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SUPPLEMENT 1 MAY–JUNE 2014 Rhinology Maintenance of Certification Review Includes Examination Review Questions Edited by Douglas D. Reh, M.D., Bradford A. Woodworth, M.D. and David Poetker, M.D. www.ajra.com Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm American Journal of Rhinology & Allergy May–June 2014 Volume 28 Number 3 Supplement 1 EDITORIAL S1 Editorial: Preparing for the Maintenance of Certification (MOC) Examination in Rhinology D. D. Reh and D. Poetker S3 Sinonasal anatomy and function D. M. Dalgorf and R. J. Harvey S7 Nasal obstruction J. L. Osborn and R. Sacks S9 Epistaxis R. Sacks, P.-L. Sacks, and R. Chandra S11 Chronic rhinosinusitis R. A. Settipane, A. T. Peters, and R. Chandra S16 Nasal polyps R. A. Settipane, A. T. Peters, and A. G. Chiu S22 Allergic fungal rhinosinusitis A. M. Laury and S. K. Wise S24 Invasive fungal rhinosinusitis P. Duggal and S. K. Wise S27 Benign sinonasal neoplasms P. T. Hennessey and D. D. Reh S31 Sinonasal malignancies R. J. Harvey and D. M. Dalgorf S35 Granulomatous diseases and chronic sinusitis M. A. Kohanski and D. D. Reh S38 Cystic fibrosis chronic rhinosinusitis: A comprehensive review M. R. Chaaban, A. Kejner, S. M. Rowe, and B. A. Woodworth S47 Pediatric rhinosinusitis: Definitions, diagnosis and management— An overview S. K. Chandran and T. S. Higgins S51 Surgery for sinonasal disease T. S. Higgins and A. P. Lane S54 Augmenting the nasal airway: Beyond septoplasty P. Simon and D. Sidle S60 The role of the nose in sleep-disordered breathing E. K. Meen and R. K. Chandra American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S68 Olfactory disorders A. Gaines S71 Nonallergic rhinitis R. A. Settipane and M. A. Kaliner S75 Allergic rhinitis R. A. Settipane and C. Schwindt S79 Determining the role of allergy in sinonasal disease R. A. Settipane, L. Borish, and A. T. Peters S82 The united allergic airway: Connections between allergic rhinitis, asthma, and chronic sinusitis C. H. Feng, M. D. Miller, and R. A. Simon S86 Immunomodulation of allergic sinonasal disease R. A. Settipane, A. T. Peters, and L. Borish S90 Subcutaneous and sublingual immunotherapy for allergic rhinitis: What is the evidence? S. K. Wise and R. J. Schlosser S95 The risk and management of anaphylaxis in the setting of immunotherapy P. Lieberman S101 Pathophysiology of hereditary angioedema B. L. Zuraw and S. C. Christiansen S107 Rhinology MOC Review - Questions About the cover: With Permission from the American Journal of Rhinology and Allergy: Singh U, Bernstein JA, Haar L, et al. Azelastine desensitization of transient receptor potential vanilloid 1: A potential mechanism explaining its therapeutic effect in nonallergic rhinitis. Am J Rhinol Allergy 28:215-224, 2014. American Journal of Rhinology & Allergy posts select in-press articles online, in advance of their appearance in the print edition. These articles, referred to as ‘‘Fast Track’’ articles are available at the American Journal of Rhinology & Allergy web site, www.AJRA.com by clicking on the ‘‘on line access’’ link, which connects to the journal’s Ingenta web site and the Fast Track link. Each print article will acknowledge the e-publication date (the date when the article first appeared online). As soon as an article is published online, it is fully citable through use of its Digital Object Identifier (DOI). A2 May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Contributing Authors Larry Borish, MD Michael Kaliner, MD University of Virginia Health System Charlottesville, Virginia, MD George Washington School of Medicine Washington, DC Mohamad Chaaban, MD Alexandra Kejner, MD University of Alabama at Birmingham Birmingham, Alabama University of Alabama at Birmingham Birmingham, Alabama Rakesh Chandra, MD Michael Kohanski, MD Vanderbilt University Nashville, Tennessee John Hopkins Sinus Center Baltimore, Maryland Swapna Chandran, MD University of Louisville School of Medicine Louisville, Kentucky Alexander G. Chiu, MD University of Arizona Tucson, Arizona Sandra Christiansen, MD Kaiser Permanente Allergy La Jolla, CA Dustin Dalgorf, MD Andrew Lane, MD John Hopkins School of Medicine Baltimore, Maryland Adrienne Laury, MD Emory University Sinus, Nasal and Allergy Center Atlanta, Georgia Phil Lieberman, MD University of Tennessee College of Medicine Germantown, Tennessee Applied Medical Research Center University of New South Wales and Macquarie University Darlinghurst, Sidney, Australia Eric Meen, MD Praveen Duggal, MD Scripps Green Hospital La Jolla, California Emory University Sinus, Nasal and Allergy Center Atlanta, Georgia CH Feng, MD Scripps Green Hospital La Jolla, California Alan Gaines, MD Warren Alpert Medical School Brown University Providence, Rhode Island Richard Harvey, MD Applied Medical Research Center University of New South Wales and Macquarie University Darlinghurst, Sidney, Australia University of Manitoba Winnipeg, Manitoba, Canada Michaela Miller, MD Jodi Osborn, MD Sydney Adventist Hospital Hornsby, Australia Anju Peters, MD Northwestern University Chicago, Illinois David Poetker, MD Medical College of Wisconsin Milwaukee, Wisconsin Douglas D. Reh, MD John Hopkins Sinus Center Baltimore, Maryland Patrick Hennessey, MD Steven Rowe, MD John Hopkins Sinus Center Baltimore, Maryland University of Alabama at Birmingham Birmingham, Alabama Thomas Higgins, MD Peta-Lee Sacks, MBBS VI Kentuckiana ENT Louisville, Kentucky University of New South Wales New South Wales, Australia American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Raymond Sacks, MD Patrick Simon, MD Australian School of Advanced Medicine Macquarie University and University of Sydney Medical School Sydney, Australia Feinberg School of Medicine Northwestern University Chicago, Illinois Rodney Schlosser, MD Scripps Green Hospital La Jolla, California Medical University of South Carolina Charleston, South Carolina Christina Schwindt, MD Allergy & Asthma Associates Mission Viejo, California Russell Settipane, MD Warren Alpert Medical School Brown University Providence, Rhode Island Douglas Sidle, MD Feinberg School of Medicine Northwestern University Chicago, Illinois Ronald Simon, MD Sarah Wise, MD Emory University Sinus, Nasal and Allergy Center Atlanta, Georgia Bradford A. Woodworth, MD University of Alabama at Birmingham Birmingham, Alabama Bruce Zuraw, MD University of California, San Di ego San Diego, California May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Editorial: Preparing for the Maintenance of Certification (MOC) Examination in Rhinology In 2000, the American Board of Medical Specialties (ABMS) adopted Maintenance of Certification (MOC), as a change in physician selfregulation.1 Specifically MOC is designed to encourage physician self-assessment, lifelong learning and continuous performance improvement. Multiple factors brought about this change, including an increase in the complexity of health care delivery that parallels improvements in development of new methods of diagnosis and treatment.2 Consumers became more interested in the delivery of appropriate health care in the setting of unsustainable cost increases, and heightened scrutiny over the use of limited funds. Additionally, technological improvements allowed for more careful monitoring of health care delivery, leading to increased accountability. The demand for increased value, quality and accountability is what effectively led to MOC.2 The idea of MOC was met with a fair amount of controversy. While most physicians support the need to demonstrate their ongoing competence through formal MOC programs, more extensive debates have focused on how to develop MOC methods, how to demonstrate competency, and how to pay for these initiatives.2 The cost-effectiveness of the MOC is also a point of debate. Many physicians were not interested in the time and financial burdens associated with the MOC, given the uncertain benefits and questionable importance. However, the risk of government agencies bypassing the ABMS to institute their own regulations exists, particularly if they are not satisfied with the stringency of the current MOC. There is also a conflict between the desire for change and the transparency of cost effectiveness data on various MOC components. Substantial evidence exists for the need of MOC; studies have shown that up to 12% of physicians fail to maintain standards and patients receive approximately 50% of the care that is indicated for their specific conditions.1 The data consistently shows that physician knowledge and skills, evidence based medicine and outcomes decline, while adverse actions by state licensing boards increase as the time from medical training increases. While various specialty boards are approaching the MOC differently, all MOC programs consist of 4 parts:3 1. 2. 3. 4. Professional standing Continuing education and self-assessment Cognitive experience Performance in practice Each part is meant to enhance physician competence with a goal towards improvement in quality of care and patient outcomes. For MOC part 1, data shows that physician communication skills impact patient satisfaction, quality of life, and outcomes, and have been linked to malpractice as well as state licensing board actions.1 Patient feedback has also been shown to motivate providers to improve communication skills. The feedback from peers and other medical personnel provide reliable, valid information for professional development. Although the data is skewed toward higher ratings, there exists enough variability to distinguish performance levels. Physicians have responded favorably to feedback from peers and coworkers. Both peer and patient assessments may be implemented with time to enhance and maintain professional standing.1 Currently the ABOto requires that all of its diplomats possess a valid ABOto certificate and hold an unrestricted medical license in each state that they practice medicine. Adverse actions taken by state licensing boards, hospitals or others against ABOto diplomats can be communicated to the ABOto via the Disciplinary Alert Notification System (DANS).1 This process allows the ABOto to maintain and enforce standards on its board certified diplomats. American Journal of Rhinology & Allergy Table 13: MOC Part III Subsecialty Areas General Otolaryngology Head and Neck surgery Otology Allergy Pediatrics/bronchoesophagology Laryngology Rhinology Facial plastic surgery Neurotology* Sleep Medicine* *For individuals subcertified in these areas Part II of the MOC process focuses on education and learning. There is increasing data that lifelong learning and continuing medical education (CME) improves physician performance and outcomes.1 Live sessions with multiple media types provide the greatest positive results. Currently the ABOto requires its diplomats to earn as many category 1 CME credits as are required by their state licensing boards. In those states in which there is no CME credit requirement, the ABOto requires a minimum of 15 hours of category 1 CME credits.3 60% of these CME credits must pertain to the specialty of Otolaryngology – Head and Neck surgery. In the future the ABOto may implement patient simulation on-line modules that will allow certified Otolaryngologists to participate in interactive patient cases. Their clinical decisions in these cases can be assessed and areas of deficiencies can be identified in order to provide feedback to assist with ongoing learning.3 The MOC Part III involves medical knowledge and clinical diagnostic reasoning. It has been shown that physicians need strong knowledge and clinical skills in order to appropriately synthesize data, a skill required while making differential diagnoses. Research shows that failure to acquire new knowledge, declining cognitive skills, and inaccuracies in self-assessment support the need for periodic assessment.1 Exam scores correlate with other measures of clinical performance, as well as peer assessment. Board certification has been shown to be associated with better quality of care and outcomes. Currently at the end of a 10 year cycle following initial board certification, diplomats must pass a computer based multiple choice examination. This examination may be made available to the MOC participants three years prior to the expiration of their certificate so that the individual has three opportunities to pass the examination. There are two components to the exam. The first part is a fundamental module that consists of questions that all otolaryngologists should know such as fluid management, ethics, antibiotics, anesthesia and patient safety. The second module is a specialty module that the examinee can choose based on the focus of their practice. These subspecialty modules are outlined in Table 1. The MOC part IV is specifically designed to help physicians assess and improve the quality of safety of their practice and health care in general. Physicians can meet these requirements either through assessment of their own practices using performance based methods or involvement in group, institutional or national QI projects. With the growing changes in health care and initiatives by the Federal government to regulate health care delivery, quality and costs, this component of the MOC will certainly grow in importance and new initiatives by ABMS and ABOto will likely be ongoing.1 The purpose of this supplement is to provide the reader with review articles4–27 and associated board style questions. This MOC Review (available at www.AJRA.com) should help Otolaryngologists Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S1 to study and enhance their medical knowledge in order to prepare them for the MOC part III 10 year examination. Specifically this MOC Review is meant to focus on topics relating to the subspecialties of Allergy and Rhinology. Douglas D. Reh, M.D. David Poetker, M.D. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. S2 Hawkins RE, Lipner RS, Ham HP, et al. American board of medical specialties maintenance of certification: Theory and evidence regarding the current framework. J Contin Educ Health Prof 33(S1):S7–S19, 2013. Van Harrison R, and Olson CA. Evolving health care systems and approaches to maintenance of certification. J Contin Educ Health Prof 33(S1):S1–S4, 2013. Miller RH. Certification and maintenance of certification in otolaryngology – head and neck surgery. Otolaryngol Clin North Am 40: 1347–1357, 2007. Dalgorf DM, Harvey RJ. Chapter 1: Sinonasal anatomy and function. Am J Rhinol Allergy. 27 Suppl 1:S3–6, 2013. Osborn JL, Sacks R. Chapter 2: Nasal obstruction. Am J Rhinol Allergy. 27 Suppl 1:S7–8, 2013. Sacks R, Sacks PL, Chandra R. Chapter 3: Epistaxis. Am J Rhinol Allergy. 27 Suppl 1:S9–10, 2013. Settipane RA, Peters AT, Chandra R. Chapter 4: Chronic rhinosinusitis. Am J Rhinol Allergy. 27 Suppl 1:S11–5, 2013. Settipane RA, Peters AT, Chiu AG. Chapter 6: Nasal polyps. Am J Rhinol Allergy. 27 Suppl 1:S20–5, 2013. Laury AM, Wise SK. Chapter 7: Allergic fungal rhinosinusitis. Am J Rhinol Allergy. 27 Suppl 1:S26–7, 2013. Duggal P, Wise SK. Chapter 8: Invasive fungal rhinosinusitis. Am J Rhinol Allergy. 27 Suppl 1:S28–30, 2013. Hennessey PT, Reh DD. Chapter 9: Benign sinonasal neoplasms. Am J Rhinol Allergy. 27 Suppl 1:S31–4, 2013. Harvey RJ, Dalgorf DM. Chapter 10: Sinonasal malignancies. Am J Rhinol Allergy. 27 Suppl 1:S35–8, 2013, 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. Kohanski MA, Reh DD. Chapter 11: Granulomatous diseases and chronic sinusitis. Am J Rhinol Allergy. 27 Suppl 1:S39–41, 2013. Chaaban MR, Kejner A, Rowe SM, Woodworth BA. Cystic fibrosis chronic rhinosinusitis: A comprehensive review. Am J Rhinol Allergy. 27(5):387–95, 2013. Chandran SK, Higgins TS. Chapter 5: Pediatric rhinosinusitis: definitions, diagnosis and management–an overview. Am J Rhinol Allergy. 27 Suppl 1:S16–9, 2013. Higgins TS, Lane AP. Chapter 12: Surgery for sinonasal disease. Am J Rhinol Allergy. 27 Suppl 1:S42–4, 2013. Simon P, Sidle D. Augmenting the nasal airway: beyond septoplasty. Am J Rhinol Allergy. 26(4):326–31, 2012. Meen EK, Chandra RK. The role of the nose in sleep-disordered breathing. Am J Rhinol Allergy. 27(3):213–20, 2013. Gaines A. Chapter 13: Olfactory disorders. Am J Rhinol Allergy. 27 Suppl 1:S45–7, 2013. Settipane RA, Kaliner MA. Chapter 14: Nonallergic rhinitis. Am J Rhinol Allergy. 27 Suppl 1:S48–51, 2013. Settipane RA, Schwindt C. Chapter 15: Allergic rhinitis. Am J Rhinol Allergy. 27 Suppl 1:S52–5, 2013. Settipane RA, Borish L, Peters AT. Chapter 16: Determining the role of allergy in sinonasal disease. Am J Rhinol Allergy. 27 Suppl 1:S56–8, 2013. Feng CH, Miller MD, Simon RA. The united allergic airway: connections between allergic rhinitis, asthma, and chronic sinusitis. Am J Rhinol Allergy. 26(3):187–90, 2012. Settipane RA, Peters AT, Borish L. Chapter 17: Immunomodulation of allergic sinonasal disease. Am J Rhinol Allergy. 27 Suppl 1:S59–62, 2013. Wise SK, Schlosser RJ. Subcutaneous and sublingual immunotherapy for allergic rhinitis: what is the evidence? Am J Rhinol Allergy. 26(1):18–22, 2012. Lieberman P. The risk and management of anaphylaxis in the setting of immunotherapy. Am J Rhinol Allergy. 26(6):469–74, 2012. Zuraw BL, Christiansen SC. Pathophysiology of hereditary angioedema. Am J Rhinol Allergy. 25(6):373–8, 2011. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Sinonasal anatomy and function Dustin M. Dalgorf, M.D., and Richard J. Harvey, M.D. ABSTRACT An understanding of paranasal sinus anatomy based on important fixed landmarks rather than variable anatomy is critical to ensure safe and complete surgery. The concept of the paranasal surgical box defines the anatomic limits of dissection. The boundaries of the surgical box include the middle turbinate medially, orbital wall laterally, and skull base superiorly. The “vertical component” of the surgical box defines the boundaries of the frontal recess and includes the middle turbinate and intersinus septum medially, medial orbital wall and orbital roof laterally, nasofrontal beak anteriorly, and skull base and posterior table of frontal sinus posteriorly. The paranasal sinuses are divided into anterior, posterior, and sphenoidal functional cavities based on their distinct drainage pathways into the nose. The ultimate goal of surgery is to create a functional sinus cavity. Application of the paranasal surgical box and its vertical component enables the surgeon to view the limits of dissection with a single position of the endoscope. This will ensure complete dissection of the functional sinonasal compartments and effectively avoid leaving behind disconnected cells from the surgical cavity, mucocele formation, mucous recirculation, overcome obstructive phenomenon and enable maximal delivery of topical therapy in the post-operative setting. This article reviews the structure and function of the nasal cartilages and turbinates. It also describes the concept of the paranasal surgical box, key anatomical landmarks and limits of dissection. Normal anatomy and common variants of normal anatomy are discussed. A thorough understanding of sinus anatomy is critical to ensure safe and complete endoscopic sinus surgery. Surgery on the paranasal sinuses is an exercise of anatomic dissection. The sinus surgeon must successfully identify certain key anatomic landmarks to delineate the limits of dissection. These defined anatomic limits establish the boundaries to which paranasal sinus surgery is confined. The concept of the paranasal surgical box forms the basic framework of functional endoscopic sinus surgery. The ultimate goal of surgery is to be able to visualize these limits with a single position of the endoscope. This will ensure removal of obstructive phenomenon, postsurgical mucociliary function that is free of recirculation, and maximal delivery of topical therapy to the sinus cavity in the postoperative setting. The boundaries of the paranasal sinus box include the middle turbinate medially, orbital wall laterally (lamina papyracea), and skull base superiorly. Within the confines of this box, a series of pneumatized air cells and variants of this normal anatomy must be dissected. The boundaries of the vertical component of this box define the frontal sinus recess and include the middle turbinate and intersinus septum medially, orbital wall laterally, nasofrontal beak anteriorly, and skull base and posterior table of the frontal sinus posteriorly. Although much focus is placed on the internal turbinosinus anatomy, the anterior third of the nasal passage has a critical functional role and can greatly influence nasal airflow. The anterior third of the nasal passage is comprised of the nasal cartilages. NASAL CARTILAGES The nasal cartilages are structures consisting of hyaline cartilage that attach to the bones of the anterior nasal aperture to form the From the Applied Medical Research Centre, St. Vincent’s Hospital, University of New South Wales, and Macquarie University, Darlinghurst, Sydney, Australia The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Richard J. Harvey, M.D., 354 Victoria Street, Darlinghurst, New South Wales, Australia, 2010 E-mail address: [email protected]; alternative: [email protected] Originally published in Am J Rhinol Allergy 27, S3–S6, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy skeletal framework of the external nose. These cartilages include the upper and lower lateral cartilages, septum, and sesamoid complex. The nasal septum has a bony portion comprised of the perpendicular plate of the ethmoid bone, vomer, and maxillary crest and the quadrangular cartilage forms the cartilaginous portion of the nasal septum. The lower lateral cartilage is divided into medial, intermediate, and lateral crus that form the natural arch of the nasal ala. The upper lateral cartilages are trapezoid-shaped cartilages that attach to the dorsal septum in the midline, nasal bones cranially, and the lower lateral cartilages caudally via the “scroll” area. All of this anatomy is located anterior to the piriform aperture (Fig. 1). The relationship and architecture of these cartilages form the external and internal nasal valves, which are critical to nasal airflow (Fig. 1). The external nasal valve is comprised of the septum medially, ala rim (lateral crus and fibrofatty/sesamoid complex) laterally, and the nasal sill inferiorly. The internal nasal valve is bounded by the septum medially, caudal edge of the upper lateral cartilage, and inferior turbinate head laterally. Both cartilage integrity and structural and anatomic abnormalities in the nasal cartilages cause nasal airflow obstruction through a narrow space, valve stenosis, or a resulting dynamic valve collapse that is exacerbated during inspiration. NASAL TURBINATES The inferior, middle, and superior nasal turbinates are internal structures found along the lateral nasal wall. The middle and superior turbinates arise from extensions of the ethmoid bones whereas the inferior turbinate is an embryologically independent osseus structure. The space between the lateral nasal wall and the inferior, middle, and superior turbinates is called the inferior, middle, and superior meatus, respectively (Fig. 2). Turbinates are structures filled with vascular channels and venous sinusoids that serve to warm and humidify air and modify nasal airflow resistance. The turbinates continuously dilate and constrict under sympathetic control in response to environmental conditions. A process occurs every 0.5–3 hours in a normal physiological phenomenon known as the “nasal cycle” resulting in alternating congestion and decongestion of the nasal cavities. Turbinate hypertrophy is a common cause of nasal obstruction in which the turbinates are either chronically congested or hypertrophied because of allergic or nonallergic triggers as part of inflammatory rhinitis conditions. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S3 Figure 1. The left internal nasal valve. (A) Sagittal CT scan with green line indicating the level of the internal nasal valve. (B) Endoscopic view of the internal nasal valve including (1) septum, (2) upper lateral cartilage, (3) head of inferior turbinate, and (4) lateral crus as part of the external nasal valve. Figure 2. The left middle meatus. (A) Coronal CT scan including the maxillary sinus outflow tract (yellow arrow), fontanelle (asterisk), medial orbital wall (arrow heads), and Haller cell (white arrow). (B) Endoscopic view of the middle meatus including (1) septum, (2) middle turbinate, (3) uncinate process, (4) ethmoid bulla, and (5) inferior turbinate. PARANASAL SINUSES The paranasal sinuses are paired structures lined by ciliated pseudostratified columnar respiratory epithelium identical to that in the lower airway. The cilia beat in a coordinated fashion to carry the mucous blanket that traps particles from the sinus into the nose through a series of well-defined pathways. The paranasal sinuses are divided into anterior, posterior, and sphenoid functional cavities based on these drainage pathways. The anterior functional cavity is comprised of the maxillary, anterior ethmoid, and frontal sinuses. These sinuses drain into the nose through the ostiomeatal complex in the middle meatus. The posterior ethmoid drains into the nose through the superior meatus and the sphenoid sinus drains through the sphenoethmoid recess located behind the superior turbinate and lateral to the septum. It is important to understand that although the anterior and posterior ethmoid cavities share a common name, they are completely separate functional entities with different drainage pathways. The Anterior Functional Cavity Uncinate Process and Maxillary Sinus. The uncinate process is a sickle-shaped bone that attaches inferiorly to the inferior turbinate and palatine bone and anterosuperiorly to the lacrimal bone. The posterosuperior attachment will be discussed later along with the frontal sinus. The true maxillary ostial opening is covered by the uncinate process and can not be viewed endoscopically in a sinus cavity that has not been previously operated on. The uncinate together with a fold of mucosa called the fontanelle (anterior and posterior) cover the opening to the maxillary sinus. Accessory ostia may be present in the fontanelle that can be mistaken for the true maxillary ostium. Failure to correctly identify the true ostia during any part of sinus surgery will result in a phenomenon known as mucous recirculation. During recirculation, mucous is directed toward the natural opening along the mucociliary drain- S4 age pathway and reenters the sinus through the accessory ostium. On completing the maxillary antrostomy, the first landmark that must be established is the roof of the maxillary sinus. This key landmark defines the floor of the orbit, which is critical in surgical orientation.1 Ethmoid Bulla. The ethmoid bulla is the largest and most consistent anterior ethmoid air cell. It attaches to the lamina papyracea laterally and has variable attachments to the skull base and basal lamella, creating a series of clefts and spaces within the middle meatus that are well described but have little significance clinically. The reader is referred to an article by Kennedy and Stamberger on sinus anatomy nomenclature for a detailed description.2 A variant of normal anatomy in this region is called a Haller cell (infraorbital ethmoid cell), which is an anterior ethmoid cell that pneumatizes into the maxillary sinus causing obstruction (Fig. 3). Removal of the ethmoid bulla is critical to define the medial orbital wall. Middle Turbinate. The basal lamella is formed by the second segment of the middle turbinate. The complex shape of the middle turbinate is divided into three segments according to the sagittal, coronal, and axial planes to which it is oriented. The basal lamella is the component that separates the anterior and posterior ethmoid cavities. This partition is not smooth, because it represents posterior projections of anterior ethmoid air cells and anterior projections of posterior ethmoid air cells. The safe working distance from the skull base established by the maxillary sinus roof is used as a reference point to proceed through the basal lamella and enter the posterior ethmoid cavity because there is no natural connection between the two cavities.1 The middle turbinate is highly variable in size, shape, and often absent secondary to disease or prior surgery and should rarely be used to guide surgery. Frontal Sinus. To dissect the frontal recess to its anatomic limits, one must understand the concept of the vertical component of the May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 3. Left sphenoethmoidal cavity and left frontal recess (A) preoperative CT axial view with bony partitions intact; (B) postoperative CT axial view with removal of bony partitions along the medial orbital wall and skull base; (C) endoscopic view of the paranasal surgical box with limits of anatomic dissection including middle turbinate (thin arrow), medial orbital wall (arrowhead), skull base (asterisk), and sphenoid sinus (thick arrow); (D) preoperative CT sagittal view with bony partitions intact; (E) postoperative CT sagittal view with removal of bony partitions from skull base and frontal recess; and (F) endoscopic view of the frontal recess with demonstration of the “vertical component” of the surgical box boundaries including (1) medial orbital wall, (2) orbital roof, (3) posterior table of frontal sinus, (4) skull base, (5) intersinus septum, and (6) middle turbinate. surgical box that defines the boundaries of the frontal recess (Fig. 3). To define the limits of the frontal recess or vertical component of the surgical box, the endoscopic surgeon must consider the various cells that may encroach on this space from the anterior, posterior, medial, and lateral directions. Agger Nasi, Posterosuperior Uncinate Process, and Frontal Ethmoidal Cells. Anterior structures encroaching on the frontal recess include the agger nasi, lateral uncinate process, and frontal cells. The agger nasi is the anterior most ethmoid air cell and its medial boarder is formed by the uncinate process.3 The uncinate process can insert into the medial orbit, skull base, or middle turbinate. Recent studies have indicated that the uncinate has multiple attachments in ⬎50% of cases.4,5 Classic teaching describing three distinct posterosuperior attachments of the uncinate process, which determines the direction of the frontal sinus drainage pathway, is neither surgically relevant nor accurate. The frontal recess is medial to the uncinate in 85% of cases as medial insertion of the uncinate to the orbita is present.4 Thus, an uncinate with only an attachment to the skull base or lateral lamella (15% of cases) leads to a surgically obvious frontal drainage lateral to the uncinate process.4 The degree of pneumatization of the agger nasi influences the position of the superior uncinate process attachment as well as the thickness of the bony nasofrontal beak. Frontal cells are ethmoid cells that pneumatize above the agger nasi toward the frontal sinus. According to the Bent and Kuhn classification, a type 1 frontal cell is a single frontal ethmoidal cell above the agger nasi, type 2 is a tier of cells above the agger nasi, type 3 is a cell pneumatizing into the floor of the frontal sinus, and type 4 is an isolated frontal ethmoidal cell within the frontal sinus. Wormald further modified this classification using multiplanar reconstructed imaging to more accurately describe type 3 cells as frontal ethmoidal cells that fill ⬍50% of the frontal sinus whereas type 4 cells filled ⬎50% of the frontal sinus.6 The nomenclature of such anatomy is academic and designed to ensure that the surgeon does not dissect into pneumatized air cells and mistake it for the frontal sinus. Supraorbital Ethmoid and Suprabulla Cells. Posterior structures encroaching on the frontal recess include supraorbital ethmoid cells, suprabulla cells, and the ethmoid bulla. Supraorbital ethmoid cells are anterior ethmoid air cells that extend superiorly and laterally over the orbital roof. These cells are recognized on imaging giving the appearance of a septated frontal sinus on coronal view and a cell located posterior and lateral to the frontal sinus on axial view. Supraorbital ethmoid cells have three clinically significant features: first, they can obstruct the frontal recess; second, they can be falsely mistaken for the true frontal sinus leading to incomplete surgery; and, finally, they are associated with a low-lying anterior ethmoid artery because they pneumatize from the skull base be- American Journal of Rhinology & Allergy hind the artery. Suprabulla or frontal bulla cells are pneumatized extensions above the ethmoid bulla up the skull base and on the posterior table of the frontal sinus. These cells can become quite large and can be mistaken for the skull base or frontal sinus. Failure to recognize this preoperatively will also result in incomplete surgical dissection of the frontal recess. Medial structures encroaching on the frontal recess include intersinus septal cells and a medially inserting uncinate process. Intersinus septal cells represent pneumatization of the frontal sinus septum. Lateral encroaching structures include frontal cells, agger nasi and a lateral uncinate process attachment. The Posterior Functional Cavity The posterior functional cavity includes the posterior ethmoid air cells. On passing the basal lamella of the middle turbinate, the posterior ethmoid sinus is entered. A variant of normal anatomy in this region is a lateral pneumatization of a posterior ethmoid cell called an Onodi cell. The clinical significance of this cell is that it can pneumatize over the optic nerve exposing it to injury during surgery. These cells can also be mistaken for the true sphenoid sinus leading to incomplete surgery if not recognized. The Sphenoid Functional Space The second key anatomic landmark during surgery is identification of the sphenoid sinus. The sphenoid ostium is located within the sphenoethmoid recess behind the superior turbinate at the level of the maxillary sinus roof.1 Identification of the sphenoid sinus assists the surgeon in determining the level of the skull base posteriorly at its lowest position. The main contents of the sphenoid sinus include the optic nerve, carotid artery, and sella turcica where the pituitary gland is located. CLINICAL PEARLS • A thorough analysis of preoperative imaging is important to recognize variants of normal anatomy and areas for potential complication to perform safe and complete surgery • Identification of the anatomic limits of dissection applying the concept of the paranasal box (with its vertical “frontal” component) delineates the surgical boundaries and provides a basic framework for endoscopic sinus surgery • Early identification of key anatomic landmarks of the maxillary sinus roof (orbital floor), medial orbital wall, and sphenoid sinus (thus posterior skull base) helps to guide the surgeon throughout the procedure and is critical during revision cases Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S5 • The ultimate goal of surgery is to create a functional sinonasal cavity. Partial posterior ethmoid dissection will fail to achieve this end point. The ability to view the limits of dissection with a single position of the endoscope will avoid leaving behind disconnected cells from the surgical cavity, mucocele formation, mucus recirculation, overcome obstructive phenomenon, and enable maximal delivery of topical therapy in the postoperative setting REFERENCES 1. S6 Harvey RJ, Shelton W, Timperley D, et al. Using fixed anatomical landmarks in endoscopic skull base surgery. Am J Rhinol Allergy 24:301–305, 2010. 2. Stammberger HR, Kennedy DW and Anatomic Terminology G. Paranasal sinuses: Anatomic terminology and nomenclature. Ann Otol Rhinol Laryngol Suppl 167:7–16, 1995. 3. Wormald PJ. The agger nasi cell: The key to understanding the anatomy of the frontal recess. Otolaryngol Head Neck Surg 129:497–507, 2003. 4. Zhang L, Han D, Ge W, et al. Anatomical and computed tomographic analysis of the interaction between the uncinate process and the agger nasi cell. Acta Otolaryngol 126:845–852, 2006. 5. Stamm A, Nogueira JF, Americo RR, and Solferini Silva ML. Frontal sinus approach: The “vertical bar” concept. Clin Otolaryngol 34:407– 408, 2009. 6. Kew J, Rees GL, Close D, et al. Multiplanar reconstructed computed tomography images improves depiction and understanding of the anatomy of the frontal sinus and recess. Am J Rhinol 16:119–123, 2002. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Nasal obstruction Jodi L. Osborn, B.Sc. (Med.), M.B.B.S.,1 and Raymond Sacks, F.C.S., F.R.A.C.S.2,3 ABSTRACT Nasal obstruction is one of the most common presenting symptoms requiring medical attention at both the primary care physician and the otorhinolaryngologists’ level. Nasal obstruction may be caused by anatomic, physiological, or neurologic factors. Complexity is added to this situation because, often, the causation may be multifactorial. Nasal obstruction is the primary symptom of persistent allergic rhinitis (AR) and affects up to 40% of the population. AR must be treated throughout the year; thus, treatment choices and patient compliance must be considered. It is interesting to note that AR directly affects an individual’s quality of life, quality of sleep, and workplace efficiency. Therefore, the magnitude of costs to both the individual and the society must be recognized. Various medical therapies and surgical techniques will be described for the treatment of nasal obstruction. N asal obstruction is a common presenting symptom to both primary care physicians and otorhinolaryngologists. It may be described as a discomfort, manifested as a sensation of insufficient airflow through the nose.1 A range of anatomic, physiological, and neurological/iatrogenic factors may cause nasal obstruction. It is therefore pertinent to always complete a detailed history and thorough physical examination of each patient to appropriately diagnose the cause of their nasal obstruction, remembering it may be multifactorial. Fraser and Kelly2 describe 11 points regarding nasal obstruction that should be covered on history: (1) bilateral, unilateral, or alternating obstruction; (2) duration of symptoms; (3) seasonal or diurnal variations; (4) associated nasal symptoms; (5) sense of smell; (6) other medical problems; (7) previous nasal surgery or trauma; (8) current and past medications; (9) illicit drug, alcohol, and tobacco use; (10) pregnancy; and (11) work/occupation.2 Examination should include assessment of external features of the nose for bony and cartilaginous deformities and evaluation for tip ptosis.2 The nasal valve is the anatomic region first described by Mink in 1903.3 It is the narrowest part of the nasal cavity and is a twodimensional opening between the caudal edge of the upper lateral cartilage and the nasal septum, with a normal angle of 15–20°.4 The internal nasal valve is what Mink originally described, whereas the external nasal valve is the nasal ala and its relationship to the nasal septum.4 Both must be reviewed for sites of obstruction, assessed using Cottle’s maneuver, modified Cottle’s maneuver, and, later, nasendoscopy.4 Anterior rhinoscopy is performed with a Thudichum speculum and a head light before any decongestant therapy2; evaluating the septum, floor of nose, inferior and middle turbinate size and mucosal surface; and identifying any masses, polyps or foreign bodies. Nasendoscopy requires decongestant spray and a flexible or rigid nasendoscope2 performed to further assess mucosal condition. If topical decongestant objectively or subjectively relieves the obstruction, this often correlates with an inflammatory condition as an underlying cause. Endoscopy should note presence of any polyps, granulomaFrom the 1Sydney Adventist Hospital, Hornsby, Australia, 2Australian School of Advanced Medicine at Macquarie University and 3Sydney Medical School at University of Sydney, Sydney, Australia The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Raymond Sacks, F.C.S., F.R.A.C.S., Sydney Adventist Hospital, The ENT Centre, Suite 12, 25–29 Hunter Street, Hornsby, NSW, Australia, 2077 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S7–S8, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy tous disease, abnormalities of middle turbinate or posterior inferior turbinate, postnasal space, and postsurgical changes such as adhesion formation or surgical scarring.5 The neck should be examined for lymphadenopathy, particularly if malignancy is suspected.2 Objective assessment of nasal obstruction includes acoustic rhinometry, nasal peak flow, and rhinomanometry. Although commonly used by investigators during studies, these measures are not universally available or accepted by clinicians; hence, they may be of minimal benefit in medical decision making.6 Investigations may include blood tests for systemic diseases or allergies (radioallergosorbent testing), skin-prick tests, sinonasal swabs if pus is seen, CT of the paranasal sinuses and magnetic resonance imaging if sinonasal neoplasm is suspected or if the patient has signs of possible central nervous system disease.2 Anatomic causes of nasal obstruction include septal deviations, either congenital or acquired, turbinate hypertrophy, or internal or external nasal valve collapse or stenosis.5 When considering causes in children, consideration should also be given to adenoid hypertrophy obstructing the posterior choanae.7 Rare causes of nasal obstruction include foreign bodies within the nose and benign or malignant masses. Physiological causes of nasal obstruction include allergic rhinitis (AR; IgE mediated) or nonallergic rhinitis, including inflammatory, infective (viral or bacterial), hormonal, autonomic, druginduced, systemic disease associated, or occupational.5 AR affects up to 40% of the population and is characterized by nasal obstruction, sneezing, clear/watery rhinorrhea, nasal itch, and ocular symptoms.8 In nonallergic rhinitis, both nasal itch and ocular symptoms, are rare. Nonallergic triggers include perfumes, cold air, weather change, smoke, and chemicals.9 Neurological causes of nasal obstruction include rhinitis medicamentosa, atrophic rhinitis, and empty nose syndrome (ENS). Rhinitis medicamentosa is a medication-induced rhinitis causing rebound nasal congestion due to overuse of topical decongestants, specifically ␣-adrenergic agents.5 Atrophic rhinitis is a chronic nasal pathology that can be classified as either primary or secondary in origin.10 Symptoms include nasal crusting and obstruction, foetor, epistaxis, anosmia or cacosmia, secondary infection, and nasal deformity.10 Classically, these symptoms are found in a roomy nasal cavity resulting from progressive atrophy of nasal mucosa and underlying bone.10 ENS is a rare complication of nasal or sinus surgery, in particular of inferior turbinectomy,11 which was first described by Kern and Moore in 1994.12 ENS has no consensual definition but is distinguished from atrophic rhinitis and is associated with loss of normal endonasal anatomy, especially the absence of one or more turbinates.13 “Paradoxical” nasal obstruction is commonly described by the patient, despite objective examination findings of permeable cavities with no obstacle seen clinically or on CT imaging, Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S7 acoustic rhinometry, or rhinomanometry.11 The pathophysiology of ENS is currently unknown, although several hypotheses exist including loss of physiological nasal functions because of decreased mucosal area, causing a lack of humidification, warming, and filtering of inhaled air.11 This in turn reduces sensory, tactile, and thermal receptors within the nose.11 Central involvement is currently under study, and debate concerns the frequent association with psychiatric disorder and psychosomatic pathologies.13 Surgical treatments for anatomic causes of obstruction include septoplasty for septal deviations/spurs. Moore and Eccles concluded that septal surgery does improve objective measures of nasal patency.14 Surgery on the inferior turbinates remains contentious and is offered to patients with turbinate hypertrophy and severe nasal obstruction despite maximum medical management.2 Current surgery remains more conservative than previous times, with a shift toward mucosal sparing techniques, to maintain normal turbinate function, such as powered submucosal turbinoplasty.2 No randomized control trials of inferior turbinate surgery versus continued medical therapy for AR or comparisons between two differing techniques after maximal medical treatments currently exist.15 Treatment options for nasal valve dysfunction are primarily surgical and are designed to either correct laxity of the lateral nasal wall or to enlarge the cross-sectional area of the nasal valve.4 Currently, there is a trend toward minimally invasive techniques, although open rhinoplastic approaches remain a robust option.4 Surgical options include any combination of (1) autologous cartilage grafts—alar batten, alar strut, spreader, splay, and butterfly; (2) suspension suture techniques—to lateralize or strengthen the lateral component of the nasal valve region; and (3) alloplastic implants—titanium, polyethylene implants. Autologous materials are preferred wherever possible. Treatment of inflammatory physiological causes of nasal obstruction are primarily medical therapies, although surgery may be needed as an additional intervention.8 International guidelines recommend the management of AR and include a combination of treating both the upper and the lower airways, using patient education, allergy avoidance, pharmacologic treatment, and specific immunotherapy.8 Specific pharmacologic therapies include (1) antihistamines—oral or topical, (2) intranasal glucocorticosteroid, (3) leukotriene antagonists, and (4) decongestants—oral or topical. Topical decongestants (␣1agonists) are very effective, although prolonged use risks rebound vasodilatation and rhinitis medicamentosa. Intranasal glucocorticosteroids are first-line pharmacotherapy for obstructive symptoms of rhinitis. Treatment of nonallergic rhinitis is very similar, involving patient education, avoiding triggers, oral decongestants, and intranasal glucocorticosteroids. Notably, cotreatment with intranasal antihistamines displays synergistic effects compared with monotherapy.15 Patients with chronic rhinosinusitis, especially those with diffuse sinonasal polyposis, may manifest nasal obstruction as a significant symptom. This may require functional endoscopic sinus surgery if there is failure of medical therapies. Neurological causes of nasal obstruction are primarily treated with patient reassurance. Treatment of rhinitis medicamentosa also requires weaning the patient off the causative agent over 7–10 days while commencing an oral or intranasal glucocorticosteroids.8 Atrophic rhinitis requires conservative treatment including (1) saline irrigation and douches, (2) nose drops—glucose-glycerine and liquid paraffin, (3) antibiotics and antimicrobials, (4) vasodilators, and (5) prosthesis.10 If surgical treatments are required, they aim to reduce the size of the nasal cavity, encourage regeneration of normal mucosa, improve lubrication of dry nasal mucosa, and increase nasal cavity vascularity.10 Treatment of ENS is primarily prevention, with current surgical techniques now favoring a conservative approach to inferior submucosal turbinoplasty.11 Medical therapies include (1) nasal la- S8 vage, (2) nasal hydration ointment, (3) directed antibacterial therapy, (4) aerosols and local corticosteroids, and (5) psychological support for patients.11 Possible surgical treatments may include creating a neoturbinate with a turbinal or septal cartilage graft to recreate turbinate volume with similar outcome aims to those with atrophic rhinitis surgery.11 CLINICAL PEARLS • Thorough history and examination of the patient is required to correctly identify causative factors. • Causes of nasal obstruction may be defined as anatomic, inflammatory, or neurological/iatrogenic/pseudoobstruction. • Causes of nasal obstruction may be isolated, although are more commonly multifactorial. • If medical treatments are available, then maximum medical therapy should be tried before considering surgical techniques. • A variety of surgical techniques are available for each causative factor. • Because nasal obstruction is commonly multifactorial, multiple surgical techniques may be required for effective treatment of an individual. • Long-term treatment will often require a combination of medical and surgical therapies. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Jessen M, and Malm L. Definition, prevalence and development of nasal obstruction. Allergy 52(suppl 40):3–6, 1997. Fraser L, and Kelly G. An evidence-based approach to the management of the adult with nasal obstruction. Clin Otolaryngol 34:151– 155, 2009. Mink PJ. Le nez Comme Vioe Respiratorie [in French]. Belgium: Presse Otolaryngol, 21:481–496, 1903. Yarlagadda BB, and Dolan RW. Nasal valve dysfunction: Diagnosis and treatment. Curr Opin Otolaryngol Head Neck Surg 19:25–29, 2011. Moche JA, and Palmer O. Surgical management of nasal obstruction. Oral Maxillofac Surg Clin North Am 24:229–237, 2012. Rhee JS, Weaver EM, Park SS, et al. Clinical consensus statement: Diagnosis and management of nasal valve compromise. Otolaryngol Head Neck Surg 143:48–59, 2010. van den Aardweg MTA, Schilder AGM, Herkert E, et al. Adenoidectomy for recurrent or chronic nasal symptoms in children. Cochrane Database Syst Rev 1:CD008282, 2010. (DOI: 10.1002/ 14651858.CD008282.) Wang DY, Tanveer Raza Md, and Gordon BR. Control of nasal obstruction in perennial allergic rhinitis. Curr Opinn Allergy Clin Immumol 4:165–170, 2004. Kim YH, Oh YS, Kim KJ, and Jang TY. Use of cold dry air provocation with acoustic rhinometry in detecting nonspecific nasal hyperreactivity. Am J Rhinol Allergy 24:260–262, 2010. Mishra A, Kawarra R, and Gola M. Interventions for atrophic rhinitis. Cochrane Database Syst Rev 2:CD008280, 2012. (DOI: 10.1002/ 14651858.CD008280.pub2.) Coste A, Dessi P, and Serrano E. Empty nose syndrome. Eur Ann Otorhinol Head Neck Dis 129:93–97, 2012. Moore EJ, and Kern EB. Atrophic rhinitis: A review of 242 cases. Am J Rhinol 15:355–361, 2001. Payne SC. Empty nose syndrome: What are we really talking about? Otolaryngol Clin North Am 42:331–337:ix-x, 2009. Moore M, and Eccles R. Objective evidence for the efficacy of surgical management of the deviated septum as a treatment for chronic nasal obstruction: A systematic review. Clin Otolaryngol 36:106–113, 2011. Jose J, and Coatesworth AP. Inferior turbinate surgery for nasal obstruction in allergic rhinitis after failed medical treatment. Cochrane Database Syst Rev 12:CD005235, 2010. (DOI: 10.1002/ 14651858.CD005235.pub2.) e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Epistaxis Raymond Sacks, F.C.S., F.R.A.C.S.,1,2 Peta-Lee Sacks, MBBS,3 and Rakesh Chandra, M.D.4 ABSTRACT Epistaxis is a common problem that may range in severity from a minor nuisance to hemodynamically significant bleeding. Vascular anatomy allows for predictable identification of suspicious bleeding sites. Historically, packing was the workhorse of management, but, currently, more directed interventions have become available. These modalities may result in improvements in both cost-effectiveness and patient comfort. T he nasal mucosa is supplied by terminal branches of the external and internal carotid arteries. Various anastomoses exist between these two systems, the most important being Kiesselbach’s plexus in the anterior nasal septum. In this location, branches of the anterior ethmoid, nasopalatine, and superior labial arteries anastomose. There is also a contribution from the terminus of the posterior septal artery. This the most common site of epistaxis, and ⬎90% of all epistaxis presentations occur in this area.1 These anastomoses are fundamental to an understanding of epistaxis and its management, underlying the significance of treating the most distal site of bleeding. Epistaxis is often characterized as either anterior or posterior. Historically, these distinctions have been arbitrary, respectively, based on whether or not the practitioner is able to identify the site of bleeding during anterior rhinoscopy. A more useful scheme stratifies the source according to whether it originates anterior or posterior to the maxillary sinus ostium. Anterior bleeding, which usually arises from Kisselbach’s plexus, generally allows for easier visualization and access. In contrast, posterior epistaxis, which usually arises from branches of the sphenopalatine artery, is more difficult to visualize. In this scenario, hemorrhage is often swallowed, resulting in difficulties assessing the amount of blood lost. ETIOLOGY Epistaxis is often idiopathic but can be occasionally caused by underlying pathology such as sinonasal tumor. As such, the following differential should be considered (Table 1). INITIAL ASSESSMENT Initial assessment of epistaxis attempts to estimate the amount of blood lost and the period over which the patient has been bleeding. The patient’s vital signs should be assessed to exclude hypovolemic shock. It may be necessary to obtain i.v. access to check for any From the 1Australian School of Advanced Medicine at Macquarie University, 2Sydney Medical School at University of Sydney, Sydney, Australia, 3School of Medical Sciences, University of New South Wales, Sydney, Australia, and 4Department of Otolaryngology–Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois R Chandra is a consultant/advisor for Intersect ENT, Gyrus/Olympus, and Sunovion and received a research grant from Intersect ENT. P-L Sacks and R Sacks have no conflicts of interest to declare pertaining to this article Address correspondence and reprint request to Raymond Sacks, F.C.S., F.R.A.C.S., Sydney Adventist Hospital, The ENT Centre, Suite 12, 25–29 Hunter Street, Hornsby, NSW, Australia, 2077 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S9 –S10, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy clotting abnormalities and to draw blood for type and screen. The patient should be asked to apply constant pressure over the lower cartilaginous part of the nose for ⬃20 minutes and to avoid swallowing blood in order that blood loss can be estimated. FURTHER EVALUATION Three steps underlie the management of epistaxis: 1. Establishing the site of bleeding 2. Stopping the bleeding 3. Treating the cause of bleeding2 The primary aims of the history are to assess the severity and duration of the nosebleed and the circumstances in which it occurred. The physician should also inquire about any other medical conditions, alcohol consumption, and any history of nosebleeds or bruising. A family history of bleeding should also be considered. Examination begins with anterior rhinoscopy. A significant amount of bleeding may require suction, a headlamp, and a nasal speculum. Topical vasoconstriction using 1% phenylephrine or 0.05% oxymetazoline combined with a topical anesthetic may also be beneficial.3 If no source of bleeding is revealed anteriorly, nasendoscopy should be performed with particular attention to mucosal and submucosal lesions or masses within the middle meatus and nasopharynx. Laboratory investigations may be required according to the severity and frequency of bleeding and may include a full blood count, coagulation studies, and hepatic and renal function tests. These tests may be particularly relevant in patients taking warfarin and in those with diseases that could result in coagulopathy. In the absence of a severe bleed or a personal or family history suggestive of a bleeding disorder, laboratory evaluation for coagulopathy is typically not indicated. Recurrent unilateral epistaxis that fails to respond to conservative management should be investigated for neoplasm, particularly in those who report symptoms of nasal obstruction, rhinorrhea, facial pain, or an abnormal cranial nerve examination.4 MANAGEMENT The approach to managing epistaxis tends to vary according to the severity and location of the bleed as well as a variety of other factors. As discussed previously, initial medical treatment aims to cease the bleeding and is often used to improve visualization during the clinical exam. ANTERIOR EPISTAXIS Should topical vasoconstriction be unsuccessful and an accessible site of bleeding can be identified, cauterization should be implemented.5 This should be performed with caution to avoid damage to Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S9 Table 1 Etiology of epistaxis Local causes Idiopathic Trauma Digit trauma Foreign body Nasal oxygen and CPAP Nasal fracture Postoperative Anatomical Septal deviation Spurs Inflammatory/infectious Viral/bacterial rhinosinusitis Allergic rhinosinusitis Granulomatous disease Environmental irritants Neoplastic Hemangioma of septum or turbinates Hemangiopericytoma Nasal papilloma Pyogenic granuloma Angiofibroma Carcinoma Drugs Topical intranasal corticosteroids Cocaine abuse Systemic causes Inherited Hemophilia Von Willebrand’s disease Hereditary hemorrhagic telangiectasia Platelet abnormalities Thrombocytopenia Platelet dysfunction Malignancy Leukemias Drugs Chemotherapy Chronic alcoholism Anticoagulants, e.g. Warfarin Anti-platelet, e.g. aspirin CPAP ⫽ continuous positive airway pressure. zation,9 and surgical arterial ligation.3 Severe cases typically require one of the two latter methods.10–11 Embolization is performed by a neurointerventional radiologist. This method is ⬎85% effective but carries risks of cerebrovascular accident if particles are released into the internal carotid system iatrogenically or via collateral circulation. Patients may also have postprocedural jaw discomfort and claudication. Presently, transnasal endoscopic sphenopalatine artery ligation or cautery is the primary surgical alternative in these intractable cases. The artery is controlled where it enters into the posterior nasal cavity via the sphenopalatine foramen. This region is situated behind the crista ethmoidalis, a landmark formed by the orbital process of the palatine bone. Overall success is also in the range of 85%, and major complications are rare. Minor complications include nasal crusting and nasal/palatal paresthesias. There is significant debate as to which of these methods, angiography with embolization or endoscopic sphenopalatine artery ligation, is preferred. However, current perspectives indicate that early treatment with either of these modalities is more successful and cost-effective than prolonged inpatient posterior packing, which is markedly uncomfortable and also carries risks including staphylococcal infection, toxic shock syndrome, and bradydysrhythmia. Often, the algorithm for management of severe intractable posterior epistaxis will depend on the resources available at a particular institution. CLINICAL PEARLS • The vast majority of epistaxis arises anteriorly, from Kiesselbach’s plexus in the anterior nasal septum. • Posterior epistaxis can be difficult to visualize but most often arises from branches of the sphenopalatine artery. • Although it may seem trivial to state, it is important to highlight that finding the exact site of the bleeding is critical for safe and efficient management. • Maintain suspicion for underlying neoplastic conditions. • Current trends favor early intervention for posterior epistaxis, with either embolization or sphenopalatine artery ligation, rather than prolonged packing. REFERENCES healthy surrounding mucosa. Cautery can be performed chemically or electrically depending on the severity of the bleed. Silver nitrate sticks, which release oxygen free radicals to coagulate tissue, are useful in minor bleeding; however, it will likely be washed away by severe bleeding before becoming effective. Electric cauterization can be applied to anesthetized mucosa and is more useful in severe bleeding. Laser cauterization has a limited role in acute epistaxis but may be used in patients with hereditary hemorrhagic telangiectasia.3,6 It is important to note that cauterization by any means should be applied only to one side of the septum to avoid perforation over a period of 4–6 weeks.4 Failure of cauterization may indicate the need for nasal packing.5 There are various types of absorbable and nonabsorbable options. Patients with nasal packing should commence topical antibiotics to avoid toxic shock syndrome.3 Other complications of nasal packing include septal hematomas, abscesses, and sinusitis. In the rare case that anterior packing should fail, ethmoidal vessels may be ligated through a Lynch incision. This approach reduces the risk of stroke and blindness associated with embolization of anterior and posterior ethmoid arteries.7 1. 2. 3. 4. 5. 6. 7. 8. 9. POSTERIOR EPISTAXIS 10. Posterior bleeding most commonly arises from branches of the sphenopalatine artery,8 which is the medial (distal) termination of the internal maxillary. The main modes of treatment in these patients include endoscopic electric cauterization, posterior packing, emboli- 11. S10 Douglas R, and Wormald PJ. Update on epistaxis. Curr Opin Otolaryngol Head Neck Surg 15:180–183, 2007. Simmen D, and Jones N. Epistaxis. In Cummings Otolaryngology: Head and Neck Surgery, 5th ed. Flint P, Haughey B, Lund V, et al. (Ed). Philadelphia, PA: Mosby, Elsevier, 682–693, 2010. Gifford TO, and Orlandi RR. Epistaxis. Otolaryngol Clin North Am 41:525–536, viii, 2008. Schlosser RJ. Clinical practice. Epistaxis. N Engl J Med 360:784–789, 2009. Kucik CJ, and Clenney T. Management of epistaxis. Am Fam Physician 71:305–311, 2005. Harvey RJ, Kanagalingam J, and Lund VJ. The impact of septodermoplasty and potassium-titanyl-phosphate (KTP) laser therapy in the treatment of hereditary hemorrhagic telangiectasia-related epistaxis. Am J Rhinol 22:182–187, 2008. Srinivasan V, Sherman IW, and O’Sullivan G. Surgical management of intractable epistaxis: Audit of results. J Laryngol Otol 114:697–700, 2000. Schwartzbauer HR, Shete M, and Tami TA. Endoscopic anatomy of the sphenopalatine and posterior nasal arteries: Implications for the endoscopic management of epistaxis. Am J Rhinol 17:63–66, 2003. Gurney TA, Dowd CF, and Murr AH. Embolization for the treatment of idiopathic posterior epistaxis. Am J Rhinol 18:335–339, 2004. Christensen NP, Smith DS, Barnwell SL, and Wax MK. Arterial embolization in the management of posterior epistaxis. Otolaryngol Head Neck Surg 133:748–753, 2005. Snyderman CH, Goldman SA, Carrau RL, et al. Endoscopic sphenopalatine artery ligation is an effective method of treatment for posterior epistaxis. Am J Rhinol 13:137–140, 1999. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Chronic rhinosinusitis Russell A. Settipane, M.D.,1 Anju T. Peters, M.D.,2 and Rakesh Chandra, M.D.3 ABSTRACT Chronic rhinosinusitis (CRS) is the second most common chronic medical condition in the United States. It represents a group of disorders characterized by inflammation of the nasal mucosa and paranasal sinuses of at least 12 weeks duration. CRS with or without nasal polyps is defined as inflammation of the nose characterized by two or more symptoms, one of which should be either nasal blockage, obstruction, congestion, or nasal discharge (anterior/posterior nasal drip); with or without facial pain/pressure; and/or with or without reduction or loss of smell. Symptomatology should be supported by obvious disease evident in either nasal endoscopy or computed tomography imaging. Although CRS is not likely to be cured by either medical or surgical therapy, it can generally be controlled. Best medical evidence supports maintenance therapy with intranasal corticosteroids and saline irrigation. For exacerbations, short to intermediate courses of antibiotics (up to 4-weeks) with or without oral corticosteroids are recommended. For patients with difficult-to-treat CRS, functional endoscopic sinus surgery provides an adjunctive therapeutic option. C hronic rhinosinusitis (CRS) represents a group of disorders characterized by inflammation of the nasal mucosa and paranasal sinuses of at least 12 weeks duration.1 According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2012,2 rhinosinusitis with or without nasal polyps (NPs) is defined as inflammation of the nose characterized by two or more symptoms, one of which should be either nasal blockage, obstruction, congestion, or nasal discharge (anterior/posterior nasal drip); with or without facial pain/ pressure; and/or with or without reduction or loss of smell. Symptomatology should be supported by obvious disease evident in either nasal endoscopy or computed tomography (CT) imaging. Endoscopic signs include NPs and/or purulent discharge from the middle meatus and/or edema/mucosal obstruction of the middle meatus.3 CT findings include mucosal changes within the ostiomeatal complex and/or sinuses. Although multiple phenotypes exist,4,5 the literature most commonly divides CRS into CRS without NPs (CRSsNPs) and CRS with NPs (CRSwNPs).6 A third entity is known as allergic fungal rhinosinusitis.7 CRSsNPs is the most common form encountered in clinical practice, accounting for ⬃60% of cases,8 and is the focus of this chapter. ASSOCIATED OR PREDISPOSING CONDITIONS OF CRS Associated diseases, predisposing factors, and environmental conditions may contribute to the development of CRS14 (Table 1). In contrast to acute rhinosinusitis, where anatomic pathology and associated obstruction of sinus ostia are of major etiologic contribution, in CRS, anatomic pathology is often a secondary phenomenon, resulting from a persistent mucosal inflammatory state. In CRSsNPs this inflammation may be mixed with a relatively greater proportion of neutrophils than in cases of CRSwNPs, which more commonly present with eosinophilic predominance. As suggested by the united allergic airway theory, eosinophilic inflammation is often present in both the upper and the lower airway.15 Supporting this theory, the incidence of rhinosinusitis is higher among individuals with asthma16; and increasing severity of asthma is associated with increasing severity of CRS and degree of sinonasal tissue eosinophilia.2,15,17 In addition to an association with asthma, increased risk of developing rhinosinusitis is observed in certain systemic conditions such as granulomatosis with polyangiitis (Wegener’s),18 cystic fibrosis, cilia dysmotility syndromes, and various immunodeficiency diseases.19 BURDEN OF ILLNESS RELATED TO CRS PATHOPHYSIOLOGY OF CRS CRS affects all major race/ethnic groups, ranks second in prevalence among all chronic conditions, afflicts ⬃16% of the U.S. population, and is associated with a significant impact on quality of life (QOL).11 In the U.S., CRS direct health care costs are estimated at $8.6 billion annually.12 When indirect costs such as missed workdays and decreased productivity at work are considered, rhinosinusitis ranks among the top 10 most costly health conditions to U.S. employers.13 The pathogenesis of CRS is attributable to a multifactorial inflammatory disorder resulting from a dysfunctional host–environment interaction involving various exogenous agents and changes in the sinonasal mucosa.2 The role of infection in the pathogenesis of CRS is limited and appears to predominantly manifest as an immunologic response to biofilm formation20,21 and/or acute infectious exacerbations. In the latter setting, the organisms that are present are similar to those found in acute rhinosinusitis (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), but with the additional presence of Pseudomonas aeruginosa, Staphylococcus aureus, coagulase-negative staphylococci, Gram-negative enteric bacteria, and various anaerobes.14 Two popular hypotheses for the pathogeneses of CRS, are the “staphylococcal superantigen hypothesis” and the “immune barrier hypothesis.” The staphylococcal superantigen hypothesis has been more often used to explain the Th2 mediated eosinophilic inflammation observed in CRSwNP. It proposes that exposure to Staphylococcus aureus enterotoxins induces an inflammatory mucosal response characterized by a Th2 lymphocytic response with inhibition of regulatory T cells, localized polyclonal IgE formation, and amplification of eosinophilic mucosal inflammation.22–24 The immune barrier hypothesis suggests that a multitude of potential defects in mechanical (epithelial) and immunologic (innate and adaptive) barriers contribute to CRS.25 Among these defects is dysfunction of 9,10 From 1Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, 2Division of Allergy-Immunology, Northwestern University, Chicago, Illinois, and 3Department of Otolaryngology–Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois RA Settipane is on the Speakers Bureau and/or a consultant and/or a research grant recipient for Bausch & Lomb, Meda, Sunovion, and Teva Respiratory. AT Peters is a speaker for Baxter. R Chandra is a consultant/advisor for Intersect ENT, Gyrus/ Olympus, and Sunovion and received a research grant from Intersect ENT Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S11–S15, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S11 blockage, postnasal drip, nasal discharge, pain or pressure, and hyposmia in 50%.2,30 Of clinical importance, many patients with facial pain are misdiagnosed as having sinusitis when migraine or facial headache is the more common etiology.2 Anterior rhinoscopy, although of limited value, remains the first step in physical examination. Nasal endoscopy provides improved visualization and information helpful to confirm diagnosis such as the observation of edema and mucosal obstruction of the middle meatus or purulent discharge from the middle meatus.2 Table 1 Associated or predisposing conditions of CRS Host factors Ciliary impairment Immunodeficiency Aspirin-exacerbated respiratory disease Granulomatous disorders (sarcoid) Vasculitis (Churg-Straus syndrome, granulomatosis with polyangiitis 关Wegener’s兴) Cystic Fibrosis Asthma Allergic rhinitis Environmental factors Allergic (allergic rhinitis and allergic fungal sinusitis) Irritants (tobacco smoke, primary and secondary) Cocaine LABORATORY TESTING IN CRS Source: Adapted from Ref. 14. CRS ⫽ chronic rhinosinusitis. membrane-bound pattern recognition receptors, which include Toll-like receptors.20 Other defects that may increase susceptibility to pathogens include decreased levels of sinonasal epithelium–derived antimicrobial proteins, such as the S100 protein family, S100A7 (psoriasin) and S100A8/A9 (calprotectin).26 Signal transducer and activator of transcription 3 (STAT3), which is a transcriptional mediator for the IL-6 family cytokines, plays a critical role in regulating host defense. Defects in this pathway may contribute to excessive inflammatory response of CRS.27 Taken together, various defects in the immune barrier result in increased microbial colonization,28,29 accentuated barrier damage, and a compensatory and damaging immune response. Although there are no routine laboratory tests recommended for CRS patients, testing may be helpful in specific settings. Cultures taken from the middle meatus under endoscopy control have ⬎80% accuracy and may be helpful in the treatment of acute bacterial exacerbations of CRS as an alternative to empiric antibiotic selection.31 Nasal cytology is of limited value in the diagnosis of CRS but may help to identify underlying eosinophilic inflammation. Nasal biopsy is indicated for the evaluation of unidentified nasal masses or to diagnose inflammatory diseases such as granulomatous disorders and vasculitis. If cystic fibrosis is suspected, consider a sweat chloride test. Ciliary dysfunction may be primary or acquired32; consider ciliary beat frequency analysis (available at only a few centers) and/or electron microscopy. Nasal fractional concentration of exhaled nitric oxide, a marker of sinus mucosal inflammation, may be elevated in CRS with patent sinus ostia33 but is consistently low in the setting if ciliary dyskinesia. Medically refractory CRS, particularly if associated with recurrent lower airway disease, warrants evaluation for common variable immunodeficiency or specific pneumococcal antibody deficiency.34,35 Although the role of antibiotics in CRS is uncertain, if the history suggests potential environmental allergy, consider assessment for specific IgE hypersensitivity.36,37 SYMPTOMS AND PHYSICAL EXAMINATION OF CRS PARANASAL SINUS IMAGING IN CRS The symptoms of CRS are typically of lesser intensity than with acute rhinosinusitis. The most common presenting symptoms of CRS are nasal CT scanning is the imaging modality of choice for the paranasal sinuses; whereas sinus x rays have been deemed to be of limited Table 2 Treatment evidence and recommendations for adults with CRSsNPs*# Therapy Level Grade§ Relevance Steroid—topical Nasal saline irrigation Bacterial lysates (OM-85 BV) Oral antibiotic therapy short term, ⬍4 wk Oral antibiotic therapy long term, ⱖ12 wk¶ Steroid—oral Mucolytics Proton pump inhibitors Decongestant oral/topical Allergen avoidance in allergic patients Oral antihistamine added in allergic patients Herbal and probiotics Immunotherapy Probiotics Antimycotics—topical Antimycotics—systemic Antibiotics—topical Ia Ia Ib II Ib i.v. III III No data i.v. No data No data No data Ib(⫺) Ib(⫺) No data Ib(⫺) A A A B C C C D D D D D D A(⫺) A(⫺) A(⫺) A(⫺) Yes Yes Unclear During exacerbations Yes, especially if IgE is not elevated Unclear No No No Yes No No No No No No No Source: Adapted from Ref. 2. *Some of these studies also included patients with CRS with nasal polyps. #Acute exacerbations of CRS should be treated like acute rhinosinusitis. §Grade of recommendation. ¶Level of evidence for macrolides in all patients with CRSsNP is Ib, and strength of recommendation C, because the two double-blind placebo-controlled studies are contradictory; indication exists for better efficacy in CRSsNP patients with normal IgE the recommendation A. No randomized controlled trials exist for other antibiotics. Ib(⫺) ⫽ Ib study with a negative outcome; A(⫺) ⫽ grade A recommendation not to use; CRS ⫽ chronic rhinosinusitis; CRSsNPs ⫽ chronic rhinosinusitis without nasal polyps. S12 May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm usefulness.2 Despite advances in cone beam CT technology, which has allowed for reduction in radiation dosages,38 significant cost and radiation exposure may still be incurred. Consider CT when unilateral signs and symptoms are present, when there are signs and symptoms suggestive of extrasinus involvement, or when the patient fails to respond to medical therapy.2 It is important to note that abnormal CT imaging findings, such as air–fluid levels, mucosal thickening, or opacification of the sinus cavities, are consistent with but not specific for rhinosinusitis. In fact, incidental abnormalities can be found in up to a fifth of the “normal” population and in the absence of symptoms, are not diagnostic of CRS.39 Adding to the diagnostic challenge, an 87% incidence of sinus disease has been 2 symptoms: one of which should be nasal obstrucon or discolored discharge +/- frontal pain, headache +/- smell disturbance Physical examinaon CT scan and/or endoscopy Consider evaluaon for allergy and potenal predisposing condions* Consider other diagnosis • • • Orbital symptoms • • • • Mild (based on severity assessment**) No serious mucosal disease at endoscopy Moderate/severe (based on severity assessment**) Mucosal disease at endoscopy Unilateral symptoms Bleeding crusng Cacosmia Peri-orbital edema/ erythema Displaced globe Double or reduced vision Ophthalmoplegia Severe frontal headache Frontal swelling Signs of meningis Neurological signs Urgent invesgaon and intervenon Topical steroids Nasal saline irrigaon No improvement aer 3 months Topical steroids Nasal saline irrigaon Culture Consider short term anbiocs for exacerbaons Consider long term anbiocs (if IgE is Normal) CT scan Improvement Consider surgery CT scan if not done before Follow-up + Nasal saline irrigaon Topical steroids Consider long term anbiocs No improvement Consider surgery Follow-up + Topical steroids Nasal saline irrigaon Culture Consider long term anbiocs Figure 1. Chronic rhinosinusitis without nasal polyps (CRSsNPs) in adults: Management algorithm for rhinologists. *See Table 1 for predisposing conditions; **For example: Visual analog score or SNOT-20. CT ⫽ computed tomography. (Source: Adapted from Ref. 2.) American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S13 reported in the early stages of the common cold as documented by CT scan.40 Still, CT scan is cost-effective in ruling out sinusitis when the diagnosis is in doubt after physical (endoscopic) examination. A negative CT scan and endoscopy in the setting of active symptoms effectively rules out CRS. Validated tools, such as the Lund-Mackay system, have become the standard to grade severity of sinus opacification and osteomeatal complex occlusion on CT.41 Magnetic resonance imaging is an alternative that offers improved definition of soft tissue with an ability to differentiate between soft tissue masses (including malignancy) and retained/obstructed secretions. However, in comparison with CT, it does not provide optimal discrimination of air, bone, and soft tissue. MEDICAL TREATMENT OF CRSsNPs Medical treatment options for CRSsNPs have been studied; and evidencebased recommendations (Table 2) and treatment algorithms have been established (Fig. 1).2 Treatment should be based on severity of symptomology using an assessment tool such as the 20-item Sino-Nasal Outcome Test or using a 0- to 10-cm visual analog scale in the context of endoscopic findings.2,42 The treatment of CRS is not curative. The underlying principle of medical management in CRS is control of inflammation and reduction of infectious exacerbations. The goal of treatment is to achieve and maintain “clinical control,” defined as “a disease state in which the patient does not suffer from bothersome symptoms, combined with a healthy or near healthy mucosa and only the need for local medication.”2 “Difficult-to-treat rhinosinusitis” is defined as “those patients who have persistent symptoms of rhinosinusitis despite appropriate treatment” or, more specifically, “patients who do not reach an acceptable level of control despite adequate surgery, intranasal corticosteroid treatment and up to two short courses of antibiotics or systemic corticosteroids in the last year.”2 The first step in CRS management is to identify and address any contributing factors (Table 1). Treatment modalities for which evidence-based “grade A” recommendations exist include intranasal corticosteroids (INCSs) and saline irrigation. Corticosteroids (CS) work by modulating the often eosinophilic inflammatory process underlying CRS.43 Because of insufficient evidence, the use of oral CS in CRSsNPs has earned only a “grade C” evidence-based recommendation and, consequently, oral CS use has been deemed optional.2,44 Evidence for the efficacy of antibiotic treatment of CRSsNPs is generally less robust than for INCS45 and, consequently, their role in the treatment of CRS is limited and most often reserved for patients with purulent sinus drainage. Oral antibacterial antibiotics and prolonged macrolide antibiotics are considered therapeutic options.46 Although there are no Food and Drug Administration–approved antibiotics for the treatment of CRS, a “grade B” evidence-based recommendation exists for antibiotic treatment (⬍4 weeks duration) of acute exacerbations of CRS.2 Antibiotics commonly used are those that are currently Food and Drug Administration approved for the treatment of acute sinusitis. The use of long-term antibiotics (for ⱖ3 months) is less strongly recommended (grade C).2 The therapeutic benefit/risk ratio of antibiotic therapy should be carefully weighed given known associated adverse effects including clostridium difficile colitis, quinolone-induced arrhythmias,47 and risk of tendonitis/tendon rupture,48 as well as macrolide-associated cardiovascular death risk.49 Neither topical nor systemic antifungal treatment is advocated for the management of CRS.2,50 Herbal treatments have been issued a grade D recommendation.2,51 Although nasal saline irrigation can provide symptomatic relief and results in improved QOL, the addition of antibiotics to the irrigation solution has failed to show benefit in double-blind, placebo-controlled trials.2 Alternate irrigation solutions include dilute baby shampoo, which has surfactant effects capable of attacking biofilms.52,53 To prevent potentially lethal amebic meningoencephalitis infection from tap water, only boiled, distilled, or filtered water should be used.54 Additionally, care should be taken to reduce irrigation bottle contamination.55–57 S14 SURGICAL TREATMENT OF CRS Surgery is reserved for patients who fail to respond to medical therapy; and only a small proportion of patients go on to need surgery.58 The primary surgical treatment option for CRS is functional endoscopic sinus surgery (FESS), the benefits of which include the relief of ostial obstruction, removal of inflammatory mucous and biofilm, and improved postoperative delivery of topical CSs to the sinus cavities, which may assist in long-term anti-inflammatory control.59 Balloon sinuplasty has been studied in CRSsNPs and offers an alternate surgical approach.60 Although trials providing high-level evidence of the efficacy of FESS are missing, there is levels II–III evidence that FESS is associated with improved symptoms (nasal obstruction and discharge) and QOL.2,61 Perioperative complications have been reported in 6%, most commonly intraoperative hemorrhage, less commonly cerebrospinal fluid leak.62 CRS SUMMARY In summary, CRS is the second most common chronic medical condition in the United States. Although it is not likely to be cured by either medical or surgical therapy, it can generally be controlled. The best medical evidence supports maintenance therapy with INCSs and saline irrigation. For exacerbations, short courses of antibiotics (up to 4-weeks) with or without oral CSs are recommended. For patients with difficultto-treat CRS, FESS provides an adjunctive therapeutic option. CLINICAL PEARLS • Twelve-week duration of symptoms is required to meet the definition of CRS. • Rhinosinusitis represents a multifactorial inflammatory disorder of the sinonasal mucosa. • Patients with “difficult-to-treat CRS” should be evaluated for immunodeficiency, particularly if there is a history of recurrent otitis media and/or pneumonia. • Based on the relative degree of tissue infiltration, CRSsNPs is more distinctly a neutrophilic process, whereas CRSwNPs is more eosinophilic. • Conditions commonly associated with CRS include asthma and NPs. • Consider CT when unilateral signs and symptoms are present, when there are signs and symptoms suggestive of extrasinus involvement, or when the patient fails to respond to medical therapy. ACKNOWLEDGEMENT The authors wish to thank Davis Settipane for his technical assistance in the creation of Figure 1. REFERENCES 1. Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: Definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 129:S1–S32, 2003. 2. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 23:1–298, 2012. 3. Dalgorf DM, and Harvey RJ. Sinonasal anatomy and function. Am J Rhinol Allergy 27:S3–S6, 2013. 4. Nakayama T, Asaka D, Yoshikawa M, et al. Identification of chronic rhinosinusitis phenotypes using cluster analysis. Am J Rhinol Allergy 26:172–176, 2012. 5. Han JK. Subclassification of chronic rhinosinusitis. Laryngoscope. 123(suppl 2):S15–S27, 2013. 6. Settipane RA, Peters AT, and Chiu AG. Nasal polyps. Am J Rhinol Allergy 27:S20–S25, 2013. 7. Laury AM, and Wise SK. Allergic fungal rhinosinusitis. Am J Rhinol Allergy 27:S26–S27, 2013. 8. Dykewicz MS, and Hamilos DL. Rhinitis and sinusitis. J Allergy Clin Immunol 125:S103–S115, 2010. 9. Collins JG. Prevalence of selected chronic conditions: United States, 1990–1992. Vital Health Stat 10:1–89, 1997. 10. Soler ZM, Mace JC, Litvack JR, and Smith TL. Chronic rhinosinusitis, race, and ethnicity. Am J Rhinol Allergy 26:110–116, 2012. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. Bhattacharyya N. Functional limitations and workdays lost associated with chronic rhinosinusitis and allergic rhinitis. Am J Rhinol Allergy 26:120–122, 2012. Bhattacharyya N. Incremental health care utilization and expenditures for chronic rhinosinusitis in the United States. Ann Otol Rhinol Laryngol 120:423–427, 2011. Bhattacharyya N. Contemporary assessment of the disease burden of sinusitis. The economic burden and symptom manifestations of chronic rhinosinusitis. Am J Rhinol Allergy 23:392–395, 2009. Georgy MS, and Peters AT. Rhinosinusitis. Allergy Asthma Proc 33:S24–S27, 2012. Feng CH, Miller MD, and Simon RA. The united allergic airway: Connections between allergic rhinitis, asthma, and chronic sinusitis. Am J Rhinol Allergy 26:187–190, 2012. Hellings PW, and Hens G. Rhinosinusitis and the lower airways. Immunol Allergy Clin North Am 29:733–740, 2009. Lin DC, Chandra RK, Tan BK, et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy 25:205–208, 2011. Kohanski MA and Reh DD. Granulomatous diseases and chronic sinusitis. Am J Rhinol Allergy 27:S39–S41, 2013. Alqudah M, Graham SM, and Ballas ZK. High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis. Am J Rhinol Allergy 24:409–412, 2010. Sun Y, Zhou B, Wang C, et al. Biofilm formation and Toll-like receptor 2, Toll-like receptor 4, and NF-kappaB expression in sinus tissues of patients with chronic rhinosinusitis. Am J Rhinol Allergy 26:104–109, 2012. Madeo J, and Frieri M. Bacterial biofilms and chronic rhinosinusitis. Allergy Asthma Proc DOI: 10.2500/aap.2013.34.3665 [Epub ahead of print date March 7, 2013]. Van Crombruggen K, Zhang N, Gevaert P, et al. Pathogenesis of chronic rhinosinusitis: Inflammation. J Allergy Clin Immunol 128:728–732, 2011. Kim DW, Khalmuratova R, Hur DG, et al. Staphylococcus aureus enterotoxin B contributes to induction of nasal polypoid lesions in an allergic rhinosinusitis murine model. Am J Rhinol Allergy 25:e255–e261, 2011. Kim ST, Chung SW, Jung JH, et al. Association of T cells and eosinophils with Staphylococcus aureus exotoxin A and toxic shock syndrome toxin 1 in nasal polyps. Am J Rhinol Allergy 25:19–24, 2011. Kern R, Conley D, Walsh W, et al., Perspectives on the etiology of chronic rhinosinusitis: An immune barrier hypothesis. Am J Rhinol 22:549–559, 2008. Tieu DD, Peters AT, Carter RT, et al. Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis. J Allergy Clin Immunol 25:667–675, 2010. Peters AT, Kato A, Zhang N, et al. Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 125:397–403.e10, 2010. Stressmann FA, Rogers GB, Chan SW, et al. Characterization of bacterial community diversity in chronic rhinosinusitis infections using novel culture-independent techniques. Am J Rhinol Allergy 25:e133–e140, 2011. Wood AJ, Fraser JD, Swift S, et al. Intramucosal bacterial microcolonies exist in chronic rhinosinusitis without inducing a local immune response. Am J Rhinol Allergy 26:265–270, 2012. Gaines A. Olfactory disorders . Am J Rhinol Allergy 27:S45–S47, 2013. Benninger MS, Payne SC, Ferguson BJ, et al. Endoscopically directed middle meatal cultures versus maxillary sinus taps in acute bacterial maxillary rhinosinusitis: A meta-analysis. Otolaryngol Head Neck Surg 134:3–9, 2006. Gudis D, Zhao KQ, and Cohen NA. Acquired cilia dysfunction in chronic rhinosinusitis. Am J Rhinol Allergy 26:1–6, 2012. Noda N, Takeno S, Fukuiri T, and Hirakawa K. Monitoring of oral and nasal exhaled nitric oxide in eosinophilic chronic rhinosinusitis: A prospective study. Am J Rhinol Allergy 26:255–259, 2012. Carr TF, Koterba AP, Chandra R, et al. Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. Am J Rhinol Allergy 25:241–244, 2011. Ocampo CJ, and Peters AT. Antibody deficiency in chronic rhinosinusitis: Epidemiology and burden of illness. Am J Rhinol Allergy 27:34–38, 2013. Kennedy JL, and Borish L. Chronic sinusitis pathophysiology: The role of allergy. Am J Rhinol Allergy DOI: 10.2500/ajra.2013.27.3906 [Epub ahead of print date April 18, 2013]. Settipane RA, Borish L, and Peters AT. Determining the role of allergy in sinonasal disease. Am J Rhinol Allergy 27:S56–S58, 2013. Leung R, Chaung K, Kelly JL, and Chandra RK. Advancements in computed tomography management of chronic rhinosinusitis. Am J Rhinol Allergy 25:299–302, 2011. American Journal of Rhinology & Allergy 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. Fokkens W, Lund V, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps group. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl 20:1–136, 2007. Gwaltney JM Jr, Phillips CD, Miller RD, and Riker DK. Computed tomographic study of the common cold. N Engl J Med 330:25–30, 1994. Metson R, Gliklich RE, Stankiewicz JA, et al. Comparison of sinus computed tomography staging systems. Otolaryngol Head Neck Surg 117:372–379, 1997. Piccirillo JF, Merritt MG Jr, and Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT20). Otolaryngol Head Neck Surg 126:41–47, 2002. Ocampo CJ, and Peters AT. Medical therapy as the primary modality for the management of chronic rhinosinusitis. Allergy Asthma Proc 34:132–137, 2013. Poetker DM, Jakubowski LA, Lal D, et al. Oral corticosteroids in the management of adult chronic rhinosinusitis with and without nasal polyps: An evidence-based review with recommendations. Int Forum Allergy Rhinol 3:104–120, 2013. Zeng M, Long XB, Cui YH, and Liu Z. Comparison of efficacy of mometasone furoate versus clarithromycin in the treatment of chronic rhinosinusitis without nasal polyps in Chinese adults. Am J Rhinol Allergy 25:e203–e207, 2011. Soler ZM, Oyer SL, Kern RC, et al. Antimicrobials and chronic rhinosinusitis with or without polyposis in adults: an evidenced-based review with recommendations. Int Forum Allergy Rhinol 3:31–47, 2013. Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 21:1468–1472, 2001. van der Linden PD, Sturkenboom MC, Herings RM, et al. Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med 163:1801–1807, 2003. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 366:1881–1890, 2012. Sacks PL IV, Harvey RJ, Rimmer J, et al. Antifungal therapy in the treatment of chronic rhinosinusitis: A meta-analysis. Am J Rhinol Allergy 26:141–147, 2012. Jiang RS, Wu SH, Tsai CC, et al. Efficacy of Chinese herbal medicine compared with a macrolide in the treatment of chronic rhinosinusitis without nasal polyps. Am J Rhinol Allergy 26:293–297, 2012. Isaacs S, Fakhri S, Luong A, et al. The effect of dilute baby shampoo on nasal mucociliary clearance in healthy subjects. Am J Rhinol Allergy 25:e27–e29, 2011. Rosen PL, Palmer JN, ÓMalley BW, and Cohen NA. Surfactants in the management of rhinopathologies. Am J Rhinol Allergy 27:177–180, 2013. Yoder JS, Straif-Bourgeois S, Roy SL, et al. Primary amebic meningoencephalitis deaths associated with sinus irrigation using contaminated tap water. Clin Infect Dis 55:e79–e85, 2012. Morong S, and Lee JM. Microwave disinfection: Assessing the risks of irrigation bottle and fluid contamination. Am J Rhinol Allergy 26:398–400, 2012. Psaltis AJ, Foreman A, Wormald PJ, and Schlosser RJ. Contamination of sinus irrigation devices: A review of the evidence and clinical relevance. Am J Rhinol Allergy 26:201–203, 2012. Woods CM, Hooper DN, Ooi EH, et al. Fungicidal activity of lysozyme is inhibited in vitro by commercial sinus irrigation solutions. Am J Rhinol Allergy 26:298–301, 2012. McNally PA, White MV, and Kaliner MA. Sinusitis in an allergist’s office: Analysis of 200 consecutive cases. Allergy Asthma Proc 18:169–175, 1997. Snidvongs K, Kalish L, Sacks R, et al. Sinus surgery and delivery method influence the effectiveness of topical corticosteroid for chronic rhinosinusitis: Systematic review and meta-analysis. Am J Rhinol Allergy 27:221–233, 2013. Koskinen A, Penttilä M, Myller J, et al. Endoscopic sinus surgery might reduce exacerbations and symptoms more than balloon sinuplasty. Am J Rhinol Allergy 26:e150–e156, 2012. Smith TL, Kern R, Palmer JN, et al. Medical therapy vs surgery for chronic rhinosinusitis: A prospective, multi-institutional study with 1-year followup. Int Forum Allergy Rhinol 3:4–9, 2013. Asaka D, Nakayama T, Hama T, et al. Risk factors for complications of endoscopic sinus surgery for chronic rhinosinusitis. Am J Rhinol Allergy 26:61–64, 2012. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S15 Nasal polyps Russell A. Settipane, M.D.,1 Anju T. Peters, M.D.,2 and Alexander G. Chiu, M.D.3 ABSTRACT Nasal polyps occur in 1– 4% of the population, usually occurring in the setting of an underlying local or systemic disease. The most common associated condition is chronic rhinosinusitis (CRS). A high prevalence of nasal polyps is also seen in allergic fungal rhinosinusitis, aspirin-exacerbated respiratory disease, Churg-Strauss syndrome, and cystic fibrosis. In the setting of CRS, nasal polyps are not likely to be cured by either medical or surgical therapy; however, control is generally attainable. The best medical evidence supports the use of intranasal corticosteroids for maintenance therapy and short courses of oral corticosteroids for exacerbations. The evidence for short- and long-term antibiotics is much less robust. For patients with symptomatic nasal polyposis nonresponsive to medical therapies, functional endoscopic sinus surgery provides an adjunctive therapeutic option. N asal polyps, which were first described over 5000 years ago as “grapes coming down the nose” by the ancient Greeks,1 are inflammatory outgrowths of sinonasal epithelium. They manifest as edematous semitransluscent lobular masses in the nasal and paranasal cavities (typically bilateral), originating from the mucosal lining of the sinuses, most commonly middle nasal meatus and ethmoid cells.2 The severity of polyposis is often classified based on the degree of polyp extension beyond the middle meatus: confined within the middle meatus, extending beyond the middle meatus, or filling the entire nasal cavity. scribed in patients with nasal polyps compared with the general population, because higher rates of nasal polyps have not been consistently observed in allergic rhinitis, the role of allergy in CRSwNPs remains unclear5,16–18 This is supported by the epidemiologic observation that the prevalence of nasal polyps in allergic rhinitis is comparable with that seen in the normal population.5 However, when atopy is present in the setting of nasal polyps, it is associated with lower quality of life scores and a higher incidence of asthma.18 HISTOPATHOLOGY OF NASAL POLYPS EPIDEMIOLOGY OF NASAL POLYPS Nasal polyps are common, affecting from 1 to 4% of the general population.3 They occur in all races,4 have a male predominance, and are more common after age 40 years.5 Childhood presentation (aged ⬍16–20 years) is rare and in the pediatric setting raises suspicion for the diagnosis of cystic fibrosis.6 CONDITIONS ASSOCIATED WITH NASAL POLYPS Nasal polyps usually occur in the setting of an underlying local or systemic disease (Table 1),7 with the most commonly observed association being chronic rhinosinusitis (CRS).8 Although many different CRS phenotypes exist,9–11 up to one-third of all cases are associated with nasal polyps.12 Compared with CRS without nasal polyps (CRSsNPs), in CRS with nasal polyps (CRSwNPs), patients generally suffer more severely, have a greater burden of symptoms, more prior surgery, higher CT scan scores, and greater use of medications.13,14 High rates of nasal polyp prevalence are also seen in allergic fungal rhinosinusitis,15 aspirin-exacerbated respiratory disease (AERD), ChurgStrauss syndrome, cystic fibrosis, primary ciliary dyskinesia, asthma, and Young’s syndrome (Table 1).7 Of note, allergy is omitted from the aforementioned list. Although a higher rate of atopy has been deFrom the 1Department of Medicine, Warren Alpert Medical School of Brown University Providence, Rhode Island, 2Division of Allergy-Immunology, Northwestern University, Chicago, Illinois, Division of Otolaryngology, 3Department of Surgery, University of Arizona, Tucson, Arizona RA Settipane is on the Speakers Bureau and/or a consultant and/or a research grant recipient for Bausch & Lomb, Meda, Sunovion, and Teva Respiratory. AT Peters is a speaker for Baxter. AG Chiu is a consultant for Olympus Gyrus Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S20 –S25, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S16 Histologically, the mucosal surface of nasal polyps consists of respiratory epithelium and an edematous stroma infiltrated by inflammatory cells.20 Polyp mucosa exhibits a markedly greater inflammatory infiltrate and a lesser density of mucous glands than inferior turbinate mucosa. In the United States and Europe, nasal polyps are accompanied by an eosinophilic infiltrate in ⬃80% of cases; whereas in Asia they are more likely to be associated with a noneosinophilic or neutrophilic infiltrate and Th1/17 cytokine skewing.21 Correlating with reduced eosinophilic inflammation, a very low rate of AERD has been observed in Chinese patients with CRSwNPs.22 It is interesting to note that over a 12-year period (from 1999 to 2011), a shift from predominantly neutrophilic to eosinophilic inflammation was recently observed in Asian (Thai) patients with CRSwNPs in association with an increase in intramucosal presence of Staphylococcus aureus.23 Neutrophilic inflammation is also a consistent finding in the nasal polyps found in cystic fibrosis.24 PATHOGENESIS OF NASAL POLYPS Because CRSwNPs is the most common condition in which polyps are observed, the discussion of the etiology, pathogenesis, and treatment of nasal polyps will be limited to this association. There is an emerging consensus that the persistent inflammation that defines CRSwNP results from dysfunctional host–environment interaction involving various exogenous agents and changes in the sinonasal mucosa.5 Several pathophysiological hypotheses have been put forth (Table 2)25; however, the initiating event, which triggers the formation of nasal polyps, remains unknown. Investigation of the potential contributory role of microorganisms to CRSwNP pathogenesis has focused on several areas including the role of sinus microbiology and the immune response to S. aureus superantigens, biofilms, and/or fungi. Subject to debate is the clinical significance of the microbiology of CRSwNPs, which is similar to CRSsNPs. Although biofilms have been observed to be highly prevalent in association with high rates of S. aureus colonization and May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 Prevalence of nasal polyposis in association with other conditions Condition Prevalence AERD Adult asthma IgE mediated Non-IgE mediated CRS in adults Rhinitis Nonallergic rhinitis Allergic rhinitis Childhood asthma/sinusitis Cystic fibrosis Children Adults Churg-Strauss syndrome Allergic fungal sinusitis Primary ciliary dyskinesia (Kartagener’s) Young’s syndrome (azoospermia) 15–23% 7% 5% 13% 33% 5% 1.5% 0.1% 10% 50% 50% 66–100% 40% ? Source: Adapted from Ref. 7. AERD ⫽ aspirin exacerbated respiratory disease; CRS ⫽ chronic rhinosinusitis. Table 2 CRSwNPs: Pathophysiological hypotheses Microorganisms Staphylococcal superantigen hypothesis Biofilms Fungal hypothesis Immune barrier hypothesis Excessive Th2 response Defects in eicosanoid pathway Source: Adapted from Ref. 25. CRSwNPs ⫽ chronic rhinosinusitis with nasal polyps. Table 3 Benign lesions simulating nasal polyps Anatomic Concha bullosa Tumors Epithelial Papilloma—inverted, everted, and cylindric Minor salivary—pleomorphic adenoma Mesenchymal Neurogenic—meningioma, schwannoma, and neurofibroma Vascular—hemangioma and angiofibroma Fibro-osseous—ossifying fibroma muscular—leiomyoma and angioleiomyoma Granulomatous/inflammatory Wegener’s granulomatosis Sarcoidosis Crohn’s disease Source: Adapted from Refs. 41 & 70. Table 4 Malignant lesions simulating polyps Epithelial Squamous cell carcinoma Adenocarcinoma Adenoid cystic carcinoma Acinic cell carcinoma Mucoepidermoid carcinoma Olfactory neuroblastoma Malignant melanoma Metastatic tumors, e.g., kidney, breast, and pancreas Undifferentiated carcinoma Mesenchymal tumors Lymphoreticular—lymphoma and plasmacytoma Rhabdomyosarcoma Chondrosarcoma Ewing’s sarcoma Source: Adapted from Refs. 41 & 71. production of specific IgE to S. aureus,26 their role is not clear. The “staphylococcal superantigen hypothesis” proposes that exposure to S. aureus enterotoxins induces a Th2 lymphocytic response with inhibition of regulatory T cells, localized polyclonal IgE formation, and amplification of eosinophilic mucosal inflammation.27–29 Except for the CRS subtype known as allergic fungal rhinosinusitis,15 evidence for fungi in the pathogenesis of CRSwNPs appears to be limited to playing a role as a disease modifier.5 The “immune barrier hypothesis” suggests that a multitude of potential defects in mechanical (epithelial) and immunologic (innate and adaptive) barriers contribute to CRS.30 Among these defects is dysfunction of membrane bound pattern recognition receptors, which include Toll-like receptors.31 Other defects that may increase susceptibility to pathogens include decreased levels of sinonasal epithelium– derived antimicrobial proteins, such as the S100 protein family, S100A7 (psoriasin), and S100A8/A9 (calprotectin).32 Signal transducer and activator of transcription 3 (STAT3), which is a transcriptional mediator for the IL-6 family cytokines, plays a critical role in regulating host defense. Defects in this pathway may contribute to the excessive inflammatory response of CRS.33 Taken together, various defects in the immune barrier result in increased microbial colonization,34,35 accentuated barrier damage, and a compensatory and damaging immune response. B-cell activating factor of the TNF family levels are elevated in nasal polyp tissue and are important in B-cell survival, proliferation, and antibody production.36 Overproduction of B-cell activating factor of the TNF family may lead to B-cell proliferation and contribute to the excessive Th2 skewing as well as the generation of local antibodies American Journal of Rhinology & Allergy that may further accentuate tissue damage. Nasal polyps from patients with CRS possess increased levels of both B cells and plasma cells, which actively produce local antibodies.37 Finally, aberrant arachidonic acid metabolism has been implicated in the pathogenesis of CRSwNPs in the subset of patients with AERD, which represents 15–23% of nasal polyp patients.38,39 Inflammation in these patients is characterized by higher respiratory tract levels of cyclooxygenase and 5-lipoxygenase products (leukotrienes) as well as increased respiratory tract expression of the cysteinyl leukotriene 1 receptor and leukotriene C4 synthase).40 DIFFERENTIAL DIAGNOSIS OF NASAL POLYPS Although nasal polyps have a characteristic appearance, other nasal masses, benign or malignant, may be mistaken for polyps (Tables 3 and 4).41 Although nasal polyps in CRS are almost always bilateral, a unilateral polypoid nasal mass raises the potential of malignancy.12 Common benign lesions mistaken for nasal polyps in adults include concha bullosa (pneumatization of the middle turbinate) and inverted papilloma,42 whereas malignant lesions such as esthesioneuroblastomas and squamous cell carcinoma often present as a unilateral mass. In children, a juvenile angiofibroma may be mistaken for a nasal polyp. The differential diagnosis of nasal masses in childhood differs from adults (Table 5).41 The occurrence of true nasal polyps in children warrants an evaluation for cystic fibrosis.7 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S17 Table 5 Differential diagnosis of a nasal mass in a child Congenital Encephalocele Glioma Dermoid cyst Nasolacrimal duct cyst Neoplasia Benign—craniopharyngioma, hemangioma, and neurofibroma Malignant—rhabdomyosarcoma Table 6 Treatment evidence and recommendations for adults with CRSwNPs* Therapy Level Grade# Topical steroids Oral steroids Oral antibiotics short term, ⬍4 wk Oral antibiotics long term ⱖ12 wk Ia Ia 1b and 1b(⫺) A A C§ Yes Yes Yes, small effect III C Capsaicin Proton pump inhibitors Aspirin desensitization Furosemide Immunosuppressants Nasal saline irrigation II II II III i.v. Ib, No data in single use No data No data No data No data in single use No data No data C C C D D D D D D D Yes, especially if IgE is not elevated, small effect No No Unclear No No Yes, for symptomatic relief No Unclear No No D D No No Ia (⫺) Ib(⫺) Ib(⫺) Ib(⫺) A(⫺) A(⫺) A(⫺) A(⫺) No No No No Source: Adapted from Ref. 41. SIGNS AND SYMPTOMS OF NASAL POLYPS Symptoms of nasal polyps range from partial to complete nasal obstruction and from hyposmia to complete anosmia.43 Symptom severity can be assessed on a 10-cm visual analog scale.5 On exam, polyps appear as semitranslucent, pale gray or pink, lobular mucosal tissue within the nasal cavity, and possess a smooth and glistening surface when light is applied. On probing, polyp tissue is mobile and easily depressed in comparison with the firm texture of the inferior turbinate or other masses. Nasal endoscopy is recommended to fully evaluate the size and location of the nasal polyps, as well as to gauge their response to medication. LABORATORY TESTING AND PARANASAL SINUS IMAGING Recommendations for laboratory testing and sinus imaging are similar for both CRSwNPs and CRSsNPs.8 MEDICAL TREATMENT OF CRSwNP Medical treatment options have been fairly well established for corticosteroids but less well for antibiotics and other immunomodulatory agents.5,44 Evidence-based recommendations are described in Table 6.5 Treatment should be based on severity of symptomology (Fig. 1).5 “Grade A” evidence-based recommendations support the use of both intranasal corticosteroids (INCSs) and oral corticosteroids, as treatments for CRSwNPs.5 Corticosteroids have broad anti-inflammatory effects.45–48 INCSs are recommended as first-line therapy for moderate to severe disease both before and after polypectomy.5 Except for aqueous mometasone,49 most topical INCS formulations are used “off –Food and Drug Administration (FDA)–approved labeling” for CRSwNPs, including both aerosol and aqueous corticosteroid preparations, as well as drops and irrigations. In a recent Cochrane review of 40 studies involving 3624 patients, topical corticosteroids improved overall symptom scores, decreased polyp score, decreased polyp size, and prevented polyp recurrence after surgery.50 In a recent meta-analysis report of the effect of topical nasal steroid therapy on symptoms of nasal polyposis, all three topical steroid preparations that were studied (fluticasone, mometasone, and budesonide) resulted in significant improvement.51 Despite the efficacy of topical steroids, when treating severely symptomatic patients, it is often preferable to prescribe short courses (ⱕ2 weeks) of oral steroids to acutely reduce polyp size.52–55 Maintenance therapy with INCSs is necessary for long-term control of the inflammation that underlies CRSwNPs. The evidence for the use of oral antibiotics is less robust.56 “Grade C” evidence-based recommendations support treatment with shortterm antibiotics (⬍4weeks) for CRS exacerbations when features suggestive of acute bacterial rhinosinusitis are present. Longer-term macrolide therapy may be an option, particularly in the setting of low circulating IgE (“grade C” recommendation).57 Oral doxycycline has been shown to have a modest effect in reducing polyp size and decreasing inflammation but the effect is less than that of oral ste- S18 Relevance Topical antibiotics Anti-IL-5 Phytotherapy Decongestant topical/oral Mucolytics Oral antihistamine in allergic patients Antimycotics—topical Antimycotics—systemic Anti leukotrienes Anti-IgE ⬎Source: Adapted from Ref. 5. *Some of these studies also included patients with CRS with nasal polyps. #Grade of recommendation. §Short-term antibiotics shows one positive and one negative study; therefore, recommendation C. ¶Ia(⫺) ⫽ Ia level of evidence that treatment is not effective; Ib(⫺) ⫽ Ib study with a negative outcome; A(⫺) ⫽ grade A recommendation not to use; CRSwNPs ⫽ chronic rhinosinusitis with nasal polyps. roids.55 The therapeutic benefit/risk ratio of antibiotic therapy should be carefully weighed given known antibiotic-associated adverse effects including Clostridium difficile colitis, quinolone-induced arrhythmias,58 and risk of tendonitis/tendon rupture59 as well as macrolideassociated cardiovascular death risk.60 With regard to topical antibiotics, only “grade D” evidence exists; and antifungal therapy, whether intranasal or oral, is not advised.5 Adequate studies of allergy immunotherapy for CRSwNPs are nonexistent.16 In AERD patients, aspirin desensitization has been shown to modulate aberrant arachidonic acid metabolism by reducing leukotriene C4 levels in nasal secretions, lowering the expression of cysteinyl leukotriene receptors and decreasing polyp recurrence rates.61,62 Anti-IgE for CRSwNPs holds promise, but trials thus far have resulted in inconsistent outcomes.63,64 Anti-IL5 warrants further investigation because of its ability to reduce eosinophilic inflammation and polyp size.65 SURGICAL TREATMENT OF NASAL POLYPS Surgery is reserved for cases when polyps are associated with severe symptoms, recurrent sinusitis, and for patients refractory to medical therapy.44 The primary surgical treatment option for CRS is functional endoscopic sinus surgery (FESS), the benefits of which include the removal of polyps, inflammatory mucin and May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 2 symptoms: one of which should be nasal obstrucon or discolored discharge +/- frontal pain, headache +/- smell disturbance Physical examinaon CT scan and/or endoscopy (size of polyps) Consider evaluaon for allergy and associated condions* Consider other diagnosis • • • Orbital symptoms • • • • Mild (based on severity assessment**) No serious mucosal disease at endoscopy Moderate (based on severity assessment**) Mucosal disease at endoscopy Topical CS spray Topical steroid spray Consider increase dose Consider CS drops Consider oral CS Severe (based on severity assessment**) Mucosal disease at endoscopy Topical CS Oral CS (short course) Review aer 1-3 months Improvement Unilateral symptoms Bleeding crusng Cacosmia Peri-orbital edema/ erythema Displaced globe Double or reduced vision Ophthalmoplegia Severe frontal headache Frontal swelling Signs of meningis Neurological signs Urgent invesgaon and intervenon Review aer 1 month No improvement Consider aspirin desensizaon for AERD Consider AFRS Improvement Connue with topical CS No improvement Consider aspirin desensizaon for AERD Consider AFRS CT scan Review every 6 months Follow up + Nasal irrigaon + Topical ± oral CS ± Long term anbiocs Surgery Figure 1. CRSwNPs in adults: Management algorithm for rhinologists. *See Table 1 for associated conditions; **For example: Visual analog score or SNOT-20. CRSwNPs ⫽ chronic rhinosinusitis with nasal polyps; SNOT-20 ⫽ 20-item Sino-Nasal Outcome test; VAS ⫽ visual analog score; CS ⫽ corticosteroid; CT ⫽ computed tomography; AERD ⫽ aspirin-exacerbated respiratory disease; AFRS ⫽ allergic fungal rhinosinusitis. (Source: Adapted from Ref. 5.) biofilms; the elimination of ostial obstruction66; and the improved postoperative delivery of topical therapy into the sinuses.5 Although trials providing high-level evidence of the efficacy of FESS are missing, there is levels II–III evidence that FESS is associated American Journal of Rhinology & Allergy with improved symptoms (nasal obstruction and discharge) and quality of life.5,67,68 Perioperative complication has been reported in 6%, most commonly intraoperative hemorrhage, less commonly CSF leak.69 Despite optimal medical and surgical therapy for nasal Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S19 polyps, the underlying inflammation often remains difficult to control; consequently, there is a fairly high recurrence rate for nasal polyps. NASAL POLYP SUMMARY In summary, nasal polyps occur in 1–4% of the population, usually occurring in the setting of an underlying local or systemic disease. The most common associated condition is CRS. High prevalence of nasal polyps are also seen in allergic fungal sinusitis, AERD, ChurgStrauss syndrome, cystic fibrosis, CRS, primary ciliary dyskinesia, asthma, and Young’s syndrome. In the setting of CRS, nasal polyps are not likely to be cured by either medical or surgical therapy; however, control is generally attainable. The best medical evidence supports the use of INCSs for maintenance therapy and short courses of oral corticosteroids (⬍4weeks) for exacerbations. The evidence for short- and long-term antibiotics is much less robust. For patients with difficult-to-treat CRSwNPs, FESS provides an adjunctive therapeutic option. 11. 12. 13. 14. 15. 16. 17. 18. 19. CLINICAL PEARLS • Nasal polyps typically arise from the middle meatus and ethmoid region. • Nasal polyps are most commonly associated with CRS. • Fifteen to 23% of nasal polyp patients have AERD. • The presence of a unilateral polypoid mass suggests a higher risk for malignancy. • Prominent symptoms of nasal polyps include nasal obstruction and hypo/anosmia. • In the pediatric population, the occurrence of nasal polyps warrants a sweat test evaluation for cystic fibrosis. • Intranasal steroids and intermittent oral steroids are the mainstay of medical therapy. • FESS is reserved for patients whose condition proves difficult to treat and who manifest persistent symptoms despite medical therapy. 20. ACKNOWLEDGEMENT 26. The authors wish to thank Davis Settipane for his technical assistance in the creation of Figure 1. 27. 21. 22. 23. 24. 25. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. S20 Brain DJ. Historical background. In Nasal Polyps: Epidemiology, Pathogenesis and Treatment. 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Medical therapy as the primary modality for the management of chronic rhinosinusitis. Allergy Asthma Proc 34:132–137, 2013. Salman S, Akpinar ME, Yigit O, and Gormus U. Surfactant protein A and D in chronic rhinosinusitis with nasal polyposis and corticosteroid response. Am J Rhinol Allergy 26:e76–e80, 2012. Park SK, Hur DY, and Urm SH. Effects of dexamethasone or methotrexate on chitinolytic activity in nasal polyps. Am J Rhinol Allergy 26:183–186, 2012. Acıoğlu E, Yigit O, Alkan Z, et al. The effects of corticosteroid on tissue lactoferrin in patients with nasal polyposis. Am J Rhinol Allergy 26:e28–e31, 2012. Small CB, Hernandez J, Reyes A, et al. Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. J Allergy Clin Immunol 116:1275–1281, 2005. Kalish L, Snidvongs K, Sivasubramaniam R, et al. Topical steroids for nasal polyps. Cochrane Database Syst Rev 12:CD006549, 2012. Rudmik L, Schlosser RJ, Smith TL, and Soler ZM. Impact of topical nasal steroid therapy on symptoms of nasal polyposis: A metaanalysis. Laryngoscope 122:1431–1437, 2012. Vaidyanathan S, Barnes M, Williamson P, et al. Treatment of chronic rhinosinusitis with nasal polyposis with oral steroids followed by topical steroids: A randomized trial. Ann Intern Med 154:293–302, 2011. Kirtsreesakul V, Wongsritrang K, and Ruttanaphol S. Does oral prednisolone increase the efficacy of subsequent nasal steroids in treating nasal polyposis? Am J Rhinol Allergy 26:455–462, 2012. American Journal of Rhinology & Allergy 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. Poetker DM, Jakubowski LA, Lal D, et al. Oral corticosteroids in the management of adult chronic rhinosinusitis with and without nasal polyps: An evidence-based review with recommendations. Int Forum Allergy Rhinol 3:104–120, 2012. Van Zele T, Gevaert P, Holtappels G, et al. Oral steroids and doxycycline: Two different approaches to treat nasal polyps. J Allergy Clin Immunol 125:1069–1076.e4, 2010. Soler ZM, Oyer SL, Kern RC, et al. Antimicrobials and chronic rhinosinusitis with or without polyposis in adults: An evidencedbased review with recommendations. Int Forum Allergy Rhinol 3:31– 47, 2013. Wallwork B, Coman W, Mackay-Sim A, et al. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope 116:189–193, 2006. Frothingham R. Rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy 21:1468–1472, 2001. van der Linden PD, Sturkenboom MC, Herings RM, et al. Increased risk of achilles tendon rupture with quinolone antibacterial use, especially in elderly patients taking oral corticosteroids. Arch Intern Med 163:1801–1807, 2003. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 366:1881–1890, 2012. White AA, and Stevenson DD. Aspirin-exacerbated respiratory disease: Update on pathogenesis and desensitization. Semin Respir Crit Care Med 33:588–594, 2012. Moebus RG, and Han JK. Immunomodulatory treatments for aspirin exacerbated respiratory disease. Am J Rhinol Allergy 26:134–140, 2012. Pinto JM, Mehta N, DiTineo M, et al. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology 48:318–324, 2010. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 131:110–116.e1, 2013. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 128:989–995.e1–8, 2011. Leung RM, Kern RC, Conley DB, et al. Osteomeatal complex obstruction is not associated with adjacent sinus disease in chronic rhinosinusitis with polyps. Am J Rhinol Allergy 25:401–403, 2011. Smith TL, Kern R, Palmer JN, et al. Medical therapy vs surgery for chronic rhinosinusitis: A prospective, multi-institutional study with 1-year follow-up. Int Forum Allergy Rhinol 3:4–9, 2013. Gunhan K, Zeren F, Uz U, et al. Impact of nasal polyposis on erectile dysfunction. Am J Rhinol Allergy 25:112–115, 2011. Asaka D, Nakayama T, Hama T, et al. Risk factors for complications of endoscopic sinus surgery for chronic rhinosinusitis. Am J Rhinol Allergy 26:61–64, 2012. Hennessey PT, and Reh DD. Benign sinonasal neoplasms. Am J Rhinol Allergy 27:S31–S34, 2013. Harvey RJ, and Dalgorf DM. Sinonasal malignancies. Am J Rhinol Allergy 27:S35–S38, 2013. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S21 Allergic fungal rhinosinusitis Adrienne M. Laury, M.D., and Sarah K. Wise, M.D., M.S.C.R. ABSTRACT Allergic fungal rhinosinusitis (AFRS) is a type of chronic rhinosinusitis in which patients classically exhibit nasal polyps, type I IgE-mediated hypersensitivity, characteristic findings on computed tomography scans, eosinophilic mucin, and positive fungal stain. New research has sought to further understand the pathophysiology of AFRS. However, this has also led to debate about the classification and predominance of this interesting disease process. Historically, patients with AFRS are immunocompetent. The disease is most prevalent in the southeast and south central United States and typically presents with sinus pressure, hyposmia, and congestion. Radiographically, cases of AFRS have a distinct appearance, often exhibiting unilateral heterogeneously dense material, which may erode and expand the paranasal sinus bony walls. Treatment typically consists of surgery, sinonasal irrigations, and topical and systemic steroids, all with the effort to decrease the fungal load and antigenic response. Immunotherapy is also often included in the treatment regimen for AFRS. A llergic fungal rhinosinusitis (AFRS) is a class of chronic rhinosinusitis (CRS) first described 30 years ago by Miller and colleagues.1 It was later characterized in 1994 by Bent and Kuhn based on the presence of five criteria: (1) atopic history, (2) nasal polyposis, (3) characteristic radiographic findings, (4) eosinophilic mucin without fungal invasion, and (5) positive fungal stain.2 Pathological findings in AFRS will often include a dense inflammatory response, predominance of eosinophils, and Charcot-Leyden crystals (a byproduct of eosinophil degranulation), as well as hyphal elements on fungal stains.3 Fungal species can vary, including Aspergillus, Alternaria, Bipolaris, and Curvularia, as well as others. Over the past 20 years several studies have expanded on our original understanding of the pathogenesis of AFRS. In patients with AFRS, evidence of increased IgE production (consistent with a type I hypersensitivity) has been established in both systemic serum levels and local sinonasal tissue, although not always in both.4 Furthermore, increased sinonasal tissue production of antigen-specific IgE includes reactivity to both fungal and nonfungal antigens.5 Additionally, Carney et al. have identified multiple Th-2 cytokines including IL-4, IL-5, IL-13, and major basic protein, as well as eosinophils and mast cells in the inflammatory cascade of AFRS patients.6 Nonetheless, the classification of AFRS as a distinct clinical entity has been called into question. Certain studies have debated the association of AFRS with eosinophilic mucin CRS (EMCRS). Ferguson has claimed AFRS to be distinct based on the diagnostic findings of unilaterality, fungal presence, and decreased incidence of asthma and aspirin sensitivity compared with EMCRS.7 In addition, Ferguson noted that patients with EMCRS have a higher incidence of IgG1 deficiency compared with AFRS patients.7 In contrast, Pant and colleagues have suggested categorization of AFRS as a subclass of EMCRS based on the findings that EM appears to be the predominant characteristic to predict the pattern of disease presentation and severity.8 Regardless of nomenclature, AFRS patients are often identified by a characteristic clinical history, presentation, and radiographic findings. Patients are typically immunocompetent, young adults who From Emory University, Sinus, Nasal, and Allergy Center, Atlanta, Georgia The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Sarah K. Wise, M.D., M.S.C.R., Emory University, Sinus, Nasal and Allergy Center, 550 Peachtree Street, MOT 9th Floor, Atlanta, GA 30308 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S26 –S27, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S22 present with a prolonged report of nasal congestion, hyposmia or anosmia, and facial pressure. In the southeastern United States, where up to 32% of patients undergoing functional endoscopic sinus surgery have been reported to have AFRS, African Americans and patients of a lower socioeconomic status have been shown to have a greater incidence and severity of AFRS.9 On physical exam, polyps are an almost universal endoscopic finding, but, additionally, in more severe cases, physical findings such as diplopia, proptosis, and telecanthus can be identified. Radiographically, AFRS patients frequently present with asymmetric, heterogeneously dense material filling and expanding one or more of their paranasal sinuses (Fig. 1). In soft tissue windows, foci of near metallic density are seen, reflecting chelation of metal salts by the fungal organisms. In more severe cases, this mucin can actually erode through surrounding bone, encroaching into spaces occupied by vital organs such as brain, orbit, and major vessels. A radiological staging system, which specifically analyzes this degree of bony remodeling, has also been developed specifically for AFRS.10 As opposed to the Lund-Mackay radiological staging system, which is based on sinus opacification, the AFRS radiological staging system uses degree of bony erosion and expansion as the defining criteria. In this system, points are assigned for each sinus wall that has undergone bony remodeling up to a maximum of ⬃3 points per sinus. Treatment of AFRS is based primarily on surgical debridement of fungal mucin and polyps, as well as the use of saline irrigations and systemic and topical steroids, all with an effort to reduce the antigenic load and inflammatory response. Systemic steroids, especially after surgical debridement, have been considered a mainstay of the treatment approach, but optimal dosing and treatment length remain controversial. It is also notable that systemic antifungal therapy is thought to have little role in the treatment of AFRS and is reserved for selected refractory cases. Specific allergen immunotherapy has also been used as a treatment in the long-term control of AFRS. The rationale behind the use of immunotherapy in the treatment paradigm for AFRS is based on the premise that immunotherapy modifies the basic allergic mechanism by inducing desensitization and an anergy state.11 Although, prospective studies are limited, one retrospective study did show a drop in reoperation rates down to 11% in AFRS patients who underwent immunotherapy versus 33% in those treated with placebo.12 CLINICAL PEARLS • AFRS has been characterized by Bent and Kuhn based on the presence of five distinct criteria: (1) atopic history, (2) nasal polyp- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 1. Coronal computed tomography (CT) scan in (A) soft tissue and (B) bone window algorithms showing left maxillary and ethmoid opacification. There are heterogeneous densities within the expanded sinus cavities, as well as erosion of the left medial maxillary wall, lamina papyracea, and ethmoid skull base. This is a classic appearance of allergic fungal rhinosinusitis (AFRS) on CT imaging. osis, (3) characteristic radiographic findings, (4) EM without fungal invasion, and (5) positive fungal stain. • Relationship of AFRS to EMCRS is debated. • Bony erosion and expansion of the sinuses is a relatively common finding in AFRS and is the criteria on which the AFRS radiographic staging system is based. • Treatment of AFRS includes surgical debridement, nasal rinses, and topical and systemic steroids. Immunotherapy has shown promise in helping to decrease reoperation rates. 2. 3. 4. 6. 7. 8. 9. REFERENCES 1. 5. Miller JW, Johnston A, and Lamb D. Allergic aspergillosis of the maxillary sinuses. Thorax 36:710, 1981. Bent JP III, and Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 111:580–588, 1994. Corey JP, Delsupehe KG, and Ferguson GJ. Allergic fungal sinusitis: Allergic, infectious, or both? Otolaryngol Head Neck Surg 113:110, 1995. Collins M, Nair S, Smith W, et al. Role of local immunoglobulin E production in the pathophysiology of noninvasive fungal sinusitis. Laryngoscope 114:1242–1246, 2004. American Journal of Rhinology & Allergy 10. 11. 12. Wise S, Ahn C, Lathers D, et al. Antigen-specific IgE in sinus mucosa of allergic fungal rhinosinusitis patients. Am J Rhinol 22:451–456, 2008. Carney A, Tan L, Adams D, et al. Th2 immunological inflammation in allergic fungal sinusitis, nonallergic eosinophilic fungal sinusitis, and chronic rhinosinusitis. Am J Rhinol 20:145–149, 2006. Ferguson BJ. Eosinophilic mucin rhinosinusitis: A distinct clinicopathological entity. Laryngoscope 110:799–813, 2000. Pant H, Schembri MA, Wormald PJ, and Macardle PJ. IgE-mediated fungal allergy in allergic fungal sinusitis. Laryngoscope 119:1046– 1052, 2009. Wise SK, Ghegan MD, Gorham E, and Schlosser RJ. Socioeconomic factors in the diagnosis of allergic fungal rhinosinusitis. Otolaryngol Head Neck Surg 138:38–42, 2008. Wise SK, Rogers GA, Ghegan MD, et al. Radiologic staging system for allergic fungal rhinosinusitis (AFRS). Otolaryngol Head Neck Surg 140:735–740, 2009. Chang H, Han DH, Mo J, et al. Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. Clin Exp Otorhinolaryngol 2:136–140, 2009. Bassichis BA, Marple BF, Mabry RL, et al. Use of immunotherapy in previously treated patients with allergic fungal sinusitis. Otolaryngol Head Neck Surg 125:487–490, 2001. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S23 Invasive fungal rhinosinusitis Praveen Duggal, M.D., and Sarah K. Wise, M.D., M.S.C.R. ABSTRACT Invasive fungal rhinosinusitis (IFRS) is a disease of the paranasal sinuses and nasal cavity that typically affects immunocompromised patients in the acute fulminant form. Early symptoms can often mimic rhinosinusitis, while late symptoms can cause significant morbidity and mortality. Swelling and mucosal thickening can quickly progress to pale or necrotic tissue in the nasal cavity and sinuses, and the disease can rapidly spread and invade the palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain. IFRS can be life threatening if left undiagnosed or untreated. While the acute fulminant form of IFRS is the most rapidly progressive and destructive, granulomatous and chronic forms also exist. Diagnosis of IFRS often mandates imaging studies in conjunction with clinical, endoscopic, and histopathological examination. Treatment of IFRS consists of reversing the underlying immunosuppression, antifungal therapy, and aggressive surgical debridement. With early diagnosis and treatment, IFRS can be treated and increase patient survival. A cute fulminant invasive fungal rhinosinusitis (IFRS) is a lifethreatening condition that requires immediate medical attention. Patients with this disease previously had abysmal survival rates of 20–50%.1 With improvements in diagnosis and treatment, recent studies reveal much improved survival, with mortality rates around 18%.2 Acute fulminant IFRS occurs almost exclusively in immunocompromised patients. These patients include those suffering from conditions such as leukemia; acquired immunodeficiency syndrome; poorly controlled diabetes mellitus or diabetic ketoacidosis; or those undergoing bone marrow transplant, chemotherapy, or long-term corticosteroid use. The most common predisposing factor to IFRS is neutropenia, especially those with ⬍1000 neutrophils/L of blood, which significantly reduces the inflammatory response and the body’s ability to battle the infection. This article will review the classification of IFRS and briefly discuss the two chronic forms of IFRS, chronic invasive fungal sinusitis and granulomatous fungal sinusitis. We will then discuss acute fulminant IFRS in more detail, including pathophysiology, diagnosis, and management. BACKGROUND IFRS is typically classified into three categories: (1) chronic, (2) granulomatous, and (3) acute fulminant.3 Chronic IFRS is a very rare disease normally defined as an invasive paranasal sinus condition occurring over a course of weeks to months. Patients may or may not be immunocompetent and can present early with rhinosinusitis-like symptoms that progress with fungal hyphae invading the sinus mucosa. Often, there are less inflammatory cells noted on biopsy compared with more acute infections. Symptoms can include periorbital edema, proptosis, blindness, cranial nerve palsies, and soft tissue involvement. Granulomatous IFRS infections have a gradual onset and have been noted to occur mainly in the Sudan, India, and Pakistan.4 The condition often affects immunocompetent patients as well. Symptoms may consist of proptosis or an enlarging mass within the nose, orbit, or paranasal sinuses. Noncaseating granulomas with giant cells and hyphae are noted. Aspergillus flavus is often the most isolated species in granulomatous cases. Acute fulminant IFRS is the most common form of invasive fungal paranasal sinus infection.5 Infection is often attributed to invasion by fungi that have previously colonized the sinuses or fungal spores that have been inhaled. The disease occurs almost exclusively in immunosuppressed and quantitatively or functionally neutropenic patients. Functional neutropenia can be caused by poorly managed diabetic mellitus and chronic steroid use. The lack of a functional and normal immune system can lead the host response to be delayed or nonexistent. Acute fulminant IFRS can progress very quickly in these patients, often in a matter of hours to days. Early symptoms include fever, nasal congestion, facial pain, epistaxis, and headache. Late symptoms may include numbness, blindness, central neurological symptoms, and even death. The disease can be rapidly fatal in 50–80% of patients if left untreated. PATHOPHYSIOLOGY Spores from various fungi are found throughout the environment and fungal exposure is common. Items such as decaying fruit, vegetables, plants, soil, old bread, and manure can all carry fungal spores. However, infection is often avoided when patients are immunocompetent. Fungal infections that are aggressive and affect immunocompromised patients are species from the genus Aspergillus and the Mucorales order, which includes Absidia, Mucor, Rhizomucor, and Rhizopus. Mucor has been highly associated with infecting diabetic ketoacidosis patients.6 Mucor and Aspergillus spread by invading arterial blood vessels. Tissue necrosis secondary to obstructed blood flow leads to pale, gray, or black infarcted tissue. Infection can also cause perineural invasion and spread across tissue planes.7 Without a properly functioning immune system, the infection is left unimpeded and can continue to progress to more vital structures. DIAGNOSIS From Emory University, Sinus, Nasal, and Allergy Center, Atlanta, Georgia The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Sarah K. Wise, M.D., M.S.C.R., Emory University, Sinus, Nasal and Allergy Center, 550 Peachtree Street, MOT 9th Floor, Atlanta, GA 30308 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S28 –S30, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S24 Proposed diagnostic criteria for IFRS include (1) mucosal thickening or air fluid levels consistent with sinusitis on imaging and (2) histopathological evidence of fungal hyphae within sinus mucosa, submucosa, blood vessels, or bone.3 Physical examination and nasal endoscopy are essential to look for signs of significant edema, pallor, ischemia, or necrosis of the nasal and paranasal sinus mucosa. Imaging, in conjunction with physical exam and endoscopy with biopsy, is crucial in the workup up of IFRS. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 2. Gomori methenamine silver (GMS) fungal stain showing blackstained fungal hyphae invading sinonasal tissue. (Photograph courtesy of Dr. Susan Muller.) Figure 1. Invasive fungal rhinosinusitis (IFRS) involving the nasal cavity and turbinate mucosa. Note the central necrotic IFRS area surrounded by pale mucosa, in contrast to the healthy, pink areas of normal nasal mucosa. (Photograph courtesy of Dr. John Delgaudio.) Presentation Early symptoms can mimic acute rhinosinusitis (nasal drainage, congestion, headaches, and facial pain). Recognition of evolving IFRS in this initial phase requires a high index of suspicion.8 After initially presenting with these acute symptoms, patients may experience a “latent” phase where pain transiently subsides, further confounding the diagnosis if clinical suspicion is insufficient. This rapidly transitions to the onset of ominous signs and symptoms that include facial or palate numbness, proptosis, visual changes, facial swelling, and dental pain. IFRS is best visualized on nasal endoscopy and most commonly affects the nasal septum, turbinates, and paranasal sinuses (Fig. 1). Swelling and mucosal thickening can quickly progress to pale or necrotic tissue in the nasal cavity and sinuses, and the disease can rapidly spread and invade the palate, orbit, cavernous sinus, cranial nerves, skull base, carotid artery, and brain. Imaging Computed tomographic (CT) imaging should quickly be used in the workup for IFRS. Findings suggestive of IFRS include edema of nasal cavity, sinus mucoperiosteal thickening, bone erosion, orbital invasion, facial soft tissue swelling, and periantral or retroantral soft tissue infiltration. None of these findings are pathognomonic for IFRS, however. The most common finding on CT for patients with IFRS is severe unilateral thickening of the nasal cavity mucosa and soft tissues including the turbinates, septum, and nasal floor.9 Bone destruction can be easily noted on CT scan and is highly suggestive of IFRS, but it is often a late finding. Magnetic resonance imaging (MRI) is another imaging modality that is useful in detecting IFRS. MRI should be considered if the orbit or intracranial involvement is suspected.10 MRI is more sensitive than CT in the early screening and diagnosis of acute fulminant IFRS.11 Although having a higher cost, MRI offers zero radiation exposure and provides slightly higher sensitivity to subtle infiltration of facial fat planes anterior and posterior to the maxillary sinus. Despite the imaging tool, suspicious clinical and radiographic findings should prompt endoscopic evaluation and biopsy. American Journal of Rhinology & Allergy Pathology The gold standard in diagnosis of IFRS is examination of the pathology with permanent section. However, permanent section and fungal stains can be time-consuming and delay diagnosis and treatment. Fungal cultures are an alternative means of diagnosis but have a low sensitivity and can take days for growth and speciation to occur. With the noted aggressiveness of IFRS, delay in immediate treatment can lead to significant morbidity and possible mortality. Frozen section pathology can provide an early diagnosis in the clinical setting.12 Bedside and intraoperative frozen section has an extremely high positive predictive value. With a positive finding of fungal hyphae invading soft tissue on frozen section, the patient should be taken to the operating room for surgical debridement. Frozen section for IFRS diagnosis has a high sensitivity and negative predictive value. Initial biopsy specimens should be taken at the border between pale/necrotic mucosa and normal-appearing mucosa, areas questionable on CT imaging, and/or the middle turbinate.13 The frozen section is a tool that can guide thorough surgical debridement and prevent further morbidity such as orbital exenteration or added invasive procedures by providing diagnosis of negative margins during surgery. Although not only helping with early diagnosis and initial treatment, the frozen section can also guide further postoperative and conservative therapy by focusing further debridement to infected areas. Permanent pathological sections often incorporate fungal stains that allow for excellent visualization of fungal hyphae within the tissue sections (Fig. 2). TREATMENT Treatment of IFRS consists of (1) reversing the underlying immunosuppression, (2) antifungal therapy, and (3) aggressive surgical debridement. Raising the absolute neutrophil count in those with quantitative neutropenia is an important step in treatment of invasive fungal disease. Improved diabetes management and control of fluctuating blood sugars is vital to helping those patients suffering from IFRS secondary to their diabetic ketoacidosis. The prognosis is extremely poor if the host immune response does not improve. Patients suffering from immunosuppressive treatment should likely halt their therapy. An attempt to resolve neutropenia may be made by using granulocyte colony stimulating factor.10 Isolation of the fungal organism is also necessary to guide antifungal therapy. Oral and i.v. antifungal agents can be implemented based on the severity of the infection, the speciation of the offending agent, and the Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S25 presence of ongoing immunosuppression or the underlying disorder. Surgical debridement is the gold standard to remove invasive fungal disease. Surgical treatment often can be approached via endoscopic techniques with or without a combination of external approaches depending on the disease extent. The most common finding at surgery is mucosal edema and/or pale mucosa.14 All pale or necrotic tissue should be removed from the paranasal sinuses and nasal cavity. Resection should be performed until bleeding tissue is visualized. Further frozen section biopsy specimens can be sent intraoperatively to show negative margins. Fungal cultures should also be sent at the time of surgery to help with identification and speciation of the fungus. Orbital exenteration may be indicated if removal of the eye may prevent spread intracranially. The underlying prognosis of IFRS is dictated by the ability to reverse the quantitative or functional neutropenic state. Surgery and antifungal therapy can help relieve the fungal burden until the immune status recovers. Patients should be monitored after their initial surgery with follow-up endoscopy, imaging, and serial debridements as needed. Long-term follow-up is indicated until remucosalization of the sinuses, resolution of crusting, and cessation of bony sequestration has occurred.15 CLINICAL PEARLS • Acute fulminant IFRS is a serious medical condition that can be life-threatening and requires urgent attention. A high index of suspicion is required in susceptible patients (e.g., immunocompromised) who present with symptoms of rhinosinusitis. • Quantitative or functional neutropenia is the most common predisposing risk factor for acute fulminant IFRS. • The most common finding on CT is severe unilateral thickening of the sinonasal mucosa and soft tissue. • Sinonasal endoscopy with biopsy, in conjunction with CT or MRI, is critical in diagnosing and evaluating the extent of IFRS and planning surgical intervention. • Reversing the underlying disorder causing immunosuppression or neutropenia, as well as emergent surgical debridement, is essential to minimize morbidity and mortality from IFRS. S26 REFERENCES 1. Gillespie MB, O’Malley BW Jr, and Francis HW. An approach to fulminant invasive fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol Head Neck Surg 124:520–526, 1998. 2. Parikh SL, Venkatraman G, and DelGaudio JM. Invasive fungal sinusitis: A 15-year review from a single institution. Am J Rhinol 18:75–81, 2004. 3. deShazo RD, O’Brien M, Chapin K, et al. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 123:1181–1188, 1997. 4. Thompson GR III, and Patterson TF. Fungal disease of the nose and paranasal sinuses. J Allergy Clin Immunol 129:321–326, 2012. 5. Epstein VA, and Kern RC. Invasive fungal sinusitis and complications of rhinosinusitis. Otolaryngol Clin North Am 41:497–524, viii, 2008. 6. Dhong HJ, Lee JC, Ryu JS, and Cho DY. Rhinosinusitis in transplant patients. Clin Otolaryngol Allied Sci 26:329–333, 2001. 7. Frater JL, Hall GS, and Procop GW. Histologic features of zygomycosis: Emphasis on perineural invasion and fungal morphology. Arch Pathol Lab Med 125:375–378, 2001. 8. DelGaudio JM, and Clemson LA. An early detection protocol for invasive fungal sinusitis in neutropenic patients successfully reduces extent of disease at presentation and long term morbidity. Laryngoscope 119:180–183, 2009. 9. DelGaudio JM, Swain RE Jr, Kingdom TT, et al. Computed tomographic findings in patients with invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 129:236–240, 2003. 10. Gillespie MB, and O’Malley BW. An algorithmic approach to the diagnosis and management of invasive fungal rhinosinusitis in the immunocompromised patient. Otolaryngol Clin North Am 33:323– 334, 2000. 11. Groppo ER, El-Sayed IH, Aiken AH, and Glastonbury CM. Computed tomography and magnetic resonance imaging characteristics of acute invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 137:1005–1010, 2011. 12. Ghadiali MT, Deckard NA, Farooq U, et al. Frozen-section biopsy analysis for acute invasive fungal rhinosinusitis. Otolaryngol Head Neck Surg 136:714–719, 2007. 13. Gillespie MB, Huchton DM, and O’Malley BW. Role of middle turbinate biopsy in the diagnosis of fulminant invasive fungal rhinosinusitis. Laryngoscope 110:1832–1836, 2000. 14. DelGaudio JM. Endoscopic transnasal approach to the pterygopalatine fossa. Arch Otolaryngol Head Neck Surg 129:441–446, 2003. 15. Otto KJ, and Delgaudio JM. Invasive fungal rhinosinusitis: What is the appropriate follow-up? Am J Rhinol 20:582–585, 2006. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Benign sinonasal neoplasms Patrick T. Hennessey, M.D. and Douglas D. Reh, M.D. ABSTRACT Benign sinonasal neoplasms are a heterogeneous group of tumors that present with similar symptoms including nasal obstruction, anosmia, rhinorrhea, and epistaxis. The proper workup and accurate diagnosis is essential for these tumors so that the appropriate treatment plan can be established. In this article of benign sinonasal neoplasms, we discuss their typical clinical presentation, histological and radiographic findings, and treatment options. I nverted papillomas occur at a rate of 0.2–6 cases per 100,000 patients per year and represent 0.5–4.0% of sinonasal tumors. Inverted papillomas occur more commonly in male subjects with a 3:1 male/female ratio and occur most commonly in the fifth and sixth decades of life. The majority of inverted papillomas (95.1%) are unilateral and most commonly originate from the lateral nasal wall (89%), with specific sites of origin being the maxillary sinus (53.9%), the ethmoid sinuses (31.6%), the septum (9.9%), the frontal sinus (6.5%), and the sphenoid sinus (3.9%).1 Symptoms of sinonasal inverted papilloma are typically nondescript and include unilateral nasal obstruction (58%), epistaxis (17%), nasal drainage (14%), and sinusitis (9%).1 Other symptoms may include headache, facial numbness, facial swelling, diplopia, or anosmia. Because of the nonspecific nature of these symptoms, many patients with inverted papilloma are not diagnosed until they have advanced disease. On nasal endoscopy inverted papillomas appear as lobulated, mucosa-covered polypoid masses with a more vascular appearance than nasal polyps, which typically are more translucent in appearance (Fig. 1). Histologically inverted papillomas are characterized by invagination of the epithelium into the underlying stroma without invasion into or through an intact basement membrane. Additionally, inflammatory changes including periosteal thickening, osteoblastic rimming, and the presence of immature bone, are often found in the bone underlying inverted papillomas.2 Although the etiology of inverted papilloma is unknown, several different mechanisms for its development have been proposed. One theory suggests that inverted papilloma is a result of sinonasal inflammation and form in much the same way as nasal polyps.3,4 Human papilloma virus has also been implicated in the pathogenesis of inverted papilloma. Human papilloma virus DNA has been identified in 32% of early stage inverted papillomas5 and up to 67% of inverted papillomas associated with squamous cell carcinoma.6 Computed tomography (CT) is a critical component of the preoperative evaluation of patients with inverted papilloma. Inverted papillomas appear on CT as a soft tissue density that heterogeneously enhances with contrast. Evidence of osteitis adjacent to inverted papilloma has been shown to be useful in identifying the site of attachment.7 However, there is no study that can definitively identify the From the Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins Sinus Center, Baltimore, Maryland The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint to Douglas D. Reh, M.D., Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins Sinus Center, 601 North Caroline Street, Baltimore, MD 21287 Originally published in Am J Rhinol Allergy 27, S31–S34, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy site of attachment preoperatively, and others have debated the significance of this radiological finding. Magnetic resonance imaging can also be useful in the preoperative assessment of inverted papilloma because this modality has a superior ability to differentiate between papilloma, adjacent inflammation, and inspissated secretions.8 Other associated findings typically seen on CT include sclerosis, calcification, lobulation, and bony erosion. It has been reported that using these features in conjunction with opacification increases the accuracy of diagnosis of sinus involvement to 83–97%.9 Multiple staging systems have been proposed for inverted papilloma. Krouse proposed a commonly used staging system based on radiographic characteristics (Table 1).10 This system is widely used because it correlates well with inverted papilloma prognosis with operative difficulty; however, it is limited by the fact that it groups inverted papillomas with extrasinonasal extension with those that have a focus of squamous cell carcinoma. These two categories of inverted papillomas can differ substantially in terms of their prognosis and surgical management. A newer staging system proposed by Cannady et al. includes three groups of inverted papillomas based on recurrence rates (Table 2).11 Although this system provides useful prognostic information, it shares some of the same limitations as the Krouse system.10 The primary treatment modality for inverted papilloma is surgical resection. Historically, inverted papillomas were treated via open approaches, including lateral rhinotomy, Caldwell-Luc, and midface degloving approaches often combined with partial or total maxillectomies. With the advent of modern endoscopic techniques the majority of inverted papillomas are now treated endoscopically. The risk of recurrence using open approaches has been reported to be 5–30%.1 In addition to the risk of local recurrence, there is up to a 7.1% risk of malignancy associated with inverted papilloma.12 Because of the high risks of recurrence and malignancy, complete resection of these tumors is essential. A meta-analysis of 10 studies with a total of 1060 inverted papilloma patients found a statistically lower rate of recurrence in patients treated endoscopically (12%) versus patients treated by open approaches (20%).13 This finding must be interpreted with caution, however, because elements of selection or sampling bias may be possible. Additionally, multiple studies advocate the use of combined open and endoscopic approaches for inverted papillomas with sites of attachment that are not easily accessible solely by endoscopic endonasal approaches.14–16 OSSEOUS AND FIBRO-OSSEOUS TUMORS Osteoma Osteomas, the most common benign tumors of the sinonasal tract, are reportedly present on 1% of routine sinus radiographic studies and are most commonly found in the frontal sinuses.1 Histologically, Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S27 Figure 1. Characteristic endoscopic endonasal appearance of middle meatal (a) sinonasal polyps and (b) inverted papillomas. Note the contrast between the translucent appearance of the polyp with the lobulated mucosa and prominent vasculature of the inverted papilloma. Table 1 Krause staging for inverted papilloma T1: Limited to one area of the nasal cavity T2: Involvement of the medial wall of the maxillary or ethmoid sinuses and/or the osteomeatal unit T3: Involvement of the superior, inferior, posterior, anterior or lateral walls of the maxillary sinus T4: Tumors with extrasinonasal spread or malignancy Source: Ref. 10. Table 2 Cannaday staging for inverted papilloma with published recurrence rates Group A: Confined to the nasal cavity, medial maxillary sinus, and ethmoid sinus (recurrence rate ⫽ 3%) Group B: Involving the lateral maxillary sinus, sphenoid sinus, or frontal sinus (recurrence rate ⫽ 19.8%) Group C: Extrasinus extension (recurrence rate ⫽ 35.3%) Source: Ref. 11. osteomas are characterized by proliferation of dense cancellous bone. Osteomas usually involve the craniofacial skeleton with 21% found within the paranasal sinuses.17 Typically, osteomas are very slow growing; however, they can have periods of rapid growth after years of inactivity. Clinically, osteomas of the sinonasal tract are seen on endoscopy as smooth mucosa covered masses that are firm on palpation. No intervention is indicated unless the osteoma is obstructing the nasal passages or sinus outflow or it is compressing critical structures such as the orbit or skull base. In patients with multiple osteomas, Gardner’s syndrome should be considered. This autosomal dominant syndrome includes multiple osteomas (at any location in the body), colon polyps, and soft tissue tumors. Gardner’s syndrome is important to recognize and diagnosis necessitates a referral to a gastroenterologist because of the high rate of malignant transformation of the colon polyps. Fibrous Dysplasia and Ossifying Fibroma Fibrous dysplasia and ossifying fibroma are grouped together because they share histological similarities that qualify them as fibroosseous lesions. Notable clinical differences are discussed here. Fibrous dysplasia is a benign but potentially disfiguring condition that occurs in 1:4000 to 1:10,000 people.18 The disease can be monostotic, polyostotic, or can present as a component of McCuneAlbright syndrome. Craniofacial fibrous dysplasia typically involves the maxilla but can also involve the zygoma, skull base, and mandible.19 It typically presents in childhood and growth tends to cease in early adulthood. The characteristic radiographic finding with fibrous dysplasia is a ground-glass appearance of the lesions S28 on CT imaging.19 Histologically, fibrous dysplasia is characterized by woven bone with nonlamellar trabeculae in S and C shapes, often described as Chinese script characters. These tumors are rarely isolated in the sinuses and surgical planning must take into account the extent of the disease. For isolated sinonasal fibrous dysplasia, observation is the favored surgical management.20 Surgery is indicated only when critical structures such as the orbit or cranial nerves are affected. Ossifying fibromas are similar to fibrous dysplasia in that both are true fibro-osseous lesions, but with a more rapid and aggressive pattern of growth. They occur in the second to fourth decade of life and occur more often in female subjects than male subjects.21 In the craniofacial skeleton, 70% of ossifying fibromas occur in the mandible and the remainder occur in the maxilla and paranasal sinuses.21 Clinically, these tumors present as ovoid or round, expansile, painless masses that are similar in radiographic appearance to fibrous dysplasia but are locally destructive.22 Unlike fibrous dysplasia, ossifying fibromas continue to grow after adolescence and can exhibit locally aggressive and destructive behavior23; therefore, attempts should be made to resect these lesions early. Despite the clinical differences between these tumors, they can be difficult to distinguish radiographically and histologically and are believed to be the same disease process on different ends of a morphological spectrum.24 Although endoscopic approaches to removal of these tumors has been described, open approaches are sometimes required to ensure adequate visualization of the tumors for complete removal.25 VASCULAR NEOPLASMS Juvenile Nasopharyngeal Angiofibroma Juvenile nasopharyngeal angiofibromas (JNAs) are rare vascular tumors of the sinonasal cavity with an incidence of 1:150,000, which occur primarily in male subjects between the age 14 and 25 years.26,27 The term implies a nasopharyngeal origin, which is a misnomer, because JNAs originate in the posterior–superior margin of the sphenopalatine foramen. Histologically, the lesion expands submucosally and is nonencapsulated, with local destruction of adjacent structures. On CT scan, anterior bowing of the posterior maxillary wall (Holman-Miller sign) is consistent with a JNA. Histologically, JNAs have a benign-appearing fibrous stroma with a high density of blood vessels. Although JNAs exhibit benign histology, they are locally aggressive and frequently extend into the orbit, paranasal sinuses, and through the skull base. They are characterized by slow growth and often are not detected until they have caused symptoms caused by invasion into adjacent structures or when they present with intractable epistaxis.26 Diagnosis is often established by history, nasal endoscopy, and radiography. Office biopsy incurs significant bleeding risk and is often deferred if clinical/radiographic features are characteristic for JNA. These May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm lesions are usually treated by preoperative embolization followed by endoscopic resection; however, combined open and endoscopic approaches are often needed for large tumors.28 Pyogenic Granuloma The etiology of pyogenic granuloma, sometimes referred to as lobular capillary hemangioma, is unknown; however, they typically occur after minor nasal mucosal trauma and are thought to be the result of a local inflammatory response.29 In the sinonasal tract pyogenic granulomas are characteristically found on the anterior nasal septum in Kiesselbach’s plexus and have often been associated with nasogastric tube placement and nose picking. Histologically, these lesions have an ulcerated surface, an underlying inflammatory infiltrate, and a core of fibrous tissue perforated by blood vessels. Pyogenic granulomas can also occur during pregnancy and it is thought that these lesions are hormonally stimulated. This theory of hormonal stimulation is supported by the observation that these lesions spontaneously regress after delivery.29 Smaller lesions can be observed and often spontaneously regress. Larger lesions can be treated with chemical or electrocautery or can be surgically excised. Sinonasal Hemangiopericytoma Sinonasal hemangiopericytomas are rare perivascular tumors, constituting ⬍1% of vascular neoplasms with only 194 descriptions in the literature.30 They primarily occur on the extremities, but can also be found in the sinonasal cavity. Sinonasal hemangiopericytomas commonly involve the ethmoid sinuses but can be found at any site in the nasal cavity. These tumors typically occur in the fifth or sixth decade and, as with other sinonasal tumors, the most common presenting symptoms are nasal obstruction and epistaxis.30 Sinonasal hemangiopericytomas typically have uniform, polygonal to spindle-shaped cells with vesicular nuclei and a characteristic staghorn appearance to blood vessels.31 Although these tumors are often benign, they can be locally invasive and rarely can undergo malignant transformation. The diagnosis is sometimes established by biopsy performed in an outpatient setting during workup of a sinonasal mass, after imaging has ruled out an intracranial connection. If epistaxis is a predominant presenting symptom or workup suggests marked vascularity, biopsy should be performed in an operating room. Unless the lesion is extensive or malignant with significant orbitocranial invasion, endoscopic resection is usually possible. Additionally, patients require close postoperative follow-up because 20% of patients have recurrence, which can occur up to 17 years after surgery.30 CONCLUSION Benign sinonasal tumors are a clinically and pathologically heterogeneous group of neoplasms. Because the majority of patients with these tumors present with nonspecific symptoms, it is important for the otolaryngologist to have knowledge of these lesions to establish proper diagnosis and treatment. The advent of modern endoscopic surgical techniques has evolved and potentially improved the treatment of these lesions. Open surgical approaches may be required for certain sinonasal tumors that can not be visualized endoscopically, but they are associated with a significant degree of morbidity as well as cosmetic deformity. Endoscopic techniques and approaches can eliminate the need for external incisions and allow for equivalent, or for some lesions better, rates of cure than traditional open approaches. CLINICAL PEARLS • Identification and resection of the nasal wall attachment are critical when removing an inverted papilloma to minimize the chance of recurrence, regardless of operative technique. Evidence of osteitis American Journal of Rhinology & Allergy adjacent to inverted papilloma has been shown to be useful in identifying the site of attachment. • In patients presenting with multiple osteomas, Otolaryngologists should have a high clinical suspicion for Gardner’s Syndrome. • Fibrous dysplasia and ossifying fibroma are histologically similar lesions with markedly different clinical behavior. It is important to differentiate fibrous dysplasia from ossifying fibroma because the latter is a more aggressive process that warrants earlier surgical intervention. • JNAs originate in the posterior–superior margin of the sphenopalatine foramen. The radiographic hallmark of JNA is anterior bowing of the posterior maxillary wall on CT scan (HolmanMiller sign). REFERENCES 1. Melroy CT, and Senior BA, Benign sinonasal neoplasms: A focus on inverting papilloma. Otolaryngol Clin North Am 39:601–617, 2006. 2. Chiu AG, Jackman AH, Antunes MB,et al. Radiographic and histologic analysis of the bone underlying inverted papillomas. Laryngoscope 116:1617–1620, 2006. 3. Orlandi RR, Rubin A, Terrell JE, et al. Sinus inflammation associated with contralateral inverted papilloma. Am J Rhinol 16:91–95, 2002. 4. Roh HJ, Procop GW, Batra PS, et al. Inflammation and the pathogenesis of inverted papilloma. Am J Rhinol 18:65–74, 2004. 5. Syrjanen KJ. HPV infections in benign and malignant sinonasal lesions. J Clin Pathol 56:174–181, 2003. 6. Katori H, Nozawa A, and Tsukuda M. Markers of malignant transformation of sinonasal inverted papilloma. Eur J Surg Oncol 31:905– 911, 2005. 7. Yousuf K, and Wright ED. Site of attachment of inverted papilloma predicted by CT findings of osteitis. Am J Rhinol 21:32–36, 2007. 8. Yousem DM, Fellows DW, Kennedy DW, et al. Inverted papilloma: Evaluation with MR imaging. Radiology 185:501–505, 1992. 9. Sham CL, King AD, van Hasselt A, and Tong MC. The roles and limitations of computed tomography in the preoperative assessment of sinonasal inverted papillomas. Am J Rhinol 22:144–150, 2008. 10. Krouse JH. Development of a staging system for inverted papilloma. Laryngoscope 110:965–968, 2000. 11. Cannady SB, Batra PS, Sautter NB, et al. New staging system for sinonasal inverted papilloma in the endoscopic era. Laryngoscope 117:1283–1287, 2007. 12. von Buchwald C, and Bradley PJ. Risks of malignancy in inverted papilloma of the nose and paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg 15:95–98, 2007. 13. Busquets JM, and Hwang PH. Endoscopic resection of sinonasal inverted papilloma: A meta-analysis. Otolaryngol Head Neck Surg 134:476–482, 2006. 14. Woodworth BA, Bhargave GA, Palmer JN,et al. Clinical outcomes of endoscopic and endoscopic-assisted resection of inverted papillomas: A 15-year experience. Am J Rhinol 21:591–600, 2007. 15. Sautter NB, Cannady SB, Citardi MJ, et al. Comparison of open versus endoscopic resection of inverted papilloma. Am J Rhinol 21:320–323, 2007. 16. Sauter A, Matharu R, Hörmann K, and Naim R. Current advances in the basic research and clinical management of sinonasal inverted papilloma (review). Oncol Rep 17:495–504, 2007. 17. Herford AS, Stoffella E, and Tandon R. Osteomas involving the facial skeleton: A report of 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol 115:e1–e6, 2013. [Epub ahead of print June 26, 2012]. 18. Ricalde P, and Horswell BB. Craniofacial fibrous dysplasia of the fronto-orbital region: A case series and literature review. J Oral Maxillofac Surg 59:157–167, 2001. 19. Anari S, and Carrie S. Sinonasal inverted papilloma: Narrative review. J Laryngol Otol 124:705–715, 2010. 20. Ooi EH, Glicksman JT, Vescan AD, and Witterick IJ. An alternative management approach to paranasal sinus fibro-osseous lesions. Int Forum Allergy Rhinol 1:55–63, 2011. 21. Su L, Weathers DR, and Waldron CA. Distinguishing features of focal cemento-osseous dysplasia and cemento-ossifying fibromas. II. A clinical and radiologic spectrum of 316 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:540–549, 1997. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S29 22. 23. 24. 25. 26. S30 Mintz S, and Velez I. Central ossifying fibroma: An analysis of 20 cases and review of the literature. Quintessence Int 38:221–227, 2007. Schreiber A, Villaret AB, Maroldi R, and Nicolai P. Fibrous dysplasia of the sinonasal tract and adjacent skull base. Curr Opin Otolaryngol Head Neck Surg 20:45–52, 2012. Toyosawa S, Yuki M, Kishino M, et al. Ossifying fibroma vs fibrous dysplasia of the jaw: Molecular and immunological characterization. Mod Pathol 20:389–396, 2007. Wenig BM, Vinh TN, Smirniotopoulos JG, et al. Aggressive psammomatoid ossifying fibromas of the sinonasal region: A clinicopathologic study of a distinct group of fibro-osseous lesions. Cancer 76:1155–1165, 1995. Scholtz AW, Appenroth E, Kammen-Jolly K, et al. Juvenile nasopharyngeal angiofibroma: Management and therapy. Laryngoscope 111: 681–687, 2001. 27. Bremer JW, Neel HB 3rd, DeSanto LW, and Jones GC. Angiofibroma: Treatment trends in 150 patients during 40 years. Laryngoscope 96:1321–1329, 1986. 28. Pryor SG, Moore EJ, and Kasperbauer JL. Endoscopic versus traditional approaches for excision of juvenile nasopharyngeal angiofibroma. Laryngoscope 115:1201–1207, 2005. 29. Neves-Pinto RM, Carvalho A, Araujo E, et al. Nasal septum giant pyogenic granuloma after a long lasting nasal intubation: Case report. Rhinology 43:66–69, 2005. 30. Duval M, Hwang E, and Kilty SJ. Systematic review of treatment and prognosis of sinonasal hemangiopericytoma. Head Neck DOI: 10.1002/hed.23074. [Epub ahead of print June 25, 2012]. 31. Middleton LP, Duray PH, and Merino MJ. The histological spectrum of hemangiopericytoma: Application of immunohistochemical analysis including proliferative markers to facilitate diagnosis and predict prognosis. Hum Pathol 29:636–640, 1998. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Sinonasal malignancies Richard J. Harvey, M.D., and Dustin M. Dalgorf, M.D. ABSTRACT Malignant tumors of the sinonasal tract are uncommon tumors of the head and neck. Patients often present in the later years of life with unilateral symptoms and potential involvement of nearby structures such as the orbit, brain, or cranial nerves. Presenting symptoms are similar to patients suffering from inflammatory sinonasal disease and thus early diagnosis relies heavily on a high clinical suspicion. There are established risk factors based on exposure to the by-products of woodworking, metal, textile, and leather industries. Sinonasal malignancies are generally divided into those of epithelial origin (squamous cell carcinoma, adenocarcinoma, and adenoid cystic carcinoma) and nonepithelial origin (olfactory neuroblastoma, chondrosarcoma, and mucosal melanoma). Accurate histopathology confirmation and staging of the tumor is critical prior to making treatment decisions. Both computed tomography and magnetic resonance imaging are required to accurately determine the extent of local disease. Treatment is based on multimodality therapy, primarily surgical excision, and postoperative radiotherapy. This article reviews the classification of malignant tumors of the paranasal sinuses, their clinical presentation, relevant diagnostic investigations, and the principals of therapy and management. M alignant neoplasms arise from a variety of tissues of origin within the sinonasal tract but are, in general, defined as epithelial or nonepithelial in origin. Malignancy of the sinonasal tract is uncommon and accounts for only 1%1,2 of all malignancies and ⬃5% of head and neck malignancy.3,4The incidence varies across geographical areas because of differences in genetic predisposition and exposure to carcinogenic factors. In Europeans, this rate is 1 per 100,000 and in Asia 3 per 100,000.5,6 It is a condition affecting older patients with 75% ⬎50 years of age at diagnosis7 and predominately male gender.8,9 As with other malignancies, the presentation may be related to local, regional, or distant disease. Defining the histology of the tumor and its stage are the key goals of investigations. Finally, treatment is generally multimodal with a combination of surgery and radiotherapy as the mainstay for most lesions. The proximity of critical structures, specifically the orbit, brain, and cranial nerves, dictate the morbidity from curative interventions. PATHOPHYSIOLOGY The World Health Organization classification10 is listed in Table 1 with the most common subtypes included. The epithelial versus nonepithelial distinction is easy and reflects the frequency of tumors. Epithelial tumors are the most common with squamous cell carcinoma (SCC), adenocarcinoma, and adenoid cystic carcinoma most commonly reported.10 The nonepithelial tumors are lymphoma (hematologic), olfactory neuroblastoma (neuroectodermal), chondrosarcoma (bone/cartilage), and mucosal melanoma (neuroectodermal). Undifferentiated nasopharyngeal carcinoma is often included in discussions on upper airway malignancy. However, it is not considered a sinonasal tumor and its origins are from epithelial and b-cell interactions of the nasopharynx. It is a common malignancy of young Southeast Asian men compared with the uncommon nature of most From the Applied Medical Research Center, St. Vincent’s Hospital and University of New South Wales, and Macquarie University, Darlinghurst, Sydney, New South Wales, Australia The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Richard J. Harvey, M.D., Applied Medical Research Center, St. Vincent’s Hospital and University of New South Wales, 354 Victoria Street, Darlinghurst, Sydney, New South Wales, Australia, 2010 E-mail address: [email protected]; alternative: [email protected] Originally published in Am J Rhinol Allergy 27, S35–S38, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy tumors discussed in this article. Its etiology is unique in that it is thought to arise from early Epstein-Barr virus infection in a genetically susceptible host. There are several associated risk factors for the development of sinonasal malignancy. The most notable is wood dust exposure and adenocarcinoma. The large-particle dust from certain hardwoods (ebony, oak, and beech) are thought to provide a 900-fold risk of developing adenocarcinoma.9,11. Less than 5 years exposure is still considered critical and the latency to tumor development is delayed (⬃40 years).9,12 Smoking has been linked to SCC.7 Metal industry products (chromate and nickel), leather and boot products and the textile industry (chrome pigments) and thorium dioxide, and imaging agents, are all risk factors for SCC.13 Evidence for the role of human papilloma virus as a primary carcinogen in the sinonasal tract is strong but inconclusive and additional studies are required.13 DIAGNOSIS The most important element in accurate diagnosis of sinonasal malignancy is clinical suspicion. The insidious onset of unilateral symptoms, the lack of previous inflammatory sinus disease or rhinitis, and the relative age of the patient (⬎50 years old for tumors compared with ⬍50 years old for inflammatory disease) should be key features that prompt exclusion of neoplasia as a cause for a patient’s symptoms. Presentation Although the presentation can be with regional symptoms (neck lumps, orbital changes, diplopia, epiphora, or cranial nerve dysfunction) and/or distant metastasis, this is relatively uncommon for most tumors and local (nasal obstruction, bleeding, discharge, and hyposmia) are the more common presenting symptoms. These symptoms share common presenting complaints of patients with inflammatory sinonasal disease, which again highlights the importance of initial clinical suspicion. Unilateral eustachian tube dysfunction can also occur. Gross macroscopic changes to hard palate mucosa or the skin are uncommon in developed countries. Endoscopic examination reveals a mass within the nasal cavity (Figs. 1 and 2). Imaging Imaging should always focus on what is trying to be achieved, viz., tumor staging. Accurate information on local tissue involvement is Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S31 Table 1 The World Health Organization classification system for sinonasal malignancies 1. Malignant epithelial a. SCC b. Adenoid cystic carcinoma c. Adenocarcinoma 2. Neuroendocrine a. Carcinoid 3. Malignant soft tissue a. Sarcomas 4. Borderline and low malignant potential tumors of soft tissue a. Hemangiopericytoma 5. Malignant tumors of bone and cartilage a. Chondrosarcoma 6. Hematolymphoid a. Lymphoma 7. Neuroectodermal a. Olfactory neuroblastoma b. Mucosal melanoma 8. Germ cell 9. Secondary a. Renal b. Lung c. Breast The main subtypes are described here with common pathologies. SCC ⫽ squamous cell carcinoma. critical for “T” staging. Most patients will undergo both computed tomography (CT) and magnetic resonance imaging (MRI; Figs. 1 and 2). There are several key principals in rationale for both modalities. First, distinguish tumor from retained mucus. The T2 MRI will highlight edematous mucus and retained secretions compared with the tumor, seen on T1 postcontrast imaging (Fig. 2). Second, the involvement of the periobita is determined by bone loss on CT and fat enhancement on MRI. Third, dural (and brain parenchyma) involvement is defined by bone loss on CT and dural enhancement on MRI (Figs. 1, 2). Perineural involvement of cranial nerves is usually defined using fine slice fat-saturated T1 postcontrast MRI. Finally, the relationship of the tumor to the intracranial course of the internal carotid artery and its branches are defined by either CT angiography or MR angiography. Regional and distant disease is commonly defined with a positron emission tomography/CT assessment. This technique is a combination of full-body CT and assessment of focal radioactive glucose uptake (18FDG) by cells. This is the most efficient form of staging and can provide standard uptake value information for subsequent follow-up.14 Imaging of the neck, chest, and abdomen as well as simple blood tests for calcium and alkaline phosphatase would also suffice. Specific investigations for bone, brain, or other metastasis is usually driven by clinical suspicion rather than routine. Pathology Obtaining histopathological confirmation of malignancy and its subtype is critical before therapy. This is usually done before treatment decision making and the use of “frozen” or intraoperative specimens is ill-advised and not recommended. This is important because some tumors such as lymphomas are unique in that they are radiosensitive and do not require surgery whereas a diagnosis of melanoma would prompt an aggressive search for metastasis before local treatment. Traditional teaching that “all” tumors should be biopsied in the operative setting is neither necessary nor practical. Such statements are designed to avoid disastrous consequences of biopsying an illdefined nasal mass. As a general rule, nasal masses that present S32 without any imaging and when the diagnosis is uncertain should not be biopsied in the office (avoiding biopsy of encephalocele or aneurysm). Likewise, masses deep within the nose (beyond the middle turbinate) should not be biopsied unless there is a special setup for controlling posterior nasal bleeding. There should also be appropriate sampling for fresh tissue (for flow cytometry), when suspicion of lymphoma exists, and needs to be available as well as formalin-fixed tissue. TREATMENT Most patients with disseminated disease rarely undergo surgical therapy. The focus of treatment is symptom control (palliation) and short courses of radiotherapy are often given. With the exception of lymphomas, chemotherapy, radiotherapy, or combinations are not curative therapies but are performed as adjuncts to surgical resection with curative intent. Radiotherapy is used to control local and regional disease. There are complex lymphatic channels in the paranasal sinuses and the skull base that prevent full excision of the lymphatic compartments during surgery. Additionally, close margins occur next to orbits, carotids, and cranial nerves that benefit from additional local therapy. Radiation therapy can be performed before surgery, termed “neoadjuvant,” or after surgery, termed “adjuvant.” When chemotherapy is added, the goal is to enhance radiotherapy, reduce tumor growth, and manage potential micrometastasis. Some centers use chemoradiotherapy, for sensitive tumors such as olfactory neuroblastoma, before surgery because this is generally quick to initiate and can reduce tumor size making surgery less technically demanding (less bulk and bleeding). With this approach, it does not mean that a lesser region of the skull base can be removed and the resection must still follow the originally involved anatomic sites. The down side is that the surgeon is working with postirradiated tissues with impaired healing. When performed after surgery, adjuvant therapy starts 4–6 weeks postsurgery, when there is a balance between early residual tumor cell killing and the skull base that has healed and the chance of wound breakdown is minimal. The orbit is a critical factor is decision making and morbidity. The decision to remove the orbit is typically considered an “allor-none” approach. It is not practical to remove portions of the orbital contents (periorbita, fat, and/or muscle) and subsequently irradiate the remaining orbital contents. This results in a nonfunctional eye with restricted ocular movements, diplopia, visual loss, poor cosmesis, and, potentially, pain. Thus, if the periorbita is not breeched on MRI or intraoperatively, the eye is spared and the close margin is acknowledged. Close observation is required and early reoperation and orbital exoneration is required if recurrence occurs. Dura, frontal lobe, and cranial nerves are routinely removed if they are involved by tumor. These structures often bring about the morbidity imparted on the patient. However, if the eye is removed, the ipsilateral cranial nerves 1–6 can be removed with minimal impact on function. Mastication remains functional with an ipsilateral loss of the trigeminal nerve. This differs greatly to the dysfunction caused by lower cranial nerve loss (7–12). The neck generally is not empirically treated with either surgery or radiotherapy in the N0 (no clinically detectable disease in the cervical lymph nodes) presentation because the risk of subclinical disease is ⬍20%. However, a case could be made for N0 therapy in olfactory neuroblastoma.15 When nodal disease occurs at presentation, the neck is typically managed with a local excision with modified radical neck dissection, although there is little evidence to suggest an advantage of selective neck or radical neck dissection as an alternative. The main complications of treatment include the early risks of cerebrospinal fluid leak, epistaxis, pneumocephalus, and meningitis. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 1. Olfactory neuroblastoma is a neuroectodermal tumor. It is radiosensitive and has a better outcome than epithelial tumors. (A) The characteristic strawberry red appearance of a mass arising from medial to the middle turbinate. (B) The postoperative magnetic resonance imaging (MRI) view. (C) The typical bone loss of the skull base must always be further assessed with an MRI (D) because it is a marker of potential intracranial involvement. Figure 2. Squamous cell carcinoma (SCC) arising in a 62-year-old smoker. (A) The endoscopic view of a friable hemorrhagic mass filling the right nasal cavity. (B) Computed tomography (CT) showing loss of skull base bone and diffuse opacification of the surrounding sinuses. The T1 postgadolinium magnetic resonance imaging (MRI) (C) showing the sphenoid centered mass and T2 series (D) showing that much of the surround sinus changes is obstructive disease secondary to the tumor. Delayed complications included sinonasal dysfunction, hypopituitarism (post-radiation therapy), post-radiation therapy cranial neuropathy, and osteoradionecrosis of the skull base. PROGNOSIS The prognosis for sinonasal malignancy is generally poor. Locoregional recurrence is a critical factor because many tumors present late and wide en bloc removal is difficult. For some tumors American Journal of Rhinology & Allergy such as olfactory neuroblastoma, adenoid cystic carcinoma, and mucosal melanoma, nodal and distant disease can occur late. Up to 15% of olfactory neuroblastomas will recur with neck nodes.15 The overall survival for SCC and adenocarcinoma is 60% at 5 years.13 Some radiosensitive tumors, such as olfactory neuroblastoma, have survival rates of ⬎80% for early stage tumors.16 Mucosal melanoma survival is worse than that for cutaneous origins with 20% 5-year rates.17 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S33 CLINICAL PEARLS 6. • Sinonasal malignancies are uncommon malignancies and nasopharyngeal carcinoma is not considered part of this group. • Unilateral nasal symptoms in an older patient without a history of inflammatory airway conditions should prompt clinical suspicion. • Both CT and MRI are required to accurately stage local tissue involvement. • The involvement of the orbit, dura, brain, palate, and cranial nerves will determine the degree of surgical resection. • As with all tumors, accurate tissue diagnosis and local, regional, and distant staging must occur before treatment decisions. • Surgery and adjuvant radiotherapy are the mainstay of therapy. Close surveillance every 3 months for 2 years and then every 6 months until 5 years is standard care. 7. 2. 3. 4. 5. S34 9. 10. 11. 12. 13. REFERENCES 1. 8. Tufano RP, Mokadam NA, Montone KT, et al. Malignant tumors of the nose and paranasal sinuses: Hospital of the University of Pennsylvania experience 1990–1997. Am J Rhinol 13:117–123, 1999. Rinaldo A, Ferlito A, Shaha AR, and Wei WI. Is elective neck treatment indicated in patients with squamous cell carcinoma of the maxillary sinus? Acta Otolaryngol 122:443–447, 2002. Le QT, Fu KK, Kaplan M, et al. Treatment of maxillary sinus carcinoma: A comparison of the 1997 and 1977 American Joint Committee on cancer staging systems. Cancer 86:1700–1711, 1999. Tiwari R, Hardillo JA, Mehta D, et al. Squamous cell carcinoma of maxillary sinus. Head Neck 22:164–169, 2000. Magnani C, Ciambellotti E, Salvi U, et al. The incidence of tumors of the nasal cavity and the paranasal sinuses in the district of Biella, 1970–1986. Acta Otorhinolaryngol Ital 9:511–519, 1989. 14. 15. 16. 17. Muir CS, and Nectoux J. Descriptive epidemiology of malignant neoplasms of nose, nasal cavities, middle ear and accessory sinuses. Clin Otolaryngol Allied Sci 5:195–211, 1980. Olsen KD. Nose and sinus tumors. In Rhinologic Diagnosis and Treatment. McCaffrey T (Ed). New York. NY: Thieme, 334–359, 1997. Wolf J, Schmezer P, Fengel D, et al. The role of combination effects on the etiology of malignant nasal tumours in the wood-working industry. Acta Otolaryngol Suppl 535:1–16, 1998. Nylander LA, and Dement JM. Carcinogenic effects of wood dust: Review and discussion. Am J Ind Med 24:619–647, 1993. Barnes L, Eveson JW, Reichart P, et al. Tumors of the nasal cavity and paranasal sinuses. In Pathology and Genetics of Head and Neck Tumors. Barnes L, Tse LLY, Hunt JL, Brandwein-Gensler M, Curtin HD, Boffetta P (Eds). Lyon, France: IARC Press, 9–80, 2005. Acheson ED, Cowdell RH, Hadfield E, and Macbeth RG. Nasal cancer in woodworkers in the furniture industry. Br Med J 2:587–596, 1968. Macbeth R. Malignant disease of the paranasal sinuses. J Laryngol Otol 79:592–612, 1965. Lund VJ, Stammberger H, Nicolai P, et al. European position paper on endoscopic management of tumours of the nose, paranasal sinuses and skull base. Rhinol Suppl 22:1–143, 2010. Zanation AM, Sutton DK, Couch ME, et al. Use, accuracy, and implications for patient management of [18F]-2-fluorodeoxyglucosepositron emission/computerized tomography for head and neck tumors. Laryngoscope 115:1186–1190, 2005. Zanation AM, Ferlito A, Rinaldo A, et al. When, how and why to treat the neck in patients with esthesioneuroblastoma: A review. Eur Arch Otorhinolaryngol 267:1667–1671, 2010. Devaiah AK, and Andreoli MT. Treatment of esthesioneuroblastoma: A 16-year meta-analysis of 361 patients. Laryngoscope 119:1412– 1416, 2009. Dauer EH, Lewis JE, Rohlinger AL, et al. Sinonasal melanoma: A clinicopathologic review of 61 cases. Otolaryngol Head Neck Surg 138:347–352. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Granulomatous diseases and chronic sinusitis Michael A. Kohanski, M.D., Ph.D., and Douglas D. Reh, M.D. ABSTRACT Nasal crusting, rhinitis, and sinusitis are presentations of common conditions; however, these can also be the presenting symptoms of an underlying systemic disorder such as an infection, malignancy, or granulomatous disease. Granulomatous diseases with head and neck manifestations include Wegener’s granulomatosis, Churg-Strauss syndrome, and sarcoidosis. These diseases are managed through a multidisciplinary approach that often includes otolaryngologists. This article presents a brief review of granulomatous diseases and their rhinologic manifestations and includes relevant diagnostic tests and systemic and local treatment options. C hronic nasal obstruction, rhinorrhea, and nasal crusting are common symptoms seen by otolaryngologists in patients with chronic rhinosinusitis (CRS). Although the management of such patients often begins with evaluation for and treatment of common infectious or allergic etiologies, these symptoms can also be a manifestation of systemic granulomatous diseases such as Wegener’s granulomatosis (WG), Churg-Strauss syndrome (CSS), or sarcoidosis. The rhinologic manifestations of these systemic diseases can often be the presenting symptoms and these patients may also show concurrent systemic symptoms relating to pulmonary, renal, or neurological involvement. Granulomatous disorders should be considered in individuals with severe CRS that is minimally responsive to surgery and/or medical therapy and these patients may require a more extensive workup. WEGENER’S GRANULOMATOSIS WG is a systemic small-to-medium vessel vasculitis characterized by necrotizing granulomas. The head and neck, lungs, and kidneys are the most common regions of the body affected by WG.1,2 Head and neck signs and symptoms of WG are seen in early manifestations of the disease. Later stages of WG are associated with progression of the vasculitis and involvement of additional organ systems. Pulmonary involvement can be in the form of asymptomatic pulmonary nodules or pulmonary infiltrates seen on chest x ray. Segmental necrotizing glomerulonephritis is often seen in the kidneys of patients with WG.3 Head and neck manifestations of WG are seen in ⬃70–95% of patients.2,3 Otologic involvement as a result of WG is relatively rare. Subglottic stenosis is also seen in people with WG and can result in life-threatening dyspnea and stridor requiring surgical intervention. The granulomatous changes associated with WG can lead to a broad range of rhinologic signs and symptoms. Mucosal inflammation (Fig. 1 a) can lead to nasal obstruction, granulation tissue, crusting, hyposmia, anosmia, rhinitis, and/or sinusitis. Chronic Staphylococcus aureus infections are often encountered in patients with WG as a result of the mucus stasis that can occur from these inflammatory From the Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins Sinus Center, Baltimore, Maryland The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Douglas D. Reh, M.D., Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins Sinus Center, 601 North Caroline Street, Baltimore, MD 21287 Originally published in Am J Rhinol Allergy 27, S39 –S41, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy changes. Major nasal obstruction, epistaxis, and structural changes to the nose can occur as a result of the vasculitic processes associated with WG. A septal perforation or a saddle nose deformity in the absence of a history of trauma or infection is suggestive of WG. Granuloma formation in the nose can also cause outflow obstruction of the nasolacrimal duct resulting in epiphora. The diagnosis of WG is clinical and is based on findings suggestive of a vasculitic/granulomatous disease state (Table 1). In a person with a vasculitic disease, the American College of Rheumatology defines a person as having WG when they meet two of the following four criteria: (1) oral ulcers or nasal discharge, (2) abnormal chest x ray or CT, (3) abnormal urine sediment (red cell casts, ⬎5 RBCs), and (4) granulomatous inflammation on biopsy.4 A chest x ray may reveal pulmonary nodules or infiltrates; urinalysis can be used to detect glomerulonephritis. WG is almost always associated with a positive c-ANCA state. In an acute flare-up, erythrocyte sedimentation rate and C-reactive protein may be elevated and blood work may reveal leukocytosis and thrombocytosis. Histologically confirmed evidence of WG is one of the four American College of Rheumatology criteria for diagnosis of WG. A biopsy specimen must show evidence of necrosis, granulomatous inflammation, and vasculitis to be diagnostic for WG. Specimens should be obtained from suspicious lesions or sites of involvement, usually from areas with sinonasal granulation tissue. Because the nose and paranasal sinuses are frequently involved in WG, the otolaryngologist may be called on to obtain samples from intranasal or sinus contents. It is important to keep in mind that ⬎50% of nasal biopsies are nondiagnostic and the majority of specimens only show acute or chronic inflammation, findings that are nonspecific for WG.2,3 Treatment of WG is geared toward suppression of the severe inflammatory cycle with a regimen of corticosteroids (e.g., prednisone) and immunosuppressive agents (e.g., cyclophosphamide and methotrexate) to induce disease remission (Fig. 1 b). TNF-␣ inhibitors, which have shown success in the treatment of rheumatoid arthritis, remain controversial in the treatment of WG and do not enhance traditional therapy with prednisone and cyclophosphamide.5 Nasal symptoms are managed conservatively with nasal irrigation, topical steroids, and topical antibiotics when concurrent infection is present. There is a limited role for surgery in the management of WG and it is best performed in patients with quiescent disease. Surgery can be helpful in relieving nasal obstruction by removing scar tissue; however, patients continue to require systemic and/or local therapy to maintain disease remission. Septal perforations may be addressed through surgical repair or with the use of silastic septal buttons to occlude the septal opening, and saddle nose deformities can be repaired with septorhinoplasty. Surgery to repair perforations and/or Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S35 Figure 1. Nasal manifestations of granulomatous diseases. (a) Inflammatory changes in nasal mucosa of a patient with Wegener’s granulomatosis (WG). (b) Induction of quiescent disease after intranasal steroid treatment of patient seen in panel a. (c) Cobblestoning in a patient with sarcoidosis-associated rhinitis. (d) Pearly submucosal nodule seen in the nasal passage of a patient with sarcoidosis. Table 1 Tests and findings associated with granulomatous disorders p-ANCA c-ANCA CBC with differential Urinalysis Chest x ray ACE level Serum calcium WG CSS Sarcoidosis ⫺ ⫹ Thrombocytosis and leukocytosis Red casts, RBCs, and proteinuria Pulmonary nodules and pulmonary infiltrates Normal Normal ⫾ ⫺ ⬎10% Eosinophilia Abnormal w/renal involvement Pulmonary infiltrates Normal Normal ⫺ ⫺ Normal Elevated urine calcium Hilar lymphadenopathy Elevated (⬃50%) Normal to elevated ACE ⫽ angiotensin-converting enzyme; CSS ⫽ Churg-Strauss syndrome; CBC ⫽ complete blood cell count; RBC ⫽ red blood cell; WG ⫽ Wegener’s granulomatosis. saddle nose should be deferred until the disease process has stabilized for 6 months to 1 year. CHURG-STRAUSS SYNDROME CSS is a small-to-medium–sized vasculitis characterized by marked eosinophilia that is associated with necrotizing granulomas with an eosinophilic core. The prodromal stage of CSS presents as asthma with nasal symptoms, including allergic rhinitis, CRS, nasal crusting, and nasal polyps.1,6 As CSS progresses to the second stage, hypereosinophilia and eosinophilic tissue infiltrates develop. This is followed by the development of a systemic vasculitis and disseminated multiorgan disease. Those with prodromal stage CSS may present to an otolaryngologist early on in the disease course because these individuals are likely to have nasal symptoms. Unfortunately, asthma and the associated nasal symptoms of CSS are both commonplace and by themselves do not necessarily indicate that a patient has CSS. It is notable that myocarditis often develops in the second and disseminated stages and that heart failure is a frequent cause of death in these patients. S36 The American College of Rheumatology devised a set of criteria for the diagnosis of CSS. Four of the following six criteria must be present to confirm a diagnosis of CSS: (1) asthma, (2) eosinophilia of ⬎10%, (3) paranasal sinus abnormality, (4) pulmonary infiltrates, (5) mononeuritis or polyneuropathy, and (6) tissue biopsy showing vasculitis with extravascular eosinophils.7 When CSS is suspected, a complete blood count with differential should be obtained to look for hypereosinophilia and a chest x ray or CT should be ordered to look for pulmonary infiltrates (Table 1). Erythrocyte sedimentation rate and C-reactive protein may be elevated in the acute phase of the vasculitis, and a p-ANCA test may also be positive. If there is a clinically suspicious lesion, a biopsy specimen can be obtained to look for signs of vasculitis and extravascular eosinophils. Biopsies are typically performed from skin or lung lesions and nasal polyp tissue may also be helpful in establishing the diagnosis. As with WG, systemic treatment of CSS involves use of corticosteroids and immunosuppressive drugs. The sinonasal manifestations of CSS can be managed symptomatically with sinus irrigations and topical steroids. In those with nasal polyps as a result of CSS, medical May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm management and endoscopic sinus surgery can provide symptomatic relief but is not curative.6 SARCOIDOSIS Sarcoidosis is a noncaseating granulomatous disease that primarily affects the lungs and lymphatic system. This disease is thought to be caused by an inflammatory process involving T-helper cells, inflammatory cytokines, and TNF-␣.8 Sarcoidosis often presents with a persistent dry cough. Other signs and symptoms include peripheral lymphadenopathy, fatigue, weight loss, night sweats, eye involvement, and skin involvement. Head and neck manifestations occur in 10–15% of patients.9 Patients can present with salivary gland swelling or xerostomia. Patients with enlarged parotid glands, uveitis, facial nerve palsy, and fever have Heerfordt’s syndrome, a rare manifestation of sarcoidosis. Sinonasal involvement is rare, occurring in ⬃1–4% of patients with sarcoidosis although there are reports that sinonasal involvement is more common.10 Sarcoidosis can present with chronic nasal crusting, rhinitis, nasal obstruction, anosmia, and epistaxis (Fig. 1 c). There can be hypertrophy of the nasal mucosa, nasal polyps, and submucosal granulation tissue that appears as a pearly nodule (Fig. 1 d).1,9,10 When evaluating a patient for sarcoidosis, it is important to rule out tuberculosis and other infectious causes. Tissue biopsy specimens of sarcoid lesions will show noncaseating granulomas and tissue cultures should also be obtained to rule out infectious etiologies. Angiotensin-converting enzyme levels can be elevated, serum calcium and urine calcium levels may also be mildly elevated, and hilar lymphadenopathy is present on chest radiography (Table 1). Nasal sarcoidosis is typically treated with topical steroids such as nasal steroid sprays, steroid irrigations, or, occasionally, intralesional injections. Systemic steroids, immunosuppressive agents, and TNF-␣ inhibitors have a role in treating recalcitrant and severe sarcoidosis, although sarcoidosis can resolve spontaneously without treatment.9 Endoscopic sinus surgery can be helpful in the management of chronic sinusitis in patients with sarcoidosis, although topical steroids are still necessary after surgical treatment to treat the associated chronic inflammation.11 DISCUSSION When considering granulomatous diseases in patients with CRS, it is important to rule out infection and neoplasms.1 Fungal and bacterial cultures as well as acid fast tissue staining should be obtained to rule out infectious causes such as actinomyces, tuberculosis, fungal infections, or rhinoscleroma (caused by Klebsiella rhinoscleromatis), which are treated with the appropriate antimicrobials or antifungals along with judicious surgical debridement when appropriate. Histopathological analysis of biopsy specimens can help identify or rule out neoplastic disease that may present as CRS. The treatment of sinus manifestations of granulomatous diseases is usually conservative with topical and systemic anti-inflammatory agents such as steroids being the mainstay therapies. Surgery is reserved for specific considerations such as saddle nose deformity with WG or recalcitrant CRS in patients with quiescent disease. The otolaryngologist should keep American Journal of Rhinology & Allergy in mind when evaluating patients with granulomatous diseases that one half of biopsies will show nonspecific inflammatory changes and there should be a strong clinical suspicion of a granulomatous disease before obtaining a biopsy specimen.12 WG, CSS, and sarcoidosis are systemic granulomatous diseases with nonspecific but often severe sinonasal manifestations. By paying careful attention to clinical signs and symptoms and providing thorough and accurate evaluations, otolaryngologists can play an important role in the multidisciplinary management and treatment of these diseases. CLINICAL PEARLS • CRS can be an early presentation for granulomatous disorders, and these diseases should be considered in patients with severe CRS. • WG is associated with severe sinonasal inflammation, granulation tissue, and a positive c-ANCA. CSS is associated with nasal polyps, asthma, and eosinophilia of ⬎10%. Sarcoidosis is often associated with an elevated angiotensin-converting enzyme level. • Nasal symptoms of WG, CSS, and sarcoidosis are usually managed conservatively with nasal irrigation, topical steroids, and topical antibiotics. • It is important to rule out infection and neoplasms when considering granulomatous diseases in patients with CRS. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Tami TA. Granulomatous diseases and chronic rhinosinusitis. Otolaryngol Clin North Am 38:1267–1278, 2005. Gottschlich S, Ambrosch P, Kramkowski D, et al. Head and neck manifestations of Wegener’s granulomatosis. Rhinology 44:227–233, 2006. Erickson VR, and Hwang PH. Wegener’s granulomatosis: Current trends in diagnosis and management. Curr Opin Otolaryngol Head Neck Surg 15:170–176, 2007. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33:1101–1107, 1990. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351–361, 2005. Bacciu A, Bacciu S, Mercante G, et al. Ear, nose and throat manifestations of Churg-Strauss syndrome. Acta Otolaryngol 126:503–509, 2006. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33: 1094–1100, 1990. Baughman RP, Lower EE, and du Bois RM. Sarcoidosis. Lancet 361:1111–1118, 2003. Mrowka-Kata K, Kata D, Lange D, et al. Sarcoidosis and its otolaryngological implications. Eur Arch Otorhinolaryngol 267:1507–1514. Zeitlin JF, Tami TA, Baughman R, and Winget D. Nasal and sinus manifestations of sarcoidosis. Am J Rhinol 14:157–161, 2000. Gulati S, Krossnes B, Olofsson J, and Danielsen A. Sinonasal involvement in sarcoidosis: A report of seven cases and review of literature. Eur Arch Otorhinolaryngol 269:891–896. van den Boer C, Brutel G, and de Vries N. Is routine histopathological examination of FESS material useful? Eur Arch Otorhinolaryngol 267:381–384. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S37 Cystic fibrosis chronic rhinosinusitis: A comprehensive review Mohamad R. Chaaban, M.D.,1 Alexandra Kejner, M.D.,1 Steven M. Rowe, M.D.,2,3 and Bradford A. Woodworth, M.D.1,3 ABSTRACT Background: Advances in the care of patients with cystic fibrosis (CF) have improved pulmonary outcomes and survival. In addition, rapid developments regarding the underlying genetic and molecular basis of the disease have led to numerous novel targets for treatment. However, clinical and basic scientific research focusing on therapeutic strategies for CF-associated chronic rhinosinusitis (CRS) lags behind the evidence-based approaches currently used for pulmonary disease. Methods: This review evaluates the available literature and provides an update concerning the pathophysiology, current treatment approaches, and future pharmaceutical tactics in the management of CRS in patients with CF. Results: Optimal medical and surgical strategies for CF CRS are lacking because of a dearth of well-performed clinical trials. Medical and surgical interventions are supported primarily by level 2 or 3 evidence and are aimed at improving clearance of mucus, infection, and inflammation. A number of novel therapeutics that target the basic defect in the cystic fibrosis transmembrane conductance regulator channel are currently under investigation. Ivacaftor, a corrector of the G551D mutation, was recently approved by the Food and Drug Administration. However, sinonasal outcomes using this and other novel drugs are pending. Conclusion: CRS is a lifelong disease in CF patients that can lead to substantial morbidity and decreased quality of life. A multidisciplinary approach will be necessary to develop consistent and evidence-based treatment paradigms. C ystic fibrosis (CF) is an autosomal recessive disorder that affects the upper and lower airways as well as the digestive system. It is considered the most lethal autosomal recessive disorder among Caucasians and is estimated to affect 1 in 2000 to 1 in 6000 births.1 Thirty years ago this disease regularly led to death in the first decade of life, usually secondary to pulmonary deterioration from opportunistic bacteria. Advancements in therapy have led to substantial improvements in survival with a current median life expectancy of 36.8 years.2 The underlying genetic basis of the disease is related to dysfunction or deficiency of the CF transmembrane conductance regulator (CFTR), an apical membrane anion (e.g., chloride and bicarbonate) channel present in respiratory and exocrine glandular epithelium.3,4 Early diagnosis of CF is crucial to allow for intervention before lung disease ensues.5 Although chronic rhinosinusitis (CRS) is a serious cause of morbidity and may drive pulmonary disease in patients with CF, it is rarely the cause of mortality related to the disease. Sinonasal symptoms can be severe and refractory despite a myriad of medical and surgical interventions leading to frustration for the patient. Quality of life indicators have From the Departments of 1Surgery/Division of Otolaryngology and 2Medicine, and the 3 Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama Presented at the North American Allergy and Rhinology Conference, Puerto Rico, February 5, 2012 BA Woodworth received funding from the Flight Attendant’s Medical Research Institute Young Clinical Scientist Award (072218) and NIH/NHLBI (1K08HL107142-01), is a consultant for ArthroCare ENT and Gyrus ENT, and he is an inventor on a patent submitted regarding the use of chloride secretagogues for therapy of sinus disease (35 U.S.C. n111(b) and 37 C.F.R n.53 (c)) in the United States Patent and Trademark Office. SM Rowe received funding from R01HL105487-01 and 1R03DK084110-01 and from Vertex Pharmaceuticals to conduct clinical trials in cystic fibrosis and he is an inventor on a patent submitted regarding the use of chloride secretagogues for therapy of sinus disease (35 U.S.C. n111(b) and 37 C.F.R n.53 (c)) in the United States Patent and Trademark Office. The remaining authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Bradford A. Woodworth, M.D., BDB 563, 1530 3rd Avenue S, Birmingham, AL 35294-0012 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, 387–395, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S38 shown that sinus disease often mirrors pulmonary function and can be predictive of pulmonary disease, particularly in the pediatric population.6 Additionally, few randomized controlled trials are currently available with regard to efficacy of therapies for CF CRS and many studies are limited by the lack of long-term follow-up.7–9 Evidence-based guidelines are deficient and management paradigms concerning disease interventions have not been standardized for all patients. The purpose of the current review is to provide an update regarding management of this unique CRS population, present a summary of the best available evidence for therapeutic interventions, and discuss exciting new strategies in drug development. GENETICS Over 1600 mutations have been described in the coding sequence of the CFTR gene, messenger RNA splice signals, and other regions.10 Mutations are generally classified into six categories according to the mechanistic basis by which they are believed to cause disease (Table 1). The first three classes (I–III) are generally associated with increased phenotypic severity. Class I mutations result in an absence of CFTR gene synthesis and develop secondary to premature termination codons, nonsense mutations (e.g., G542X mutation, the “X” referring to existence of a premature stop codon), or other out of frame mutations (insertions or deletions).11 CFTR is normally transcribed and translated in class II mutations, but the protein folds incorrectly and is recognized as defective in the endoplasmic reticulum during intracellular trafficking. The protein is degraded before it reaches the site of action at the cell surface. The class II F508del mutation (deletion of a phenylalanine residue at the 508 position) is the most common genetic mutation and accounts for ⬃70% of defective alleles.12 Class III mutations consist of full-length CFTR protein present in normal quantities at the cell surface, but disrupted regulation or gating of the chloride transporter leads to a lack of ion channel activity (e.g., G551D mutation).13 Although class III mutations possess minimal to no CFTR-dependent transport, class IV defects represent abnormalities of chloride conductance and may have partial activity in vivo. Such mutations may lead to a CF pulmonary phenotype that is less severe than other forms of the disease (e.g., R117H mutation).14 Class V mutations produce decreased quantities of CFTR transcripts and, thus, fewer functional CFTR channels at the cell surface.11,12 Finally, May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 CF genetic mutations Mutation Class Class I Class II Class III Class IV Class V Class VI Mechanism Premature truncation or nonsense mutation Loss of phenylalanine at 508 position (del508) Disrupted regulation or gating of channel Abnormality of chloride conductance Decreased quantities of mature CFTR transcripts Defect in stability of protein and high turnover Gene Result Absence of CFTR gene Protein Result Chloride Channel Phenotype Example Gene intact and with normal transcription Degraded before reaching cell membrane Abnormal folding and degradation in ER Absent Very severe G542X Absent (deficient in mild forms) Usually very severe F508del (most common mutation) Gene intact and with normal transcription Present in normal quantity Minimal function Severe G551D Gene intact and with normal transcription Present Partial function Less severe R117H Gene intact but aberrant splicing at variable frequency Gene intact with normal transcription Decreased number of full-length CFTRs Full function but in low quantity Variable 2789 ⫹ 5G 3 A Present but with decreased stability Functional but high turnover with overall decreased number Less severe 4236delTC CF ⫽ cystic fibrosis; CFTR ⫽ cystic fibrosis transmembrane conductance regulator; ER ⫽ emergency room. Table 2 Summary of therapies Author’s Principals of Evaluation/Management/Therapy Topical nasal saline irrigations improve QOL Topical steroids decrease CF NPs Topical antibiotics, postsurgical and culture directed Macrolide therapy to decrease NPs Postoperative topical dornase alfa High-dose ibuprofen for CRS with NPs Ivacaftor for G511D mutation FESS (maxillary antrostomy and anterior ethmoidectomy) improves QOL indicators FESS improves pulmonary outcomes Modified medial maxillectomy improves QOL indicators Evidence Grade of Recommendation B (extrapolated from level 1 evidence in CRS) B (one level 1 study with high risk of bias ⫹ extrapolation from eosinophilic CRS/NP level 1) B B A (two level 1 studies showing benefit) C (one retrospective study) N/A B B B Grades of recommendation: A, consistent level 1 studies; B, consistent level 2 or 3 studies or extrapolations from level 1 studies; C, level 4 studies or extrapolations from level 2 or 3 studies; D, level 5 evidence or troublingly inconsistent or inconclusive studies of any level. QOL ⫽ quality of life; CF ⫽ cystic fibrosis; CRS ⫽ chronic rhinosinusitis; FESS ⫽ functional endoscopic sinus surgery; NPs ⫽ nasal polyps. class VI mutations create defects in the stability of the protein leading to accelerated turnover at the cell surface and insufficient quantities of CFTR under steady-state conditions.15 SPECTRUM OF DISEASE: VARIANCE IN PHENOTYPIC EXPRESSION exhibit at least one characteristic phenotypic feature, have a family history of CF, or have a positive neonatal screening test. In addition to these requisites, the patients must also have positive testing with either an increased sweat chloride concentration (⬎60 mmol/L), genetic tests showing two CF causing mutations, or demonstration of an abnormal ancillary test indicative of CFTR abnormality (e.g., nasal epithelial ion transport or intestinal current measurement).18 Classic CF Patients with classic CF tend to have class I–III mutations and develop upper and lower airway disease, exocrine pancreatic insufficiency, absence of the vas deferens, and highly elevated sweat chloride concentration, although specific genetic mutations may be associated with increased phenotypic severity (Table 2). For example, the most common mutation F508del homozygosity does not predict disease severity on its own, but this genotype is shown to be an independent risk factor in other manifestations of CF, including reduced mineral bone density and earlier colonization with Pseudomonas aeruginosa.16,17 The diagnosis of classic CF is made when patients American Journal of Rhinology & Allergy Atypical CF Individuals with atypical CF provide a diagnostic challenge as standard diagnostics, including that sweat chloride testing can be normal.19 This group is currently described in the Cystic Fibrosis Foundation consensus document as individuals who show a CF phenotype in at least one organ system and have normal (⬍40 mmol/L) or borderline (40–60 mmol/L) sweat chloride values.18 These patients tend to have pancreatic exocrine sufficiency in the setting of milder lung or sinonasal disease. They may present with a classic CF phenotype in only a single organ system. This underscores the impor- Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S39 tance of CF testing in patients with persistent, refractory CRS who do not exhibit classic pulmonary or gastrointestinal CF manifestations. Individuals with nonclassic CF carry two CFTR mutations, at least one of which is usually a “mild/variable” mutation.20 CFTR-Related Diseases CFTR-related diseases encompass well-known pathological disorders that appear to be influenced by CFTR genotype, including allergic bronchopulmonary aspergillosis, idiopathic bronchiectasis, and CRS. Wang et al.21 performed genetic testing on 147 non-CF patients with severe CRS and discovered a 7% incidence of CFTR mutations compared with the presence of 2% in 123 healthy controls (p ⫽ 0.04). Nasal potential difference measurements also documented a slight reduction in CFTR-mediated anion transport in carriers, but not to the levels seen with CF. In another study of 58 children with CRS, seven (12%) carried a single CF mutation, which was much higher than the expected frequency of 4%.22 Although these illnesses appear to be influenced by CFTR dysfunction, they are also influenced by nonCFTR genes and environmental exposures. However, the influence of CFTR indicates that many treatment regimens may be directly applicable to the management of non-CF CRS—specifically, the importance of improving mucus clearance in susceptible individuals. CYSTIC FIBROSIS CHRONIC RHINOSINUSITIS Pathophysiology of CRS The lining of the sinonasal epithelium is comprised of airway surface liquid containing a low viscosity periciliary fluid layer (sol) around the respiratory cilia and a superficial mucus (gel) layer, which function to trap and sweep inhaled particles into the digestive tract through coordinated mucociliary clearance (MCC). Intact MCC is considered the airway’s innate defense against disease.23 MCC is grossly impaired in CF because of alterations in the transepithelial passage of anions (chloride and bicarbonate) caused by genetic mutations in the CFTR.24 Disturbances in anion transport result in increased viscosity of mucins that is 30–60 times higher than patients without CF. Tenacious secretions obstruct sinus ostia and create hypoxic conditions with increased edema, secondary ciliary dyskinesia, and subsequent bacterial overgrowth.25,26 Hypoxia has also been shown to affect CFTR transcription and function in epithelium in patients with normal CFTR.27 Patients with classic CF have a high incidence of CRS approaching 100%.25 CF patients also have a high incidence of nasal polyposis associated with CRS (7–48%).28 Nasal polyps (NPs) associated with CF are typically mediated by neutrophilic Th1-mediated inflammation rather than eosinophilic Th2-mediated inflammation seen in atopic and aspirin-sensitive CRS with NPs.29 Claeys et al.30 showed that the Th1 inflammatory mediators IL-8 and myeloperoxidase actually dominate in CF NP compared with eosinophilic cationic protein, eotaxin, and IgE in non–CF NPs. In addition, the antimicrobial peptide (human defensin 2) and pattern recognition receptor Toll-like receptor 2 were significantly increased in CF NPs as well. Other innate defense proteins such as surfactant protein (SP) A, SP-B, and SP-D are also upregulated in CF.31–34 Other molecular differences between CF and non CF polyps include a significantly higher level of lipoxin A4 and slightly elevated cyclooxygenase 2 in CF polyps.35 Onset of bacterial infection and colonization in CF CRS may instigate inflammatory pathways with Toll-like receptors recognizing pathogen-associated molecular patterns with production of these antimicrobial peptides.36–38 The chronic inflammation seen in the sinuses after bacterial contamination also results in goblet cell hyperplasia, squamous metaplasia, and the loss of ciliated cells.26 Mucocele formation is common in CF patients39,40 and its presence in children should be diagnostic of CF unless proven otherwise.41 Decreased paranasal sinus development (hypoplasia) is also a distinguishing characteristic noted in CF patients.42–45 The reasons for this S40 lack of development and the effects of specific CF genotypes on phenotypic expression of sinus development are unclear. One prevailing theory considers that ongoing inflammatory mucosal disease leads to decreased pneumatization similar to poor temporal bone pneumatization in chronic otitis media.46 The general lack of chronic ear disease in CF patients and normal temporal bone development argues against this hypothesis.47 However, genotype does appear to influence paranasal sinus development as individuals homozygous for the F508del mutation have shown a significantly increased frequency of underdeveloped frontal (98%), maxillary (70%), and sphenoid (100%) sinuses when compared with other genetic mutations (69, 8, and 50%, respectively), suggesting CFTR may be a primary contributor to sinus development.45 Studies from the recently developed CF pig model support the premise that CFTR dysfunction as opposed to chronic infection is responsible for decreased sinus pneumatization because pigs lacking intact CFTR have sinus underdevelopment before the development of infection.48 Microbiology Numerous bacteria are frequently isolated from sinus cultures of CF patients including P. aeruginosa, Staphylococcus aureus, Escherichia coli, Burkholderia cepacia, Acinetobacter species, Stenotrophomonas maltophilia, Haemophilus influenza, Streptococci, and anaerobes.49–52 Muhlebach et al.53 studied lower airway and throat cultures and reported that P. aeruginosa as well S. aureus are the most common bacterial species found in CF patients. There is a higher frequency of Pseudomonas colonization in the lower airways in patients who have CRS with NPs and is more likely to start in the sinuses at a younger age and progress to involve both the upper and the lower airways.54,55 This was confirmed by Godoy et al.56 who showed a significant association between sinus cultures and lower airway cultures from bronchoalveolar lavage. Genotypes of sinus bacteria were also shown to be concordant with the lower airway, indicating the sinuses also may serve as a reservoir for recurrent lung infection,57 increasing the importance of maximizing sinus health. There are increased patterns of antimicrobial resistance secondary to multiple antibiotic exposures and increased prevalence of resistant bacteria within the community, particularly S. aureus. This is problematic because methicillin-resistant S. aureus colonization and infection in the respiratory tract of CF patients is associated with significantly worse overall survival.58 In addition to bacteria, fungi are commonly isolated from CF patients with Candida species being the most prevalent. It is considered a colonizer in pulmonary cultures.59 The use of inhaled steroids in CF patients along with improved culture techniques are likely contributors to increased fungal recovery. Fungus was also retrieved in 33% of patients in a study by Wise et al.,60 with two patients fulfilling the criteria for allergic fungal rhinosinusitis. The implications of these findings are unclear and further studies are required to examine the potential pathogenic role of these fungi. Clinical Manifestations Symptoms of CRS, when present, frequently include rhinorrhea, nasal obstruction, mouth breathing, headache, anosmia, and restless sleep.61,62 Other symptoms include facial pain, activity intolerance, halitosis, and voice changes.63–65 When associated with nasal CRS with NPs, the most common complaint is nasal obstruction whereas in patients without NPs, the most common complaint is headache or facial pain.25 Mouth breathing coupled with thick anterior and posterior nasal discharge may be the result of sinonasal polyposis. CF patients may also have facial deformation such as broadening of the nasal bridge, hypertelorism, and proptosis from chronic polyp expansion.26 NPs are frequently seen on rhinoscopy, which are usually multiple and bilateral.66 Rhinoscopy or nasal endoscopy may also show medial bulging of the lateral nasal wall.67 Unfortunately, physical examina- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm tion findings do not correlate or fluctuate with ongoing changes in clinical status.9 Imaging Radiographic abnormalities are frequent and often multiple in CF patients. The prevalence and detection of these abnormalities has improved dramatically with the increased use and improvement in CT scans. Findings on CT scan can aid in the diagnosis of CF, particularly among children, including demineralization and medial displacement of the uncinate process with inspissated secretions in the maxillary sinuses. Imaging is often crucial in this patient population because of the loss of important anatomic landmarks in particularly severe cases. Imaging may also be of use during surgical planning but also intraoperatively by using stereotactic imaging in conjunction with an endoscopic view. Management Management of CF sinusitis can be a daunting task, but most treatment recommendations dictate conservative management with medical therapy in lieu of primary surgical intervention.68 Few prospective studies exist to address medical management strategy of patients with CF sinusitis. Conservative therapy is favored with the use of sinus irrigations, mucolytics, oral steroids, and oral or i.v. antibiotics, as well as topical antibiotic and steroid therapeutic delivery. Patients who fail medical management or who present with complications such as bone erosion are good candidates for sinus surgery. The need for surgical management of the sinuses in CF patients continues to be controversial. Several studies showing severe CF sinusitis as a risk factor for forced expiratory volume in 1 second (FEV1) decline and thus worsened prognosis in children suggest aggressive treatment may have a role in select patients.69–71 Medical Management Medical management consists of nasal saline irrigations as well as medications including antibiotics, decongestants, antihistamines, topical and systemic steroids, dornase alfa, and N-acetyl cysteine as well as surfactant lavage.72,73 Evidence regarding several interventions is discussed later. Nasal Saline Irrigations. Irrigations with isotonic and hypotonic saline solutions serve to mechanically debride crusting along the sinonasal mucosa while hypertonic saline has the added theoretical benefit of decongestion by osmosis.74 A Cochrane meta-analysis concluded that quality of life in non-CF patients is improved with saline irrigation when compared with nontreatment.72 Unfortunately, no studies are available regarding the use of saline nasal irrigations in the CF CRS population, and thus recommendations for its use are extrapolated from studies in non-CF patients and the benefit is indicated in the pulmonary airways with nebulized hypertonic saline.75,76 The patients usually are instructed to use nasal irrigations using larger-volume, low-pressure irrigation bottles for comfort. A cadaver study showed the effects of irrigation are greatly enhanced after endoscopic sinus surgery (ESS). The squeeze bottle/neti pot devices provided the best saline irrigation delivery to the paranasal sinuses and are probably the best devices to administer topical delivery of antibiotics and steroids as well.77 Topical Steroids. Topical steroids are particularly effective for patients with allergic rhinitis as well as eosinophilic NPs in adults and children.78 CF NPs are neutrophilic and generally less responsive to steroids, but polyp size reduction and improvement in symptoms has been noted, particularly when using the Mygind’s position or upside down positioning.78–80 Hadfield et al.79 performed a randomized controlled trial (46 participants) comparing topical steroid (betamethasone) nasal drops with placebo and reported significant reduction in polyp size. It was noted in a later Cochrane review that the risk of bias was high in this study because ⬎50% of people enrolled did not American Journal of Rhinology & Allergy complete follow-up.81 However, high-dose topical steroid rinses with budesonide have shown no alteration of the hypothalamic–pituitary axis in several studies.82,83 Low-absorption topical steroid irrigations appear to be a reasonable strategy in CF CRS, although further randomized controlled trials are required. Topical Antibiotics. In a systematic review on the use of topical antimicrobials delivered in sinonasal irrigation by Lim et al.,84 the authors noted that there was no sufficient evidence to justify their use in CRS patients in general, but a high level of evidence was reported regarding use in the CF CRS population (IIb).85 Topical antibiotics have fewer adverse effects than oral antibiotics and may achieve a higher drug concentration at the target site.26 Topical tobramycin has been shown to be effective in reducing symptoms and reveals improvements in endoscopic scores in sinusitis.84 Because of the increased risk of recurrent CRS exacerbations after surgery, aggressive topical management is generally recommended. The use of topical antibiotics postoperatively has also been associated with reduced recurrence of CF sinus exacerbations86 with another study showing improved control of sinus disease for at least 2 years after surgery.52 Macrolide Antibiotics. Macrolides with 14 and 15 membered rings (e.g., azithromycin and clarithromycin) down-regulate inflammatory responses and are effective for the treatment of chronic airway inflammatory diseases including diffuse panbronchiolitis, CRS, and CF. Besides clinical improvement in nasal obstruction and nasal secretions,87 macrolides have been shown to decrease production of IL-8 by nasal epithelial cells88 and they correlate with improvement in eosinophilic CRS with NPs.89 Although there are no discrete studies establishing clinical benefit for CRS in the CF population, similar CFrelated pathophysiology between the sinonasal and pulmonary airways indicates this medication class is likely a valuable therapeutic addition for CF-associated sinus inflammation.90 Proper dosage and scheduling is controversial, but use for CF-associated pulmonary disease is 500 mg, 3 times/wk and is supported by randomized, controlled trials.91 Oral Antibiotics. In addition to macrolides, ciprofloxacin has been used prophylactically in patients with CF. Although studies for CFassociated sinus disease are lacking, an analysis of individuals progressing to pulmonary exacerbation who were provided oral antibiotics for an average of 13.4 days were found to have circumvented the need for i.v. antibiotics in up to 80% of the time92 Ibuprofen. There have been positive results with the use of highdose ibuprofen on the progression of pulmonary disease in children with CF.93 In a small series of 12 CF patients with NPs treated with high-dose ibuprofen therapy for pulmonary disease, the absence of polyps was noted at some point during treatment. In addition, clinical regression of NPs was noted in five patients during ibuprofen therapy.94 Confirmatory studies are required to evaluate the effectiveness of this drug in CF CRS. Dornase Alfa. Dornase alfa is a recombinant human deoxyribonuclease that hydrolyzes DNA polymers, reduces DNA fragment length, and reduces the viscosity of CF purulent secretions.95 Clinically, it has been shown to reduce the risks of pulmonary exacerbations, improve FEV1, and slow the continued rate of decline of lung function in CF patients ⬎5 years old.96–98 Nasal nebulized dornase alfa has also shown clinical efficacy in CF CRS. Cimmino et al.,99 in a double-blind placebo-controlled trial, reported on the use of nebulized dornase alfa in early postoperative CF ESS. There was a significant improvement in the nasal symptoms and endoscopic findings, as well as FEV1. Mainz et al.100 also reported significant improvement in quality of life (as measured by the 20-item Sino-Nasal Outcome Test) in a double-blind placebo-controlled crossover trial with nebulized dornase alfa compared to normal saline. Novel Therapeutics: Targeting the Basic Defect New therapeutic strategies for CF that target rescue of CFTR activity have recently been approved for select CF patients, and are in development in other groups of patients. Based on a dramatic ad- Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S41 vancement in our understanding of the production, processing, and function of the CFTR channel, small molecules identified by high throughput drug screening that restore activity to the mutant CFTR protein have been discovered and developed for clinical use.101–104 The three drugs that have entered clinical testing in CF include ivacaftor (Kalydeco, formerly VX-770; Vertex Pharmaceuticals, Cambridge, MA), lumacaftor (formerly VX-809), and ataluren (formerly PTC124). Ivacaftor, which potentiates mutant CFTR already present in the cell surface, caused significant improvement in lung function and other outcomes in clinical trials for patients with the G551D CFTR mutation and was recently approved by the Food and Drug Administration for use in individuals aged ⱖ6 years with at least one copy of this mutation.105 In this form of CF, mutant protein is present in normal quantities on the cell surface, but the channel exhibits severely defective gating. Although the effect on the CF sinuses still has not been studied, it is presumed that augmenting CFTR would generate pronounced improvement in the MCC of the sinus cavities, resulting in improved sinus disease outcomes. This will be evaluated in part during a postapproval study in G551D patients currently in progress. The F508del CFTR mutation is a more challenging target, because channels are “misfolded” and degraded in the endoplasmic reticulum before reaching the cell surface. Lumacaftor, another molecule discovered by high throughput screening, “corrects” the processing of the protein to improve delivery of CFTR to the plasma membrane. Clinical trials are currently using VX-770 and VX-809 together in an attempt to improve therapeutic effects and will be advanced to phase 3 testing.106,107 Ataluren is another small molecule currently under investigation in clinical trials.108 This drug induces translational readthrough of nonsense mutations in CFTR in vitro and in vivo and has shown activity in some but not all proof of concept CF trials. Ivacaftor and other CFTR modulators109are being advanced in CF patients with additional CFTR mutations; if successful, these new treatments could also provide relief of CFTR-mediated mucosal abnormalities that drive CF CRS pathogenesis. Other approaches designed to improve mucociliary transport in CF include targeting other apical ion channels to improve airway surface liquid hydration. Drugs that either inhibit epithelial sodium channels or stimulate alternative chloride pathways such as calcium-activated chloride channels are also under active investigation.110,111 Surgical Management Surgical Indications. The low incidence of self-reported symptoms (20%) despite the presence of radiographic and endoscopic sinus disease in the vast majority of CF patients reflects the difficulties in assessing the indications for surgical management. In general, CF patients with persistent symptoms who have failed medical management are often considered appropriate candidates for functional ESS (FESS). Surgical management of the sinuses in CF patients is also thought to improve pulmonary outcomes and is used to justify intervention in asymptomatic individuals. This has been shown in other diseases such as asthma, where Stammberger112 reported a 70% improvement in asthma symptoms and Lund113 reported pulmonary improvement in two-thirds of the postsurgical patients after ESS. However, pulmonary outcomes after surgical intervention for CF sinusitis are mixed. Several studies reported no change in objective outcomes for children and adults such as hospital admissions and pulmonary status, but showed improvements in clinical symptoms and quality of life.64,114 The best data to support surgical intervention in asymptomatic individuals derive from the identification of identical P. aeruginosa clones isolated in the sputum and the bronchoalveolar lavage of CF lung transplant patients before and after their transplant.115 Several studies have reported on the effect of sinus surgery as well as postoperative nasal care as a better means for controlling the sinuses as a reservoir for pulmonary infection.86,116 A retrospective chart review of patients who received lung transplantation and had subsequent FESS found a significant decrease in rehospitalization rates.117 Surgery coupled with daily nasal irrigations led to a signifi- S42 cant reduction in the incidence of tracheobronchitis as well as pneumonia and bronchiolitis obliterans syndrome in this population.117 With conflicting evidence regarding surgical indications, it is understandable that the percentage of CF patients requiring surgical management of their disease varies considerably. Virgin et al.118 used the pediatric health information services database to investigate the number patients with CF who had sinus surgery during a 3-year period at the 43 largest pediatric hospitals in the United States. The frequency of FESS in CF patients varied from 3 to 47% among centers with a positive correlation between hospital size, number of CF patients, and percentage of patients that adhered to the Cystic Fibrosis Foundation guidelines. FESS Outcomes. Standard FESS includes maxillary antrostomy, anterior and posterior ethmoidectomy, sphenoidotomy, and, depending on the age of the patient and presence of frontal sinuses, a frontal sinusotomy. Multiple studies have been conducted to report on the safety and effectiveness of FESS in CF patients.9,119–123 Complication rate after FESS in CF patients (11.5%) was found to be similar to the rate of non-CF FESS complications (0–17%).121 Khalid et al. reported on the outcomes of sinus surgery in adult patients both with and without CF.114 Although baseline CT and endoscopy scores were significantly worse in CF patients, the overall quality of life improvements as well as the degree of endoscopic improvement was similar between the two groups. The quality of life scales used in this study were the Rhinosinusitis Disability Index and the Chronic Sinusitis Survey. However, overall failure rates requiring revision surgery range from 13 to 89% in the literature.52,61,122,124,125 As a result, many CF patients have had multiple surgeries by the time they reach adulthood. Often used as a quality indicator, the need for revision surgery can be difficult to assess. In one study, CT findings were a significant predictor for revision sinus surgery.126 Patients with higher LundMckay scores were found to require revision surgery. However, almost all patients with CF have abnormal findings on CT scan,127 including asymptomatic non-CF patients (18–72%),128,129 but not all require surgery. In CRS patients, CT does not correlate well with symptom scores.130,131 McMurphy et al.132 found no significant difference between the preoperative and postoperative Lund-MacKay scores of pediatric CF patients after initial surgery or in subsequent scans despite medical or surgical interventions. Persistence or worsening of radiographic abnormalities after FESS has been shown in several other studies.120,133 Thus, CT imaging changes alone is probably not an appropriate indicator for recurrence/failure or predicting patient perception of disease except in the development of a mucocele or orbital complication.125,134–136 The presence of NP was found to assess the future likelihood of requiring revision FESS in several studies. In a study by Rowe-Jonce and Mackay122 regarding FESS for CF sinusitis with NPs, the reported rate of revision or return to preoperative symptom severity was 50% with 18–24 months of clinical follow-up. Rickert et al.137 found that preoperative grading of NPs in CF patients was predictive of the need for future surgical revisions. In their study with a longer follow-up of 7.3 years, the reported revision rate for patients with severe polyps was significantly higher (58%) compared with patients with no polyps (28%). The time for surgery was also significantly different between the groups tested with patients who had severe polyps requiring surgery in a shorter period of time. Pediatric FESS Outcomes. The pediatric patient population is unique because of the anatomic development peculiar to each age group. Treatment algorithms focus on maximizing medical therapy although surgical intervention has shown to improve patients whose disease course is recalcitrant to therapy. Most CF patients who undergo FESS exhibit improved symptom profile; however, radiographic and endoscopic scores are rarely significantly changed postoperatively.138 Similarly, data on pulmonary outcomes is mixed. Although short-term improvement in lung function has been observed in children, longterm effects have not been found to be significant.139 Other retrospec- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 1. Coronal CT scans showing the preoperative appearance of a patient with cystic fibrosis (CF) after traditional maxillary antrostomies with completely opacified maxillary sinuses (left, white arrow) and postoperative appearance after bilateral modified endoscopic medial maxillectomies and revision sinus surgery (right). The coronal CT image is posterior to the anterior one-third of the inferior turbinate. (Adapted with permission from Ref. 145.) tive studies on CF patients fail to show improved pulmonary function tests after sinus surgery.139,140 One pediatric study showed significant improvement in pulmonary function tests after FESS up to the first 2 years postoperatively.141 This was not shown in patients with low socioeconomic status. So far, there are no reports of adverse effects of FESS on facial growth in pediatric patients.123 Extensive Surgical Intervention Outcomes. The maxillary sinus is a chronic refractory problem area in CF patients because the normal MCC pathway is through the natural ostium and against gravity. Because MCC is impaired, accumulation of mucopurulence in the largest of the sinus cavities is commonplace on CT imaging and endoscopic findings despite previous “adequate” maxillary antrostomies. This is one reason CT findings are unchanged after FESS in CF patients because the maxillary sinus reaccumulates mucopurulence quickly despite the use of nasal irrigations. In essence, the sinuses in CF patients are similar to large abscesses that may be drained temporarily but ultimately lack real change within the cavities because the mucosa will never have normal function because of their underlying genetic defect. Thus, the ultimate treatment goals of aggressive surgical intervention are to establish permanent “access” rather than “ventilation” to the sinus cavities, permitting additional medicinal, mechanical, and physical means for the removal of desiccated mucus. The modified endoscopic medial maxillectomy (MEMM) involves removal of the medial maxillary wall marsupializing the maxillary sinus into the nasal cavity, but without sacrificing the head of the inferior turbinate or lacrimal system (Figs. 1 and 2). Accumulation of secretions becomes less frequent due to the open cavity and elimination of the physiological requirement of drainage through narrow anatomic ostia. In addition, the procedure allows physical debridement of mucus and polypoid edema in the clinic, improved clearance of mucus with nasal saline irrigations, and increased access for topical delivery of therapeutics. Multiple studies have been conducted regarding the role of this more aggressive surgery in the management of CF sinusitis. A retrospective study in 2006 was the first investigation regarding the use of MEMM in patients with CF CRS and it showed a low complication rate.142 Shatz143 also reported on a very aggressive surgical approach to the maxillary sinuses in CF children with prior history of FESS. In this study, there was a significant reduction in symptoms and duration of hospitalization as well as FEV1 after bilateral Caldwell-Luc and endoscopic medial maxillectomies in a cohort of 15 pediatric CF patients.143 Cho et al.144 reported results of this technique (referred to as a maxillary mega-antrostomy) and also found it to be safe and effective. In a recent prospective study, FESS and MEMM combined with a comprehensive postoperative medical management regimen (culture-directed antibiotics, oral steroid taper, and topical steroid/ American Journal of Rhinology & Allergy Figure 2. Transnasal endoscopic view of a left maxillary sinus after modified endoscopic medial maxillectomy. A 30° endoscope is inserted past the anterior one-third of the inferior turbinate revealing a well-healed maxillary cavity with no secretions retained in the floor of the sinus (arrow). (Adapted with permission from Ref. 145.) antibiotic irrigations) was associated with marked improvement in sinus disease outcomes including a decrease in symptoms (22-item Sino-Nasal Outcome Test) and objective findings (Lund Kennedy scores) at 1 year of clinical follow-up.145 In this study, FEV1 was not significantly changed, but there was significant reduction in the hospital admissions for pulmonary exacerbations in the year postsurgery compared with the year before. Results from these investigations lends support to a more extensive surgical approach in CF sinusitis, but further studies are warranted to determine whether this treatment paradigm will provide longterm symptom improvement and confer advantages in CF pulmonary outcomes. CONCLUSION CRS continues to be an important issue in the management of patients with CF, particularly given the improved survival rates associated with this disease. CF is a lifelong disease that requires long-term surveillance, vigilance, and compliance. Quality of life and decreased hospitalization will potentially become quality indicators Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S43 in the management of this patient group, and a multidisciplinary approach is necessary to develop consistent treatment paradigms for this difficult entity. 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Bacteriology of the maxillary sinuses in patients with cystic fibrosis. J Infect Dis 146:589–593, 1982. Halvorson DJ, Dupree JR, and Porubsky ES. Management of chronic sinusitis in the adult cystic fibrosis patient. Ann Otol Rhinol Laryngol 107:946–952, 1998. Mak GK, and Henig NR. Sinus disease in cystic fibrosis. Clin Rev Allergy Immunol 21:51–63, 2001. Moss RB, and King VV. Management of sinusitis in cystic fibrosis by endoscopic surgery and serial antimicrobial lavage. Reduction in May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. recurrence requiring surgery. Arch Otolaryngol Head Neck Surg 121:566–572, 1995. Muhlebach MS, Miller MB, Moore C, et al. Are lower airway or throat cultures predictive of sinus bacteriology in cystic fibrosis? 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Ibuprofen therapy and nasal polyposis in cystic fibrosis patients. J Otolaryngol 36:309–314, 2007. 95. Shak S, Capon DJ, Hellmiss R, et al. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci U S A 87:9188–9192, 1990. 96. Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 331:637–642, 1994. 97. Quan JM, Tiddens HA, Sy JP, et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr 139:813– 820, 2001. 98. Harms HK, Matouk E, Tournier G, et al. Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group. Pediatr Pulmonol 26:155–161, 1998. 99. Cimmino M, Nardone M, Cavaliere M, et al. 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DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S45 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. S46 Rowe SM, Varga K, Rab A, et al. Restoration of W1282X CFTR activity by enhanced expression. Am J Respir Cell Mol Biol 37:347– 356, 2007. Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 363:1991–2003, 2010. Kim Chiaw P, Eckford PD, and Bear CE. Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy. Essays Biochem 50:233– 248, 2011. Pettit RS. Cystic fibrosis transmembrane conductance regulatormodifying medications: The future of cystic fibrosis treatment. Ann Pharmacother 46:1065–1075, 2012. Peltz SW, Welch EM, Jacobson A, et al. Nonsense suppression activity of PTC124 (ataluren). Proc Natl Acad Sci U S A 106:E64, 2009. Zhang S, Smith N, Schuster D, et al. Quercetin increases cystic fibrosis transmembrane conductance regulator-mediated chloride transport and ciliary beat frequency: Therapeutic implications for chronic rhinosinusitis. Am J Rhinol Allergy 25:307–312, 2011. Jones AM, and Helm JM. Emerging treatments in cystic fibrosis. Drugs 69:1903–1910, 2009. Kellerman D, Rossi Mospan A, Engels J, et al. Denufosol: A review of studies with inhaled P2Y(2) agonists that led to Phase 3. Pulm Pharmacol Ther 21:600–607, 2008. Stammberger H. Endoscopic endonasal surgery–Concepts in treatment of recurring rhinosinusitis. Part II. Surgical technique. Otolaryngol Head Neck Surg 94:147–156, 1986. Lund VJ, Holmstrom M, and Scadding GK. Functional endoscopic sinus surgery in the management of chronic rhinosinusitis. An objective assessment. J Laryngol Otol 105:832–835, 1991. Khalid AN, Mace J, and Smith TL. Outcomes of sinus surgery in adults with cystic fibrosis. Otolaryngol Head Neck Surg 141:358– 363, 2009. Mainz JG, Hentschel J, Schien C, et al. Sinonasal persistence of Pseudomonas aeruginosa after lung transplantation. J Cyst Fibrosr 11:158–161, 2011. Lewiston N, King V, Umetsu D, et al. Cystic fibrosis patients who have undergone heart-lung transplantation benefit from maxillary sinus antrostomy and repeated sinus lavage. Transplant Proc 23: 1207–1208, 1991. Holzmann D, Speich R, Kaufmann T, et al. Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: A 10-year experience. Transplantation 77:134–136, 2004. Virgin FW, Huang L, Roberson D, and Sawicki G. Inter-hospital variation in the frequency of sinus surgery in pediatric patients with cystic fibrosis. Pediatr Pulmonol Suppl 47:358, 2012. Schulte DL, and Kasperbauer JL. Safety of paranasal sinus surgery in patients with cystic fibrosis. Laryngoscope 108:1813–1815, 1998. Cuyler JP. Follow-up of endoscopic sinus surgery on children with cystic fibrosis. Arch Otolaryngol Head Neck Surg 118:505–506, 1992. Albritton FD, and Kingdom TT. Endoscopic sinus surgery in patients with cystic fibrosis: An analysis of complications. Am J Rhinol 14:379–385, 2000. Rowe-Jones JM, and Mackay IS. Endoscopic sinus surgery in the treatment of cystic fibrosis with nasal polyposis. Laryngoscope 106: 1540–1544, 1996. Van Peteghem A, and Clement PA. Influence of extensive functional endoscopic sinus surgery (FESS) on facial growth in children with cystic fibrosis. Comparison of 10 cephalometric parameters of the midface for three study groups. Int J Pediatr Otorhinolaryngol 70: 1407–1413, 2006. Jaffe BF, Strome M, Khaw KT, and Shwachman H. Nasal polypectomy and sinus surgery for cystic fibrosis–A 10 year review. Otolaryngol Clin North Am 10:81–90, 1977. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. Yung MW, Gould J, and Upton GJ. Nasal polyposis in children with cystic fibrosis: A long-term follow-up study. Ann Otol Rhinol Laryngol 111:1081–1086, 2002. Becker SS, de Alarcon A, Bomeli SR, et al. Risk factors for recurrent sinus surgery in cystic fibrosis: Review of a decade of experience. Am J Rhinol 21:478–482, 2007. April MM, Zinreich SJ, Baroody FM, and Naclerio RM. Coronal CT scan abnormalities in children with chronic sinusitis. Laryngoscope 103:985–990, 1993. Lesserson JA, Kieserman SP, and Finn DG. The radiographic incidence of chronic sinus disease in the pediatric population. Laryngoscope 104:159–166, 1994. Diament MJ, Senac MO Jr, Gilsanz V, et al. Prevalence of incidental paranasal sinuses opacification in pediatric patients: A CT study. J Comput Assist Tomogr 11:426–431, 1987. Smith TL, Mendolia-Loffredo S, Loehrl TA, et al. Predictive factors and outcomes in endoscopic sinus surgery for chronic rhinosinusitis. Laryngoscope 115:2199–2205, 2005. Stewart MG, Donovan DT, Parke RB Jr, and Bautista MH. Does the severity of sinus computed tomography findings predict outcome in chronic sinusitis? Otolaryngol Head Neck Surg 123:81–84, 2000. McMurphy AB, Morriss C, Roberts DB, and Friedman EM. The usefulness of computed tomography scans in cystic fibrosis patients with chronic sinusitis. Am J Rhinol 21:706–710, 2007. Eggesbo HB, Sovik S, Dolvik S, and Kolmannskog F. CT characterization of inflammatory paranasal sinus disease in cystic fibrosis. Acta Radiol 43:21–28, 2002. Tandon R, and Derkay C. Contemporary management of rhinosinusitis and cystic fibrosis. Curr Opin Otolaryngol Head Neck Surg 11:41–44, 2003. Nishioka GJ, and Cook PR. Paranasal sinus disease in patients with cystic fibrosis. Otolaryngol Clin North Am 29:193–205, 1996. Krzeski A, Kapiszewska-Dzedzej D, Jakubczyk I, et al. Extent of pathological changes in the paranasal sinuses of patients with cystic fibrosis: CT analysis. Am J Rhinol 15:207–210, 2001. Rickert S, Banuchi VE, Germana JD, et al. Cystic fibrosis and endoscopic sinus surgery: Relationship between nasal polyposis and likelihood of revision endoscopic sinus surgery in patients with cystic fibrosis. Arch Otolaryngol Head Neck Surg 136:988–992, 2010. Rosbe KW, Jones DT, Rahbar R, et al. Endoscopic sinus surgery in cystic fibrosis: Do patients benefit from surgery? Int J Pediatr Otorhinolaryngol 1 61:113–119, 2001. Jarrett WA, Militsakh O, Anstad M, and Manaligod J. Endoscopic sinus surgery in cystic fibrosis: effects on pulmonary function and ideal body weight. Ear Nose Throat J 83:118–121, 2004. Madonna D, Isaacson G, Rosenfeld RM, and Panitch H. Effect of sinus surgery on pulmonary function in patients with cystic fibrosis. Laryngoscope 107:328–331, 1997. Kovell LC, Wang J, Ishman SL, et al. Cystic fibrosis and sinusitis in children: Outcomes and socioeconomic status. Otolaryngol Head Neck Surg 145:146–153, 2011. Woodworth BA, Parker RO, and Schlosser RJ. Modified endoscopic medial maxillectomy for chronic maxillary sinusitis. Am J Rhinol 20:317–319, 2006. Shatz A. Management of recurrent sinus disease in children with cystic fibrosis: A combined approach. Otolaryngol Head Neck Surg 135:248–252, 2006. Cho DY, and Hwang PH. Results of endoscopic maxillary megaantrostomy in recalcitrant maxillary sinusitis. Am J Rhinol 22:658– 662, 2008. Virgin F, Rowe SM, Wade MB, et al. Extensive surgical and comprehensive postoperative medical management for severe, recalcitrant cystic fibrosis chronic rhinosinusitis. Am J Rhinol Allergy 26:70–75, 2012. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Pediatric rhinosinusitis: Definitions, diagnosis and management—An overview Swapna K. Chandran, M.D.,1 and Thomas S. Higgins, M.D., M.S.P.H.2 ABSTRACT Rhinosinusitis is common in the pediatric population; however, diagnostic and management techniques often differ when compared with adult rhinosinusitis. Multidisciplinary guidelines have outlined the diagnostic criteria for pediatric rhinosinusitis. Although acute rhinosinusitis is a more infectious phenomenon, chronic sinusitis involves a more multifactorial etiology. This article outlines some of the definitions of rhinosinusitis, diagnosis and management of pediatric sinusitis, and the complications of rhinosinusitis seen in the pediatric population. R hinosinusitis is a common clinical problem with significant morbidity, resulting in 31 million1 office and emergency room visits per year in the United States. Children have between six and eight viral upper respiratory infections per year and up to 13% can be complicated by bacterial rhinosinusitis.2 Defining the varied manifestations of rhinosinusitis has proven to be difficult, secondary to the numerous causes of the condition: viral, bacterial, allergic, nonallergic, fungal, and even idiopathic. Commonly divided into acute and chronic, other terms have also been used, including subacute and recurrent acute rhinosinusitis. Acute sinusitis is often thought to be infectious in nature, whereas chronic rhinosinusitis is often from other inflammatory processes that are not necessarily infectious in nature, such as gastroesophageal reflux disease and cystic fibrosis.3 The paranasal sinuses are common sites of infection for children and adolescents. Viral upper respiratory infections (rhinitis) often predisposes to infectious rhinosinusitis.2 These infections are typically not considered life-threatening; however, serious sequelae can occur rarely. This article will give an overview of the current definitions of rhinosinusitis according to recently published guidelines and also outline some of the rare but life-threatening complications that may occur in pediatric rhinosinusitis. Current guidelines and controversies in diagnosis and management will also be discussed. DEFINITIONS (AMERICAN ACADEMY OF PEDIATRICS GUIDELINE WITH AMERICAN ACADEMY OF OTOLARYNGOLOGY GUIDELINE) Definitions of the infections involving the upper respiratory tract and paranasal sinuses have been described in published guidelines by both the American Academy of Pediatrics (AAP) as well as the American Academy of Otolaryngology.2,4 Table 1 outlines the types of infections that are mainly classified by duration and severity of symptoms. Associated symptoms of cough, fatigue, hyposmia, anosmia, 1 From the Department of Otolaryngology Head and Neck Surgery, University of Louisville School of Medicine, Louisville, Kentucky, and 2Kentuckiana Ear, Nose & Throat, P.S.C., Louisville, Kentucky The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Thomas S. Higgins, M.D., M.S.P.H., Kentuckiana Ear, Nose & Throat, P.S.C., 6420 Dutchmans Parkway, Number 380, Louisville, KY 40205 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S16 –S19, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy maxillary dental pain, and ear fullness and pressure also are present with acute rhinosinusitis. A sinus infection can be caused by one or more bacteria isolated in a high-density field.2–4 Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most commonly isolated pathogens. Pseudomonas aeruginosa and Staphylococcus aureus are also commonly isolated organisms,5 although more often isolated in chronic rhinosinusitis. The role of bacterial infections in chronic rhinosinusitis is controversial, although bacterial superantigen5biofilms and osteitis of the sinuses may play a role.3 METHODS OF DIAGNOSIS The multidisciplinary task forces strongly recommend the use of clinical diagnostic criteria as outlined previously in making a diagnosis of rhinosinusitis. Imaging studies are often controversial in young patients, secondary to radiation exposure and often there is a need for sedation in obtaining a suitable radiographic image. In general, for both adults and children, imaging studies are not recommended in acute sinusitis unless a complication or alternative diagnosis is suspected. In children, imaging studies are not necessary to confirm a diagnosis of clinical sinusitis in children ⬍6 years of age (recommendation 2a of the AAP guidelines2). Computed tomography of the paranasal sinuses should be reserved for patients in whom surgery is being considered (recommendation 2b of the AAP guidelines2). It should be noted, however, that abnormal findings on a radiograph do not make a diagnosis of rhinosinusitis, but merely serves to confirm a diagnosis.6 MANAGEMENT In general, it is well accepted that viral upper respiratory infections can be treated symptomatically with analgesic, antipyretic, and decongestant medications (either topical or systemic).2 Decongestants in children should be used cautiously because there are few studies on the efficacy and side effect profile of decongestants in pediatric patients. Concomitant decongestant and antihistamine use remains controversial in the treatment of infection and inflammation of the pediatric upper respiratory system. Nasal saline irrigation in the pediatric population has both been shown to be effective and well tolerated in children with rhinosinusitis.7,8 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S47 Figure 1. Chandler’s classification of orbital complications of acute sinusitis. (A) Periorbital inflammatory edema caused by venous congestion. (B) Orbital cellulitis. (C) Subperiosteal abscess (purulence between the ethmoid bone and orbital periosteum. (D) Orbital abscess (purulence within the orbit). (E) Cavernous sinus thrombosis. (Adapted from Ref. 14.) S48 May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1. Types of infections classified by duration and severity of symptoms Type Duration Acute viral ⬍10 days Acute bacterial ⬎10 days ⬍30 days Subacute bacterial Recurrent acute bacterial 30–90 days (1–3 mo) Episodic ⬍30 days separated by at least 10 days without symptoms ⬎90 days (3 mo) Chronic Symptoms Nasal drainage Symptoms do not worsen Purulent nasal drainage Nasal obstruction Facial pain/pressure/fullness Worsening symptoms after 10 days Mucopurulent drainage New respiratory symptoms on residual respiratory Acute Rhinosinusitis Antibiotics are recommended for the management of acute bacterial sinusitis to achieve a more rapid clinical cure (recommendation 3 of the AAP guidelines2). In most cases, amoxicillin should be used as first-line therapy2,4 unless there are factors indicating presence of bacterial species that are likely to be resistant to penicillins. These factors include (1) attendance in day care, (2) recent antimicrobial treatment, and (3) age ⬍2 years.2 Chronic Rhinosinusitis Long-term, broad-spectrum antibiotics have been the cornerstone of management of pediatric chronic rhinosinusitis, in contrast to adults. The use of long-term broad-spectrum antibiotics is variable and many patients are refractory perhaps secondary to biofilm growth or other inflammatory causes of disease.5,9 Both oral and i.v. antibiotics have been studied and have been shown to have successful results. The most commonly used antibiotic is amoxicillin/clavulanate or ampicillin sodium with sulbactam sodium when i.v. studies were performed. The role of surgery in the pediatric population is controversial. Although functional endoscopic sinus surgery is shown to be effective in up to 60–80%9,10 of pediatric patients who underwent surgery, some authors have expressed concerns of interference with facial growth and sinus development. Adenoidectomy as first-line surgical treatment with or without maxillary sinus irrigation and/or antrostomy has also evolved in the management of pediatric chronic rhinosinusitis. This offers a less invasive treatment at reduction of bacterial load and aeration of the paranasal sinus. Results have shown 60–85% efficacy at symptom improvement.10,11 Complications of Pediatric Rhinosinusitis The most common complication of acute rhinosinusitis is orbital extension of infection.12 The progression of orbital complications is illustrated in Fig. 1.13 These complications most often occur in older American Journal of Rhinology & Allergy Complete Complete Episodic Nasal obstruction Facial pain/pressure/fullness Decreased sense of smell AND Purulent mucus or edema in the middle meatus or ethmoid region Polyps Radiographic imaging showing inflammation of the paranasal sinuses Acute bacterial sinusitis superimposed on chronic sinusitis Symptom Resolution Complete Persistent respiratory symptoms such as cough and nasal obstruction Rhinorrhea New symptoms resolve with treatment and old remain children. Diagnosis includes computed tomography to evaluate the extent of disease. Management should include ophthalmology consultation and broad-spectrum antibiotics. Surgical management is indicated in certain cases. Studies have recently shown that a trial of antibiotics can be used, however, in small subperiosteal abscesses. Intracranial complications also arise, although are much rarer than orbital complications. The spectrum progresses from meningitis, epidural, and subdural empyemas to frontal lobe abscess. Treatment again requires broad-spectrum antibiotics and a combination of sinus and neurosurgical procedures to eradicate infection.14 CONCLUSION Pediatric rhinosinusitis is a disease distinct from adult rhinosinusitis. Rhinosinusitis is difficult to define secondary to the varied pathophysiological mechanisms involved, especially in chronic disease. Management is also difficult because of controversies surrounding pediatric patients. Guidelines have helped to make diagnosis and management easier and it has become clear that multidisciplinary approaches to management are necessary. CLINICAL PEARLS • Children experience an average of 6 – 8 viral upper respiratory infections per year, of which up to 13% can be complicated by bacterial rhinosinusitis • Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most commonly isolated pathogens in acute bacterial rhinosinusitis of children • Factors associated with penicillin resistant bacteria in acute rhinosinusitis in children include (1) attendance in day care, (2) recent antimicrobial treatment, and (3) age ⬍ 2 years • The most common complication of acute rhinosinusitis in children is orbital extension of infection • Orbital complications of acute rhinosinusitis in children include Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S49 eyelid edema, subperiosteal abscess, orbital cellulitis, orbital abscess and cavernous sinus thrombosis. • Intracranial complication of acute rhinosinusitis in children are rare and include meningitis, epidural and subdural empyemas and frontal lobe abscess. REFERENCES 1. 2. 3. 4. 5. 6. S50 International Rhinosinusitis Advisory Board. Infectious rhinosinusitis in adults: Classification, etiology, and management. Ear Nose Throat J 76:1–22, 1997. American Academy of Pediatrics, Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical management guideline: Management of sinusitis. Pediatrics 108:798–808, 2001. Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: Establishing definitions for clinical research and patient care. Otolaryngol Head Neck Surg 131:S1–S62, 2004. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: Adult sinusitis. Otolaryngol Head Neck Surg 137:S1–S31, 2007. Criddle MW, Stinson A, Savliwala M, and Coticchia J. Pediatric chronic rhinosinusitis: A retrospective review. Am J Otolaryngol 29:372–378, 2008. Kronemer KA, and McAlister WH. Sinusitis and its imaging in the pediatric population. Pedatr Radiol 27:837–846, 1997. 7. Wang YH, Yang CP, Ku MS, et al. Efficacy of nasal irrigation in the treatment of acute sinusitis in children. Int J Pediatr Otorhinolaryngol 73:1696–1701, 2009. 8. Jeffe JS, Bhushan B, and Schroeder JW Jr. Nasal saline irrigation in children: A study of compliance and tolerance. Int J Pediatr Otorhinolaryngol 76:409–413, 2012. 9. Adappa ND, and Coticchia JM. Management of refractory chronic rhinosinusitis in children. Am J Otolaryngol 27:384–389, 2006. 10. Thottam PJ, Haupert M, Saraiya S, et al. Functional endoscopy sinus surgery (FESS) alone vs. balloon catheter sinuplasty (BCS) and ethmoidectomy: A comparative outcome analysis in pediatric chronic rhinosinusitis. Int J Pediatr Otorhinolaryngol 76:1355–1360, 2012. 11. Ramadan HH, Bueller H, Hester ST, and Terrell AM. Sinus balloon catheter dilation after adenoidectomy failure for children with chronic rhinosinusitis. Arch Otolaryngol Head Neck Surg 138:635– 637, 2012. 12. Brook I. Microbiology and antimicrobial treatment of orbital and intracranial complications of sinusitis in children and their management. Int J Pediatr Otorhinolaryngol 73:1183–1186, 2009. 13. Ward RF, and April MM. Complications of sinusitis in the pediatric population. Op Tech Otolaryngol Head Neck Surg 7:305–309, 1996. 14. Hicks CW, Weber JG, Reid JR, et al. Identifying and managing intracranial complications of sinusitis in children. Pedatr Infect Dis J 30:222–226, 2011. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Surgery for sinonasal disease Thomas S. Higgins, M.D., M.S.P.H.,1 and Andrew P. Lane, M.D.2 ABSTRACT Surgery for chronic rhinosinusitis is an effective complement to a well-designed medical regimen. Functional endoscopic sinus surgery is among the most common surgeries performed for sinonasal disease refractory to maximal medical therapy. Nasal surgery techniques, such as septoplasty and inferior turbinate surgery, may assist in both relieving the symptom of nasal obstruction and providing access for sinus surgery. Although rare, open sinus techniques are occasionally required. S urgery for sinonasal disease is effective for recalcitrant rhinosinusitis after failed medical therapy. Sinus surgery has evolved over the past few decades to a safer and more effective treatment modality. Before the 1980s, sinus surgery was mainly performed with open approaches using skin incisions for access. Functional endoscopic sinus surgery (FESS) is now the standard of care for most cases of surgical sinus disease; open approaches are rarely required. PREOPERATIVE ASSESSMENT As with any surgery, a discussion with the patient of the risks, benefits, and alternatives of sinus surgery is important. The risks include bleeding, infection, anesthetic risks, scarring, recurrence of disease, cerebrospinal fluid leak, nasolacrimal duct leak, vision/eye injury, and, if a septoplasty is planned, nasoseptal perforation. A systems-based medical evaluation, including but not limited to careful assessment of cardiac, pulmonary, and bleeding risk factors, should be performed before undergoing surgery. Patients are candidates for sinus surgery if they meet the criteria for chronic rhinosinusitis (CRS) and are resistant to maximal medical therapy. It is important to note, however, that surgery should be considered an adjunct therapeutic modality performed along with ongoing medical therapy, not a replacement to medical therapy. A computed tomography of the sinuses should be obtained to define the extent of disease and for surgical planning. Stereotactic navigation, which requires fine-cut images, should be considered for complex cases, especially for revision sinus surgery, extensive polyposis, and difficult anatomy. SINUS SURGERY TECHNIQUES Sinus surgery can be divided by approach and location: (1) approach (endoscopic versus open) and (2) location (maxillary sinus, ethmoid sinus, sphenoid sinus, frontal sinus, etc.). Table 1 summarizes the classification of sinus surgery. ENDOSCOPIC SINUS SURGERY The goal of ESS is to enlarge the natural drainage pathways of the sinuses to improve mucociliary clearance and to permit better peneFrom 1Kentuckiana Ear, Nose & Throat, P.S.C., Louisville, Kentucky, and 2Division of Rhinology, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Andrew P. Lane, M.D., Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins Outpatient Center, 6th Floor, 601 North Caroline Street, Baltimore, MD 21287 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S42–S44, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy tration of medical therapy. Several outcome studies have shown improvement in sinonasal symptoms, signs, and quality of life after FESS. A systematic review of outcome studies after FESS, including 11 prospective studies and 5 studies using validated quality-of-life measures, found that all 45 studies showed improvement in CRS-related symptoms and quality of life.1 Techniques important to any ESS operation include mucosal preservation and control of intraoperative bleeding. Mucosal stripping disrupts the small submucosal vascular system, leading to oozing into the surgical field. Topical vasoconstrictors may be used to improve visualization of the surgical field. A systematic review of topical vasoconstrictors showed that most topical vasoconstrictors have very few side effects and reduce bleeding. Some commonly used vasoconstrictor agents include oxymetazoline/xylometazoline, cocaine, and epinephrine. It is important to note that these agents should be used judiciously in patients with cardiovascular risk factors and the pediatric population.2 Endoscopic maxillary antrostomy is the most common endoscopic sinus procedure performed. The important aspects of this surgery include an adequate uncinectomy and identification of the natural ostium with incorporation into the surgical antrostomy. Maxillary antrostomy with tissue removal is documented when extensive debris or a mass is removed along with the antrostomy. Another technique, termed endoscopic maxillary mega-antrostomy or endoscopic medial maxillectomy, in which the posterior aspect of inferior turbinate and a wide antrostomy are performed, may be beneficial in cases of refractory disease and tumor excisions.3 Endoscopic ethmoidectomy may be performed as a partial (or anterior) or total ethmoidectomy, depending on the extent of disease. The ethmoid bulla is removed to reveal the basal lamina, the dividing point of the anterior and posterior ethmoid sinuses. The lamina papyracea and basal lamella should be identified, and care should be taken to not obstruct the frontal outflow tract. If a concha bullosa (an aerated middle turbinate) is encountered, resection of its lateral wall may be performed to open the sinus and widen the middle meatus. The basal lamella of the middle turbinate is entered to reach the posterior ethmoid cells, with care taken to avoid destabilization of the horizontal attachment during inferior dissection. The surgeon should also recognize that the skull base typically slants inferiorly as the ethmoid dissection continues posteriorly; therefore, the trajectory of dissection should be more horizontal to avoid causing an iatrogenic cerebrospinal fluid leak. In addition, overzealous superomedial dissection can risk injury to the thin bone of the lateral lamella of cribriform plate, which is the most common site of iatrogenic cerebrospinal fluid leak. Complete dissection of the ethmoid sinus includes removing all partitions with visual identification of lamina Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S51 Table 1 Summary of common sinus surgery techniques Location Maxillary sinus Ethmoid sinus Sphenoid sinus Frontal sinus Septum Inferior turbinates Endoscopic papyracea, superior turbinate, anterior face of the sphenoid sinus, and the skull base. Endoscopic sphenoidotomy may be performed via transnasal or transethmoidal approaches. The transnasal approach is typically used for isolated sphenoid sinus disease with favorable anatomy. The endoscope is guided to the sphenoethmoid recess until the natural os of the sphenoid is identified and enlarged transnasally. This approach has the advantage of not requiring an ethmoidectomy; however, the nasal anatomy is not always favorable for this approach and access for postoperative debridements can be difficult. The transethmoidal approach is performed more commonly. After a total ethmoidectomy, the sphenoid face and superior turbinate are identified. At this point, the sphenoid sinus may be opened either by removing the lower portion of the superior turbinate with identification of the sphenoid os or through the anterior face of the sphenoid sinus. Definitive identification of the skull base, medial orbital wall, and superior turbinate is essential to performing a safe sphenoidotomy. Endoscopic frontal sinusotomy is the most complex procedure in ESS. The anatomy can be highly variable and imprecise dissection can lead to scarring and recalcitrant frontal sinus disease. Because the frontal outflow tract drains to the middle meatus, an anterior ethmoidectomy is the first-line treatment for frontal sinus disease; however, certain patients, such as those with aspirin triad disease or a frontal intersinus septal cell, are more likely to fail with this procedure alone. A frontal sinusotomy requires careful analysis of the radiographic anatomy to obtain a three-dimensional understanding of frontal recess cells before surgery. Intraoperatively, the relationship of the frontal sinus outflow tract to the orbit, skull base, and anterior ethmoid artery must be delineated. The agger nasi cell, if present, is removed. Depending on the specific anatomic features, other frontal cells may need to be opened. Endoscopic frontal sinus procedures have been divided into Draf types, which were described by Dr. Wolfgang Draf. Draf type 1 involves removal of anterior ethmoid cells and uncinate process to open the frontal outflow tract and removal of any frontal cells. Draf type 2 (standard endoscopic frontal sinusotomy) involves resection of the frontal sinus floor from the nasal septum to the lamina papyracea to enlarge each frontal outflow tract maximally. Draf type 3, or modified Lothrop procedure, involves all components of a Draf type 2 procedure with additional resection of anterior–superior nasal septum and connection of both frontal sinuses into a single cavity. SINUS DILATION PROCEDURES Sinus dilation procedures using balloon technology can be used in select patients for the maxillary, sphenoid, and frontal sinuses. This S52 Open Maxillary antrostomy Maxillary antrostomy with tissue removal Maxillary dilation procedure Endoscopic medial maxillectomy Ethmoidectomy Concha bullosa resection Sphenoidotomy Sphenoidotomy with tissue removal Draf 1 frontal sinusotomy Draf 2 frontal sinusotomy Draf 3 frontal sinusotomy (modified Lothrop procedure) Septoplasty Inferior turbinate outfracture Inferior turbinate cauterization Inferior turbinate submucosal resection Inferior turbinate resection Caldwell-Luc procedure Maxillectomy External ethmoidectomy (Lynch approach) Frontal sinus trephination Osteoplastic flap with obliteration Osteoplastic flap without obliteration procedure is not approved for dilation of the ethmoid sinuses. Studies are currently underway to evaluate the benefits, risks, and indications of this technique as an alternative or adjunct to ESS. A recent Cochrane review to evaluate studies comparing balloon sinuplasty and conventional ESS found only one study that had not yet been published in a peer-reviewed journal that met the reviews inclusion criteria. The authors concluded that there was an urgent need for randomized controlled trials to better evaluate these modalities.4 Although efficacy studies are ongoing, the procedure so far seems to have a good safety profile in general,5 although surgical complications have been reported.6 OPEN SINUS PROCEDURES Open approaches to the sinuses are occasionally used as an adjunct during complicated cases. They also may be used in acute sinusitis with impending complications, to rapidly drain an infected sinus or mucocele under pressure, where an endoscopic approach would be difficult because of severe inflammation. A Caldwell-Luc approach may be used to access to the anterior and inferior maxillary sinus. A frontal sinus trephination may be used to access difficult-to-reach areas of the frontal sinus. Refractory frontal sinus disease may also be managed with osteoplastic flap with or without obliteration. Other external techniques are rarely required unless endoscopic sinus equipment is not available. SEPTOPLASTY AND INFERIOR TURBINATE REDUCTION Concomitant nasal obstruction surgery may be indicated in patient chronic rhinitis or deviated septum. Septoplasty is a common procedure performed in which mucoperichondrial and mucoperiosteal flaps are raised and the portions of deviated septum are removed. This procedure is typically performed for nasal airway obstruction but may also be performed in conjunction with sinus surgery for improved access. Inferior turbinate surgery is a commonly performed procedure for nasal airway obstruction. Inferior turbinate outfracture is a mucosa-preserving technique performed to lateralize the bony portion of the inferior turbinate. The inferior turbinates may also be reduced in size using techniques that may remove bone or erectile submucosal tissue. If possible, preserving the inferior turbinate mucosa is preferred to limit the risk of empty nose syndrome in which the lack of inferior turbinate causes a paradoxical sensation of nasal congestion even though the appearance of the airway is extremely wide. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm CONCLUSION CRS is a common inflammatory disease with a ubiquitous etiologic profile. Surgical intervention is commonly required for recalcitrant disease, not as a cure, but as a means of permitting better penetration of medical therapy. This article provides an overview of the techniques of sinus surgery. • Stereotactic navigation may be beneficial when dissection is performed along the skull base and orbit, especially in cases of revision surgery. REFERENCES 1. CLINICAL PEARLS • Surgery is effective for rhinosinusitis refractory to medical therapy. Surgery should be considered an adjunct modality used along with medical therapy, not in place of medical therapy. • Preoperative workup for ESS in recalcitrant rhinosinusitis includes a thorough medical evaluation; CT scan of the sinuses; and a discussion of the risks, benefits, alternatives, and complications of the procedures. • Sinonasal surgical techniques are categorized by the approach and sinus location. • ESS is safe and effective for the management of most cases of rhinosinusitis. Sinus dilation techniques allow in-office dilation of the sinuses and as an adjunct to ESS in the operating room. Open approaches are still occasionally required. American Journal of Rhinology & Allergy 2. 3. 4. 5. 6. Smith TL, Batra PS, Seiden AM, and Hannley M. Evidence supporting endoscopic sinus surgery in the management of adult chronic rhinosinusitis: A systematic review. Am J Rhinol 19:537–543, 2005. Higgins TS, Hwang PH, Kingdom TT, et al. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope 121:422–432, 2011. Cho DY, and Hwang PH. Results of endoscopic maxillary megaantrostomy in recalcitrant maxillary sinusitis. Am J Rhinol 22:658– 662, 2008. Ahmed J, Pal S, Hopkins C, and Jayaraj S. Functional endoscopic balloon dilation of sinus ostia for chronic rhinosinusitis. Cochrane Database Syst Rev 6:CD008515, 2011. Taghi AS, Khalil SS, Mace AD, and Saleh HA. Balloon sinuplasty: Balloon-catheter dilation of paranasal sinus ostia for chronic rhinosinusitis. Expert Rev Med Devices 6:377–382, 2009. Tomazic PV, Stammberger H, Koele W, and Gerstenberger C. Ethmoid roof CSF-leak following frontal sinus balloon sinuplasty. Rhinology 48:247, 2010. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S53 Augmenting the nasal airway: Beyond septoplasty Patrick Simon, M.D., and Douglas Sidle, M.D., F.A.C.S. ABSTRACT Background: Nasal airway obstruction is a common complaint of patients presenting to otolaryngology clinics and can be caused by a variety of anatomic factors. A number of advances in the surgical management of nasal airway obstruction have been made over the last century. The objective of this article is to provide descriptions of the surgical procedures used to augment specific anatomic deviations that lead to obstruction of the nasal airway. Methods: The descriptions of surgical procedures were derived from a literature review as well as the empiric knowledge of the senior author. Preoperative considerations of nasal anatomy, the nasal airway, and the L-strut are detailed. Results: Functional rhinoplasty techniques are reviewed including septoplasty, extracorporeal septoplasty, spreader grafts, batten grafts, alar rim grafts, and correction of caudal septal deviation. Conclusion: The symptom, nasal obstruction, may arise from a number of different anatomic and physiological elements. The rhinoplasty surgeon must consider these contributing elements and manage accordingly, to achieve optimal results. N asal obstruction is one of the most common complaints of patients presenting to otolaryngology clinics. A number of different anatomic factors may contribute to the subjective sensation of decreased nasal airflow. Septoplasty is frequently performed on patients with anatomic changes of the nasal septum that impinge on the nose’s function as an airway. Although this procedure will produce improvement in nasal function in a majority of patients with simple deviation, augmentation of the nasal valves must also be considered. The salient nasal anatomy of the nasal septum, internal nasal valve (INV), and external nasal valve (ENV) is reviewed in regard to their contributions to the nasal airway. The common surgical approaches to address the problems of nasal valve stenosis, nasal valve collapse, and other anatomic distortions of the nasal airway are described. PREOPERATIVE NASAL EVALUATION The nasal airway serves as the primary conduit for inspired air to reach the lower respiratory tract. The effects of ecogeographical evolution has produced significant individual variation in the size and shape of the human nose.1 Thus, the anatomic contribution to the complaint of nasal obstruction must be elucidated before embarking on surgical repair. Historical information that must be ascertained includes prior surgeries, trauma, allergic, and sinus symptoms. Furthermore, subjective questionnaires such as the Nasal Obstruction Symptom Evaluation2 should be used to characterize the patient’s complaint. Preoperative assessment should include anterior rhinoscopy to find septal deviation, nasal endoscopy to rule out polyposis, Cottle maneuvers and external dilators to define dynamical valve collapse, and trials of decongestants to determine the contribution of mucosal congestion. Care must be taken to rule out previously undiagnosed congenital abnormalities such as choanal atresia/stenosis or pyriform aperture stenosis. Objective testing such as rhinomanometry and acoustic rhinometry may be performed to provide a numerical stratification of the patient’s complaints and have been shown to predict postoperative patient satisfaction.3 Based on these assessments the clinician may develop a surgical plan individualized to the patient’s anatomic disposition. From the Northwestern Memorial Hospital, Department of Otolaryngology–Head and Neck Surgery, Chicago, Illinois Presented at the Northwestern University Feinberg School of Medicine, Summer Sinus Course, July 22–23, 2011, Chicago, Illinois The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Douglas Sidle, M.D., F.A.C.S., Northwestern Memorial Hospital, Department of Otolaryngology–Head and Neck Surgery, Northwestern University Feinberg School of Medicine, 676 North St. Clair, Suite 1325, Chicago, IL 60611 E-mail address: [email protected] (Am J Rhinol Allergy 26, S326 –S331, 2012; doi: 10.2500/ajra.2012.26.3786) Copyright © 2014, OceanSide Publications, Inc., U.S.A. S54 ANATOMY OF THE NASAL AIRWAY External Nasal Valve The axially positioned nostrils guard the entrance to the bilateral nasal cavities. The nostrils are bordered laterally by the ala and medially by the columella. The nasal vestibule defines the area within the external nasal aperture. The soft tissue envelope and the medial footplates of the lower lateral cartilages (LLCs) support the most caudal portion of the columella. The alar subunit is composed of the soft tissue envelope and the lateral crura of the LLCs. The skin of the ala and lower third of the nose is thick, relative to the upper nose, contains an abundance of sebaceous glands, and is intimately associated with the attached musculature. The bony correlate for the posterior termination of the ENV is the pyriform aperture. The cartilaginous extent of the ENV ends at the scroll region joining the LLC and the upper lateral cartilage (ULC; Fig. 1). Internal Nasal Valve The INV is the point of greatest resistance in the nasal airway. The caudal inferior turbinate forms the inferiolateral border of the INV. The ULC provides the lateral border of the INV as it continues superiorly toward the septum. At its junction with the nasal septum an angle of 10–15° is created. Medially, the INV is defined by the nasal septum and the valve is completed at the maxillary crest and floor of the nose. Septum The nasal septum is a midline structure that divides the nasal airway into two nasal cavities. It is firmly invested by mucoperichondrium, anteriorly, and mucoperiosteum, posterior and inferiorly. Its cartilaginous component, the quadrangular cartilage, forms its caudal-most extent, contributing to both the ENV and the INV. Additionally, the quadrangular cartilage defines the anterior nasal dorsum. Along the dorsum the ULCs are supported medially and are separated from the septum by fibrous attachments and its mucosal investment. At its most cephalic position the cartilage meets the paired nasal bones. At this junction, the “keystone” region of the nose, an area of stability essential to the support and structure of the nose, is located. Inferiorly, the cartilaginous septum firmly rests on the maxillary crest and is bound by the decussating fibrous attachments at the junction of the perichondrium with the periosteum. The inferior septum is continued posteriorly by the vomer. Superior to the vomer, the septum approaches the nasal bones, the floor of the frontal sinus, May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 1. This series of pictures represents the nasal keystone area (solid black circle), internal nasal valve (dashed black oval), and external nasal valve (dashed white oval). and the anterior skull base through the perpendicular plate of the ethmoid. The dynamic contribution of the septum to nasal airflow is the septal body. This poorly understood vasoerectile structure has been localized to the region anterior to the middle turbinate, above the nasal floor, and caudally approaching the nasal valve region.4 The septal body invests an observed thickening at the junction of the cartilaginous and bony septum. Furthermore, this region has a rich venous sinusoidal composition, thus, indicating a compliment to the nasal turbinates in regulating airflow.5 Neurovascular Anatomy The vascular contributions that are significant to rhinoplasty primarily arise from the facial, sphenopalatine, and ophthalmic arteries. The facial arteries provide blood supply to the caudal nasal septum and nasal sidewall through the superior labial and the angular arteries, respectively. The anterior ethmoid branch of the ophthalmic artery contributes to the dorsal septum and the dorsal nasal tip through dorsal nasal artery. The sphenopalatine artery contributes to the septal blood supply through its posterior septal branches. The first and second branches of the trigeminal nerve provide sensation of temperature, pain, and changes in pressure (i.e., airflow). The sensation of airflow is most profound at the skin-lined vestibule where end-sensory mechanoreceptors serve to refine the tactile perception.6 Alternatively, beyond the vestibule, the nasal mucosa has a more primitive end-sensory arrangement, where no specialization of the nerve endings or overlying epithelium exists, and arborization of the nerve occurs terminally.7 Previous studies have shown that anesthetizing the anterior nose results in a significant subjective sensation of nasal obstruction when compared with anesthesia of the nasal mucosa.8 SURGICAL MANAGEMENT Deviated Nasal Septum and Septoplasty Deviation of the nasal septum is a common finding in patients seeking attention for nasal obstruction and is commonly secondary to three etiologies: congenital, traumatic, or iatrogenic. Previous epidemiological studies have revealed that the finding of a straight septum is present in only 42% of newborns and in adults, only 21%.9 Trauma American Journal of Rhinology & Allergy Figure 2. The “L-strut” is depicted here in a sagittal orientation. The importance of preserving of at least 1cm of cartilage both caudally and dorsally is demonstrated here. The strut maintains the articulation cephalically at the keystone, and caudally at the anterior nasal spine, while providing support along the dorsum, and at the nasal tip. to the nose may result in a variety of bony and cartilaginous fractures as well as dislocation of the cartilage off the maxillary crest.10 The fractured cartilage may heal in a variety of orientations but often results in anatomic deviation. Previous nasal surgeries may predis- Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S55 Figure 3. (Upper left) During extracorporeal septoplasty the quandrangular cartilage is resected en bloc. (Upper right) The PDS™ Flexible Plate (Ethicon Inc., Somerville, NJ) is fashioned into the desired reconstructed septum. (Lower left) Septal remnants are positioned onto the plate to achieve a straightened profile along its caudal and dorsal sides. (Lower right) The reconstructed septum is secured to the maxillary crest and nasal dorsum. Figure 4. Spreader grafts are depicted here in lateral, frontal and in cross-sectional views. The functional contribution of these grafts to the INV is best demonstrated on the cross-sectional view. pose the septum to deviation through asymmetrical external forces and scar formation during healing.11 The standard approach to correction of cartilaginous septal deviation, first popularized by Killian12 and Freer,13 involves a submucous dissection of the quadrangular cartilage and removal of the deviation with preservation of mucoperichondrial flaps. Once the deviated segment of the septum has been exposed bilaterally it may be straightened through a variety of techniques. Conservatively, the deviated cartilage may be weakened on its concave side by crosshatching with partial thickness incisions to relieve intracartilaginous tension. Alternatively, the deviation may be submucosally resected leaving a caudal-dorsal “L-strut” for support (Fig. 2). Caudal Septal Deviation The deviated caudal septum requires attention beyond the traditional septoplasty approach. These deviations are important on both S56 the esthetic and the functional levels. The caudal septum, if significantly deviated, may be noticeable on both frontal and lateral views of the face given its relationship to the lobule and columella. Furthermore, the septum contributes to both the ENV and the INV, and the caudal septum provides that contribution. Finally, the caudal septum provides essential structure to the nose and without an appropriate ⬃1–2 cm of caudal strut significant deformities such as saddle nose and tip ptosis may develop. Correction of caudal septal deviation has been approached in a number of different ways, depending on the nature of the deformity. In the situation where the caudal septum has excessive vertical length and is positioned lateral to the anterior nasal spine, the swinging door technique, a technique first popularized by Metzenbaum,14 can be used. A complete transfixion incision may be necessary to raise bilateral mucoperichondrial flaps and expose the caudal septum from the anterior septal angle to the anterior nasal spine. Sharp incision may be May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm necessary to maintain a continuous flap through the dense decussating fibers. The redundant cartilage is resected, leaving the caudal septum only attached superiorly. The now freed inferior portion of the caudal septum is anchored to the anterior nasal spine with sutures. Pastorek15 proposed a modification of the swinging door technique. The deviated caudal septum may be transposed over the anterior nasal spine to the nasal cavity opposite the deviation without further resection of cartilage; this appropriately named “doorstop” technique, prevents the cartilage from returning to its original position. Sedwick et al. found resolution of subjective nasal obstruction in 51/62 of his patients with caudal deviations treated with the aforementioned techniques.16 Mild to moderate deviations may be dealt with in a manner similar to that previously described. Likewise, the deviated portion of the septum may be scored or morselized on the concave side to weaken the cartilage. The limitation of this technique is the propensity of the deviations to recur over time, this may be improved with the placement of Mustarde-type sutures through the deviation.17 Alternatively, batten grafting may be applied to the weakened caudal septum. These grafts are typically harvested from the posterior quadrangular cartilage or the perpendicular plate of the ethmoid. The batten grafts are then secured along the weakened cartilage to support and stabilize its corrected position. Extension of longer spreader grafts from the ULC onto the caudal septum may also be used to stabilize the cartilage. The main point of criticism of the use of the grafting techniques is the tendency of the overlapping grafts to widen the caudal septum and subsequently narrow the INV and ENV; thus, these grafts must be adequately thinned before securing to the septum.18 Kridel19 popularized the tongue-in-groove technique for the management of caudal septal deviation. This technique requires the cephaloposterior advancement of the medial crura of the LLCs onto the caudal septum. The medial crura are then secured to the caudal septum providing enhanced stability and correction of the deviation. In Kridel et al.’s series of 108 patients with caudal septal deviation good functional outcomes were noted.19 The main criticism of this technique, again, is widening of the columella. Extracorporeal Septoplasty More severe deviations or loss of significant portions of the septum necessitate reconstruction through extracorporeal septoplasty. The execution of this procedure requires en bloc removal of the residual cartilaginous and bony septum for extracorporeal reshaping, followed by reinsertion in a straightened dorsal and caudal septal configuration. Gubish,20 who performed the procedure ⬎2000 times, found the open approach superior to the endonasal approach for the improved visualization it provided for dissection and replantation. Subperichondrial dissection was performed to expose the cartilaginous and bony septum. The ULCs are sharply incised extramucosally from their junction with the dorsal septum and dissected laterally. The dorsal septum is then freed from the aforementioned “keystone” area where there is essential attachment of the dorsal septal cartilage to the nasal bones and perpendicular plate of the ethmoid. An inferiorly based osteotomy may be necessary to separate the caudal septum from the anterior nasal spine and maxillary crest. Once the septum has been freed from its bony attachments, it is removed and its structure is examined. The reconstructed septum must contain straight sections caudally and through the dorsum to recreate the L-strut (Fig. 2). This may be achieved by rotation of the septal specimen to reorient a straight posterior septum or by weakening deviated cartilage through scoring techniques previously described. Most21 has described a modification of this technique that preserves the dorsal septum at the keystone area, which minimizes the destabilization of the nose and irregularities of the dorsum. The current authors prefer to maintain a 1.5- to 2-cm keel of intact dorsal septal cartilages attached to the nasal bones and ethmoid plate to aid in repositioning of the reconstructed cartilaginous septum. American Journal of Rhinology & Allergy Figure 5. Alar batten grafts are secured in an underlay fashion. The grafts extend toward the pyriform aperture, beyond the lateral crus, for enhanced stability. In circumstances where only weakened or crooked cartilage segments remain the septal plate may be supported with grafts from the bony septum, auricular or costal cartilage grafts. Alternatively, a polydioxanone, PDS Flexible Plate (Ethicon, Inc., Somerville, NJ) may be used to augment reconstructed septum18,20(Fig. 3). Boenisch,22,23 in a series of 369 extracorporeal septoplasty patients, in which the PDS foil was used, reported no short- or long-term complications such as rejection, infection, or necrosis. Moreover, residual cartilage fragments are often sutured along the reconstructed dorsal septum, as spreader grafts, to widen the INV at the ULC. The reconstructed septal plate is then secured in place to the columella/medial crura, ULC, keystone area, and maxillary crest with nonresorbable sutures.18,20,24,25 In 404 patients undergoing extracorporeal septoplasty, Gubish found that 96% of his patients reported improvement in their nasal breathing. The most common postoperative complaint was irregularity of the dorsum, seen in 8% of patient.20 Surgical Management of the INV Obstruction of nasal airflow through the INV is usually a result of changes in its major components: the dorsal septum, the ULC, or the caudal inferior turbinate. There are a variety of procedures available to manage obstruction caused by inferior turbinate hypertrophy and they are beyond the scope of this article. Obstruction at the level of the INV caused by dorsal septal deviation is typically resolved through the procedures previously described such as submucosal resection, as well as extracorporeal septoplasty. Once these two key areas are properly addressed, the contribution of the ULC may become the focus of the surgeon. Weakness or absence of the ULC typically arises in the patient who has previously undergone septorhinoplasty. An obvious sign of insufficiency of the ULC is the inverted-V deformity where the caudal end of the nasal bones is visible and creates a discontinuity with the middle nasal vault. This defect is created when resection of the broad dorsal septum allows the ULC to collapse medially, thus narrowing the middle nasal vault and INV to less than its normal 10–15°. The common surgical management of this situation is accomplished through the use of spreader grafts, first described by Sheen.26 The spreader grafts are matchstick-shaped pieces of autologous cartilage typically harvested from septal or costal cartilage. They will sit in an extramucosal pocket between the caudal septum and ULC and are secured in place with nonresorbable sutures (Fig. 4). These grafts serve to broaden the dorsal septum and widen the angle between the septum and ULC, thus enlarging the INV. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S57 Figure 6. Alar rim grafts are depicted here in lateral, frontal, and basal views. They are inserted through the marginal incisions and improve the strength and stability of the ala. A second procedure for dealing with weakened or deficient ULC, which are causing dynamic inspiratory collapse, is the splay or butterfly graft. In this procedure, described by Clark and Cook,27 cartilage grafting material is typically harvested from conchal cartilage. The graft is placed over the septal dorsum with its V-orientation facing caudally. The graft is secured to the lateral wings of the ULC. The resulting splay created by the inherent strength of the cartilage serves to stabilize the ULC from collapsing during inspiration. To prevent pollybeak deformity during this procedure, the graft must be adequately thinned or the dorsal septum reduced to maintain a smooth dorsal line on profile. Similarly, flaring sutures use the same principle as butterfly graft. Sutures are secured to the lateral/caudal ULC, pass over the dorsal septum, and are secured to the contralateral ULC. With tightening along the midline a flaring effect is created.28 Care must be taken to avoid the risk of a “cheese-wire” effect and loosening. In the situation where reduction of the bony and cartilaginous dorsum leaves an open middle vault, Gassner29 describes a dorsal onlay graft that simultaneously reconstructs the INV. In this procedure a posterior septal graft is harvested between ⬃8 and 9 mm wide, with length variable depending on the amount of dorsum to be reconstructed. The dorsal septum must be reduced along its length to receive the graft and maintain a continuous dorsal profile. The graft fits horizontally within the middle vault and is secured to the septum and ULC with sutures. The ULCs are sutured to the undersurface of the onlay graft, thus laterally rotating the graft and maintaining a wider, more natural, septal-ULC angle. Similarly, the modified Skoog dorsal reduction proposed by Hall et al.30 resects an en bloc dorsal graft that is reshaped extracorporeally, replanted, and secured to the ULC and septum. These two procedures provide functional reconstruction of the middle vault and INV while concurrently addressing irregularities of the dorsal profile. Surgical Management of the ENV Unlike obstruction at the level of the INV, obstruction of the ENV and intervalve area tend not to be related to previous nasal surgery. Weakness and instability of the ENV is often a byproduct of normal S58 anatomic development and aging. These patients will present with nasal morphology such as narrow nostrils, recurvature of the lateral crus of the LLC, overprojected tip, and weak sidewalls that predispose the patient to obstruction.31 Toriumi noted that cephalic orientation of the lateral crus will decrease the support of the ala during inspiration and allow for collapse.32 Based on these preoperative findings, augmentation of the support of the lateral crura and ala are the primary interventions to correct ENV dysfunction. Lateral crural strut grafts are cartilaginous grafts that are sutured along the lateral crura of the LLC to improve the strength of the cartilage. The indications for their use are weak or deformed lateral crura. They typically will extend laterally out over the pyriform aperture for enhanced support. They are secured either over (subcutaneous) or under (submucosal) the length of the lateral crus by nonresorbable suture. In some cases, they may be used to completely replace a deficient or missing lateral crus of the LLC. Alar batten grafts have been the staple of augmentation of the ENV. They are autologous cartilage grafts typically taken from septal or conchal cartilage. Depending on the point of maximal collapse on preoperative dynamic testing, the batten grafts may be placed at different points along the nasal sidewall. Weakness may be seen at the level of the lateral crus, the intervalve area, or at the caudal end of the ULC. The batten grafts are placed in subcutaneous or submucosal pockets that are tailored to the exact dimensions of the graft, and the dissection is carried laterally toward the pyriform aperture. If precise pockets are created, the grafts may be simply placed and do not require suturing. In his review, Toriumi32 noted that subcutaneous grafts may add fullness to the supraalar region but was acceptable by his patients. Alternatively, Kenyon advocated a submucosal positioning of the graft for cosmesis as well as the empiric mechanical advantage of an underlay graft in improving the support and stability of the ala (Fig. 5).31 Using these techniques in 80 patients, Cervelli et al. described a 90% functional postoperative score of excellent.21,33 Finally, alar rim grafts are an additional measure are used during rhinoplasty to augment the ENV. They are often used as adjuncts to the previously mentioned surgical techniques.34 Common indications include alar retraction, dynamic collapse of the ala during inspiration, May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm or alar contour deformity. The grafts are fashioned from quadrangular or costal cartilage, and suggested dimensions are a 2-to 3-mm width and 15- to 25-mm length.35 They are placed within a pocket created along the alar margin. If the pocket is formed to the correct dimension, they may be simply placed and the incision closed (Fig. 6). The tip of the rim graft is thinned to prevent contour deformity in the area of the soft tissue triangle. Alternatively, a resorbable stitch may be placed around the graft to prevent migration. CONCLUSION Nasal obstruction is a common complaint and will present in a number of anatomic variations. Performing submucous resection septoplasty in patients with concomitant nasal valve obstruction will often result in dissatisfied patients who are now without the convenient abundance of autologous quadrangular cartilage. The use and indications for open versus endonasal approaches must be thoroughly reviewed preoperatively so that the operation undertaken is appropriate for the intended outcomes.36 It is imperative that the rhinological surgeon considers the multiple contributing elements that lead to anatomic obstruction and is knowledgeable of the complete armamentarium of techniques used to functionally improve the nasal airway. ACKNOWLEDGMENTS The authors thank Shelia Macomber for her work on the illustrations used in this article. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Churchill SE, Shackelford LL, Georgi JN, and Black MT. Morphological variation and airflow dynamics in the human nose. Am J Hum Biol 16:625–638, 2004. Stewart MG, Witsell DL, Smith TL, et al. Development and validation of the Nasal Obstruction Symptom Evaluation (NOSE) scale. Otolaryngol Head Neck Surg 130:157–163, 2004. Pirila T, and Tikanto J. Acoustic rhinometry and rhinomanometry in the preoperative screening of septal surgery patients. Am J Rhinol Allergy 23:605–609, 2009. Cole P. The four components of the nasal valve. Am J Rhinol 17:107– 110, 2003. Costa DJ, Sanford T, Janney C, et al. Radiographic and anatomic characterization of the nasal septal swell body. Arch Otolaryngol Head Neck Surg 136:1107–1110, 2010. Wrobel BB, and Leopold DA. Olfactory and sensory attributes of the nose. Otolaryngol Clin North Am 38:1163–1170, 2005. Cauna N, Hinderer KH, and Wentges RT. Sensory receptor organs of the human nasal respiratory mucosa. Am J Anat 124:187–209, 1969. Jones AS, Wight RG, Crosher R, and Durham LH. Nasal sensation of airflow following blockade of the nasal trigeminal afferents. Clin Otolaryngol Allied Sci 14:285–289, 1989. Gray LP. Deviated nasal septum. Incidence and etiology. Ann Otol Rhinol Laryngol Suppl 87:3–20, 1978. Lee M, Inman J, Callahan S, and Ducic Y. Fracture patterns of the nasal septum. Otolaryngol Head Neck Surg 143:784–788, 2010. Yeo NK, and Jang YJ. Rhinoplasty to correct nasal deformities in postseptoplasty patients. Am J Rhinol Allergy 23:540–545, 2009. American Journal of Rhinology & Allergy 12. Killian G. Die submukose Fensterresektion der Nasenscheiderwand. Arch Laryngol Rhinol (Berl) 16:326, 1904. 13. Freer O. The correction of deflections of the nasal septum with minimum of traumatism. JAMA 38:636–692, 1902. 14. Metzenbaum M. Replacement of the lower end of the dislocated septal cartilage vs. submucous resection of the dislocated end of the septal cartilage. Arch Otolaryngol 1929:282–292. 15. Pastorek NJ, and Becker DG. Treating the caudal septal deflection. Arch Facial Plast Surg 2:217–220, 2000. 16. Sedwick JD, Lopez AB, Gajewski BJ, and Simons RL. Caudal septoplasty for treatment of septal deviation: Aesthetic and functional correction of the nasal base. Arch Facial Plast Surg 7:158–162, 2005. 17. Ellis MS. Suture technique for caudal septal deviations. Laryngoscope 90:1510–1512, 1980. 18. Haack J, and Papel ID. Caudal septal deviation. Otolaryngol Clin North Am 42:427–436, 2009. 19. Kridel RW, Scott BA, and Foda HM. The tongue-in-groove technique in septorhinoplasty. A 10-year experience. Arch Facial Plast Surg 1:246–256, 1999. 20. Gubisch W. Twenty-five years experience with extracorporeal septoplasty. Facial Plast Surg 22:230–239, 2006. 21. Most SP. Anterior septal reconstruction: Outcomes after a modified extracorporeal septoplasty technique. Arch Facial Plast Surg 8:202–207, 2006. 22. Boenisch M, and Nolst Trenite GJ. Reconstruction of the nasal septum using polydioxanone plate. Arch Facial Plast Surg 12:4–10, 2010. 23. Boenisch M, and Nolst Trenite GJ. Reconstructive septal surgery. Facial Plast Surg 22:249–254, 2006. 24. Heppt W, and Gubisch W. Septal surgery in rhinoplasty. Facial Plast Surg 27:167–178, 2011. 25. Gubisch W. Extracorporeal septoplasty for the markedly deviated septum. Arch Facial Plast Surg 7:218–226, 2005. 26. Sheen JH. Spreader graft: A method of reconstructing the roof of the middle nasal vault following rhinoplasty. Plast Reconstr Surg 73:230– 239, 1984. 27. Clark JM, and Cook TA. The “butterfly” graft in functional secondary rhinoplasty. Laryngoscope 112:1917–1925, 2002. 28. Park SS. The flaring suture to augment the repair of the dysfunctional nasal valve. Plast Reconstr Surg 101:1120–1122, 1998. 29. Gassner HG, Friedman O, Sherris DA, and Kern EB. An alternative method of middle vault reconstruction. Arch Facial Plast Surg 8:432– 435, 2006. 30. Hall JA, Peters MD, and Hilger PA. Modification of the Skoog dorsal reduction for preservation of the middle nasal vault. Arch Facial Plast Surg 6:105–110, 2004. 31. Ballert JA, and Park SS. Functional considerations in revision rhinoplasty. Facial Plast Surg 24:348–357, 2008. 32. Toriumi DM, Josen J, Weinberger M, and Tardy ME Jr. Use of alar batten grafts for correction of nasal valve collapse. Arch Otolaryngol Head Neck Surg 123:802–808, 1997. 33. Cervelli V, Spallone D, Bottini JD, et al. Alar batten cartilage graft: Treatment of internal and external nasal valve collapse. Aesthetic Plast Surg 33:625–634, 2009. 34. Apaydin F. Nasal valve surgery. Facial Plast Surg 27:179–191, 2011. 35. Boahene KD, and Hilger PA. Alar rim grafting in rhinoplasty: Indications, technique, and outcomes. Arch Facial Plast Surg 11:285–289, 2009. 36. Phillips PS, Stow N, Timperley DG, et al. Functional and cosmetic outcomes of external approach septoplasty. Am J Rhinol Allergy 25:351–357, 2011. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S59 The role of the nose in sleep-disordered breathing Eric K. Meen, M.D., and Rakesh K. Chandra, M.D. ABSTRACT Background: Sleep-disordered breathing (SDB) is a spectrum of airway collapse, ranging from primary snoring to profound obstructive sleep apnea (OSA). Studies have shown an association between impaired nasal breathing and SDB; consequently, treatments of nasal obstruction are often used in an attempt to improve disease severity. The authors performed a review of the literature to determine the impact of nasal obstruction and the effectiveness of nonsurgical and surgical interventions on SDB. Methods: Relevant literature up to 2012 on the association between nasal obstruction and SDB and effectiveness of nonsurgical and surgical treatment of the nose in SDB were reviewed. Results: The literature is mostly limited to uncontrolled case series in which patient groups, interventions, disease definitions, and outcome measures are not standardized. Nasal medications, including intranasal steroids and nasal decongestants, have not been shown to improve either snoring or OSA. Nasal dilators have no impact on OSA but may improve snoring. Surgery for nasal obstruction does not improve objective indicators of SDB but can improve subjective elements of disease, such as snoring, sleepiness, and quality of life. Nasal surgery can facilitate continuous positive airway pressure use in cases where nasal obstruction is the factor limiting compliance. Conclusion: Nasal obstruction plays a modulating, but not causative, role in SDB. Nasal interventions may improve subjective aspects of snoring and OSA but do not improve objective indicators of disease. Standardization of methods and higher evidence level studies will further clarify the benefit of nasal interventions in the treatment of SDB. S leep-disordered breathing (SDB) represents a group of disorders frequently encountered by otolaryngologists. It is characterized as a spectrum of airway collapse, ranging from primary uncomplicated snoring at one extreme, to profound obstructive sleep apnea (OSA) on the other. Both are common disorders whereby OSA affects 2–4% of men and 1–2% of women in middle age,1 and snoring can affect up to 50% of middle-aged men and postmenopausal women.2 Both primary snoring and OSA are characterized by multisite obstruction, and the role of pharyngeal collapse is well established as key to the underlying pathophysiology of the disease.3 In contrast, the contribution of nasal obstruction to SDB and the effect of treating nasal obstruction on SDB are less clear. Furthermore, nasal patency is affected by a constellation of fixed and dynamic variables. Examples of the former include the size of the piriform aperture and deviation of the nasal septum, and the latter includes collapsibility of the upper lateral and alar nasal cartilages (nasal valves) and inflammatory factors such as allergic rhinitis. The exact contribution of each of these elements is subject to variation, such that the exact treatment of nasal obstruction in the setting of SDB must be individualized. Some patients benefit from directed nasal surgery (e.g., septoplasty, inferior turbinate reduction, and nasal valve augmentation), whereas others require medical therapy (e.g., intranasal corticosteroids), and in practice, these treatment modalities are often used in combination. This review will seek to define the role of the nose in the pathophysiology of SDB and will examine current data regarding the efficacy of various medical and surgical treatments for nasal obstruction in the overall management of SDB. Studies were acquired via a search of the PubMed database for terms relating to nasal obstruction or treatment thereof (nasal obstruction, rhinitis, intranasal steroids (INSs), decon- From the Department of Otolaryngology–Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois Presented at the North American Rhinology & Allergy Conference, February 4, 2012, Puerto Rico R Chandra is a consultant for Gyrus ACMI The remaining author has no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Eric K. Meen, M.D., Department of Otolaryngology, University of Manitoba, 601– 400 Tache Avenue, Winnipeg, Manitoba, Canada R2H3C3 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, 213–220, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S60 gestants, nasal dilators, nasal surgery, septoplasty, and turbinate reduction) and any of the following: SDB, snoring, OSA, or continuous positive airway pressure (CPAP). ROLE OF THE NOSE IN THE PATHOPHYSIOLOGY OF SDB The nose is the initial point of entry of air under normal conditions, under which it contributes one-half to two-thirds of total airway resistance.4 This has led to the hypothesis that nasal obstruction can contribute to SDB. Some have likened the upper airway collapse in OSA to a Starling resistor model, wherein the upper airway is characterized as a hollow tube, with the nose representing partial obstruction at the inlet and the pharynx representing a collapsible downstream segment. Based on this model, increased obstruction in the nose will result in increased negative pressure in the pharynx, resulting in additional pharyngeal collapse.5 If nasal obstruction is sufficiently severe, a transition to oral breathing may occur. However, studies have shown this transition to be physiologically disadvantageous. Under normal conditions, nasal breathing is the primary route of airflow, responsible for ⬃92 and 96% of inhaled ventilation during periods of wakefulness and sleep, respectively.6 These authors also indicated that transitioning to a primarily oral airflow results in an increase in upper airway resistance by 2.5 times.7 In these studies, nasal airflow was measured from the fraction of inspired ventilation that passed through the nasal portion of an oronasal mask, and upper airway resistance was calculated from the differential pressure between the mask and a catheter tip placed in the supraglottic pharynx. Anatomic factors that appear to be associated with increased resistance during oral breathing include increased collapsibility of the pharyngeal lumen and posterior retraction of the tongue.8 Numerous studies have documented an association between nasal obstruction and SDB. The Wisconsin Sleep Cohort Study, comprised of 911 patients, showed that patients with nasal obstruction were more likely to exhibit primary snoring and report increased daytime sleepiness. The study failed, however, to show a statistically significant increase in the apnea hypopnea index (AHI) when symptoms of congestion were present.9 A similar follow-up study of 1032 subjects indicated that patients with nasal congestion every night were considerably more likely to exhibit simple and habitual snoring (odds ratios, 3 and 3.33, respectively), and the authors concluded that nasal obstruction was a strong independent risk factor for these conditions. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 RCT of pharmacologic therapy for SDB Reference Craig et al.20 Patient Characteristics Study Design and Intervention Subjective Outcomes Objective Outcomes Sixty-nine patients with Pooled results from three Decreased congestion, Measured only in allergic rhinitis (OSA double-blind, placebosleep problems, and fluticasone study, patients excluded) controlled crossover daytime in which there was studies; specific steroid somnolence no change in AHI varied between studies Meltzer et al.53 Thirty patients with allergic rhinitis Double-blind parallel study; mometasone vs placebo (saline) Kiely et al.24 Ten simple snorers (AHI, ⬍10; median, 3.0), 13 OSA patients (AHI, ⬎ 10; median, 26.5) Double-blind crossover study; fluticasone vs placebo (saline) Kerr et al.25 Ten OSA patients; six had significant nasal obstruction McLean et al.26 Ten OSA patients, all with significant nasal obstruction Clarenbach et al.27 Twelve OSA patients, all with nasal obstruction Single-blind crossover study; topical oxymetazoline and internal nasal dilator for one night vs placebo Single-blind crossover design; oxymetazoline and external nasal dilator vs placebo Double-blind crossover study; xylometazoline vs placebo Comments Significant negative correlation between reduction in congestion and improvement in sleep AHI of patients in both groups ranged from 0 to 19.5 Decreased nasal No change in AHI or congestion, daytime snoring sleepiness, and improved QOL measures Improved daytime Decrease in AHI from Rhinitis present in all alertness in non30.3 to 23.3 in OSA patients (type not OSA patients; no group on specified); no OSA change in OSA fluticasone (p ⬍ patient cured patients; no change 0.05); no change in in snoring non-OSA group Improved nasal Small decrease in No data on snoring respiration and arousals/hr; no sleep quality change in AHI No change in sleepiness No change in sleep quality or sleepiness Improvement in nasal Only one patient had resistance, AHI, AHI decreased to and sleep ⬍15; no data on architecture snoring Improved nasal No data on snoring resistance; no improvement in AHI AR ⫽ allergic rhinitis; OSA ⫽ obstructive sleep apnea; AHI ⫽ apnea hypopnea index; QOL ⫽ quality of life; SDB ⫽ sleep-disordered breathing; RCT ⫽ tandomized controlled trial. Other cross-sectional studies have also found nasal resistance to be a strong determinant of snoring.10,11 Several series have evaluated the connection between nasal obstruction and AHI. In a prospective study of 528 subjects with snoring, Lofaso et al. showed that patients with OSA (defined in the study by an AHI of ⬎15) had greater nasal resistance when compared with those with an AHI of ⬍15, although the nasal obstruction was only responsible for 2.3% of the total AHI variance.12 Virkulla et al. evaluated cephalometric factors, AHI, and nasal resistance, and showed that increased nasal resistance was an independent predictor of increased AHI in nonobese patients.13 In a study of patients with nasal obstruction secondary to allergic rhinitis, McNicholas et al. found a direct association between nasal resistance and the frequency and duration of obstructive apneas during sleep.14 Taken together, this series of investigations supports the hypothesis that nasal obstruction may contribute to the overall AHI. Studies assessing the effect of induced nasal obstruction have further supported the correlation between impaired nasal breathing and SDB. In a study on eight healthy subjects, Suratt et al. showed that nasal packing with petroleum gauze caused a marked increase in obstructive apneas and hypopneas during sleep.15 In another study in healthy volunteers, Lavie et al. showed an increase in number of apneas, nonapneic-related microarousals, and wake time within sleep after artificially occluding the nasal passages.16 In a similar study of healthy subjects, Zwillich et al. found that nasal occlusion caused increased apneas, sleep arousals and awakenings, loss of deep-stage sleep, and subjectively poorer sleep quality.17 In a more recent study American Journal of Rhinology & Allergy evaluating the impact of postoperative nasal packing on sleep parameters, Regli et al. noted significant worsening in the AHI in patients with OSA and worsening in both the AHI and in the oxygen desaturation index in patients without OSA.18 Friedman et al.19 also indicated that postoperative nasal packing worsened the respiratory disturbance index, duration of snoring, and oxygen desaturation index, but only in patients with mild OSA, and not in those with moderate/ severe OSA. The authors concluded that nasal obstruction therefore had a greater effect on milder disease, but was not a factor as the severity of OSA increased. In summary, physiological and epidemiological studies support that nasal obstruction contributes to snoring and is likely to impact AHI in OSA, although to what extent remains unclear. Regarding the overall effect on the pathophysiology of SDB, it is likely that nasal obstruction functions as a disease modifier, rather than a primary causative factor. EFFECTIVENESS OF NONSURGICAL TREATMENTS FOR NASAL OBSTRUCTION ON SDB Nasal Steroids Several well-conducted randomized controlled trials (RCTs) have evaluated the effect of INSs on sleep quality in allergic rhinitis, and these are summarized in Table 1. In 2005, Craig et al. released a pooled study of 69 patients with allergic rhinitis,20 combining the results of Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S61 Table 2 RCTs of nasal dilators for SDB Reference Patient Characteristics Study Design and Intervention Subjective Outcomes Objective Outcomes Comments Höijer et al.28 Ten patients with snoring or observed apneas; none had nasal obstruction; mean apnea index of 18 Eighteen snorers with UARS (defined as AHI of ⬍15) and excessive daytime sleepiness; no data on nasal complaints Twelve snorers with nasal obstruction and chronic rhinitis; mean AHI of 6 Nonblinded crossover; Nozovent vs no intervention No change in daytime somnolence Decreased snoring events, apnea index, and minimum oxygen saturation Decreased nasal resistance with dilator Double-blind crossover study; Breathe Right vs placebo strips No data on change in sleepiness Decreased desaturation time, improved sleep architecture; no change in AHI or arousal index Double-blind crossover study; Breathe Right vs placebo strips Not assessed Eighteen snorers with nocturnal nasal obstruction; range of AHI (0–26.5) Thirty-eight OSA patients (RDI ⬎ 20) undergoing CPAP titration; no data on nasal complaints Single-blind crossover study; Breathe Right vs placebo strips Not assessed Nonblinded crossover study; Nozovent vs no intervention Not assessed Decrease in snoring frequency not but loudness; no change in AHI, arousal index, or sleep architecture No improvement in ODI, snoring, or sleep architecture; AHI increased with dilator No change in RDI with dilator; small decrease in CPAP pressure with dilator (⬍1 cm H2O) Increased nasal cross-sectional area with dilator; no data on change in snoring Decrease in nasal resistance with dilator nearly significant with dilator Increased nasal cross-sectional area with dilator Bahammam et al.29 Pevernagie et al.30 Djupesland et al.32 Schönhofer et al.31 UARS ⫽ upper airway resistance syndrome; AHI ⫽ apnea hypopnea index; OSA ⫽ obstructive sleep apnea; RDI ⫽ respiratory disturbance index; CPAP ⫽ continuous positive airway pressure; ODI ⫽ oxygen desaturation index; RCT ⫽ randomized controlled trial; SDB ⫽ sleep-disordered breathing. three prior studies done by their group,21–23 which all used the same methodology, differing only in which nasal steroid was used. In all of their studies, OSA was an exclusion criterion, and the presence of snoring was not assessed. The data, however, were illustrative of a significant decrease in not only nasal congestion, but also in daytime somnolence. The authors also observed improved sleep quality and noted a significant negative correlation between the decrease in nasal congestion and improved sleep quality. In the sole study that evaluated AHI,21 no difference was observed between steroid and placebo arms. More recently, in a study assessing the effect of intranasal mometasone on rhinitis-disturbed sleep, Meltzer et al. also showed an improvement in daily peak nasal inspiratory flow, sleep quality, and quality of life (QOL) measures. All patients in their study were assessed with polysomnography (PSG) and had a variable AHI ranging from 0 to 19.5; no change in AHI or snoring was noted between treatment and placebo arms. Taken together, the aforementioned studies support the ability of INSs to improve nasal congestion and sleep quality in patients with allergic rhinitis (so-called rhinitis-disturbed sleep) but showed no improvement in objective sleep parameters (e.g., AHI), when that was included as an outcome measure. Although the impairment in sleep quality associated with nasal congestion due to allergic rhinitis is not technically considered SDB, these results do highlight the effect of impaired nasal breathing on overall sleep quality. In the sole study evaluating the effect of INS therapy on objective sleep measures of SDB patients, Kiely et al.24 assessed the effect of INS on patients with either primary snoring or OSA, all of whom had concurrent rhinitis. In patients with OSA, they found a significant decrease in AHI (from 30.3 to 23.3; p ⬍ 0.05) and in nasal resistance; changes in the primary snoring group were not significant, and the degree of snoring was not significant in either group. Minor subjective improvements were seen in the snoring group, but not the OSA group. The authors concluded that intranasal fluticasone was sometimes effective in reducing AHI in some OSA patients, and this was S62 hypothesized as being attributable to the impact of the topical steroid on nasal airflow. Notably, however, in none of the OSA patients did the AHI decrease to a normal level. Decongestants Three RCTs have evaluated the effect of topical decongestants in SDB—one combined with an internal nasal dilator,25 one combined with an external nasal dilator,26 and another with decongestant alone.27 An improvement in AHI26 was noted in only one of those studies, and only one patient showed a decrease to ⬍15. Small improvements in sleep architecture were found in two of the studies.25,26 Improved sleep quality was only noted in the series by Kerr et al.,25 but improvements in sleepiness were not seen in any of the three studies, and none addressed the symptoms of snoring. Although Clarenbach et al.27 found an improvement in nasal resistance, the lack of meaningful improvement on other subjective or objective parameters suggests that nasal decongestants in the treatment of SDB at night are of limited usefulness. Nasal Dilators If the nose plays a major role in the pathophysiology of SDB, it stands to reason that dilating its most narrow part, the internal nasal valve, could improve snoring or OSA. Both external (Breathe Right, GlaxoSmithKline, Philadelphia, PA) and internal (Nozovent, Scandinavian Formulas, Inc., Sellersville, PA) nasal dilators have been developed to accomplish this, and five RCTs have evaluated their effects in the setting of SDB (Table 2). Results between the studies are not consistent. Höijer et al.28 showed a decrease in the apnea index from 18 to 6.4 in a group of mainly mild OSA patients; no subjective improvement in sleepiness was noted, however. In the only other study evaluating subjective sleep quality, Bahammam et al.29 also reported no improvement in sleepiness. Although three of the studies indicated no change in AHI with use of a nasal dilator,29–31 Djupe- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm sland et al.32 actually found an increased AHI with the dilator when compared with the placebo strip. In a study of OSA patients undergoing CPAP titration, Schönhofer et al.31 found a small decrease in CPAP pressure that was not clinically significant (⬍1 cm H2O). That study was the only one of the five to not assess nasal patency at all, whereas the other four all showed an increase in nasal patency. Two of the studies indicated a decrease in snoring events.28,30 In summary, nasal dilators have been shown to improve nasal patency in patients with SDB, and may reduce the severity of snoring, but the current evidence does not support their use in the treatment of OSA, including as an adjunct to facilitating CPAP tolerance. EFFECTIVENESS OF SURGICAL TREATMENT OF NASAL OBSTRUCTION FOR SDB The intent of nasal surgery for SDB includes improvement of nasal obstruction, snoring, and OSA. Additionally, the primary goal may be to improve tolerance of CPAP in patients with nasal obstruction. Literature addressing the success of nasal surgery for treatment of SDB is mostly limited to uncontrolled case series. Patients groups within these studies are heterogeneous, with respect to background details, as well as type or degree of SDB. Definitions for SDB are also not standardized, and so inclusion criteria of “OSA” may capture relatively different patient populations between studies. Surgical treatments are not standardized between studies or within individual studies, in which patients may have undergone several different operations, or combinations thereof. Reported outcome measures are highly variable, with differential emphasis on both subjective and objective measures, and specific data collected within each category is often different (e.g., nonstandardized reporting of PSG results). Definitions of surgical success also vary widely and are not evidence based.33 Despite the inherent limitations, however, a review of the available literature still permits some conclusions to be drawn. To evaluate the effect of nasal surgery on SDB, 15 studies, conducted between 2002 and 2012, were assessed. Thirteen of these were assessed in a meta-analysis conducted by Li et al. in 2011, and two newer suitable studies were evaluated as well. Table 3 contains a summary of these reports. Together, despite ubiquitous success in improving nasal resistance, studies have established a consistent failure of nasal surgery to improve AHI and highly variable success in treating most other objective sleep indices. In their meta-analysis, Li et al. indicated that nasal surgery led to no change in the weighted AHI (35.3–33.5; p ⫽ 0.69),34 and when considered individually, with one exception,35 none of the studies showed a decrease in AHI. When considering all patients who met the criteria for success in individual studies, the pooled success rate was 16.7%. As alluded to previously, definitions of success varied widely and included reduction of AHI by 50% and to ⬍20,36 reduction of AHI by 50% and to ⬍15,37 respiratory disturbance index of ⬍15,35 AHI of ⬍5,38 and having at least a 50% “apnea improvement ratio.”39 Because of the variable definition and low rate of success, predictors of surgical success still have not been convincingly elucidated. Studies have also inconsistently shown improvement in other objective indicators of OSA, including lowest oxygen saturation,40,41 improved arousal index,42 improved sleep architecture and efficiency,38,41,43,44 and shortened apnea and hypopnea duration.38,41 Despite reaching statistical significance in some of these parameters, the changes were often small and may not have reached the level that is clinically important. This limitation, in addition to the inconsistency of the results, renders the overall value of nasal surgery in addressing these objective sleep parameters unclear. In summary, although individual patients may be surgically “cured,” the weight of the evidence suggests that nasal surgery is ineffective in reliably improving AHI and other objective sleep parameters of OSA. When snoring is assessed objectively, the effect of nasal surgery is unclear. Several studies have shown failure of nasal surgery to improve duration35,43,45 and intensity45 of snoring, and Choi et al. showed a modest decrease in snoring duration.44 In contrast, when American Journal of Rhinology & Allergy snoring is assessed subjectively, patients consistently report improvement after nasal surgery. Friedman et al.46 reported an improvement in snoring in 28% of patients and complete cessation in 6%, and Virkkula et al. showed an improvement in subjective snoring frequency, irritation, and quality in 26, 50, and 38% of patients, respectively.43 In another study, comprised of 27 patients with snoring and nasal obstruction due to nasal polyps, most of whom did not have OSA, all patients reported improvement of snoring after endoscopic sinus surgery, with improvement in 67%, and complete resolution in the other 33%.47 Using a similar visual analog scale, Sufioğlu et al. showed a statistically significant drop in snoring severity after nasal surgery.38 In three studies of patients with OSA and snoring, Li et al. showed a consistent improvement in subjective snoring as reported by patients and their bed partners.36,48,49 In one of these investigations, they also reported improvement in 86% of patients, and complete snoring cessation in another 12%.49 In summary, snoring has been shown to consistently improve subjectively but not objectively after nasal surgery. The degree of subjective improvement is widely variable, and studies still have not revealed subgroups in which snoring improvement is more likely. In contrast to the consistent failure of nasal surgery to improve objective OSA parameters, more focus has been placed recently on the impact of nasal surgery on subjective outcomes of OSA. Of the reviewed studies, 11 addressed the degree of sleepiness. Only two failed to show an improvement,43,45 and a significant improvement was found in nine.36–38,40–42,46–48 In the majority of these, sleepiness was assessed with the Epworth Sleepiness Scale, and in most cases, scores fell to within the normal range, indicating that the decreases were also clinically significant. Li et al. also assessed the impact of nasal surgery on overall QOL in OSA patients and found that nasal surgery resulted in significant improvements in six of eight domains of the 36-item short form health survey. Despite the failure of nasal surgery to reliably lower the AHI and other objective indices of OSA, subjective improvements should not be discounted. Sleepiness is often the most troublesome symptom in OSA patients, and any reduction in it likely represents an important clinical difference to the individual patient, who often presents seeking subjective improvement of symptoms rather than a numerical improvement in their AHI. An additional limitation of focusing exclusively on PSG parameters is that they have shown little correlation with daytime somnolence and QOL.50 Nasal surgery appears to play a clear role in improving CPAP tolerance in patients with concurrent nasal obstruction. CPAP tolerability remains a significant obstacle in the management of OSA. Compliance rates of ⬍70% have been reported, and nasal obstruction or discomfort is frequently cited as a factor in CPAP intolerance.51 Several studies have shown a positive effect of nasal surgery on CPAP pressures and compliance. In a study of 40 OSA patients with nasal obstruction, Friedman et al. found a significant reduction in required CPAP pressure levels after nasal surgery.46 In a similar study group of patients who were refractory to CPAP, Nakata et al. showed a significant decrease in CPAP pressure after nasal surgery and ultimate device compliance in all 12 patients.40 In a randomized, double-blind, placebo-controlled trial assessing the effect of radiofrequency treatment of inferior turbinate hypertrophy, Powell et al. observed that patients in the treatment arm reported significant improvement in both nasal patency and CPAP tolerance, changes that were not present in the control group.52 Taken together, the available literature reveals that although nasal surgery does not improve SDB objectively, it can reliably improve objective CPAP titration levels, often leading to improved device compliance. CONCLUSION Physiological and epidemiological studies support that the nose plays a modulating role in the pathophysiology of SDB but does not act as a primary causative factor. Further investigation will likely Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S63 S64 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm May–June 2014, Vol. 28, No. 3 Forty patients with snoring and nasal obstruction; some with OSA (mean AHI, 13.6) Forty patients with snoring and nasal obstruction; some with OSA (AHI, 14) Forty-nine patients with OSA and nasal obstruction from septal deviation (mean AHI, 31.5 vs 30.6) Virkkula et al.45 Virkkula et al.43 Case series; patients underwent septo ⫾ ITR, or ESS Forty-nine patients with OSA and nasal obstruction (mean AHI, 44.6) Fifty-two patients with OSA, snoring, and nasal obstruction Nakata et al.41 Li et al.49 Case series; patients underwent septo and ITR Case series; patients underwent septo ⫾ ITR Fifty-one patients with OSA and nasal obstruction (mean AHI, 37.4) Case series; patients underwent septo and/or ITR, or septorhinoplasty Randomized, single-blinded control trial; septo ⫾ ITR, vs sham surgery Case series; patients underwent septo and/r ITR Case series; patients underwent septo and/or ITR Li et al.48 Koutsourelakis et al.37 Nakata et al.40 Kim et al.35 Case series; patients underwent various combinations of septo, ITR, septorhino, nasal tip surgery, and ESS Case series; patients underwent septo ⫾ ITR Case series; patients underwent septoplasty (septo) ⫾ ITR Fifty patients with OSA, nasal obstruction, and snoring (mean RDI, 31.6) Twenty-six patients with snoring and nasal obstruction; some with OSA (mean AHI, 29.2) Twenty-one patients with OSA, nasal obstruction, and snoring (mean RDI, 39) Twelve OSA patients with nasal obstruction and refractory to CPAP Friedman et al.46 Verse et al.42 Study Design and Intervention Patient Characteristics Reference Table 3 Selected trials assessing effect of surgery on SDB Improvement in snoring on patient and bed partners scales Improvement in snoring on patient and bed partners scales; improved sleepiness; improved QOL Decreased sleepiness Decrease in sleepiness with surgery Improved snoring intensity; no change in sleepiness No difference in sleepiness Substantial improvement in daytime sleepiness Not addressed Significant decrease in daytime sleepiness Decreased snoring; increased daytime energy Subjective Outcomes Decreased nasal resistance; improved sleep architecture and efficiency; small increase in lowest O2 saturation; no change in AHI, but shortened apnea time Decreased nasal resistance; no change in AHI No change in AHI or lowest O2 saturation Decrease in RDI (39–29.1) and ODI; duration of snoring unchanged No difference in AHI; modest improvement in lowest O2 saturation; decrease in nasal resistance Decrease nasal resistance; no change in snoring time or intensity, or in AHI, ODI, or arousals; improved architecture No change in snoring time; no change in AHI, ODI, or arousals No change in AHI or oxygen saturation RDI increased (31.6–39.5); no change in oxygen saturation Decrease in nasal resistance; mean AHI unchanged; decrease in arousal index Objective Outcomes Snoring improved in 86% of patients and eliminated in 12%; small tonsil size predicted greater snoring improvement Snoring time was the only objective outcome of snoring evaluated Decrease in nasal resistance in surgery group; snoring not assessed; success in four patients (15%) QOL improvement in six of eight SF-36 subscales Snoring not evaluated subjectively CPAP titration levels decreased after surgery Snoring not assessed CPAP titration levels decreased after surgery Comments American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S65 Improved sleep efficiency, architecture, and snoring time; no change in AHI or arousals or minimum O2 levels Improved apnea–hypopnea duration and sleep architecture; no change in AHI, lowest O2 levels, or arousals Twenty-eight patients with OSA and nasal obstruction (mean AHI, 32.5) Case series; patients underwent various combinations of septo, ITR, septorhino, and ESS Improved sleepiness and snoring Improved snoring and sleepiness in surgical group compared with preoperative scores and to medical group Not assessed Nonrandomized, parallel study; surgical (septoplasty and ITR) vs medical (INS, decongestant, saline lavage, or oral antihistamines) Case series; patients underwent combination of septo ⫾ ITR ⫾ ESS Not assessed Case series; patients underwent septo ⫾ ITR or ESS Sixty-six patients OSA, snoring, and nasal obstruction (mean AHI, 38 in surgical group and 25.9 in medical group) Twenty-two patients with OSA and nasal obstruction (mean AHI, 40.4) Improved nasal resistance; no change in AHI, lowest O2 saturation, arousals, or sleep architecture Preoperative and postoperative AHI and nasal resistance not compared; decrease in AHI of responders vs nonresponders; no other data reported No change in AHI, minimum O2 saturation, or sleep architecture Improvement in sleepiness and snoring Case series; patients underwent ESS Objective Outcomes Twenty-seven patients with nasal obstruction due to nasal polyps and snoring (mean AHI, 6.7) Thirty-five patients with OSA and nasal obstruction; AHI reported for responders (43.7) and nonresponders (43.4) Subjective Outcomes Study Design and Intervention Patient Characteristics Decrease in CPAP titration levels, but not significant (p ⫽ 0.062) Subjective snoring not assessed Eight (23%) responders (mean AHI decreased to 18.5); 27 nonresponders (mean AHI unchanged); high soft palate and wide retroglossal space predicted success Seven (16%) patients classified as meeting “success” All patients reported improved snoring postoperatively Comments UARS ⫽ upper airway resistance syndrome; AHI ⫽ apnea hypopnea index; OSA ⫽ obstructive sleep apnea; RDI ⫽ respiratory disturbance index; CPAP ⫽ continuous positive airway pressure; ITR ⫽ inferior turbinate reduction; ESS ⫽ endoscopic sinus surgery; INS ⫽ intranasal steroids; ODI ⫽ oxygen desaturation index; QOL ⫽ quality of life; SDB ⫽ sleep-disordered breathing. Sufioğlu et al.38 Choi et al.44 Li et al.36 Morinaga et al.39 Tosun et al.47 Reference Table 3 Continued continue to show the variable, idiosyncratic relationship between nasal airflow and the spectrum of SDB, although it may clarify subgroups of SDB patients in whom nasal obstruction plays a more prominent role. Treatment of nasal obstruction can improve elements of the disease, in addition to improving baseline nasal obstruction. Specifically: • Nasal steroids can improve subjective sleep quality and sleepiness in rhinitis patients, but their ability to successfully treat snoring and OSA has not been established. • Nasal decongestants do not effectively treat OSA. Their efficacy in the management of snoring has not been assessed. • Nasal dilators may provide small improvements in snoring but are not effective in the treatment of OSA. • Nasal surgery has not been convincingly shown to improve snoring objectively, but the majority of studies show a subjective improvement. The odds of snoring improvement and complete cessation vary widely, and the literature currently does not allow accurate prediction of which patients will respond. • Nasal surgery is very unlikely to improve objective parameters of OSA, particularly AHI. Although individual patients may achieve successful results depending on the outcome measures considered, cure of OSA is the exception, not the rule. Conversely, ample evidence supports subjective improvement of OSA patients. This contradiction suggests that although nasal surgery can be offered to improve symptoms of nasal obstruction, sleepiness, and QOL, nasal surgery is not effective as a primary treatment for OSA. Nasal surgery nonetheless appears to reliably augment CPAP compliance when nasal patency is the limiting issue. Efforts to conduct higher evidence level studies and to standardize disease definitions, patient groups, surgical interventions, and outcome measures will likely further clarify the role of nasal interventions in the overall treatment of SDB in the future. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. S66 Stradling J. Obstructive sleep apnoea: Definitions, epidemiology, and natural history. Thorax 50:683–689, 1995. Young T, Paltq M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. . N Engl J Med 328:1230– 1235, 1993. Quinn S, Huang L, Ellis P, et al. The differentiation of snoring mechanisms using sound analysis. Clin Otolaryngol 21:119–123, 1996. Ferris B, Mead J, and Opie L. Partitioning of respiratory flow resistance in man. J Appl Physiol 19:653–658, 1964. Park S. Flow-regulatory function of upper airway in health and disease: A unified pathogenetic view of sleep-disordered breathing. Lung 64:311–333, 1993. 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DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S67 Olfactory disorders Alan Gaines, M.D. ABSTRACT Decreased sense of smell can lead to significant impairment of quality of life, including taste disturbance and loss of pleasure from eating with resulting changes in weight, and difficulty in avoiding health risks such as spoiled food or leaking natural gas. Recent epidemiological reports have shown that despite fairly low self-reported prevalence of these disorders in large population studies, when validated smell identification or threshold tests are used they reveal quite a high prevalence of hyposmia and anosmia in certain groups, especially the elderly. Several different pathophysiological processes, such as head trauma, aging, autoimmunity, and toxic exposures, can contribute to smell impairment, with distinct implications concerning prognosis and possible treatment. Otolaryngologists are most likely to see this symptom in patients with chronic rhinosinusitis, and this now appears to be caused more by the mucosal inflammation than by physical airway obstruction. A lthough standardized, validated tests of vision and hearing are long-accepted tools, the use of validated tests for patients with possible smell disorders has lagged behind. In part, this could be because of the lack of a “quick fix” to ameliorate a deficit if one is found (such as eyeglasses or hearing aids). However, there are several tests available to diagnose and quantify a patient’s sense of smell as discussed in detail in a recent article.1 The University of Pennsylvania Smell Identification Test, a 40-item “scratch and sniff” test with the patient forced to identify each odor as one of four available responses for each item, is common in U.S. studies. Another commonly used approach is to determine the detection threshold of a specific odor, given increasingly diluted vials to sniff according to specific protocols to see the lowest concentration that the patient can reliably detect. However, this process requires some technician training and takes somewhat longer. Subjective questions or visual analog scales are less satisfactory. EPIDEMIOLOGY Several studies have shown that there are gender-related differences in smell identification, with most studies showing women as having superior ability to detect, identify, and discriminate smells.1,2 These gender differences seem to be especially prominent in the young and the elderly subjects.2 Although it is not always a presenting complaint, many studies show the incidence of decreased olfactory function increasing very significantly with age, to 50% or more of those ⬎65 years of age.1,2 Interestingly, a significant disconnect between self-reported problems and measured dysfunction has been reported,3 which highlights the need for awareness of smell impairment in the elderly even if not reported by the patient. At least a portion of this age-related loss of smell function can be attributed to the association of anosmia and hyposmia with several neurodegenerative diseases, including Parkinson’s disease and multiple sclerosis.1,3,4 From the Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island The author has no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Alan Gaines, M.D., Allergy and Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S45–S47, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S68 COMMON ETIOLOGIES/ASSOCIATIONS Anosmia and hyposmia can be related to several different presumed etiologies.5 These include fairly rare congenital problems, associations with neurodegenerative and autoimmune diseases, symptoms that develop after head trauma or after exposure to a toxin, either local or systemic, postviral disease, and, finally, symptoms associated with sinonasal inflammation, which will be addressed in its own section. Congenital anosmia in its more extreme form can be found in association with certain genetic syndromes such as Kallman syndrome,6 but there are also twin studies7 and other research indicating more subtle genetic influences on smell discrimination, and there will likely be more work forthcoming in this area in the near future because large-scale population studies screening hundreds of different gene polymorphisms are becoming more common. An association has long been recognized between smell dysfunction and neurodegenerative and psychiatric diseases, and there are indications that these may be connected in part through autoimmune mechanisms.1,4,8 Odor information gathered from the olfactory bulb is normally transmitted both to the cortex9 and to the limbic system, where it appears pleasant or unpleasant odors trigger neurochemical changes in different areas of the amygdala. Olfactory disorders are among the earliest signs of Parkinson’s disease, as well as Alzheimer’s disease, multiple sclerosis, and even schizophrenia and depression, and cortex and amygdala are frequently involved in these neuropsychiatric diseases. Smell dysfunction related to head trauma can be present in as many as 15–30% of cases1,10 and has long been thought to be associated with stretching or shearing of the olfactory nerves in the course of a sudden head contusion.11 According to this theory, the observed findings of decreased volume of the olfactory bulb in these patients may be caused by decreased sensory input.12 However, a recent report of delayed anosmia several weeks after trauma and magnetic resonance imaging (MRI) showing scarring in the region of the olfactory bulb indicate that direct brain trauma could also be a relevant factor in some cases.11 A role for direct brain injury is also supported by many studies showing abnormalities on MRI in frontal lobes as well as olfactory bulbs, and a recent study with single-photon emission computed tomography (CT) even implicating hypoperfusion of parietal and temporal lobes in patients with posttraumatic anosmia compared with patients with similar trauma but normal sense of smell.10 Sports concussions can also have an apparent gradual effect on olfaction as well.13 MRI of May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm the brain, to rule out the aforementioned entities, should be considered in all cases where history is suggestive or where the clinical picture is not suggestive of a specific cause (e.g., chronic rhinosinusitis and nasal polyposis). This will also reveal intracranial lesions such as an olfactory meningioma. Local exposures to toxins such as ammonia, gasoline, hairdressing chemicals, and others can cause permanent smell dysfunction.14 Adverse reactions to pharmaceuticals can also cause toxic damage to the olfactory function, both systemically15 (especially with chemotherapy) and locally, such as the cases of anosmia found to be caused by the topical application of intranasal preparations containing zinc, which were marketed as a treatment for upper respiratory infections.14 It is also not uncommon to have onset of anosmia/hyposmia during a particularly severe upper respiratory infection, but with the olfactory dysfunction persisting long after the other symptoms have resolved.5 This postviral anosmia is also poorly responsive to treatment, and it may be another of the factors behind the cumulative increase in smell disorders with increasing age. There is some evidence this postviral anosmia may be centrally mediated.16 RHINOSINUSITIS AND ANOSMIA ASSOCIATED WITH INFLAMMATION The subgroup of patients with olfactory disorders likely to be most relevant to the practicing allergist and rhinologist is the patient with chronic rhinosinusitis, with or without nasal polyps, who complains of decreased or even total loss of their sense of smell. Although it may be tempting to assume that this may be related to airflow with the odor-related molecules not having access to the olfactory mucosa, this is rarely the case because there is little correlation between airway patency and olfactory function except in marked obstruction.1 There is a wider correlation, although, between disease severity as measured by overall symptoms, endoscopy, CT scans, etc., and olfactory function.1,17,18 Unfortunately, however, functional endoscopic sinus surgery even with polypectomy results in limited improvement in olfactory symptoms as measured by simple report or visual analog scales1,18–20 and significantly less if any improvement in more detailed assessments of olfaction.1,19,20 One explanation for this is that rather than the impairment in smell being just from blocked access to the olfactory mucosa, the mucosal inflammation itself contributes to the decreased function.1,21 In nasal biopsy specimens obtained from patients with chronic rhinosinusitis and control patients, histopathological examination of the olfactory mucosa revealed erosion of the olfactory epithelium as well as squamous metaplasia and intermixing of goblet cells.21 The percentage of sensory neurons in the olfactory epithelium was also decreased in patients with chronic rhinosinusitis. Even compared with the other patients with chronic rhinosinusitis, those with anosmia had the most epithelial erosion and the highest density of infiltrating eosinophils.21,22 detailed measures of olfactory function.1,19,20 A recent study showed that in nasal polyposis the status of the olfactory cleft, especially the anterior portion, on CT could help predict olfactory response to endoscopic surgery.24 However, ethmoid histology did not help with such a prediction.22 Given the major role of inflammation in this type of olfactory dysfunction, it is not surprising that there is significant improvement in symptoms often seen with oral corticosteroids, and much of this effect is retained with continued use of topical steroids.25,26 Topical steroids have also been shown to help with the hyposmia of allergic rhinitis.27 As in other inflammatory diseases, such as asthma, the effects of even a strong anti-inflammatory medications such as corticosteroids may be limited by remodeling and longerterm changes that have taken place as well. Although this treatment may result in less than complete resolution, it does currently appear to be the most effective medical treatment for olfactory disorders associated with chronic rhinosinusitis. CLINICAL PEARLS • Olfactory disorders are common, especially in elderly people, and can have a significant effect on quality of life. • Although there are many possible contributors to the loss of the sense of smell, the specialist frequently sees this in patients with chronic rhinosinusitis, with and without nasal polyps. MRI should be strongly considered in patients without this clinical picture. • Although some patients do benefit as far as restored olfaction from sinus surgery when there may have been a component of obstruction impeding airflow to the olfactory epithelium, anti-inflammatory treatment with topical or occasionally systemic steroids appears to be the most consistently beneficial treatment. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. TREATMENT Unfortunately, treatment of most forms of anosmia and hyposmia is very limited. Very little has been shown effective to treat congenital or age-related olfactory dysfunction or even that associated with toxic exposures, although these may occasionally improve on their own. Prognosis for recovery of normal function in head trauma–related anosmia is also poor, with, generally, there being little if any response even to systemic steroids.11,12,23 Early research currently underway into the possibility of surgical approaches to restore olfactory function such as transplantation of the olfactory epithelium does offer some hope for future developments.23 As mentioned previously, there is some potential for improvement of anosmia associated with chronic rhinosinusitis after endoscopic sinus surgery and polyp removal in certain patients, especially if one looks at symptom scores, with less effect on more American Journal of Rhinology & Allergy 9. 10. 11. 12. 13. Doty RL. Office procedures for quantitative assessment of olfactory function. Am J Rhinol 21:460–473, 2007. Doty RL, Shaman P, Applebaum SL, et al. Smell identification ability: Changes with age. Science 226:1441–1443, 1984. Smith W, and Murphy C. Epidemiological studies of smell: Discussion and perspectives. Ann N Y Acad Sci 1170:569–573, 2009. Fleiner F, Dahlslett SB, Schmidt F, et al. Olfactory and gustatory function in patients with multiple sclerosis. Am J Rhinol Allergy 24:e93–e97, 2010. Harris R, Davidson TM, Murphy C, et al. Clinical evaluation and symptoms of chemosensory impairment: One thousand consecutive cases from the Nasal Dysfunction Clinic in San Diego. Am J Rhinol 20:101–108, 2006. Hasan KS, Reddy SS, and Barsony N. Taste perception in Kallmann syndrome, a model of congenital anosmia. Endocr Pract 13:716–720, 2007. Segal NL, Topolski TD, Wilson SM, et al. Twin analysis of odor identification and perception. Physiol Behav 57:605–609, 1995. Moscavitch SD, Szyper-Kravitz M, and Shoenfeld Y. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: The olfactory and immune system interrelationship. Clin Immunol 130:235–243, 2009. Kokan N, Sakai N, Doi K, et al. Near-infrared spectroscopy of orbitofrontal cortex during odorant stimulation. Am J Rhinol Allergy 25: 163–165, 2011. Atighechi S, Salari H, Baradarantar MH, et al. A comparative study of brain perfusion single-photon emission computed tomography and magnetic resonance imaging in patients with post-traumatic anosmia. Am J Rhinol Allergy 23:409–412, 2009. Wu AP, and Davidson T. Posttraumatic anosmia secondary to central nervous system injury. Am J Rhinol 22:606–607, 2008. Jiang RS, Chai JW, Chen WH, et al. Olfactory bulb volume in Taiwanese patients with posttraumatic anosmia. Am J Rhinol Allergy 23:582–584, 2009. Charland-Verville V, Lassonde M, and Frasnelli J. Olfaction in athletes with concussion. Am J Rhinol Allergy 26:222–226, 2012. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S69 14. Smith WM, Davidson TM, and Murphy C. Toxin-induced chemosensory dysfunction: A case series and review. Am J Rhinol Allergy 23:578–581, 2009. 15. Doty RL, and Bromley SM. Effects of drugs on olfaction and taste. Otolaryngol Clin North Am 37:1229–1254, 2004. 16. Kim YK, Hong SL, Yoon EJ, et al. Central presentation of postviral olfactory loss evaluated by positron emission tomography scan: A pilot study. Am J Rhinol Allergy 26:204–208, 2012. 17. Litvack JR, Mace JC, and Smith TL. Olfactory function and disease severity in chronic rhinosinusitis. Am J Rhinol Allergy 23:139–144, 2009. 18. Jiang RS, Lu FJ, Liang KL, et al. Olfactory function in patients with chronic rhinosinusitis before and after functional endoscopic sinus surgery. Am J Rhinol 22:445–448, 2008. 19. Soler ZM, Mace J, and Smith TL. Symptom-based presentation of chronic rhinosinusitis and symptom-specific outcomes after endoscopic sinus surgery. Am J Rhinol 22:297–301, 2008. 20. Jiang RS, Su MC, Liang KL, et al. Preoperative prognostic factors for olfactory change after functional endoscopic sinus surgery. Am J Rhinol Allergy 23:64–70, 2009. S70 21. Yee KK, Pribitkin EA, Cowart BJ, et al. Neuropathology of the olfactory mucosa in chronic rhinosinusitis. Am J Rhinol Allergy 24:110–120, 2010. 22. Soler ZM, Sauer DA, Mace JC, and Smith TL. Ethmoid histopathology does not predict olfactory outcomes after endoscopic sinus surgery. Am J Rhinol Allergy 24:281–285, 2010. 23. Yagi S, and Costanzo RM. Grafting the olfactory epithelium to the olfactory bulb. Am J Rhinol Allergy 23:239–243, 2009. 24. Kim DW, Kim JY, and Jeon SY. The status of the olfactory cleft may predict postoperative olfactory function in chronic rhinosinusitis with nasal polyposis. Am J Rhinol Allergy 25:e90–e94, 2011. 25. Hellings PW, and Rombaux P. Medical therapy and smell dysfunction. B-ENT. 5(suppl 13):71–75, 2009. 26. Mullol J, Obando A, Pujols L, and Alobid I. Corticosteroid treatment in chronic rhinosinusitis: The possibilities and the limits. Immunol Allergy Clin North Am 29:657–668, 2009. 27. Sivam A, Jeswani S, Reder L, et al. Olfactory cleft inflammation is present in seasonal allergic rhinitis and is reduced with intranasal steroids. Am J Rhinol Allergy 24:286–290, 2010. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Nonallergic rhinitis Russell A. Settipane, M.D.,1 and Michael A. Kaliner, M.D.2 ABSTRACT Rhinitis is characterized by one or more of the following nasal symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching. It is classified as allergic or nonallergic, the latter being a diverse syndrome that is characterized by symptoms of rhinitis that are not the result of IgE-mediated events. Excluding infectious rhinitis and underlying systemic diseases, clinical entities that can be classified among the disorders that make up the nonallergic rhinitis syndromes include gustatory rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), atrophic, drug-induced (rhinitis medicamentosa), hormone induced, senile rhinitis (of the elderly), rhinitis associated with chronic rhinosinusitis with or without nasal polyps, and the idiopathic variant formerly known as vasomotor rhinitis but more accurately denoted as nonallergic rhinopathy (NAR). The prevalence of nonallergic rhinitis has been observed to be one-third that of allergic rhinitis, affecting ⬃7% of the U.S. population or ⬃22 million people. NAR is the most common of the nonallergic rhinitis subtypes, comprising at least two-thirds of all nonallergic rhinitis sufferers. Although certain precipitants such as perfume, strong odors, changes in temperature or humidity, and exposure to tobacco smoke are frequently identified as symptom triggers, NAR may occur in the absence of defined triggers. The diagnosis of nonallergic rhinitis is purely clinical and relies on a detailed history and physical exam. Skin testing or in vitro testing to seasonal and perennial aeroallergens is required to make the diagnosis of nonallergic rhinitis. Because of the heterogeneous nature of this group of disorders, treatment should be individualized to the patient’s underlying pathophysiology and/or symptoms and is often empiric. T he Joint Task Force Rhinitis Practice Parameter defines rhinitis as characterized by one or more of the following nasal symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching.1 Rhinitis can be classified as allergic2 or nonallergic; the latter being a diverse syndrome that is characterized by periodic or perennial symptoms of rhinitis that are not the result of IgE-dependent events.1 Excluding infectious rhinitis and underlying systemic diseases that may be associated with chronic rhinitis symptoms (Table 1),3 there are a number of separate clinical entities that can be classified among the disorders that make up the nonallergic rhinitis syndromes (Table 2).3 As will be discussed in greater detail, these entities include gustatory rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), atrophic, drug-induced (rhinitis medicamentosa), hormone induced, senile rhinitis (of the elderly), rhinitis associated with chronic rhinosinusitis with or without nasal polyps,4,5 and the idiopathic variant known as vasomotor rhinitis, which is more accurately defined as nonallergic rhinopathy (NAR).6 EPIDEMIOLOGY The prevalence of nonallergic rhinitis has been observed to be one-third that of allergic rhinitis, affecting ⬃7% of the U.S. population or ⬃22 million people.7 Vasomotor rhinitis is the most common of the nonallergic rhinitis subtypes, comprising at least two-thirds of all nonallergic rhinitis sufferers.8 Many patients with rhinitis actually suffer from a combination of both nonallergic and allergic rhinitis. So-called “mixed rhinitis” occurs in ⬃44–87% of patients with allergic From 1Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, and 2Department of Medicine, George Washington School Of Medicine, Washington, D.C. RA Settipane is on the Speakers Bureau and/or a consultant and/or a research grant recipient for Baush & Lomb, Meda, Sunovion, and Teva Respiratory. MA Kaliner is a consultant/advisor for ISTA, Sunovion, and Meda; speaker for Alcon, ISTA, Sunovion, Meda, and Genentech; and honorarium for Meda, Genentech, and Sunovion Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S48 –S51, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy rhinitis; and this form of rhinitis is more common than either pure allergic rhinitis or nonallergic rhinitis.9 Risk factors for nonallergic rhinitis include female sex and age of ⬎40 years.10 VASOMOTOR RHINITIS (NAR) Vasomotor rhinitis is alternatively referred to as idiopathic, nonallergic, noninfectious rhinitis, and, most recently, as NAR.6 The Joint Task Force Rhinitis Practice Parameter defines vasomotor rhinitis as a “heterogeneous group of patients with chronic nasal symptoms that are not immunologic or infectious in origin and are usually not associated with nasal eosinophilia.”1 The underlying pathophysiology is unknown and may involve incipient, local atopy (entopy),11 dysfunction of nociceptive nerve sensor and ion channel proteins, and autonomic dysfunction as found in chronic fatigue syndrome and other functional disorders.12 Essential to the diagnosis of vasomotor rhinitis is the absence of conditions and other causes listed in Tables 1 and 2. Primary symptoms are nasal congestion and/or rhinorrhea. In contrast to allergic rhinitis, nasal pruritus, sneezing, and conjunctival symptoms are rare. Patterns of symptom occurrence may be perennial, persistent, intermittent, or seasonal and may occur in response to climatic changes in temperature, humidity, and barometric pressure.13,14 It is important to emphasize that although certain precipitants such as perfume or strong odors are frequently identified as symptom triggers (Table 3), NAR (vasomotor rhinitis) may occur in the absence of defined triggers.6 The first step in treatment is avoidance of factors that may be contributing such as cigarette smoke and other environmental triggers.15 Compared with allergic rhinitis, less rigorous safety and efficacy pharmaceutical treatment data exist for nonallergic rhinitis. However, there is a growing body of evidence for the efficacy of topical therapies, including topical antihistamine nasal sprays,16–18 intranasal steroids,19 and intranasal ipratropium bromide20 (for rhinorrhea). Recently, a combination product containing both a topical antihistamine (azelastine) and a topical nasal steroid (fluticasone propionate), was conducted in a mixed population of patients with either perennial allergic rhinitis or vasomotor rhinitis, and was shown to be efficacious.21 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S71 Table 1 Medical conditions associated with NAR symptoms Metabolic Acromegaly Pregnancy Hypothyroidism Autoimmune Sjögren’s syndrome SLE Relapsing polychondritis Churg-Straus Granulomatous diseases (sarcoidosis and Wegener’s granulomatosis) Other Cystic fibrosis Cilia dyskinesia syndromes Immunodeficiency Amyloidosis Chronic fatigue syndrome GERD/LPR Source: Adapted from Ref. 3. NAR ⫽ nonallergic rhinopathy; SLE ⫽ sytemic lupus erythematous; GERD ⫽ gastroesophageal reflux disease; LPR ⫽ laryngeal pharyngeal reflux. Table 2 Nonallergic, noninfectious chronic rhinitis not caused by anatomical/mechanical causes Nonallergic rhinopathy (vasomotor rhinitis) Gustatory rhinitis NARES Atrophic rhinitis Drug-induced (including rhinitis medicamentosa) Hormone induced (including pregnancy rhinitis) Rhinitis of elderly subjects Chronic rhinitis associated with chronic rhinosinusitis with or without nasal polyps Source: Adapted from Ref. 3. NARES ⫽ nonallergic rhinitis with eosinophilia syndrome. Table 3 Precipitants of nonallergic rhinopathy (vasomotor rhinitis) Changes in climate (such as temperature, humidity, and barometric pressure) Strong smells (such as perfume, cooking smells, flowers, and chemical odors) Environmental tobacco smoke Pollutants and chemicals (e.g., volatile organics) Exercise Alcohol ingestion GUSTATORY RHINTIS Beer and wine may produce nasal congestion by direct nasal vasodilation and may exacerbate most forms of rhinitis. The syndrome of watery rhinorrhea occurring immediately after ingestion of foods, particularly hot and spicy foods, is known as gustatory rhinitis and is vagally mediated.22 Preprandial treatment with topically sprayed ipratropium bromide is often efficacious.23,24 NONALLERGIC RHINITIS WITH EOSINPOHILIA SYNDROME NARES is a perennial disorder that usually manifests in middleaged adults and may be responsible for up to one-third of all cases of nonallergic rhinitis.25 Common symptoms include sneezing paroxysms, profuse, clear rhinorrhea, nasal pruritus, and reduced sense of S72 smell.1 NARES is marked by eosinophilia (5–20%) on nasal cytology in the setting of negative assessment for aeroallergen-specific IgE.1 The etiology for this condition is unknown; however, in some settings, it may be a precursor to nasal polyps, asthma, and aspirinexacerbated respiratory disease.26 NARES patients characteristically respond well to topical nasal corticosteroids. ATROPHIC RHINITIS The hallmark features of atrophic rhinitis include progressive atrophy of the nasal mucosa, the development of hardened nasal crusts, anosmia, and the presence of a foul odor or fetor emanating from the patient’s nose.27 Primary atrophic rhinitis is most prevalent in developing countries in subtropical and temperate climate zones. Etiology is unknown but bacterial infection is thought to be primarily or secondarily involved, including Klebsiella ozaenae, Staphylococcus aureus, Proteus mirabilis, and Escherichia coli.1 Secondary atrophic rhinitis, which is the more prevalent form in the United States and developed countries, is less severe and less progressive. It may be iatrogenically induced (“empty nose syndrome” due to aggressive sinonasal surgery, particularly inferior turbinectomy) or may result from underlying granulomatous disease28 (tuberculosis, leprosy, and syphilis, and autoimmune processes such as sarcoidosis and Wegener’s granulomatosis.) Management of atrophic rhinitis includes nasal saline irrigation, antibiotics, and surgical approaches to reduce the nasal cavity size by providing tissue augmentation as a means to help restore nasal anatomy toward the premorbid state.27,29 RHINITIS MEDICAMENTOSA Rhinitis medicamentosa is a term most commonly used to describe the rebound nasal congestion that occurs with the repetitive and prolonged use of a topical, ␣-adrenergic, decongestant/vasoconstrictor agent such as oxymetazoline and phenylephrine. Although these medications are generally safe to use for up to 3 consecutive days, continued use for ⬎5–7 days may result in tachyphylaxis and rebound congestion. Turbinate hypertrophy and a “beefy red” appearance of the nasal mucosa are classic findings. A similar rebound nasal congestion may result from the use of cocaine. Rhinitis medicamentosa, manifesting as nasal congestion, may also occur with certain oral medications, including ␣-receptor antagonists used in the treatment of benign prostatic hypertrophy and phophodiesterase-5-selective inhibitors used to treat erectile dysfunction. Treatment consists of stopping the offending agent. For topical decongestants, symptom control during the withdrawal process often requires a short course of systemic corticosteroids (oral preferred). HORMONE-INDUCED RHINITIS Pregnancy, menstrual cycle–associated hormonal changes, and, more controversially, oral contraceptives may be associated with nasal congestion and rhinorrhea.30 Preexisting rhinitis is often exacerbated by the physiological changes of pregnancy (expanded blood volume, vascular pooling, plasma leakage, and smooth muscle relaxation). Because rhinitis occurs in approximately one-fifth of pregnancies, it is often referred to as “pregnancy rhinitis.” Most commonly, this condition presents as nasal congestion peaking in the last 6 weeks of pregnancy and resolving within 2 weeks of delivery䡠1 Impact on quality of life can be significant.31 Although a complete discussion of the treatment of rhinitis during pregnancy is beyond the scope of this article and is reviewed elsewhere,1 it is sufficient to note that the main treatment concern during pregnancy is safety and that nasal saline alone can be efficacious.32 RHINITIS OF ELDERLY PATIENTS Rhinitis in elderly patients may be caused by the same types of rhinitis that are common in other age populations; however, the May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm prevalence rates of the various types may differ.30 For example, because elderly subjects are more likely to be receiving prescription medications, rhinitis medicamentosa may be a more prevalent cause or contributor to chronic rhinitis in this age group.1 Additionally, both NAR and rhinitis sicca (dry nasal tissues) are more commonly seen in elderly subjects. The latter may occur secondary to Sjögren’s syndrome, atrophic rhinitis, or as a normal part of aging. However, a more common complaint of elderly subjects is chronic clear rhinorrhea, which may result from NAR and/or cholinergic hyperactivity. Treatment is specific to the underlying condition. Although for rhinitis sicca, treatment with the liberal use of nasal saline sprays is appropriate, the watery rhinorrhea resulting from NAR has been shown to respond to intranasal ipratropium bromide in subjects ⬎60 years of age.23 Ipratropium bromide should be used with caution in patients with preexisting glaucoma or prostatic hypertrophy.24 DIFFERENTIAL DIAGNOSIS The differential diagnosis of rhinitis includes other conditions that mimic rhinitis symptoms. These include systemic diseases with nasal manifestations (Table 1) and anatomic abnormalities, such as a deviated septum, turbinate hypertrophy, nasal valve collapse, nasal tumors, and foreign bodies.33 Refractory unilateral clear rhinorrhea may be the result of a cerebral spinal fluid (CSF) leak, resulting from head trauma, basal skull fracture, a postoperative complication of sinus surgery, or spontaneous CSF leak. Diagnostically, 2-transferrin is a more sensitive and specific indicator of CSF fluid than is the presence of glucose.34 The diagnosis of nonallergic rhinitis is purely clinical and relies on a detailed history and physical exam. Skin testing35 or in vitro testing36 to seasonal and perennial aeroallergens with negative results is required to make the diagnosis. Recent research suggests the possibility that in a small subset of patients, the synthesis of specific IgE may be localized and limited to occurring only in the nasal mucosa.37 This condition, referred to as “entopy,” can be diagnosed by a positive nasal allergen provocation test and/or detection of nasal specific IgE (research tools) and in the setting of a negative skin test or negative assessment for serum specific IgE.38,39 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. SUMMARY 20. Nonallergic rhinitis is a common condition that results in a substantial burden of disease. Because of the heterogeneous nature of this group of disorders, treatment should be individualized to the patient’s underlying pathophysiology and/or symptoms and is often empiric. 21. 22. 23. CLINICAL PEARLS • Nonallergic rhinitis affects 20 million people in the United States, is more prevalent in women. • NAR (vasomotor rhinitis) is the most common type of nonallergic rhinitis, representing more than two-thirds of sufferers. • Classically, symptoms of NAR are nonspecific but may be triggered by irritant odors, perfumes, alcohol, and weather changes. • With regard to pharmacotherapy of vasomotor rhinitis, preferred treatments include intranasal steroids and intranasal antihistamines. When symptom relief with either agent is not effective, combination of the two may produce greater benefit. 2. 25. 26. 27. 28. REFERENCES 1. 24. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin Immunol 122:S1–S84, 2008. Settipane RA, and Schwindt C. Allergic rhinitis. Am J Rhinol Allergy 27:S52–S55, 2013. American Journal of Rhinology & Allergy 29. 30. Kaliner M. Classification of nonallergic rhinitis syndromes with a focus on vasomotor rhinitis, proposed to be known henceforth as nonallergic rhinopathy. WAO J 2:98–101, 2009. Settipane RA, Peters AT, and Chandra R. Chronic rhinosinusitis. Am J Rhinol Allergy 27:S11–S15, 2013. Settipane RA, Peters AT, and Chiu AG. Nasal polyps. Am J Rhinol Allergy 27:S20–S25, 2013. Kaliner M, Baraniuk JN, Benninger M, et al. Consensus definition of nonallergic rhinopathy, previously referred to as vasomotor rhinitis, nonallergic rhinitis, and/or idiopathic rhinitis. WAO J 2:119–120, 2009. Settipane RA, and Charnock DR. Epidemiology of rhinitis: Allergic and nonallergic. Clin Allergy Immunol 19:23–34, 2007. Settipane RA. Epidemiology of vasomotor rhinitis. WAO J 2:115–118, 2009. Bernstein JA. Allergic and mixed rhinitis: Epidemiology and natural history. Allergy Asthma Proc 31:365–369, 2010. Settipane RA. Rhinitis: A dose of epidemiological reality. Allergy Asthma Proc 24:147–154, 2003. Çomoğlu Ş, Keles N, and Değer K. Inflammatory cell patterns in the nasal mucosa of patients with idiopathic rhinitis. Am J Rhinol Allergy 26:e55–e62, 2012. Baraniuk JN. Pathogenic mechanisms of idiopathic nonallergic rhinitis. WAO J 2:106–114, 2009. Bernstein JA, Salapatek AM, Lee JS, et al. Provocation of nonallergic rhinitis subjects in response to simulated weather conditions using an environmental exposure chamber model. Allergy Asthma Proc 33: 333–340, 2012. Kim YH, Oh YS, Kim KJ, and Jang TY. Use of cold dry air provocation with acoustic rhinometry in detecting nonspecific nasal hyperreactivity. Am J Rhinol Allergy 24:260–262, 2010. Håkansson K, von Buchwald C, Thomsen SF, et al. Nonallergic rhinitis and its association with smoking and lower airway disease: A general population study. Am J Rhinol Allergy 25:25–29, 2011. Lieberman P. The role of antihistamines in the treatment of vasomotor rhinitis. WAO J 2:156–161, 2009. Smith PK, and Collins J. Olopatadine 0.6% nasal spray protects from vasomotor challenge in patients with severe vasomotor rhinitis. Am J Rhinol Allergy 25:e149–e152, 2011. Lieberman P, Meltzer EO, LaForce CF, et al. Two-week comparison study of olopatadine hydrochloride nasal spray 0.6% versus azelastine hydrochloride nasal spray 0.1% in patients with vasomotor rhinitis. Allergy Asthma Proc 32:151–158, 2011. Meltzer EO. The treatment of vasomotor rhinitis with intranasal corticosteroids. WAO J 2:166–176, 2009. Naclerio R. Anticholinergic drugs in nonallergic rhinitis. WAO J 2:162–165, 2009. Meda Pharmaceuticals, Inc. Dymista package insert. Somerset, NJ; 2013. Last revision April 2012. Raphael G, Raphael MH, and Kaliner M. Gustatory rhinitis: A syndrome of food-induced rhinorrhea. J Allergy Clin Immunol 83:110– 115, 1989. Malmberg H, Grahne B, Holopainen E, and Binder E. Ipratropium (Atrovent) in the treatment of vasomotor rhinitis of elderly patients. Clin Otolaryngol Allied Sci 8:273–276, 1983. Bronsky EA, Druce H, Findlay SR, and Hampel FC. A clinical trial of ipratropium bromide nasal spray in patients with perennial nonallergic rhinitis. J Allergy Clin Immunol 95:1117–1122, 1995. Settipane GA, and Klein DE. Non allergic rhinitis: Demography of eosinophils in nasal smear, blood total eosinophil counts and IgE levels. N Engl Reg Allergy Proc 6:363–366, 1985. Moneret-Vautrin DA, Hsieh V, Wayoff M, et al. Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: Nasal polyposis, intrinsic asthma, and intolerance to aspirin. Ann Allergy 64:513–518, 1990. Banks TA, and Gada SM. Clinical pearls and pitfalls: atrophic rhinitis. Allergy Asthma Proc 34:185–187, 2013. Kohanski MA, and Reh DD. Granulomatous diseases and chronic sinusitis. Am J Rhinol Allergy 27:S39–S41, 2013. Modrzyński M. Hyaluronic acid gel in the treatment of empty nose syndrome. Am J Rhinol Allergy 25:103–106, 2011. Settipane RA. Other causes of rhinitis: mixed rhinitis, rhinitis medicamentosa, hormonal rhinitis, rhinitis of the elderly, and gustatory rhinitis. Immunol Allergy Clin North Am 31:457–467, 2011. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S73 31. 32. 33. 34. S74 Gilbey P, McGruthers L, Morency AM, and Shrim A. Rhinosinusitis-related quality of life during pregnancy. Am J Rhinol Allergy 26:283–286, 2012. Hermelingmeier KE, Weber RK, Hellmich M, et al. Nasal irrigation as an adjunctive treatment in allergic rhinitis: A systematic review and meta-analysis. Am J Rhinol Allergy 26:e119–e125, 2012. Shah R, and McGrath KG. Nonallergic rhinitis. Allergy Asthma Proc 33(suppl 1):S19–S21, 2012. Sampaio MH, de Barros-Mazon S, Sakano E, and Chone CT. 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DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Allergic rhinitis Russell A. Settipane, M.D.,1 and Christina Schwindt, M.D.2 ABSTRACT Allergic rhinitis affects 60 million of the U.S. population, 1.4 billion of the global population, and its prevalence appears to be increasing. The duration and severity of allergic rhinitis symptoms place a substantial burden on patient’s quality of life, sleep, work productivity, and activity. The health impact of allergic rhinitis is compounded by associated complications and comorbidities including asthma, otitis media, sinusitis, and nasal polyps. Allergic rhinitis symptoms result from a complex, allergen-driven mucosal inflammatory process, modulated by immunoglobulin E (IgE), and caused by interplay between resident and infiltrating inflammatory cells and a number of vasoactive and proinflammatory mediators, including cytokines. This allergic response may be characterized as three phases: IgE sensitization, allergen challenge, and elicitation of symptoms. A thorough allergic history is the best tool for the diagnosis of allergic rhinitis, the establishment of which is achieved by correlating the patient’s history and physical exam with an assessment for the presence of specific IgE antibodies to relevant aeroallergens determined by skin testing or by in vitro assay. Management of allergic rhinitis includes modifying environmental exposures, implementing pharmacotherapy, and, in select cases, administering allergen-specific immunotherapy. Intranasal therapeutic options include antihistamines, anticholinergic agents, corticosteroids (aqueous or aerosol), mast cell stabilizers, saline, and brief courses of decongestants. Selection of pharmacotherapy is based on the severity and chronicity of symptoms with the most effective medications being intranasal corticosteroids and intranasal antihistamines, which can be used in combination (separately or in fixed dose) for more difficult to control allergic rhinitis. T he Joint Task Force Rhinitis Practice Parameter defines rhinitis as characterized by one or more of the following nasal symptoms: congestion, rhinorrhea (anterior and posterior), sneezing, and itching.1 Rhinitis is classified as allergic or nonallergic, the latter being a diverse syndrome.2 Allergic rhinitis is classified as seasonal (commonly known as hay fever), resulting from sensitivity to pollen allergens (tree, grass, or weed); perennial, resulting from indoor allergens (such as animal dander and/or dust mites); intermittent; or occupational.1 An international rhinitis guideline, Allergic Rhinitis and Its Impact on Asthma, alternatively categorizes allergic rhinitis as intermittent or persistent and in terms of severity as mild or moderate–severe, which is useful to help guide initial therapy.3 EPIDEMIOLOGY AND BURDEN OF ILLNESS Allergic rhinitis affects ⬃10–30% of the U.S. population (totaling 60 million), 1.4 billion of the global population, and its prevalence appears to be increasing.4,5 Mixed rhinitis (combined allergic and nonallergic rhinitis) occurs in ⬃44–87% of patients with allergic rhinitis and is more common than either pure allergic rhinitis or nonallergic rhinitis.6 The duration and severity of allergic rhinitis symptoms have been shown to place a substantial burden on patient’s quality of life (QoL), sleep, work productivity, and activity.7,8 Risk factors for allergic rhinitis include1 family history of atopy,2 serum IgE of ⬎100 IU/mL before age 6 years,3 higher socioeconomic class, and4 presence of a positive allergy skin-prick test.1 The health impact of allergic rhinitis is further compounded by associated complications and comorbidities including asthma, otitis media, From 1Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, and 2Allergy and Asthma Associates, Southern California Research, Mission Viejo, California RA Settipane is on the Speakers Bureau and/or a consultant and/or a research grant recipient for Baush & Lomb, Meda, Sunovion, and Teva Respiratory. C Schwindt has no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S52–S55, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy sinusitis, and nasal polyps.9 Allergic rhinitis and associated comorbid illnesses result in substantial costs, both direct (medical treatment expenditures) and indirect (because of reduced work productivity and lost days from work.)10,11 When these costs are added, allergic rhinitis is estimated to be the fifth most costly chronic disease in the United States.3,12 Pathophysiology Allergic rhinitis symptoms result from a complex, allergen-driven mucosal inflammatory process, modulated by immunoglobulin E (IgE), and caused by interplay between resident and infiltrating inflammatory cells and a number of vasoactive and proinflammatory mediators, including cytokines.1,13 The immunologic reaction that underlies the acute symptoms of allergic rhinitis is defined as a type I reaction according to the 1963 Gell and Coombs classification of hypersensitivity reactions.14,15 This type of reaction takes place when aeroallergens (pollens, molds, animal danders, dust mite fecal particles, cockroach residues, etc.) enter the nose and precipitate the release of inflammatory mediators from tissue mast cells residing in the nasal mucosa.16 This allergic response may be characterized as three distinct phases: sensitization, challenge, and elicitation.17 Sensitization refers to the production of the specific IgE antibody that occurs when a genetically predisposed individual inhales aeroallergen, which is subsequently presented by antigen-presenting cells to CD4⫹ T cells in local lymph nodes. In the setting of a Th2 cytokinerich milieu, allergen-stimulated Th2 cells proliferate and release cytokines (IL-4, IL-5, IL-9, and IL-13), which lead to the plasma cell production of allergen-specific IgE antibodies.17 The challenge phase occurs on reexposure, when the same aeroallergen is recognized by specific IgE antibodies that have become bound to mast cells in the nasal mucosa. Cross-linking of two adjacent FcRI on mediator cell membranes initiates a signal, leading to the degranulation and release of mediators that elicit symptoms. The third phase of the allergic response is referred to as the elicitation phase, which, in the laboratory, has been characterized as comprised of an early phase and late-phase response.17 Clinically, nasal symptoms of the early phase response occur within 5–30 minutes and correlate with the mast cell mediator response (histamine, tryptase, chymase, prostaglandin D2, and cysteinyl leukotrienes). This is followed in 60–70% of subjects by increased nasal symptoms 4–8 hours Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S75 later because of a late-phase response characterized by influx into the nasal mucosa of inflammatory cells (eosinophils, basophils, and T lymphocytes), which become activated and further produce mediators. These mediators contribute to vasodilation, plasma leakage, increased mucous secretion, and stimulation of afferent nerves. As a consequence, both the early phase and late-phase responses are characterized by pruritus, sneezing, congestion, and rhinorrhea; however, in the late phase, congestion is predominantly observed.1 Another important clinical observation, which is a manifestation of the latephase reaction, is a phenomenon referred to as priming, where repeated exposure to an allergen results in the nasal mucosa becoming increasingly allergen sensitive such that exposure to lesser amounts of allergen is capable of eliciting symptoms.18 Priming also contributes to a general increase in nasal hyperreactivity to nonallergic triggers (irritants) as well. Recent research suggests that in a small subset of patients, the synthesis of specific IgE may be localized and limited to occurring only in the nasal mucosa.19 This condition, referred to as “entopy,” can be diagnosed in the setting of a positive nasal allergen provocation test and/or detection of nasal-specific IgE (research tool) in the absence of systemic atopy (negative skin test and in vitro assessment for serum specific IgE).13 Evaluation and Diagnostic Studies More so than the physical exam, a thorough allergic history is the best tool for the diagnosis of allergic rhinitis. It should include assessment of the following: a determination of the pattern, chronicity, seasonality and triggers of nasal and related symptoms, family history, current medications, response to previous treatments, presence of coexisting conditions, occupational exposure, and a detailed environmental history.1 The history should also consider the impact of rhinitis symptoms on the patient’s QoL, including symptoms of fatigue, sleep disturbances, learning and attention problems, absenteeism, and presenteeism (impaired functionality) at work and/or school.1 Provocation of symptoms by allergen exposure and occurrence of associated ocular symptoms (itching, redness, and tearing) are key historical features that strongly suggest allergic causation. It is important to note that findings on nasal examination are not specific for the diagnosis of allergic rhinitis.1 Although the nasal mucosa of the symptomatic allergic rhinitis patient commonly appears pale and boggy, with turbinate swelling, and clear nasal secretions, these findings may also be seen in nonallergic rhinitis. Although an otoscope is commonly used for examination of the nose, better assessment is achieved by the use of nasal speculum and light source. When necessary, a more thorough exam may be achieved using special techniques such as rigid or flexible nasal endoscopy. The nasal exam should include assessment for the following abnormalities: reduced patency of nasal valve, alar collapse, transverse external crease, external deformity such as saddle nose, septal abnormalities (deviation, spurs, erosions, ulcers, perforation, prominent vessels, or excoriation), nasal turbinate abnormalities (hypertrophy, edema, pallor, erythema, and crusting), discharge (amount, color, and consistency), nasal polyps, nasal masses, and foreign bodies.1 To assess septal integrity, translumination of the septum from the contralateral nares should result a pink glow; visualization of a white light indicates septal perforation (“white light test”). It is important to document the integrity of the nasal septum before instituting intranasal therapy. The diagnosis of allergic rhinitis is established by correlating the patient’s history and physical exam with an assessment for the presence of specific IgE antibodies to relevant aeroallergens as preferably determined by skin testing20 or by in vitro assay.21 Nasal cytology is not routinely used in the assessment of allergic rhinitis, but may confirm the presence of eosinophilic inflammation, which has predictive value for bronchial hyperresponsiveness.22 S76 Table 1 Oral and intranasal medications used for the treatment of allergic rhinitis Oral Therapies Sedating antihistamines Cetirizine/levocetirizine Diphenhydramine Carbinoxamine maleate Clemastine Chlorpheniramine Brompheniramine Triprolidine Acrivastine Nonsedating antihistamines Loratadine/desloratadine Fexofenadine Decongestants Pseudoephedrine Phenylephrine Leukotriene receptor antagonists Montelukast35,36 Zafirlukast Fixed combination products Antihistamine/decongestants Systemic corticosteroids Intranasal Therapies Intranasal corticosteroids24 Beclomethasone dipropionate HFA25,26 Ciclesonide HFA27–29 Ciclesonide aqueous Flunisolide Fluticasone furoate30,31 Fluticasone propionate Mometasone furoate32 Triamcinolone acetonide Intranasal antihistamines Azelastine33 Olopatadine34 Decongestants Oxymetazoline Phenylephrine Ipratropium bromide 0.03% Mast cell stabilizers Cromolyn sodium Fixed combination products FP/azelastine44,45 Saline42 FP ⫽ fluticasone propionate; HFA ⫽ hydrofluoroalkane. Treatment Management of allergic rhinitis includes modifying environmental exposures, implementing pharmacotherapy, and, in select cases, administering allergen-specific immunotherapy. Environmental management is specific to the allergens identified by history and corroborated by diagnostic testing for allergic sensitivities. For dust-mite allergen, the key area to address is the bedroom, where exposure is proportional to the quantity and age of the fabric as well as the indoor humidity. Mattresses, pillows, box springs, and comforters should be encased in material impermeable to dust-mite particles. Bed linens should be washed in hot water (120°F), carpets removed, and indoor humidity kept below 50%. For animal dander allergen, there is no substitute for complete removal of the pet from the home. For mold spore allergen, interventions include moisture control, improved ventilation, leak repair, and, in severe cases, extensive remediation. Unfortunately, in exquisitely sensitive patients, despite best efforts to implement environmental control measures, symptoms may persist because of small amounts of retained allergen. Therefore, treatment of allergic rhinitis frequently necessitates pharmacotherapy. Physicians must take into account safety; efficacy; cost-effectiveness; severity of symptoms; and patient preference, satisfaction, and adherence when recommending medications.23 Two routes of administration exist for the administration of medications used for the treatment of allergic rhinitis: oral and intranasal (see Table 1).24–36 By the time the patient sees a rhinologist, they have frequently exhausted oral options (antihistamines and decongestants) because many of these agents are available without a prescription. Other oral options include leukotriene receptor antagonists for mild disease and short courses of systemic corticosteroids for the most severe cases. Intranasal therapeutic options include H1-receptor antagonists, anticholinergic agents, corticosteroids (aqueous or aerosol), mast cell stabilizers, saline, and brief courses of decongestants. Selection of pharmacotherapy is usually based on the severity and chronicity of symptoms with the most effective single agent medications being intranasal corticosteroids and intranasal antihistamines.37,38 If rhinorrhea is the primary symptom, an anticholinergic May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm agent may be added. For ocular symptoms, although some relief frequently results from an intranasal antihistamine or an intranasal corticosteroid, an ocular H1-receptor antagonist/mast cell stabilizer is recommended for optimal benefit.39,40 In pregnancy, impact of rhinitis on QoL can be significant.41 Although a complete discussion of the treatment of allergic rhinitis during pregnancy is beyond the scope of this article and is reviewed elsewhere,1 it is sufficient to note that the main treatment concern during pregnancy is safety. In this regard, nasal saline irrigation has been shown to be efficacious in allergic rhinitis.42 After initial therapeutic intervention, ongoing monitoring of rhinitis control should guide therapeutic changes. A recently validated tool, the Rhinitis Control Assessment Test, can help identify patients who are inadequately controlled.43,44 When control is not adequately achieved, the environment should be reassessed and medical therapy maximized. Additionally, stepping up to the combination of an intranasal antihistamine and an intranasal corticosteroid (either separately or fixed-dose combination) has been shown to provide greater symptomatic relief than monotherapy with either of the individual agents.45,46 Another therapeutic alternative, allergen-specific immunotherapy, should be considered when symptoms can not be adequately controlled by environmental avoidance measures combined with maximal pharmacotherapy.47,48 The decision to begin immunotherapy may also depend on the patient’s preference/acceptability, adherence, and the adverse effects of medications.49 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. CLINICAL PEARLS 16. • The diagnosis of allergic rhinitis is established by correlating the patient’s history and physical exam with an assessment for the presence of specific IgE antibodies to relevant aeroallergens as preferably determined by skin testing. • To assess nasal septal integrity, translumination of the septum from the contralateral nares should result in a pink glow; visualization of a white light indicates septal perforation. • The phenomenon referred to as “priming” is a manifestation of the late-phase reaction, where repeated exposure to an allergen results in the nasal mucosa becoming increasingly allergen sensitive such that exposure to lesser amounts of allergen are capable of eliciting symptoms • A recently validated tool, the Rhinitis Control Assessment Test, can help identify patients who are inadequately controlled. • Stepping up to the combination of an intranasal antihistamine and an intranasal corticosteroid (either separately or fixed dose combination) has been shown to provide greater symptomatic relief than monotherapy with the individual agents. • Allergen-specific immunotherapy should be considered when symptoms can not be adequately controlled by environmental avoidance measures combined with maximal pharmacotherapy and may also depend on the patient’s preference/acceptability, adherence, and the adverse effects of medications. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. REFERENCES 1. 2. 3. 4. 5. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin Immunol 122:S1–S84, 2008. Settipane RA, and Kaliner MA. Nonallergic rhinitis. Am J Rhinol Allergy 27:S48–S51, 2013. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 63 (suppl):8–160, 2008. Settipane RA, Charnock DR. Epidemiology of rhinitis: allergic and nonallergic. Clin Allergy Immunol 19:23–34, 2007. Katelaris CH, Lai CK, Rhee CS, et al. Nasal allergies in the AsianPacific population: results from the Allergies in Asia-Pacific Survey. Am J Rhinol Allergy 25 Suppl 1:S3–15, 2011. American Journal of Rhinology & Allergy 27. 28. 29. 30. Bernstein JA. Allergic and mixed rhinitis: Epidemiology and natural history. Allergy Asthma Proc 31:365–369, 2010. Meltzer EO, Blaiss MS, Naclerio RM, et al. Burden of allergic rhinitis: Allergies in America, Latin America, and Asia-Pacific adult surveys. Allergy Asthma Proc 33(suppl 1):S113–S141, 2012. Abdulrahman H, Hadi U, Tarraf H, et al. Nasal allergies in the Middle Eastern population: Results from the “Allergies in Middle East Survey.” Am J Rhinol Allergy 26(suppl 1):S3–S23, 2012. Settipane RA. Complications of allergic rhinitis. Allergy Asthma Proc 20:209–213, 1999. Bhattacharyya N. Functional limitations and workdays lost associated with chronic rhinosinusitis and allergic rhinitis. Am J Rhinol Allergy 26:120–122, 2012. de la Hoz Caballer B, Rodríguez M, Fraj J, et al. Allergic rhinitis and its impact on work productivity in primary care practice and a comparison with other common diseases: The Cross-sectional study to evAluate work Productivity in allergic Rhinitis compared with other common dIseases (CAPRI) study. Am J Rhinol Allergy 26:390– 394, 2012. Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31:375–380, 2010. Broide DH. Allergic rhinitis: Pathophysiology. Allergy Asthma Proc 31:370–374, 2010. Coombs RRA, and Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In Clinical Aspect of Immunology, 3rd ed. Gell PGH, Coombs RRA, and Lachman PJ (Eds). Oxford, U.K.: Blackwell Scientific Publications, 575–596, 1975. Uzzaman A, and Cho SH. Classification of hypersensitivity reactions. Allergy Asthma Proc 33(suppl 1):S96–S99, 2012. Shah R, and Grammer LC. An overview of allergens. Allergy Asthma Proc 33(suppl 1):S2–S5, 2012. Luccioli S, Escobar-Gutierrez A, Bellanti JA. Allergic diseases and asthma. In Immunology IV: Clinical applications in heath and disease. Bethesda: I Care, 685–765, 2012. Connell JT. Quantitative intranasal pollen challenges. 3. The priming effect in allergic rhinitis. J Allergy 43:33–44, 1969. Rondón C, Campo P, Galindo L, et al. Prevalence and clinical relevance of local allergic rhinitis. Allergy 67:1282–1288, 2012. Carr TF, and Saltoun CA. Skin testing in allergy. Allergy Asthma Proc 33(suppl 1):S6–S8, 2012. Settipane RA, Borish L, and Peters AT. Determining the role of allergy in sinonasal disease. Am J Rhinol Allergy 27:S56–S58, 2013. Canbaz P, Uskudar-Teke H, Aksu K, et al. Nasal eosinophilia can predict bronchial hyperresponsiveness in persistent rhinitis: Evidence for united airways disease concept. Am J Rhinol Allergy 25: 120–124, 2011. Bukstein D, Luskin AT, and Farrar JR. The reality of adherence to rhinitis treatment: Identifying and overcoming the barriers. Allergy Asthma Proc 32:265–271, 2011. Blaiss MS. Safety update regarding intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc 32:413–418, 2011. van Bavel JH, Ratner PH, Amar NJ, et al. Efficacy and safety of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with seasonal allergic rhinitis. Allergy Asthma Proc 33:386–396, 2012. Meltzer EO, Jacobs RL, LaForce CF, et al. Safety and efficacy of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with perennial allergic rhinitis. Allergy Asthma Proc 33:249–257, 2012. Berger WE, Mohar DE, LaForce C, et al. A 26-week tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis. Am J Rhinol Allergy 26:302–307, 2012. Ratner PH, Andrews C, Martin B, et al. A study of the efficacy and safety of ciclesonide hydrofluoroalkane nasal aerosol in patients with seasonal allergic rhinitis from mountain cedar pollen. Allergy Asthma Proc 33:27–35, 2012. Mohar D, Berger WE, Laforce C, et al. Efficacy and tolerability study of ciclesonide nasal aerosol in patients with perennial allergic rhinitis. Allergy Asthma Proc 33:19–26, 2012. Han D, Liu S, Zhang Y, et al. Efficacy and safety of fluticasone furoate nasal spray in Chinese adult and adolescent subjects with intermittent or persistent allergic rhinitis. Allergy Asthma Proc 32:472–481, 2011. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S77 31. 32. 33. 34. 35. 36. 37. 38. 39. S78 Fokkens WJ, Rinia B, van Drunen CM, et al. No mucosal atrophy and reduced inflammatory cells: Active-controlled trial with yearlong fluticasone furoate nasal spray. Am J Rhinol Allergy 26:36–44, 2012. Yamada T, Yamamoto H, Kubo S, et al. Efficacy of mometasone furoate nasal spray for nasal symptoms, quality of life, rhinitisdisturbed sleep, and nasal nitric oxide in patients with perennial allergic rhinitis. Allergy Asthma Proc 33:e9–e16, 2012. Lieberman P, Meltzer EO, LaForce CF, et al. Two-week comparison study of olopatadine hydrochloride nasal spray 0.6% versus azelastine hydrochloride nasal spray 0.1% in patients with vasomotor rhinitis. Allergy Asthma Proc 32:151–158, 2011. Meltzer EO, Blaiss M, and Fairchild CJ. Comprehensive report of olopatadine 0.6% nasal spray as treatment for children with seasonal allergic rhinitis. Allergy Asthma Proc 32:213–220, 2011. Ciebiada M, Gorska-Ciebiada M, Barylski M, et al. Use of montelukast alone or in combination with desloratadine or levocetirizine in patients with persistent allergic rhinitis. Am J Rhinol Allergy 25:e1– e6, 2011. Yamamoto H, Yamada T, Sakashita M, et al. Efficacy of prophylactic treatment with montelukast and montelukast plus add-on loratadine for seasonal allergic rhinitis. Allergy Asthma Proc 33:e17–e22, 2012. Fairchild CJ, Durden E, Cao Z, and Smale P. Outcomes and cost comparison of three therapeutic approaches to allergic rhinitis. Am J Rhinol Allergy 25:257–262, 2011. Carr WW, Ratner P, Munzel U, et al. Comparison of intranasal azelastine to intranasal fluticasone propionate for symptom control in moderate-to-severe seasonal allergic rhinitis. Allergy Asthma Proc 33:450–458, 2012. Meier EJ, Torkildsen GL, Gow JA, et al. Bepotastine Besilate Ophthalmic Solutions Study Group. Integrated phase III trials of bepotastine besilate ophthalmic solution 1.5% for ocular itching associated with allergic conjunctivitis. Allergy Asthma Proc 33:265–274, 2012. 40. Baroody FM, Logothetis H, Vishwanath S, et al. Effect of intranasal fluticasone furoate and intraocular olopatadine on nasal and ocular allergen-induced symptoms. Am J Rhinol Allergy 27:48–53, 2013. 41. Gilbey P, McGruthers L, Morency AM, and Shrim A. Rhinosinusitisrelated quality of life during pregnancy. Am J Rhinol Allergy 26:283– 286, 2012. 42. Hermelingmeier KE, Weber RK, Hellmich M, et al. Nasal irrigation as an adjunctive treatment in allergic rhinitis: A systematic review and meta-analysis. Am J Rhinol Allergy 26:e119–e125, 2012. 43. Meltzer EO, Schatz M, Nathan R, et al. Reliability, validity, and responsiveness of the Rhinitis Control Assessment Test in patients with rhinitis. J Allergy Clin Immunol 131:379–386, 2013. 44. Schatz M, Zeiger RS, Chen W, et al. A comparison of the psychometric properties of the Mini-Rhinitis Quality of Life Questionnaire and the Rhinitis Control Assessment Test. Am J Rhinol Allergy 26:127– 133, 2012. 45. Meltzer EO, LaForce C, Ratner P, et al. MP29–02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: A randomized, doubleblind, placebo-controlled trial of efficacy and safety. Allergy Asthma Proc 33:324–332, 2012. 46. Carr W, Bernstein J, Lieberman P, et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol 129:1282–1289.e10, 2012. 47. Georgy MS, and Saltoun CA. Allergen immunotherapy: Definition, indication, and reactions. Allergy Asthma Proc 33(suppl 1): S9–S11, 2012. 48. Uzzaman A, and Story R. Allergic rhinitis. Allergy Asthma Proc 33(suppl 1):S15–S18, 2012. 49. Settipane RA, Peters AT, and Borish L. Immunomodulation of allergic sinonasal disease. Am J Rhinol Allergy 27:S59–S62, 2013. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Determining the role of allergy in sinonasal disease Russell A. Settipane, M.D.,1 Larry Borish, M.D.,2 and Anju T. Peters, M.D.3 ABSTRACT The contributing role of specific IgE sensitization in the pathophysiology of sinonasal diseases including rhinitis, chronic rhinosinusitis (CRS), and nasal polyps is explored. Although it is estimated that sensitization to environmental allergens is present in 75% of patients with rhinitis, the role of allergy in CRS and nasal polyps is less certain. However, when atopy is present in the setting of nasal polyps, it is associated with worse quality of life and a higher incidence of asthma. Several theories have been put forth whereby inhalant aeroallergen exposure could drive the inflammatory response that occurs both in the nose and in the sinuses. Tools available to determine the presence of allergic sensitization include skin tests for immediate hypersensitivity, in vitro testing for allergen-specific IgE, and nasal allergen provocation testing. Whether by skin testing or in vitro testing, the identification of specific IgE requires clinical correlation with the history and physical exam. S pecific IgE sensitization plays a major contributory role in the pathophysiology of upper and lower respiratory diseases including rhinitis and asthma. Although it is estimated that allergic sensitization to environmental allergens is present in 75% of patients with rhinitis,1 the role of allergy in chronic rhinosinusitis (CRS) and nasal polyps is less certain.2 In this article the role of allergy in sinonasal disease is explored, followed by an overview of diagnostic testing tools for determining immediate hypersensitivity. EPIDEMIOLOGY OF ALLERGIC RHINITIS IN CRS There exists a high degree of overlap between CRS3 and allergic rhinitis,4 but this relationship may be more coincidental than etiologic.5 Eighty-two percent of patients in an academic institution who underwent sinus surgery were noted to have one or more positive skin-prick test results to inhalant allergens. This was significantly higher than that found in the National Health and Nutrition Examination Study III (54.3%) but comparable with the rhinitis control group (72%) that did not have CRS.6 Although IgE-mediated hypersensitivity occurs in patients with CRS, the weight of the available evidence suggests that allergic rhinitis contributes in a variable but limited way to the mucosal inflammation of CRS.2 For example, in a retrospective study of pediatric patients, allergy was shown to be a risk factor for protracted symptoms despite endoscopic sinus surgery; however, there is no evidence to support the theory that failure to address allergy adversely affects the probability of success in sinus surgery.7 With regard to nasal polyps, the prevalence in a population with allergic rhinitis is comparable with that seen in the normal population8; and allergy does not appear to be a risk factor for the development of nasal polyps.9,10 Additionally, the presence of allergy does From the 1Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, 2Department of Medicine, Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health System, Charlottesville, Virginia, and 3Division of Allergy-Immunology, Northwestern University, Chicago, Illinois RA Settipane received a research grant from Genentech (clinical trial). L Borish is funded by NIH RO1 AI057483 and UO1 AI100799. AT Peters is a speaker for Baxter Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S56 –S58, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy not correlate with polyp size, symptom scores, grading of severity by CT (Lund-Mackay), or rate of polyp recurrence.11 However, the presence of atopy in the setting of nasal polyps has been shown to be associated with lower quality of life scores and a higher incidence of asthma.12 Furthermore, there appears to be some subsets of CRS where IgE sensitization may play a greater role. Among these are patients with severe CRS with nasal polyps (CRSwNPs)13 who often manifest chronic hyperplastic eosinophilic sinusitis in association with multiple positive skin tests,5 allergic fungal rhinosinusitis,14 and patients with local polyclonal IgE in the absence of systemic atopy, the potential etiology of which is discussed in this article.15 THEORIES FOR ALLERGIC RHINITIS/CRS PATHOPHYSIOLOGICAL LINKAGE Discussion is warranted regarding several theories whereby inhalant aeroallergen exposure could drive the inflammatory response when it occurs concomitantly in the nose and sinuses (Table 1).5 A “direct aeroallergen reaction” is thought to be unlikely because breathing alone does not drive aeroallergens into the sinuses of patients who have not had their sinus ostia altered by surgery.5 Except for the CRS subtype known as allergic fungal rhinosinusitis,14 evidence for “sensitization to colonizing fungi” in the pathogenesis of CRS appears to be limited to playing a role as a disease modifier.2 There exists greater supporting evidence for a “systemic allergic inflammatory process” involving the local nasal airway, nasal-associated lymphatic tissue, the bone marrow, and the sinuses. Supporting this concept, nasal allergen challenge has been shown to result in inflammatory changes within both the ipsilateral, but strikingly, also the contralateral maxillary sinus cavity, marked by a significant increase in maxillary sinus eosinophils.16 Finally, the “sensitization to colonizing bacteria” hypothesis proposes that in CRSwNPs, exposure to Staphylococcus aureus enterotoxins, induces an inflammatory mucosal response, resulting in a skewing of T lymphocytes toward a Th2 phenotype, proinflammatory cytokine release, localized polyclonal IgE responses, Treg inhibition, and accentuated eosinophil and mast cell activity.17–19 Superantigen-induced polyclonal IgE in airway disease has been postulated to contribute to chronic inflammation by continuously activating mast cells. In studies where tissue fragments from nasal polyp patients were stimulated with anti-IgE, mast cells were activated, indicating that mucosal IgE antibodies in nasal polyp tissue are functional and able to activate mast cells.20 The polyclonal IgE response may be directed at bystander pathogens Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S79 Table 1 Putative mechanisms linking allergic rhinitis to CRS Direct aeroallergen reaction Sensitization to colonizing fungi Systemic allergic inflammation Sensitization to colonizing bacteria Source: Adapted from Ref. 5. CRS ⫽ chronic rhinosinusitis. such as the Staphylococcus enterotoxin. The role of IgE sensitization to bystander pathogens is supported by anti-IgE clinical trial outcomes showing improvement in nasal polyps irrespective of the presence of allergic sensitization to aeroallergens.21,22 Whether by skin testing or in vitro testing, the identification of specific IgE requires clinical correlation with the history and physical exam.24 In circumstances where the history strongly suggests allergen sensitivity, but testing for specific IgE is negative, a nasal allergen provocation test and/or detection of local nasal specific IgE may confirm the diagnosis.35 In this condition, referred to as “entopy,” local IgE production may be limited to the nasal mucosa in patients who would otherwise be diagnosed as having nonallergic rhinitis.36,37 Finally, despite advances in evidence-based medicine, unproven tests continue to be promoted for the determination of allergic sensitization. These include IgG4-specific antibody tests, cytotoxic tests, provocation–neutralization, electrodermal testing, applied kinesiology, iridology, and hair analysis.38 Currently, there is neither evidence nor an immune/mechanistic basis to suggest that these tests are useful. SUMMARY DIAGNOSTIC TESTING FOR IMMEDIATE HYPERSENSITIVITY Despite uncertainties regarding the contribution of allergy to CRS, knowledge of specific allergic sensitizations may provide benefit to patients who suffer from associated rhinitis symptoms. The primary tools available to determine the presence of IgE-mediated hypersensitivity23 include skin tests and in vitro tests for allergen-specific IgE. Although both techniques are able to identify specific IgE-mediated hypersensitivity, skin testing by prick/puncture technique is the preferred diagnostic approach because of its overall sensitivity, specificity, and rapidity of performance.24–28 Skin testing detects the presence of allergen-specific IgE bound to mast cells by eliciting allergeninduced mast cell degranulation and a resultant histamine wheal/ flare response. For a detailed description of the skin test procedure, the reader is referred to diagnostic testing practice parameters.24 Factors that may affect interpretation and reliability of prick/puncture tests include the skill of the tester, the test instruments, extremes of age, skin color, skin reactivity (including dermatographism), and reagent potency. Additionally, concurrent medications affect the validity of skin testing; in particular, first-/second-generation antihistamines and tricyclic antidepressants should be held for 3–7 days depending on the agent, and H2-antagonists for 1 day.24 Although -adrenergic blocking agents do not interfere with the skin test response, caution with their concomitant use is warranted because of the potential of -blockers to impede epinephrine treatment of anaphylaxis, which is a rare but potential adverse reaction of skin testing.29 Because of this risk, a physician should always be available to administer emergency epinephrine if necessary.30–32 Ideally, objective wheal-and-flare responses are recorded in millimeters, along with positive and negative controls. In the clinical setting of strongly suspected hypersensitivity, intracutaneous tests (at 100- to 1000-fold more dilute) may be applied if prick/puncture tests are negative. Intracutaneous tests are associated with increased risk of inducing anaphylaxis, which can be fatal.33 This is more of a safety concern when/if intracutaneous tests are performed without preceding prick/puncture tests. Interpretation of intracutaneous tests may be confounded by false positive results because of irritant effects of the testing reagent. Immunoassays measuring serum-specific IgE concentrations (kIU/L) have good sensitivity/specificity and can predict respiratory responses after allergen exposure.24,28 These assays provide information that is not equivalent to skin testing but is considered complementary.34 The clinical efficacy of a total IgE measurement is limited; it is much more valuable to measure serum-specific IgE. There are circumstances when serum-specific IgE immunoassays may be preferable to skin testing such as in the setting of generalized dermatitis, concomitant medications that may suppress the skin test, uncooperative patients, or when the history suggests an unusually greater risk of anaphylaxis from skin testing.24 S80 Specific IgE sensitization plays a contributing role in sinonasal disease, particularly in rhinitis, but also to an undetermined and variable extent in CRS and nasal polyps. Although it is estimated that allergic sensitization to environmental allergens is present in 75% of patients with rhinitis, the role of allergic contribution to CRS is less certain. However, when atopy is present in the setting of nasal polyps, it is associated with worse quality of life and a higher incidence of asthma. Several theories have been put forth whereby inhalant aeroallergen exposure could drive the inflammatory response that occurs both in the nose and sinuses. In patients with CRS or nasal polyps, when the history suggests the presence of allergic sensitization, skin testing is the preferred test for the determination of immediate hypersensitivity. In certain clinical settings, in vitro testing for allergenspecific IgE provides an additional diagnostic tool. Finally, a nasal allergen provocation test may confirm the presence of local allergy in the setting of negative skin tests, but its efficacy is limited because of labor intensity and because it is confounded by the potential for false positive results. Whether by skin testing or in vitro testing, the identification of specific IgE sensitization, when clinically correlated with the history and physical exam, allows the clinician to best determine and treat the allergic contribution to sinonasal disease. Once an allergic contribution has been determined, the clinician must weigh the medical evidence as to what therapeutic interventions, including immunotherapy,39 are appropriate. CLINICAL PEARLS • Although specific IgE sensitization can be determined by in vitro assay, prick/puncture skin test technique provides more rapid results, which, unlike in vitro tests, are not influenced by high total IgE levels. • Interpretation of skin testing may be confounded by extremes of age, skin color, dermatographism, and antihistamine use. • Interpretation of skin testing should be performed by an experienced practitioner, in the presence of positive and negative controls. • Because skin testing may potentially result in anaphylaxis, a physician should always be available to administer epinephrine if necessary. • Whether by skin testing or in vitro testing, the identification of specific IgE requires clinical correlation with the history and physical exam to make the diagnosis of allergy. • In a condition known as entopy, specific IgE sensitization can only be identified in the nasal mucosa and can not be found systemically. REFERENCES 1. 2. Settipane RA. Rhinitis: A dose of epidemiological reality. Allergy Asthma Proc 24:147–154, 2003. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 23:1–298, 2012. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Settipane RA, Peters AT, and Chandra R. Chronic rhinosinusitis. Am J Rhinol Allergy 27:S11–S15, 2013. Settipane RA, and Schwindt C. Allergic rhinitis. Am J Rhinol Allergy 27:S52–S55, 2013. Kennedy JL, and Borish L. Chronic sinusitis pathophysiology: The role of allergy. Am J Rhinol Allergy DOI: 10.2500/ajra.2013.27.3906 [Epub ahead of print date April 18, 2013]. Tan BK, Zirkle W, Chandra RK, et al. Atopic profile of patients failing medical therapy for chronic rhinosinusitis. Int Forum Allergy Rhinol 1:88–94, 2011. Lee TJ, Liang CW, Chang PH, and Huang CC. Risk factors for protracted sinusitis in pediatrics after endoscopic sinus surgery. Auris Nasus Larynx 36:655–660, 2009. Kern R. Allergy: A constant factor in the etiology of so-called mucous nasal polyps. J Allergy 4:483, 1993. Erbek SS, Erbek S, Topal O, et al. The role of allergy in the severity of nasal polyposis. Am J Rhinol. 2007 21:686–690, 2007. Settipane GA. Epidemiology of nasal polyps. In Nasal Polyps: Epidemiology, Pathogenesis and Treatment. Settipane GA, Lund VJ, Bernstein JM, and Tos M (Eds). Providence, RI: OceanSide Publications, 17–24, 1997. Pearlman AN, Chandra RK, Chang D, et al. Relationships between severity of chronic rhinosinusitis and nasal polyposis, asthma, and atopy. Am J Rhinol Allergy 23:145–148, 2009. Dávila I, Rondón C, Navarro A, et al. Aeroallergen sensitization influences quality of life and comorbidities in patients with nasal polyposis. Am J Rhinol Allergy 26:e126–e131, 2012. Settipane RA, Peters AT, and Chiu AG. Nasal polyps. Am J Rhinol Allergy 27:S20–S25, 2013. Laury AM, and Wise SK. Allergic fungal rhinosinusitis. Am J Rhinol Allergy 27:S26–S27, 2013. Bachert C, Gevaert P, Holtappels G, et al. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 107:607–614,2001. Baroody FM, Mucha SM, Detineo M, et al. Nasal challenge with allergen leads to maxillary sinus inflammation. J Allergy Clin Immunol 121:1126–1132.e7, 2008. Van Crombruggen K, Zhang N, Gevaert P, et al. Pathogenesis of chronic rhinosinusitis: Inflammation. J Allergy Clin Immunol 128: 728–732, 2011. Kim DW, Khalmuratova R, Hur DG, et al. Staphylococcus aureus enterotoxin B contributes to induction of nasal polypoid lesions in an allergic rhinosinusitis murine model. Am J Rhinol Allergy 25:e255– e261, 2011. Kim ST, Chung SW, Jung JH, et al. Association of T cells and eosinophils with Staphylococcus aureus exotoxin A and toxic shock syndrome toxin 1 in nasal polyps. Am J Rhinol Allergy 25:19–24, 2011. Zhang N, Holtappels G, Gevaert P, et al. Mucosal tissue polyclonal IgE is functional in response to allergen and SEB. Allergy 66:141–148, 2011. American Journal of Rhinology & Allergy 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. Pinto JM, Mehta N, DiTineo M, et al. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology 48:318–324, 2010. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 131:110–116.e1, 2013. Uzzaman A, and Cho SH. Classification of hypersensitivity reactions. Allergy Asthma Proc 33(suppl 1):S96–S99, 2012. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: An updated practice parameter. Ann Allergy Asthma Immunol 100 (suppl 3):S1–S148, 2008. Tripathi A, and Kim JS. Diagnosis of immediate hypersensitivity. In Patterson’s Allergic Diseases, 7th ed. Grammer LC, and Greenberger PA (Eds). Philadelphia, PA: J.B. Lippincott, Williams & Wilkins, 123–135, 2009. Tripathi A, and Patterson R. Clinical interpretations of skin test results. Immunol Allergy Clin North Am 21:291–300, 2001. Carr TF, and Saltoun CA. Skin testing in allergy. Allergy Asthma Proc 33(suppl 1):S6–S8, 2012. Makhija M, and O’Gorman MRG. Common in vitro tests for allergy and immunology. Allergy Asthma Proc 33(suppl 1):S108–S111, 2012. Greenberger PA, and Ditto AM. Anaphylaxis. Allergy Asthma Proc 33:S80–S83, 2012. Lieberman P. The risk and management of anaphylaxis in the setting of immunotherapy. Am J Rhinol Allergy 26:469–474, 2012. Phillips JF, Lockey RF, Fox RW, et al. Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. Allergy Asthma Proc 32:288–294, 2011. Wallace DV. Anaphylaxis in the allergist’s office: Preparing your office and staff for medical emergencies. Allergy Asthma Proc 34: 120–131, 2013. Bernstein DI, Wanner M, Borish L, et al. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol 113:1129–1136, 2004. Calabria CW, Dietrich J, and Hagan L. Comparison of serum-specific IgE (ImmunoCAP) and skin-prick test results for 53 inhalant allergens in patients with chronic rhinitis. Allergy Asthma Proc 30:386– 396, 2009. Rondón C, Campo P, Togias A, et al. Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol 129: 1460–1467, 2012. Khan DA. Allergic rhinitis with negative skin tests: Does it exist? Allergy Asthma Proc 30:465–469, 2009. Settipane RA, and Kaliner MA. Nonallergic rhinitis. Am J Rhinol Allergy 27:S48–S51, 2013. Shah R, and Greenberger PA. Unproved and controversial methods and theories in allergy-immunology. Allergy Asthma Proc 33(suppl 1):S100–S10 2, 2012. Settipane RA, Peters AT, and Borish L. Immunomodulation of allergic sinonasal disease. Am J Rhinol Allergy 27:S59–S62, 2013. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S81 The united allergic airway: Connections between allergic rhinitis, asthma, and chronic sinusitis Charles H. Feng, M.D.,1 Michaela D. Miller, M.D.,1 and Ronald A. Simon, M.D.2 ABSTRACT Background: The united allergic airway is a theory that connects allergic rhinitis (AR), chronic rhinosinusitis, and asthma, in which seemingly disparate diseases, instead of being thought of separately, are instead viewed as arising from a common atopic entity. Objective: This article describes patients with such diseases; explores ideas suggesting a unified pathogenesis; elucidates the various treatment modalities available, emphasizing nasal corticosteroids and antihistamines; and provides an update of the literature. Methods: A literature review was conducted. Conclusion: The aggregation of research suggests that AR, asthma, and chronic rhinosinusitis are linked by the united allergic airway, a notion that encompasses commonalities in pathophysiology, epidemiology, and treatment. A llergic rhinitis (AR) occurs when the nasal passages become inflamed; it is characterized by rhinorrhea, nasal congestion, postnasal drip, and itchiness of the nose. The inflammatory cascade in AR involves an immediate IgE-mediated mast cell response and a late-phase response of basophils, eosinophils, and T cells driven by the cytokines IL-4 and IL-5.1 In adults, risk factors for AR include eczema and a family history of atopy.2 In children, risk factors for AR include maternal cigarette smoking and higher blood IgE levels.3 Since the onset of the Industrial Revolution, AR has become the most common atopic disorder in the United States, affecting 20–40 million people annually, including up to 30% of adults and 40% of children.4,5 Asthma, on the other hand, involves inflammation of the bronchial tree and can cause wheezing, shortness of breath, coughing, and chest tightness. This condition, compared with AR, is far more prevalent at a younger age and affects 10% of children and 8% of adults.6 Although AR, on the spectrum of medical afflictions, is considered a relatively benign disease, patients with AR can have an impaired quality of life, with difficulty sleeping, exhaustion during the day, cognitive disturbances, and mood changes.7 Having AR also causes socioeconomic consequences, because patients are forced to take time off from school and work.8,9 Patients with asthma, by contrast, are more likely to have physical limitations, impacting both their activities of daily living, such as going up stairs and performing chores, and their ability to exercise. However, in patients with both asthma and AR, there are more physical limitations when compared with ARonly patients, but no further impairment in quality of life.7 From the 1Department of Internal Medicine, 2Division of Allergy and Immunology, Scripps Green Hospital, La Jolla, California Presented at the North American Rhinology & Allergy Conference, February 4, 2012, Puerto Rico CH Feng and MD Miller contributed equally to this work RA Simon is part of the Speaker Bureau for GlaxoSmithKline, Merck, Astra-Zeneca, and Novartis. The remaining authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Charles Feng, M.D., 10666 Torrey Pines Road MS:403C, La Jolla, CA 92037 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 26, 187–190, 2012 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S82 ALLERGIC RHINITIS AND ASTHMA AR and asthma, rather than being considered two distinct diseases, can be unified by the concept of a “united airway,” where allergic symptoms of the upper and lower airways can be thought of as manifestations of a common atopic entity.10 Epidemiological evidence suggests a strong relationship between AR and asthma. AR can occur in ⬎75% of patients with asthma, whereas asthma can affect up to 40% of patients with AR.11 Both diseases, which are IgE mediated, can be triggered by similar allergens, including mold, animal dander, and house-dust mites.12,13 Temporally, AR often occurs before the onset of asthma. In a 10-year longitudinal study of children with AR, asthma was eventually found in 19% of cases, and in 25% of the sample size, asthma and AR developed simultaneously.12 Indeed, AR is a risk factor for asthma, and its presence is related to asthma severity. For example, in a 23-year follow-up study of almost 2000 college students, patients with AR, when compared with controls without AR, were about three times more likely to develop asthma.14 This idea was confirmed by a 15-year prospective study of Finnish twins, which found that in patients with AR, male patients were four times and female patients were six times as likely to get asthma when compared with patients without AR.15 Taking this notion one step further, Guerra et al.11 found that, after adjusting for age, sex, atopic status, years of follow-up, smoking status, and the presence of chronic obstructive pulmonary disease, AR was still an independent risk factor for asthma. Of importance, AR and asthma were linked, autonomous of the fact that they shared atopy as a common causal agent. In addition to the epidemiological evidence, several clinical reports point to a common pathophysiological relationship between AR and asthma. In the 1980s, allergists noted not only that AR patients hyperresponsive to methacholine had a greater risk of developing asthma, but also that the increase in bronchial reactivity was correlated with the pollen season.16,17 These findings were confirmed in studies led by Ciprandi and colleagues, who showed that in a majority of patients with AR but no asthma, there is an increase in bronchial hyperreactivity (BHR) after methacholine challenge.17,18 Moreover, in the subset of patients with BHR, there is impairment in spirometry, including forced vital capacity, forced expiratory volume in 1 second (FEV1), and forced expiratory flow at 25–75%.17,18 More recently, Ciprandi et al.19 showed that ⬃2⁄3 of patients with AR showed reversibility to bronchodilation testing (defined as an increase of ⬎12% in May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm basal FEV1 values), despite having normal baseline FEV1 measurements. In fact, a forced expiratory flow at 25–75% value of ⱕ58.5% predicts BHR and reversibility in patients with AR, and an FEV1 ⬍83% is a good marker for early bronchial impairment in children with AR.20,21 Four mechanisms have been postulated to account for the relationship between asthma and AR.22 First, the nose, by virtue of its anatomic location, warms, filters, and humidifies inhaled air. In fact, exercise-induced bronchospasm is caused by cooling and drying in the airways, which occurs with obligate mouth breathing during vigorous activity. In addition, via the numerous submucosal glands located in the nasal passages, the nose is able to sterilize air through the release of antibacterial enzymes. With AR, nasal function may be partially or completely lost as the congestion forces the patient to become a mouth breather. Second, during an exacerbation of AR, the inflammatory products from the upper airways may be aspirated directly into the lower airways. Third, nasal inflammation may result in local cytokine release into the bloodstream, which eventually causes bronchoconstriction in the lower airways. Fourth, a nasal– bronchial reflex may exist, where histamine and bradykinin stimulate the afferent nasal sensory nerve. The neural signal then travels to the central nervous system and activates the efferent vagus nerve, resulting in bronchial smooth muscle hyperreactivity. The etiology for the connection between asthma and AR is likely multifactorial. The data supporting a nasal–bronchial reflex is controversial. Although nasal blockage and aspiration of nasal contents have long been accepted as contributing factors, there is a growing body of evidence that suggests that a systemic response plays an important role in the AR–asthma relationship. For example, in patients with seasonal AR but no asthma, nasal allergen testing not only instigates bronchial airway responsiveness, but also increases eosinophil counts in the sputum samples of these patients.23 In another study, bronchial and nasal biopsy specimens were taken before and 24 hours after nasal allergen testing in patients with AR. At the 24-hour time point, there was an increase in eosinophils in both the nasal and the bronchial epithelium.24 By the same token, segmental bronchial provocation in nonasthmatic AR patients resulted in inflammation in the nose, as well as an increase in peripheral blood eosinophilia.25 Supporting the idea from a different angle, a study showed that eosinophil infiltration was present on nasal biopsy in asthmatic patients who did not have AR.26 Ultimately, the eosinophilia, in both the upper and the lower airways results from an increase in inflammatory cytokines, especially IL-5.27,28 If AR and asthma are linked, then it should not be surprising that treating AR will also improve asthma symptoms. This was first noticed in 1984, when intranasally administered beclomethasone and flunisolide were, in asthmatic patients, found to markedly reduce self-reports of shortness of breath and wheezing.29 Subsequent more quantitative studies supported this notion. For instance, 4 weeks of intranasal budesonide was found to reduce the severity of exerciseinduced asthma in children, as measured by FEV1,30 and 5 weeks of intranasal beclomethasone led to a decrease in bronchial responsiveness.31 Furthermore, in a separate crossover study, patients with AR but no asthma were found to have decreased bronchial hyperresponsiveness after 2 weeks of intranasal beclomethasone, but no change from baseline after 2 weeks of bronchial beclomethasone.32Although these studies, taken together, suggest that treating AR will help control asthma, it is important to note that their sample sizes were small, ranging from 11 to 26 patients. Indeed, a much larger study of 262 subjects randomized patients to either 6 weeks of intranasal fluticasone, inhaled fluticasone, their combination, or inhaled placebo, and found that only inhaled fluticasone—and not intranasal fluticasone— was effective in controlling bronchial reactivity.33 Thus, whether nasal steroids are effective in treating asthma is still subject to debate. Although nasal corticosteroids are of questionable efficacy, antihistamines, the first-line treatment for AR, have been shown to be highly American Journal of Rhinology & Allergy effective in treating asthma. Antihistamines, when compared with nasal corticosteroids, are systemic, rather than local, medications that directly target the histamine receptors on mast cells and T cells, in the process stabilizing these cells and promoting anti-inflammatory activities. The presence of histamine receptors in both the nasal passages and the lungs, and the fact that AR and asthma are simultaneously improved with antihistamines, provides further support for the united airway hypothesis. One of the first large studies indicating that an antihistamine treats AR as well as asthma randomized 186 patients with both conditions to receive placebo or cetirizine, a second-generation H1-antagonist, for 6 weeks.34 Cetirizine-treated patients reported a significant improvement in chest tightness, wheezing, shortness of breath, cough, and nocturnal asthma when compared with controls. Similarly, a study published by Spector et al.35 evaluated pulmonary function tests in 12 asthmatic patients who were given varying doses of oral cetirizine (5,10, and 20 mg) as well as albuterol. All three cetirizine doses were found to significantly improve pulmonary function measures throughout the 8-hour testing period and provided a demonstrable bronchodilatory effect. At the same time, the administration of both albuterol and cetirizine appears to have an additive bronchodilatory effect. And finally, Ubier et al.36 randomized asthmatic patients to either cetirizine at 10 mg daily or placebo for 2 weeks, after which there was a marked improvement in bronchial hyperresponsiveness, as measured by methacholine challenge. The use of antihistamines in combination with other medications has also shown promise in asthma treatment. In a randomized trial conducted by Corren et al.,37 193 patients with a history of seasonal AR and asthma were administered a combination of loratadine and pseudoephedrine, or placebo, for 6 weeks. Both groups were evaluated daily for nasal symptoms, chest symptoms, albuterol use, and peak expiratory flow rates, as well as with weekly spirometry. By the end of the study, the total nasal symptom score, total asthma symptom score, peak expiratory flow rates, weekly FEV1, and asthma quality of life measures were all significantly improved when compared with placebo. Ultimately, the treatment of AR not only reduces the physical symptoms of asthma, but also has beneficial socioeconomic consequences. One retrospective cohort study examined, over the course of a year, the rate of asthma-related emergency room (ER) visits and hospitalizations in patients with asthma and AR after they were treated with AR medications.38 Of 4944 subjects, 3587 patients were treated for AR, and 1357 patients were untreated. Asthma-related hospitalizations fell from 2.3 to 0.9 (61% decrease), and the incidence of two or more asthma-related ER visits decreased from 1.3 to 0.6 per patient (54% reduction). These findings were corroborated in a casecontrol study, which showed that patients with both AR and asthma, who were treated with intranasal corticosteroids, had a significantly lower risk of both asthma-related ER visits and hospitalizations.39 Moreover, treatment with both intranasal steroids and second-generation antihistamines was associated with an even lower risk of ER visits or hospitalization. ALLERGIC RHINITIS AND SINUSITIS Patients afflicted with allergies have a predisposition for developing sinusitis. One study determined that both disorders exist in the same patient 25–70% of the time,40 and another study found that 72 of 121 patients with chronic nasal symptoms and positive skin tests for allergies had positive sinus computed tomography scans showing sinusitis.41 By the same token, asthma severity is associated with a more severe clinical presentation of rhinosinusitis.42 Moreover, Berrettini et al.43 found a statistically significant increase in sinusitis on computed tomography scans in patients with perennial AR when compared with a control group, and Baroody et al.44 determined that nasal allergen challenge induced eosinophilic inflammation in the maxillary sinus. Finally, in a cohort of patients with chronic sinusitis Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S83 who were challenged with nasal allergen provocation tests, 41 positive nasal responses occurred in 29 patients. Of the 41 nasal responses, 31 were associated with radiographic changes on Water’s view sinus radiographs, including increased mucosal edema and opacification of the sinuses, suggesting that nasal allergens trigger changes in the mucosal membranes of patients with sinusitis.45 The etiology of the link between AR and sinusitis is, akin to the etiology between AR and asthma, likely multifactorial. Anatomically, patients with AR have edematous nasal mucosa, damaged nasal cilia, and overproduction of secretions, which could lead to a blockage of ostial drainage from the sinuses. This blockage results in stagnant debris that then becomes infected. From an immunologic perspective, eosinophils, more prevalent during an AR flare, can cause chronic inflammation in the mucosa, even when bacteria are not present.43 Notably, patients with both allergies and sinusitis, when compared with patients with nonallergic sinusitis, have a distinct cytokine profile, with nasal polyp tissue that shows an increase in granulocyte macrophage colony-stimulating factor, IL-3, IL-4, and IL-5, along with an increased density of CD3⫹ T lymphocytes.46 Although chronic rhinosinusitis (CRS) can develop independently of allergic pathways, there is a group of patients, diagnosed with allergic fungal rhinosinusitis (AFRS), whose sinusitis and nasal polyposis are related to allergic inflammation. Hutcheson et al.47 compared the antibody responses in 64 patients with AFRS to 35 patients with CRS and found no evidence of allergic disease. In the AFRS cohort, serum total IgE, mean IgG anti–Alternaria-specific antibodies, and the mean number of IgE antifungal antibody bands on immunoblotting, were all increased, showing that AFRS is a distinct entity from CRS, with a unique allergic etiology. Although the existence of AFRS does not necessarily support the notion of a united airway, the fact that sinusitis can arise directly from allergic inflammation indicates the close relationship between allergies and rhinosinusitis. Of course, AFRS is not the only clinical entity associated with nasal polyposis—nasal polyps are found in a number of other diseases, including cystic fibrosis, aspirin-exacerbated respiratory disease, and Churg-Strauss syndrome.48 Furthermore, a retrospective study revealed that of 4986 hospitalized patients, 6.7% of asthmatic patients, 5% of CRS patients, and 2.2% of rhinitis patients had nasal polyps.49 Interestingly, IgE-mediated pathways are thought to play a role in the pathogenesis of nasal polyposis, providing further support for the connection between allergies and sinusitis. Specifically, Bernstein et al.50 discovered increased serum levels of IgE antibodies to both Staphylococcal enterotoxin B and toxic shock syndrome toxin in CRS patients with nasal polyps, when compared with controls. Moreover, there were high levels of IgE against Staphylococcal enterotoxin A and B in the nares of these same patients. Thus, Staphylococcus aureus exotoxins may act as superantigens in the nasal mucosa of CRS patients. Subsequently, IgE antibodies directed against these exotoxins create a local allergic inflammatory reaction, resulting in the growth of nasal polyps. Indeed, the presence of S. aureus actively affects the clinical course of rhinosinusitis by augmenting the inflammatory response in nasal polyposis while also increasing local IgE production in the nares. attention should be given to the management of any concurrent AR as well. The information we have, to date, although promising, leaves a number of questions that still require addressing. What is the exact inflammatory cascade that leads a patient with AR to independently have bronchial hyperactivity, and vice versa? Has the severity and epidemiology of the diseases changed with the onset of a new generation of medications? What is the optimal treatment of patients with both AR and asthma? And how can we better elucidate the relationship between sinusitis and asthma? We eagerly await the answers in future studies. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. CONCLUSION The aggregation of research suggests that AR and asthma are, in fact, one syndrome in two parts of the respiratory tract—this notion is supported pathophysiologically, epidemiologically, and through numerous clinical studies. Being afflicted with AR is often the harbinger of asthma at a future date. By the same token, allergies are associated with an increased likelihood of having sinusitis, with a common pathophysiology, and possibly treatment, tying the two disorders together. Ultimately, we can posit that the united airway—where AR, asthma, and sinusitis are inextricably linked—truly exists. Thus, when entertaining a diagnosis of asthma, an evaluation of the upper airways should be considered.51 In addition, when treating sinusitis, S84 18. 19. 20. 21. Broide DH. Allergic rhinitis: Pathophysiology. Allergy Asthma Proc 31:370–374, 2010. Sibbald B, and Rink E. Epidemiology of seasonal and perennial rhinitis: Clinical presentation and medical history. Thorax 46:895– 901, 1991. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics 94:895–901, 1994. Nathan RA, Meltzer EO, Selner JC, and Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol 99:S808– S814, 1997. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: Complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. Am Acad Allergy Asthma Immunol 81:478–518, 1997. Centers for Disease Control. Asthma in the US: Growing every year. Available online at www.cdc.gov/vitalsigns/asthma; accessed August 24, 2011. Leynaert B, Neukirch C, Liard R, et al. Quality of life in allergic rhinitis and asthma: A population-based study of young adults. Am J Respir Crit Care Med 162:1391–1396, 2000. Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31:375–380, 2010. Bernstein JA. Allergic and mixed rhinitis: Epidemiology and natural history. Allergy Asthma Proc 31:365–369, 2010. Marple BF. Allergic rhinitis and inflammatory airway disease: Interactions within the unified airspace. Am J Rhinol Allergy 24:249–254, 2010. Guerra S, Sherrill DL, Martinez FD, and Barbee RA. Rhinitis is an independent risk factor for adult-onset asthma. J Allergy Clin Immunol 109:419–425, 2002. Bosquet J; and the ARIA Working Group. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 108:S147–S334, 2001. Stevenson DD, Mathison DA, Tan EM, and Vaughan JH. Provoking factors in bronchial asthma. Arch Intern Med 135:777–783, 1975. Settipane RJ, Hagy GW, and Settipane GA. Long-term risk factors for developing asthma and allergic rhinitis: A 23-year follow-up study of college students. Allergy Proc 15:21–25, 1994. Huovinen E, Kaprio J, Laitinen LA, and Koskenvuo M. Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Chest 115:928–936, 1999. Braman SS, Barrows AA, DeCotiis BA, et al. Airway hyperresponsiveness in allergic rhinitis: A risk factor for asthma. Chest 91:671– 674, 1987. Ciprandi G, Cirillo I, Tosca MA, and Vizzaccaro A. Bronchial hyperreactivity and spirometric impairment in patients with perennial allergic rhinitis. Int Arch Allergy Immunol 133:14–18, 2004. Ciprandi G, Cirillo I, Tosca MA, and Vizzaccaro A. Bronchial hyperreactivity and spirometric impairment in patients with seasonal allergic rhinitis. Respir Med 98:826–831, 2004. Ciprandi G, Cirillo I, Pistorio A, et al. Impact of allergic rhinitis on asthma: Effects on bronchodilation testing. Ann Allergy Asthma Immunol 101:42–46, 2008. Ciprandi G, Capasso M, and Tosca MA. Early bronchial involvement in children with allergic rhinitis. Am J Rhinol Allergy 25:e30–e33, 2011. Ciprandi G, Signori A, and Cirillo I. Relationship between bronchial hyperreactivity and bronchodilation in patients with allergic rhinitis. Ann Allergy Asthma Immunol 106:460–466, 2011. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Togias A. Mechanisms of nose-lung interaction. Allergy 54:95–105, 1999. Bonay M, Neukirch C, Grandsaigne M, et al. Changes in airway inflammation following nasal allergic challenge in patients with seasonal rhinitis. Allergy 61:111–118, 2006. Braunstahl GJ, Overbeek SE, Kleinjan A, et al. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 107:469– 476, 2001. Braunstahl GJ, Kleinjan A, Overbeek SE, et al. Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit Care Med 161:2051–2057, 2000. Gaga M, Lambrou P, Papageorgiou N, et al. Eosinophils are a feature of upper and lower airway pathology in non-atopic asthma, irrespective of the presence of rhinitis. Clin Exp Allergy 30:663–669, 2000. Becky Kelly EA, Busse WW, and Jarjour NN. A comparison of the airway response to segmental antigen bronchoprovocation in atopic asthma and allergic rhinitis. J Allergy Clin Immunol 111:79–86, 2003. Kurt E, Aktas A, Gulbas Z, et al. The effects of natural pollen exposure on inflammatory cytokines and their relationship with nonspecific bronchial hyperresponsiveness in seasonal allergic rhinitis. Allergy Asthma Proc 31:126–131, 2010. Welsh PW, Stricker WE, Chu CP, et al. Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc 62:125–134, 1987. Henriksen JM, and Wenzel A. Effect of an intranasally administered corticosteroid (budesonide) on nasal obstruction, mouth breathing, and asthma. Am Rev Respir Dis 140:1014–1018, 1984. Corren J, Adinoff AD, Buchmeier AD, and Irvin CG. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol 90:250–256, 1992. Aubier M, Levy J, Clerici C, et al. Different effects of nasal and bronchial glucocorticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis. Am Rev Respir Dis 146:122–126, 1992. Dahl R, Nielsen LP, Kips J, et al. Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma. Allergy 60:875– 881, 2005. Grant JA, Nicodemus CF, Findlay SR, et al. Cetirizine in patients with seasonal rhinitis and concomitant asthma: Prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 95:923–932, 1995. Spector SL, Nicodemus CF, Corren J, et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J Allergy Clin Immunol 96:174–181, 1995. American Journal of Rhinology & Allergy 36. Aubier M, Neukirch C, Peiffer C, and Melac M. Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma. Allergy 56:35–42, 2001. 37. Corren J, Harris AG, Aaronson D, et al. Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and asthma. J Allergy Clin Immunol 100:781–788, 1997. 38. Crystal-Peters J, Neslusan C, Crown WH, and Torres A. Treating allergic rhinitis in patients with comorbid asthma: The risk of asthma-related hospitalizations and emergency department visits. J Allergy Clin Immunol 109:57–62, 2002. 39. Corren J, Manning BE, Thompson SF, et al. Rhinitis therapy and the prevention of hospital care for asthma: A case-control study. J Allergy Clin Immunol 113:415–419, 2004. 40. Furukawa CT. The role of allergy in sinusitis in children. J Allergy Clin Immunol 90:515–517, 1992. 41. Iwens P, and Clement PA. Sinusitis in allergic patients. Rhinology 32:65–67, 1994. 42. Lin DC, Chandra RK, Tan BK, et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy 25:205–208, 2011. 43. Berrettini S, Carabelli A, Sellari-Franceshini S, et al. Perennial allergic rhinitis and chronic sinusitis: Correlation with rhinologic risk factors. Allergy 54:242–248, 1999. 44. Baroody FM, Mucha SM, Detineo M, and Naclerio RM. Nasal challenge with allergen leads to maxillary sinus inflammation. J Allergy Clin Immunol 121:1126–1132, 2008. 45. Pelikan Z, and Pelikan-Filipek M. Role of nasal allergy in chronic maxillary sinusitis—Diagnostic value of nasal challenge with allergen. J Allergy Clin Immunol 86:484–491, 1990. 46. Hamilos DL, Leung DY, Wood R, et al. Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis. J Allergy Clin Immunol 96:537–544, 1995. 47. Hutcheson PS, Schubert MS, and Slavin RG. Distinctions between allergic fungal rhinosinusitis and chronic rhinosinusitis. Am J Rhinol Allergy 24:405–408, 2010. 48. Settipane GA. Epidemiology of nasal polyps. Allergy Asthma Proc 17:231–236, 1996. 49. Settipane GA, and Chafee FH. Nasal polyps in asthma and rhinitis: A review of 6,037 patients. J Allergy Clin Immunol 59:17–21, 1977. 50. Bernstein JM, Allen C, Rich G, et al. Further observations on the role of Staphylococcus auerus exotoxins and IgE in the pathogenesis of nasal polyposis. Laryngoscope 121:647–655, 2011. 51. Slavin RG. The upper and lower airways: The epidemiological and pathophysiological connection. Allergy Asthma Proc 29:553–556, 2008. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S85 Immunomodulation of allergic sinonasal disease Russell A. Settipane, M.D.,1 Anju T. Peters, M.D.,2 and Larry Borish, M.D.3 ABSTRACT IgE hypersensitivity is important to the pathogenesis of allergic diseases and the development and persistence of airway inflammation. Allergic immunomodulation encompasses various therapies that attempt to suppress or modify the immune mechanisms responsible for IgE-mediated disease. These include allergy immunotherapy (AIT) in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), as well as the emergence of biological agents, such as anti-IgE, for allergic respiratory disease. Clinical evidence strongly supports the efficacy and safety of AIT for the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, but for chronic rhinosinusitis evidence is lacking. In allergic rhinitis, the decision to initiate AIT depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, the adverse effects of medication, the severity and duration of symptoms, and their effect on quality of life. AIT has the potential to produce sustained long-lasting immune modulation and possibly avoid or reduce lifelong requirements for medical therapy. Although SLIT is currently being evaluated, SCIT remains the preferred form of AIT in the United States because of robust efficacy data, availability of allergen extracts, and current Food and Drug Administration approval. However, SLIT holds the potential for greater patient safety and convenience. Other immunomodulators such as anti-IgE also hold promise, but require further investigation. A llergic immunomodulation encompasses various third-line therapies that attempt to suppress or modify the immune mechanisms responsible for IgE-mediated disease. These include allergy immunotherapy (AIT) in the forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), as well as the emergence of biological agents for upper and lower airway disease such as anti-IgE.1–3 AIT is defined as the repeated administration of relevant allergens4 to patients with IgE-mediated conditions for the purpose of providing protection against allergic symptoms and inflammatory reactions associated with the natural exposure to the these allergens.1 In this article, SCIT, SLIT, and anti-IgE are briefly reviewed; however, for a more in-depth discussion regarding AIT, the reader is referred to recently published practice parameters relating to rhinitis5 and AIT1 as well as a recent AIT consensus report.6 SUBCUTANEOUS IMMUNOTHERAPY SCIT: Description and Indications SCIT, commonly referred to as “allergy shots,” is the oldest form of AIT, dating back over 100 years, where allergen is administered subcutaneously for the purpose of inducing allergen-specific immune tolerance.7 In allergic rhinitis,8 SCIT may be considered if symptoms are not controlled by allergen avoidance and pharmacotherapy or if the patient prefers not to take medications or has medication-induced adverse effects. In addition, SCIT may be considered if the patient desires to avoid or reduce the need for long-term pharmacotherapy.1 However, before SCIT can be considered, it is imperative that the From the 1Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, 2Division of Allergy-Immunology, Northwestern University, Chicago, Illinois, and 3Department of Medicine, Asthma and Allergic Disease Center, Carter Immunology Center, University of Virginia Health System, Charlottesville, Virginia RA Settipane received a research grant from Genentech (clinical trial). AT Peters is a speaker for Baxter. L Borish is funded by NIH RO1 AI057483 and UO1 AI100799 Address correspondence and reprint requests to Russell A. Settipane, M.D., Allergy & Asthma Center, 95 Pitman Street, Providence, RI 02906 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, S59 –S62, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S86 patient has evidence of sensitization to relevant aeroallergens on either skin9 or in vitro10 testing in the context of a compatible clinical history.11 It is not appropriate to recommend AIT based solely on results of skin testing or in vitro–specific IgE tests, without appropriate clinical correlation.1 With regard to chronic rhinosinusitis (CRS) and nasal polyps12,13 the role of an allergic contribution is uncertain.14 Guideline recommendations for the use of SCIT in CRS are assigned the lowest strength, level D, because of limited evidence.15 There are no randomized prospective studies on SCIT in CRS; one retrospective study indicated that immunotherapy may decrease the use of antibiotics and improve sinonasal symptoms in patients with recurrent rhinosinusitis.16 Unfortunately, this study was limited not only by its retrospective nature, but also by the absence of objective assessment of sinusitis severity. However, based on a recent report of SCIT efficacy in mixed rhinitis,17 an argument can perhaps be made for a trial of SCIT in select patients with coexisting CRS and allergic rhinitis. SCIT: Mechanism The immunologic response to SCIT is characterized by decreased sensitivity of end organs and changes in the humoral and cellular responses to the administered allergens. A number of possible mechanisms for the beneficial effects of immunotherapy have been suggested. Key to this process is the induction of a T-cell–tolerant state.6 Allergen-specific peripheral T-cell tolerance mediated by IL-10 and transforming growth factor  causes deviation toward a regulatory T (Treg) cell response, which leads to a normal, healthy immune response to mucosal antigens. In addition to mediating T-cell tolerance, IL-10 regulates specific antibody isotype formation and skews the specific response from an IgE- to an IgG4-dominated phenotype. Treg cells acting through their production of IL-10 suppress both total and allergen-specific IgE and simultaneously increase IgG4 production. Observed immunologic changes (Table 1)18–20 in response to SCIT include the modulation of T- and B-cell responses by the generation of allergen-specific Treg cells; increases in allergen-specific IgG4, and IgA; decrease in IgE; and decreased tissue infiltration of mast cells and eosinophils. Additionally, successful SCIT is associated with a change toward a nonallergic Th1 cytokine profile (Th1 skewing), which occurs within the constraints of a high IL-10 milieu, allowing the associated interferon ␥ responses to ameliorate allergic inflamma- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 Immunologic changes associated with SCIT Antibody changes Increase in allergen-specific IgG (specifically IgG4) Early increase and late decrease in serum allergen-specific IgE Decrease in seasonal rise of allergen-specific IgE Cellular changes Decreased mediator release from mast cells, basophils, and eosinophils Reduction of tissue mast cells and eosinophils Induction of regulatory T cells and suppression of Th2 ⬎ Th1 cells Increased secretion of IL-10 and TGF- Decrease in histamine-releasing factors Source: Adapted from Refs. 15–17. SCIT ⫽ subcutaneous immunotherapy; TGF ⫽ transforming growth factor. tion without producing the associated proinflammatory influences of the interferon.21 SCIT: Efficacy and Safety in Allergic Rhinitis Clinical research has been robust with multiple double-blind, placebo-controlled, randomized clinical trials and meta-analyses indicating SCIT to be effective in a dose-dependent manner for the nasal and ocular symptoms of allergic rhinitis.1,22 Additionally, SCIT acts as a long-lasting disease modifier of allergic rhinitis altering the natural history of the disease, having been shown to result in sustained benefit after discontinuation. Double-blind, placebo-controlled trials have shown that 3–4 years of grass pollen AIT remains effective for at least 3 years and up to 12 years after the discontinuation of the injections.6,23 In children SCIT has been shown to prevent the development of new sensitizations and possibly to prevent new onset asthma.1 SCIT-associated anaphylactic fatalities are rare (1 in 2.5 million injections) with ⬃3.4 fatal reactions annually in the United States.24 Large local reactions at the site of the injection are much more common, occurring in ⬃9% of injection visits.25 An important area of clinical research is the relationship between large local reactions and systemic reactions. Unfortunately, evidence regarding the risk of systemic anaphylaxis in patients with local reactions is limited to retrospective studies, which are somewhat contradictory25,26; however, it appears that large local reactions do not predict the occurrence of a systemic anaphylactic reaction in the subsequent dose and that dose adjustments based on local reactions do not appear to prevent systemic reactions. Given the risk of anaphylaxis, SCIT should be administered only in a setting where the prompt recognition and treatment of anaphylaxis (with epinephrine) is available,27–30 the preferred location being in the medical facility of the physician who prepared the patient’s AIT extract. Patients should remain in the supervised medical facility and be monitored for at least 30 minutes postinjection.1 Some experts advocate for prescribing automatic injectable epinephrine to all SCIT patients to address the rare occurrences of anaphylaxis beyond the 30-minute wait time.30 Risk factors for severe SCIT reactions include symptomatic asthma, concomitant use of -adrenergic blockers, and administration of injections during the height of the pollen season.1 Patients with asthma must be assessed for degree of control before the administration of each SCIT injection. schedule interval is slowly increased to a range of every 2–4 weeks. Based on studies that show long-lasting disease modification and sustained benefit after SCIT is discontinued, AIT guidelines recommend 3–5 years duration of treatment. It is the persistence of benefit and apparent alteration of the natural history of allergic rhinitis that underlies SCIT’s cost savings in comparison with standard pharmacotherapies.31,32 Studies comparing cost-effectiveness between patients treated for 3 years with SCIT versus those treated with pharmacotherapy alone have indicated a potential cost savings as high as 80% with SCIT.32 Despite these benefits, adhering to a 3- to 6-month long weekly build-up schedule can be challenging for patients. This has led to investigations with ultrashort (4 dose) courses33 and accelerated schedules (referred to as “cluster” or “rush” schedules)1; however, the advantage of convenience associated with accelerated schedules is partially negated by higher rates of systemic allergic reactions that range from 14.7 to 38% in premedicated subjects (corticosteroids/ antihistamines).1,34 SUBLINGUAL IMMUNOTHERAPY SLIT: Description and Mechanism SLIT refers to sublingual application of allergen for the purpose of inducing allergen-specific tolerance. This form of AIT has the potential to be more convenient and safer than SCIT. Although considered experimental in the United States, SLIT is widely used in Europe, and variations of SLIT are currently being used by some U.S. practitioners.1 The precise mechanisms by which SLIT works remain unclear, but similar to SCIT, it likely includes promoting modified Th1 and Treg activity.35 SLIT: Efficacy and Safety Clinical trials now underway in the United States have demonstrated efficacy in adults and children but are limited to the study of single allergen preparations such as grass or ragweed pollen.36,37 A 2010 meta-analysis of SLIT revealed significant symptom improvement with SLIT for both seasonal and perennial allergic rhinitis.38 Similar to SCIT, SLIT appears to result in sustained long-lasting therapeutic benefits. In the patients receiving SLIT for at least 3 years, the clinical benefit persisted for at least 7 years and there were 75% less new sensitizations in SLIT-treated patients compared with controls.39 A 2013 systemic review of 63 studies with 5131 participants concluded that the available data provides a moderate grade level of evidence to support the effectiveness of sublingual immunotherapy for the treatment of allergic rhinitis, but high-quality studies are still needed to answer questions regarding optimal dosing strategies.40 A 2012 meta-analysis of studies comparing SCIT versus SLIT in patients with seasonal allergic rhinoconjunctivitis to grass pollen provides solid evidence that although SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications, this higher efficacy occurs at the expense of a substantially greater anaphylaxis rate with SCIT.41 Although SLIT appears to have a more favorable safety profile, local reactions (oral pruritus and edema) are common, occurring in 40% of patients; and anaphylaxis, although rare, has been reported.1 Several barriers exist for the implementation of SLIT, the foremost being availability. No reagents are currently available in the United States; and only a few single allergen preparations are in development, making this an unrealistic option for polysensitized (i.e. most) allergic rhinits patients. MONOCLONAL ANTI-IgE SCIT: Administration Schedules Monoclonal Anti-IgE: Description SCIT is usually initiated with injections administered one to three times weekly starting at a low dose unlikely to cause anaphylaxis. After 3–6 months the maintenance phase begins, and the injection The sole Food and Drug Administration (FDA)–approved anti-IgE therapy in the United States is omalizumab, which is a recombinant humanized monoclonal anti-IgE antibody. Omalizumab is FDA ap- American Journal of Rhinology & Allergy Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S87 proved only for adults and adolescents (aged ⱖ12 years) with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen, and whose symptoms are inadequately controlled with inhaled corticosteroids.42 Monoclonal Anti-IgE: Mechanism By selectively targeting and binding to circulating IgE, omalizumab therapy results in a reduction of IgE binding to receptors on mast cells, basophils, and dendritic cells43,44 and a down-regulation of their expression of cell surface IgE receptors. This ultimately leads to a decrease in the release of mediators in response to allergen exposure. The end result is a reduction of both the acute (early phase) allergic response and the subsequent (late-phase response) inflammatory and physiological consequences.45 • SLIT, although not currently approved for use in the United States, has been shown to be more effective than placebo; and available data suggest that SLIT is safer than SCIT. REFERENCES 1. 2. 3. 4. 5. Monoclonal Anti-IgE: Efficacy and Safety Clinical data for the use of omalizumab in asthma have been robust, preliminary trials performed in patients with upper respiratory diseases have also demonstrated efficacy in patients with seasonal and perennial allergic rhinitis.46–49 Omalizumab has been shown to be an effective adjunct to SCIT.50 Adding omalizumab to SCIT improves its safety and tolerability during build-up, the likelihood of the patient reaching the maintenance phase, and the therapy’s overall effectiveness.6 Finally, anti-IgE for CRS with nasal polyps holds promise, but the two trials reported thus far have not demonstrated the same degree of benefit.3,51 Safety concerns with omalizumab include anaphylaxis, which has resulted in the FDA issuing a black box warning. This anaphylaxis can be associated with a protracted course and delayed onset of symptoms even 12–24 hours after an injection.52,53 Retrospective evaluation of omalizumab-associated anaphylaxis cases has not identified potential risk factors to identify patients at risk.53 In addition, initial clinical trials suggested a higher rate of malignancy associated with omalizumab; however, a recent pooled analysis of a larger number of patients does not show a causal link between omalizumab and malignancy.54 Further investigation is necessary to define efficacy, safety, and cost-effectiveness in upper respiratory disease states. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. SUMMARY 16. IgE hypersensitivity is important to the pathogenesis of allergic diseases and the development and persistence of airway inflammation. Clinical evidence strongly supports the efficacy and safety of SCIT for the treatment of allergic respiratory diseases including allergic rhinitis, allergic conjunctivitis, and allergic asthma, but for CRS evidence is lacking. Although not quite as robust, efficacy and safety data for SLIT in allergic rhinitis and asthma is growing. AIT should be considered in allergic rhinitis patients who experience poor symptom control or adverse effects resulting from medications. SCIT remains the preferred form of AIT in the United States because of robust efficacy data, availability of allergen extracts, and current FDA approval. However, SLIT holds the potential for greater patient safety and convenience. Other immunomodulators such as anti-IgE also hold promise, but require further investigation. 17. 18. 19. 20. 21. CLINICAL PEARLS • With regard to respiratory allergy, specific AIT is indicated for the treatment of seasonal and perennial allergic rhinitis, but not for CRS. • Most systemic reactions to SCIT usually occur within 30 minutes of treatment. Therefore, patients should wait in a medical facility for a full 30 minutes after a SCIT injection. • Asthma control must be assessed before each SCIT injection in patients who also have asthma. AIT injections are contraindicated in poorly controlled asthma. S88 22. 23. 24. 25. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: A practice parameter third update. J Allergy Clin Immunol 127(suppl): S1–S55, 2011. Wise SK, and Schlosser RJ. Subcutaneous and sublingual immunotherapy for allergic rhinitis: What is the evidence? Am J Rhinol Allergy 26:18–22, 2012. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 131:110–116.e1, 2013. Shah R, and Grammer LC. An overview of allergens. Allergy Asthma Proc 33(suppl 1):S2–S5, 2012. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin Immunol 122:S1–S84, 2008. Burks AW, Calderon MA, Casale T, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/ European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013 Mar 13 DOI: 10.1016/ j.jaci.2013.01.049. [Epub ahead of print]. Larenas Linnemann DE. One hundred years of immunotherapy: review of the first landmark studies. Allergy Asthma Proc 33:122– 128, 2012. Settipane RA, and Schwindt C. Allergic rhinitis. Am J Rhinol Allergy 27:S52–S55, 2013. Carr TF, and Saltoun CA. Skin testing in allergy. Allergy Asthma Proc 33(Suppl 1):S6–8, 2012. Makhija M, and O’Gorman MR. Common in vitro tests for allergy and immunology. Allergy Asthma Proc 33(Suppl 1):S108–S111, 2012. Settipane RA, Borish L, and Peters AT. Determining the role of allergy in sinonasal disease. Am J Rhinol Allergy 27:S56–S58, 2013. Settipane RA, Peters AT, and Chandra R. Chronic rhinosinusitis. Am J Rhinol Allergy 27:S11–S15, 2013. Settipane RA, Peters AT, and Chiu AG. Nasal polyps. Am J Rhinol Allergy 27:S20–S25, 2013. Kennedy JL, and Borish L. Chronic sinusitis pathophysiology: The role of allergy. Am J Rhinol Allergy DOI: 10.2500/ajra.2013.27.3906 [Epub ahead of print date April 18, 2013]. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl 23:1–298, 2012. Nathan RA, Santilli J, Rockwell W, and Glassheim J. Effective of immunotherapy for recurring sinusitis associated with allergic rhinitis as assessed by Sinusitis Outcomes Questionnaire. Ann Allergy Asthma Immunol 92:668–672, 2004. Smith AM, Rezvani M, and Bernstein JA. Is response to allergen immunotherapy a good phenotypic marker for differentiating between allergic rhinitis and mixed rhinitis? Allergy Asthma Proc 32:49–54, 2011. Frew A. Allergen immunotherapy. J Allergy Clin Immunol 125:S306– S313, 2010. Grammer LC, and Harris KE. Principles of immunologic management of allergic diseases due to extrinsic antigens. In Patterson’s Allergic Diseases, 7th ed. Grammer LC, and Greenberger PA (Eds). Philadelphia, PA: Lippincott, Williams & Wilkins, 187–196, 2009. Georgy MS, and Saltoun CA. Allergen immunotherapy: Definition, indication, and reactions. Allergy Asthma Proc 33(suppl 1):S9–S11, 2012. Akdis M, and Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 119:780–791, 2007. Calderon MA, Penagos M, Sheikh A, et al. Sublingual immunotherapy for allergic conjunctivitis: Cochrane systematic review and metaanalysis. Clin Exp Allergy 41:1263–1272, 2011. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 341:468–475, 1999. Bernstein DI, Wanner M, Borish L, et al. Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology. Twelveyear survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol 113:1129–1136, 2004. Calabria CW, Stolfi A, and Tankersley MS. The REPEAT study: Recognizing and evaluation periodic local reactions in allergen im- May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. munotherapy and associated systemic reactions. Ann Allergy Asthma Immunol 106:49, 2011. Roy SR, Sigmon JR, Olivier J, et al. Increased frequency of large local reactions among systemic reactors during subcutaneous allergen immunotherapy. Ann Allergy Asthma Immunol 99:82–86, 2007. Greenberger PA, and Ditto AM. Anaphylaxis. Allergy Asthma Proc 33(suppl 1):S80–S83, 2012. Lieberman P. The risk and management of anaphylaxis in the setting of immunotherapy. Am J Rhinol Allergy 26:469–474, 2012. Phillips JF, Lockey RF, Fox RW, et al. Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine. Allergy Asthma Proc 32:288–294, 2011. Wallace DV. Anaphylaxis in the allergist’s office: Preparing your office and staff for medical emergencies. Allergy Asthma Proc 34: 120–131, 2013. Hankin CS, Cox L, and Bronstone A. The health economics of allergen immunotherapy. Immunol Allergy Clin North Am 31:325–341, 2011. Hankin CS, Cox L, Bronstone A, et al. AIT: Reduced health care costs in adults and children with allergic rhinitis. J Allergy Clin Immunol 131:1084–1091, 2013. DuBuske LM, Frew AJ, Horak F, et al. Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 32:239–247, 2011. Cox L. Accelerated immunotherapy schedules: Review of efficacy and safety. Ann Allergy Asthma Immunol 97:126–137, 2006. Guida G, Boita M, Scirelli T, et al. Innate and lymphocytic response of birch-allergic patients before and after sublingual immunotherapy. Allergy Asthma Proc 33:411–415, 2012. Nayak AS, Atiee GJ, Dige E, et al. Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis. Allergy Asthma Proc 33:404–410, 2012. Blaiss M, Maloney J, Nolte H, et al. Efficacy and safety of timothy grass AIT tablets in North American children and adolescents. J Allergy Clin Immunol 127:64–71, 71.e1–4, 2011. Radulovic S, Wilson D, Calderon M, and Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 66:740–752, 2011. Marogna M, Spadolini I, Massolo A, et al. Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study. J Allergy Clin Immunol 126:969–975, 2010. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: A systematic review. JAMA 309:1278–1288, 2013. Di Bona D, Plaia A, Leto-Barone MS, et al. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal American Journal of Rhinology & Allergy allergic rhinitis: A meta-analysis-based comparison. J Allergy Clin Immunol 130:1097–1107.e2, 2012. 42. Genentech, Inc. XOLAIR prescribing information. South San Francisco, CA; 2007. Last revision July, 2010. 43. Soresi S, and Togias A. Mechanisms of action of anti-immunoglobulin E therapy. Allergy Asthma Proc 27:S15–S23, 2006. 44. Prussin C, Griffith D, Boesel K, et al. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 112:1147–1154, 2003. 45. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 155:1828–1834, 1997. 46. Adelroth E, Rak S, Haahtela T, et al. Recombinant humanized mAbE25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 106:253–259, 2000. 47. Nayak A, Casale T, Miller SD, et al. Tolerability of retreatment with omalizumab, a recombinant humanized monoclonal anti-IgE antibody, during a second ragweed pollen season in patients with seasonal allergic rhinitis. Allergy Asthma Proc 24:323–329, 2003. 48. Chervinsky P, Casale T, Townley R, et al. Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis. Ann Allergy Asthma Immunol 91:160–167, 2003. 49. Berger WE. Treatment of allergic rhinitis and other immunoglobulin E-mediated diseases with anti-immunoglobulin E antibody. Allergy Asthma Proc 27:S29–S32, 2006. 50. Kuehr J, Brauburger J, Zielen S, et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol 109:274–280, 2002. 51. Pinto JM, Mehta N, DiTineo M, et al. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology 48:318–324, 2010. 52. Cox L, Lieberman P, Wallace D, et al. American Academy of Allergy Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report. J Allergy Clin Immunol 128:210–212, 2011. 53. Limb SL, Starke PR, Lee CE and Chowdhury BA. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol 120:1378–1381, 2007. 54. Busse W, Buhl R, Vidaurre CF, et al. Omalizumab and the risk of malignancy: Results from a pooled analysis. J Allergy Clin Immunol 128:983–989, 2012. e Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S89 Subcutaneous and sublingual immunotherapy for allergic rhinitis: What is the evidence? Sarah K. Wise, M.D.,1 and Rodney J. Schlosser, M.D.2 ABSTRACT Background: Increasing interest in sublingual immunotherapy (SLIT) among practitioners and patients has resulted in numerous publications and clinical trials in recent years. With the clinical growth of SLIT, discussions of its efficacy, safety, and immunologic effects have intensified, as have comparisons to subcutaneous immunotherapy (SCIT). In the United States, SCIT has been the traditional form of immunotherapy for inhalant allergy and is the only immunotherapy method approved by the U.S. Food and Drug Administration at this time. The similarities and differences between SLIT and SCIT are often discussed, yet clinical studies directly comparing these immunotherapy methods are scarce. Methods: A literature review of specific issues and controversies between SLIT and SCIT for allergic rhinitis was conducted. Results: Safety, efficacy, and immunologic effects of these two immunotherapy techniques are reviewed. Conclusion: Unanswered questions relating to SLIT are examined. A ccording to the 2009 National Health Interview Survey, 7.8% of adults and 9.8% of children in the United States had been diagnosed with hay fever in the preceding 12 months.1,2 There were 13.1 ambulatory care visits for allergic rhinitis in 2006.3 Based on these few figures, the public health impact of allergic rhinitis is evident. Although many allergic rhinitis patients have been successfully treated with environmental control measures, pharmacotherapy, and subcutaneous immunotherapy (SCIT), interest in sublingual immunotherapy (SLIT) has grown considerably in recent years. A search of published literature under the topic “sublingual immunotherapy” revealed 21 citations in English in 1999; this has grown to 737 English citations in a 2011 search of the PubMed database (www.ncbi.nlm. nih.gov/pubmed). At the time of this article preparation, there were 57 clinical SLIT trials listed at www.clinicaltrials.gov. Twelve of these trials are registered in the United States and 32 are registered in Europe. With the rapidly growing interest in SLIT for allergic rhinitis, comparisons with traditional SCIT have markedly increased. In this brief review of SLIT and SCIT, we will highlight specific similarities, differences, and controversies of these two immunotherapy techniques. Recent findings relating to safety, efficacy, future research needs, and unanswered questions regarding SLIT and SCIT will be discussed (Table 1). IMMUNOTHERAPY SAFETY Systemic reactions and anaphylaxis are noted complications of immunotherapy. In a 2007 Cochrane meta-analysis of SCIT for seaFrom the 1Department of Otolaryngology–Head and Neck Surgery, Emory University, Atlanta, Georgia, and 2Ralph H. Johnson Veterans Affairs Medical Center and, Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina Presented at the North American Rhinology & Allergy Conference, February 5, 2011, Puerto Rico The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Rodney J. Schlosser, M.D., Department of Otolaryngology–Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Avenue, MSC 550, Charleston, SC 29425 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, 18 –22, 2012 Copyright © 2014, OceanSide Publications, Inc., U.S.A. S90 sonal allergic rhinitis, which included 51 randomized placebo-controlled trials, epinephrine was given for adverse reactions in 0.13% of participants on active treatment (19 of 14,085 injections).4 No fatalities were reported in this meta-analysis. Fatal reactions from SCIT in clinical practice are reported at a rate of 1 in 2–2.5 million injections, resulting in 3.4 deaths/year.5,6 Potential contributors to fatal SCIT reactions include delay in epinephrine administration, previous immunotherapy reactions, suboptimal asthma control, administration of injections during peak allergy season, and alterations in antigen extracts.6 In addition to fatal SCIT reactions, there is a systemic reaction rate of 0.05–3.2% of injections (0.84–46.7% of patients) per year and a near-fatal reaction rate of 23 per year (5.4 per 1 million injections).6–9 Serious systemic and fatal reactions due to SCIT are relatively rare. However, the potential for a fatal systemic reaction caused by treatment for a nonfatal condition such as allergic rhinitis gives many practitioners pause. The potential for fatal systemic reactions from SCIT was highlighted in the 1986 report of the British Committee on the Safety of Medicines.10 Based on 26 anaphylaxis-related deaths in this report, the safety of SCIT was questioned and strict criteria for SCIT administration in the United Kingdom were initiated. These new regulations included a postinjection observation period of 2 hours and the requirement that injections be given in a facility with full CPR capabilities. Subsequently, interest increased in noninjection routes of immunotherapy administration, including oral (swallow), sublingual, bronchial, and intranasal. Of these, sublingual administration was the most promising with regard to its clinical efficacy, tolerability, and safety. The safety profile of SLIT is one of the least controversial aspects in its overall comparison with SCIT. Before 2006, there were no literature reports of anaphylaxis due to SLIT. Between 2006 and 2009, there were six published cases of anaphylaxis or possible anaphylaxis related to SLIT.11–15 Certain factors have been hypothesized as contributors to SLIT anaphylaxis, including rush escalation or no escalation, use of latex antigen, multiple antigen therapy, treatment during peak pollen season, previous intolerance to SCIT, and noncompliance with treatment regimens. In the 2010 Cochrane systematic review of SLIT for allergic rhinitis, Radulovic et al. report that there were no cases of anaphylaxis and no requirement for the use of adrenaline in 60 randomized, placebocontrolled trials.16 This Cochrane review did note mild-to-moderate systemic reactions in both treatment and placebo groups. Treatment May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 Highlights of SCIT and SLIT for allergic rhinitis Safety Efficacy Single vs multiantigen therapy Dosing Fatal reactions from SCIT occur at a rate of 1 in 2–2.5 million injections, resulting in 3.4 deaths/yr Between 2006 and 2009, there were six published cases of possible or confirmed anaphylaxis during SLIT; no fatalities have been reported with SLIT Any patient undergoing immunotherapy should be educated on the potential risk of anaphylaxis and the proper use of emergency epinephrine injectors A 2007 Cochrane review of SCIT for seasonal allergic rhinitis showed significantly decreased symptom scores and medication use In 2010, a Cochrane review of SLIT for allergic rhinitis noted significant symptom reduction overall, and for multiple subgroups (i.e., seasonal and perennial antigens, adults and children, and short and long duration of therapy); medication scores were also significantly decreased Large-scale controlled studies directly comparing SCIT and SLIT are lacking The efficacy of multiantigen SCIT and SLIT remains controversial; well-designed, controlled studies of multiantigen SCIT and SLIT are needed The optimum SCIT maintenance dose for most antigens is 5–20 g of major allergen Optimum SLIT dosing has not been fully elucidated, although the median monthly SLIT maintenance dose is 49 times the monthly SCIT maintenance dose SCIT ⫽ subcutaneous immunotherapy; SLIT ⫽ sublingual immunotherapy. discontinuation was attributed to adverse events in 41 of 824 SLIT participants and 12 of 861 placebo participants; this included both local and systemic reactions, although discontinuation for local reactions was more common. Because SLIT is a potentially attractive option for the treatment of respiratory allergy in children, it is also important to evaluate adverse events in this patient group. Two meta-analyses have been dedicated to SLIT in the pediatric population. In 2006, Penagos et al. noted no severe systemic or lethal events in a meta-analysis of 10 SLIT trials for allergic rhinitis in children, although 1 of the included studies reported 3 patients with severe asthma attributed to SLIT overdose.17 Similarly, a 2008 meta-analysis of SLIT for allergic asthma in children reported no fatal or severe systemic reactions in nine included studies.18 In a postmarketing survey of single and multiple antigen SLIT in 433 children receiving 40,169 SLIT doses, 13 events were judged to be of moderate severity and required medical advice.19 There was no emergency treatment required, and no difference was seen in adverse events between single and multiple antigen regimens. SLIT has also been reported safe in children ⱕ5 years of age.20,21 Although the safety profile of SLIT is often quoted as being superior to SCIT, the practitioner must remain aware of the risks of immunotherapy in general. Regardless of the route of immunotherapy selected, patients should be educated on expected side effects versus worrisome systemic reactions. SCIT doses are routinely given in the physician’s office, especially during escalation. It has also been suggested that the first dose of SLIT be given in the physician’s office; after this, SLIT doses are routinely administered at home. Because the risk of anaphylaxis exists for both SCIT and SLIT, many also advocate that any patient receiving immunotherapy should carry an emergency epinephrine injector and be fully educated on its appropriate use. IMMUNOTHERAPY EFFICACY The efficacy of SLIT for allergic rhinitis, when compared with SCIT, incites greater controversy. A Cochrane systematic review of injection immunotherapy for seasonal allergic rhinitis was published in 2007 by Calderon et al.4 This meta-analysis included 51 double-blind, placebo-controlled, randomized trials of specific immunotherapy for seasonal allergic rhinitis to tree, grass, or weed pollens. Fifteen trials were assessed for standard mean difference (SMD) of symptom scores and showed a significant reduction of symptoms in the immunotherapy group (SMD, ⫺0.73; 95% CI, ⫺0.97 to ⫺0.50; p ⬍ 0.00001). Data from 13 trials showed significant medication reduction in the immunotherapy group (SMD, ⫺0.57; 95% CI, ⫺0.82 to ⫺0.33; p ⬍ 0.00001). Demonstration of increased SCIT efficacy in symptom control has American Journal of Rhinology & Allergy also been shown for longer durations of maintenance therapy (up to 3 years), although the increased efficacy evidence from this study is weak versus SCIT therapy duration of 1 year.22 Recent large meta-analyses of SCIT efficacy for perennial allergic rhinitis have not been performed. In a 2011 Cochrane systematic review of 88 randomized controlled SCIT trials for allergic asthma, however, therapy with mite antigen was shown to have a marginal benefit in asthma symptoms (SMD, ⫺0.48; 95% CI, ⫺0.96–0.00).23 SCIT for cat and dog allergens did not show improvement in asthma symptoms in this meta-analysis. In contrast, objective measures of bronchial hyperreactivity improved with SCIT in this Cochrane review for mite immunotherapy (SMD, ⫺0.98; 95% CI, ⫺1.39 to ⫺0.58), pollen (SMD, ⫺0.55; 95% CI, ⫺0.84 to ⫺0.27), and animal dander (SMD, ⫺0.61; 95% CI, ⫺0.95 to ⫺0.27).23 Bronchial hyperreactivity was not significantly improved with SCIT for other allergens. As clinical interest in SLIT has grown over the last 10 years, large randomized controlled trials and meta-analyses have been reported with increasing frequency. The first randomized clinical trial of lowdose SLIT with dust-mite antigen included 20 patients and was reported in 1986 by Scadding and Brostoff.24 Multiple large-scale randomized, double-blind, placebo-controlled SLIT efficacy trials have been published in the last 5 years, beginning with the 2006 studies of Durham et al.25 and Dahl et al.26 Both the Durham (855 patients randomized) and Dahl (634 patients randomized) studies were multicenter multinational trials of pre- and coseasonal administration of Timothy grass tablets in patients with symptomatic seasonal allergic rhinitis, and both showed statistically significant reduction is allergic rhinitis symptoms and medication use versus placebo groups.25,26 The most recent meta-analysis of SLIT for allergic rhinitis was published in 2010 by Radulovic et al.16 For symptom assessment, 49 randomized placebo-controlled trials were included with 2333 total participants receiving SLIT and 2256 receiving placebo. The SMD for symptom scores favored SLIT at ⫺0.49 (95% CI, ⫺0.64 to ⫺0.34; ⬍0.00001). Subgroup analysis revealed significant symptom improvement with SLIT for seasonal and perennial allergens, adults and children, treatment durations ranging from ⬍6 months to ⬎12 months, and major allergen content of 5–20 g and ⬎20 g. With regard to individual antigens, there was significant symptom improvement for house-dust mites, grass pollen, ragweed, Parietaria, and trees. Medication scores were assessed in 38 studies and revealed an SMD of ⫺0.32 (95% CI, ⫺0.43 to ⫺0.21; p ⬍ 0.00001). A metaanalysis of SLIT for allergic rhinitis in pediatric patients was published in 2006 by Penagos et al.17 Ten pediatric studies, including 484 patients, were evaluated and revealed significant reduction in symptoms (SMD, ⫺0.56; 95% CI, 1.01–0.10; p ⫽ 0.02) and medication use Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S91 Table 2 SLIT vs SCIT comparison studies Author Year Allergen Study Design Quirino et al.35 1996 Grass pollen Double-blind, double-dummy Mungan et al.32 1999 Dust mite Single-blind, placebo controlled No. of Patients SCIT (n ⫽ 10) SLIT (n ⫽ 10) No placebo group SCIT (n ⫽ 10) SLIT (n ⫽ 15) Placebo (n ⫽ 11) Khinchi et al.34 2004 Birch pollen Randomized, double-blind, double-dummy, placebo-controlled Mauro et al.36 2007 Birch pollen Randomized, double-blind, double-dummy Eifan et al.33 2010 Dust mite Open label, randomized, controlled SCIT (n ⫽ 21) SLIT (n ⫽ 18) Placebo (n ⫽ 19) SCIT (n ⫽ 19) SLIT (n ⫽ 15) SCIT (n ⫽ 16) SLIT (n ⫽ 16) Pharmacotherapy (n ⫽ 16) Study Findings Significant reduction in symptoms and medications for SCIT and SLIT groups 1 Total specific IgG, 1 specific IgG4, and 2 skin reactivity for SCIT only 2 Rhinitis and asthma symptoms with SCIT 2 Rhinitis symptoms with SLIT 2 Skin reactivity with SCIT 1 Specific IgG4 with SCIT Significant reduction in symptoms and medications for SCIT vs placebo and SLIT vs placebo No difference between SCIT and SLIT groups No difference in mean symptom–medication score between SCIT and SLIT 1 Specific IgG4 with SCIT 2 Rhinitis and asthma symptom scores, total medication score, and skin reactivity with SCIT and SLIT 2 Specific IgE with SCIT and SLIT SCIT ⫽ subcutaneous immunotherapy; SLIT ⫽ sublingual immunotherapy. (SMD, ⫺0.76; 95% CI, 1.46–0.06; p ⫽ 0.03) with SLIT. Subgroup analyses indicated that treatment duration of ⬎18 months and SLIT with pollen extracts were beneficial over shorter treatment durations and dust-mite antigens in children. Meta-analyses of SLIT have also been performed with regard to specific antigens. A meta-analysis specific for seasonal grass pollen SLIT treatment was also performed by Di Bona et al.27 This metaanalysis included 19 randomized, placebo-controlled SLIT trials, with 2971 total patients. It was found that grass allergen SLIT significantly reduced symptoms (SMD, ⫺0.32; 95% CI, ⫺0.44 to ⫺0.21) and medication use (SMD, ⫺0.33; 95% CI, ⫺0.50 to ⫺0.16) versus placebo. Similarly, a meta-analysis of SLIT for house-dust mite allergic rhinitis showed significant symptom reduction in 194 active SLIT participants versus 188 placebo participants (SMD, ⫺0.95; 95% CI, ⫺1.77 to ⫺0.14; p ⫽ 0.02).28 Significant medication reduction was also seen with SLIT for house-dust mite allergic rhinitis (SMD, ⫺1.88; 95% CI, ⫺3.65 to ⫺0.12; p ⫽ 0.04). Often-discussed benefits of immunotherapy are the long-lasting and preventative effects that can be seen after treatment. Recent studies have shown such effects with SLIT. In an open, randomized study of 216 children with allergic rhinitis with or without asthma, Marogna et al. showed a decrease in new sensitizations in children receiving SLIT (3.1%) versus controls (34.8%; odds ratio, 16.85; 95% CI, 5.73–49.13).29 In addition, after 3 years, there was a decrease in positive methacholine challenge results in the SLIT group. A largescale (257 patients) double-blind, placebo-controlled trial of SLIT in patients with grass pollen allergy by Durham et al. showed sustained reduction in rhinoconjunctivitis symptoms and medication scores in the SLIT group at the 1-year time point after cessation of a 3-year SLIT program.30 Finally, Marogna et al. have noted that clinical benefit persists for 8 years after SLIT treatment is given for a 4- to 5-year duration; new sensitizations were also reduced in SLIT groups.31 Controlled studies involving both SCIT and SLIT treatment groups for direct comparison are relatively lacking.32–36 A summary of the characteristics of five SCIT versus SLIT comparison studies is shown in Table 2. In 2010, a prospective, randomized, open-label three- S92 parallel-group trial was conducted in 48 children with allergic rhinitis or allergic asthma who were monosensitized to house-dust mites.33 Both SLIT and SCIT showed significant reduction in rhinitis symptom score and medication score, as well as significant reduction of serumspecific dust-mite IgE, compared with pharmacotherapy. A placebocontrolled double-blind double-dummy study in 71 adult patients (all patients received both sublingual medication and subcutaneous injections) was reported by Khinchi et al. in 2004.34 In this study, both SLIT and SCIT showed efficacy versus placebo. There was no statistically significant difference between SLIT and SCIT groups; however, the study was not powered to detect a difference in the immunotherapy groups if one truly existed. Finally, a comparison of the magnitude of effects seen in SLIT and SCIT Cochrane reviews was performed by Cox in 2008, noting that the magnitude of effects seen with SCIT may be larger than that with SLIT.7 Although large clinical studies directly comparing the efficacy of SCIT and SLIT have not been performed, certain patients and practitioners may be willing to accept slightly reduced efficacy of SLIT in the face of a significantly higher safety profile and convenience. In 2009, the World Allergy Organization Position Paper on Sublingual Immunotherapy discussed a number of important points regarding the current status of SLIT efficacy.37 Among these points, although SLIT meta-analyses have shown benefit in the treatment of allergic rhinitis in adults and allergic rhinitis and asthma in children, there are limitations in the overall conclusions of these meta-analyses imposed by the significant heterogeneity of the studies included in them. Second, the efficacy and dose dependence of SLIT for grass pollen allergy in adults and children has been well demonstrated in large, sufficiently powered, double-blind, randomized, controlled trials. UNANSWERED QUESTIONS Single Antigen Therapy versus Multiantigen Therapy One of the biggest sources of discussion in the SCIT versus SCIT debate is the clinical use of single antigens versus multiple antigens in May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm immunotherapy prescriptions. Although most clinical trials of specific immunotherapy (SCIT and SLIT) have tested the effects of only 1 antigen, the average SCIT preparation in the United States includes 10 antigens.38 In the 2010 Cochrane systematic review of SCIT for allergic asthma, only 6 of 88 trials tested multiple antigens.23 In the 2010 Cochrane review of SLIT for allergic rhinitis, only one trial involved multiple antigens.16 Some difficulties in treating with multiple-antigen immunotherapy in a controlled clinical trial setting include identifying potential subjects with a similar multiantigen allergy profile in the absence of other positive reactions, as well as accurately assessing symptoms related to specific allergy triggers when multiple environmental triggers may be present. Although efficacy has been shown with multiantigen SLIT (over single-antigen SLIT and placebo) in some studies,39 a recent multiantigen SLIT study in the United States failed to establish significant differences in symptoms versus single-antigen SLIT or placebo.40 The belief that immunotherapy is more effective in patients who are sensitized to only a single antigen tends to be more prevalent outside the United States, whereas practitioners treating allergy in the United States are more inclined to treat with multiple antigens in an immunotherapy prescription.17,38 It is interesting to note, however, that a recent open study in 51 Italian children with allergic polysensitization found that allergic sensitization to multiple allergens should not be considered a barrier to treatment with SLIT. In this study by Ciprandi et al., treatment groups included single-antigen, dual-antigen, and multiple-antigen therapies, with significant improvements noted in symptoms, medication use, and number of sensitizations after 12 months of therapy.41 The efficacy of multiantigen SLIT requires further clarification, especially in light of the suggestion that multiantigen treatment may have contributed to the few cases of SLIT anaphylaxis.11,13 CONCLUSIONS SCIT has long been an accepted form of treatment for allergic rhinitis, but interest in SLIT has grown considerably in recent years. This has sparked debate regarding the benefits and shortcomings of each of these immunotherapy methods. The safety of SLIT is not routinely questioned, although a few cases of nonfatal anaphylaxis have been reported. Recent meta-analyses of SLIT for allergic rhinitis have shown overall efficacy, as well as efficacy in multiple subgroup analyses. However, questions have been raised regarding the magnitude of SLIT efficacy versus SCIT, and few controlled studies have been performed to directly compare SLIT and SCIT. Many unanswered questions remain regarding SLIT and its comparison with SCIT, including the clinical practice of multiantigen therapy, which is not routinely tested in randomized clinical trials. REFERENCES 1. 2. 3. 4. 5. 6. Optimum Immunotherapy Dosing Although standardization of antigens and regulation of antigen maintenance dose brings about some controversy with regard to SCIT, the recommended optimal maintenance dose for most SCIT published was published in a 1998 World Health Organization Position Paper.42,43 An optimal dose for SCIT has been defined as ‘‘the dose of an allergen vaccine inducing a clinically relevant effect in the majority of patients without causing unacceptable side effects” and is typically 5–20 g of major allergen per dose (50–250 of major allergen per year). A recommended treatment dose for SLIT is less clear. Because of different antigen production and standardization techniques worldwide, translation of clinical trial antigen doses to daily clinical practice may be difficult. At this time, there is no universally accepted SLIT dosing schedule. However, published SLIT doses are notably higher than SCIT doses. Furthermore, maintenance schedules differ between SLIT (typically given daily) and SCIT (typically given monthly). An individual SLIT dose may range from 0.0006 to 21 times an individual SCIT dose, but the median monthly SLIT dose is ⬃49 times higher than the median SCIT dose (range, 0.017 to ⬎500 times higher).44 Many studies have indicated that improvement in clinical response occurs more frequently with moderate-to-high SLIT doses, but the optimal SLIT dose still has not been fully elucidated for most antigens.45–47 A notable exception is the optimal SLIT maintenance dose for grass pollen antigen. Dose-finding studies by Durham et al. and Didier et al. have identified that the most advantageous maintenance dose for SLIT with grass pollen is between 15 and 25 g of major allergen daily.25,45 Finally, because of the safety and tolerability of SLIT, maintenance treatment has often been given preseasonally or coseasonally in clinical trials treating for a single seasonal antigen.25,26 This is in contrast to year-round monthly SCIT maintenance injections. The effect of these seasonal SLIT dosing schedules has not been extensively studied with regard to the potential for recurrence of symptoms long term. American Journal of Rhinology & Allergy 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Pleis J, Ward B, and Lucas J. Summary health statistics for U.S. Adults: National Health Interview Survey 2009. Vital Health Statistics Series 10, No. 249, 2010. Bloom B, Cohen R, and Freeman G. Summary health statistics for U.S. Children: National Health Interview Survey 2009. Vital Health Statistics Series 10, No. 244, 2010. Schappert S, and Rechtsteiner E. Ambulatory medical care utilization estimates for 2006. National Health Statistics Rep 8:1–32, 2008. Calderon M, Alves B, Jacobson M, et al. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Syst Rev 1:CD001936, 2007. Cox L, Larenas-Linneman D, Lockey R, and Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol 125:569–574, 2010. Bernstein D, Wanner M, Borish L, and Liss G. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol 113:1129–1136, 2004. Cox L. Sublingual immunotherapy and allergic rhinitis. Curr Allergy Asthma Rep 8:102–110, 2008. Amin H, Liss G, and Bernstein D. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol 117:169– 175, 2006. Stewart G, and Lockey R. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol 90:567–578, 1992. Committee on the Safety of Medicines update: Desensitizing vaccines. BMJ 293:948, 1986. Dunsky E, Goldstein M, Dvorin D, and Belecanech G. Anaphylaxis to sublingual immunotherapy. Allergy 61:1235, 2006. Antico A, Pagani M, and Crema A. Anaphylaxis by latex sublingual immunotherapy. Allergy 61:1236–1237, 2006. Eifan A, Keles S, Bahceciler N, and Barlan I. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Allergy 62:567–568, 2007. Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Allergy 63:374, 2008. de Groot H, and Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 64:963– 964, 2009. Radulovic S, Calderon M, Wilson D, and Durham S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 12:CD002893, 2010. Penagos M, Compalati E, Tarantini F, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: A meta-analysis of randomized, placebocontrolled, double-blind trials. Ann Allergy Asthma Immunol 97: 141–148, 2006. Penagos M, Passalacqua G, Compalati E, et al. Metaanalysis of the efficacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest 133:599–609, 2008. Agostinis F, Foglia C, Landi M, et al. The safety of sublingual immunotherapy with one or multiple pollen allergens in children. Allergy 63:1637–1639, 2008. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S93 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. S94 di Rienzo V, Minelli M, Musarra A, et al. Post-marketing survey on the safety of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy 35:560–564, 2005. Fiocchi A, Paino G, La Grutta S, et al. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol 95:254–258, 2005. Giovannini M, Braccioni F, Sella G, et al. Comparison of allergen immunotherapy and drug treatment in seasonal rhinoconjunctivitis: A 3-years study. Eur Ann Allergy Clin Immunol 37:69–71, 2005. Abramson M, Puy R, and Weiner J. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 8:CD00118, 20106. Scadding G, and Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy 16:483–491, 1986. Durham S, Yang W, Pedersen M, et al. Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 117: 802–809, 2006. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 118:434–440, 2006. Di Bona D, Plaia A, Scafidi V, et al. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis. J Allergy Clin Immunol 126:558–566, 2010. Compalati E, Passalacqua G, Bonini M, and Canonica G. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: Results of a GA2LEN meta-analysis. Allergy 64:1570–1579, 2009. Marogna M, Thomassetti G, Bernasconi A, et al. Preventative effects of sublingual immunotherapy in childhood: An open randomized controlled study. Ann Allergy Asthma Immunol 101:206–211, 2008. Durham S, Emminger W, Capp A, et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQstandardized grass allergy immunotherapy tablet. J Allergy Clin Immunol 125:121–128, 2010. Marogna M, Spadolini I, Massolo A, et al. Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study. J Allergy Clin Immunol 126:969–975, 2010. Mungan D, Misirligil Z, and Gurbuz L. Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite-sensitive patients with rhinitis and asthma—A placebo controlled study. Ann Allergy Asthma Immunol 82:485–490, 1999. Eifan A, Akkoc T, Yildiz A, et al. Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: An open randomized controlled trial. Clin Exp Allergy 40:922–932, 2010. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. Khinchi M, Poulsen L, Carat F, et al. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: A randomized, placebo-controlled, double-blind, double-dummy study. Allergy 59:45–53, 2004. Quirino T, Iemoli E, and Siciliani E. Sublingual versus injective immunotherapy in grass pollen allergic patients: A double blind (double dummy) study. Clin Exp Allergy 26:1253–1261, 1996. Mauro M, Russelo M, Incorvaia C, et al. Comparison of efficacy, safety and immunologic effects of subcutaneous and sublingual immunotherapy in birch pollinosis: A randomized study. Eur Ann Allergy Clin Immunol 39:119–122, 2007. Canonica G, Bosquet J, Casale T, et al. Sub-lingual Immunotherapy: World Allergy Organization Position Paper 2009. Allergy 64(suppl 91):1–59, 2009. Nelson H. Multiantigen immunotherapy for allergic rhinitis and asthma. J Allergy Clin Immunol 123:763–769, 2009. Marogna M, Spadolini I, Massolo A, et al. Effects of sublingual immunotherapy for multiple or single allergens in polysensitized patients. Ann Allergy Asthma Immunol 98:274–280, 2007. Amar S, Harbeck R, Sills M, et al. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol 124:150–156, 2009. Ciprandi G, Cadario G, Di Gioacchino G, et al. Sublingual immunotherapy in children with allergic polysensitization. Allergy Asthma Proc 31:227–231, 2010. Bosquet J, Lockey R, and Malling H. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 102:558–562, 1998. van Rhee R. Indoor allergens: Relevance of major allergen measurements and standardization. J Allergy Clin Immunol 119:270–277, 2007. Cox L, Linnemann D, Nolte H, et al. Sublingual immunotherapy: A comprehensive review. J Allergy Clin Immunol 117:1021–1035, 2006. Didier A, Malling H, Worm M, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 120:1338– 1345, 2007. Horak F, Jaeger S, Worm M, et al. Implementation of pre-seasonal sublingual immunotherapy with a five-grass pollen tablet during optimal dosage assessment. Clin Exp Allergy 39:394–400, 2008. Malling H, Montagut A, Melac M, et al. Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis. Clin Exp Allergy 39: 387–393, 2009. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm The risk and management of anaphylaxis in the setting of immunotherapy Phil Lieberman, M.D. ABSTRACT Background: Anaphylactic events due to immunotherapy are probably not completely preventable. There is always an inherent risk surrounding the administration of an allergen to an individual who is sensitized to the substance administered. Methods: There are, however, effective measures to reduce the risk of these events, and to optimize the assurance of a good outcome in the face of such an event. Results: Of prime importance in preventing these episodes is the regular assessment of the patient’s health status, especially in regard to asthma, and the careful attention to the prevention of dosing errors. Conclusion: Of equal importance, in regard to assuring a good outcome should such an event occur, are the rapid recognition of symptoms and the immediate injection of epinephrine, the drug of choice for the treatment of any episode of anaphylaxis. B ecause allergen immunotherapy introduces an allergen into an allergic individual, hypersensitivity reactions are probably unavoidable. There are, however, measures to minimize the risk and effective therapy to treat any such reactions. This is a review of procedures that have been suggested to minimize these risks and protocols designed to treat such reactions if they do occur. It draws heavily on consensus statements and evidence-based guidelines. The three references used extensively are the most recent allergen immunotherapy parameter,1 the most recent update of the anaphylaxis parameter,2 and a consensus publication on systemic reactions to immunotherapy sponsored by the World Allergy Organization.3 The most recent immunotherapy practice parameter1 states, “Although there is a low risk of severe systemic reactions with appropriately administered allergen immunotherapy, life-threatening and fatal reactions do occur.” Because such reactions are life-threatening, although they are extremely rare, it is imperative that actions be taken to minimize them and protocols designed to treat them rapidly and efficiently are in place. INCIDENCE Allergic disease exerts a significant toll on the health care system4 and allergen immunotherapy is an effective and cost-effective therapy in the treatment of allergic respiratory tract disease.5 With this therapy, however, as noted, anaphylactic reactions are probably inevitable. Unfortunately, the exact incidence of these events is unknown. In addition, although we have some data, the exact incidence of near fatal or fatal reactions is also imprecisely established. The reasons for this are numerous. For example, reaction rates differ with the dose and technique used, the allergen used, and the definition applied to define a reaction. For example, severe systemic reactions occur at markedly different rates depending on the frequency of administration of allergy injections. With conventional immunotherapy, the rates of severe systemic reactions are probably ⬍1%, whereas with rush immunotherapy reported reaction rates have been in some instances ⬎30%.6–9 In addition, as with any adverse reaction to a therapeutic agent, From Allergy and Asthma Care, Germantown, Tennessee Presented at the North American Rhinology & Allergy Conference, Puerto Rico, February 4, 2011 The author has no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Phil Lieberman, M.D., Allergy and Asthma Care, 7205 Wolf River Boulevard, Germantown, TN 38138 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 27, 469 – 474, 2013 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy reporting rates are probably not completely trustworthy. Also, response rates to surveys designed to assess incidence are usually, low, ⬍30%.10 Another difficulty innate to the determination of the incidence of such reactions is that data gathering techniques are limited for the most part to retrospective analyses or surveys taken of allergists practicing immunotherapy. In addition, there are reviews of such studies. For example, in the previously mentioned World Allergy Organization document,3 it was concluded that by analyzing reaction rates reported from studies between 1995 and 2010, the percentage of systemic reactions per injection with conventional immunotherapy protocols was ⬃0.2%. One example of survey collected data was published by Amin et al.10 in 2006. This survey was sent to members of the American Academy of Allergy, Asthma, and Immunology seeking information about reactions encountered in their practice. The desire was to evaluate the incidence of fatal and near fatal reactions. There were 646 respondents. Two hundred seventy-three reported near fatal reactions between 1990 and 2001. This gave an incidence of 23 per year, or 5.4 events per million injections. The authors performed the study because they noted that in previous evaluations, there were very few if any descriptions of serious or near fatal systemic reactions. In these previous studies, they noted that it was reported that 5–7% of patients receiving immunotherapy experienced reactions, but there was no mention of the number that were fatal or near fatal or a detailed description of these events.11–13 Before this survey of fatal and near fatal episodes there were other studies in North America that were performed to characterize and estimate the incidence of reactions to immunotherapy. Lockey et al.14 reported 24 fatal reactions that occurred between 1973 and 1984. They estimated that there was one fatal reaction per 2.8 million injections. Reid et al.15 recorded 15 immunotherapy-related deaths between 1985 and 1989. They estimated one fatality in every 2 million injections. Bernstein and colleagues performed a survey that documented 41 fatal reactions between 1990 and 2001.16 Their estimate was that there was one fatal reaction per every 2.5 million injections. FACTORS THAT MAY PREDISPOSE OR INCREASE THE SEVERITY OF SYSTEMIC REACTIONS DURING IMMUNOTHERAPY Many factors have been identified that may enhance the risk of a systemic reaction during immunotherapy or make such a reaction more severe (Table 1). Very few of these, however, have been definitively established as a predisposing factor. Data collected regarding many such factors show conflicting results. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S95 Table 1 Factors that may increase the frequency or enhance the severity of a reaction during immunotherapy Asthma Dosing errors Concomitant medication Administration of injections during the pollen season First injection from a new vial A high level of sensitivity to the allergen administered A history of a previous systemic reaction to allergen injections Preceding large local reactions ASTHMA The presence of asthma may not increase the risk of a reaction, but asthma is a risk factor for a severe reaction, and if the asthma is unstable, it enhances this risk.17 In addition, it increases the risk of fatal reactions.10 CONCOMITANT MEDICATION Although -adrenergic blocking agents do not seem to affect the frequency of the occurrence of systemic reactions to immunotherapy, they are a risk factor for a more serious event and can complicate therapy.1,17 The issue of patients treated with immunotherapy and simultaneously receiving a -adrenergic blocker is one that is commonly encountered and one that has generated intense interest as well as some controversy.18,19 This controversy has been generated in part because of the difficulties that are presented to the clinician when substitutions for -blockers need to be made before the initiation of immunotherapy and because in some instances immunotherapy can be carefully performed even in patients who are receiving venom while on -adrenergic blockers.20 In addition, it has been shown that -adrenergic blockers may not increase the risk of anaphylactic events to radiocontrast material.21 However, there clearly are data that support the fact that -adrenergic blockers may increase the risk of anaphylaxis after the administration of a known allergen, complicate its therapy, and worsen the severity of an event.14,22–46 Taken together, overall, it appears quite clear that -adrenergic blocking agents can have an adverse effect on the outcome of an anaphylactic episode and perhaps can increase the predisposition toward these episodes. They may do so in several ways. When a patient is taking a -adrenergic blocker, there is a diminished response to the -adrenergic effects of epinephrine. This may make a patient less responsive to the endogenous compensatory response produced by the patient’s own production of epinephrine as well as exogenously administered epinephrine given for therapy. In addition, it should be clarified that in a case of anaphylaxis, the relative contraindication extends not only to unselective -adrenergic agents but also to relatively selective -adrenergic blockers. This is because, in contrast to asthma, one is concerned not only with the -adrenergic effect on smooth muscle in the lungs but also with the -adrenergic effect on the cardiovascular system.3 Thus, it is desirable, in patients receiving immunotherapy, to, when possible, discontinue the use of -adrenergic agents. Angiotensinconverting enzyme inhibitors clearly increase the risk of an anaphylactic event during immunotherapy to venoms, but no such risk has been noted, to date, regarding systemic reactions to inhalants. PRECEDING LARGE LOCAL REACTIONS Data regarding the occurrence of large local reactions are difficult to interpret in that results have been somewhat conflicting. Originally, studies failed to find that preceding large local reactions were a risk factor for a systemic event.46,48 At least, in these studies, there was no difference in the incidence of systemic reactions in a group of patients where dose adjustments were made based on the occurrence of large local reactions versus a group in which the large local reac- S96 Table 2 Unusual clinical manifestations of fatal and near fatal anaphylactic reactions due to the administration of immunotherapy Upper airway obstruction is more frequent Severe cardiovascular manifestations are more frequent Gastrointestinal symptoms occur only rarely Cutaneous manifestations are less common Bronchospasm occurs more frequently Table 3 Actions designed to diminish the risk of an anaphylactic event during immunotherapy A general health assessment and, specifically, an assessment of the state of a patient’s asthma at the time of the injection should be made A peak expiratory flow might be performed to assist in this evaluation, and if asthma is active, consideration of withholding the injection should be made Dosage adjustments should be made in patients having any manifestation of a systemic reaction and continuing immunotherapy Consideration should be given to making dosage adjustments in those patients who are highly sensitive A minimum of 30 min wait time after an injection for all patients, and if patients are at increased risk, consideration of extending this wait time should be made The patient should be educated regarding manifestations of anaphylaxis and told to report any symptoms immediately Careful attention to dosing errors and proper identification of the patient should be done prior to administration of injection The dosage should be lowered when a freshly prepared extract is administered and when there has been a significant amount of time between injections (patients late for injections) Source: Adopted and modified from Ref. 1. tions were not used to alter the immunotherapy dose. It was concluded that large local reactions were not accurate predictors of a subsequent systemic event. However, another investigation performed as a retrospective review designed to compare the frequency of preceding large local reactions in patients who had a systemic reaction versus a matched “control group” of subjects not experiencing a systemic reaction found that there was a significant increase in the frequency of large local reactions in patients who had experienced a systemic reaction.49 These data are difficult to interpret as far as their clinical significance; however, overall, it appears as if large local reactions are not adequate predictors of a future systemic event in that dosage adjustments based on local reactions fail to alter the frequency of systemic events. Nonetheless, individuals who have experienced a systemic event have a higher incidence of large local reactions than those who have never had a systemic reaction. ADMINISTRATION OF INJECTIONS DURING THE POLLEN SEASON As with large local reactions, data are conflicting on whether or not immunotherapy injections given during the pollen season is a risk factor compared with injections administered outside the pollen season. Some studies have shown that there is no difference in the incidence of reactions when injections are given “in season” versus when they are given “out of season.”50,51 However, in the previously mentioned study by Amin and colleagues,10 the administration of injections during the pollen season was reported by 46% of respondents. In addition, it was hypothesized May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 4 Equipment suggested for treatment of an in-office anaphylactic event comparing two recent parameters published by the joint task force Allergen Immunotherapy: A Practice Parameter, Third Update 1 Stethoscope and sphygmomanometer Tourniquet, syringes, hypodermic needles, and i.v. catheters (e.g., 14–18G) Aqueous epinephrine 1:1000 w/v Equipment to administer oxygen by mask Intravenous fluid setup Antihistamine for injection Corticosteroids for intramuscular or i.v. injection Equipment to maintain airway Glucagon (patients taking -blockers) The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update2 Universal Equipment Stethoscope and sphygmomanometer Injectable aqueous epinephrine 1:1000 Oxygen and equipment for administering Intravenous fluids and equipment for administering them Tourniquets, syringes, hypodermic needles, and large bore needles (e.g., 14G or 16G) The following equipment and supplies should be considered depending on the availability of emergency support services: One-way valve face mask with oxygen inlet port Diphenhydramine or similar injectable antihistamine Corticosteroids for i.v. use Vasopressor for i.v. use Some clinicians may strongly consider the following: Glucagon Automatic defibrillator Oral airway Source: Refs. 1 and 2. that “priming” during the season could be a predisposing factor in regard to near fatal reactions. Thus, as with local reactions, it is difficult to make a definitive statement on whether administration of injections during the pollen season is a risk factor, but data, to date, seem to imply that administration during the season may increase the risk of systemic reactions. DOSING ERRORS Dosing errors account for a significant number of anaphylactic reactions to immunotherapy. In the Amin et al.10 study they were the second most common factor reported to be associated with events, accounting for 26% of episodes. FIRST INJECTION FROM A NEW VIAL In two studies,15,16 the first injection from a new vial of extract was a risk factor for a systemic event. Because of this it has been suggested that the dose be lowered when a new vial is started.1 There is no accepted consensus as to the amount the dose should be lowered. Table 5 Practices and procedures to be in place for the management of an anaphylactic event Office facilities administering allergy injections should have an established action plan to treat anaphylaxis It is advisable to rehearse such a plan periodically It is advisable to maintain a review of the treatment cart to make sure all medications are up to date and all equipment is present Physicians and office staff should maintain clinical proficiency regarding therapy of anaphylaxis All telephone numbers for paramedical rescue squads and hospital emergency rooms should be available Immunotherapy injections should be administered by healthcare professionals trained in the treatment of anaphylaxis The drugs that patients take should be reviewed on a regular basis to make sure they are not taking a medication that might affect the treatment of an event A flow sheet for treatment of anaphylactic events should be available, and treatment measures and dosages recorded on this flow sheet should an event occur Source: Adopted from Ref. 3. A HIGH LEVEL OF SENSITIVITY TO THE ALLERGEN ADMINISTERED A high level of sensitivity to the allergen being administered has been found to be a risk factor for systemic events.1 A HISTORY OF A PREVIOUS SYSTEMIC REACTION TO ALLERGEN INJECTIONS It is interesting to note that some patients experiencing a severe reaction on occasion report previous milder events occurring earlier in the course of immunotherapy.10 TIMING OF SYSTEMIC REACTIONS RELATED TO THE ADMINISTRATION OF THE INJECTION It is clear that most systemic reactions occur within 30 minutes after an injection. In addition, almost all severe systemic reactions start within this period of time.1,3 However, fatal reactions can begin later than 30 minutes postinjection, and systemic reactions can occur in rare instances more than 2 hours after the shot is given.1,17 Of note, while speaking of timing, it is also necessary to American Journal of Rhinology & Allergy recognize that, although rare, biphasic reactions to immunotherapy can occur. Thus, patients can be treated successfully, discharged from the office, and then experience a recurrence of symptoms.52,53 Based on an overall assessment of this information, a 30-minute waiting period for all patients receiving allergen immunotherapy has been suggested.1 Because anaphylactic episodes to immunotherapy can occur after patients have left the physician’s office after a 30-minute wait,17 consideration has been given to supplying patients receiving allergen immunotherapy a prescription for an automatic epinephrine injector, and that the patient be required to have this injector with them on days when they receive their injections. To the author’s knowledge, however, there is no consensus recommendation regarding this issue. Therefore, at least at this time, it appears that whether or not to issue epinephrine injectors to patients who are treated with immunotherapy remains at the discretion of the physician caring for the patient. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S97 Anaphylaxis preparedness 1 Patient presents with possible/probable acute anaphylaxis 2 NO Initial assessment supports potential anaphylaxis? e.g.: nonlocalized urticaria after immunotherapy 3 Consider other diagnosis 4 YES Immediate intervention: Assess airway, breathing, circulation, mentation Inject epinephrine and reevaluate for repeat injection if necessary Supine position (if cardiovascular involvement suspected) 5 NO Good clinical response? Subsequent emergency care that may be necessary depending on response to epinephrine: Consider: Call 911 and request assistance Recumbent position with elevation lower extremity Establish airway O2 Repeat epinephrine injection if indicated IV fluids if hypotensive; Rapid volume expansion Consider inhaled bronchodilators if wheezing H1 and H2 Antihistamines Corticosteroids 6 NO YES Observation Length and setting of observation c must be individualized Autoinjectable epinephrine 9 YES Make sure patient has telephone number of physician on call, and take patient's telephone number to consider calling later to assess her/his condition and answer any questions References: 10 Good clinical response? Call 911 if not already done Consider: Epinephrine intravenous infusion Other intravenous vasopressors Consider Glucagon 7 Cardiopulmonary arrest during anaphylaxis: CPR and ACLS measures Prolonged resuscitation efforts encouraged (if necessary) Consider: High-dose epinephrine Rapid volume expansion Atropine for asystole or pulseless electric activity Transport to emergency dept or ICU 8 21 Figure 1. Algorithm for the treatment of an anaphylactic event in the outpatient setting (i.v.). (Adopted from Ref. 2.) CLINICAL MANIFESTATIONS The clinical manifestations of anaphylaxis during immunotherapy are similar to those occurring in anaphylactic reactions to any injected allergen. However, there are salient features of fatal and near fatal events that are of note10 (Table 2). For example, although cutaneous features are the most common clinical manifestations in anaphylactic reactions taken as a whole,54 in near fatal and fatal immunotherapy reactions they do not predominate.10 Respiratory failure and hypotension or shock are the most frequently recorded events. Over 90% of patients with fatal reactions experience respiratory failure, and hypotension occurs in 88% of near fatal events and 81% of fatal reactions. Cutaneous signs appeared in 70% of near fatal reactions and in only 29% of those that were fatal. This may be because of the fact that the hypotensive state of these patients prevents blood flow from reaching the skin.54 S98 A striking finding was that when patients exhibited a history of poorly controlled or labile asthma, there was a prominently increased risk of fatal events, and most of these who did have reactions experienced fatal rather than near fatal episodes.10 PREVENTION In light of these findings, there have been several suggestions to reduce the incidence and severity of systemic reactions due to immunotherapy1,3,10 (Table 3). Because asthma is clearly one of the most important risk factors, it has been suggested that patients not receive allergy injections when their asthma is unstable or when their peak expiratory flow is “considered low for that patient” or “is substantially reduced compared with the patient’s baseline value.”1 It has also been suggested that the absolute value of the forced expiratory volume at 1 second be used as a measure to exclude patients from receiving immunotherapy. In this regard, it has been proposed that an May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm forced expiratory volume at 1 second below 70% of their predicted value should eliminate an asthmatic patient for consideration of the institution of aeroallergen immunotherapy.17 Patients who have experienced systemic reactions should have dosage adjustments made. The amount the dose should be adjusted is dependent on the physician’s judgment in regard to that particular patient. Obviously, this decision can be based on the severity of the event in question. In some instances, it may be decided that immunotherapy should be discontinued. The degree of allergen sensitivity has been considered a risk factor for anaphylactic events occurring during immunotherapy.3 Thus, consideration of dose adjustments can be made in patients who show a high degree of sensitivity as manifested by skin test reactivity. Any risk factor would lead the physician administering immunotherapy to consider a wait of ⬎30 minutes. This includes a previous reaction, a high degree of skin test sensitivity, a patient with asthma, etc. It is important that the patient recognize the early manifestations of an anaphylactic episode and be told to report any manifestation immediately. Episodes can begin insidiously, and patients may ignore the early clinical expressions of a harbinger of a more severe reaction. Thus, any patient receiving immunotherapy should be acquainted with all of the manifestations of anaphylaxis and be told to report any of these manifestations, as noted, promptly. As mentioned earlier, dosing areas are one of the most common causes of anaphylaxis to immunotherapy injections. Therefore, measures should be in place to minimize the chance of error. Efforts should be made to enhance the distinction between different dilutions of extract. Color coding systems can be used to accomplish this. The person administering the injection should clearly identify the patient by name and assure that the vial from which the injection is drawn is for that patient. Careful record keeping as to dates and doses for each injection should be used. The patient’s medication regimen should be frequently monitored to see if there have been changes in medication (e.g., the addition of a -blocker), which might signify an increased risk for a reaction. In addition, as noted previously, consideration should be given to lowering the dose when a freshly prepared extract is administered, and a schedule for reduction of dosing should be available to delineate dose reductions due to an inordinate lapse of time between injections. SUGGESTED EQUIPMENT IN THE OFFICE FOR TREATMENT OF A SYSTEMIC REACTION There have been a number of articles written that have mentioned what equipment should be available for the treatment of an in-office anaphylactic reaction.54 Two recent documents1,2 list such equipment, and their suggestions are compared in Table 4. In addition to the equipment noted in Table 4, any facility in which allergy injections are administered should have certain procedures in place to facilitate a rapid response to an event (Table 5).3 MANAGEMENT OF ANAPHYLAXIS The management of an anaphylactic event occurring to immunotherapy is identical to the management of an episode due to exposure to any other injected allergen. Epinephrine is the drug of choice and should be given at the first sign of an anaphylactic episode.1–3 A delay in the administration of epinephrine has been found to be a risk factor for poor outcomes and, in some studies, for a biphasic reaction.55 Epinephrine can be administered every 5–10 minutes as necessary, and this can be liberalized based on clinical judgment. Intravenous administration can be considered if needed because of a poor response to intramuscular or subcutaneous injection, but it is preferably administered where cardiovascular monitoring is available. Immediate assessment of vital signs and the airway should be performed, and the patient should be placed in a supine position with American Journal of Rhinology & Allergy legs elevated. Oxygen should be started simultaneously with the initial evaluation. Patients should stay in this recumbent position until the cardiovascular system is stable. Fatalities have been associated with prematurely assuming the upright position.56 If there is a good and rapid response to these early measures consisting of oxygen, epinephrine, and positioning, the patient can be observed (the length of time must be individualized) and then discharged from the facility. It is suggested that they be supplied with a prescription for an automatic epinephrine injector at that time because symptoms can recur. They should be given the phone number where the physician on call can be reached should symptoms reappear. One could also consider, at the time of administration of epinephrine, calling for emergency services, but that is usually done if there is no quick and adequate response to the initial therapy. Of course, this decision is dependent on the severity of the symptoms at the time of the initial evaluation. In addition, should the blood pressure remain low, i.v. fluids should be administered, for wheezing an inhaled bronchodilator given, and consideration should be given to the i.v. administration of an H1/H2-antihistamine and corticosteroids. An algorithm outlining the treatment of an office event is shown in Fig. 1. In conclusion, anaphylactic episodes due to allergen immunotherapy probably are unavoidable, but there are strategies available to minimize the frequency of their occurrence and to enhance the outcome of these events. Of primary importance is a level of awareness and the institution of treatment immediately should any manifestation of an anaphylactic event occur. REFERENCES 1. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: A practice parameter. J Allergy Clin Immunol 127:S1–S55, 2011. 2. Lieberman P, Nicklas R, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 Update. J Allergy Clin Immunol 126:477–480, 2010. 3. Cox L, Larenas-Linnemann D, and Lockey R. Speaking the same language: The World Allergy Organization subcutaneous immunotherapy systemic reaction grading system. J Allergy Clin Immunol 125:569–574, 2010. 4. Blaiss MS. Allergic rhinitis: Direct and indirect costs. Allergy Asthma Proc 31:375–380, 2010. 5. Alzakar RH, and Alsamarai AM. Efficacy of immunotherapy for treatment of allergic asthma in children. Allergy Asthma Proc 31:324– 330, 2010. 6. Larenas-Linnemann D. Subcutaneous and sublingual immunotherapy in children: Complete update on controversies, dosing, and efficacy. Curr Allergy Asthma Rep 8:465–474, 2008. 7. Bernstein DI, Epstein T, Murphy-Berendts K, and Liss GM. Surveillance of systemic reactions to subcutaneous immunotherapy injections: Year 1 outcomes of the ACAAI and AAAAI collaborative study. Ann Allergy Asthma Immunol 104:530–535, 2010. 8. Windom H, and Lockey R. An update on the safety of specific immunotherapy. Curr Opin Allergy Clin Immunol 8:571–576, 2008. 9. Portnoy J, Bagstad K, Kanarek H, et al. Premedication reduces the incidence of systemic reactions during inhalant rush immunotherapy with mixtures of allergenic extracts. Ann Allergy 73:409–418, 1994. 10. Amin HS, Liss GM, and Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol 117:169–175, 2006. 11. Ragusa FV, Passalacqua G, Gambardella R, et al. nonfatal systemic reactions to subcutaneous immunotherapy: A 10-year experience. J Investig Allergol Clin Immunol 7:151–154, 1997. 12. Greenberg MA, Kaufman CR, Gonzalez GE, et al. Late and immediate systemic-allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol 77:865–870, 1986. 13. Ragusa VF, and Massolo A. Non-fatal systemic reactions to subcutaneous immunotherapy: A 20-year experience comparison of two 10-year periods. Allergy Immunol (Paris) 36:52–55, 2004. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S99 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. Lockey RF, Benedict LM, Turkeltaub PC, and Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 79:660–677, 1987. Reid MJ, Lockey RF, Turkeltaub PC, and Platts-Mills TA. Survey of fatalities from skin testing and immunotherapy 1985–1989. J Allergy Clin Immunol 92:6–15, 1993. Bernstein DI, Wanner M, Borish L, and Liss GM. Twelve-year survey of fatal reactions to allergen injections and skin testing. J Allergy Clin Immunol 113:1129–1136, 2004. Nelson HS (Ed). Allergen Immunotherapy. In: Immunotherapy for Inhalant Allergens. Philadelphia, PA: Mosby, an affiliate of Elsevier, Inc., 1657–1678, 2009. Lieberman P, Kemp S, Oppenheimer J, et al. Letter to the editor. J Allergy Clin Immunol 116:3933–3936, 2005. Miller MM, and Miller MM. Beta-blockers and anaphylaxis: Are the risks overstated? J Allergy Clin Immunol 116:931–933, 2005. Muller UR, and Haeberli G. Use of beta-blockers during immunotherapy for hymenoptera venom allergy. J Allergy Clin Immunol 115:606–610, 2005. Greenberger PA, Meyers SN, and Kramer BL. Effects of beta-adrenergic and calcium channel antagonists on the development of anaphylactoid reactions from radiographic contrast media during cardiac angiography. J Allergy Clin Immunol 80:698–672, 1987. Lang DM, Alpern MB, Visintainer PF, and Smith ST. Increased risk for anaphylactoid reactions from contrast media in patients on betaadrenergic blockers or with asthma. Ann Intern Med 115:270–276, 1991. Lang DM, Alpern MB, Visintainer PF, and Smith ST. Elevated risk of anaphylactoid reactions from radiographic contrast media is associated with both beta-blocker exposure and cardiovascular disorders. Arch Intern Med 153:2033–2040, 1993. Hepner MJ, Ownby DR, Anderson JA, et al. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 86:407–411, 1990. Alarn MM, Alvarez del Real G, and Hsieh FH. Cardiopulmonary resuscitation (CPR) in patients with acute anaphylaxis taking betablockers. J Allergy Clin Immunol 115:S38, 2005 (Abs). Jacobs RL, Rake GW, Fournie DC, et al. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 68:125–127, 1981. Newman BR, and Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy 47:35–37, 1981. Awai LW, and Makori YA. Insect sting anaphylaxis and beta-adrenergic blockade: A relative contraindication. Ann Allergy 53:43–49, 1984. Laxenaire MC, Torrens J, and Moneret-Vautrin DA. Fatal anaphylactic shock in a patient treated with beta-blockers (French). Ann Fr Anesth Reanim 3:453–455, 1984. Benitah E, Nataf P, and Herman D. Anaphylactic complications in patients treated with beta-blockers: Apropos of 14 cases (French). Therapie 41:139–142, 1986. Comaille G, Leynadier F, Modiano D, and Dry J. Severity of anaphylactic shock in patients treated with beta-blockers (French). Presse Med 14:790–791, 1985. Toogood JH. Beta-blocker therapy and the risk of anaphylaxis. Can Med Assoc J 136:929–932, 1987. Berkelman RI, Finton RJ, and Elsea WR. Beta-adrenergic antagonists and fatal anaphylactic reactions to oral penicillin (letter). Ann Intern Med 104:134, 1986. Capellier G, Boillot A, and Cordier A. Anaphylactic shock in patients treated with beta-blockades (French). Presse Med 18:181, 1989. Stark BJ, and Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 78:76–83, 1986. S100 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. Hamilton G. Severe adverse reactions to urography in patients taking beta-adrenergic blocking agents. Can Med Assoc J 133:122–126, 1985. Zaloga GP, DeLacey W, Holmboe B, and Chernow B. Glucagon reversal of hypotension in a case of anaphylactic shock. Ann Intern Med 105:65–66, 1986. Kim Y. Interaction between beta-blockers and epinephrine on hemodynamics of spontaneously hypertensive rats. Res Commun Chem Pathol Pharmacol 80:3–19, 1993. Matsummura Y, Tan EN, and Vaughn JH. Hypersensitivity to histamine and systemic anaphylaxis in mice with pharmacologic betaadrenergic blockade: Protection by nucleotides. J Allergy Clin Immunol 58:387–394, 1976. Forfang K, and Simonsen S. Effects of atenolol and pindolol on the hypokalemia and cardiovascular responses to adrenaline. Eur J Clin Pharmacol 37:23–26, 1989. Raptis S, Rosenthal J, Wetzel D, and Moulopoulos S. Effects of cardioselective and non-cardioselective beta-blockade on adrenalineinduced metabolic and cardiovascular response in man. Eur J Clin Pharmacol 20:17–22, 1981. Madowitz JS, and Schweiger MJ. Severe anaphylactoid reaction to radiographic contrast media. J Am Med Assoc 241:2813–2815, 1979. Brummett RE. Warning to otolaryngologists using local anesthetics containing epinephrine: Potential serious reaction occurring in patients treated with beta-adrenergic receptor blockers. Arch Otolaryngol 110:561, 1984. Anonymous. Physician’s Desk Reference. Montvale, NJ: Thomson PDR, 3337, 2005. Bousquet J, Lockey RF, Malling HJ, et al. WHO position paper: Allergen immunotherapy: Therapeutic vaccines for allergic diseases. Allergy 53(suppl 44):1–42, 1998. Lang DM. Anaphylactoid and anaphylactic reactions, hazards of betablockers. Drug Saf J 12:299–304, 1996. Tankersley MS, Butler KK, Butler WK, and Goetz DW. Local reactions during allergen immunotherapy do not require dose adjustment. J Allergy Clin Immunol 106:840–843, 2000. Kelso JM. The rate of systemic reactions to immunotherapy injections is the same whether or not the dose is reduced after a local reaction. Ann Allergy Asthma Immunol 92:225–227, 2004. Roy SR, Sigmon JR, Olivier J, et al. Increased frequency of large local reactions among systemic reactors during subcutaneous allergen immunotherapy. Ann Allergy Asthma Immunol 99:82–86, 2007. Lin MS, Tanner E, Lynn J, et al. Nonfatal systemic allergic reactions induced by skin testing and immunotherapy. Ann Allergy 71:557– 562, 1993. Tikelman DG, Cole WQ, and Tunno J. Immunotherapy: A one year prospective study to evaluate risk factors of systemic reactions. J Allergy Clin Immunol 95:8–14, 1995. Confino-Cohen R and Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Ann Allergy Asthma Immunol 104:73–78, 2010. Scranton SE, Gonzalez EG, and Waibel KH. Incidence and characteristics of biphasic reactions after allergen immunotherapy. J Allergy Clin Immunol 123:493–498, 2009. Lieberman P. Anaphylaxis. In Middleton’s Allergy: Principles and Practice. Atkinson F, Bochner B, Busse W, Holgate S, Lemanske R, and Simons FER (Eds). Philadelphia, PA: Mosby, an affiliate of Elsevier, Inc., 1027–1051, 2009. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 95:217–228, 2005. Pumphrey R. Fatal posture in anaphylactic shock. J Allergy Clin Immunol 112:451–452, 2003. e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Pathophysiology of hereditary angioedema Bruce L. Zuraw, M.D.,1 and Sandra C. Christiansen, M.D.2 ABSTRACT Background: Laryngeal angioedema may be associated with significant morbidity and even mortality. Because of the potential severity of attacks, both allergists and otolaryngologists must be knowledgeable about the recognition and treatment of laryngeal angioedema. This study describes the clinical characteristics and pathophysiology of bradykinin-mediated angioedema. Methods: A literature review was conducted concerning the clinical characteristics and pathophysiology of types I and II hereditary angioedema (HAE), type III HAE, acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. Results: The diagnosis of type I/II HAE is relatively straightforward as long as the clinician maintains a high index of suspicion. Mutations in the SERPING1 gene result in decreased secretion of functional C1INH and episodic activation of plasma kallikrein and Hageman factor (FXII) of the plasma contact system with cleavage of high molecular weight kininogen and generation of bradykinin. In contrast, there are no unequivocal criteria for making a diagnosis of type III HAE, although a minority of these patients may have a mutation in the factor XII gene. Angioedema attacks and mediator of swelling in acquired C1INH deficiency are similar to those in type I or II HAE; however, it occurs on a sporadic basis because of excessive consumption of C1INH in patients who are middle aged or older. ACE inhibitor-associated angioedema should always be considered in any patient taking an ACE inhibitor who experiences angioedema. ACE is a kininase, which when inhibited is thought to result in increased bradykinin levels. Bradykinin acts on vascular endothelial cells to enhance vascular permeability. Conclusion: Laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema. Novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and from histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders. L aryngeal angioedema can be associated with significant morbidity or even mortality.1–3 Treatment of laryngeal angioedema is therefore of critical importance to many physicians, most notably allergists, otolaryngologists, primary care physicians, and emergency medicine physicians. Effective treatment of laryngeal angioedema requires both an accurate diagnosis of the cause of the swelling as well as an appreciation of the underlying pathophysiology of the process. This review will summarize both the clinical characteristics and the pathophysiology of several of the most important causes of laryngeal angioedema. Laryngeal angioedema, like all angioedema and urticaria, results from increased vascular permeability with movement of fluid from the vascular space to the interstitial space.4–7 This may occur from either a histamine-mediated process or a bradykinin-mediated process. The current review will focus on the pathophysiology of recurrent angioedema that is believed to be caused by bradykinin. The specific forms of recurrent angioedema covered will be hereditary angioedema (HAE), acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema (Fig. 1). Most of the discussion will focus on HAE because it is the most completely understood of these conditions. The accompanying article by Christiansen will then review the treatment of laryngeal angioedema.8 From the 1Department of Medicine, University of California, San Diego, and San Diego Veteran’s Affairs Medical Center, La Jolla, California, and 2Department of Allergy, Kaiser Permanente and University of California, San Diego, California Presented at the First North American Rhinology and Allergy Conference, Puerto Rico, February 3, 2011 B. Zuraw received grant support from ViroPharma, Pharming, and Shire and is a consultant for ViroPharma, Shire, Santarus, Dyax, and CSL Behring; S. Christiansen has no conflicts to declare pertaining to this article Address correspondence and reprint requests to Bruce L. Zuraw, M.D., 9500 Gilman Drive, Mailcode 0732, La Jolla, CA 92093-0732 E-mail address: [email protected] Originally published in Am J Rhinol Allergy 25, 373–378, 2011 Copyright © 2014, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy HAE WITH LOW C1INH ACTIVITY HAE was first accurately described by Dr. William Osler in 1888.1 Dr. Osler recognized the strong heritable nature of the disease and provided a very comprehensive description of the attacks in multiple generations of a single family. HAE is inherited in an autosomal dominant manner. It affects both male and female gender equally. Approximately 50% of the children of an affected parent will inherit the disease. In addition, the disease does not skip generations. Surveys of HAE patients and their families have revealed that only ⬃75% of patients with HAE have a positive family history of angioedema, with the other 25% of HAE patients having de novo mutations.9 HAE is a rare disease, with an estimated prevalence of 1 per 50,000 in the general population.10–12 There is no known ethnic difference in the prevalence of HAE. Because it is so uncommon, an accurate diagnosis of HAE must begin with the physician having a high index of suspicion based on the clinical characteristics (Table 1).11,13,14 Patients with HAE typically have recurrent angioedema without urticaria. The most commonly affected locations of swelling in HAE are the extremities, the gastrointestinal tract, the external genitourinary tract, the face, and the oropharynx/larynx. The probability that a given attack will involve the skin or abdomen is nearly 50% each. All other attack locations, including genitourinary and laryngeal attacks, account for only 3.6% of attacks.15 Attacks of swelling in HAE patients are usually prolonged, with the swelling typically slowly increasing over ⬃24 hours and then resolving even more slowly over the subsequent 2–4 days. A clinical observation that is useful for suggesting that a patient might have HAE is the lack of a clear response to the standard medicines used to treat allergic swelling (antihistamines, corticosteroids, and epinephrine).11,13 Attacks are frequently but not always preceded by prodromal symptoms, most classically a serpiginous nonpruritic rash called erythema marginatum.13,16 The swelling in HAE is often quite severe and may be associated with considerable morbidity and even mortality.11,13,14 The most Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S101 Figure 1. Bradykinin-mediated angioedema. Hereditary angioedema (HAE), acquired C1 inhibitor (C1INH) deficiency, and angiotensin-converting enzyme (ACE) inhibitor-associated angioedema are all thought to result from bradykinin. Types I and II HAE as well as acquired C1INH deficiency are characterized by low C1INH functional activity, based on decreased synthesis or increased catabolism, respectively. The decreased C1INH activity prevents effective regulation of the contact system and results in enhanced bradykinin generation. Type III HAE may involve enhanced factor XII activity in at least some patients. The enhanced factor XII activity may lead to increased plasma kallikrein activation and enhanced bradykinin generation. ACE is an endopeptidase that degrades bradykinin, among other substrates. ACE inhibitors, therefore, may decrease the normal catabolism of bradykinin and lead to elevated bradykinin levels. feared swelling in HAE is laryngeal attacks, which can occlude the airway and result in asphyxiation.17–22 Intubation may be lifesaving in an HAE patient with severe laryngeal angioedema; however, difficulty due to the distorted upper airway occasionally requires tracheotomy to preserve the airway. It is critically important to consider all patients with HAE at risk for asphyxiation because of laryngeal attacks, irrespective of whether they have ever had a laryngeal attack in the past or how severe their disease is. Over 50% of patients report having experienced at least one laryngeal attack.15 Abdominal attacks frequently cause significant morbidity, including severe abdominal pain, nausea and vomiting, and orthostatic hypotension due to third spacing of fluid. The severe nature of these symptoms can mimic a surgical abdomen, and many HAE patients have undergone unnecessary abdominal surgery for HAE attacks. Patients frequently require treatment in the emergency department or even hospitalization for abdominal attacks. Narcotic addiction has been a problem in some HAE patients, because of the need for repeated treatments with potent opiate painkillers. Although often considered benign by physicians, even extremity attacks can prevent patients from going to work or attending school when they involve the dominant hand or the feet. Approximately 50% of the patients began swelling before the age of 10 years, and almost all patients reported onset of symptoms before the age of 20 years.13 Despite the importance of making the diagnosis, a delay of ⬃10–20 years between symptom onset and proper diagnosis has been observed.13,23 Attacks occur unpredictably, with varying frequency and severity. The average frequency of attacks in untreated HAE patients is unclear but variable. Disease severity is highly variable both between and sometimes within kindreds. Furthermore, no simple relationship has been observed between disease severity and plasma C1INH levels. Although most attacks occur without a clear precipitating factor, stress and minor trauma are each well recognized to be capable of provoking HAE attacks. Additionally, many women report that exogenous estrogens (from oral contraceptives or hormonal replace- S102 ment therapy) significantly worsen attack frequency and severity. Pregnancy is associated with increased disease severity in about one-third of women; however, another third of women report lessened angioedema during pregnancy. A striking finding, however, is the lack of swelling that occurs at the time of parturition.13 Once a diagnosis of HAE is suspected, confirming the diagnosis is usually straightforward and is based on laboratory measurement of the complement C4 level as well as the C1INH level or activity (Table 2).11,24 PATHOPHYSIOLOGY OF HAE WITH LOW C1INH ACTIVITY In 1963, Dr. Virginia Donaldson found that patients with HAE were deficient in C1INH activity while their unaffected relatives as well as patients with other forms of angioedema and normal controls all had normal C1INH activity.25 Two years later, Dr. Fred Rosen discovered that ⬃15% of HAE patients had normal C1INH levels but low C1INH activity (type II HAE) as opposed to the more common pattern of low C1INH levels and activity.26 C1INH is a member of the serine protease inhibitor (serpin) superfamily.27 Like other serpin inhibitors (such as ␣-1-antitrypsin and antithrombin), C1INH functions like a “molecular mousetrap.”28 Most of the structure is very rigid and under considerable stress; however, the reactive mobile loop, located at the top of the protein is mobile. The reactive mobile loop contains the active site where C1INH is attacked by its target proteases. Once a protease cleaves the peptide bond at the active site, there is a large-scale rearrangement of C1INH in which an arm of the reactive mobile loop inserts into the central -sheet, trapping the target protease. There is a 1:1 stoichiometric relationship between the protease and C1INH, and each molecule of protease inhibited consumes one molecule of C1INH. The mechanism of inhibition thus involves a suicide inactivation.29 The C1INH gene, SERPING1, is organized into eight exons with intervening introns. Disease causing mutations are scattered throughout the gene, in fact ⬎200 different mutations associated with types I May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Table 1 Distinguishing bradykinin-mediated angioedemas based on clinical characteristics Characteristic Type I HAE Type II HAE Type III HAE Acquired C1INH Deficiency ACE Inhibitor Associated Age of onset Childhood or teenage Childhood or teenage Middle age or older Adult Family history Predilection for specific swelling sites Prodrome Predominantly affects women Associated with using an ACE inhibitor Usually ⫹ None Usually ⫹ None Negative None Negative Especially face Often No Often No Teenage or young adult Essential Especially face and extremities Probably not Yes Probably not No No No Noⴱ Noⴱ Noⴱ Noⴱ Yes ⴱMay be made worse by an ACE inhibitor. ACE ⫽ angiotensin-converting enzyme; C1INH ⫽ C1 inhibitor; HAE ⫽ hereditary angioedema. Table 2 Distinguishing bradykinin-mediated angioedemas based on laboratory profile Test Type I HAE Type II HAE Type III HAE Acquired C1INH Deficiency ACE Inhibitor Associated C1INH antigenic level C1INH functional level C4 C1q Factor XII mutation Low Low Low Normal Absent Normal Low Low Normal Absent Normal Normal Normal Normal Occas found Low Low Low Low Absent Normal Normal Normal Normal Absent ACE ⫽ angiotensin-converting enzyme; C1INH ⫽ C1 inhibitor; HAE ⫽ hereditary angioedema. and II HAE have been described. Interestingly, mutations in the reactive mobile loop near or at the active site result in a dysfunctional protein that characterizes type II HAE. There is evidence that type I HAE often involves failure of the nascent protein to fold properly within the endoplasmic reticulum. The mechanism by which a deficiency of C1INH causes increased vascular permeability and angioedema has been the subject of intense investigation over the past 30 years. Incubation of HAE plasma ex vivo at 37°C generates a factor that caused smooth muscle contraction and increased vascular permeability.30 This “vascular permeability-enhancing factor” was correctly assumed to be the mediator of swelling in HAE; however, the final characterization of the factor remained elusive and controversial for many years. C1INH is the principle inhibitor of several complement and contact system proteases as well as a minor inhibitor of coagulation factor XIa and plasmin.27 During HAE attacks, each of these plasma proteolytic cascades is activated with the potential to generate several vasoactive compounds. Two potential mediators of swelling in HAE were identified as likely candidates to mediate enhanced vascular permeability in HAE: C2 kinin, generated through activation of the classic complement and fibrinolytic pathways,31 and bradykinin, generated through activation of the contact system.32 Despite initial suggestions that C2 kinin represented the vascular permeability-enhancing activity, compelling laboratory and clinical data have conclusively shown that bradykinin is the primary mediator of swelling in HAE.32–42 The nanopeptide bradykinin is generated when active plasma kallikrein cleaves high molecular weight kininogen.43 Plasma kallikrein is activated from its inactive zymogen by the protease factor XII, and both plasma kallikrein and factor XII are normally inhibited by C1INH (Fig. 1). The released bradykinin moiety potently increases vascular permeability by binding to its cognate receptor (the bradykinin B2-receptor) on vascular endothelial cells. Given the plethora of evidence supporting bradykinin as the mediator of swelling in HAE, it was of little surprise that drugs targeting bradykinin generation or action have shown efficacy during angioedema attacks.44,45 American Journal of Rhinology & Allergy TYPE III HAE In 2000, two separate groups described a familial form of angioedema in which the C1INH was absolutely normal.46,47 Clinically, this new type of HAE (which is often called type III HAE) resembles types I and II HAE, although type III HAE presents at a somewhat older age and appears to have fewer abdominal and more facial attacks (Table 1).48 Type III HAE was initially thought to occur exclusively in women, particularly during times of increased estrogen exposure. Subsequently, affected men have been found49,50; and the strength of the relationship between estrogen exposure and angioedema is shown to be modest.48 At the current time, there are no firm criteria for making a diagnosis of type III HAE; however, it should be considered in patients with recurrent angioedema who have a strong family history of angioedema as well as normal C1INH antigenic and functional levels and a normal C4 level (Table 2). A mutation in the factor XII gene (Thr328Lys or Thr328Arg) that cosegregated with disease presence was described in some families with type III.51 This mutation was reported to cause a gain-of-function in factor XII activity, an observation that was particularly exciting because a gain-of-function in factor XII would be expected to result in enhanced generation of bradykinin and thus explain the pathogenesis of this disorder (Fig. 1). Since then it has become clear that only a minority of families with type III HAE have a mutation in factor XII.48 Furthermore, a recent study failed to confirm the gain-of-function in the mutant factor XII.52 The genetic heterogeneity of type III HAE suggests that this diagnosis may encompass a heterogeneous group of disorders. Because type III HAE can clearly cause severe laryngeal angioedema, the lack of clear diagnostic or pathophysiological understanding of this disease is of significant concern and requires additional research. ACQUIRED C1INH DEFICIENCY In addition to its deficiency on a hereditary basis, C1INH deficiency also occurs in a sporadic acquired form (acquired C1INH deficiency).53 These patients, who typically present in middle age or Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S103 older, experience recurrent angioedema that is similar if not identical to HAE attacks.54 Patients with acquired C1INH deficiency are also at significant risk for laryngeal attacks. Hereditary and acquired C1INH deficiencies are, however, relatively simple to differentiate based on the lack of family history and much later age of onset in the acquired form (Table 1). Laboratory evaluation of acquired C1INH deficiency typically shows low C4 levels as well as low C1INH levels and activity similar to type I HAE; however, the C1q level is also frequently reduced in acquired C1INH deficiency but not in HAE (Table 2).55 The primary basis for the C1INH deficiency in acquired C1INH deficiency is increased catabolism of C1INH rather than decreased secretion of functional C1INH as found in HAE (Fig. 1).56,57 The increased C1INH catabolism in acquired C1INH deficiency often related to underlying conditions. Many of these patients have tumors, particularly lymphoreticular malignancies, or other diseases that may consume C1INH.58,59 Importantly, successful treatment of the underlying disease may resolve the acquired C1INH deficiency.60 Patients with acquired C1INH deficiency also frequently have autoantibodies directed to C1INH, not infrequently associated with a monoclonal gammopathy of unknown significance.61,62 The autoantibody has been shown to interfere with normal C1INH-protease interactions, favoring the degradation of C1INH into a smaller cleaved dysfunctional protein.39,63 CONCLUSIONS ACE INHIBITOR-ASSOCIATED ANGIOEDEMA REFERENCES ACE inhibitors are a class of commonly used antihypertensive medications that are well recognized to be associated with angioedema in rare patients.64 The angioedema associated with ACE inhibitor tends to show a predilection for involving the face, lips, tongue, and throat (Table 1).65 The overall prevalence of ACE inhibitor-induced angioedema is estimated to range from 1 per 1000 patients using these drugs.66 A recent large study among patients in the United States Veterans Affairs system revealed an overall incidence of 1.97 cases per 1000 patients initiating ACE inhibitor therapy (compared with 0.51 cases per 1000 in patients initiating therapy with an antihypertensive drug other than an ACE inhibitor.67 Substantial variation in the risk of developing angioedema are seen among subsets of patients with black patients having a nearly fourfold increase in risk and women having a 1.5-fold increase in risk. The risk of developing angioedema while using an ACE inhibitor is highest during the 1st month of treatment but does not disappear even in patients who have been taking an ACE inhibitor for years.67,68 The angioedema resulting from use of an ACE inhibitor occurs on a class-specific rather than a drug-specific basis. All patients who develop angioedema without urticaria while taking an ACE inhibitor should be suspected of potentially having ACE inhibitor-associated angioedema. Because this angioedema tends to be recurrent and potentially life-threatening when involving the larynx,69,70 patients who develop ACE inhibitor-associated angioedema must discontinue the use of all ACE-I drugs. Although there has been concern about switching patients who experience angioedema on an ACE inhibitor to an angiotensin receptor blocker, several studies have shown that there is no evidence of increased risk when such a patient is switched to an angiotensin receptor blocker.71–73 The pathophysiology of ACE inhibitor-associated angioedema is thought to relate to decreased catabolism of bradykinin. ACE, also known as kininase 2, is an endopeptidase that degrades a variety of peptides including bradykinin (Fig. 1). A drug (omapatrilat) that inhibited both ACE and neutral endopeptidase (which is also involved in the degradation of bradykinin) had a substantially increased risk of angioedema.74 Furthermore, patients with a history of ACE inhibitor-associated angioedema were more likely than patients who tolerated ACE inhibitors without angioedema to have decreased plasma aminopeptidase P (another endopeptidase involved in the degradation of bradykinin) activity.75 Other studies suggest that in addition to bradykinin, substance P (a peptide also degraded by ACE) may be involved in ACE inhibitor-associated angioedema.76 S104 Bradykinin is a pluripotent peptide mediator, exerting different effects depending on the tissue in which it is generated. When generated in the vascular space, bradykinin can mediate enhanced vascular permeability—leading to movement of fluid from the vasculature space into the interstitial fluid (angioedema). Mechanistic studies have suggested (and in some cases proven) that increased levels of bradykinin are responsible for the angioedema associated with HAE, acquired C1INH deficiency, and ACE inhibitor-associated angioedema. Recognition of this fact is critically important because bradykinin-mediated angioedema is different in many key respects than the more common histamine-mediated angioedema. Severe laryngeal swelling is not infrequently encountered in bradykinin-mediated angioedema, and bradykinin-mediated angioedema does not respond to the drugs typically used to treat histamine-mediated angioedema. Furthermore, novel therapies are becoming available that for the first time provide effective treatment for bradykinin-mediated angioedema. Because the characteristics and treatment of these angioedemas are quite distinct from each other and histamine-mediated angioedema, it is crucial that the physician be able to recognize and distinguish these swelling disorders. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 95:362– 367, 1888. Zilberberg M, Jacobsen T and Tillotson G. The burden of hospitalizations and emergency department visits with hereditary angioedema and angioedema in the United States, 2007. Allergy Asthma Proc 31:511–519, 2010. Lumry WR, Castaldo AJ, Vernon MK, et al. The humanistic burden of hereditary angioedema: Impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc 31:407–414, 2010. Asero R, Riboldi P, Tedeschi A, et al. Chronic urticaria: A disease at a crossroad between autoimmunity and coagulation. Autoimmun Rev 7:71–76, 2007. Davis AE III. The pathogenesis of hereditary angioedema. Transfus Apher Sci 29:195–203, 2003. Agostoni A, Cicardi M and Porreca W. Peripheral edema due to increased vascular permeability: A clinical appraisal. Int J Clin Lab Res 21:241–246, 1992. Donaldson VH, Ratnoff OD, Dias Da Silva W, and Rosen FS. Permeability-increasing activity in hereditary angioneurotic edema plasma. II. Mechanism of formation and partial characterization. J Clin Invest 48:642–653, 1969. (PMCID: 322269.) Christiansen SC and Zuraw BL. Hereditary angioedema: Management of laryngeal attacks. Am J Rhinology & Allergy 25:379–382, 2011. Pappalardo E, Cicardi M, Duponchel C, et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 106:1147–1154, 2000. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 6:24, 2010. (PMCID: 2921362.) Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 359:1027–1036, 2008. Bygum A. Hereditary angio-oedema in Denmark: A nationwide survey. Br J Dermatol 161:1153–1158, 2009. Frank MM, Gelfand JA and Atkinson JP. Hereditary angioedema: The clinical syndrome and its management. Ann Intern Med 84:586– 593, 1976. Agostoni A and Cicardi M. Hereditary and acquired C1-inhibitor deficiency: Biological and clinical characteristics in 235 patients. Medicine (Baltimore) 71:206–215, 1992. Bork K, Meng G, Staubach P and Hardt J. Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med 119:267–274, 2006. Prematta MJ, Kemp JG, Gibbs JG, et al. Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks. Allergy Asthma Proc 30:506–511, 2009. May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. Papadopoulou-Alataki E. Upper airway considerations in hereditary angioedema. Curr Opin Allergy Clin Immunol 10:20–25, 2010. Bork K, Hardt J, Schicketanz KH and Ressel N. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med 163:1229–1235, 2003. Bork K and Ressel N. Sudden upper airway obstruction in patients with hereditary angioedema. Transfus Aphers Sci 29:235–238, 2003. Bork K and Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc 134:1088–1094, 2003. Bork K, Siedlecki K, Bosch S, et al. Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc 75:349–354, 2000. Agostoni A, Cicardi M, Cugno M and Storti E. Clinical problems in the C1-inhibitor deficient patient. Behring Inst Mitt 93:306–312, 1993. Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: Patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 94:498–503, 2005. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: Consensus document. Clin Exp Immunol 139:379–394, 2005. Donaldson VH and Evans RR. A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor of C’1-esterase. Am J Med 35:37–44, 1963. Rosen FS, Pensky J, Donaldson V and Charache P. Hereditary angioneurotic edema: Two genetic variants. Science 148:957–958, 1965. Davis AE III. C1 inhibitor and hereditary angioneurotic edema. Annu Rev Immunol 6:595–628, 1988. Lomas DA, Belorgey D, Mallya M, et al. Molecular mousetraps and the serpinopathies. Biochem Soc Trans 33:321–330, 2005. Patston PA, Gettins P, Beechem J and Schapira M. Mechanism of serpin action: Evidence that Cl inhibitor functions as a suicide substrate. Biochemistry 30:8876–8882, 1991. Donaldson VH, Ratnoff OD, Da Silva WD and Rosen FS. Permeability-increasing activity in hereditary angioneurotic edema plasma. II. Mechanism of formation and partial characterization. J Clin Invest 48:642–653, 1969. Donaldson VH, Rosen FS and Bing DH. Role of the second component of complement (C2) and plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Trans Assoc Am Physicians 40:174–183, 1977. Curd JG, Prograis L Jr., and Cochrane CG. Detection of active kallikein in induced blister fluids of hereditary angioedema patients. J Exp Med 152:742–747, 1980. Curd JG, Yelvington M, Burridge N, et al. Generation of bradykinin during incubation of hereditary angioedema plasma. Mol Immunol 19:1365, 1982. Fields T, Ghebrehiwet B and Kaplan AP. Kinin formation in hereditary angioedema plasma: Evidence against kinin derivation from C2 and in support of “spontaneous” formation of bradykinin. J Allergy Clin Immunol 72:54–60, 1983. Lammle B, Zuraw BL, Heeb MJ, et al. Detection and quantitation of cleaved and uncleaved high molecular weight kininogen in plasma by ligand blotting with radiolabeled plasma prekallikrein or factor XI. Thromb Haemost 59:151–161, 1988. Berrettini M, Lammle B, White T, et al. Detection of in vitro and in vivo cleavage of high molecular weight kininogen in human plasma by immunoblotting with monoclonal antibodies. Blood 68:455–462, 1986. Schapira M, Silver LD, Scott CF, et al. Prekallikrein activation and high- molecular-weight kininogen consumption in hereditary angioedema. N Engl J Med 308:1050–1054, 1983. Nussberger J, Cugno M, Amstutz C, et al. Plasma bradykinin in angio-oedema. Lancet 351:1693–1697, 1998. Zuraw BL and Curd JG. Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients. J Clin Invest 78:567–575, 1986. Zuraw BL, Lammle B, Sugimoto S, et al. Cleavage of high molecular weight kininogen in plasma during attacks of angioedema in hereditary angioedema. J Allergy Clin Immunol 79:177, 1987. Shoemaker LR, Schurman SJ, Donaldson VH and Davis AE. Hereditary angioneurotic oedema: Characterization of plasma kinin and vascular permeability-enhancing activities. Clin Exp Immunol 95:22– 28, 1994. American Journal of Rhinology & Allergy 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. Han ED, MacFarlane RC, Mulligan AN, et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 109:1057–1063, 2002. Cochrane CG and Griffin JH. The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 33:241–306, 1982. Zuraw BL and Christiansen SC. New promise and hope for treating hereditary angioedema. Expert Opin Investig Drugs 17:697–706, 2008. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 119:1497–1503, 2007. Binkley KE and Davis A III. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 106:546–550, 2000. Bork K, Barnstedt SE, Koch P and Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356:213–217, 2000. Bork K, Wulff K, Hardt J, et al. Hereditary angioedema caused by missense mutations in the factor XII gene: Clinical features, trigger factors, and therapy. J Allergy Clin Immunol 124:129–134, 2009. Bork K, Gul D and Dewald G. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men. Br J Dermatol 154:542–545, 2006. Martin L, Raison-Peyron N, Nothen MM, et al. Hereditary angioedema with normal C1 inhibitor gene in a family with affected women and men is associated with the p.Thr328Lys mutation in the F12 gene. J Allergy Clin Immunol 120:975–977, 2007. Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 79:1098–1104, 2006. Bork K, Kleist R, Hardt J and Witzke G. Kallikrein-kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys. Blood Coagul Fibrinolysis 20:325–332, 2009. Caldwell JR, Ruddy S, Schur PH and Austen KF. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin Immunol Immunopathol 1:39–52, 1972. Zingale LC, Castelli R, Zanichelli A and Cicardi M. Acquired deficiency of the inhibitor of the first complement component: Presentation, diagnosis, course, and conventional management. 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Acquired C1 esterase inhibitor deficiency and angioedema: A review. Medicine 58:321–328, 1979. Jackson J and Feighery C. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med 318:122–123, 1988. Jackson J, Sim RB, Whelan A and Feighery C. An IgG autoantibody which inactivates C1-inhibitor. Nature 323:722–724, 1986. Malbran A, Hammer CH, Frank MM and Fries LF. Acquired angioedema: Observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor. J Allergy Clin Immunol 81: 1199–1204, 1988. Brown NJ and Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 97:1411–1420, 1998. Byrd JB, Adam A and Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am 26:725–737, 2006. Slater EE, Merrill DD, Guess HA, et al. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 260:967–970, 1988. Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S105 67. 68. 69. 70. 71. Miller DR, Oliveria SA, Berlowitz DR, et al. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 51:1624–1630, 2008. Agostoni A, Cicardi M, Cugno M, et al. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology 44:21– 25, 1999. Brown NJ, Snowden M and Griffin MR. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA 278:232–233, 1997. Roberts DS, Mahoney EJ, Hutchinson CT, et al. Analysis of recurrent angiotensin converting enzyme inhibitor-induced angioedema. Laryngoscope 118:2115–2120, 2008. Cicardi M, Zingale LC, Bergamaschini L and Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: Outcome after switching to a different treatment. Arch Intern Med 164:910–913, 2004. S106 72. 73. 74. 75. 76. Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: A randomised controlled trial. Lancet 372:1174–1183, 2008. Johnsen SP, Jacobsen J, Monster TB, et al. Risk of first-time hospitalization for angioedema among users of ACE inhibitors and angiotensin receptor antagonists. Am J Med 118:1428–1429, 2005. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 17:103–111, 2004. Adam A, Cugno M, Molinaro G, et al. Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors. Lancet 359: 2088–2089, 2002. Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension 51:141–147, 2008. (PMCID: 2749928.) e May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Rhinology MOC Review - Questions 1. Which of the following is an effect of intranasal steroid therapy in a patient with nasal congestion and sleep disordered breathing A. Increases daytime somnolence B. Improves sleep quality C. Improves Apnea-Hypopnea Index when used with nasal dilators D. Reduces Apnea-Hypopnea Index to near physiologic levels 2. Which is a cause of anaphylaxis associated with immunotherapy? A. Use of an ACE inhibitor on patient receiving injections for inhalant allergen B. Prior history of immunotherapy C. History of pneumonia D. Dosing errors 3. A patient presents with recurrent unilateral epistaxis, nasal obstruction, and numbness along the V2 distribution. Nasal endoscopy reveals a frond –like mass in the posterior nasal cavity. The most appropriate next step in management is: A. Biopsy in the office setting B. Biopsy in the operating room C. Treatment with antibiotics D. CT and MRI scan 4. Which of the following is the most effective single agent medication for allergic rhinitis? A. Oral antihistamine B. Montelukast C. Nasal steroid spray D. Ipratroprium bromide 5. Which of the following surgical maneuvers most likely cause empty nose syndrome? A. Septoplasty B. Internal nasal valve augmentation C. Inferior turbinate resection D. Reduction of concha bullosa 6. Which pathogen is not typically associated with invasive fungal sinusitis? A. Candida B. Aspergillus C. Rizomucor D. Rizopus 7. What is the most common location of sinonasal inverted papillomas? A. Sphenoid sinus B. Maxillary sinus C. Nasal septum D. Ethmoid sinus 8. The edematous mucosa observed in allergic rhinitis results from an inflammatory cascade characterized by: A. IgE-mediated cell response B. Mucopurulence C. Overexpression of MUC5 D. IL-2 overexpression 9. What type of pathologic response characterizes staphylococcal superantigen stimulation? A. Th2 lymphocytic response B. Predominant neutrophilic response C. Dysfunction of membrane-bound pattern recognition receptors D. Stimulation of regulatory T cells American Journal of Rhinology & Allergy 10. Which of the following is a Bent and Kuhn criteria for allergic fungal rhinosinusitis? A. Atopic history B. Thickened mucus C. Neutrophils D. Hyphae invading the tissues 11. All of the following are appropriate methods to improve the internal nasal valve except: A. Submucosal resection of the caudal inferior turbinate B. Spreader grafts C. Alar batten grafts D. Butterfly grafts 12. Which of the following is true regarding the modified endoscopic medial maxillectomy procedure for cystic fibrosis patients? A. Physical debridement of mucus from the maxillary sinus is less challenging B. There is no improved access over regular maxillary antrostomy C. The maxillary sinus can be cured of chronic mucus transport dysfunction D. There is a high likelihood further endoscopic sinus surgery will be required for the maxillary sinus 13. Which of the following is the primary mediator that increases vascular permeability in both hereditary and ACE inhibitor-associated angioedema? A. Angiotensin B. Histamine C. Bradykinin D. Alpha-1-antitrypsin 14. Which symptom(s) is/are most characteristic of gustatory rhinitis? A. Fetid odor B. Watery rhinorrhea with coffee C. Nasal puritus, sneezing, and conjunctivitis with spicy foods D. Anosmia 15. A heterogenous group of patients with chronic nasal symptoms that are not immunologic or infectious in origin and are usually not associated with eosinophilia best describes: A. Gustatory rhinitis B. Non-allergic rhinitis with eosinophilia syndrome C. Rhinitis medicamentosa D. Non-allergic rhinitis 16. Challenging an individual with an aeroallergen and demonstrating a significant increase in mucosal eosinophils in the mucosa on the challenged side as well as the contralateral nasal cavity supports which theory for a pathophysiologic relationship between allergy rhinitis and CRS? A. Sensitization to colonizing fungi B. Systemic allergic inflammatory process C. Sensitization to colonizing bacteria D. Sensitization to IgE 17. The recombinant monoclonal anti-IgE antibody omalizumab is FDA approved for which indication? A. Inadequately controlled moderate to severe resistant, IgE mediated asthma B. IgE mediated urticaria C. Allergic rhinitis D. Severe bee venom allergies 18. Which is one of the four diagnostic criteria for Wegener’s granulomatousis? Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S107 A. B. C. D. Elevated liver enzymes Presence of extravascular eosinophils on biopsy Oral ulcers or nasal discharge Positive c-ANCA 19. What is the most common risk factor for acute fulminant invasive fungal sinusitis? A. Elevated blood sugars B. Neutropenia C. Fungal colonization D. Allergic fungal sinusitis 20. First line surgical therapy for pediatric chronic rhinosinusitis is A. Balloon sinuplasty B. Bilateral maxillary antrostomies C. Adenoidectomy D. Ethmoidectomy 21. All of the following interventions are useful for acute epistaxis except: A. Administration of topical vasoconstrictive agent B. Pinching the bridge of the nose C. Silver nitrate cautery D. Sphenopalatine artery ligation 22. Which of the following medical interventions has the highest level of evidence and grade of recommendations as a treatment for chronic rhinosinusitis with nasal polyposis? A. Guaifenesin B. Topical anti-mycotics C. Topical nasal steroids D. Short term oral antibiotics 23. The next most appropriate step in management for an elderly male with gradual onset of anosmia with a negative sinus CT scan and normal nasal endoscopy is: A. High dose oral steroids and topical steroids B. A three week course of broad spectrum antibiotic C. Neurologic evaluation D. Endoscopic sinus surgery 24. When hereditary angioedema affects the head and neck, the most common area of involvement is: A. Larynx B. Face C. Auricle D. Soft palate 25. A patient from sub-Sahara Africa comes in with atrophy of the nasal mucosa, anosmia, and a foul odor. Culture of the nasal crusts would likely grow: A. Klebsiella ozaenae B. Streptococcus pneuoniae C. Varicella zoster D. Pseudomonas aeruginosa 26. Which of the following medications can impact the validity of skin testing for allergen-specific IgE? A. First-, but not second-generation antihistamines B. Beta-adrenergic blocking agents C. Second-, but not first-generation antihistamines D. Tricyclic antidepressants 27. When performing an endoscopic ethmoidectomy, violation of the lateral lamella of the cribriform plate may occur. This is usually due to a dissection carried too far A. Posteriolaterally B. Inferiolaterally C. Superiolaterally D. Superiomedially S108 28. CT imaging of the paranasal sinuses has which of the following advantages over MRI? A. Improved definition of soft tissues B. Optimal discrimination of bone C. Negligible radiation exposure D. Optimal differentiation of soft tissue masses 29. Which of the following is a potential complication of failure to communicate the enlarged natural ostium of the maxillary sinus with an accessory ostium during endoscopic sinus surgery? A. Mucus re-entry into the antrum B. Intraoperative optic nerve injury C. Obstruction of the ethmoid infundibulum due residual tissue D. Stenosis of the natural ostium 30. Which is not an anatomic cause of nasal obstruction? A. Deviated septum B. Allergic rhinitis C. Turbinate hypertrophy D. Adenoid hypertrophy 31. Which of the following is not a potential contributor to fatal SCIT reactions? A. Prior immunotherapy reactions B. Alteration in immunotherapy allergen extracts C. Multiple antigen therapy D. Suboptimal asthma control during immunotherapy 32. What is the most common clinical sign in all anaphylactic reactions? A. Diffuse urticaria B. Respiratory failure C. Hypotension D. Gastrointestinal discomfort 33. Fibrous dysplasia and ossifying fibromas can be most easily differentiated on the basis of which factor? A. CT appearance B. Histology C. Location D. Clinical behavior 34. Which is a possible complication of sphenopalatine artery ligation for posterior epistaxis: A. Palatal anesthesia B. It carries a risk of cerebrovascular accident C. It carries a risk of toxic shock syndrome D. Jaw claudication 35. The most common intraoperative complication during functional endoscopic sinus surgery (FESS) on patient’s with nasal polyps is: A. Cerebrospinal fluid leak B. Intraoperative hemorrhage C. Orbital injury D. Loss of smell 36. Which type of chronic anosmia is most likely to improve, at least transiently, after a course of oral and topical steroids? A. Post-traumatic anosmia B. Post-viral induced anosmia C. Anosmia following anterior skull base surgery D. Anosmia associated with chronic rhinosinusitis with nasal polyps 37. What is the most appropriate indication for endoscopic sinus surgery in a cystic fibrosis patient? A. Nasal polyposis with significant symptoms refractory to extended culture-directed antibiotic treatment. B. Chronic symptoms with brittle lung function awaiting a lung transplant May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm C. Extensive mucosal thickening on CT scan with minimal symptoms D. Purulence seen on endoscopy despite medical management 38. Nasal surgery has which of the following effects on sleep disordered breathing? A. Decreased CPAP tolerance B. Reduction of day-time somnolence C. Reduction in Apnea-Hypopnea Index D. Objective improvement in snoring 39. The internal nasal valve includes which of the following anatomic sites as one of its boundaries? A. Alar rim laterally B. Nasal sill inferiorly C. Septum medially D. Pyriform aperture laterally 40. Which is the most common radiographic findings on CT scan of allergic fungal rhinosinusitis? A. Lytic bony lesions B. Symmetric, homogenous opacification of the paranasal sinuses C. Foci of near metallic density D. Evidence of telecanthus 41. Which of the following is true of SLIT? A. Meta-analysis shows that multi-antigen therapy is effective B. The optimum SLIT dose is well defined. C. SLIT is as effective as SCIT D. No deaths due to anaphylaxis have been reported 42. Which describes a type 4 orbital complication based on Chandler’s classification? A. Preseptal cellulitis: eyelid swelling, erythema, no limitation of extraocular eye motion B. Subperiosteal abcess: pus between periorbita and lamina papyracea C. Orbital abcess: collection of pus within orbital tissues D. Orbital cellulitis: diffuse, postseptal edema of orbital contents without discrete abscess 43. Allergen specific peripheral T-cell tolerance is predominately mediated by A. IL-4 B. IL-5 C. IL-7 D. IL 10 American Journal of Rhinology & Allergy 44. Diagnostic criteria for Churg Strauss include all of the following except: A. Asthma B. The presence of nasal polyps C. Peripheral eosinophilia 10% D. Polyneuropathy 45. What are the most common benign sinonasal tumors? A. Juvenile Nasopharyngeal Angiofibroma B. Inverted papilloma C. Osteomas D. Fibrous dyplasia 46. Which of the following sinonasal malignancies harbors the poorest 5 year survival? A. Squamous cell carcinoma B. Adenocarcinoma C. Mucosal melanoma D. Olfactory neuroblastoma 47. The primary symptom that is significantly worse in the late phase response of Type I hypersensitivity is: A. Nasal congestion B. Pruritis C. Sneezing D. Rhinorrhea 48. What is the relationship between the drainage pathway of the supraorbital ethmoid air cell and that of the frontal sinus? The supraorbital ethmoid drains: A. Anteromedial B. Anterolateral C. Posteromedial D. Posterlateral 49. A patient presents with a history consistent with acute sinusitis. Which of the following is an indication for CT scan? A. Symptoms persistent for 2 weeks B. Failure of a 5-day course of antibiotics C. Periorbital erythema D. Culture positive for pneumococcus 50. Where can the sphenoid ostium be located? A. Superior to the most posterior ethmoid air cell B. Lateral to the most posterior ethmoid air cell C. Anterior to the most posterior ethmoid air cell D. Medial to the most posterior ethmoid air cell Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm S109 Rhinology MOC Review - Answers Question number Answer Article title Article starting page number 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. B D D C C A B A A A C A C B D B A C B C B C C B A D D B A B C A D A B D A B C C D C D B C C A D C D The role of the nose in sleep-disordered breathing The risk and management of anaphylaxis in the setting of immunotherapy Sinonasal malignancies Allergic rhinitis Nasal obstruction Invasive fungal rhinosinusitis Benign sinonasal neoplasms The united allergic airway: Connections between allergic rhinitis, asthma, and chronic sinusitis Chronic rhinosinusitis Allergic fungal rhinosinusitis Augmenting the nasal airway: Beyond septoplasty Cystic fibrosis chronic rhinosinusitis: A comprehensive review Pathophysiology of hereditary angioedema Nonallergic rhinitis Nonallergic rhinitis Determining the role of allergy in sinonasal disease Immunomodulation of allergic sinonasal disease Granulomatous diseases and chronic sinusitis Invasive fungal rhinosinusitis Pediatric rhinosinusitis: Definitions, diagnosis and management—An overview Epistaxis Nasal polyps Olfactory disorders Pathophysiology of hereditary angioedema Nonallergic rhinitis Determining the role of allergy in sinonasal disease Surgery for sinonasal disease Chronic rhinosinusitis Sinus anatomy and function Nasal obstruction Subcutaneous and sublingual immunotherapy for allergic rhinitis: What is the evidence? The risk and management of anaphylaxis in the setting of immunotherapy Benign sinonasal neoplasms Epistaxis Nasal polyps Olfactory disorders Cystic fibrosis chronic rhinosinusitis: A comprehensive review The role of the nose in sleep-disordered breathing Sinus anatomy and function Allergic fungal rhinosinusitis Subcutaneous and sublingual immunotherapy for allergic rhinitis: What is the evidence? Pediatric rhinosinusitis: Definitions, diagnosis and management—An overview Immunomodulation of allergic sinonasal disease Granulomatous diseases and chronic sinusitis Benign sinonasal neoplasms Sinonasal malignancies Allergic rhinitis Sinus anatomy and function Chronic rhinosinusitis Surgery for sinonasal disease S60 S95 S31 S75 S7 S24 S27 S82 S11 S22 S54 S38 S101 S71 S71 S79 S86 S35 S24 S47 S9 S16 S68 S101 S71 S79 S51 S11 S3 S7 S90 S95 S27 S9 S16 S68 S38 S60 S3 S22 S90 S47 S86 S35 S27 S31 S75 S3 S11 S51 S110 May–June 2014, Vol. 28, No. 3 Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Copyright © Oceanside Publications, Inc. All rights reserved. DO NOT COPY For permission to copy go to https://www.oceansidepubl.com/permission.htm Save the Date! ginny North American Rhinology & Allergy Conference February 5-8, 2015 Boca Raton ~ Florida Jointly Sponsored by the American College of Allergy, Asthma and Immunology (ACAAI) and North American Rhinology & Allergy Conference (NARAC) NARAC dually represents ENTs and allergists, with the goal of improving the accuracy of diagnosis and effectiveness of treatments for rhinologic and allergic diseases. NARAC features lectures, panel discussions and PBL breakout sessions. ~ NARAC Poster Session ~ Call for Abstracts* *Abstracts publishable in American Journal of Rhinology & Allergy www.NARAConference.org Copyright © Oceanside Publications, Inc. All rights reserved. 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