Methods
The study was approved by both hospital IRB-committees and informed
consent was obtained from the patients or parents/caregivers. The study
was conducted between 2015 ā 2018. Patients above the age of 4 years
with a confirmed diagnosis of
CF10,
FEV1 ā„80% predicted, clinically stable, and with no
pulmonary exacerbations (PEx) in the four weeks prior to the study, were
recruited from two CF Centers, the Hadassah Medical Center in Jerusalem,
Israel, and the Vall dā Hebron Hospital in Barcelona, Spain.
Demographic data e.g., age, gender, CFTR-mutations, body mass index
(BMI), pancreatic status [pancreatic insufficiency (PI) or sufficiency
(PS)] and the presence of CF-related diabetes (CFRD), were obtained
from patient files. Spirometry was measured according to ATS/ERS
guidelines11.
FEV1 results were transformed into Z-scores using the
Global Lung Function Initiative calculator (version 3.3.1). Multiple
breath washout (MBW) test was performed using the Exhalyzer D (EcoMedics
AG, Duernten, Switzerland), according to ERS/ATS Consensus
Guidelines12, and was carried out on the same visit
day of the spirometry in order to correlate the results. Mean LCI
calculated from a minimum of two technically valid and repeatable tests
was reported. Analysis of MBW data was performed using the nitrogen
washout FRC/LCI software (Spiroware).
All chest high resolution computed tomography (HRCT) scans performed
during the study period (up to one year before or after spirometry and
LCI tests) were examined by an experienced radiologist or by a
specifically trained pediatric pulmonologist. HRCT scans were analyzed
based on the modified Brody score; hyperaeration of the lungs was
assessed instead of air trapping as expiratory images were not available
for all patients13. Subscores for the presence and
severity of bronchiectasis, mucous plugging, bronchial wall thickening,
parenchyma, and focal hyperaeration in each lobe were calculated.
Parenchymal findings of ground glass opacities, consolidations, and
cysts or bullae were considered in determining a single parenchymal
subscore. The sum of subscores comprised the lung Total Brody Score
(TBS) for each patient, ranging from 0 to 207. Pulmonary exacerbations
(PEx) were defined as acute clinical deterioration, including malaise,
anorexia, dyspnea, fever, increased cough, change in sputum
quantity/quality, worsening in nutritional status and/or decline in
pulmonary function, requiring addition or change of oral (PO) or
intravenous (IV) antibiotics (Abx). Pulmonary exacerbations were
subdivided into minor exacerbations, requiring PO antibiotics andmajor exacerbations, if IV Abx had to be initiated. Expectorated
or induced sputum samples for microbiologic analysis are routinely
collected from CF patients at each visit to the CF Center. Respective
data were retrieved from patient files and/or electronic medical
records. Chronic P. aeruginosa (PA) infection was defined by the
Leeds criteria, i.e. >50% of the sputum samples over the
preceding 12 months were positive14. Chronic PA
infection, the number and type of PEx and duration of Abx treatment in
days, during the previous year, were evaluated for each spirometry, LCI
and HRCT test time point performed by each patient. A six-minute walk
test (6MWT) was performed according to ATS
guidelines15. The 6MWT results (i.e. six-minute walk
distance [6MWD]) were transformed into Z-scores based on reference
data16,17 using the following formula: {value found ā
normal value / standard deviation}.