Impact of Respiratory Virus Infections in Exacerbation of Acute and Chronic Rhinosinusitis

  • Kai Sen Tan
  • Yan Yan
  • Hsiao Hui Ong
  • Vincent T. K. Chow
  • Li Shi
  • De-Yun Wang
Rhinosinusitis (J Mullol, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Rhinosinusitis


Rhinosinusitis (RS) is a symptomatic disease classification of many causes and is a major economic burden worldwide. It is widely accepted that RS is further classified into acute (ARS) and chronic (CRS) rhinosinusitis based on the duration of the symptoms, and that viral infection plays a large role in initiating or potentiating the disease. In this review, we examine the role of respiratory virus infection in the exacerbation of ARS and CRS. We explore the epidemiology of viral exacerbation of ARS and CRS and highlight key viruses that may cause exacerbation. We also review the current understanding of viral infections in the upper airway to further explain the putative underlying mechanisms of inflammatory events in ARS and CRS exacerbation. Advances in accurate diagnosis of the etiologic respiratory viruses of ARS and CRS symptoms which can lead to better disease management are also surveyed. In addition to the current treatments which provide symptomatic relief, we also explore the potential of harnessing existing antiviral strategies to prevent ARS and CRS exacerbation, especially with improved viral diagnostic tools to guide accurate prescription of antivirals against causative respiratory viruses.


Acute rhinosinusitis Antivirals Bacterial infection Chronic rhinosinusitis Diagnosis Exacerbation Treatment Viral infection 


Compliance with Ethical Standards

Conflict of Interest

Kai Sen Tan, Yan Yan, Hsiao Hui Ong, Vincent T. K. Chow, Li Shi, and De-Yun Wang declare that they have no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Declaration of All Sources of Funding

This study was supported by grants from the National Medical Research Council (NMRC/CIRG/1362/2013 and NMRC/CIRG/1458/2016).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Hoggard M, Wagner Mackenzie B, Jain R, et al. Chronic rhinosinusitis and the evolving understanding of microbial ecology in chronic inflammatory mucosal disease. Clin Microbiol Rev. 2017;30:321–48. This review summarizes the current stage of understanding in the role of viruses in CRS and the current gaps in identifying the viral diversity in CRS microbiome CrossRefPubMedGoogle Scholar
  2. 2.
    •• Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinology Suppl. 2012;23:1–298. This article is the keynote article on rhinosinusitis and includes the latest understanding, mechanisms, findings, diagnosis and management of ARS and CRS Google Scholar
  3. 3.
    Li C, Shi L, Yan Y, et al. Gene expression signatures: a new approach to understanding the pathophysiology of chronic rhinosinusitis. Curr Allergy Asthma Rep. 2013;13:209–17.CrossRefPubMedGoogle Scholar
  4. 4.
    •• Eloy P, Poirrier AL, De Dorlodot C, et al. Actual concepts in rhinosinusitis: a review of clinical presentations, inflammatory pathways, cytokine profiles, remodeling, and management. Curr Allergy Asthma Rep. 2011;11:146–62. This review summarizes the current understanding of ARS and CRS mechanism of exarcerbation, immune cells’ roles and profiles and the role of different microbes in the exacerbation CrossRefPubMedGoogle Scholar
  5. 5.
    Wang DY, Wardani RS, Singh K, et al. A survey on the management of acute rhinosinusitis among Asian physicians. Rhinology. 2011;49:264–71.PubMedGoogle Scholar
  6. 6.
    Hamilos DL. Chronic rhinosinusitis: epidemiology and medical management. J Allergy Clin Immunol. 2011;128:693–707.CrossRefPubMedGoogle Scholar
  7. 7.
    Shi JB, Fu QL, Zhang H, et al. Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities. Allergy. 2015;70:533–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe--an underestimated disease. A GA(2)LEN study. Allergy. 2011;66:1216–23.CrossRefPubMedGoogle Scholar
  9. 9.
    Orlandi RR, Kingdom TT, Hwang PH, et al. International consensus statement on allergy and rhinology: rhinosinusitis. Int Forum Allergy Rhinol. 2016;6(Suppl 1):S22–209.CrossRefPubMedGoogle Scholar
  10. 10.
    Yan Y, Gordon WM, Wang DY. Nasal epithelial repair and remodeling in physical injury, infection, and inflammatory diseases. Curr Opin Otolaryngol Head Neck Surg. 2013;21:263–70.CrossRefPubMedGoogle Scholar
  11. 11.
    •• Vareille M, Kieninger E, Edwards MR, Regamey N. The airway epithelium: soldier in the fight against respiratory viruses. Clin Microbiol Rev. 2011;24:210–29. This review comprehensively covers the role of airway epithelial in responses against invading pathogen, and is used to reinforce the understanding of nasal antiviral immune responses in leading to ARS and CRS exacerbation CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    • Braciale TJ, Sun J, Kim TS. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol. 2012;12:295–305. This review covers the comprehensive overview of innate and adaptive antiviral immune responses against respiratory viruese in the lungs; which were used as a basis to reinforce the understanding of nasal antiviral immune responses CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Deng Y, Yan Y, Tan KS, et al. MicroRNA-146a induction during influenza H3N2 virus infection targets and regulates TRAF6 levels in human nasal epithelial cells (hNECs). Exp Cell Res. 2017;352:184–92.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Yan Y, Tan KS, Li C, et al. Human nasal epithelial cells derived from multiple subjects exhibit differential responses to H3N2 influenza virus infection in vitro. J Allergy Clin Immunol. 2016;138:276–81. This article provides the pathogenesis of influenza A virus and the mechanism of innate antiviral responses in the nasal epithelium to reinforce the understanding of respiratory viruses’ role in leading to ARS and CRS exacerbation CrossRefPubMedGoogle Scholar
  15. 15.
    Mahdavinia M, Keshavarzian A, Tobin MC, et al. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin Exp Allergy. 2016;46:21–41.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tacon CE, Wiehler S, Holden NS, et al. Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-kappaB. Am J Respir Cell Mol Biol. 2010;43:201–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Othumpangat S, Regier M, Piedimonte G. Nerve growth factor modulates human rhinovirus infection in airway epithelial cells by controlling ICAM-1 expression. Am J Physiol Lung Cell Mol Physiol. 2012;302:L1057–66.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    van Kempen M, Bachert C, Van Cauwenberge P. An update on the pathophysiology of rhinovirus upper respiratory tract infections. Rhinology. 1999;37:97–103.PubMedGoogle Scholar
  19. 19.
    Pawelczyk M, Kowalski ML. The role of human parainfluenza virus infections in the immunopathology of the respiratory tract. Curr Allergy Asthma Rep. 2017;17:16.CrossRefPubMedGoogle Scholar
  20. 20.
    Bianco A, Whiteman SC, Sethi SK, et al. Expression of intercellular adhesion molecule-1 (ICAM-1) in nasal epithelial cells of atopic subjects: a mechanism for increased rhinovirus infection? Clin Exp Immunol. 2000;121:339–45.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Chuang CY, Kao CL, Huang LM, et al. Human bocavirus as an important cause of respiratory tract infection in Taiwanese children. J Microbiol Immunol Infect. 2011;44:323–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Cho GS, Moon BJ, Lee BJ, et al. High rates of detection of respiratory viruses in the nasal washes and mucosae of patients with chronic rhinosinusitis. J Clin Microbiol. 2013;51:979–84.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Costa C, Garzaro M, Boggio V, et al. Detection of herpesviruses 1-6 and community-acquired respiratory viruses in patients with chronic rhinosinusitis with nasal polyposis. Intervirology. 2014;57:101–5.CrossRefPubMedGoogle Scholar
  24. 24.
    •• Ginocchio CC, Mc Adam AJ. Current best practices for respiratory virus testing. J Clin Microbiol. 2011;49(Suppl 9):44–8. This review conveyed the different viral diagnostic tools available that can be applied in the diagnosis of respiratory virus type in ARS and CRS exacerbations CrossRefGoogle Scholar
  25. 25.
    McAdam AJ, Riley AM. Developments in tissue culture detection of respiratory viruses. Clin Lab Med. 2009;29:623–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Landry ML. Developments in immunologic assays for respiratory viruses. Clin Lab Med. 2009;29:635–47.CrossRefPubMedGoogle Scholar
  27. 27.
    Dunn JJ, Ginocchio CC. Can newly developed, rapid immunochromatographic antigen detection tests be reliably used for the laboratory diagnosis of influenza virus infections? J Clin Microbiol. 2015;53:1790–6.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Selvarangan R, Abel D, Hamilton M. Comparison of BD Directigen EZ RSV and Binax NOW RSV tests for rapid detection of respiratory syncytial virus from nasopharyngeal aspirates in a pediatric population. Diagn Microbiol Infect Dis. 2008;62:157–61.CrossRefPubMedGoogle Scholar
  29. 29.
  30. 30.
    Mahony JB, Petrich A, Smieja M. Molecular diagnosis of respiratory virus infections. Crit Rev Clin Lab Sci. 2011;48:217–49.CrossRefPubMedGoogle Scholar
  31. 31.
    Chen MI, Barr IG, Koh GC, et al. Serological response in RT-PCR confirmed H1N1-2009 influenza a by hemagglutination inhibition and virus neutralization assays: an observational study. PLoS One. 2010;5:e12474.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cruz AT, Cazacu AC, Greer JM, Demmler GJ. Performance of a rapid assay (Binax NOW) for detection of respiratory syncytial virus at a children’s hospital over a 3-year period. J Clin Microbiol. 2007;45:1993–5.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Borek AP, Clemens SH, Gaskins VK, et al. Respiratory syncytial virus detection by Remel Xpect, Binax now RSV, direct immunofluorescent staining, and tissue culture. J Clin Microbiol. 2006;44:1105–7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Chan Y, Kuhn FA. An update on the classifications, diagnosis, and treatment of rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2009;17:204–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Dong G, Peng C, Luo J, et al. Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations. PLoS One. 2015;10:e0119115.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
  37. 37.
    • Hayden FG. Advances in antivirals for non-influenza respiratory virus infections. Influenza Other Respir Viruses. 2013;7(Suppl 3):36–43. This review covers the types of treatments available for non-influenza rspiratory viral infections CrossRefPubMedGoogle Scholar
  38. 38.
    •• Ison MG. Antiviral treatments. Clin Chest Med. 2017;38:139–53. This review comprehensively covers current available antiviral drugs against respiratory viral infections CrossRefPubMedGoogle Scholar
  39. 39.
    Tang PK. Palivizumab prophylaxis in preterm infants. Lancet Respir Med. 2017;5:171.CrossRefPubMedGoogle Scholar
  40. 40.
    Sugrue RJ. Interactions between respiratory syncytial virus and the host cell: opportunities for antivirus strategies? Expert Rev Mol Med. 2006;8:1–17.CrossRefPubMedGoogle Scholar
  41. 41.
    Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian influenza. Antivir Res. 2008;78:91–102.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kiso M, Takahashi K, Sakai-Tagawa Y, et al. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc Natl Acad Sci U S A. 2010;107:882–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Baranovich T, Wong SS, Armstrong J, et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol. 2013;87:3741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Belser JA, Lu X, Szretter KJ, et al. DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection. J Infect Dis. 2007;196:1493–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Moss RB, Hansen C, Sanders RL, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis. 2012;206:1844–51.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    DeVincenzo JP, Whitley RJ, Mackman RL, et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med. 2014;371:711–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Mackman RL, Sangi M, Sperandio D, et al. Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study. J Med Chem. 2015;58:1630–43.CrossRefPubMedGoogle Scholar
  48. 48.
    Wang G, Deval J, Hong J, et al. Discovery of 4′-chloromethyl-2′-deoxy-3′,5′-di-O-isobutyryl-2′-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem. 2015;58:1862–78.CrossRefPubMedGoogle Scholar
  49. 49.
    DeVincenzo J, Cehelsky JE, Alvarez R, et al. Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV). Antivir Res. 2008;77:225–31.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Kai Sen Tan
    • 1
  • Yan Yan
    • 1
  • Hsiao Hui Ong
    • 1
  • Vincent T. K. Chow
    • 2
  • Li Shi
    • 3
  • De-Yun Wang
    • 1
  1. 1.Department of Otolaryngology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.Department of Microbiology and Immunology, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  3. 3.Department of OtolaryngologyThe Second Hospital of Shandong UniversityJinanChina

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