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Severe asthma Pathophysiology and treatment

Severe asthma Pathophysiology and treatment. Louis-Philippe Boulet MD, FRCPC, FCCP Institut de cardiologie et de pneumologie de l'Université Laval, Hôpital Laval, Quebec City, Canada. Synopsis. Definition and pathophysiology of severe asthma

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Severe asthma Pathophysiology and treatment

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  1. Severe asthmaPathophysiology and treatment Louis-Philippe Boulet MD, FRCPC, FCCP • Institut de cardiologie et de pneumologie de l'Université Laval, Hôpital Laval, • Quebec City, Canada

  2. Synopsis • Definition and pathophysiology of severe asthma • Evaluation of severe asthma and co-morbidities • Current treatment guidelines • New therapeutic options • Research needs and future developments

  3. Direct costs of asthma in Brazil: a comparison between controlled and uncontrolledasthmatic patients. Santos LA, Oliveira MA, Faresin SM, Santoro IL, Fernandes AL. Braz J Med Biol Res. 2007;40:943-8. • Cross-sectional study to determine costs related to patients with uncontrolled and controlled asthma. • Ninety asthma patients were enrolled (45 uncontrolled/45 controlled). • Uncontrolled asthmatics accounted for higher health care expenditures than controlled patients • Costs with medications in the last month (uncontrolled): • Mild: $1.60 ($6.50) • Moderate: $ 9.60 ($19.00) • severe asthma $25.00 ($49.00 )

  4. Canadian Asthma Consensus Guidelines Pred • Regularly verify: • Asthma control • Triggers • Compliance • Inhaler technique • Co-morbidities Maintenance treatment Add-on meds Inhaled corticosteroids Low Moderate High Fast-acting bronchodilator Environmental control, education, action plan and follow-up Severe Moderately severe Moderate Very mild Mild

  5. Severe/Refractory asthma* (ATS) Major characteristics To achieve control to level of mild-moderate persistent asthma: • Treatment with oral CS > 50% of past year • Continuous use of high doses of CS Minor characteristics • Requirement for additional daily Rx with a controller medication • Asthma Sx requiring a SABA daily or near daily • Persistent airway obstruction (FEV1 less than 80%, diurnal variability more than 20%) • 3 or more steroid bursts per year • Prompt deterioration with 25% or less reduction of oral CS or ICS • Near fatal event in the past * At least 1 major and 2 minor criteria

  6. Definition of severe asthma The term, “severe refractory asthma” applies to patients who remain difficult to control despite an extensive re-evaluation of diagnosis, management, and following an observational period of at least 6 months by an asthma specialist. Chanez, Wenzel, Anderson, Anto, Bel, Boulet, et al JACI 2007

  7. Asthma Severity vs ControlWhy is asthma sometimes difficult to control ? • 1. Wrong diagnosis Vocal cord dysfunction, poor PFT technique, hyperventilation, COPD, CHF, neoplasm, vasculitis, … • 2. Undertreatment • Often from under-evaluation of severity • 3. Poor adherence • compliance <50% misunderstanding of Rx • poor instructionsfears and misconceptions • cost psychosocial factors • 4. Unidentified exacerbating factors + co-morbidity • Allergens and occupational exposures, smoking • drugs (-blockers, salicylates) • GERD, Rhino-sinusitis, Obesity • 5. Unresponsive to therapy

  8. 4.0 3.5 3.0 3.5 2.5 2.0 3.0 1.5 2.5 1.0 2.0 0.5 1.5 0 1 2 3 4 5 6 7 8 9 10 12 11 1.0 0.5 0 1 2 3 4 5 6 7 8 9 10 11 12 5.0 2.5 4.5 4.0 2.0 3.5 3.0 1.5 2.5 2.0 1.0 1.5 1.0 0.5 0.5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 Patterns of compliance to inhaled ICSUse vs Prescribed Regular non-compliance Regular compliance 2A 1A Irregular compliance Irregular non-compliance 1B 2B Weeks Lacasse , Boulet 2005

  9. Phenotyping severe asthma • Severe asthma is a heterogeneous condition, which includes several different phenotypes. • Phenotyping severe asthma will: • improve our understanding of underlying mechanisms, natural history and prognosis, • help to guide current and possibly future treatment and provide clues for novel therapeutic interventions.

  10. Clearly identifiable asthma phenotypes seen in a refractory asthma clinic based on a combination of clinical features, physiology and patttern of airway inflammation Wardlaw et al. Clin Exp Allergy 2005;35:1254-1262.

  11. Clearly identifiable asthma phenotypes seen in a refractory asthma clinic based on a combination of clinical features, physiology and patttern of airway inflammation Wardlaw et al. Clin Exp Allergy 2005;35:1254-1262.

  12. Severe asthma: TH2-type inflammation + ? Persistent inflammation despite corticosteroid therapy

  13. IS inflammatory cells in asthma according to the severity Louis et al. Am. J. Respir. Crit. Care Med. 161: 9-16

  14. Pathophysiology of severe asthma • The pathophysiology of severe asthma remains poorly understood. • Infiltrating inflammatory cells including mast cells, eosinophils, macrophages, neutrophils, and lymphocytes, are present in the airways of the majority of severe asthmatics and persist despite steroid therapy, but their relevance to the clinical manifestations of the disease remains uncertain. • Mild asthma : Th2 mediated inflammationSevere asthma: Other types of inflammation/ processes involved ?

  15. Neutrophils and severe asthma Jakanon AJRCCM 1999 Controls/mild/moderate/severe

  16. Remodeling in severe asthma Wenzel et al. AJRCCM 1999;160:1001

  17. Airway remodelling in severe asthma • Epithelial cell and smooth muscle abnormalities are observed in the majority of fatal and/or severe asthmatics and likely contribute to airway narrowing. • Large and small airway wall thickening is observed in many severe asthmatics, but emerging evidence suggests that parenchymal abnormalities may also influence airflow limitation in severe disease.

  18. Risk factors for the development of severe asthma • Genetic factors • e.g. Polymorphisms of ADAM-33 or related to medications’ responses • Environmental factors • e.g. Allergen & smoke exposure • Exacerbating factors/ Co-morbidities • e.g. Rhinosinusitis, GOR, recurrent respiratory infections, obesity, psychologic dysfunction, SAHS,… Dolan CM, et al: Ann Allergy Asthma Immunol 2004; 92(1):32-9.

  19. Genetics • Emerging evidence suggests genetic factors play a role in asthma severity. • Partial phenotypes (BHR, IgE, decline in lung function) have proven useful in genetic studies of severe asthma. • Genes by environment interactions are likely to be of critical importance in the development of severe asthma [ETS, LPS].

  20. Allergens and Sensitizing Agents • Atopy is less frequent in severe asthma as compared to mild to moderate asthma. • Certain allergen exposures are associated with severe asthma (cockroach, Alternaria). Occupational sensitizers can induce persistent severe asthma. • NSAIDs trigger asthma exacerbations in of a large subgroup of patients with severe asthma.

  21. Smoking and asthma: clinical consequences • Increased asthma morbidity and severity • Reduced asthma control • Increased health care use • Increased rate of decline in pulmonary function • Reduced response of asthma medications

  22. Factors influencing asthma severity Increase in the odds of having Severe Asthma • Age 3% • Female vsmale gender 60% • Pollen & pet allergy 85% • Not having a prescription 59% filled due to cost • Daily smoking 66% Stallberg et al Resp Med 2007

  23. Characteristics of patients with severe asthma with and without extensive sinus disease Ten Brinke et al. JACI 2002;109:621-626.

  24. Comparative airway inflammatory and clinical features in asthmatic patients with or without polypoid rhinitis * 100 90 ANP + 80 ANP - * * * A + 70 A - 60 50 40 ACSS SCORE 30 20 10 0 Clinical Physiological Inflammatory • p < 0,05 vs ANP + • Results are presented as means

  25. Associations with infections • Mycoplasma Pneumoniae • Chlamydia Pneumoniae • Viral infections • Rhinovirus • Adenovirus • RSV • Sinusitis

  26. Possible reasons for steroid “resistance” Eosinophilic inflammation unresponsive to CS - Lymphocytic process unresponsive to CS ( Altered transcription factor binding, Increased GCR b R, decrease histone deacetylation)- Isolated eosinophilic process unresponsive to CS ( Hypereosinophilic syndrome, ASA-asthma) Neutrophilic inflammation - Small airways inflammationNo inflammation (only structural changes) Wenzel AJRCCM 2005

  27. Evaluation of severe asthma Medical historyHistory of asthma • age of onset • family history of asthma • management of disease, response to treatment Exacerbations • frequency of severe asthma exacerbations • number of hospitalisations and ICU admissions Environmental exposures • exposure to allergens, occupational agents, chemicals/pollutants • smoking history

  28. Evaluation of severe asthma Co-morbidities and co-factors • rhinosinusitis or previous surgery for nasal polyps • use of aspirin, NSAID’s, -blockers, ACE-inhibitors, estrogens • gastro-oesophageal reflux disease • obstructive sleep apnea • influence of menstruation • adherence with medications • history of psychiatric disease and psychosocial circumstances

  29. Evaluation of severe asthma Physical examination (specific points of attention) • body mass index • evidence of co-morbidities e.g. nasal polyps • evidence of alternative diagnoses e.g. cardiac failure • evidence of adverse effects of treatment

  30. Evaluation of severe asthma 1) Confirmation of the diagnosis A) Lung volumes and DLCO B) HRCT C) Methacholine challenge / laryngoscopy 2) Evaluation of confounding/exacerbating factors A) pH probe B) Sinus CT C) IgE level – skin testing D) Compliance evaluation 3) Evaluation of asthma phenotype A) Skin testing – response to allergens B) Eosinophilic phenotype (IS) Wenzel AJRCCM 2005

  31. Evaluation of severe asthma Baseline investigations • Health status and asthma control questionnaires • Serum IgE, peripheral blood eosinophil count • Allergy skin tests • Assessment of airway inflammation • Assessment of lung volumes • Consider additional tests for co-morbidities alternative diagnoses Outcome measures • Health status and asthma control questionnaires • Assessment of airway inflammation • Number and severity of exacerbations and use of healthcare • Lung function

  32. Outcomes to assess severe asthma • Spirometric measures • multiple objective outcomes should be assessed, including health status, disease control, exacerbations, airway inflammation and lung function. • Non-invasive measures of airway inflammation • sputum cell counts and supernatants, • exhaled nitric oxide (FeNO) • breath condensates for pH and isoprostanes.

  33. Subject demographics and medication use ‡ Three-way comparison, significant because of differences between mild vs moderate and severe.* Three-way comparison significant; all groups are different. Moore et al. JACI 2007;119:405-413.

  34. Subject demographics and medication use Moore et al. JACI 2007;119:405-413.

  35. Moore et al. JACI 2007;119:405-413.

  36. Frequency of ATS severity§ criteria by disease severity ND, Not determined.* Three-way comparison significant; all groups are different.† Three-way comparison, significant because of differences between severe vs mild and moderate.‡ Includes subject report of SABA prophylactic before exercise.§ Baseline FEV1 ≤ 80%; measurement with bronchodilator withhold; ATS definition does not require withhold of bronchodilators. Moore et al. JACI 2007;119:405-413.

  37. Wenzel et al. AJRCCM 1999;160:1001-1008.

  38. Conditions associated with asthma Diseases that mimic asthma Unusual asthma triggers • Bronchiectasis • Constrictive bronchiolitis • COPD • CHF • Dysfunctional breathlessness • Vocal cord dysfunction • Upper airway obstruction • ABPS • Chung-Strauss syndrome • Eosinophilic pneumonia • Thyrotoxicosis • Occupational exposure • Domestic irritants • Respiratory infections • Drugs (aspirin, NSAIDs, ACE inhibitors, ß blockers) • Food (eg, sulphite sensitivity) • Smoking • Inflammed upper airways • Acid reflux • Stress • Chronic rhinosinusitis • Gastro-oesophageal reflux • Anxiety, panic-fear, depression • Dysfunctional breathlessness • Vocal cord dysfunction • Obesity • Obstructive sleep apnoea Holgate and Polosa. Lancet 2006;368:780-793.

  39. Management of severe asthma • Inhaled corticosteroids and bronchodilators are the mainstay of treatment for severe persistent asthma. • Complete absence of response to CS in severe asthma is rare. Corticosteroid-dependent asthma is more common (“Resistance to CS”) • Despite intensive multi-drug treatment (with high dose inhaled + oral corticosteroids, long-acting ß2-agonists, and other controller medications), many patients with severe asthma remain uncontrolled and there is urgent need for new, more effective medications.

  40. Treatment of severe asthma • Methotrexate • Gold salts • Cyclosporin • IV IG • Anectodal evidences • Marginal effects • Side-effects ++ • Cost (IV IG)

  41. Asthma: targets for treatment J Allergy Clin Immunol 2000;106:5

  42. The Allergic Cascade isInterrupted by Omalizumab Omalizumab complexes with free IgE Allergen-driven B-cell secretes IgE IgE FcRI Omalizumab Mast cell B-cell

  43. Reductions in Exacerbations with Omalizumab in High-risk Asthma p=0.007  56% p<0.001 Holgate S, et al: Curr Med Res Opin 2001; 17(4):233-40. 254 patients pooled from studies 008 and 009

  44. Omalizumab Placebo QoL significantly improved overalland across all domains AQLQ score (change from baseline, LSM) 0.95* 0.91** 0.91** 0.9** 0.89** 1.0 0.8 0.6 0.4 0.2 0 Activities Emotions Symptoms Environment Overall *p=0.002; **p<0.001 AQLQ = Asthma Quality of Life Questionnaire; LSM = Least Squares Mean

  45. Side Effects • Anaphylaxis occurred rarely in clinical studies: • 3 out of 3854 patients (<0.1%) without other identifiable allergic triggers • Patients should be observed after injection, w/ medications available in case of hypersensitivity reaction • In cases of severe hypersensitivity reaction, omalizumab should be discontinued • Malignancy: • Nonsignificant numerical imbalance between treatment and control groups in clinical trials • 20 of 4336 (0.5%) omalizumab-treated patients • 5 of 2432 (0.2%) control patients Xolair Product Monograph

  46. Berry et al. NEJM 2006

  47. Conclusions • Severe/difficult asthma is responsible for high human and economic costs • More studies are needed to understand its physiopathology • There are various phenotypes of severe asthma and they should be documented • The investigation should be done in a systematic way • New modes of therapy should be searched

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