ASTHMA PHENOTYPES And Endotype

WORD ASTHMA DAY 2015ABU-SITTA HOSPITAL

Phenotypes Expanding Our Understanding of Asthma

Challenges in Treating a Heterogeneous Disease

Need for Phenotype DefinitionsAsthma has always been susceptible to phenotypes

1 -according to asthma trigger2 -according to severity

3 -according to response to treatment

Need for phenotypes •Enhance interpretation of studies

•Promote appropriate comparisons among studies

•Facilitate genetics research in which phenotype is correlated with genotype

Asthma genotypesThere is no one gene for asthma.the following genes to be associated with asthma (IL13, IFNGR2, EDN1, and IL4R), atopy (FLG, CHIA, IL18, TBXA2R, TLR10, IL4R, IFNGR2, LTA, and VDR), airway hyperresponsiveness (TLR9, TBXA2R, VDR, and NOD2), and atopic asthma (TLR10, IFNGR2, STAT6, VDR, and C3).

Read More :://http . . / / /10.1513/ .6.3.324www atsjournals org doi full pats a#.VUPoENLtmko

Asthma PhenotypesDefine 9 phenotypes in 3 generalcategories:

-Trigger-induced asthma1 )Allergic

2 )Non-allergic3 )Aspirin-exacerbated respiratory

disease (AERD)4 )Infection

5 )Exercise-induced

Asthma Phenotypes -Clinical presentation of asthma

6 )Pre-asthma wheezing in infants -Episodic (viral) wheeze -Multi-trigger wheezing

7 )Exacerbation-prone asthma

Asthma Phenotypes8 )Asthma associated with apparent

irreversible airflow limitation - Inflammatory markers of asthma

9 )Eosinophilic and neutrophilic asthma

Trigger-induced asthma1 )Allergic

2 )Non-allergic3 )Aspirin-exacerbated respiratory

disease (AERD)4 )Infection

5 )Exercise-induced

Allergic •the most common phenotype.

•Higher prevalence in children. •Defined based on sensitization ±

clinical correlation.

Non-allergicsensitization cannot be demonstratedNegative skin prick or RAST testingNormal or low IgEOnset: Late, adult

Non-allergicNo personal or family history of allergyMore severe than allergic asthmaless responsive to steroidsIncidence: 10-33%

3) Aspirin sensitive asthma PROBABLE CRITERIA, WHENHISTORY OF ASPIRIN SENSITIVITYIS ABSENT IN A SUBJECT WITH ASTHMA:Chronic rhinosinusitis with nasal

polyps •Adult onset (over age 20 years)

•Peripheral blood eosinophilia

�Samter Triad

���Aspirin sensitive asthma

1 .Prevalence by history is variable (3-5%) but may be present in up to 21% of adults and5% of children.

2 .Aspirinsensitive asthma more in female.3 .Usual age of onset of symptoms is 30-34

years of age.4 .No known racial predisposition.

5 .No known association with lower socioeconomic status.

Aspirin sensitive asthma1 .Familial cases reported but relatively

rare (5.5%).2 .Association with HLA-DQw2 and DPB1.

3 .Genetic polymorphisms found in leukotriene C4 synthase

(LTC4S),prostaglandin E2 receptor genes.

A ��SA1 .Associated with more severe, refractory asthma, representing

A major risk factor for severe asthma in outpatients.2 .ASA may induce severe, lifethreatening asthma attacks.

3 .Rhinorrhea and nasal congestion are usually the first symptoms .of aspirinsensitive

4 .asthma and are commonly poorly responsive to pharmacologicalTreatment.

5 .Symptoms manifest within 1-3 hours of ingestion of aspirin and other NSAD.

1

Asthma PhenotypesTrigger-induced asthma

1 )Allergic2 )Non-allergic

3 )Aspirin-exacerbated respiratorydisease (AERD)

4 )Infection5 )Exercise-induced

respiratory tract infection1 -new onset of disease .

2 -exacerbations of the disease.3 -Co-morbid condition (e.g. sinusitis).

4 -persistence and/or severity of the disease

Exercise-induced (EIB) •No apparent gender disparity

•No known racial predisposition •No known association with socioeconomic

status •No known association with smoking

EIBEIB is generally thought to be due to evaporativeheat and water loss from the airway and variousinflammatory mediators and cells have beenInvolved in its pathogenesis.EIB occurs after the cessation of exercise,usually within 3-5 minutes, with peakbronchoconstriction occurring at 10-15 minutes.

Usually defined as ≥ 10% decrease in FEV1 after exercise.

Clinical presentation of asthma

A child who wheezes in early life.

WheezingPhenotypePre-Asthma Wheezing

(Tucson Children’s Respiratory)

1 -Never wheezed 51.5% 2 -transient early wheezers 19.9%

3 -late-onset wheezers 15%4 -persistent wheezer s 13.7%

7) Exacerbation-prone asthma

Relation to Severe Asthma Factors for Severe Exacerbations

•Low FEV1 •African American Ethnicity

•History of Pneumonia •Early Age of Onset

•NSAID Exacerbated Airway Disease •Worsening Asthma Symptoms with

Menses

8) Asthma associated with apparentirreversible airflow limitationEvidence of both airway obstruction

(reduced FEV1/FVC ratio )and a reducedFEV1 in a patient treated with bothanti-inflammatory agents

(glucocorticosteroids )and bronchodilators(beta-agonists))

9) Eosinophilic and neutrophilic asthma

Eosinophilic asthma

•Eosinophilic inflammation associatedwith poor asthma control, increasedbronchodilator response, lower lungfunction and exacerbations in ICStreated pts

•More common in aspirin-sensitiveasthma, in association with nasal polypsand in later onset disease

>2% eosinophils in sputum

Neutrophilic asthma .Less atopy,Older , Later onset asthma

•Much less well described and defined thaneosinophilic asthma

•Seems to increase with increasingseverity/CS use

“ •Definition”/neutrophil % cut-off unclearand may depend on sputum processingmethod

–Can be seen in association with eosinophilphenotype

IL-5

Eosinophils

ECPMBP

IL-8

Neutrophils

NE

Macrophages and Epithelial Cells

Allergens

Activated TH2 Cells

MMP-9

EosinophilicAsthma

NeutrophilicAsthma

Particulates, Pollutants ,Virus, Endotoxin

Acquired Immunity

InnateImmunityTLRIgE

NF-kB

Oxidativestress

Macrophages and Epithelial Cells

Allergens

Activated TH2 Cells

EosinophilicAsthma

NeutrophilicAsthma

Particulates, Pollutants, Virus,Endotoxin, Bacteria

Acquired Immunity

InnateImmunityTLRIgE

Inflammatory cell activation

hyperresponsiveness

ICS X X LABA

X LABA

Remodelling: ASM, mast cells

Summary: Asthma Phenotypes

•Define 9 phenotypes in 3 general categories: -Trigger-induced asthma

1 )Allergic2 )Non-allergic

3 )Aspirin-exacerbated respiratory disease (AERD)4 )Infection

5 )Exercise-induced -Clinical presentation of asthma

6 )Pre-asthma wheezing in infants -Episodic (viral) wheeze -Multi-trigger wheezing

7 )Exacerbation-prone asthma8 )Asthma associated with apparent irreversible airflow

limitation -Inflammatory markers of asthma

9 )Eosinophilic and neutrophilic asthma

Asthma phenotypes- Asthma is not a single disease.

– A patient can have >1 phenotype – Specific questions for future research to refine

definitions