This document summarizes the agenda and discussion topics for a biomarker working group meeting on September 25th in Amsterdam. The group will discuss publishing updates, including a perspective article comparing NICE and GINA statements on FeNO and a review on the role of eosinophils in airways disease. They will also discuss potential research ideas using data from the Optimum Patient Care Research Database (OPCRD), including evaluating FeNO and eosinophils as predictors of outcomes in COPD. Additional biomarker data will be added to OPCRD, including IgE testing. The group agreed to further discuss selecting some initial research projects and set a date for their next meeting.

1. DATE: SATURDAY SEPTEMBER 25TH
VENUE: Wyndham Apollo Hotel, Amsterdam
MEETING ROOM: Boardroom
TIME: 15:00-17.30PM
CHAIR: Leif Bjermer, Respiratory Medicine and
Allergology, Department of Clinical Sciences Lund,
Lund University, Lund, Sweden
REG BIOMARKERS
WORKING GROUP

2. Agenda

3. Letter to the Editor / Editorial discussing differences between
NICE & GINA statements on FeNO
Review on the role of eosinophils / inflammometry in airways
disease
Publication Updates

4. Editorial for Review…
Perspective Article: discussing differences between NICE & GINA
statements on FeNO (focus on inflammometry)
• Target journal: npj Primary Care Medicine
(previously drafted for Respiratory Medicine; revised target JACI: In
Practice but also discussed; Lancet Respiratory Medicine also
suggested by Zuzana Diamant on Sept 24th)
• Next steps: Kjell Alving developing first draft (for review at ERS
meeting)
• Motivated by new UK NICE Guidance: which:
o Recommends FeNO (in addition to spirometry) in all patients to
help diagnose asthma. If obstruction is detected on spirometry, a
responsiveness test will also be carried out.
o Does not recommend FeNO to help guide on-going management
(due to limitations in the current evidence)

5. Biomarker review paper
• Working title: Inflammometry in obstructive airway disease – time for
a reappraisal
• Concept: A review of eosinophils/inflammometry in airways disease
• Rationale:
o Mike Thomas received feedback on his EAACI talk (on blood
eosinophils as predictors of future risk in asthma and COPD) that
suggested a lack of understanding of the potential value of blood
eosinophils as a biomarker in primary care.
o There would be value in a review paper to discuss the potential
utility of blood eosinophils for primary care respiratory medicine
o The review should focus on clinically accessible biomarkers and
provide useful guidance to primary care clinicians
• Target journal: Nature Primary Care Respiratory Medicine
• Next steps: Editor has approved concept in theory; agree authorship
at ERS ...

6. OPCRD Data Queries
Specific Ideas proposed
Extension of OPC biomarker data collection
Future Study Ideas

7. OPCRD Queries following Barcelona

8. Research ideas prompted by the data
• FeNO as a predictor of ICS response in COPD
o Helgo Magnussen
• FeNO as a predictor of COPD exacerbations
o Bernardino Alcázar
• Others...?

9. OPCRD FeNO data & expansion plans
• Study ideas relating to FeNO as a biomarker in
COPD:
o Immediately infeasible in OPCRD: ≤100 COPD patients
with FeNO data
• Short-term: other datasets…?
• Medium- / longer-term:
o iHARP in COPD
– FeNO will be collected (and linked to routine records in
OPCRD)
– Status: Service expansion proposal
– Funding to be confirmed
– Intentions to start to implement Q3 2015

10. Additional OPCRD Biomarker updates
• The Optimum Patient Care Clinical Service will
be integrating a new IgE point care test into the
service (skin prick test that provides IgE reading)
o Use in uncontrolled ≥Step 3 (primarily) ± those with
poor inhaler technique
o Devices approved for use; anticipate implementation
Q1 2016
• The OPC Research Database will contain
additional IgE data available for research shortly
thereafter.

11. Research ideas discussed in Barca (I)
1. Evaluate the utility of blood eosinophils as a predictor of
outcomes:
o Identify steroid naïve patients with a normal blood eosinophil count
o Evaluate whether their outcomes are worse if they are treated (vs not
treated) with ICS
2. Elevated FeNO & Blood Eosinophils: Identify patients with both
blood eosinophil data & FeNO data and evaluate whether
presence of both (i) raised blood eos and (ii) raised FeNO are
associated with increased exacerbation risk
o A similar study was previously carried out in the National Health and
Nutrition Examination Survey (NHANES) database.
o Data from Uppsala suggest that, independently, neither raised FeNO nor
raised blood eosinophils is predictive, but when jointly / both are raised, the
have a strong link with mortality.

12. Research ideas discussed in Barca (II)
3. Utility of blood eosinophils as a predictor of response to
therapy – dual bronchodilation vs ICS/LABA:
o Compare outcomes for COPD patients who initiate treatment as
ICS/LABA therapy with those initiating LABA/LAMA therapy
o Stratify the results by blood eosinophils count
o LABA/LAMA patient numbers in the OPCRD are currently low – this
may need to be a future study
o There are currently sufficient numbers to compare outcomes for
ICS/LABA vs Triple therapy (stratified by blood eosinophil count)
ahead to comparing ICS/LABA to dual bronchodilation, when
numbers permit.
– A protocol has already been drafted by REG for the ICS/LABA vs
Triple therapy in collaboration with Alberto Papi (study funding still
to be found)

13. Research ideas discussed in Barca (II)
4. Link between smoking and FeNO level: the NHANES
database contains an objective marker of cigarette
exposure (serum cotinine).
5. Consider pulmonary vs systemic drivers of high
blood eosinophils, e.g.:
o If FeNO decreases but blood eosinophil count does not, it may
suggest the presence of small airways disease and indicate a
trial of extra-fine particle ICS. Alternatively high blood eosinophil
(in those with low FeNO) may suggest the presence of another
condition that is not being adequately managed.
o High blood eosinophils may be a marker of systemic risk – there
are data to suggest that COPD patients with cardiovascular
disease are at increased risk of mortality if treated with tiotropium
rather than ICS/LABA. It is uncertain whether the risk is driven by
systemic inflammation in general, or by systematic inflammation
associated with COPD exacerbations.

14. Research ideas discussed in Barca (II)
6. Link between eosinopenia and increase risk of pneumonia: Price et al
suggest:
o Any link is very weak and it is difficult to evaluate as pneumonia incidence
is very low.
o Pneumonia incidence is dose related and pneumonia
o Pneumonia incidence tends to be higher in patients using standard
particle ICS therapies rather than extra-fine particle ICS formulations –
likely as a higher dose of standard particle ICS was required to achieve
equivalent effects in the lungs.
7. Consider opportunities to use biomarkers in the upper airway: FeNO
levels in the nose tend to be low in patients with obstruction as it is produced
in the sinuses:
o This could be a topic of future research interest
o Action: identify the number of patients in the OPCRD with rhinitis who also
have FeNO data.
– N=306

15. Agree some seed projects… & date of next meeting
What’s next for the group…?