Publications by authors named "Sally Wenzel"

305 Publications

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: results from SARP-3.

J Allergy Clin Immunol 2021 Feb 9. Epub 2021 Feb 9.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS. Electronic address:

Background: Currently there is limited knowledge of what imaging assessments of asthma are associated with accelerated longitudinal lung function decline.

Objectives: We aimed to assess whether quantitative computerized tomography (qCT) metrics are associated with longitudinal lung function decline and morbidity in asthma.

Methods: We analyzed 205 qCT scans of adult asthma patients, and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future lung function change, future exacerbation rate, and changes in validated measurements of morbidity.

Results: Greater baseline wall area percent (WA%) (β=-0.15, 95% CI -0.26 to -0.05, P<0.01), hyperinflation% (β=-0.25, 95% CI -0.41 to -0.09, P<0.01), and Jacobian gradient measurements (cranial-caudal β=10.64, CI 3.79 to 17.49, P<0.01; posterior-anterior β=-9.14, CI -15.49 to -2.78, P<0.01) were associated with more severe future lung function decline. Additionally, greater WA% (rate ratio=1.06, CI 1.01 to 1.10, P=0.02), air-trapping% (rate ratio=1.01, CI 1.00 to 1.02, P=0.03), and lower Jacobian determinant mean (rate ratio=0.58, CI 0.41 to 0.82, P<0.01) and Jacobian determinant standard deviation (rate ratio=0.52, CI 0.32 to 0.85, P=0.01) were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.

Conclusions: Baseline qCT measures of more severe airway remodeling, more small airways disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2021.01.029DOI Listing
February 2021

Mixed Sputum Granulocyte Longitudinal Impact on Lung Function in the Severe Asthma Research Program.

Am J Respir Crit Care Med 2021 Feb 5. Epub 2021 Feb 5.

The University of Arizona Arizona Health Sciences Center, 12217, Division of Genetics, Genomics and Precision Medicine, Tucson, Arizona, United States.

Rationale: Reports indicate longitudinal variability in sputum differential cell counts while others describe stability. Highly variable sputum eosinophil percents are associated with greater lung function loss than persistently elevated eosinophil percents, but elevated neutrophils are linked to more severe asthma.

Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.

Methods: The Severe Asthma Research Program (SARP 3) cohort underwent comprehensive phenotype characterization at baseline and annually over three years. Adult subjects with acceptable sputum were assigned to one of 3 longitudinal sputum groups: Eosinophils predominantly <2%, predominantly >2%, or highly variable (>2SD determined from independent, repeated baseline eosinophil %s). Subjects were similarly assigned to 1 of 3 longitudinal neutrophil groups with a 50% cut-point.

Measurements And Main Results: The group with predominantly <2% sputum eosinophils had highest lung function (pre bronchodilator FEV1%predicted, p<0.01 and FEV1/FVC ratio, p<0.001) at baseline and throughout three years compared to other eosinophil groups. Healthcare utilization did not differ although the highly variable eosinophil group reported more asthma exacerbations at year 3. Longitudinal neutrophil groups showed few differences. However, combination of predominantly >2% eosinophil and >50% neutrophil groups resulted in the lowest prebronchodilator FEV1%predicted (p=0.049) compared to predominantly <2% eosinophils +<50% neutrophils.

Conclusions: Subjects with predominantly >2% sputum eosinophils in combination with predominantly >50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare utilization.
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http://dx.doi.org/10.1164/rccm.202009-3713OCDOI Listing
February 2021

Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol 2020 Dec 17. Epub 2020 Dec 17.

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown.

Objective: Our aim was to explore the expression, regulation, and function of STING in CRSwNP.

Methods: STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro.

Results: STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13-induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP.

Conclusions: Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.
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http://dx.doi.org/10.1016/j.jaci.2020.12.623DOI Listing
December 2020

Severe Adult Asthmas: Integrating Clinical Features, Biology and Therapeutics to Improve Outcomes.

Authors:
Sally E Wenzel

Am J Respir Crit Care Med 2020 Dec 16. Epub 2020 Dec 16.

University of Pittsburgh, 6614, Environmental and Occupational Health, Pittsburgh, Pennsylvania, United States.

Evaluation and effective management of asthma and in particular severe asthma remains at the core of pulmonary practice. Over the last 20-30 years, there is increasing appreciation that "severe asthma", encompasses multiple different subgroups or phenotypes each with differing presentations. Using clinical phenotyping, in combination. with rapidly advancing molecular tools and targeted monoclonal antibodies (human knock-outs), the understanding of these phenotypes and our ability to treat them have greatly advanced. Type-2 (T2) Hi and Lo severe asthmas are now easily identified. Fraction exhaled nitric oxide (FeNO) and blood eosinophil counts can be routinely employed in clinical settings to identify these phenotypes and predict responses to specific therapies, meeting the initial goals of precision medicine. Integration of molecular signals, biomarkers and clinical responses to targeted therapies has enabled identification of critical molecular pathways and in certain phenotypes advanced them to near endotype status. Despite these advances, little guidance is available to determine which class of biologic is appropriate for a given patient and current "break-through" therapies remain expensive and even inaccessible to many patients. Many of the most severe asthmas, with and without T2-biomarker elevations, remain poorly understood and treated. Yet, conceptual understanding of "the severe asthmas" has evolved dramatically in a mere 25 years, leading to dramatic improvements in the lives of many.
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http://dx.doi.org/10.1164/rccm.202009-3631CIDOI Listing
December 2020

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate to Severe Asthma.

Am J Respir Crit Care Med 2020 Dec 8. Epub 2020 Dec 8.

Brigham and Women's Hospital, 1861, Pulmonary and Critical Care Division, Boston, Massachusetts, United States.

Rationale: It is unclear why select patients with moderate to severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of severe decline in lung function.

Objective: To evaluate corticosteroid response phenotypes as longitudinal predictors of lung decline.

Methods: Adults with in the NHLBI Severe Asthma Research Program (SARP3; (1, 2)) who had undergone a course of intramuscular triamcinolone at baseline and ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/year; mild decline, >0.5 to 2.0% loss/year; no change, 0.5% loss/year to <1% gain/year; improve, ≥1% gain/year. Regression models were used to develop predictors of severe decline.

Measurements And Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (tdFEV1; derived by baseline subtraction) was related to the 4-yr change in lung function or slope category in univariable models (p < 0.001). For each 5% decrement in the tdFEV1, there was a 50% increase in the odds of being in the severe decline group (OR 1.5, 95% CI 1.3 to 1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and BMI.

Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk of severe decline in lung function.
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http://dx.doi.org/10.1164/rccm.202002-0454OCDOI Listing
December 2020

The emerging role of quantitative imaging in asthma.

Br J Radiol 2020 Dec 3:20201133. Epub 2020 Dec 3.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.

Quantitative imaging of the lung has proved to be a valuable tool that has improved our understanding of asthma. CT, MRI, and positron emission tomography have all been utilized in asthma with each modality having its own distinct advantages and disadvantages. Research has now demonstrated that quantitative imaging plays a valuable role in characterizing asthma phenotypes and endotypes, as well as potentially predicting future asthma morbidity. Nonetheless, future research is needed in order to minimize radiation exposure, standardize reporting, and further delineate how imaging can predict longitudinal outcomes. With future work, quantitative imaging may make its way into the clinical care of asthma and change our practice.
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http://dx.doi.org/10.1259/bjr.20201133DOI Listing
December 2020

Exploration of plasma interleukin-27 levels in asthma patients and the correlation with lung function.

Respir Med 2020 12 29;175:106208. Epub 2020 Oct 29.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China. Electronic address:

Background: IL-27 attenuates allergic inflammation and improves lung function in mouse models of allergic asthma. However, plasma IL-27 levels of asthma patients and the association with clinical features remain poorly understood.

Methods: This study examined plasma IL-27 protein expression in untreated asthma patients and controls, analyzed its correlation with Th2 inflammation and lung function, and evaluated the effect of corticosteroids on IL-27 expression.

Results: Plasma IL-27 levels were lower in untreated asthma patients compared to controls. Plasma IL-27 levels were inversely correlated with sputum IL-5 mRNA expression in Th2 group. The Th2IL-27 subgroup suffered from the highest airway hyperresponsiveness (AHR) and the worst pulmonary function. The patients in Th2IL-27 subgroup were less likely to be atopic and had the worst improvement of symptoms after four weeks of standard treatment. In vitro, dexamethasone could decrease the expression of IL-27 in THP-1 cell line. The majority of asthma patients had further decreased IL-27 levels after standard treatment, whereas patients with sustained high levels of IL-27 post-treatment had more blood neutrophils at baseline compared with those without.

Conclusions: The results indicate that low levels of IL-27 in peripheral blood are closely related to Th2 inflammation and lung function of asthma patients. Low IL-27 levels in combination with high Th2 inflammation identify an asthma phenotype with high AHR and substantial response to corticosteroids. Understanding of this interaction could help to elucidate the inherent inflammation heterogeneity of asthma.
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http://dx.doi.org/10.1016/j.rmed.2020.106208DOI Listing
December 2020

Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma.

J Allergy Clin Immunol 2020 Oct 29. Epub 2020 Oct 29.

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Va. Electronic address:

Background: Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity.

Objective: We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma.

Methods: Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry.

Results: Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma.

Conclusion: Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease.
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http://dx.doi.org/10.1016/j.jaci.2020.10.024DOI Listing
October 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Authors:
Alexander G Bick Joshua S Weinstock Satish K Nandakumar Charles P Fulco Erik L Bao Seyedeh M Zekavat Mindy D Szeto Xiaotian Liao Matthew J Leventhal Joseph Nasser Kyle Chang Cecelia Laurie Bala Bharathi Burugula Christopher J Gibson Amy E Lin Margaret A Taub Francois Aguet Kristin Ardlie Braxton D Mitchell Kathleen C Barnes Arden Moscati Myriam Fornage Susan Redline Bruce M Psaty Edwin K Silverman Scott T Weiss Nicholette D Palmer Ramachandran S Vasan Esteban G Burchard Sharon L R Kardia Jiang He Robert C Kaplan Nicholas L Smith Donna K Arnett David A Schwartz Adolfo Correa Mariza de Andrade Xiuqing Guo Barbara A Konkle Brian Custer Juan M Peralta Hongsheng Gui Deborah A Meyers Stephen T McGarvey Ida Yii-Der Chen M Benjamin Shoemaker Patricia A Peyser Jai G Broome Stephanie M Gogarten Fei Fei Wang Quenna Wong May E Montasser Michelle Daya Eimear E Kenny Kari E North Lenore J Launer Brian E Cade Joshua C Bis Michael H Cho Jessica Lasky-Su Donald W Bowden L Adrienne Cupples Angel C Y Mak Lewis C Becker Jennifer A Smith Tanika N Kelly Stella Aslibekyan Susan R Heckbert Hemant K Tiwari Ivana V Yang John A Heit Steven A Lubitz Jill M Johnsen Joanne E Curran Sally E Wenzel Daniel E Weeks Dabeeru C Rao Dawood Darbar Jee-Young Moon Russell P Tracy Erin J Buth Nicholas Rafaels Ruth J F Loos Peter Durda Yongmei Liu Lifang Hou Jiwon Lee Priyadarshini Kachroo Barry I Freedman Daniel Levy Lawrence F Bielak James E Hixson James S Floyd Eric A Whitsel Patrick T Ellinor Marguerite R Irvin Tasha E Fingerlin Laura M Raffield Sebastian M Armasu Marsha M Wheeler Ester C Sabino John Blangero L Keoki Williams Bruce D Levy Wayne Huey-Herng Sheu Dan M Roden Eric Boerwinkle JoAnn E Manson Rasika A Mathias Pinkal Desai Kent D Taylor Andrew D Johnson Paul L Auer Charles Kooperberg Cathy C Laurie Thomas W Blackwell Albert V Smith Hongyu Zhao Ethan Lange Leslie Lange Stephen S Rich Jerome I Rotter James G Wilson Paul Scheet Jacob O Kitzman Eric S Lander Jesse M Engreitz Benjamin L Ebert Alexander P Reiner Siddhartha Jaiswal Gonçalo Abecasis Vijay G Sankaran Sekar Kathiresan Pradeep Natarajan

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
October 2020

Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials.

Lancet Respir Med 2021 01 24;9(1):43-56. Epub 2020 Sep 24.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, AZ, USA.

Background: Fevipiprant, an oral antagonist of the prostaglandin D receptor 2, reduced sputum eosinophils and improved lung function in phase 2 trials of patients with asthma. We aimed to investigate whether fevipiprant reduces asthma exacerbations in patients with severe asthma.

Methods: LUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (<250 cells per μL or ≥250 cells per μL), patient age (<18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per μL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting.

Findings: Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (<1%) patients in the fevipiprant 450 mg group and three (<1%) in the placebo group.

Interpretation: Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant.

Funding: Novartis.
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http://dx.doi.org/10.1016/S2213-2600(20)30412-4DOI Listing
January 2021

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations.

J Biopharm Stat 2020 Sep 17:1-12. Epub 2020 Sep 17.

University of Chicago, Chicago, IL.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.
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http://dx.doi.org/10.1080/10543406.2020.1821705DOI Listing
September 2020

Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.

J Allergy Clin Immunol 2020 Aug 11. Epub 2020 Aug 11.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 
Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.
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http://dx.doi.org/10.1016/j.jaci.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876167PMC
August 2020

Automated quantification of COVID-19 severity and progression using chest CT images.

Eur Radiol 2021 Jan 13;31(1):436-446. Epub 2020 Aug 13.

Department of Radiology, Xi'an Jiaotong University The First Affiliated Hospital, Xi'an, Shaanxi, China.

Objective: To develop and test computer software to detect, quantify, and monitor progression of pneumonia associated with COVID-19 using chest CT scans.

Methods: One hundred twenty chest CT scans from subjects with lung infiltrates were used for training deep learning algorithms to segment lung regions and vessels. Seventy-two serial scans from 24 COVID-19 subjects were used to develop and test algorithms to detect and quantify the presence and progression of infiltrates associated with COVID-19. The algorithm included (1) automated lung boundary and vessel segmentation, (2) registration of the lung boundary between serial scans, (3) computerized identification of the pneumonitis regions, and (4) assessment of disease progression. Agreement between radiologist manually delineated regions and computer-detected regions was assessed using the Dice coefficient. Serial scans were registered and used to generate a heatmap visualizing the change between scans. Two radiologists, using a five-point Likert scale, subjectively rated heatmap accuracy in representing progression.

Results: There was strong agreement between computer detection and the manual delineation of pneumonic regions with a Dice coefficient of 81% (CI 76-86%). In detecting large pneumonia regions (> 200 mm), the algorithm had a sensitivity of 95% (CI 94-97%) and specificity of 84% (CI 81-86%). Radiologists rated 95% (CI 72 to 99) of heatmaps at least "acceptable" for representing disease progression.

Conclusion: The preliminary results suggested the feasibility of using computer software to detect and quantify pneumonic regions associated with COVID-19 and to generate heatmaps that can be used to visualize and assess progression.

Key Points: • Both computer vision and deep learning technology were used to develop computer software to quantify the presence and progression of pneumonia associated with COVID-19 depicted on CT images. • The computer software was tested using both quantitative experiments and subjective assessment. • The computer software has the potential to assist in the detection of the pneumonic regions, monitor disease progression, and assess treatment efficacy related to COVID-19.
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http://dx.doi.org/10.1007/s00330-020-07156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755837PMC
January 2021

Interleukin-22 Inhibits Respiratory Syncytial Virus Production by Blocking Virus-Mediated Subversion of Cellular Autophagy.

iScience 2020 Jul 10;23(7):101256. Epub 2020 Jun 10.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, MUH 628 NW, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address:

Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular autophagic machinery, and knockdown of LC3B ablated virus production. RSV subverted LC3B with evidence of co-localization and caused a significant reduction in autophagic flux, both reversed by IL-22 treatment. Our findings inform a previously unrecognized anti-viral effect of IL-22 that can be harnessed to prevent RSV-induced severe respiratory disease.
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http://dx.doi.org/10.1016/j.isci.2020.101256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317237PMC
July 2020

Expression of SARS-CoV-2 receptor ACE2 and coincident host response signature varies by asthma inflammatory phenotype.

J Allergy Clin Immunol 2020 08 10;146(2):315-324.e7. Epub 2020 Jun 10.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Environmental Medicine and Occupational Health, Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Electronic address:

Background: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019.

Objective: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection.

Methods: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets.

Results: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes.

Conclusions: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.
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http://dx.doi.org/10.1016/j.jaci.2020.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283064PMC
August 2020

PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells.

Proc Natl Acad Sci U S A 2020 06 8;117(25):14376-14385. Epub 2020 Jun 8.

Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260;

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.
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http://dx.doi.org/10.1073/pnas.1921618117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321965PMC
June 2020

Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency.

Am J Respir Crit Care Med 2020 10;202(7):973-982

Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin.

Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers. To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers. Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers. Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number. Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.
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http://dx.doi.org/10.1164/rccm.201909-1813OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528796PMC
October 2020

ACE2, TMPRSS2, and furin gene expression in the airways of people with asthma-implications for COVID-19.

J Allergy Clin Immunol 2020 07 22;146(1):208-211. Epub 2020 May 22.

National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (Respiratory theme) and College of Life Sciences, University of Leicester, Leicester, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2020.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243787PMC
July 2020

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids.

Am J Respir Crit Care Med 2020 07;202(1):83-90

Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among patients with asthma may identify subgroups at risk for COVID-19 morbidity. To determine the relationship between demographic features and sputum ACE2 and TMPRSS2 gene expression in asthma.: We analyzed gene expression for ACE2 and TMPRSS2, and for ICAM-1 (intercellular adhesion molecule 1) (rhinovirus receptor as a comparator) in sputum cells from 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects. Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes were similar in asthma and health. Among patients with asthma, male sex, African American race, and history of diabetes mellitus were associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to sex, race, and use of ICS. Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.
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http://dx.doi.org/10.1164/rccm.202003-0821OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328313PMC
July 2020

High-Dose Vitamin D3 for Critically Ill Vitamin D-Deficient Patients.

N Engl J Med 2020 04;382(17):1669-1670

University of Pittsburgh, Pittsburgh, PA.

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http://dx.doi.org/10.1056/NEJMc2000993DOI Listing
April 2020

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

J Allergy Clin Immunol 2020 Nov 13;146(5):1016-1026. Epub 2020 Apr 13.

Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown.

Objective: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma.

Methods: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines.

Results: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders.

Conclusions: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.
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http://dx.doi.org/10.1016/j.jaci.2020.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554083PMC
November 2020

Clinical Research Needs for the Management of Chronic Rhinosinusitis with Nasal Polyps in the New Era of Biologics: A National Institute of Allergy and Infectious Diseases Workshop.

J Allergy Clin Immunol Pract 2020 05 4;8(5):1532-1549.e1. Epub 2020 Mar 4.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address:

The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come.
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http://dx.doi.org/10.1016/j.jaip.2020.02.023DOI Listing
May 2020

Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma.

Lancet 2020 02;395(10221):371-383

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.
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http://dx.doi.org/10.1016/S0140-6736(19)33005-3DOI Listing
February 2020

genotype identifies glucocorticoid responsiveness in severe asthma.

Proc Natl Acad Sci U S A 2020 01 13;117(4):2187-2193. Epub 2020 Jan 13.

Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive (1245A) allele limits conversion, whereas the adrenal permissive (1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEVPP). (1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEVPP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined ( = 318). Validation was performed in a second cohort (SARP I&II; = 184). DHEA-sulfate is associated with FEVPP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEVPP compared with noGC patients (54.3% vs. 75.1%; < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEVPP difference in GC vs. noGC patients (73.4% vs. 78.9%; = 0.39). Results were independently confirmed: FEVPP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 ( < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 ( = 0.92). The adrenal restrictive (1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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http://dx.doi.org/10.1073/pnas.1918819117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995013PMC
January 2020

Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?

Physiol Rev 2020 07 9;100(3):983-1017. Epub 2020 Jan 9.

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Pulmonary Allergy Critical Care Medicine, Departments of Medicine and of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pediatrics, Emory University, Atlanta, Georgia.

While the term has long been known to describe heterogeneous groupings of patients, only recently have data evolved which enable a molecular understanding of the clinical differences. The evolution of transcriptomics (and other 'omics platforms) and improved statistical analyses in combination with large clinical cohorts opened the door for molecular characterization of pathobiologic processes associated with a range of asthma patients. When linked with data from animal models and clinical trials of targeted biologic therapies, emerging distinctions arose between patients with and without elevations in type 2 immune and inflammatory pathways, leading to the confirmation of a broad categorization of type 2-Hi asthma. Differences in the ratios, sources, and location of type 2 cytokines and their relation to additional immune pathway activation appear to distinguish several different (sub)molecular phenotypes, and perhaps endotypes of type 2-Hi asthma, which respond differently to broad and targeted anti-inflammatory therapies. Asthma in the absence of type 2 inflammation is much less well defined, without clear biomarkers, but is generally linked with poor responses to corticosteroids. Integration of "big data" from large cohorts, over time, using machine learning approaches, combined with validation and iterative learning in animal (and human) model systems is needed to identify the biomarkers and tightly defined molecular phenotypes/endotypes required to fulfill the promise of precision medicine.
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http://dx.doi.org/10.1152/physrev.00023.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474260PMC
July 2020

Severe asthma during childhood and adolescence: A longitudinal study.

J Allergy Clin Immunol 2020 01 14;145(1):140-146.e9. Epub 2019 Oct 14.

Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, Ohio. Electronic address:

Background: Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma.

Objective: We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence.

Methods: Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually.

Results: At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P < .001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/μL.

Conclusions: In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population.
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http://dx.doi.org/10.1016/j.jaci.2019.09.030DOI Listing
January 2020

Development and initial validation of the Asthma Severity Scoring System (ASSESS).

J Allergy Clin Immunol 2020 01 8;145(1):127-139. Epub 2019 Oct 8.

Department of Medicine, University of Wisconsin, Madison, Wis.

Background: Tools for quantification of asthma severity are limited.

Objective: We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations.

Methods: Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics.

Results: ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall.

Conclusions: The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.
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http://dx.doi.org/10.1016/j.jaci.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949388PMC
January 2020