Severe asthma

Topic outline
• Introduction
• Epidemiology
• Definition
• Characteristics
• Management
• Take home message

Introduction
• The prevalence of asthma has continued to
increase significantly
• Fortunately, most patients with asthma can
achieve good control of their disease
• A significant proportion of patients with asthma
remains symptomatic despite treatment with
high-dose ICSs, inhaled LABAs, and, even in some
cases, systemic corticosteroids
Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21

Introduction
• This group has been defined as having severe
asthma, refractory asthma, or treatment-resistant
asthma
• Severe asthma remains a major challenge for the
clinician because these patients require the
greatest degree of health care and experience the
most morbidity

Epidemiology
• The Severe Asthma Research Program (SARP)
from the National Heart, Lung, and Blood
Institute (NHLBI)
– 15% of asthmatic patients are in this group
Jarjour NN,et al. Am J Respir Crit Care Med 2012;185:356-62

• intermittent asthma 62.9%
• mild persistent asthma 10.5%
• moderate persistent asthma 17.6%
• severe persistent asthma 9.0%
Respirology 2004;9:373-378

Definition
• Severe asthma
• Difficult-to-treat asthma
• Difficult/therapy-resistant asthma
• Refractory asthma

Definition
• Definitions of “severe asthma” by the WHO
1. Untreated severe asthma
2. Difficult-to-treat severe asthma
3. Treatment-resistant severe asthma
- Asthma for which control is not achieved despite the
highest level of recommended treatment: refractory
asthma and corticosteroid-resistant asthma
- Asthma for which control can be maintained only with
the highest level of recommended treatment
most challenging
Bousquet J,et al. J Allergy Clin Immunol 2010;126:926-38

• Definitions “Refractory asthma” by ATS workshop , SARP
(Severe Asthma Research Program)
ATS. Am J Respir Crit Care Med 2000;162:2341-51.
1/2
2/7

Definition
Definitions “difficult/therapy-resistant asthma”
• by The European Respiratory Society task force (1999)
• Patients with poorly controlled asthma who require
continued requirement for short-acting beta 2-agonists
despite delivery of a reasonable dose of inhaled
corticosteroids
• Patients may require courses of oral corticosteroids or a
regular dose of oral corticosteroids to maintain
reasonable control of the disease
• regular follow-up with a respiratory specialist for 6
months

GINA2008
GINA. Eur Respir J 2008;31:143-78.

• definitions of patients with severe asthma
focus on
persons who require primarily large
doses of ICSs in attempts to achieve
disease control

Adults
Eur Respir J 2003; 22:470-7
European Network For Understanding Mechanisms Of Severe Asthma

Eur Respir J 2003; 22:470-7European Network For Understanding Mechanisms Of Severe Asthma
Age 17–65 yrs

Non
atopy
• fewer positive reactions in the severe asthma group
• no significant differences : Alternaria and Aspergillus fumigatus
Eur Respir J 2003; 22:470-7

• lower FEV1 values with less reversibility after bronchodilator
Eur Respir J 2003; 22:470-7

• significantly greater number of neutrophils in their sputum
• no difference in the number, or proportion, of eosinophils or other leukocytes
Eur Respir J 2003; 22:470-7

• significantly greater urinary eosinophil protein X (EPX) and urinary
leukotriene E4
Eur Respir J 2003; 22:470-7

• Persistent symptoms and abnormal lung
function, despite high-dose regular use of
controller and reliever medications, is
accompanied by a component of irreversible
airflow obstruction, neutrophilic inflammation,
ongoing mediator release and reduced
association with atopy.
Eur Respir J 2003; 22:470-7

Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.

Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.similar age and sex distribution

• Symptoms were significantly higher in
children with severe versus mild-to-
moderate asthma
– Composite symptom scores, including
cough, sputum production, chest
tightness, wheezing, shortness of breath, and
nocturnal awakenings in the 3 months before
enrollment

Subjects with severe asthma also had lower baseline FEV1 values but
showed greater reversibility after bronchodilator administration
No significant correlations were observed between spirometry variables
and symptom scores

Bronchoprovocation testing
• Mean PC20 was significantly lower in severe asthma
(1.69 ± 2.28 vs 10.24 ± 10.47 mg/mL; P = .010)
• remained different between the 2 groups after
controlling for serum IgE and the number of positive skin
prick responses (P = .011)

Allergic sensitization
• children with severe asthma had significantly higher
serum IgE (821 ± 1066 vs 301 ± 413 kU/L; P = .002)
• more positive skin prick reactions to aeroallergens (mean
5 ± 3 vs 3 ± 3; P = .009),
– weed mix (34% vs 6%; P =.023)
– Dfarinae (79% vs 50%; P = .039)
– Dermatophagoides pteryn (86% vs 56%; P = .024)
• not different with regard to animal dander, tree, or mold
sensitization
• The percentage of eosinophils in peripheral blood was not
different

(*P < .05)
severe asthma
severe asthma
6-month period of observation

• Children with severe asthma have greater airway
obstruction, increased markers of allergic
sensitization, increased bronchial
hyperresponsiveness to methacholine, and lung
hyperexpansion
• Both the obstructive changes in lung function and
elevated FENO persist over time despite adjustments
in ICS treatment

Jenkins HA, et al. Chest 2003;124:1318-24.

Jenkins HA, et al. Chest 2003;124:1318-24.
children with severe asthma tended to be more responsive to glucocorticoids in vitro
and tended to have less impairment in lung function than adult counterparts

Jarjour NN,et al. Am J Respir Crit Care Med 2012;185:356-62

Management
Proposals for the management of severe asthma
• Accurate diagnosis (need PEF or spirometry)
• Accurate assessment of severity
• Assessment and prevention of risk factors
• Assessment and control of comorbidities
• Appropriate therapy (ICS, SABAs, LABAs), given with an
appropriate drug delivery device
• Assessment of control (WHO-PEN, asthma control
questionnaires, symptoms, and so forth)
• Ongoing support in self-management and patient education
• Well-trained health professionals
**WHO Package of Essential Interventions for Noncommunicable Diseases [WHO-PEN]

Accurate Dx
radiographic imaging

Comorbidities
• Rhinitis
• Sinusitis
• Gastroesophageal reflux disease
• Allergic bronchopulmonary aspergillosis
(ABPA), or other allergic mycoses
• Persistent respiratory tract infections
(Mycoplasma or Chlamydophilia pneumonia)
• Psychological diseases esp. depression

Expert Panel Report 3:
Guidelines for the Diagnosis and and management of asthma

Omalizumab
(humanized monoclonal anti-IgE antibody)

• randomized, placebo-controlled, double-blind study
• 28-week treatment phase
• 419 pts (12–75 yr) inadequately controlled with
high-dose ICS and LABA with reduced lung function
• omalizumab (209 pts) vs placebo (210 pts)
• Omalizumab dose of at least 0.016 mg/kg per IU/ml of IgE
subcutaneously (based on the patient’s bodyweight and total
serum IgE level ) was administered every 2 or 4 weeks
Humbert M, et al. Allergy 2005;60:309-16

• Total emergency visits in the treated-group were reduced
by 44% ( 0.24 vs 0.43, P = 0.038 )
• Clinically meaningful improvement asthma quality of life
questionnaire (AQLQ) ( > 0.5-point from baseline) was
observed in the treated-group as compared to placebo
(60.8% vs 47.8%, p =0.008)
• Mean morning PEF significant greater for omalizumab
than placebo ( P= 0.042)
• The FEV1 (% predicted) was significantly improved with
omalizumab compared with placebo
(difference = 2.8% predicted ( P=0.043))

Safety and tolerability
similar in Omalizumab and Placebo

• pooled data from 7 studies
• severe persistent asthma
• 12-79 yrs
• 4308 patients (2511 omalizumab , 1797 control)
• omalizumab was added to current asthma therapy
and
– compared with placebo (in five double-blind studies)
– or with current asthma therapy alone (in two open-label
studies)
Bousquet J, et al. Allergy 2005;60:302-8

Asthma exacerbations
Reduced asthma exacerbation 38% in omalizumab group

Emergency visits
Reduced ER visit 47 % in omalizumab group

Relative rates of asthma exacerbations across subgroups
in pooled studies
Point estimates and 95% confidence intervals for asthma exacerbation rate ratio (omalizumab : control)
Improvement with omalizumab was seen regardless of
age, sex, baseline FEV1, baseline serum IgE, dosind
schedule

Other treatment
Pharmacologic
• Anti IL-5 : Mepolizumab, Reslizumab
• Anti IL-13 : Anrukinzumab , Lebrikizumab
• Anti IL-4 : Pascolizumab
Non-pharmacologic
• Bronchial thermoplasty

• randomized, double-blind, placebo-controlled,
parallel-group study
• 61 subjects who had refractory eosinophilic
asthma and a history of recurrent severe
exacerbations
• Mepolizumab (29 subjects) VS Placebo (32) at
monthly intervals for 1 year
– 750 mg Mepolizumab IV
Haldar P, et al.NEJM 2009;360:973-84
Inclusion criteria :
-refractory asthma according to ATS criteria
-sputum eosinophil > 3% on at least one occasion in previous 2 years despite high-dose
corticosteroid treatment
-at least two exacerbations requiring rescue prednisolone in previous 12 months

Age 21-72 yr

The mean number of exacerbations :
2.0 in mepolizumab group
VS 3.4 in placebo group
(relative risk, 0.57; 95% CI , 0.32 to 0.92;
P = 0.02).

Safety
acceptable adverse-
event and side-
effect profile

Conclusion
Mepolizumab
• significantly fewer severe exacerbations
• Significant improvement in the score on the AQLQ
• significantly lowered eosinophil counts in the
blood and sputum
• There were no significant differences between the
groups with respect to symptoms, FEV1 after
bronchodilator use, or airway hyperresponsiveness
• The only serious adverse events reported were
hospitalizations for acute severe asthma

• Anti-IL-5 therapy may not provide benefit
to all patients with severe asthma
• It does appear to have a therapeutic
potential to reduce exacerbations in
subgroups with severe eosinophilic disease

• monoclonal antibody to IL-13
• randomized, double-blind, placebo-controlled
study
• 219 adults who had asthma that was
inadequately controlled despite inhaled
glucocorticoid therapy
Corren J,et al. NEJM 2011;365:1088-98

At week 12
P = 0.02
P = 0.03
P = 0.61
Relative changes in FEV1 were
evident after 1 week of
treatment and were sustained
throughout the study

P=0.045

Conclusion
• Treatment with lebrikizumab was associated
with a significant improvement in pre-
bronchodilator FEV1
• No significant reductions in exacerbations rate
and asthma symptoms
• Prespecified marker, serum periostin, could
potentially be used to identify patients with
asthma who may have an increased response to
lebrikizumab treatment
• This finding requires replication

Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.

• Multicenter, Randomized, Double-Blind, Sham-
Controlled Clinical Trial
• 30 investigational sites in six countries
• randomized (2:1)
• 288 adult subjects (18–65 years of age)
• randomized to BT or sham control underwent
three bronchoscopy procedures

*Posterior probability of superiority = 95.5%.
†Posterior probability of superiority = 99.9%.

• The proportion of subjects having severe exacerbations in each
subsequent year (years 2, 3, 4, and 5) compared with the first year after
BT were not significantly different
• The decrease in severe exacerbation rates that was achieved in the
posttreatment period after BT in year 1 was maintained out to 5 years
JACI.2013, Aug 30

• The decrease in rates of ED visits that was achieved after BT in year 1 was
maintained out to 5 years
JACI.2013, Aug 30

• BT is an effective and safe therapy
• A single BT treatment comprising 3 procedures
provides long-term benefit to at least 5 years
• Whether BT is a disease modifying therapy will
depend on the results of future appropriately
designed clinical studies
JACI.2013, Aug 30

Personalized treatment

Take home message
• Severe asthma : Persons who require primarily large
doses of ICSs in attempts to achieve disease control
• Because treatment non adherence is common at all
levels of asthma severity  always needs to be
considered before concluding that a medication is
not effective
• Accurate diagnosis (need PEF or spirometry)
• Assessment and control of comorbidities

Take home message
• Severe asthma is a protean disease
• A better understanding of the different
phenotypic variants may allow for not only
greater understanding of the disease but
also direction for improved treatment
strategies

Severe asthma

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Notes de l'éditeur