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DOI 10.37219/2528-8253-2025-1-2-52

Naumenko O, Krynychko L, Motaylo O
THE ROLE OF NASAL MICROBIOME IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Naumenko Oleksandr
Bogomolets National Medical University; Kyiv, Ukraine
First vice-rector, Doctor of Medical Sciences, Professor, Corresponding member of the National Academy of Science of Ukraine
Email: naumenko16t@ukr.net
ORCID ID: https://orcid.org/0000-0002-9001-7580
Scopus Author ID: 7005396556
Krynychko Liliia
Bogomolets National Medical University; Kyiv, Ukraine
Assistant of the Department of Otorhinolaryngology
MD, PhD
Email: krinichko@bigmir.net
ORCID ID: https://orcid.org/0000-0002-2067-9925
Motaylo Oleksiy
Bogomolets National Medical University; Kyiv, Ukraine
Assistant of the Department of Otorhinolaryngology
MD, PhD
Email: motailo.oleksii@gmail.com
ORCID ID: https://orcid.org/0000-0001-6159-4285

Abstract

Background: Chronic rhinosinusitis (CRS) is one of the most common diseases of the upper respiratory tract, affecting 5-15% of the population in different regions worldwide. Despite decades of research, the exact pathogenesis of CRS remains debatable, and the role of the nasal microbiome requires detailed investigation.

Objective: To analyze and systematize current data (2018-2025) regarding the role of the nasal cavity and paranasal sinus microbiome in the pathogenesis of chronic rhinosinusitis and to conduct a meta-analysis.

Materials and Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar databases. Twenty-one studies meeting the inclusion criteria were selected. The quality assessment was performed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias 2 tool for randomized controlled trials. A meta-analysis was conducted using a random-effects model. The quality of evidence was evaluated using the GRADE system.

Results: The meta-analysis revealed a statistically significant increase in the prevalence of Haemophilus influenzae in patients with CRS (OR: 2.00; 95% CI: 1.08-3.72; p=0.0276) and a decrease in the relative frequency of Corynebacterium spp. (mean difference: -5.44%; 95% CI: -8.88 to -2.00; p=0.0019). A significant reduction in bacterial diversity indices in CRS patients was established (SMD: -0.62; 95% CI: -0.90 to -0.34; p<0.0001). No statistically significant differences in the prevalence of Staphylococcus aureus were found between CRS patients and the control group; however, a strong positive correlation between Staphylococcus aureus levels and the proinflammatory cytokine IL-8 was identified (r=0.67; 95% CI: 0.55-0.76; p<0.0001).

Conclusions: The meta-analysis confirms the concept of microbial dysbiosis as an important pathogenetic mechanism in chronic rhinosinusitis. Reduced bacterial diversity, increased prevalence of Haemophilus influenzae, and decreased presence of commensal Corynebacterium spp. are characteristic features of microbiome changes in CRS. Different CRS phenotypes are characterized by specific microbial profiles, emphasizing the importance of a personalized approach to diagnosis and treatment.

Keywords: chronic rhinosinusitis, microbiome, dysbiosis, Staphylococcus aureus, Haemophilus influenzae, Corynebacterium, bacterial diversity, meta-analysis.

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References

  1. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. Executive summary of EPOS 2020 including integrated care pathways. Rhinology. 2020;58(2):82-111. doi: 10.4193/Rhin20.601.
  2. Hastan D, Fokkens WJ, Bachert C, Newson RB, Bislimovska J, Bockelbrink A, et al. Chronic rhinosinusitis in Europe – an underestimated disease. A GA2LEN study. 2011;66(9):1216-1223. doi: 10.1111/j.1398-9995.2011.02646.x.
  3. 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;70:533-539. doi: 10.1111/all.12577.
  4. Orlandi RR, Kingdom TT, Hwang PH. International consensus statement on allergy and rhinology: rhinosinusitis. Int Forum Allergy Rhinol. 2016;6(suppl 1):S22-S209. doi: 10.1002/alr.21694.
  5. Bhattacharyya N. Incremental health care utilization and expenditures for chronic rhinosinusitis in the United States. Ann Otol Rhinol Laryngol. 2011 Jul;120(7):423-7. doi: 10.1177/000348941112000701.
  6. Levi L, Havazelet S, Reuven Y, Elmograbi A, Badir S, Shraga Y, et al. Patterns of recurrence in patients with CRSwNP who underwent complete FESS. European Archives of Oto-Rhino-Laryngology. 2024;281(11), 5847-5856. doi: 10.1007/s00405-024-08832-5.
  7. Lam K, Schleimer R, Kern RC. The etiology and pathogenesis of chronic rhinosinusitis: a review of current hypotheses. Curr Allergy Asthma Rep. 2015;15:41. doi: 10.1007/s11882-015-0540-2.
  8. Sivasubramaniam R, Douglas R. The microbiome and chronic rhinosinusitis. World J Otorhinolaryngol Head Neck Surg. 2018 Oct 31;4(3):216-221. doi: 10.1016/j.wjorl.2018.08.004. 
  9. Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, Schleimer RP. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin Exp Allergy. 2016 Jan;46(1):21-41. doi: 10.1111/cea.12666.
  10. Ramakrishnan VR, Feazel LM, Gitomer SA, Ir D, Robertson CE, Frank DN. The microbiome of the middle meatus in healthy adults. PLoS One. 2013 Dec 30;8(12):e85507. doi: 10.1371/journal.pone.0085507.
  11. Biswas K, Hoggard M, Jain R, Taylor MW, Douglas RG. The nasal microbiota in health and disease: variation within and between subjects. Front Microbiol. 2015 Mar 2:9:134. doi: 10.3389/fmicb.2015.00134.
  12. Feazel LM, Robertson CE, Ramakrishnan VR, Frank DN. Microbiome complexity and Staphylococcus aureus in chronic rhinosinusitis. 2012 Feb;122(2):467-72. doi: 10.1002/lary.22398.
  13. Hauser LJ, Feazel LM, Ir D, Wagner BD, Robertson ChE, Frank DN, Ramakrishnan VR. Sinus culture poorly predicts resident microbiota. Int Forum Allergy Rhinol. 2015 Jan;5(1):3-9. doi: 10.1002/alr.21428.
  14. Boase S, Foreman A, Cleland E, Tan L, Melton-Kreft R, Pant H,  et al. The microbiome of chronic rhinosinusitis: culture, molecular diagnostics and biofilm detection. BMC Infect Dis. 2013 May 8:13:210. doi: 10.1186/1471-2334-13-210.
  15. Hoggard M, Biswas K, Zoing M, Mackenzie BW, Taylor MW, Douglas Evidence of microbiota dysbiosis in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2017 Mar;7(3):230-239. doi: 10.1002/alr.21871.
  16. Mackenzie WB, Waite DW, Hoggard M, Douglas RG, Taylor MW, Biswas K. Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis. Environ Microbiol. 2017 Jan;19(1):381-392. doi: 10.1111/1462-2920.13632.
  17. Shi P, Wei H, Liu X, Dong S, He S, Zeng Y, et al. The nasal bacteria microbiome comparison among fungal ball sinusitis, chronic sinusitis with polyps. Indian Journal of Microbiology. 2023 Mar;63(1):120-128. doi: 10.1007/s12088-023-01062-z.
  18. Abreu NA, Nagalingam NA, Song Y, Roediger FC, Pletcher SD, Goldberg AN, Lynch Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis. Sci Transl Med. 2012 Sep 12;4(151):151ra124. doi: 10.1126/scitranslmed.3003783.
  19. Bachert C, Zhang N, van Zele T. Staphylococcus aureus enterotoxins as immune stimulants in chronic rhinosinusitis. Clin Allergy Immunol. 2007;20:163-175.
  20. Ou J, Wang J, Xu Y, Kong Y, Chen Sh, Shi Staphylococcus aureus superantigens are associated with chronic rhinosinusitis with nasal polyps: a meta-analysis. Eur Arch Otorhinolaryngol. 2014 Oct;271(10):2729-36. doi: 10.1007/s00405-014-2955-0.
  21. Chalermwatanachai T, Zhang N, Holtappels G, Bachert C. Association between mucosal organisms with patterns of inflammation in chronic rhinosinusitis. PLoS One. 2015 Aug 14;10(8):e0136068. doi: 10.1371/journal.pone.0136068.
  22. Pu K, Zhang Z, Li L. Associations between gut microbiota and chronic sinusitis: A bidirectional Mendelian randomization study. Immun Inflamm Dis. 2024 Jul;12(7):e1328. doi: 10.1002/iid3.1328.
  23. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Kumar KA, Kramper M, et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg. 2015 Apr;152(2 Suppl):S1-S39. doi: 10.1177/0194599815572097.
  24. Smith SS, Kim R, Douglas R. Is there a role for antibiotics in the treatment of chronic rhinosinusitis? J Allergy Clin Immunol. 2022 May;149(5):1504-1512. doi: 10.1016/j.jaci.2022.02.004.
  25. Smith KA, Smith TL, Mace JC, Rudmik L. Endoscopic sinus surgery compared to continued medical therapy for patients with refractory chronic rhinosinusitis. Int Forum Allergy Rhinol. 2014 Oct;4(10):823-7. doi: 10.1002/alr.21366.
  26. Hauser LJ, Ir D, Kingdom TT, Robertson CE, Frank DN, Ramakrishnan VR. Investigation of bacterial repopulation after sinus surgery and perioperative antibiotics. Int Forum Allergy Rhinol. 2016 Jan;6(1):34-40. doi: 10.1002/alr.21630.
  27. Cope EK, Goldberg AN, Pletcher SD, Lynch SV. Compositionally and functionally distinct sinus microbiota in chronic rhinosinusitis patients have immunological and clinically divergent consequences. 2017 May 12;5(1):53. doi: 10.1186/s40168-017-0266-6.
  28. Tomassen P, Vandeplas G, Van Zele T, Cardell L-O, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016 May;137(5):1449-1456.e4. doi: 10.1016/j.jaci.2015.12.1324.
  29. Zhu Z, Lan J, Wei R, Xu Y, Hong Y, Bao W, He G. Microbiome and Th cytokines association in chronic rhinosinusitis with or without nasal polyp. Laryngoscope Investig Otolaryngol. 2023 Mar 8;8(2):335-345. doi: 10.1002/lio2.1026.
  30. Mackenzie WB, Baker J, Douglas RG, Taylor MW, Biswas K. Detection and quantification of Staphylococcus in chronic rhinosinusitis. Int Forum Allergy Rhinol. 2019 Dec;9(12):1462-1469. doi: 10.1002/alr.22425.
  31. Rom D, Bassiouni A, Eykman E, Liu Z, Paramasivan S, Alvarado R, Harvey RJ. The association between disease severity and microbiome in chronic rhinosinusitis. 2019 Jun;129(6):1265-1273. doi: 10.1002/lary.27726.
  32. Mackenzie WB, Zoing M, Clow F, Waite DW, Radcliff FJ, Taylor MW, et al. Characterising clinical Staphylococcus aureus isolates from the sinuses of patients with chronic rhinosinusitis. Sci Rep. 2021 Nov 9;11(1):21940. doi: 10.1038/s41598-021-01297-0.
  33. Park IH, Lee JS, Park JH, Kang SH, Hong SM, Park IS, et al. Comparison of the human microbiome in adults and children with chronic rhinosinusitis. PLoS One. 2020 Dec 2;15(12):e0242770. doi: 10.1371/journal.pone.0242770.
  34. De Boeck I, Wittouck S, Martens K, Claes J, Jorissen M, Steelant B, et al. Anterior nares diversity and pathobionts represent sinus microbiome in chronic rhinosinusitis. mSphere. 2019 Nov 27;4(6):e00532-19. doi: 10.1128/mSphere.00532-19.
  35. Koeller K, Herlemann DP, Schuldt T, Ovari A, Guder E, Podbielski A, et al. Microbiome and culture based analysis of chronic rhinosinusitis compared to healthy sinus mucosa. Front Microbiol. 2018 Apr 17:9:643. doi: 10.3389/fmicb.2018.00643.
  36. Vaughn A, Shaver C, Clark D. Association Between Culture and Culture-Independent Microtyping in Recalcitrant Chronic Rhinosinusitis. Ear Nose Throat J. 2019 Feb;98(2):94-97. doi: 10.1177/0145561318823371.
  37. Renteria AE, Maniakas A, Mfuna LE, Asmar MH, Gonzalez E, Desrosiers M. Low‐dose and long‐term azithromycin significantly decreases Staphylococcus aureus in the microbiome of refractory CRS patients. Int Forum Allergy Rhinol. 2021 Feb;11(2):93-105. doi: 10.1002/alr.22653.
  38. Dellière S, Dannaoui E, Fieux M, Bonfils P, Gricourt G, Demontant V, et al. Analysis of microbiota and mycobiota in fungal ball rhinosinusitis: specific interaction between Aspergillus fumigatus and Haemophilus influenza? J Fungi (Basel). 2021 Jul 10;7(7):550. doi: 10.3390/jof7070550.
  39. Gan W, Zhang H, Yang F, Liu S, Liu F, Meng J. The influence of nasal bacterial microbiome diversity on the pathogenesis and prognosis of chronic rhinosinusitis patients with polyps. Eur Arch Otorhinolaryngol. 2021 Apr;278(4):1075-1088. doi: 10.1007/s00405-020-06370-4.
  40. Kim JH, Kim SH, Lim JY, Kim D, Jeong IS, Lee DK, Jang YJ. Association between the sinus microbiota with eosinophilic inflammation and prognosis in chronic rhinosinusitis with nasal polyps. Exp Mol Med. 2020 Jun;52(6):978-987. doi: 10.1038/s12276-020-0458-1.
  41. Gan W, Yang F, Tang Y, Zhou D, Qing D, Hu J, et al. The difference in nasal bacterial microbiome diversity between chronic rhinosinusitis patients with polyps and a control population. Int Forum Allergy Rhinol. 2019 Jun;9(6):582-592. doi: 10.1002/alr.22297.
  42. Connell JT, Bouras G, Yeo K, Fenix K, Cooksley C, Bassiouni A, et al. Characterising the allergic fungal rhinosinusitis microenvironment using full‐length 16S rRNA gene amplicon sequencing and fungal ITS sequencing.  2024 Nov;79(11):3082-3094. doi: 10.1111/all.16240.
  43. Koutsourelakis I, Halderman A, Khalil S, Hittle LE, Mongodin EF, Lane AP. Temporal instability of the post-surgical maxillary sinus microbiota. BMC Infect Dis. 2018 Aug 30;18(1):441. doi: 10.1186/s12879-018-3272-9.
  44. Takeda K, Sakakibara S, Yamashita K, Motooka D, Nakamura S, El Hussien MA, et al. Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2019 Mar;143(3):1163-1175.e15. doi: 10.1016/j.jaci.2018.07.006.
  45. Božić DD, Pavlović B, Milovanović J, Jotić A, Čolović J, Ćirković I. Antibiofilm effects of amoxicillin-clavulanic acid and levofloxacin in patients with chronic rhinosinusitis with nasal polyposis. Eur Arch Otorhinolaryngol. 2018 Aug;275(8):2051-2059. doi: 10.1007/s00405-018-5049-6.
  46. Wei HZ, Li YC, Wang XD, Lu XX, Hu CH, He S, Liu X. The microbiology of chronic rhinosinusitis with and without nasal polyps. Eur Arch Otorhinolaryngol. 2018 Jun;275(6):1439-1447. doi: 10.1007/s00405-018-4931-6.
  47. Ulusoy B, Muderris T, Callioglu EE, Bozdemir K, Oguzhan T, Kutluhan A, et al. Effects of endoscopic endonasal sinus surgery on nasal flora in patients with chronic rhinosinusitis with nasal polyps. Annals of Medical Research. 2019;26(8):1683-1687. https://dx.doi.org/10.5455/annalsmedres.2019.05.294.
  48. De Bonnecaze G, Chaput B, Dupret-Bories A, Vergez S, Serrano E. Functional outcome after long-term low-dose trimethoprim/sulfamethoxazole in chronic rhinosinusitis with purulence: a prospective study. J Laryngol Otol. 2018 Jul;132(7):600-604. doi: 10.1017/S0022215118000452.
  49. Dobretsov KG, Kolenchukova O, Sipkin A, Bellussi LM, Ciprandi G, Passali D. A randomized, double-blind, placebo-controlled study to investigate the use of bacteriophages in patients with chronic rhinosinusitis with nasal polyps. Otolaryngol Pol. 2021 Jun 30;75(6):33-37. doi: 10.5604/01.3001.0015.0084.
  50. Malik BA, Khanam SF, Nisar J, Qazi SM. Microbiology and Antimicrobial Sensitivity Patterns of Chronic Rhinosinusitis – 2020. Ann Clin Otolaryngol. 2021;6(2):1054. https://www.researchgate.net/publication/357934112_Annals_of_Clinical_Otolaryngology_Microbiology_and_Antimicrobial_Sensitivity_Patterns_of_Chronic_Rhinosinusitis_-2020.
  51. Gupta N, Raza A, Galib R, Chandra K. A clinical study with changes in microbiological flora in chronic rhinosinusitis. Asian J Med Sci. 2023;14(9):171-175. doi: 10.3126/ajms.v14i9.53809.
  52. Lang M, Bereza D, Kulak-Waśniewska M, Moreau I, Polańska P, Sokołowska K, Woch B. The influence of the sinonasal microbiome on the development and management of rhinosinusitis. J Educ Health Sport. 2025;77:56769. https://doi.org/10.12775/JEHS.2025.77.56769.
  53. Michalik M, Krawczyk B. Chronic rhinosinusitis – microbiological etiology, potential genetic markers, and diagnosis. Int J Mol Sci. 2024 Mar 11;25(6):3201. doi: 10.3390/ijms25063201.
  54. Ccami-Bernal F, Barriga-Chambi F, Ortiz-Benique ZN, Ferrary E, Torres Variability of the microbiota in chronic rhinosinusitis: A scoping review. OTO Open. 2024 Oct 8;8(4):e70029. doi: 10.1002/oto2.70029.