This presentation throws light on the endotypes/phenotypes of Asthma and the newer biologicals which are used to treat severe Asthma.

1. Endotypes/Phenotypes and the
newer biologicals of Asthma
Dr. Abhishek Tandon
MD (Respiratory Medicine) Resident
Pt. B.D. Sharma PGIMS Rohtak

2. Phenotype and endotype
• Phenotype- Observable properties of an organism that are
produced by the interactions of the genotype and the
environment,
• Endotype – A specific biological pathway that explains the
observable properties of a phenotype

3. • Schematic representation of the
asthma syndrome and its phenotypes
and endotypes.
• The asthma syndrome is
multidimensional, involving clinical,
physiologic, and pathologic domains
that coexist but are not necessarily
related.
• Groups of patients with asthma may
share observable characteristics or
phenotypes (P) as well as specific
biological mechanisms or endotypes
(E).
• Phenotypes and endotypes form the
‘foundation’ of understanding the
asthma syndrome.
• Note that a phenotype may be
explained by more than one endotype
and that an endotype may be present
in more than one phenotype.

4. Elucidating asthma phenotypes and endotypes: progress towards personalized
medicine. Ann Allergy Asthma Immunol 2016.116;394-401.

6. Asthma phenotypes and evolving endotypes
The acceptance of various phenotypes and endotypes is
evolving .
Large-scale longitudinal studies are needed to determine
whether phenotypes with proposed distinct biologic
pathways represent true endotypes.
Features of phenotypes and evolving endotypes will be
looked into in detail.

7. TH2 mediated asthma
• Asthma has largely been viewed as
a TH2-mediated process strongly
linked to atopy and eosinophilic
inflammation.
• Increased levels of eosinophils in
the sputum, bronchioalveolar
lavage, or blood characterize
eosinophilic asthma.
Non TH2 mediated asthma
• Non-TH2 mediated asthma likely
represents a significant
proportion of all asthma cases,
but it is not as well understood
as TH2-mediated asthma.
• These patients tend to respond
poorly to corticosteroid therapy,
and currently, there have been
no large-scale successful
therapeutic trials in this group.

8. • While several non-invasive biomarkers exist for the detection of the
th2-high endotype [blood eosinophils, serum IgE, serum periostin,
and exhaled nitric oxide],sputum cytometry is currently the most
clinically validated quantitative and responsive method to assess
airway inflammation. Perceived difficulties implementing this
approach in routine clinical practice have limited its widespread use.

9. TH2 mediated
asthma
Early onset
allergic
Late onset
eosinophilic
AERD
ABPM
Non-TH2
mediated asthma
-
Neutrophilic
Extensive
remodelling
Obesity
related
• TH2 – T helper cell type 2
• AERD – Aspirin exacerbated respiratory disease
• ABPM – Allergic Bronchopulmonary Mycosis
• EIB – Exercise induced Bronchoconstriction

10. TH2 MEDIATED ASTHMA

11. Early ONSET ALLERGIC ASTHMA
• Allergic asthma is the most studied asthma phenotype, accounting for
approximately 50% of subjects with asthma.
• This process begins in childhood or adolescence in most cases, with
evidence of hypersensitivity to environmental allergens.
• Early onset allergic asthma is linked with other allergic diseases, including
allergic rhinitis and atopic dermatitis, and can range from mild to severe.
• From a pathobiologic standpoint, this phenotype is linked with high Th2
cytokines, including increased total serum immunoglobulin E (IgE) and
allergen-specific Ig E.
• There appears to be a probable genetic component to early-onset asthma,
as evidenced by the presence of a strong family history of asthma in this
group.
• Other biomarkers for th2 asthma include increased forced exhaled nitric
oxide (FeNO), sputum eosinophils, and serum periostin levels.
• Treatment – Corticosteroid responsive , Th2 targeted biologics – anti- Ig E,
anti IL-13, anti-IL-5 and anti-IL-4.

12. Late onset persistent eosinophilic asthma
• This group of patients show recurrent exacerbations, marked eosinophilia, less
atopy, and later onset of asthma.
• The key drivers of inflammation in this group are unknown but believed to be
unrelated to allergic triggers.
• Th2 and LT pathways seems to be the genetic pathway.
• These patients with asthma tend to have decreased pulmonary function and
persistent sputum eosinophilia despite corticosteroid use compared with
subjects with allergic asthma.
• Potential biomarkers are sputum eosinophils and peripheral blood eosinophils.
• Treatment – Poor control with ICS therapy, ?antibody to IL-5 , ?LT modifiers.

13. AERD (Aspirin exacerbated respiratory disease)
• Adult onset
• It consists of asthma, chronic rhinosinusitis with nasal polyposis, and
respiratory reactions after ingestion of nonsteroidal anti-inflammatory drugs.
• There is intense eosinophilic inflammation of nasal and bronchial tissues.
• Pathophysiologically, AERD is characterized by increased cysteinyl leukotriene
production (cys-LT) and increased expression of leukotriene c4 synthase (LT-4
synthase).
• Potential biomarkers – eosinophilia, increased Ig E.
• Cysteinyl leukotriene receptor antagonists (eg, montelukast) and 5-
lipoxygenase inhibitors (eg, zileuton) have been shown to have beneficial
effects in patients with AERD.

14. ABPM (Allergic Bronchopulmonary Mycoses)
• Adult onset
• Severe asthma caused by a hypersensitivity reaction to fungal colonization of the airways,
typically by aspergillus fumigatus. It involves the propagation of fungi along the airway.
• Association with cystic fibrosis, suggests that an abnormality in epithelial function could
predispose to this condition.
• This endotype is associated with central bronchiectasis, cough with mucus production,
increased mold-specific IgE and IgG, eosinophilia, and obstructive lung physiology.
• Pathobiology – Mixed adaptive immunity and eosinophilia
• Potential biomarkers - blood and sputum eosinophilia, fungus specific IgE and IgG.
• Systemic corticosteroids remain the mainstay of therapy; anti-IgE therapy and antifungal
therapy have shown benefit in case series.

15. EIB (exercise induced bronchoconstriction)
• Younger age of onset
• Exercise-induced bronchoconstriction is bronchoconstriction triggered by
exercise, mostly representing a mild phenotype of asthma.
• More common in athletes with atopy.
• Variable eosinophilic inflammation.
• The genetic and inflammatory nature of this phenotype is poorly understood
but is believed to be, at least in part, mediated by Th2 and LT pathway.
• No distinct genetic predisposition or biomarker has been identified thus far.
• Cys-LT modifiers and beta- agonists are the usual treatment administered.

16. NON – TH2 MEDIATED ASTHMA

17. NEUTROPHILIC ASTHMA
• Lung airway neutrophilia might be associated with lower lung function,
more air trapping, and thickening airway walls.
• Sputum neutrophilia has been reported in severe asthma and sudden-
onset fatal asthma.
• Novel mechanisms implicated in this form of asthma include activation of
immune responses to bacteria, viruses, or diet; activation of neutrophil
elastase; and impaired nuclear recruitment of histone deacetylase.
• Potential biomarker is sputum neutrophils
• Treatment - Corticosteroids are less effective in this phenotype. Some
studies suggest that neutrophilic asthma might be more responsive to
macrolide antibiotics.

18. Extensive remodelling asthma
• Asthma with fixed airflow limitation
• Characterized by an accelerated decrease of lung function and irreversible or
only partly reversible airflow obstruction. Remodeling of the airway can occur
anywhere from the large to the small airways.
• Its pathogenesis involves epithelial damage, collagen deposition in the
subepithelial reticular basement membrane, smooth muscle hyperplasia and
hypertrophy, increased smooth muscle mass, mucus gland hypertrophy, and
angiogenesis.
• Release of profibrotic cytokines, such as epidermal growth factor and
transforming growth factor-B, from damaged epithelial cells leads to fibroblast
proliferation and myofibroblast activation, transforming growth factor-B, IL-11,
and IL-17 have been implicated in the formation of subepithelial fibrosis.
• Studies have identified the presence of a subset of patients who might be
predisposed to remodeling despite treatment with ICS.

19. OBESITY RELATED ASTHMA
• Adult onset
• More common in females
• It is unclear whether obesity is a mere confounder or a principal
component of an asthma phenotype. Obesity can lead to changes in
respiratory dynamics that mimic symptoms of asthma or lead to a
generalized proinflammatory state.
• Further evidence of a possible obesity-driven phenotype comes from a
study by Dixon et al who demonstrated that, after bariatric surgery,
patients had improvement in airway hyperresponsiveness to
methacholine challenge.

20. Other common phenotypes of asthma
• Exacerbation prone asthma
• Occupational asthma
• Catamenial (perimenstrual) asthma
• Asthma-COPD overlap

21. OCCUPATIONAL ASTHMA
• WORK SENSITIZED (HIGH mw >5000 daltons)- Ig E mediated
Asthma with latency
• IRRITANT INDUCED (low MW <5000 daltons) – Non Ig E mediated
Asthma without latency
Irritant asthma
Reactive airway dysfunction syndrome
(RADS)
• WORK EXACERBATED ASTHMA (aggravated) - >250 workplace culprit substances
Estimated 16 % of all adult onset asthma

22. Catamenial (perimenstrual) asthma
• In around 20 % of women asthma worsens perimentrually
• More common in older women , higher BMI , longer duration and more severe
asthma
• Pathogenesis remains undetermined. Possible fall in progesterone level or
increased bronchoconstriction due to increased level of prostaglandin PGF2a may
be responsible for such an exacerbation in symptoms. Increased emotional stress
during menstrual cycle, enhanced autonomic lability and escalated bronchial wall
hydration possibly aggravate the symptoms of asthma.
• Aspirin exacerbated asthma is more commonly associated with this phenotype
• Add-on treatments are oral contraceptives and /or LTRA .

23. Asthma – copd overlap(aco)
• Age of onset is usually above 40 years, but may have had symptoms in
childhood or early adulthood.
• Exertional dyspnea are persistent but variability may be prominent.
• Airflow limitation not fully reversible , but often with current or historical
variability. Persistent airflow limitation may be seen between symptoms.
• Frequently there is history of doctor diagnosed asthma, allergies, exposure to
noxious particles. Family history of asthma and allergies are also common.
• Exacerbations may be more common than COPD but reduced by treatment.
Comorbidities can contribute to impairment.
• Eosinophils and/or neutrophils may be present in sputum
• For ACO, treat with ICS in a low or moderate dose(depending on level of
symptoms)
• Add on treatment with LABA and /or LAMA is usually also necessary. If there
are features of asthma ,avoid LABA monotherapy .

24. Exacerbation prone asthma
A patient is said to have suffered from a severe exacerbation if any of the
following are present:
1. Systemic steroids had been used to treat the attack, or the
maintenance dose required to be escalated for at least for 3 days
2. An emergency visit due to asthma had to be made to a health-care
facility, during which systemic steroids were administered.
It is necessary to understand more about this subgroup of patients
because of a higher morbidity and mortality among them.

25. • Uncontrolled asthma poses an emotional as well as
the physical burden on patients and results in a great
economic burden.
• “Exacerbation-prone phenotype” asthmatics are a
cluster of patients who may suffer from more frequent
and severe exacerbations than other asthmatics.
• Factors such as inadequate symptom control,
improper adherence to medications, and incorrect use
of inhalers are responsible for frequent asthma
exacerbations.

26. Jain N, Satish K, Abhyankar N,Velayudhan N, Gurunathan J. Repeated exacerbation
of asthma: An intrinsic phenotype of uncontrolled asthma. Lung India
2019;36:131-8.

27. • It has been observed that a large number of asthmatics in India
exaggerate their control over the disease
• The AP-AIM study (Asia Pacific – asthma insight and management
study) in 2015 surveyed 400 asthmatic patients in India and found
that 91% of the patients were of the impression that their disease
was well controlled. However, when the level of control in these
patients was assessed objectively using the global initiative for
asthma (GINA) guidelines, it was noted that not even one of them
had well-controlled asthma, and 40% were suffering from
uncontrolled asthma.

28. Why is phenotypic characterization necessary?
• Since asthma is a hereditary disease, it might be possible that a genetic influence is
associated with the severity of the disease.
• It has been postulated that certain marks on the human genome may be more
susceptible to modification by exposure to environmental factors, thereby bringing about
the various phenotypes of this disease.
• If so, understanding the “exacerbation-prone phenotype” as a distinct entity will aid in
guiding the treatment and enhancing our knowledge of the natural history, inherent
mechanisms, and prognosis of the disease.
• Within asthmatics, the responsiveness to treatment may vary from person to person.
While some patients respond quickly to low-dose treatment, others may show a poor
response.
• Neutrophils, as well as eosinophils, might be present in severe disease, as opposed to the
presence of eosinophils alone in mild or moderate asthma.

29. INFLAMMATORY ENDOTYPES

30. Svenningsen S and Nair P
Asthma Endotypes and an
Overview of Targeted
Therapy for Asthma. Front.
Med.2017 4:158.

31. INFLAMMATORY
ENDOTYPES
EOSINOPHILIC
(>3%eosinophils,
<64%neutrophils)
NEUTROPHILIC
(<=3%eosinophils,
>=64%neutrophils)
MIXED
GRANULOCYTIC
(EOSINOPHILS AND
NEUTROPHILS
ELEVATED)
(>3%eosinophils,
>=64%neutrophils)
PAUCIGRANULOCYTIC
(EOSINOPHILS NOR
NEUTROPHILS
ELEVATED)
(<=3%eosinophils,
<64%neutrophils)
The nature of bronchitis assessed by sputum cytometry can be
stratified into four groups based on the percentage of sputum
granulocytes

32. • Quantitative cytometry of induced or spontaneous sputum is currently the most
sensitive and specific non-invasive method to directly characterize the type and
severity of airway inflammation in asthma.
• Patients with mixed-granulocytic asthma have more severe airflow obstruction,
a higher frequency of exacerbations and daily wheeze, and increased health care
utilization than patients with either eosinophilic or neutrophilic bronchitis alone
• It is also important to note that asthmatics who exhibit concordant blood and
sputum eosinophilia experience more airway symptoms than those with isolated
blood or sputum eosinophilia alone .

33. INFLAMMATORY ENDOTYPE-GUIDED
THERAPEUTIC STRATEGY

35. Management of the T2-High Endotype
• Eosinophilic bronchitis indicates a T2-driven mechanism
and is usually steroid responsive. When bronchitis is
eosinophilic in nature with a differential cell count of more
than 3% , inhaled corticosteroids should be initiated and
the dose titrated to keep the sputum eosinophil count
below 3%.
• In situations where high-dose inhaled corticosteroids do
not control sputum eosinophilia, oral corticosteroids are
required. In corticosteroid-treated patients, absent
eosinophils may suggest that the current steroid dose is
unwarranted and therefore should be reduced to avoid
over-treatment.

36. Anti-Ig E treatment (omalizumab)
• First recombinant humanised Ig G1 MAB, which targets and binds free Ig E,
interrupting the Ig E-mediated asthma inflammatory cascade at an early stage,
and thus reducing both early and late asthmatic responses

37. Anti-IL-5 treatment
• IL-5 is expressed primarily in eosinophils and basophils.
• Il-5 promotes the differentiation, expansion and survival of
eosinophils. It is also responsible for eosinophil activation
and degranulation
• Mepolizumab and reslizumab - bind to human IL-5
• Benralizumab - targets the IL-5 receptor

38. Mepolizumab
• It decreases exacerbation, improves lung function and quality of life, also
has steroid sparing effect.
• In November 2015, the us FDA approved mepolizumab (administered
once every 4 weeks by s.c. Injection) for patients with severe eosinophilic
asthma and a history of exacerbations, followed 1 month later by
European medicines agency (EMA) approval.
• Mepolizumab was also incorporated in the latest gina recommendations
as an add-on treatment option in step 5 of the treatment plan

39. Reslizumab
• It decreases exacerbation, improves lung function and quality of life,
also has steroid sparing effect
• In march 2016, the FDA approved reslizumab (administered once
every 4 weeks by i.v. Infusion) for patients ⩾18 years of age with
asthma elevated blood eosinophils who are inadequately controlled
on ICS.

40. Benralizumab
• By targeting the IL-5 receptor, it prevents the binding of IL-5
and depletes the cells expressing the IL-5 receptor (mainly
eosinophils but also basophils) by inducing apoptosis.
• It reduces annual exacerbation rates, and improved fev1 and
asthma symptoms control, while being well tolerated. It also
has steroid sparing effect.
• Benralizumab was recently approved by the FDA and EMA for
severe eosinophilic asthma treatment.

42. • When considering severe refractory eosinophilic asthma and anti-IL-5
treatments, it is not easy to define which drug to choose between
mepolizumab, reslizumab, and benralizumab

47. Bronchial thermoplasty
• Bronchial thermoplasty is a new bronchoscopic therapy delivering
radiofrequency energy to the airways with the aim to reduce airway smooth
muscle mass and smooth muscle hypertrophy.
• Despite the initial enthusiasm about this new treatment modality, real-life
studies reported reduced rates of clinical improvement and higher rates of
adverse events compared with clinical trials.
• Furthermore, this technique is an interventional procedure, not widely
available, and many experts in the medical community have raised questions
and concerns about its long-term efficacy and safety.

48. THANK YOU