Severe Asthma
20-9-13
Suparat
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 c...
Introduction
• This group has been defined as having severe
asthma, refractory asthma, or treatment-resistant
asthma
• Sev...
Epidemiology
• The Severe Asthma Research Program (SARP)
from the National Heart, Lung, and Blood
Institute (NHLBI)
– 15% ...
• intermittent asthma 62.9%
• mild persistent asthma 10.5%
• moderate persistent asthma 17.6%
• severe persistent asthma 9...
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. T...
• Definitions “Refractory asthma” by ATS workshop , SARP
(Severe Asthma Research Program)
ATS. Am J Respir Crit Care Med 2...
Definition
Definitions “difficult/therapy-resistant asthma”
• by The European Respiratory Society task force (1999)
• Pati...
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 ach...
Characteristics
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 ...
• 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...
• 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...
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, i...
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
Subjects with severe asthma also had lower baseline FEV1 val...
Bronchoprovocation testing
• Mean PC20 was significantly lower in severe asthma
(1.69 ± 2.28 vs 10.24 ± 10.47 mg/mL; P = ....
Allergic sensitization
• children with severe asthma had significantly higher
serum IgE (821 ± 1066 vs 301 ± 413 kU/L; P =...
Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
(*P < .05)
severe asthma
severe asthma
6-month period of obs...
• Children with severe asthma have greater airway
obstruction, increased markers of allergic
sensitization, increased bron...
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 ...
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 assessme...
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), o...
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 controlle...
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 impr...
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)
• oma...
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 group
Bousquet J, et al. Allergy 2005;60:302-8
Relative rates of asthma exacerbations across subgroups
in pooled studies
Point estimates and 95% confidence intervals for...
Other treatment
Pharmacologic
• Anti IL-5 : Mepolizumab, Reslizumab
• Anti IL-13 : Anrukinzumab , Lebrikizumab
• Anti IL-4...
• randomized, double-blind, placebo-controlled,
parallel-group study
• 61 subjects who had refractory eosinophilic
asthma ...
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...
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
• sig...
• Anti-IL-5 therapy may not provide benefit
to all patients with severe asthma
• It does appear to have a therapeutic
pote...
• monoclonal antibody to IL-13
• randomized, double-blind, placebo-controlled
study
• 219 adults who had asthma that was
i...
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 ...
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 si...
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
• ran...
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 ...
JACI.2013, Aug 30
• The proportion of subjects having severe exacerbations in each
subsequent year (years 2, 3, 4, and 5) compared with the ...
• 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 lea...
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 contr...
Take home message
• Severe asthma is a protean disease
• A better understanding of the different
phenotypic variants may a...
Severe asthma
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Severe asthma

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Severe asthma

Presented by Suparat Sirivimonpan, MD.

20130920

Published in: Health & Medicine
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  • Other groups have approached the definition of severe asthma from a slightly different angle.
  • ใช้ในผู้ใหญ่ อายุ 21-72 ปี
  • Severe asthma

    1. 1. Severe Asthma 20-9-13 Suparat
    2. 2. Topic outline • Introduction • Epidemiology • Definition • Characteristics • Management • Take home message
    3. 3. 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
    4. 4. 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
    5. 5. 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
    6. 6. • intermittent asthma 62.9% • mild persistent asthma 10.5% • moderate persistent asthma 17.6% • severe persistent asthma 9.0% Respirology 2004;9:373-378
    7. 7. Definition
    8. 8. Definition • Severe asthma • Difficult-to-treat asthma • Difficult/therapy-resistant asthma • Refractory asthma
    9. 9. 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
    10. 10. • 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
    11. 11. 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
    12. 12. GINA2008 GINA. Eur Respir J 2008;31:143-78.
    13. 13. • definitions of patients with severe asthma focus on persons who require primarily large doses of ICSs in attempts to achieve disease control
    14. 14. Characteristics
    15. 15. Adults Eur Respir J 2003; 22:470-7 European Network For Understanding Mechanisms Of Severe Asthma
    16. 16. Eur Respir J 2003; 22:470-7European Network For Understanding Mechanisms Of Severe Asthma Age 17–65 yrs
    17. 17. Non atopy • fewer positive reactions in the severe asthma group • no significant differences : Alternaria and Aspergillus fumigatus Eur Respir J 2003; 22:470-7
    18. 18. • lower FEV1 values with less reversibility after bronchodilator Eur Respir J 2003; 22:470-7
    19. 19. • 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
    20. 20. • significantly greater urinary eosinophil protein X (EPX) and urinary leukotriene E4 Eur Respir J 2003; 22:470-7
    21. 21. • 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
    22. 22. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
    23. 23. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.similar age and sex distribution
    24. 24. • 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.
    25. 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
    26. 26. 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.
    27. 27. 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.
    28. 28. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25. (*P < .05) severe asthma severe asthma 6-month period of observation
    29. 29. • 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.
    30. 30. Jenkins HA, et al. Chest 2003;124:1318-24.
    31. 31. Jenkins HA, et al. Chest 2003;124:1318-24.
    32. 32. 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
    33. 33. Jarjour NN,et al. Am J Respir Crit Care Med 2012;185:356-62
    34. 34. Management
    35. 35. 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]
    36. 36. Bousquet J,et al. J Allergy Clin Immunol 2010;126:926-38 Accurate Dx radiographic imaging
    37. 37. 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
    38. 38. Expert Panel Report 3: Guidelines for the Diagnosis and and management of asthma
    39. 39. GINA Guideline 2011
    40. 40. Omalizumab (humanized monoclonal anti-IgE antibody)
    41. 41. • 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
    42. 42. Humbert M, et al. Allergy 2005;60:309-16
    43. 43. • 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
    44. 44. Safety and tolerability similar in Omalizumab and Placebo Humbert M, et al. Allergy 2005;60:309-16
    45. 45. • 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
    46. 46. Asthma exacerbations Reduced asthma exacerbation 38% in omalizumab group Bousquet J, et al. Allergy 2005;60:302-8
    47. 47. Emergency visits Reduced ER visit 47 % in omalizumab group Bousquet J, et al. Allergy 2005;60:302-8
    48. 48. Relative rates of asthma exacerbations across subgroups in 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
    49. 49. Other treatment Pharmacologic • Anti IL-5 : Mepolizumab, Reslizumab • Anti IL-13 : Anrukinzumab , Lebrikizumab • Anti IL-4 : Pascolizumab Non-pharmacologic • Bronchial thermoplasty
    50. 50. • 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
    51. 51. Age 21-72 yr Haldar P, et al.NEJM 2009;360:973-84
    52. 52. 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
    53. 53. Haldar P, et al.NEJM 2009;360:973-84
    54. 54. Haldar P, et al.NEJM 2009;360:973-84
    55. 55. Haldar P, et al.NEJM 2009;360:973-84 Safety acceptable adverse- event and side- effect profile
    56. 56. 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
    57. 57. • 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
    58. 58. • 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
    59. 59. Corren J,et al. NEJM 2011;365:1088-98
    60. 60. Corren J,et al. NEJM 2011;365:1088-98
    61. 61. 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
    62. 62. Corren J,et al. NEJM 2011;365:1088-98
    63. 63. P=0.045 Corren J,et al. NEJM 2011;365:1088-98
    64. 64. 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
    65. 65. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
    66. 66. • 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.
    67. 67. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
    68. 68. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
    69. 69. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
    70. 70. *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.
    71. 71. JACI.2013, Aug 30
    72. 72. • 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
    73. 73. • 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
    74. 74. JACI.2013, Aug 30
    75. 75. • 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
    76. 76. Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21 Personalized treatment
    77. 77. 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
    78. 78. 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
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