ASTHMA: PATHOLOGY AND MANAGEMENT
| DIAGNOSIS AND TREATMENT—Anne Dixon, MD, Assistant Professor, Department of Medicine, Division of
Pulmonary Disease and Critical Care Medicine, University of Vermont College of Medicine, Burlington
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| Prevalence: increasing worldwide, especially in English-speaking countries; common in adults; new-onset
asthma diagnosed at any age; hygiene hypothesis—infants and children in developed world have insufficient exposure
to bacteria, resulting in development of immune system along allergic pathway and predisposition to development
of eczema, hayfever, and asthma; obesity—higher the body mass index (BMI), higher the risk for
asthma; shown for women (Nurses Health Study), men, and children worldwide
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| Pathophysiology: airway narrowing due to broncho-constriction and inflammation; bronchoconstriction—mediated
by 1) neural networks in large airways, eg, in stress, and 2) allergens, eg, from cat; early (acute) response to
allergen, eg, latex, may not be noticed, and patient may not connect allergen to symptoms; inflammation and
remodeling—ongoing; inflammation generated by acute response; lymphocytes and eosinophils essential inflammatory
cells; as smooth muscle constricts (asthmatics have more smooth muscle), airway epithelium produces
increasing amounts of mucus and becomes damaged; matrix of tissue laid down under epithelium, causing
thickening of airway; hypersecretion of mucus may lead to misdiagnosis of asthma as bronchiectasis; in fatal
asthma, airway edematous and inflamed, full of mucus and cellular debris, and unable to exchange air
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| Diagnosis: lung function tests required; spirometry—flow-volume loop shows inability to exhale completely;
peak flow reduced; airflow limitation reversible; forced expiratory volume in 1 sec (FEV1 ); nonasthmatics can
exhale ≈90% of inhaled air in 1 sec, asthmatics take longer; bronchodilators—reverse airflow limitation; in
adults, 12% and 200 mL improvement in FEV1 or forced vital capacity (FVC; total amount of air exhaled); vocal
cord dysfunction—can cause paroxysmal difficulty in breathing and may be misdiagnosed as asthma; limitation
of inspiratory flow; patients present with inspiratory wheeze; patients with asthma also may have vocal cord
dysfunction; voice changes occur, and pharmacologic treatment does not work; speech therapy used to teach patient
how to get air in by relaxing vocal cords; other diagnostic maneuvers—methacholine challenge (not diagnostic
unless symptoms also present; false positives possible); exercise challenge; breathing cold air
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| Triggers of asthma: allergic triggers—dust mites; pollen from trees, grasses, and weeds (not flowers); animals
(eg, cats, dogs); cold air; exercise; stress and anxiety (vicious cycle); tobacco smoke; aspirin (patients with aspirin-sensitive
asthma experience flushing and wheezing ≈3 hr after taking aspirin; crossreaction with nonsteroidal
anti-inflammatory drugs [NSAIDs])
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 | Occupational asthma: with latency—allergen-driven phenomenon; occurs, eg, in health care workers exposed to latex;
similar to exposure to cats or other allergens; asthma often preceded by long period of rhinitis and itchy eyes;
other causes include diisocyanates in paints, wood, and animal proteins; reactive airways dysfunction syndrome—
occurs after catastrophic exposure in people with no previous asthma symptoms, eg, responders at “Ground Zero”
exposed to smoke; other causes include formaldehyde, chlorine, and ammonia; may not resolve, ie, symptoms
identical to those of asthma continue indefinitely
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| Viral infections: studies show exposure to respiratory syncytial virus (RSV) in infancy can cause not only severe
bronchiolitis at that time, but also persistent asthma
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| Classification of asthma: based on symptoms and guides treatment; intermittent—symptoms once or twice
weekly; treat with rescue inhaler; mild persistent—symptoms at least twice weekly and nocturnal awakening; consider
anti-inflammatory therapy (inhaled corticosteroids [ICS]); moderate persistent—daily and nocturnal symptoms;
ICS plus another agent required; severe persistent—daily symptoms, frequent exacerbations, nocturnal
awakening; treat with ICS plus 2 other agents
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| Treatment: rescue therapy (inhalers)—1) β-agonists, eg, albuterol; first-line therapy; cause relaxation of smooth
muscle; work in 10 to 15 min; 2) anticholinergic agents; second-line therapy; note—chlorofluorocarbon
(CFC) inhalers being replaced by hydrofluoroalkane (HFA) inhalers for environmental reasons; may be more
effective than CFC inhalers
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| Anti-inflammatory therapy: ICS do not prevent loss of lung function, but decrease risk for exacerbation; loss of
lung function caused not so much by inflammation, as by deposition of extracellular matrix and thickening of
membrane (no current treatment); dosage—before increasing dose of ICS, try long-acting β-agonist (LABA);
meta-analysis shows that patients on high-dose ICS have more exacerbations than those on modest doses of
LABA; LABA more effective, with lower risk for side effects; LABA—2 available, formoterol and salmeterol;
black box warning on salmeterol result of using it alone, without ICS; β-agonists work only on smooth
muscle, and may mask inflammation; ICS needed for inflammation
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| Other agents: leukotriene antagonists—montelukast (Singulair) and zafirlukast (Accolate) prevent smooth muscle
constriction and inflammation; add-on therapy, well liked by patients; genetic polymorphism predicts patient
response; ask patients if drug working; in study, some patients had 30% improvement in FEV1 , while
others had no response; leukotriene antagonists approved for treating allergic rhinitis, so patients with upper airway
symptoms or hay fever usually do well on these agents; zileuton—works more proximally in leukotriene
pathway and can block neutrophil-mediated inflammation; may have theoretic advantages in severe asthma; qid
dosing; requires monitoring of liver function; not first- or second-line; omalizumab (Xolair)— used in severe
asthma; allows reduction of dose of ICS; works well in allergic asthmatics; injection given 2 to 4 times
monthly; dose based on weight and total IgE levels; some obese asthmatics would require large volume; “black-
box” warning due to risk for anaphylaxis; may increase risk for malignancy; theophylline—still used but at
lower levels than in past due to toxicity (aim for serum level of ≈6 µ/mL); typical dose 300 mg/day of long-acting
form; can have anti-inflammatory effect; study showed decreased exacerbations, even without ICS; more
effective and less expensive than montelukast
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| Other causes of exacerbations: sinus disease—can aggravate asthma; screen for upper airway disease in asth-
matics, because treating it appears to help asthma; gastroesophageal reflux—problem because of direct reflux of
acid into airway or because it causes bronchospasm; study shows asthmatics treated with proton pump inhibitor
had better peak flow; pneumococcal infections—asthmatics at increased risk for pneumococcal infections; pneumococcal
vaccine indicated in severe asthma; influenza—exacerbates asthma; flu shot indicated (does not cause
and may prevent exacerbation of asthma)
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| Monitoring asthma: use peak flow (most common), induced sputum, or exhaled nitric oxide; ask patients about
frequency of symptoms, whether symptoms awaken them at night, and how often they use rescue inhaler
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| SLEEP AND ASTHMA—Conrad Iber, MD, Professor, Department of Medicine, University of Minnesota Medical
School, and Director of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, Minneapolis
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| Sleep-related effects: nocturnal worsening of asthma; circadian rhythms, sleep state, position during sleep, and
sleep apnea affect intensity of asthma; interactions not simple and go both ways; some direct evidence of neural
feedback to airway receptors contiguous to respiratory and sleep centers, so sleep-initiating centers may have direct
neural effect (mostly unexplored area)
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| Circadian rhythms: asthma exists within patients’ rhythms; circadian alerting effect throughout day and early
evening competes with sleep drive that accumulates throughout day; alerting signal drops off suddenly at bedtime
and allows initiation of sleep; circadian rhythm correlates with body core temperature, melatonin, bronchomotor
activity in airway, hormone levels, and β-adrenergic responsiveness; circadian system driven
mainly by suprachiasmatic nucleus; tightly coupled rhythms—include core temperature, melatonin, and cortisol;
nadir of cortisol level at midnight, then gradual increase to peak in morning
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| Asthma rhythms: during sleep and early morning, increase in intensity of wheezing, breathlessness, chest tightness,
cough, and other objective measures of asthma; peak flow rate maximum in afternoon and minimum in
early morning; patients who complain of nocturnal asthma often have worst drop in peak flow at ≈4AM; during
sleep—lungs become smaller (resistance increases and volume decreases); even if lung inflated to normal
level, resistance remains higher, ie, effect of sleep on airway resistance substantial and independent of lung
size; mediators (eg, eosinophils, CD4 cells, macrophages)—attuned to circadian rhythms and accumulate in
airway in nocturnal asthma; defined circadian effects—include airway inflammation, altered mechanics, decreased
β-adrenergic density and function, and decreased glucocorticoid receptor affinity; interaction with
clinical disease (eg, reflux, sleep apnea) and with environmental conditions; at night, blunted response to β-
adrenergic agents; study data (Sutherland et al)—nocturnal asthmatics have accentuated response to cortisol
and corticotropin during day, compared to non-nocturnal asthmatics and controls; melatonin may be proinflammatory
agent in airway
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| Burden of asthma: nocturnal awakenings—seen in most asthmatics; frequency variable; French study—
patients reported less burden of asthma on self-administered questionnaire than in structured interview with
family physician; study data—awakenings associated with 20% drop in peak flow rate occurred >2 nights/wk
in 10% of asthmatics and <2 nights/wk in 19% of asthmatics; higher prevalence of complaints of daytime
sleepiness, nocturnal awakenings, restless sleep, and snoring in those who also had wheezing
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| Abnormalities of gas exchange: may be present in patients with hyperinflation due to severe asthma; diaphragm
flattened and contracts poorly, affecting gas exchange, particularly during rapid eye movement (REM) sleep;
parallels abnormalities seen in other obstructive lung diseases, eg, chronic obstructive pulmonary disease
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| Sleep apnea and asthma: strength of relationship not known; also unknown how much caused by rhinitis; patients
with allergic rhinitis have sleep apnea during allergy season but not during remainder of year (may be due
to nasopharyngeal swelling); part of interaction between asthma and sleep apnea may be driven by nose; study
data—small case series; coexistence of asthma and snoring common; snoring and apnea more prevalent in patients
with asthma-related symptoms; recurrent asthma exacerbations more common in patients with diagnosed
obstructive sleep apnea; in patients with rhinitis, risk for snoring increased, and complaints of daytime sleepiness
common; association with rhinitis common theme; unknown whether treatment of sleep apnea efficacious
in treating asthma
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| Targeted chronotherapy: case series show improvement in intensity of nocturnal asthma with evening doses of
ICS or afternoon doses of systemic steroids, compared to morning dosing; older study suggested evening dose of
theophylline more effective than morning dose; meta-analysis suggests evening dose of LABA effective; in subset
of individuals, chronotherapy may be appropriate
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| Summary: nocturnal worsening of asthma involves multiple pathways, including increased mediators, decreased
responsiveness, increased proinflammatory agents, and mechanical changes independent of lung volume; drivers
include circadian rhythms, sleep state, and position effects; causal relationship to sleep apnea not demonstrated;
rhinitis may cause sleep apnea in subset of patients; limited empiric data support treatment of reflux and
use of targeted chronotherapy in treatment of nocturnal asthma
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| Questions and answers: melatonin—used in delayed sleep phase syndrome and advanced sleep phase syndrome
to change internal clock; no data to support risk related to melatonin in asthmatics; theoretic risk because
of proinflammatory effects and use of supraphysiologic doses; continuous positive airway pressure—no convincing
evidence for use as alternative therapy for asthma
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Suggested Reading
American Lung Association Asthma Clinical Research Centers et al: Randomized comparison of strategies
for reducing treatment in mild persistent asthma. N Engl J Med 356:2027, 2007; Apter AJ: Advances in adult
asthma 2006: its risk factors, course, and management. J Allergy Clin Immunol 119:563, 2007; Ball TM et al: Cortisol
circadian rhythms and stress responses in infants at risk of allergic disease. J Allergy Clin Immunol 117:306,
2006; Beach J et al: A systematic review of the diagnosis of occupational asthma. Chest 131:569, 2007; Calhoun
WJ: Nocturnal asthma. Chest 123:399S, 2003; Dixon AE et al: Allergic rhinitis and sinusitis in asthma: differential
effects on symptoms and pulmonary function. Chest 130:429, 2006; Dixon AE et al: Asthma in American Indian
adults: the Strong Heart Study. Chest 131:1323, 2007; Ekici A et al: Association of asthma-related symptoms
with snoring and apnea and effect on health-related quality of life. Chest 128:3358, 2005; Elliott WJ: Timing treatment
to the rhythm of disease. A short course in chronotherapeutics. Postgrad Med 110:119, 2001; Federico MJ et
al: History of serious asthma exacerbations should be included in guidelines of asthma severity. J Allergy Clin Immunol
119:50, 2007; Holgate ST et al: The mechanisms, diagnosis, and management of severe asthma in adults. Lancet
368:780, 2006; Landstra AM et al: Role of serum cortisol levels in children with asthma. Am J Respir Crit
Care Med 165:708, 2002; Leger D et al: Allergic rhinitis and its consequences on quality of sleep: An unexplored
area. Arch Intern Med 166:1744, 2006; Majde JA et al: Links between the innate immune system and sleep. J Allergy
Clin Immunol 116:1188, 2005; Mallia P et al: How viral infections cause exacerbation of airway diseases.
Chest 130:1203, 2006; Marceau C et al: Persistence, adherence, and effectiveness of combination therapy among
adult patients with asthma. J Allergy Clin Immunol 118:574, 2006; Nelson HS: Advances in upper airway diseases
and allergen immunotherapy. J Allergy Clin Immunol 119:872, 2007; Ogawa Y et al: The role of leukotrienes in
airway inflammation. J Allergy Clin Immunol 118:789, 2006; Erratum in: J Allergy Clin Immunol. 2007
Feb;119(2):296.Panzer SE et al: Circadian variation of sputum inflammatory cells in mild asthma. J Allergy Clin
Immunol 111:308, 2003; Papi A et al: Rescue use of beclomethasone and albuterol in a single inhaler for mild
asthma. N Engl J Med 356:2040, 2007; Passalacqua G et al: Allergic rhinitis and its impact on asthma update: allergen
immunotherapy. J Allergy Clin Immunol 119:881, 2007; Redline S et al: Effects of varying approaches for
identifying respiratory disturbances on sleep apnea assessment. Am J Respir Crit Care Med 161:369, 2000; Strunk
RC; Childhood Asthma Management Program Research Group: Childhood Asthma Management Program:
lessons learned. J Allergy Clin Immunol 119:36, 2007; Sutherland ER et al: Elevated serum melatonin is
associated with the nocturnal worsening of asthma. J Allergy Clin Immunol 112:513, 2003; Sutherland ER: Nocturnal
asthma. J Allergy Clin Immunol 116:1179, 2005.
Educational Objectives
| The goal of this program is to improve the diagnosis and treatment of asthma and help elucidate the role of circadian
rhythms in asthma. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Describe the pathophysiology of asthma, including the role of allergic triggers, occupational exposures, and viral
infections.
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| 2. Explain the use of lung function tests in the diagnosis and classification of asthma.
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| 3. Treat asthma with rescue therapy, anti-inflammatory therapy, and other modalities.
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| 4. Describe circadian effects on the burden of asthma.
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| 5. Explore the relationship between sleep apnea and asthma.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Dixon’s lecture was given at the 33rd annual Vermont Family Medicine Review Course, presented June 5-8, 2007,
in Burlington, VT, by the University of Vermont College of Medicine. Dr. Iber addressed the 65th annual course in Allergy
and Clinical Immunology, presented April 20, 2007, in Minneapolis by the University of Minnesota Medical
School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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