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

Abstract

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.

Keywords: Acute rhinosinusitis; Antivirals; Bacterial infection; Chronic rhinosinusitis; Diagnosis; Exacerbation; Treatment; Viral infection.

Fig. 1

Putative underlying mechanisms of viral-induced ARS and CRS exacerbation. The figure shows the chain of events leading to ARS and CRS exacerbation from common respiratory virus infections (rhinovirus and influenza virus). When a respiratory virus infects its respective host cells in the nasal epithelium, the intracellular pathogen sensors TLRs 3, 7, and 9 are activated to initiate an antiviral cellular response via the activation of STAT1/2 and NF-κB transcription factors. These activated transcription factors then induce the expression of interferons (IFNs), interferon-stimulated genes (ISGs), chemokines, and cytokines against the virus. The cascade of intracellular events leads to the recruitment of innate responders such as neutrophils, macrophages, and dendritic cells, and in turn activates Th1 adaptive responses against the invading respiratory pathogen. This cascade of inflammatory events against the virus culminates in the symptoms of ARS and its exacerbation, especially if persistent infection occurs due to insufficient viral clearance. Furthermore, the priming of the nasal epithelium against viral infection potentiates its environment to be suitable for secondary bacterial infection which may further exacerbate the symptoms. The infection, if kept unchecked, may result in continued inflammation and expression of remodeling genes that may transition into chronic symptoms of CRS, which increases the susceptibility against further viral infection, causing further exacerbation of symptoms. The putative underlying mechanisms are summarized based on existing literature [••, ••, ••, •, ••]. ARS acute rhinosinusitis, CD cluster of differentiation, CRS chronic rhinosinusitis, DCs dendritic cells, IFN interferon, IL interleukin, ISGs interferon stimulated genes, STAT signaling transducers and activators of transcription, TLR toll-like receptor, MMP matrix metalloproteinase, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, TGF transforming growth factor, Th1 T-helper 1

Fig. 2

Current antiviral drugs against respiratory viruses and their mechanisms of action. The figure shows a representative respiratory virus infection (influenza) in the host cell. Other than vaccines, which do not act directly on viral replication in the host cell, other antivirals target specific virus components required for the replication cycle: (1) viral entry receptor—fludase; (2) viral fusion—presatovir, palivizumab; (3) preventing transcription/replication—ribavirin, taribavirin, cidofovir, favipiravir, ALS-8176; (4) preventing translation—ALN-RSV01; (5) preventing viral excision—oseltamivir, laninamivir, peramivir, zanamivir. The antivirals and their mechanisms are summarized based on existing literature [•, ••, –41]. mRNA messenger RNA, vRNP viral ribonucleoprotein, siRNA small interfering RNA, ALS-8176 deoxy-3′,5′-di-O-isobutyryl-2′-fluorocytidine, ALN-RSV01 asvasiran sodium