Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children

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Abstract

Background

Exhaled nitric oxide (eNO) is a noninvasive test that measures airway inflammation. Insufficient information is available concerning correlations between eNO and biologic, physiologic, and clinical characteristics of asthma in children currently not taking controller medications.

Objective

The aim of this study was to find correlations between eNO and other characteristics of children with mild to moderate asthma currently not taking medications.

Methods

Children aged 6 to 17 years with mild to moderate persistent asthma, taking only albuterol as needed, were characterized during 2 visits 1 week apart before being randomly assigned into a clinical trial. At the screening visit, online measurements of eNO, spirometry before and after bronchodilator, and biomarkers of peripheral blood eosinophils, serum eosinophil cationic protein, total serum IgE, and urinary leukotriene E4 were obtained. During a week characterization period before randomization, symptoms were recorded on a diary and peak expiratory flows were measured twice daily using an electronic device. At the randomization visit, eNO was repeated followed by a methacholine challenge and aeroallergen skin testing. Correlations and rank regression analyses between eNO and clinical characteristics, pulmonary function, and biomarkers were evaluated.

Results

eNO was significantly correlated with peripheral blood eosinophils (r = .51, P < .0001), IgE (r = .48, P < .0001), and serum eosinophil cationic protein (r = .31, P = .0003) but not with urinary leukotriene E4 (r = .16, P = .08). A moderate correlation was found between eNO and the number of positive aeroallergen skin tests (r = .45, P < .0001). eNO did not correlate with FEV1 % predicted but was weakly correlated with FEV1/forced vital capacity (r = −.19, P = .032), bronchodilator response (r = .20, P = .023), and FEV1 PC20 methacholine (r = −.31, P = .0005). No significant correlations were found between eNO and clinical characteristics or morning or evening peak expiratory flow measurements. The rank regression analysis demonstrated that 5 variables accounted for an R square of .52 (eosinophils [P < .0001], IgE [P = .0023], age [P < .0001], months of inhaled corticosteroid use in the year before study entry [P = .01], and FEV1 PC20 [P = .0061]).

Conclusions

These findings suggest that eNO provides information about the asthmatic state consistent with information from other markers of inflammation. It is a noninvasive technique that could be used in decisional management of children with asthma.

Section snippets

Study population

Participants aged 6 to less than 18 years were successfully screened, characterized, and randomly assigned into the clinical trial, Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid (CLIC), at the 5 clinical centers of the Childhood Asthma Research and Education (CARE) Network funded by the National Heart, Lung, and Blood Institute (NHLBI). CLIC was designed to determine characteristics of children with asthma who had favorable responses to both a

Demographics and lung function results

Demographic characteristics and lung function results obtained during screening of the children entered into the trial are shown in Table II. The 144 participants had a mean age of 11 years, with 41% females and 48% minorities. Forty-one percent had used a controller medication, and 28% had used an ICS for a mean of 2.5 ± 3.5 months in the 12 months before entry but not in the last month before trial enrollment. Spirometry results at baseline demonstrated values for FVC and FEV1% predicted

Discussion

Although there have been many studies of eNO in asthma, the group of children enrolled in the CLIC trial offers several advantages in further defining the role of eNO in assessing asthma control and airway inflammation. The 144 children have mild to moderate persistent asthma clinically and by pulmonary function criteria (Table II) but differ from other groups of children in whom eNO has been studied in that they had not received oral or inhaled corticosteroids for at least 1 month and no other

Clinical centers

National Jewish Medical and Research Center, Denver: Stanley J. Szefler, MD (Principal Investigator); Gary Larsen, MD (Co-Investigator); Joseph Spahn, MD (Co-Investigator); Ronina Covar, MD (Co-Investigator); Andrew Liu, MD (Co-Investigator); D Sundström (Coordinator); Amy Grumann, RN (Coordinator); Melanie Phillips (Coordinator); Michael White (Research Assistant).

University of Wisconsin, Clinical Science Center, Madison: Robert F. Lemanske Jr, MD (Principal Investigator); Christine A.

Resource centers

Chair's Office, National Jewish Medical and Research Center, Denver: Lynn M. Taussig, MD (Study Chair).

Project Office, National Heart, Lung and Blood Institute, Bethesda: James Kiley, PhD (Director of the NHLBI Division of Lung Diseases); Virginia Taggart, MPH (NHLBI Project Scientist); Gail Weinmann, MD (Executive Secretary, Data Safety Monitoring Board); Gang Zeng, PhD.

Data Coordinating Center, Penn State University College of Medicine, Hershey: Vernon M. Chinchilli, PhD (Principal

Committees

Data and Safety Monitoring Board: Thomas F. Boat, MD (Chair), Children's Hospital Medical Center, Cincinnati; William C. Bailey, MD, The University of Alabama at Birmingham; Mary Kay Garcia, PhD, RN, CPNP; Carolyn M. Kercsmar, MD, Case Western Reserve University, Cleveland; H. William Kelly, PharmD, University of New Mexico Health Sciences Center, Albuquerque; Lester Lyndon Key Jr, MD, Medical University of South Carolina, Charleston; James Tonascia, PhD, Johns Hopkins University, Baltimore;

Pharmaceutical suppliers

GlaxoSmithKline, Inc, Research Triangle Park, NC; Merck & Co, Inc, West Point, Pa.

Equipment support

Lincoln Diagnostics (Multi-Test II kits), Decatur, Ill; Monaghan Medical (Aerochamber and masks), Plattsburgh, NY; MEMS, Medication Event MonitoringSystems, AARDEX, Zug, Switzerland; Aerocrine, Incorporated, Chicago, Ill; VIASYS Healthcare GmbH, Hoechberg, Germany.

References (47)

  • B Horn et al.

    Total eosinophil counts in the management of bronchial asthma

    N Engl J Med

    (1975)
  • F Lowell

    The total eosinophil count in obstructive pulmonary disease: editorial

    N Engl J Med

    (1975)
  • SA Little et al.

    Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma

    Thorax

    (2000)
  • JK Sont et al.

    Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group

    Am J Respir Crit Care Med.

    (1999)
  • R Green et al.

    Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial

    Lancet

    (2002)
  • SJ Szefler et al.

    Significant variability in response to inhaled corticosteroids for persistent asthma

    J Allergy Clin Immunol

    (2002)
  • SL Jones et al.

    The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control

    Am J Respir Crit Care Med

    (2001)
  • F Buchvald et al.

    FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr.

    Am J Respir Crit Care Med.

    (2001)
  • J Hunt et al.

    Airway nitrogen oxide measurements in asthma and other pediatric respiratory diseases

    J Pediatr

    (2000)
  • R Covar et al.

    Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma

    J Pediatr

    (2003)
  • S Kharitonov et al.

    Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients

    Eur Respir J

    (1996)
  • Program for Childhood Asthma Management Program spirometry manual. Version 3.0. National Technical Information Service;...
  • American Thoracic Society

    Standardization of spirometry, 1994 update

    Am J Respir Crit Care Med

    (1995)
  • H Eigen et al.

    Spirometric pulmonary function in healthy preschool children

    Am J Respir Crit Care Med

    (2001)
  • Program for Childhood Asthma Management Program for methacholine challenge testing, Version 3.0. National Technical...
  • R Crapo et al.

    Guidelines for methacholine and exercise challenge testing-1999

    This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med

    (2000)
  • American Thoracic Society

    Recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999

    Am J Respir Crit Care Med

    (1999)
  • J Westcott et al.

    Immunoaffinity resin for purification of urinary leukotriene E4

    Lipid Mediators

    (1998)
  • Program for Childhood Asthma Management Program allergy and skin test manual, Version 2.0. National Technical...
  • H Mitchell et al.

    Design and methods of the National Cooperative Inner-City Asthma Study

    Pediatr Pulmonol

    (1997)
  • X Wang et al.

    Pulmonary function between 6 and 18 years of age

    Pediatr Pulmonol

    (1993)
  • PJ Franklin et al.

    A community study of exhaled nitric oxide in healthy children

    Am J Respir Crit Care Med

    (1999)
  • DL Bratton et al.

    Exhaled nitric oxide before and after montelukast sodium therapy in school-age children with chronic asthma: a preliminary study

    Pediatr Pulmonol

    (1999)
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    Supported by Grants 5U10HL064287, 5U10HL064288, 5U10HL064295, 5U10HL064307, 5U10HL064305 from the National Heart, Lung, and Blood Institute.

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