Publications by authors named "Rohit Katial"

72 Publications

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

Int Forum Allergy Rhinol 2020 11 15;10(11):1218-1225. Epub 2020 Jun 15.

Department of Radiology, National Jewish Health, Denver, CO.

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 (FEV ) percent predicted (rho = -0.21, p < 0.001), FEV /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.
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http://dx.doi.org/10.1002/alr.22588DOI Listing
November 2020

Safety of Reslizumab in Uncontrolled Asthma with Eosinophilia: A Pooled Analysis from 6 Trials.

J Allergy Clin Immunol Pract 2020 02 9;8(2):540-548.e1. Epub 2019 Aug 9.

Department of Medicine, Pediatrics, and Radiology, Washington University School of Medicine, St Louis, Mo.

Background: Intravenous reslizumab, a monoclonal IL-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of reslizumab in larger populations.

Objective: To investigate the safety profile of intravenous reslizumab 3.0 mg/kg by analyzing data from 6 asthma clinical trials: 5 placebo-controlled (duration ≤52 weeks) and 1 open-label extension (up to 2 years of treatment).

Methods: Patients were aged 12 to 75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 received reslizumab 3.0 mg/kg.

Results: Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than in the reslizumab group (67% and 6%). Asthma, nasopharyngitis, and upper respiratory tract infection were the most common AEs with placebo and reslizumab. Three cases of anaphylaxis, related to reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with more than 12 months of reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for more than 12 months was no higher than in patients with shorter treatment durations.

Conclusions: This analysis confirms that treatment with intravenous reslizumab for more than 12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.
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http://dx.doi.org/10.1016/j.jaip.2019.07.038DOI Listing
February 2020

Biomarkers in Allergy and Asthma.

Immunol Allergy Clin North Am 2018 11;38(4):xiii-xiv

Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA. Electronic address:

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http://dx.doi.org/10.1016/j.iac.2018.07.001DOI Listing
November 2018

Exhaled Nitric Oxide: An Update.

Immunol Allergy Clin North Am 2018 11 21;38(4):573-585. Epub 2018 Sep 21.

Division of Allergy and Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.

Fractional concentration of exhaled nitric oxide (FENO) is a biomarker used to identify allergic airway inflammation. Because it is noninvasive and easy to obtain, its utility has been studied in the diagnosis and management of several respiratory diseases. Much of the research has been done in asthma, and many studies support the use of FENO in aiding diagnosing asthma, predicting steroid responsiveness, and preventing exacerbations by guiding medication dosage and assessing adherence.
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http://dx.doi.org/10.1016/j.iac.2018.06.001DOI Listing
November 2018

Bronchoprovocation Testing in Asthma: An Update.

Immunol Allergy Clin North Am 2018 11;38(4):545-571

National Jewish Health, 1400 Jackson Street (J321), Denver, CO 80206, USA. Electronic address:

Bronchial hyperresponsiveness (BHR) is defined as a heightened bronchoconstrictive response to airway stimuli. It complements the cardinal features in asthma, such as variable or reversible airflow limitation and airway inflammation. Although BHR is considered a pathophysiologic hallmark of asthma, it should be acknowledged that this property of the airway is dynamic, because its severity and even presence can vary over time with disease activity, triggers or specific exposure, and with treatment. In addition, it is important to recognize that there is a component that is not reflective of a specific disease entity.
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http://dx.doi.org/10.1016/j.iac.2018.06.010DOI Listing
November 2018

United States trends in mortality rates for primary immunodeficiency diseases.

J Allergy Clin Immunol Pract 2019 Mar 9;7(3):1045-1048. Epub 2018 Oct 9.

Division of Allergy and Clinical Immunology, National Jewish Health, Denver, Colo.

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http://dx.doi.org/10.1016/j.jaip.2018.09.030DOI Listing
March 2019

Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps.

J Allergy Clin Immunol Pract 2019 02 5;7(2):589-596.e3. Epub 2018 Sep 5.

Global Respiratory R&D, Teva Branded Pharmaceutical Products R&D Inc., Malvern, Pa.

Background: An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps.

Objective: These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity.

Methods: Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/μL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history.

Results: Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life.

Conclusions: Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.
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http://dx.doi.org/10.1016/j.jaip.2018.08.021DOI Listing
February 2019

Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.

Immun Inflamm Dis 2018 06 11;6(2):322-331. Epub 2018 Apr 11.

Department of Medicine, College of Medicine, University of Arizona Health Sciences, Tucson, Arizona, USA.

Rationale: Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR.

Objectives: An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect.

Methods: Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis.

Measurements And Main Results: This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022.

Conclusions: In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.
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http://dx.doi.org/10.1002/iid3.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946144PMC
June 2018

Rigor Is Needed When Making Comparative Analyses of Biologics in Severe Asthma.

Am J Respir Crit Care Med 2018 06;197(11):1508-1510

2 GlaxoSmithKline Brentford, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201712-2455LEDOI Listing
June 2018

Efficacy and safety of dupilumab in perennial allergic rhinitis and comorbid asthma.

J Allergy Clin Immunol 2018 07 31;142(1):171-177.e1. Epub 2018 Jan 31.

Sanofi, Bridgewater, NJ.

Background: Dupilumab, an anti-IL-4 receptor α mAb, inhibits IL-4/IL-13 signaling, key drivers of type 2/T2 immune diseases (eg, atopic/allergic disease). In a pivotal, phase 2b study (NCT01854047), dupilumab reduced severe exacerbations, improved lung function and quality of life, and was generally well tolerated in patients with uncontrolled persistent asthma despite using medium-to-high-dose inhaled corticosteroids plus long-acting β2-agonists.

Objective: To examine dupilumab's effect on the 22-item Sino-Nasal Outcome Test (SNOT-22) total score and its allergic rhinitis (AR)-associated items in asthma patients with comorbid perennial allergic rhinitis (PAR).

Methods: A post hoc analysis reporting data from the phase 2b study for the 200 and 300 mg every 2 week (q2w) doses under investigation in phase 3 (NCT02414854) was carried out. PAR was defined at study entry as a specific response to typical perennial antigens (IgE ≥0.35 Ku/L).

Results: Overall, 241 (61%) patients had PAR. In asthma patients with PAR, dupilumab 300 mg q2w versus placebo significantly improved SNOT-22 total score (least squares mean difference, -5.98; 95% CI, -10.45 to -1.51; P = .009) and all 4 AR-associated symptoms evaluated (nasal blockage, -0.60; 95% CI, -0.96 to -0.25; runny nose, -0.67; 95% CI, -1.04 to -0.31; sneezing, -0.55; 95% CI, -0.89 to -0.21; postnasal discharge, -0.49; 95% CI, -0.83 to -0.16; all P < .01). Dupilumab 200 mg q2w demonstrated numerical, but not statistically significant, decreases in SNOT-22 total score (-1.82; 95% CI, -6.46 to 2.83; P = .443 vs placebo) and in each AR-associated symptom. In patients without PAR, no differences were observed for these measures versus placebo.

Conclusions: Dupilumab 300 mg q2w significantly improved AR-associated nasal symptoms in patients with uncontrolled persistent asthma and comorbid PAR.
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http://dx.doi.org/10.1016/j.jaci.2017.11.051DOI Listing
July 2018

Asthma Yardstick: Practical recommendations for a sustained step-up in asthma therapy for poorly controlled asthma.

Ann Allergy Asthma Immunol 2017 02;118(2):133-142.e3

Academic Services Connection Inc, Canandaigua, New York.

Current asthma guidelines recommend a control-based approach to management that involves assessment of impairment and risk followed by implementation of treatment strategies individualized according to the patient's needs and preferences. The fact that many patients still experience severe symptoms that negatively affect quality of life suggests that asthma control remains an objective to be achieved. Tools are available to help patients (and families) manage the day-to-day and short-term variability in asthma symptoms; however, when and how to implement a sustained step-up in therapy is less clear. The Asthma Yardstick is a comprehensive update on how to conduct a sustained step-up in asthma therapy for the patient with not well-controlled or poorly controlled asthma. Patient profiles and step-up strategies are based on current guidelines, newer data, and the authors' combined clinical experience and are intended to provide a practical and clinically meaningful guide toward the goal of well-controlled asthma for every patient. The development of this tool comes in response to the continued need to proactively address the sustained loss of asthma control at all levels of severity.
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http://dx.doi.org/10.1016/j.anai.2016.12.010DOI Listing
February 2017

Changing Paradigms in the Treatment of Severe Asthma: The Role of Biologic Therapies.

J Allergy Clin Immunol Pract 2017 Mar - Apr;5(2S):S1-S14. Epub 2017 Jan 29.

Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colo.

Cytokine antagonists are monoclonal antibodies that offer new treatment options for refractory asthma but will also increase complexity because they are effective only for patients with certain asthma subtypes that remain to be more clearly defined. The clinical and inflammatory heterogeneity within refractory asthma makes it difficult to manage the disease and to determine which, if any, biologic therapy is suitable for a specific patient. The purpose of this article is to provide a data-driven discussion to clarify the use of biologic therapies in patients with refractory asthma. We first discuss the epidemiology and pathophysiology of refractory asthma. We then interpret current evidence for biomarkers of eosinophilic or type 2-high asthma so that clinicians can determine potential treatments for patients based on knowledge of their effectiveness in specific asthma phenotypes. We then assess clinical data on the efficacy, safety, and mechanisms of action of approved and pipeline biologic therapies. We conclude by discussing the potential of phenotyping or endotyping refractory asthma and how biologic therapies can play a role in treating patients with refractory asthma.
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http://dx.doi.org/10.1016/j.jaip.2016.11.029DOI Listing
September 2017

A renewed focus on safety, efficacy, and use of inhaled corticosteroids in asthma.

Authors:
Rohit K Katial

Ann Allergy Asthma Immunol 2016 12;117(6):575-576

National Jewish Health, University of Colorado Denver, Denver, Colorado. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2016.04.012DOI Listing
December 2016

Mechanisms of Benefit with Aspirin Therapy in Aspirin-Exacerbated Respiratory Disease.

Immunol Allergy Clin North Am 2016 11;36(4):735-747

Division of Allergy and Immunology, National Jewish Health, University of Colorado, 1400 Jackson Street, K624, Denver, CO 80206, USA. Electronic address:

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by severe persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and an intolerance to aspirin and other NSAIDs that preferentially inhibit COX-1. For more than 30 years, aspirin desensitization has proven to be of significant long-term benefit in carefully selected patients with AERD. Despite this, the exact mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. In this article, we review the current understanding of the mechanisms of aspirin desensitization and discuss future areas of investigation.
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http://dx.doi.org/10.1016/j.iac.2016.06.011DOI Listing
November 2016

Biologics in practice: A unique opportunity for allergist/immunologist expertise.

Authors:
Rohit K Katial

Ann Allergy Asthma Immunol 2016 Aug;117(2):105-7

National Jewish Health, Denver, Colorado. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2016.05.021DOI Listing
August 2016

Severe Asthma: A Heterogeneous Disease.

Authors:
Rohit K Katial

Immunol Allergy Clin North Am 2016 08;36(3):xv-xvi

National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA. Electronic address:

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http://dx.doi.org/10.1016/j.iac.2016.05.001DOI Listing
August 2016

Chronic Rhinosinusitis and Aspirin-Exacerbated Respiratory Disease.

Immunol Allergy Clin North Am 2016 08;36(3):503-14

Department of Allergy and Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA. Electronic address:

Patients with severe asthma and concomitant chronic rhinosinusitis often have severe, refractory upper and lower airway inflammation. This inflammation has been proposed to be similar throughout the upper and lower airways leading to the unified airways concept. This article reviews chronic rhinosinusitis with and without nasal polyps, and the subgroup with aspirin-exacerbated respiratory disease, while focusing on the relationship with asthma. Additionally, diagnosis and treatment with current and newer therapies are discussed.
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http://dx.doi.org/10.1016/j.iac.2016.03.011DOI Listing
August 2016

Clinical Examination of Tissue Eosinophilia in Patients with Chronic Rhinosinusitis and Nasal Polyposis.

Otolaryngol Head Neck Surg 2016 07 15;155(1):173-8. Epub 2016 Mar 15.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado, USA

Objective: (1) Describe clinical and histopathologic findings in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). (2) Determine if tissue and serum eosinophilia predicts disease severity in CRSwNP.

Study Design: Case series with chart review.

Setting: Academic hospital specializing in respiratory and allergic disease.

Subjects: Patients with CRSwNP treated from 2008 to 2010.

Methods: Clinical data were collected; sinus computed tomography (CT) scans were scored according to the Lund-Mackay system; and surgical specimens were evaluated for degree of tissue eosinophilia. Statistical analysis was performed to compare eosinophilia with indicators of disease severity.

Results: Seventy CRSwNP patients were included, with a mean Lund-Mackay score of 16.7; 62.1% of patients had severe asthma, and 62.9% were aspirin sensitive. Elevated tissue eosinophil level did not correlate with medication usage, olfactory symptoms, or Lund-Mackay scores, nor did it correlate with presence of asthma or aspirin-sensitivity (P = .09). Patients with mild asthma had significantly more tissue eosinophils versus patients with severe asthma, possibly because of the high amount of chronic corticosteroid use in severe asthmatics. There was no correlation between tissue and serum eosinophil counts (P = .97), but there was a significant positive correlation between CT score and peripheral eosinophil level (P < .05).

Conclusions: Higher serum eosinophil levels may indicate more extensive mucosal disease as measured on CT scan. Neither serum nor tissue eosinophilia predicted disease severity in our retrospective analysis of CRSwNP patients, and serum eosinophil level did not serve as a marker of tissue eosinophilia.
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http://dx.doi.org/10.1177/0194599816637856DOI Listing
July 2016

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

J Allergy Clin Immunol 2016 08 23;138(2):579-85. Epub 2016 Feb 23.

National Jewish Health, Denver, Colo.

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.
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http://dx.doi.org/10.1016/j.jaci.2015.11.038DOI Listing
August 2016

Venom Allergy.

J Allergy Clin Immunol Pract 2016 Jan-Feb;4(1):184-5; quiz 186

Division of Allergy and Clinical Immunology, National Jewish Health, Denver, Colo.

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http://dx.doi.org/10.1016/j.jaip.2015.09.016DOI Listing
October 2016

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

Clin Infect Dis 2016 Apr 6;62(8):986-94. Epub 2016 Jan 6.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1093/cid/civ1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803104PMC
April 2016

Vocal cord dysfunction: a review.

Asthma Res Pract 2015 22;1. Epub 2015 Sep 22.

National Jewish Health, Denver, CO USA.

Vocal cord dysfunction (VCD) is a term that refers to inappropriate adduction of the vocal cords during inhalation and sometimes exhalation. It is a functional disorder that serves as an important mimicker of asthma. Vocal cord dysfunction can be difficult to treat as the condition is often underappreciated and misdiagnosed in clinical practice. Recognition of vocal cord dysfunction in patients with asthma-type symptoms is essential since missing this diagnosis can be a barrier to adequately treating patients with uncontrolled respiratory symptoms. Although symptoms often mimic asthma, the two conditions have certain distinct clinical features and demonstrate specific findings on diagnostic studies, which can serve to differentiate the two conditions. Moreover, management of vocal cord dysfunction should be directed at minimizing known triggers and initiating speech therapy, thereby minimizing use of unnecessary asthma medications. This review article describes key clinical features, important physical exam findings and commonly reported triggers in patients with vocal cord dysfunction. Additionally, this article discusses useful diagnostic studies to identify patients with vocal cord dysfunction and current management options for such patients.
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http://dx.doi.org/10.1186/s40733-015-0009-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142347PMC
September 2015

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

AAPS J 2015 May 11;17(3):546-57. Epub 2015 Mar 11.

Office of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.
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http://dx.doi.org/10.1208/s12248-015-9733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406956PMC
May 2015

Recommendations for the pharmacologic management of allergic rhinitis.

Allergy Asthma Proc 2014 May-Jun;35 Suppl 1:S20-7

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.
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http://dx.doi.org/10.2500/aap.2014.35.3761DOI Listing
September 2015

Moving toward clarity in the treatment of allergic rhinitis.

Authors:
Rohit K Katial

Allergy Asthma Proc 2014 May-Jun;35 Suppl 1:S1-2

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http://dx.doi.org/10.2500/aap.2014.35.3759DOI Listing
September 2015

Delayed Anaphylaxis to Red Meat Associated With Specific IgE Antibodies to Galactose.

Allergy Asthma Immunol Res 2015 Jan 9;7(1):92-4. Epub 2014 Jun 9.

Department of Allergy and Immunology, National Jewish Medical and Research Center, University of Colorado, Denver, CO, USA.

A novel delayed anaphylactic reaction to red meat, associated with tick bites and IgE antibodies against galactose-α-1, 3-galactose (α-gal), was reported in 2009 in the US, Australia and Europe. In this case, serum specific IgE to galactose-α-1, 3-galactose (>100 kU/L) and IgE to multiple non-primate mammalian proteins were positive. However, the pathogenesis of this disease remains unclear. We report the first case in Asia of delayed anaphylactic reaction to red meat, which was induced by bites from the hard tick, Hematophagous ixodidae. We confirmed the increased concentration of IgE reactive epitopes in non-primate mammalian organs, which may be rich in α-gal proteins in lymphatic and endothelial tissues. All confirmed ticks associated with this disorder in the literature and in our case belonged to the hard tick family. We hypothesize that hard tick saliva is enriched with blood-type substances, such as oligosaccharides, from the non-primate mammal victim's blood after days to weeks of blood sucking, which sensitizes humans through the injection route while blood sucking.
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http://dx.doi.org/10.4168/aair.2015.7.1.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274476PMC
January 2015

Asthma in the elderly: what we know and what we have yet to know.

World Allergy Organ J 2014 30;7(1). Epub 2014 May 30.

Faculty of Medicine Clinical and Experimental Sciences, University of Southampton, Hampshire, United Kingdom.

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.
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http://dx.doi.org/10.1186/1939-4551-7-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137434PMC
August 2014

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

Ann Allergy Asthma Immunol 2013 Nov 20;111(5):337-41. Epub 2013 Aug 20.

University of Colorado School of Medicine, Aurora, Colorado.

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.
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http://dx.doi.org/10.1016/j.anai.2013.07.017DOI Listing
November 2013

IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling.

J Allergy Clin Immunol 2013 Oct 16;132(4):912-21.e1-5. Epub 2013 Aug 16.

Division of Allergy and Immunology, Department of Medicine, National Jewish Health, Denver, Colo; Zhangshan Hospital, Fudan University, Shanghai, China.

Background: TH2 cells play a critical role in the pathogenesis of allergic asthma. Established TH2 cells have been shown to resist reprogramming into TH1 cells. The inherent stability of TH2 cells poses a significant barrier to treating allergic diseases.

Objective: We sought to understand the mechanisms by which CD4(+) T cells from asthmatic patients resist the IL-27-mediated inhibition.

Methods: We isolated and cultured CD4(+) T cells from both healthy subjects and allergic asthmatic patients to test whether IL-27 can inhibit IL-4 production by the cultured CD4(+) T cells using ELISA. Culturing conditions that resulted in resistance to IL-27 were determined by using both murine and human CD4(+) T-cell culture systems. Signal transducer and activator of transcription (STAT) 1 phosphorylation was analyzed by means of Western blotting and flow cytometry. Suppressor of cytokine signaling (Socs) mRNA expression was measured by using quantitative PCR. The small interfering RNA method was used to knockdown the expression of Socs3 mRNA.

Results: We demonstrated that CD4(+) T cells from asthmatic patients resisted the suppression of IL-4 production mediated by IL-27. We observed that repeated exposure to TH2-inducing conditions rendered healthy human CD4(+) T cells resistant to IL-27-mediated inhibition. Using an in vitro murine culture system, we further demonstrated that repeated or higher doses of IL-4 stimulation, but not IL-2 stimulation, upregulated Socs3 mRNA expression and impaired IL-27-induced STAT1 phosphorylation. The knockdown of Socs3 mRNA expression restored IL-27-induced STAT1 phosphorylation and IL-27-mediated inhibition of IL-4 production.

Conclusions: Our findings demonstrate that differentiated TH2 cells can resist IL-27-induced reprogramming toward TH1 cells by downregulating STAT1 phosphorylation and likely explain why the CD4(+) T cells of asthmatic patients are resistant to IL-27-mediated inhibition.
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http://dx.doi.org/10.1016/j.jaci.2013.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788709PMC
October 2013

Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia.

J Allergy Clin Immunol 2013 Nov 16;132(5):1086-1096.e5. Epub 2013 Jul 16.

Faculté de médecine, département de médecine, Université Laval, Quebec City, Quebec, Canada. Electronic address:

Background: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity.

Objectives: We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood.

Methods: In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive.

Results: The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts.

Conclusion: Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.
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http://dx.doi.org/10.1016/j.jaci.2013.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172321PMC
November 2013
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