Review of Pathophysiology and Treatment


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


>5000 deaths annually
± Highest in blacks ages 15-24 

Hospitalizations highest in blacks & children

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. symptoms & chronicity . airflow limitation.

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

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

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

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

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

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

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

dry air) .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.

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

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

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

 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 .

severe airway inflammation early intervention with anti-inflammatory therapy suggests prevention of permanent airflow limitation . Airflow limitation ± Airway remodeling attributed to chronic.

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

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

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

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

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  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  Goals of therapy ± Prevent symptoms ± Maintain (near) ³normal´ 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 .

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

 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 Added patient/family satisfaction to treatment goals  Periodic assessment of 6 domains of patient health are recommended:  ± S&S. PF. pt. quality of life./provider communication. hx. of exacerbations. satisfaction . pharmacotherapy. pt.

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

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

Asthma treatment effectiveness
± PF monitoring
long term daily PF monitoring in moderate-tosevere 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

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

. Asthma treatment effectiveness ± Monitoring Drug Therapy patient compliance inhaler technique frequency of use the short-acting beta2 agonist frequency of oral steroid ³burst´ therapy dose changes of inhaled anti-inflammatory meds.

should be reassessed Q 6 mos ± uncontrolled &/or severe persistent should be seen more often . 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.

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

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 .

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 .leukotriene receptor antagonist zileuton . Long-term control medications ± Leukotriene modifiers zafirlukast .

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

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

 Corticosteroids ± Dose dependent on product and delivery device ± 2 X/day use is common in moderate-tosevere persistent asthma ± 1 or 2 X/day may be used in mild persistent asthma .

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

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 . cold dry air. Cromolyn & nedocromil ± Similar anti-inflammatory reactions inhibits bronchospasm (exercise.

 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 longterm 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. and basophils that: contract bronchial smooth muscle increase vascular permeability increase mucus secretions attract & activate inflammatory cells in airways . eosinophils.

 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 .

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 ± Zafirlukast .

 Leukotriene modifiers ± Zileuton . warfarin.5-lipoxygenase inhibitor provides immediate & sustained improvement in FEV1 (mean 15% > placebo) in mild-tomoderate asthma moderate asthmatics had fewer exacerbations requiring oral steroids attenuates bronchospasm from exercise & from aspirin in sensitive people inhibits metabolism of theophylline. terfenadine and must be monitored .

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 2agonists in severe asthma exacerbations ± Effectiveness in long-term management not demonstrated .

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

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

beta 2 agonist Q 4-6 hr moderate-to-severe symptoms .short course of systemic steroids recommended plus above .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 .

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

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

 Moderate persistent asthma (step 3 care) ± Increase inhaled steroids to medium dose OR ± Add long-acting bronchodilator to a lowmedium 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) .

long-term basis use lowest dose monitor closely attempt to reduce or take off when control established . 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.

PRN bronchodilators ± Step 2 symptomatic tx > 2x/wk start daily anti-inflammatory therapy .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 .

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

 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 .

after initial tx.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. and at frequent intervals) .

CXR. These lab studies are NOT routinely recommended . ECG). then assess oxygenation by pulse oximetry Lab studies will vary with situation (CBC. electrolytes. serum theophylline level.± Perform laboratory studies FEV1 or PEF <50% pred.

people who are on steroids) systemic steroids administered when admitted methylxanthines are not recommended . (3 tx Q 20 min. moderate-tosevere asthma. continuous therapy an option) Consider anti-cholinergics oral systemic corticosteroids (unresponsive to initial beta2 agonist therapy. inhaled short-acting bronchodilator for all pts.± Treatment: O2 (Sa O2 90-95).

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

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 ± Intubation shouldn¶t be delayed once ARF is identified Permission hypercapnia is recommended ventilator strategy . Treatment: ± Emergency dept.

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