Airway Disease: Current Concepts/Clinical Advances

Educational Objectives

The goal of this program is to improve the management of airway disease. After hearing and assimilating this pro­gram, the clinician will be better able to:

1.   Explain the relationship of bacteria and superantigens to chronic rhinosinusitis (CRS).

2.   Discuss the role of antifungal agents and allergy immunotherapy in the management of CRS.

3.   Describe the immunologic changes seen with sublingual immunotherapy (SLIT).

4.   Discuss the advantages and disadvantages of SLIT.

5.   Explain the concept of a unified airway.

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, Pfizer, and sanofi-aventis, is on the Speakers’ Bureaus of Pfizer and MedPointe, owns stock in Novacal Pharmaceuticals, and is on the Advisory Boards of GlaxoSmithKline and ALK-Abelló. Addition­ally, Dr. Marple presents information that is related to off-label use of medication. Dr. Reisacher and the planning com­mittee reported nothing to disclose.

Acknowledgements

Dr. Marple was recorded at Annual Clinic Day, held December 3, 2008, in Uniondale, NY, and sponsored by the Nas­sau Surgical Society and the Brooklyn and Long Island Chapters of the American College of Surgeons. Dr. Reisacher was recorded at the 2nd Annual Otolaryngology Update, held October 16-17, 2008, in New York, NY, and sponsored by the Department of Otolaryngology  –  Head and Neck Surgery at Columbia University and New York Presbyterian Hospital. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

What’s New in the Treatment of Rhinosinusitis

Bradley F. Marple, MD, Professor and Vice Chair, Department of Otolaryngology  – Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas

Background: acute rhinosinusitis (ARS)  —  inflammatory disorder that lasts £1 mo; chronic rhinosinusitis (CRS) lasts >12 wk; bacterial ARS is complication of viral upper respiratory tract infection, in which nasopharyngeal flora translocated to paranasal sinuses; clearance of sinuses impaired, causing bacterial superinfection; from defini­tions and supported by how problem managed, assumption made that CRS continuation of ARS, ie, CRS develops if appropriate antibiotic not chosen; proposal  —  CRS is clinical syndrome similar to asthma; eosinophil-driven pro­cess of unknown etiology, possibly caused not only by bacteria, but also fungi, allergy, superantigen, or biofilm (separately or in combination); CRS later defined to include physical finding (eg, imaging, rhinoscopy) that corrob­orates inflammation; inflammation axiomatic; bacteria, if involved, instigate inflammatory response; not necessar­ily caused by bacteria; different etiologic starting points lead to T_h2-predominant inflammatory cascade, resulting in phenotypic expression of CRS, with or without polyposis

Relationship of bacteria to CRS: studies document that in CRS, bacteria recovered from cultured tissue; when pa­tients undergo surgery, major change in flora seen within nose and paranasal sinuses, including increases in gram-negative and coliform organisms, and appearance of Pseudomonas; bacteria not eradicated after surgery; little out­come data supporting treatment with antibiotics; studies show that patients generally improve with antibiotics, but once medications discontinued, patients revert to former condition; question of whether bacteria inflammatory in­stigator

Superantigen: stimulates CD4 helper T (T_h) cells in antigen (Ag)-independent fashion, bypassing Ag specificity and activating large percentage of total body T-cell pool (reason for systemic behavior of patients as in, eg, gram-nega­tive sepsis); question of whether staphylococci colonizing nose eliciting superantigen, driving formation of nasal polyps and ongoing eosinophilic inflammation (suggested in some studies); local activity, as identified by Ag rec­ognition for staphylococcal enterotoxin, seen more in patient with nasal polyps; in theory, process interrupted in various ways; can attempt to identify and eradicate etiologic agent, but possible to have >1 unifying etiologic agent; another method may be to attack inflammatory cascade

Medical therapy for CRS: traditional agents  —  broad-spectrum antibiotics, typically long term; topical nasal ste­roid; large support for culture-directed antibiotics; limited outcomes data for intravenous antibiotics; adjunctive therapy  —    decongestants; antihistamines; corticosteroids

Corticosteroids: affect patients broadly; applied to tissue systemically or topically; transported across cell mem­brane and bind to glucocorticoid receptor (cytoplasmic); turn on nucleus, leading to broad effect; interrupt in­flammatory cascade at several levels and at high levels (reason for clinical effectiveness); study  —  participants preselected for surgery for CRS separated into topical corticosteroid-naive or topical corticosteroid-treated; both groups cultured and determined that group on steroids had fewer bacteria; speaker’s interpretation that if function of nose improved, nose takes care of itself; study data  —  improvement seen in patients placed on itraconazole; another study found that in patients with atopic dermatitis, CD4 cells stimulated in presence of azole antifungals had down-regulation of inflammatory cytokines; azoles effective anti-inflammatory agents

Macrolides: diffuse panbronchiolitis  —  inflammatory fibrotic disease process with high mortality rate; does not re­spond to systemic corticosteroids; responds to erythromycin; became therapy of choice, and 5-yr survival rate of 26% improved to 10-yr survival rate of 94%; in nasal polyps, macrolides behave like prednisolone (immunomod­ulatory effect)

Topical antifungals: theory suggested that chronic inflammation driven by immunologic recognition of fungus trapped in nose; fungus present in environment; control study  —  slight, yet statistically significant, improvement in computed tomography (CT) scores in participants treated with amphotericin B for 4 mo, compared to controls; however, Alternaria did not respond to amphotericin B; European study  —  compared irrigation with or without amphotericin B; found no difference, although 30% improvement seen in both groups

Allergy immunotherapy: study by Durham  —  difference in behavior of T cells seen in patients treated with immu­notherapy for 3 yr; patients shifted from T_h2-mediated inflammation to T_h1-mediated; CRS T_h2-mediated; thought that if allergic rhinitis controlled, may down-regulate inflammation (unable to prove)

Biofilms: present in patients with CRS; good cause-and-effect data lacking; in animal study, topical tobramycin inef­fective at removing biofilm; another study found topical mupirocin effective at removing biofilm

Surfactants: mucopolysaccharide secreted by bacteria to create safe environment; study  —  looked at citric acid with ionic surfactants pulse-irrigated into surfaces containing biofilms; found effective but decimated cilia in mucosa; another study  —  found baby shampoo effective in 1% dose range; however, not favored by patients and creates suds in irrigation fluid; saline  —  meta-analysis shows  relief of symptoms

Sublingual Immunotherapy

Dr. Marple 

Subcutaneous immunotherapy (SCIT): success measured by decrease in Ag-specific IgE, increase in Ag-specific IgG, resolution of symptoms in season and off season, and decrease in elevation of IgE in response to Ag; 85% to 90% of patients have clinically significant symptomatic relief

Noninjection IT routes: with oral route, Ag does not survive harsh gastric environment; bronchial inhalation exacer­bates bad outcomes, eg, asthma

Sublingual immunotherapy (SLIT): advantages  —  effective and safe; convenient; needle anxiety avoided; cost-ef­fective; standard of care in European IT; basic science  —  question of whether material absorbed and whether ap­propriate immunologic changes present that result in positive clinical outcome; absorption  —  Mistrello (1993) showed that in rat, only 1% of material placed in oral cavity bioavailable by systemic measure; Bagnasco (1997, 2001) found radio-labeled Ag on floor of mouth migrated to local lymphatics in floor of mouth; Passalacqua (2007) found that with sublingual spit technique, 70% of radioactivity retained in mouth; immunologic changes  —  study found that in dogs, over 10-wk period of immunization, Ag-specific IgG increases, with decrease in Ag-specific IgE (in humans, period of 3-6-mo); early studies of SLIT showed decrease in IgE and absence of postseasonal ele­vation of IgE in response to Ag exposure; IgG1 and IgG4 behaved appropriately; conflicting studies about whether effect seen in immunoglobulin changes; other changes include reduction in T-cell proliferation, decrease in inter­cellular adhesion molecule (ICAM) expression (absence of diapedesis of inflammatory cells to site of inflamma­tion); eosinophil cationic protein (ECP) and interleukin (IL)-13, and prolactin down-regulated; study data  —  Marcucci (2003) demonstrated appropriate decrease in IgE and tryptase in patients treated with SLIT when sec­ondarily exposed to Ag, compared to patients on placebo; Yuksel (1999) showed decreased urinary leukotrienes as measure of inflammation in patients treated with SLIT; efficacy   —  of 36 studies reviewed, SLIT determined effec­tive in 30; demonstrated for rhinitis, conjunctivitis, asthma, and asthma prevention

SLIT compared to SCIT: all (6) studies showed equivalence, except one study which showed that SLIT less effec­tive in asthma; Cochrane meta-analysis  —  2 studies compared SLIT to SCIT and showed same results; observation that total dose delivered probably important; low-dose SLIT or SCIT not effective;  Ag level must be at target ther­apeutic doses

Safety of SLIT: no reported deaths or life-threatening reactions; mild reactions seen (eg, gastric upset, swelling at base of tongue, itching of oral cavity) if dosage escalated too rapidly; large studies showed 0.5 to 1 adverse event in 1000 doses; in high-risk population, no serious adverse events noted

Dosing schedule: protocol  —  12-wk escalation that utilizes 5-fold dilutional process; vial 1 weakest and vial 4 main­tenance (3 drops daily); slow escalation decreases associated local symptoms and side effects

Safety precautions: dropper bottles recommended (rather than injectable bottles); patient must have epinephrine (eg, EpiPen) at home

Disadvantages of SLIT: lack of familiarity; not yet approved by Food and Drug Administration; not covered by third-party payers (out-of-pocket expense)

Allergies and the Unified Airway

William R. Reisacher, MD, Assistant Professor of Otolaryngology, Weill Cornell Medical College, New York, NY

Background: unified airway  —  concept that upper and lower airway not separate entities (as once thought), but one functional unit that responds to common inflammatory processes; different mechanisms assumed to produce either allergies or asthma; treatment strategies for allergies or asthma also different; thought that management of one con­dition had little bearing on outcome of other

Epidemiology: Settipane et al (1994) reported that patients with allergic rhinitis 3 times more likely to develop asthma than general population (25% vs 7%-10%); also reported that prevalence of allergic rhinitis in people with asthma 4 to 6 times higher than in general population; 78% of patients with asthma experience nasal symptoms, and 38% of patients with chronic rhinitis have asthma; type of atopic disorder found in parent predictive of type of atopic disorder child will have; study found that patients with allergic rhinitis 4 times more likely to develop asthma than their nonallergic counterparts, and in two-thirds of patients, allergies developed before onset of asthma; study by Pederson found that 75% of patients developed allergic rhinitis and asthma within 2 yr of each other, and in 25% of patients, within 1 yr of each other

Shared pathophysiology: structures of upper and lower airway share similar respiratory mucosa and similar inflam­matory process, with eosinophils and mast cells as major effector cells in allergic rhinitis and asthma; mast cells control early-phase response, while eosinophils major orchestrator of late-phase (cellular) response; shared airway inflammation  —  in study by Ponikau of 22 patients with refractory CRS, all sinus specimens showed heterogeneous eosinophilic inflammation, epithelial shedding, and thickening of basement membrane (also seen in asthma; similar in allergic and nonallergic subjects); damage associated with presence of extracellular major basic protein produced by eosinophils; ECP also important; epithelial damage in airway chronic, with hypertrophy of muscle and mucous glands, and thickened basement membrane

Airway protection: functions of upper airway include warming, humidification, and filtration of air to facilitate gas exchange; Keller reported that 86% of patients with lower respiratory disease reported concurrent nasal symptoms; in patients with asthma, oral breathing of cold air associated with decrease in forced expiratory volume in 1 sec (FEV₁; not seen if breathing cold air through nose); upper airway also prevents particles from going into lower air­way; materials placed in upper airway of patients with depressed consciousness later recovered from lower airway; however, in patients with CRS and asthma, radiolabeled allergens not recovered in lower airway; allergens <10 μ penetrate peripheral lung and alveoli

Airway crosstalk: possible mechanisms include nasobronchial reflex, hematogenous spread of inflammatory media­tors, and role of bone marrow; nasobronchial reflex  —  present in humans and animal models; nasal stimulation with chemicals, silica, cold air, and mechanical stimuli triggers reflex, which causes bronchoconstriction; blocked by certain medications (eg, anticholinergics, lidocaine) or ganglionic blockade; afferent fibers from trigeminal nerve synapse with parasympathetic fibers from vagus nerve, triggering bronchoconstriction; studies failed to dem­onstrate rapid changes in oxygenation or pulmonary function during testing in animal models; hematogenous spread of inflammatory mediators  —  Braunstahl et al (2000) found that in patients with allergies but not asthma, af­ter direct bronchial allergen stimulation, eosinophilic inflammation seen in area stimulated as well as in unchal­lenged bronchial and nasal mucosa; also performed nasal challenge and looked at bronchial and nasal biopsies, pulmonary symptom scores, and peak expiratory flow (PEF); found that allergic patient demonstrated increased tis­sue eosinophilia and increased expression of inflammatory mediators (ICAM and vascular cell adhesion molecule [VCAM]) in nasal and bronchial areas; pulmonary symptoms noted within few hours of challenge, and PEF de­creased for first 24 hr; role of bone marrow  —  in murine model, specific nasal challenge with allergen produced lo­cal nasal inflammatory response, with increases in eosinophils, basophils, and hematopoietic stem cells in bone marrow; T_h2 lymphocytes produce cytokine pattern more consistent with allergy; cells migrate from nasal and si­nus area to bone marrow, where they stimulate production and maturation of other inflammatory cells that re-enter general circulation and travel to lower respiratory tract; same mechanism may occur with upper airway

Effects of medical management: Rachelefsky et al (1984)  —79% of children with asthma and CRS able to discon­tinue bronchodilator therapy after being medically managed with antibiotics, with pulmonary function tests (PFTs) normalizing in majority of children; Watson et al (1993)  —  patients with allergic rhinitis and mild asthma treated with intranasal beclomethasone demonstrated improved symptom scores and decreased bronchial hyperreactivity; Dietemann et al (1992)  —participants with asthma and dust mite allergy treated with benzyl benzoate or placebo and followed for 12 mo; found improvement in symptom scores, but no improvement in medication scores and FEV₁

Effects of immunotherapy: Walker et al (2001)  —  significant reduction in symptom scores and bronchial hyperreac­tivity in participants with seasonal asthma treated with SCIT for 2 yr; Moller et al (2002)  —  200 children (150 had no history of asthma) treated with Ag-specific SCIT for 3 yr; significant improvement in symptom scores and bron­chial hyperreactivity; 42% of control group developed asthma (only 24% of treatment group); implication that treating upper airway improves symptoms of lower airway but also has potential to delay and possibly prevent de­velopment of lower airway disease

Effects of surgical management: endoscopic sinus surgery in adult and pediatric patients with asthma and CRS re­sulted in improvement of symptoms, reduction in visits to emergency department, hospitalizations, and acute care visits; however, no improvement in PFTs

Overlapping role of medications: antihistamines  —  histamine and its metabolites found in sputum, lavage solution, and urine after allergen challenge in patients with allergies and asthma; produces dose-dependent bronchoconstric­tion, and degree of histamine sensitivity correlates with severity of asthma; no improvement in PFT; leukotriene receptor antagonists  —1000 times more potent than histamine in inducing nasal response

Suggested Reading

Bagnasco M et al: Absorption and distribution kinetics of the major Parietaria judaica allergen (Par j 1) administered by noninject­able routes in healthy human beings. J Allergy Clin Immunol 100:122, 1997; Bohle B et al: Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol 120:707, 2007; Braman SS et al: Airway hyperresponsiveness in allergic rhinitis. A risk factor for asthma. Chest 91:671, 1987; Braunstahl GJ et al: Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 107:469, 2001; Braunstahl GJ: The unified immune system: respiratory tract-nasobronchial interaction mechanisms in allergic airway disease. J Allergy Clin Immunol 115:142, 2005; Dietemann A et al: A double-blind, placebo controlled trial of so­lidified benzyl benzoate applied in dwellings of asthmatic patients sensitive to mites: clinical efficacy and effect on mite allergens. J Allergy Clin Immunol 91:738, 1993; Galli J et al: Damage to ciliated epithelium in chronic rhinosinusitis: what is the role of bacterial biofilms? Ann Otol Rhinol Laryngol 117:902, 2008; Greenberger PA et al: Sublingual immunotherapy and subcutaneous immuno­therapy: issues in the United States. J Allergy Clin Immunol 120:1466, 2007; Passalacqua G et al: Global Allergy and Asthma Euro­pean Network. Allergic rhinitis and its impact on asthma update: allergen immunotherapy. J Allergy Clin Immunol 119:881, 2007; Ponikau JU et al: Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial. J Allergy Clin Immunol 115:125, 2005; Rachelefsky G: Treating exacerbations of asthma in children: the role of sys­temic corticosteroids. Pediatrics 112:382, 2003; Tosun F et al: Intranasal fungi and chronic rhinosinusitis: what is the relationship? Ann Otol Rhinol Laryngol 116:425, 2007; Watson WT et al: Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness. J Allergy Clin Immunol 91:97, 1993; Wilson JA et al: A clinical study of the prophylactic use of betamethasone valerate and sodium cromoglycate in the treatment of seasonal allergic rhinitis. J Laryngol Otol 90:201, 1976.