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Type: Thesis
Title: The role of viruses in chronic rhinosinusitis
Author: Goggin, Rachel Katherine
Issue Date: 2020
School/Discipline: Adelaide Medical School
Abstract: The original research contents of this PhD thesis followed an extensive review of the literature in terms of the viral contribution to chronic rhinosinusitis (CRS); this is described in chapter one. Understanding of the aetiopathogenesis of the disease is of course integral to CRS prevention and treatment. It is also a subject of debate; the roles of bacteria, fungi and disordered innate and adaptive immunity have been investigated. Viruses, however, have received little attention. A commonly encountered clinical paradigm is that of a patient complaining of a viral upper respiratory tract infection (URTI) with the development of CRS symptoms thereafter. This has been investigated in population virome studies, however results regarding any relationship between viruses and CRS these have been inconsistent. Most of these studies have been limited in terms of size, seasonality, viral collection methods and the viral species for which investigators assayed. None have validated their collection methods or investigated for any association between viral presence and more severe disease. In addition to these none have investigated virally-induced changes in the bacterial microbiome in CRS. Microbial disarray is an area of burgeoning interest in many chronic disease processes, CRS included. Respiratory viruses are known to augment local bacterial binding, penetration and persistence. Could virus-induced respiratory epithelial changes be contributing to the disease also? In order to investigate the above, the first step is to establish and validate a robust sinonasal viral collection method. This is described in the second chapter of this thesis. Sterile cytology brushes under direct endoscopic vision were used for this. 24 patients had two sites sampled immediately prior to endoscopic sinus surgery; the middle and inferior meatuses (MM and IM). Sample DNA and RNA were extracted and underwent PCR for a panel of common respiratory viruses, including the Herpesviridae and endogenous retrovirus 3 (ERV3). The former were chosen for their near-omnipresence in the adult sinuses, and the latter as a marker of sample quality. 18/24 were positive for virus in at least one site, including 8 who were positive at both sites. Only 3 of those 8 demonstrated the same viral species at both sites. 6 showed no virus at either site. All samples demonstrated ERV3 well within published ranges indicating adequate sample quality. From this we concluded that the cytobrushes are an effective method for viral sampling in the nose and sinuses. We also identified a significant discord in viral species between the MM and IM. As such we recommended that both sites are sampled in order to gain truly representative data. The third chapter of this thesis addresses the shortcomings of published population virome studies. The collection method detailed in the previous paragraph was used to sample from 288 patients over the period of one year. Disease severity data were also collected from these patients (Sino-Nasal Outcome Test 22 scores (SNOT-22), Adelaide Disease Severity Scores (ADSS), Lund MacKay scores (LMS) and Lund Kennedy scores (LKS)). Virus was found to be significantly more prevalent in CRS patients without nasal polyps (CRSsNP) than in controls or CRS patients with nasal polyps (CRSwNP). Viral presence was also found to be associated with significantly worse objective disease (LMS and LKS) but not subjective disease (SNOT-22 and ADSS). This is the first and only CRS virome study to encompass all subsets of the disease, to allow for seasonal variation in viral presence, and to use validated sample collection and processing techniques. We confirmed the long-held suspicion that viruses are more common in patients with CRS. As such we highlighted viruses as important potential targets for CRS prevention and therapy. The fourth chapter investigates the role of eosinophilia and T cell infiltrates in virus-positive versus virus-negative CRS and controls. Sinonasal tissue samples were taken and analysed for presence of eosinophils, CD8⁺, CD103⁺ and CD8⁺/CD103⁺ double-positive T cells (Trms). CRS was found to be associated with increased eosinophil and CD8⁺ CD103⁺ T cells in excess of that seen in virus-positive controls, implicating viruses in CRS aetiopathogenesis. The study detailed in the fifth chapter aimed to investigate virus-associated changes in the bacterial CRS sinonasal microbiome again by taking brushings of the sinonasal mucosa. These were analysed for viral presence and the bacterial microbiome was also characterised, using 16S ribosomal RNA gene-targeted amplicon sequencing. Patients were divided into control, non-polyp and polyp groups. Half of each group was virus-positive. No significant differences were seen in relative abundances of the bacterial genera detected, their diversity or stability in any of the groups. A trend towards greater relative abundance of Haemophilus spp. was seen in patients reporting a viral illness two to four weeks prior. This early microbiome shift may represent a nidus for superinfection contributing to the development of CRS.
Advisor: Vreugde, Sarah
Psaltis, Alkis
Wormald, PJ
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020
Keywords: Chronic rhinosinusitis
T cell
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