Nejm 2001;344:350; Jama 1997;278:1855

Cause:

Innumerable allergens including house dust mites, animal dander, actinomyces in car air conditioners (Nejm 1984;311:1619) and other mold spores, cockroach allergens (Nejm 1997;336:1356), and soybean dust (Nejm 1989;320:1097)

Genetic autosomal dominant susceptibility on chromosome 5, co-inherited w atopy susceptibility (Nejm 1995;333:894), as well as various mutations of interleukin-4 and its receptor (Nejm 1997;337:17,20, 1766)

Pathophys:

Airway inflammation. Multiple types including exercise-induced (Nejm 1994;330:1362), cholinergic, as well as older distinctions between “extrinsic/familial atopic” plus exposure by age 1 yr to house mite antigens (Nejm 1990;323:502); and intrinsic/idiopathic or infectious type associated with h/o bronchiolitis (10-30% will go on to asthma—Peds 1963;31:859), bronchiectasis, chronic bronchitis, and eventually COPD and emphysema. Some argue that all are really allergic (extrinsic) (Nejm 1989;320:271) w eosinophilic and mast cell infiltration of lower airway submucosa and smooth muscle (Nejm 2002;346:1699)

Morning wheezing due to circadian decrease in epinephrine and perhaps steroids as well (Nejm 1980;303:263). In extrinsics, IgE is sensitizing. ASA sensitivity caused by incr leukotriene production and sensitivity to it in nasal and other airway mucosa causing asthma and nasal polyps (Nejm 2002;347:1493, 1524; Ann IM 1997;127:472). Food sulfites precipitate (Med Let 1986;28:74) as does first- and secondhand cigarette smoke (Nejm 1993;328:1665)

4-5% of US population increasing overall (Nejm 1994;331:1584) and greater prevalence in low-income groups (Nejm 1994;331:1542) has led to the “hygiene hypothesis.” Incid may be decr by incr enviromental endotoxin exposure (Nejm 2002;347:869, 911, 930)

Sx:Quadrad of dyspnea, wheezing, cough, and sputum production; exercise and/or cold induction caused by respiratory tract heat loss directly and through evaporation in dry air (Nejm 1979;301:763) w pattern of bronchoconstriction lasting 20+ min, 3-8 min after cessation of exercise (Nejm 1998;339:192); URI induction often; h/o occupational irritants; h/o allergen induction

Si:Wheezing, though may only have dyspnea on exertion or cough (Nejm 1979;300:633); dyspnea; cyanosis late; papilledema with acutely increased pCO₂; nasal polyps (30% of extrinsics); paradoxical pulse from “tethered heart” within the mediastinum, correlates with severity (Nejm 1973;288:66)

Annual decrement in FEV₁ % twice as great in asthmatics as in normals (Nejm 1998;339:1194). Overall mortality not increased (Nejm 1994;331:1537); acute attack prognosis worse if have diminished sensitivity to hypoxia (Nejm 1994;330:1329). 25% of child asthmatics have sx as adults (Nejm 2003;349:1414). Childhood asthma crs not affected by inhaled steroids (Nejm 2006;354:1985, 1998, 2058)

Respiratory arrest with respiratory acidosis, not arrhythmia, is most common mode of death (Nejm 1991;324:285); exacerbations induced by NSAID, esp ASA, in 5-10%, esp those with nasal polyps

Pneumococcal infections 3× as frequent as in nonasthmatics (Nejm 2005;352:2082)

Multifocal atrial tachycardia associated with hypoxia, aminophylline, and catechol rx (Nejm 1968;279:344)

in pregnancy (rv of management—Jama 1997;278:1865); associated with premature labor and RDS of newborn (Nejm 1985;312:742)

r/o vocal cord dysfunction, a frequent mimicker; conversion reaction? (Nejm 1983;308:1566); pulmonary emboli; CHF, gastroesophageal reflux disease trigger

Lab:

Chem:Theophyllin levels to optimize dose; IgE levels may correlate with dx, severity.

Hem:Eosinophil elevation correlates with severity (Nejm 1990;323:1033); sputum eosinophils also helpful to tell from COPD

Path:Mucous metaplasia of ciliated epithelial cells into goblet cells

PFTs:Before and after bronchodilators; FEV₁ % reductions. Intrinsics are rarely normal between attacks, but extrinsics are. Peak flows done at home by pt are useful in management. Methacholine challenge test for dx. Fraction of nitric oxide in exhaled air (FENO) levels correlate w need for more inhaled steroids, keep <15 ppb (Nejm 2005;352:2163); not validated as management tool

Skin testing:Basically documents if is atopic or not; may have value deciding if omalizumab (Xolair) recombinant human IgE antibody will work

Xray:Chest to r/o pneumothorax (Nejm 1983;309:336) and pneumonitis; atelectasis

Rx: (Nejm 2009;360:1002):

ACUTE

Catechols (Med Let 1999;41:51), ₂ selective, via inhaler with spacer or via nebulizer q1h × 3; all equi-effective and similar cost ($30/mo) at 2 puffs q 3-6 h (Med Let 1987;29:11); use prn sx, not prophylactically:

• Albuterol (Proventil, Ventolin, and others) 0.1-0.15 mg/kg/dose up to 5 mg/dose if >40 lb q 2 h (Guidelines for asthma, National Asthma Education Program, NIH 1991)
• Bitolterol (Tornalate)
• Terbutaline (Brethine) 250 µgm/puff Steroid bolus, eg, 100-300 mg iv hydrocortisone, then q 6-8 h help (Nejm 1986;314:150), or prednisone 2 mg/kg po; but takes 6+ h, so no rush (Ann IM 1990;112:822); follow up with 8+ d of tapering prednisone to prevent acute recurrence (Nejm 1991;324:788) or 10 d level (40 mg po qd) rx w no taper (Lancet 1993;341:324); not inhaled steroids (Nejm 2000;343:689)

Iprotropium 500 mgm (2.5 cc) neb clearly helps w severe exacerbations (Nejm 2010;363:755, 1755; Am J Med 1999;107:363; Ann Emerg Med 1999;34:8) but only acutely while in hosp or ED

Fluids, depending on initial hydration status, as much as 360 cc/m² in 1st h, then 1500 cc/m²/24 h; too much can cause pulmonary edema (Nejm 1977;297:592); with 2 mEq Kcl/kg/24 h, 3 mEq Na/kg/24 h, and NaCO₃ if pH <7.35 and/or it takes >1 h to decrease pCO₂; O₂

Bipap or respirator if pH low and pCO₂ up and stays there despite initial efforts; beware pneumothorax

Occasionally:

• Aminophylline (Nejm 1993;119:1155, 1216; Ann IM 1991;115:241, 323) 5.6 mg/kg load over 20-30 min then 0.5 mg/kg/h; but efficacy and safety in doubt (ACP J Club 2001;134:97)
• Anesthesia for status asthmaticus when all else fails

CHRONIC(Med Let 2000;42:19)

Spacers with CFC but not HFA and powder inhalers; commercial or homemade w 500 cc plastic soda bottle (Lancet 1999;354:979); may reduce compliance due to bulkiness and inconvenience

Monitor with peak flow meters at home and have pt take short crs of steroids anytime peak flow falls >2 SDs below mean for 2 out of 3 consecutive days (Ann IM 1995;123:488)

Dust-free bedroom if skin test shows sensitive to dust or house mites; cover pillows and mattress (? not effective—Nejm 2003;349:207, 225), damp-mop, cover hot air vents, all produce dramatic effects (Peds 1983;71:418); and rarely, if this fails, desensitization to house dust mite antigens, danders, and pollens like ragweed (Am J Respir Crit Care 1995;151:969), which has minimal (Nejm 1996;334:501, 531) to no benefit (Nejm 1997;336:324)

Influenza vaccine, safe and efficacious in children and adults (Nejm 2001;345:1529)

Medications (J Allergy Clin Immunol 2002;110:5); but use of prn -agonists may be more harmful than no use at all because of rapid tachyphylaxis (Ann IM 2004;140:803)

• Step 1 (Fig 16.1) for mild, intermittent sx, short-acting -agonist (Nejm 1996;335:841, 1995;333:499) inhaler prn, like those listed above; associated with 2× increased death rates or even higher if use >2 canisters/mo (Nejm 1992;326:503; BMJ 1991;303:1426); in nebulizers, or metered dose inhalers and with inhaler devices for kids and uncooperative adults (Nejm 1986;315:870)
• Step 2 for mild persistent sx, prn short-acting -agonist inhaler as above 1, LTRA (see below) or low-dose inhaled steroids (Nejm 1995;332:868) like
• Beclomethasone (Beclovent), triamcinolone (Azmacort), or flunisolide (Aerobid) metered dose inhaler (MDI) 2 puffs bid-tid (Nejm 1991;325:388; 1989;321:1517; Med Let 1985;27:5); safe long term in children (Nejm 1993;329:1702) and adults? (Nejm 1994;331:700 vs 737); or
• Budesonide (Pulmicort, Turbuhaler) dry powder inhaler (DPI) (Med Let 1998;40:15) 200 µgm (low dose) to 800 µgm (high dose) qd-bid, also available in a very expensive nebulizer form (Med Let 2001;43:6); adrenal suppression at 800 µgm bid (Am J Med 2000;108:269), and stunts growth at least for 1st yr in children (Nejm 2000;343:1054, 1024, 1113; 1997;337:1659)
• Fluticasone (Flovent) (Med Let 1996;38:84) MDI or as Flovent Rotadisk DPI (Med Let 1998;40:15) in 44 (low), 110 (med), and 220 µgm/inh doses
• Cromolyn canister (Med Let 1994;36:37) inhaler best choice in children (Nejm 1992;326:1540) and good in some adults, esp those w eosinophilia and incr IgE levels; $65/canister
• Nedocromil (Tilade) (Med Let 1994;36:37, 1993;35:62), similar to cromolyn; $37/canister
• Step 3 for moderate persistent sx, prn short acting inhaled -agonist as above + medium dose (2-3 puffs tid-qid) inhaled steroids as above 1
• Ipratropium (Atrovent) inhaler alone or w albuterol (Combivent), esp in elderly or for -blocker-induced disease
• Long-acting -agonist; all incr sudden death so use only if must and then with inhaled steroid always to mitigate, and not under age 11 yr (Nejm 2009;360:1592, 1671; Ann IM 2006;144:904, 936)
• Can be used w other prn short-acting catechols (Am J Med 1999;107:209);
• Salmeterol (Serevent) (Med Let 1994;36:37) 2 puffs or 1 puff of powder form (50 µgm) bid; $60/canister unlike most others, which are $20-30/canister. Also available combined w fluticasone 100, 250, or 500 µgm as Advair Diskus powder inhaler bid (Nejm 2007;356:775; Med Let 2001;43:31); $103/mo
• Formoterol (Foradil) (Med Let 2001;43:39; Nejm 1997;337:1405) 1 puff pwdr (12 µgm) inhalation bid; w steroids as Symbicort; or as arformoterol (Brovana) (Med Let 2007;49:53) 15 mcg/2 cc neb, isomer of formoterol
• Theophylline (Nejm 1997;337:1405, 1412; 1996;334:1380) rarely used, but low-dose therapy w only 250-375 mg bid despite low blood levels, used w inh steroids as good as long-acting -agonists; long-acting forms like Theo-dur etc, 400 mg qd, can be increased to 600-800 mg qd. Long duration of action so helpful for hs use (Ann IM 1993;119:1216) as are long-acting -agonists. Levels are increased by BCPs, erythromycin, flu shots, allopurinol, cimetidine, coffee; decreased by phenytoin, nicotine, phenobarbital. Toxic sx: seizures, tachycardia, NVD, tremor (Ann IM 1991;114:748); no impairment of school performance (Nejm 1992;327:926)
• Step 4 for severe persistent sx, high-dose inh steroids like budesonide or others above + whatever it takes including po steroids

Other meds:

• Leukotriene receptor antagonists (LTRAs) (ACP J Club 2004;141:73) of unpredictable benefit; near equivalence to inhaled glucocorticoids for chronic use, beta-agonists for exacerbations in RCT (Nejm 2011;364:1695)
• Montelukast (Singulair) (Jama 1998;279:1181; Med Let 1998;40:71) 5 mg (child over 6 yr) chewable or 10 mg po (adult) tab hs; $70/mo
• Zafirlukast (Accolate) (Ann IM 1997;127:472; 1997;126:177; Med Let 1996;38:111) 20 mg po bid, not under age 12 yr; less effective than inh steroids to decr inflammation; use esp for ASA-induced asthma and exercise exacerbations in pts already on -agonists; adv effects: many drug interactions, causes or unmasks (Jama 1998;279:455) Churg-Strauss eosinophilic vasculitis, rare severe hepatitis (Ann IM 2000;133:964); $60/mo
• Zileuton (Zyflo) (Med Let 1997;39:18; Jama 1996;275:931) 600 mg po qid; similarly inhibits production but not a receptor antagonist; $82/mo
• Antibiotics if acute or chronic infection, like tetracycline, erythromycin (beware theophylline levels), trimethoprim-sulfa
• Proton pump inhibitor like omeprazole 40 mg po qd if any reflux sx or if is resistant to rx, although studies don’t show benefit (Nejm 2009;360:1487; ACP J Club 2000;132:15)
• IgE antibody, omalizumab (Xolair) sc q2-4wk, reduces exacerbations and steroid use in severe asthma, NNT = 6-12 (Nejm 2006;354:2689; Cochrane—ACP J Club 2004;140:13); $10 000/yr
• Etanercept, TNG -antagonist, 25 mg biw may help in refractory asthma (Nejm 2006;354:697, 754)

of exercise-induced asthma (Nejm 1998;339:192)

• Chronic inhaled steroids
• Inhaled albuterol, cromolyn, or nedocromil 15 min before exercise
• LRAs like montelukast 10 mg po qd (Nejm 1998;339:147), better long term than salmeterol (Ann IM 2000;132:97)

of aspirin-sensitive asthma and polyps (Nejm 2002;347:1493, 1524), helped by oral ASA desensitization and polyps by topical nasal lysine aspirin

Figure 16.1 Stepwise Approach for Managing Asthma in Adults and Children Older Than Age 5 Years

	Symptoms	Lung Function	Long-term Control Medication
Step 4 Severe Persistent	Continual Symptoms Limited Physical Activity Frequent Exacerbations Nighttime Symptoms Frequent	FEV1 or PEF 60% Predicted PEF Variability >30%	Daily Medication Inhaled Corticosteroid (High Dose) and Long-Acting Inhaled ß2-Agonist and Oral Corticosteroids, but Attempt to Reduce Dose and Maintain Control With Inhaled Corticosteroids *May Add Leukotriene Receptor Antagonist
Step 3 Moderate Persistent	Daily Symptoms Daily Use of Inhaled Short Acting ß2 -Agonists Exacerbations Affect Activity Exacerbations 2 Times a Week, May Lost Days Nighttime Symptoms >1 Time a Week	FEV1 or PEF >60% - <80%, Predicted PEF Variability >30%	Daily Medication Inhaled Corticosteroid (Medium Dose) or Inhaled Corticosteroid (Low to Medium Dose) and Long-Acting Inhaled ß2-Agonist Especially for Nighttime Symptoms *May Add Leukotriene Receptor Antagonist
Step 2 Mild Persistent	Symptoms >2 Times a Week But <1 Time a Day Exacerbations May Affect Activity Nighttime Symptoms >2 Times a Month	FEV1 or PEF 80% Predicted PEF Variability 20%-30%	Daily Medication Inhaled Corticosteroid (Low Dose) or Cromolyn or Nedocromil Alternatives: Leukotriene Receptor Antagonist, Sustained release Theophyline
Step 1 Mild Intermittent	Symptoms 2 Times a Week Asymptomatic and Normal PEF Between Exacerbations Exacerbations Brief (Few Hours to Few Days); Intensity May Vary Nighttime Symptoms 2 Times a Month	FEV1 or PEF 80% Predicted PEF Variability <20%	None

↓ Step Down

Review Treatment Every 1 to 6 Months; a Gradual Stepwise Reduction in Treatment May Be Possible.

↑ Step Up

If Control Is Not Maintained, Consider Step Up, First Review Patient Medication Technique, Adherence, and Environmental Control (Avoidance of Allergens or Other Factors That Contribute to Asthma Severity).

Reproduced with permission from Busse WW. A 72 year old woman with severe asthma. J Am Med Assoc. 2000;284:2225. Copyright 2000, American Medical Association, all rights reserved.

Outline

• Step 4 Severe Persistent
• Step 3 Moderate Persistent
• Step 2 Mild Persistent
• Step 1 Mild Intermittent