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Asthma Review of Pathophysiology and Treatment


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


Introduction >5000 deaths annually Highest in blacks ages 15-24 Hospitalizations highest in blacks & children

Pathogenesis and Definition: 

Pathogenesis and Definition 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 Airway inflammation (AI) contributes to hyperresponsiveness, airflow limitation, symptoms & chronicity


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


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


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


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


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 : 

Airway Inflammation & Lung Function 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: 

Airway Inflammation & Lung Function 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)


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


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


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


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


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: 

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


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 Asthma Specialist


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 : 

Severe Persistent Asthma Symptoms Continual Limited physical activity Frequent exacerbations Frequent nighttime symptoms Lung Function FEV1 or PEF < 60% of predicted PEF variability >30%

Moderate Persistent Asthma : 

Moderate Persistent Asthma Symptoms Daily symptoms Daily use of inhaled short-acting beta2 agonist Exacerbations affect activity; > 2 X/wk; may last days Nighttime symptoms >1 time/wk Lung Function FEV1 or PEF > 60% - < 80% predicted PEF variability >30%

Mild Persistent Asthma: 

Mild Persistent Asthma Symptoms Symptoms > 2 X/wk but <1 X/day Exacerbations may affect activity Nighttime symptoms > 2 X/mo Lung Function FEV1 or PEF > 80% predicted PEF variability 20-30%

Mild Intermittent Asthma: 

Mild Intermittent Asthma 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 Lung Function FEV1 or PEF > 80% predicted PEF variability < 20%

Asthma Management: 

Asthma Management 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


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


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


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


Patient education: How & when to do PF monitoring

Differences from 1991 Panel : 

Differences from 1991 Panel Added patient/family satisfaction to treatment goals 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


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 Emphasis that all pts. regardless of severity recognize early deterioration

Assessment Measures: 

Assessment Measures 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


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


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


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


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


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.


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


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: 

Pharmacologic Therapy 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


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


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 recommended for >12yrs with mild persistent asthma. Further study needed


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: 

Treatment/Long Term Control 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


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


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


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


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


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


Methylxanthines Provides mild-moderate bronchodilation Low dose has mild anti-inflammatory action Sustained release form used as alternative but not preferred to long-acting beta2 agonists to control nocturnal symptoms Use may be necessary because of cost or patient compliance


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


Leukotriene modifiers Zafirlukast & zileuton (oral tabs) improves lung fx and diminishes symptoms & need for short-acting beta2 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


Leukotriene modifiers Zafirlukast - leuktriene receptor antagonist attenuates late response to inhaled allergen and post-allergen induced bronchospasm modest improvement in FEV1 (11% > placebo) improved symptoms reduced albuterol use Warning - increases warfarin half-life and PT & PTT must be monitored with dose adjustment when indicated


Leukotriene modifiers Zileuton - 5-lipoxygenase inhibitor provides immediate & sustained improvement in FEV1 (mean 15% > 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: 

Asthma Treatment/Quick Relief Short-acting beta2 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


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


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


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: 

Intermittent Asthma Step 1 Short-acting inhaled beta 2 agonists PRN IF NEEDED >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: 

Persistent Asthma Mild, moderate or severe Daily long-term control recommended 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


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


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 (+/-)


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


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: 

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


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


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: 

Emergency Department Treatment Start treatment when asthma exacerbation recognized 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 FEV1 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: O2 (Sa O2 90-95), 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 beta2 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 : 

Hospitalization 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


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

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