Rhinosinusitis - Synopsis - Peters AT, Patel G (Updated 2021)
Updated: January 2021
Originally Posted: June 2005
Updated by:
Anju T. Peters, MD
Northwestern University
Feinberg School of Medicine
Chicago, IL
United States
Gayatri Patel, MDNorthwestern University
Feinberg School of Medicine
Chicago, IL
United States
Original authors:
Mark D. Scarupa, MD
Associate, Institute for Asthma and Allergy
Chevy Chase and Wheaton, Maryland
Clinical Instructor, Johns Hopkins Asthma and Allergy Center
Baltimore, MD
Michael A. Kaliner, MD FAAAAI
Medical Director, Institute for Asthma and Allergy
Chevy Chase and Wheaton, Maryland
Professor of Medicine, George Washington University School of Medicine
Washington, DC
Rhinosinusitis (RS) is inflammation of the nasal cavity and paranasal sinuses.1 The term “rhinosinusitis” is preferred over “sinusitis” because inflammation of the sinus cavities is almost always accompanied by inflammation of the nasal cavities.2 Acute RS has a one-year prevalence of 6-15%, and chronic rhinosinusitis (CRS) affects approximately 12% of the US population.1, 3 Rhinosinusitis is associated with a significant negative impact on the quality of life and has high healthcare costs due to medical visits, prescriptions and over the counter medications, sinus surgeries, and missed days from work and school. The vast majority of patients with RS see primary care physicians. Other specialists, including allergists and otolaryngologists, also see patients with rhinosinusitis, especially those difficult to treat.
Classification
RS is often classified based on the duration of symptoms and inflammation.
Acute rhinosinusitis (ARS) is defined as symptoms lasting less than 12 weeks. ARS is further classified based on duration and presumed etiology as
- Viral rhinosinusitis (VRS)
- Acute bacterial rhinosinusitis (ABRS)
- Uncomplicated ABRS is a lack of evidence of infection extending outside of nasal and paranasal cavities
- Complicated ABRS is the presence of clinical evidence of involvement outside of nasal and paranasal cavities including orbital, intracranial/neurologic, or soft tissue extension
Recurrent acute rhinosinusitis (RARS) consists of 4 or more episodes of acute bacterial rhinosinusitis (ABRS) in a year. 2,4
Chronic rhinosinusitis (CRS) is defined as symptoms lasting longer than 12 weeks. CRS is further classified based on clinical phenotype and endotype inflammatory patterns5 as:
- Phenotypes:
- CRS without nasal polyps (CRSsNP)
- CRS with nasal polyps (CRSwNP)
- Aspirin exacerbated respiratory disease (AERD)
- Allergic fungal rhinosinusitis (AFRS)
- Endotypes (predominant cytokines):
- Type 1 (IFN-g)
- Type 2 (IL-5, and IL-13)
- Type 3 (IL-17)
Acute rhinosinusitis (ARS) and recurrent acute rhinosinusitis (RARS)
Most ARS are viral in origin and improve on their own. It is important to distinguish viral from bacterial RS to avoid prescribing unnecessary antibiotics that are not effective for viral infections.
ABRS is suspected when symptoms of an upper respiratory tract infection persist longer than 10 days or when symptoms worsen after an initial improvement (i.e., double sickening).1, 4, 6 Only about 0.5% to 2% of VRS become ABRS.7 Most common bacteria responsible for ABRS are Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. Staphylococcus aureus is also isolated in adults with ABRS. ABRS is primarily a clinical diagnosis, and radiographic imaging with a sinus computed tomography (CT) scan is recommended only if a complication or alternative diagnosis is suspected. RARS presents similarly with four or more episodes of acute rhinosinusitis; however, patients are asymptomatic in between episodes of acute infection.
Symptoms: Symptoms suggestive of ARS include nasal congestion or obstruction, facial or dental pain, purulent rhinorrhea, post-nasal drainage, headache, and cough. Additional signs associated with ABRS can include fever, severe pain, unilateral disease, fatigue, hyposmia, ear fullness, or pressure.
Physical examination: A head, ears, eyes, nose, and throat examination should be done. Pulmonary evaluation may also be needed. Clinical examination may include tenderness on palpation overlying the sinuses, purulent nasal or oropharyngeal secretions. Fever may or may not be present. Attention should be paid to the periorbital and cheek areas of the face to look for cellulitis or extra sinus involvement. Culture from the nasal cavity is not useful.
Therapy: Supportive therapy with analgesics and nasal saline irrigation may provide symptomatic relief.
Topical decongestants may improve symptoms but should not be used for more than 3 to 5 consecutive days to avoid rebound congestion.
Topical intranasal ipratropium bromide is an anti-cholinergic spray that may reduce primary symptoms of rhinorrhea associated with viral symptoms. Caution should be used in the elderly due to its anticholinergic effects.
Topical intranasal steroids improve symptoms when used as monotherapy in mild to moderate ARS.4, 8, 9
There is no evidence that antihistamines, oral decongestants, or guaifenesin provide significant symptomatic relief of ARS.
Antibiotics for uncomplicated ARS in adults provides marginal benefit in most cases and needs to be evaluated in context of potential side effects.10 Careful patient selection based on signs and symptoms are essential in deciding who may benefit from antibiotics. Based on guidelines, antibiotics are recommended if patients don’t improve by 7-10 days after ARS diagnosis or if symptoms worsen at any time.2, 4 Antibiotics should be used earlier if there is evidence of complications such as periorbital swelling or redness. Antibiotics for ABRS that are recommended by European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), International Consensus Statement on Allergy and Rhinology (ICAR), and Infectious Diseases Society of America (IDSA) guidelines are noted in Table 1. Guidelines recommend 7-10 days of therapy with antibiotics.2, 4
If antibiotics are used, intranasal corticosteroid spray can be used as an adjunct in ARS.9, 11, 12
Endoscopic surgical intervention is required when there is a risk of intracranial complication or a patient with periorbital or orbital abscess.
Table 1. Antibiotics for acute bacterial rhinosinusitis
| Primary antibiotic choice | Secondary antibiotic choice |
| 2020 EPOS clinical guidelines1 | |
| Amoxicillin/penicillin | n/a |
| 2021 ICAR clinical practice guidelines4 | |
| Amoxicillin ±clavulanate | Trimethoprim-sulfamethoxazole, doxycycline, or a fluoroquinolone (options if failed amoxicillin ±clavulanate or if penicillin allergy) |
| 2012 IDSA clinical practice guidelines2 | |
| Amoxicillin-clavulanate | Levofloxacin (if Type I hypersensitivity to ß lactam in children or adults); Doxycycline (if ß lactam allergy in adults); Clindamycin & third-generation cephalosporin such as cefixime or cefpodoxime (if non-type 1 hypersensitivity in children) |
n/a: not available
EPOS: European Position Paper on Rhinosinusitis and Nasal Polyps
ICAR: International Consensus Statement on Allergy and Rhinology
IDSA: Infectious Diseases Society of America
Chronic rhinosinusitis (CRS)
The prevalence of CRS worldwide ranges from about 8% in China, 8.4% in Korea, 11% in Europe, and 12% in the United States.13-16
The exact etiology of CRS remains unknown. A combination of exogenous exposures and host factors may be responsible for the inflammation that is characteristic of CRS. CRS is diagnosed when patients have sinonasal symptoms greater than 12 weeks in conjunction with evidence of inflammation on endoscopy and/or sinus CT scan.1 CRS is often categorized as CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRS is a heterogeneous disease and is characterized by type 1 (IFN-g), type 2 (IL-5 and IL-13), and/or type 3 (IL-17A) inflammation.5, 17 Approximately 85% of patients with CRSwNP and 50% of patients with CRSsNP from the United States exhibit type 2 inflammation.5, 18 This is in contrast to parts of Asia which historically have had lower type 2 signature profiles in CRS patients, but this data is evolving.19
A subgroup of patients with CRSwNP and asthma has worsening respiratory symptoms with aspirin and nonsteroidal anti-inflammatory drug (NSAID) ingestion, which is classified as aspirin-exacerbated respiratory disease (AERD).
Another subgroup of patients with CRSwNP has allergic fungal sinusitis (AFRS). Bent and Kuhn diagnostic criteria are used to help differentiate AFRS from other subtypes of CRSwNP. They include type I hypersensitivity to fungi, nasal polyps, characteristic CT findings, eosinophilic mucus without fungal invasion, and positive fungal stain.
Symptoms: Symptoms of CRS can be varied but should include two of the following symptoms: one of the symptoms should either be nasal blockage/obstruction/congestion or nasal discharge, ±facial pain/pressure, ±reduced or loss of smell (or ±cough if evaluating in children).1
Physical examination: A head, ears, eyes, nose, and throat examination should be done. Pulmonary evaluation may also be needed given the high rates of coexisting asthma. Examination either by nasal endoscopy or anterior rhinoscopy may show purulent mucus or edema in the middle meatus or ethmoid area, or show polyps (semi-translucent, pale gray growth which typically arises from ethmoid or middle meatus region).
Computed tomography (CT): A sinus CT may be needed for objective confirmation of sinonasal inflammation and to distinguish CRS from other conditions with similar symptoms (for example, allergic rhinitis, atypical facial pain).
Aeroallergen allergy testing (in vivo or in vitro): allows identification and treatment of allergic rhinitis that often coexists with and may modify CRS.
Therapy: Saline nasal irrigation can be recommended for CRS as some data suggests improved symptoms and quality of life.1
Topical intranasal corticosteroids have strong evidence for benefit and are the first-line treatment for both CRSsNP and CRSwNP; they are well tolerated and have minimal adverse effects.20-22 A problem frequently encountered, however, with intranasal corticosteroids delivered by low-volume devices (i.e., spray bottle) is reduced penetration into the sinuses.23 Use of large-volume corticosteroid irrigation (budesonide or mometasone) provides better distribution and penetration, which improves subjective sino-nasal symptoms and quality of life as well as objective radiographic and endoscopic disease severity compared to traditional nasal spray. 24, 25
Exhalation Delivery System for Fluticasone (EDS-FLU) is a novel delivery technique that uses exhalation with a closed palate to improve corticosteroid deposition deeper in the nasal cavity.26, 27 To date, this is approved only for CRSwNP.
Bioabsorbable mometasone sinus implants were also developed to improve corticosteroid delivery in sinuses. Two are currently approved: mometasone furoate implant 370 μg elutes corticosteroid for approximately 30 days and designed as post-operative placement for CRSsNP and CRSwNP; this is approved in the US and Europe.28 There is also a mometasone furoate implant 1350 μg approved in the US for CRSwNP patients who have had ethmoid sinus surgery and can be placed in the office setting.29
Short-term oral corticosteroids for CRSwNP shrink nasal polyps and reduce inflammation.30 Benefits and risks should be weighed carefully as significant adverse effects can occur with systemic corticosteroid use.31, 32
Antibiotics are used for acute exacerbations of CRS; however, there is limited evidence for their efficacy.6, 33
Aspirin desensitization, a pharmacologic induction of drug tolerance during which tolerance to aspirin is induced and maintained, is a potential therapeutic option for patients with AERD. This procedure consists of administering incremental oral doses of aspirin over 1-2 days until a dose of 650 mg of aspirin can be taken. Limited data suggest aspirin desensitization is most efficacious after surgery in some patients.34
Dupilumab, an anti-IL4R∝ monoclonal antibody, is the first FDA-approved biologic agent for CRSwNP in the United States (US) and Europe. Dupilumab improves nasal polyp size, nasal congestion, sense of smell, quality of life, and decreases systemic corticosteroids and/or nasal polyp surgery.35
Omalizumab, an anti-IgE monoclonal antibody, has completed two phase 3 trials in subjects with CRSwNP. Omalizumab improves nasal polyp size, total nasal symptom score, individual symptoms, and quality of life.36 It has recently been approved for use in the US and Europe for nasal polyps.
Mepolizumab, an anti-IL5 monoclonal antibody, has completed a phase 3 trial in patients with CRSwNP. Early unpublished results show improvement in nasal polyp score and nasal obstruction score.
Benralizumab, an anti-IL5R∝ monoclonal antibody, is currently being evaluated in CRSwNP. One phase 3 US trial has been completed with results unpublished. A second phase 3 trial with sites throughout Asia is presently ongoing.
Currently, there are no biomarkers to facilitate patient selection or predict biologic response. There are no head-to-head studies that have compared biologics in a randomized fashion.
Functional endoscopic sinus surgery may be considered in patients who fail medical therapy.
Oral antihistamines and leukotriene antagonists have no specific role in CRS management unless indicated for a comorbid condition.
Common modifying factors associated with rhinosinusitis
Allergic rhinitis: Although no direct causality between RS and allergic rhinitis (AR) has been established, they often coexist. AR is present in 25-31% of patients with ARS and 40-84% with CRS suggesting at least an association between the two conditions.37-39 The relationship between AR with individual CRS phenotypes has also been examined, but results are conflicting.40 Some evidence suggests that patients with CRSwNP have increased allergen sensitization. Tan and colleagues observed a higher median number of positive skin prick tests to environmental allergens in CRSwNP compared to CRSsNP, although this was not statistically significant.38
Asthma: The association is supported by the high prevalence of CRS and recurrent ARS in asthmatics. Sinus disease was observed in 45% of patients in the Severe Asthma Research Program (SARP) cohort.41 Asthma severity and frequency of asthma exacerbations are directly correlated to the severity of sinus disease.42-44 Studies suggest that medical and/or surgical treatment of rhinosinusitis improves asthma control; therefore, asthmatics who have difficult-to-control disease should be assessed for rhinosinusitis.45, 46
Immunodeficiencies: Antibody deficiencies such as IgA deficiency, common variable immunodeficiency, and specific antibody deficiency have been documented in patients with CRS and RARS.47 Screening for immunodeficiencies in patients with refractory CRS and recurrent infections, especially when associated with bronchiectasis or pneumonia, is essential to disease management. Evaluation of immunodeficiency most often includes quantitative immunoglobulins (IgG, IgA, and IgM), pre-immunization and post-immunization antibody responses to tetanus toxoid and pneumococcal polysaccharide vaccines.
Cystic fibrosis: The prevalence of CRS is nearly 100% in patients with cystic fibrosis (CF).48 CF screening should be considered in patients who experience CRS at an early age and in any child with nasal polyps.
Table 2 lists some of the other diseases associated with rhinosinusitis.
Table 2. Diseases associated with rhinosinusitis
| Asthma |
| Granulomatosis with polyangiitis (Wegener’s granulomatosis) |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) |
| Immunodeficiencies: common variable immune deficiency, IgA deficiency, specific antibody deficiency, acquired immunodeficiency syndrome (AIDS) |
| Genetic abnormalities: cystic fibrosis, ciliary dyskinesia, Young’s syndrome |
| Gastroesophageal reflux disease |
| Sleep apnea |
| Sarcoidosis |
| Allergic rhinitis |
References
1. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58(Suppl S29):1-464.
2. Chow AW, Benninger MS, Brook I, Brozek JL, Goldstein EJC, Hicks LA, et al. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. Clinical Infectious Diseases. 2012;54(8):e72-e112.
3. National Center for Health Statistics CfDCaP. National Health Interview Survey. Summary Health Statistic Tables for U.S. Adults.
4. Orlandi RR, Kingdom TT, Smith TL, Bleier B, DeConde A, Luong A, et al. International Consensus Statement on Rhinology and Allergy: Rhinosinusitis. Int Forum Allergy Rhinol. 2020.
5. Stevens WW, Peters AT, Tan BK, Klingler AI, Poposki JA, Hulse KE, et al. Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2019.
6. Peters AT, Spector S, Hsu J, Hamilos DL, Baroody FM, Chandra RK, et al. Diagnosis and management of rhinosinusitis: a practice parameter update. Ann Allergy Asthma Immunol. 2014;113(4):347-85.
7. Gwaltney JM, Jr. Acute community-acquired sinusitis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1996;23(6):1209-25.
8. Meltzer EO, Bachert C, Staudinger H. Treating acute rhinosinusitis: comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, and placebo. J Allergy Clin Immunol. 2005;116(6):1289-95.
9. Zalmanovici Trestioreanu A, Yaphe J. Intranasal steroids for acute sinusitis. The Cochrane database of systematic reviews. 2013;2013(12):CD005149-CD.
10. Lemiengre MB, van Driel ML, Merenstein D, Liira H, Mäkelä M, De Sutter AIM. Antibiotics for acute rhinosinusitis in adults. Cochrane Database of Systematic Reviews. 2018(9).
11. Nayak AS, Settipane GA, Pedinoff A, Charous BL, Meltzer EO, Busse WW, et al. Effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis. Ann Allergy Asthma Immunol. 2002;89(3):271-8.
12. Dolor RJ, Witsell DL, Hellkamp AS, Williams J, John W., Califf RM, Simel DL, et al. Comparison of Cefuroxime With or Without Intranasal Fluticasone for the Treatment of RhinosinusitisThe CAFFS Trial: A Randomized Controlled Trial. JAMA. 2001;286(24):3097-105.
13. Shi JB, Fu QL, Zhang H, Cheng L, Wang YJ, Zhu DD, et al. Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities. Allergy. 2015;70(5):533-9.
14. Hirsch AG, Stewart WF, Sundaresan AS, Young AJ, Kennedy TL, Scott Greene J, et al. Nasal and sinus symptoms and chronic rhinosinusitis in a population-based sample. Allergy. 2017;72(2):274-81.
15. Hastan D, Fokkens WJ, Bachert C, Newson RB, Bislimovska J, Bockelbrink A, et al. Chronic rhinosinusitis in Europe--an underestimated disease. A GA²LEN study. Allergy. 2011;66(9):1216-23.
16. Ahn J-C, Kim J-W, Lee CH, Rhee C-S. Prevalence and Risk Factors of Chronic Rhinosinusitus, Allergic Rhinitis, and Nasal Septal Deviation: Results of the Korean National Health and Nutrition Survey 2008-2012. JAMA Otolaryngology–Head & Neck Surgery. 2016;142(2):162-7.
17. Yip J, Monteiro E, Chan Y. Endotypes of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2019;27(1):14-9.
18. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016;137(5):1449-56.e4.
19. Zhang Y, Gevaert E, Lou H, Wang X, Zhang L, Bachert C, et al. Chronic rhinosinusitis in Asia. J Allergy Clin Immunol. 2017;140(5):1230-9.
20. Snidvongs K, Kalish L, Sacks R, Craig JC, Harvey RJ. Topical steroid for chronic rhinosinusitis without polyps. Cochrane Database Syst Rev. 2011(8):Cd009274.
21. Kalish L, Snidvongs K, Sivasubramaniam R, Cope D, Harvey RJ. Topical steroids for nasal polyps. Cochrane Database Syst Rev. 2012;12:Cd006549.
22. Chong LY, Head K, Hopkins C, Philpott C, Schilder AG, Burton MJ. Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;4:Cd011996.
23. Thomas WW, 3rd, Harvey RJ, Rudmik L, Hwang PH, Schlosser RJ. Distribution of topical agents to the paranasal sinuses: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2013;3(9):691-703.
24. Harvey RJ, Snidvongs K, Kalish LH, Oakley GM, Sacks R. Corticosteroid nasal irrigations are more effective than simple sprays in a randomized double-blinded placebo-controlled trial for chronic rhinosinusitis after sinus surgery. Int Forum Allergy Rhinol. 2018;8(4):461-70.
25. Tait S, Kallogjeri D, Suko J, Kukuljan S, Schneider J, Piccirillo JF. Effect of Budesonide Added to Large-Volume, Low-pressure Saline Sinus Irrigation for Chronic Rhinosinusitis: A Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2018;144(7):605-12.
26. Sindwani R, Han JK, Soteres DF, Messina JC, Carothers JL, Mahmoud RA, et al. NAVIGATE I: Randomized, Placebo-Controlled, Double-Blind Trial of the Exhalation Delivery System With Fluticasone for Chronic Rhinosinusitis With Nasal Polyps. Am J Rhinol Allergy. 2019;33(1):69-82.
27. Leopold DA, Elkayam D, Messina JC, Kosik-Gonzalez C, Djupesland PG, Mahmoud RA. NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis. J Allergy Clin Immunol. 2019;143(1):126-34.e5.
28. Smith TL, Singh A, Luong A, Ow RA, Shotts SD, Sautter NB, et al. Randomized controlled trial of a bioabsorbable steroid-releasing implant in the frontal sinus opening. Laryngoscope. 2016;126(12):2659-64.
29. Kern RC, Stolovitzky JP, Silvers SL, Singh A, Lee JT, Yen DM, et al. A phase 3 trial of mometasone furoate sinus implants for chronic sinusitis with recurrent nasal polyps. Int Forum Allergy Rhinol. 2018;8(4):471-81.
30. Martinez-Devesa P, Patiar S. Oral steroids for nasal polyps. Cochrane Database Syst Rev. 2011(7):Cd005232.
31. Hox V, Lourijsen E, Jordens A, Aasbjerg K, Agache I, Alobid I, et al. Benefits and harm of systemic steroids for short- and long-term use in rhinitis and rhinosinusitis: an EAACI position paper. Clinical and Translational Allergy. 2020;10(1):1.
32. Poetker DM, Reh DD. A comprehensive review of the adverse effects of systemic corticosteroids. Otolaryngol Clin North Am. 2010;43(4):753-68.
33. Head K, Chong LY, Piromchai P, Hopkins C, Philpott C, Schilder AG, et al. Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2016;4:Cd011994.
34. Shah SJ AW, Ponduri A, Pelletier T, Ren Z, Keskin T, Roizen G, Rosenstreich D, Ferastraoaru D, Jerschow E. . Endoscopic sinus surgery improves aspirin treatment response in aspirin-exacerbated respiratory disease patients. Int Forum Allergy Rhinol. 2019;9(12):1401-8.
35. Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019.
36. Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. Journal of Allergy and Clinical Immunology. 2020.
37. Emanuel IA, Shah SB. Chronic rhinosinusitis: allergy and sinus computed tomography relationships. Otolaryngol Head Neck Surg. 2000;123(6):687-91.
38. Tan BK, Zirkle W, Chandra RK, Lin D, Conley DB, Peters AT, et al. Atopic profile of patients failing medical therapy for chronic rhinosinusitis. Int Forum Allergy Rhinol. 2011;1(2):88-94.
39. Savolainen S. Allergy in patients with acute maxillary sinusitis. Allergy. 1989;44(2):116-22.
40. Marcus S, Roland LT, DelGaudio JM, Wise SK. The relationship between allergy and chronic rhinosinusitis. Laryngoscope investigative otolaryngology. 2018;4(1):13-7.
41. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315-23.
42. Lin DC, Chandra RK, Tan BK, Zirkle W, Conley DB, Grammer LC, et al. Association between severity of asthma and degree of chronic rhinosinusitis. Am J Rhinol Allergy. 2011;25(4):205-8.
43. ten Brinke A, Grootendorst DC, Schmidt JT, De Bruïne FT, van Buchem MA, Sterk PJ, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol. 2002;109(4):621-6.
44. Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, et al. Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med. 2017;195(3):302-13.
45. Cao Y, Hong H, Sun Y, Lai Y, Xu R, Shi J, et al. The effects of endoscopic sinus surgery on pulmonary function in chronic rhinosinusitis patients with asthma: a systematic review and meta-analysis. Eur Arch Otorhinolaryngol. 2019;276(5):1405-11.
46. Ragab S, Scadding GK, Lund VJ, Saleh H. Treatment of chronic rhinosinusitis and its effects on asthma. Eur Respir J. 2006;28(1):68-74.
47. Keswani A, Dunn NM, Manzur A, Kashani S, Bossuyt X, Grammer LC, et al. The Clinical Significance of Specific Antibody Deficiency (SAD) Severity in Chronic Rhinosinusitis (CRS). The journal of allergy and clinical immunology In practice. 2017;5(4):1105-11.
48. Oomen KPQ, April MM. Sinonasal manifestations in cystic fibrosis. International journal of otolaryngology. 2012;2012:789572-.