Submitted:
29 April 2024
Posted:
30 April 2024
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Abstract
Background: Modulator therapies improve weight and body mass index (BMI) in cystic fibrosis (CF) patients. We aimed to compare the nutritional risk index (NRI) in adult CF patients receiving modulator (MT) or only non-modulator (conventional) therapies (non-MT).
Methods: A single-center prospective cohort study was conducted between June-December 2023. The NRI based on weight gain and albumin was calculated at beginning and end of a 12 weeks period in both groups. This design was pragmatic, since based on individual patient access to MT for 12 weeks.
Results: 107 patients were included [mean (SD) age: 23.85 (4.98) years, 54.7% male, 46.7% MT]. In the MT group, mean (SD) weight (kg) and albumin (g/dL) increased significantly [changes: +3.09 (2.74) and +0.17 (0.37); p
Keywords:
cystic fibrosis
; adults
; nutritional risk index
; nutritional therapy
; modulators
; rare disease
; orphan disease
1. Background
Cystic fibrosis (CF) is an autosomal recessive disease caused by a mutation in the gene encoding the CF Transmembrane Regulator (CFTR) protein. Mutations of the CFTR protein in the lungs result in thick mucus and infections. The CFTR protein is also found in the pancreas. This can lead to pancreatic insufficiency, inflammation, dysmotility, and malabsorption [1].
Patients with CF typically have a lower body weight than peer healthy individuals. Pancreatic exocrine insufficiency leading to intestinal malabsorption and decreased food intake, along with increased energy expenditure during infections, contribute to difficulties in maintaining body weight. Low body mass index (BMI) in CF is associated with impaired lung function and increased mortality. Therefore, guidelines from the Cystic Fibrosis Foundation recommend to maintain a BMI of ≥22 kg/m2; in adult women and ≥23 kg/m2; in adult men [2].
Weight gain after modulator therapy has been evaluated in several studies. In a phase 3 study of elexacaftor-tezacaftor-ivacaftor in F508del heterozygotes, the absolute change from baseline in body weight after 24 weeks of treatment was +3.4 kg compared to +0.5 kg for placebo, with a +2.9 kg difference between groups (95% CI, 2.3 to 3.4) [3]. In patients receiving ivacaftor for G551D mutations, mean (standard deviation, SD) weight significantly increased from 52.1 (20.4) kg to 54.2 (20.8) kg after 3 months (p<0.001) [4]. The albumin level was also significantly increased after one year in patients treated with lumacaftor-ivacaftor (p<0.001) [5].
The Nutritional Risk Index (NRI), originally developed for surgical patients [6,7], has been utilized both in medical and surgical inpatients [8] as well as outpatients with heart failure [9]. It has also been applied at baseline and after transplantation in lung transplant candidates, including patients with or without CF. The NRI, a screening tool rarely utilized in chronic lung diseases previously, is a simple instrument encompassing albumin, weight, and the ratio of ideal body weight (IBW), which can only be detected through medical records and has the potential to stratify nutritional risk based on an individual's score [10]. Combining both anthropometric and biochemical parameters allows for a more comprehensive assessment of nutritional status, indirectly evaluating calorie intake through assessing factors known to influence albumin levels, such as systemic inflammation, kidney and liver function [11,12].
The NRI was calculated for patients using the following formula: (15.19 × serum albumin [g/dL]) + (41.7 × weight [kg]) / IBW [kg] [13]. Patients were grouped according to NRI categories of malnourishment: non-malnourished (>100), mild (97.6-100), moderate (83.5-97.5), and severe malnourishment (< 83.5) [14]. IBW was used instead of usual body weight because it is less subjective [9]. The aim of this study was to compare the NRI in adults with CF access to modulator treatment for 12 weeks in addition to conventional therapies, or without access to modulator treatment, and to analyze the change in NRI between both groups during this 12-weeks period.
2. Methods
2.1. Study Design
This prospective single-center cohort study was conducted from June to December 2023. Patients with CF over 18 years old, followed by the pulmonary medicine outpatient clinic of a tertiary care university hospital, were included. Patients who declined to provide written consent, those who had undergone lung or liver transplantation, and individuals who had been hospitalized within the preceding month were excluded from the study. Due to the fact that modulator therapies are not reimbursed in Turkey, and individual access to treatment is currently available for only three months time intervals, based on a court decision [15], patients were evaluated 12 weeks (3 months) after the start of modulator treatment. To enable comparison, CF patients without modulator therapy were also assessed at 12-week intervals. The study was approved by the Local Ethics Committee.
2.2. Data Collection
Data were prospectively collected by a clinical pharmacist routinely attending a pulmonary medicine outpatient clinic where the largest number of adults with CF are followed up nationally. Age, gender, genotype, presence of pancreatic insufficiency, CF-related diabetes mellitus and liver disease, use of oral nutritional supplements, pancreatic enzyme replacement and type of modulator therapies were determined as demographic data of patients who were started and not started modulator treatment according to the results of genetic analysis. Subsequently, albumin, weight, BMI, and NRI scores were obtained simultaneously from the modulator and non-modulator therapy groups at the beginning and end of the 12-week period to assess nutritional risk.
2.3. Statistical Analysis
It was planned to include at least a total of 70 patients, 35 patients each in the modulator and non-modulator groups, with an effect size of 0.80, 95% power, and 5% margin of error within the foreseen study period. The calculation of sample size was made with G-power 3.0.10 program.
As descriptive statistics, mean and SD or median and range for numerical variables and number and percentage values for categorical variables were given. The normality assumption was analyzed by Kolmogorov-Smirnov test. In the comparison of numerical data, Mann-Whitney U test was used for non-normally distributed data. The Pearson Chi-Square test was used to compare independent groups in terms of categorical variables. All statistical tests were applied with a 95% confidence interval and the statistical significance level was accepted as p<0.05.
3. Results
3.1. Demographic and Clinical Characteristics
A total of 107 patients were included [mean (SD) age: 23.85 (4.98) years, 54.7% male, 46.7% with modulator therapy]. All demographic data of the patients were similar between both groups (p>0.05), except for pancreatic insufficiency and pancreatic enzyme replacement therapy (p<0.05) (Table 1).
3.2. Nutritional Risk Index
In the modulator therapy group, mean (SD) albumin (g/dL), weight (kg), BMI (kg/m2), and NRI score significantly increased (4.08 [0.44] vs. 4.25 [0.39], 54.65 [13.05] vs. 57.74 [12.85], 19.88 [3.66] vs. 21.02 [3.53], and 100.65 [11.80] vs 104.18 [10.40], respectively; p<0.001). On the contrary, in non-modulator therapy group, mean (SD) albumin (g/dL), weight (kg), BMI (kg/m2), and NRI score significantly decreased (4.26 [0.48] vs. 4.13 [0.60], 57.97 [10.62] vs. 56.98 [11.28], 20.72 [2.95] vs. 20.36 [3.19], and 104.10 [10.10] vs 102.58 [12.39], respectively; p<0.001). The weight, BMI, albumin, and NRI values of groups at the beginning and end of 12 weeks period are summarized in Table 2.
At baseline, and at the end of the 12-week period, changes in modulator and non-modulator therapy groups were detected in weight (IQR 1.00, 4.50 and IQR 1.00, 4.50), BMI (IQR 0.38, 1.79 and IQR 0.38, 1.79), albumin (IQR -0.005, 0.39 and IQR -0.005, 0.39), NRI score (0.52, 8.32 and 0.52, 8.32), respectively (Table 3).
NRI scores were categorized after calculation. The number of patients without malnutrition risk increased from 24 to 35 patients in MT group, while it decreased from 38 to 34 in non-MT group. In addition, the number of patients with severe malnutrition decreased in modulator therapy group, while it increased in non-modulatory therapy group (Table 4).
In the modulator therapy group, the NRI category improved in 22 (44%) patients, and worsened in 3 (6%) patients (p<0.001). On the contrary, the NRI category improved in 2 (3.5%) patients and worsened in 10 (17.5%) patients in the non-modulator therapy group (p<0.001) (Table 4). When comparing elexacaftor/tezacaftor/ivacaftor (ETI) to otodulator therapies, the baseline mean (SD) albumin 4.03 (0.46) g/dL vs 4.22 (0.38) g/dL (p=0.237), weight 51.62 (11.43) kg vs 65.36 (13.28) kg (p=0.001), BMI 19.20 (3.54) kg/m2 vs 22.28 (3.16) kg/m2 (p=0.12), NRI 98.60 (11.98) vs 106.64 (9.14) (p=0.044) respectively. At the end of 12 weeks, ETI vs other therapies mean (SD) albumin 4.24 (0.41) g/dL vs 4.31 (0.34) g/dL (p=0.535), weight 54.77 (10.87) kg vs 68.27 (14.27) kg (p=0.004), BMI 20.37 (3.29) kg/m2 vs 23.31 (3.51) kg/m2 (p=0.016), NRI 103.95 (9.85) vs 109.76 (9.11) (p=0.066). When elexacaftor/tezacaftor/ivacaftor was compared to other modulator therapies, no significant difference was observed for albumin, weight, BMI or NRI score (p>0.05).
4. Discussion
Nutritional screening tools have been developed in children and adolescents with CF [16,17]. To the best of our knowledge, a nutritional screening tool has not yet been validated in adult patients with CF. On the other hand, Schonenberger and Tóth used the Nutritional Risk Score (NRS-2002) in their studies on adult patients [18,19]. In our study, we used NRI and showed that there was a significant improvement in the group receiving MT compared to the group not receiving MT.
While it is known that BMI and dietary intake increase with ETI therapy [1], it has not yet been evaluated for malnutrition risk before and after modulator therapies. The current study described the risk of malnutrition over time and its relationship to other variables in patients with and without modulator therapies.
In the study of Sheikh et al., the increase in BMI was 4.4% in a 3-month period with 48 patients (p<0.001), similar to our study [20]. In the study of Bianu et al. examining metabolic changes after lumacaftor treatment with 12 adult patients, albumin level non-significantly increased to 0.2±0.7 after 3 months (p=0.168) contrary to our study (p<0.001) [21]. The large number of adult CF patients in our study may explain this situation. NRI increased after 12 weeks because albumin and weight data were included in the NRI formula. While the malnutrition risk categories of patients using modulator therapy improved, the categories of patients in the non-modulator therapy group worsened significantly (p<0.001). Although weight, albumin, and NRI values were significantly higher in the non-modulator therapy group than in the modulator therapy group at baseline, this difference decreased 12 weeks after treatment with higher values in the modulator therapy group.
Drugs with a higher potency for CFTR correction appear to be associated with a greater weight gain [22]. In this study, when ETI and other modulator therapies were compared, no significant difference was found in the increase in weight and albumin over time and the decrease in the risk of malnutrition. This may be due to the fact that the number of patients receiving ETIs was higher than the others and the albumin and weight values of patients receiving other modulator therapies were higher than those receiving ETIs at baseline.
It has not been evaluated in this study, but in previous studies, decreased lung function and anthropometric measurements were also associated with the risk of malnutrition [23].
This study had several strengths and limitations. There was a significant difference between the two groups in terms of pancreatic enzyme use and pancreatic insufficiency at baseline. Patients could not be followed up in terms of pancreatic insufficiency after modulator therapy, and patients may have stopped using enzymes due to improvements in gastrointestinal symptoms. Recommending the intake of modulator therapy with fatty foods in order to increase their absorption may also increase calorie intake.
One of the strengths of the study is that according to 2021 European Cystic Fibrosis Society Patient Registry data, there are 352 patients aged ≥18 in Turkey [24] and most of these patients are followed by our center and involved in this study. We think that our study population represents adult CF patients in Turkey.
5. Conclusions
The prevalence of malnutrition is high in CF patients. Modulator therapies reduce the risk of malnutrition, but not all patients can access the treatments. NRI is a useful tool to detect malnutrition risk and assist with the prescription or evaluation of the efficacy of medical and nutrition interventions in adult CF patients.
Declarations
Funding
This research received no external funding.
Authors’ Contributions
Conceptualization, N.Y and E.D.A.; Methodology, N.Y.; Software, N.Y. and E.D.A.; Validation, N.Y; Formal Analysis, N.Y.; Investigation, E.D.A.; Resources, E.D.A.; Data Curation, E.D.A.; Writing – Original Draft Preparation, N.Y. and E.D.A.; Writing – Review & Editing, O.K., K.A., K.D. and E.D.; Visualization, O.K., K.D. and E.D.; Supervision, E.D. and A.F.K.; Project Administration, K.A. and A.F.K.
Ethics approval and consent to participate
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Hacettepe University. Informed consent was obtained from all subjects involved in the study.
Consent for publication
Not applicable.
Availability of data and materials
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to restrictions privacy and ethical.
Acknowledgements
The authors would like to thank all of the study participants, pulmonologists, and nurses for their assistance with the study data collection.
Competing interests
The authors declare that they have no competing interests.
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Table 1.
Demographic data of patients.
| Variables | Modulator therapy group (n=50) | Non-modulator therapy group (n=57) | p Value |
|---|---|---|---|
|
Gender, n (%) Female Male |
26 (52) 24 (48) |
23 (40.4) 34 (59.6) |
0.228b |
| Age (years), mean (SD) | 24.12 (5.08) | 23.71 (4.91) | 0.680a |
|
Genotype f508del/f508del f508del/other Other/other Unknown |
18 (36) 10 (20) 22 (44) 0 |
4 (7) 12 (21.1) 35 (61.4) 6 (10.5) |
<0.001b |
| Pancreatic insufficiency, n (%) | 40 (80) | 54 (94.7) | 0.020b |
| CF related diabetes mellitus, n (%) | 9 (18) | 7 (12.3) | 0.408b |
| CF related liver disease, n (%) | 10 (20) | 14 (24.6) | 0.572b |
| Oral nutritional supplements, n (%) | 23 (46) | 30 (52.6) | 0.494b |
| Pancreatic enzyme replacement, n (%) | 40 (80) | 54 (94.7) | 0.020b |
|
Modulator therapy, n (%) Elexacaftor/tezacaftor/ivacaftor (ETI) Tezacaftor/ivacaftor Ivacaftor |
39 (78) 1 (2) 10 (20) |
- |
CF: Cystic Fibrosis. a Independent t test, b Pearson's chi-squared test.
Table 2.
Variables at baseline at the and end of the 12 weeks period in both groups.
| Variables | Modulator therapy group (n=50) |
Non-modulator therapy group (n=57) |
p Value* |
|---|---|---|---|
| Albumin (g/dL), mean (SD) At the beginning of 12 weeks period At the end of 12 weeks period |
4.08 (0.44) 4.25 (0.39) |
4.26 (0.48) 4.13 (0.60) |
0.029 0.410 |
| Weight (kg), mean (SD) At the beginning of 12 weeks period At the end of 12 weeks period |
54.65 (13.05) 57.74 (12.85) |
57.97 (10.62) 56.98 (11.28) |
0.049 0.918 |
| Body mass index (kg/m2), mean (SD) At the beginning of 12 weeks period At the end of 12 weeks period |
19.88 (3.66) 21.02 (3.53) |
20.72 (2.95) 20.36 (3.19) |
0.121 0.349 |
| Nutritional risk index, mean (SD) At the beginning of 12 weeks period At the end of 12 weeks period |
100.65 (11.80) 104.18 (10.40) |
104.10 (10.10) 102.58 (12.39) |
0.044 0.145 |
Table 3.
Changes detected in patients over the 12-week follow-up period with and without modulator therapy.
Table 3.
Changes detected in patients over the 12-week follow-up period with and without modulator therapy.
| Variables | Modulator therapy group (n=50) |
Non-modulator therapy group (n=57) |
p Value |
|---|---|---|---|
| Albumin (g/dL) | 0.17 (0.37) (-0.63)-1.24 |
-0.12 (0.30) (-1.24)-0.46 |
p<0.001 |
| Weight (kg) | 3.09 (2.74) (-1)-10.50 |
-0.99 (1.73) (-8)-4 |
p<0.001 |
| Body mass index (kg/m2) | 1.14 (0.97) (-0.36)-4.26 |
-0.36 (0.69) (-3.13)-1.29 |
p<0.001 |
| Nutritional risk index | 4.86 (6.72) (-8.90)-27.40 |
-2.67 (5.07) (-21.40)-7 |
p<0.001 |
Values are expressed as mean (standard deviation) and minimum-maximum.
Table 4.
NRI categories at baseline and after 12 weeks in both groups.
| NRI categories | Modulator therapy group (n=50) | Non-modulator therapy group (n=57) |
|---|---|---|
| Baseline, n(%) Non-malnourished (>100) Mild (97.6-100) Moderate (83.5-97.5) Severe malnourishment (< 83.5) |
24 (48) 7 (14) 14 (28) 5 (10) |
38 (66.7) 4 (7) 14 (24.6) 1 (1.8) |
| After 12 weeks, n (%) Non-malnourished (>100) Mild (97.6-100) Moderate (83.5-97.5) Severe malnourishment (< 83.5) |
35 (70) 8 (16) 6 (12) 1 (2) |
34 (59.6) 4 (7) 15 (26.3) 4 (7) |
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