Elsevier

The Lancet

Volume 372, Issue 9643, 20–26 September 2008, Pages 1065-1072
The Lancet

Articles
Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(08)61448-8Get rights and content

Summary

Background

Preliminary evidence is equivocal about the role of exhaled nitric oxide (NO) in clinical asthma management. We aimed to assess whether measurement of exhaled NO, as a biomarker of airway inflammation, could increase the effectiveness of asthma treatment, when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults.

Methods

We did a randomised, double-blind, parallel-group trial at ten centres in the USA. We screened 780 inner-city patients, aged 12–20 years, who had persistent asthma. All patients completed a run-in period of 3 weeks on a regimen based on standard treatment. 546 eligible participants who adhered to treatment during this run-in period were then randomly assigned to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO. The primary outcome was the number of days with asthma symptoms. We analysed patients on an intention-to-treat basis. This trial is registered with clinicaltrials.gov, number NCT00114413.

Findings

During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups (1·93 [95% CI 1·74 to 2·11] in the NO monitoring group vs 1·89 [1·71 to 2·07] in the control group; difference 0·04 [−0·22 to 0·29], p=0·780). Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids (difference 119 μg per day, 95% CI 49 to 189, p=0·001) than controls. Adverse events did not differ between treatment groups (p>0·1 for all adverse events).

Interpretation

Conventional asthma management resulted in good control of symptoms in most participants. The addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids, without clinically important improvements in symptomatic asthma control.

Funding

US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Introduction

Asthma is a complex respiratory disorder that is characterised by variable and recurring symptoms, airflow obstruction, and underlying airway inflammation. In 2007, the US National Heart, Lung and Blood Institute (NHLBI) updated its Guidelines for the Diagnosis and Management of Asthma,1, 2 and proposed that treatment to achieve asthma control should aim both to regulate the manifestations of impairment (ie, symptoms, need for rescue treatment, limitations of activity, and pulmonary function) and to reduce future risk.

Asthma symptoms and exacerbations are theoretically linked to underlying inflammation of airways, but are not direct indicators of inflammation. Measurement of biomarkers that are more closely associated with airway inflammation could improve asthma control by enabling treatment to be better directed. One such marker of airway inflammation is the fraction of exhaled nitric oxide (NO),3 which has been shown to increase during periods of uncontrolled asthma4, 5, 6, 7, 8, 9, 10, 11, 12 and decrease during treatment with anti-inflammatory agents.13, 14, 15, 16, 17, 18, 19, 20, 21 Previous trials have assessed the use of fraction of exhaled NO as an alternative to conventional modification of treatment based on symptoms and pulmonary function.22, 23, 24, 25 However, in practice, clinicians would be more likely to monitor exhaled NO as an additional way to monitor airway inflammation, rather than as a replacement. Therefore, we believe that a clinically more relevant question is whether the addition of NO monitoring to guideline-based management can improve management of asthma. We aimed to assess the effectiveness of measurement of fraction of exhaled NO as an adjunct to guideline-directed management of asthma in a population of inner-city adolescents and young adults who were characterised by high levels of atopy, allergen exposure, and poor asthma control.26, 27, 28, 29, 30

Section snippets

Participants

We designed a randomised, double-blind, parallel-group trial at ten centres in cities across the USA. We initially screened participants on the basis of census tracts. Each census tract had between 2500 and 8000 people and was designed to be homogeneous with respect to population characteristics, economic status, and living conditions. We restricted eligibility to residents of urban census tracts in which at least 20% of households had incomes below the federal poverty threshold. Eligible

Results

Between September, 2004, and December, 2005, we screened 780 patients and excluded 234 who refused consent, did not adhere to treatment during the run-in period, or were active smokers (figure 1). The mean age of the 546 patients who were enrolled and randomly assigned was 14·4 years (IQR 13–16). At enrolment, 422 (77%) of the 546 participants did not have good control of their asthma symptoms (control level >1). 313 (57%) of the 546 participants were assessed to have control levels of 3 or 4,

Discussion

We sought to determine whether measurement of fraction of exhaled NO added value to commonly used control measures for asthma treatment based on national guidelines.1, 2 Whereas other studies on fraction of exhaled NO have typically replaced usual measures of symptoms and pulmonary function with NO as the basis for determining asthma treatment, we aimed to assess its use in combination with standard symptom-based approaches to treatment. We showed that use of current guidelines for asthma

References (38)

  • R Evans et al.

    A randomized clinical trial to reduce asthma morbidity among inner-city children: results of the National Cooperative Inner-City Asthma Study

    J Pediatr

    (1999)
  • M Maniscalco et al.

    Exhaled nitric oxide in severe obesity: effect of weight loss

    Respir Physiol Neurobiol

    (2007)
  • Expert Panel Report 3: Guidelines for the diagnosis and management of asthma

    (2007)
  • Expert Panel Report 3 (EPR-3): Guidelines for the diagnosis and management of asthma-summary report 2007

    J Allergy Clin Immunol

    (2007)
  • AF Massaro et al.

    Expired nitric oxide levels during treatment of acute asthma

    Am J Respir Crit Care Med

    (1995)
  • RG Stirling et al.

    Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group

    Thorax

    (1998)
  • SE Crater et al.

    Expired nitric oxide and airway obstruction in asthma patients with an acute exacerbation

    Am J Respir Crit Care Med

    (1999)
  • 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)
  • I Meyts et al.

    Exhaled nitric oxide corresponds with office evaluation of asthma control

    Pediatr Pulmonol

    (2003)
  • Cited by (0)

    View full text