Publications by authors named "Bruce D Levy"

169 Publications

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

FcεR1 expressing nociceptors trigger allergic airway inflammation.

J Allergy Clin Immunol 2021 Jan 13. Epub 2021 Jan 13.

Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Canada. Electronic address:

Background: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice.

Objective: We now sought to identify the cellular mechanisms by which these sensory neurons are activated upon allergen exposure.

Methods: We used calcium microscopy and electrophysiological recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor specific FcεR1γ knockdown (TRPV1::FcεR1γ) mice to assess whether this targeted invalidation would impact the severity of allergic inflammation in response to allergen challenges.

Results: Lung-innervating jugular nodose complex ganglion (JNC) neurons express the high-affinity IgE receptor FcεR1 and the levels of this receptor increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE, with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE/allergen immune complexes, through the release of substance P (SP) from their peripheral terminals, directly amplifies T2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1::FcεR1γ mice or in bone marrow-transplanted FcεR1α mice. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse JNC neurons and human iPSC-derived nociceptors.

Conclusions: Allergen-sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1 expressing vagal sensory neurons, and T2 cells, which helps both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy; FcεR1γ expressed by nociceptors.
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http://dx.doi.org/10.1016/j.jaci.2020.12.644DOI Listing
January 2021

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

Plasma Levels of Proresolving and Prophlogistic Lipid Mediators: Association With Severity of Respiratory Failure and Mortality in Acute Respiratory Distress Syndrome.

Crit Care Explor 2020 Oct 12;2(10):e0241. Epub 2020 Oct 12.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA.

Objectives: Acute respiratory distress syndrome is characterized by an overly exuberant inflammatory state in the lung. Specialized proresolving mediators are endogenous agonists for the resolution of lung inflammation and injury in health, yet their association with acute respiratory distress syndrome severity and outcomes remains to be defined. In the current study, we investigate associations between plasma levels of specialized proresolving mediators and acute respiratory distress syndrome severity and mortality.

Design: Translational pilot study nested within a large prospective cohort of patients with risk factors for acute respiratory distress syndrome.

Setting: ICU from a large medical center.

Patients: Twenty-six Caucasian patients with acute respiratory distress syndrome and available plasma from early in critical illness.

Interventions: None.

Measurements And Main Results: Here, in samples from 26 acute respiratory distress syndrome patients, we examined plasma levels of select specialized proresolving mediators that promote lung injury resolution in preclinical systems, namely lipoxin A and maresin 1, and select prophlogistic lipid mediators linked to acute respiratory distress syndrome pathogenesis, namely cysteinyl leukotrienes and thromboxane B. These mediators were detected by sensitive enzyme-linked immunosorbent assay: lipoxin A (assay range) (8.2-5,000 pg/mL), maresin 1 (7.8-1,000 pg/mL), cysteinyl leukotrienes (7.8-1,000 pg/mL), and thromboxane B (15.6-2,000 pg/mL). Lower plasma levels of specialized proresolving mediators were associated with increased duration of ventilatory support and ICU length of stay. Even in this small sample size, trends were evident for increased cysteinyl leukotrienes to specialized proresolving mediator ratios (cysteinyl leukotrienes/maresin 1 and cysteinyl leukotrienes/lipoxin A) in acute respiratory distress syndrome nonsurvivors.

Conclusions: Lower specialized proresolving mediator levels in acute respiratory distress syndrome patients may disrupt timely resolution of lung inflammation and/or injury and contribute to clinical severity and mortality.
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http://dx.doi.org/10.1097/CCE.0000000000000241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553505PMC
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

Parroting Lymphoma.

N Engl J Med 2020 10;383(14):1376-1381

From the Departments of Medicine (J.D.A., V.T.H., B.D.L., J.L.) and Pathology (K.T.W.), Brigham and Women's Hospital, Boston.

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http://dx.doi.org/10.1056/NEJMcps1915728DOI Listing
October 2020

Fully-automated and field-deployable blood leukocyte separation platform using multi-dimensional double spiral (MDDS) inertial microfluidics.

Lab Chip 2020 09;20(19):3612-3624

Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA and Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

A fully-automated and portable leukocyte separation platform was developed based on a new type of inertial microfluidic device, multi-dimensional double spiral (MDDS) device, as an alternative to centrifugation. By combining key innovations in inertial microfluidic device designs and check-valve-based recirculation processes, highly purified and concentrated WBCs (up to >99.99% RBC removal, ∼80% WBC recovery, >85% WBC purity, and ∼12-fold concentrated WBCs compared to the input sample) were achieved in less than 5 minutes, with high reliability and repeatability (coefficient of variation, CV < 5%). Using this, one can harvest up to 0.4 million of intact WBCs from 50 μL of human peripheral blood (50 μL), without any cell damage or phenotypic changes in a fully-automated operation. Alternatively, hand-powered operation is demonstrated with comparable separation efficiency and speed, which eliminates the need for electricity altogether for truly field-friendly sample preparation. The proposed platform is therefore highly deployable for various point-of-care applications, including bedside assessment of the host immune response and blood sample processing in resource-limited environments.
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http://dx.doi.org/10.1039/d0lc00675kDOI Listing
September 2020

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19.

bioRxiv 2020 Sep 2. Epub 2020 Sep 2.

A recent estimate suggests that one in five deaths globally are associated with sepsis . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity and our lack of insight into sepsis immunopathology . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.
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http://dx.doi.org/10.1101/2020.09.02.280180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480031PMC
September 2020

The Atlas of Inflammation Resolution (AIR).

Mol Aspects Med 2020 08 3;74:100894. Epub 2020 Sep 3.

Department of Systems Biology and Bioinformatics, University of Rostock, 18051, Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa. Electronic address:

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.
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http://dx.doi.org/10.1016/j.mam.2020.100894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733955PMC
August 2020

WITHDRAWN: The Atlas of Inflammation Resolution (AIR).

Mol Aspects Med 2020 Aug 29:100893. Epub 2020 Aug 29.

Department of Systems Biology and Bioinformatics, University of Rostock, 18051, Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa. Electronic address:

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http://dx.doi.org/10.1016/j.mam.2020.100893DOI Listing
August 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

Human NK Cell Cytoskeletal Dynamics and Cytotoxicity Are Regulated by LIM Kinase.

J Immunol 2020 Aug 8;205(3):801-810. Epub 2020 Jul 8.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

NK cells provide immune surveillance and host protection against viruses and tumors through their cytotoxic effector function. Cytoskeletal rearrangement is necessary for NK cell lytic granule trafficking and immune synapse formation to trigger apoptosis of targeted cells. LIM kinase (LIMK) regulates F-actin remodeling by phosphorylating cofilin to inhibit actin severing and depolymerization. In this study, in human NK cells, the glucocorticoid dexamethasone downregulated LIMK expression, F-actin accumulation at the immune synapse, lytic granule trafficking, and cytotoxicity. In contrast, the specialized proresolving mediator lipoxin A promoted NK cell LIMK expression, lytic granule polarization to the immune synapse and cytotoxicity. Using a LIMK inhibitor, we show that LIMK activity is necessary for NK cell cytotoxicity, including lipoxin A's proresolving actions. Together, our findings identify LIMK as an important control mechanism for NK cell cytoskeletal rearrangement that is differentially regulated by glucocorticoids and specialized proresolving mediators to influence NK cell cytotoxicity.
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http://dx.doi.org/10.4049/jimmunol.2000186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391245PMC
August 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

Life at the Editorial "COVID Frontline". The American Thoracic Society Journal Family.

Am J Respir Crit Care Med 2020 06;201(12):1457-1459

National Heart and Lung Institute Imperial College London London, United Kingdom.

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http://dx.doi.org/10.1164/rccm.202005-1516EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301742PMC
June 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

Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care: NHLBI Working Group Report.

Am J Respir Crit Care Med 2020 Mar 9. Epub 2020 Mar 9.

NHLBI, 35035, Division of Lung Diseases, Bethesda, Maryland, United States;

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.
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http://dx.doi.org/10.1164/rccm.201908-1595WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427373PMC
March 2020

An immune-cell signature of bacterial sepsis.

Nat Med 2020 03 17;26(3):333-340. Epub 2020 Feb 17.

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

Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14 monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n = 1,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.
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http://dx.doi.org/10.1038/s41591-020-0752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235950PMC
March 2020

Vagal sensory neurons drive mucous cell metaplasia.

J Allergy Clin Immunol 2020 06 16;145(6):1693-1696.e4. Epub 2020 Jan 16.

FM Kirby Neurobiology Center, Children's Hospital Boston, Boston, Mass; Department of Neurobiology, Harvard Medical School, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.01.003DOI Listing
June 2020

Leukocyte function assessed via serial microlitre sampling of peripheral blood from sepsis patients correlates with disease severity.

Nat Biomed Eng 2019 12 11;3(12):961-973. Epub 2019 Nov 11.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Dysregulated leukocyte responses underlie the pathobiology of sepsis, which is a leading cause of death. However, measures of leukocyte function are not routinely available in clinical care. Here we report the development and testing of an inertial microfluidic system for the label-free isolation and downstream functional assessment of leukocytes from 50 μl of peripheral blood. We used the system to assess leukocyte phenotype and function in serial samples from 18 hospitalized patients with sepsis and 10 healthy subjects. The sepsis samples had significantly higher levels of CD16 and CD16 neutrophils and CD16 'intermediate' monocytes, as well as significantly lower levels of neutrophil-elastase release, O production and phagolysosome formation. Repeated sampling of sepsis patients over 7 days showed that leukocyte activation (measured by isodielectric separation) and leukocyte phenotype and function were significantly more predictive of the clinical course than complete-blood-count parameters. We conclude that the serial assessment of leukocyte function in microlitre blood volumes is feasible and that it provides significantly more prognostic information than leukocyte counting.
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http://dx.doi.org/10.1038/s41551-019-0473-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899180PMC
December 2019

Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes.

J Allergy Clin Immunol 2020 01 14;145(1):335-344. Epub 2019 Oct 14.

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Electronic address:

Background: Cysteinyl leukotrienes (CysLTs) are potent prophlogistic mediators in asthmatic patients; however, inhibition of CysLT receptor 1 is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators (LMs) derived from docosahexaenoic acid, namely maresin conjugates in tissue regeneration (MCTRs), were recently discovered. Therefore their production and actions in the lung are of considerable interest.

Objective: We sought to determine MCTR production, bioactions, and mechanisms in the human lung and in patients with experimental allergic airway inflammation.

Methods: LM metabololipidomic profiling of the lung was performed by using liquid chromatography with tandem mass spectrometry. Donor-derived human precision-cut lung slices were exposed to leukotriene (LT) D, MCTRs, or both before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in the setting of ovalbumin- and house dust mite-induced lung inflammation.

Results: Lipidomic profiling showed that the most abundant cysteinyl LMs in healthy human lungs were MCTRs, whereas CysLTs were most prevalent in patients with disease. MCTRs blocked LTD-initiated airway contraction in human precision-cut lung slices. In mouse allergic lung inflammation MCTRs were present with temporally regulated production. With ovalbumin-induced inflammation, MCTR1 was most potent for promoting resolution of eosinophils, and MCTR3 potently decreased airway hyperreactivity to methacholine, bronchoalveolar lavage fluid albumin, and serum IgE levels. MCTR1 and MCTR3 inhibited lung eosinophilia after house dust mite-induced inflammation.

Conclusion: These results identified lung MCTRs that blocked human LTD-induced airway contraction and promoted resolution of murine allergic airway responses when added exogenously. Together, these findings uncover proresolving mechanisms for lung responses that can be disrupted in patients with disease.
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http://dx.doi.org/10.1016/j.jaci.2019.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308163PMC
January 2020

Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.

Immunity 2019 10 8;51(4):709-723.e6. Epub 2019 Oct 8.

Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.
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http://dx.doi.org/10.1016/j.immuni.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076585PMC
October 2019

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

The Element of Surprise.

N Engl J Med 2019 10;381(14):1365-1371

From the Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcps1811547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029838PMC
October 2019

A Model of Self-limited Acute Lung Injury by Unilateral Intra-bronchial Acid Instillation.

J Vis Exp 2019 08 30(150). Epub 2019 Aug 30.

Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School;

Selective intra-bronchial instillation of hydrochloric acid (HCl) to the murine left mainstem bronchus causes acute tissue injury with histopathologic findings similar to human acute respiratory distress syndrome (ARDS). The resulting alveolar edema, alveolar-capillary barrier damage, and leukocyte infiltration predominantly affect the left lung, preserving the right lung as an uninjured control and allowing animals to survive. This model of self-limited acute lung injury enables investigation of tissue resolution mechanisms, such as macrophage efferocytosis of apoptotic neutrophils and restitution of alveolar-capillary barrier integrity. This model has helped identify important roles for resolution agonists, including specialized pro-resolving mediators (SPMs), providing a foundation for the development of new therapeutic approaches for patients with ARDS.
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http://dx.doi.org/10.3791/60024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236023PMC
August 2019

Estimated Ventricular Size, Asthma Severity, and Exacerbations: The Severe Asthma Research Program III Cohort.

Chest 2020 02 12;157(2):258-267. Epub 2019 Sep 12.

Applied Chest Imaging Laboratory, Brigham and Women's Hospital, Boston, MA.

Background: Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size.

Methods: We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression.

Results: Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations.

Conclusions: In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations.

Trial Registry: ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2019.08.2185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005378PMC
February 2020

The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

Eur Respir J 2019 10 24;54(4). Epub 2019 Oct 24.

Channing Division of Network Medicine, Dept of Medicine, Brigham and Women's Hospital, Boston, MA, USA

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (β 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interaction=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze alterations of sphingolipid metabolism dependent on the 17q21 genotype.
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http://dx.doi.org/10.1183/13993003.00761-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181456PMC
October 2019

Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma.

Am J Respir Crit Care Med 2019 05;199(9):1076-1085

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.

Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation. We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase. We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all values <0.001). In studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase. High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.
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http://dx.doi.org/10.1164/rccm.201810-1869OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515873PMC
May 2019

Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma.

Am J Respir Crit Care Med 2019 06;199(11):1358-1367

14 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Corticosteroids (CSs) are the most effective asthma therapy, but responses are heterogeneous and systemic CSs lead to long-term side effects. Therefore, an improved understanding of the contributing factors in CS responses could enhance precision management. Although several factors have been associated with CS responsiveness, no integrated/cluster approach has yet been undertaken to identify differential CS responses. To identify asthma subphenotypes with differential responses to CS treatment using an unsupervised multiview learning approach. Multiple-kernel -means clustering was applied to 100 clinical, physiological, inflammatory, and demographic variables from 346 adult participants with asthma in the Severe Asthma Research Program with paired (before and 2-3 weeks after triamcinolone administration) sputum data. Machine-learning techniques were used to select the top baseline variables that predicted cluster assignment for a new patient. Multiple-kernel clustering revealed four clusters of individuals with asthma and different CS responses. Clusters 1 and 2 consisted of young, modestly CS-responsive individuals with allergic asthma and relatively normal lung function, separated by contrasting sputum neutrophil and macrophage percentages after CS treatment. The subjects in cluster 3 had late-onset asthma and low lung function, high baseline eosinophilia, and the greatest CS responsiveness. Cluster 4 consisted primarily of young, obese females with severe airflow limitation, little eosinophilic inflammation, and the least CS responsiveness. The top 12 baseline variables were identified, and the clusters were validated using an independent Severe Asthma Research Program test set. Our machine learning-based approaches provide new insights into the mechanisms of CS responsiveness in asthma, with the potential to improve disease treatment.
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http://dx.doi.org/10.1164/rccm.201808-1543OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543720PMC
June 2019