Understanding Inflammation, InFection and Interventions in Severe Exacerbations of Cystic Fibrosis

Participants will be recruited by staff within the care of UK CF centres. Initial discussions will occur either during routine outpatient reviews, telephone consultations or during admissions. Consent will take place prior to any other procedures. The investigators will provide the option of re-using baseline stable visits from the CF-Tracker study as stable visits for the UNIFIED-CF study. Consent to do this is specifically taken in UNIFIED, the investigators have added this as an option, and participants can opt to repeat the visit.

Participants will be people living with cystic fibrosis being cared for at a participating centre in the UK. The study will enrol only those who are considered to be at risk for severe exacerbation in the next 24 months. Up to 300 participants will be recruited across 6 sites (expected number needed to get 125 exacerbations = 200).

Participants will be assessed during a period of clinical stability. Participants taking part in another hub study (CF-Tracker, IRAS: 338539) where the same data and samples are being collected will not need to repeat this visit and will be given the option of re-using the outcomes from the previous visit, or participants can also opt to repeat the visit.

If a participant has had a stable baseline visit but has not undergone any eligible CF exacerbations, they will be monitored for two years. They will be invited to a second stable baseline visit to repeat the same measurements after 12 months (range 10-14 months).

If participants are admitted to one of the participating CF units for treatment of a pulmonary exacerbation, they will be eligible to take part in the Exacerbation Treatment arm of the UNIFIED study and will be monitored during their admission for up to a maximum of 17 days. In this arm, participants will undergo repeated assessments at pre-specified timepoints before and during their treatment at Pre-IV antibiotic baseline, Day 3 (range = day 2-4), Day 7 (range = day 6-8), Day 10 (range = day 9-12) and discharge day, alongside standard clinical care. A follow-up visit will take place after 6-14 weeks once the participant has returned to clinical stability. After this follow-up visit their will be no further participation.

Inclusion criteria

• Confirmed diagnosis of cystic fibrosis (CF), defined as presence of two pathogenic CF-causing CFTR mutations AND clinical features consistent with a diagnosis of CF, OR presence of at least one pathogenic CF-causing CFTR mutation AND sweat chloride (before use of CFTR modulators) >60mmol/L AND clinical features consistent with a diagnosis of CF.
• Receiving care from a UK Adult Cystic Fibrosis Centre taking part in the study.
• EITHER:

• Have had at least 1 previous exacerbation of CF lung disease, treated with intravenous antibiotics, in the previous 12 months.

OR

• Enrolled in the CF-Tracker study (IRAS ID 338539) within the last 24 months (dated from date of completion of baseline Tracker visit)
• In case of treatment for an exacerbation, likely to be treated with a ß-lactam or an anti-pseudomonal penicillin, combined with tobramycin or colistin, per CF Trust and NICE guidelines for 1st-line CF therapies.
• Able to produce sputum (spontaneous or induced) at baseline visit.
• Able to understand the patient information sheet, willing to consent to study protocol.

Exclusion criteria

• When attending for the baseline visit participants should be clinically stable at the time of the visit. This is defined as no acute change in their baseline symptoms or presence of new viral symptoms. They should not be on additional antibiotics or anti-viral therapies for any reason (above their usual medications), and should have completed any such additional therapies at least 4 weeks prior.
• Extensive antibiotic allergies or intolerances that mean they could not be treated with standard CF antibiotic regimens, as outlined in section 5.6.
• Subjects with infection with Mycobacteria tuberculosis
• Subjects with active ABPA, defined as receiving treatment for ABPA currently or within the last 4 months, or those considered at risk of requiring treatment for ABPA in the next 12 months.
• Subjects receiving long term oral steroids at an equivalent dose of 10mg or more per day of prednisolone.
• Subjects receiving any other form of long term immune-suppressant therapy.
• Subjects with non-tuberculous mycobacteria (NTM) infection who are undergoing active eradication therapy. Subjects with chronic NTM infection who are not on eradication therapy, and not expecting to start this within the next 12 months, are not excluded.
• Any other condition, co-morbidity or other feature that, in the opinion of the investigator would render the subject unable to complete the protocol or unsuitable for inclusion.
• Planning on participating in a clinical trial of a novel experimental investigational medical product in the next 12 months.