Full Length Article

# Dietary intake remains unchanged while nutritional status improves in children and adults with cystic fibrosis on Elexacaftor/Tezacaftor/ Ivacaftor

<figure><img src="image_1.png" /></figure>

R. Enaud<sup>a, b</sup>, J. Languepin<sup>c</sup>, M. Lagarrigue<sup>d</sup>, A. Arrouy<sup>d, e</sup>, J. Macey<sup>f</sup>, S. Bui<sup>b</sup>, M. Dupuis<sup>g</sup>, L. Roditis<sup>d</sup>, C. Flumian<sup>h</sup>, E. Mas<sup>d, e, h, i, *</sup>, M. Mittaine<sup>d</sup>

ARTICLE INFO

Article history:

Received 5 December 2024

Accepted 24 April 2025

Keywords:

Cystic fibrosis

CFTR modulator

Dietary intake

Nutrition

Children

Adults

SUMMARY

**Background:** Cystic fibrosis (CF) is a genetic disorder involving multi-organ dysfunction, with nutritional status playing a crucial role in disease progression. Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator therapy, particularly the combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), has shown numerous clinical benefits, including significant improvements in nutritional status. However, the factors driving this nutritional improvement, especially the potential role of increased dietary intake, remain underexplored. This study aimed to assess changes in nutritional status and dietary intake in patients with CF (pwCF) treated with ETI.

**Methods:** 62 pwCF (36 children, 26 adults) were analyzed in a prospective, realworld, multicenter study (https://clinicaltrials.gov/study/NCT06072365). Dietary intakes were assessed via 3-day food diaries collected at baseline (M0) and one year after ETI treatment initiation (M12).

**Results:** Over the first year of ETI treatment, Body Mass Index (BMI) significantly increased with a median BMI Z-score gain of 0.2 (IQR: 0.7) for children and median BMI gain of 1.0 kg/m² (IQR: 1.8) for adults. Notably, these gains occurred without a significant increase in median daily caloric intake (2216 kcal (IQR: 750) at M0 vs. 2266 (IQR: 733) kcal at M12). Pancreatic enzyme requirements and calprotectin decreased significantly with ETI (p < 0.001 and p < 0.01, respectively), indicating improved pancreatic function and intestinal inflammation in some patients. Seven patients became overweight after one year of ETI.

**Conclusion:** ETI therapy enhances nutritional status in pwCF, independently of increased caloric intake. Further research is essential to refine dietary recommendations under ETI treatment, aiming to prevent overweight and obesity while optimizing health outcomes.

© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction

Cystic fibrosis (CF) is a severe autosomal recessive disease characterized by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein [1]. This protein functions as an anion channel and is expressed in several organ systems, including the lungs and gastrointestinal (GI) tract. In

<footnote><sup>a</sup> University of Bordeaux, INSERM U1045, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France</footnote>

<footnote><sup>b</sup> Bordeaux University Hospital, CRCM pédiatrique, CIC 1401, Bordeaux, France</footnote>

<footnote><sup>c</sup> Limoges University Hospital, Paediatric Cystic Fibrosis Reference Center (CRCM), Limoges, France</footnote>

<footnote><sup>d</sup> Centre de ressources et de compétences pour la mucoviscidose, Hôpital des Enfants, CHU de Toulouse, Toulouse, France</footnote>

<footnote><sup>e</sup> Service de Gastroentérologie, Hépatologie, Nutrition et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse, Toulouse, France</footnote>

<footnote><sup>f</sup> Bordeaux University Hospital, Adult CF center, France</footnote>

<footnote><sup>g</sup> Adult Cystic Fibrosis Center, Pulmonology, CHU Toulouse, France</footnote>

<footnote><sup>h</sup> Centre d'Investigation Clinique 1436, CHU de Toulouse, Toulouse, France</footnote>

<footnote><sup>i</sup> Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France</footnote>

<footnote>* Corresponding author. Service de Gastroentérologie, Hépatologie, Nutrition, Diabétologie et Maladies Héréditaires du Métabolisme 330, avenue de Grande-Bretagne TSA 70034 31059 Toulouse Cedex 9, France.
E-mail address: mas.e@chu-toulouse.fr (E. Mas).</footnote>
the respiratory system, defective CFTR protein leads to airway dehydration, chronic airway obstruction and inflammation, recurrent infections and chronic colonization, all of which result in progressive decline in respiratory function. In the GI tract, it causes exocrine pancreatic insufficiency (EPI), chronic intestinal inflammation and malnutrition in most patients [2].

Nutrition plays a critical role in the management and prognosis of CF, as adequate nutritional status is associated with improved lung function and overall survival [3]. Therefore, managing the nutritional status of patients with CF (pwCF) is critical to improve their overall health and quality of life. Early intervention with energy- and fat-rich diets, and sometimes nutritional support, are an integral part of management [4]. Despite these efforts, malnutrition was still common in pwCF before CFTR protein modulators era [5].

The advent of CFTR protein modulators, in particular the combination therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI), has revolutionized the treatment of CF. These modulators are designed to partially restore the function of the CFTR protein, thereby improving respiratory function [6,7]. ETI treatment has also been associated with significant weight gain in pwCF, presumably due to improved appetite, better food intake and overall improved health [8]. However, direct studies of changes in nutritional intake with ETI therapy remain limited.

The aim of this study was to evaluate dietary intake's evolution in pwCF treated with ETI. By examining changes in dietary habits and nutritional status, we aim to better understand the impact of ETI therapy on the health of pwCF.

# 2. Materials and methods

## 2.1. Study population

NUTRIMUCO (https://clinicaltrials.gov/study/NCT06072365) was a prospective, multicenter, observational study conducted across 3 French care centers located in Toulouse, Bordeaux and Limoges. Both adult and pediatric pwCF who met the eligibility criteria for ETI treatment based on French regulatory approval at the time of the study and able to give informed consent were recruited. Exclusion criteria included patients who were unable to read, write or understand French well enough in order to provide a reliable dietary record, lung transplant recipients, pregnant or lactating women, and patients who had used another CFTR modulator within 6 months prior to baseline. Informed consent was obtained from all participants, and the study received a favorable ethical approval from the Ethical Committee (CPP 2021/65 on 09/27/2021).

## 2.2. Data collection

Data were collected from October 2021 to October 2023 with 2 time points for each patient, just before the initiation of ETI treatment (M0) and one year after its initiation (M12). For all patients, medical history, demographic data (age, sex), gene mutations, clinical data, including weight, height, FEV1% predicted (ppFEV1), and the dose of pancreatic enzymes on the day of visits were collected from the patients' medical records. Sweat chloride values, as well as fecal elastase and calprotectin levels, were also recorded. The measurement techniques used for these analyses may have differed between centres, but remained identical at M0 and M12 for the same patient.

BMI was calculated and expressed as Z-score from French references for children and as absolute values for adults [9]. The nutritional status was considered normal between -1 and +1 BMI Z-score for children (approximately between 15th and 85th percentile) and between 18.5 and 25 BMI for adults, underweight if

BMI Z-score < -1 for children (approximately <15th percentile) and BMI <18.5 for adults, and overweight if BMI Z-score >+1 for children (approximately >85th percentile) and BMI >25 for adults.

## 2.3. Dietary data

A three-days paper-based food diary was completed at home by patients or their parents for each visit. This diary included a detailed record of all meals and snacks, as well as dietary supplements and medications, for three consecutive days (one weekday and two weekend days). Patients or their parents recorded the amount of food consumed, using either weight measurements or standard household units. Instructions for completing the food diary were standardized across centers. These instructions were dispensed at inclusion to each patient and/or patient's family by the CF center nutritionist. Additionally, precise instructions to fill in the dietary record were written at the top of the food report document. Patients were specifically informed to report the type of food consumed, the cooking method used, and the type of fat incorporated in the meal preparations.

Food records were completed within the week preceding their consultation at the Cystic Fibrosis center, so that the center dietician could check the accuracy of the report. The reports from all centers were then collected by a single dietitian who reviewed the recorded information and conducted the whole reports analysis.

The nutrient composition of the foods was calculated using Nutrilog® software (Version 3.20) (Nutrilog Europe Society, Marans, France), based on the French food composition database CIQUAL 2020 (https://ciqual.anses.fr/) [10]. Macronutrient intake was expressed as grams per day (g/d), and percentage of total caloric intake per day for protein, fat and carbohydrate. Reports with less than two days of accurately reported quantities (either detailed portion weights or household measures) were excluded from the analysis.

## 2.4. Statistical analysis

Statistical analyses were conducted using R software® (version 4.2.2; R Foundation, Vienna, Austria). Continuous variables were summarized by the mean and standard deviation as well as by the median and interquartile range (IQR). Categorical variables were described using frequencies and percentages. Comparisons of numerical variables between M0 and M12 were made using paired t-tests or Wilcoxon signed-rank tests, depending on the distribution of differences. The Shapiro-Wilk test was used to assess the normality of a variable. A p-value <0.05 was considered statistically significant.

# 3. Results

A total of 108 patients with CF naïve from modulators (51 children and 57 adults) were included. Forty-six were excluded from the final analysis for the following reasons: 2 discontinued their modulator treatment during the study, 12 had missing dietary records at M0 and 20 at M12, 9 with incomplete food reports, 2 became pregnant during the follow-up, and 1 patient died. Compared to the patients included in the final analysis, the excluded population differed in several characteristics. Adults represented a higher proportion of the excluded group (74 % vs. 42 % respectively, p = 0.002), and exocrine pancreatic insufficiency was less frequent (74 % vs. 94 %). In addition, a higher proportion of excluded patients had a non-underweight nutritional status, which is either normal or overweight, at baseline (96 % vs. 81 %). There were no significant differences between the two groups in terms of
<table><caption>**Table 1**
Patient characteristics at baseline (M0) (n = 62).</caption><thead><tr><th></th><th>No. of missing values</th><th>Value</th></tr></thead><tbody><tr><td><strong>Female gender</strong></td><td>0</td><td>33 (53 %)</td></tr><tr><td><strong>Age (year)</strong></td><td>0</td><td>15.6 (10.9)</td></tr><tr><td>Children/Adults</td><td></td><td>36 (58 %)/26 (42 %)</td></tr><tr><td><strong>CFTR Mutations</strong></td><td>0</td><td></td></tr><tr><td>F508del homozygous</td><td></td><td>6 (10 %)</td></tr><tr><td>F508del heterozygous</td><td></td><td>56 (90 %)</td></tr><tr><td><strong>ppFEV1 (%)</strong></td><td>0</td><td>77.0 (30.0)</td></tr><tr><td><strong>Sudoral chlorine (mmol/L)</strong></td><td>18</td><td>96.0 (17.0)</td></tr><tr><td><strong>Exocrine pancreatic insufficiency</strong></td><td>0</td><td>58 (94 %)</td></tr><tr><td>Pancreatic enzymes (lipase units/ kg/day)</td><td>4</td><td>7096 (4441)</td></tr><tr><td><strong>BMI</strong></td><td>0</td><td></td></tr><tr><td>BMI Z-score<sup>a</sup></td><td></td><td>-0.3 (0.9)</td></tr><tr><td>BMI (kg/m<sup>2</sup>)<sup>b</sup></td><td></td><td>20.9 (4.8)</td></tr><tr><td><strong>Nutritional status</strong></td><td>0</td><td></td></tr><tr><td>Underweight</td><td></td><td>12 (19 %)</td></tr><tr><td>Normal</td><td></td><td>44 (71 %)</td></tr><tr><td>Overweight</td><td></td><td>6 (10 %)</td></tr><tr><td><strong>Fecal calprotectin (µg/g)</strong></td><td>44</td><td>211.5 (372.2)</td></tr></tbody></table>

Data are expressed as n (%) and median (IQR).

BMI, Body Mass Index; CFTR, Cystic fibrosis conductance regulator; ppFEV1, percentage of predicted forced expiratory volume in 1s.

<sup>a</sup> Only for children.

<sup>b</sup> Only for adults.

sweat chloride, lung function (ppFEV₁) or CFTR genotypes (Table S1).

In the final analysis, data from 62 pwCF were analyzed, including 36 children and 26 adults. The median age was 13.3 years (IQR: 11.6) for children and 26.5 (IQR: 34.0) for adults, with a sex ratio male/female of 0.9. The characteristics of the cohort at baseline are reported in Table 1. Over these patients, 94 % had EPI supplemented with pancreatic enzymes. Regarding nutritional status, the median BMI Z-score in children was −0.3 (IQR: 0.9) and the median BMI in adults was 20.9 kg/m² (IQR: 4.8). Nineteen percent of patients were considered underweight at baseline, and 10 % overweight.

There was no significant difference of energy intakes with ETI with a median of 2216 Kcal/day (IQR: 750) at M0 and 2266 Kcal/day (IQR: 733) at M12 (Fig. 1). However, the nutritional status, as assessed by BMI, improved significantly with ETI treatment in both children (p = 0.036) and adults (p < 0.001) (Fig. 2). Over the first year of ETI treatment, the median weight gain was 3.5 kg (IQR: 5.1) for the whole cohort, 4.8 kg (IQR: 4.7) for children and 2.8 kg (IQR: 4.6) for adults. The median BMI Z-score gain was 0.2 (IQR: 0.7) for children and the median BMI gain was 1.0 kg/m² (IQR: 1.8) for

adults (Table 2). Forty-one patients out of 62 (66 %) had a higher BMI Z-score at M12 compared to baseline. Seven patients out of 62 (11 %), 3 adults and 4 children, became overweight after one year of ETI treatment whereas their BMI was normal before starting the treatment.

As patients gained weight, energy intake expressed as median energy per body weight per day (Kcal/kg/day) decreased significantly from 52.6 kcal/kg/day (IQR:26.4) to 44.6 (IQR: 22) (p = 0.001) (Table 2). In the subgroup of 41 (66 %) patients who increased their BMI Z-score, no significant evolution of energy intake was noted, neither in the subgroup of 21 (34 %) who did not increase their BMI (Fig. 3).

Regarding the macronutrient intakes, the main findings was that protein or carbohydrate consumption did not change, while we found a significant small increase of the lipid consumption (+2.2 %, p = 0.01) (Table 2).

It should be noted that there was a decrease of the amounts of pancreatic enzymes from 7130 (IQR: 4243) lipase units/kg/day to 5862 (IQR: 5084) (p < 0.001) among the 56 patients for whom this data was available at both baseline and M12. One patient even stopped pancreatic enzyme replacement therapy. For the 11 patients with fecal calprotectin assays available at both baseline and M12, we observed a significant decrease, with levels dropping from 222 µg/g (IQR: 379) to 30 µg/g (IQR: 64), respectively (p < 0.01); only one patient had a slight increase (Fig. 4).

Finally, as expected, sweat chloride concentration decreased between baseline and M12 with ETI from 96.0 (IQR: 17.0) to 45.5 mmol/L (IQR: 29.2) (p < 0.001). Lung function improved, with the median ppFEV1 increasing from 77.0 % (IQR: 30.0) at baseline to 99.0 % (IQR: 27.5) at M12 (p < 0.001) (Table 1). This improvement was significant both for children and adults (both p-values <0.001), with no statistical difference of improvement between the two groups (p = 0.65, independent t-test). At baseline, 21 patients had a ppFEV1 below 70 % (5 children and 16 adults), while at M12, 10 patients (2 children and 8 adults) still had an FEV1 below 70 %.

## 4. Discussion

The introduction of CFTR modulators, particularly ETI, represents a major advancement in CF treatment, significantly improving respiratory function and reducing sweat chloride levels. Beyond these known benefits, our study demonstrates a notable improvement in nutritional status with ETI, independently of any increase in daily caloric intake.

<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Evolution of energy intakes after 1 year of treatment.</figcaption></figure>

No significant evolution of energy intake was observed neither in children (n = 36; p = 0.74), nor in adult population (n = 26; p = 0.75).
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Evolution of BMI after 1 year of ETI treatment.
Children BMI expressed as Z-score improved significantly (n = 36; p = 0.036). Adults BMI also improved significantly (n = 26; p < 0.01).</figcaption></figure>

<table><caption>**Table 2**
Nutritional status and Macronutrient changes with ETI.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Total cohort (n = 62)</th><th colspan="3">Children (n = 36)</th><th colspan="3">Adults (n = 26)</th></tr><tr><th>M0</th><th>M12</th><th>p-value</th><th>M0</th><th>M12</th><th>p-value</th><th>M0</th><th>M12</th><th>p-value</th></tr></thead><tbody><tr><td><strong>BMI<sup>a</sup></strong></td><td></td><td></td><td></td><td>-0.3 (0.9)</td><td>-0.3 (1.2)</td><td>0.036</td><td>20.9 (4.8)</td><td>21.9 (4.5)</td><td>&lt;0.001</td></tr><tr><td><strong>Nutritional status</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Underweight</td><td>12 (19 %)</td><td>8 (13 %)</td><td></td><td>6 (17 %)</td><td>3 (8 %)</td><td></td><td>6 (23 %)</td><td>5 (19 %)</td><td></td></tr><tr><td>Normal</td><td>44 (71 %)</td><td>42 (68 %)</td><td></td><td>26 (72 %)</td><td>26 (72 %)</td><td></td><td>18 (69 %)</td><td>16 (61 %)</td><td></td></tr><tr><td>Overweight</td><td>6 (10 %)</td><td>12 (19 %)</td><td></td><td>4 (11 %)</td><td>7 (19 %)</td><td></td><td>2 (8 %)</td><td>5 (19 %)</td><td></td></tr><tr><td><strong>Energy intake (Kcal/day)</strong></td><td>2216 (750)</td><td>2266 (733)</td><td>0.99</td><td>2162 (683)</td><td>2210 (697)</td><td>0.74</td><td>2234 (693)</td><td>2378 (752)</td><td>0.75</td></tr><tr><td><strong>Energy intake (Kcal/kg/day)</strong></td><td>52.6 (26.4)</td><td>44.6 (22.0)</td><td>0.001</td><td>60.8 (27.1)</td><td>51.4 (24.9)</td><td>0.004</td><td>43.8 (22.9)</td><td>42.2 (18.5)</td><td>0.14</td></tr><tr><td><strong>Macronutrient</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Protein (%)</td><td>15.2 (4.8)</td><td>15.9 (3.6)</td><td>0.71</td><td>14.5 (4.9)</td><td>15.3 (3.1)</td><td>0.94</td><td>16.0 (5.2)</td><td>16.4 (4.3)</td><td>0.96</td></tr><tr><td>Lipids (%)</td><td>36.8 (5.6)</td><td>39.0 (8.9)</td><td>0.01</td><td>38.0 (5.8)</td><td>39.0 (8.0)</td><td>0.07</td><td>35.6 (5.5)</td><td>38.8 (8.6)</td><td>0.11</td></tr><tr><td>Carbohydrates (%)</td><td>44.9 (9.5)</td><td>43.2 (10.1)</td><td>0.09</td><td>45.5 (7.7)</td><td>43.9 (7.0)</td><td>0.18</td><td>44.0 (9.6)</td><td>41.7 (10.9)</td><td>0.45</td></tr></tbody></table>

Data are expressed as n (%) and median (IQR).

BMI, Body Mass Index.

<sup>a</sup> Expressed as Z-score for children and as absolute values for adults.

## 4.1. No dietary changes but confirmation of nutritional improvement

The improvement of BMI is in agreement with previous studies evaluating nutritional improvement on ETI treatment [11–15]. This study confirms that the weight gain obtained in pwCF after initiation of treatment with ETI is not due to a calorie intake increase. No changes were observed in carbohydrates nor in protein consumption. The slight increase in lipid percentage consumption could be enhanced by the fact that ETI treatment needs to be taken with a fatty meal. Although statistically significant (+2.2 %, p = 0.01), this increase in lipid consumption remained within the recommended macronutrient distribution for pwCF and was not accompanied by an increase in total energy intake, suggesting that it is not clinically meaningful. It especially highlights that lipid consumption does not decrease despite nutritional improvement. Carnovale et al. did not find significant differences in calorie intake in 12 pwCF aged 31.9 ± 7.7 years, after 12 months of ETI therapy [16]. No change was observed on proteins, lipids, carbohydrates, fibers, calcium consumption in this small cohort. Caley et al. even found a significant decrease of energy intake, while improving their BMI, for 40 CF adults treated by ETI [15]. Our study confirms this important result in both adult and pediatric populations.

The improvement in nutritional status while eating habits mostly remain stable after one year suggests that this improvement is independent of an increase in energy intake. We can speculate that their caloric requirements should have decreased with an

improvement of their lung status or inflammatory state. Regarding the respiratory status, there was a significant ppFEV1 improvement (p < 0.001); moreover, even if NUTRIMUCO study did not look at pulmonary exacerbations, other studies reported a decreased after ETI initiation [12,14]. The results of the CF Germany registry have shown a 76 % decrease of pulmonary exacerbations rates after 1-year ETI treatment [14]. This improvement might explain a lower energy intake requirement after ETI initiation.

## 4.2. Digestive modifications could explain nutritional improvement

Several factors may contribute to improved intestinal absorption. Gelfond et al. observed that ivacaftor therapy increased intestinal pH, potentially enhancing absorption by improving the dissolution of enteric-coated enzymes and reducing bile acid precipitation [17]. Stallings et al. reported that ivacaftor was associated with an improved coefficient of fat absorption [18]. In our cohort, we also observed a reduction in fecal calprotectin levels, a marker of intestinal inflammation, under ETI therapy, indicating decreased intestinal inflammation. This finding aligns with previous studies on different CFTR modulators [19–21]. The reduction in intestinal inflammation may further contribute to enhanced intestinal absorption during ETI treatment.

In addition to reduced intestinal inflammation, ETI treatment induced changes of the intestinal microbiome, with an improvement of diversity [22]. Looking at the intestinal microbiota could be of interest while several taxa were associated with the risk of
<figure><img src="image_4.png" /><figcaption>**Fig. 3. Evolution of energy intakes according to nutritional changes after ETI initiation.**
No change was found in energy intakes at M12 in 41 patients with an increased BMI (p = 0.11), neither in those with a BMI decrease (n = 21; p = 0.31), in both adults and children.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 4. Evolution of fecal calprotectin after ETI initiation.**</figcaption></figure>

becoming overweight after modulator initiation [23]. This risk was associated with a lower abundance of *Eggerthella lenta*, *Rumino-coccus*, and *Bacteroides*, and a higher abundance of *Bacteroides stercoris*.

The observed improvement in nutritional status under ETI therapy also raises the question of a possible restoration of exocrine pancreatic function. However, our study cannot address this point, as fecal elastase values were too frequently missing to allow meaningful analysis. Pancreatic enzyme doses significantly decreased from 7130 (IQR: 4243) to 5862 (IQR: 5084) units of lipase/kg/day (p < 0.001), as previously described [24], but this reduction should not be directly interpreted as evidence of pancreatic recovery. It may rather reflect improved well-being, dietary modifications, or patient-initiated adjustments. Notably, one patient in our cohort discontinued enzyme replacement therapy entirely.

Previous studies have reported an increase in fecal elastase levels under ETI, particularly in younger patients, with a negative correlation between elastase improvement and age at treatment initiation [25]. Furthermore, a study involving 137 adolescents and adults with CF showed increased serum lipid and fat-soluble vitamin (A and D) levels after ETI initiation, which may reflect improved intestinal absorption capacity [26].

### 4.3. Risk of overweight and obesity in patients with CF

Furthermore, the risk of becoming overweight or even obese should be carefully considered following ETI initiation. Of note, 7 out of 62 patients became overweight after 1 year of ETI treatment. This risk is due, on one hand, to a reduction in resting energy requirements, improved intestinal absorption, and decreased intestinal inflammation [11], and, on the other hand, to the lack of change in dietary habits after ETI initiation, as observed in this study. Obesity and its comorbidities have been infrequently studied in CF, largely due to the historically limited life expectancy of these patients. Further research is essential to understand how overweight and obesity may impact morbidity and mortality in pwCF, especially regarding lung function, diabetes risk, and cardiovascular disease.

### 4.4. Study limitations

One main limit of our study was that alimentary reports were completed at home by patients and/or their parents. The quality and precision of the records were heterogenous, inherent to any study reporting home alimentary consumption. Meanwhile, we tried to limit this bias; oral and written instructions to fulfill the report were given to each patient and/or family by a CF dietician at inclusion and all the reports were only analyzed by one dietician, using the French CIQUAL 2020 database.

Moreover, the dropout rate was relatively high, with 42 % of the initially included participants excluded from the final analysis, primarily due to missing or incomplete dietary records. While no significant differences were observed between excluded and analyzed patients in terms of ppFEV₁, sweat chloride concentration, or CFTR genotype, the excluded group included a higher proportion of adults, fewer patients with exocrine pancreatic insufficiency, and a greater proportion of individuals with a non-underweight nutritional status. This may reflect a lower perceived relevance of participating in a nutritional study among adults or patients with satisfactory nutritional status, possibly contributing to incomplete data collection in this subgroup. Nonetheless, in our analyzed cohort, weight gain was also observed in adults and in patients with normal or elevated baseline nutritional status, underlining the
relevance of continuing nutritional follow-up in all patient profiles. It raises the question of how to effectively engage this subgroup, which may be less motivated or aware of the importance of nutritional monitoring, especially in the context of clinical improvement under CFTR modulators. As nutritional needs evolve with ETI treatment, such populations might be more difficult to reach for reassessment and adaptation of dietary management.

Meanwhile, this study highlights the importance of dietary habits, induced early in infancy and the difficulty to change it. As proposed in the ESPEN-ESPGHAN-ECFS guidelines on nutrition care for CF, appropriate dietary counseling should be provided for patients with CF starting on CFTR modulator therapy, which should include advices about limiting and managing weight gain [4]. Further studies are needed to develop specific dietary recommendations, including nutrient adjustments, as ETI improves intestinal absorption and glucose metabolism in pwCF [27,28]. Moreover, some changes could modify the intestinal microbiota, reducing intestinal inflammation and improving the gut–lung axis [29]. These changes of dietary habits could improve the body composition, while an increase of fat mass was reported on ETI treatment [13,30]. This risk seems more important in pwCF who were initially underweight [30].

## 5. Conclusion

Our study confirms the difficulty to change nutritional habits, even under ETI treatment. Personalized dietitian counseling at ETI initiation is necessary to prevent overweight and obesity. As ETI treatment will be available for younger patients, dietary counseling to eligible patients will have to be close to advices to the general population, since diversification.

## Author contribution

Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Roles/Writing – original draft; Writing – review & editing.

Enaud R: Conceptualization; Investigation; Methodology; Formal analysis; Roles/Writing – original draft.

Languepin J: Investigation; Writing – review & editing.

Lagarrigue M: Conceptualization; Roles/Writing – original draft.

Arrouy A: Conceptualization; Data curation; Project administration.

Macey J: Investigation; Writing – review & editing.

Bui S: Investigation; Writing – review & editing.

Dupuis M: Investigation; Writing – review & editing.

Roditis L: Investigation; Writing – review & editing.

Flumian C: Data curation; Formal analysis; Methodology.

Mas E: Formal analysis; Methodology; Supervision; Validation; Roles/Writing – original draft.

Mittaine M: Conceptualization; Funding acquisition; Project administration; Supervision.

## Declaration of Generative AI and AI-assisted technologies in the writing process

The whole text was initially written whitout Generative AI. Generative AI was partially used to correct some English formulation or to improve formulation of a few sentences.

## Funding statement

This study was funded by the association "MucoSud".

## Conflict of interest

RE is co-coordinator of the French national cohort "Lum Iva Biota", which received grants from Vertex; LR received grant from Vertex for training. MM received consulting fees from Vertex for Nutritional advice.

## Acknowledgments

We thank the patients and their families for their participation in the study as well as all nurses, physicians, and clinical research coordinators who were involved in the study.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clnu.2025.04.027.

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