Abstract
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a group of multifactorial and heterogeneous disorders with a significant economic strain on society, likely made up of different endotypes, each with a unique pathomechanism. In addition to the traditional clinical measures, there is a recognized need for reliable biomarkers to provide predictive information regarding diagnosis, endotypes, treatment responses, and future risk of recurrence. Fueled by the advances in basic research, various biomarkers have been explored in recent years. Biomarkers of CRSwNP can originate from a variety of sources, including nasal secretions, nasal biopsies, exhaled breath, and peripheral blood. In this review, we aim to summarize the existing and emerging biomarkers available for the evaluation and management of CRSwNP. Currently, eosinophil count in nasal mucosa has proved particularly valuable for endotyping, assessing disease severity, and predicting steroid responsiveness and surgical outcomes. Blood eosinophilia may be used as a surrogate for tissue eosinophilic inflammation, whereas its utility remains limited. Type 2 cytokines, such as IL-4, IL-5, and IL-13, and IgE have been identified as potential therapeutic targets. Moreover, matrix metalloproteinases (MMP)-9 is linked to healing quality after sinus surgery. Nasal nitric oxide (nNO) appears to fill the niche as a noninvasive measure for sinus ostial patency. In addition, recent data have shown some promising biomarkers involved in corticosteroid resistance and olfactory dysfunction. However, rigorous validation using large cohort studies is necessary before these biomarkers can be mainstreamed into clinical practice.
Similar content being viewed by others
References
Fokkens WJ, Lund VJ, Mullol J et al (2012) EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50:1–12
Stevens WW, Schleimer RP, Kern RC (2016) Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract 4:565–572
Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW, Naclerio RM, Schleimer RP, Ledford D (2013) Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 131:1479–1490
Taylor DR (2011) Using biomarkers in the assessment of airways disease. J Allergy Clin Immunol 128:927–934 (quiz 935–936)
Oyer SL, Mulligan JK, Psaltis AJ, Henriquez OA, Schlosser RJ (2013) Cytokine correlation between sinus tissue and nasal secretions among chronic rhinosinusitis and controls. Laryngoscope 123:E72–E78
Phillips PS, Sacks R, Marcells GN, Cohen NA, Harvey RJ (2011) Nasal nitric oxide and sinonasal disease: a systematic review of published evidence. Otolaryngol Head Neck Surg 144:159–169
Liu Z, Kim J, Sypek JP, Wang IM, Horton H, Oppenheim FG, Bochner BS (2004) Gene expression profiles in human nasal polyp tissues studied by means of DNA microarray. J Allergy Clin Immunol 114:783–790
Upton DC, Welham NV, Kuo JS, Walker JW, Pasic TR (2011) Chronic rhinosinusitis with nasal polyps: a proteomic analysis. Ann Otol Rhinol Laryngol 120:780–786
Cao PP, Li HB, Wang BF et al (2009) Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol 124:478–484, 484.e1–2
Ikeda K, Shiozawa A, Ono N, Kusunoki T, Hirotsu M, Homma H, Saitoh T, Murata J (2013) Subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil. Laryngoscope 123:E1–E9
Wen W, Liu W, Zhang L et al (2012) Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy. J Allergy Clin Immunol 129:1522–1528.e5
Ishitoya J, Sakuma Y, Tsukuda M (2010) Eosinophilic chronic rhinosinusitis in Japan. Allergol Int 59:239–245
Bachert C, Zhang L, Gevaert P (2015) Current and future treatment options for adult chronic rhinosinusitis: focus on nasal polyposis. J Allergy Clin Immunol 136:1431–1440 (quiz 1441)
Snidvongs K, Lam M, Sacks R, Earls P, Kalish L, Phillips PS, Pratt E, Harvey RJ (2012) Structured histopathology profiling of chronic rhinosinusitis in routine practice. Int Forum Allergy Rhinol 2:376–385
Ottaviano G, Cappellesso R, Mylonakis I et al (2015) Endoglin (CD105) expression in sinonasal polyposis. Eur Arch Otorhinolaryngol 272:3367–3373
Kountakis SE, Arango P, Bradley D, Wade ZK, Borish L (2004) Molecular and cellular staging for the severity of chronic rhinosinusitis. Laryngoscope 114:1895–1905
Soler ZM, Sauer D, Mace J, Smith TL (2010) Impact of mucosal eosinophilia and nasal polyposis on quality-of-life outcomes after sinus surgery. Otolaryngol Head Neck Surg 142:64–71
Lou H, Meng Y, Piao Y, Wang C, Zhang L, Bachert C (2015) Predictive significance of tissue eosinophilia for nasal polyp recurrence in the Chinese population. Am J Rhinol Allergy 29:350–356
Tokunaga T, Sakashita M, Haruna T et al (2015) Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy 70:995–1003
Matsuwaki Y, Ookushi T, Asaka D et al (2008) Chronic rhinosinusitis: risk factors for the recurrence of chronic rhinosinusitis based on 5-year follow-up after endoscopic sinus surgery. Int Arch Allergy Immunol 146(Suppl 1):77–81
Sakuma Y, Ishitoya J, Komatsu M et al (2011) New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis. Auris Nasus Larynx 38:583–588
Zuo K, Guo J, Chen F, Xu R, Xu G, Shi J, Li H (2014) Clinical characteristics and surrogate markers of eosinophilic chronic rhinosinusitis in Southern China. Eur Arch Otorhinolaryngol 271:2461–2468
Roufosse F, Weller PF (2010) Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol 126:39–44
Gevaert P, Bachert C, Holtappels G et al (2003) Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy 58:371–379
Bachert C, Zhang N, Holtappels G et al (2010) Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J Allergy Clin Immunol 126:962–968, 968.e1–6
Gevaert P, Calus L, Van Bruaene N, Van Zele T, Bachert C (2015) Allergic sensitization, high local IL-5 and IgE predict surgical outcome 12 years after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol 135:AB238
Van Zele T, Holtappels G, Gevaert P, Bachert C (2014) Differences in initial immunoprofiles between recurrent and nonrecurrent chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy 28:192–198
Tomassen P, Vandeplas G, Van Zele T et al (2016) Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol 137:1449–1456.e4
Gevaert P, Lang-Loidolt D, Lackner A et al (2006) Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol 118:1133–1141
Gevaert P, Van Bruaene N, Cattaert T et al (2011) Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol 128:989–995.e1–e8
Pauwels B, Jonstam K, Bachert C (2015) Emerging biologics for the treatment of chronic rhinosinusitis. Expert Rev Clin Immunol 11:349–361
Bachert C, Mannent L, Naclerio RM et al (2016) Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 315:469–479
Kato A (2015) Immunopathology of chronic rhinosinusitis. Allergol Int 64:121–130
Lam EP, Kariyawasam HH, Rana BM et al (2016) IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa. J Allergy Clin Immunol 137:1514–1524
Mjosberg JM, Trifari S, Crellin NK et al (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12:1055–1062
Shaw JL, Fakhri S, Citardi MJ, Porter PC, Corry DB, Kheradmand F, Liu YJ, Luong A (2013) IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps. Am J Respir Crit Care Med 188:432–439
Lam M, Hull L, McLachlan R et al (2013) Clinical severity and epithelial endotypes in chronic rhinosinusitis. Int Forum Allergy Rhinol 3:121–128
Shin HW, Kim DK, Park MH et al (2015) IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol 135:1476–1485.e7
Cayrol C, Girard JP (2014) IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol 31:31–37
Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H (2008) A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 121:1484–1490
Lee HY, Rhee CK, Kang JY et al (2014) Blockade of IL-33/ST2 ameliorates airway inflammation in a murine model of allergic asthma. Exp Lung Res 40:66–76
Reh DD, Wang Y, Ramanathan M Jr, Lane AP (2010) Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33. Am J Rhinol Allergy 24:105–109
Ozturan A, Eyigor H, Eyigor M, Osma U, Yilmaz MD, Selcuk OT, Renda L, Gultekin M (2017) The role of IL-25 and IL-33 in chronic rhinosinusitis with or without nasal polyps. Eur Arch Otorhinolaryngol 274:283–288
Kim DK, Jin HR, Eun KM, Mo JH, Cho SH, Oh S, Cho D, Kim DW (2016) The role of interleukin-33 in chronic rhinosinusitis. Thorax
Nagarkar DR, Poposki JA, Tan BK et al (2013) Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol 132:593–600.e12
Liao B, Cao PP, Zeng M et al (2015) Interaction of thymic stromal lymphopoietin, IL-33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps. Allergy 70:1169–1180
Gauvreau GM, O’Byrne PM, Boulet LP et al (2014) Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 370:2102–2110
Stevens WW, Lee RJ, Schleimer RP, Cohen NA (2015) Chronic rhinosinusitis pathogenesis. J Allergy Clin Immunol 136:1442–1453
Hulse KE, Norton JE, Suh L et al (2013) Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J Allergy Clin Immunol 131:1075–1083, 1083.e1–7
De Schryver E, Devuyst L, Derycke L, Dullaers M, Van Zele T, Bachert C, Gevaert P (2015) Local immunoglobulin e in the nasal mucosa: clinical implications. Allergy Asthma Immunol Res 7:321–331
Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P (2001) Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 107:607–614
Gevaert P, Calus L, Van Zele T et al (2013) Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 131:110–116.e1
Tan BK, Li QZ, Suh L et al (2011) Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 128:1198–1206.e1
Goncalves C, Pinaffi JV, Carvalho JF et al (2007) Antineutrophil cytoplasmic antibodies in chronic rhinosinusitis may be a marker of undisclosed vasculitis. Am J Rhinol 21:691–694
Watelet JB, Dogne JM, Mullier F (2015) Remodeling and repair in rhinosinusitis. Curr Allergy Asthma Rep 15:34
Bassiouni A, Chen PG, Wormald PJ (2013) Mucosal remodeling and reversibility in chronic rhinosinusitis. Curr Opin Allergy Clin Immunol 13:4–12
Li X, Meng J, Qiao X et al (2010) Expression of TGF, matrix metalloproteinases, and tissue inhibitors in Chinese chronic rhinosinusitis. J Allergy Clin Immunol 125:1061–1068
Malinsky RR, Valera FC, Cavallari FE, Kupper DS, Milaneze C, Silva JS, Tamashiro E, Anselmo-Lima WT (2013) Matrix metalloproteinases and their impact on sinusal extension in chronic rhinosinusitis with nasal polyps. Eur Arch Otorhinolaryngol 270:1345–1348
Yeo NK, Eom DW, Oh MY, Lim HW, Song YJ (2013) Expression of matrix metalloproteinase 2 and 9 and tissue inhibitor of metalloproteinase 1 in nonrecurrent vs recurrent nasal polyps. Ann Allergy Asthma Immunol 111:205–210
Wang LF, Chien CY, Chiang FY, Chai CY, Tai CF (2012) Corelationship between matrix metalloproteinase 2 and 9 expression and severity of chronic rhinosinusitis with nasal polyposis. Am J Rhinol Allergy 26:e1–e4
Watelet JB, Claeys C, Van Cauwenberge P, Bachert C (2004) Predictive and monitoring value of matrix metalloproteinase-9 for healing quality after sinus surgery. Wound Repair Regen 12:412–418
Watelet JB, Demetter P, Claeys C, Van Cauwenberge P, Cuvelier C, Bachert C (2005) Neutrophil-derived metalloproteinase-9 predicts healing quality after sinus surgery. Laryngoscope 115:56–61
Van Zele T, Gevaert P, Holtappels G et al (2010) Oral steroids and doxycycline: two different approaches to treat nasal polyps. J Allergy Clin Immunol 125:1069–1076.e4
Huvenne W, Zhang N, Tijsma E et al (2008) Pilot study using doxycycline-releasing stents to ameliorate postoperative healing quality after sinus surgery. Wound Repair Regen 16:757–767
Wang M, Wang X, Zhang N et al (2015) Association of periostin expression with eosinophilic inflammation in nasal polyps. J Allergy Clin Immunol 136:1700–1703.e1–e9
Takayama G, Arima K, Kanaji T et al (2006) Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 118:98–104
Ohta N, Ishida A, Kurakami K et al (2014) Expressions and roles of periostin in otolaryngological diseases. Allergol Int 63:171–180
Zhang W, Hubin G, Endam LM, Al-Mot S, Filali-Mouhim A, Desrosiers M (2012) Expression of the extracellular matrix gene periostin is increased in chronic rhinosinusitis and decreases following successful endoscopic sinus surgery. Int Forum Allergy Rhinol 2:471–476
Kim DW, Kulka M, Jo A et al (2016) Cross-talk between human mast cells and epithelial cells by IgE-mediated periostin production in eosinophilic nasal polyps. J Allergy Clin Immunol
Delclaux C, Malinvaud D, Chevalier-Bidaud B, Callens E, Mahut B, Bonfils P (2008) Nitric oxide evaluation in upper and lower respiratory tracts in nasal polyposis. Clin Exp Allergy 38:1140–1147
Colantonio D, Brouillette L, Parikh A, Scadding GK (2002) Paradoxical low nasal nitric oxide in nasal polyposis. Clin Exp Allergy 32:698–701
Jeong JH, Yoo HS, Lee SH, Kim KR, Yoon HJ, Kim SH (2014) Nasal and exhaled nitric oxide in chronic rhinosinusitis with polyps. Am J Rhinol Allergy 28:e11–e16
Bommarito L, Guida G, Heffler E, Badiu I, Nebiolo F, Usai A, De Stefani A, Rolla G (2008) Nasal nitric oxide concentration in suspected chronic rhinosinusitis. Ann Allergy Asthma Immunol 101:358–362
Lee JM, McKnight CL, Aves T, Yip J, Grewal AS, Gupta S (2015) Nasal nitric oxide as a marker of sinus mucosal health in patients with nasal polyposis. Int Forum Allergy Rhinol 5:894–899
Vaidyanathan S, Williamson P, Anderson K, Lipworth B (2010) Effect of systemic steroids on humming nasal nitric oxide in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol 105:412–417
Mullol J, Obando A, Pujols L, Alobid I (2009) Corticosteroid treatment in chronic rhinosinusitis: the possibilities and the limits. Immunol Allergy Clin North Am 29:657–668
Pujols L, Mullol J, Picado C (2010) Importance of glucocorticoid receptors in upper and lower airways. Front Biosci (Landmark Ed) 15:789–800
Grzanka A, Misiolek M, Golusinski W, Jarzab J (2011) Molecular mechanisms of glucocorticoids action: implications for treatment of rhinosinusitis and nasal polyposis. Eur Arch Otorhinolaryngol 268:247–253
Hamilos DL, Leung DY, Muro S, Kahn AM, Hamilos SS, Thawley SE, Hamid QA (2001) GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone. J Allergy Clin Immunol 108:59–68
Valera FC, Queiroz R, Scrideli C, Tone LG, Anselmo-Lima WT (2009) Evaluating budesonide efficacy in nasal polyposis and predicting the resistance to treatment. Clin Exp Allergy 39:81–88
Milara J, Peiro T, Armengot M, Frias S, Morell A, Serrano A, Cortijo J (2015) Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 135:470–476
Milara J, Morell A, Ballester B, Armengot M, Morcillo E, Cortijo J (2017) MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 139:855–862.e13
Rombaux P, Huart C, Levie P, Cingi C, Hummel T (2016) Olfaction in chronic rhinosinusitis. Curr Allergy Asthma Rep 16:41
Mori E, Matsuwaki Y, Mitsuyama C, Okushi T, Nakajima T, Moriyama H (2013) Risk factors for olfactory dysfunction in chronic rhinosinusitis. Auris Nasus Larynx 40:465–469
Hulse KE, Stevens WW, Tan BK, Schleimer RP (2015) Pathogenesis of nasal polyposis. Clin Exp Allergy 45:328–346
Schlosser RJ, Mulligan JK, Hyer JM, Karnezis TT, Gudis DA, Soler ZM (2016) Mucous cytokine levels in chronic rhinosinusitis-associated olfactory loss. JAMA Otolaryngol Head Neck Surg 142:731–737
Tsybikov NN, Egorova EV, Kuznik BI, Fefelova EV, Magen E (2016) Neuron-specific enolase in nasal secretions as a novel biomarker of olfactory dysfunction in chronic rhinosinusitis. Am J Rhinol Allergy 30:65–69
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Funding
There was no funding for this study.
Rights and permissions
About this article
Cite this article
Yao, Y., Xie, S., Yang, C. et al. Biomarkers in the evaluation and management of chronic rhinosinusitis with nasal polyposis. Eur Arch Otorhinolaryngol 274, 3559–3566 (2017). https://doi.org/10.1007/s00405-017-4547-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00405-017-4547-2