In Belgium, ETI reimbursement for eligible patients with cystic fibrosis was very late (September 2022). Under ETI treatment, substantial improvement is well documented after 2 weeks. Yet, little is known about what more precisely happens during these 14 days. We aimed to monitor this period closely. In this prospective observational study (NCT05599230), the first 20 patients meeting the following criteria were recruited: ≥ 12 y of age, medical and psychological stability, owning a smartphone, Grade A acceptability of spirometry and FEV1 repeatability at the baseline visit preceding the Monday on which treatment was started. Home spirometry (Spirobank) was recorded on the 3 days prior to the start of treatment and then daily for 14 days, as was a respiratory symptoms score (RRS) and a diary of events experienced by each patient. Baseline data and those collected at the next visit, after 6 weeks of treatment, were also compared. Mean age (± SD) of the 20 patients (8M) was 29.4 (± 11.1) years, mean FEV1 84.2 (± 17.7) pr, mean BMI z-score: 0.18 (± 0.82). Except for 7 patients carrying a F508del/min F genotype, all were already on modulators (I: 2, T/I: 11 of whom 4 F508del/res F). After 6 weeks under ETI, FEV1 increased on average by 10.3% VA (p < 0.0001). Compared with the average of the 3 days before the start of treatment, the RSS deteriorated significantly on D1 (p < 0.05), then improved from D6 onwards. The quality of FEV1 measurements at home was high (grade A: 82%). FEV1 improvement became significant from D6 onwards too. In one patient, a 25% decrease in FEV1 was observed at D4, which quickly responded to a three-day course of oral steroids. Providing detailed information to patients before starting the treatment proved to be valuable. Respiratory benefit was significant from day 6. The most troublesome events occurred during the first 4 days of treatment. Starting treatment on a Monday seems to be advisable.

Cystic fibrosis care is expensive. In Belgium, its financial support is not provided by powerful charities but by the national health system, which also sponsors the Belgian Cystic Fibrosis Registry. Recent data allow to better evaluate the quality of care for patients with cystic fibrosis in our country. Overall, it is high but varies from one centre to another. Similarly, use of the main symptomatic treatments is heterogeneous. Access to lung transplantation is one of the fluidest in the world. However, Belgium was one of the last medicalised countries to implement a neonatal screening programme for cystic fibrosis. It also lags behind in regard of the reimbursement of modulators of the CTFR gene function. This is especially detrimental for the lack of reimbursement of a recent highly effective combination of three modulators. The cost of this triple therapy is opaque and far too high. However, its effectiveness is impressive and, in the long term, around 90 % of Belgian patients with cystic fibrosis are expected to greatly benefit from it.

In cystic fibrosis, lung disease is early and insidious. It almost always conditions the prognosis. A pragmatic way of looking at prognostic factors is to distinguish those on which care management has little (environmental factors) or no grip (genetic factors) and those related to the quality of care, the latter being crucial. Recently, a triple-combination CFTR («Cystic Fibrosis Transmembrane conductance Regulator») modulator regimen has been shown a highly effective therapy. Ultimately, at least 90 % of Belgian patients with cystic fibrosis should benefit from this drug. However, its official price is extremely high (712 €/day), lacks transparency and illustrates problematic aspects of current orphan legislations. For the majority of citizens in Western Europe, a social ideal still prevails that healthcare should be accessible to all in an equitable fashion. Somewhere between this price and the necessity for national health systems based on solidarity to keep the costs of orphan drugs at a sustainable level, patients are looking like hostages.

INTRODUCTION:Small airways' involvement in cystic fibrosis (CF) pulmonary disease is a very early event, which can progress sub-clinically and insidiously since it is poorly reflected by commonly used lung function tests. STATE OF ART:Sensitive and discriminative tools are available to investigate small airways function. However their complexity and/or invasiveness has confined their use to research purposes and to some specialized research teams. By contrast, the multiple breath washout (MBW) test is more affordable and non-invasive. Lung clearance index (LCI), which is the most used derived parameter, is reproducible and much more sensitive than spirometry in detecting small airways disease. However, MBW is operator dependent. PERSPECTIVES:The recent commercialization of devices assessing LCI launches MBW as a potential tool in routine clinical care, although its use currently remains mostly dedicated to research purposes. However, important differences in LCI between various equipment settings raise a number of theoretical questions. Specific algorithms should be refined and more transparent. Standardization of MBW is still an ongoing process. Whether other MBW derived indices can prove superior over LCI deserves further study. CONCLUSIONS:In CF, LCI is now a well-established outcome in research settings to detect early lung function abnormalities and new treatment effects, especially in patients with mild lung disease. In these patients, LCI seems an attractive tool for clinicians too. Yet, further investigation is needed to define clinically significant changes in LCI and to which extent this index can be useful in guiding clinical decisions remains to be studied.

BackgroundThe sweat test is the current gold standard for the diagnosis of cystic fibrosis (CF). CF is unlikely when sweat chloride (Clsw) is lower than 30mmol/L, Clsw>60 is suggestive of CF, with intermediate values between 30 and 60mmol/L. To correctly interpret a sweat chloride value, the biological variability of the sweat chloride has to be known.MethodsSweat tests performed in two centers using the classic Gibson and Cooke method were retrospectively reviewed (n=5904). Within test variability of Clsw was measured by comparing results from right and left arm collected on the same day. Between test variability was calculated from subjects with sweat tests performed on more than one occasion.ResultsWithin test variability of Clsw calculated in 1022 subjects was low with differences between −3.2 (p5) and +3.6mmol/L (p95). Results from left and right arm were classified differently in only 3 subjects.Between test variability of Clsw in 197 subjects was larger, with differences between −18.2mmol/L (p5) and +14.1mmol/L (p95) between repeat tests. Changes in diagnostic conclusion were seen in 55/197 subjects, the most frequent being changing from indeterminate to ‘CF unlikely’ range (48/102).ConclusionVariability of sweat chloride is substantial, with frequent changes in diagnostic conclusion, especially in the intermediate range.

Background CF is the leading cause of BE in affluent countries and overall it is clearly the most threatening one. Objective To compare outcomes in children with CF and children with non CF BE. Methods 4 Belgian academic Paediatric Pulmonology Units listed all children with non CF BE under care in 2011. From electronic medical files, they then extracted data concerning the 20 first children (by alphabetical order) meeting the following criteria: non-CF BE (CT), 6– Results Main etiologic diagnoses in Group A (n = 80) were PCD (29%), idiopathic BE (21%), immune deficiency (16%), post-infectious (11%), bronchiolitis obliterans (10%), aspiration (6%). Mean BMI (Z score) (±SD) were similar in both groups (A: −0.23±1.19, B: −0.47±1.03, p = 0.18). FVC and FEV1 (% pr, GLI) were lower in group A (FVC: 88.3±19.1 vs 95.9±12.5, p 1 y were available for 62 children with non CF BE (mean duration: 4.1 y). Over this period, mean spirometric and anthropometric outcomes did not decline. Conclusion At a mean age of 11 y, spirometric data of children with CF are more favorable than those of children with non CF BE, suggesting the latter could benefit from the CF model of care.

A stable 20-year-old patient with CF (M, F508del/F508del, last FEV1: 92% pr) was admitted for sudden onset of high-grade fever, FEV1 drop (72% pr) without increased cough, diffuse pain and generalized lymphadenopathies. Initial check-up revealed the presence of prominent and very recent bilateral hilar lymphadenopathies along with a marked inflammatory syndrome. In 4 weeks, IgG level has risen from 15.7 to 30.4 g/L. Within 24 hours, the patient developed a generalized non-pruritic purpuric rash. Despite broad-spectrum IV AB (tobramycin and ceftazidime), daily fever persisted (up to 40°C). On the 6th day, the clinical picture worsened and became life-threatening with impaired renal function, multiple serositis, need for supplemental oxygen, hepatic cytolysis and coagulation abnormalities, major hypergammaglobulinemia (43.9 g/L) and marked hypereosinophilia (4.870/µL). At this point, all non-essential drugs were interrupted with the exception of ceftazidime. Within 7 days, clinical, biological and radiological features all improved. The patient was released under his previous outpatient treatment and without precise diagnosis as all hematologic, autoimmune and viral detection tests were negative. He came back 2 days later due to the recurrence of malaise, fever, rash and biological abnormalities. Rifampicin and moxifloxacin were immediately interrupted and the picture resolved quickly. The patient then disclosed that he kept taking these drugs (no more prescribed) till day 6 of the hospitalization. We concluded that our patient suffered from a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, rifampicin being the most likely causal agent.

Background In CF children, LCI is a more sensitive index of lung disease than FEV1. However, some studies included significant proportions of children with abnormal FEV1 and data obtained using commercially available devices are still limited. Objective To compare diagnostic performance of LCI measurements using two commercially available devices in a clinic where median FEV1 of children (6— Methods Children were studied under stable condition, in the setting of a routine visit. Before spirometry, MBWN2 was performed in duplicate using both the Exhalyzer D (Ecomedics, Switzerland) and the EasyOne Pro (NDD, Switzerland), in random order on the same session. Agreement between devices was assessed by Bland–Altman plot. Diagnostic performance of LCI was defined as the proportion of patients with LCI z-score >2 (reference values derived from duplicate measurements in 47 healthy children). Results 2 acceptable LCI values were obtained with both devices in 44 children with CF [25 M, mean (SD) age: 12.9 y (3.7), range: 6–18]. All had normal FEV1: mean (SD) 100% (14.1) according to GLI. Mean LCI was 9.81 (2.23) with EM and 8.35 (1.86) with NDD, corresponding to +5 and +2.5 SD respectively; mean difference (95% confidence interval) was 1.46 (–1.75, 4.67). The proportion of patients with normal FEV1 but high LCI was 32/44 (73%) with EM and 18/44 (41%) with NDD, p = 0.001. Diagnostic performances of FEF25–75 and LCI NDD were comparable. Conclusion In this group of CF children with normal FEV1, EM yielded higher LCI values and was significantly more sensitive than NDD in detecting ventilation abnormalities.

Objectives: We used to introduce spirometry to 5 year old (yo) children with the aim of having reliable results by the age of 6. In 2009 we attempted this with 4yos. In 2011 a 2.5yo girl was keen to copy her 4yo sibling so was allowed to try spirometry simply to avoid conflict. Since she made a reproducible effort we decided to attempt this in all 3yos. Methods: Spirometry was carried out in clinic by the physiotherapist who knew which blowing techniques the children had learned during airway clearance, such as bubble PEP. A CareFusion MicroLab spirometer was used with the child incentive. Children aged 3 with good comprehension attempted the test. The parents understood the potential unreliability of the test. The children were asked to perform one long blow similar to blowing out birthday candles. The reaction of the incentive cartoon was explained. The flow-volume loop was checked between blows and further explanation given if necessary. The best of 3 attempts was recorded. Results: Some children took a second breath and others did not complete the blow, particularly after the incentive was met. During successive visits this usually improved. Overall 9 of 10 3−4yos produced reproducible results, 5 of whom had useful results at age 3. Several children have had these repeated on multiple clinic visits showing good lung growth with age. Conclusion:We have demonstrated that it is feasible during normal appointments to undertake reproducible spirometry in a significant proportion of children as young as 3. With the new global lung initiative normal ranges extending to younger age groups we will be able to make an earlier start in following individual trends in lung function.

Background:In CF, lung clearance index (LCI) measured by a multiple breath nitrogen washout (MBWN2) is time consuming in patients with advanced respiratory disease.Shortening the test would increase its feasibility.Objective: To assess repeatability and diagnostic performance of LCI in CF adults, from two acceptable runs until 1/40 th (LCI 2.5 , conventional test), 1/25 th (LCI 4 ) or 1/20 th (LCI 5 ) of starting N 2 concentration.Methods: Retrospective analysis of MBWN2 tests performed in duplicate in adults with CF, using the Exhalyzer D (Ecomedics, Switzerland).Time to complete 2 measurements + between resting time (i.e.1.5× washout time), diagnostic performance and repeatability were assessed for LCI 2.5 , LCI 4 and LCI 5 .Results: Data from 34 CF adults were analysed (15 M, median age: 24.5 y, IQR: 21-32; mean±SD FEV1: 84.5±19.8%pr).Mean (SD) LCI 2.5 was 13.73 (3.63).Corresponding values for LCI 4 and LCI 5 were 9.52 (2.29) and 8.14 (1.83) respectively.Compared to LCI 2.5 , repeatability of LCI 4 and LCI 5 were similar, but only the former had similar diagnostic performance and a predictive value (R 2 ) for LCI 2.5 >0.9 (R 2 = 0.92).Mean time needed to complete 2 LCI 4 measurements was 9.9 min vs 15.6 min for LCI 2.5 (p < 0.001, time saving: 38%).Restricting the analysis to the 6 patients with highest LCI (19.01±1.59;mean FEV1: 76% pr, range: 62-96), mean session duration decreased from 21.3 to 11.7 min (time saving: 45%).Conclusion: In this study, LCI 4 appears to be a reliable and more feasible test in CF patients with moderate to severe lung disease.Supported by the Belgian CF Association.