Severe asthma in

Precision Medincine Era

Craiu Mihai
INSMC „Alessandrescu-Rusescu”
UMF „Carol Davila” Bucuresti
Accurate assessment of asthma severity is essential
to predict future risk and impairment and to guide
asthma management (GINA 2018)
The NAEPP and GINA guidelines divide asthma
severity based on
• lung function (FEV1),
• daytime and nocturnal symptoms,
• frequency of rescue bronchodilator use.

https://ginasthma.org/2018-gina-report-
global-strategy-for-asthma-management-
and-prevention/
 A Task Force, supported by the ERS and
Severe asthma ATS, reviewed the definition and provided
recommendations and guidelines on the
evaluation and treatment of severe
asthma in children and adults *

• When the diagnosis of asthma is confirmed and comorbidities

addressed, severe asthma is defined as asthma that requires
treatment with high dose ICS plus a second controller and/or systemic
corticosteroids to prevent it from becoming "uncontrolled" or that
remains "uncontrolled" despite this therapy.

*Chung KF, Wenzel SE, Brozek JL, Bush A et al – International ERS/ATS

guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J.
2014;43(2):343. Epub 2013 Dec 12.
Chung KF, Wenzel SE, Brozek JL, Bush A et al –
International ERS/ATS guidelines on definition,
evaluation and treatment of severe asthma.
Eur Respir J. 2014;43(2):343. Epub 2013 Dec 12.
Chung KF, Wenzel SE, Brozek JL, Bush A et al –
International ERS/ATS guidelines on definition,
evaluation and treatment of severe asthma.
Eur Respir J. 2014;43(2):343. Epub 2013 Dec 12.
Severe or therapy-resistant asthma is increasingly
recognised as a major unmet need

Current classification and

management approaches in
asthma do not reflect the
heterogeneous characteristics
of this disease.
Clustering and Machine learning techniques
 Using modeling approaches,
Moore and Co describe five distinct
clinical phenotypes of asthma that
suggest differences in
pathophysiologic mechanisms
Clustering by age, baseline FEV1,
maximal FEV1 after SABA

Mostly older obese women with late-onset nonatopic asthma,

moderate reductions in FEV(1), and frequent oral corticosteroid use
to manage exacerbations.
Heterogeneity in asthma expression is multidimensional,
including variability in clinical, physiologic, and
pathologic parameters - Leicester study *

* Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M,

et al. Cluster analysis and clinical asthma phenotypes.
Am J Respir Crit Care Med 2008;178:218–24.

Alexandru B.
Wei Wu et al - Unsupervised phenotyping of Severe Asthma
Research Program participants using expanded lung data. J
Allergy Clin Immunol 2014;133(5):1280-8

Clinically recognizable patient clusters:

an early onset allergic asthma cluster, a
very severe, systemic CS dependent
cluster, a late onset nasal polyp cluster,
and a cluster of women with symptom
predominant early onset disease.

Concordant vs Discordant Symptoms/Inflammation

 Genetic and environmental components
of the aetiology of asthma
• Recent genetic studies, including meta-
analyses of large-scale genome-wide
association studies (GWAS), have
successfully identified several genetic loci
that influence asthma susceptibility,
providing a better understanding of the
pathogenesis of this complex disorder
major susceptibility locus on
chromosome 17q21 harboring
the ORMDL3 gene

Nieuwnhuis MA et al – Combining Genome Wide Association Study and lung eQTL analysis provides evidence for
novel genes associated with asthma. Allergy 2016;71(12):1712-20
 Siroux V et al – Genetic heterogeneity of asthma phenotypes
identified by a clustering approach. Eur Respir J 2014;43:439-52
Severe asthma approach in clinic
A child is not a small adult!
 Uncontrolled asthma / severe asthma versus
other disease
In children with recurrent lung signs and symptoms that exhibit
bronchospasm one should exclude :
CF
PCD
Alfa1-AntiTripsin Deficiency
Bronchopulmonary Dysplasia
Foreign body aspiration
Tracheo-bronchomalacia
etc.
 REAL-LIFE MEDICINE

FROM AN IDEAL SCENARIO TO ROMANIAN REALITY*

• A 14 questions document was used in ED of INSMC between

1st Nov – 31st Dec 2008.

* Craiu M, Stan I - Modalitati de evaluare ale prescolarului cu wheezing recurent

insuficient controlat. CNPP Craiova 2012
MATERIAL AND METHOD
• We included children with asthma/recurrent wheezing
presented for an unscheduled visit in ED due to an
exacerbation

• Parents of these children responded to questionnaire

• After responding they provided a demonstration on how they

delivered inhaled medication
QUESTIONAIRE

Questions were targeting triggering factors that are subject of

a certain degree of control:
• Controller medication (Y/N)
• Inhalation technique (5 questions)
• Family smoking habits (3 questions)
• Environmental pollution (2 questions)
• Exercise-induced Broncho-constriction (2 questions)
• Education for asthma (Y/N)
 RESULTS

• 220 potential candidates with exacerbation 220

• 88 uncompliant [self-statement] were 88

excluded necomplianti

• 132 children were included 27 WAP 101+ 4-

132 COMPLIANT PATIENTS
27 (20.45%) had a written action plan.
101 patients (76.51%) had an identifiable factor;
Only 4(3.03%) did not present any documentable factors for being
uncontrolled
Probably difficult to treat/severe
PACIENTI
asthmaCOMPLIANTI
cases

4
27

101
Dr House and asthma inhaler

Anna :
Do I look line an
idiot?
 SPACER USAGE
FOLOSIREA SPACER

15

86

• Only 15 (14.85%) patients used correctly the spacer

device
• 86 (85.15%) had one or several handling errors
• Improvisation
• Age-inadequate spacer
• Incomplete device (lack of valves)
Only 19 parents (18.81%) were shaking the
pMDI device before usage
AGITAT FLACONUL

19

82
 Only 12 parents
DESCARCAREA (11.88%)
"STATICA" were
A SPACER providing static
discharge by regular detergent washing
12

89

Fluticasone deposition on spacer’s

plastic-walls due to static charges
In 88.12% cases on spacer’s internal walls werelarge
amounts of active medication
 Only 23 parents (22.77%) presented an aproprite sealing of
the spacer acording to child’s age (with or w/o mask).
PIERDEREA ETANSEITATII

23

78
34 children (33.66%) were compliant with delivery technique
4 of the “inpatient” patients (5.97%) had ADHD diagnosis!

INADECVARE TEHNICA - RABDARE

NOT patient during inhalation

34

67
 RW SUBGROUP & EDUCATION

• 27 (16.07%) of RW children were enrolled for prospective surveillance

for up to 6 months after retraining in :
• Inhalation technique,
• Trigger avoidance,
• PIS usage in order to evaluate a „flare-up” of asthma.
 Education was significantly associated with less
exacerbations (p = 0.0231 , 95% CI - 0.0085 to 0.0623)

M Craiu, P Avram, AV Cochino, I Stan - Evaluation of controlable

triggering factors for exacerbation in preschool viral wheeze.
Abstract 1244, ERS Wien 2009
 Follow-up…

• Education is essential

• But does it produce also a functional impact on patients?

• Prospective follow-up during winter of a subgroup of 17 (of the 27 compliant

children using WAP, from previous study) that received a rigorous retraining.
 EVALUATION

• Hands-on training.

• Video-training with You tube short videos [link provided on WAP]

• After training PFTs - baseline

 CONTROL IN 2-6 MONTHS

• Programed monthly visits – not unscheduled, due to exacerbation!

• Retraining at each visit

• Repeated PFTs
 RESULTS
FEV1 valuesVEMS
EVOLUTIA after retraining/videotraining
DUPA INSTRUIRE
You Tube videos

1
17 150 2
16 3
100
15 4
50
14 5
0

13 6

12 7
11 8
10 9
CURRENT ON-LINE EDUCATION in INSMC
 SOCIAL MEDIA EDUCATION IMPACT IN PEDIATRIC ASTHMA
PATIENTS *
OR = 0.1143 in study group
[p 0.0151, 95% CI 0.0199 – 0.6571]
Unscheduled ED visit
20

18

16

14

12

10

0
1 2

* Mihai Craiu, Iustina Violeta Stan – Social media education decreases unscheduled outpatient visits in paediatric
asthma patients. Archives of Disease in Childhood 2017;102 Suppl2:A4-A4
 Uncontrolled asthma & severe asthma

• Only 50% of uncontrolled / difficult to treat asthma patients have

severe asthma *

* Chung KF et al – International ATS/ERS guidelines on definition, evaluation and treatment of

severe asthma. ERJ 2014;43(2):343-73.
Cluster analysis offers a novel multidimensional
approach for identifying asthma phenotypes that exhibit
differences in clinical response to treatment algorithms

Patients with severe asthma generally benefit

from consultations with an asthma specialist to
optimise their management, which may include
the potential initiation of biologic agents that
have made a breakthrough in the treatment of
severe disease.
 Severe asthma treatment options
• In severe allergic asthma we can target IgE or eosinophils. There are
several distinct tools available:

• Omalizumab, a monoclonal antibody against immunoglobulin E

• Mepolizumab or reslizumab, anti-interleukin-5 (anti-IL-5) mAbs or
benralizumab, an anti-IL-5 receptor mAb, are effective in reducing
exacerbations in patients with severe eosinophilic asthma
• Dupilumab, a mAb against IL-4-receptor-α blocking IL-4/IL-13
 Severe asthma treatment options

• Omalizumab, a monoclonal antibody (mAb) against immunoglobulin E

(anti-IgE), was the first biologic developed for the treatment of severe
allergic asthma and consistent results of randomised controlled trials
(RCTs) even in children*

Chipps BE etal – Omalizumab in children with uncontrolled allergic asthma: Review of

clinical trial and real-world experience. J Allergy Clin Immunol 2017;139(5):1431-44
 BIOLOGICALS IN SEVERE Th2 ASTHMA

Bousquet J et al – Care pathways for the selection of a biologic in severe asthma. Eur Respir J 2017 50: 1701782
Buhl R et al – Severe eosinophilic asthma: a roadmap
to consensus. Eur Respir J 2017 49: 1700634
Case scenario

• Daniel A 11 years old boy

• His mother RN

• Severe allergic asthma with multiple perennial triggers

• Uncontrolled in spite of High-dose ICS+LABA

Significant inflammation - >> FeNO
Eosinophil count

Sept 2015
20

18

16

14

12

10

0
1 2 3 4 5
Training for PEF metry
Functional impact of Omalizumab
ACT 15

PEF 101%
PFTs after restart of Omalizumab
10th Oct 2018
Let’s hear Daniel’s opinion about his disease

Madalina Camelia Dianu - Project of Group 1 / XVth Series 5th year medical students
Severe asthma is not undertreated asthma
nor difficult-to-treat asthma
 Perspective for severe asthma

Tailored treatment & Precission medicine