Sinonasal Mucus Research Articles

Outcome measures for chronic rhinosinusitis with nasal polyps.

With the recent proliferation of novel therapeutics for chronic rhinosinusitis with nasal polyps (CRSwNP), there is an immediate need for comprehensive means to assess CRSwNP disease status as well as to determine treatment efficacy. Outcome measures exist in different forms. Patient-reported outcome measures (PROMs) allow patients to provide direct input about their condition that is not possible to obtain in any other way. Common constructs that are measured using PROMs include quality of life or the burden of disease manifestations (e.g., symptom severity). Outcomes may also include the results of objective diagnostic testing/measurement of clinical signs or measured using psychophysical tests. Biomarkers represent an emerging class of outcome measures for CRSwNP and are chosen to directly reflect the active pathophysiologic processes of CRSwNP in the peripheral blood, sinus/polyp tissues, and sinonasal mucus. Narrative review of the literature, identifying and describing outcome measures that may be used in the evaluation of CRSwNP and for assessment of treatment responses. In this review, we identify many different outcome measures for CRSwNP that fall under the categories of PROM, objective test, psychophysical test or biomarker. We describe the history of each - including seminal studies - and demonstrate the formal validation, psychometric performance, and limitations of each. PROMs, objective tests, psychophysical tests and biomarkers represent different classes of outcome measures that are complementary means of assessing CRSwNP disease status and treatment efficacy. The choice or interpretation of a CRSwNP outcome measure should be undertaken with full knowledge of its formal validation, psychometric performance, and limitations.

Examination of Sex Differences in a Chronic Rhinosinusitis Surgical Cohort.

Sex discrepancies have been reported in chronic rhinosinusitis (CRS), but limited data exist exploring sex-specific biological processes and sinonasal quality of life. Prospective cohort. Academic medical center. Demographics, clinical data, and sinonasal mucus were collected from patients with CRS presenting for surgical consideration over a 5-year period. A random forest model and linear regression were used to assess predictor variables for the 22-item Sino-Nasal Outcome Test (SNOT-22) and subdomains. Enzyme-linked immunosorbent assays were used to measure substance P and tryptase in a subset of mucus samples to explore biological differences by sex. In total, 520 patients were studied (mean age 48.3 years, 50.9% female). Males were older (50.1 vs 46.6 years, P = .008), had more polyp disease (48.2% vs 35.5%, P = .004), and had higher mean Lund-Mackay CT score (11.3 vs 9.5, P = .004). Females had a higher overall mean SNOT-22 (40.9 vs 46.9, P = .001) and higher scores in ear/facial, psychological, and sleep domains (P < .01). Age, objective disease measures, and sex were top predictors for total SNOT-22. Neither mucus substance P or tryptase, alone or paired with sex, correlated with total SNOT-22. Analysis of mucus biomarkers by sex revealed correlation between mucus tryptase in females with the extranasal subdomain (P = .01). Sex differences exist in CRS disease manifestations and presentation for surgical consideration. Detection of mucus (substance P and tryptase) was reliable, but in this exploratory study, we were not able to establish neurogenic or allergic inflammatory processes as a large source of differential disease features between sexes.

Aspirin Exacerbated Respiratory Disease Can be Accurately Identified Using Sinonasal Mucus Lipid Biomarkers

Patients with aspirin exacerbated respiratory disease (AERD) frequently present with severe chronic rhinosinusitis with nasal polyposis (CRSwNP). Prior work by our group has identified potential inflammatory subtypes of AERD in patients using mucus-derived lipid biomarkers. In this study, we hypothesized that these biomarkers could be used to non-invasively diagnose AERD.

Autologous fibrin sealant co-delivered with antibiotics is a robust method for topical antibiotic treatment after sinus surgery

Background Most patients with cystic fibrosis have the risk of pathogenic bacteria being exchanged between their sinuses and lungs. Aims A method for topical application of antibiotics where the antibiotics persist for a long period of time is needed. Material and methods Ten patients with cystic fibrosis and bacterial sinusitis were included. Autologous platelet rich fibrin was mixed with an antibiotic solution and sprayed onto the mucosa at the end of an endoscopic sinus surgery; Colistin, a Ciprofloxacin-Colistin combination or Tobramycin was used. The antibiotic concentration was measured in the sinonasal mucus four, seven and 13 days after surgery. Results Nine patients had Pseudomonas aeruginosa in their nose/sinuses at the time of surgery; in eight of these P. aeruginosa was not detected by culture at the final visit. In the majority of the ten included patients the antibiotics were continuously released for more than 7 days. No severe side effects were seen. Conclusions Autologous platelet rich fibrin co-delivered with antibiotics is a feasible method for topical antibiotic treatment in supplementary to sinus surgery. Significance We expect that this treatment is successful for eradication of sinonasal bacterial infections in immunosuppressed patients suffering from recalcitrant sinus infections. The efficacy should be evaluated in randomized controlled trials.

Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial

Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state. Doxycycline concentrations measured in the mucus were significantly lower compared to that in the serum (mean mucus/serum ratio = 0.16, p < 0.001) and the tissue (mean mucus/tissue ratio = 0.18, p < 0.0001). Roxithromycin concentrations in the mucus were also significantly lower compared to that in the serum (mean mucus/serum ratio = 0.37, p = 0.002) and the tissue (mean mucus/tissue ratio = 0.60, p < 0.001). Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complexity of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

C3a receptor antagonism as a novel therapeutic target for chronic rhinosinusitis.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease with an unknown etiology. Recent studies have implicated the complement system as a potential modulator of disease immunopathology. We preformed proteomic pathway enrichment analysis of differentially increased proteins, and found an enrichment of complement cascade pathways in the nasal mucus of individuals with CRSwNP as compared to control subjects. Sinonasal mucus levels of C3 correlated with worse subjective disease severity, whereas no significant difference in systemic C3 levels could be determined in plasma samples. Given that human sinonasal epithelial cells were the predominate sinonasal source of C3 and C3a staining, we focused on their role in in-vitro studies. Baseline intracellular C3 levels were higher in CRSwNP cells, and following exposure to Aspergillus fumigatus (Af) extract they released significantly more C3 and C3a. Inhibition of C3aR signaling led to a decrease in Af-induced C3 and C3a release, both in-vitro and in-vivo. Finally, we found in-vivo that C3aR deficiency or inhibition significantly reduced inflammation and CRS development in a mouse model of Af induced CRS. These findings demonstrate that local sinonasal complement activation correlates with subjective disease severity, and that local C3aR antagonism significantly ameliorates Af induced CRS in a rodent model.

Mucus T helper 2 biomarkers predict chronic rhinosinusitis disease severity and prior surgical intervention.

Chronic rhinosinusitis (CRS) is a diverse clinical syndrome with a heterogeneous pathophysiology. Early attempts to identify CRS endotypes and biomarkers have largely relied on analysis of surgically obtained tissue, thus limiting their practical utility. This study examined the ability of mucus T helper 2 (Th2) biomarkers to predict CRS disease severity and clinical characteristics. CRS (n = 90) and healthy control subjects (n = 17) were prospectively enrolled prior to surgical intervention and mucus levels of interleukin (IL)-4, IL-5, and IL-13 were determined using a multiplex cytometric bead assay. Data for relevant cytokines was then scaled, normalized, and later combined to develop standardized metrics indicative of Th2-associated inflammation. Th2-high and Th2-low subgroups were consequently identified and validated against factors associated with disease severity and clinical outcomes. Mucus levels of IL-5 and IL-13 were elevated in CRS subjects compared to controls, while no significant difference was noted for IL-4. IL-5 and IL-13 high CRS were associated with worse objective measures of disease severity and greater rates of revision surgery. Similar relationships were noted for both cytokines when CRS with nasal polyps (CRSwNP) patients were analyzed separately. Th2-high CRS and Th2-low CRS were then categorized using a scaled IL-5/IL-13 metric. Th2-high CRS was characterized by an increased number of subjects with nasal polyps and comorbid asthma, and worse symptom and computed tomography (CT) scores. The Th2-associated cytokines, IL-5 and IL-13, are detectable in sinonasal mucus and their levels can be used to define Th2-high and Th2-low CRS. Identification of Th2-high and Th2-low endotypes using mucus-based biomarkers could facilitate stratification of CRS subgroups and guide personalized therapies.

Toll-like receptor activation by sino-nasal mucus in chronic rhinosinusitis

The sino-nasal disease chronic rhinosinusitis (CRS) is primarily an inflammatory condition that manifests in several ways. However, the aetiology of this complex disease is poorly understood. The aim of this study was to explore the association between toll-like receptor (TLR) activation, host immune response and sino-nasal mucus in healthy and diseased patients. The activation of TLR2/1 and TLR4 by sino-nasal mucus from 26 CRS patients and 10 healthy controls was measured. In addition, 7 inflammatory cytokines, bacterial community composition and bacterial abundance within the sino-nasal mucus were measured using molecular and diagnostic tools. TLR activity was observed in 9/36 samples, including 2 healthy controls. There was a strong, positive correlation between members of the Gammaproteobacteria (Haemophilus, Enterobacter, Pseudomonas) and TLR2/1 and TLR4 activity. Bacterial abundance and cytokine (tumour necrosis factor) abundance were also positively correlated with TLR activity. These findings suggest that a small proportion (20-30%) of individuals in each sub-group are more predisposed to TLR activity, which may be related to bacterial composition, diversity and abundance in the sinuses.

Expression of immunoglobulin D is increased in chronic rhinosinusitis

BackgroundImmunoglobulin (Ig) D is largely localized to the upper airway and reacts with colonizing respiratory pathogens. ObjectiveTo determine whether chronic rhinosinusitis (CRS) is associated with increased IgD expression. MethodsWe performed immunofluorescent staining for cytoplasmic IgD, IgA, IgM, and surface plasma cell marker CD138 (syndecan-1) in sinus tissue of patients with CRS with and without nasal polyps (CRSwNP and CRSsNP, respectively) and control subjects without CRS (n = 6 each). Sinonasal mucus antibody levels of patients with CRSwNP or CRSsNP and control subjects were measured by enzyme-linked immunosorbent assay (n = 13, 11, and 9 subjects, respectively). Cells per square millimeter and antibody levels were compared by analysis of variance. Histopathology was performed with sinus tissue from subjects in the 3 groups (n = 6, 8, and 13 subjects respectively). ResultsCells expressing cytoplasmic IgD exceeded those with cytoplasmic IgA and IgM and represented most CD138+ plasma cells in the lamina propria. The frequencies of IgD+ plasma cells were significantly higher in patients with CRSsNP and CRSwNP compared with control subjects (P < .01). Only patients with CRSwNP showed increased frequencies of IgM and IgA plasma cells (P < .01). In contrast to high plasma cell frequencies in tissues, the levels of secreted IgD were lower than those of IgA, IgM, and IgG but were highest in the CRSwNP group compared with the other groups (P < .05). ConclusionIgD plasma cells are prominent in sinus tissues and are increased in CRS. That IgD protein also shows the lowest concentration of antibodies in secretions suggests that its activity might be targeted to the tissue rather than secretions.

Toll-like receptor activation by sino-nasal mucus in chronic rhinosinusitis.

The sino-nasal disease chronic rhinosinusitis (CRS) is primarily an inflammatory condition that manifests in several ways. However, the aetiology of this complex disease is poorly understood. The aim of this study was to explore the association between toll-like receptor (TLR) activation, host immune response and sino-nasal mucus in healthy and diseased patients. The activation of TLR2/1 and TLR4 by sino-nasal mucus from 26 CRS patients and 10 healthy controls was measured. In addition, 7 inflammatory cytokines, bacterial community composition and bacterial abundance within the sino-nasal mucus were measured using molecular and diagnostic tools. TLR activity was observed in 9/36 samples, including 2 healthy controls. There was a strong, positive correlation between members of the Gammaproteobacteria (Haemophilus, Enterobacter, Pseudomonas) and TLR2/1 and TLR4 activity. Bacterial abundance and cytokine (tumour necrosis factor) abundance were also positively correlated with TLR activity. These findings suggest that a small proportion (20-30%) of individuals in each sub-group are more predisposed to TLR activity, which may be related to bacterial composition, diversity and abundance in the sinuses.

Impact of intraoperative hydrodebrider treatment on postoperative sinonasal inflammation.

The impact of intraoperative hydrodebrider sinus irrigation (HSI) during endoscopic sinus surgery (ESS) on postoperative inflammation, endoscopy, and patient-reported outcomes has not been studied. A clinical trial of 12 patients with symmetric chronic rhinosinusitis were prospectively randomized to HSI on one side after undergoing bilateral ESS. The contralateral side was not treated with any irrigation and served as an internal control. Preoperative computed tomography, endoscopic, 22-item Sino-Nasal Outcome Test (SNOT-22), and symptom visual analog scale (VAS) scores for each side were obtained. At 1 and 3 months postsurgery, endoscopy, SNOT-22, and sinus VAS were recorded. Sinonasal mucus levels of interleukin (IL)-6, IL-10, IL-17a, and tumor necrosis factor (TNF) alpha were measured at the time of surgery, 1 and 3 months, postoperatively, from each side. VAS scores improved on both sides (p < 0.05) and SNOT-22 improved at all postoperative time points (p < 0.05). Endoscopic scores of HSI-treated sides did not improve compared with baseline. HSI had no additional significant impact on postoperative VAS at any time point. HSI significantly decreased IL-17a levels when compared with the control side at 1 month (p = 0.034) and 3 months (p = 0.031). No significant change was seen in TNF-alpha, IL-6, or IL-10 on either side at any time point. Intraoperative HSI at the time of ESS failed to establish any improvement in postoperative endoscopy or most local cytokine levels after ESS.

Rheologic Properties of Sinonasal Mucus in Patients with Chronic Sinusitis

Mucociliary clearance is impaired in chronic rhinosinusitis (CRS). Clearance of sinonasal secretions is influenced by its rheological properties. The purpose of this study was to describe the rheological properties of sinonasal mucus in patients with CRS and correlate them with disease severity. Twenty-three adult subjects with CRS underwent collection of sinonasal secretions. Samples were analyzed using the AR2000 cone and plate rheometer (TA Instruments, New Castle, DE) to determine the dynamic viscosity and elasticity. These properties were used to calculate mucus clearance indices. All patients completed the Sinonasal Outcome Test (SNOT-20). Recent sinus computed tomography (CT) scans were electronically reviewed and scored according to the Lund-McKay staging system. The mean dynamic elasticity and viscosity of sinus mucus at 1 Hz were 78.24 +/- 103.4 Pa and 22.09 +/- 29.62 Pa, respectively. The mean elasticity and viscosity values at 10 Hz were 118.9 +/- 155.5 Pa and 32.36 +/- 45.58 Pa, respectively. Three indices of disease severity (SNOT-20 score, Lund-McKay score, and nasal polyps) correlated with increased mucus viscoelasticity and/or worsened mucociliary clearance indices (MCIs). This study establishes the range of rheological properties of sinonasal mucus in patients with CRS and suggests an association between disease severity and MCIs.