Exploring eicosanoids as biomarkers in severe chronic rhinosinusitis with nasal polyps

• Chronic rhinosinusitis (CRS) is one of the most common inflammatory chronic conditions, leading to a persistent nasal congestion, nasal discharge, and a loss of smell. Despite sinus surgery and frequent use of oral corticosteroids, a large proportion of individuals with CRS are difficult to treat and have recurrent inflammation. They are usually referred to as individuals with recalcitrant disease and having recurrent nasal polyps (NPs; CRSwNP). The disease poses a significant impact on the patients' health-related quality of life (HrQoL), mainly because of a complete loss of smell. Pharmacological treatment with biological therapies has recently been developed, targeting mediators of the type 2 inflammatory response. However, not everyone benefits from the biological therapy, and it has proven difficult to identify and characterise patients that are responsive to these new medications. Eicosanoids, being arachidonic acid derived bioactive lipid mediators, has been shown to be implicated in CRSwNP. Although there is a clear link between an imbalanced biosynthesis of pro- and anti-inflammatory eicosanoids and type 2 inflammation, to date research has not focused on them as biomarkers in CRSwNP.The overall aim of this thesis was to explore the potential role of eicosanoids as biomarkers and characterise changes over time in HrQoL as well as the degree of smell loss in patients with severe recalcitrant CRSwNP. The project involved immunoassay analysis of levels of various inflammatory mediators, including a selection of eicosanoids, in nasal tissue, nasal secretions and urine from patients with CRSwNP as well as gene expression analyses regarding biosynthetic enzymes and receptors for eicosanoids in nasal tissues. HrQoL was assessed with SNOT-22 and RAND-36, along with point-of-care tests as eosinophil blood count, fractional exhaled nitric oxide (FeNO) and smell tests with Burghart Sniffin’ Sticks.Levels of eicosanoids in nasal secretions were found to associate with the disease severity, defined as the extent of NP growth (paper I). One of the eicosanoids, leukotriene E4 (LTE4), were correlated to the degree of smell loss (paper I). An increase in LTE4 between six and 12 months after surgery was demonstrated in patients with recurrent NPs (paper II). Recurrent NPs were identified endoscopically 12 months after surgery and a distinct eicosanoid profile involving LTE4, prostaglandin D2 and 15(S) hydroxyeicosatetraenoic acid was found to be more common in those with recurrence (paper II). A similar eicosanoid profile, based on measurements from nasal tissue samples instead, was also associated with NP recurrence (paper III).Levels of eicosanoids in nasal tissue and nasal secretions were correlated suggesting that analysis of biomarkers in nasal secretions reflects release from the nasal tissue (paper III). Patients with recurrent NPs had elevated blood eosinophil counts before their surgery, and their sense of smell was significantly impaired both before and after (paper IV). This finding suggests that loss of smell may be the first symptom during recurrence. Although measures of HrQoL could not distinguish patients with recurrent NPs, there was a strong correlation to the degree of smell loss suggesting that loss of smell has a significant impact on the HrQoL (paper IV).In summary, the results from this thesis contribute to an extended knowledge regarding characteristics relevant for identifying severe recalcitrant CRSwNP. Characteristics of interest included a distinct eicosanoid profile, severe loss of smell and eosinophil involvement, all of which may be possible prognostic markers for severe recalcitrant CRSwNP with rapid NP growth. It may be concluded that such biomarkers can guide the choice of treatment for these severely ill patients – repeated surgery or pharmacological treatment with the newly developed biological therapies.

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MEDICIN OCH HÄLSOVETENSKAP  -- Hälsovetenskap (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Health Sciences (hsv//eng)

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