Biologic treatment for severe chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyps is often severe, debilitating and difficult to treat. Biologics that target key inflammatory pathways have the potential to treat this disease; this study aimed to evaluate their effectiveness. METHODOLOGY: Systematic review and meta-analysis of randomised controlled trials of biologics in chronic rhinosinusitis with nasal polyps. Primary outcomes were extent of disease, objective disease severity and disease-specific quality of life, with outcomes measured at different end-of-treatment timepoints in different studies (range 16-52 weeks). RESULTS: Eleven trials were identified with 2035 participants. Ten studies reported change in polyp size, estimating a reduction of -1.25 in the treatment group. Six studies reported reduction in Lund-Mackay score where the pooled mean difference was -4.90. Five studies included peak nasal inspiratory flow with a pooled mean difference of 33.54, indicating improved nasal airflow. Seven studies reported change in olfactory score with an overall pooled effect of 6.56 suggesting improved olfaction. The SNOT-22 score in nine studies gave an overall pooled effect of -14.53, indicating improved quality of life. CONCLUSIONS: Biologics can be effective in treating nasal polyps, with reduction in polyp size and extent of disease, and improved sense of smell and quality of life. There is significant heterogeneity in the outcomes for individual biologics, highlighting the need for further studies.

Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: The one airway concept revisited.

Allergic rhinitis (AR), chronic rhinosinusitis (CRS) and asthma often co-exist. The one airway model proposes that disease mechanisms occurring in the upper airway may mirror lower airway events. Airway remodelling is the term used to describe tissue structural changes that occur in a disease setting and reflect the dynamic process of tissue restructuring during wound repair. Remodelling has been long identified in the lower airways in asthma and is characterized by epithelial shedding, goblet cell hyperplasia, basement membrane thickening, subepithelial fibrosis, airway smooth muscle hyperplasia and increased angiogenesis. The concept of upper airway remodelling has only recently been introduced, and data so far are limited and often conflicting, an indication that more detailed studies are needed. Whilst remodelling changes in AR are limited, CRS phenotypes demonstrate epithelial hyperplasia, increased matrix deposition and degradation along with accumulation of plasma proteins. Despite extensive research over the past years, the precise cellular and molecular mechanisms involved in airway remodelling remain incompletely defined. This review describes our current rather limited understanding of airway remodelling processes in AR, CRS and asthma and presents mechanisms both shared and distinct between the upper and lower airways. Delineation of shared and disease-specific pathogenic mechanisms of remodelling between the sinonasal system and the lung may guide the rational design of more effective therapeutic strategies targeting upper and lower airways concomitantly and improving the health of individuals with inflammatory airway diseases.

Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together-a real life study.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma often coexist and thus treating both with one intervention is an attractive strategy. OBJECTIVE: To prospectively evaluate whether treatment with the monoclonal antibody against IgE Omalizumab for severe allergic asthma also effectively treats co-existent CRSwNP. METHODS: SNOT-22 and the ACQ-7 scores were recorded at 4 and 16 weeks of treatment in a cohort of patients with both CRSwNP and severe refractory allergic asthma treated with Omalizumab (n=13) according to UK guidelines for their severe asthma. SNOT-22 in a surgery only treated CRSwNP with asthma group (n=24) was compared. RESULTS: Rapid improvement was seen at 4 weeks and 16 weeks of treatment in both CRSwNP and asthma control. The improvement in CRSwNP with Omalizumab was similar to that seen in a group of patients who received upper airway surgery. CONCLUSION: Omalizumab treatment for severe allergic asthma also improves co-existent CRSwNP. Further clinical studies of current and emerging biological agents for severe asthma should include upper airway outcomes. These agents may be effective for severe CRSwNP and comparative studies with surgery are warranted.

BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007).

This is an updated guideline for the diagnosis and management of allergic and non-allergic rhinitis, first published in 2007. It was produced by the Standards of Care Committee of the British Society of Allergy and Clinical Immunology, using accredited methods. Allergic rhinitis is common and affects 10-15% of children and 26% of adults in the UK, it affects quality of life, school and work attendance, and is a risk factor for development of asthma. Allergic rhinitis is diagnosed by history and examination, supported by specific allergy tests. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. Combination therapy with intranasal corticosteroid plus intranasal antihistamine is more effective than either alone and provides second line treatment for those with rhinitis poorly controlled on monotherapy. Immunotherapy is highly effective when the specific allergen is the responsible driver for the symptoms. Treatment of rhinitis is associated with benefits for asthma. Non-allergic rhinitis also is a risk factor for the development of asthma and may be eosinophilic and steroid-responsive or neurogenic and non- inflammatory. Non-allergic rhinitis may be a presenting complaint for systemic disorders such as granulomatous or eosinophilic polyangiitis, and sarcoidoisis. Infective rhinitis can be caused by viruses, and less commonly by bacteria, fungi and protozoa.

Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (NP) and allergic rhinitis (AR) is characterized by local Th2 inflammation and up-regulation of IgE; however, IgE in NP is 'polyclonal' and allergen specific, whereas IgE in AR is 'oligoclonal' and allergen specific. Germinal center (GC) reactions occur in AR, while only the formation of GC-like structures in NP is described. The aim of this study was to investigate the involvement of local IgE production, class switch recombination, and receptor revision in NP. METHODS: We compared the levels of local IgE, germline gene transcripts, and mature Ig mRNA expression, recombination activating gene (RAG1 and RAG2), key markers of Th2 inflammation, and GC reactions in NP tissue vs AR and control tissue. Nasal mucosa was immunostained for the co-expression of RAG1 and RAG2 in B cells, plasma cells, and T cells, using dual or triple immunofluorescence (IF). RESULTS: In NP, local IgE level and key markers of local class switching are increased compared with AR and normal controls (NC). In NP, switch circle transcripts reveal ongoing local class switch recombination to IgE. Up to 30% of B cells, plasma cells, and T cells in nasal polyps re-express both RAG1 and RAG2, required for receptor revision. RAG1 and RAG2 mRNA concentrations are increased in NP and correlated with the magnitude of inflammation and the presence of S. aureus enterotoxin (superantigen)-specific IgE in the nasal polyp mucosa. CONCLUSION: Our results provide the first evidence of local receptor revision and class switching to IgE, and B-cell differentiation into IgE-secreting plasma cells in NP.

Activin-A: a novel critical regulator of allergic asthma.

Activin-A is a pleiotropic cytokine that belongs to the TGF-ß superfamily and plays an important role in fundamental biological processes, such as development and tissue repair. Growing evidence proposes a crucial role for activin-A in immune-mediated responses and associated diseases, with both enhancing and suppressive effects depending on the cell type, the cytokine micromilieu and the context of the response. Several recent studies have demonstrated a striking increase in activin-A expression in experimental models of asthma, as well as, in the asthmatic airway in humans. Importantly, a strong immunoregulatory role for activin-A in allergic airway disease, with suppression of T helper (Th) type 2 cell-driven allergic responses and protection against the development of cardinal features of the asthmatic phenotype was revealed by in vivo functional studies. Activin-A-mediated immunosuppression is associated with induction of functional allergen-specific regulatory T cells. In human asthma, although activin-A levels are increased in the airway epithelium and submucosal cells, the expression of its signalling components is markedly decreased, pointing to decreased regulation. Nevertheless, a rapid activation of the activin-A signalling pathway is observed in the airway of individuals with asthma following inhalational allergen challenge, suggestive of an inherent protective mechanism to control disease. In support, in vitro studies using human airway epithelial cells have demonstrated that endogenous activin-A suppresses the release of inflammatory mediators, while it induces epithelial repair. Collectively, compelling evidence suggests that activin-A orchestrates the regulation of key events involved in the pathogenesis of allergic asthma. The critical role of activin-A in allergic airway responses places this cytokine as an exciting new therapeutic target for asthma.

Developments in the field of allergy in 2008 through the eyes of Clinical & Experimental Allergy.

In 2008, many thousands of articles were published on the subject of allergic disease with over 200 reviews, editorials and original papers in Clinical & Experimental Allergy alone. These represent a considerable amount of data and even the most avid reader could only hope to assimilate a small fraction of this knowledge. There is therefore a pressing need for the key messages that emerge from a journal such as Clinical & Experimental Allergy to be summarized by experts in the field in a form that highlights the significance of the developments and sets them in the context of important findings in the field published in other journals. This also has the advantage of making connections between new data in conditions such as asthma, where articles often appear in different sections of the journal. As can be seen from this review, the body of work is diverse both in terms of the disease of interest and the discipline that has been used to investigate it. However, taken as a whole, we hope that the reader will gain a flavour of where the field is mature, where there remain controversies and where the cutting edge is leading.

Sulphation of the salivary mucin MG1 (MUC-5B) is not correlated to the degree of its sialylation and is unaffected by cystic fibrosis.

Defective acidification of intracellular organelles, particularly the trans-Golgi network, has been proposed to explain the decreased sialylation and increased sulphation of secreted proteins in cystic fibrosis (CF). To test this hypothesis we compared expression of sulphate and sialic acid on three salivary mucins namely MG1 (MUC-5B), MG2 (MUC-7) and GL. Proteins in whole mouth saliva (WMS) from four individuals were separated by fast protein liquid chromatography (FPLC) on a Superdex 200 column and the partially purified mucins slot-blotted and assayed for sulphate content by staining with Alcian Blue. Sulphation varied with the individual and with the mucin: MG1 was the most sulphated and contributed almost the entire sulphate content of WMS. These results allowed us to test small volumes of WMS from 20 CF patients and age- and sex-matched controls for estimates of sulphate content on MG1. Wherever possible sulphate on MG1 was also visualised by staining washed SDS-PAGE gels with Alcian Blue at pH 1.0. To assess the sialic acid content of salivary mucins, electroblots of SDS-PAGE gels were probed with labelled Triticum vulgaris agglutinin. In summary, our results show MG1 to be the main sulphated protein in whole mouth saliva and there are large differences in the expression of sulphate and of sialic acid on this mucin, both in control and CF groups. CF led neither a decrease in sialylation nor an increase in sulphation and direct comparisons of sialic acid content with sulphate in MG1 failed to reveal any obvious link between the two in health or in disease. Our data thus do not support the hypothesis of defective acidification as the underlying cause of altered glycosylation in CF, but point instead to inter-individual differences in expression/functioning of terminal glycosyltransferases for published observations. We thank the European Union Biomed II programme for support.

Altered sialyl- and fucosyl-linkage on mucins in cystic fibrosis patients promotes formation of the sialyl-Lewis X determinant on salivary MUC-5B and MUC-7.

Destruction of the lungs as a consequence of recurrent infections with microorganisms such as Pseudomonas aeruginosa remains the underlying cause of most morbidity and mortality in cystic fibrosis (CF). We have hypothesized that changes in the glycosylation of key tracheal mucins such as MUC5B and MUC7 might increase the risk of pulmonary disease in CF patients. However, in preference to sputum we have examined the sugar-chains on these mucins in saliva because in the latter not only can the glycoproteins be collected from controls, but they are essentially free from modifications made following bacterial infection in disease. Proteins in ductal or whole-mouth saliva from 20 CF patients with the Delta F-508 CFTR mutation and age-and sex-matched controls were separated by SDS-PAGE and blotted onto nitrocellulose and then probed with labelled lectins of known specificity. Linkage of terminal sialic acid on the blotted mucins was determined using Sambucus nigra agglutinin (detects the 2-->6 linkage) and Maackia amurensis agglutinin (the 2-->3 linkage). Fucose was detected by Ulex europaeus agglutinin-1 (1-->2 linkage) and Aleuria aurantia agglutinin (1-->3 linkage). We found that each mucin shows a characteristic glycosylation pattern and in controls most of the sialic acid is 2-->6 linked on MG1 (MUC 5B) and 2-->3 linked on MG2 (MUC 7). CF is associated with a shift from a 2-->6 linkage to a 2-->3 linkage on MG1 with some patients showing almost no 2-->6 linkage; 2-->3 linkage on MG2 is similarly increased in disease in some individuals. The expression of fucose on these mucins is also raised in CF patients. These shift to a 2-->3 linkage of sialic acid, and with increased fucosylation this promotes the formation of sialyl-Lewis X antigen detected on CF mucins in our study. These changes will be tested for their correlation with the severity of lung disease. We gratefully acknowledge support from the European Union Biomed-II Programme.

Anaemia in lung transplant patient caused by parvovirus B19.

The case history is presented of a lung transplant patient who developed prolonged parvovirus B19 infection with severe transfusion dependent anaemia. The patient was treated with intravenous immunoglobulin after which the haemoglobin rose, together with a reticulocytosis. The patient then remained transfusion free and the virus cleared more than three months after the initial immunoglobulin treatment. The clinical and social implications for this group of patients are discussed.

Experience of totally implantable venous access devices (TIV ADs) in adults with cystic fibrosis over a 13-year period.

Totally implantable venous intravenous access devices (TIVADs) have an essential role in the frequent delivery of antibiotics in cystic fibrosis (CF) patients. This study at the Royal Brompton Hospital (RBH) reports the experience of TIVADs in patients attending the RBH adult CF unit implanted at the RBH and elsewhere over a 13-year period. The case notes of adult CF patients who had undergone TIVAD insertion were reviewed retrospectively. The patients were divided into those who had the insertion carried out at the RBH and those who had the device inserted elsewhere. All devices were cared for the at the RBH. A total of 115 devices in 74 patients were reviewed. The median duration of function of 109 devices was 1429 days (range 2-3989) or 3.9 years, with a total exposure of 91,188 days or 249.8 years. There was no significant difference between devices inserted at the RBH and those inserted elsewhere (P= 0.59). Thirty-four patients had devices installed without complications. Forty patients had complications in 62 devices. The incidence of complications was 34.5% at the devices inserted at RBH and 73.7% elsewhere (P<0.001). Of the 115 devices, mechanical complications occurred in 42 (36%) with a median time of diagnosis of 373 days (range 1-2554), infectious complications occurred in 16 (14%), with a median time of diagnosis of 413 days (range 40-2556) and symptomatic venous thrombosis occurred in four (3.5%). RBH-inserted devices had significantly fewer mechanical complications (P<0.001) compared with those inserted elsewhere. The group as a whole had fewer infectious complications than in most other reported series. We conclude that TIVADs provide effective and long-term intravenous access and have fewer complications if they are inserted and cared for at a centre with special expertise in their insertion and management.