Allergen skin test responses in broad U.S. asthma population in those with and without rhinitis.

Background: Asthma and allergic rhinitis are pathologically interlinked conditions. Despite skin testing (ST) being pivotal for evaluating allergic sensitization, U.S. data that date back to 1960s on ST reactivity patterns in subjects with asthma remain sparse. Objective: The purpose of this study was to elucidate seasonal, perennial ST responses, and their relationship with asthma severity, early versus late onset disease, and immunoglobulin E (IgE) levels. Methods: Five hundred patients with asthma were randomly selected from the National Jewish Health electronic medical record over a 3-year span. Demographic, clinical, and allergen ST reactivity data for a battery of seasonal and perennial allergens were procured, including total IgE levels, asthma onset, and severity, by using t-tests, χ² tests, and Analysis of Variance (ANOVA), patterns of reactivity were assessed for overall, seasonal, and perennial allergens in relation to IgE levels, asthma onset, and severity. Results: Of the 500 patients, 398 were analyzed. 63.3% were women, 50.1% had adult-onset asthma, and 86.1% had rhinitis; 75.3% tested positive to one or more allergens, with men demonstrating higher overall (p = 0.039) and perennial (p = 0.035) sensitization. ST reactivity varied based on the presence of rhinitis for seasonal (p = 0.028) but not perennial (p = 0.733) allergens. Asthma severity was not significantly associated with ST reactivity (p > 0.10). ST positivity for perennial (p < 0.001) but not seasonal (p = 0.128) allergens was higher in childhood-onset asthma versus adult-onset asthma despite both groups having a large percentage of reactors. Elevated IgE levels correlated with ST reactivity (p < 0.01). Conclusion: Our study represents a unique comprehensive evaluation of ST reactivity in a U.S. asthma population, which is lacking in the literature, when factoring in asthma onset, severity, and IgE levels. Our findings underscore the importance of allergen sensitization in asthma, regardless of severity, concurrent rhinitis symptoms, or asthma onset, which challenge some of the prevailing assumptions about the relationship between allergen sensitization and asthma onset.

Clinical and economic burden of chronic rhinosinusitis with nasal polyposis: A U.S. administrative claims analysis.

Background: Limited data exist on the clinical and economic burden of chronic rhinosinusitis with nasal polyposis (CRSwNP). Objective: To describe patient characteristics, health-care resource utilization (HCRU), and health-care costs among patients with CRSwNP with and without comorbid asthma (primary analysis) and with surgical management of nasal polyps (secondary analysis). Methods: This was a retrospective study of patients diagnosed with CRSwNP conducted using administrative claims data from January 1, 2013, through March 31, 2019. Study outcomes were assessed over a 2-year follow-up. Results were stratified by baseline asthma status (primary analysis) and presented separately for patients with surgically managed CRSwNP (secondary analysis). Results: The primary analysis included 10,999 patients with CRSwNP (2649 with asthma, 8350 without asthma). Patients with versus without asthma had higher medication use, HCRU, and all-cause medical costs (mean ± standard deviation $34,667 ± $42,234 versus $27,122 ± $45,573; p < 0.001) across the full follow-up period. CRSwNP-related medical costs were significantly higher for patients with versus without asthma in year 2 of follow-up. In the surgical management analysis (n = 4943), most categories of medication use and CRSwNP-related HCRU declined from baseline levels during follow-up, and CRSwNP-related pharmacy costs in year 2 were less than half of baseline levels. Conclusion: Patients diagnosed with CRSwNP and asthma had a greater burden of illness than those without asthma. Higher CRSwNP-related medical costs in year 2 of follow-up for patients with asthma may indicate worsening symptoms over time. Among patients with surgically managed CRSwNP, HCRU and costs increased in year 1 of follow-up but decreased below baseline levels in year 2, potentially reflecting improved symptom severity.

Nonsteroidal anti-inflammatory-induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization provides long-term clinical benefits. The exact mechanisms of aspirin desensitization are not clearly understood. OBJECTIVE: We sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on T-cell activation of the IL-4 pathway in aspirin-sensitive patients with asthma and control subjects. METHODS: A total of 11 aspirin-sensitive patients with asthma, 10 aspirin-tolerant patients with asthma, and 10 controls without asthma were studied. PBMCs were stimulated with an anti-CD3 antibody and IL-4 or IL-12, with and without the presence of NSAIDs. The expression of phosphorylated signal transducers and activators of transcription 6 (pSTAT6), phosphorylated signal transducers and activators of transcription 4, and IL-4 was detected in CD4 T cells by flow cytometry. RESULTS: Stimulation with a combination of anti-CD3 and IL-4 induced pSTAT6 in CD4 T cells from all subjects. The induction of pSTAT6 was significantly higher in aspirin-sensitive patients with asthma than in controls subjects. The increase in pSTAT6 was inhibited in a dose-dependent manner by aspirin and indomethacin and minimally by sodium salicylate. This inhibition was strongest in aspirin-sensitive patients. Two-group comparisons showed significant differences in pSTAT6 inhibition by all concentrations of indomethacin and aspirin: between aspirin-sensitive and aspirin-tolerant groups and between aspirin-sensitive and control groups. No differences were found between aspirin-tolerant and control groups at all 3 concentrations. The inhibition of pSTAT6 was associated with reduced IL-4 expression. CONCLUSIONS: NSAIDs inhibited signal transducers and activators of transcription 6 signaling in CD4 T cells. This inhibition was significantly higher in aspirin-sensitive patients than in aspirin-tolerant subjects and was associated with reduced expression of IL-4. These findings have implications for clinical benefits of aspirin desensitization in aspirin-sensitive patients with asthma.

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

Recommendations for the pharmacologic management of allergic rhinitis.

Allergic rhinitis (AR) affects at least 60 million people in the United States each year, resulting in a major impact on patient quality of life, productivity, and direct and indirect costs. As new therapies, data, and literature emerge in the management of AR, there is a need to communicate and disseminate important information to health care professionals to advance the practice of medicine and lessen the disease burden from AR. Treatment recommendations for AR have not been updated since the 2012 Food and Drug Administration approval of nonaqueous intranasal aerosol agents using hydrofluoroalkane propellants and the first aqueous intranasal combination product. Here, we present an updated algorithm for the pharmacologic treatment of AR that includes these new treatment options. Treatment recommendations are categorized by disease severity (mild versus moderate/severe) and duration of symptoms (episodic versus nonepisodic, with episodic defined as <3 days/wk or for <3 weeks). Preferred treatments are suggested, as well as alternative options for consideration by clinicians in the context of individual patient needs. This recommendation article also outlines the importance of treatment monitoring, which can be conducted using the recently developed Rhinitis Control Assessment Test. Successful therapeutic outcomes depend on multiple factors, including use of the most effective pharmacologic agents as well as patient adherence to therapy. Therefore, it is imperative that rhinitis patients not only receive the most effective therapeutic options, but that they also understand and are able to adhere to the comprehensive treatment regimen. Successful treatment, with all of these considerations in mind, results in better disease outcomes, improved quality of life for patients, and greater economic productivity in the home and workplace.

Characterization and treatment of patients with chronic rhinosinusitis and nasal polyps.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs) may be subdivided into aspirin-sensitive (AS) and aspirin-tolerant (AT) populations. These cohorts are not well characterized. OBJECTIVE: To examine phenotypic characteristics and determine the extent of medical/surgical interventions in patients with CRS+NP and to compare the AS with the AT subset in the CRS+NP sample. METHODS: Retrospective chart review was performed at a tertiary academic respiratory hospital. Data included patient demographics, asthma severity, peripheral eosinophilia, Lund-Mackay computed tomographic score, symptomatic dysosmia, and therapeutic interventions. RESULTS: Of the 182 patients included, 81 had aspirin sensitivity (45%) and 101 had aspirin tolerance (55%). Asthma was present in 94% of patients with CRS+NP (100% in AS subgroup vs 89% in AT subgroup, P = .001). Eighty-eight percent of the CRS+NP sample had moderate to severe persistent asthma. In the AS and AT subgroups, asthma severity was similar (P > .6). The CRS+NP sample showed a mean computed tomographic score of 14.0 (44% with eosinophilia and 46% with dysosmia). More severe sinus disease was noted in the AS group (Lund-Mackay computed tomographic scores, P = .002; olfactory symptoms, P = .001). Serum eosinophil levels were not statistically different between groups (51% in AS group, 39% in AT group, P > .1). CONCLUSION: This study is one of the broadest reviews of patients with CRS+NP, with unique findings in the high prevalence of asthma in AS and AT patients, greater olfactory dysfunction in AS patients, and a minority of patients with CRS+NP and circulating eosinophils. Most AS patients do not have increased circulating eosinophils, as is often believed. These results shed further light on the association between asthma and upper respiratory tract disease in those with nasal polyposis.

Association Between Elevated Blood Eosinophils and Chronic Kidney Disease Progression: Analyses of a Large United States Electronic Health Records Database.

Background: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting. Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] <60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3-4. The primary outcomes were CKD progression and all-cause mortality. Results: We found that high eosinophilic levels (bEOS ≥300 cells/µL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥300 cells/µL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with <300 cells/µL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression. Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.

Variations in expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in nasal mucosa of aspirin-sensitive versus aspirin-tolerant patients with nasal polyposis.

BACKGROUND: Matrix metalloproteinases (MMPs) are key enzymes responsible for extracellular matrix degradation contributing to the progressive histological changes seen in lower airway disease, including asthma. MMP-9 and TIMP-1 have also shown some role in the pathogenesis of chronic rhinosinusitis (CRS) and nasal polyposis (NP). OBJECTIVE: We aim to determine variability in expression of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in sinus tissue from distinct patient populations presenting with nasal polyposis. METHODS: The expression of MMP-9 and TIMP-1 was investigated in nasal polyp tissue from 6 aspirin-sensitive (AS) and 6 aspirin-tolerant (AT) patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis (CRSwNP). Sinus mucosa from 6 patients with chronic rhinosinusitis without nasal polyposis (CRSsNP) was used as control. The MMP-9 and TIMP-1 expression was measured using immunofluorescence technique and graded using manual and computerized methods. RESULTS: Expression of TIMP-1 was significantly reduced in the AS group when compared with both the AT and CRSsNP (control) groups (P < .001). The MMP-9/TIMP-1 ratio was significantly increased in the AS group when compared with other patient groups (P < .001). The MMP- 9 expression was similar between study and control groups. CONCLUSION: These results support the importance of MMP-9 and TIMP-1 expression in nasal polyp formation. The decreased expression of TIMP-1 in AS patients may promote the effects of MMP-9 expression and thus contribute to tissue remodeling and inflammatory changes. This finding may lead to further understanding of disease severity and resistance to treatment in this group of patients, as well as the pathogenesis of nasal polyps.

Long-term treatment with fluticasone propionate/salmeterol via Diskus improves asthma control versus fluticasone propionate alone.

This 52-week study was designed to assess the safety and efficacy of fluticasone propionate/salmeterol combination (FSC) 250/50 micrograms versus fluticasone propionate (FP) 250 micrograms in subjects with persistent asthma symptomatic on open-label FP 100 micrograms. The primary objective of this study was to show that FSC 250/50 micrograms was superior to FP 250 micrograms at increasing pulmonary function as measured by forced expiratory volume in 1 second over a 52-week treatment period. A secondary objective was to compare the rate of asthma attacks defined as (1) a sustained 2-day decrease in morning peak expiratory flow or increase in albuterol use for 2 consecutive days, (2) an asthma exacerbation requiring systemic corticosteroids, or (3) an unscheduled clinic or hospital visit for acute asthma symptoms. Three hundred six subjects received FSC 250/50 micrograms and 315 subjects received FP 250 micrograms. Both treatments were administered twice daily. Treatment with FSC 250/50 micrograms resulted in a significant improvement in lung function compared with FP 250 micrograms (p < 0.001). Additionally, treatment with FSC 250/50 micrograms resulted in a reduction in the rate of exacerbations of asthma (i.e., requiring systemic corticosteroids or unscheduled urgent care intervention) compared with FP 250 micrograms (0.170 versus 0.273, respectively; p = 0.017). There was no differentiation between treatments for less severe attacks of asthma. FSC 250/50 micrograms showed consistently greater improvement in lung function, symptom control, and decreased albuterol use. In addition, FSC 250/50 micrograms-treated subjects experienced fewer severe asthma exacerbations than subjects treated with FP 250 micrograms.

The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases.

BACKGROUND: Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear. OBJECTIVE: The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months. METHODS: Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment. RESULTS: There was a significant elevation in both the exhaled nitric oxide level (P = .03) and sputum tryptase level (P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 (P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated (r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated (r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) (r = -0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months. CONCLUSION: Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while T(H)1 marker FLT3-L increases.

Adding montelukast to fluticasone propionate/salmeterol for control of asthma and seasonal allergic rhinitis.

Limited information exists comparing fluticasone propionate/salmeterol combination (FSC) versus montelukast (MON) in patients with coexistent asthma and allergic rhinitis. The purpose of this study was to compare the addition of MON to patients receiving FSC on asthma control while experiencing asthma and allergy symptoms. Additionally, the effect of fluticasone propionate aqueous nasal spray (FPANS) and MON were assessed in allergic rhinitis control. Symptomatic patients (n = 1385) with asthma and seasonal allergic rhinitis were randomized to receive FSC, 100/50 micrograms twice daily; FSC twice daily + FPANS, 200 micrograms once daily; FSC twice daily + MON, 10 mg once daily; or MON once daily for 4 weeks during the allergy pollen season. Patients recorded peak expiratory flow, rescue albuterol use, and asthma and rhinitis symptoms. No additional improvements in overall asthma control were seen when MON was added to FSC. Treatment with FSC produced significant (p < 0.001) improvements in all clinical and patient-reported measures versus MON. FSC + FPANS was superior to FSC + MON (p < or = 0.001) in improving daytime and nighttime total nasal symptom scores. Adverse events were similar. In patients with asthma and allergic rhinitis, adding MON to FSC provided no additional benefit in asthma control. FSC resulted in superior improvement in asthma control compared with MON. FPANS also provided superior nasal symptom control versus MON in allergic patients treated with FSC for asthma. Optimal disease control in patients with asthma and allergic rhinitis should be achieved by the most effective therapy directed toward each disease component.

Volumetric assessment of paranasal sinus opacification on computed tomography can be automated using a convolutional neural network.

BACKGROUND: Computed tomography (CT) plays a key role in evaluation of paranasal sinus inflammation, but improved, and standardized, objective assessment is needed. Computerized volumetric analysis has benefits over visual scoring, but typically relies on manual image segmentation, which is difficult and time-consuming, limiting practical applicability. We hypothesized that a convolutional neural network (CNN) algorithm could perform automatic, volumetric segmentation of the paranasal sinuses on CT, enabling efficient, objective measurement of sinus opacification. In this study we performed initial clinical testing of a CNN for fully automatic quantitation of paranasal sinus opacification in the diagnostic workup of patients with chronic upper and lower airway disease. METHODS: Sinus CT scans were collected on 690 patients who underwent imaging as part of multidisciplinary clinical workup at a tertiary care respiratory hospital between April 2016 and November 2017. A CNN was trained to perform automatic segmentation using a subset of CTs (n = 180) that were segmented manually. A nonoverlapping set (n = 510) was used for testing. CNN opacification scores were compared with Lund-MacKay (LM) visual scores, pulmonary function test results, and other clinical variables using Spearman correlation and linear regression. RESULTS: CNN scores were correlated with LM scores (rho = 0.82, p < 0.001) and with forced expiratory volume in 1 second (FEV1 ) percent predicted (rho = -0.21, p < 0.001), FEV1 /forced vital capacity ratio (rho = -0.27, p < 0.001), immunoglobulin E (rho = 0.20, p < 0.001), eosinophil count (rho = 0.28, p < 0.001), and exhaled nitric oxide (rho = 0.40, p < 0.001). CONCLUSION: Segmentation of the paranasal sinuses on CT can be automated using a CNN, providing truly objective, volumetric quantitation of sinonasal inflammation.

Assessing nasal symptom control.

Rhinitis is a common chronic disease that significantly impacts morbidity, health care costs, work and school productivity, and quality of life. Therefore, appropriate management is paramount to help to reduce the burden of disease. In current clinical practice, there are no validated instruments widely used to assess rhinitis control. In this review, we describe the tools available for assessing nasal symptom control in patients with rhinitis. The recently developed Allergic Rhinitis Control Assessment is a promising tool with demonstrated validity, reliability, and ease of use. Health care providers are encouraged to use the rhinitis-specific tools and incorporate other objective measures, such as rhinoscopy and rhinometric techniques, when evaluating patients with rhinitis. Further research is needed to evaluate the benefits and shortcomings of the available rhinitis- and rhinosinusitis-specific instruments to establish their role in clinical practice.

Intranasal antihistamines for allergic rhinitis: examining the clinical impact.

Allergic rhinitis is likely the most common medical complaint to a clinical allergist and immunologist affecting between 10 and 30% of all adults. This disease causes significant impact on quality of life as well as creating a financial burden on society with decreased work productivity and medication costs. Often, many allergy sufferers do not adhere to the medication recommendations provided by their physician most often because these therapies have not provided relief. Although in the past, the mainstay of treatment for allergic rhinitis has been environmental avoidance, immunotherapy, nasal corticosteroids, and oral antihistamines, the most recent rhinitis diagnosis parameters published by the American Academy of Allergy, Asthma and Immunology have also discussed the importance of other often overlooked therapies. More specifically, the new guidelines discuss a place for the use of intranasal antihistamines as first-line therapy as well as potentially providing superior relief to second-generation oral antihistamines. The guidelines also identify the biphasic nature of the allergic response with both phases consisting of nasal pruritus, sneezing, rhinorrhea, and congestion with the late phase predominated by nasal congestion. It is important to understand how intranasal antihistamines fit into these latest guidelines as first-line therapy and to understand how they may be beneficial to the symptoms associated with allergic rhinitis. It is equally important to identify the individuals who have had less success with their current therapies to determine if intranasal antihistamines would be an important adjunct in therapy.

Establishing the onset of action of intranasal corticosteroids: is there an ideal study design?

Intranasal corticosteroids (INs) are considered the most effective pharmaceutical treatments for nasal allergic rhinitis (AR) symptoms and are recommended as first-line therapy for moderate-to-severe symptoms. United States Food and Drug Administration (FDA) guidelines for clinical development of drug products for AR describe three study types used to determine medication onset of action: (1) standard phase 3 efficacy studies, (2) park-setting studies, and (3) environmental exposure chamber studies. This study was designed to review the U.S. FDA guidelines and discuss published studies of each type examining INS onset of action. Medline searches were conducted using the terms "onset of action" and each of the following: "beclomethasone," "budesonide," "ciclesonide," "fluticasone furoate," "fluticasone propionate," "mometasone furoate," and "triamcinolone." Studies included in the analysis were of subjects with seasonal or perennial AR; were double-blind, placebo-controlled, and randomized; and reported onset-of-action data. Published studies of all three types describing INS onset of action vary widely in compliance with guideline recommendations and in the calculated onset of these medications. The usefulness of the study types used to assess AR therapies-standard efficacy, park setting, and environmental exposure chamber-can be assessed based on each study's ability to reproduce real-world settings, limit variability of allergen exposure, limit variation in study design, and ensure patient adherence to study drug. Studies conducted in an environmental exposure chamber to determine onset of action for INSs may be of superior design because outcomes are significantly less variable and more reproducible than those of other types.