Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma

Exhaled nitric oxide (Fe(NO)) is a biomarker of airway inflammation in mild to moderate asthma. However, whether Fe(NO) levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classifica...

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Published in	American journal of respiratory and critical care medicine Vol. 181; no. 10; pp. 1033 - 1041
Main Authors	Dweik, Raed A., Sorkness, Ronald L., Wenzel, Sally, Hammel, Jeffrey, Curran-Everett, Douglas, Comhair, Suzy A. A., Bleecker, Eugene, Busse, William, Calhoun, William J., Castro, Mario, Chung, Kian Fan, Israel, Elliot, Jarjour, Nizar, Moore, Wendy, Peters, Stephen, Teague, Gerald, Gaston, Benjamin, Erzurum, Serpil C.
Format	Journal Article
Language	English
Published	New York, NY American Thoracic Society 15.05.2010
Subjects	A. Asthma and Allergy Adrenal Cortex Hormones - therapeutic use Adult Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Asthma Asthma - diagnosis Asthma - drug therapy Asthma - metabolism Asthma - physiopathology Biological and medical sciences Biomarkers - analysis Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis Breath Tests Classification Female Forced Expiratory Volume Genotype & phenotype Humans Inflammation Intensive care medicine Logistic Models Male Medical sciences Multivariate Analysis Nitric oxide Nitric Oxide - analysis Nitric Oxide - metabolism Phenotype Respiratory Function Tests Severity of Illness Index Skin Tests Spirometry Steroids Transfusions. Complications. Transfusion reactions. Cell and gene therapy Human Lung disease Intensive care Respiratory disease exhaled breath Asthma airway reactivity Phenotype Nitric oxide Risk factor severe asthma Bronchus disease Obstructive pulmonary disease Resuscitation
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ISSN	1073-449X 1535-4970 1535-4970
DOI	10.1164/rccm.200905-0695OC

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Summary:	Exhaled nitric oxide (Fe(NO)) is a biomarker of airway inflammation in mild to moderate asthma. However, whether Fe(NO) levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by Fe(NO) levels would identify a more reactive, at-risk asthma phenotype. Fe(NO) and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 non-severe) and 49 healthy subjects enrolled in the Severe Asthma Research Program. Fe(NO) levels were similar among patients with severe and non-severe asthma. The proportion of individuals with high Fe(NO) levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high Fe(NO) had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High Fe(NO) identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care. Grouping of asthma by Fe(NO) provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conflict of Interest Statement: R.A.D. received more than $100,001 from Actelion, more than $100,001 from Gilead, and more than $100,001 from Novartis in industry-sponsored grants. R.L.S. received up to $1,000 from Synairgen in consultancy fees, and more than $100,001 from Modus Biological Membranes in industry-sponsored grants. The spouse/life partner of R.L.S. received $5,001–$10,000 from GlaxoSmithKline in advisory board fees, and $5,001–$10,000 from GlaxoSmithKline and $1,001–$5,000 from AstraZeneca in lecture fees. S.W. received $1,001–$5,000 from Amgen, $10,001–$50,000 from GlaxoSmithKline, $1,001–$5,000 from Wyeth, and $1,001–$5,000 from Genentech in consultancy fees; $1,001–$5,000 from GlaxoSmithKline, $10,001–$50,000 from Amira, $10,001–$50,000 from Epigenesis, and $5,001–$10,000 from Novartis in advisory board fees; $1,001–$5,000 from Critical Therapeutics and $1,001–$5,000 from Genentech in lecture fees; $50,001–$100,000 from GlaxoSmithKline, $5,001–$10,000 from Amgen, $10,001–$50,000 from MedImmune, $50,001–$100,000 from Ception, and $10,001–$50,000 from Aerovance in industry-sponsored grants; and holds stock ownership or options in Amira and Epigenesis. J.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.C.-E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.A.A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.B. received up to $1,000 from Alexion, $1,001–$5,000 from AstraZeneca, $1,001–$5,000 from Boehringer Ingelheim, up to $1,000 from Dainippon–Sumitomo, up to $1,000 from Funxional Therapeutics, Ltd., $1,001–$5,000 from Novartis, and $1,001–$5,000 from TEVA in consultancy fees; $1,001–$5,000 from Altair, $1,001–$5,000 from Amgen, $1,001–$5,000 from Abbott Laboratories, $1,001–$5,000 from Asthmatx, Inc., $1,001–$5,000 from Bristol–Meyers Squib, $1,001–$5,000 from Centocor, up to $1,000 from Genentech, up to $1,000 from GlaxoSmithKline, $1,001–$5,000 from Merck, $1,001–$5,000 from Schering Plough, $1,001–$5,000 from Pfizer, and $1,001–$5,000 from Wyeth in advisory board fees; $1,001–$5,000 from Merck in lecture fees; and $10,001–$50,000 from Novartis, $5,001–$10,000 from Centocor, more than $100,001 from GlaxoSmithKline, more than $100,001 from MedImmune, and $50,001–$100,000 from Ception in industry–sponsored grants. W.J.C. received $10,001–$50,000 from AstraZeneca and $5,001–$10,000 from Sepracor in consultancy fees, and $5,001–$10,000 from Merck in advisory board fees. M.C. received $10,001–$50,000 from Asthmatx, $1,001–$5,000 from Schering, $1,001–$5,000 from Electrocore, and $1,001–$5,000 from BMS in consultancy fees; $5,001–$10,000 Genentech in advisory board fees; $50,001–$100,000 from AstraZeneca, $10,001–$50,000 from Boehringer Ingelheim, $10,001–$50,000 from Pfizer, $5,001–$10,000 from Genentech, and $5,001–$10,000 from Merck in lecture fees; more than $100,001 from Asthmatx, more than $100,001 from Amgen, more than $100,001 from Centocor, more than $100,001 from Ception, and more than $100,001 from GlaxoSmithKline in industry-sponsored grants; $1,001–$5,000 from Elsevier in royalties; and $10,001–$50,000 from Pfizer, more than $100,001 from Genentech, more than $100,001 from MedImmune, more than $100,001 from Merck, and more than $100,001 from Novartis in contracted research. K.F.C. received $1,001–$5,000 from Gilead for ad hoc consulting; $1,001–$5,000 from GlaxoSmithKline, $1,001–$5,000 from Chiesi, $1,001–$5,000 from Merck, and $1,001–$5,000 from Boehringer Ingelheim for serving on an advisory board; $1,001–$5,000 from AstraZeneca, $1,001–$5,000 from GlaxoSmithKline, and $1,001–$5,000 from Chiesi in nonpromotional lecture fees; $10,001–$50,000 from Novartis for a phase 3 clinical trial, $1,001–$5,000 from Schering Plough for a phase 3 clinical trial, $1,001–$5,000 from AstraZeneca for phase 3 research, and $50,001–$100,000 from GlaxoSmithKline (collaborative) in industry-sponsored grants; and holds a patent from Imperial Innovations on use of p38 MAPK inhibitors to reverse corticosteroid resistance in airway disease. E.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.J. received $10,001–$50,000 from Asthmatx for review of CT scans, concept discussions, and advisory group meetings; $1,001–$5,000 from GlaxoSmithKline and $1,001–$5,000 from Genentech in advisory board fees; $1,001–$5,000 from Merck and Co. in lecture fees; and more than $100,001 from GlaxoSmithKline and more than $100,001 from Genentech in industry-sponsored grants. W.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.T. received $10,001–$50,000 from Merck and Co. and up to $1,000 from Aerocrine in lecture fees. The B.G. laboratory received up to $1,000 from Galleon in consultancy fees, more than $100,001 from Galleon in industry-sponsored grants, and more than $100,001 from the NIH in sponsored grants; $1,001–$5,000 from Williams and Connelly as an expert witness; holds patents from Galleon (for control of breathing: therapy), Respiratory Research (for breath condensate analysis), Airbase (for asthma treatment), and N30 (for asthma and CF treatment); and has received $5,001–$10,000 from Respiratory Research in royalties. S.C.E. received more than $100,001 from Asthmatx as an investigator in industry-sponsored grants. Supported by HL69170, AI70649, HL04265, HL68863, HL69116, HL69174, HL69167, HL069155, HL69130, HL69149, HL69170, HL069349, ACRN U10HL74225, P01/U01HL67663, and P01/U01 HL67663; by a Third Frontier grant (TECH09-003) from the Ohio Department of Development; and by M01 RR018390 from the National Center for Research Resources. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200905-0695OC on February 4, 2010 A list of contributors can be found at the end of the article. The Severe Asthma Research Program (SARP) is a multicenter asthma research group funded by the NHLBI and consisting of the following contributors (Steering Committee members are marked with an asterisk): Brigham and Women's Hospital, Boston, MA—Elliot Israel,* Bruce D. Levy, Gautham Marigowda; Cleveland Clinic, Cleveland, OH—Serpil C. Erzurum,* Raed A. Dweik, Suzy A. A. Comhair, Marcelle Baaklini, Daniel Laskowski, Jacqueline Pyle; Emory University, Atlanta, GA—W. Gerald Teague,* Anne M. Fitzpatrick, Eric Hunter; Imperial College School of Medicine, London, UK—Kian F. Chung,* Mark Hew, Alfonso Torrego, Sally Meah, Mun Lim; National Jewish Medical and Research Center, Denver, CO—Sally E. Wenzel,* Diane Rhodes; University of Pittsburgh, Pittsburgh, PA—William J. Calhoun,* Melissa P. Clark, Renee Folger, Rebecca Z. Wade; Bill T. Ameredes, Dori Smith; University of Virginia, Charlottesville, VA—Benjamin Gaston,* Peter Urban; University of Wisconsin, Madison, WI—William W. Busse,* Nizar Jarjour, Erin Billmeyer, Ronald L. Sorkness, Cheri Swenson, Gina Crisafi; Wake Forest University, Winston-Salem, NC—Eugene R. Bleecker,* Deborah Meyers, Wendy Moore, Stephen Peters, Annette Hastie, Gregory Hawkins, Jeffrey Krings, Regina Smith; Washington University in St. Louis, St. Louis, MO—Mario Castro,* Leonard Bacharier, Iftikhar Hussain, Jaime Tarsi; Data Coordinating Center, Denver, CO—James R. Murphy,* Douglas Curran-Everett; NHLBI, Bethesda, MD—Patricia Noel.
ISSN:	1073-449X 1535-4970 1535-4970
DOI:	10.1164/rccm.200905-0695OC