Respiratory Effectiveness Group Interstitial Lung Disease (ILD) Working Group Meeting, held in London during the ERS 2016 Congress.

1. INTERSTITIAL LUNG
DISEASE WORKING
GROUP MEETING
CHAIR: Luca Richeldi
DATE: Tuesday September 6th
TIME: 10-11.30am
VENUE: Hotel Novotel London Excel, Western Gateway, London
ROOM: Board Room
– Global Characterisation of ILD
Diagnostic practice
– Missed Diagnostic Opportunities in IPF

2. Agenda
• Global Characterisation of ILD Diagnostic
Practice
o Identifying Participant Sites
• Missed diagnostic opportunities in IPF:
retrospective cohort study:
o Results Summary

3. Attendees (RSVPs)
Confirmed
• Carole Youakim
• Claudia Valenzuela
• Keertan Dheda (now meeting at 4pm)
• Luca Richeldi
• Maria Molina Molina
• Lurdes Planas
• Pilar Ortega
• Simon Walsh
• Steven Nathan (changed to tentantive)
• Toby Maher (changed to tenatntive)
• Ggiovanni Ferrara
• Vincent Cottin
• Aileen Wang
• Camilo Roa
• Paolo Spagnolo
• David Price
• Paola Rottoli
• Sergey Adveev
• Zuo Jun Xu
• Klaus-Uwe Kirchgaessler (supporter)
• Demosthenes Bouros
• Arata Azuma
• Mariano Maezzi
• Antonio Morais
• Andrew Worsfold
• Alison Chisholm
• Thao Le
Dial ins
• Camera Corte (yes)
• Ivan Rosas (possibly)
• Kevin Brown (improbable - time zone issue)
• Andrew Wilson (probable)
• Mike Rosenblyth (supporter) (improbable -
timezone issue)
Tentative
• Fernando Martinez
• Kevin Flaherty
• Mark Jones
• Martin Kolb
• Ulrich Costabel

4. GLOBAL ILD DIAGNOSTIC
CHARACTERIZATION STUDY

5. Background (I)
• REG’s focus is real-life research
o Raising the quality and profile of real-life research methodologies
o Using real-life research to address unmet research needs and
address gaps in the evidence base
• Efficacious IPF therapies resulted interest in a need to better
understand the reality of ILD diagnostic practice to optimise
treatment outcomes
• Initial concept – utilise the REG ILD Working Group network to
conduct a diagnostic agreement study:
o Discussion around variability in diagnostic agreement within ILD.
o Would a range of MDTs within this network agree on the
diagnoses if given the same set of “test cases”

6. Background (II)
• Questions when designing the agreement study:
o What would be appropriate definition of an MDT?
o What would be the right case mix for inclusion?
o What does real-life diagnostic practice look like?
• There is limited knowledge of how diagnosis takes place
outside specialist centres
• As a precursor to evaluating agreement, it’s necessary to
understand how ILDs (in particular IPF) are diagnosed in
routine care

7. Agreement Study: Phase I Outputs
• Characterise the ILD diagnostic process globally,
especially in countries/territories where little is currently
known.
• Provide valuable insight as to current diagnostic
practices to inform the robust design of Phase II.
• Develop a characterised global network of ILD centres
for engagement in Phsae II and future research:
o The Phase II diagnostic agreement/accuracy study
o Future ILD and IPF research (RCT and real-life studies)

8. Outputs: Phase II
• Evaluate agreement and accuracy of ILD MDT
diagnosis across a range of global sites and healthcare
settings
• Identify features of current MDT diagnostic practice
associated with accurate diagnosis (including the
effect of bronchoscopic sampling for diagnosis)
• Produce a series of best practice recommendations to
optimise the pathway to accurate ILD diagnosis for future
practice.

9. Timeline & Status
ATS 2015: first working group meeting, Denver
(developed proposal June–Aug)
ATS 2016: reviewed draft questionnaire
(Updated June; ethics secured June;
Global leads invited July/August)
ERS, Sept 2015: shared study protocol with
working group and potential supporters
(Funding secured Oct–Dec 2015)

10. Timeline & Status
ATS 2015: first working group meeting, Denver
(developed proposal June–Aug)
ATS 2016: reviewed draft questionnaire
(Updated June; ethics secured June;
Global leads invited July/August)
ERS, Sept 2015: shared study protocol with
working group and potential supporters
(Funding secured Oct–Dec 2015)
Application prepared June
Approval secured July 24th
Obline questionnaire

11. Timeline & Status
ATS 2015: first working group meeting, Denver
(developed proposal June–Aug)
ATS 2016: reviewed draft questionnaire
(Updated June; ethics secured June;
Global leads invited July/August)
ERS, Sept 2015: shared study protocol with
working group and potential supporters
(Funding secured Oct–Dec 2015)
ERS, Sept 2016: utilise the working
group network to identify participant sites
& support language translation

12. Centre Recruitment: principles (I)
• Centre Inclusion: Not restricted to expert / specialist centres; a broad a
range of different diagnostic settings will be included
• Objective: The study will help to characterise and describe range and
variation in diagnostic practice
• Local Expertise: Local experts will guide participation in their country to
ensure a range of relevant healthcare settings / centres are included
• Descriptive study: No conclusions about practice approach prevalence
(e.g. what is ‘usual practice’) will be made, i.e.:
o A range of centers in each country is required to reflect the variation
in practice within each country
o The selection of participating centers does not need to be
representative of practice in that country, overall

13. Cascade Approach
• Regional Leads will be asked to:
o Provide country lead names
• Country leads will be asked to to:
o Advise as to translation requirements
o Support translation(s) (personally, or nominate colleague)
o Forward to a number of ILD Centres known to them
• Participating centres will be asked to:
o Complete the questionnaire
o Send it to other centres in their network

14. We are here
Cascade Recruitment
STEP 1 ACTIONS:
CO-PIs Actions
Identify Regional Leads /
Experts in key global areas:
(i) Continental Regions
(ii) BRIC Countries
STEP 2 ACTIONS: Regional &
BRIC Country Leads
Identify National Leads or (BRIC)
sub-country leads
STEP 3 ACTIONS:
National & Area Leads
(i)Confirm & support language
translations
(ii) Complete the questionnaire
(iii) Send the questionnaire to
(e.g.) 10 national ILD centres
STEP 4 ACTIONS:
ILD Centre Leads (invited at Step 3)
(i) Complete the questionnaire
(ii) Send the questionnaire to members
of their community network

15. International Roll Out
• Regional/Continent & National (BRIC) Leads:
o Contacted (July);
o Briefed & Confirmed (August)
To guide participant centre engagement around the world
REGIONAL LEADS
GLOBAL REGION CONTACT NAME
BRAZIL IVAN ROSAS
RUSSIA SERGEY ADVEEV
INDIA ZARIR UDWADIA
CHINA ZUO JUN XU
NORTH AMERICA
FERNANDO MARTINEZ
KEVIN FLAHERTY
EUROPE
LUCA RICHELDI
SIMON WALSH
SOUTH & CENTRAL AMERICA IVAN ROSAS
MIDDLE EAST CAROLE YOUAKIM
AFRICA KEERTAN DHEDA
ASIA-PACIFIC
ARATA AZUMA (JAPAN / ASIA)
TAMERA CORTE (AUSTRALIA / NEW ZEALAND)

16. Example approach – Latin America
• Registry efforts in recent years have identified lead contacts for most
countries in Latin American (except Bolivia) and Central American
• Each national lead can be contacted and asked how they would
envisage contacting their national peers e.g.:
o What resources would they use to identify participants and email addresses,
o How many contacts they have
o How they would recommend we contact those centres)
• Invitations can then be sent to a number (e.g. 20-50) of centres in
each country along with the questionnaire link and a cover note
outlining the broad objectives of the study
• Turnaround should be relatively rapid and feasible within the
proposed 2-month data collection period
• Translation will be important, especially in Brazil, but should be a
minor effort to implement

17. Identification of Country Leads
& Participants
Help us to:
– Identify National Leads
– Translate the questionnaire

18. Translations
• Local language translations will be offered as:
o Necessary in some countries
o Desire standardization of approach across all countries (i.e. translate for all not some)
• Translation support required:
o Preliminary translations can be provided for the following languages, but review and
tailoring will be required by a native speaker:
– English – UK; Esperanto; Estonian; Finnish; French; German; Greek; Gujarati; Hebrew; Hindi; Hungarian; Italian;
Japanese; Khmer; Korean; Latvian; Lithuanian; Macedonian; Mongolian; Myanmar; Norwegian; Persian; Polish;
Portuguese; Romanian; Russian; Serbian; Slovak; Slovenian; Spanish (Latin America); Spanish (Spain); Swahili;
Swedish; Tamil; Thai; Turkish; Ukrainian; Urdu; Vietnamese; Welsh
– Test (in Italian) suggests preliminary translation is ~80% accurate
– Text will be provided in a Word Document that can be edited / corrected
o Where a preliminary translation is not possible; a native speaker must be identified to
support
• Questions are clear and straight forward, so forward translation only will be sufficient

19. IDENTIFYING OPPORTUNITIES
FOR EARLIER DIAGNOSIS OF
IDIOPATHIC PULMONARY FIBROSIS
IN ROUTINE CARE IN THE UK:
A HISTORICAL CLINICAL COHORT STUDY
A STUDY BY THE RESPIRATORY EFFECTIVNESS GROUP’S
INTERSTITIAL LUNG DISEASE WORKING GROUP
PRINCIPAL INVESTIGATOR: Prof. Luca Richeldi
STUDY REFERENCE: REG-RES1510

20. Realities of Current IPF Diagnosis
1 2
1. British Lung Foundation: https://www.blf.org.uk/Page/IPF-Patient-differential-diagnosis-of-COPD. (Last accessed February 2016); 2. NHS
Choices Pulmonary Fibrosis (idiopathic) (http://www.nhs.uk/conditions/pulmonary-fibrosis/pages/introduction.aspx) (Last accessed February 2016)
Figure reproduced from the Inspiration: Idiopathic Pulmonary Fibrosis (IPF) Report February 2016; produced by Action for Pulmonary Fibrosis, BLF and Boehringer Ingelheim (BI)

21. Look back to move forwards
• Time to look upstream…:
o What happens to patients in the lead up to their diagnosis
o Are opportunities for earlier diagnosis being missed in primary care
o How can non-specialists be supported to help identify potential IPF and
earlier referral to specialist care…?
• Identify common patterns (trends) in healthcare resource utilization
(HRU) and identify potential “red flags” to to aid earlier diagnosis
Diagnosis
& potential
treatment
IPF Management
Pre-
diagnosis

22. REG ILD WG Study Aims
• With a view to identifying potential opportunities for earlier
referral to specialists and (ultimately) earlier diagnosis of
IPF, the study aims to:
1. Characterise the clinical features of patients at the time of
their IPF diagnosis
2. Evaluate patients’ patterns of HRU in the years preceding
their IPF diagnosis
3. Develop optimum code lists for IPF database research, i.e.
variation in 1 & 2 for sensitive versus specific code lists

23. Collaborators
Steering Committee
• Luca Richeldi: University of Southampton, Southampton, UK
• David Price: University of Aberdeen, Aberdeen, UK
• Carlo Vancheri: University of Catania, Catania, Italy
• Christopher Ryerson: University of British Columbia, Vancouver Canada
• Ian Glaspole: Alfred Hospital, Melbourne, Australia
• Ganesh Ragu: University of Washington, Washington, USA
• Kevin Flaherty: University of Michigan Medical School, Ann Arbor, MI, USA
• Vincent Cottin: Claude Bernard Lyon University, Lyon, France
• Toby Maher: National Institute for Health Research (NIHR) Clinician Scientist and Physician on
the Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK
• Andrew Wilson: Norwich Medical School, University of East Anglia, Norwich, UK
• Alan Kaplan: Family Physician Airways Group of Canada, Ontario, Canada
• Martin Kolb: McMaster University, Hamilton, Ontario, Canada
• Simon Walsh: ‎Consultant Thoracic Radiologist at Kings College Hospital, London, UK
REG Research Leads
• Alison Chisholm: Chief Scientific Officer, REG, UK
• Anjan Nibber: Researcher, REG, UK
• David Price: REG Founder

24. Design & data source
Design
• Historical follow-up study using electronic medical records and
linked questionnaire data from the Optimum Patient Care Research
Database (OPCRD)
Data source
• The Optimum Patient Care Research
Database (OPCRD) is a UK primary care
database available to REG:
o Quality-controlled, longitudinal, primary-care database
o Contains anonymous data from ≥550 UK general practices
& ~2.5 million patients
o Captured via the OPC asthma and COPD clinical review service
– Respiratory “enriched” database
o Ethical approval for medical research

25. Study duration & design
Study Period: 10-year period (2005–2015)
Evaluation Period: will consist of:
• An index date at which patients receive their IPF diagnosis
• Characterisation period: 2-10 years continuous EMR pre diagnosis
• Where available, exploratory outcome period to evaluate time to death
Historical evaluation of
healthcare resource utilisation
Period 2-10 years
Index date, i.e. date of:
• Primary analysis: specific IPF diagnosis
• Secondary analysis: broad IPF diagnosis
(exploratory analysis of time to death)
Evaluation of clinical
characteristics at
time of diagnosis
Post IPF diagnosis

26. Patient eligibility: inclusion criteria
• A diagnostic (Read) code for IPF
o Specific* IPF Read code
o Broad* IPF Read code
• Diagnosed with IPF between 2005 and 2015
• ≥2 years’ continuous clinical records in the years
immediately preceding their index diagnosis
• Aged ≥40 years or older at index date
* Code lists defined on next slide

27. IPF Read Codes
Reviewed by working group members from primary & secondary
care and prior experience of IPF research within UK EMRs:
Read Code Read Term
H563.00 Idiopathic fibrosing alveolitis
H563.12
(including: H563.11)
Cryptogenic fibrosing alveolitis
(Hamman - Rich syndrome)
H563z00 Idiopathic fibrosing alveolitis NOS
H563300 Usual interstitial pneumonitis
H563.13 Idiopathic pulmonary fibrosis
XE0Yb Idiopathic pulmonary fibrosis
X102v Usual interstitial pneumonitis
H563z Idiopathic fibrosing alveolitis NOS
H563100 Diffuse pulmonary fibrosis
H563200 Pulmonary fibrosis
Broad
primary
analysis
Specific
primaryanalysis

28. Patient eligibility: exclusion criteria
• Comorbid*:
o Connective tissue disorder (CTDs)
o Allergic alveolitis
o Sarcoidosis
o Pneumoconiosis
o Asbestosis
No additional exclusion criteria will be applied to ensure the
study population includes the broadly heterogeneous
patient population treated in routine primary care in the UK
*Read Code ever during the observation period

29. Characterization at IPF Diagnosis
Patients will be stratified by broad vs specific IPF code and
characterized in terms of:
• Demographics
• Lifestyle factors
• Comorbidities: Respiratory, Other
• Obstructive lung disease (OLD) pharmacotherapy in the year
preceding index date
• Symptom severity (mMRC)
• Lung function (FVC, FVC %pred, FEV1, FEV1/FVC)
• Obstructive lung disease characteristics:
o COPD GOLD status
o Blood eosinophilia (≥0.5 x 109/ L)

30. Outcomes: trends in HRU
• Consultations:
o Lower respiratory (LR)
consultations
o LR Consultation resulting in a
course of antibiotic drugs (on the
same day)
o LR Consultation resulting in a
course of oral steroids (on the
same day)
• Hospitalisations (in-patient
attendances) with a code for a:
o LR complaint on the same day
o LR complaint within 14 days
• Chest X-ray / radiology
• Cough
• Therapies
o Prescriptions for antibiotics
o Prescriptions for oral steroids:
– Acute
– Maintenance
• Emergency Room / Accident &
Emergency (A&E) attendances
coded for a:
o LR complaint on the same day
Longitudinal trends in HRU preceding IPF diagnosis:
• 10-year annual trends
• 2-year quarterly trends (last 2 years before diagnosis)

31. RESULTS
(SUMMARY / ANALYSIS ON-GOING)

32. Flow Diagram

33. Clinical features of patients at the
time of their IPF diagnosis
In this routine care IPF population from the UK:
• Demographics
o Mean age: 72-73 years
o Men accounted for 62-65% of the population
o Approximately 1/3 were never smokers; 2/3 current or ex-smokers
• Comorbidities
o 13-25% had obstructive lung disease (13-15% asthma; 19-25% COPD)
o Approximately 50% of patients:
– Had cardiovascular disease (46-53%)
– Consulted for cough (40-52%; ~10% in the 2 years preceding IPF diagnosis)
• Respiratory therapies
o 18-26% of patients received ≥1 prescription for SABA in the year preceding
IPF diagnosis
o Prescribing of all other obstructive lung disease therapies (ICS, LABA,
LAMA, combinations) was low (<10%)

34. Patterns of HRU in the years
preceding their IPF diagnosis
• All markers of respiratory HRU increased annually over
the 10-years and quarterly within the last 2 years leading
up to patient’s IPF diagnosis:
o Primary care events
– LR consultations, LR antibiotics and oral steroids (acute and
maintenance)
o Secondary care attendances
– Hospital admissions, Out patient department attendances,
Accident & emergency attendances
o Other:
– Cough events, Chest X-rays, Incidence of pneumonia

35. Code lists: specific vs broad
• Compared with patients with a “specific” IPF diagnostic code, those with a “broad”
diagnostic label were similar in terms of their:
o Demographic presentation at the time of diagnosis
o Escalating trends in HRU in the years preceding IPF diagnosis
o Lung function: Similar mean(SD) FVC: 3.1(6.8) vs. 2.5(0.9) (p=0.405)
• Comorbidities broad IPF patients had:
o Similar burden of:
– Chronic respiratory conditions (incl. asthma; excl COPD); heart failure,
rhinitis, bronchiectasis, eczema, osteoporosis, cerebrovascular disease,
sleep apnoea, depression and anxiety
o Higher burden of :
– COPD, cardiovascular disease, ischaemic heart disease, Hypertension,
diabetes, myocardial infraction, GERD,CKD, lung cancer, cough
• Drug usage: broad IPF patients had higher use of short-acting bronchodilator therapy
in the year preceding IPF diagnosis (26 vs 18%)