (thymic stromal lymphopoietin) • Direct mast cell activation  release of proinflammatory cytokines and lipid mediators • Bind to receptor on DC  upregulating CD40, OX40, and CD80 Enhancing Th2 polarization IL-25, IL-33: directly on the naïve T cells to promote Th2 immune deviation Not predominant IL-4 production: minimizes B cell class switching to IgE(Ag specific IgE is not prominent)
  • 18. Non-allergic Eosinophilic Asthma • Th2, Th17: Dual positive in some patients • “Late onset EA” • IL-6, IL-1b, IL-23 • MEK(MAP-ERK kinase 1) • IL-1b–mediated inflammation • Corticosteroid insensitive • Type 2 cytokine: inh IL-8 (Eo>PMN) Middleton 8th edition Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 19. Staphylococcal Enterotoxin: Non-allergic EA • Superantigen production • Polyclonal IgE production in the airways  non-Ag-specific mast cell activation • Suppression of Treg • Production of cytotoxic Ab to epithelial proteins (i.e., cytokeratin-18) • corticosteroid insensitivity Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 Middleton 8th edition
  • 20. Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 Periostin, TGF-B: AW remodeling Aspergillus protein: processed by DC (HLA- DR2/DR5) potent T2 inflammation, directly epithelial cell damage. Genetic risk: IL-4 receptor, IL-10 promotor, TLR, surfactant protein A polymorphisms ↑expressed levels of 15-LOX-1 in airways of severe asthma patients Exacerbation-prone asthma
  • 21. PGD2 Receptor Type Middleton 8th edition • PGD2: Major mast cell–derived prostanoid, also from eosinophils • DP2 also is known as CRTH2 (chemoattractant receptor–like molecule expressed on Th2, ILC2 cells) • DP2 is preferentially expressed by IL-4+/IL-13+ T cells more than by interferon (IFN)-γ+ T cells, ↑in severe asthma Allergic inflammation(↑PDE) Delays Th2 apoptosis, Stimulates Th2 to produce IL-4, 5, 13
  • 22. Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012
  • 23. Anti IL-5: Mepolizumab • Steroid Reduction with Mepolizumab Study (SIRIUS)1 • Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA)2 • Severe asthma • AEC ≥ 150 cells/mcL at screening or 300 cells/mcL in last year 1. Bel EH,et al.; Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. NEJM 2014;371:1189–1197. 2. Ortega HG,et al.; Mepolizumab treatment in patients with severe eosinophilic asthma. NEJM 2014;371:1198–1207.
  • 24. Bel EH,et al.; Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. NEJM 2014;371:1189–1197. • Steroid sparing • ↓Exacerbation: 1.44/2.12 • ↑QoL, Improve ACQ-5 • (FEV1: nonsignificant diff) Mepolizumab 100mg sc or placebo was administered subcutaneously once every 4 weeks until week 20
  • 25. Ortega HG,et al.; Mepolizumab treatment in patients with severe eosinophilic asthma. NEJM 2014;371:1198–1207. 75mg IV dose or 100mg sc, or placebo every 4 weeks for 32 weeks • ↓Exacerbation: 0.83/0.93/1.74 per patient per year • ↑pre BD FEV1 from BL: 100 ml /98 ml compared to placebo • ↑QoL, improve ACQ-5
  • 26. IL-5 Receptor Antagonist: Benralizumab Bleecker ER, et al.; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with highdosage inhaled corticosteroids and long-acting b2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;388:2115–2127. 17 countries, 347 centers Age 12–75 years 48 weeks add-on Tx 1ry outcome: Annual AE Exacerbations, FEV1 in the benralizumab-treated and placebo cohorts diverged at 4 week Benralizumab q 8 wk in Eo≥300: improve ACQ-6
  • 27. Anti IL-13: Tralokinumab1, Lebrikizumab2 Tralokinumab 300mg sc every 2 or 4 weeks for 52 weeks1 • Not ↓exacerbation rates in severe uncontrolled asthma compared with placebo, • Improve FEV1 in Tralokinumab 300mg sc every 2 weeks • Post-hoc subgroup analysis (Tralokinumab 300mg sc every 2 weeks) : DPP-4 = improvements in preBD FEV1, ACQ-6, and AQLQ(S) Periostin = preBD FEV1, ACQ-6, exacerbation rate Lebrikizumab 250 mg sc every 4 weeks for 6 months2 • 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) 1. Brightling CE, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 2015;3:692–701. 2. Corren J, et al. Lebrikizumab Treatment in Adults with Asthma. N Engl J Med 2011;365:1088-98.
  • 28. Anti IL-4/13 : Dupilumab • Fully human anti-interleukin-4 receptor α monoclonal antibody • Dupilumab 200 mg or 300 mg sc every 2 weeks or every 4 weeks, or placebo, over a 24-week period • Dupilumab 300 mg q 2 weeks: the greatest ↑lung function in the overall population (also ↑lung function in AEC ≥ 300 ,< 300 subgroup) • Dupilumab q 2 weeks: the greatest ↓annualised rates of exacerbation in the overall population (70–70.5%) • AEC ≥ 300 : 71.2–80.7% • AEC < 300 : 59.9–67.6% Wenzel S, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting b2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31–44. 174 study sites across 16 countries or regions Adults (aged ≥18 years) 1ry outcome: FEV1 in L change from baseline at 12th week In patients with uncontrolled persistent asthma • ↑lung function in AEC ≥ 300 • ↓severe exacerbations irrespective of baseline AEC • Favourable safety profile
  • 29. PGD2 Receptor 2 Antagonist: Fevipiprant • Persistent, moderate-to-severe asthma and ↑sputum eosinophil count (≥2%) • Fevipiprant (225 mg twice per day orally) or placebo for 12 week • Mean %sputum Eo was reduced by 4.5 times (1.3 times in the placebo group) • Difference between groups 3.5 times, 95% CI 1·7–7·0; p=0·0014). • Favourable safety profile Gonem S, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med 2016;4:699–707. Single-centre 1ry outcome: change in sputum Eo% from baseline to 12 weeks
  • 30. Biologics for EA Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 For non IL-5 specific EA endotypes (also benefit in NEA)
  • 31. Non-eosinophilic Asthma • Sputum Eo < 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 Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 32. Neutrophilic asthma • Older age • Impaired lung function • Less bronchodilator reversibility • Less atopy • Trigger factors activate TLR4 and CD14 on epithelial cells, MØ NF-kB activation ↑IL-8 (recruit activated neutrophils into the airways) • Impaired MØ efferocytosis (phagocytosis of apoptotic cells) • The p38 kinases(MAPK): induced by environmental triggers • ↑inflammasome activity • NK, NKT-like cells: corticosteroid insensitivity Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 33. MAPK Family: p38 Kinase • MAPK: dephosphorylation enz  generally halt prot. 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 inflammation Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 Middleton 8th edition
  • 34. Non-eosinophilic Asthma: Th2/T2 Low Asthma phenotypes: the evolution from clinical to molecular approaches : nature medicine VOLUME 18 | NUMBER 5 | MAY 2012 Th171 • Induced by chr.infection, inhale exposure • Neutrophilic, mixed granulocytic • Severe, frequent exacerbation, steroid resistance • Mucus hypersecretion • SM hypertrophy, AW remodeling Neutrophilic asthma: clue for chr.subclinical infection1 1.Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 35. Air Pollutant, Smoking, Occupational Asthma • 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 Noneosinophilic Asthma: AJRCCM Jan 2018 Middleton 8th edition
  • 36. Paucigranulocytic Asthma • 40% NEA • Well controlled, mild intermittent in SARP cohort • Some: severe, may not response to ICS • Dysfunction of AW SM, n., vascular tissues • AW SM: secrete cytokines, chemokines • ↑Bronchospasm: muscarinic, adrenergic pathways • Tx by muscarinic(LAMA), B2 antagonist(↓bronchospasm), bronchial thermoplasty(↓exacerbation in severe paucigranulocytic asthma) • Aberrant repair mechanism: AW remodeling Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 37. Obesity Related Asthma (EA, NEA) • Eosinophilic (Early onset eosinophilic) • Metabolic: ↓CD4 effector cell function • High fat diet: ↑BM Eo • TNF-α: ↑AW hyperresponsiveness • Surfactant protein A lipid: ↑type 2 inflammation • Adipokines ex leptin: ↑AW hyperresponsiveness, serum IgE (Adiponectin: ↓AW hyperresponsiveness) Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 • Non-eosinophilic (late onset, female predominant) • Neutrophilic, paucigranulocytic • ↑AW Resistance, easy to closure • Reverse with weight reduction • Activated MØ  inflammation in adipose tissue  ↑IL-6, TNFα, leptin • AW hyperresponsiveness: • O3  ↓lung function, ↑IL-6, ↑AW PMN • Fat, antioxidants, lycopene consumption Obese asthma mouse model: hi-fat diet AW hyperreactive from IL-17A(ILC3) • Modifying dietary fat intake: important in asthma Mx
  • 38. Wood LG, et al. A high-fat challenge increases airway inflammation and impairs bronchodilator recovery in asthma. J Allergy Clin Immunol 2011;127:1133–1140. • Nonobese (BMI < 30 kg/m2) and obese (BMI ≥30 kg/m2) • Age > 18 years with stable asthma, nonsmokers • AHF: Asthma high-fat • AHF-NonO: Asthma high-fat/high energy—nonobese • AHF-O:Asthma high-fat/high energy—obese ALF • ALF: Asthma low-fat/low-energy • HCHF: Healthy controls high-fat • 4 hours postmeal, AHF-NonO  • ↑sputum % PMN • ↑TLR4 mRNA expression • ↑FEV1/FVC were lower in the high-fat versus low-fat groups. • After the high-trans fatty acid meal, sputum % neutrophils were significantly higher than after the non-trans meal • Activation of the innate immune response by fatty acids in the airways • Modifying dietary fat intake: important in asthma Mx
  • 39. Lipoxin = endo. Arachidonate ↓Eo,PMN trafficking,toxic degranulation EH: Epoxide hydrolase Metabolize lipoxin Viral infection Chronic infection
  • 40. Tx in NEA(1) Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 No proven targeted biologic, lacking clinical studies
  • 41. Tx in NEA(2) Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 No proven targeted biologic, lacking clinical studies
  • 42. Non-pharmacologic Mx in NEA • Smoking cessation • Avoidance environmental triggers/pollutants • Tx comorbid: weight reduction • Look for chronic subclinical infection • Dietary modification • Low fat, low trans fat1 • Adequate antioxidants2 • Lycopene rich supplements2 • Bronchial thermoplasty: paucigranulocytic asthma Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018 1. Wood LG, et al. A high-fat challenge increases airway inflammation and impairs bronchodilator recovery in asthma. J Allergy Clin Immunol 2011;127:1133–1140. 2. Wood LG, Garg ML, Powell H, Gibson PG. Lycopene-rich treatments modify noneosinophilic airway inflammation in asthma: proof of concept. Free Radic Res 2008;42:94–102.
  • 43. Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for (Omics) Technology, BioMed Research International, 2018
  • 44. Tara F. Carr, Eosinophilic and Noneosinophilic Asthma: AJRCCM Jan 2018
  • 45. Severe Asthma Evaluation • Age of onset • Symptom • Comorbidity: AR, obesity, chronic rhinosinusitis • Acute exacerbation • Lung function: fixed/reversible airflow obstruction • Cellular inflammation • Treatment response: corticosteroid insensitivity