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The term rhinosinusitis describes an inflammation of the mucosal lining of the nose and sinuses; however, recent evidence points to the need to differentiate patients with chronic rhinosinusitis without nasal polyps from those with nasal polyps. Asthma comorbidity is especially common in nasal polyp disease and may be associated with aspirin-exacerbated respiratory disease. Of interest, asthma comorbidity is uncommon in some parts of the world but common in others. A further analysis of the inflammatory patterns also revealed that nasal polyps do not represent one single entity; interleukin (IL)-5-positive nasal polyps can be differentiated from IL-5-negative forms by different inflammatory patterns (predominance of eosinophils vs neutrophils). Staphylococcus aureus superantigens frequently colonize IL-5-positive nasal polyps and may amplify the eosinophilic inflammation, induce a polyclonal local IgE formation, and increase the risk of asthma comorbidity. Recent findings in severe asthma patients confirm the role of superantigens in lower airway disease.

Purpose of Review: Chronic rhinosinusitis with nasal polyps often represents a chronic severe inflammatory disease of the upper airways and may serve as a model for lower airway diseases such as late-onset intrinsic asthma. Enterotoxins derived from Staphylococcus aureus have been implicated in the pathophysiology of nasal polyps as disease-modifying factors; recent findings using therapeutic proof-of-concept approaches support this hypothesis., Recent Findings: Nasal polyps (chronic rhinosinusitis with nasal polyps) are characterized by a T-helper-2 dominated cytokine pattern that includes interleukin-5 and formation of immunoglobulin E. This is in contrast to chronic rhinosinusitis without polyps, which exhibits T-helper-1 biased cytokine release. It is now evident that the cytokine environment is decisive regarding the impact of S. aureus derived enterotoxins, which function as superantigens. S. aureus enterotoxin B further shifts the cytokine pattern in nasal polyps toward T-helper-2 cytokines (increases greater than twofold for interleukin-2, interleukin-4 and interleukin-5), but it disfavours the T-regulatory cytokines interleukin-10 and transforming growth factor-beta1. Furthermore, S. aureus derived enterotoxins influence local immunoglobulin synthesis and induce polyclonal immunoglobulin E production, which may contribute to severe inflammation via activation of mast cells., Summary: From this new understanding of chronic rhinosinusitis with nasal polyps, new therapeutic approaches emerge such as anti-interleukin-5, anti-immunoglobulin E, and antibiotic treatment. These may enlarge the nonsurgical armentarium.

Chronic rhinosinusitis with nasal polyps often represents a chronic severe inflammatory disease of the upper airways. Nasal polyps (chronic rhinosinusitis with nasal polyps) are characterized by a T-helper-2 dominated cytokine pattern including high interleukin-5 while chronic rhinosinusitis without polyps exhibits T-helper-1 biased cytokine releas with high IFN-gamma concentrations. S. aureus derived enterotoxins function as superantigens and in nasal polyps a significant higher colonisation and immune response to enterotoxins has been found. Furthermore, S. aureus derived enterotoxins influence local immunoglobulin synthesis and induce polyclonal immunoglobulin E production, which may contribute to severe inflammation via activation of mast cells. From this new understanding of chronic rhinosinusitis with nasal polyps, new therapeutic approaches emerge such as anti-interleukin-5, anti-immunoglobulin E, and antibiotic treatment. These may enlarge the nonsurgical armentarium. Furthermore more evidence is now available that this model of disease modification by superantigens is also applicable to lower airway diseases like late-onset asthma.

Nasal polyps represent a severe eosinophilic inflammation of the upper airways which is characterized by poor impact of therapeutic intervention and frequent recurrences. Based on distinct cytokine, mediator and cell profiles, chronic sinonasal disease in Caucasians can be differentiated into several subgroups such as chronic rhinosinusitis without nasal polyps, chronic rhinosinusitis with nasal polyps, and nasal polyps in cystic fibrosis patients,. In Caucasians, nasal polyps showed a Th2 polarisation with high IL-5 concentrations, while chronic rhinosinusitis without polyps was characterized by a Thl polarisation with high levels of IFN-gamma. In the Caucasian nasal polyps we found that significantly more nasal polyp patients are colonized with S. aureus and that colonization increased in patients with concomitant asthma and aspirin sensitivity. Although there was no major difference in the presence of enterotoxin genes in S. aureus strains derived from nasal polyp or control patients, we found an increased immune response to S. aureus enterotoxins in nasal polyps, which resulted in a more pronounced eosinophilic inflammation and higher total IgE production in those polyps affected. We suggest that S. aureus superantigens amplify the inflammation in about 50% of nasal polyps, resulting in a strong Th2 polarisation, eosinophil activation, and an overproduction of IgG4 and IgE. These findings imply new therapeutic approaches apart from the currently used topical and systemic steroid therapy for nasal polyposis. In three double blind placebo controlled studies it was shown that firstly, oral corticosteroids only led to a short term reduction of polyp size. Secondly that a low dose of doxycycline treatment for 20 days had a sustained clinically relevant effect on polyp size for more than 3 months and thirdly we also showed a significant effect on polyp size by selective antagonizing IL-5 with a monoclonal antibody.

Background: Chronic rhinosinusitis (CRS) with nasal polyps (NP) represents a persistent inflammation often characterized by local hyper-immunoglobulinaemia and the presence of specific IgE to Staphylococcus aureus enterotoxins (SAEs). We aimed to study the systemic and local production of Igs in relation to plasma cells, B cells and specific IgE to SAEs., Methods: Concentrations of IgE, IgG, IgM, IgA, IgG subclasses and specific IgE to SAE were determined on tissue homogenates and serum from 15 CRS patients with NP, 15 CRS without NP and 10 control patients. Tissue cryo-sections were stained for CD19, CD20 and CD138 to demonstrate B and plasma cells., Results: IgA, IgG and IgE concentrations were significantly higher in tissue homogenates, but not in serum, of NP compared with CRS and control subjects. NP with specific IgE to SAEs had significantly higher concentrations of IgG and IgE, and also showed a significantly higher fraction of IgG4 (P=0.003) and a lower fraction of IgG2 (P=0.04) than those without specific IgE production. Furthermore, naïve CD19(+) B cell and plasma cell counts (CD138(+)) were significantly higher in NP tissue compared with controls or CRS., Conclusions: The difference in IgE, IgG and IgA expression between NP tissue and serum, supported by increased numbers of plasma cells, suggests a local production of these Igs in NP in response to a chronic microbial trigger. The local immune response to SAE is associated with a further increased production of IgE and IgG, and a shift in IgG subclasses.

Gram-positive Staphylococcus aureus germs constitutively have the possibility to release classical and egc-locus-derived enterotoxins which show superantigen activity, and effectively modify the functions of T and B cells, eosinophils, and other inflammatory and structural cells. The stimulation may lead to a type 2 T helper cell-polarized eosinophilic inflammation as well as a multiclonal IgE production, aggravating airway disease in the upper and lower respiratory tract. Recently, S. aureus has been demonstrated to reside intraepithelially, and potentially to release superantigens into the tissue from within the epithelial cells. An immune defect, either in the innate or adaptive immunity, might be responsible for this phenomenon. Follicle-like structures and lymphocyte accumulations, specifically binding enterotoxins, can be found within the mucosal tissue. Interestingly also, IgE antibodies to enterotoxins can be found in the majority of aspirin-sensitive patients, in nasal polyps and severe asthma alike. We here summarize the current evidence from animal and human studies for an active role of staphylococcal enterotoxins (SEs) in allergic rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease and finally early childhood wheezing, and discuss the similarities between those disease manifestations. As a principle, the occurrence of IgE antibodies to SEs correlates with disease severity in terms of total IgE formation, inflammatory markers and clinical expression of the disease. Preliminary evidence from animal models underlines the high potency of SEs to induce or modulate disease, and a few pilot intervention trials may serve as proof of concept for the impact of SEs on disease severity. However, therapeutic approaches are so far limited and empirical, and need further improvement to tackle this currently underestimated clinical challenge.

Although the etiology of nasal polyposis is still not revealed, insights in the pathogenesis have largely expanded over the last years. Usually nasal polyps occur in adults, are bilateral and are characterized by a manifest tissue eosinophilia. Deposition of plasma-proteins (albumin), potentially driven by subepithelial eosinophilic inflammation, seems to be an early and key pathogenic factor in the development of nasal polyps. Accumulation and activation of eosinophils is favoured by low TGF-beta1 concentrations and overproduction of IL-5 and eotaxin. In nasal polyps high IgE concentrations are measured. Our findings indicate that this IgE is produced locally. Total IgE and the expression of specific IgE is unrelated to skin prick tests, but correlates with the degree of eosinophilia. In addition, we demonstrated the organisation of secondary lymphoid tissue in nasal polyps and a polyclonal hyper-immunoglobulinemia E, associated with the presence of IgE specific to Staph. aureus enterotoxins (SAE), colonization with Staph. aureus and increased eosinophilic inflammation in a relevant subgroup of NP patients (about 50%). In about half of the nasal polyps we thus find a local immune response against SAE. SAE can hereby act as conventional allergens, triggering T- en B-cells to produce sIgE against SAE. On the other hand, SAE can also act as superantigens and induce polyclonal B-cell activation and hyper-immunoglobulinemia. In addition, the presence of IgE antibodies to SAEs seems to be associated with the severity of asthma and nasal polyposis disease. Nasal and oral corticosteroids are currently the standard treatment for NP. This treatment however, is not always sufficient and oral corticosteroids have several side effects. Often surgery is required, which in turn is not free of complications and recurrencies. Increasing insights in the pathophysiology of NP opens perspectives for new pharmacological treatment options, with eosinophilic inflammation, IgE and Staph. aureus as potential targets.

Nasal polyps represent an often severe T-cell-orchestrated eosinophilic upper airway disease with currently unknown pathogenesis, often associated with lower airway disease, such as asthma. Superantigens, predominantly derived from Staphylococcus aureus, are potent activators of T cells, induce the synthesis of IgE in B cells, and have direct effects on pro-inflammatory cells, such as eosinophils. IgE antibodies to S. aureus enterotoxins have been described in polyp tissue, linked to a local polyclonal IgE production and an aggravation of eosinophilic inflammation. Furthermore, such IgE antibodies have also been described in the sera of patients with asthma, and linked to severity of disease and steroid insensitivity. This review summarizes our current understanding of the possible role of S. aureus enterotoxins in chronic severe airway disease, such as nasal polyposis.

Chronic rhinosinusitis is one of the most common health care challenges, with significant direct medical costs and severe impact on lower airway disease and general health outcomes. The diagnosis of chronic rhinosinusitis (CRS) currently is based on clinical signs, nasal endoscopy and CT scanning, and therapeutic recommendations are focussing on 2 classes of drugs, corticosteroids and antibiotics. A better understanding of the pathogenesis and the factors amplifying mucosal inflammation therefore seems to be crucial for the development of new diagnostic and therapeutic tools. In an effort to extend knowledge in this area, the WP 2.7.2 of the GA2LEN network of excellence currently collects data and samples of 1000 CRS patients and 250 control subjects. The main objective of this project is to characterize patients with upper airway disease on the basis of clinical parameters, infectious agents, inflammatory mechanisms and remodeling processes. This collaborative research will result in better knowledge on patient phenotypes, pathomechanisms, and subtypes in chronic rhinosinusitis. This review summarizes the state of the art on chronic rhinosinusitis and nasal polyposis in different aspects of the disease. It defines potential gaps in the current research, and points to future research perspectives and targets. [ABSTRACT FROM AUTHOR]