Asthma and lower airway disease
Determinants of exhaled nitric oxide levels in healthy, nonsmoking African American adults

https://doi.org/10.1016/j.jaci.2007.09.031Get rights and content

Background

Asthma is a significant cause of morbidity and mortality for African Americans. Fraction of exhaled nitric oxide (FeNO) levels are increased in patients with asthma, and airway levels of nitric oxide metabolites regulate airway inflammation and airway diameter. More needs to be known about the factors that regulate FeNO. There is a need for FeNO reference values for African Americans.

Objective

We sought to establish reference values and identify factors associated with FeNO levels in healthy African American adults.

Methods

FeNO levels were measured in 895 healthy, nonsmoking African Americans between the ages of 18 and 40 years. FeNO measurements were repeated in 84 subjects. Factors potentially associated with FeNO were measured, including blood pressure, height, weight, and serum total IgE, eosinophil cationic protein, C-reactive protein, and nitrate levels. Data on respiratory symptoms, including upper respiratory tract infection (URI) symptoms, were collected. Univariate and multivariate analyses of the relationship between these variables and FeNO levels were performed.

Results

In healthy, nonsmoking African Americans FeNO levels were stable during repeated measurements (intraclass correlation coefficient, 0.81). Sex (P < .0001), serum total IgE levels (P < .0001), and current URI symptoms (P = .0002) contributed significantly to FeNO variability but together accounted for less than 50% of the variation in FeNO levels.

Conclusion

The high correlation between repeated measurements of FeNO and the low correlation coefficients of known factors associated with FeNO suggest that other factors might contribute substantially to variability of FeNO levels in African Americans.

Section snippets

Subject recruitment and enrollment

Healthy subjects between the ages of 18 and 40 years were recruited from students and employees at 4 local university campuses. The study was originally powered to target an enrollment of 1000 African American subjects (994 were actually enrolled, and 99 were excluded because of smoking; n = 895). Informed consent was obtained as part of a protocol approved by the Duke University Institutional Review Board.

After obtaining informed consent, subjects were asked to provide their birth dates and

Subject characteristics and reproducibility of FeNO measurements

The characteristics of the 895 subjects enrolled in the study are listed in Table I. FeNO measurements were repeated for 84 of these subjects between 5 and 850 days apart (median, 143 days apart). There was an excellent correlation between the first and second FeNO measurements for each subject (intraclass correlation coefficient, 0.81; Fig 1).

Factors associated with variability of FeNO levels

We used univariate analyses to determine the relationship of FeNO levels to the factors listed in Table I. There were significant differences in FeNO

Discussion

We believe that our study represents the largest analysis to date of factors associated with FeNO levels in healthy African Americans. We found significant associations of sex, serum total IgE and ECP levels, and URI symptoms with FeNO levels (Table I, Table II). The modest associations of these factors, which together accounted for less than 50% of the variability in FeNO levels, suggest that other unknown factors might contribute substantially to the variability of FeNO levels. Therefore we

References (58)

  • A.C. Olin et al.

    Height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample

    Chest

    (2006)
  • H. Ohmori et al.

    Selective augmenting effects of nitric oxide on antigen-specific IgE response in mice

    Immunopharmacology

    (2000)
  • S. Rakoff-Nahoum et al.

    Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis

    Cell

    (2004)
  • K.C. Barnes

    Genetic epidemiology of health disparities in allergy and clinical immunology

    J Allergy Clin Immunol

    (2006)
  • R. Xu et al.

    Interleukin-1beta-induced nitric oxide production in rat aortic endothelial cells: inhibition by estradiol in normal and high glucose cultures

    Life Sci

    (1999)
  • S. Saito et al.

    Effects of estrogen on nitric oxide synthase expression in rat aorta allograft and smooth muscle cells

    J Heart Lung Transplant

    (1999)
  • M.R. Hobbs et al.

    A novel NOS2 promoter polymorphism associated with protection from severe malaria in children from Tanzania and Kenya

    Lancet

    (2002)
  • K. Alving et al.

    Increased amount of nitric oxide in exhaled air of asthmatics

    Eur Respir J

    (1993)
  • C.M. Salome et al.

    Exhaled nitric oxide measurements in a population sample of young adults

    Am J Respir Crit Care Med

    (1999)
  • P.J. Franklin et al.

    A community study of exhaled nitric oxide in healthy children

    Am J Respir Crit Care Med

    (1999)
  • M. Azzawi et al.

    Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma

    Am Rev Respir Dis

    (1990)
  • S.A. Kharitonov et al.

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

    Eur Respir J

    (1996)
  • A.D. Smith et al.

    Use of exhaled nitric oxide measurements to guide treatment in chronic asthma

    N Engl J Med

    (2005)
  • R.A. Dweik et al.

    NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response

    Proc Natl Acad Sci U S A

    (2001)
  • L.G. Que et al.

    Protection from experimental asthma by an endogenous bronchodilator

    Science

    (2005)
  • S. Carraro et al.

    S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus

    Am J Physiol Lung Cell Mol Physiol

    (2006)
  • American Thoracic Society et al.

    ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005

    Am J Respir Crit Care Med

    (2005)
  • D.R. Taylor et al.

    Exhaled nitric oxide measurements: clinical application and interpretation

    Thorax

    (2006)
  • O. Sacco et al.

    Total and allergen-specific IgE levels in serum reflect blood eosinophilia and fractional exhaled nitric oxide concentrations but not pulmonary functions in allergic asthmatic children sensitized to house dust mites

    Pediatr Allergy Immunol

    (2003)
  • Cited by (36)

    • Fraction of exhaled nitric oxide in healthy elderly Tunisian subjects

      2015, Nitric Oxide - Biology and Chemistry
      Citation Excerpt :

      Previous studies [8–10,12,13] showed a significant correlation between FeNO values and atopy. For that reason, and as done by other authors [21,34–38], the atopic status of the present study subjects was determined (using questionnaire) and only healthy non-atopic subjects were included. According to Jacinto et al. [15], the methodology of establishing normal FeNO values should be uniform and the formulation of norms should be based on a predetermined physiological model with endogenous and stable factors such as sex, age, and height.

    • The role of fractional exhaled nitric oxide in asthma management

      2014, Otolaryngologic Clinics of North America
    • Reference values and factors associated with exhaled nitric oxide: U.S. youth and adults

      2013, Respiratory Medicine
      Citation Excerpt :

      Gender was an independent predictor in adolescents and adults, but not for the children. Gender has also been widely reported as a determinant of FeNO with higher levels among males compared with females, especially in studies of adults [20,22–25,42,43], however; there are inconsistent results with some studies showing no association of FeNO with gender [19,26,30,35,44]. Height was a significant predictor of FeNO levels in all three age groups, independent of all other covariates, including gender.

    View all citing articles on Scopus

    Supported by the Sandler Program for Asthma Research; ES011185 from the National Institute of Environmental Health Sciences; and MO1-RR-30 from the National Center for Research Resources, Clinical Research Centers Program, National Institutes of Health.

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

    View full text