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

Severe asthma Pathophysiology and treatment

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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 - PowerPoint PPT Presentation

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Page 1: 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

Severe asthma

Pathophysiology and treatment

Page 2: Severe asthma Pathophysiology and treatment

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

Page 3: Severe asthma Pathophysiology and treatment

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 )

Page 4: Severe asthma Pathophysiology and treatment

Regularly verify:Asthma controlTriggersCompliance Inhaler techniqueCo-morbidities

Environmental control, education, action plan and follow-up

Fast-acting bronchodilator

Very mild Mild

Maintenance treatment

Add-on meds

Pred

Moderate Moderately severe

Severe

Low Moderate HighInhaled corticosteroids

Canadian Asthma Consensus Guidelines

Page 5: Severe asthma Pathophysiology and treatment

Severe/Refractory asthma* (ATS)

Major characteristics

To achieve control to level of mild-moderate persistent asthma:

1. Treatment with oral CS > 50% of past year

2. Continuous use of high doses of CS

Minor characteristics

1. Requirement for additional daily Rx with a controller medication

2. Asthma Sx requiring a SABA daily or near daily

3. Persistent airway obstruction (FEV1 less than 80%, diurnal variability more than 20%)

4. 3 or more steroid bursts per year

5. Prompt deterioration with 25% or less reduction of oral CS or ICS

6. Near fatal event in the past

* At least 1 major and 2 minor criteria

Page 6: Severe asthma Pathophysiology and treatment

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

Page 7: Severe asthma Pathophysiology and treatment

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. UndertreatmentOften from under-

evaluation of severity

3. Poor adherence

compliance <50% misunderstanding of Rx

poor instructions fears and misconceptions

cost psychosocial factors

4. Unidentified exacerbating factors + co-morbidityAllergens and occupational exposures, smokingdrugs (-blockers, salicylates)GERD, Rhino-sinusitis, Obesity

5. Unresponsive to therapy

Page 8: Severe asthma Pathophysiology and treatment

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Regular compliance

Irregular compliance

Regular non-compliance

Irregular non-compliance

Patterns of compliance to inhaled ICSUse vs Prescribed

Page 9: Severe asthma Pathophysiology and treatment

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.

Page 10: Severe asthma Pathophysiology and treatment

Clearly identifiable asthma phenotypes seen in a refractory asthma clinic based on a combination of clinical features, physiology and patttern of airway inflammation

Pnenotype Sub-phenotypes Clinical characteristics Treatment Possible pathogenesis

Marked variability in airflow obstruction and AHR

Eosinophilic and pauci-eosinophilic

Airways symptomatic; high requirement for ß2-agonists

Bronchodilators particularly effective

Disorder of airway smooth muscle function

Inflammatory (eosinophilic)

Brittle and drifters Symptomatic only during exacerbations; brittle patients have sudden falls in lung function whereas drifters more predictably deteriorate

Anti-inflammatory drugs (mainly glucocorticoids) most effective; systemic treatment required in severe cases

Marked eosinophilic inflammation sometimes associated with identifiable environmental trigger but often of unknown cause

Fixed airflow obstruction

Type 1 and 2 superimposed

Persistent airflow obstruction despite optimal treatment; chronic breathlessness major symptom

No specific treatment available

Structural remodelling of the airways particularly associated with increased airway smooth muscle

Wardlaw et al. Clin Exp Allergy 2005;35:1254-1262.

Page 11: Severe asthma Pathophysiology and treatment

Clearly identifiable asthma phenotypes seen in a refractory asthma clinic based on a combination of clinical features, physiology and patttern of airway inflammation

Pnenotype Sub-phenotypes Clinical characteristics Treatment Possible pathogenesis

Non-eosinophilic

Neutrophilic and pauci-inflammatory

Otherwise typical asthma although poorly responsive to steroids; some have a bacterial trigger for exacerbations

Antibiotics in selected cases. Avoid overuse of glucocorticoids

Unknown

Asthmatic smokers

Asthmatic smokers and COPD with asthmatic features

Usually combine features of both asthma and COPD

Relatively unresponsive to steroids

Complex interaction between effects of tobacco and underlying asthma

Eosinophilic bronchiectasis

Allergic bronchopulmonary aspergillosis (ABPA) and non-ABPA

Usually a marked peripheral blood eosinophilia; exacerbations often complicated by infection as well as inflammation

Antibiotics and systemic steroids

Allergic reaction to fungal elements in some cases

Wardlaw et al. Clin Exp Allergy 2005;35:1254-1262.

Page 12: Severe asthma Pathophysiology and treatment

Severe asthma: TH2-type inflammation + ?

Persistent inflammation despite corticosteroid therapy

Page 13: Severe asthma Pathophysiology and treatment

Louis et al. Am. J. Respir. Crit. Care Med. 161: 9-16

IS inflammatory cells in asthma according to the severity

Page 14: Severe asthma Pathophysiology and treatment

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 ?

Page 15: Severe asthma Pathophysiology and treatment

Jakanon AJRCCM 1999

Controls/mild/moderate/severe

Neutrophils and severe asthma

Page 16: Severe asthma Pathophysiology and treatment

Wenzel et al. AJRCCM 1999;160:1001

Remodeling in severe asthma

Page 17: Severe asthma Pathophysiology and treatment

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.

Page 18: Severe asthma Pathophysiology and treatment

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.

Page 19: Severe asthma Pathophysiology and treatment

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].

Page 20: Severe asthma Pathophysiology and treatment
Page 21: Severe asthma Pathophysiology and treatment

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.

Page 22: Severe asthma Pathophysiology and treatment

Smoking and asthma: clinical consequencesSmoking 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

Page 23: Severe asthma Pathophysiology and treatment

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

Page 24: Severe asthma Pathophysiology and treatment

Extensive sinus disease (n = 21)

Limited sinusdisease (n = 68) P value

Age (y)* 50.4 ± 14.8 42.7 ± 13.1 .02

Female sex (%) 61.9 69.1 .54

Age at onset of asthma (y)† 35.0 (1.0-63) 11.5 (0.5-68) <.001

Asthma duration (y)† 12.0 (2-43) 23 (2-63) .01

Maintenance oral steroids (%) 38.1 26.9 .33

Nasal corticosteroids (%) 57.1 30.9 .03

Dose ICS (µg/d)† 1600 (1600-3600) 1600 (1600-6400) .50

Smoking history (pack-years)† 1 (0-10) 0 (0-10) .09

History aspirin/NSAID sensitivity 4/5 6/19 .05

Positive atopic status (%) 47.6 63.2 .20

ICS, Inhaled corticosteroids, beclomethasone equivalent; NSAID, nonsteroidal anti-inflammatory drug. *Mean ± SD †Median (range).

Ten Brinke et al. JACI 2002;109:621-626.

Characteristics of patients with severe asthma with and without extensive sinus disease

Page 25: Severe asthma Pathophysiology and treatment

Comparative airway inflammatory and clinical features in asthmatic patients with or without polypoid rhinitis

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ANP -

A +

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•p < 0,05 vs ANP +Results are presented as means

ACSS SCORE

Page 26: Severe asthma Pathophysiology and treatment

Associations with infections

Mycoplasma Pneumoniae

Chlamydia Pneumoniae

Viral infections– Rhinovirus– Adenovirus– RSV

Sinusitis

Page 27: Severe asthma Pathophysiology and treatment

Possible reasons for steroid “resistance”

Eosinophilic inflammation unresponsive to CS

- Lymphocytic process unresponsive to CS ( Altered transcription factor binding, Increased GCR 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

Page 28: Severe asthma Pathophysiology and treatment

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

Page 29: Severe asthma Pathophysiology and treatment

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

Page 30: Severe asthma Pathophysiology and treatment

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

Page 31: Severe asthma Pathophysiology and treatment

Evaluation of severe asthma1) 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

Page 32: Severe asthma Pathophysiology and treatment

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

Page 33: Severe asthma Pathophysiology and treatment

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.

Page 34: Severe asthma Pathophysiology and treatment

Subject demographics and medication use

Demographics Mild (n=164)

Moderate (n=70)

Severe(n=204) P value

 Current age (y) 31 ± 12 38 ± 12 41 ± 13 <.00001‡

 Age of asthma onset (y) 15 ± 13 18 ± 15 16 ± 16 .37

 Asthma duration (y) 17 ± 11 20 ± 14 25 ± 14 <.0001*

 Sex (% female) 72% 56% 64% .05

 Race (% white/African American/other)

69/25/6 66/29/5 67/26/7 .92

‡ 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.

Page 35: Severe asthma Pathophysiology and treatment

Asthma medications Mild (n=164)

Moderate (n=70)

Severe(n=204) P value

 ICSs#     58% 100% 98% <.0001‡

 OCSs#   0% 0% 32% ND

 LABAs§ 48% 80% 89% .001*

 Leukotriene modifiers 22% 26% 51% <.0001†

 Omalizumab 0.1% 0% 12% <.0001†

 Theophyllines 0% 4% 18% <.0001

 Anticholinergic agents 4% 6% 20% <.0001†

Subject demographics and medication use

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

Page 36: Severe asthma Pathophysiology and treatment

Clinical characteristics of subjects

Mild n Moderate n Severe n P value

Baseline lung function 164 70 204

 FEV1 % predicted 94 ± 11 66 ± 11 62 ± 22<.0001‡

 FVC % predicted 100 ± 12 81 ± 13 77 ± 20 <.0001

 FEV1/FVC (%) 80 ± 7 67 ± 10 65 ± 13 <.0001‡

Best lung function 157 60 185

 FEV1 % predicted 102 ± 11 79 ± 12 77 ± 21 <.0001‡

 FVC % predicted 103 ± 13 91 ± 14 91 ± 18 <.0001‡

 Maximal % change in FEV1 9 ± 7 20 ± 16 20 ± 24 <.0001‡

Methacholine PC20 (log

mg/mL).24 ± .62 133 −.11 ± .54 46 −.06 ± .70 87 .0002‡

FeNO (ppb) 42 ± 48 120 45 ± 39 55 40 ± 38 135 .72

Blood eosinophils (log) −.72 ± .42 151 −.63 ± .46 63 −.75 ± .51 180 .19

Total serum IgE (log) 2.0 ± .75 151 2.1 ± .63 63 2.0 ± .76 159 .44

≥1 positive skin test (%) 85% 164 87% 70 71% 204 .0007†

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

Page 37: Severe asthma Pathophysiology and treatment

Frequency of ATS severity§ criteria by disease severity

Mild (n = 164)

Moderate (n = 70)

Severe (n = 204)

P value

Major criteria

 OCSs for ≥50% of year 0.6% 0% 32% ND

 High-dose ICSs 0% 0% 98% ND

Minor criteria

 Daily 2nd controller medication 52% 79% 94% <.0001*

 Daily SABA‡ 27% 44% 75% <.0001*

 Persistent airflow obstruction§ 0% 100% 78% ND

 ≥1 urgent care visits/y 16% 31% 54% <.0001*

 ≥3 OCS bursts/y 5% 13% 54% <.0001†

 Deterioration with reduced corticosteroids

32% 60% 78% <.0001*

 Near-fatal event in the past 4% 6% 23% <.0001†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.

Page 38: Severe asthma Pathophysiology and treatment

Clinical Characteristics of Severe Asthma

Eosinophil (-) (n = 14)

Eosinophil (+)

(n = 20)p Value

Age, yr* 28 ± 3 34 ± 3 0.22

M/F 7/7 8/12 0.68

Cauc/AA + Hisp 12/2 16/4 0.67

Asthma duration, yr*

22 ± 3 19 ± 3 0.51

Steroid dose, mg/d*

27 ± 4 29 ± 5 0.85

Intubation (Y/N) 1/13 12/8 0.004

*Values are mean ± SEM. Wenzel et al. AJRCCM 1999;160:1001-1008.

Page 39: Severe asthma Pathophysiology and treatment

Holgate and Polosa. Lancet 2006;368:780-793.

Diseases that mimic asthma

• Bronchiectasis

•Constrictive bronchiolitis

•COPD

•CHF

•Dysfunctional breathlessness

•Vocal cord dysfunction

•Upper airway obstruction

•ABPS

•Chung-Strauss syndrome

•Eosinophilic pneumonia

•Thyrotoxicosis

• Chronic rhinosinusitis

•Gastro-oesophageal reflux

•Anxiety, panic-fear, depression

•Dysfunctional breathlessness

•Vocal cord dysfunction

•Obesity

•Obstructive sleep apnoea

• Occupational exposure

•Domestic irritants

•Respiratory infections

•Drugs (aspirin, NSAIDs, ACE inhibitors, ß blockers)

•Food (eg, sulphite sensitivity)

•Smoking

•Inflammed upper airways

•Acid reflux

•Stress

Conditions associated

with asthma

Unusual asthma triggers

Page 40: Severe asthma Pathophysiology and treatment

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.

Page 41: Severe asthma Pathophysiology and treatment
Page 42: Severe asthma Pathophysiology and treatment

Treatment of severe asthma

• Methotrexate• Gold salts• Cyclosporin• IV IG

• Anectodal evidences• Marginal effects• Side-effects ++• Cost (IV IG)

Page 43: Severe asthma Pathophysiology and treatment

Asthma: targets for treatment

J Allergy Clin Immunol 2000;106:5

Page 44: Severe asthma Pathophysiology and treatment

The Allergic Cascade isInterrupted by Omalizumab

B-cell

IgE

Omalizumab complexeswith free IgE

Omalizumab Mast cell

Allergen-driven B-cell secretes IgE

FcRI

Page 45: Severe asthma Pathophysiology and treatment

Reductions in Exacerbations with Omalizumab in High-risk Asthma

Holgate S, et al: Curr Med Res Opin 2001; 17(4):233-40. 254 patients pooled from studies 008 and 009

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Page 46: Severe asthma Pathophysiology and treatment

QoL significantly improved overalland across all domains

0,46

0,57

0,40,44 0,46

AQLQ score (change from baseline, LSM)Omalizumab

Placebo

*p=0.002; **p<0.001AQLQ = Asthma Quality of Life Questionnaire; LSM = Least Squares Mean

0.91**

0.9**

0.95* 0.89

**

0.91**

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0.6

0.4

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Page 47: Severe asthma Pathophysiology and treatment

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

Page 48: Severe asthma Pathophysiology and treatment

Berry et al. NEJM 2006

Page 49: Severe asthma Pathophysiology and treatment
Page 50: Severe asthma Pathophysiology and treatment

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