• Information
  1. Introduction
  2. Definitions
  3. Diagnosis
  4. Differential Diagnosis
  5. Treatment Overview
  6. Current Recommendations for Chronic Asthma Control

A. Introduction

1. Chronic reversible obstructive airways disease
   1. Inflammation of bronchi and bronchioles
   2. Potential for progressive decline in pulmonary function
2. About 5% of USA population is affected, both sexes equally
   1. Thus, about 10 million persons in USA have some kind of asthma
   2. About 5 million of these are children
   3. About 2/3 of all asthma cases are classified mild
3. Asthma typically begins in childhood
   1. About 50% of children outgrow asthma
   2. The other 50% develop persistent asthma
   3. However, asthma death rates have increased over time
4. Adult onset asthma usually accompanies moderate to severe allergy (atopy)
5. Selected Asthma Societies
   1. National Asthma Education and Prevention Program 301-251-1222
   2. Asthma and Allergy Foundation of America 800-727-8462
   3. American Academy of Allergy, Asthma and Immunology 800-822-2762
   4. American College of Allergy, Asthma and Immunology 800-842-7777

B. Definitions

1. Components Required for Asthma Diagnosis
   1. Reversible airway obstruction
   2. Airway hyperreactivity
   3. Airway inflammation
2. Histological Correlates
   1. Bronchial mucosal infiltration by eosinophils, macrophages, lymphocytes
   2. Macrophages and eosinophils activated by IgE
   3. Chronic eosinophilic bronchitis - asthma
3. Classification [1,3]
   1. Mild Intermittant - symptoms <3 days/week, FEV1 >80% of predicted (normal)
   2. Mild Persistent - symptoms >2 days/week, nocturnal 3-4/month, FEV1 >80%
   3. Moderate - daily symptoms, nightly symptoms more than weekly, FEV1 60-80%
   4. Severe - continuous symptoms, frequent exacerbations, frequent nocturnal, FEV1 <60%
   5. Specific asthma precipitant syndromes: exercise induced, cold-induced, allergic, others
4. Asthma Syndromes
   1. Intrinsic Asthma - usually begins later in life, lack of allergic diathesis
   2. Extrinsic Asthma - atopy; allergic, specific predisposing stimuli
   3. Exercise Induced Asthma (EIA)
   4. Cold Induced Asthma
   5. Triad Asthma
   6. Occupational (Industrial) Asthma
   7. Cough variant asthma is not uncommon
   8. Asthma exacerbated by gastroesophageal reflux disease (GERD; see below)
5. Exercise Induced Asthma (EIA)
   1. Persons with airway reactivity can develop bronchoconstriction with physical activity
   2. Associated with fluxes of heat and water within bronchial tree
   3. Role of inflammatory mediators is controversial
   4. Airway obstruction may begin just after completion of exercise
6. Triad Asthma
   1. Triad of: Nasal polyps (with sinusitis), aspirin allergy, asthma
   2. Yellow food dye and bisulfite allergies are very common
   3. Urticaria may occur
   4. Leukotrienes may be particularly important in pathogenesis
   5. Patients should receive glucocorticoids prior to removal of polyps
   6. This can help prevent anaphylactic reactions which can occur with polyp removal
7. Life-Threatening Asthma Episodes
   1. Clear inducers of fatal or near-fatal episodes are poorly quantitated
   2. Air pollution, emotional upsets, and inappropriate therapies all contribute
   3. Unclear role for indoor pollution and occupational exposures
   4. Insufficient treatment of early parts of fatal/near-fatal episodes likely most important
   5. Deaths related to tranquilizers, sedatives, and ß-blockers are well documented

C. Diagnosis

1. Usually based on symptoms
   1. These include wheezing, shortness of breath, cough
   2. Symptoms correlate poorly with severity of bronchospasm or bronchial hyperreactivity
   3. Patients at highest risk for asthma deaths have decreased early symptoms
   4. Goal of diagnosis is to objectively measure severity of bronchospasm
   5. However, pulmonary function tests are generally essential in all evaluations
2. History
   1. Family History
   2. Exposure to cigarette and other smoke
   3. Allergies, especially to aspirin or environmental factors
3. Physical Findings
   1. Inspiratory and expiratory wheezing
   2. Accessory muscle use and pulsus paradoxicus (often without wheezing) in severe flare
   3. Hyperinflation by examination and on chest radiograph
   4. The physical exam is of limited utility in determining degree of bronchospasm
   5. Thus, physical exam should rarely, if ever, be used as sole means of evaluation
4. Pulmonary Function Tests (PFTs)
   1. Very helpful for diagnosis and for quantifying level of bronchospasm
   2. However, PFTs can remain abnormal long after recovery from flare
   3. Reduction in FEV1 (obstructive defect) is most common finding
   4. Reduction in FEV1/FVC ratio
   5. Mean maximal flow rate (MMF) is more sensitive test for asthma than FEV1/FVC
   6. Increased lung volumes
   7. Normal or increased DLCO
   8. Peak expiratory flow (PEF) determination - normal is usually >500L/min
   9. PEF may be best means of evaluating severity of bronchospasm and for home monitoring
5. Bronchial Provocation
   1. Methacholine or histamine challenge is most sensitive test for asthma
   2. Cough variant asthma may be suggested with positive methacholine test [4]
   3. Varification of asthma usually depends on response to ß-adrenergic agonists
6. Other Testing
   1. Chest Radiograph - rule out underlying pneumonia, edema
   2. Blood Counts - especially for eosinophils
   3. Arterial Blood Gas (ABG) - increased A-a Gradient
   4. Serum level of IgE
   5. Dermal Hypersensitivity to various antigens (RAST, questionable usefulness)
7. Asthma should classified by severity and treated appropriately (see above)
8. Acute asthma attacks must be treated aggressively and considered potentially fatal

D. Differential Diagnosis

1. Asthma Subclassifications (as above)
2. Bronchospasm Associated Conditions
   1. Non-bacterial (usually viral) upper-respiratory infection (URI)
   2. Chronic Sinusitis
   3. Post-nasal drip syndromes (such as allergies, others)
   4. GERD
   5. Pulmonary edema ("cardiac asthma")
3. Churg-Strauss Syndrome
4. Allergic Bronchopulmonary Aspergillosis (ABPA)
5. Chronic cough may be associated with asthma, GERD, or post-nasal drip
6. Churg-Strauss Vasculitis Syndrome [5]
   1. Combination of severe asthma, eosinophilia, hyper-IgE production and vasculitis
   2. ANCA related, polyarteritis nodosa-type leukocytoclastic vasculitis
   3. Patients usually with allergies (atopy) as well
   4. Consider in patients with refractory asthma, particularly with eosinophilia

E. Treatment Overview [2,3,6]

1. Goals in Children (Box in Ref [1])
   1. Prevent chronic and troublesome symptoms
   2. Prevent acute exacerbations leading to professional healthcare intervention
   3. Maintain healthy activity levels
   4. Prevent nocturnal symptoms
   5. Maintain normal pulmonary function
   6. Optimal pharmacotherapy with minimal or no adverse effects
   7. Meet expectations of patient and family
2. Both acute and chronic therapies are used
   1. Acute therapy focuses on bronchodilation for immediate effects
   2. Acute therapy of moderate or severe attacks also uses glucocorticoids
   3. Chronic therapy includes inhaled glucocorticoids or mast cell stabilizers
   4. Chronic low-dose inhaled glucocorticoids associated with reduced risk of asthma death []
   5. Chronic therapy also includes treating allergies, removing/avoiding initiating factors
   6. Goal is chronic asthma therapy is to prevent asthma exacerbations
   7. Patients with moderate and mild asthma are currently reasonably well managed
   8. Patients with severe asthma require chronic systemic glucocorticoids and do less well
   9. At the present time, there are no good "steroid sparing" agents for asthma
3. Direct Bronchodilators
   1. ß2-agonists inhalants - mainstay of therapy
   2. Ipatropium Bromide (anti-cholinergic) - some efficacy when added to ß2-agonists
   3. Theophylline - strictly second line agent with synergistic activity
   4. Epinephrine - only for severe flares
4. Anti-Inflammatory Agents
   1. Glucocrticoids - inhaled and systemic
   2. Cromolyn compounds - cromolyn, nedocromil; block mast cell activation
   3. Leukotriene inhibitors (LTI) - zafirlukast or monteleukast
   4. Theophylline may have some anti-inflammatory activity
   5. Antihistamines and cyclooxygenase inhibitors are generally ineffective
5. Glucocorticoids
   1. Inhaled highly preferable to systemic glucocorticoids
   2. Mainstay of therapy for moderate persistent and severe persistent asthma
   3. In children age 2-3 years at high risk for asthma, inhaled fluticasone did not change the development of asthma symptoms or lung function [12]
   4. Inhaled fluticasone for 2 years slightly and termporarily reduced growth [12]
   5. Inhaled budesonide for intermittent wheezing did not reduce progression to persistent wheezing in infants up to age 3 year [13]
   6. Thus, inhaled glucocorticoids provide symptomatic but not disease modifying benefits in infants
6. Treatment of Allergies
   1. Anti-Histamines may improve allergy and asthma symptoms
   2. Dust mite immunotherapy may improve asthma symptoms in some patients [7]
   3. Ragweed immunotherapy did not improve symptoms in allergic patients [8]
7. Peak Expiratory Flow Monitors
   1. Can be used to evaluate severity and modify treatment
   2. Best used in home setting for patients to chronically monitor bronchospasm level
   3. Unclear if any real benefit on long term outcomes [3]
8. Inactivated influenza vaccine is safe and beneficial; asthmatics should receive it [9]

F. Current Recommendations for Chronic Asthma Control

1. Mild Intermittent (Step 1)
   1. ß-2 adrenergic agonists should be used only prn if possible
   2. Cromylin Sodium (especially in children) or Nedocromil
2. Mild Persistent (Step 2)
   1. Daily anti-inflammatory: cromolyn or nedocromil or low-dose inhaled glucocorticoid
   2. LTI may also be used effectively in some cases
   3. Short-acting bronchodilator prn for symptoms
3. Moderate Persistent (Step 3)
   1. Daily anti-inflammatory: moderate dose inhaled glucocorticoid ± nedocromil
   2. Long acting ß-agonist or LTI may also be used
   3. Short-acting bronchodilator prn for symptoms
4. Severe Persistent (Step 4)
   1. Daily anti-inflammatory: high dose inhaled glucocorticoid + long acting ß2-agonist
   2. Alternative or additive: LTI and/or sustained release theophylline
   3. Oral Glucocorticoids should be used for persistent symptoms
   4. Taper oral glucocorticoids as expeditiously as possible while maintaining control
   5. Short-acting inhaled ß2-agonists should be continued prn
5. EIA
   1. ß2-agonists (usually short acting) for difficult to control symptoms
   2. Salmeterol (long acting ß2-agonist) is effectively for up to ~12 hours initially [10]
   3. However, the long duration of action of salmeterol is lost with chronic use [10]
   4. Cromylin compounds are effective also with essentially no side effects
   5. Montelukast (LT inhibitor) taken qd protects against EIA over a 12 week study [11]
6. PEF Meters may be useful for moderate and severe asthmatics to guide therapy

References

1. Wood RA. 2002. JAMA. 288(6):745
2. Busse WW and Lemanske RF. 2001. NEJM. 344(5):350
3. Naureckas ET and Solway J. 2001. NEJM. 345(17):1257
4. Irwin RS, French CT, Smyrnios NA, Curley FJ. 1997. Arch Intern Med. 157(17):1981
5. Thomson CC, Tager AM, Weller PF. 2002. NEJM. 346(6):438 (Case Discussion)
6. Kay AB. 2001. NEJM. 344(2):109
7. Weber RW. 1998. JAMA. 278(22):1881
8. Creticos PS, Reed CE, Norman PS, et al. 1996. NEJM. 334(8):501
9. American Lung Association. 2001. NEJM. 345(21):1529
10. Nelson JA, Strauss L, Skowronski M, et al. 1998. NEJM. 339(3):141
11. Leff JA, Busse WW, Pearlman D, et al. 1998. NEJM. 339(3):147
12. Guilbert TW, Morgan WJ, Zeigner RS, et al. 2006. NEJM. 354(19):1985
13. Bisgaard H, Hermansen MN, Loland L, et al. 2006. NEJM. 354(19):1998