Impact of appetite stimulants on growth parameters in children with cystic fibrosis

doi:10.21203/rs.3.rs-4915720/v1

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Impact of appetite stimulants on growth parameters in children with cystic fibrosis

https://doi.org/10.21203/rs.3.rs-4915720/v1

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Objectives

Malnutrition is prevalent among children with cystic fibrosis (CF),often resulting from frequent pulmonary exacerbations and intestinal malabsorption.In addition to providing sufficient calorie intake through enteral formulas, appetite stimulants may help address nutritional deficiencies and improve overall prognosis.

Methods

This retrospective study included children who received CH as an appetite stimulant for at least three consecutive months.Data on CH-related adverse effects, z-scores for weight,height,body mass index(BMI), and percentage of forced expiratory volume in 1 second(FEV1%)were collected from medical records.Z-scores of growth parameters were calculated at baseline(CH initiation),three months before baseline,and three and six months after treatment.

Results

The study included 45 children with a mean age of 11 years.Only one patient was on modulator therapy and another was being monitored for pancreatic insufficiency,while one had diabetes.All but one were using formula diet simultaneously.Significant improvements in weight and BMI z-scores were observed from baseline to three months of CH therapy(p = 0.004 and p = 0.006,respectively),with no significant changes noted in the three months before treatment.A modest increase in weight and BMI z-scores was seen from three to six months of therapy.Additionally,FEV₁ z-scores significantly increased from baseline to three months of therapy, with no further improvement observed in the subsequent three months.

Conclusion

Six months of CH therapy was associated with significant improvements in weight and BMI z-scores,particularly within the first three months.No adverse effects were reported.Given the deceleration in the rate of increase in anthropometric z-scores from the third to sixth month, a three-month duration of CH therapy appears to be optimal and sufficient for children with CF.

Health sciences/Health care/Nutrition

Health sciences/Health care/Paediatrics

appetite stimulant

BMI

children

cyproheptadine

cystic fibrosis

nutrition

weight

Maintaining proper nutrition in patients with cystic fibrosis (CF) is vital, given the strong association between nutritional status and clinical outcomes. In CF, poor nutrition, often caused by impaired digestion and absorption due to pancreatic insufficiency, is closely linked to frequent pulmonary exacerbations.¹ Consequently, weight loss and malnutrition contribute to diminished lung function, leading to a lower quality of life and increased morbidity and mortality. Therefore, achieving and sustaining adequate nutrition is a key objective in CF management to improve survival rates.²

Meeting the energy requirements of patients with CF is often challenging due to energy loss from malabsorption and the increased metabolic demands associated with lung disease. Poor appetite further contributes to inadequate weight gain in children with CF. Traditional approaches to address malnutrition involve supplementary feeding, either orally or via gastrostomy and nasogastric tubes. However, insufficient appetite can hinder adequate intake of enteral solutions, leading to minimal improvements in weight gain. Additionally, tube feeding methods are invasive, costly, and can negatively affect a patient's physical appearance and self-esteem.³ Recent studies have shown that Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators can positively impact weight gain, but access to these treatments remains limited for many patients worldwide, and most are ineligible due to specific CFTR mutations.

Appetite stimulants provide a non-invasive alternative for enhancing the nutritional status of CF patients. Cyproheptadine (CH), a first-generation antihistamine with antiserotonergic properties, is recognized for its secondary effect of stimulating appetite. Despite not being officially approved for this use, CH has been investigated as an appetite enhancer in several conditions, including cancer cachexia, anorexia nervosa, and malnutrition, demonstrating favorable outcomes and minimal side effects, primarily mild, transient sedation.⁴

Despite its potential advantages, research on the use of CH in CF patients is still limited. Currently, there is no widely accepted protocol for employing appetite stimulant therapy, nor is there a standardized approach or optimal duration for its use. This retrospective study seeks to address these gaps in the literature by investigating whether CH administration results in weight gain in children with CF, assessing whether short-term treatment is effective, and identifying any associated side effects.

2.1. Study Design and Population

This retrospective cohort study was conducted in the Department of Pediatric Pulmonology at our referral CF center from July 2019 to June 2023. During this period, 399 children under the age of 18 with a confirmed diagnosis of CF were monitored.⁵ The study focused on children with CF who, despite following a prescribed formula diet, did not achieve optimal body mass index (BMI) levels. These children were prescribed CH as an appetite stimulant for a minimum of three consecutive months. Patients were excluded if they were on other appetite-altering medications (such as long-term oral corticosteroids), if they were noncompliant with the CH treatment, or if they lacked sufficient anthropometric data at the required study intervals.

At the commencement of CH (baseline), data on demographic characteristics (age, gender, CF genetic mutations), anthropometric parameters (weight, height), lung function measurements [forced expiratory volume at 1 second (FEV₁)], pancreatic sufficiency status, CF-related diabetes (CFRD) status, use of oral or enteral supplementation and CFTR modulator therapy utilization of the patients were extracted from the medical records. Additionally, weight, height, BMI and spirometry test results from 3 months prior to the baseline and at three and six months of continuous CH treatment were retrieved for each patient. Spirometry tests were not conducted for children under 5 years old who were unable to perform an acceptable test. Spirometry measurements were interpreted based on American Thoracic Society and European Respiratory Society guidelines, with FEV1 expressed as a percentage of predicted normal values and FEV1 z-scores calculated to account for age, height, sex, and ethnicity.^{6, 7}

Medical records were also reviewed to identify any adverse effects of the medication. Anthropometric measurements were taken according to World Health Organization (WHO) guidelines. BMI values were calculated from weight and height measurements, and BMI z-scores were derived using the national reference values.⁸ The daily dosage of CH prescribed ranged from 2 mg to 4 mg, typically administered once daily.

The primary aim of this study was to determine whether appetite stimulants resulted in increased weight or improved BMI z-scores in children with CF. The secondary objective was to evaluate any side effects associated with CH.

Ethical approval

was obtained from the Clinical Research Ethics Committee of our university (reference number: SBA 24/145). As this study was conducted retrospectively, the analysis of the data obtained from medical records did not necessitate obtaining informed consent from the participants.

2.3. Statistical Methods

Statistical analyses were performed using SPSS statistical software, version 21 (IBM Corp., Armonk, NY, USA). Normally distributed continuous variables were analyzed using student t-test and expressed as mean ± standard deviation (SD). Non-normally distributed continuous variables were analyzed using Mann-Whitney U test and expressed as median (interquartile range-IQR). The variables, which are suitable for normal distribution, were assessed by Shapiro-Wilk tests. Categorical variables were presented as percentages (%) and analyzed using Chi-square test or Fisher’s exact test. Repeated measures ANOVA or Friedman's test followed by Wilcoxon test was performed for repeated measurements. Values of p < 0.05 were considered statistically significant.

3.1. Demographic and clinical characteristics of the children

A total of 45 children who were prescribed cyproheptadine (CH) for at least three months were included in this study. At the initiation CH therapy, the mean age of the participants was 11.04 ± 3.54 years, with 20 of the patients (44.4%) being male.

The majority of patients (97.7%) were pancreatic insufficient. One patient had concurrent CFRD. All but one patient had previously been on a formula diet, and only one patient was receiving CFTR modulator therapy. Fifteen patients were homozygous for the F508del mutation, while three were heterozygous. The baseline demographic characteristics of the study population are detailed in Table 1.

Table 1

Baseline characteristics
	n = 45
Age, mean ± SD	11.04 ± 3.54
Male, n (%)	20 (44.4%)
Pancreatic status PI, n (%) PS, n (%)	44 (97.7%) 1 (2.3%)
Genotype F508del homozygous, n (%) F508del heterozygous, n (%)	15 (0.33%) 3 (6.66%)
Subjects with CFRD, n (%)	1 (2.3%)
Subjects on enteral formula, n (%)	44 (97.7%)
Subjects on modulator treatment	1 (2.2%)
CFRD: Cystic Fibrosis Related Diabetes

Table 2. Changes in anthropometric measurements and FEV₁% over time
					p-value
	3 months before baseline	Baseline (at commencement of CH)	3. month	6. month	Before baseline vs. baseline	Baseline vs. 3. month	3. month vs. 6. month
Weight, z-score	-1.90 ± 0.97	-1.96 ± 1.08	-1.68 ± 1.29	-1.53 ± 1.00	0.169	0.006	0.025
Height, z-score	-1.44 ± 0.95	-1.40 ± 0.89	-1.28 ± 0.93	-1.29 ± 0.80	0.523	0.196	0.606
BMI, z-score	-1.55 ± 0.77	-1.48 ± 0.93	-1.11 ± 1.15	-1.03 ± 0.98	0.909	0.010	0.038
FEV₁%	77.96 ± 25.52	73.30 ± 28.12	76.30 ± 26.52	71.21 ± 30.03	0.095	0.130	0.191
FEV₁ z-score	-2.80 ± 1.75	-3.08 ± 1.96	-2.43 ± 2.14	-2.57 ± 2.25	0.209	0.041	0.638
BMI: body mass index; CH: cyproheptadine; FEV₁: forced expiratory volume at 1 second

The youngest participant was 4 years old. Five participants were under 5 years old and were therefore unable to perform pulmonary function tests. Pulmonary function test data were unavailable for some children at various time points during the study.

3.2. Assessment of growth parameters

Despite the lack of significant changes in height z-scores, the increases in weight and BMI z-scores following CH therapy were statistically significant (Table 2).

In the three months preceding CH therapy, the weight z-score showed a slight, non-significant decrease (from − 1.90 ± 0.97 to -1.96 ± 1.08, p = 0.169). However, after starting CH, the weight z-score improved significantly from − 1.96 ± 1.08 at baseline to -1.68 ± 1.29 after three months of treatment (p = 0.006). A further, albeit smaller, significant increase was observed from − 1.68 ± 1.29 at three months to -1.53 ± 1.00 at six months (p = 0.025) (Fig. 1).

Regarding BMI, the z-score showed a non-significant increase in the three months prior to CH therapy (from − 1.55 ± 0.77 to -1.48 ± 0.93, p = 0.909). However, the improvement in BMI z-score from baseline to three months of CH therapy was statistically significant (p = 0.010), with a continued, though smaller, significant increase from three to six months (p = 0.038) (Fig. 2).

The patient on CFTR modulator therapy gained 3.5 kg over six months, with an increase in BMI from 14.08 to 14.98 by the end of the study period.

No adverse events necessitating discontinuation of CH treatment were observed among the participants.

3.2. Assessment of pulmonary function tests

Due to age constraints, five patients were unable to perform spirometry as they were under five years old. Among the remaining 40 patients, spirometric data were missing for some at different time points.

Spirometric data were available for 23 children both at baseline and three months before CH therapy. At the third and sixth months of CH treatment, spirometric data were available for 18 and 17 children, respectively.

FEV1 z-scores were calculated to adjust for age, height, sex, and ethnicity. While FEV1% did not show significant changes across time periods, the FEV1 z-score significantly increased from − 3.08 ± 1.96 to -2.43 ± 2.14 within the first three months of CH therapy (p = 0.041). A decrease in the FEV1 z-score was observed between three and six months of therapy, but this change was not statistically significant (p = 0.638) (Table 2).

Given the limited research on the use of appetite stimulants in individuals with CF, further studies are needed to validate their effectiveness in promoting weight gain and to better understand their side effect profiles. Our study indicates that while there was no significant change in weight and BMI z-scores during the three months prior to the initiation of CH therapy, a six-month course of CH was associated with significant improvements in these parameters, with the most notable increases occurring within the first three months. The observed deceleration in the rate of z-score increases from the third to the sixth month suggests that a three-month duration of CH therapy may be optimal and sufficient for promoting growth in children with CF.

To our knowledge, this is the first study conducted in our country that examines the use of CH as an appetite stimulant in children with CF. Moreover, this study represents only the second instance in the literature demonstrating improvements in spirometric parameters following CH therapy in this patient population.

Several studies have investigated the use of appetite stimulants in conditions such as malnutrition, anorexia nervosa, renal failure, cancer, and AIDS, but research on their use in individuals with CF remains limited. In 2012, Epifanio et al. conducted a double-blind, placebo-controlled trial involving 25 children aged 5 to 18 years.³ The participants were divided into two groups, with one group receiving CH (4 mg three times daily) for 12 weeks, while the other received a placebo. The study found that the average weight gain in the CH group was significantly higher than in the placebo group (1.61 kg vs. 0.67 kg, p = 0.036). Furthermore, the intervention group showed an increase in BMI of 0.46 kg/m², whereas no improvement was observed in the placebo group (p = 0.027). However, the changes in pulmonary function were not statistically significant. In another study, Grunert et al. retrospectively analyzed 15 patients who were prescribed CH for more than 12 months due to suboptimal nutritional status.² The results showed a significant increase in BMI z-score, with a mean change of + 0.91 over 12 months of CH treatment compared to a decrease of -0.52 in the 12 months prior to treatment (p = 0.0002). There was also a trend toward improved lung function during the 12 months of CH treatment compared to the 12 months prior, though this did not reach statistical significance (+ 2.79% vs. -6.2%; p = 0.07). A recent Cochrane review summarized four randomized controlled trials (RCTs) on the use of CH and megestrol as appetite stimulants in children and adults with CF.⁹ Two of the studies focused on the benefits and risks of megestrol acetate in managing CF-related anorexia^{10, 11}, while the other two examined the efficacy and side effects of CH in both children and adults with CF. Both RCTs involving CH found significant improvements in weight z-scores at 3 months compared to the placebo groups, though no significant changes were observed in FEV₁.^{3, 4} The most common adverse reactions to CH were mild, temporary sedation and fatigue, whereas megestrol acetate was associated with glucose dysregulation as the most significant side effect.

A very recent study published in 2023 evaluated the use of appetite stimulants in children with CF, including 62 participants-56 in the CH group and 6 in the mirtazapine group-all of whom had been on appetite stimulants for at least six months.¹² The study observed significant improvements in weight z-score, BMI z-score, and mean FEV1 during the first 3 months, followed by a positive trend from months 3 to 6. However, from months 6 to 12, weight, weight percentile, and weight z-score plateaued, suggesting that extending the duration of appetite stimulant therapy may not yield further benefits in anthropometric outcomes. Statistically significant increases in BMI, BMI percentile, and BMI z-score were noted from baseline to the third month of therapy, with a continuing positive trend toward the sixth month. However, from months 6 to 12, a plateau in BMI changes was observed, similar to the stabilization seen in weight parameters. Consequently, the authors suggested that it may be more effective to use appetite stimulants for 3-month periods, with washout intervals in between.

Our findings align with the existing literature, showing a significant increase in weight and BMI z-scores, particularly during the initial 3 months of treatment, with no adverse effects reported. Additionally, our study suggests that a 3-month course of CH therapy is sufficient to achieve the desired anthropometric improvements while minimizing the risk of potential side effects. Therefore, utilizing appetite stimulants for 3-month intervals with washout periods appears to be a reasonable strategy to optimize benefits in growth parameters. Additionally, our study is among the first, aside from Kennedy et al., to demonstrate an improvement in FEV1 following CH therapy..¹²

Regarding dosage and frequency, there is no consensus on the optimal regimen for appetite stimulants. Most patients in our study received CH with a mean total daily dose of 3.34 mg, administered once or twice daily. This dosing scheme is similar to the one reported by Grunert et al., where a total daily dose of 0.1–0.32 mg/kg/day was divided into two doses.² We implemented a comparable administration regimen in our study as well.

This study had limitations due to its retrospective design, which often leads to missing data and an inability to control for all potential confounding factors. Additionally, while no adverse effects from CH were reported, the assessment of side effects relied solely on patient self-reporting, which may lack objectivity and reliability. The small sample size further limits the study's power to demonstrate the full impact of the observed changes.

In conclusion, despite not being a randomized controlled trial, this study adds valuable insights to the literature by demonstrating that CH can effectively improve growth parameters in children with CF. Given the challenges of accessing modulator therapy in our country, the role of CH in aiding weight gain is particularly significant. Larger studies are needed to further validate these findings, especially in regions where access to modulator therapy is limited.

Funding: None

Conflict of Interest: All authors declare that they have no conflict of interest.

This study was performed at Ihsan Dogramaci Children’s Hospital, University of Hacettepe, Ankara, Turkey.

DATA AVAİLABİLİTY STATEMENT

The data that support the findings of this study are available on request from the corresponding author, [BS].

ACKNOWLEDGMENTS

We would like to thank all the nursing and technical personnel in the Pulmonology Laboratory of the Department of Pulmonary for continuous support throughout the duration of this study.

ACKNOWLEDGEMENTS

We would like to thank all the nursing and technical personnel in the Pulmonology Laboratory of the Department of Pulmonary for continuous support throughout the duration of this study.

AUTHOR CONTRIBUTIONS

conception or design of the work: N.E., B.S., D.A., B.C.Y., R.A.; acquisition, analysis, or interpretation of data for the work: E.G., H.H.G.; H.D.; I.N.S.T.; H.O.; E.Y.; D.D., U.Ö.; drafting the work or reviewing: N.E.; final approval of the version to be published: N.E.; E.Y., D.D., U.Ö.

FUNDING

No funding.

STATEMENT OF ETHICS

Ethical approval was obtained from the Clinical Research Ethics Committee of our university (reference number: SBA 24/145).

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

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There is NO conflict of interest to disclose.

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You are reading this latest preprint version

Impact of appetite stimulants on growth parameters in children with cystic fibrosis

Status:

Version 1

Abstract

Figures

1. INTRODUCTION

2. METHODS

2.1. Study Design and Population

2.3. Statistical Methods

3. RESULTS

3.1. Demographic and clinical characteristics of the children

3.2. Assessment of growth parameters

3.2. Assessment of pulmonary function tests

4. DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1