A. Introduction

1. Chronic obstructive airways disease with reversible component
   1. Inflammation of bronchi and bronchioles
   2. Potential for progressive irreversible decline in pulmonary function
2. About 5% of USA population is affected, both sexes equally [3]
   1. Thus, about 10 million persons in USA have some kind of asthma
   2. About 2/3 of these persons have mild asthma
   3. About 10% of asthmatics have severe asthma with significant impairment [12]
   4. Asthma increased in children from 3.6% in 1980 to 5.8% in 2003; unclear causes [3]
3. Asthma typically begins in childhood [8]
   1. More than 50% of children outgrow asthma
   2. More than 25% of children with wheezing had persistence or recurrence into adulthood [8]
   3. Two years of inhaled fluticasone in children at high risk for asthma did not reduce development of asthma symptoms or lung function [13]
4. Adult onset asthma usually accompanies moderate to severe allergy (atopy)
5. Decline in Respiratory Function with Chronic Asthma
   1. Estimated that there is ~50% increase in decline in FEV1 at age 60 with asthma
   2. Thus, normal FEV1 age 60 for 1.75 meter man is ~3 liters
   3. FEV1 found in chronic asthmatic men at age 60 was ~2 liters
6. Asthma Mortality
   1. In 1989-1991, 5000 deaths were due to asthma (~1:2000 persons with disease)
   2. Strong correlation of mortality rates with demographics
   3. Poor inner-city minorities have the highest rates, males > females
   4. Household income alone correlates poorly with death rates from asthma
   5. Inner city households have highest rates
   6. Nearly half of all asthma deaths occur in hospitals
   7. Asthma deaths have increased over time
7. 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 [1,2]

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 / Severity [5,12]
   1. Intermittant - symptoms less than weekly, FEV1 >80% of predicted
   2. Mild - symptoms less than once daily, may have nocturnal symptoms, FEV1 >80%
   3. Moderate - daily symptoms, nightly symptoms more than weekly, FEV1 60-80%
   4. Severe - continuous symptoms, frequent exacerbations, frequent nocturnal, FEV1 <60% with resistance to high dose inhaled glucocorticoids [4,12]
   5. Specific asthma precipitant syndromes: exercise induced, cold-induced, allergic, others
   6. Most mild-moderate asthma associated with atopy (allergy)
4. Asthma Syndromes
   1. Intrinsic Asthma - usually begins later in life, lack of allergic diathesis
   2. Extrinsic Asthma - atopy; allergic, specific predisposing stimuli, usually begins early age
   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) [2]
   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 (LT) may be particularly important in pathogenesis
   5. Linked to elevated cysteinyl LT receptor (CysLT1) expression [7]
   6. Patients should receive glucocorticoids prior to removal of polyps
   7. 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. Pathophysiology [7]

1. Overview [7]
   1. MIld-moderate asthma is a disease of airway inflammation, bronchial hyperresponsiveness
   2. Severe (refractory) asthma includes fixed airway obstruction and tissue remodeling
   3. Early and late phases of airway dysfunction due to inflammation occur
   4. Early phases include smooth muscle mediated bronchoconstriction
   5. Eosinophils, mast cells, basophils
   6. Acute bronchoconstriction in adults usually triggered by environmental factors
   7. Picornavirus, adenovirus, rhinovirus are likely triggers for many acute asthma attacks [12,37]
   8. Viruses induce production of inflammatory mediators that trigger bronchoconstriction
   9. Late phase is inflammatory: leukocyte infiltration, increased capillary permeability
   10. Sloughing of epithelial cells and airway plugging with debris and mucus also occur
   11. In mild-moderate asthma, these changes are essentially reversible
2. Severe Asthma [12]
   1. Usually defined functionally as daily symptoms with required oral glucocorticoids
   2. Chronic inflammation with poor clearance of triggering agents
   3. This leads to bronchial epithelial damage, increase in neutrophils, tissue remodeling, thickened airways, and irreversible (fixed) defects
   4. Smooth muscle proliferation occurs over time, may be glucocorticoid resistant [40]
   5. Exposure to tobacco and other smoke increases neutrophil response and glucocorticoid resistance
   6. Some link with asthma risk and severity with certain haplotypes, including the glycine-16 ß2-adrenergic receptor polymorphism [29]
   7. Association with polymorphisms in ADAM33 protein, involved in tissue remodeling
   8. Histopathology is chronic inflammation with scarring, increased TNFa and TGFß
   9. "Wound healing" phenotype is found in many patients
3. Infections and Immune Response
   1. Various kinds of infections early in childhood may reduce risk of asthma [3]
   2. This may be due to early "bias" of the immune system to Th1 cytokine production
   3. Exposure of young children to other children (especially daycare) reduces risk of developing asthma by 20-60% [9]
   4. Animals in the house can also reduce risk of developing asthma
   5. Exposure to cat allergen can produce IgG4 antibody responses rather than IgE which may be a form of protective or tolerizing Th2 response [10]
   6. House dust mite sensitization was major risk for developing asthma in children [10]
   7. Cold viruses (rhinoviruses and others), chlamydia and mycoplasma associated with asthma exacerbations and severity [12]
   8. Exposure to farming during age <1 associated with 1% asthma versus 11% controls [11]
4. Smooth Muscle Bronchoconstriction
   1. Histamine
   2. Cysteinal leukotrienes (LTs): LT-C4, -D4, -E4 (see below)
   3. Prostaglandins - increased risk with specific prostanoid receptor variants [41]
   4. Neurokinin A
   5. Calcitonin gene related peptide
   6. Bradykinin
   7. Thromboxane A2
   8. Nitric oxide
5. Mucosal Edema
   1. Histamine
   2. LTC4, D4, E4 bind CysLT1 receptor
   3. Substance P (binds NK1 receptor)
   4. Platelet Activating Factor (PAF)
   5. Bradykinin
6. T Cell Derived Inflammatory Mediators [7,12]
   1. T cells may be triggered initially by viral infections, especially bronchial epithelium
   2. Type 2, CD4+ T helper cells (Th2) appear to be central to development of asthma
   3. The Th2 cytokines may be produced mainly by "natural killer CD4+ T cells" [6]
   4. These natural killer CD4+ T cells have invariant T cell receptor and recognize glycolipid antigen in association with CD1d [6,21] but are probably not increased in asthma [45]
   5. The Th2 cells produce IL4, IL5, IL13, and GM-CSF
   6. IgE, eosinophils and mast cells are stimulated by products of Th2 cells
   7. IL12B promotor polymorphism may contribute to asthma severity [33]
   8. Elevated YKL-40 (chitinase-like protein associated with Th2 cells) levels in serum and lung tissue in severe asthma [25]
7. IgE
   1. A subset of asthmatics have high IgE levels
   2. Increased IgE is likely due to effects of IL4
   3. Th2 bias: IL4 increases (and IFN gamma decreases) IgE production
   4. Increased serum IgE levels associated with bronchial hyperresponsiveness
   5. Possible link between bronchial hyperreactivity and high affinity IgE receptor alleles
   6. Cockroach and other allergies may strongly contribute to symptoms
   7. However, early exposure to house dust mite and cat allergens (IgE responses) in children does not increase the risk of developing asthma [16]
8. Leukocyte Infiltrates in Asthma
   1. Eosinophils, mast cells and macrophages primarily involved in mild-moderate asthma
   2. Neutrophils and Th1 stimulated CD8+ T cells appear in severe, refractory asthma [12]
   3. Increased eosinophils are likely due to effects of IL5, IL3, and GM-CSF
   4. Mast cell infiltation into smooth muscle likely important in pathogenesis [17]
   5. Increases in alveolar and bronchial macrophages also occur
   6. Cannot presently predict which patients have mast cell, eosinophil or IgE predominance
   7. Atopic patients with BHR often overexpress interferon gamma (Th1 cytokine) [42]
9. Eosinophils [18]
   1. IL5 appears to be the major stimulator of eosinophil generation in asthma
   2. Eosinophils are then attracted to tissues by chemokines
   3. Eotaxins (1,2,3) are most specific chemokines for eosinophil recruitment
   4. RANTES, MCP-3 and -4, MIP-1a, TARC MDC, and I-309 are also eosinophil attractants
   5. Platelet activation factor (PAF, a lipid) also increases eosinophil activity
   6. Leukotriene (LT) E4 also has eosinophil chemoattractant activity
   7. ICAM-1 may play a role in eosinophil homing and adhesion
   8. Inflamed bronchial epithelium upregulate ICAM-1
   9. Antibodies to ICAM-1 lower eosinophil binding
   10. Glucocorticoids are potent anti-eosinophilic agents
   11. Note that ß-adrenergic agonists and theophylline have no effects on eosinophils
   12. Anti-IL5 Ab reduce peripheral and sputum eosinophils but had no effect on asthma []
10. LTs
    [Figure] "Leukotriene Synthesis"
    1. Development of LT inhibitors (LTI) has shown clear role of LTs in asthma
    2. LTD4 and LTE4 stimulate eosinophil recruitment
    3. Aspirin allergies in setting of asthma, rhinosinusitis linked to elevated cysteinyl leukotriene receptor (CysLT1) expression [35]
    4. Both CysLT1 receptor and 5-lipoxygenase inhibitors are effective in asthma
    5. Novel FLAP inhibitors (protein which associates with 5-lipoxygenase) being developed
    6. LTI usually permit reductions in doses of other asthma treatments
    7. LTI may be particularly useful in patients with allergic and triad asthma
11. Nitric Oxide (NO) and Related Molecules
    1. NO levels are elevated in expired air from children with asthma
    2. NO may play a protective role in bradykinin mediated bronchoconstriction
    3. S-nitrosothiol is a naturally occurring bronchodilator
    4. S-nitrosothiol levels are reduced >90% in children with severe asthma versus normals
12. Tumor Necrosis Factor Alpha (TNFa) [12,15]
    1. Patients with severe, refractory asthma have increased TNFa and its pathway mediators
    2. Associated with neutrophil infiltrates, tissue remodeling
    3. Peripheral blood monocyte membrane-bound TNFa, TNFa receptor 1, and TACE increased
    4. Etanercept, a TNFa blocker, for 10 weeks lead to improvements in refractory asthma
13. Air pollution, including ozone and particulates, causes exacerbations in asthmatic children [20]
14. Breastfeeding does not affect risk of allergies, atopy, or asthma [34]
15. Asthma associated with reduced risk for diabetes mellitus type 1, vasculitis, rheumatoid arthritis (all T helper cell type 1 autoimmune diseases) [14]

D. 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. Carefully Assess Patients at High Risk for Asthma Death
   1. Highest risk patients have a history of ventilatory failure from asthma
   2. High risk for asthma deaths may have reduced perception of dyspnea
   3. Patients with blunted hypoxic drive have increased risk of death as well
3. History
   1. Family History
   2. Exposure to cigarette and other smoke
   3. Allergies, especially to aspirin or environmental factors
   4. GERD may exacerbate asthma
   5. Smoking significantly increases the decline in FEV1 due to chronic asthma
4. 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
5. 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
6. Bronchial Provocation
   1. Methacholine or histamine challenge is most sensitive test for asthma
   2. Cough variant asthma may be suggested with positive methacholine test
   3. Varification of asthma usually depends on response to ß-adrenergic agonists
7. 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)
   6. Serum YKL-40 levels may correlate with severity, progression (see above) [25]
8. Asthma should classified by severity and treated appropriately (see above) [1,2]
9. Acute asthma attacks must be treated aggressively and considered potentially fatal

E. 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 - Other Causes
   1. GERD
   2. Post-nasal drip
   3. Bronchiectasis
6. Churg-Strauss Vasculitis Syndrome [22]
   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

F. Treatment Overview [2,5,23]

1. 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 [24]
   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
   10. Adjusting therapy based on sputum eosinophil counts reduces exacerbations, hospitalizations [36]
2. Direct Bronchodilators
   1. ß2-agonists inhalants - short-acting for prn only; long-acting for control
   2. Ipatropium Bromide (anti-cholinergic) - some efficacy when added to ß2-agonists
   3. Theophylline (Aminophylline) - 2nd/3rd line agent; good nocturnal control
   4. Epinephrine - only for severe flares
3. Anti-Inflammatory Agents [39]
   1. Glucocrticoids - inhaled and systemic are the most effective anti-asthmatic agents [39]
   2. Cromolyn compounds - nedocromil, cromolyn; block mast cell degranulation
   3. Leukotriene receptor blockers (LTI) - montelukast or zafirlukast
   4. Theophylline also may have some anti-inflammatory activity
   5. Methotrexate - mild to moderate steroid sparing activity (questionable)
   6. Cyclosporin A - mild steroid sparing activity, may try in very severe patients
   7. Antihistamines and cyclooxygenase inhibitors are generally ineffective
   8. Early chronic inhaled fluticosone in preschool infants with wheezing did not prevent lung function decline or hyper-responsiveness [44]
4. Treatment of Allergies
   1. Anti-Histamines may improve allergy and asthma symptoms
   2. Dust mite immunotherapy may improve asthma symptoms in some patients
   3. Ragweed immunotherapy did not improve symptoms in allergic patients
   4. Anti-IgE antibody (omalizumab) treatment often effective in asthma with high IgE levels
   5. Anti-IgE antibody also improves symptoms, reduces medications, in severe asthma [4]
5. Peak Expiratory Flow (PEF) 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 [5]
   4. Doubling dose of inhaled glucocorticoid when peak flows begin to decline does not reduce risk of acute attack [38]
6. In patients with GERD, acid suppression improves asthma symptoms
7. Respiratory function declines with chronic asthma, so treatment is very important
   1. Average decline (normal aging) in FEV1 is 22mL per year in men without asthma
   2. Average decline in (smokers and nonsmokers) in FEV1 is 38mL per year with asthma
   3. In men, FEV1 at age 60 is ~3 liters without asthma versus ~2 liters with asthma
8. Inactivated influenza vaccine is safe and beneficial; asthmatics should receive it [27]

G. Acute Asthma Attacks

1. Physician and patient must decide if emergency room evaluation is required
2. Nearly all acute asthma attacks unresponsive to inhaled ß-agonists should be evaluated
3. Failure to treat acute attacks early and aggressively may lead to severe progression
4. Recommended Emergency Room Evaluation [28]
   1. Triage for patients with extremely severe disease (see below)
   2. Rapid, initial history, clinical and physical exams
   3. Albuterol nebulizer every 20 minutes x 3
   4. Ipatropium bromide (Atrovent®) nebulizer added to ß2-agonists may be beneficial
   5. Intravenous steroid bolus with taper in any subject requiring >1 nebulizer
   6. Evaluation at 60 minutes: consider discharge, further outpatient therapy, or hospitalize
   7. Aminophylline may be considered in severe cases
   8. If admitted to hospital, consider MICU for frequent observation, nebulization
   9. Attempt to determine if initiating factor is present (such as bronchitis, pollution)
5. In many asthma cases evaluated in emergency room, arterial blood gas is strongly advised
6. Chest radiography may be useful in patients to evaluate for pneumonia, etc.

H. Severe Asthma Attack [19]

1. Characteristics
   1. Wheezing, which depends on moderate air flow, may be minimal or absent
   2. Use of accessory breathing muscles
   3. History of multiple emergency department admissions
   4. Peak expiratory flow <60% of predicted
   5. Arterial pO2 <60mm and/or pCO2 >40mm (that is, normal or increased)
   6. Many cases of severe asthma exacerbations should be treated in intensive care unit
2. Ascertain if history of intubation or use of epinephrine
3. Immediate oxygen and ß2-agonist therapy
   1. Nebulization with ß2-agonist such as albuterol, metoproteranol, salbutamol
   2. Severe asthma impedes entrance of nebulized drug to small airways
   3. Intravenous salbutamol in children reduced hospital stay and oxygen requirements [30]
   4. Terbutaline sulfate SC or IV can also be used
4. Epinephrine SC 0.3cc of 1:1000 - avoid in heart disease, elderly
5. Solumedrol IV 80-125mg bolus (1-2mg/kg in children)
6. Aminophylline Load IV
   1. Bolus (4-6mg/kg IV) then IV drip (0.6mg/kg/hr)
   2. May be used in combination with iv ß-agonists, but increased tachycardia is common
   3. Better tolerated than epinephrine
7. Mechanical Ventilation should be used early as needed

I. Current Recommendations for Chronic Asthma Control

1. Mild Intermittent (Episodic; Step 1)
   1. Short-acting ß2-adrenergic agonists should be used only prn
   2. Cromylin Sodium (especially in children) or Nedocromil (Tilade®)
   3. If short-acting ß2-agonists required twice weekly, move to Step 2
   4. Intermittent inhaled budesonide (400µg/day) did not prevent progression from episodic to persistent wheezing in the first 3 years of life [26]
2. Mild Persistent (Step 2)
   1. Inhaled glucocorticoids are strongly recommended in adults
   2. Alternative: nedocromil or cromolyn (children) OR LTI OR long-acting ß2-agonists
   3. Short-acting ß2-adrenergic agonists prn
   4. If nocturnal symptoms problematic, use long-acting ß2-agonists or theophylline
3. Moderate Persistent (Step 3)
   1. Agents as above, including moderate dose inhaled glucocorticoids
   2. LTI may permit reduction in need for ß2-agonists or glucocorticoids
   3. Theophylline - overnight asthma attacks, poor respiratory function, Step 3
   4. Oral ß2-agonists - more side effects than theophylline, Step 3/4
4. Severe Persistent Asthma (Steps 3 and 4)
   1. High dose inhaled or (preferably) oral glucocorticoids
   2. Often in setting of bacterial exacerbation (bronchitis) or upper respiratory virus
   3. Steroid tapering after 10d 40mg/day prednisone is not required in most patients
   4. Tapering concern arises mainly with disease rebound
   5. Adrenal suppression not usually a problem with <10 day regimens
   6. Very reasonable to add a LTI which can reduce symptoms and/or glucocorticoid use
   7. Theophylline or oral long-acting ß2-agonists can be added
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 [31]
   3. However, the long duration of action of salmeterol is lost with chronic use [31]
   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 [32]
6. PEF Meters may be useful for moderate and severe asthmatics to guide therapy

Resources

Aa Gradient

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