David B. Conley

Perspectives on the etiology of chronic rhinosinusitis: an immune barrier hypothesis.

Background Chronic rhinosinusitis (CRS) has been defined as persistent symptomatic inflammation of the nasal and sinus mucosa resulting from the interaction of multiple host and environmental factors. Recent studies have implicated Alternaria fungi or toxigenic Staphylococcus aureus as critical agents in CRS pathogenesis. The emphasis on environmental agents in CRS etiology has focused interest toward elimination of those agents as the prime mechanism of therapy. This viewpoint is in marked contrast to the current perspective on some other chronic inflammatory epithelial disorders that afflict the skin, lungs, and gut, wherein host factors are believed to predispose to disease expression in the presence of ubiquitous environmental agents. Methods The current review evaluates CRS etiology from this perspective and considers that CRS develops, in part, as an outcome of a dysfunctional host response. Specifically, evidence from our laboratory and others will be reviewed indicating that CRS is associated with a failure of the mechanical and immunologic barriers across the nasal mucosa. The hypothesis would further propose that genetic and epigenetic variation predisposes susceptible individuals to barrier failure in the presence of environmental stress leading to CRS. Results From this unifying perspective, bacteria and fungi are seen as disease modifiers rather than primary etiologic agents. Conclusion The goal is to place concepts of CRS pathophysiology in a framework consistent with a current understanding of chronic inflammation in general and epithelial disease in particular.

Outcome analysis of endoscopic sinus surgery in patients with nasal polyps and asthma

Objective: To investigate the efficacy of endoscopic sinus surgery (ESS) in the management of chronic sinusitis and asthma in patients with nasal polyps and steroid‐dependent asthma. Study Design: Retrospective chart review. Methods: The study included 17 patients who underwent ESS with nasal polyps, steroid‐dependent asthma with or without aspirin sensitivity and a minimum of 1 year postoperative follow‐up. Nine patients were ASA sensitive, and eight patients were ASA tolerant. Chronic sinusitis and asthma were evaluated using subjective (patient complaints) and objective (computed tomography scans, pulmonary function tests, steroid doses) criteria. Preoperative data were compared with data obtained 12 to 18 months postESS. Tissue samples were graded for degree of inflammation and edema. Results: Thirteen of the 17 (76.5%) patients reported improved clinical symptoms postESS. The postoperative Lund‐Mackay scores were statistically lower for the 17 patients (P < .0001). The group experienced improvement in postoperative forced expiratory volume at 1 second (FEV1) (P < .014). Twelve of 17 (70.6%) experienced reduction in systemic steroid usage (P < .048). The ASA sensitive patients did not have a statistical improvement in postoperative FEV1 (P > .08) and sinonasal symptoms (P > .16) compared with the ASA tolerant group. Polyp tissue from the ASA sensitive patients demonstrated more edema and more inflammation on average than ASA tolerant polyps, but the results were not statistically significant. Conclusion: ESS demonstrates a beneficial effect on the sinonasal and asthma symptomatology in patients with nasal polyps and asthma using objective measures. Subset of aspirin‐tolerant patients have statistically better outcome for sinonasal symptoms and pulmonary function testing than aspirin‐sensitive patients.

Relationships between severity of chronic rhinosinusitis and nasal polyposis, asthma, and atopy.

Background The effect of comorbid conditions such as asthma and atopy on the severity of chronic rhinosinusitis (CRS) and the presence of nasal polyps (NPs) remains an area of investigation. We sought to elucidate the relationship among these entities. Methods The study population included 106 consecutive patients who were referred to a multidisciplinary, university-based allergy and sinus clinic that underwent computed tomography (CT) scan, skin-prick testing, and had CRS. Data were analyzed to determine Lund-MacKay score (LMS), presence of NPs, asthma status, and sensitivity to seven classes of aeroallergens. Results Skin tests were positive in 52 cases and negative in 54 cases. Although, there was no statistical relationship between LMS and atopic status in the entire group, among the asthmatic subgroup, mean LMS was greater in nonatopic asthmatic patients than in atopic asthmatic patients. Asthmatic patients had a higher LMS than nonasthmatic patients (p < 0.0001). Asthmatic patients were more likely than nonasthmatic patients to have NPs (57.6% versus 25%; p = 0.0015), regardless of atopic status. Mean LMS was higher in NP patients compared with nonpolyp patients (p < 0.0001), independent of atopic status. Mean LMS was not affected by sensitivity to any particular allergen, with the exception of cockroach-allergic patients who were more likely to have an LMS of >10 (p = 0.0236) and had more severe maxillary sinus involvement (p = 0.0391). Conclusion These data indicate a strong relationship between CRS severity, as measured by LMS, and chronic airway inflammatory diseases, asthma, and NPs. The association between LMS and atopic status appears weak. The present study suggests that CRS is an inflammatory disease that occurs independently of systemic IgE-mediated pathways.

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

BACKGROUND Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. OBJECTIVES The objective of this study was to investigate the role of TSLP in patients with CRS. METHODS We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. RESULTS Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. CONCLUSION TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP.

Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps

BACKGROUND The polypoid form of chronic rhinosinusitis (chronic rhinosinusitis with nasal polyps [CRSwNP]) is a highly prevalent disease that often requires surgical intervention for treatment. Nasal polyps contain large quantities of B lymphocytes and immunoglobulin as well as eosinophils. OBJECTIVES The objective of this study was to investigate the expression of B cell-activating factor of the TNF family (BAFF), an important regulator of class-switch recombination and immunoglobulin production, in patients with chronic rhinosinusitis (CRS). METHODS We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We assayed mRNA for BAFF and B-lymphocyte markers, CD20 and transmembrane activator and calcium-modulator and cyclophilin ligand interactor, by using real-time PCR, and assayed BAFF protein by using ELISA and immunohistochemistry. RESULTS BAFF mRNA was significantly increased in nasal polyps from patients with CRSwNP (P < .001) compared with inferior turbinate tissue from patients with CRS or healthy subjects. BAFF protein was also elevated in polypoid tissue and nasal lavage from patients with CRSwNP. Immunohistochemistry showed considerable BAFF staining in mucosal epithelial cells in nasal polyps along with unidentified cells in the lamina propria. Expression of mRNA for BAFF in sinonasal tissue was significantly correlated with CD20 and transmembrane activator and CAML interactor in sinus tissue. IgA, an immunoglobulin isotype known to activate eosinophils, was also significantly elevated in the polypoid tissue. CONCLUSION Overproduction of BAFF in nasal polyps may contribute to the pathogenesis of CRSwNP via the local induction of IgA and activation of eosinophils.

Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps

BACKGROUND IL-6 activates T(H)17 cells and regulates the response of B lymphocytes and regulatory T cells. The IL-6 receptor and the membrane protein, glycoprotein 130 (gp130), form an active signaling complex that signals through signal transducer and activator of transcription 3 (STAT3) and other signaling molecules. Both the IL-6 receptor (IL-6R) and gp130 can be found in soluble forms that regulate the pathway. OBJECTIVE We measured IL-6 signaling components and IL-17 in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls to assess the IL-6 pathway in CRS. METHODS IL-6, soluble IL-6R, soluble gp130 (sgp130), and IL-17 were measured in sinus tissue extracts and in nasal lavage fluid by either cytokine bead array or ELISA. phosphoSTAT3 (p-STAT3) was determined by Western blot and by immunohistochemistry. RESULTS IL-6 protein was significantly (P < .001) increased in CRSwNP compared with CRSsNP and controls. Soluble IL-6R was also increased in nasal polyp compared with control tissue (P < .01). Despite elevated IL-6 and sIL-6R, IL-17A, E, and F were undetectable in the sinus tissue from most of the patients with CRS and controls. p-STAT3 levels were reduced in the polyp tissue, possibly indicating reduced activity of IL-6 in the tissue. sgp130 was elevated in CRSwNP compared with CRSsNP and controls. CONCLUSION p-STAT3 levels are decreased in CRSwNP despite increased levels of IL-6 and sIL-6R and are associated with the absence of an IL-17 response. This may be a response to elevated levels of sgp130, a known inhibitor of IL-6 signaling. These results indicate that IL-6 and its signaling pathway may be altered in CRSwNP.

Superantigens and chronic rhinosinusitis: detection of staphylococcal exotoxins in nasal polyps.

Objective/Hypothesis: The role of infectious agents in the etiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) remains unclear. Recent studies have provided indirect evidence of exposure to staphylococcal exotoxins in the blood and polyp tissue of patients with CRSwNP. These exotoxins have the capacity to act as superantigens, bypassing normal antigen processing and directly stimulating a massive inflammatory response. The objective of the study was to analyze mucus and polyp tissue samples from patients with CRSwNP for the presence of staphylococcal exotoxins.

Association between severity of asthma and degree of chronic rhinosinusitis.

Background There is a clinical association between asthma and chronic rhinosinusitis (CRS). This study was designed to determine whether severity of coexistent asthma affects the clinical presentation of CRS. Methods Cross-sectional analysis was performed of prospectively collected data in 187 patients with CRS who were evaluated in a large, tertiary academic nasal and sinus center. Patients were stratified into three groups based on asthma status using National Institutes of Health criteria: (1) nonasthmatic, (2) intermittent/mild asthma, (3) or moderate/severe asthma. Results Mean Lund-Mackay scores were 9.7, 11.6, and 15.6, respectively. ANOVA testing with post-hoc Tukey analysis revealed that Lund-MacKay scores were significantly greater in group 3 than either group 1 (p < 0.05) or group 2 (p < 0.01). The prevalence of allergic sensitization was 72.4, 82.8, and 100% in groups 1, 2, and 3, respectively (p = 0.03). The prevalence of nasal polyposis was 31.4% in group 1, 48.3% in group 2, and 94.4% in group 3 (p < 0.0001). No differences were observed regarding demographic factors or the incidence of the triad of aspirin sensitivity, asthma, and nasal polyposis among those with different severities of asthma. Conclusion Increasing severity of asthma is associated with advancing radiological severity of CRS and a greater prevalence of allergic sensitization and nasal polyposis. This large adult series shows that asthma severity may have a significant correlation with the presentation of CRS. This study adds to the growing support for the unified airway theory.

Medical therapy vs surgery for chronic rhinosinusitis: a prospective, multi‐institutional study with 1‐year follow‐up

This study evaluated 1‐year outcomes in patients with chronic rhinosinusitis (CRS) who were considered surgical candidates by study criteria and elected either medical management or endoscopic sinus surgery (ESS). In addition, some patients initially enrolled in the medical treatment arm crossed over to the surgery arm during the study period and their respective outcomes are evaluated.

Long-term effects of FloSeal packing after endoscopic sinus surgery.

Background A previous study by our group showed increased adhesions and granulation tissue in ethmoid cavities packed with FloSeal (FS) compared with those packed with thrombin-soaked gelatin foam after endoscopic sinus surgery (ESS). That study included 20 patients whose cavities were graded 6–8 weeks postoperatively. The goal of this study was to report long-term follow-up on this cohort. Methods At least 1 year follow-up was available in 18/20 patients. The number of office procedures required to lyse adhesions during the follow-up period was tabulated also. Pathology was available from one patient who underwent lysis of adhesions on an FS side. The histopathological findings are presented. Results The mean follow-up period was 21.4 (±2.3) months, and none of the 18 patients required revision ESS during this interval. The overall incidence of adhesions (p = 0.013) and the number requiring lysis of adhesions (p = 0.046) were both greater in the FS group. During the interval between previous study evaluation (6–8 weeks postop) and last follow-up, five FS sides required a total of seven procedures to lyse adhesions. Silent adhesions were observed in an additional five FS sides. Although asymptomatic adhesions were observed in two thrombin-soaked gelatin sides at last examination, none underwent lysis. Biopsy of an adhesion from a patient packed with FS 25 months earlier revealed incorporated foreign material. Conclusion FS appears to be associated with scar tissue formation and may be incorporated into recovering mucosa. Use of FS may increase the degree of postoperative care required after ESS.