Chronic Hyperplastic Eosinophilic Sinusitis Research Articles

Mechanism and clinical evidence of immunotherapy in allergic rhinitis.

Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroallergens. It causes increased inflammation throughout the body and may be complicated by other otolaryngological pathologies such as chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Allergic rhinitis is an IgE-mediated disease and immunotherapy can be a possible approach for patients to limit the use of antihistamines and corticosteroids. There is evidence that allergen immunotherapy can prevent the development of new sensitizations and reduce the risk of later development of asthma in patients with allergic rhinitis. However, some patients do not benefit from this approach and the efficacy of immunotherapy in reducing the severity and relapse of symptoms is still a matter of debate. This review highlights new aspects of allergic rhinitis with a particular focus on the impact of sexual dimorphism on the disease manifestation and efficacy to the allergen specific immunotherapy.

Allergic Rhinitis and Treatment Modalities: A Review of Literature.

Allergic rhinitis is a highly prevalent disease affecting the quality of life of millions of patients. Immunotherapy, medication, and allergen avoidance are all part of the treatment for allergic rhinitis. Allergic rhinitis causes an increase in inflammation throughout the body. As a result, asthma, chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media are all associated with allergic rhinitis. Treatment that is effective should target systemic inflammation and its underlying causes. It has a negative impact on work productivity and academic achievement in both children and adults. Understanding the pathophysiology of allergic rhinitis, how it relates to its comorbid disorders, and how different therapy choices affect the pathophysiology of both allergic rhinitis and its related comorbidities are essential for providing effective treatment. As the quality of air around us is changing, there is an increased chance of allergies. Along with nasal and ocular symptoms that are directly linked to the allergic process, these symptoms' interference with sleep results in daytime tiredness and a decreased quality of life. In this paper, we look at pathogenesis, causes, signs, symptoms, and treatment modalities in patients with allergic rhinitis.

Certain subphenotypes of aspirin-exacerbated respiratory disease distinguished by latent class analysis

Aspirin-exacerbated respiratory disease (AERD) is recognized as a distinct asthma phenotype. It usually has a severe course accompanied by chronic hyperplastic eosinophilic sinusitis with nasal polyps, blood eosinophilia, and increased concentrations of urinary leukotriene E4 (LTE4). More insightful analysis of individual patients shows this group to be nonhomogeneous. We sought to identify any likely subphenotypes in a cohort of patients with AERD through the application of latent class analysis (LCA). Clinical data from 201 patients with AERD (134 women) were collected from questionnaires. Standard spirometry, atopy traits, blood eosinophilia, and urinary LTE4 concentrations were evaluated. LCA was applied to identify possible AERD subphenotypes. Four classes (subphenotypes) within the AERD phenotype were identified as follows: class 1, asthma with a moderate course, intensive upper airway symptoms, and blood eosinophilia (18.9% of patients); class 2, asthma with a mild course, relatively well controlled, and with low health care use (34.8% of patients); class 3, asthma with a severe course, poorly controlled, and with severe exacerbations and airway obstruction (41.3% of patients); and class 4, poorly controlled asthma with frequent and severe exacerbations in female subjects (5.0% of patients). Atopic status did not affect class membership. Patients with particularly intensive upper airway symptoms had the highest levels of blood eosinophilia and the highest concentrations of urinary LTE4. LCA revealed unique AERD subphenotypes, thus corroborating the heterogeneity of this population. Such discrimination might facilitate more individualized treatment in difficult-to-treat patients.

Prominent role of IFN-γ in patients with aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin-tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their overexpression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs). We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN-γ in the differentiation of eosinophils. Quantitative real-time PCR was performed for TH1 and TH2 signature cytokines on tissue from control subjects, patients with chronic hyperplastic eosinophilic sinusitis, and patients with AERD, and their cellular source was determined. The influence of IFN-γ on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined. Gene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH2 cytokine signature; however, AERD was distinguished from chronic hyperplastic eosinophilic sinusitis by the prominent expression of IFN-γ. Intracellular and immunohistochemical cytokine staining revealed that the major sources of these cytokines were the eosinophils themselves. IFN-γ promoted the maturation of eosinophil progenitors, as measured by increased mRNA and surface expression of CCR3 and sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8). Additionally, IFN-γ increased the expression of genes involved in leukotriene synthesis that led to increased secretion of CysLTs. IFN-γ-matured eosinophil progenitors were also primed, as demonstrated by their enhanced degranulation. High IFN-γ levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.

Aspirin sensitivity and desensitization for asthma and sinusitis

NSAIDs-including aspirin (ASA)-that inhibit cyclooxygenase (COX)-1 induce nonallergic hypersensitivity reactions consisting of attacks of rhinitis and asthma. Such reactions occur exclusively in a subset of asthmatic patients who also have underlying nasal polyps and chronic hyperplastic eosinophilic sinusitis. We now refer to their underlying inflammatory disease of the entire respiratory tract as aspirin-exacerbated respiratory disease. This review focuses on descriptions of these patients; methods available to diagnose ASA-exacerbated respiratory disease; the unique ability of all NSAIDs that inhibit COX-1 to cross-react with ASA; lack of cross-reactivity with selective COX-2 inhibitors; an update on pathogenesis; and current thoughts about treatment, including ASA desensitization and daily ingestion of ASA itself.

Expression of cysLT1 and cysLT2 Receptor in Chronic Hyperplastic Eosinophilic Sinusitis

Elevated production of cysteinyl leukotrienes (cysLTs) from sinus tissues and abundant sinus eosinophils are characteristic features of chronic hyperplastic eosinophilic sinusitis (CHS). CysLTs exert their action through G-protein-coupled receptors named cysLTs receptor type I (cysLT1R) and type II (cysLT2R). These expressions of cysLT receptors in the sinus mucosa have yet to be clarified and the relationship between eosinophilia and the expression of these receptors remains obscure. We compared the expressions of cysLT1R and cysLT2R in the sinus mucosa in patients with CHS, non-eosinophilic chronic sinusitis (NECS), and control sinus tissues; and analyzed the correlation between the expression of CysLTRs and the presence of sinus eosinophils by immunohistochemistry and real-time PCR. A significantly higher percentage of eosinophils expressing cysLT2R protein was observed in patients with CHS compared with NECS and controls. In addition, cysLT2R mRNA expression in CHS was significantly higher than in NECS and controls. Furthermore, a positive correlation was observed between cysLT2R mRNA expression and the number of infiltrated eosinophils. In contrast, the cysLT1R mRNA expression did not differ significantly among these groups. The effect of cysLTs on sinus eosinophils may be mediated through the cysLT2R in patients with CHS. These results may suggest the therapeutic benefit of cysLT2R antagonists in CHS.

Revisiting the link between allergic rhinitis and asthma

Introduction Allergic rhinitis (AR) and asthma are the most common atopic diseases with an increasing prevalence during the last decade. Whereas AR is an immunoglobulin (Ig) E-mediated inflammation of the nasal mucosa, IgE-mediated inflammation of the airways can either manifest as AR, asthma, or both. In fact, the vast majority of patients with asthma have rhinitis, and rhinitis is a major independent risk factor for asthma in cross-sectional and longitudinal studies. Although the temporal relation of AR and asthma may be variable, AR often precedes asthma. This relationship between rhinitis and asthma has been further confirmed by functional and immunological evidence, challenge studies of the nose and the bronchi, and indirectly by observing the therapeutic effects of drugs used mainly for rhinitis on the symptoms of asthma. Moreover, this link also involves other aspects, such as viral infections and bronchial hyperreactivity, chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media.

The relationship between rhinosinusitis and asthma sinusitis

Chronic sinusitis comprises numerous disorders characterized by inflammation, mucous gland hyperplasia, and remodeling. Chronic hyperplastic eosinophilic sinusitis (CHES) is characterized by unrestrained proliferation of eosinophils, Th2-like lymphocytes, fibroblasts, goblet cells, and mast cells. The pathology of CHES is similar to that of asthma, and it is frequently diagnosed in association with asthma. It has been reported that exacerbations of CHES occur temporally with worsening of asthma; however, in the absence of well-controlled studies, this linkage remains unproven. In this article, the potential mechanisms linking these two diseases are examined.

Expression of Leukotriene C4 Synthase and Plasminogen Activator Inhibitor 1 Gene Promoter Polymorphisms in Sinusitis

Studies have described polymorphisms in genes involved with both leukotriene synthesis and remodeling. Leukotriene C4 synthase (LTC4S) is the critical terminal pathway enzyme involved in regulation of cysteinyl leukotriene (CysLT) synthesis. An A-to-C base exchange in the promoter region of the LTC4S gene influences its expression. The plasminogen activator inhibitor (PAI) 1 gene is associated with tissue fibrosis. The presence of either 4G or 5G residues in the promoter region has been associated with altered transcription. The role of these polymorphisms was investigated in patients with sinusitis and polyps. We performed a prospective study of patients undergoing endoscopic sinus surgery at a university hospital between 1996 and 2004. Demographic data and sinus tissue were collected from patients. Patients were classified into four groups: controls, chronic hyperplastic eosinophilic sinusitis (CHES), aspirin exacerbated respiratory disease (AERD), and chronic inflammatory sinusitis (CIS). DNA was analyzed for the LTC4S and the PAI-1 promoter polymorphisms using standard PCR techniques. There were 133 patients with 76 women and 57 men (mean age, 42 years). Sixty-six people were in the control group, 16 people were in the CIS group, 51 people were in the CHES group, and 22 people were in the AERD group. The LTC4S allelic frequencies were controls, A = 0.81 and C = 0.19; CIS, A = 0.73 and C = 0.27; CHES, A = 0.69 and C = 0.31; AERD, A = 0.67 and C = 0.33. The C allele was more frequent in CHES versus controls (p = 0.04). The PAI-1 allele frequencies were controls, 5G = 0.55 and 4G = 0.45; CIS, 5G = 0.47 and 4G = 0.53; CHES, 5G = 0.56 and 4G = 0.44; AERD, 5G = 0.54 and 4G = 0.46. Increased expression of the 4G allele of the PAI-1 gene was observed in CIS; however, this genetic variance between the four groups was not statistically different (p > 0.05). There appears to be a genetic component that contributes to nasal polyp formation in sinusitis. Although the LTC4S polymorphism has previously been associated with aspirin-sensitive asthma, this is the first demonstration that the polymorphism is associated with CHES and this is independent of aspirin sensitivity.

Fungi in Chronic Hyperplastic Eosinophilic Sinusitis: Reasonable Doubt

Chronic hyperplastic eosinophilic sinusitis (CHES) is a T-helper (Th)2-like, lymphocyteinitiated, eosinophil-rich inflammatory disease. The complex immune interactions required to orchestrate these processes begin with the presentation of antigen by mature dendritic cells to Th lymphocytes that display the appropriate antigen-specific T-cell receptor. The objective of sinus research must be to identify and target that antigen; this will lead to the cure for this condition. This article reviews numerous models that may be responsible for the pathophysiology of this disorder, including putative roles for allergens, bacteria, and bacterial-derived superantigens, as well as recent interest in fungal-derived antigens. Additionally, we speculate that whatever the inciting cause of CHES may be, it is plausible that once initiated, cellular differentiation pathways may lead to the development of an antigen-independent permanent phase. More than one of these may be valid in different subjects and, furthermore, this list almost assuredly does not explain all cases of CHES. The concept that fungal antigens colonizing the sinuses are responsible for CHES represents an intriguing, but unproven, hypothesis. Presently, the case for the fungus remains circumstantial. The case for fungi will be proved only with definitive proof that T-cells within the sinuses are actively responding to fungal antigens present in the sinus and with the further demonstration that removal of those fungal antigens ameliorates the disease.

Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a disease of intense eosinophilic inflammation that can produce fibrosis, hyperplasia, and remodeling. To investigate the usefulness of quantifying severity of chronic hyperplastic eosinophilic sinusitis in predicting the presence of AERD. Data were compared between asthmatic patients who reported exacerbations after aspirin ingestion and those who did not. The primary outcome measure was severity of sinusitis using a validated computed tomography (CT) scan-based scoring system. Indices of lower airway remodeling and other markers of inflammation were also evaluated. Twenty-one patients with AERD were compared with 19 patients with aspirin-tolerant asthma (ATA). Patients were well matched for asthma severity as shown by their similar lung function as measured by postbronchodilator forced expiratory volume in 1 second. Patients with AERD were distinguished by their sinus CT scores (AERD patients: 16.9; 95% confidence interval [CI], 13.4-21.3; ATA patients: 6.2; 95% CI, 4.2-9.1; P < .001), and they were considerably more likely to have nasal polyps (AERD patients: 90%; ATA patients: 26%; P < .001). In addition, AERD patients demonstrated increased total lung capacity (AERD patients: 107.9%; 95% CI, 99.9%-117.6%; ATA patients: 98.0%; 95% CI, 93.7%-102.5%; P = .05), reflecting a trend toward increased air trapping. No significant differences occurred in diffusing capacity, exhaled nitric oxide, eosinophilia, or exhaled breath condensate pH. AERD can be distinguished from ATA by the extent of hyperplasia on CT scan and the presence of nasal polyps. We hypothesize that AERD represents a remodeling process that affects both the upper and lower airways.

Alternative medical treatment strategies for chronic hyperplastic eosinophilic sinusitis

Chronic rhinosinusitis (CRS) is one of the most common chronic illnesses in the United States. Although CRS has been viewed traditionally as an infectious disease, treatment focused on antibiotics and surgery has not infrequently provided disappointing results. Recently much of CRS has been shown to be an eosinophilic inflammatory disease and new anti-inflammatory treatments are being studied. This review discusses medical management for chronic hyperplastic eosinophilic sinusitis, including antifungal treatment, low-dose macrolide treatment, antilipid mediator therapy, and new immune-modifying treatments.

Overexpression of leukotriene C4 synthase (LTC4S) and plasminogen activator inhibitor 1 (PAI-1) gene promoter polymorphisms in sinusitis

Rationale We have investigated the genetic predisposition of two forms of sinusitis: chronic hyperplastic eosinophilic sinusitis (CHES) and chronic inflammatory sinusitis (CIS). Studies have described polymorphisms in genes involved with both leukotriene synthesis and remodeling. A polymorphism in the promoter of the LTC4S gene has been identified that is a C-to-A base exchange that influences gene expression. The PAI-1 gene has been associated with tissue fibrosis and could be involved in polyp formation. This gene has a polymorphism consisting of either 4G or 5G residues in the promoter which alters transcription of the PAI-1 gene. We have investigated the role of these polymorphisms in CHES and CIS. Methods DNA was obtained from patients undergoing nasal polyp surgery or from control donors with no history of sinus disease. Polyp tissue underwent blinded pathological examination and scored for the presence of eosinophils. Polyps were classified into two groups based on the presence (CHES) or the absence of eosinophils (CIS). DNA was analyzed for the LTC4S or PAI-1 promoter polymorphisms. Results Our studies demonstrated that the A allele for the LTC4S gene was found at a higher frequency in patients with both CHES and CIS (q=0.28) when compared to a control group without disease (q=0.19) consistent with the described expression of leukotrienes. The 4G allele of the PAI-1 gene promoter was found at a higher frequency in patients with CIS (q=0.56) when compared to controls (q=0.38) or CHES (q=0.43). Conclusions There appears to be a genetic component that contributes to nasal polyp formation in sinusitis.

The role of allergy in chronic rhinosinusitis.

Chronic hyperplastic eosinophilic sinusitis is characterized by unregulated proliferation of eosinophils, T helper cell type 2 (T H 2)-like lymphocytes, fibroblasts, goblet cells, and mast cells. In more than 50% of subjects, it is found in association with the allergic rhinitis. The instillation of allergens onto the nasal mucosa is associated with worsening inflammation within the sinuses and an influx of eosinophils. The activation of T H 2-like lymphocytes in the allergic nares leads to the differentiation and activation of immune cells, including eosinophils and basophils, from precursors present in the nasal tissue and bone marrow. The presence of specific adhesion and chemotactic molecules in the sinuses promotes the recruitment of these newly generated cells from the circulation.

Characterization of Interleukin-4–Stimulated Nasal Polyp Fibroblasts

Chronic hyperplastic eosinophilic sinusitis is an inflammatory disease that results in the accumulation of eosinophils, fibroblasts, mast cells, and goblet cells at the site of injury. A common feature of this disease is the presence of nasal polyposis (NP). The current studies were designed to assess the contribution of interleukin (IL)-4 to fibroblast-mediated inflammation in chronic hyperplastic eosinophilic sinusitis/NP. In addition, we hypothesized that cysteinyl leukotrienes (CysLT) may directly influence fibroblast-mediated fibrotic and remodeling pathways in this disorder. Fibroblasts were isolated from NP tissue. All fibroblast lines expressed the IL-4 receptor. IL-4 induced changes in mRNA and protein expression of fibrotic (transforming growth factor-beta1 and -beta2) and inflammatory cytokines and chemokines (IL-6 and CCL11) by fibroblasts as measured by semiquantitative and quantitative polymerase chain reaction, RNase protection assay, and enzyme-linked immunosorbent assay. The expression of CysLT and other proinflammatory lipid receptors on fibroblasts was evaluated. CysLT1 and CysLT2 receptors were not expressed on fibroblasts; however, LPA(1) receptor was constitutively expressed and LPA(2) receptor expression was upregulated by IL-4. The metabolic cascade involved in CysLT synthesis was not expressed in fibroblasts and could not be induced by IL-4 treatment.

Cysteinyl leukotriene expression in chronic hyperplastic sinusitis–nasal polyposis: Importance to eosinophilia and asthma

Background: Chronic hyperplastic eosinophilic sinusitis (CHS) results from the unregulated proliferation of eosinophils, TH2-like lymphocytes, goblet cells, mast cells, and fibroblasts and is present in most patients with asthma. The frequent coexpression of these disorders and their shared pathophysiology suggests that these are similar disorders affecting the upper and lower airways. Objective: We evaluated the expression of cysteinyl leukotrienes (CysLTs) in sinus tissue from subjects with CHS compared with that seen in healthy sinus tissue. Methods: Nasal polyp and sinus tissue was evaluated from 58 individuals undergoing elective functional endoscopic sinus surgery. The diagnosis of CHS was demonstrated through the presence of eosinophilia and activated (EG2+) eosinophils, as determined by means of tissue immunohistochemistry. Data were compared with those from both nasal polyp tissue without eosinophilic inflammation and healthy control sinus tissue obtained from the sinus ostiomeatal complex at the time of surgery for unrelated disorders. CysLTs were quantified by means of ELISA in lipid-extracted tissue. Activation of the metabolic pathway leading to CysLT synthesis was demonstrated by ribonuclease protection. Subjects were genotyped for leukotriene C4 (LTC4) synthase C-to-A promoter polymorphism. Results: CysLT concentrations were significantly higher in tissue obtained from subjects with CHS (776.7 ± 201.9 pg/g tissue) compared with that seen in healthy sinus tissue (355.7 ± 101.6 pg/g tissue, P < .03). CysLT concentrations within noneosinophilic nasal polyps (328.0 ± 116.4 pg/g tissue) were similar to those in control tissue. The presence of CysLTs in CHS was associated with increased expression of LTC4 synthase mRNA. The C-to-A promoter polymorphism was associated with trends toward the increased presence of CHS and CysLTs. Conclusions: CHS is characterized by the increased presence of CysLTs when compared with concentrations seen in tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue. These studies support the use of LT modifiers as anti-inflammatory agents that might have clinical benefit in patients with these disorders. (J Allergy Clin Immunol 2003;111:342-9.)