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Asthma

. Christopher H. Fanta, M.D.

Partners Asthma Center
Brigham and Women’s Hospital
Harvard Medical School

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Defining Features of Asthma

  • Reversible airways obstruction;
  • Airway inflammation; and
  • Non-specific bronchial hyperresponsiveness

What Can Be Done to Reduce Airway Inflammation?

  • Protect against the inciters of inflammation
  • Treat with anti-inflammatory drugs


Allergic Sensitivity + Intense Allergen Exposure --> More Severe Asthma


Choices Among Anti-Inflammatory Drugs

  • Inhaled corticosteroids
  • Mast cell stabilizing drugs
    - Cromolyn
    - Nedocromil
  • Leukotriene modifying drugs


National Asthma Education and Prevention Program

Staging Asthma Severity

Expert Panel Report I
(1991)
Expert Panel Report II
(1997)
Mild Asthma Mild Intermittent Asthma
Moderate Asthma
Mild Persistent Asthma
Severe Asthma
Moderate Persist. Asthma
Severe Persistent Asthma


Mild (Persistent) Asthma

  • Symptoms of asthma > 2 times per week but fewer than once a day
  • More than two nocturnal awakenings per month
  • Peak flow measurements may vary by up to 30%


Inhaled Corticosteroids and the Risk of Death from Asthma

  • Nested case-control design.
  • 30,569 patients from Saskatchewan, ages 5-44, using anti-asthmatic drugs 1975-91.
  • 66 deaths, matched with 2681 controls
  • Risk of death decreased by 21% for each canister of ICS used in year prior to death.

Suissa S, et al. NEJM 2000; 343:332.


Benefits of Inhaled Corticosteroids

  • Improved lung function
  • Decreased bronchial hyperresponsiveness
  • Fewer asthmatic symptoms
  • Improved health-related quality of life
  • Fewer asthmatic exacerbations
  • Decreased risk of death or near-death from asthma


Inhaled Steroids and “Airway Remodeling” (?)

The Childhood Asthma Management Program:

  • 1051 children ages 5-12 with mild-mod asthma.
  • Treatment Groups: Budesonide 200 mg/day, Nedocromil 8 mg/day, or Placebo
  • Primary end-point: DFEV1 (% of predicted).
  • Finding: No difference between ICS and placebo over 4-6 years of follow-up.

NEJM 2000; 343:1054.


Relative Potency of Inhaled Steroids

  Relative Receptor
Blinding Affinity
Relative Skin
Blanching Potency
Beclomethasone 0.4 600
Triamcinolone 3.6
330
Flunisolide 1.8 330
Budesonide 9.4 980
Fluticasone 18.0 1200


Once-Daily Dosing of Inhaled Corticosteroids

In patients with mild persistent asthma, budesonide (Pulmicort®) has been approved for once-daily dosing.

Other inhaled corticosteroids can likely be used equally effectively in the same way.


Inhaled Corticosteroids and Risk of Ocular Hypertension

  • Database from prescription claims in Quebec for persons > 65 years old
  • Approx. 10,000 cases of ocular hypertension or open-angle glaucoma treated by ophthalmologists and 38,000 controls without these diagnoses
  • Percent of cases using inhaled steroids (2.8%) no different than percent of controls (2.7%)
  • An increased risk of ocular hypertension or open-angle glaucoma was found among persons who had used high-dose inhaled steroids continuously for last 3 months or longer (relative risk = 1.44).
  • High-dose inhaled steroids:
    - Beclomethasone > 32 puffs/day;
    - Beclomethasone DS > 16 puffs/day;
    - Triamcinolone > 16 puffs/day; and
    - Flunisolide > 6 puffs/day

Garbe E, et al., JAMA 1997;277:722


Reported Adverse Effects of Regular Beta-Agonist Use

  • Worse asthma control
  • Increased risk of death or near-death due to asthma
  • Accelerated decline in lung function


Comparison of Regularly Scheduled with As-Needed Use of Albuterol in Mild Asthma

Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE, Lazarus SC, Lemanske RF, Martin RJ, Peters SP, Sorkness C, Szefler SJ for the National Heart, Lung and Blood Institute’s Asthma Clinical Research Network

255 patients followed for 16 weeks
No difference found between groups for:

  • Morning peak flow
  • Peak flow variability
  • FEV1
  • Airway responsiveness (PC20)
  • Supplemental albuterol
  • Asthma symptoms
  • Quality of life

NEJM 1996;335:841

Salmeterol vs. High-Dose ICS.
(Greening et al., Lancet 1994;344:219)

  • 426 patients at 99 general practitioner centers
  • Symptomatic despite BDP 400 µg/day
  • Randomized to:
    BDP 400 µg/day plus salmeterol 50 µg BID
    vs. BDP 1000 mg.day
  • Double-blind, double-dummy 6 months trial

Actions of Leukotrienes

  • Potent and sustained bronchoconstriction
  • Mucus hypersecretion
  • Edema formation
  • Eosinophil chemoattraction

Leukotriene-Modifying Drugs

  • Leukotriene receptor blockers
    - Zafirlukast (Accolate®)
    - Montelukast (Singulair®)

  • Lipoxygenase inhibitor
    - Zileuton (Zyflo®)

Fluticasone/Salmeterol Combo vs Fluticasone plus Montelukast

Study Design:

  • 3-week run-in period on FP 100 µg BID by DPI
  • Patients still symptomatic with FEV1 50 – 80%
  • 447 patients randomized to FP/Salm Combo (plus placebo) vs. FP plus montelukast 10 mg
  • 12-week trial with primary outcome: a.m. PEFR

Nelson HS, et al. JACI 200; 106:1088.

Use of Leukotriene Blocking Drugs:.One Viewpoint

  • Aspirin-sensitive asthma
  • Mild-to-moderate asthma in persons fearful or intolerant of inhaled steroids
  • Patients with severe asthma on high-dose inhaled steroids
  • Steroid-dependent asthma


Overview of Asthma Therapy:.Prevention and Relief

Preventers (Controllers)
- Anti-inflammatory agents
- Long-acting bronchodilators
- Leukotriene blockers

Relievers
- Quick-acting bronchodilators
- Short course of oral steroids


Evolving Concepts of Asthma.Treatment: 2000s

  • Pathogenic Understanding
    - Asthma as Allergic Type-1 Immunologic Reaction Expressed in the Airways
  • Potential Therapeutic Implications:
    - Anti-IgE Monoclonal Antibody
    - Interleukin 4 soluble receptor
    - Adhesion molecule antagonists
    - Interruption of TH-2 co-stimulation pathways


Principles of Care

  • Principle goal: rapid reversal of airflow obstruction
  • Repetitive administration of inhaled beta-agonists
  • Early addition of systemic corticosteroids
  • Correction of hypoxemia
  • Close monitoring, including serial measurements of lung function


Bronchodilator Efficacy Study
Mean Change in Ventricular Rate at 15 Minutes and Glucose &
Potassium One Hour After First Dose (Week 0)

Treatment
Mean
Change in
Ventricular
Rate (bpm)
Mean
Change in
Glucose
(mg/ dL)
Mean
Change in
Potassium
(mEq/L)
Levalbuterol
0.63 mg (n=72)
2.4*
4.6
-0.2*
Levalbuterol
1.25 mg (n=73)
6.9
10.3
-0.3
Racemic albuterol
2.50 mg (n=74)
5.7
8.2 -0.3
Placebo
(n=75)
-2.8*
-0.2* -0.2*

Nelson HS, et al., JACI, Dec. 1998, 943-952. *p<0.05 vs Rac. Alb. 2.50 mg

Oral vs. Intravenous Corticosteroids

When given in comparable doses, there is no difference in efficacy between oral and intravenous corticosteroids for acute, severe asthma.

References:
Harrison BD, et al. Lancet 1986; 1(8474):181-4
Jonsson S, et al. Chest 1988; 94:732-6
Ratto D, et al. JAMA 1988; 260:527-9
Barnett PL, et al. An Emerg Med 1997; 29:212-7

Risk Factors for Fatal Asthma

  • Prior intubation/ICU care for asthma
  • Multiple hospitalizations/E.D. visits for asthma
  • Persistent severe airflow obstruction
  • Poverty/Inner-city residence/Persons of color
  • Depression/Psychosis


Preventive Strategies

  • Early recognition of deterioration
  • Prompt patient-provider communication
  • Written “asthma action” plan
  • Intensification of anti-asthma medications, often including a short course of oral corticosteroids

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