Given the large number of patients infected with SARS-CoV-2, it is vital that the extent
of PC-ILD is determined; its natural history defined particularly whether it is
time-limited inflammation and reversible, or develops into persistent, or even
progressive, fibrosis. Determining the natural history of PC-ILD, and risk factors as
well as biomarkers related to outcome such as disease progression, will enable a precise
approach to treatments such as immunomodulation or antifibrotic therapy [6],
stratification into clinical trials, prognostication and appropriate service provision.
This will facilitate assessment and prioritisation of both conventional and novel
therapies used in the treatment of COVID-19 during the acute phase to mitigate the
subsequent development of PC-ILD. By exploring the long-term implications of SARS-CoV-2
infection across the full spectrum of COVID-19 disease ranging from non-hospitalised
patients managed in the community with mild symptoms to those requiring mechanical
ventilation, we will define the risk factors for PC-ILD including disease severity, host
genetic factors and the effects of antiviral and immunomodulatory treatment administered
during the acute phase of the illness. The UKILD Post COVID study is a prospective
multicentre observational cohort study that will be managed through the Imperial College
National Heart and Lung Institute and funded by the UKRI Medical Research Council and an
NIHR professorship (RGJ).

The PHOSP COVID study (ISRCTN10980107) is a national consortium that provides a platform
to study the long-term consequences of COVID19 hospitalisations [18]. An expected 10,000
individuals hospitalised by COVID-19 are to be included in baseline assessments after
testing positive on PCR for SARS-C0V-2 and will be recruited through the PHOSP platform.
The study described here will aim to recruit a further 2000 individuals, with proven
COVID-19, who were not hospitalised but presented to Long-COVID clinics with persistent
respiratory symptoms such as breathlessness or cough and are referred for cross-sectional
imaging (computer tomography, CT) at baseline (3 months weeks after their first COVID-19
symptoms) [19]. A total of up to 12,000 people will be assessed for longitudinal follow
up into the UKILD-Post COVID study. Following assessment of Post COVID patients at
baseline (~3-6 months post infection as defined above), those with clinical and
radiological features suggestive of ILD will be included into the UKILD-Post COVID study
population. Where there are contraindications for CT and if clinically indicated,
participants will be eligible for a research-guided 3D ultrashort echo time (UTE) proton
MRI as a surrogate for CT. Where individuals meet criteria for initial study inclusion
(COVID-19 and clinical indication for CT scanning) but have no clinical, radiological or
physiological features of ILD they will be invited to enroll as part of the control
cohort for follow up.

This protocol details the research partnership between Imperial (BREATHE Respiratory hub
partner), and partner organizations.

2 STUDY OBJECTIVES

2.1 Primary objective The primary objective of the study is to determine the prevalence
of ILD at 12 months following SARS-CoV-2 infection and whether clinical severity
correlates with severity of ILD in survivors.

2.2 Secondary objectives

1. to further define the PC-ILD population, in particular, to describe the emerging
phenotypes and risk factors of PC-ILD

2. to determine the natural history of PC-ILD phenotypes longitudinally

3. to explore pathomechanisms of PC-ILD for candidate prognostic and theranostic
biomarkers.

2.3 The primary endpoint

1. The primary endpoint of the study is as radiologically confirmed diagnosis of
fibrotic or non-fibrotic ILD in the 12 months following COVID-19. Sub-studies will
have a co-primary endpoint of change in the radiological extent of PC-ILD.

2.4 The secondary endpoints

1. progressive lung function impairment between 3 and 12 months, defined as ≥10%
relative decline in FVC, or ≥10% relative decline in DLco, or increasing
radiological extent of PC-ILD using image analysis [20].

2. Resolution of ILD, as defined by ≥10% relative improvement in FVC, DLco, or
reduction of radiological extent.

3. Persistence of ILD in those not meeting definition of progression or resolution

4. Presence of interstitial lung abnormalities (ILA) on radiological images that do not
meet definition of ILD.

5. A comprehensive series of clinical, molecular, MRI and biochemical parameters will
be assessed as biomarkers.

Pre-recruitment evaluations Screening and Eligibility Assessment Patients will be
assessed by the clinical teams for eligibility against the inclusion or exclusion
criteria.

The clinical teams at the recruiting sites will confirm that patients have been infected
with SARS-CoV2 before approaching them. Participants must satisfy all the approved
inclusion and exclusion criteria of the protocol. Participants will then be invited to
participate and informed consent will be obtained at the start of visit 1. Pre-screening
for eligibility will take place prior to consent. It will be done by the direct care team
using patient notes. There will be no access to patient identifiable data outside of the
direct care team prior to consent.

Screening and eligibility for PHOSP COVID/C-MORE participants For PHOSP-COVID
participants, screening and eligibility assessment will occur as per the REC approved
protocol (IRAS ID 285439).

All patients can be directed to other relevant post-COVID studies, including but not
restricted to POSTCODE and XMAS.

3 STUDY DESIGN Prospective observational study of hospitalised and non-hospitalised
patients post- infection with SARS-CoV-2. The study aims to recruit 2000 individuals,
with proven COVID-19, who were not hospitalised but presented to Long-COVID clinics with
persistent respiratory symptoms such as breathlessness or cough and are referred for
cross-sectional imaging (computer tomography, CT) at baseline (3 months weeks after their
first COVID-19 symptoms). The study will run for 18 months.

Description of study procedure(s) History and Examination (10 mins) : Medical history,
allergies, medications and anthropometric measurements including height, weight, and body
mass index will be recorded during the study visit (or taken from the hospital notes. Or
PHOPS data)

Blood sample collection (10 mins) :

Samples will be taken for plasma/ serum for epithelial and endothelial damage biomarkers,
coagulation and genetics Questionnaires (45 mins) Participants will be provided with
seven questionnaires; 36 Short-Form Survey (SF-36), Clinical Frailty Scale (CFS), Patient
Health Questionnaire 9 (PHQ9), Montreal Cognition Assessment (MOCA), Dyspnoea-12 score,
EQ5D-5L, FACIT-F at the end of each study visit.

There are no investigations required for participants co-enrolled in the PHOSP-COVID
study.

3.3 Baseline and follow up assessments Initial patient approach Eligibility assessment by
clinical team Study information and invitation letter provided to eligible patients

Visit 1 (~3 months) (Post COVID-19 infection patients)

1. Review of eligibility with participant

2. Obtain written informed consent

3. History and anthropometric measurements, e.g. height, weight, body mass index (BMI)

4. Blood sample (6-10 ml) collection

5. Pulmonary function test (20 minutes)

6. Optional 6-minute walk test (6MWT) (10 minutes)

7. Quality of Life questionnaire (SF-36) (10 minutes)

8. Clinical Frailty Scale (CFS) (5 minutes)

9. Personal health questionnaire (PHQ) (10 minutes)

10. Montreal Cognitive Assessment MOCA (10 minutes)

11. Dyspnea 12 score (10 minutes)

12. EQ5D-5L (10 minutes)

13. FACIT-F questionnaire (10 minutes)

Optional Visit 2 (~6 months) (Post COVID-19 infection patients and matched controls) All
visit 1 assessments will be repeated.

Visit 3 (~12 months) (Post COVID-19 infection patients) All visit 1 assessments will be
repeated. Visits will be scheduled to take place over 1 day. Visit 2 is optional, Visits
1 and 3 are obligatory.

3.3 Monitoring of clinical events and re-analysis of previous scans (clinically
indicated) Clinical outcome data and images from clinical scans for all COVID-19 patients
will also be collected from around the time of infection and hospitalisation and follow
up. Laboratory analyses and chest imaging results undertaken for clinical reasons will
also be collected. Access to participant medical records and any relevant hospital data
that is recorded as part of routine standard of care; i.e., CT-Scans, blood results and
disease progression data etc. will be obtained with patient consent from hospital
electronic patient records and NHS digital

3.4 Sample Handling Blood samples for the analysis of serum inflammatory markers, serum
biomarkers of endothelial and epithelial injury and coagulation studies, viral serology,
viral PCR, and whole genome sequencing, ribonucleic acid sequencing and flow cytometry in
blood will be collected. Analysis of venous blood samples will be performed in local NHS
laboratories. If the Participant consents approximately 10 ml of blood will be stored in
the Division of Cardiovascular Medicine for further analysis as part of collaborations
with other groups. Samples will not be collected from participants who are also
participating in PHOSP-COVID

Withdrawal Criteria

Early Discontinuation/Withdrawal of Participants : During the course of the study a
participant may choose to withdraw early from the study treatment at any time. This may
happen for several reasons, including but not limited to:

- The occurrence of what the participant perceives asintolerable AE.

- Inability to comply with study procedures

- Participant decision

According to the design of the study, participants may have the following three options
for withdrawal;

1. Participants may withdraw from active follow-up and further communication but allow
the study team to continue to access their medical records and any relevant hospital
data that is recorded as part of routine standard of care; i.e., CT-Scans, blood
results and disease progression data etc.

2. Participants can withdraw from the study but data and samples obtained up until the
point of withdrawal to be retained for use in the study analysis. No further data or
samples would be collected after withdrawal.

3. Participants can withdraw completely from the study and withdraw samples collected
up until the point of withdrawal. The samples already collected would not be used in
the final study analysis.

4. In addition, the Investigator may discontinue a participant from the study at any
time if the Investigator considers it necessary for any reason including, but not
limited to:

- Ineligibility (either arising during the study or retrospectively having been
overlooked at screening)

Participants that choose to withdraw from the study will not be replaced. The type of
withdrawal and reason for withdrawal will be recorded in the CRF. If the participant is
withdrawn due to an adverse event, the Investigator will arrange for follow-up visits or
telephone calls until the adverse event has resolved or .

ASSESMENT AND FOLLOW UP Optional follow up and assessment

As previously detailed in section 3.3 above, participants will agree to a final follow up
assessment and an optional interim assessment

Optional Visit 2 (~6 months) (Post COVID-19 infection patients and matched controls) All
visit 1 assessments will be repeated. All visit 1 assessments will be repeated.

Visits will be scheduled to take place over 1 day. Visit 2 is optional, visits 1 and 3
are obligatory. For research specific visits, participants will be offered reimbursement
for travel expenses. This includes reimbursement for petrol, car parking, taxis.

Clinical outcome data and images from clinical scans for all COVID-19 patients will also
be collected from around the time of infection and hospitalisation and follow up.
Laboratory analyses and chest imaging results undertaken for clinical reasons will also
be collected. Access to participant medical records and any relevant hospital data that
is recorded as part of routine standard of care; i.e., CT-Scans, blood results and
disease progression data etc. will be obtained with patient consent from hospital
electronic patient records and NHS digital. The end of the study will be the point at
which the final patient follow-up and assessment have been completed.

A detailed Image Management protocol for the UKILD-Post COVID Study provides a
comprehensive outline of the purpose, operation, methods, policies, and governance of
Image collection for UKILD. It describes the procedures used to collect and store images.
(appendix 1)

STATISTICS AND DATA ANALYSIS

The prevalence of MDT-confirmed PC-ILD at both early (up to 6 months) and again at late
(10-15 month) time-points and will be assessed within the total study population. The
prevalence of broader radiological abnormalities and phenotypic patterns will also be
assessed in a descriptive analysis, together with demographics, haematological and
biochemical profiles, physiological performance, and patient-reported outcome measures.
Analyses will be performed overall and stratified according to hospitalised and
non-hospitalised, as well as severity of infection in hospitalised patients defined
above.

Baseline and longitudinal changes in biomarkers reflecting PC-ILD evolution, including
circulating factors and cell-types from detailed serological and cellular analysis, will
be assessed in multilevel models for repeated measures to test associations according to
the presence or absence of PC-ILD at late time points (10-15 months), and according to
progression, resolution, or persistence of radiological patterns over follow up time
points.

Analyses will be performed using standard epidemiological and statistical genetics
methodology. This will include cross-sectional and longitudinal studies, and analyses of
disease prevalence and incidence.

Analysis design and choice of controls will be dependent upon the precise nature of the
research question. Identification of risk factors for a specific COVID-19 sequela would
involve controls both from within UKILD-Long COVID (without the sequela) and
serology-positive controls with prospective questionnaire and healthcare record linkage
from Longitudinal Population Studies (for example, UK Biobank, Coronagenes, EXCEED) and
pre-existing disease cohorts. Analyses aiming to characterise and understand the clinical
features, subtypes and trajectories of sequelae (for example, sarcopaenia) would evaluate
the cross-sectional and longitudinal clinical data and biomarkers of UKILD-Long COVID
participants who are presenting with the sequelae being studied.

The participant organisations making uo the UKILD-long COVID study group have extensive
experience of development of, and collaborative use of, disease-specific and general
population cohort studies both nationally and internationally enabling access to control
populations and alignment of research strategies for rapid validation and replication of
findings.

Statistical significance thresholds will be defined in advance of each analysis and will
take into account issues of multiple testing and a priori evidence.

Data and all appropriate documentation will be stored for a minimum of 10 years after the
completion of the study, including the follow-up period.

Project statistician: Dr Iain Stewart email:

iain.stewart@imperial.ac.uk National Heart and Lung Institute Guy Scadding Building, Cale
Street, London, SW3 6LY