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Abstract

Background:

There are currently no early parameters that allow prediction of long-term responses to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator treatment on an individual level.

Objectives:

To identify early parameters measured within 7 to 14 days after initiation of treatment with a CFTR modulator to assess CFTR modulator efficacy.

Study design:

Prospective observational study of patients diagnosed with CF who begin elexacaftor/tezacaftor/ivacaftor (ETI) therapy at 3 CF clinics in Switzerland (Geneva, Lausanne, Lucerne).

Methods:

Standardized measurements were taken within 2 months prior to and 7 to 14 days after starting CFTR modulator treatment.

Results:

ETI treatment was started on 47 patients [median age: 12 years] of whom 12 (26%) were switching from lumacaftor/ivacaftor (n = 8) or tezacaftor/ivacaftor (n = 4) to ETI. A significant early treatment effect was observed for BMI z-score (p < 0.001) and inflammatory parameters (white blood cells (p = 0.006), neutrophils (p = 0.006), immunoglobulin G (p = 0.012), and fecal calprotectin (p = 0.002)). In CFTR functional assays, sweat chloride concentration and nasal potential difference testing [Δlow-chloride+isoproterenol, Sermet score, and Wilschanski index] improved significantly (all p < 0.001). Improvement was also observed in lung function (FVC, FEV₁, MMEF_25-75, LCI_2.5%) (all p < 0.001). No changes were found for blood pressure, SpO₂, respiratory rate, erythrocyte sedimentation rate, C-reactive protein, and fecal elastase.

Conclusion:

This study identified clinical, biologic, and functional parameters showing treatment effect early after initiation of CFTR modulator therapy. These parameters may serve as potential predictors of long-term responses to CFTR modulator treatment.

Plain language summary

Early signs of treatment response after 7 to 14 days in patients with cystic fibrosis starting new CFTR modulator therapy

Cystic Fibrosis (CF) is a genetic disease that mainly affects the lungs and other organs. A newer group of medications, known as CFTR modulators, has significantly improved treatment options for people with CF. One of the most effective combinations is elexacaftor, tezacaftor, and ivacaftor (ETI). However, not all patients respond equally well to this treatment, and the reasons for these differences are still not fully understood. In addition, ETI is only approved for certain genetic variants, meaning that about 10% of people with CF cannot currently receive it—despite research suggesting that many of them could benefit. Identifying early on who is likely to respond well to ETI could help avoid unnecessary side effects and healthcare costs for those unlikely to benefit. In our study, we aimed to identify early signs that could predict whether a patient will respond positively to ETI therapy. We followed 47 patients with CF (median age: 12 years) at three hospitals in Switzerland. We measured various health indicators - such as weight, markers of inflammation, CFTR function tests, and lung function - just before starting ETI and again 7 to 14 days after treatment began. Even within this short period, we observed improvements in body weight, blood and gut inflammation, lung function, and CFTR function (based on sweat chloride levels and nasal potential difference tests). These early improvements could help predict long-term benefits of CFTR modulator treatment. Our ongoing research is investigating whether these early indicators can reliably support doctors in making more personalized treatment decisions for people with CF.

Keywords

CFTR modulator treatment elexacaftor ivacaftor nasal potential difference short-term response tezacaftor

Introduction

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators have revolutionized the care of patients with cystic fibrosis (CF), notably the highly effective combination elexacaftor, tezacaftor, and ivacaftor (ETI).^1,2 ETI has led to substantial improvements in lung function, nutritional status, and quality of life for many people with CF and has become the standard of care for eligible patients in high-income countries.³ However, the response to CFTR modulators varies from patient to patient, and the mechanisms driving this variability remain poorly understood.⁴ There is currently no parameter that allows prediction of long-term responses to CFTR modulator treatment on an individual level.⁵ The European Medicines Agency has approved ETI for patients aged ⩾2 years carrying at least one F508del CFTR variant, and the United States Food and Drug Administration (FDA) extended access to 177 rare CFTR variants. Currently, however, around 20% of patients with CF are ineligible to receive ETI therapy in Europe.⁶ This raises important clinical and ethical questions, particularly considering emerging evidence suggesting that many patients with non-approved variants could still benefit from CFTR modulators.^7
–9

Considering the impossibility of properly studying CFTR modulator efficacy in clinical trials for all genotypes (>2000 CFTR variants identified so far), Burgel et al. proposed a 6-week ETI treatment trial to individually assess its efficacy.¹⁰ The study identified many ETI responders, of whom 49% carried no CFTR variant currently approved by the FDA. Estimates showed that responders to ETI could represent more than half of those who are currently not eligible, potentially reducing the non-eligible population from 17% to 8%–10% of patients with CF. Although a 6-week trial is feasible in clinical practice, it would be ideal to identify treatment responders as early as possible after having started treatment.

There is, therefore, a strong need for identifying early markers that can predict long-term treatment response to ETI. Early stratification of responders and nonresponders would minimize possible side effects, mostly occurring in the first weeks, reduce unnecessary treatment costs in nonresponders, and avoid the risks associated with administering a CFTR modulator to patients who do not respond to the treatment.

We hypothesized that individual clinical parameters, or a combination of them, measured early after initiating CFTR modulator therapy, could predict long-term treatment outcomes, supporting a more personalized and effective approach to CF care. To test this hypothesis, this study aimed to identify early markers that show significant changes within the first 7 to 14 days of treatment.

Methods

Inclusion and exclusion criteria

We included patients with CF aged 4 months or older who started ETI treatment as part of routine care in our multi-center national prospective observational study with data from three CF centers in Switzerland (Geneva, Lausanne, Lucerne). Patients who were unable or unwilling to provide informed consent, had missing CFTR assays, or underwent assessments outside the predefined timeframe were excluded from the study. Data from June 2020 to December 2022 were analyzed. All visits and the majority of the studied parameters were integrated into the routine standard of care for patients undergoing CFTR modulator treatment, as required by the Swiss Federal Office of Public Health (FOPH) and proposed by international guidelines or expert advice.^11,12 The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material).¹³

Patient characteristics and assessment timeline

Patient characteristics included demographics (age, gender, CF center, ethnic group), CFTR genotype, medical history, and treatment. The first assessment (“Baseline”) was performed within 2 months prior to starting CFTR modulator treatment. A second assessment (“D7-14”) was performed between 7 and 14 days after starting treatment. In both visits, symptoms were recorded, clinical parameters were assessed (height, weight, body mass index (BMI) z-score, SpO₂, respiratory rate, systolic and diastolic blood pressure), biological markers were measured (see below), and CFTR functional assays (sweat test and nasal potential difference (NPD) test) and lung function tests were performed.

Biological markers

CF is a chronic inflammatory disease that primarily affects the lungs and digestive system. Blood tests can provide insight into the immune response, persistent lung inflammation, and disease progression. In addition, markers of intestinal inflammation help monitor gastrointestinal complications and pancreatic function. The biological markers evaluated included blood inflammation (white blood cell count, erythrocyte sedimentation rate, C-reactive protein, immunoglobulin G), liver function (ASAT, ALAT, total bilirubin), gastrointestinal inflammation (fecal calprotectin), and pancreatic function (fecal elastase) parameters.

Nasal potential difference measurements

NPD evaluates ion transport across the nasal epithelium, providing a direct measure of CFTR function, and helps to determine how well CFTR modulators restore chloride transport. Measurement of the NPD test was carried out in accordance with the standard operating procedure of the ECFS.¹⁴ After initial perfusion with Ringer’s lactate (basal potential), changes in electric potential were recorded after perfusion with amiloride in Ringer’s lactate (Δ amiloride), amiloride in low-chloride solution (Δ low-chloride), further addition of isoproterenol (Δ isoproterenol), and finally, Adenosine Triphosphate (ATP) in both nostrils. Key outcome parameters included the response to Epithelial sodium Channel (ENaC) inhibition (i.e., Δ amiloride), the response to CFTR stimulation (i.e., Δ low-chloride+isoproterenol), and composite scores for CF diagnosis, such as the Wilschanski index (e ^{Δ low-chloride + isoproterenol / Δ amiloride}, normal value < 0.7) and the Sermet score (−(0.11 × Δ low-chloride + isoproterenol) – (0.05 × Δ amiloride), normal value > 0.27).

Lung function measurements

To assess airway obstruction and CF-related lung damage, we evaluated lung function measurements including functional vital capacity (FVC), forced expiratory volume in the first second (FEV₁), maximal mid-expiratory flow at 25%–75% of FVC (MMEF_25-75), and lung clearance index at 2.5% of starting end tidal nitrogen concentration (LCI_2.5%).

Statistical analyses

Statistical analyses were carried out using IBM SPSS Statistics, Version 25. Baseline and D7-14 data were compared with a paired t-test or Wilcoxon signed rank test. A p-value of < 0.05 was considered statistically significant.

Results

ETI treatment was started in 47 patients, of whom 12 (26%) were switching from lumacaftor/ivacaftor (n = 8) or tezacaftor/ivacaftor (n = 4) to ETI. Patients were switching to a new treatment as part of routine care. A detailed flow chart of the study population recruitment is shown in Figure 1. The first assessment was performed at a median of 27 days (0–78 days) before ETI start, and assessment D7-14 at a median of 10 days [7–14 days] after ETI start. We observed significant changes in numerous parameters between baseline assessment and assessment D7-14.

Figure 1.

Flow chart of the study population recruitment.

Patient characteristics

Baseline patient characteristics are shown in Table 1. Mean age at baseline was 12.5 years (SD: 4.5), ranging from 6 years to 30 years. All patients were Caucasian. Two patients had a pulmonary exacerbation at baseline, but none showed an exacerbation at the second assessment. Airways microbiology samples were obtained in all patients; in 24 (51%) by cough swab, in 23 (49%) by sputum, and in 1 (2%) by broncho-alveolar lavage. In 37 (78%) patients, pathogens were detected, including Staphylococcus aureus (n = 29, 62%), Haemophilus influenzae (n = 5, 11%), Stenotrophomonas maltophilia (n = 4, 9%), and Pseudomonas aeruginosa (n = 3, 6%). None of the patients had CF-related diabetes.

Table 1.

Baseline patient characteristics.

Features	Patients starting ETI(n = 47)
	n (%)
Total population
Male	25 (53)
Age
0-5 years	0 (0)
6-11 years	23 (49)
12-17 years	22 (47)
⩾18 years	2 (4)
Center for clinical visit
Lausanne	23 (49)
Lucerne	20 (43)
Geneva	4 (9)
Medical history
Pancreatic insufficiency	46 (98)
Chronic Pseudomonas aeruginosa^a	4 (9)
Treatment at baseline
Hypertonic saline^b	34 (72)
Azithromycin^b	6 (13)
Dornase alfa^b	34 (72)
CFTR modulator	12 (26)
LUM/IVA	8 (17)
TEZ/IVA	4 (9)
Genotype
Homozygote F508del variant	23 (49)
Heterozygote F508del variant	24 (51)
Other	0 (0)
Exacerbations
In the previous year
none	26 (55)
1–3 exacerbations	16 (34)
>3 exacerbations	5 (11)
Severe exacerbation in the previous year^c	11 (23)

Defined as ⩾3 positive cultures in the last 6 months.

For ⩾6 months.

Requiring hospitalization or IV antibiotics.

Clinical parameters

After 7–14 days of CFTR modulator treatment, BMI z-score, which was normal at baseline in all but two patients, increased slightly by 0.17 (p ⩽ 0.001, Table 2 or panel a of Figure 2). No significant differences were found for SpO₂, respiratory rate, and blood pressure (Table 2).

Table 2.

Clinical parameters and biological markers.

Features	ETI courses (n = 47)
Features	Baseline		Assessment D7-14		Absolute change from baseline	p-Value
	n	mean (SD)	n	mean (SD)
Clinical parameters
BMI z-score	45	−0.48 (0.82)	41	−0.31 (0.73)	0.17	<0.001
SpO₂ (%)	46	98.09 (1.60)	44	98.16 (1.18)	0.07	0.763
Respiratory rate (per minute)	29	20.38 (2.51)	28	19.61 (3.03)	−0.77	0.301
Systolic blood pressure (mmHg)	41	108.15 (11.15)	37	106.86 (11.73)	−1.29	0.771
Diastolic blood pressure (mmHg)	41	64.54 (9.24)	37	64.86 (8.81)	0.32	0.918
Blood tests
White blood cells (Giga/l)	46	8.51 (2.53)	43	7.45 (2.63)	−1.06	0.006
Neutrophils (Giga/l)	46	4.91 (2.42)	43	3.96 (2.18)	−0.95	0.006
Erythrocyte sedimentation rate (mm/h)	43	10.86 (12.27)	44	10.93 (12.06)	0.07	0.356
C-reactive protein (mg/l)	44	2.48 (10.58)	42	0.62 (1.79)	−1.86	0.594
Immunoglobulin G (g/l)	45	10.06 (4.67)	45	10.23 (4.75)	0.17	0.012
ASAT (U/l)	29	32.14 (14.06)	26	38.88 (17.42)	6.74	0.010
ALAT (U/l)	44	34.48 (19.76)	47	48.94 (42.94)	14.46	0.003
Total bilirubin (µmol/l)	28	9.54 (8.40)	27	15.04 (14.65)	5.5	<0.001
Gamma-GT (U/l)	44	15.36 (8.74)	44	19.50 (17.93)	4.14	0.026
Stool tests
Fecal calprotectin (µg/g)	42	152.33 (153.30)	35	75.77 (58.43)	−76.56	0.002
Fecal elastase (ug/g)	45	31.33 (159.95)	34	12.79 (51.72)	−18.54	0.60

p-Values (Bold significance).

Figure 2.

Evolution from baseline to 7–14 days after start of ETI treatment in clinical parameters (a), biological markers (b–g), CFTR functional assays (h–k), and lung function tests (l–o). Horizontal black bars indicate mean values. The dotted black lines show the evolution of means, and the colored solid lines show the evolution for each patient. Dotted horizontal lines represent ULN/LLN (a, l–n) or cut-offs in healthy patients (b, c, h–k, o). No cut-offs are depicted in d-g as normal values depend on age. Patients with no prior CFTR modulator treatment and patients with switch of CFTR modulator are illustrated in different colors (individual Graphs in high-resolutation in the Supplemental Material).

Biological markers

Blood and stool results are displayed in Table 2 and Figure 2 (panel b-g), showing a significant reduction of systemic and digestive tract inflammation. Fecal calprotectin, which was elevated in 27 (82%) patients at baseline, decreased and normalized in 15 (56%) of them (panel c). Only four patients (15%) with elevated fecal calprotectin reported mild abdominal discomfort. Most of our patients did not experience gastrointestinal symptoms or changes in stool within 7–14 days of starting or switching CFTR modulator treatment. For fecal elastase (panel b), no significant differences were found. Blood leucocytes and neutrophils decreased, while there was a slight increase in IgG (panels d-f). An increase in neutrophils was seen in 12 (26%) patients. Of them, 10 (83%) patients had positive airway microbiology at baseline (Staphylococcus aureus, Haemophilus influenzae, or Pseudomonas aeruginosa), and 7 (58%) had upper airway infection symptoms in one of the assessments. No significant changes were found for erythrocyte sedimentation rate and C-reactive protein (Table 2). Serum transaminases, which indicate hepatic injury, increased significantly from baseline to D7-14, but no patient showed a > 5x ULN elevation in transaminases or a > 3x ULN bilirubin elevation (Table 2 and panel g). None of our patients showed severe side effects of ETI treatment or complained about mental fogginess. Thus, no patient required therapy discontinuation. Significant modifications from baseline to D7-14 were also observed for aspartate transaminase (p = 0.010), total bilirubin (p < 0.001), and gamma-GT (p = 0.026) as seen in Table 2.

CFTR functional assays

At baseline, all patients had abnormal sweat chloride values (chloride ⩾60 mmol/L, Table 3 and panel h of Figure 2). At D7-14, all of them showed an improvement. 31 (87%) patients had intermediate values (chloride 30–59 mmol/L) and 4 (9%) had normal values (chloride < 30mmol/L). NPD measurements were available at both assessments in 24 (51%) patients, as seen in Table 3. In the response to chloride-free solution plus isoproterenol, as a measure of total chloride conductance in NPD measurement, the number of patients with normal values (< −7mV) increased from 2 (8%) at baseline to 16 (67%) at D7-14 (panel i). Further, Δamiloride (p = 0.016), Δlow-chloride (p = 0.002), and Δisoproterenol (p = 0.001) showed significant improvement (Table 3). Regarding the two main CF diagnostic scores in NPD, the number of patients with normal values increased from 2 (8%) to 16 (67%) for the Wilschanski index and from no patient to 10 (42%) for the Sermet score (panels j and k). Conversely, two patients with F508del/1717-1G > A and F508del/Q39X genotypes showed worsening of ionic transport in NPD measurement. Both started ETI without a prior CFTR modulators course and showed a good response in sweat chloride (−47mmol/l and −52mmol/l) and lung function testing (FEV₁ + 17% and +9%, LCI_2.5% −4.02 and −1.13).

Table 3.

CFTR functional assays.

Test	ETI courses (n = 47)
Test	Baseline	Assessment D7-14	Absolute change from baseline	p-Value
Sweat test, mean (SD)	n (%) = 46 (98)	n (%) = 47 (100)
Sweat chloride (mmol/l)	99.96 (12.50)	48.43 (16.86)	−51.53	<0.001
NPD test, mean (SD)	n (%) = 24 (51)	n (%) = 24 (51)
Ringer’s lactate (basal potential) (mV)	−49.63 (15.60)	−37.22 (16.79)	12.41	0.010
Ringer’s lactate + amiloride (mV)	−18.72 (17.88)	−15.34 (9.50)	3.38	0.290
Amiloride + low-chloride (mV)	−19.53 (16.29)	−21.44 (12.66)	−1.91	0.689
Amiloride + low-chloride + isoproterenol (mV)	−20.76 (16.29)	−27.89 (13.83)	−7.13	0.123
Amiloride + low-chloride + isoproterenol + ATP (mV)	−34.74 (19.58)	−38.15 (17.70)	−3.41	0.530
Δ amiloride (mV)	−29.28 (12.22)	−21.88 (11.73)	7.40	0.016
Δ low-chloride (mV)	−0.82 (3.83)	6.10 (7.74)	6.92	0.002
Δ isoproterenol (mV)	1.23 (3.68)	6.45 (4.66)	5.22	0.001
Δ low-chloride + isoproterenol (mV)	−0.42 (5.35)	−12.55 (9.52)	−12.13	<0.001
Sermet score	−1.42 (0.75)	0.29 (0.96)	1.71	<0.001
Wilschanski index	1.05 (0.33)	0.60 (0.22)	−0.45	<0.001

p-Values (Bold significance).

Lung function tests

Regarding lung function in Table 4 and Figure 2 (panels l–o), FEV₁ was reduced in 11 (23%) patients at baseline, and increased in 42 (91%) patients, with an improvement > 10% of baseline in 24 (52%) patients (panel m). Thirty-five (76%) patients showed an increase of FVC, and 41 (89%) an increase of MMEF_25-75 (panels l and n). Absolute values, percentages predicted, and FEV₁/FVC also improved (Table 4). LCI_2.5%, which was abnormal in 38 (86%) patients at baseline, improved in 40 (95%) patients at D7-14 (panel o). If a responder is defined as a reduction in sweat chloride > 20mmol/l or an increase in FEV₁ >10%,¹⁰ all our patients were treatment responders to ETI.

Table 4.

Lung function tests.

Test	ETI courses (n = 47)
Test	Baseline	Assessment D7-14	Absolute change from baseline	p-Value
Spirometry, mean (SD)	n (%) = 47 (100)	n (%) = 46 (97)
FVC (L)	2.72 (1.02)	2.87 (1.00)	0.15	<0.001
FVC (%pred)	94.64 (16.08)	99.78 (14.74)	5.14	<0.001
FVC (z-score)	−0.48 (1.40)	−0.08 (1.28)	0.40	0.001
FEV₁ (L)	2.17 (0.83)	2.42 (0.87)	0.25	<0.001
FEV₁ (%pred)	87.74 (19.25)	96.76 (18.82)	9.02	<0.001
FEV₁ (z-score)	−1.11 (1.60)	−0.38 (1.59)	0.73	<0.001
MMEF_25-75 (L/s)	2.17 (1.03)	2.72 (1.21)	0.55	<0.001
MMEF_25-75 (%pred)	74.70 (29.11)	91.13 (33.45)	16.43	<0.001
MMEF_25-75 (z-score)	−1.50 (1.57)	−0.73 (1.58)	0.77	<0.001
FEV₁ / FVC	0.80 (0.10)	0.85 (0.09)	0.05	<0.001
MBW test, mean (SD)	n (%) = 45 (96)	n (%) = 44 (94)
LCI 2.5%	8.94 (1.84)	7.23 (1.47)	−1.71	<0.001

p-Values (Bold significance).

Discussion

We identified numerous parameters showing significant modification as early as 10 days after ETI initiation. These parameters represent potential early predictors of long-term response to CFTR modulator treatment.

Weight gain has already been shown after 1–12 months of ETI treatment^15,16 but our study is the first one to show a weight increase within 10 days of treatment. Fecal calprotectin—a gastrointestinal inflammatory marker predicting pulmonary exacerbations and lung function decline in patients with CF¹⁷—showed a rapid and sharp improvement in nearly all patients, with almost half of them reaching complete normalization after 10 days of ETI. No similar short-term data are available, but studies reported a comparable decrease in fecal calprotectin values after 1 month of CFTR modulator treatment, sustained at 6 months.¹⁸ Blood neutrophilia, a hallmark of systemic inflammation in CF,¹⁹ decreased significantly. Comparable results have been shown after 6–12 months of treatment,^20,21 but to our knowledge, there has been no study looking at inflammatory parameters after such a short period of ETI therapy. Sweat chloride values decreased in a magnitude comparable to what others have found after 4 weeks of treatment (−39 mmol/L to −45 mmol/L).^15,22,23 NPD has been used to assess the response to new therapies in patients with CF.²⁴ One study reported a patient with a normalized Wilschanski index of 0.66 after 2 weeks of ETI treatment.²⁵ Another study showed improvement of NPD values (Δ low-chloride + isoproterenol: −9.9 mV) 2-4 months after ETI therapy start,²⁶ which compares to our results. ETI led to a significant improvement of pulmonary function in 70%–85% of our study population, depending on the parameter assessed (FVC, FEV₁, and MMEF_25-75) after 10 days of treatment. Other studies reported short-term effects on lung function with a FEV₁ improvement of 15% after 2 weeks²⁷ and of 10%–14% after 4 weeks of ETI therapy.¹⁵ LCI has demonstrated great sensitivity to detect subtle changes in lung function, which could provide important information on the efficacy of CFTR modulator therapy, notably in patients with normal spirometry. Herein, we showed a significant improvement in LCI (−1.7), which is similar to the findings of Appelt et al., who observed an improvement after 2 weeks (−1.4) that was maintained after 4 and 16 weeks of ETI treatment (−2.0 and −2.2).²⁷

Our study has limitations. Twelve of our patients were already treated with a CFTR modulator at baseline, and the effect of ETI may thus have been underestimated. In addition, there were no non-F508del patients or patients with more severe disease included, which makes translatability to these patients questionable. Further, as our measurements were performed as early as 7–14 days after initiation of CFTR modulator treatment, potential late-responders would not be identified by these early biomarkers. Finally, we did not include subjective outcome measurements such as quality of life, which might also have shown significant short-term improvements after ETI treatment started.

Conclusion

An increasing number of rare CFTR variants appear to be responsive to ETI, and current eligibility criteria for ETI have been proven to be unreliable.⁹ As in silico or in vivo predictors are not enough to anticipate the effect of ETI,²⁸ a combination with clinical markers seems to be the key to predict clinical responsiveness to ETI treatment. Herein, we identified multiple biomarkers with measurable short-term responses to ETI. Further work will assess if these parameters, taken individually or in combination, allow prediction of long-term response to ETI and accurate differentiation of responders and nonresponders.

Supplemental Material

sj-docx-1-tar-10.1177_17534666251376211 – Supplemental material for Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis

Supplemental material, sj-docx-1-tar-10.1177_17534666251376211 for Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis by Pascal Heer, Clara Fernandez Elviro, Angela Koutsokera, Anne Mornand, Isabelle Rochat, Nicolas Regamey and Sylvain Blanchon in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

We thank the patients and their families for participating in this study. We thank the CF nursing staff of the hospitals of Geneva (RN Nadège Gabent), Lausanne (RN Caroline Dutoit, RN Isabelle Huart, RN Laurence Mioranza), and Lucerne (RN Sonja Ettlin, RN Lucia Eichhorn) for their help with patient sample collection. We would also extend our thanks to the Pediatric Clinical Research Unit of Lausanne (Rebecca Oppenheim, Florence Bellanger, Samantha Zerbib).

Declarations

ORCID iDs

Pascal Heer

Angela Koutsokera

Anne Mornand

Nicolas Regamey

Sylvain Blanchon

Supplemental material

Supplemental material for this article is available online.

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