The role of allergy in chronic rhinosinusitis.
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Chronic Disease↗
Biomedical subjects
Larry Borish
Publications and source records attributed to Larry Borish.
Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.
BACKGROUND: Patients with severe and difficult-to-treat asthma represent a small percentage of asthma patients, yet they account for much of the morbidity, mortality, and cost of disease. The goal of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is to better understand the natural history of asthma in these patients. OBJECTIVE: To describe the methods and baseline characteristics of the TENOR study cohort. METHODS: The TENOR study is a 3-year, multicenter, observational study of patients with severe or difficult-to-treat asthma. From January through October 2001, more than 400 US pulmonologists and allergists enrolled patients. Patients 6 years or older who were considered to have severe or difficult-to-treat asthma by their physicians were eligible. Patients have been receiving care for 1 year or more, have a smoking history of 30 pack-years or less, and have current high medication or health care utilization in the past year. Data are collected semiannually. RESULTS: A total of 4,756 patients enrolled and completed a baseline visit. Overall, 73% of the TENOR study patients are adults, 10% are adolescents, and 16% are children. According to physician evaluation, 48% of patients have severe asthma, 48% have moderate asthma, 3% have mild asthma, and 96% have difficult-to-treat asthma. Severe asthmatic patients have the highest health care utilization in the past 3 months (P < .001). CONCLUSIONS: The TENOR study is the largest cohort of patients with severe or difficult-to-treat asthma. Although patients are equally divided into moderate or severe asthma categories, most are considered difficult-to-treat. The TENOR study highlights the lack of control in moderate-to-severe asthma and provides a unique opportunity to examine factors related to health outcomes in this understudied population.
Adolescent↗
Molecular and cellular staging for the severity of chronic rhinosinusitis.
OBJECTIVES: To correlate objective and subjective clinical parameters with molecular, cellular, and histologic markers and to acknowledge the importance of these basic science parameters in a severity classification system for chronic rhinosinusitis (CRS). STUDY DESIGN: Retrospective analysis of prospectively collected data of consecutive patients undergoing endoscopic sinus surgery for CRS in an academic institution. METHODS: The preoperative computed tomography (CT) scans of all patients with CRS scheduled for surgery were graded according to Lund and Mackay. The patients completed a Sino-Nasal Outcome Test (SNOT)-20 questionnaire and had a preoperative nasal endoscopy performed, which was graded by assigning an endoscopy score according to Lanza and Kennedy. Subjects had a medical questionnaire regarding presence of aspirin sensitivity, allergic rhinitis, asthma, and medication usage. Subjects also underwent pulmonary function testing and had skin tests for allergies. At the time of surgery, blood was drawn to determine the level of peripheral eosinophilia and the degree of polymorphisms of the leukotriene C4 synthase gene. Sinus mucosal and polyp tissue was examined pathologically for the number of eosinophils per high-powered filed (HPF) and was stained for EG2 to determine the portion of activated eosinophils. Leukotriene C4 levels (pg/g of tissue) were determined using a sensitive competitive enzyme immunoassay. Endoscopy and SNOT-20 scores were reevaluated 1 year after surgery. Data were analyzed for disease-severity correlation to recommend a severity classification system for CRS that incorporates the contribution of clinical, molecular, cellular, and histologic parameters. RESULTS: The presence of polyps resulted in higher preoperative CT scores and higher preoperative and postoperative symptom scores. Average preoperative CT scores were significantly higher in asthmatics and allergy patients and correlated with endoscopy scores. Patients with more than five eosinophils/HPF of sinus tissue had higher frequency of polyps and asthma and higher CT and endoscopy scores than patients without sinus tissue eosinophilia (less than or equal to 5 cells/HPF sinus tissue). The subgroup of patients with eosinophilic nasal polyps (eosinophilic hyperplastic rhinosinusitis) had more severe disease by CT and endoscopy than the subgroup of patients with nasal polyps (hyperplastic rhinosinusitis) but without eosinophilia. Similarly, patients without polyps but with tissue eosinophilia had more severe disease than patients without polyps and without eosinophilia. Leukotriene C4 levels were elevated in all patient groups. Symptom scores did not correlate with any of the parameters. CONCLUSION: We suggest the following severity classification system for CRS: 1) eosinophilic chronic hyperplastic rhinosinusitis (ECHRS): patients with polyps and sinus tissue eosinophilia; 2) noneosinophilic chronic hyperplastic rhinosinusitis (NECHRS): patients with polyps but without sinus tissue eosinophilia; 3) eosinophilic chronic rhinosinusitis (ECRS): patients without polyps but with sinus tissue eosinophilia; 4) noneosinophilic chronic rhinosinusitis (NECRS): patients without polyps and without sinus tissue eosinophilia.
Chronic Disease↗
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.
Cell Line↗
Allergic rhinitis: systemic inflammation and implications for management.
Allergic rhinitis triggers a systemic increase of inflammation. Within minutes of allergen exposure, immune cells release histamine, proteases, cysteinyl leukotrienes, prostaglandins, and cytokines. Some produce the early symptoms, while others augment the production, systemic circulation, and subsequent infiltration of the nasal mucosa with inflammatory cells that sustain the symptoms. Systemic circulation of inflammatory cells permits their infiltration into other tissues where chemoattractant and adhesion molecules already exist. Consequently, allergic rhinitis is linked to comorbid conditions: asthma, chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Effective therapy should be directed at underlying inflammation and its systemic manifestations. It should improve the rhinitis and the comorbid conditions. Antihistamines relieve early symptoms by blocking basophil- and mast cell-generated histamine, but they do not significantly influence the pro-inflammatory loop. They are often little better than placebo. Oral corticosteroids provide the systemic anti-inflammatory efficacy, but their toxicity precludes such an approach. Intranasal corticosteroids effectively target the local inflammatory processes of rhinitis, reducing local inflammatory cells within the nares, but they do not directly access tissues involved in the comorbid conditions. Leukotriene modifiers have both systemic anti-inflammatory effects and an acceptable safety profile.
Anti-Allergic Agents↗
Sinus computed tomography scan and markers of inflammation in vocal cord dysfunction and asthma.
BACKGROUND: The inappropriate closure of the vocal cords is characteristic of vocal cord dysfunction (VCD). These patients present with wheezing and frequently receive a misdiagnosis of asthma. OBJECTIVE: To demonstrate the ability of computed tomography (CT) scored for the presence and extent of sinus disease and markers of inflammation to distinguish patients with VCD from patients with asthma. METHODS: Comparisons of 13 patients with VCD were made to 77 patients presenting to the emergency room with acute asthma, 31 non-acute asthmatic patients, and 65 nonasthmatic controls. Evaluation consisted of exhaled nitric oxide gas (eNO), circulating eosinophils, and total serum immunoglobulin (Ig)E, as well as the sinus CT scan. RESULTS: Extensive sinus CT changes were present in 23 of 74 acute asthmatic patients, 5 of 29 non-acute asthmatic patients, and 2 of 59 nonasthmatic controls. In addition, absolute eosinophil counts, eNO, and total IgE were significantly elevated among the asthmatic patients. Sinus symptoms reported by questionnaire did not predict sinus CT findings. Among the patients with VCD, none had extensive sinus disease. They also had normal eNO, low IgE, and normal eosinophil count. Five of the patients presenting to the emergency room who were identified as acute asthmatic were identified with VCD by laryngoscopy and were all characterized by the absence of significant inflammation on their sinus CT scan, low IgE, and normal eosinophil count. CONCLUSIONS: Among patients presenting with intermittent or reversible airway obstruction, patients with VCD can be distinguished from asthma by minimum or absence of inflammation in their sinuses as shown by CT scan. Clinical symptom scores are not predictive of presence or extent of sinus disease in most cases.
Adolescent↗
5. Genetics of hypersensitivity.
Genetics provides the basis for the host response to a variety of environmental factors that can play a role in the generation of complex genetic diseases, such as asthma and atopy. An understanding of the genetic bases for these conditions is therefore essential to understand their pathophysiology. Studies of the genetics of asthma and atopy have suffered from several daunting challenges. These include the recognition that these are conditions caused by numerous genes, with each gene assuming variable roles in different individuals. In addition, each gene presumably contributes only a small percentage to a given individual's genetic risk of asthma. This has led to the current situation, in which studies often demonstrate a lack of replication that can be explained by their being insufficiently powered. Furthermore, the pathophysiologies of asthma and atopy are incompletely understood, and the lack of clearly defined phenotypes also contributes to the inadequacies of the current literature. Nonetheless, regions of the human genome have been reproducibly associated with asthma and atopy. These regions have undergone intense study, and many genetic variants within them have been implicated as asthma and allergy genes. In addition, through candidate gene approaches, several genetic polymorphisms have been convincingly linked to increased risks for the development of asthma and atopy. Many of these genes are associated with alterations in responsiveness to therapeutic agents used in the treatment of these conditions. These genetic studies have an exciting potential for individually tailoring the therapeutic regimen to a given subject's genotype. It is to be hoped that they will also define new targets for the next generation of asthma and allergy therapeutic agents.
Animals↗
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, T(H)2-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 C(4) (LTC(4)) 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 LTC(4) 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.
Adult↗
The failure of interleukin-10-deficient mice to develop airway hyperresponsiveness is overcome by respiratory syncytial virus infection in allergen-sensitized/challenged mice.
Interleukin-10-deficient mice develop a robust pulmonary inflammatory response but no airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) following allergen sensitization and challenge. In the present study, we investigated the effect of respiratory syncytial virus (RSV) infection on AHR and pulmonary inflammation in allergic IL-10-/- mice. Unlike littermate control mice, RSV-infected or ovalbumin (OVA)-sensitized/challenged IL-10-/- mice failed to develop significant AHR. In contrast, sensitized/challenged IL-10-/- mice infected with RSV did develop AHR accompanied by increased eosinophil numbers, both in bronchoalveolar lavage (BAL) and pulmonary tissue, and mucin production in airway epithelium. The cytokine profile in OVA-sensitized/challenged IL-10-/- mice was skewed toward a Th1 response but after RSV infection, this response was more of a Th2 type, with increased IL-5 levels in the BAL. Studies with an RSV mutant that lacks the G and SH genes showed equal enhancement of the AHR response as the parental wild-type strain, indicating that G protein is not essential to this response. These data suggest that RSV infection can overcome the failure of development of AHR in allergic IL-10-/- mice.
Analysis of Variance↗
The role of leukotrienes in upper and lower airway inflammation and the implications for treatment.
OBJECTIVE: This article reviews the proinflammatory effects of the cysteinyl leukotrienes (CysLTs) in the upper and lower airways, along with evidence of their role in allergic rhinitis and chronic hyperplastic sinusitis with nasal polyposis (CHS/NP). After reading this article, readers should have a greater understanding of the effects of the CysLTs on both upper and lower airways and their implications for treatment. DATA SOURCES: Relevant and appropriately controlled studies on the inflammatory processes associated with leukotrienes (LTs) were reviewed. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from peer-reviewed journals and data generated from the author's laboratory. RESULTS: The CysLTs possess proinflammatory effects that contribute to the increase of tissue eosinophilia. Emerging data support their importance in diseases of the upper airways, including allergic rhinitis and CHS/NP. The LT modifiers may be appropriate agents for treating inflammatory disorders of the upper airways because of their proven effectiveness in reducing inflammation in asthma. Results from studies in patients with allergic rhinitis demonstrated improved nasal rhinorrhea, sneezing, and congestion. LT modifiers have improved nasal congestion and restored the sense of smell in patients with CHS/NP. CONCLUSIONS: The LT receptor antagonists have proven to be an effective antiinflammatory treatment for asthma. Emerging data indicate that LTs play a pivotal role in inflammatory upper airway disease, providing a growing rationale for the use of LT receptor antagonists to treat allergic rhinitis and CHS/NP.
Adult↗
Endothelin-1: a useful marker for asthmatic inflammation?
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Animals↗
Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer.
BACKGROUND: beta(2)-Adrenergic agonists interact with specific receptors on T lymphocytes to mediate anti-inflammatory activities. However, anti-inflammatory effects are not observed when beta(2)-adrenergic agonists are administered in vivo as racemates. OBJECTIVE: We hypothesized that anti-inflammatory influences are mediated by the (R)-isomer and are masked in the additional presence of the (S)-isomer. METHODS: Antigen-specific T-cell lines were generated in the presence of recombinant human IL-2 and tetanus with or without varying concentrations of (R)- and (S)-isomers of albuterol alone or in combination. Parallel lines were generated in the presence of propranolol. Cells were briefly pulsed with PHA and evaluated for proliferation, apoptosis, and cytokine secretion. RESULTS: (R)-Albuterol significantly inhibited T-cell proliferation (77.0% +/- 9.7% of control at 10(-8) mol/L and 61.1% +/- 9.0% at 10(-7) mol/L). No influence was observed with (S)-albuterol alone. However, the addition of (S)-albuterol to (R)-albuterol mediated a dose-dependent increase in proliferation. At equivalent concentrations of the 2 isomers, proliferation was unchanged from the control, whereas at 10(-6) mol/L (S)-albuterol, proliferation was enhanced. Both the inhibitory effects of (R)-albuterol alone and the stimulating influence of (R)- plus (S)-albuterol were blocked in the additional presence of propranolol. (R)-Albuterol at 10(-8) mol/L inhibited IL-2 and IFN-gamma production. Racemic albuterol (10(-8) mol/L each) had no influence on cytokine production; however, the combination of 10(-8) mol/L (R)-albuterol with 10(-6) (S)-albuterol stimulated production of IL-2 and IL-13. No effects were observed on apoptosis or cell viability. CONCLUSION: These studies confirm the beta-adrenergic receptor-specific anti-inflammatory effects of (R)-albuterol. The racemate had minimal influences on proliferation or cytokine production. The presence of excess (S)-albuterol resulted in proinflammatory influences. We hypothesize that the (S)-isomer functions as an inverse agonist to switch the function of the beta(2)-adrenergic receptor.
Adrenergic beta-Agonists↗
Cysteinyl leukotrienes in chronic hyperplastic rhinosinusitis.
OBJECTIVES: Our study was designed to demonstrate that, similar to asthma, eosinophilic chronic rhinosinusitis is a disease characterized by activation and the expression of cysteinyl leukotrienes (LTs). METHODS: Nasal polyp tissue was evaluated from 28 consecutive individuals undergoing elective polypectomy in whom neutrophils were not present on pathologic examination. Tissue was analyzed for pathosis with particular attention to the presence of eosinophils. Patients with moderate to high levels of mucosal eosinophils were classified as having eosinophilic rhinosinusitis (ECRS). Those with few or absent mucosal eosinophils were classified as having noneosinophilic rhinosinusitis (NECRS). Cysteinyl LTs were quantified by a sensitive competitive enzyme immunoassay, and the levels of cysteinyl LTs were compared in the groups. RESULTS: There were 20 patients with ECRS and 8 patients with NECRS. Cysteinyl LTs were identified in polyp tissue from 24 of 28 subjects and were >5 pg/gm tissue in 15 of 28. The average level of LTC(4) in patients with few mucosal eosinophils was 38.3 pg/g. The average amount in those with moderate to large amounts of mucosal eosinophils was 36.7 pg/g. There was no significant difference between the 2 groups. CONCLUSION: ECRS and NECRS can be considered diseases of excessive expression of cysteinyl LTs. LT expression occurs in patients who demonstrate few or no mucosal eosinophils, which indicates that cell lines other than eosinophils may be responsible for LT production in chronic rhinosinusitis.
Biomarkers↗
Expression of leukotriene C4 synthase and plasminogen activator inhibitor 1 gene promoter polymorphisms in sinusitis.
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Adult↗