Bronchial asthma, Asthma phenotypes, newer bronchodilators, personalised medicine in asthma, pharmacogenetics of current drugs, immunotherapy, vaccination, bronchial thermoplasty, surgical management

1. Dr. Jebin Abraham
Department of Pulmonary Medicine
GMC Patiala

2. ASTHMA STATISTICS
• Asthma affects about 334 million people worldwide.*
• Burden of disability is high.
• Asthmatics in India -18 million.
• Approximately 489000 people die per year from the
disease.**
*Global asthma report 2014
**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma:
Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1)
May 16, 2017 2

3. OVERVIEW
• Asthma phenotypes
• Biomarkers of Asthma
• Newer Drugs
• Advances in inhalation
therapy
• Personalised Medicine
• Pharmacogenetics
• Immunotherapy
• Vaccination in Asthma
• Bronchial Thermoplasty
• Surgical Management of
Asthma
May 16, 2017 3

4. Asthma phenotypes
• Asthma is a heterogeneous disease, with different
underlying disease processes.
• Recognizable clusters of demographic, clinical and/or
pathophysiological characteristics are often called
‘asthma phenotypes’.
• In patients with more severe asthma, some
phenotype-guided treatments are available.
*Definition, description and diagnosis of asthma, GINA 2016
May 16, 2017 4

5. • Allergic asthma:
-Often commences in childhood and is associated
with a past and/or family history of allergic disease
-Induced sputum - Eosinophilic airway inflammation.
-Usually respond well to inhaled corticosteroid (ICS)
treatment.
May 16, 2017 5

6. • Non-allergic asthma:
-Some adults have asthma that is not associated with
allergy.
-The cellular profile of the sputum of these patients
may be neutrophilic, eosinophilic or contain only
a few inflammatory cells (paucigranulocytic).
-Patients with non-allergic asthma often respond less
well to ICS.
May 16, 2017 6

7. • Late-onset asthma:
- Some adults, particularly women, present with
asthma for the first time in adult life.
- These patients tend to be non-allergic
- Often require higher doses of ICS or are relatively
refractory to corticosteroid treatment.
May 16, 2017 7

8. • Asthma with fixed airflow limitation:
- Some patients with long-standing asthma develop
fixed airflow limitation that is thought to be due
to airway wall remodelling.
• Asthma with obesity:
- Some obese patients with asthma have prominent
respiratory symptoms and little eosinophilic
airway inflammation.
*Wenzel SE. Asthma phenotypes: the evolution from clinical to
molecular approaches. Nat Med 2012;18:71625./*GINA2016
May 16, 2017 8

9. Biomarkers of Asthma
Biomarkers are objectively measured and
evaluated indicators of normal biological
processes, pathogenic processes or
pharmacological responses to a therapeutic
intervention
May 16, 2017 9

10. Exhaled Breath Condensate
• EBC is the exhalate from breath, that has been
condensed, typically via cooling using a collection
device.
• A matrix of biomarkers- Volatile and non volatile
substances.
*Liu J, Conrad DH, Chow S, Tran VH, Yates DH, Thomas PS. Collection devices influence
the constituents of exhaled breath condensate. Eur Respir J. 2007 Oct;30(4):807-8.
May 16, 2017 10

11. Possibilities
• Determining host
inflammatory responses
to injury in the lung
• Possible single noninvasive
sampling
method for point-of-care
real-time analysis
May 16, 2017 11

12. H2O2 and TBAR
• Hydrogen peroxide and Thiobarbituric acid- reactive
products: Increased levels in Asthma.
• Increase in levels associated with a drop in FEV1.
• Significant reduction with treatment with ICS which
remained stable for 2 weeks after discontinuation.
• May be a good measure for monitoring improvement
with treatment.
* Dohlman AW, Black HR, Royall JA. Expired breath hydrogen peroxide is a marker of acute
airway inflammation inpediatric patients with asthma. Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):955-60.
May 16, 2017 12

13. Nitrotyrosine
• A stable end product of peroxynitrite.
• Studied on three asthma groups:
- Mild (steroid naïve)
- Moderate (on ICS)
- Severe (on oral CS)
• Increased levels were found in the first Group
*Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of
patients with asthma. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1273-6.
May 16, 2017 13

14. Isoprostanes
• Compounds formed by non-enzymatic peroxidation
of membrane phopholipids during oxidative stress
• Levels are elevated in all asthma with higher levels in
more severe disease*
• However correlation with PFT is not good
• Recent Meta-analysis- Use in Asthma unclear**
*Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of
oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med. 1999 Jul;160(1):216-20.
**Peel AM, Crossman-Barnes CJ, Tang J, Fowler S, Davies G, Wilson A, Loke Y. Biomarkers in adult asthma: a systematic
review of 8-isoprostane in exhaled breath condensate. J Breath Res. 2017 Jan 19.
May 16, 2017 14

15. Leukotrienes
• Airway smooth muscle contraction,
microvascular leakage, mucus hypersecretion.
• Increased levels of LTB4 in asthma which
increase with severity
• No correlation with FEV1
*Becher G, Winsel K, Beck E, Neubauer G, Stresemann E. [Breath condensate as a method of
noninvasive assessment of inflammation mediators from the lower airways]. Pneumologie.
1997 Apr;51 Suppl 2:456-9.
May 16, 2017 15

16. pH
• Acute asthma associated with pH decline
of two-log
• Normalised with corticosteroid therapy
• Suggested that serial measures can help
titrate therapy
*Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P, Loukides S. pH in expired breath
condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med. 2002 May
15;165(10):1364-70.May 16, 2017 16

17. Future Prospects for EBC in asthma
• Some markers persist despite ICS
• Leukotriene pathway is not suppressed by steroids
• Persistent elevation of leukotrienes may be used to
initiate therapy with specific inhibitors
• If rise in markers precedes physiological changes
greater utility is likely
May 16, 2017 17

18. FeNO
• The most studied biomarker of Asthma
• Can be analyzed in a quick and easy way
• Comfortable for school-age children
• Correlate with bronchial hyper-responsiveness,
blood eosinophils, serum eosinophil cationic protein
(ECP), and atopic status/ immunoglobulin E (IgE)
levels in children
• Levels tend to be reduced by corticosteroid
treatment .
May 16, 2017 18

19. • If the fraction is high, patients are more likely to
respond to ICS.
• Values > 50 ppb*
in adults and >35ppb in children
High eosinophilic inflammation.
• Conversely, values <25 ppb in adults and <20 ppb in
children Low responsiveness to corticosteroids
is less likely.
* Dweik RA, et al; An official ATS clinical practice guideline: interpretation of exhaled nitric oxide
levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011 Sep 1;184(5):602-15.May 16, 2017 19

20. May 16, 2017 20

21. • Use of FeNO to guide asthma therapy in children
may be beneficial in a subset of children,but it
cannot be universally recommended for all children
with asthma.*
• Not recommended at present for deciding whether
to treat patients with possible asthma with ICS.**
*Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for
children with asthma. Cochrane Database Syst Rev. 2016 Nov 9;11:CD011439.
** GINA 2016
May 16, 2017 21

22. Volatile Organic Compounds
• Also known as e-Nose.
• It involves the profiling of multiple metabolic compounds
originating from the lungs and upper airways.
• The technique used – Gas chromatography coupled with
Mass spectrometry (GC-MS),
• This method has been found to differentiate between adults
with asthma, COPD, and healthy controls.
• In children with asthma, VOC analysis enables prediction of
subsequent exacerbations.
*Bos LD, Sterk PJ, Fowler SJ. Breathomics in the setting of asthma and chronic
obstructive pulmonary disease. J Allergy Clin Immunol. 2016 Oct;138(4):970-976.
May 16, 2017 22

23. • Breath analysis by e-Nose has even been found to
predict response to steroids in patients with asthma
more accurately than sputum eosinophils or FeNO.*
* van der Schee MP et al. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp
Allergy. 2013 Nov;43(11):1217-25.
May 16, 2017 23

24. Induced Sputum
• Induced sputum is a relatively safe, semi-invasive method
• Can be performed even in school-age children.
• Different cellular compositions have been described in
children (eosinophilic, neutophilic, mixed granulocytic, and
paucigranulocytic), which may relate to different asthma
phenotypes.
• It has been shown that sputum eosinophil numbers are higher
in atopic as compared to non-atopic childhood asthma.
• Sputum IL-26 Biomarker of non Th2 mediated, non-
eosinophilic type Asthma
*Konradsen JR et al., The cytokine interleukin-26 as a biomarker in
pediatric asthma. Respir Res. 2016 Mar 31;17:32.
May 16, 2017 24

25. Blood Eosinophil Counts
• In adults, high blood eosinophil numbers show
associations with higher total IgE, lower FEV1, more
exacerbations.
• A marker of response to corticosteroids.
• High eosinophil counts to be a potential biomarker
capable of reflecting successful omalizumab
treatment effects
*Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing
successful omalizumab treatment effects. J Allergy Clin Immunol. 2013 Aug;132(2):485-6.
May 16, 2017 25

26. Immunoglobulin
• Serum IgE levels can provide important
information for the clinical diagnosis of atopic
asthma.
• Measuring allergen-specific IgE levels
sensitizing allergens, enabling the
avoidance of trigger factors.
• Total IgE levels general predisposition
towards atopic asthma.
May 16, 2017 26

27. Basophil allergen threshold sensitivity
(CD-sens)
• A relatively new development
• It may enable improved assessment of the degree of
response to a given allergen
• Alternative to clinical allergen provocation tests,
performed in vitro.
• Involves the detection of CD63 on basophils.
• CD-sens is also possible biomarker of response to
treatment with Omalizumab.
*Nilsson C, Nordvall L, Johansson SG, Nopp A. Successful management of severe cow's milk allergy
with omalizumab treatment and CD-sens monitoring. Asia Pac Allergy. 2014 Oct;4(4):257-60
May 16, 2017 27

28. Periostin
• Up-regulated by type 2 cytokines IL-4 and IL-13.
• Serum periostin can predict the efficacy of anti-IL-13
antibodies (lebrikizumab) and anti-IgE antibodies
(omalizumab)
• Periostin-high asthma patients have several unique
characteristics, including eosinophilia, high fraction
of nitric oxide, aspirin intolerance, nasal disorders,
and late onset.
*Izuhara K, Ohta S, Ono J. Using Periostin as a Biomarker in the
Treatment of Asthma. Allergy Asthma Immunol Res. 2016
Nov;8(6):491-8.
May 16, 2017 28

29. YKL-40
• Biomarker of non-type 2 driven Asthma.
• Elevated in the serum of both children and adults
with severe asthma.
• Increased circulating YKL-40 consistently associates
with reduced lung function.
• Associates with measures of airway remodeling such
as bronchial wall thickness and subepithelial fibrosis
and increases the proliferation of bronchial smooth
muscle cells.
May 16, 2017 29

30. • Serum YKL-40 estimation may be done using ELISA,
RIA or Real-Time Surface Plasmon Resonance
Technology*
• Cord blood YKL-40 levels could already serve as
potential biomarkers for milder forms of asthma.**
*Naglot S, Aggarwal P, Dey S, Dalal K. Estimation of Serum YKL-40 by Real-Time Surface Plasmon
Resonance Technology in North-Indian Asthma Patients. J Clin Lab Anal. 2016 Sep 12.
**Usemann J, Frey U, Mack I, Schmidt A, Gorlanova O, Röösli M, Hartl D, Latzin P. CHI3L1
polymorphisms, cord blood YKL-40 levels and later asthma development. BMC Pulm Med. 2016
May 18;16(1):81.May 16, 2017 30

31. Serum CCSP level
• Club Cell Secretory Protein
• Independently related to small airway
hyperresponsiveness.
• Measured by Computed Tomodensitometry.
*Bommart S, Marin G, Molinari N, Knabe L, Petit A, Chanez P, Gamez AS, Devautour C, Vachier I, Bourdin
A. CCSP Serum Level is A Surrogate Marker of Small Airway Involvment in Asthma. J Allergy Clin Immunol.
2017 Jan 17. pii: S0091-6749(17)30039-8.
May 16, 2017 31

32. Urinary Eicosanoids
• Different prostaglandins (PGs)  both pro- (e.g.,
PGD2) and anti-inflammatory (e.g., PGE2) processes.
• But measurement is difficult rapid metabolism
• As an alternative to blood- Urinary metabolites
measured.
• Liquid chromatography coupled to mass
spectrometry (LC-MS)- technique .
• 11β-PGF2α-Reflects Mast cell activation
• LTE4- Reflects eosinophil activation
*Balgoma D et al.,Quantification of lipid mediator metabolites in human urine from asthma patients by
electrospray ionization mass spectrometry: controlling matrix effects. Anal Chem. 2013 Aug 20;85(16):7866-74.
May 16, 2017 32

33. Eosinophil-Derived Neurotoxin
• Measured in the urine
• Eosinophil protein X (EPX)
• Advantage -Reflect eosinophil activation, rather than
eosinophil numbers.
• Further studies required for relevance of use.
*James A, Hedlin G. Biomarkers for the Phenotyping and Monitoring of
Asthma in Children. Curr Treat Options Allergy. 2016;3(4):439-52.
May 16, 2017 33

34. Soluble L-Selectin
• L-Selectin is described to have important role in the
development of allergic airway inflammation
in asthma.
• Recently suggested to be an independent biomarker
of Asthma.
• Levels measured in blood.
*Nadi E, Hajilooi M, Pajouhan S, Haidari M. Soluble L-Selectin as an Independent
Biomarker of Bronchial Asthma. J Clin Lab Anal. 2015 May;29(3):191-7.
May 16, 2017 34

35. Other biomarkers
• Thymic stromal lymphopoetin (TSLP)
• 25-OH Vitamin D
• Chemokine ligand 5 (CCL5)
• Hematopoietic prostaglandin D synthase
(HPGDS)
• Neuropeptide S receptor 1 (NPSR1)
May 16, 2017 35

36. NEWER BRONCHODILATORS
Why the need for newer BD?
• Once daily dosing convenient and hence improves compliance
and adherence
• BDs that provide rapid relief provide patients with
reassurance after first dose and thus improve compliance
• Once-daily agents may also affect stability of airway tone,
with reduced fluctuations in airway patency leading to
increased morning FEV1
Murphy et al. Turning a Molecule into a Medicine: the Development of Indacaterol as a Novel Once-Daily
Bronchodilator Treatment for Patients with COPD. Drugs (2014) 74:1635–57
May 16, 2017 36

37. Ultra long acting Beta 2 Agonists
• Indacaterol
• Vilanterol
• Olodaterol
• Carmoterol
• Milveterol
• Abediterol
• GSK-642444
• PF-610355
May 16, 2017 37

38. Indacaterol
• Rapid onset and sustained bronchodilation
• It is delivered as an aerosol formulation through
a dry powder inhaler.
• It is licensed only for the treatment of chronic
obstructive pulmonary disease (COPD).
• Long-term data in patients with asthma are lacking.
• Not effective as LAMA in preventing exacerbations
• Side effects- nausea, fainting, chest pain, palpitations
etc
May 16, 2017 38

39. Vilanterol
• Rapid onset
• Approved in may 2013 in combination with Fluticasone
furoate (DPI)
• May be used both in Asthma or COPD as once
daily medication
• Flu Fu + Vil comparable in efficacy to Salmeterol + FP in
both asthma and COPD
• Studies comparing them with LAMA are required
*Woodcock A et al. Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol
combination in adult and adolescent patients with persistent asthma: a randomized trial. Chest. 2013 Oct;144(4):1222-9
May 16, 2017 39

40. Olodaterol
• Rapid onset of action
• Long duration of action ~ 24 hrs
• Dose 5-10 mcg via Respimat® breath actuated
inhaler
• May also have anti-inflammatory and antifibrotic
effects
• In asthma, evidence of bronchodilator efficacy of
Olodaterol was demonstrated with statistically and
clinically significant improvements over placebo.
*O'Byrne PM et al., Dose-finding evaluation of once-daily treatment with olodaterol,
a novel long-acting β2-agonist, in patients with asthma: results of a parallel-group
study and a crossover study. Respir Res. 2015 Aug 18;16:97.May 16, 2017 40

41. Long Acting Muscarinic Agonist
•There are emerging data from key clinical trials to
show that LAMA may confer bronchodilator effects and
improved control when used in addition to inhaled
corticosteroid (ICS) alone or in conjunction with long
acting β-adrenoceptor agonists (LABA).
* Lipworth BJ. Emerging role of long acting muscarinic
antagonists for asthma. Br J Clin Pharmacol. 2014 Jan;77(1):55-62.
May 16, 2017 41

42. Newer LAMA
• Aclidinium bromide
• Glycopyrronium bromide
• Umeclidinium bromide
• CHF-5407
• TD-4208
• AZD8683
• V-0162
May 16, 2017 42

43. Aclidinium bromide
• Aclidinium is a quaternary ammonium; Hence low
systemic exposure
• May be used od or bd
• Dose 400 mcg BD approved by FDA
• Delivered via Genuair® DPI
• Rapid onset of action compared to tiotropium
• Side effects- Urinary retention, blurring of vision,
allergic reactions etc
May 16, 2017 43

44. Glycopyrronium
• Fast onset of action, IV/inhalation/oral
• Used 50 mcg od
• Delivered via Breezhaler® DPI device
• 3 major trials – GLOW 1, 2, 3
• Better than placebo as well as tiotropium in some
studies
• Side effects: Hyperthermia, dry mouth etc
Watz H et al., Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate
to severe COPD - A randomised, multicentre, crossover trial. Pulm Pharmacol Ther. 2017 Feb;42:13-20.
May 16, 2017 44

45. Umeclidinium
• Novel LAMA with strong affinity to M3 Receptors
• Faster and longer acting compared to Tiotropium
• Approved in combination with Vilanterol as DPI
(125/25 mcg or 62.5/25 mcg)
• Improvement in FEV1 when compared with
monotherapies for both doses.
• No difference in exacerbation rates or dyspnea
scores
*Lee LA, Briggs A, Edwards LD, Yang S, Pascoe S. A randomized, three-period crossover study of umeclidinium as
monotherapy in adult patients with asthma. Respir Med. 2015 Jan;109(1):63-73.
May 16, 2017
45

46. MABA therapy
• Combination of LABA and LAMA in a single
fixed dose system
• Synergistic effect as they act via diff pathways
• Batefenterol, AZD2115 and AZD8871- in
clinical trials
• Predominance of either LAMA or LABA activity
*Cazzola M, Lopez-Campos JL, Puente-Maestu L. The MABA approach: a new option
to improve bronchodilator therapy. Eur Respir J. 2013 Oct;42(4):885-7.
May 16, 2017 46

47. QVA 149
• Fixed dose combination of 110 μg indacaterol
+ 50 μg glycopyrronium
• DPI administered OD via Breezhaler®
• Series of 8 Phase III trials done as part of
IGNITE program
• Approved in Europe, FDA approval pending
• QVA149 - better in reducing exacerbations than
Glycopyrronium/Tiotropium alone, but similar to
LABA+ICS
*Metzdorf N, Hallmann C, Disse B. Impact of tiotropium on exacerbations versus
glycopyrronium and QVA149. Expert Rev Respir Med. 2015;9(6):675-6.
May 16, 2017 47

48. Novel class of Bronchodilator
• Recently, agonists of Bitter taste receptors (TAS2R),
including Quinine, Chloroquine and Saccharine, have
been identified as a novel class of Bronchodilator.
• Calcium sensing receptor(CaSR) blockers-
bronchodilator effect
*Deshpande DA, Wang WC, McIlmoyle EL, et al. Bitter taste receptors on airway smooth muscle
bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 2010;16(11):1299–1304
May 16, 2017 48

49. PDE4 Inhibitors
• PDE4 inhibition leads to elevated levels of
intracellular cAMP
• It leads to suppression of inflammatory cell influx
and function.
• Also inhibits of mucin production from airway
epithelial cells and alterations in airway smooth
muscle tone
• Dual PDE3/4 Inhibitor- RPL554nebulization in
asthma
May 16, 2017 49

50. Cilomilast
• It is orally active, second-generation PDE4 inhibitor
• Currently FDA approved for use in COPD.
Roflumilast
• Orally active, Long-acting PDE4 inhibitor
• Its primary clinical use is in the prevention of
exacerbations in severe COPD.
• Has an inhibitory effect on allergen-induced
responses in asthma
• Side effects: Nausea, diarrhea, weight loss etc
May 16, 2017 50

51. CRTh2 antagonists
• Prostaglandin (PG)D2 is
released from mast cells,
Th2 cells, and dendritic cells
and activates DP2-
receptors, also known as
chemoattractant
homologous receptor
expressed on Th2 cells
(CRTh2), which mediate
chemotaxis of Th2 cells and
eosinophils.
May 16, 2017 51

52. Setipiprant
• A selective, orally available antagonist of
the Prostaglandin D2 receptor 2 (DP2)
• Initially researched as a treatment for allergies and
inflammatory disorders, particularly asthma.
• No sufficient advantages over existing drugs.
Fevipiprant
• Acts as a selective, orally available antagonist of
the prostaglandin D2 receptor 2 (DP2 or CRTh2).
• As of 2016, it is in phase II clinical trials for the
treatment of asthma
May 16, 2017 52

53. Ciclesonide
• A new ICS that is locally activated in the lower airway
epithelium.
• Consequently with very low systemic bioavailability.
• Negligible risk of local or systemic side effects even
for long-term high-dose treatment.
• Cleaved by Esterases in bronchial epithelium.
• Available as inhaler/nasal spray alone or in
combination
• Side effects: head ache, nose bleeds etc
May 16, 2017 53

54. Ramatroban
• A thromboxane receptor antagonist.
• It is also a DP2 receptor antagonist.
• It has also been used for the treatment of asthma.
*Endo S, Akiyama K. [Thromboxane A2 receptor antagonist in
asthma therapy]. Nihon Rinsho. 1996 Nov;54(11):3045-8.
May 16, 2017 54

55. Mapracorat
•Anti-inflammatory drug belonging to the experimental
class of selective glucocorticoid receptor
agonists (SEGRAs)
•In clinical trials for the topical treatment of atopic
dermatitis, allergic conjunctivitis etc
May 16, 2017 55

56. FLAP inhibitors
• The enzyme 5-lipoxygenase (5'-LO) works
through 5'lo-activating protein (FLAP).
• Several novel 5'-LO and FLAP inhibitors are
currently in clinical development.
• Drugs like Meclofenamate Sodium and
Zileuton.
May 16, 2017 56

57. Cytokine Blockade
• Involves blockade of cytokines involved in TH2 responses or
their receptors
• IL-4 & IL-13 - Regulates immunoglobulin E (IgE) formation,
particularly in severe asthma.
May 16, 2017 57

58. Pitrakinra
• A mutated form of IL-4 that blocks IL-4Rα.
• Reduces the late response to inhaled allergen in mild
asthmatics when given by nebulization.
• Clinical trials are currently in progress.*
• Anti IL-13 Ab- Dupilumab- Reduced exacerbations
• Anti IL-17Rα Ab- Brodalumab-Ineffective in asthma
*Antoniu SA. Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and
eczema. Curr Opin Investig Drugs. 2010 Nov;11(11):1286-94.
May 16, 2017 58

59. Antisense Oligonucleotides
•Inhaled antisense oligonucleotides that block the
common β chain of IL-5 and GM-CSF (granulocyte-
macrophage colony-stimulating factor) receptors
together with the chemokine receptor CCR3 (TPI ASM8)
has effect in reducing allergen responses and airway
inflammation.
May 16, 2017 59

60. Anti IL-5 Therapy
• Mepolizumab and Reslizumab
• Reduce exacerbations in refractory eosinophilic
inflammation
• For Step 5 treatment, add-on treatment options for
patients with severe asthma uncontrolled on Step 4
treatment now also include Mepolizumab for patients
aged ≥12 years with severe eosinophilic asthma*
• An antibody against the IL-5 receptor (IL-5Rα)
Benralizumab is also being studied in clinical trials.**
*GINA 2016 Guidelines
*Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a
multicentre, doubleblind, placebo-controlled trial. Lancet 2012;380:651-9.
**Wang B, Yan L, Yao Z, Roskos LK. Population Pharmacokinetics and Pharmacodynamics of Benralizumab in
Healthy Volunteers and Patients With Asthma. CPT Pharmacometrics Syst Pharmacol. 2017 Jan 21.May 16, 2017 60

61. Lumiliximab
• A monoclonal antibody that targets CD23.
•Is well tolerated and reduces IgE concentrations in
patients with mild asthma.
•Clinical efficacy has not been reported.
*Reichert JM. Technology evaluation: lumiliximab, Biogen Idec. Curr Opin Mol Ther. 2004 Dec;6(6):675-83.
May 16, 2017 61

62. Anti-TNF therapies
• Several uncontrolled or small studies suggested that
anti-TNF therapies (TNF blocking antibody Infliximab or
soluble receptor Etanercept) may be useful in reducing
symptoms, exacerbations, and airway hyper-
responsiveness in patients with severe asthma.
Chemokine Receptor Antagonists
• CCR3 and CXCR2 antagonists
• CXCR2 antagonists- In neutrophilic asthma, disappointing
results
*Nair P et al., Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum
neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy2012;42:1097–1103.
May 16, 2017 62

63. PPARγ AGONISTS
•Peroxisome proliferator-activated receptor gamma agonists
have a wide spectrum of anti-inflammatory effects, including
inhibitory effects on macrophages, T cells and neutrophilic
inflammation.
•Polymorphisms of the PPARγ gene  increased risk of asthma.
• Rosiglitazone small improvement in lung function in smoking
asthmatic patients.
May 16, 2017 63

64. SCF and c-kit blockers
• Stem cell factor (SCF) is a key regulator of mast cell survival in
the airways.
• Acts via the receptor c-kit on mast cells.
• Blockade of SCF or c-kit is very effective in animal models of
asthma
• Suggesting that this pathway may be a good target for new
asthma therapies.
• Masitinib is a potent tyrosine kinase inhibitor that blocks c-kit
(as well as platelet-derived growth factor receptors) and
provides some symptomatic benefit in patients with severe
asthma.
• More selective c-kit inhibitors are in development
May 16, 2017 64

65. Kinase Inhibitors
• SPLEEN TYROSINE KINASE (SYK) that is involved in activation
of mast cells and other immune cells and several small
molecule SYK inhibitors are in development.
• p38 MAPK (Mitogen- Activated protein kinase) Inhibitors-
Effective in steroid resistant inflammation (Eg. Losmapimod)
• JANUS ACTIVATED KINASE (JAK) inhibitors- Anti inflammatory,
Under development.
• PHOSPHOINOSITIDE -3- KINASE (PI3K) Inhibitors- Possible role
in steroid resistant asthma.
Barnes PJ. Kinases as novel therapeutic targets in asthma and COPD. Pharmacol Rev2016;68:788–815.
May 16, 2017 65

66. Inflammasome Inhibitors
• NLRP3 Inflammasome- mediate pro-inflammatory
cytokines
• NLRP3 Inhibitors like CRID-3 recently discovered-
May be useful in severe asthma
Anti-oxidants
• NOX-4 Inhibitors: Inhibit Reactive Oxygen Species
formation
*Gross NJ, Barnes PJ. New Therapies for Asthma and Chronic Obstructive Pulmonary
Disease. Am J Respir Crit Care Med. 2017 Jan 15;195(2):159-166.
May 16, 2017 66

67. Advances in Inalation Therapy
• New technology for delivering inhaled drugs by metered dose
inhaler.
• Using the new hydrofluoroalkane propellant instead of the
old chlorofluorocarbon propellant.
• Maintains the drug in a solution- better nebulised in ultrafine
particles
• Improvement in the device - slow plume speed and better
lung penetration.
• Effectively reaching the smaller airways, especially in more
severe asthmatics.
May 16, 2017 67

68. No clinically significant differences in efficacy or
safety were observed comparing small and standard
particle size ICS medications for the treatment
of asthma.
*El Baou C, Di Santostefano RL, Alfonso-Cristancho R, Suarez EA, Stempel D, Everard ML, Barnes N. Effect
of inhaled corticosteroid particle size on asthma efficacy and safety outcomes: a systematic literature
review and meta-analysis. BMC Pulm Med. 2017 Feb 7;17(1):31.
May 16, 2017 68

69. • ‘Co- suspension technology’*
• Dose- counters- User friendly
• The 'Single-inhaler Maintenance And Reliever
Therapy' (MART) has been developed.
• A rapid-onset bronchodilator (e.g., Formoterol) and
an ICS (e.g., Budesonide) at the time of the
occurrence of asthma symptoms allows the delivery
of higher doses of ICS at very beginning stages of
exacerbations.
*Fabbri LM et al. Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ delivery
technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD. Respir
Res 2016;17:109.May 16, 2017 69

70. PERSONALISED MEDICINE IN
ASTHMA MANAGEMENT
• There is heterogeneity in patient responses to current asthma
medications.
• Significant progress has been made identifying genetic
polymorphisms that influence the efficacy and potential for
adverse effects to asthma drugs.
• Pharmacogenetics holds great promise to maximise clinical
outcomes and minimize adverse effects.
• Genome-wide association studies have begun to identify
genes underlying asthma (e.g., IL1RL1), which represent
future therapeutic targets.
May 16, 2017 70

71. PHARMACOGENETIC EFFECTS OF
CURRENT THERAPIES
• 1. Beta2 –adrenergic receptor agonists
(e.g., salbutamol and salmeterol)
-Act by binding to the b2 -adrenergic receptor, a
G-protein-coupled receptor encoded by an intron-
less gene (ADRB2) located on chromosome 5q31.32.
-Most studies have focused on the role of
nonsynonymous coding-region polymorphisms
Arg16Gly, Gln27Glu, Val34Met and Thr164Ile
May 16, 2017 71

72. -Arg16 variant has been associated with an
enhanced acute response to b2 -adrenergic
receptor agonist.
-But it also showed a decline of asthma
control following prolonged use.
May 16, 2017 72

73. 2.Leukotriene modifiers
(e.g., montelukast, zarfirlukast and zileuton)
• Evidences suggests that polymorphisms spanning the
ALOX5 gene influence clinical responses to LTRAs and
LTSIs;
-OATP2B1 polymorphism- Reduced morning
plasma concentrations of Montelukast
-Resulting in lack of clinical benefit
• MRP1 polymorphism Causes a differential response
to zileuton and montelukast therapy (FEV1 change)
May 16, 2017 73

74. • CYSLT2 polymorphism- Associated with morning PEF
variations in subjects taking montelukast
• LTC4S A plymorphism- Associated with LTRA and LTSI
(Zileuton) response (FEV1 change)
May 16, 2017 74

75. 3.Corticosteroids
(e.g., prednisolone and beclomethasone)
• CRHR1 and STIP1- Associated with corticosteroid
response (FEV1 change)
• TBX21 - Improvements in BHR with corticosteroid
treatment
• FCER2 - Associated with asthma exacerbations in the
presence of corticosteroids
Michael Portelli & Ian Sayers (2012) Genetic basis for personalized medicine in
asthma, Expert Review of Respiratory Medicine, 6:2, 223-36
May 16, 2017 75

76. Immunotherapy in Asthma
Administration of gradually increasing
quantities of specific allergens to patients with
IgE-mediated conditions till a dose is reached
which is effective in reducing disease severity
from natural exposure.
May 16, 2017 76

77. Indications in Asthma
• Demonstration that disease is due to IgE mediated allergy
• Insufficient response to environmental control or
pharmacotherapy
• Environmental control not feasible
• Significant side effects of pharmacotherapy
• Poor compliance to therapy
• Both nasal and bronchial symptoms
May 16, 2017 77

78. Mechanism of immunotherapy
• Allergen→Th2stimulation→IgE
• Later exposure →immediate mediator release
→eosinophilic & basophilic inflammation
• IT Allergens →T regulatory cells (CD4+CD25+)
→IL-10 Th1↑ IFN-γ↑, Th2↓
May 16, 2017 78

79. • Blocking Antibody
Natural allergen exposure after IT
↓
IgG4 instead of IgE
↓
blocks Ag
↓Immediate mediators ↓late phase
Less mast cells altered TH1/TH2 ratio
May 16, 2017 79

80. Routes of Immunotherapy
• Subcutaneous, Oral, Sublingual, Nasal or Bronchial
Routes
Rush IT: Can provide hypo-sensitization in short time
IT or Inhaled Steroids ?
• Immunotherapy resulted in slow but steady
improvement which did not decline as rapidly as
budesonide on cessation
*W.A. Shaikh. Clinical & Experimental Allergy 1997
May 16, 2017 80

81. Recommendations
• Allergen-specific immunotherapy may be an
option if allergy plays a prominent role, e.g.
asthma with allergic rhinoconjunctivitis.*
• Indian guidelines do not recommend multiple
allergen immunotherapy
• Single allergen therapy may be considered in
demonstrated skin allergy by trained
personnel at higher centres**
*GINA 2016
**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma:
Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1)
May 16, 2017 81

82. Vaccination in Asthma
• Influenza contributes to some acute asthma
exacerbations.
• Patients with moderate-severe asthma are advised
to receive an influenza vaccination every year.*
• However, vaccination is not expected to reduce the
frequency or severity of asthma exacerbations.
• Indian guidelines- Not recommended
• Others- Pneumococcal vaccine
*GINA2016
May 16, 2017 82

83. Role of Vit D
• Several cross-sectional studies have shown that low
serum levels of Vitamin D are linked to impaired lung
function, higher exacerbation frequency and reduced
corticosteroid response.
• However, to date, Vitamin D supplementation has
not been associated with improvement in asthma
control or reduction in exacerbations.
May 16, 2017 83

84. Bronchial Thermoplasty
May 16, 2017 84May 16, 2017 84
Short-acting Beta2-agonists
Low-dose Inhaled Corticosteroids (ICS)
Low-dose ICS +
Long-acting Beta2-agonists (LABA)
or Medium-dose ICS
Medium-dose ICS + LABA
High-dose ICS + LABA
and Consider Omalizumab
High-dose ICS + LABA +
Oral Corticosteroids
and Consider Omalizumab
Adapted from National Asthma Education and Prevention Program (NAEPP) Guidelines. Expert Panel Report 3: Guidelines for the
Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, NIH Publication No. 07-4051, Revised August 2007.
1
22
3
4
5
6
Alternatives
Needed
Stepwise Approach

85. May 16, 2017 85
Asthmatic Airway
Role of Airway Smooth Muscle in Asthma
Normal Airway Asthma Attack

86. Bronchial Thermoplasty
ASM Treatment Approach
May 16, 2017 86
Reduces Airway Smooth Muscle (ASM)
Reduces Bronchoconstriction
Reduces Asthma Exacerbations
Improves Asthma Quality of Life

87. • A procedure that delivers thermal energy to the airways via a
bronchoscope to reduce excess airway smooth muscle and
limit its ability to constrict the airways
• Outpatient hospital procedure - 3 treatment sessions,
routinely under moderate sedation
• Complementary treatment, and not a replacement, to current
asthma reliever and controller medications
• Shown to increase the level of asthma control and improve
quality of life in patients with severe asthma
May 16, 2017 87

88. May 16, 2017 88
The Alair®
Bronchial Thermoplasty System
• Alair Catheter – a flexible tube with
an expandable wire array at the tip
(introduced into the lungs through
a standard bronchoscope)
• Alair Radiofrequency (RF)
Controller – supplies energy via
the Catheter to heat the airway
wall

89. Recommendations
• Bronchial thermoplasty may be considered for some
adult patients with severe asthma.*
• Not recommended in India, as good quality evidence
is lacking **
*GINA 2016
**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma:
Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1):S3-S42.
May 16, 2017 89

90. Surgical Management
Laryngeal Nerve Resection
• Unilateral resection of the internal branch of the
superior laryngeal nerve
• Helped prevent/cure asphyxias in chronic severe
asthma
• Cough reflex, respiratory control and phonation not
affected.
• This approach is of interest for patients with severe
and/or uncontrolled bronchial asthma in settings
with limited access to drug treatment.
Kurbon U, Dodariyon H, Davlatov A, Janobilova S, Therwath A, Mirshahi M. Surgical treatment of bronchial
asthma by resection of the laryngeal nerve. BMC Surg. 2015 Oct 8;15:109.
May 16, 2017 90

91. Asthma and Palm Dermatoglyphs
• Single nucleotide polymorphisms (SNPs) in the IL-4
(IL-4R) gene close association
with asthma severity.
• A close association between asthma and a distinctive
palm dermatoglyphic pattern was observed
• Thus, genetic variation in IL-4R may be associated
with the development of asthma and the distinctive
palm pattern
*Sun L, Xue W, Li J, Zhou Z, Han W. Palm dermatoglyphs and interleukin-4 receptor
polymorphisms in asthma. Biomed Rep. 2017 Jan;6(1):21-26.
May 16, 2017 91

92. Asthma Action Plans
• Smartphone AAP*
• Adolescents - satisfied users
• Possible clinical benefit in uncontrolled asthma.
• Asthma Management Mobile App for Adolescents-
under assessment**
*Perry TT, Marshall A, Berlinski A, Rettiganti M, Brown RH, Randle SM, Luo C, Bian J. Smartphone-based vs
paper-based asthma action plans for adolescents. Ann Allergy Asthma Immunol. 2017 Jan 19. pii: S1081-
1206(16)31362-X.
**Sage A, Roberts C, Geryk L, Sleath B, Tate D, Carpenter D. A Self-Regulation Theory-Based Asthma
Management Mobile App for Adolescents: A Usability Assessment. JMIR Hum Factors. 2017 Feb 1;4(1):e5.
May 16, 2017 92