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
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
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 )
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
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
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
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
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Lacasse , Boulet 2005
Regular compliance
Irregular compliance
Regular non-compliance
Irregular non-compliance
Patterns of compliance to inhaled ICSUse vs Prescribed
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.
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.
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.
Severe asthma: TH2-type inflammation + ?
Persistent inflammation despite corticosteroid therapy
Louis et al. Am. J. Respir. Crit. Care Med. 161: 9-16
IS inflammatory cells in asthma according to the severity
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 ?
Jakanon AJRCCM 1999
Controls/mild/moderate/severe
Neutrophils and severe asthma
Wenzel et al. AJRCCM 1999;160:1001
Remodeling in severe asthma
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.
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.
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].
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.
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
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
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
Comparative airway inflammatory and clinical features in asthmatic patients with or without polypoid rhinitis
0
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ANP +
ANP -
A +
A -
Clinical Physiological Inflammatory
*
***
•p < 0,05 vs ANP +Results are presented as means
ACSS SCORE
Associations with infections
Mycoplasma Pneumoniae
Chlamydia Pneumoniae
Viral infections– Rhinovirus– Adenovirus– RSV
Sinusitis
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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
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.
Treatment of severe asthma
• Methotrexate• Gold salts• Cyclosporin• IV IG
• Anectodal evidences• Marginal effects• Side-effects ++• Cost (IV IG)
Asthma: targets for treatment
J Allergy Clin Immunol 2000;106:5
The Allergic Cascade isInterrupted by Omalizumab
B-cell
IgE
Omalizumab complexeswith free IgE
Omalizumab Mast cell
Allergen-driven B-cell secretes IgE
FcRI
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
0,65 0,69
1,1
1,56
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All patients High-risk patients
Mea
n a
nn
ual
ized
ast
hm
a ex
acer
bat
ion
rat
e
Omalizumab Control
p<0.001
p=0.007
56%
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**
1.0
0.8
0.6
0.4
0.2
0Activities Emotions Symptoms Environment Overall
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
Berry et al. NEJM 2006
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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