DEALING WITH DIFFICULT DISEASES OF THE AIRWAY
From the Annual Wake Forest University School of Medicine James A. Harrill Lecture
Educational Objectives
| The goal of this program is to improve the diagnosis and management of airway-compromising disease. After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. Describe the pathophysiology of the allergic response.
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| 2. Discuss the role of immunomodulatory therapies in managing chronic or recurrent rhinosinusitis.
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| 3. Diagnose and manage relapsing polychondritis.
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| 4. Assess underlying disease in patients with nasal polyps.
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| 5. Discuss the relationship between asthma and nasal polyps.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the
planning committee 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 following has been
disclosed: Dr. Marple is a consultant for Alcon, Allux Medical, Pfizer, and Sanofi-Aventis, is on the Speakers’ Bureau
of Pfizer, and on the advisory board of GlaxoSmithKline and ALK-Abello. Dr. Mims and the planning committee
reported nothing to disclose.
Acknowledgments
Drs. Marple and Mims were recorded at the 27th Annual James A. Harrill Lecture, presented by Wake Forest University
School of Medicine, and held May 4-5, 2008, in Winston-Salem, NC. The Audio-Digest Foundation thanks the
speakers and Wake Forest University School of Medicine for their cooperation in the production of this program.
| THE ROLE OF ALLERGY IN RHINOSINUSITIS —Bradley F. Marple, MD, Professor and Vice Chair, Department
of Otolaryngology–Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas
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| Introduction: chronic rhinosinusitis—phenotypic expression of inflammatory disease; multiple etiologies;
allergy—hypersensitivity to innocuous antigens, primarily mediated by IgE (type-1 hypersensitivity response)
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| Incidence of allergy: varies, depending on population; 25% to 30% in United States and other industrialized countries;
impact—very low rate of mortality but high costs (≈$8 billion/yr in direct costs, plus undetermined indirect
costs)
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| Pathophysiology: genetic and environmental components; initial exposure to antigen—antigen contacts mucosal
surface (eg, conjunctiva; respiratory tract; gastrointestinal tract); dissolves and passively migrates across mucosal
border; phagocytized by antigen-presenting cells, which cleave antigenic determinant (epitope) and bind it to major
histocompatability complex on cell surface; antigen recognition—antigen-presenting cell sensitizes antigen-naive
TH2 cell (transfers antigen-specific information through direct contact); sensitized T cell can sensitize other T cells
and B cells; sensitized B cell differentiates into plasma cell, producing antigen-specific IgE (or other immunoglobulin);
IgE binds to Fc receptors on surface of mast cells; subsequent exposure—antigen cross-links with sensitized
mast cell on mucosal surface, resulting in degranulation and release of histamines and inflammatory mediators;
various cytokines involved throughout process
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| Chronic rhinosinusitis: eosinophilic and noneosinophilic forms, each associated with different cytokine profiles;
chronic infectious (ie, noneosinophilic) form predominated by interleukin (IL)-8 and interferon (IFN)-γ chronic
noninfectious (ie, eosinophilic) form predominated by IL-5 and IL-13; IL-5 has role in recruiting eosinophils to site
of inflammation and in prolonging life cycle of eosinophils; allergic rhinitis predominated by IL-5 and IL-4 (has
important role in maturation of B cells)
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| TH cell differentiation: when stressed, TH1 cells produce IL-1, IL-2, IL-8, and IFN-γ, whereas TH2 cells primarily
produce IL-4 and IL-5 (associated with eosinophilic inflammation and allergic disease); TH1 cells mediate humoral
immune response to bacterial infection; TH2 cells mediate immune response against parasites (too large to be phagocytized
by macrophages; toxic mediators required); hygiene hypothesis—in industrialized countries, low exposure
to parasites and early exposure to antibiotics results in shifting of balance toward TH2 cells; goal of therapy—
return to normal balance
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| Evidence: observational and clinical studies show evidence of relationship between allergic disease and rhinosinusitis
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| Acute rhinosinusitis: patients with recurrent acute bacterial rhinosinusitis have higher incidence of allergic rhinitis
or positive findings on allergy tests than does general population
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| Chronic rhinosinusitis: associated with higher prevalence of allergy (51% vs ≈25% in general population); patients
who undergo sinus surgery have particularly high prevalence of allergy (but, sampling may be biased);
severity of inflammation correlates with increased allergic sensitivity
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| Allergic rhinitis: associated with higher failure rate of surgery for chronic rhinosinusitis; associated with increased
risk for chronic rhinosinusitis (relative risk, 4.5), need for surgery (3.8), and other problems
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| Sinus inflammation and allergen exposure: radiography and rhinomanometry show evidence of inflammation after
nasal allergen challenge; treating patients with ragweed allergy (during ragweed season) did not reduce mucoperiosteal
findings on computed tomography (CT), but symptoms improved; imaging shows sinus inflammation increases
during peak allergy season, even in regions of sinuses not accessible to antigens
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| Effect of allergy treatment: immunotherapy may have benefit; study showed that immunotherapy resulted in improvements
on all measures (compared to controls) among patients with allergic fungal sinusitis (AFS)
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| Characterization of allergic rhinitis: comorbidity that could influence severity of disease; cofactor that, if controlled,
may improve management of chronic rhinosinusitis
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| Treatment approaches: blocking allergic response (eg, antihistamines; antileukotrienes) does nothing to immunologic
process that drives allergic response; modulation of immune response (eg, immunotherapy; anti-IgE therapy)
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| Immunotherapy: may result in production of blocking antibodies, which interfere with antigen and inhibit allergic
reaction; associated with decreased symptoms (treatment effect persists after treatment ends); results in shifting of
balance of TH cells, with relative decrease in TH2 cells as shown by reduced production of IL-4; adjunctive
immunotherapy—improves outcomes after sinus surgery; effect on chronic rhinosinusitis—significant improvements
in sinus pain, discolored mucus, lost days of work, and need for surgery
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| Anti-IgE therapy: blocks Fab fragment of IgE; binds circulating IgE; blocks IgE on B cells; cleaves IgE from mast
cells; down-regulates T cells; improves symptoms among patients with acute and chronic rhinosinusitis; decreases
levels of IgE, reduces systemic eosinophilia, and improves quality-of-life (QOL) scores among patients with seasonal
allergic rhinitis; associated with improved QOL but little effect on local production of IgE among patients
with perennial allergic rhinitis
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| Conclusions: evaluation for allergy recommended for patients with chronic inflammatory rhinosinusitis; insufficient
evidence to recommend intervention, but benefit likely
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| RELAPSING POLYCHONDRITIS PRESENTING AS AIRWAY OBSTRUCTION IN A CHILD —James W.
Mims, MD, Assistant Professor, Department of Otolaryngology, Wake Forest University, Winston-Salem, NC
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| Initial presentation: girl, 13 yr of age, presents to emergency department (ED); previously diagnosed with allergy-
induced asthma; history of dyspnea with exertion, but no wheezing; patient taking fluticasone/salmeterol (Advair) and
prednisone for ≈1 wk (symptoms improved somewhat); in ED, patient short of breath and coughs frequently (barking
cough); biphasic stridor worse on inspiration than expiration
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| Investigations and initial management: transnasal fiberoptic laryngoscopy (TFL) reveals laryngeal edema but
no mass or obstruction; slight saddle nose; findings on chest radiograph similar to those seen with croup; nonspecific
findings on CT; corticosteroids administered; patient admitted to hospital; airway endoscopy attempted, but
airway becomes severely inflamed, requiring rescue; magnetic resonance imaging (MRI) shows symmetric swelling
and inflammation but no evidence of mass; patient improves with dexamethasone (eg, Decadron); purified protein
derivative (tuberculin; PPD) test negative; sedimentation rate 17 mm/hr; no positive findings on culture;
steroids tapered
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| Second presentation: few weeks after discontinuing steroids, patient presents with difficulty breathing; asthma
ruled out; spirometry results 24% and 18% of predicted; patient admitted to pediatric intensive care unit (PICU);
insufficient improvement with dexamethasone; tracheotomy tube placed; patient treated for mild symptoms of reflux;
biopsies show evidence of nonspecific inflammation; nasal examination reveals small perforation with
smooth surrounding tissue; no other findings; steroids tapered
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| Ear involvement: shortly after discontinuation of steroids, patient presents with severe otitis media and ear pain;
no improvement with antibiotics or myringotomy; pain eventually resolves spontaneously; steroids tapered; tracheotomy
tube plugged; spirometry readings normal; tracheotomy tube removed
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| Nose involvement: patient presents with nose pain; biopsy of septum shows evidence of chondritis; patient hospitalized
for breathing difficulties; steroids resumed
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| Disease progression: 16 mo after initial presentation, patient has red swollen painful ear (similar to cellulitis; hallmark
of relapsing polychondritis); indomethacin initiated; breathing normal
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| Diagnosis and subsequent management: diagnosis—relapsing polychondritis; management—methotrexate results
in severe exacerbation requiring high doses of steroids (eventually tapered and discontinued); methotrexate
therapy successfully resumed (administered once weekly with folic acid and leucovorin); patient has had no exacerbations
for 1 yr; vitamin D supplemented to treat osteopenia caused by prolonged course of steroids
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Relapsing Polychondritis
| Epidemiology: rare disorder (especially in children); incidence, 3.5 per million; approximately equal prevalence
among men and women; average age at onset, 46 yr
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| Diagnosis: difficult; made average of 3 yr after initial presentation; ≈33% of patients see ≥5 physicians before diagnosis
made; no hallmark sign or symptom distinguishes disorder; no specific diagnostic tests; general findings—
sedimentation rates sometimes elevated (but not in early disease); ≈33% of patients have antibodies to type II collagen;
test for urinary acid mucopolysaccharides useful, but may be difficult to obtain; many kinds of cartilage and
tissues rich in proteoglycans affected; diagnostic criteria (first suggested by McAdam et al, 1976) include several
otolaryngologic manifestations; histology—for confirmation of diagnosis, but no pathognomonic findings; common
findings include cartilage inflammation, vacuolations, presence of inflammatory cells and (later) fibrous tissue;
signs and symptoms (partial list)—auricular chondritis (≈50% of patients); vertigo; hearing loss; airway
problems; auricular cellulitis (earlobe and tragus generally spared); saddle-nose deformity; eye irritation; rash
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| Prognosis and management: mortality (≈6%) due to tracheal collapse or cardiac valve dysfunction; immunosuppressive
therapy required; best evidence for methotrexate, but rescue required; adverse effects—methotrexate increases
risk for lymphoma, is teratogenic, increases photosensitivity, and potentially hepatotoxic (monitor liver
function tests monthly); continued screening—osteoporosis; valve disease; hearing loss
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| Pearls: endoscopy may exacerbate acutely inflamed trachea; “asthma” and stridor increase risk for suspicion; continued
collaboration with other specialties important; slow steroid taper (3 mo) preferred; spirometric findings useful
in management
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| NASAL POLYPOSIS: DIAGNOSIS AND MANAGEMENT —Dr. Marple
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| Introduction: nasal polyposis—expression of underlying disease, not independent diagnosis; incidence—≈2%; higher
among patients with asthma or aspirin-sensitivity syndrome; other associated disease states—cystic fibrosis (CF);
Churg-Strauss syndrome; AFS; childhood asthma and rhinitis; allergy—association with nasal polyposis recognized
since 1930s; population studies suggest relationship, but not causal
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| Types of polyps: typical inflammatory eosinophilic—well-developed mucosal border composed of respiratory epithelium;
some goblet cell hyperplasia; increased numbers of eosinophils (most prevalent in subepithelial space and
near mucosa) and mast cells; represents ≈90% of polyps; fibro-inflammatory—likely represents maturation of typical
inflammatory polyp; increased fibrous differentiation; stroma contains seromucinous glands and blood vessels;
increased lymphocytic infiltrate (T cells likely have role in perpetuating disease process); increased numbers of fibroblasts;
less responsive to corticosteroids (partly due to down-regulation of steroid receptors); seromucinous
hyperplastic—stroma filled with seromucinous glands; resembles benign glandular neoplasm, but malignant characteristics
absent; atypical stromal—cells appear abnormal, mimicking malignancy (eg, melanoma, neurogenic sarcoma);
immunohistochemical staining important
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| Polyp formation: rabbit model—process begins with damaged endothelium; subepithelium begins to extrude; dysregulated
surface inhibition allows epithelial cells to invade submucosa; microcavitations form and coalesce, creating
cleavage plane; migratory epithelialization occurs; key event—initial mucosal damage
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| Asthma and polyps: ≈20% of patients with asthma have nasal polyps (greatly increases with aspirin sensitivity);
reducing polyps (using steroids or surgery) improves inflammatory disease; surgical debulking likely removes
source of locoregional inflammation, thereby down-regulating inflammatory process (some evidence for decreased
production of inflammatory cytokines in nose); patients with asthma have higher rates of recurrence after surgery
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| Other associated conditions: bacterial infection—Staphylococcus aureus colonization occurs in some patients; patients
produce local reaction to staphylococcal endotoxin, suggesting role in inflammatory process; CF—
important to work up all pediatric patients with nasal polyps for CF
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| Evaluation: x-rays—look for evidence of AFS or destructive process (eg, mucocele, encephalocele); complete blood
cell count (CBC) with differential—eosinophils represent 5% to 6% of CBC in patients with allergy; higher proportions
may suggest Churg-Strauss syndrome, primary hypereosinophilia, or lymphoreticular malignancy; laboratory
tests—look for hypothyroidism, Wegener’s granulomatosis, and sarcoidosis; perform sweat chloride test in children;
test for allergies (including food allergies); histopathology—biopsy required for all patients with unilateral
nasal polyposis
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| Treatment: goals—improve sinonasal symptoms; establish nasal patency; restore olfaction (sometimes difficult);
control recurrence; pharmacotherapy—intranasal corticosteroids decrease inflammation and polyposis; budesonide
and mometasone approved for management; anecdotal evidence supports use of systemic corticosteroids; antileukotrienes
may improve symptoms, but do not appear to result in objective improvement of polyps; macrolides may
have role because of immunomodulatory effect; surgery—recurrence rate, ≈40%; majority of patients report improvement
in symptoms at 2 to 3 yr, even without adjunctive therapy; most recurrences occur in frontal recess
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| Closing remarks: identify and treat underlying disease; evaluate and treat polyps; continue to manage underlying disease
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Suggested Reading
Awad OG et al: Sinonasal outcomes after endoscopic sinus surgery in asthmatic patients with nasal polyps: a difference
between aspirin-tolerant and aspirin-induced asthma? Laryngoscope 118:1282, 2008; Baroody FM: Interfacing
medical and surgical management for chronic rhinosinusitis with and without nasal polyps. Clin Allergy
Immunol 20:321, 2007; Bonfils P, Avan P: Evaluation of the surgical treatment of nasal polyposis. II: Influence of
a non-specific bronchial hyperresponsiveness. Acta Otolaryngol 127:847, 2007; Cansiz H et al: Relapsing polychondritis:
a case with subglottic stenosis and laryngotracheal reconstruction. J Otolaryngol 36:E82, 2007; Hatipoglu
U, Rubinstein I: Anti-inflammatory treatment of chronic rhinosinusitis: a shifting paradigm. Curr Allergy
Asthma Rep 8:154, 2008; Li JY, Fang SY: Allergic profiles in unilateral nasal polyps of bilateral chronic rhinosinusitis.
Am J Rhinol 22:111, 2008; McAdam LP et al: Relapsing polychondritis: prospective study of 23 patients
and review of the literature. Medicine (Baltimore) 55:193, 1976; Meltzer EO et al: Intranasal corticosteroids in the
treatment of acute rhinosinusitis. Curr Allergy Asthma Rep 8:133, 2008; Pearlman AN, Conley DB: Review of current
guidelines related to the diagnosis and treatment of rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 16:226,
2008; Penn R, Mikula S: The role of anti-IgE immunoglobulin therapy in nasal polyposis: a pilot study. Am J Rhinol
21:428, 2007; Rehl RM et al: Mucosal remodeling in chronic rhinosinusitis. Am J Rhinol 21:651, 2007; Ryan
MW: Disease associated with chronic rhinosinusitis: what is the significance? Curr Opin Otolaryngol Head Neck Surg
16:231, 2008; Small CB et al: Onset of symptomatic effect of mometasone furoate nasal spray in the treatment of
nasal polyposis. J Allergy Clin Immunol 121:928, 2008; Terrier B et al: Complete remission in refractory relapsing
polychondritis with intravenous immunoglobulins. Clin Exp Rheumatol 26:136, 2008.
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