Pontus Stierna

EAACI Position Paper on Rhinosinusitis and Nasal Polyps Executive Summary

OS document, initated by the Academy ofAllergology and Clinical Immunology (EAACI) andapproved by the European Rhinologic Society (ERS), isintended to be state-of-the art for the specialist as well asfor the general practitioner:• to update their knowledge of rhinosinusitis and nasalpolyposis;• to provide an evidence-based documented revision ofthe diagnostic methods;• to provide an evidence-based revision of the availabletreatments;• to propose a stepwise approach to the management ofthe disease;• to propose guidance for definitions and outcomemeasurements in research in different settings.This executive summary focuses on definitions, diagnosisand treatment and the relation to allergy and lowerairway disease. The whole document is published at theEAACI website (http://www.eaaci.org) and in the JournalRhinology (Supplement 18, March 2005).Definition of rhinosinusitis/nasal polypsRhinitis and sinusitis usually coexist and are concurrentin most individuals; thus, the correct terminology is nowrhinosinusitis.In 2001 the WHO put together a working group onrhinitis and its impact on asthma (ARIA) (9). In thisgroup rhinitis was classified according to duration andseverity. Because rhinitis and sinusitis are so closelylinked the definition of CRS/NP in the EPOS document isdeveloped from the ARIA classification of rhinitis andbased on symptomatology, duration and severity ofdisease.The diagnosis of rhinosinusitis is made by a widevariety of practitioners, including allergologists, otolar-yngologists, pulmonologists, primary care physicians andmany others. Due to the large differences in technicalpossibilities to diagnose and treat rhinosinusitis/nasalpolyps by various professions, definitions of CRS/NPshould be tailored to the individual group.Clinical definition of rhinosinusitis/nasal polypsRhinosinusitis (including nasal polyps) is defined as:• Inflammation of the nose and the paranasal sinusescharacterised by two or more symptoms:– blockage/congestion– discharge: anterior/post nasal drip– facial pain/pressure– reduction or loss of smelland either• Endoscopic signs:– polyps– mucopurulent discharge from middle meatus– oedema/mucosal obstruction primarily in middlemeatusand/or• CT changes:– mucosal changes within ostiomeatal complex and/or sinusesSeverity of disease. The disease can be divided intoMILD and MODERATE/SEVERE based on total visualanalogue scale (VAS) score (0–10 cm): MILD ¼ VAS0–4, MODERATE/SEVERE ¼ VAS 5–10.To evaluate the total severity the patient is asked toindicate on a VAS the question:How troublesome are your symptoms of rhinosinusitis?Not troublesome Most troublesome

EVIDENCE THAT THE BETA -ISOFORM OF THE HUMAN GLUCOCORTICOID RECEPTOR DOES NOT ACT AS A PHYSIOLOGICALLY SIGNIFICANT REPRESSOR

Alternative splicing of the human glucocorticoid receptor (hGR) primary transcript generates two receptor isoforms, hGRα and hGRβ, with different carboxyl termini diverging at amino acid 727. By reverse transcriptase-polymerase chain reactions it was previously demonstrated that the hGRβ message had a widespread tissue distribution. To demonstrate the presence of hGRβ as protein we produced specific rabbit antisera to hGRβ, as well as a hGRβ-specific mouse monoclonal IgM antibody, by peptide immunizations. By SDS-polyacrylamide gel electrophoresis and Western immunoblotting we showed that hGRβ is endogenously expressed at the protein level in HeLa cells and human lymphatic leukemia cells. Using an antibody directed against an epitope shared by both isoforms we showed a relatively lower expression of the hGRβ form. We also showed that hGRβ bound to hsp90 by immunoprecipitation of in vitro translated hGRβ in reticulocyte lysate with hsp90-specific antibodies, a coprecipitation occurring also in the presence of dexamethasone. We could not demonstrate that hGRβ inhibited the effects of dexamethasone-activated hGRα on a glucocorticoid-responsive reporter gene. In conclusion, low hGRβ expression levels and hGRβ-hsp90 interaction maintained in the presence of ligand and lack of inhibition of hormone-activated hGRα effects challenge the concept of the hGRβ isoform as a proposed dominant negative inhibitor of hGRα activity.

Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance

OBJECTIVE Primary glucocorticoid resistance is characterized by decreased sensitivity to cortisol signalling. We have performed genetic analysis of the glucocorticoid receptor (GR) gene in 12 unrelated patients with primary cortisol resistance as defined by a pathological dexamethasone suppression test.

NF-κB mediated glucocorticoid response in the inner ear after acoustic trauma

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10–30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre‐treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25–60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF‐κB, whereas pre‐treatment with the drugs (metyrapone and RU 486) blocked NF‐κB nuclear transport into spiral ganglion nuclei. An NF‐κB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma‐induced translocation of NF‐κB and resulted in a hearing loss (45–60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF‐κB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Changes in immune regulation in response to examination stress in atopic and healthy individuals

Background Stress can aggravate the allergic inflammation, but determinants of disturbed immune regulation are largely unknown.

Experimentally induced polyps in the sinus mucosa : a structural analysis of the initial stages

To document polyp formation in the sinus mucosa, the authors of this study subjected New Zealand white rabbits to different modes of manipulation intended to induce inflammation of the maxillary sinus. These manipulations included a combination of bacterial infection and mechanical trauma, the deposition of agarose into the sinus cavity, and the deposition of N‐formyl‐methionyl‐leucyl‐phenylalanine, a chemotactic peptide, into the sinus cavity. A majority of animals developed polyps, which were examined by light and electron microscopy.

Regeneration of Maxillary Sinus Mucosa following Surgical Removal Experimental Study in Rabbits

A rapid regeneration of the epithelium takes place in the maxillary sinus in rabbits after experimental operative removal of the mucosa. Two weeks postoperatively the previously denuded areas have reepithelialized. The subepithelial glands, however, do not seem to regenerate. The normal sinus mucosa contains numerous serous glands in the lamina propria, but in the regenerated mucosa these glands are replaced by dense connective tissue. Atypical glands and polyp formations are sometimes encountered, but goblet cells are sparse. Furthermore, the sinus cavity on the operated side is reduced in size compared with the nonoperated side because of fibrosis and periosteal reactions including bone degradation and neogenesis. This study indicates that although the mucosa is reepithelialized within 2 weeks, the regeneration of the lamina propria is incomplete, and reactive cellular processes such as bone remodeling, fibroblast proliferation, and formation of polyps and “atypical glands” are characteristic of regenerating mucosa.

Histopathological observations in chronic maxillary sinusitis

Biopsy samples from the maxillary sinus mucosa of patients with purulent, non-purulent and recurrent sinusitis were studied histologically and compared with those from a maxillary sinus of patients with no previous history of sinus disease on the side of sampling. Basement membrane thickening, atypical gland formation, goblet cell hyperplasia, mononuclear inflammatory cell infiltration and subepithelial oedema were observed in all groups irrespective of the appearance of the effusion. Although the inflammatory variables in selected areas of the mucosa seemed to show an increase in severity with the increasingly severe forms of sinusitis, neither the endoscopic mucosal appearance nor the nature of the sinus effusion corresponded to any specific histological pattern.

Nasal Polyps in Cystic Fibrosis: Clinical Endoscopic Study With Nasal Lavage Fluid Analysis

STUDY OBJECTIVES Nasal polyps frequently appear in patients with cystic fibrosis (CF). The aims of this study were to focus on what problems (symptoms, endoscopic findings, and laboratory correlates) nasal polyps cause the CF patient, and how these correlate to the total health situation of this patient group. PATIENTS AND STUDY DESIGN The clinical histories, endoscopic investigations of the nasal cavity, and analyses of nasal lavage fluid of 44 patients with CF complicated with nasal polyposis have been compared with those of 67 CF control subjects. The patients were examined at annual control examinations (with pulmonary tests, working capacity, liver tests, and bacterial and blood tests) from 1995 to 1996 at Stockholm Cystic Fibrosis Center, Huddinge University Hospital. All patients were > 2 years of age. The endoscopic findings were related to the actual pulmonary function, inflammatory blood parameters, colonizing pathogens, antibodies (Staphylococcus aureus and Pseudomonas aeruginosa), and genotype. RESULTS The patients with nasal polyps differed with respect to chronic colonization of P aeruginosa in sputum samples and had a higher occurrence of serum antibodies against the same species. The two groups did not differ in pulmonary functions, inflammatory parameters, or genotype. The polyps found were mainly small (within the meatus media) and gave no significant increase in ongoing clinical symptoms such as rhinorrhea, nasal obstruction, or hyposmia. Neither was any significantly marked finding concerning the nose (mucosal swellings, secretion, etc.) made in the polyp patients. The patients with CF scored slightly lower in a smell identification test in comparison with the healthy control group. The nasal lavage fluid was analyzed (in 93 of the 111 patients) for the occurrence of P aeruginosa (by polymerase-chain reaction [PCR]), interleukin [IL]-5, IL-8, and lysozyme. The lysozyme and IL-8 content was equal in the two CF groups but increased in comparison with the healthy control group. P aeruginosa was not detected with PCR in any nasal lavage fluid. No measurable levels of IL-5 in the nasal lavage were found. CONCLUSIONS There was a higher frequency of chronic colonization of P aeruginosa in the lower respiratory tract in patients with nasal polyps. Otherwise, nonsevere nasal polyposis was not an indicator of lower respiratory tract morbidity in CF patients.

Experimental maxillary sinusitis induced by Bacteroides fragilis. A bacteriological and histological study in rabbits.

Experimental anaerobic maxillary sinusitis was induced in New Zealand White rabbits by blocking the ostium and inoculating Bacteroides fragilis, strain NCTC 9343. The animals were examined histologically and bacteriologically after 5 days, and 2, 3 and 4 weeks. All the infected sinuses displayed signs of moderate or severe inflammation throughout the study period. Ciliary damage and desquamation, hyperplasia and metaplasia of the epithelium were characteristic features. Furthermore, heavy leukocyte- and, particularly, round cell-infiltration, fibrosis, periosteal hyperplasia and bone degradation and -formation were also frequently encountered. The secretory cell count in the epithelium increased, including the regeneration of goblet cells. After 4 weeks no obvious recovery could be seen, and the inducing microorganism was re-isolated in the majority of cases. In comparison with experimental pneumococcal sinusitis, the B. fragilis infection exerts a more prolonged and severe inflammation.