Severe Asthma20-9-13
Suparat Sirivimonpan, MD.
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
Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21
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
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
DefinitionDefinitions “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
Characteristics
Adults
Eur Respir J 2003; 22:470-7.
European Network For Understanding Mechanisms Of Severe Asthma
Eur Respir J 2003; 22:470-7.European 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
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
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)
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
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
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.(*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
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
Jenkins HA, et al. Chest 2003;124:1318-24.
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
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
Bousquet J,et al. J Allergy Clin Immunol 2010;126:926-38
**WHO Package of Essential Interventions for Noncommunicable Diseases [WHO-PEN]
Bousquet J,et al. J Allergy Clin Immunol 2010;126:926-38
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
Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21
Expert Panel Report 3:Guidelines for the Diagnosis and and management of asthma
GINA Guideline 2011
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
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))
Humbert M, et al. Allergy 2005;60:309-16
Safety and tolerability
similar in Omalizumab and Placebo Humbert M, et al. Allergy 2005;60:309-16
• 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
Bousquet J, et al. Allergy 2005;60:302-8
Emergency visits
Reduced ER visit 47 % in omalizumab groupBousquet J, et al. Allergy 2005;60:302-8
Relative rates of asthma exacerbations across subgroupsin pooled studies
Point estimates and 95% confidence intervals for asthma exacerbation rate ratio (omalizumab : control)
Bousquet J, et al. Allergy 2005;60:302-8
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
Haldar P, et al.NEJM 2009;360:973-84
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).
Haldar P, et al.NEJM 2009;360:973-84
Haldar P, et al.NEJM 2009;360:973-84
Haldar P, et al.NEJM 2009;360:973-84
Haldar P, et al.NEJM 2009;360:973-84
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
Haldar P, et al.NEJM 2009;360:973-84
• 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
Corren J,et al. NEJM 2011;365:1088-98
Corren J,et al. NEJM 2011;365:1088-98
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
Corren J,et al. NEJM 2011;365:1088-98
P=0.045
Corren J,et al. NEJM 2011;365:1088-98
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
Corren J,et al. NEJM 2011;365:1088-98
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
Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
*Posterior probability of superiority = 95.5%. †Posterior probability of superiority = 99.9%.
Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
JACI.2013, Aug 30
• 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
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
Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21
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
Top Related