The evaluation of FeNO for predicting response to ICS in subjects with Non-Specific Respiratory Symptoms (NSRS)

Existing treatments for patients presenting with non-specific respiratory symptoms suggesting of asthma have a one-size-fits-all approach, often involving the prescription of inhaled corticosteroids (ICS). However, not all patients respond to ICS in the same manner, as such identification of patients most likely to respond to ICS would minimise inappropriate treatment and limit side-effects and unnecessary healthcare costs. FeNO (fraction exhaled nitric oxide) is easily measured in routine clinical visits and showed potential as a biomarker for ICS responsiveness in small clinical trials. However, current technology for the measurement of FeNO is expensive and there is a need for an affordable technology to measure FeNO in primary care. Therefore, the NSRS project was initiated to develop an affordable and reliable FeNO measurement technology which can be implemented as part of routine primary care in Singapore.

The NSRS project is the first systematic, investigative and experimental project in Singapore and the world to assess the interaction between FeNO, measured by the NIOX device, and response to ICS within a large randomised placebo-controlled clinical trial. This project brought together experts from multiple specialities, including PhD holders, medical doctors, statisticians, epidemiologists, database experts and clinical trial recruiters. The overall design of the trial, including the electronic data capture form and primary measure of asthma control, was decided by discussion with the panel of experts and review of pre-existing literature and international guidelines. The panel of experts agreed on the Asthma Control Questionnaire with 6 questions + FEV1 (ACQ7) to be the most appropriate outcome measure for patients with non-specific respiratory symptoms.

This project was conducted as a 6-week double-blind randomised placebo-controlled trial including undiagnosed patients, aged 18–80 years, with non-specific, persistent respiratory symptoms, across 26 primary care centres and hospitals in the UK and Singapore. The clinical trial phase of this project represents a huge undertaking for OPRI to ensure the proper conduct of the trial per protocol and ethical approval and ensuring sufficient numbers of patients were recruited and completed the trial. There are also technical uncertainties faced by the company in the effectiveness of NIOX in providing reliable FeNO measurement in the Singapore population.

Patients were randomly assigned to 4 weeks of treatment with extrafine inhaled corticosteroids (ICS) or placebo, stratified by baseline FeNO measurement using NIOX: normal, intermediate, and high. A total of 214 patients were analysed. We observed a significant interaction between baseline FeNO with the change in ACQ7 mean score within the ICS treatment group. Higher baseline FeNO reading was predictive of a larger change in ACQ7 score in the ICS treatment group compared to the placebo group. This result shows that FeNO measurement with NIOX provides an easy and non-invasive tool to assist physicians in making ICS prescribing decision for patients with non-specific respiratory symptoms. The result of this research was published in Lancet Respiratory Medicine (impact factor: 21.5).

In the next phase of the study, we will be working with our collaborators from the Commonwealth Scientific and Industrial Research Organisation (CSIRO) to develop a novel affordable tool (ideally within $10) for measure FeNO in primary care. We will also attempt to create a device capable of utilising the processing power of the ubiquitous smartphone for FeNO measurement.


David B Price, Roland Buhl, Adrian Chan, Daryl Freeman, Elizabeth Gardener, Clifford Godley, Kevin Gruffydd-Jones, Lorcan McGarvey, Ken Ohta, Dermot Ryan, Jörgen Syk, Ngiap Chuan Tan, TzeLee Tan, Mike Thomas, Sen Yang, Priyanka Raju Konduru, Marcus Ngantcha, Martina Stagno d’Alcontres, Therese S Lapperre. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2017.
[PubMed] [Full Text]


The role of FeNO in cough management: a randomised controlled trial
Price DB, Buhl R,Chan A, Freeman D, Gardener E, et al.
Am J Respir Crit Care Med 2018; 197: A1368. [Poster] [Full Text]

Predictive value of FeNO in patients with non-specific respiratory symptoms: a randomised controlled trial.
Price D, Buhl R, Copland A, Freeman D, Godley C, et al.
Eur Respir J 2017; 50(suppl 61): PA3886. [Poster] [Full Text]