TAAI Erasmus Research Initiative to Fight CF: Monitoring Inflammation in CF Lung disease into a new Era

Progressive destruction of the lungs is the main cause of shortened life
expectancy in cystic fibrosis (CF). Inflammation and respiratory infections
play a key role in CF lung disease. Previous studies have shown that an
increase in inflammatory markers predicts structural lung damage like
bronchiectasis in infants with CF. Close monitoring of people with CF (pwCF) is
crucial to adequately provide optimal care. Pulmonary management of pwCF is
focused on treating infections and pulmonary exacerbations, and maintaining
lung health by doing sports and stimulation of muco-ciliary clearance, to
prevent or at least slowdown progressive structural lung damage. To evaluate
treatment and incite timely interventions it is important for the pulmonary
physician to be well informed about the condition of the lungs. The main
monitoring tools in regular CF care are lung function, sputum cultures, symptom
reporting and more recently imaging by chest computed tomography (CT-scan) or
magnetic resonance imaging (MRI). Strangely enough, there are currently no
monitoring tools used in clinics to measure inflammation in the lung, although
this is a main factor for progressive lung disease. We are on the edge of a new
era for CF. The recently approved highly effective modulators therapy (HEMT)
such as elexacaftor/tezacaftor/ivacaftor [ETI, Kaftrio®] will change the course
of the disease. ETI has shown to be highly effective by improving lung function
substantially and reducing pulmonary exacerbations by 3-fold. In studies with
the first cystic fibrosis transmembrane conductance regulator (CFTR)
modulators, like ivacaftor and lumacaftor/ivacaftor, it is shown that although
lung function improves and pulmonary exacerbations are reduced, that
inflammation in the lungs is still present. Long term follow-up with the first
generation of CFTR modulators shows a decline in lung function overtime,
although it is less steep than before treatment. For ETI there is no long term
follow-up data yet, and it is also not known how inflammation in the lungs will
change by using ETI. Monitoring pwCF on HEMT may be different than before, as
lung damage seen on chest-CT will be less apparent and lung function will
improve considerably, therefore not being adequate markers anymore for subtle
changes in the lungs. Thus, the focus of monitoring in the era of highly
effective CFTR modulators needs to change preferably focussing on changes in
inflammation in the lungs. A good monitoring tool should be minimally invasive,
quick and give an accurate value with good sensitivity and specificity.
Currently inflammatory markers in sputum and broncho-alveolar lavage (BAL) are
now the most commonly used methods to assess inflammation in the lungs. But BAL
entails a bronchoscopy which is rather invasive, and sputum is not always
available. Breathomics, which is analysis of volatile organic compounds (VOC*s)
in exhaled breath, has great potential as a non-invasive test to monitor
inflammation in the lungs. This can be done by using either an electronic nose
(eNose) or gas chromatography-mass spectrometry (GC-MS). Other promising
markers and techniques are: inflammatory markers in blood (cytokines and
micro-RNA (miRNA)) and urine. Therefore, we aim to develop innovative minimally
invasive monitoring techniques that can identify lung inflammation in pwCF
when using highly effective CFTR modulators (ETI), compared to patients who
are not on CFTR modulators. For validation these innovative techniques will be
compared to inflammatory markers in sputum, spirometry and validated symptom
and quality of life scores.

The overall aim of the study is to develop innovative minimally invasive
monitoring techniques that can identify lung inflammation in pwCF when using
highly effective modulators, compared to patients whom are not eligible for
CFTR modulators (control group) yet.

Primary objective is to assess whether measuring VOCs with GC-MS is a sensitive
method to monitor changes in lung inflammation in pwCF.

Secondary objectives are:
- To assess whether eNose is a sensitive method to monitor changes in lung
inflammation in pwCF.
- To explore the usefulness of other inflammatory markers in blood and urine.

Explorative cohort study aimed to develop innovative minimally invasive
monitoring techniques that can identify lung inflammation in pwCF when using
highly effective CFTR modulators. (eNose, GC-MS, inflammatory markers in urine
and blood), compared to a control group: pwCF not using CFTR modulators.
Furthermore, we will in compare this techniques with inflammatory markers in
induced sputum, conventional spirometry, symptom and quality of life scores.

The burden of this study is considered low. PwCF who are eligible to start with
ETI will be included, and a group of patients who are not. The start of ETI is
part of the routine care, and is already approved by the European medicines
agency (EMA) for this indication. The study visits will be combined with the
routine checks as much as possible. At the study visits there will be extra
tests for the study, next to the routine care, which will entail around 30
min-1 hour extra time next to the clinic visit. To limit their burden of the
study for the age group 6-11, we will not conduct all measurements.
Patients >12 years: At all visits there will be exhaled breath sampling, 3
extra vials of blood with a blooddraw, induced sputum, urine sample and 2
questionnaires.
Patients <12 years: At all visits there will be exhaled breath sampling and 1
questionnaire will be done through a interview with the child. On the last
visit 2 extra vials of blood will be collected. For patients 6-18 years of age
a multiple breath washout (MBW) for LCI will be scheduled at study visits.
Exhaled breath and urine sampling will cause a negligible burden. For pwCF
receiving ETI treatment a laboratory blood tests are part of routine patient
care. For pwCF, whom are not eligible to receive ETI treatment, a blood draw is
not always part of routine care. If so, they can opt out for an extra
blooddraw for the study if this is not performed during routine care. Induced
sputum will be obtained by inhaling hypertonic saline and after that sputum
needs to be coughed up with airway clearance techniques. This is something that
patients need to do daily themselves at home, so this will cause only a minor
burden. LCI mainly cost time, but no burden, because it does not require
contrast administration. Subjects may opt out for blood, induced sputum, LCI
and urine samples, but there always need to be an exhaled breath sampling with
eNose and GC-MS. For none of the tests any risks are associated. There will be
no direct benefits for the participating subjects, but the study will provide
valuable information for future development of non-invasive monitoring
techniques.