2018 Section 5 - Rhinology and Allergic Disorders

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Rhinology and Allergic Disorders

Home Study Course

Hsc Home Study Course

Section 5 September 2018

© 2018 American Academy of Otolaryngology—Head and Neck Surgery Foundation The global leader in optimizing quality ear, nose, and throat patient care

THE HOME STUDY COURSE IN OTOLARYNGOLOGY — HEAD AND NECK SURGERY

SECTION 5

Rhinology and Allergic Disorders

September 2018

2001 - 2002

SECTION FACULTY: Benjamin Saul Bleier, MD* Adam J. Folbe, MD, MS, FARS, FACS* Devyani Lal, MD, FARS* Charles S. Ebert, Jr, MD, MPH, FACS, FARS, FAAOA Oswaldo A. Henriquez Ajami, MD Stella Lee, MD Abtin Tabaee, MD Kevin C. Welch, MD

American Academy of Otolaryngology - Head and Neck Surgery Foundation 1650 Diagonal Road, Alexandria, VA 22314

Section 5 suggested exam deadline: October 10, 2018 Expiration Date: August 6, 2019; CME credit not available after that date

Introduction The Home Study Course is designed to provide relevant and timely clinical information for physicians in training and current practitioners in otolaryngology - head and neck surgery. The course, spanning four sections, allows participants the opportunity to explore current and cutting edge perspectives within each of the core specialty areas of otolaryngology. The Selected Recent Material represents primary fundamentals, evidence-based research, and state of the art technologies in Rhinology and Allergic Disorders. The scientific literature included in this activity forms the basis of the assessment examination. The number and length of articles selected are limited by editorial production schedules and copyright permission issues, and should not be considered an exhaustive compilation of knowledge on rhinology and allergic disorders. The Additional Reference Material is provided as an educational supplement to guide individual learning. This material is not included in the course examination and reprints are not provided. Needs Assessment AAO-HNSF’s education activities are designed to improve healthcare provider competence through lifelong learning. The Foundation focuses its education activities on the needs of providers within the specialized scope of practice of otolaryngologists. Emphasis is placed on practice gaps and education needs identified within eight subspecialties. The Home Study Course selects content that addresses these gaps and needs within all subspecialties. Target Audience The primary audience for this activity is physicians and physicians-in-training who specialize in otolaryngology-head and neck surgery. 1. Discuss current definitions of Adult Rhinosinusitis 2. Implement current evidence-based treatment strategies for Allergic Fungal Sinusitis 3. Explain rates and some potential causes of revision sinus surgery 4. Describe tissue characteristics that are associated with subtypes of chronic rhinosinusitis 5. Assess therapy and prognostication for patients with allergic fungal rhinosinusitis subtype 6. Incorporate evidence-based medical therapy in the management of allergic fungal rhinosinusitis 7. Discuss evidence for outcomes following balloon sinus dilation 8. Compare the efficacy of balloon dilation versus ESS 9. Articulate the outcomes following steroid eluting sinus stent placement both in the OR and in the clinic 10. Discuss the comparison of outcomes between endoscopic and open resection of sinonasal adenocarcinoma 11. Describe the pros and cons of open versus endoscopic resection of craniopharyngioma 12. Implement evidence-based use of lumbar drains following endoscopic CSF leak repair Outcome Objectives The participant who has successfully completed this sections should be able to:

Medium Used The Home Study Course is available as printed text. The activity includes a review of outcomes objectives, selected scientific literature, and a self-assessment examination. Method of Physician Participation in the Learning Process The physician learner will read the selected scientific literature, reflect on what they have read, and complete the self-assessment exam. After completing this section, participants should have a greater understanding of rhinology and allergic disorders as they affect the head and neck area, as well as useful information for clinical application. Accreditation Statement The American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO-HNSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation The AAO-HNSF designates this enduring material for a maximum of 40.0 AMA PRA Category 1 Credit(s) ™. Physicians should claim credit commensurate with the extent of their participation in the activity. ALL PARTICIPANTS must achieve a post-test score of 70% or higher for passing completions to be recorded and a transcript to be produced. Residents’ results will be provided to the Training Program Director. PHYSICIANS ONLY : In order to receive Credit for this activity a post-test score of 70% or higher is required . Two retest opportunities will automatically be available if a minimum of 70% is not achieved. Disclosure The American Academy of Otolaryngology Head and Neck Surgery/Foundation (AAO-HNS/F) supports fair and unbiased participation of our volunteers in Academy/Foundation activities. All individuals who may be in a position to control an activity’s content must disclose all relevant financial relationships or disclose that no relevant financial relationships exist. All relevant financial relationships with commercial interests 1 that directly impact and/or might conflict with Academy/Foundation activities must be disclosed. Any real or potential conflicts of interest 2 must be identified, managed, and disclosed to the learners. In addition, disclosure must be made of presentations on drugs or devices, or uses of drugs or devices that have not been approved by the Food and Drug Administration. This policy is intended to openly identify any potential conflict so that participants in an activity are able to form their own judgments about the presentation. [1] A “Commercial interest” is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2 “Conflict of interest” is defined as any real or potential situation that has competing professional or personal interests that would make it difficult to be unbiased. Conflicts of interest occur when an individual has an opportunity to affect education content about products or services of a commercial interest with which they have a financial relationship. A conflict of interest depends on the situation and not on the character of the individual. Estimated time to complete this activity: 40.0 hours

2018 SECTION 5 RHINOLOGY AND ALLERGIC DISORDERS FACULTY

*Co-Chairs: Benjamin Saul Bleier, MD, FARS, Associate Professor, Director of Endoscopic Skull Base Surgery, Co-Director Center for Thyroid Eye Disease and Orbital Surgery Department of Otolaryngology, Massachusetts Eye an Ear Infirmary, Harvard Medical School, Boston, Massachusetts. Disclosure: Consulting Fee: Canon, Karl Storz, Olympus, Sinopsys; Stock/Stock Options: Arrinex, Interscope. Adam J. Folbe, MD , MS, FARS, FACS, Vice Chair, Academic Affairs, Division of Otolaryngology- Head and Neck Surgery Rhinology and Endoscopic Skull Base Surgery, Oakland University School of Medicine William Beaumont Hospital, Royal Oak, Michigan. Disclosure: Medical Director: Intrinsic Medical imaging; Stock/Stock Options: Intrinsic Medical Imaging; Stock/Stock Options: Quintree Medical. Devyani Lal, MD , FARS , Associate Professor & Consultant, Otolaryngology- Head & Neck Surgery; Consultant (Joint Appointment), Neurological Surgery; Associate Dean, Mayo Clinic School for Continuous Professional Development, Mayo Clinic, Phoenix, Arizona. Disclosure: No relationships to disclose Faculty: Charles S. Ebert, Jr, MD, MPH, FACS, FARS, FAAOA , Associate Professor, Department of Otolaryngology-Head & Neck Surgery Division of Rhinology, Allergy, and Endoscopic Skull Base Surgery University of North Carolina- Chapel Hill, Chapel Hill, North Carolina. Disclosure: Consultant: Acclarent. Oswaldo A. Henriquez Ajami, MD , Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Division of Rhinology-Endoscopic Skull Base Surgery, Emory University School of Medicine, Atlanta, Georgia. Disclosure: No relationships to disclose. Stella E. Lee, MD , Assistant Professor of Otolaryngology; Director, Division of Sinonasal Disorders and Allergy, University of Pittsburgh, Pittsburgh, Pennsylvania. Disclosure: Research Funding: Sanofi; Research Funding: Allakos, Inc. Abtin Tabaee, MD, Associate Professor, Department of Otolaryngology Weill Cornell Medical College- New York Presbyterian Hospital, New York, New York. Disclosure: Consulting Fee: Spirox; Stock/Stock Options: Spirox. Kevin C. Welch, MD , Associate Professor; Department of Otolaryngology- Head & Neck Surgery; Northwestern University, Feinberg School of Medicine; Chicago, Illinois. Disclosure: No relationships to disclose.

Planner(s): Linda Lee, AAO─HNSF Education Program Manager Stephanie Wilson, Stephanie Wilson Consulting, LLC; Production Manager Richard V. Smith, MD, chair, AAO-HNSF Education Steering Committee Stacey T. Gray, MD, chair, AAO-HNSF Rhinology

No relationships to disclose No relationships to disclose

Expert Witness: various legal firms

No relationships to disclose

and Allergy Education Committee

This 2018-19 Home Study Course Section 5 does not include discussion of any drugs and devices that have not been approved by the United States Food and Drug Administration.

Disclaimer The information contained in this activity represents the views of those who created it and does not necessarily represent the official view or recommendations of the American Academy of Otolaryngology – Head and Neck Surgery Foundation.

Suggested Section 5 Exam submission deadline; course closes

October 10, 2018:

August 6, 2019

EVIDENCE BASED MEDICINE The AAO-HNSF Education Advisory Committee approved the assignment of the appropriate level of evidence to support each clinical and/or scientific journal reference used to authenticate a continuing medical education activity. Noted at the end of each reference, the level of evidence is displayed in this format: [EBM Level 3] .

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001) Level 1

Randomized 1 controlled trials 2 or a systematic review 3 (meta-analysis 4 ) of randomized controlled trials 5 . Prospective (cohort 6 or outcomes) study 7 with an internal control group or a systematic review of prospective, controlled trials. Retrospective (case-control 8 ) study 9 with an internal control group or a systematic review of retrospective, controlled trials. Case series 10 without an internal control group (retrospective reviews; uncontrolled cohort or outcome studies). Expert opinion without explicit critical appraisal, or recommendation based on physiology/bench research.

Level 2

Level 3

Level 4

Level 5

Two additional ratings to be used for articles that do not fall into the above scale. Articles that are informational only can be rated N/A , and articles that are a review of an article can be rated as Review. All definitions adapted from Glossary of Terms, Evidence Based Emergency Medicine at New York Academy of Medicine at www.ebem.org .

1 A technique which gives every patient an equal chance of being assigned to any particular arm of a controlled clinical trial. 2 Any study which compares two groups by virtue of different therapies or exposures fulfills this definition. 3 A formal review of a focused clinical question based on a comprehensive search strategy and structure critical appraisal. 4 A review of a focused clinical question following rigorous methodological criteria and employing statistical techniques to combine data from independently performed studies on that question. 5 A controlled clinical trial in which the study groups are created through randomizations. 6 This design follows a group of patients, called a “cohort”, over time to determine general outcomes as well as outcomes of different subgroups. 7 Any study done forward in time. This is particularly important in studies on therapy, prognosis or harm, where retrospective studies make hidden biases very likely. 8 This might be considered a randomized controlled trial played backwards. People who get sick or have a bad outcome are identified and “matched” with people who did better. Then, the effects of the therapy or harmful exposure which might have been administered at the start of the trial are evaluated. 9 Any study in which the outcomes have already occurred before the study has begun. 10 This includes single case reports and published case series.

OUTLINE

September 2018, Section 5

RHINOLOGY AND ALLERGIC DISORDERS

I.

Rhinology A. Chronic Sinusitis i. Diagnosis ii.

Imaging criteria

iii.

Guidelines

B. Phenotypes/Endotypes i. Microbiome ii.

Allergic fungal rhinosinusitis (AFRS)

C. Surgical Outcomes

II.

Allergic, Non-Allergic, and Immunologic A. Food B. Sublingual Immunotherapy (SLIT) C. Biologics

III.

Office-Based Procedures A. Sinus i. Balloon dilation ii. Stents

IV.

Skull Base A. Tumor Outcomes i.

Open vs. endoscopic

ii.

Lumbar drains vs. no drains

TABLE OF CONTENTS Selected Recent Materials - Reproduced in this Study Guide

2018 SECTION 5 RHINOLOGY AND ALLERGIC DISORDERS

ADDITIONAL REFERENCE MATERIAL................................................................................i - iv

I.

Rhinology A. Chronic Sinusitis i. Diagnosis

Stevens WW, Lee RJ, Schleimer RP, Cohen NA. Chronic rhinosinusitis pathogenesis. J Allergy Clin Immunol . 2015; 136(6):1442-1453. EBM level 3....................................................................................1-12

Summary : Recent advancements in the understanding of chronic rhinosinusitis (CRS) pathogenesis are the focus of this review. The authors describe the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, and CRS with nasal polyps. Imaging criteria Batra PS, Setzen M, Li Y, et al. Computed tomography imaging practice patterns in adult chronic rhinosinusitis: survey of the American Academy of Otolaryngology–Head and Neck Surgery and American Rhinologic Society membership. Int Forum Allergy Rhinol . 2015; 5(6):506-512. EBM level N/A..................................................................................................................................................13-19 Summary : This paper is a publication of survey results disseminated to the AAO-HNS and ARS regarding the use of CT imaging in the management of adult chronic rhinosinusitis. It covers initial use, insurance denials, and radiation exposure. Likness MM, Pallanch JF, Sherris DA, et al. Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis. Otolaryngol Head Neck Surg . 2014; 150(2):305-311. EBM level 3b.....................................................................................................................................................20-26 Summary : This paper presents a multicenter, prospective study involving patients with chronic rhinosinusitis who undergo imaging, then receive an intramuscular corticosteroid treatment, and have follow-up CT imaging. The series involves useful analysis of imaging scoring methods.

ii.

Lim S, Ramirez MV, Garneau JC, et al. Three-dimensional image analysis for staging chronic rhinosinusitis. Int Forum Allergy Rhinol . 2017; 7(11):1052-1057. EBM level 3b...............................27-32

Summary : This article reviews the utility of a novel 3D imaging analysis in patients who undergo CT imaging for symptoms of chronic rhinosinusitis.

iii.

Guidelines Orlandi RR, Kingdom TT, Hwang PH. International Consensus Statement on Allergy and Rhinology: Rhinosinusitis executive summary. Int Forum Allergy Rhinol . 2016; 6 Suppl 1:S3-S21. EBM level 3.......................................................................................................................................................33-51 Summary : This is a large clinical consensus statement on the definitions, diagnosis, and management of adult rhinosinusitis as published by the ARS that breaks down an extensive amount of data regarding all adult rhinosinusitis, in particular chronic rhinosinusitis.

B. Phenotypes/Endotypes i. Microbiome

Lal D, Keim P, Delisle J, et al. Mapping and comparing bacterial microbiota in the sinonasal cavity of healthy, allergic rhinitis, and chronic rhinosinusitis subjects. Int Forum Allergy Rhinol . 2017; 7(6):561- 569. EBM level 3....................................................................................................................................52-60 Summary : This study compared the regional microbiome between the middle and inferior meatus. The authors found that differences between patients in both sites was greater than within the same patient in terms of composition, taxon presence, and abundance. Unlike healthy controls and allergic rhinitis and CRSwNP patients, patients with CRSsNP demonstrated decreased diversity and increased anaerobes in the middle meatus relative to the inferior meatus. In contrast, CRSwNP patients were enriched in Staphylococcus or Alloiococcus , consistent with previous culture-based findings. These findings reinforce evidence for microbial involvement in CRS subtypes. Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol . 2016; 137(5):1449-1456. EBM level 2.......................................................................................................................................................61-72 Summary : This was a multicenter case-control study. Surgical tissue of CRS and control subjects was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin–specific IgE, and albumin. Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with CRS phenotypes. The authors believe that the cluster of inflammatory cytokines associated with a CRS phenotype further differentiated them and provided a more accurate description of the inflammatory mechanisms involved. Allergic fungal rhinosinusitis (AFRS) Gan EC, Thamboo A, Rudmik L, et al. Medical management of allergic fungal rhinosinusitis following endoscopic sinus surgery: an evidence-based review and recommendations. Int Forum Allergy Rhinol . 2014; 4(9):702-715. EBM level 3a.........................................................................................................73-86 Summary : This article reviews the evidence for the treatment AFRS after endoscopic sinus surgery. The available evidence supports the use of systemic and topical nasal corticosteroids, while nonstandard topical nasal corticosteroids, oral antifungals, and immunotherapy are options for refractory AFRS. Lu-Myers Y, Deal AM, Miller JD, et al. Comparison of socioeconomic and demographic factors in patients with chronic rhinosinusitis and allergic fungal rhinosinusitis. Otolaryngol Head Neck Surg . 2015; 153(1):137-143. EBM level 2b.....................................................................................................87-93 Summary : This article contrasts two endotypes of chronic rhinosinusitis: CRS and AFRS. The authors found that patients with CRS tend to have higher incomes, have more access to primary care, are older at time of diagnosis, and have lower Lund-MacKay scores and total IgE than those with AFRS. Masterson L, Egro FM, Bewick J, et al. Quality-of-life outcomes after sinus surgery in allergic fungal rhinosinusitis versus nonfungal chronic rhinosinusitis. Am J Rhinol Allergy . 2016; 30(2):e30-e35. EBM level 4.......................................................................................................................................................94-99 Summary : This article contrasts quality-of-life (QOL) outcomes in patients with AFRS to those with CRS. The authors report significantly greater improvements in QOL scores for patients with AFRS at 9 and 12 months postoperatively compared to those with CRS without nasal polyps.

ii.

Plonk DP, Luong A. Current understanding of allergic fungal rhinosinusitis and treatment implications. Curr Opin Otolaryngol Head Neck Surg . 2014; 22(3):221-226. EBM level 5.................................100-105

Summary : This article discusses the pathophysiological concept of epithelial cell-driven immune response being a major contributor to the development of AFRS. The authors also review diagnostic criteria and the surgical and medical management of the disease process.

Ryan MW, Clark CM. Allergic fungal rhinosinusitis and the unified airway: the role of antifungal therapy in AFRS. Curr Allergy Asthma Rep . 2015; 15(12):75. EBM level 3a..............................................106-111

Summary : This article summarizes the diagnostic criteria and pathophysiology for AFRS. The authors also present evidence against the use of antifungal treatment within the sinonasal cavities for most chronic sinusitis; however, the use of antifungal therapy for AFRS has yet to be fully disproven. C. Surgical Outcomes Haxel BR, Boessert P, Weyer-Elberich V, Fruth K. Course of olfaction after sinus surgery for chronic rhinosinusitis. Laryngoscope Investig Otolaryngol . 2017; 2(5):269-275. EBM level 2.........................112-118 Summary : This articles examines the return of olfaction after endoscopic sinus surgery (ESS) in patients with CRS. The authors demonstrated that improvement of olfaction starts at 2 weeks post-ESS and continues until 6 months, with CRSsNP patients achieving faster improvement.

Rudmik L, Xu Y, Alt JA, et al. Evaluating surgeon-specific performance for endoscopic sinus surgery. JAMA Otolaryngol Head Neck Surg . 2017; 143(9):891-898. EBM level 3........................................................119-126

Summary : This article evaluates the surgeon-specific performance for endoscopic sinus surgery (ESS) using revision rate as the quality metric. The authors report a revision rare of 10.6%, and list the presence of nasal polyps as one of the factors that increase the likelihood of revision ESS.

Stein NR, Jafari A, DeConde AS. Revision rates and time to revision following endoscopic sinus surgery: a large database analysis. Laryngoscope . 2018; 128(1):31-36. EBM level 4............................................127-132

Summary : This article looks into the prevalence of endoscopic sinus surgery revision surgery as well as the factors that may predict it. The authors’ findings suggest a revision rate of 6.65%. Predictive factors include presence of nasal polyps and female gender. Sukato DC, Abramowitz JM, Boruk M, et al. Endoscopic sinus surgery improves sleep quality in chronic rhinosinusitis: a systematic review and meta-analysis. Otolaryngol Head Neck Surg . 2018; 158(2):249-256. EBM level 1................................................................................................................................................133-140 Summary : This article evaluated the impact of endoscopic sinus surgery on sleep quality in patients with CRS. The authors conclude that surgery provides for substantial improvement with respect to CRS, with a smaller improvement seen in the apnea-hypopnea index.

II.

Allergic, Non-Allergic, and Immunologic A. Food

Du Toit G, Sayre PH, Roberts G, et al. Effect of avoidance on peanut allergy after early peanut consumption. N Engl J Med . 2016; 374(15):1435-1443. EBM level 2c.........................................................................141-149

Summary : This study indicates that prolonged consumption of peanut-containing foods may be protective, and 4 years of consuming peanut was sufficient to induce a state of tolerance. In this group, a 12-month period of peanut avoidance was not associated with increased prevalence of peanut allergy. Greenhawt M. The National Institutes of Allergy and Infectious Diseases sponsored guidelines on preventing peanut allergy: a new paradigm in food allergy prevention. Allergy Asthma Proc . 2017; 38(2):92-97. EBM level 1a........................................................................................................................................................150-155 Summary : Early introduction of appropriate peanut-containing food in infants ages 4 to 11 months with either moderate-to-severe eczema, egg allergy, or both was shown to help prevent the development of peanut allergy. Introduction to peanut-containing foods as early as 4 to 6 months of life is recommended for infants with severe eczema, egg allergy, or both after allergy specialist evaluation, at approximately 6 months for infants with mild-to-moderate eczema, and without restriction for infants without eczema or food allergy. B. Sublingual Immunotherapy (SLIT) Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol . 2016; 137(2):339-349e.10. EBM level 1a................................................................................156-176 Summary : The evidence of the effectiveness of SCIT and SLIT are reviewed. Both strategies to treat allergic rhinitis appear to be effective. Head-to-head studies suggest that SCIT may be slightly more effective than SLIT, but SLIT is safer. C. Biologics Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA . 2016; 315(5):469-479. EBM level 1b..............................................................................................................................................177-187 Summary : Dupilumab is an IL-4, IL-13 inhibitor which was shown in this randomized, double-blind, placebo- controlled trial to be effective in treating patients with chronic rhinosinusitis with nasal polyposis. Subcutaneous dupilumab therapy significantly improved subjective and objective outcome measures including SNOT-22, UPSIT, polyp, and Lund-Mackay scores.

Casale TB. Biologics and biomarkers for asthma, urticaria, and nasal polyposis. J Allergy Clin Immunol . 2017; 139(5):1411-1421. EBM level 1a....................................................................................................188-198

Summary : Biologics target specific immune pathways and have been shown to be effective in asthma, urticaria, and nasal polyps. Clinical trials are currently underway for agents that block IgE, IL-4, IL-13, and IL-5 for the treatment of nasal polyps.

Rivero A, Liang J. Anti-IgE and anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and meta-analysis. Ann Otol Rhinol Laryngol . 2017; 126(11):739-747. EBM level 1...............199-207

Summary : Rivero and Liang conducted a systematic review and meta-analysis of anti-IgE and anti-IL5 biologic therapy in the treatment of nasal polyposis. The authors searched PubMed, OVID MEDLINE, and Cochrane Central from 2000 to 2015 and found seven eligible studies (four randomized control trials, one case-control, and two case series). Meta-analysis was performed on five studies. The authors present their results in terms of improvement in nasal polyp score, sinus symptoms, and sinus CT improvement. Office-Based Procedures A. Sinus i. Balloon dilation Chandra RK, Kern RC, Cutler JL, et al. REMODEL larger cohort with long-term outcomes and meta- analysis of standalone balloon dilation studies. Laryngoscope . 2016; 126(1):44-50. EBM level 1...................................................................................................................................................208-214 Summary : This is a prospective, randomized study comparing balloon catheter dilation versus endoscopic sinus surgery. The study also includes a meta-analysis on stand-alone balloon trials with 24-month follow up. Overall statistical improvement in SNOT-20, sick days, acute infections, and antibiotic usage was noted with balloon dilation, though no statistically significant difference was noted when compared to ESS. Levy JM, Marino MJ, McCoul ED. Paranasal sinus balloon catheter dilation for treatment of chronic rhinosinusitis: a systematic review and meta-analysis. Otolaryngol Head Neck Surg . 2016; 154(1):33-40. EBM level 2.........................................................................................................................................215-222 Summary : This paper presents a well-performed and well-written systematic review and meta-analysis on balloon catheter dilation studies to date. A variety of study methodologies was noted. Multiple studies reported improved SNOT-20 outcomes and CT findings. Stents Forwith KD, Han JK, Stolovitzky JP, et al. RESOLVE: bioabsorbable steroid-eluting sinus implants for in-office treatment of recurrent sinonasal polyposis after sinus surgery: 6-month outcomes from a randomized, controlled, blinded study. Int Forum Allergy Rhinol . 2016; 6(6):573-581. EBM level 1...................................................................................................................................................223-231 Summary : This article presents a randomized, controlled, blinded study evaluating steroid-eluting stent versus sham procedure in a cohort of CRS with nasal polyp patients and a prior history of sinus surgery. The 6-month follow-up data presented a statistically improved NOSE score, endoscopy scores, and less need for surgery. The study was industry sponsored. Lavigne F, Miller SK, Gould AR, et al. Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study. Int Forum Allergy Rhinol . 2014; 4(5):381-389. EBM level 4...................................................................................................................................................232-240 Summary : This is a prospective, multicenter study reporting SNOT-22 and endoscopy grading for 12 patients with a prior history of endoscopic sinus surgery and CRSwNP treated with a steroid-dissolving implant placed in the office setting. Improved symptoms and endoscopy findings were noted. ii.

III.

IV.

Skull Base A. Tumor Outcomes i.

Open vs. endoscopic Meccariello G, Deganello A, Choussy O, et al. Endoscopic nasal versus open approach for the management of sinonasal adenocarcinoma: a pooled-analysis of 1826 patients. Head Neck . 2016; 38 Suppl 1:E2267-E2274. EBM level 3a.................................................................................................241-248 Summary : This paper presents a systematic review of 39 articles comprising 1826 patients who underwent endoscopic versus open surgery for sinonasal adenocarcinoma. The endoscopic approach was associated with lower rates of complication and local failure and improved overall survival, when taking all patients into consideration without controlling for tumor stage. Mortuaire G, Leroy X, Vandenhende-Szymanski C, et al. Comparison of endoscopic and external resections for sinonasal intestinal-type adenocarcinoma. Eur Arch Otorhinolaryngol . 2016; 273(12):4343-4350. EBM level 4.......................................................................................................249-256 Summary : This is a single-institution, retrospective series of 43 patients with intestinal-type adenocarcinoma of the ethmoid sinus who underwent open versus endoscopic resection. Overall, the T- stage was similar between groups. The disease-free survival was not different between groups out to a follow-up of 6.6 years. Moussazadeh N, Prabhu V, Bander ED, et al. Endoscopic endonasal versus open transcranial resection of craniopharyngiomas: a case-matched single-institution analysis. Neurosurg Focus . 2016; 41(6):E7. EBM level 4...................................................................................................................................................257-263 Summary : This is a single-institution retrospective series of 26 cases of midline craniopharyngioma treated with endoscopic versus open transcranial approach. Among cases deemed possible to achieve a gross total resection (GTR), the endoscopic approach provided improved rates of GTR and fewer complications. Lumbar drains vs. no drains Ahmed OH, Marcus S, Tauber JR, et al. Efficacy of perioperative lumbar drainage following endonasal endoscopic cerebrospinal fluid leak repair. Otolaryngol Head Neck Surg . 2017; 156(1):52-60. EBM level 3a.................................................................................................................................................264-272 Summary : This article presents a systematic review of literature regarding lumbar drain (LD) use. Ultimately, 12 articles comprising 508 cases met inclusion criteria. The use of LD was not associated with a statistically significant lower rate of postoperative cerebrospinal fluid leak. The authors conclude that more studies are necessary.

ii.

SEPTEMBER 2018, SECTION 5 ADDITIONAL REFERENCES

Adappa ND, Zhang Z, Palmer JN, et al. The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int Forum Allergy Rhinol . 2014; 4(1):3-7.

Amine M, Lininger L, Fargo KN, Welch KC. Outcomes of endoscopy and computed tomography in patients with chronic rhinosinusitis. Int Forum Allergy Rhinol . 2013; 3(1):73-79.

Anderson M, Stokken J, Sanford T, et al. A systematic review of the sinonasal microbiome in chronic rhinosinusitis. Am J Rhinol Allergy . 2016; 30(3):161-166.

Baguley C, Brownlow A, Yeung K, et al. The fate of chronic rhinosinusitis sufferers after maximal medical therapy. Int Forum Allergy Rhinol . 2014; 4(7):525-532.

Bleier BS, Castelnuovo P, Battaglia P, et al. Endoscopic endonasal orbital cavernous hemangioma resection: global experience in techniques and outcomes. Int Forum Allergy Rhinol . 2016; 6(2):156-161.

Brietzke SE, Shin JJ, Choi S, et al. Clinical consensus statement: pediatric chronic rhinosinusitis. Otolaryngol Head Neck Surg . 2014; 151(4):542-553.

Carlson-Jones JA, Paterson JS, Newton K, et al. Enumerating virus-like particles and bacterial populations in the sinuses of chronic rhinosinusitis patients using flow cytometry. PLoS One . 2016; 111(5):e0155003.

D'Anza B, Tien D, Stokken JK, et al. Role of lumbar drains in contemporary endonasal skull base surgery: meta-analysis and systematic review. Am J Rhinol Allergy . 2016; 30(6):430-435.

DeConde AS, Mace JC, Alt JA, et al. Investigation of change in cardinal symptoms of chronic rhinosinusitis after surgical or ongoing medical management. Int Forum Allergy Rhinol . 2015; 5(1):36- 45. Divekar R, Rank M, Squillace D, et al. Unsupervised network mapping of commercially available immunoassay yields three distinct chronic rhinosinusitis endotypes. Int Forum Allergy Rhinol . 2017; 7(4):373-379.

Dixon BJ, Daly MJ, Chan H, et al. Augmented real-time navigation with critical structure proximity alerts for endoscopic skull base surgery. Laryngoscope . 2014; 124(4):853-859.

Farquhar D, Kim L, Worrall D, et al. Propensity score analysis of endoscopic and open approaches to malignant paranasal and anterior skull base tumor outcomes. Laryngoscope . 2016; 126(8):1724-1729.

Gan EC, Habib AR, Hathorn I, Javer AR. The efficacy and safety of an office-based polypectomy with a vacuum-powered microdebrider. Int Forum Allergy Rhinol . 2013; 3(11):890-895.

Gan EC, Habib AR, Rajwani A, Javer AR. Omalizumab therapy for refractory allergic fungal rhinosinusitis patients with moderate or severe asthma. Am J Otolaryngol . 2015; 36(5):672-677.

Garneau J, Ramirez M, Armato SG 3rd, et al. Computer-assisted staging of chronic rhinosinusitis correlates with symptoms. Int Forum Allergy Rhinol . 2015; 5(7):637-642.

i

Hamilos DL. Drivers of chronic rhinosinusitis: inflammation versus infection. J Allergy Clin Immunol . 2015; 136(6):1454-1459.

Han JK. Subclassification of chronic rhinosinusitis. Laryngoscope . 2013; 123 Suppl 2:S15-S27.

Harvey RJ, Nalavenkata S, Sacks R, et al. Survival outcomes for stage-matched endoscopic and open resection of olfactory neuroblastoma. Head Neck . 2017; 39(12):2425-2432.

Harvey RJ, Parmar P, Sacks R, Zanation AM. Endoscopic skull base reconstruction of large dural defects: a systematic review of published evidence. Laryngoscope . 2012; 122(2):452-459.

Hauser LJ, Ir D, Kingdom TT, et al. Investigation of bacterial repopulation after sinus surgery and perioperative antibiotics. Int Forum Allergy Rhinol . 2015; 6(11):34-40.

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Reprinted by permission of J Allergy Clin Immunol. 2015; 136(6):1442-1453.

Mechanisms of allergic diseases

Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

Chronic rhinosinusitis pathogenesis

Whitney W. Stevens, MD, PhD, a * Robert J. Lee, PhD, b,c * Robert P. Schleimer, PhD, a,d and Noam A. Cohen, MD, PhD b,e,f Chicago, Ill, and Philadelphia, Pa

There are a variety of medical conditions associated with chronic sinonasal inflammation, including chronic rhinosinusitis (CRS) and cystic fibrosis. In particular, CRS can be divided into 2 major subgroups based on whether nasal polyps are present or absent. Unfortunately, clinical treatment strategies for patients with chronic sinonasal inflammation are limited, in part because the underlying mechanisms contributing to disease pathology are heterogeneous and not entirely known. It is hypothesized that alterations in mucociliary clearance, abnormalities in the sinonasal epithelial cell barrier, and tissue remodeling all contribute to the chronic inflammatory and tissue-deforming processes characteristic of CRS. Additionally, the host innate and adaptive immune responses are also significantly activated and might be involved in pathogenesis. Recent advancements in the understanding of CRS pathogenesis are highlighted in this review, with special focus placed on the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, or CRS with nasal polyps. (J Allergy Clin Immunol 2015;136:1442-53.) Key words: Chronic rhinosinusitis, nasal polyps, mucociliary clearance, epithelial cells, inflammation, microbiome From a the Division of Allergy-Immunology, Department of Medicine, d the Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago; b the Departments of Otorhinolaryngology–Head and Neck Surgery and c Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia; e the Philadel- phia Veterans Affairs Medical Center, Surgical Service; and f the Monell Chemical Senses Center, Philadelphia. Some of the research described in this review and effort directed towards writing the review was supported by USPHS grants R01DC013588, R21DC013886 (to N.A.C.), and R03DC013862 (to R.J.L.); National Institutes of Health grants T32 AI083216 and R01 AI104733 (to R.P.S.); the Ernest S. Bazley Foundation (to R.P.S.); the Chronic Rhinosinusitis Integrative Studies Program U19-AI106683 (to R.P.S.), and a philan- thropic contribution from the RLG Foundation (to N.A.C.). Disclosure of potential conflict of interest: R. J. Lee has received a grant from the National Institutes of Health (NIH). R. P. Schleimer has received grants from the NIH; has consultant arrangements with Intersect ENT, GlaxoSmithKline, Allakos, Aur- asense, Merck, BioMarck, and Sanofi; and has stock/stock options with Allakos, Aurasense, and BioMarck. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication September 29, 2015; revised October 21, 2015; accepted for publication October 21, 2015. Corresponding author: Robert P. Schleimer, PhD, Division of Allergy-Immunology, 240 E Huron St, McGaw Rm M-318, Chicago, IL 60611. E-mail: rpschleimer@ northwestern.edu . 0091-6749/$36.00 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2015.10.009 Terms in boldface and italics are defined in the glossary on page 1443. *These authors contributed equally to this work. These authors contributed equally to this work.

Abbreviations used

ASL: Airway surface liquid CF: Cystic fibrosis CFTR: Cystic fibrosis transmembrane conductance regulator CRS: Chronic rhinosinusitis

CRSsNP: Chronic rhinosinusitis without nasal polyps CRSwNP: Chronic rhinosinusitis with nasal polyps MCC: Mucociliary clearance NO: Nitric oxide NOS: Nitric oxide synthase PAMP: Pathogen-associated molecular pattern T2R: Taste family type 2 receptor Treg: Regulatory T UT: Uncinate tissue

Chronic rhinosinusitis (CRS) is characterized by chronic inflammation of the sinonasal mucosa and clinically associated with sinus pressure, nasal congestion, rhinorrhea, and a decreased sense of smell persisting for greater than 12 weeks. 1 CRS can be subdivided into 2 major categories based on whether nasal polyps are present (chronic rhinosinusitis with nasal polyps [CRSwNP]) or absent (chronic rhinosinusitis without nasal polyps [CRSsNP]). 2 Although CRS is estimated to affect more than 10 million patients in the United States and leads to $22 billion in total annual costs, 1,3 there are other diseases, such as cystic fibrosis (CF), that also involve chronic sinonasal inflammation and nasal polyp formation that have important clinical implications. A better understanding of CRS pathogenesis is needed to advance the current diagnostic and treatment strategies available for affected patients. THE SINONASAL MICROBIOME Much like the gut, the sinonasal cavity has a resident flora that maintains an environment conducive to respiratory health. Sub- stantial effort has recently been made using culture-independent techniques (ie, molecular diagnostics) to attempt to understand and define the microbial community or microbiome of the human sinonasal cavity in the healthy and diseased (CRS) states. 4-10 No consistent patterns have emerged in the diseased state to implicate a specific organism or organisms as causative, but data suggest an imbalance (or dysbiosis) is found in patients with CRS with a decrease in microbial diversity. Another concept that has emerged is that the correct balance of microbes within the local microbiome might be immunomodulatory and that an imbalance shifts an important regulator of local inflammation. 11 Puzzles that remain include the existence of similar microbial species in

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J ALLERGY CLIN IMMUNOL VOLUME 136, NUMBER 6

‘‘gel’’ formed by mucins produced by goblet cells and submucosal glands. 13 Mucins are large thread-like glycoproteins 14 with ‘‘sticky’’ carbohydrate side chains 15 that can bind surface adhe- sins on microorganisms, 15 including Mycoplasma pneumoniae , 16 H influenzae , 17 M catarrhalis , 18 Pseudomonas aeruginosa , 19 and Pseudomonas cepacia . 20 The mucus layer rests on top of a less-viscous fluid periciliary layer that surrounds the cilia of airway epithelial cells and allows them to beat rapidly (approximately 8-15 Hz). Membrane-tethered mucins on the apical membrane of ciliated cells can form a ‘‘lubricating’’ brush-like structure that keeps the mucus and PLC layers separate to facilitate MCC. 21 Coordinated and directional ciliary beating (known as the metachronal wave 22 ) facilitates transport of debris-laden mucus through the sinonasal cavity to the oropharynx, where it is swallowed or expectorated. MCC is regulated by small-molecule neurotransmitter (eg, adenosine trisphosphate and acetylcholine) and neuropeptide (eg, vasoactive intestinal peptide and substance P) receptors that regulate mucus and fluid secretion 23 and ciliary beating, 24 as well as receptors for bacterial products 25 and mechanical stresses. 26 NADPH OXIDASE: An enzyme involved in the production of reactive oxygen species. REACTIVE OXYGEN SPECIES (ROS): Chemically reactive molecules that are generated during the metabolism of oxygen. During times of stress, high levels of ROS can result in significant tissue damage. REGULATORY T CELLS: A subset of CD4 T cells that are important in promoting immunologic tolerance and might express the transcription factor forkhead box protein 3 and/or secrete the suppressive cytokines TGF- b and IL-10. S100 PROTEINS: A family of more than 20 different low-molecular- weight proteins that all share a similar conformational structure and play a role in a variety of cellular processes. S100A7 (also known as psoriasin) has antimicrobial properties and is important in cell differentiation. S100A8/9 (also known as calprotectin) also has antimicrobial properties and can bind to essential metals, such as calcium and zinc. TIGHT JUNCTION: A complex of cell adhesion proteins, including occludin, claudin family proteins, and JAM family proteins, that is largely responsible for creating an intact epithelial cell barrier. TISSUE PLASMINOGEN ACTIVATOR: A serine protease that is the major enzyme responsible for the breakdown of fibrin clots. TOLL-LIKE RECEPTORS: A class of protein receptors that recognize different conservedmolecules derived frompathogens. These receptors play a critical role in the activation of the innate immune response. TYPE 1 INFLAMMATORY RESPONSE: A type of immune response characterized by production of inflammatory cytokines, such as IFN- g and IL-12, which are important in cell-mediated immunity and phagocyte-dependent inflammation. TYPE 2 INFLAMMATORY RESPONSE: A type of immune response characterized by production of the inflammatory cytokines IL-4, IL-5, and IL-13 that is important for the clearance of large extracellular pathogens. This type of inflammation is observed in patients with allergic disease. TYPE 2 INNATE LYMPHOID CELLS: A type of innate immune cell that produces type 2 cytokines, including IL-5 and IL-13, and might be important in a variety of type 2 inflammatory responses. TYPE I INTERFERONS: A subgroup of cytokines that play a predominant role in the host defense against viruses.

both healthy subjects and patients with CRS, although in different abundances 8 ; the fact that traditional pathogenic microbes, such as Streptococcus pneumoniae , Haemophilus influ- enzae , Moraxella catarrhalis , Stenotrophomonas maltophilia , and Enterobacter species, are also found in healthy cavities, although at lower abundances 8 ; and how innate and adaptive immune mechanisms (described below) can discriminate between bacterial species to help set the nasal microbiome. MUCOCILIARY CLEARANCE: THE FOUNDATION OF SINONASAL INNATE IMMUNITY The upper airways play an important role in removing particulates and pathogens from inspired air through mucociliary clearance (MCC), 12 a specialized function unique to the airway epithelium. MCC is the primary physical defense of the respiratory tract, complementing the physical epithelial barrier ( Fig 1 ). MCC relies on both mucus production and transport. The airway surface liquid (ASL) lining the respiratory tract consists of 2 layers. The top is an antimicrobial-rich mucus GLOSSARY ACANTHOLYSIS: Disruption of intercellular connections, such as desmosomes, resulting in loss of cohesion between epithelial cells and either basement membrane or basal cells. ACANTHOSIS: Abnormal but benign proliferation of the epithelium. ADHERENS JUNCTIONS: A complex of cell adhesion proteins, including the transmembrane protein E-cadherin and the intracellular components p120-catenin, b -catenin, and a -catenin, which is also important in epithelial barrier function. These types of junctions are basal to tight junctions. BACTERIAL CpG: A pathogen-associated molecular pattern that is abundant in microbial genomes but not vertebrate genomic DNAs and is recognized by Toll-like receptor 9. CD4 1 T CELLS: A subset of T cells that express CD4 and help orchestrate an immune response by secreting a variety of different cytokines and promoting B-cell activation. CD8 1 T CELLS: A subset of T cells that express CD8 and can destroy target cells through the production of cytotoxic granule proteins, such as granzyme B and perforin. CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR): An anion channel that conducts chloride and thiocyanate ions across epithelial cell membranes. Mutations in the gene encoding CFTR are associated with cystic fibrosis. D-DIMER: Smallprotein fragmentgeneratedfromthebreakdownoffibrin. DESMOSOMES: A complex of cell adhesion proteins, including desmoplakin, desmoglein, and plakoglobin, that is also important in epithelial barrier function. FACTOR XIIa: A coagulation factor also known as Hageman factor that is responsible for stabilizing a fibrin clot. FIBRIN: An important protein, also known as Factor Ia, that is the critical component within a blood clot on activation and cross-linking. FILAGGRIN: An epidermal protein important in barrier function of the skin that is mutated in patients with some forms of atopic dermatitis. GOBLET CELL: Modified simple columnar epithelial cell which functions to secrete mucus. LPS: A major component of the outer membrane of gram-negative bacteria that elicits a strong inflammatory response by engaging Toll-like receptor 4. LPS is also referred to as endotoxin.

The Editors wish to acknowledge Kristina Bielewicz, MS, for preparing this glossary.

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