Asthma phenotypes and endotypes

Asthma Phenotypes and Endotypes

Gamal Rabie Agmy, MD, FCCP Professor of chest Diseases, Assiut university

Definition of Asthma

A chronic inflammatory disorder of the airways

Many cells and cellular elements play a role

Chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing

Widespread, variable, and often reversible airflow limitation

Source: Peter J. Barnes, MD

Asthma Inflammation: Cells and Mediators

Asthma is a complex disease or a syndrome

that includes several disease variants.

The term asthma, like ‘arthritis’, equates to a

definition of grouped clinical and physiological

characteristics. These characteristics could

identify syndromes, phenotypes or even

multiple diseases rather than a single disease.

◙ For revealing the complexity and the

heterogeneity of this disease, asthma patients

were grouped into subtypes called phenotypes.

◙ Term ‘phenotype’ describes subtypes of

asthma focused on ‘clinically observable

characteristics’ of a disease.

Therefore, there are many ‘definitions’ for asthma phenotypes,

many of which are related to differences in symptoms and

severity rather than to differences in underlying mechanisms. but

this kind of subtyping does little to help understand prognosis

and target therapy.

When a link can be made between clinical characteristics and

molecular pathways, the term endotype can be introduced

to describe distinct subtypes with a defining etiology and

consistent pathobiologic mechanisms.

The definition of a true phenotype (or endotype)

requires an underlying pathobiology with

identifiable biomarkers and genetics .

Gene-expression profiling allows definition of

expression signatures to characterize patient

subgroups, predict response to treatment, and

offer novel therapies.

Th2-associated asthma

These patients are characterized by atopy,

eosinophilic inflammation and favorable response

to corticosteroids.

Early-onset allergic asthma

Late-onset persistent eosinophilic asthma

Exercise induced asthma

Early-onset allergic asthma

Clinical characteristics:

This group of asthmatic patients developed their disease in

childhood, and maintained their symptoms into adulthood. .

The majority of early-onset allergic asthma is mild but that

an increasing complexity of immune processes leads to

greater severity.

Most people with asthma are likely to have this phenotype.

Positive skin prick tests, specific IgE antibodies in serum,

eosinophilia in the peripheral blood .

Genetics:

Early-onset allergic patients commonly have a

family history of asthma, suggesting a genetic

component.

►Several Th2 cytokine SNPs

►higher numbers of mutations in TH2-related genes

(IL4, IL13, IL4Rα ) associated with greater severity

of disease.

Biomarkers:

Positive SPT, elevated IgE/elevated FeNO

Th2 cytokines IL-4 ,IL-5 , IL-9, IL-13, and periostin measured in

sputum, BAL, serum and bronchial biopsies.

Treatment responses:

►Corticosteroid-responsive.

►Th2 Targeted therapy:

Anti IgE (omalizumab)in Severe allergic asthma.

Anti–IL-13( lebrikizumab) in Allergic asthma with dominant IL-

13 activation . Surrogate marker predicting better response is

high circulating levels of periostin. .

Inhaled IL-4Rα antagonist . Surrogate

marker predicting better response is IL-4

receptor a polymorphism.

Late-onset persistent eosinophilic asthma


The majority of this group develops disease in adult

life, often in the late 20s to 40s.

Severe from onset, Severe exacerbations with persistent

sputum eosinophilia (>2%), despite corticosteroid therapy.

less clinical allergic responses( non atopic) than early-

onset asthma.

It is often associated with sinus disease.

Genetics:

Few patients in this group have a family

history of asthma.

little is known regarding the genetics of adult

onset persistent asthma.

Biomarkers:

Lung eosinophilia. Persistent sputum eosinophilia (≥2%)

The lack of clinical allergy in this phenotype suggests that the TH2

process differs from and is probably more complex than the one

associated with the early-onset allergic phenotype but the presence

of IL-13 and IL-5 in the lower airways confirm Th2 pathway.

Some individuals show sputum neutrophilia intermixed with their

eosinophilic process. This mixed inflammatory process implies

that there are interactions of additional immune pathways with

TH2 immunity, including activation of pathways related to IL-33

and IL-17 .

Elevations in FeNO


• persistent eosinophilia in late-onset disease inspite of ICS implies that

the TH2 process in this type of asthma is refractory to corticosteroids

but high systemic doses of corticosteroids are generally able to

overcome this refractoriness in late-onset asthma.

• IL-5 targeted therapy may show much better efficacy in this

endotype, compared in early-onset allergic asthma patients, as IL-5

dependent eosinophilia may be more important in this potential

endotype. (decreasing exacerbations and systemic corticosteroid

requirements)

• IL-4 and IL-13 targeted therapy pathway.

AERD is probably a subendotype or a similar endotype. It is an

acquired condition on top of an intrinsic or less frequently

allergic asthma and thus, despite its peculiar sensitivity to

NSAIDs, still has major overlap with these conditions.

Clinical characteristics :

• AERD is frequently progressive severe asthma starts late in

life and is associated with eosinophilia and sinus disease

Polyposis.

• Response to aspirin challenge

Aspirin exacerbated airway disease

(AERD)

Genetics :

• LT-related gene polymorphisms.

• Gene-expression study identified upregulation of periostin a potent

regulator of fibrosis and collagen deposition has also been identified

in polyps of and in airway epithelial cells of patients with AIA.

Overexpression of periostin has been associated with accelerated cell

growth and angiogenesis(subtype).

Biomarkers:

high cysteinyl leukotriene level.

Treatment responses :

• Many patients require systemic corticosteroids to control

their sinusitis and asthma.

• Leukotriene modifiers especially 5-LO inhibitors can have a

robust impact on the AERD subset.

• Downregulation of periostin after treatment of asthmatic

patients with corticosteroids suggests that normalization of

periostin expression is a part of the therapeutic effects of

corticosteroids. This opens a possibility of specifically

targeting periostin in future therapies for nasal polyps and

asthma


• Exercise induced asthma refers to asthma whose symptoms

are experienced primarily after exercise. EIA is a milder

form of TH2 asthma.

• Consistent with a relationship to TH2 processes, EIA

common in atopic athletes and high percentages of

eosinophils and mast cells and their mediators .

Exercise induced asthma

Biomarkers:

• Th2 cytokines and cysteinyl leukotriene

Genetics:

• No distinct genetic factors .


• Leukotriene modifiers high LTE4/FENO ratio is Surrogate

marker predicting better response.

• IL-9 targeted therapy has been shown effective on patients

of this group, which implies that Th2 immunity is involved in

the pathophysiology of EIA.

The lack of efficacy of Th2 targeted therapy suggests that a

subgroup of asthma develops in the absence of Th2 immunity.

Little is understood about the non Th2 asthma and its related

molecular elements.

• Obesity-related asthma

• Neutrophilic asthma

• Smoking asthma

Non Th2-associated asthma

Whether obesity is a driving component in asthma development

or a mere confounder or comorbidity of its presence remains

controversial.

It is likely that obesity differentially impacts asthma that

develops early in life, as compared to later in life, being a more

prominent independent contributor in later onset disease.

So a distinct obesity-related asthma phenotype seems to occur

only in non-TH2 asthma.

, ..

Clinical characteristics :

Patients in this group are commonly women, obese, late onset

(mid-40s), less allergic (obesity is neither a risk factor for atopy

nor a risk factor for allergic asthma).with a high burden of

symptoms.

Biomarkers:

High expression of non Th2 mediators such as tumor

necrosis factor (TNF)-a, IL-6 .

Hormones of obesity, such as adiponectin, leptin, and resistin

either alone or in association with increased oxidative stress.

Elevations in an endogenous inhibitor of iNOS, asymmetric

dimethyl arginine (ADMA).

lower amounts of FeNO, fewer eosinophils.


Patients of this subgroup usually respond poorly to corticosteroids.

Bariatric surgery induced weight loss was associated with profound

improvements in lung function and symptoms in obese asthma.

However, the effect of weight loss on bronchial hyper responsiveness

was only shown in late-onset, nonallergic (non-Th2) asthma patient,

consistent with late onset obese asthma being a separate endotype. This

is further supported by the increase in ADMA in association with

worsening severity and control in late onset obese asthma only.

Clinical characteristics and biomarkers:

It remains controversial whether neutrophilia is an independent driving

component, a synergistic factor with eosinophilia or just a consequence of

corticosteroid therapy.

Still unclear whether this represents a unique form of asthma or just a

different stage of severity or persistent bacterial colonization or infection of

the airways on the background of a previously eosinophilic asthma.

Airway pathophysiology in neutrophilic asthma is characterized by (fixed)

airflow limitation more trapping of air, thicker airway walls (as

measured by CT) .

Novel mechanisms implicated in the pathogenesis of

noneosinophilic asthma involve the activation of innate immune

responses with a possible role of bacteria, viruses.

Neutrophilia can also co-exist with eosinophilia, and this identifies

the people with the most severe asthma and emphasizes the

complexity of the immunobiology of severe asthma in which

multiple different innate and adaptive immune pathways and cells

may have roles.

Impaired nuclear recruitment of histone deacetylase (HDAC).

The role of TH17 immunity

Biomarkers:

IL-8, IL-17A, LTB4, and possibly IL-32.

IL-1 and TNF-α pathways are upregulated and associated with

neutrophilic inflammation in a sputum gene-expression study.

low levels of FeNO.


Corticosteroids are less effective in patients of this subgroup.

Macrolide antibiotics may have some efficacy on neutrophilic

asthma, By modulating the innate immune response in the

lung, by reducing the expression of neutrophilic markers .

Restoration of HDAC 2 nuclear recruitment with theophylline.

Anti-TNF-α responsive( infliximab )

The efficacy of IL-17 targeted therapy in this subtype of

asthma awaits evidence from ongoing clinical trials.

Smoking has a complex relationship with asthma. It is

associated with deteriorating lung function and resistance to

corticosteroids.

Smoking asthma has been associated with neutrophilia in lung

tissue.

It is unknown if smoking asthma is a subtype of neutrophilic

asthma or an independent endotype . Since not all smoking

asthma is accompanied by neutrophilia, it is more likely that

there is only a partial overlap between neutrophilic asthma and

smoking asthma.

Some reports have suggested that smoking is associated with

elevated total IgE and that active smoking may increase the risk of

sensitization to workplace allergens.

However, little is understood regarding the role of genetics,

biomarkers or pathobiology.

FeNO levels are decreased by smoking and could help to

differentiate asthmatic subjects from non-asthmatic subjects.

Treatment responses

Quitting smoking

Restoration of HDAC 2 nuclear recruitment with theophylline.

The intensity of the colors represents the range of severity; the relative sizes

of the subcircles suggest relative proportions of affected individuals

Lötvall et al.2011 proposed endotyping asthma into six classes

depending on several parameters used to define an endotype.

Aspirin sensitive asthma

Allergic asthma (adults)

Severe late-onset hypereosinophilic

ABPM

API-positive preschool wheezer

Asthma in cross country skiers

The principle of personalized or individualized medicine is to

'bring the right drug to the right patient at the right dose', such

that therapeutic efficacy is maximized and the side effects are

kept to a minimum.

The consideration of disease endotypes in treatment design

should be able to bridge the present era of treating asthma

based on family history, patient characteristics and laboratory

test, to the future era of personalized medicine where

treatment scheme will be based on individual biological data

such as genomic, proteomic and metabolic profiles.

Health & Medicine

Asthma phenotypes and endotypes