ASTHMA UPDATE
From the 66th Annual Course, Allergy and Clinical Immunology, presented by University of Minnesota Medical School
Educational Objectives
| The goals of this program are to improve the management of asthma and prevent disease progression. After
hearing and assimilating this program, the clinician will be better able to:
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 | 1. Describe the 2 major components of asthma and discuss treatment approaches for each.
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| 2. Identify triggers for asthma and anticipate exacerbations.
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| 3. Assess disease severity and design a management plan based on classification.
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| 4. Discuss the role of adjustable therapy in asthma management.
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| 5. Increase compliance by educating patients about the importance of optimal asthma management.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Hagan
has a minor financial interest in Teva Pharmaceutical Industries. Dr Busse and the planning committee reported nothing
to disclose.
Acknowledgments
Drs. Hagan and Busse were recorded at 66th Annual Course, Allergy and Clinical Immunology, presented by University
of Minnesota Medical School, Department of Medicine, Pediatrics, Laboratory Medicine and Pathology, Asthma and
Allergy Program and Office of Continuing Medical Education, and held April 4, 2008, in Minneapolis, MN
| ASTHMA CONCEPTS AND DIAGNOSIS —John B. Hagan, MD, Assistant Professor of Medicine, and Consultant,
Division of Allergic Diseases, Mayo Clinic College of Medicine, Rochester, MN
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| Definition of asthma: chronic inflammatory disorder of airways that involves mast cells, eosinophils, T lymphocytes,
macrophages, neutrophils, and epithelial cells; inflammation causes recurrent episodes of wheezing, breathlessness,
chest tightness, and coughing (especially at night or early morning); obstruction of airflow widespread but variable,
and often reversible spontaneously or with treatment; various stimuli trigger bronchial hyperresponsiveness; lung
function may decrease irreversibly
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| Bronchospasm: bronchial hyperresponsiveness; smooth muscle around mainstem bronchus contracts and narrows bronchus,
reducing airflow (measured by spirometry); methacholine challenge—flow-volume curve generated as patient
takes deep breath then exhales for 6 sec; patient inhales methacholine then repeats maneuver; in susceptible individuals,
methacholine-induced bronchospasm alters flow-volume curve; reversal with albuterol may be incomplete
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| Inflammation: second component of asthma; does not respond to albuterol; involved with airway remodeling
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| Airway remodeling: case—man, 38 yr of age, with history of allergies (onset in adulthood) and complaints of
coughing and wheezing; forced expiratory volume in 1 sec (FEV1 ) 64% of normal, and improved 14% after albuterol
given (ie, FEV1 still relatively low); effects of chronic asthma—denuded epithelium (lining of bronchial lumen breaks
down and sloughs off; patient may cough up as yellow sputum); number of mucus glands may increase in chronic
asthma; changes in blood vessels; thickened reticular basement membrane (lamina reticularis; may occur in children
and adults; also may occur in patients with cough-variant asthma); changes in interstitial matrix, elastic fibers, collagen,
and proteins; increased vascularity, microvascularity, and vasodilation; reversibility—temporary reversal of
some effects may occur after inhaling corticosteroids; hyperplasia and hypertrophy—goblet cell hyperplasia and hypertrophy
of smooth muscle surrounding airway may occur
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| Diagnosis: recurrence of symptoms important; clinical features may be sufficient for diagnosis; diagnostic tests—
spirometry; methacholine challenge; exhaled nitric oxide (elevated); sputum eosinophils (present); bronchial biopsy
useful for determining phenotype
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| Triggers: case continued—exposure to cats triggers symptoms (including contact irritation and classic allergy
symptoms); skin test positive for cat allergy (specific IgE confirmed); ragweed allergy accounts for seasonal
symptoms
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| Allergic triggers: antigen challenge results in immediate reduction in FEV1 (may resolve when antigen removed);
some individuals also have late-phase reaction (≈8 hr after exposure), characterized by eosinophilic response
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| Other triggers: environmental factors; irritants (eg, tobacco smoke); exercise; cold air; emotion; viral infections;
drugs (eg, β-blockers; aspirin in some individuals); foods or food additives (eg, sulfites); viral infections—
increase among school-aged children in September (in Canada); virus transmitted to younger siblings and adults;
infection commonly triggers exacerbation of asthma symptoms, resulting in seasonal increase in asthma-associated
hospitalizations
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| Differential diagnosis: history aids diagnosis; differential includes chronic obstructive pulmonary disease, congestive
heart failure, pulmonary embolism, cough secondary to angiotensin-converting enzyme inhibitor, vocal cord dysfunction,
fixed airway obstruction (eg, subglottic stenosis), and eosinophilic pneumonia
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| Heterogeneity: asthma heterogeneous disorder; different phenotypes likely associated with different pathologies and responses
to treatment; phenotypes—fatal; exercise-induced; noncompliant; intrinsic; extrinsic; neutrophilic; others
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| Treatment: bronchospasm—short-acting bronchodilators (eg, albuterol, pirbuterol); long-acting bronchodilators (eg,
salmeterol; formoterol); anticholinergic agents; inflammation—inhaled corticosteroids (eg, mometasone; fluticasone,
budesonide, triamcinolone, beclomethasone); leukotriene inhibitors; cromolyns; anti-IgE (may reduce bronchospasm
and inflammation)
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| Assessment: symptoms (during previous 1-2 mo); clinical evaluations (eg, auscultation); Asthma Control Test
(www.asthmacontrol.com; patient responds to 5 questions, using 5-point scale); exhaled nitric oxide—potentially useful
for adjusting maintenance doses of inhaled corticosteroids; however, study failed to show reduced frequency of exacerbations
or reduction in total amount of inhaled corticosteroids used over 12 mo, compared to current guidelines;
sputum eosinophils—regular assessment (every 1-2 mo) helps guide treatment and reduce exacerbations
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| Anticipating problems: important to assess risk for serious complications and establish management plan; risk factors
for severe or fatal asthma—nocturnal awakenings (especially if frequency increases); unscheduled visits (related
to asthma) to health care provider; emergency department visits; asthma-related hospitalizations; intubation; overuse
of bronchodilator; chronic need for inhaled or systemic corticosteroids; repeated need for prednisone boost and taper
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| Treatment compliance: noncompliance common (20%-80%); yet, regular use of inhaled corticosteroids associated
with decreased rates of asthma-associated death; patient education and follow-up important
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| Response to inhaled corticosteroids: most patients with well-defined asthma respond, with progressive improvement
in FEV1 and bronchial hyperresponsiveness over 3 to 6 wk of use (but function and symptoms worsen within 2
wk if medications discontinued)
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| ASTHMA GUIDELINES —William W. Busse, MD, George R. and Elaine Love Professor, and Chair, Department of
Medicine, University of Wisconsin School of Medicine and Public Health, Madison
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| Role of guidelines: evidence-based recommendations apply to populations, but individualized approach necessary;
developing field of pharmacogenetics may help customize management for individuals; goals—provide evidence-
based consensus about diagnosis, assessment, treatment, and education (patients and clinicians); improve care (has resulted
in increased awareness of disease and increased patient awareness about what to expect from care); provide information
and interpretation to clinicians and patients
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| Classification of disease severity: determines initial treatment; levels of severity—intermittent; persistent (mild,
moderate, and severe); original demarcations (relatively arbitrary) recently modified to reflect level of impairment
and risk
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| Impairment: based on frequency of symptoms, nighttime awakenings, need for rescue medication, interference with
normal activity, and lung function
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| Risk: exacerbations (potentially life-threatening; affect quality of life; costly); disease progression and loss of lung
function; adverse effects from medications
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| Intermittent asthma: preferred treatment—short-acting β-agonist (step 1); exacerbations (eg, that occur with upper
respiratory infections) require additional treatment
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| Mild persistent asthma: preferred treatment—low-dose inhaled corticosteroids (step 2)
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| Evidence supporting use of inhaled corticosteroids: Inhaled Steroid Treatment as Regular Therapy in Early
Asthma (START) study randomized \>7000 patients to budesonide (200 µg/day for children ≤11 yr of age; 400 µg/day
for adults) or placebo; additional therapy added, as necessary, by primary health care provider; after 3 yr, all participants
received inhaled corticosteroids; results—budesonide associated with significantly more symptom-free days,
reduced need for short-acting β-agonist, and reduced risk for severe asthma-related event; of patients who experienced
asthma exacerbations, only those started on placebo had associated reduction in lung function (ie, budesonide appears
to prevent damage associated with exacerbations); implications—early treatment with inhaled corticosteroids may
prevent progressive loss of lung function in adults with asthma (effect not shown in children); early vs delayed initiation
of therapy—early intervention with inhaled corticosteroids associated with reduced need for other medications,
including long-acting β-agonists
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| Symptom-driven combination therapy: study design—all patients stabilized using beclomethasone (500 µg/
day), then randomized to 1 of 4 treatment arms; treatment arms—as-needed combination therapy (beclomethasone
plus albuterol); as-needed albuterol monotherapy; regular therapy with beclomethasone (bid, with albuterol as
needed); regular combination therapy (bid); results—≈95% of patients receiving as-needed combination therapy had
no asthma exacerbations; ≈90% of those using combination therapy regularly had no exacerbations; regular beclomethasone
no different from as-needed combination; no markers to indicate which patients will benefit from using
symptom-driven therapy
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| Moderate persistent asthma: step 3—medium-dose inhaled corticosteroids or low-dose inhaled corticosteroids
plus long-acting β-agonist; step 4—medium-dose inhaled corticosteroids plus long-acting β-agonist; long-acting β-
agonists—Salmeterol Multicenter Asthma Research Trial (SMART) raised concern that long-acting β-agonists may
increase risk among some patients with severe asthma; specific subpopulation at risk not identified; rates of hospitalization
and death have not increased (suggesting limited detrimental effect)
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| Optimal control: Gaining Optimal Asthma Control (GOAL) study addressed methods for and rates of achieving optimal
control of asthma; study design—step-wise therapy begins with fluticasone, 100 µg bid, or combination therapy
(50 µg fluticasone/100 µg salmeterol); doses of combination therapy increased, in step-wise manner, until
control achieved (or highest dose reached); phase 1 results—“well-controlled” asthma (very infrequent symptoms
or need for short-acting β-agonist) achieved in 65% to 70% of steroid-naive patients and in 30% to 50% of patients
with more severe asthma (previously treated with low- or high-dose corticosteroids); combination therapy more effective
than monotherapy for most patients; conclusions—disease severity affects ability to achieve optimal control
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| Benefits of achieving optimal control: reduced frequency of exacerbations (especially when combination therapy
used); fewer symptoms; response to corticosteroids—factors associated with exacerbations and airflow obstruction
likely different from those associated with symptoms; corticosteroid response differs for each; maintenance of
control—longer duration leads to additional benefit (fewer exacerbations, possibly due to reverse remodeling of
airways)
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| Adjustable therapy: compliance with aggressive therapy often difficult to achieve; adjustable approaches used in
Canada and Europe; study (O’Byrne et al, 2005)—randomized patients to high-dose budesonide plus short-acting β-
agonist, low-dose budesonide plus short-acting β-agonist, or low-dose budesonide plus long-acting β-agonist (formoterol;
combination used for maintenance and symptom relief); adjustable therapy (partly based on symptoms) with
budesonide and formoterol reduced severe exacerbations by ≈50%, compared to other approaches, and only slightly
increased average daily dose of inhaled corticosteroids; unanswered questions—mechanism of action (why does combination
improve control when doubling dose of corticosteroids does not?); patient selection (which patients most
likely to benefit from approach?)
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| Severe persistent asthma: new guidelines add 2 steps (5 and 6) to management scheme; patients have more severe
symptoms and airflow obstruction; step 5—high-dose inhaled corticosteroids plus long-acting β-agonist; step 6—
high-dose inhaled corticosteroids, long-acting β-agonist, plus low-dose systemic corticosteroids
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| Omalizumab: recommended for patients with severe persistent asthma; study—placebo-controlled trial; average age,
FEV1 , need for rescue medication, and clinical symptoms scores similar between treatment and control groups; patients
had some response to bronchodilators (may be important for patient selection); treatment with omalizumab
decreased exacerbations by ≈30%; mechanism of action—omalizumab decreases IgE levels, but baseline level of
IgE and degree of atopy may not determine responsiveness; patient selection criteria—positive skin test for ≥1 allergy;
IgE levels within defined range (important for determining dose); predictors of response—current beclomethasone
therapy (odds ratio for benefit, ≈1.9); FEV1 ≤65% of predicted (odds ratio, 1.15); emergency treatment for
asthma during previous 12 mo (odds ratio, 1.6); patients who have all 3 predictors most likely to have benefit (odds
ratio, 4.2); more research needed—to elucidate role of IgE in asthma; known that level of IgE related to severity of
disease, but method of interaction unknown; which patients most likely to respond to anti-IgE agents also unknown
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| Future directions: exhaled nitric oxide (eNO)—elevated in patients with uncontrolled asthma, and generally decreases
after initiating treatment with inhaled corticosteroids; eNO may not predict exacerbations, but does indicate
whether inflammatory process reduced and whether patient compliant with treatment; sputum eosinophils—presence
indicates high risk for exacerbation, but difficulty of technique limits utility in most practices; preventing
exacerbations—emerging data suggest exacerbations lead to progressive loss of lung function; preventing exacerbations
(by treating causes, eg, respiratory infections) important; preventing disease progression—elucidating pathophysiology
associated with impaired lung function may help direct therapy and prevent disease progression; defining
phenotypes—recognizing heterogeneity of disease, and defining phenotypes (and possibly genotypes) should lead to
more effective therapies; preventing asthma expression—identification of initiating events (which likely occur early in
life) may lead to therapies that mitigate expression
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Suggested Reading
Bateman ED et al: Rate of response of individual asthma control measures varies and may overestimate asthma control:
an analysis of the GOAL study. J Asthma 44:667, 2007; Busse WW et al: The Inhaled Steroid Treatment as Regular
Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in
mild persistent asthma. J Allergy Clin Immunol Apr 9, 2008 [Epub ahead of print]; Busse WW et al: Effect of omalizumab
on the need for rescue systemic corticosteroid treatment in patients with moderate-to-severe persistent IgE-mediated
allergic asthma: a pooled analysis. Curr Med Res Opin 23:2379, 2007; Cheng JW, Arnold RJ:
Pharmacoeconomic review of medical management of persistent asthma. Allergy Asthma Proc 29:109, 2008; Hanania
NA: Targeting airway inflammation in asthma: current and future therapies. Chest 133:989, 2008; Hashimoto S et al:
Viral infection in asthma. Allergol Int 57:21, 2008; O’Byrne PM: Acute asthma intervention: insights from the STAY
study. J Allergy Clin Immunol 119:1332, 2007; O’Byrne PM: Exacerbations of asthma and COPD: definitions, clinical
manifestations and epidemiology. Contrib Microbiol 14:1, 2007; Papi A et al: Rescue use of beclomethasone and albuterol
in a single inhaler for mild asthma. N Engl J Med 356:2040, 2007; Pauwels RA et al: Early intervention with
budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 361:1071, 2003; Schatz M: Pharmacotherapy
of asthma: what do the 2007 NAEPP guidelines say? Allergy Asthma Proc 28:628, 2007; Smith AD et al: Use
of exhaled nitric oxide measurements to guide treatment in chronic asthma. New Engl J Med 352:2163, 2005; Spencer
S et al: Validation of a guideline-based composite outcome assessment tool for asthma control. Respir Res 8:26, 2007;
Steiss JO et al: Reduction of the total IgE level by omalizumab in children and adolescents. J Asthma 45:233, 2008;
Woodcock AA et al: Improvement in asthma endpoints when aiming for total control: salmeterol/fluticasone propionate
versus fluticasone propionate alone. Prim Care Respir J 16:155, 2007.
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