Chronic Rhinosinusitis

Abstract

A 50-year-old woman with nonallergic rhinitis, asthma, and aspirin intolerance presented with worsening symptoms of nasal congestion, purulent drainage, and anosmia. Nasal polyps were visualized on anterior rhinoscopy, and there was evidence of chronic rhinosinusitis (CRS) on imaging studies during work-up for another medical condition. Over a 2-year period she had numerous bouts of acute exacerbations of CRS which required multiple courses of antibiotics; however, she was unwilling to undergo surgery to reduce polyp burden. She successfully underwent aspirin desensitization and experienced partial relief of symptoms with daily aspirin ingestion.Nasal obstruction is a common symptom that can result from multiple causes, including mucosal disorders (eg, allergic and nonallergic rhinitis, rhinosinusitis, sarcoid) and structural disorders (eg, nasal septal deviation, tumors, mucoceles). The various causes and work-up for nasal obstruction are discussed with emphasis placed on CRS, which is a prevalent disease characterized by inflammation of the nose and paranasal sinuses for a duration of >12 weeks. The different subtypes of CRS, including CRS with and without nasal polyps, allergic fungal rhinosinusitis, and aspirin-exacerbated respiratory disease, are discussed along with pathogenesis, diagnosis, and treatment options. A 50-year-old woman with nonallergic rhinitis, asthma, and aspirin intolerance presented with worsening symptoms of nasal congestion, purulent drainage, and anosmia. Nasal polyps were visualized on anterior rhinoscopy, and there was evidence of chronic rhinosinusitis (CRS) on imaging studies during work-up for another medical condition. Over a 2-year period she had numerous bouts of acute exacerbations of CRS which required multiple courses of antibiotics; however, she was unwilling to undergo surgery to reduce polyp burden. She successfully underwent aspirin desensitization and experienced partial relief of symptoms with daily aspirin ingestion. Nasal obstruction is a common symptom that can result from multiple causes, including mucosal disorders (eg, allergic and nonallergic rhinitis, rhinosinusitis, sarcoid) and structural disorders (eg, nasal septal deviation, tumors, mucoceles). The various causes and work-up for nasal obstruction are discussed with emphasis placed on CRS, which is a prevalent disease characterized by inflammation of the nose and paranasal sinuses for a duration of >12 weeks. The different subtypes of CRS, including CRS with and without nasal polyps, allergic fungal rhinosinusitis, and aspirin-exacerbated respiratory disease, are discussed along with pathogenesis, diagnosis, and treatment options. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted.Date of Original Release: May 2013. Credit may be obtained for these courses until June 30, 2014.Copyright Statement: Copyright © 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Christopher J. Ocampo, MD, PhD, and Leslie C. Grammer, MD.Activity Objectives1.Appreciate the multiple causes and differential diagnosis in patients presenting with nasal obstruction.2.Recognize the presentation of the various subtypes of chronic rhinosinusitis.3.Initiate appropriate treatment options for aspirin-exacerbated respiratory disease.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: C. J. Ocampo is employed by Northwestern Medical Faculty Foundation, has received research support from the National Institutes of Health, and has received payment for preparing review articles from the American Journal of Rhinology & Allergy. L. C. Grammer has received consultancy fees from Astellas; is employed by Northwestern Medical Faculty Foundation, Northwestern University; has received research support from the National Institutes of Health, the Food Allergy & Anaphylaxis Network, and S&C Electric; has received lecture fees and travel support from the AAAAI; and receives royalties from UpToDate, Lippincott Williams & Wilkins, and the British Medical Journal. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci-inpractice.org/. Fax or other copies will not be accepted. Date of Original Release: May 2013. Credit may be obtained for these courses until June 30, 2014. Copyright Statement: Copyright © 2012-2014. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Christopher J. Ocampo, MD, PhD, and Leslie C. Grammer, MD. Activity Objectives1.Appreciate the multiple causes and differential diagnosis in patients presenting with nasal obstruction.2.Recognize the presentation of the various subtypes of chronic rhinosinusitis.3.Initiate appropriate treatment options for aspirin-exacerbated respiratory disease. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: C. J. Ocampo is employed by Northwestern Medical Faculty Foundation, has received research support from the National Institutes of Health, and has received payment for preparing review articles from the American Journal of Rhinology & Allergy. L. C. Grammer has received consultancy fees from Astellas; is employed by Northwestern Medical Faculty Foundation, Northwestern University; has received research support from the National Institutes of Health, the Food Allergy & Anaphylaxis Network, and S&C Electric; has received lecture fees and travel support from the AAAAI; and receives royalties from UpToDate, Lippincott Williams & Wilkins, and the British Medical Journal. A 50-year-old white female minister presented to the Allergy-Immunology outpatient clinic for worsening symptoms of nasal congestion. She had been followed for 6 years; the initial diagnoses were nonallergic rhinitis and persistent asthma. She also described severe nasal congestion and profuse rhinorrhea after aspirin or ibuprofen ingestion. For the first 4 years, she had done relatively well in managing her rhinitis symptoms with intranasal steroids. At that point, she had an urgent visit after a month of increasing nasal congestion, purulent discharge, and anosmia. She denied fever, facial pain, or sinus pressure. Nasal polyps (NPs) and pus were first visualized. She was treated with azithromycin (Z-Pak × 2) and prednisone (30 mg daily for 5 days) with improvement, but not complete resolution, of symptoms. At follow-up 5 months later, she reported recurrence of uncontrolled sinusitis symptoms, with enlarged polyps visualized on examination. She was placed on a 3-week course of amoxicillin-clavulanate, and further evaluation with computerized tomography (CT) of the sinuses was recommended on at least 2 occasions, but the patient did not comply. She did not have exacerbations of asthma and was maintained on low-dose fluticasone-salmeterol; spirometry was normal. Two months later she presented for increasing right eye swelling over a 3-week period and was noted to have proptosis of the right orbit. Magnetic resonance imaging (MRI) showed a soft tissue abnormality in the medial aspect of the right orbit (Fig 1, A). A biopsy of the right orbital mass obtained through a superior nasal-anterior orbitotomy showed noncaseating granulomatous changes, consistent with a diagnosis of ocular sarcoidosis. The CT imaging studies showed near complete opacification of the right ethmoid sinuses and moderate mucosal thickening of the bilateral maxillary sinuses (Fig 1, B and C ). In addition, multiple polypoid lesions were noted in the nasal cavity (Fig 1, C ). Humoral immune function was evaluated. Total quantitative immunoglobulins were normal, and specific antibody titers to Streptococcus pneumoniae were adequate. Additional laboratory studies (comprehensive metabolic panel, complete blood cell count with differential, angiotensin-converting enzyme level, and anti-neutrophil cytoplasmic antibody) were within normal limits. She was treated for several months with a tapering schedule of prednisone, which resolved the orbital sarcoid (as evidenced by resolution of abnormalities on repeat MRI studies and complete resolution of proptosis) and controlled her symptoms of chronic rhinosinusitis (CRS). However, after discontinuation of prednisone, the patient resumed having acute exacerbations of CRS which required antibiotics. She refused further prednisone and functional endoscopic sinus surgery (FESS). Her nasal congestion showed some improvement with montelukast; however, she could not continue the medication because she believed it caused mood changes. Zafirlukast did not help; because of the need for liver function tests, she did not want zileuton. While she was taking montelukast, aspirin desensitization was performed. During the first attempt she ingested a total of 325 mg of aspirin but experienced significant rhinorrhea and sneezing; her spirometry did not change and she had no lower respiratory symptoms. She was maintained on 81 mg of aspirin twice daily, and 2 weeks later she tolerated progressively higher doses with minimal reaction. She took 650 mg of aspirin twice daily with improvement but experienced another exacerbation that required antibiotics. The plan was that she will agree to FESS to reduce her polyp burden; intensive medical therapy will continue. The differential diagnosis for nasal obstruction is broad (Table I). Causes for nasal obstruction can be divided into mucosal disorders: rhinitis (allergic and nonallergic), rhinosinusitis (acute and chronic, with multiple subtypes), and structural disorders such as nasal septal deviation or mucocele. Nasal congestion can also be due to the effects of medications (Table I).Table IDifferential diagnosis of nasal obstructionMucosal disorders RhinitisAllergic: perennial; seasonalNonallergic: infectious; vasomotor; eosinophilic; hormonal RhinosinusitisAcute: viral; bacterialChronic: without nasal polyps; with nasal polyps; allergic fungal rhinosinusitis; aspirin-exacerbated respiratory diseaseOther: Wegener granulomatosis; sarcoid; Churg-Strauss syndromeStructural disorders Nasal septal deviation Mucocele Other: concha bullosa, foreign body, adenoid hypertrophy, tumorMedications Aspirin, NSAIDs Oral contraceptives Vasodilators Erectile dysfunction medications Ocular topical beta blockers Nasal decongestants (rhinitis medicamentosa) Open table in a new tab Initially, the patient had symptoms of persistent rhinitis, which is characterized by at least one of the following: nasal congestion, rhinorrhea, sneezing, and pruritus.1Wallace D. Dykewicz M. Bernstein D. Blessing-Moore J. Cox L. Khan D.A. et al.The diagnosis and management of rhinitis: an updated practice parameter.J Allergy Clin Immunol. 2008; 122: S1-84Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar An essential component of the history is identifying symptom triggers, because rhinitis can be caused by both allergic and nonallergic stimuli. It is important to work up allergic rhinitis (AR) in a person with CRS, because the prevalence of AR is estimated to be 60% in CRS.2Hamilos D.L. Chronic rhinosinusitis: epidemiology and medical management.J Allergy Clin Immunol. 2011; 128 (quiz 708-9): 693-707Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar However, it is important to note that the association of CRS with AR does not imply causation, because studies have failed to show causality.3Karlsson G. Holmberg K. Does allergic rhinitis predispose to sinusitis?.Acta Otolaryngol Suppl. 1994; 515: 26-29Crossref PubMed Scopus (82) Google Scholar, 4Kirtsreesakul V. Naclerio R. Role of allergy in rhinosinusitis.Curr Opin Allergy Clin Immunol. 2004; 4: 17-23Crossref PubMed Scopus (33) Google Scholar, 5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Evaluation for a possible allergic trigger for rhinitis symptoms includes a thorough history and physical examination, with confirmatory diagnostic skin prick testing for specific IgE to a panel of relevant environmental allergens.1Wallace D. Dykewicz M. Bernstein D. Blessing-Moore J. Cox L. Khan D.A. et al.The diagnosis and management of rhinitis: an updated practice parameter.J Allergy Clin Immunol. 2008; 122: S1-84Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar The patient had negative skin prick testing to environmental allergens and thus her condition was initially diagnosed as nonallergic rhinitis, which can mimic AR, because symptoms can be similar and perennial or periodic.1Wallace D. Dykewicz M. Bernstein D. Blessing-Moore J. Cox L. Khan D.A. et al.The diagnosis and management of rhinitis: an updated practice parameter.J Allergy Clin Immunol. 2008; 122: S1-84Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar Acute rhinosinusitis (ARS) is defined as the sudden onset of symptoms of nasal congestion/obstruction/congestion or nasal discharge, along with facial pain/pressure or hyposmia/anosmia for a duration of <12 weeks.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Children may present with associated fever and cough. A diagnosis of ARS is made clinically on the basis of history and physical examination. In most cases, ARS is viral in origin, with only approximately 0.5% to 2% developing a secondary bacterial infection; acute bacterial rhinosinusitis (ABRS) is suspected when the upper respiratory infection has persisted beyond 10 to 14 days (Table II).5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google ScholarTable IIRhinosinusitis types and key featuresAcute rhinosinusitis (<12 weeks' duration) Viral origin in vast majority of cases Symptomatic treatment, typically resolves without antibiotics Consider antibiotics with symptoms lasting longer than 10-14 daysChronic rhinosinusitis subtypes (>12 weeks’ duration) Chronic rhinosinusitis without nasal polypsPredominantly TH1 inflammationProminent symptoms of facial pain and purulent drainage Chronic rhinosinusitis with nasal polypsPresence of nasal polypsPredominantly TH2 inflammationProminent symptoms of nasal obstruction, hyposmia/anosmia Allergic fungal rhinosinusitisFungal hyphae isolated from allergic mucinFungal-specific IgE present in the serumTypically unilateral diseaseHyperdensities within opacified sinuses (allergic mucin)Exclusion of other fungal diseases Aspirin-exacerbated respiratory diseasePresence of nasal polypsIdiosyncratic reaction to aspirin or other NSAIDsDifficult to control asthmaDifficult to control sinus disease Open table in a new tab Because the patient’s symptoms were >12 weeks in duration, the diagnosis is not ARS. However, she had frequent exacerbations of sinusitis with worsening of symptoms that mimicked ABRS. CRS is defined as inflammation of the nose and paranasal sinuses lasting 12 weeks or longer. The prevalence estimates of CRS range from 5% to 15% of the adult population in the United States and Europe.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar The prevalence of physician-diagnosed disease with the use of objective criteria is estimated to be only 2%.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar The 4 characteristic signs and symptoms of CRS are nasal congestion, facial pain/pressure, anterior or posterior nasal drainage, and hyposmia or anosmia.2Hamilos D.L. Chronic rhinosinusitis: epidemiology and medical management.J Allergy Clin Immunol. 2011; 128 (quiz 708-9): 693-707Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar At least 2 of these symptoms should be present for 12 weeks or longer, when considering the diagnosis of CRS. Objective measures, such as direct endoscopic examination or dedicated sinus CT imaging studies, can be used to confirm the diagnosis of CRS.6Bhattacharyya N. Clinical and symptom criteria for the accurate diagnosis of chronic rhinosinusitis.Laryngoscope. 2006; 116: 1-22Crossref PubMed Scopus (158) Google Scholar, 7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar However, dedicated imaging and rhinoscopy should be used only after initial treatment fails or with recurrence of symptoms. CRS can be associated with a number of complications. Physical examination findings that suggest a possible complication include severe headache, facial swelling, significant periorbital edema, visual changes, proptosis, abnormal extraocular movements, ophthalmoplegia, and meningeal signs.8Dykewicz M. 7. Rhinitis and sinusitis.J Allergy Clin Immunol. 2003; 111: S520-S529Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar In these cases emergent evaluation is indicated to prevent permanent visual impairment or infectious progression to meningitis, cavernous sinus thrombosis, or brain abscess. Our patient presented with CRS and an orbital mass, which has an extensive differential diagnosis (Table III), but was found to have orbital sarcoidosis from which she recovered completely.Table IIIDifferential diagnosis of chronic rhinosinusitis with orbital massOrbital sarcoidosisOrbital cellulitisWegener granulomatosisChurg-Strauss syndromeGraves diseaseLymphomaOrbital apex syndrome (because of chronic invasive fungal rhinosinusitis)Periocular xanthogranuloma associated with adult-onset asthmaIgG4-related orbital inflammatory pseudotumor Open table in a new tab CRS remains a challenge to diagnose because its symptoms mimic many other conditions, its onset is often insidious in nature, physicians do not inquire about disease-specific symptoms such as anosmia, and/or clinicians lack the training to perform nasal endoscopy.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Adding to the challenge, it is a disease composed of multiple phenotypes, each with unique characteristics that are lumped into the broad term chronic rhinosinusitis.9Meltzer E. Hamilos D. Rhinosinusitis diagnosis and management for the clinician: a synopsis of recent consensus guidelines.Mayo Clinic Proc. 2011; 86: 427-443Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar These various subtypes of CRS have unique presentations and management options (Table II), although the exact division of subtypes remains controversial. Chronic rhinosinusitis without nasal polyps (CRSsNP) is the most prevalent subtype, accounting for approximately 60% to 65% of cases of CRS. In general, persons with CRSsNP have more prominent symptoms of facial pain and purulent discharge.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar Histologically, the mucosal lining shows basement membrane thickening, goblet cell hyperplasia, limited subepithelial edema, and prominent fibrosis and mononuclear cell infiltrate.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar Immunologically, more skewing occurs toward a TH1 phenotype.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 10Van Zele T. Claeys S. Gevaert P. Van Maele G. Holtappels G. Van Cauwenberge P. et al.Differentiation of chronic sinus diseases by measurement of inflammatory mediators.Allergy. 2006; 61: 1280-1289Crossref PubMed Scopus (579) Google Scholar Although both eosinophils and neutrophils are part of the inflammatory milieu, eosinophils are less prominent in the mucosa of patients with CRSsNP, suggesting this subtype can be characterized as having more of a neutrophilic process.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar, 7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar CRSsNP in the pediatric population has similar signs and symptoms as adult CRS, with chronic cough slightly more prominent than in adults.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Diagnosis of CRS in children is more challenging, given the large overlap of symptoms with common childhood nasal diseases and difficulties with the physical examination.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Another important distinction in pediatric CRS is the prominent role of the adenoids, because it is hypothesized they harbor biofilms that act as a bacterial reservoir.11Zuliani G. Carron M. Gurrola J. Coleman C. Haupert M. Berk R. et al.Identification of adenoid biofilms in chronic rhinosinusitis.Int J Pediatr Otorhinolaryngol. 2006; 70: 1613-1617Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar In addition, biofilms may also contribute to chronic inflammation and increased resistance by protecting bacteria from host defense mechanisms and antibiotics.5Fokkens W.J. Lund V.J. Mullol J. Bachert C. Alobid I. Baroody F. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2012.Rhinol Suppl. 2012; (3p preceding table of contents, 1-298)PubMed Google Scholar Chronic rhinosinusitis with nasal polyps (CRSwNP) occurs in approximately 20% of persons with CRS. In general, persons with CRSwNP present with symptoms of prominent nasal obstruction and hyposmia/anosmia and complain less of facial pain.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar This subtype tends to be more refractory to conventional medical treatment, requires more surgical intervention, and has greater morbidity.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar On physical examination large polyps can sometimes be visualized with anterior rhinoscopy alone. They appear translucent, have a yellow gray color, lack sensitivity, and typically arise around the ostiomeatal complex at the middle meatus.12Scadding G. Durham S. Mirakian R. Jones N. Drake-Lee A.B. Ryan D. et al.BSACI guidelines for the management of rhinosinusitis and nasal polyposis.Clin Exp Allergy. 2008; 38: 260-275Crossref PubMed Scopus (157) Google Scholar Some polyps may only be detected with CT imaging studies. In approximately 80% to 90% of white patients with CRSwNP there is a prominent tissue eosinophilia.13Gevaert P. Van Bruaene N. Cattaert T. Van Steen K. Van Zele T. Acke F. et al.Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis.J Allergy Clin Immunol. 2011; 128: 989-995.e1-8Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar In whites, CRSwNP occurs almost exclusively in adults; in children, cystic fibrosis should be considered. Histologically there is epithelial damage, a thickened basement membrane, edematous and fibrotic stromal tissue, and reduced numbers of vessels and glands.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar Immunologically, there is more of a TH2 skewing; however, this likely is an oversimplification of a complex process.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar, 10Van Zele T. Claeys S. Gevaert P. Van Maele G. Holtappels G. Van Cauwenberge P. et al.Differentiation of chronic sinus diseases by measurement of inflammatory mediators.Allergy. 2006; 61: 1280-1289Crossref PubMed Scopus (579) Google Scholar Markers of allergic inflammation, such as eosinophil cationic protein, IL-4, and IL-5, do not differ locally in the sinonasal mucosa between atopic and nonatopic persons with nasal polyposis.7Meltzer E.O. Hamilos D.L. Hadley J.A. Lanza D.C. Marple B.F. Kicklas R.A. et al.Rhinosinusitis: establishing definitions for clinical research and patient care.J Allergy Clin Immunol. 2004; 114: 155-212Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar The histopathologic criteria required for the diagnosis of allergic fungal rhinosinusitis (AFRS) are (1) allergic mucin present on gross and/or histopathologic examination; (2) either (a) methenamine silver stain of allergic mucin positive for fungal hyphae but no fungal hyphae are seen in the mucosa (with or without positive fungal culture) or (b) silver stain negative and positive fungal culture; (3) sinus mucosal H&E stain characteristic for AFRS; and (4) exclusion of other histopathologic fungal diseases.14Schubert M. Goetz D. Evaluation and treatment of allergic fungal sinusitis, I: demographics and diagnosis.J Allergy Clin Immunol. 1998; 102: 387-394Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar An important acute process that should be excluded is acute invasive fungal rhinosinusitis in an