Severe asthma
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  • Other groups have approached the definition of severe asthma from a slightly different angle.
  • ใช้ในผู้ใหญ่ อายุ 21-72 ปี

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  • 1. Severe Asthma 20-9-13 Suparat
  • 2. Topic outline • Introduction • Epidemiology • Definition • Characteristics • Management • Take home message
  • 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. 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. 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. • 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. Definition
  • 8. Definition • Severe asthma • Difficult-to-treat asthma • Difficult/therapy-resistant asthma • Refractory asthma
  • 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. • 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. 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. GINA2008 GINA. Eur Respir J 2008;31:143-78.
  • 13. • definitions of patients with severe asthma focus on persons who require primarily large doses of ICSs in attempts to achieve disease control
  • 14. Characteristics
  • 15. Adults Eur Respir J 2003; 22:470-7 European Network For Understanding Mechanisms Of Severe Asthma
  • 16. Eur Respir J 2003; 22:470-7European Network For Understanding Mechanisms Of Severe Asthma Age 17–65 yrs
  • 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. • lower FEV1 values with less reversibility after bronchodilator Eur Respir J 2003; 22:470-7
  • 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. • significantly greater urinary eosinophil protein X (EPX) and urinary leukotriene E4 Eur Respir J 2003; 22:470-7
  • 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. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.
  • 23. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25.similar age and sex distribution
  • 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. 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. 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. 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. Fitzpatrick AM,et al.J Allergy Clin Immunol 2006;118:1218-25. (*P < .05) severe asthma severe asthma 6-month period of observation
  • 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. Jenkins HA, et al. Chest 2003;124:1318-24.
  • 31. Jenkins HA, et al. Chest 2003;124:1318-24.
  • 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. Jarjour NN,et al. Am J Respir Crit Care Med 2012;185:356-62
  • 34. Management
  • 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. Bousquet J,et al. J Allergy Clin Immunol 2010;126:926-38 Accurate Dx radiographic imaging
  • 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. Expert Panel Report 3: Guidelines for the Diagnosis and and management of asthma
  • 39. GINA Guideline 2011
  • 40. Omalizumab (humanized monoclonal anti-IgE antibody)
  • 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. Humbert M, et al. Allergy 2005;60:309-16
  • 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. Safety and tolerability similar in Omalizumab and Placebo Humbert M, et al. Allergy 2005;60:309-16
  • 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. Asthma exacerbations Reduced asthma exacerbation 38% in omalizumab group Bousquet J, et al. Allergy 2005;60:302-8
  • 47. Emergency visits Reduced ER visit 47 % in omalizumab group Bousquet J, et al. Allergy 2005;60:302-8
  • 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. Other treatment Pharmacologic • Anti IL-5 : Mepolizumab, Reslizumab • Anti IL-13 : Anrukinzumab , Lebrikizumab • Anti IL-4 : Pascolizumab Non-pharmacologic • Bronchial thermoplasty
  • 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. Age 21-72 yr Haldar P, et al.NEJM 2009;360:973-84
  • 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. Haldar P, et al.NEJM 2009;360:973-84
  • 54. Haldar P, et al.NEJM 2009;360:973-84
  • 55. Haldar P, et al.NEJM 2009;360:973-84 Safety acceptable adverse- event and side- effect profile
  • 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. • 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. • 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. Corren J,et al. NEJM 2011;365:1088-98
  • 60. Corren J,et al. NEJM 2011;365:1088-98
  • 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. Corren J,et al. NEJM 2011;365:1088-98
  • 63. P=0.045 Corren J,et al. NEJM 2011;365:1088-98
  • 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. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
  • 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. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
  • 68. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
  • 69. Castro M,et al. Am J Respir Crit Care Med 2010;181:116-24.
  • 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. JACI.2013, Aug 30
  • 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. • 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. JACI.2013, Aug 30
  • 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. Bell MC, Busse WW.J Allergy Clin Immunol: In Practice 2013;1:110-21 Personalized treatment
  • 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. 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