Nasal mucus is proving to be a useful means by which to study the pathogenesis of chronic rhinosinusitis (CRS). Given the increase in publications examining nasal mucus and the lack of a review on this topic, we will focus on this noninvasive approach to studying CRS. Particular attention will be drawn towards inflammatory cytokines and biomarkers and their influence on disease severity.
Methods
A literature review of papers published in English pertaining to nasal mucus was performed using the PubMed database. The search utilized combinations of the following keywords: sinusitis, polyps, sample collection, nasal mucus, or nasal secretion. Studies solely on acute or bacterial sinusitis, allergic rhinitis, or cystic fibrosis were not included.
Results
A wide variety of materials and methods have been used to collect nasal mucus. Numerous assay types have been performed with the most common being ELISA, cytometric bead array, and proteomics. Most studies have focused on examining the levels of Th1/Th2 cytokines along with chemokines associated with type 2 immunity. Other factors identified include growth factors, senescence-associated proteins, complement, and antimicrobial defenses have also been identified. Nasal mucus cytokines have proven useful in cluster analysis and predicting postoperative improvement in Sino-nasal Outcome Test (SNOT-22) scores. One limitation of the use of nasal mucus is that some studies have suggested that nasal mucus does not always reflect the tissue microenvironment.
Conclusions
Nasal mucus represents a critical tool by which to examine the sinonasal microenvironment in a noninvasive manner. Unlike studies of tissue, it can be utilized in both surgically and medically managed patients and avoids the trauma of biopsies. However, studies are still needed to determine the most effective method for nasal mucus collection. Studies should also take care to confirm that nasal mucus markers do, in fact, reflect the levels of the product studied in the tissue.
NaclerioRMMeierHLKagey-SobotkaA, et al.Mediator release after nasal airway challenge with allergen. Am Rev Respir Dis. 1983;128(4):597–602.
2.
MasseyCJDiaz Del ValleFAbuzeidWM, et al.Sample collection for laboratory-based study of the nasal airway and sinuses: a research compendium. Int Forum Allergy Rhinol. 2020;10(3):303–313.
3.
LiberatiAAltmanDGTetzlaffJ, et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100-e.
4.
ChungYWChaJHanS, et al.Apolipoprotein E and periostin are potential biomarkers of nasal mucosal inflammation. A parallel approach of in vitro and in vivo secretomes. Am J Respir Cell Mol Biol. 2020;62(1):23–34.
5.
ParkSJJunYJLeeKJ, et al.Chronic rhinosinusitis with nasal polyps and without nasal polyps is associated with increased expression of lysophosphatidic acid-related molecules. Am J Rhinol Allergy. 2014;28(3):199–207.
6.
MinHJYoonJ-HKimC-H. HSP70 Is associated with the severity of inflammation in chronic rhinosinusitis. Am J Rhinol Allergy. 2016;30(4):e101–e1e6.
7.
MinHJKimSJKimTHChungHJYoonJHKimCH. Level of secreted HMGB1 correlates with severity of inflammation in chronic rhinosinusitis. Laryngoscope. 2015;125(7):E225–E230.
8.
DeroeeAFNaraghiMSontouAFEbrahimkhaniMRDehpourAR. Nitric oxide metabolites as biomarkers for follow-up after chronic rhinosinusitis surgery. Am J Rhinol Allergy. 2009;23(2):159–161.
9.
PonikauJUWinterLAKephartGM, et al.An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein. Int Forum Allergy Rhinol. 2015;5(1):28–35.
10.
Besançon-WateletCBénéMCMontagnePFaureGCJankowskiR. Eosinophilia and cell activation mediators in nasal secretions. Laryngoscope. 2002;112(1):43–46.
11.
ShimizuSGabazzaECOgawaT, et al.Role of thrombin in chronic rhinosinusitis-associated tissue remodeling. Am J Rhinol Allergy. 2011;25(1):7–11.
12.
SchmidCHabermannWBraunH, et al.Released intranasal eosinophilic major basic protein as a diagnostic marker for polypoid chronic rhinosinusitis. Otolaryngology-Head and Neck Surgery: Official Journal of American Academy of Otolaryngology-Head and Neck Surgery. 2010;143(3):386–391.
13.
TewfikMALatterichMDiFalcoMRSamahaM. Proteomics of nasal mucus in chronic rhinosinusitis. Am J Rhinol. 2007;21(6):680–685.
14.
CottrillEEChenBAdappaND, et al.Expression of dermcidin in human sinonasal secretions. Int Forum Allergy Rhinol. 2017;7(2):154–159.
15.
SeiberlingKAConleyDBTripathiA, et al.Superantigens and chronic rhinosinusitis: detection of staphylococcal exotoxins in nasal polyps. Laryngoscope. 2005;115(9):1580–1585.
16.
RankMAHaganJBSamantSAKitaH. A proposed model to study immunologic changes during chronic rhinosinusitis exacerbations: data from a pilot study. Am J Rhinol Allergy. 2013;27(2):98–101.
17.
KramerMFOstertagPPfrognerERaspG. Nasal interleukin-5, immunoglobulin E, eosinophilic cationic protein, and soluble intercellular adhesion molecule-1 in chronic sinusitis, allergic rhinitis, and nasal polyposis. Laryngoscope. 2000;110(6):1056–1062.
18.
KramerMFBurowGPfrognerERaspG. In vitro diagnosis of chronic nasal inflammation. Clin Exp Allergy. 2004;34(7):1086–1092.
19.
PericAVojvodicDRadulovicVVukomanovic-DurdevicBMiljanovicO. Correlation between cytokine levels in nasal fluid and eosinophil counts in nasal polyp tissue in asthmatic and non-asthmatic patients. Allergol Immunopathol (Madr). 2011;39(3):133–139.
20.
GrogerMBerntAWolfM, et al.Eosinophils and mast cells: a comparison of nasal mucosa histology and cytology to markers in nasal discharge in patients with chronic sino-nasal diseases. Eur Arch Otorhinolaryngol. 2013;270(10):2667–2676.
21.
San NicoloMHogerleCGellrichDEderKPfrognerEGrogerM. The time course of nasal cytokine secretion in patients with aspirin-exacerbated respiratory disease (AERD) undergoing aspirin desensitization: preliminary data. Eur Arch Otorhinolaryngol. 2020;277(2):445–452.
22.
Spadijer MirkovicCPericAVukomanovic DurdevicBVojvodicD. Effects of fluticasone furoate nasal spray on parameters of eosinophilic inflammation in patients with nasal polyposis and perennial allergic rhinitis. Ann Otol Rhinol Laryngol. 2017;126(8):573–580.
23.
WateletJ-BGevaertPHoltappelsGVan CauwenbergePBachertC. Collection of nasal secretions for immunological analysis. European Archives of Oto-Rhino-Laryngology and Head & Neck. 2004;261(5):242–246.
24.
OyerSLMulliganJKPsaltisAJHenriquezOASchlosserRJ. Cytokine correlation between sinus tissue and nasal secretions among chronic rhinosinusitis and controls. Laryngoscope. 2013;123(12):E72–E78.
25.
SansoniERSautterNBMaceJC, et al.Vitamin D3 as a novel regulator of basic fibroblast growth factor in chronic rhinosinusitis with nasal polyposis. Int Forum Allergy Rhinol. 2015;5(3):191–196.
26.
TurnerJHChandraRKLiPBonnetKSchlundtDG. Identification of clinically relevant chronic rhinosinusitis endotypes using cluster analysis of mucus cytokines. J Allergy Clin Immunol. 2018;141(5):1895–1897.e7.
27.
KaoSSRamezanpourMBassiouniA, et al.Barrier disruptive effects of mucus isolated from chronic rhinosinusitis patients. Allergy. 2020;75(1):200–203.
28.
TurnerJHLiPChandraRK. Mucus T helper 2 biomarkers predict chronic rhinosinusitis disease severity and prior surgical intervention. Int Forum Allergy Rhinol. 2018;8(10):1175–1183.
29.
MuellerSKNoceraALDillonST, et al.Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2019;9(2):177–186.
30.
LiuJ-XLiaoBYuQ-H, et al.IL-37-Mex3B-TLR3 axis in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2020;145(1):160–172.
31.
KaoSSBassiouniARamezanpourM, et al.Proteomic analysis of nasal mucus samples of healthy patients and patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2021;147(1):168–178.
32.
WuDYanBWangYZhangLWangC. Charcot-Leyden crystal concentration in nasal secretions predicts clinical response to glucocorticoids in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2019;144(1):345–348.e8.
33.
RiechelmannHDeutschleTRozsasiAKeckTPolzehlDBürnerH. Nasal biomarker profiles in acute and chronic rhinosinusitis. Clin Exp Allergy. 2005;35(9):1186–1191.
34.
ChowdhuryNILiPChandraRKTurnerJH. Baseline mucus cytokines predict 22-item Sino-Nasal Outcome Test results after endoscopic sinus surgery. Int Forum Allergy Rhinol. 2020;10(1):15–22.
35.
ChowdhuryNIChandraRKLiPElyKTurnerJH. Investigating the correlation between mucus cytokine levels, inflammatory cell counts, and baseline quality-of-life measures in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2019;9(5):538–544.
36.
Al BadaaiYDiFalcoMRTewfikMASamahaM. Quantitative proteomics of nasal mucus in chronic sinusitis with nasal polyposis. J Otolaryngol Head Neck Surg. 2009;38(3):381–389.
37.
MulliganJKPatelKWilliamsonT, et al.C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis. Mucosal Immunol. 2018;11(5):1375–1385.
WateletJBGevaertPBachertCHoltappelsGvan CauwenbergeP. Secretion of TGF-betal, TGF-beta2, EGF and PDGF into nasal fluid after sinus surgery. Eur Arch Otorhinolaryngol. 2002;259(5):234–238.
40.
HanXWuDSunZ, et al.Type 1/type 2 inflammatory cytokines correlate with olfactory function in patients with chronic rhinosinusitis. Am J Otolaryngol. 2020;41(5):102587.
41.
WuJChandraRKLiPHullBPTurnerJH. Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis. Laryngoscope. 2018;128(9):E304–E310.
42.
SiuJKlinglerLWangY, et al.Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial. Xenobiotica. 2020;50(12):1443–1450.
43.
MuellerSKNoceraALDillonSTWuDLibermannTABleierBS. Highly multiplexed proteomic analysis reveals significant tissue and exosomal coagulation pathway derangement in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2018;8(12):1438–1444.
44.
MuellerSKWendlerONoceraA, et al.Escalation in mucus cystatin 2, pappalysin-A, and periostin levels over time predict need for recurrent surgery in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2019;9(10):1212–1219.
45.
SolerZMSchlosserRJBodnerTE, et al.Endotyping chronic rhinosinusitis based on olfactory cleft mucus biomarkers. J Allergy Clin Immunol. 2021;147(5):1732–1741.e1.
46.
SmithTLSchlosserRJSolerZM, et al.Olfactory cleft mucus inflammatory proteins in CRS: a case-control study. Int Forum Allergy Rhinol. 2021;11(9):1321–1335.
47.
SolerZMYooFSchlosserRJ, et al.Correlation of mucus inflammatory proteins and olfaction in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2020;10(3):343–355.
48.
MuellerSKNoceraALWorkmanA, et al.Significant polyomic and functional upregulation of the PAPP-A/IGFBP-4/5/IGF-1 axis in chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2020;10(4):546–555.
49.
KohanskiMAWorkmanADPatelNN, et al.Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2018;142(2):460–469.e7.
50.
NoceraALMeurerATMiyakeMMSadowPMHanXBleierBS. Secreted P-glycoprotein is a noninvasive biomarker of chronic rhinosinusitis. Laryngoscope. 2017;127(1):E1–E4.
51.
ShimizuSOgawaTTakezawaKTojimaIKouzakiHShimizuT. Tissue factor and tissue factor pathway inhibitor in nasal mucosa and nasal secretions of chronic rhinosinusitis with nasal polyp. Am J Rhinol Allergy. 2015;29(4):235–242.
52.
PerićAVojvodićDRadulovićV. Cytokine profiles in nasal fluid in patients with nasal polyps: a flow cytometric study. J Med Biochem. 2010;29(1):28–33.
53.
DébatHEloitCBlonF, et al.Identification of human olfactory cleft mucus proteins using proteomic analysis. J Proteome Res. 2007;6(5):1985–1996.
54.
NaraghiMDeroeeAFEbrahimkhaniMKianiSDehpourA. Nitric oxide: a new concept in chronic sinusitis pathogenesis. Am J Otolaryngol. 2007;28(5):334–337.
55.
BanglawalaSMMulliganJKPsaltisAJ, et al.Impact of intraoperative hydrodebrider treatment on postoperative sinonasal inflammation. Am J Rhinol Allergy. 2014;28(5):438–442.
56.
HattenKMPalmerJNLeeRJAdappaNDKennedyDWCohenNA. Corticosteroid use does not alter nasal mucus glucose in chronic rhinosinusitis. Otolaryngology–Head and Neck Surgery. 2015;152(6):1140–1144.
57.
WoodsCMTanSUllahSFrauenfelderCOoiEHCarneyAS. The effect of nasal irrigation formulation on the antimicrobial activity of nasal secretions. Int Forum Allergy Rhinol. 2015;5(12):1104–1110.
58.
PerićAVojvodićDMatković-JožinS. Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the ‘regulated on activation, normal T cell expressed and secreted’ chemokine in the nasal secretions of patients with nasal polyposis. J Laryngol Otol. 2012;126(5):495–502.
59.
YamadaTFujiedaSMoriSYamamotoHSaitoH. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14(3):143–148.
60.
RebuliMESpeenAMClappPWJaspersI. Novel applications for a noninvasive sampling method of the nasal mucosa. Am J Physiol Lung Cell Mol Physiol. 2017;312(2):L288–L296.
61.
KaoSSBassiouniARamezanpourM, et al.Proteomic analysis of nasal mucus samples of healthy patients and patients with chronic rhinosinusitis. (1097-6825 (Electronic)).
62.
LüFXEschRE. Novel nasal secretion collection method for the analysis of allergen specific antibodies and inflammatory biomarkers. J Immunol Methods. 2010;356(1-2):6–17.
63.
KlimekLRaspG. Norm values for eosinophil cationic protein in nasal secretions: influence of specimen collection. Clin Exp Allergy. 1999;29(3):367–374.
64.
StevensWWOcampoCJBerdnikovsS, et al.Cytokines in chronic rhinosinusitis. Role in eosinophilia and aspirin-exacerbated respiratory disease. Am J Respir Crit Care Med. 2015;192(6):682–694.
65.
ShimizuSKouzakiHKatoTTojimaIShimizuT. HMGB1-TLR4 Signaling contributes to the secretion of interleukin 6 and interleukin 8 by nasal epithelial cells. Am J Rhinol Allergy. 2016;30(3):167–172.
66.
MuellerSK. Exosomes and chronic rhinosinusitis. World J Otorhinolaryngol – Head and Neck Surgery. 2018;4(3):175–178.
67.
AliMSWilsonJAPearsonJP. Mixed nasal mucus as a model for sinus mucin gene expression studies. Laryngoscope. 2002;112(2):326–331.
68.
YooFSolerZMMulliganJK, et al.Olfactory cleft mucus proteins associated with olfactory dysfunction in a cohort without chronic rhinosinusitis. Int Forum Allergy Rhinol. 2019;9(10):1151–1158.
69.
CampoPdel Carmen Plaza-SeronMEguiluz-GraciaI, et al.Direct intranasal application of the solid phase of ImmunoCAP® increases nasal specific immunoglobulin E detection in local allergic rhinitis patients. Int Forum Allergy Rhinol. 2018;8(1):15–19.
70.
BeringsMArasiSDe RuyckN, et al.Reliable mite-specific IgE testing in nasal secretions by means of allergen microarray. J Allergy Clin Immunol. 2017;140(1):301–303.e8.
