Respiratory microbiome and clinical data analysis for the prediction of acute exacerbations in COPD

Chronic obstructive pulmonary disease (COPD) is characterised by progressive
airflow limitation. With a global prevalence of 5-10%, COPD is one of the most
common diseases of the respiratory tract and was the most prevalent chronic
respiratory disease in 2017. Worldwide, more than 3 million deaths are
attributed to the disease annually.

The clinical course of the disease is characterised by periods of relative
clinical stability and periods of an acute worsening of symptoms
(exacerbations). Exacerbations are a major reason for the loss of quality of
life, and for healthcare utilization.

The vast majority of acute exacerbations are linked to acute bacterial or viral
respiratory infections, which aggravate respiratory symptoms and precipitate
inflammatory processes. Patients experience a worsening of symptoms like
dyspnoea, cough or mucus production that is beyond day-to-day variation and
requires an adaptation of the medication.

While frequency and severity of exacerbations vary from patient to patient,
patients suffering from frequent exacerbations experience a faster
deterioration of lung function and higher burden of symptoms. In-hospital
mortality of patients admitted to the hospital due to an acute exacerbation
lies between 2.5 and 14%, with one year mortality rates following a severe
(i.e. hospitalised) exacerbation of 23-43%.The prevention and early detection
of exacerbations is therefore a crucial goal in the management of COPD.

In order to predict individual exacerbation risk, current tools rely solely on
sociodemographic and anamnestic/clinical data. Although these approaches have
gained complexity and accuracy by integrating more and more data into their
calculations, they currently do not consider microbiological findings and
dynamics of bacterial colonisation of the respiratory tract. However, there is
growing evidence that dynamics of microbial community composition within the
respiratory tract of COPD patients are associated with the development of
exacerbations and their outcome.

A longitudinal analysis of the sputum microbiota of patients with COPD found
that bacterial communities were relatively stable over time within most
subjects, but found this stability to be lower during acute exacerbations.
Moreover, the study found that microbiota profiles differed between different
exacerbation phenotypes and aetiologies. Temporary changes of the sputum
microbiota have also been observed in another cohort, which described four
distinct clusters of microbiota composition, three of which were characterised
by dysbiosis and were significantly different from a stable core microbiota.
Moreover, respiratory microbiota composition was found to be distinct in
patients with frequent exacerbations and associated with one-year survival
following hospitalisation for an acute exacerbation of COPD. These findings
suggest that monitoring changes in microbiota composition of the respiratory
tract could be used to assess the individual short-term risk of acute
exacerbations of COPD, and, in combination with clinical parameters be a useful
tool for risk stratification in the prevention of COPD exacerbations.

REDALERT*s goal is to combine the ISPro technology and geneXplain platform to
develop an integrated solution for routine RTM analysis with:

A) novel processing methods for ISPro to accurately characterize the RTM and
the relative abundance and shifts therein of microbiota
B) clinical decision-making algorithms based on the geneXplain platform to
predict exacerbations from RTM samples and associated clinical patient data

The study is a prospective, longitudinal, observational two-centre study.

Patient recruitment:
Patients will be recruited and screened for eligibility among in- and
outpatients at the Departments of Respiratory Medicine at University Hospital
Frankfurt and Maastricht University Medical Centre. Patients can be approached
both during acute as well as exacerbated disease state; however, clinical
stability is a requirement for the baseline examination and commencement of
data recording. Visits consists of inclusion visit, baseline examination,
remote visits, half-yearly visits and exacerbation visits.

Inclusion visit:
For inclusion in the study, the patients* eligibility for participation in the
study is checked by a study physician. Written informed consent is obtained
before enrolment in the study.

Baseline examination (V1):
Takes place after the informed consent form is signed.
A baseline examination will be conducted before commencement of data recording
and during a period of clinical stability, i.e. at least 4 weeks after the last
acute exacerbation had occurred, and at least 4 weeks after the last treatment
with antibiotics or systemic corticosteroids. If these
conditions are fulfilled at the time of inclusion into the study, inclusion
visit and baseline examination can be combined. For patients not fulfilling
these criteria, the baseline examination is conducted at a later time point
(when the criteria are fulfilled).

The baseline examination consists of a medical history, physical examination,
and collection of biomaterials for additional analyses (a throat swab, sputum
sample). Co-morbidities, current and recent medication as well as COPD-related
health-care utilisation and/or medications related to exacerbations in the past
12 months will be documented. An assessment of COPD-related symptoms will be
made using the COPD assessment test and the modified Medical Research Council
(mMRC) dyspnoea score. As a reference prediction tool, probabilities of the
occurrence of exacerbations will be calculated using the ACCEPT tool.

During the baseline visit participants will moreover be instructed how to
self-collect throat swabs and sputum samples for the remote visits and prepare
them for shipment. If possible, the self-collection of samples will be
performed once under supervision by a member of the
study staff.

Remote visits:
Remote visits (sampling only, additional sampling points to V1, V4 and
Exacerbation visits):

One week (+/- 2 days) after baseline visit (V1), one week (+/- 2 days) after
visit at six months (V4), Four weeks (+/-4 days) after acute exacerbation visit
(AECOPD).In order to analyse the short-term variability of the respiratory
microbiota and to determine microbiota profiles after recovery from an acute
exacerbation, patients are asked to self-collect a throat swab and
spontaneously expectorated sputum and hand the samples in or mail them to the
study centres within 5 days. If samples are to be sent by mail, participants
will receive appropriate shipping material and instructions beforehand.

Full remote visit:
Two months (V2), four months (V3), eight months (V5) and ten months (V6) after
baseline visit; all +/- 7 days

During structured phone interviews, patients are asked if they experienced an
acute exacerbation since the last study visit. Moreover, they are asked about
respiratory infections, changes in their medication, and COPD-related
healthcare utilisation since the last visit, in order to identify possibly
unreported/undetected exacerbations in the period since last visit. Symptom
scores (CAT, mMRC) and exacerbation risk assessment using the ACCEPT tool are
recorded. Patients are asked to self-collect a throat swab and spontaneously
expectorated sputum and hand the samples in or mail them to the study centres
within 5 days. If samples are to be sent by mail, participants will receive
appropriate shipping material and instructions beforehand.

Half-yearly visit:
Six months (V4) and 12 months (V7) after baseline visit (+/- 14 days)

Patients are asked to return to the study centre for physical examinations, a
regular check-in for the study procedures and handing out the remainder of the
study materials. The CAT score, mMRC score and aforementioned questionnaires
will be
recorded. The exacerbation risk assessment (ACCEPT tool) will be updated. Where
applicable, the documentation of co-morbidities will be updated.Throat swabs
and sputum samples will be collected.

Exacerbation visits:
Patients experiencing an acute exacerbation, defined as an acute worsening of
respiratory symptoms resulting in additional therapy, will be asked to contact
the study centre within 3 days of onset.

Patients are asked to self-collect a throat swab and sputum sample and send
them to the study centre within 5 days. Respiratory symptoms, CAT and mMRC will
be recorded.Four weeks after the exacerbation, patients are again asked to
self-collect respiratory samples (throat swab, sputum) and send them to the
study centre. If patients seek treatment for an acute exacerbation at the study
site, sampling and questionnaires can also be performed at the centre.
Likewise, collection of respiratory samples can be performed on site instead of
remotely, if a regular visit coincides with the sampling window for the samples
collected four weeks after an acute exacerbations.

The invasive nature of this study is very mild and the risk to the subjects is
very low/negligible. However, the results of this study can contribute
significantly in a better/more personalized treatment for a very large patient
group. The results aim to ultimately improve individual treatment of COPD,
thereby improving quality of life and reducing the death rate from this
disease.