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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

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severe asthma pathophysiology and treatment
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
synopsis
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
slide3

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 )
slide4

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

severe refractory asthma ats
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

definition of severe asthma
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 control why is asthma sometimes difficult to control
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
patterns of compliance to inhaled ics use vs prescribed

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

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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

phenotyping severe asthma
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.
slide10

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.

slide11

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.

slide12

Severe asthma: TH2-type inflammation + ?

Persistent inflammation despite corticosteroid therapy

slide13

IS inflammatory cells in asthma according to the severity

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

pathophysiology of severe asthma
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 ?
slide15

Neutrophils and severe asthma

Jakanon AJRCCM 1999

Controls/mild/moderate/severe

slide16

Remodeling in severe asthma

Wenzel et al. AJRCCM 1999;160:1001

airway remodelling 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
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
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
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 consequences
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
factors influencing asthma severity
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

slide24

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

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

slide25
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
associations with infections
Associations with infections
  • Mycoplasma Pneumoniae
  • Chlamydia Pneumoniae
  • Viral infections
    • Rhinovirus
    • Adenovirus
    • RSV
  • Sinusitis
possible reasons for steroid resistance
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

evaluation of severe asthma
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 asthma1
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 asthma2
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 asthma3
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

evaluation of severe asthma4
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
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.
slide34

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.

slide35

Subject demographics and medication use

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

slide37

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.

slide39

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.

management of severe asthma
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.
slide42

Treatment of severe asthma

  • Methotrexate
  • Gold salts
  • Cyclosporin
  • IV IG
  • Anectodal evidences
  • Marginal effects
  • Side-effects ++
  • Cost (IV IG)
asthma targets for treatment
Asthma: targets for treatment

J Allergy Clin Immunol 2000;106:5

the allergic cascade is interrupted by omalizumab
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

reductions in exacerbations with omalizumab in high risk asthma
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

qol significantly improved overall and across all domains

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

side effects
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

conclusions
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