The Use of Fractional Exhaled Nitric Oxide in the Identification of Non-adherence in Difficult Asthma

Hypothesis:

In a difficult asthma population, a significant reduction in fractional exhaled nitric oxide (FeNO) or sputum eosinophils after a directly observed inhaled steroid challenge will distinguish non-adherent subjects from subjects with refractory asthma.

Study Design The study will consist of two phases. The development phase will identify the response of FeNO / sputum eosinophils after directly observed inhaled steroid challenge, in non-adherent subjects and define cut-off values for a positive and negative test and identify the optimum length of steroid challenge. The validation phase will trial and validate the test in a 'real life' clinical setting.

Phase 1 - Development Phase

During this phase, two groups will be studied:

• Non-adherent group - subjects with < 50% prescription filling in previous 6 months and persistently high FeNO.
• Adherent group - subjects with high prescription filling (> 75%) and persistently high FeNO.

On Day 0, subjects will have a FeNO measurement will be repeated, perform induced sputum and complete an asthma control questionnaire. After inhaler technique is deemed satisfactory, all subjects will be directly observed taking 1600μg of inhaled budesonide via Turbohaler (or bioequivalent dose of Budesonide via MDI / spacer). On the next 6 days, the investigator will visit the subjects and perform FeNO measurements, followed by directly observed inhalation of 1600 μg of inhaled budesonide via appropriate inhaler device.

On Day 7, subjects will undergo FeNO measurement, induced sputum and an asthma control questionnaire. Following who fail to suppress their FeNO level will receive an intramuscular injection of Triamcinolone 80mg and will be asked to attend the clinic weekly for 4 weeks for measurement of FeNO levels and induced sputum.

Based on results the investigators will:

• Identify if there is a clearly different response in FeNO / sputum eosinophils in adherent and non-adherent groups during a 7 day treatment period, with observed high dose inhaled steroid therapy, which will define the clinical utility of the technique.
• Define cut-off values for a positive test (i.e. which is consistent with non-adherence) and a negative test which should mean adherence and consequently refractory asthma.
• Define the optimal length of steroid challenge for the validation phase based on clinical ease of use and differentiation precision.

Phase 2 - Validation in a real life Clinical Setting

Having defined the test, the validation phase will involve prospectively recruited subjects, who have a raised FeNO but the investigators will not have access to their prescription records at this stage. These subjects will undergo the steroid challenge defined above and will be deemed adherent or non-adherent. After the steroid challenge has been performed, this will be compared to prescription records and patient confrontation to identify if the challenge identifies non-adherence.

Phase 1 Inclusion Criteria:

• Subjects with difficult to control asthma
• FeNO > 45 ppb at a flow rate of 50 ml/sec on 2 sequential occasions at clinical review
• Non-adherent group: < 50% prescription filling of inhaled corticosteroid therapy in the previous 6 months
• Adherent group: > 75% prescription filling of inhaled corticosteroid therapy in the previous 6 months

Phase 1 Exclusion Criteria:

• Current smoker
• Pregnancy
• Other significant respiratory disease

Phase 2 Inclusion Criteria:

• Subjects with difficult to control asthma
• FeNO > 45 ppb at a flow rate of 50 ml/sec on 2 sequential occasions at clinical review

Phase 2 Exclusion Criteria:

• Current smoker
• Pregnancy
• Other significant respiratory disease