THE COMPROMISED AIRWAY
| NATURAL HISTORY OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)—John B.
Hagan, MD, Division of Allergic Diseases, Mayo Clinic, Rochester, MN
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| Asthma: patients—typically have younger age of onset; rarely use tobacco; have variable degrees of dyspnea, cough, or
wheeze, and >50% incidence of allergies; disease characterized by—airway reversibility; marked bronchial hyperresponsiveness;
steroid responsiveness; methacholine challenge—if performed in dose-response fashion, no plateau;
lung parenchyma—intact; diffusing lung capacity for carbon monoxide (DLCO) typically normal, but can be high;
chest normal on computed tomography (CT), but some bronchial tube thickening may be present with severe asthma
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| Chronic obstructive pulmonary disease: when compared to asthmatics, patients with COPD—have older age of onset;
use tobacco; develop progressive dyspnea, cough, and predominant sputum production; less likely to have allergies;
have variable degrees of bronchial hyperresponsiveness; experience plateau with methacholine challenge and variable response
to steroids; have damaged lung parenchyma; emphysema—visible on CT; DLCO low
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| Inflammatory characteristics: genetic correlation noted between asthma and COPD; cells of interest in—asthma (eosinophils
prominent; mast cells; CD4+ lymphocytes; natural killer T [NKT] cells; macrophages); COPD (neutrophils prominent;
macrophages; CD8+ lymphocytes; eosinophils)
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 | Inflammatory mediators: asthma and COPD—L2 cells; leukotriene B4; interleukin-4 (IL-4); asthma—IL-5; IL-13;
histamine; chemoattractants for eosinophils (eotaxin; Regulated on Activation, Normal T cell Expressed and Secreted
[RANTES]); COPD—IL-8; chemoattractant for neutrophils, ie, tumor necrosis factor-α (TNF-α), granulocyte colony-stimulating
factor (GM-CSF), and growth-regulated oncogene-α (GRO-α)
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COPD
| National Heart, Lung, and Blood Institute (NHLBI)/World Health Organization (WHO) Global Initiative for
Chronic Obstructive Lung Disease (GOLD) criteria for staging and treating COPD: stage 0—all smokers at risk
for COPD; normal forced expiratory volume in 1 sec (FEV1 ); patients must stop smoking; everyone ≥65 yr of age should
receive influenza vaccine; stage 1 —mild COPD; FEV1 >80%; spirometry normal; patients cough and have some symptoms;
administer short-acting bronchodilators to relieve intermittent dyspnea; stage 2—moderate COPD; FEV1 from 50%
to 79%; administer long-acting bronchodilator for relief of persistent dyspnea; add inhaled corticosteroids when bronchodilator
therapy does not control dyspnea or patient has repeated disease exacerbations; consider pulmonary rehabilitation if
dyspnea persists despite use of long-acting bronchodilators and inhaled corticosteroids; stage 3—FEV1 range 30% to
49%; add pulmonary rehabilitation to protocol; long-term O2 therapy necessary to correct arterial hypoxemia; stage 4—
severe; FEV1 <30%; includes long-term smokers and individuals with chronic respiratory failure or right heart failure
that complicates other gradations of reduced FEV1 ; options include lung transplantation or other surgery
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| Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index: superior to FEV1 alone for
predicting survival in later stages of COPD; variables assessed to determine index score—FEV1 (in percent); distance
walked in 6 min; Modified Medical Research Council Dyspnea Scale (MMRCDS) score; declining body-mass index
(BMI); mortality risk higher in patient with end-stage COPD who—loses weight; reports more dyspnea when ambulating;
notices decrease in distance walked; has low FEV1
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Asthma
| Pathologic changes: thickening of reticular basement membrane, ie, lamina reticularis—occurs early in disease process;
can develop in children and individuals with cough-variant asthma; deposition by active myofibroblasts includes
immunoglobulin, types I and III collagen, tenascin, and fibrin; laminin not involved; altered interstitial matrix—elastic
fiber network and elastolytic process may be abnormal; hyperplasia of collagen may occur; submucosa may contain fibronectin,
laminin, and tenascin; bronchoalveolar lavage (BAL) shows increase in fibronectin [this correlates with TGF-
β]; increase in number and size of submucosal blood vessels—identified as redness on high-magnification bronchovideoscopy;
high-dose fluticasone can decrease number of vessels, vascular area, and thickness of basement membrane;
additional changes associated with asthma—smooth muscle hyperplasia and hypertrophy; mast cell infiltration of airway
smooth muscle; increased volume of mucous cells
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| Sputum and asthma: eosinophils strongly related to inflammation in asthma; monitoring eosinophil count in sputum—
helps in evaluation of severity of inflammation in lung; enhances efficacy of inhaled corticosteroid therapy; sputum
induction—safe; must be accompanied by FEV1 monitoring; eosinophils—have several granular proteins that can be
measured in sputum; lysed or degranulated cells can complicate effort to obtain accurate counts; measurement of granular
proteins under investigation as surrogate to counting eosinophils; data show—increase in pediatric bronchial epithelial
cells with denuded epithelium; myeloperoxidase (neutrophil marker) and exhaled nitric oxide (eNO) increase with age
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| Eosinophils and asthma: eosinophil count >10% in sputum indicative of uncontrolled eosinophilic inflammation and
poorly controlled asthma; as asthma severity increases—eosinophils in sputum and blood increase; total IgE increases;
neutrophil levels relatively unchanged; data show oral and inhaled corticosteroid therapy—do not halt increasing
eosinophil levels; do not change neutrophil levels
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| GASTROESOPHAGEAL REFLUX DISEASE (GERD) AND ASTHMA —Neil Stollman, MD, Associate Clinical Professor
of Medicine, University of California, San Francisco, School of Medicine
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| Gastroesophageal reflux disease: common, chronic, relapsing; defined as symptoms or damage produced by reflux of
gastric contents into esophagus; requires long-term maintenance therapy; goals of therapy—heal damaged esophagus;
prevent complications and relapse; weakened lower esophageal sphincter (LES)—basis of obsolete etiologic concept;
now considered relatively unimportant factor, since most patients with GERD have normal resting tone in LES; decrease
in basal LES pressure during transient lower esophageal sphincter relaxations (tLESRs)—not swallow-related;
lasts 60 to 90 sec; probably main pathophysiologic factor; impaired esophageal acid clearance allows acid and bile to remain
in place longer and to damage esophageal mucosa; normal individuals—also experience reflux; normal esophageal
function, swallow activity, and saliva eliminate refluxate and prevent damage; other factors promoting GERD—
impaired swallowing function; hiatal hernia (permissive but not primary pathophysiologic factor); inability of diabetic to
empty stomach contents (produces pressure gradient that favors reflux rather than forward flow of gastric contents); bile
reflux (combination of stomach acid and bile acts synergistically to cause more severe damage); bottom line—problems
in ≥1 normal anti-GERD defense mechanism create disease predisposition
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| Spectrum of clinical presentation: heartburn and regurgitation—typical symptoms; can occur with concomitant erosive
esophagitis (as defined by esophagoscopy) or nonerosive esophageal reflux disease (NERD); atypical disease
manifestations—chest pain (GERD considered primary cause of unexplained noncardiac chest pain); reflux laryngitis;
asthma; erosion of tooth enamel; esophageal complications of special concern—erosion or ulceration; scarring or
stricture formation; Barrett’s esophagus
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| Nonerosive esophageal reflux disease: most GERD patients have NERD; esophagitis—once considered key indicator of
GERD; current data show minority of people presenting with heartburn and reflux actually have esophagitis; current
concept—absence of esophagitis does not preclude GERD; when compared to individuals with GERD, patients with
NERD—harder to treat; probably have more severe symptomatology; have lower treatment response rates
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| Diagnosis of GERD: generally made without testing; highly predictive clinical factors include—heartburn and acid regurgitation;
worsening symptoms when bending over or lying in bed; symptom improvement with administration of
antacids; points—initiate empiric therapy in patients who describe classic history of heartburn and acid regurgitation;
disease severity cannot be predicted from endoscopic findings; endoscopic findings cannot be predicted from disease
severity
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| Endoscopy: overused; lacks sufficient sensitivity for diagnosing GERD; primarily used as screening tool for Barrett’s
esophagus; when selecting candidates for endoscopy, look for—characteristics predictive of Barrett’s esophagus risk,
ie, chronic (duration in years, not intensity) symptoms in white men (adenocarcinoma of esophagus is disease of white
men); alarm symptoms, including dysphagia, bleeding, weight loss, and family history of upper gastrointestinal cancer;
patients refractory to treatment (exclude other diagnosis)
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| Barium swallow radiography: useless as screening tool; sensitivity and specificity poor; does not show esophageal lining
or detect esophagitis and Barrett’s esophagus; barium esophagram for patient with dysphagia—can be performed
prior to endoscopy; helps surgeon triage patient for further evaluation, eg, cancer patients require ultrasonography
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| 24-hr pH probe: gold standard; accurate; sensitive; specific; cumbersome; useful for evaluating patients with sporadic
symptoms (physician can correlate pH results with symptoms) and disease refractory to medical therapy; pH results
correlate well with symptoms and acid exposure in esophagus, poorly with esophagitis
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| Manometry: cumbersome; measures esophageal pressures; useful for evaluating motility disorder; use limited to preoperative
evaluation of patients with GERD, eg, to exclude poor peristalsis before tightening valve
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| Management: initiate—empiric therapy if patient has history typical for GERD and no weight loss, dysphagia, or anemia;
endoscopic screening for Barrett’s if patient has long-term symptoms or requires continuous therapy; lifestyle
modifications—not considered major intervention or primary therapeutic option; unlikely to be effective; patients interested
in making lifestyle changes should—avoid foods that worsen reflux by lowering LES tone (eg, acidic and
fatty foods; chocolate; coffee; alcohol; peppermint); eat smaller meals; avoid snacks at bedtime; avoid tight clothing; stop
smoking; lose weight; use blocks to elevate head of bed by 5° (using pillows to provide elevation bends patient at waist
and increases intra-abdominal pressure, facilitating reflux); H2-blockers—useful; cost effective; require tid or qid administration
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| Proton pump inhibitors (PPIs): treatment mainstay; most effective agents; more convenient than H2 -blockers (PPI administered
once daily); cost decreasing; all PPIs achieve similar excellent rates of efficacy; step-down therapy—
replaced step-up approach; mandates initial administration of PPIs; patients who do not need PPIs removed from protocol;
cost-effective because of reduced number of office visits; PPIs—slow onset of efficacy when compared to antacids
or H2 -blockers; should be taken 30 to 60 min before breakfast; should not be taken on prn basis; for prn relief—calcium
carbonate (Tums); famotidine, calcium carbonate, magnesium hydroxide (Pepcid Complete)
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| Surgery: candidates include patients who—have well documented GERD confirmed by endoscopy and/or esophageal
pH monitoring; experience persistent symptomatic esophagitis after failed medical therapy; are young and reluctant to
continue long-term medical therapy; caveat—individuals unresponsive to medical therapy most likely will be unresponsive
to surgery; predictors of successful antireflux surgery—typical GERD symptoms; resolution of symptoms with
acid-suppression therapy; presence of large hiatal hernia; surgery vs drugs—5-yr data show both PPIs and surgery
achieved ≈80% remission rates; 13-yr data show surgery may not eliminate need for medical therapy (efficacy of medical
therapy may be enhanced by surgery); endoscopic options—investigational; include techniques for tightening lower
esophageal valve
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| Reflux-induced asthma: features suggestive of reflux etiology—adult-onset asthma; absent history of allergy; ineffective
asthma therapy; concomitant wheezing and heartburn; prevalence of pathologic reflux in asthmatics—pH data
document 30% to 80% association (does not imply causality); problems encountered when determining causality—
reflex-mediated bronchoconstriction can occur in absence of direct acidification of tracheobronchial tree; most patients
with pathologic pH studies have silent reflux and normal endoscopic examinations
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| Data evaluating efficacy of PPI therapy in asthmatics: 24-wk lansoprazole study—used bid dosing; generated statistically
significant reduction in disease exacerbations; therapeutic intervention limited to acid suppression; high-dose, 8-wk
rabeprazole study—used bid dosing; evaluated peak flow rates, not asthma exacerbations; among patients with positive
pH study results, PPI therapy achieved numerical and statistically significant improvement in peak flow rates; additional
findings—3- to 6-mo trials showed positive results (4-wk trials did not show much change in patient status); bid dosing
proved more effective (once-daily dosing relatively ineffective); points—patients with atypical GERD may require higher
levels of acid suppression, ie, diagnostic trials may require bid therapy; physician and patient must lower expectations of
when symptoms will improve, ie, GERD-induced asthma, cough, and chest pain take months to go away; bottom line—
consider using bid trial of PPIs to eliminate GERD as cause of asthma
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| Surgical trials in asthma: view favorable results with caution; nonrandomized studies relied on relatively small number of
subjects; while subjective assessment of symptoms improved, pulmonary function generally did not
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| If extraesophageal GERD suspected in asthmatic: initiate high-dose PPI trial for ≤3 mo; if patient improves, consider
GERD as cause of asthma and continue PPI therapy; if patient does not improve, use 24-hr pH probe to determine accuracy
of initial diagnosis (if diagnosis accurate, continue treatment; if diagnosis wrong, look for real cause)
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Educational Objectives
| The goal of this program is to educate the listener about current concepts in diseases of the airway. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Identify the clinical and inflammatory characteristics of chronic obstructive pulmonary disease (COPD) and asthma.
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| 2. Describe the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging criteria for staging and treating
COPD.
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| 3. Review the clinical merits of sputum analysis in evaluating patients with asthma.
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| 4. Diagnose and manage patients who present with gastroesophageal reflux disease (GERD).
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| 5. Assess the role of reflux in the development of asthma.
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Discussed on This Program
Calcium carbonate [Tums, others]
Famotidine, calcium carbonate, magnesium hydroxide [Pepcid Complete]
Fluticasone propionate [several trade names and preparations]
Lansoprazole [Prevacid]
Methacholine chloride [Provocholine]
Metoclopramide [Reglan, others]
Omeprazole [Prilosec, Prilosec OTC, Rapinex, Zegerid]
Prednisone [Deltasone, Liquid Pred, Meticorten, Orasone, Panasol-S, Prednicen-M, Prednisone Intensol Concentrate,
Strerapred, Strerapred DS ]
Rabeprazole sodium [Aciphex]
Ranitidine HCl [Zantac, Zantac 75, Zantac EFFERdose, Zantac GELdose ]
Suggested Reading
DeVault KR, Castell DO: Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J
Gastroenterol 100:190, 2005; Hagan JB et al: Inhibition of interleukin-5 mediated eosinophil viability by fluticasone 17-
propionate: comparison with other glucocorticoids. Clin Exp Allergy 28:999, 1998; Harding SM: Gastroesophageal reflux:
a potential asthma trigger. Immunol Allergy Clin North Am 25: 131, 2005; James AL et al: Time to death, airway
wall inflammation and remodeling in fatal asthma. Eur Respir J 26:429, 2005; Kim CK, Hagan JB: Sputum tests in the
diagnosis and monitoring of asthma. Ann Allergy Asthma Immunol 93:112, 2004; Lindberg A et al: Ten-year cumulative
incidence of COPD and risk factors for incident disease in symptomatic cohort. Chest 127:1544, 2005; Sontag SJ: The
spectrum of pulmonary symptoms due to gastroesophageal reflux. Thorac Surg Clin 15:353, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Stollman is affiliated with Astra Pharmaceuticals, Janssen Pharmaceutica, and Wyeth Pharmaceuticals.
Dr. Hagan gave his scientific presentation at the 63rd Annual Course on Allergy and Clinical Immunology, presented
April 8, 2005, in Minneapolis, by the University of Minnesota Medical School; Dr. Stollman gave his scientific presentation
at the 14th Annual Educational Symposium of the Allergy, Asthma, and Immunology Foundation of Northern
California: Therapeutic Strategies: 2005, held February 5, 2005, in San Francisco. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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