Predicting Steroid Response Using Exhaled Nitric Oxide
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

Summary: 
      Asthma affects 6% of the UK population and costs the NHS 1 billion pounds per year. £473
      million alone is spent on inhaled steroid treatment which is designed to reduce inflammation
      in the breathing tubes.

      Unfortunately knowing whether a patient is on just the right amount of steroid treatment is
      difficult, as asthma is a variable disease and the measures currently used to decide on
      increasing or decreasing steroid treatment bare little resemblance to the actual amount of
      inflammation present. Doctors may not reduce treatment as swiftly as necessary if a patient's
      asthma is well controlled because of concern over asthma attacks; this can result in
      potential over treatment with inhaled steroids. Although steroid treatment is safe, side
      effects can occur, and costs are large, so a strategy helping avoid over treatment would be
      beneficial both to patients and to the NHS.

      As the investigators can more accurately measure airway inflammation present in the breathing
      tubes, using a chemical called nitric oxide present in a patient's breath, the investigators
      might be able to more accurately predict which patients could safely reduce their steroid
      treatment. Measuring nitric oxide is simple, and involves breathing into a special machine
      (similar to a roadside breathalyser). In this study the investigators will measure nitric
      oxide in patients with well controlled asthma, and reduce their asthma treatment by 50%. The
      investigators will then follow up the patients and remeasure their nitric oxide. At the end
      of the study the investigators will see if measurements of nitric oxide predicted which
      patients could safely step down their treatment. If successful this could help reduce the
      overall cost to the NHS of inhaled steroids and reduce steroid associated side effects.
    

Detailed description: 
      The principal objective is to establish whether a baseline measurement of airway
      inflammation, as measured in exhaled breath, or a variation in this measurement over time,
      can predict which patients can safely step down their asthma treatment without experiencing a
      loss of asthma control.

      This study is designed to show whether a policy utilising measurements of exhaled nitric
      oxide (present in the breath) in guiding asthma treatment will be feasible, and is worth
      testing in a future prospective study.

      The secondary objectives are to establish if this approach is feasible, safe and cost
      effective, when compared to current clinical guidelines.

      Asthma is defined by the presence of symptoms associated with variable airflow obstruction,
      airway inflammation and airway hyperresponsiveness. Inhaled corticosteroids are one of the
      most commonly used treatments in asthma, currently £473 million per year is spent on these
      medications alone in the UK. Guidelines recommend that treatment decisions are based on
      assessment of symptoms and airflow obstruction. However, as there is no clear relationship
      between symptom control, airflow obstruction and airway inflammation, there is a risk that
      patients can be over treated. In the U.K. 80% of patients with asthma are managed in primary
      care; assessment of airway inflammation is not applicable in this setting, and management
      relies on the assessment of peak flow and symptoms.

      Recently the concentration of nitric oxide present in exhaled breath (FENO) has been
      evaluated as a tool for assessing asthma. FENO is elevated in patients with asthma, is
      reduced by treatment with inhaled corticosteroids(8) and correlates with airway inflammation
      measured using bronchial biopsies and induced sputum. It is particularly applicable for
      monitoring asthma in primary care as the test is easy to perform, provides an immediate
      result, and inexpensive portable monitors are now available. FENO appears to be a very
      specific, but not sensitive, marker of airway inflammation and using a low level of FENO to
      predict lack of treatable airway inflammation may be successful. Evidence from a study in
      children suggests that this strategy may be successful. However, most studies using FENO to
      guide ICS dose have not adopted this approach and have instead been randomised controlled
      trials using a step up/ down protocol whereby a high FENO leads to a step up in ICS dose, and
      a low FENO leads to a step down in dose. They have attempted to both reduce asthma
      exacerbations despite also trying to reduce steroid dose. These studies have not met their
      primary endpoints and have been reviewed in a Cochrane report. In the study by Shaw et al. a
      similar amount of ICS was used over the duration of the study in both the group managed by
      FENO and the control group; there was however a difference at the end of the study, with the
      FENO group using significantly less ICS. In the study by Smith et al. the daily dose of ICS
      was significantly lower at all time points, however the study results are not applicable as
      patients did not receive long acting β2 agonists, and the ICS dose in the control group was
      artificially inflated. These trials lend weight to the idea that utilising a step down
      approach to FENO and ICS may be successful. Importantly there was no significant difference
      in asthma exacerbation rates between control or treatment group in either study, suggesting
      that an approach utilising by FENO is inherently safe. Other studies support this
      supposition; one study suggested a close correlation between loss of asthma control and ICS
      reduction, and another study demonstrated that within 2 weeks of a reduction in ICS, FENO
      rises back to baseline, however exact cut off values for a simple step down strategy have
      never been sought, despite evidence that this would constitute the best approach.

      Most patients are at step 2-3 of the asthma guidelines, receiving ICS doses of between
      200-800mcgs, and are managed in primary care; guidelines for a 50% reduction in ICS at 3
      months are based on sparse evidence. If a low FENO can identify patients who can step down
      their ICS treatment without a risk of worsening asthma, a strategy using FENO is likely to be
      adopted into current guidelines.
    

Intervention name(s): 50% step down reduction in inhaled corticosteroid dose
Intervention type(s): Other
Intervention description(s): All participants will have their inhaled corticosteroid dose reduced by 50%
Intervention model: Single Group Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Asthma; Inhaled Corticosteroids; Exhaled Nitric oxide; Airways inflammation; Step down; Predicting response