Phenotypes and Endotypes of asthma

1. Asthma Phenotypes….
Dr. Rohit
Aster Medcity

2. Asthma
• Word from Greek- aáζɛιν (aazein) = to breathe with open
mouth or to pant
• It first appeared in Homer's Iliad meaning short of
breath, and probably was first used in a medical sciences
by Hippocrates.
• Till 19th century, asthma was rarely mentioned in
medical publications.
• Not until the 1960s that airway inflammation was
recognised as an underlying substrate – then started
bronchodilator, steroids ….

3. Definition
• Heterogeneous disease, usually characterised by chronic airway
inflammation. It is defined by the history of respiratory symptoms such as
wheeze shortness of breath, chest tightness and cough that vary over time
and intensity, together with variable expiratory airflow limitation. (GINA -
2018)
• Is not a single disease, but a syndrome where the main complaint is dyspnoea.

6. A plea to abandon asthma as a disease
concept
-Till 19th century fever- as a disease
- Asthma is unlikely to be a single disease entity
- It is a complex cluster of disease phenotypes
and subphenotypes

7. Asthma Phenotypes
• Was considered as a single disease
• Recent studies focused on heterogeinity
• Consists of multiple phenotypes
• Phenotype – Observable properties of an organism that are produced by
the interactions of the genotype and the environment
• Initially based on clinical characteristics
• Now linked to biology of phenotype through a statistically based
process.
• But they may not strongly correlate with sp pathological process or
treatment responses
• Molecularly and genitically focussed asthma cohorts, improves
understanding and targeted approaches to Mx.

8. Clinically observed
characteristics to describe
phenotypes
CLINICAL
Age, gender, race
Early onset
Asthma in smokers
Premenstrual asthma
Exercise induced asthma
Occupational
Co-morbidities(Atopy,
GERD,AR, AERD,
Obesity, food allergy)
Low FEV1
Fixed air way obstruction
Collapsible airways
Rapid decline in lung function
Physiologic

9. Inhaled steroid sensitivity
Oral steroid sensitivity
LTRA sensitivity
SABA/LABA toxcity prone
Anti IgE responsive
Response to RX
Prognosis
Vital risk
Long term
outcome
Brittle asthma
Near fatal asthma
Benign Asthma
Frequent exacerbator
COPD prone
Relapsing asthma

10. Pathological
Inflammation
predominant
Extensive
remodelling
Eosinophilic
Neutrophilic
Mixed
Pauci- granulocytic
Goblet cell hyperplasia &
mucus production
SMC hyperplasia
Thicker small air way
Decreased alveolar
attachments and elastin

11. • There are many definitions for phenotypes
• Not depending on underlying mechanisms
• May not help to understand prognosis or target
therapy

12. Asthma Endotypes
• Is a specific biological pathway that explains the
observable properties of a phenotype
• Biologically distinct groups
• Endotype are defined by a distinct functional or
pathophysiological mechanism
• Molecular analysis revealed 2 distinct endotypes
• Th2 high andTh2 low
• Based on expression levels of genes encoding – IL13,
IL5,IL4, cytokine expression & steroid response

13. No present system of subgrouping
achieves all requirements for a true
Phenotype or Endotype.

14. Paradigm shifts in asthma
classification
Tailored,
personalized
care

15. ALLERGIC (EXTRINSIC)
ASTHMA
• Early onset
• Atopy
• Identifiable triggers
• AR,eczema
• Family h/o
NON ALLERGIC
(INTRINSIC) ASTHMA
• Late onset
• AERD
• Not much understanding.
Pathobiological studies suggestedTH2
cytokines were similar in both, and inhaled
steroids were effective in mild to moderate of
these.

16. Inflammatory subtypes in asthma: Assessment and
identification using induced sputum- By Simpson Et
al- 2006 Respirology
1. Eosinophilic
2. Neutrophilic
3. Mixed Granulocytic
4. Paucigranulocytic

17. Phenotype categorization is based on
• Age of onset
• Course,
• Severity
• Atopy
• Response to therapy
• Presence of bronchitis
• Sputum analysis
• FeNo
• More objective categorization using statistical methods – cluster
analysis

18. Cluster Analysis and Clinical Asthma
Phenotypes–AJRCCM–2008 by Halder Et al -
UK
• Primary care(184)- mild – mod asthma
• Secondary care(187)- refractory asthma
• Longitudinal data of 68 pts with predominantly
refractory asthma
• Clinical characters and outcomes- 12months
• for the identification of clinical asthma
phenotypes.
• Categorized to five clusters

20. • SARP cohort
• 726 pts(304 severe asthma) – data analysed for 34 phenotypic
variables
• Cluster 1 – 110: early onset atopic asthma, normal lung function
treated with two or fewer controller medications (82%) and minimal
health care utilization.
• Cluster 2 – 321: early-onset atopic asthma and preserved lung
function but increased medication requirements (29% on three or
more medications) and health care utilization.
• Cluster 3 – 59: mostly older obese women with late-onset nonatopic
asthma, moderate reductions in FEV1, and frequent oral
corticosteroid use to manage exacerbations.
• Clusters 4 – 120 : Early onset type, atopic, serious asthma
• Cluster 5 - 116: Adult onset, atopic, severe asthma
Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma
Research Program – Moore Et al 2009 - AJRCCM

21. 1.Mild atopic A.
2.Mild- mod AA
3.Late onset Non AA
4.Severe AA
5.Severe asthma

22. Identifying adult asthma phenotypes using a clustering
approach- Siroux et al. 2011- ERJ (ECRHS)II
• Phenotype A (36.1%)- active treated allergic
childhood-onset asthma: with atopic asthma and
active disease
• B (19.2%)- active treated adult-onset asthma,
older subjects with adult-onset asthma - more
females
• C 28%- inactive/mild untreated allergic asthma
• D 15% -inactive/mild untreated nonallergic
asthma

23. • Results of three studies were more similar
• All three- age at disease onset- a key differentiating
factor
• Early onset- more atopic/ allergic condition with a range
of severities
• Later onset- eosinophilic inflammation, obesity, more in
women, generally less allergic
• Cluster approach brings a less biased methodology
• It does not specifically link the undetlying pathobiology
to the clinical characteristics.

24. MOLECULAR MECHANISMS

25. T-helper Type 2–driven Inflammation Defines Major
Subphenotypes of Asthma- Woodruff et all- 2009, AJRCCM
• To determine clinical heterogeneity reflects
heterogeneity in underlying molecular mechanisms
related toTh2 inflammation
• 42 pt- mild to mod asthma/ 28 controls(steroid naive)
• Analysed airway epithelial brushings for expression of
three genes upregulated byTh2 cytokine – IL 13
- POSTN – Encodes periostin
- CLCA1- Encode Ca activated Cl channel regulator
- SERPINB2- Encodes serpin peptidase inhibitor B2

26. • Gene expression Analysis- 2 subgroupsTh2 high(50%)
andTh2 low(similar to controls)
• Differed
- in expression of IL5, IL 13 in Bronchial Bx,
- Airway hyperresponsivenss, Atopy
- serum IgE, Blood and tissue Eosinophlia,
- subepithelial fibrosis, mucin gene expression
• Th2 high pt responded more to Inhaled steroids than
Th2 low.

27. Conclusion:
• 1. At least 2 distinct molecular phenotypes byTh2
inflammation
• Current models do not explain NonTh2 asthma,
responds poorly to current therapies

28. • Several Endotypes have been proposed not none have been agreed.
• Large scale longitudinal studies are needed to determine phenotypes
represent true endotypes

29. GINA- 2018: Some of the most
common phenotypes
1. Allergic asthma
2. Non-allergic asthma
3. Late onset asthma
4. Asthma with Fixed airway obstruction
5. Asthma with obesity.

30. Sally E Wenzel 2012 –
Phenotypes
TH 2 ASSOCIATED
• Early onset allergic
asthma
• Late onset persistent
eosinophilic asthma
• Exercise induced
asthma
NON TH2 ASSOCIATED
• Obesity related
asthma
• Neutrophilic asthma
Desai & Oppenheimer 2015- ABPM(Th2), AERD, Extensive remodelling

31. Th2 associated asthma
• Strongly linked to atopy and eosinophilic
inflammation
• Atopic and allergic asthma phenotypes
• Type I hypersensitivity
• Responds to steroids
• Early onset and late onsetTh2 asthma.

33. Non Th2 asthma
• Little known about underlying elements
• Affect 50% or more asthma pts(steroid naive)
• Show less airway obstruction and hyper reactivity.
• May not have childhood asthma history.
• Poorly respond to steroid therapy

35. Early onset allergic asthma
• Most common phenotype
• Originates in early childhood or adeolescence
• Atopic and allergic component
• Associated with other atopies-AR, atopic dermatitis
• But not all early onset asthma isTh2(Low IgE/ Steroid non
responsive)
• Genetic component – strong family history
• Thick subbasement membrane
• More eosinophils, mast cells,Th2 cytokines
• Can present with mild to severe disease

36. Biomarkers
• HighTh2 cytokines – IgE and allergen sp.IgE
• High FeNO(> 30-35 ppb), High sputum eosinophilia(>2%)
,periostin, IL-4/5/9/13
Treatment:
• Respond to corticosteroids
TH2Targeted therapy-
• Anti IgE- Omalizumab
• Anti IL 13 (Lebrikizumab)
• Anti –IL4α

37. Late onset persistent
eosinophilic asthma
• Later onset of asthma (late 20- 40 yrs)
• Sputum(>2%), serum, bronchoscopy- eosinophilia
• Recurrent exacerbation
• Persistent sputum E despite steroid Rx
• Less allergic form of asthma, but 75% pts can have atopy
• Associated with Sinusitis, polyps
• Less family history
• Often severe from onset, with severe exacerbations

38. • Low lung functions
• Lack of allergy suggests more complex
mechanism- than in early onset disease
• Additional pathways related to IL33, IL17.
• AERD- subphenotype
• Th2 Biomarkers are present
• FENO/ Elevated sputum eosinophils +

39. Treatment
• 50% of steroid treated pts lung and blood E can
persists.
• Increase percentage- increasing severity
• IndicatesTh2 process is refractory to steroids
• But high dose can overcome refractoriness
• AERD subset- responds to leukotriene modifiers
• Anti IL5 in severe late onset asthma- reduced E,
exacerbations and steroid requirement.

40. AERD: aspirin exacerbated resp
disease
• Subphenotype of late onsetTh2 eosinophilic
asthma
- adult onset, progressive severe asthma
- eosinophilic
- sinusitis, nasal polyps
- Non IgE mediated response to Aspirin or COX1 inh

42. • Intense eosinophilic inflammation of nasal and bronchial
tissues.
• Increased cysteinyl leukotriene production (Biomarker)
• Increased expression of Leukotriene C4 synthase
Treatment
• Cysteinyl leukotriene receptor antagonist- monteleukast
& 5- lipoxygenase inhibitor(zileuton)
• Require steroids to control sinusitis and asthma
• Use COX 2 inhibitor/ Paracetamol
• Aspirin desensitization+ daily aspirin Rx- improve
symptoms, reduce nasal polyps/ sinusitis

43. Exercise- induced asthma

44. Exercise – Induced asthma
• Mild phenotype of asthma
• Asthma symptoms are experienced primarily after
exercise.
• Younger age of onset
• More frequent and severe in cold, dry conditions
• More common in atopic athletes
• 10-15% decline in FEV1 – to sustained exercises
• High sputum and tissue E.
• Due to mast cell activation byTh2 cytokines

45. Biomarker:
• Th2 cytokines and cysteinyl leukotrienes
Genetics:
• No specific genetic factors identified.
Treatment:
• Training and sufficient warm up
• Leukotriene modifiers suppress EIA
• IL -9 targeted therapy

46. O
Obesity related Asthma

47. Obesity related asthma.
• Obesity – a driving component in asthma
development or just a confounder or comorbidity –
remains controversial.
• Misdiagnosis of asthma due to
- Obesity associated with deconditioning
- Increased energy expenditure
- Greater dyspnoea
- Increased GERD

48. • Obesity – lower FENO, lower eosinophils, reduced
steroid response
• High expression ofTNF-α, IL-6 and leptins
• Usually adult onset >40 yrs
• Minimal allergic symptoms

49. Other factors contribute to asthma in obese:
• Breathing at low lung volume – unloads smooth
muscles- allowing it to shorten excessively -lead to
AHR
• Deep breathing- potent bronchodilator-
compromised in obese.
• Adiponectin from fat tissue- affect AHR.
• Asymptomatic AHR is common in obese

50. Treatment
• Respond poorly to steroids
• Bariatric Sx and weight reduction programmes
shown to improve asthma symptoms
• But wt reduction- shown to worsenTh2 asthma

51. Effects of obesity and bariatric surgery on airway
hyperresponsiveness, asthma control and inflammation – Dixon et
al 2011 JACI
• 23 asthmaticsVs 21 Non asthmatics- undergoing
Bariatric Sx.
• Baseline asthmatics have low lung functions and
BAL lymphocytes
• Post Surgery- 12m: Asthmatics – significant
improvement in A control score& A quality of life,
higher PC20 (improved AHR)
• BAL lymphocytes & CD4T cell cytokines were
increased (IFN –γ,TNFα, IL 5,6, 13,17)

52. Conclusion:
• Airway hyperresponsiveness improves with bariatric
surgery in obese with normal IgE
• Change is AHR is not related toTh cell inflammation.
• Phenotypes
• 1- Non atopic late onset asthma with AHR – who improve
with wt loss (asthma developing due to obesity)
• 2-Early onset atopic obese- may not respond to wt
reduction(asthma complicated by co existence of
obesity)
• Weight loss may be a critical intervention to improve
AHR in non- atopic individuals

53. Neutrophilic asthma
• Neutrophilia is generally seen in corticosteroid-treated
patients.
• Neutrophilia- severe asthma & sudden onset fatal
asthma
• Corticosteroids inhibit neutrophil apoptosis
- low lung functions
- Air trapping
- -air way thickening
- Greater expression of MMP
- Increased sputum neutrophilia( > 65%)

54. • Secondary to activation of immune response to
bacteria, virus or diet
• Th17 inflammation strongly linked
• Bacterial colonization of airway due to defective
phagocytosis-also- neutrophilia
• Biomarkers: IL-18/17A/32/1/TNF α
• Low FENO

55. Treatment
• steroids are less effective
• More responsive to macrolide – by modulating
immune response by reducing expression of
neutrophilic markers
• AntiTNF -α responsive (infliximab)
• IL-17 targeted studies on trial.

56. Other phenotypes

57. Allergic Bronchopulmonary
Mycosis- ABPM
• Endotype of severe asthma
• Hypersensitivity reaction to fungal colonisation of
airways
• Usually Aspergillus fumigatus
• Abnormal epithelial function predispose- CF
• Bronchiectasis, mucous production, sp IgE,IgG,
Eosinophilia
• Steroids/ Antifungal/ Anti-IgE

58. Extensive Remodelling Asthma
• Irreversible or partly reversible airflow obstruction
• Accelerated decrease in Lung function
• Remodelling can occur anywhere- large to small air
ways
• Epithelial damage, collagen deposition in
basement membrane, smooth muscle hyperplasia
and hypertrophy, mucous gland hypertrophy

59. • Release of profibrotic cytokine
- EGF
-TGF- B
- IL -11, IL-17
• Cause subepithelial fibrosis
• Poorly respond to steroids.

60. Smoking related asthma
• Complex relationship with asthma
• Decline in lung function, Low FENO
• Resistance to steroids
• Associated with neutrophilia in lung tissue
• Unknown – independent endotype or subtype of
neutrophilic asthma
• Not all smoking related asthma have neutrophilia-
? overlap

61. Treatment
• Quitting smoking
• 6 weeks smoking cessation – improved lung
function & decrease sputum neutrophilia
• Theophylline

62. Perimenopausal onset asthma
• Onset within a year of last menstrual period
• Non atopic
• Usually severe asthma
• Majority sputum- neutrophilic

63. Catamenial asthma/
Perimenstrual asthma
• 20% - women asthma worsen- perinmenstrual
phase
• Usually seen in older age, high BMI, more severe
asthma
• Often have dysmenorrhea, PMS, longer bleeding,
shorter cycles
• Rx: Asthma Rx+ Oral contraceptive/ LTRA

65. Comorbidities & confounders –
alter asthma phenotypes
• Exposure to smoke – Neutrophilic inflammation, oxidative
stress
• Smoking - accelerate decline in lung function & impaired
responsiveness to steroids.
• Hormonal changes- Menarche, menopause, pregnancy
- EnhancedTh2 activation
-Worsen or improve during pregnancy, exacerbation before
menses
• Infections- viruses & Bacteria – initiate atopic asthma in
children/ adult onset asthma/ exacerbate asthma
• Occupational exposure – initiate or worsen asthma

66. Asthma Management
• Asthma Mx must be individualised
• Tailored not only to severity but also to phenotypic
characteristics.

67. Symptom based Mx Vs
Biomarkers
• Symptoms are subjective- under or over estimated
by patients
• Use inflammatory biomarkers in sputum, blood,
bronchial tissue or exhaled breath
• More objective measurement
• Correlate with disease activity
• Predict exacerbations
• More expensive, special equipment and personnel

68. Anti Leukotrienes, Bronchodilators,
Low doseAzee or Bronchial
thermoplasty
High dose ICS, little bronchodilation

70. Newer targeted Rx for Th2 phenotypes
Th 2
Target
Drug Asthma Response
Free IgE Omalizumab Severe asthma, Atopy+ IgE Reduces exacerbations,
Reduction in OCS
IL-4Rα Dupilimumab Mod-severe A,
Sputum/Blood Eosinophilia
Asthma control, FEV1
maintained, ICS tapered
IL- 5 Mepolizumab Severe asthma , Blood E Reduced Exacerbations, Better
FEV1, OCS tapered
IL-5 Reslizumab Severe astham+ sputum E Reduced Exacerbations, Better
FEV1
IL-5α Benralizumab Severe, On high OCS, High
FENO/ E
Some decrease in exacerbation
IL-13 Lebrikizumab Severe on ICS+ LABA,IgE,
serum E, periostin high
Improvement in FEV1
IL-13 Tralokinumab Severe A, Atopy, E, Small improvement in FEV1

71. Non Th2 targeted treatment
Treatment Response
Anti-IL-17Rα. No effect in symptoms, FEV1
Anti- CD25 (Daclizumab) Improve FEV1 and asthma control –
under research
CXCR2 antagonsit Reduction in sputum N, no improvement
in A control
Anti-TNF α(Golimumab) Side effects- infections, malignancies

72. Major mechanisms of asthma onset.
Michael R. Edwards et al. Eur Respir J 2017;49:1602448
©2017 by European Respiratory Society
Addressing unmet needs in understanding asthma mechanisms –
ERJ 2017

73. Conclusion
Grouping asthma patients into phenotypes and
endotypes based on clinical characteristics, underlying
molecular or pathological mechanism helps in personalized
therapy and management of asthma

74. THANK YOU