Asthma Review of Pathophysiology and Treatment

Introduction n Chronic inflammatory disease of the airways n Most common childhood chronic disease n Affects ~4.8 million (CDC, 1995) n >100 million days of restricted activity n 470,000 hospitalizations/yr

Introduction n >5000 deaths annually –Highest in blacks ages n Hospitalizations highest in blacks & children

Pathogenesis and Definition n Key points –Chronic inflammatory disorder of the airways –Immunohistopathologic features < denudation of airway epithelium < collagen deposition beneath basement membrane < edema < mast cell activation

–Immunohistopathologic features < inflammatory cell infiltration –Neutrophils (sudden, fatal asthma) –Eosinophils –Lymphocytes n Airway inflammation (AI) contributes to hyperresponsiveness, airflow limitation, symptoms & chronicity

n AI causes types of airflow limitation: –Bronchoconstriction, edema, mucus plug formation, airway wall remodeling n Atopy is strongest predisposing factor for developing asthma

n Working definition of asthma (1995, NHLBI) –Asthma is a chronic inflammatory disorder of the airways in which many cells & cellular elements play a role (mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, & epithelial cells).

–In susceptible individuals, inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night/early morning. These episodes are associated with variable airflow obstruction often reversible spontaneously/treatment

n Child-onset asthma –Associated with atopy –IgE directed against common environmental antigens (house-dust mites, animal proteins, fungi –Viral wheezing Infants/children, allergy/allergy history associated with continuing asthma through childhood

n Adult-onset asthma –Many situations –Allergens important –Non-IgE asthma have nasal polyps, sinusitis, aspirin sensitivity or NSAID sensitivity –Idiosyncratic asthma less understood

n Adult-onset asthma –Occupational exposure < animal products, biological enzymes, plastic resin, wood dusts, metal < removal from workplace may improve symptoms although symptoms persist in some

Airway Inflammation & Lung Function n The cells that influence &/or regulate inflammation results in different types of AI: –Acute - early recruitment of cells –Subacute - cells activated to cause more persistent inflammatory pattern –Chronic - persistent level of cell damage & repair. Abnormal changes may be permanent

Airway Inflammation & Lung Function n Airway hyperresponsiveness –Exaggerated bronchoconstrictor response –Post exposure wheezing & dyspnea –Degree correlates to asthma severity –Measured by methacholine/histamine inhalation challenge or non-drug stimuli (cold, dry air)

n Airway hyperresponsiveness –Correlation to airway inflammation clear but complex < airway inflammation markers < tx. of asthma & modification of ai markers reduce symptoms & hyperresponsiveness

n Airflow limitation –Acute bronchoconstriction < IgE -dependent mediator release from mast cell (leukotrienes, histamine, tryptase, prostaglandins) < aspirin /NSAID < non-IgE response (cold air, exercise, irritants)

n Airflow limitation –Acute bronchoconstriction < stress - mechanisms ?? < Airway edema < mediators –increase microvascular permeability/ leakage –mucosal thickening & airway swelling < airway rigidity

n Airflow limitation –Chronic mucus plug formation < secretions & inspissated plugs < persistent airflow limitation in severe intractable asthma –Airway remodeling < irreversible component of airflow limitation secondary to structural airway matrix changes

n Airflow limitation –Airway remodeling < attributed to chronic, severe airway inflammation < early intervention with anti-inflammatory therapy suggests prevention of permanent airflow limitation

Measures of Assessment and Monitoring n Asthma diagnosis criteria –+ episodic symptoms of airflow obstruction –Airflow obstruction partially reversible –R/O alternative dx

n Techniques to establish diagnosis –History –Physical exam (resp. tract, skin, chest) –Spirometry to demonstrate reversibility –Additional studies : < evaluate alternative dx., ID precipitating factors < assess severity, ID potential complications n Asthma Specialist

n Differences from 1991 Expert Panel –Severity classifications: < mild intermittent < mild persistent < moderate persistent < severe persistent –Questions added to aid dx & assessment –Referral criteria refined –PEF diurnal variation recommendations

Severe Persistent Asthma n Symptoms –Continual –Limited physical activity –Frequent exacerbations –Frequent nighttime symptoms n Lung Function –FEV 1 or PEF < 60% of predicted –PEF variability >30%

Moderate Persistent Asthma n Symptoms –Daily symptoms –Daily use of inhaled short-acting beta 2 agonist –Exacerbations affect activity; > 2 X/wk; may last days –Nighttime symptoms >1 time/wk n Lung Function –FEV 1 or PEF > 60% - < 80% predicted –PEF variability >30%

Mild Persistent Asthma n Symptoms –Symptoms > 2 X/wk but <1 X/day –Exacerbations may affect activity –Nighttime symptoms > 2 X/mo n Lung Function –FEV 1 or PEF > 80% predicted –PEF variability 20-30%

Mild Intermittent Asthma n Symptoms –Symptoms < 2 X/wk –Asymptomatic and normal PEF between exacerbations –Exacerbations brief (few hrs - few days); intensity may vary –Nighttime symptoms < 2 X/mo n Lung Function –FEV 1 or PEF > 80% predicted –PEF variability < 20%

Asthma Management n Goals of therapy –Prevent symptoms –Maintain (near) “normal” PF –Maintain normal activity –Prevent exacerbations & minimize ER visits/hospitalizations –Optimal drug tx, minimal problems –Patient/family satisfaction

n Recommended monitoring –S & S –PFT –Quality of life/functional status –Exacerbations –Drugs –Patient/provider communication & satisfaction

n Monitor using clinician assessment/pt. self-assessment n Spirometry tests –Initial assessment –Post tx after patient’s symptoms and PF stabilize –Minimally Q 1-2 yrs

n Written action plan based on: –Signs & symptoms &/or PEF n Patient education: –Recognition need for additional therapy

n Patient education: –How & when to do PF monitoring

Differences from 1991 Panel n Added patient/family satisfaction to treatment goals n Periodic assessment of 6 domains of patient health are recommended: –S&S, PF, quality of life, hx. of exacerbations, pharmacotherapy, pt./provider communication, pt. satisfaction

n PF measurements changes –Changed from 2 X daily to morning –If morning <80% of personal best PEF, more frequent monitoring may be desired –Discussion of inconsistencies in measurement among PF meters added n Emphasis that all pts. regardless of severity recognize early deterioration

Assessment Measures n Asthma treatment effectiveness –Monitor signs & symptoms - daytime, nocturnal, early morning symptoms response to short-acting Beta agonist –Pulmonary function (spirometry, PF) < patients with moderate-to-severe persistent asthma should learn how to monitor PEF at home < PF during exacerbations in pts. with moderate- to-severe asthma is recommended

n Asthma treatment effectiveness –PF monitoring < long term daily PF monitoring in moderate-to- severe asthma is helpful < if long-term PF monitoring is NOT used, short term period of PF monitoring is recommended –establish individual’s personal best –identify time relationships between changes in PF to exposure –evaluate response to chronic maintenance therapy

n Personal best –2-3 wk period pt. records early afternoon PEF –Measure after each use of short-acting beta-2 agonist for symptom relief –? course of oral steroids to establish personal best –Don’t use outlyer PEF values

n Asthma treatment effectiveness –Monitoring quality of life/functional status < missed work, school < activities < sleep < changes in caregivers activities due to child’s asthma –Monitoring asthma exacerbation history < self-treated, or by HC providers

n Asthma treatment effectiveness –Monitoring asthma exacerbation history < unscheduled visits/telephone calls/urgent or emergent care < frequency, severity & causes of exacerbations < hospitalization info - length of stay, intubation, ICU

n Asthma treatment effectiveness –Monitoring Drug Therapy < patient compliance < inhaler technique < frequency of use the short-acting beta2 agonist < frequency of oral steroid “burst” therapy < dose changes of inhaled anti-inflammatory meds.

n Asthma treatment effectiveness –Periodic assessment by clinician and patient < clinician assessment –medical history and physical exam with PFT –mild intermittent-to-mild persistent asthma under control for 3 mos. should be reassessed Q 6 mos –uncontrolled &/or severe persistent should be seen more often

n Asthma treatment effectiveness –Periodic assessment by clinician and patient < patient self-assessment –daily diary - symptoms, PF, med. use –periodic self-assessment filled out at the time of the clinic visit - self perception of asthma control, self-skills, satisfaction < population based assessment - HMO’s

Pharmacologic Therapy n Long-term control medications –corticosteroids < inhaled form < systemic steroids used to gain prompt control of disease when initiating inhaled tx –cromolyn sodium or nedocromil < mild-to-moderate anti-inflammatory medications (may be used initially in children) < preventive tx. prior to exercise or unavoidable exposure to known allergens

n Long-term control medications –Long-acting beta2-agonists < used concomitantly with anti-inflammatory meds for long-term symptom control especially nocturnal symptoms < prevents exercise-induced bronchospasm –Methylxanthines < sustained-release theophylline used as adjuvant to inhaled steroids for prevention of nocturnal symptoms

n Long-term control medications –Leukotriene modifiers < zafirlukast - leukotriene receptor antagonist < zileuton - 5-lipoxygenase inhibitor is alternative therapy to low doses of inhaled steroids/nedocromil/cromolyn < alternative tx to low dose inhaled steroids/cromolyn/nedocromil 12yrs with mild persistent asthma. Further study needed

n Quick relief medications –Short acting beta2-agonists - relief of acute symptoms –Anticholinergics - may provide additive benefit to beta2 drugs in severe exacerbation. May be alternative to beta2-agonists –Systemic steroids - moderate-to-severe persistent asthma in acute exacerbations or to prevent recurrence of exacerbations

Treatment/Long Term Control n Corticosteroids –Most potent and effective –Reduction in symptoms, improvement in PEF and spirometry, diminished airway hyperresponsiveness, prevention of exacerbations, possible prevention of airway wall remodeling –Suppresses: cytosine production, airway eosinophilic recruitment, chemical mediators

n Corticosteroids –Dose dependent on product and delivery device –2 X/day use is common in moderate-to- severe persistent asthma –1 or 2 X/day may be used in mild persistent asthma

n Cromolyn & nedocromil –Have distinctive properties –Similar anti-inflammatory reactions < blocks Cl - channels < modulate mast cell mediator release < modulate eosinophilic recruitment < inhibits early and late asthmatic response to antigen challenge

n Cromolyn & nedocromil –Similar anti-inflammatory reactions < inhibits bronchospasm (exercise, cold dry air, bradykinin aerosol) < nedocromil more potent in inhibiting bronchospasm in the above situations –Both reduce asthma symptoms < improve PF < reduce need for short acting beta2 agonists

n Cromolyn & nedocromil –Dosing requirements < recommended for both 4 X/day < nedocromil effective at 2 X/day –Clinical response for both is less predictable than steroids –Both have strong safety profile

n Long-acting beta- 2 agonists –Relax airway smooth muscle –Duration of action >12 hrs –Not used in acute exacerbations –Adjunct to anti-inflammatory tx for long- term symptom control especially nocturnal symptoms

n Methylxanthines –Provides mild-moderate bronchodilation –Low dose has mild anti-inflammatory action –Sustained release form used as alternative but not preferred to long-acting beta 2 agonists to control nocturnal symptoms –Use may be necessary because of cost or patient compliance

n Leukotriene modifiers –Leukotrienes are potent biochemical mediators released from mast cells, eosinophils, and basophils that: < contract bronchial smooth muscle < increase vascular permeability < increase mucus secretions < attract & activate inflammatory cells in airways

n Leukotriene modifiers –Zafirlukast & zileuton (oral tabs) < improves lung fx and diminishes symptoms & need for short-acting beta 2 agonists –Studies in mild-moderate asthma showing modest improvements –Alternative to low-dose inhaled steroids for pts. with mild persistent asthma –Further study in of other groups needed

n Leukotriene modifiers –Zafirlukast - leuktriene receptor antagonist < attenuates late response to inhaled allergen and post-allergen induced bronchospasm placebo) < improved symptoms < reduced albuterol use –Warning - increases warfarin half-life and PT & PTT must be monitored with dose adjustment when indicated

n Leukotriene modifiers –Zileuton - 5-lipoxygenase inhibitor placebo) in mild-to- moderate asthma < moderate asthmatics had fewer exacerbations requiring oral steroids < attenuates bronchospasm from exercise & from aspirin in sensitive people < inhibits metabolism of theophylline, warfarin, terfenadine and must be monitored

Asthma Treatment/Quick Relief n Short-acting beta 2 agonists –Relax airway smooth muscle and increase in airflow in <30 minutes –Drug of choice for treating symptoms and exacerbations and EIB –Use of >1 canister/mo indicates inadequate control and indicates need to intensify anti-inflammatory tx –Regularly scheduled use NOT recommended

n Anticholinergics –Cholinergic innervation important in regulation of airway smooth muscle tone –Ipratropium bromide (quaternary derivative of atropine without its’ side effects) –Additive benefit with inhaled beta 2 - agonists in severe asthma exacerbations –Effectiveness in long-term management not demonstrated

n Systemic steroids –speed resolution of airflow obstruction –reduce rate of relapse n Medications to reduce oral steroid dependence –Troleandomycin, cyclosporin, gold, methotrexate, IV immunoglobulin, dapsone, hydroxychloroquine

n Medications to reduce oral steroid dependence –Recommended use in pts. under supervision of asthma specialist –Complicated application because of variable effects, potential toxicity, & limited clinical experience

Intermittent Asthma n Step 1 –Short-acting inhaled beta 2 agonists PRN 2 X/wk PATIENT SHOULD BE MOVED TO THE NEXT STEP OF CARE (exception is EIB or viral infections) –Viral infections < mild symptoms - beta 2 agonist Q 4-6 hr < moderate-to-severe symptoms - short course of systemic steroids recommended plus above

Persistent Asthma n Mild, moderate or severe –Daily long-term control recommended n Mild persistent asthma (step 2 care) –Daily anti-inflammatory meds - inhaled steroids (low dose) or cromolyn or nedocromil –Sustained release theophylline alternative but not preferred

n Mild persistent asthma (step 2 care) –Zafirlukast or zileuton considered in pts. >12 yrs –Quick relief medications must be available < short-acting beta 2 agonists < intensity depends upon severity of exacerbation

n Moderate persistent asthma (step 3 care) –Increase inhaled steroids to medium dose OR –Add long-acting bronchodilator to a low- medium dose of inhaled steroids OR –Increase to medium dose steroid then lower dose & add nedocromil (+/-)

n Moderate persistent asthma (if not adequately controlled) –Increase to high dose inhaled steroids & add long-acting bronchodilator (serevent or theophylline)

n Severe persistent asthma (step 4) –If not controlled on high dose of inhaled steroids and long-acting bronchodilator ADD oral systemic steroids on a regularly scheduled, long-term basis < use lowest dose < monitor closely < attempt to reduce or take off when control established

Infants and Young Children n Diagnosis difficult –If suspected a diagnostic trial of inhaled bronchodilators and anti-inflammatory drugs may be helpful n Infants & young children (<5 yrs) –Step 1 - PRN bronchodilators –Step 2 symptomatic tx > 2x/wk start daily anti-inflammatory therapy

n Infants & young children < Trial of cromolyn or nedocromil (low dose inhaled steroids are alternative) < Monitor response to anti-inflammatory tx –After control established, attempt step down therapy –Step 3 care < Higher dose steroids to establish control - step down in 2-3 mos. ~ add nedocromil or theophylline instead of increasing steroid

n Infants & young children –Exacerbations by viral infections < consider systemic steroids –Consider consultation with asthma specialist in those requiring step 2 care –Should consult with asthma specialist in those requiring step 3 care

Emergency Department Treatment n Start treatment when asthma exacerbation recognized n While tx is being given: –Take a more detailed history –Complete physical examination –Perform laboratory studies < PEF on presentation, after initial tx. and at frequent intervals)

–Perform laboratory studies < FEV 1 or PEF <50% pred. then assess oxygenation by pulse oximetry < Lab studies will vary with situation (CBC, electrolytes, serum theophylline level. CXR, ECG). These lab studies are NOT routinely recommended

–Treatment: < O 2 (Sa O ), < inhaled short-acting bronchodilator for all pts. (3 tx Q 20 min, continuous therapy an option) < Consider anti-cholinergics < oral systemic corticosteroids (unresponsive to initial beta 2 agonist therapy, moderate-to- severe asthma, people who are on steroids) < systemic steroids administered when admitted < methylxanthines are not recommended

–Treatment: < Aggressive hydration NOT recommended for older children and adults (may be necessary with infants and sm. children) < Antibiotics NOT recommended unless infection present (fever, purulent sputum) < CPT NOT recommended < Mucolytics NOT recommended < Sedation NOT recommended

Hospitalization n Decision to hospitalize depends upon: < duration < severity (symptoms & airflow obstruction) < course & severity of previous exacerbations < medication use at time of exacerbation < access (medical care & meds) < home conditions < psychiatric illness

n Treatment: –Emergency dept. treatment –Intubation shouldn’t be delayed once ARF is identified < Permission hypercapnia is recommended ventilator strategy