Twelve-year follow-up study after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a therapeutic challenge because of the high recurrence rate. Surgical intervention should be considered in patients who fail to improve after medical treatment. We monitored recurrence and revision surgery over 12 years after endoscopic sinus surgery in CRSwNP patients. METHODS: In this prospective cohort study, 47 patients with CRSwNP, who underwent primary or revision extended endoscopic sinus surgery, were followed. Clinical symptoms and total nasal endoscopic polyp score were evaluated before, 6 years and 12 years after surgery. RESULTS: Twelve years after surgery, 38 out of 47 patients (80.9%) were available for examination. There still was a significantly better symptom score and total nasal endoscopic polyp score compared to before surgery (P < 0.001). Within the 12-year follow-up period, 30 out of 38 patients developed recurrent nasal polyps, of which 14 patients underwent additional revision surgery. Comorbid allergic sensitization and tissue IL-5 levels were found to be significant predictors for the need of revision surgery. CONCLUSIONS: This long-term cohort study, investigating the outcome after surgery in CRSwNP, showed that, despite the low number of patients, 78.9% of patients with CRSwNP were subject to recurrence of the disease and 36.8% to revision surgery over a 12-year period.

Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis.

BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE: We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS: Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS: Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION: Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

Pathophysiology of chronic rhinosinusitis.

Chronic rhinosinusitis (CRS), a disease presenting with chronic symptoms such as nasal obstruction, rhinorrhea, hyposmia and facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflammatory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorganisms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease subgroups and their etiologies is an important and challenging task for future research.

Tissue remodeling in chronic rhinosinusitis.

PURPOSE OF REVIEW: To summarize the current knowledge on remodeling in chronic sinus disease. RECENT FINDINGS: Chronic sinus disease is characterized by persistent inflammation of the nasal and paranasal mucosa and is currently classified into two major subgroups on the basis of the absence (CRSsNP) or presence (CRSwNP) of nasal polyps. Transforming growth factor-beta and matrix metalloproteinases are critical factors involved in the remodeling process. SUMMARY: Remodeling is clearly present in chronic sinus disease. Transforming growth factor-beta has been implicated as an important factor in remodeling processes involved in chronic sinus disease, and serves as a main switch for different remodeling patterns in chronic sinus disease.

Chronic sinusitis and rhinitis: clinical terminology "Chronic Rhinosinusitis" further supported.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities, either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). The etiology and pathophysiology is unknown; some specialists define rhinitis and sinusitis as one clinical entity, whereas others regard both as separate dis-eases. We therefore investigated the immunological background of the chronically inflamed nasal and sinusal mucosa. METHODS: Protein levels of the inflammatory mediators ILl-beta, IL-5, ECP, INF-gamma, and TGF-beta were assessed in ethmoidal mucosal samples from CRSsNP and CRSwNP patients, and compared with the expression profile in nasal inferior turbinate (17) mucosa of the same patient groups. Nasal tissue of patients without disease served as control. RESULTS: In CRSwNP, increased levels of IL-5 and ECP were not only observed in ethmoidal samples, but also in the nasal IT-mucosa. TGF-beta levels were lower in polyps, reaching significance versus ethmoidal mucosa of CRSsNP. In CRSsNP, INF-gamma levels are up-regulated in both ethmoidal and nasal mucosa compared to control tissue. CONCLUSION: On the basis of similar inflammatory mediator profiles, we conclude that rhinitis accompanies chronic sinusitis, supporting the consensus term "rhinosinusitis". On the other hand, CRSsNP and CRSwNP should be regarded as distinct clinical entities.

TGF-beta signaling and collagen deposition in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. OBJECTIVE: The objective was to analyze the presence of TGF-beta isoforms, receptors, intracellular signaling, and collagen deposition in chronic rhinosinusitis. METHODS: Sinonasal mucosal samples obtained from chronic rhinosinusitis with nasal polyps (CRSwNP; n = 13), chronic rhinosinusitis without nasal polyps (CRSsNP; n = 13), and controls (n = 10) were analyzed for TGF-beta isoforms 1 and 2 by means of ELISA and IHC, and for TGF-beta R1, 2, and 3 by RT-PCR and IHC. As downstream proteins, phospho-Smad 2 (pSmad 2) and collagen were analyzed by performing immunostaining and picrosirius red staining, respectively. RESULTS: TGF-beta 1 and 2 protein concentrations, TGF-beta receptor (R) I and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly higher in CRSsNP versus controls. In CRSwNP, TGF-beta 1 protein concentration, TGF-beta RII and TGF-beta RIII mRNA expression, the number of pSmad 2-positive cells, and total collagen amount were significantly lower versus controls. Only TGF-beta 2 protein was found higher in CRSwNP versus controls. CONCLUSION: A high TGF-beta 1 protein expression, increased TGF-beta RI expression, and a high number of pSmad 2-positive cells all indicate an enhanced TGF-beta signaling in CRSsNP, whereas a low TGF-beta 1 protein concentration, a decreased expression of TGF-beta RII, and a low number of pSmad 2-positive cells in CRSwNP indicate a low level of TGF-beta signaling in CRSwNP. These findings are compatible with the remodeling patterns observed, reflected by a lack of collagen in CRSwNP, and excessive collagen production with thickening of the collagen fibers in the extracellular matrix in CRSsNP.

Chronic rhinosinusitis with and without nasal polyps: what is the difference?

Chronic rhinosinusitis is a heterogeneous group of chronic sinus diseases that may consist of clearly different disease entities. Further investigation of the pathomechanisms of chronic rhinosinusitis and the introduction of appropriate disease markers have recently facilitated disease classification. Evaluation of inflammatory cell profiles, the differentiation of T-effector cells, characterization of remodeling processes such as fibrosis or edema formation, and innate or adaptive immunity products such as Toll-like receptors and immunoglobulins all provide tools to identify distinct disease entities within the group of chronic sinus diseases. This disease differentiation will not only increase our knowledge of the pathophysiology of sinusitis but may lead to new diagnostic and therapeutic strategies specifically targeted and adapted to the diagnosed disease entity.

Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian (south Chinese), patients with polyps. OBJECTIVE: We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. METHODS: Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. RESULTS: Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio = 0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor alpha and significant downregulation of Foxp3 expression and TGF-beta1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in T(H)2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a T(H)1/T(H)17 cell pattern versus control tissue. CONCLUSION: Nasal polyps (CRSwNP) from white and Asian patients are both characterized by T-cell activation and impaired regulatory T-cell function; however, T-effector cells in the samples from white patients were T(H)2-biased, whereas samples from their Asian counterparts demonstrated a T(H)1/T(H)17 polarization.

T-cell regulation in chronic paranasal sinus disease.

BACKGROUND: Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a T(H)2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant T(H)1 milieu. OBJECTIVE: We aimed to study the direct tissue expression of transcription factors for T-cell subpopulations, including T regulatory cells, in relation to the cytokine expression patterns in the different disease subgroups. METHODS: The expression of forkhead box P3 (FOXP3), T-box transcription factor (T-bet), GATA-3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-beta1 and IL-10, and T(H)1/ T(H)2/ T(H)17 cytokines (IFN-gamma, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP, and 10 control samples. Additional protein measurements were performed for TGF-beta1 and IFN-gamma. RESULTS: In CRSwNP, we observed a significantly lower FOXP3 mRNA and TGF-beta1 protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with controls, whereas RORc was not significantly different compared with controls. In CRSsNP, FOXP3, T-bet, GATA-3, and RORc expression was not significantly different from controls, whereas TGF-beta1 mRNA, IFN-gamma mRNA, and protein were significantly higher in CRSsNP compared with controls. For IL-17, no significant differences were noted among all groups. CONCLUSION: We demonstrate for the first time a decreased FOXP3 expression accompanied by an upregulation of T-bet and GATA-3 and a downregulation of TGF-beta1 in CRSwNP versus controls and CRSsNP.