{"doi":"10.1002/ppul.26797","title":"Body composition in children with cystic fibrosis treated with CFTR modulators versus modulator naïve individuals","abstract":null,"journal":"Pediatric Pulmonology","year":2024,"id":647494,"datarank":0.31740420095377275,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.04864028056956449,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.04864028056956449,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":3,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":453317,"name":"Elizabeth Hente","orcid":"0000-0001-9779-0165","position":1,"is_corresponding":false},{"id":1687010,"name":"Md M. Hossain","orcid":null,"position":2,"is_corresponding":false},{"id":1094263,"name":"William D. Hardie","orcid":"0000-0001-9311-8099","position":3,"is_corresponding":false},{"id":1687011,"name":"Michelle Hjelm","orcid":"0000-0003-4474-8021","position":4,"is_corresponding":false},{"id":453319,"name":"Thomas F. Boat","orcid":"0000-0003-3075-1166","position":5,"is_corresponding":false},{"id":1687009,"name":"Carolyn Dress","orcid":"0000-0002-9990-2981","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Body composition in children with cystic fibrosis treated with CFTR modulators versus modulator naïve individuals","abstract":"Increasing numbers of children with cystic fibrosis (CF) are overweight (body mass index [BMI]: 85th–94th percentile) or obese (BMI > 95th percentile).1 While higher BMI was historically associated with better lung function, recent studies demonstrate that lung function and health are advantaged by fat-free body mass, not fat mass.2, 3 Excess thoracoabdominal adiposity has potential for negative downstream effects on the respiratory system including altered diaphragm mobility, reduced chest wall expansion, and reduced lung compliance.4 Mono and dual cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation is associated with increases of weight and fat mass,5 however, the effect of these modulators on body composition and its functional correlates in children with CF has not been comprehensively documented. We compared body composition, upper extremity muscle strength, and spirometry for grade school aged children with CF who had and had not been treated with a mono or dual modulator for multiple years. We hypothesized that children with CF and previous modulator therapy would demonstrate an increase of BMI and fat mass as compared to those who were modulator naïve. A second aim was to provide data on the differences in peripheral skeletal muscle and strength of children in these groups. This combined cross-sectional and retrospective group comparison study was approved by the Cincinnati Children's Hospital Institutional Review Board. Children with CF ages 6–11 years of age who were poised to initiate elexacaftor/tezacaftor/ivacaftor (ETI) and could perform pulmonary function testing were recruited and stratified into previous (n = 27) and no previous (n = 11) modulator treatment groups. Age, sex, phenotype, and genotype comparisons of the two groups are recorded in Table 1. Modulator treatment record and previous BMI data were extracted from the medical record retrospectively. BMI percentiles and z scores based on Center for Disease Control (CDC) growth charts were used to standardize data for age and sex. BMI data were recorded starting at time of modulator initiation for those on modulator and approximately 3.5 years, the average duration of modulator therapy, before study enrollment for those naïve to modulator. Previous modulator therapy included lumacaftor/ivacaftor (n = 17), elexacaftor/ivacaftor (n = 4), and ivacaftor (n = 5). Height, weight, body composition, hand grip strength, and spirometry were all measured on a single day. Body composition assessment was performed via segmental multifrequency bioelectrical impedance analysis (BIA) using InBody 770 equipment. When compared to the historical gold standard of body composition evaluation, dual-energy X-ray absorptiometry using the four-component model, this BIA technology shows close agreement across BMI levels of children.6 Body composition kilogram data were converted to indices for standardization. Hand-grip strength was assessed using a Jamar hydraulic hand dynamometer, averaging three successive measurements with each hand. Spirometry was carried out in the clinical pulmonary function testing laboratory using American Thoracic Society protocol guidelines and reference values derived from Global Lung Function Initiative equations.7, 8 The demographic and clinical characteristics of the two therapy groups were reported as mean ± standard deviation for continuous data and as percent frequency for categorical data. Wilcoxan rank sums test was used to compare the equality of the two group means for continuous data and the Fisher exact test was used for categorical data to compare the independence of the two groups. The significance of difference was defined as p < .05. Significant differences were noted between those who had been treated with modulator versus those naïve to modulator therapy (Table 1). Children in the modulator treatment group had been on therapy for an average of 3.7 years, with a range of 1.9–4.5 years. Those naïve to modulator were younger on average at study enrollment (8.3 vs. 9.7 years, p = .05). The two groups were otherwise similar based on genotype, phenotype, race, sex, and socioeconomic status (Medicaid eligibility). All but three children, two within the modulator group, had CFTR genotypes with one or two F508del allele(s), and all subject genotypes have been characterized as having minimal or very low levels of CFTR function. Children on modulator therapy had a significantly greater BMI z score (0.72 vs. 0.04, p = .03), fat mass index (5.03 vs. 3.40 kg/m2, p = .04), and percent body fat (25.5% vs. 17.7%, p = .01). There was no significant difference between groups for lean mass index (13.88 vs. 13.49 kg/m2, p = .58), skeletal muscle mass index (7.11 vs. 6.73 kg/m2, p = .37), hand grip strength (27.6 vs. 25.2 lbs, p = .60), or percent predicted forced expiratory volume in 1 s (ppFEV1) (101% vs. 104%, p = .70). See Figure 1 for graphical representation of these results. On average, the BMI percentile of children in the modulator therapy group increased by 13.7% while receiving modulator therapy. While the greatest increase was seen in the first year of treatment (on average, an increase of 11.8% for the BMI percentile), modest gains continued in subsequent years. In contrast, children in the modulator naïve group experienced a 9.8% decrease of their BMI percentile, from 60.2% to 50.4%, during a 3.5 year interval before assessment. Our comparison of data from modulator-treated and modulator naïve children with CF offered a novel opportunity to identify long-term modulator effects on body weight and composition, as well as muscle strength and lung function, of preadolescent children with CF. Data from these groups suggest that modulator therapy was associated with a greater BMI, fat mass and percent body fat, but not skeletal muscle mass or strength, compared with children naïve to modulator therapy. The absence of appreciable modulator effect on skeletal muscle mass and strength may in part explain why ppFEV1 was not significantly different in our groups. These outcomes suggest that modulator-linked weight gain over several years is often not ideal weight gain. Excess fat and paucity of skeletal muscle have well documented adverse consequences for health, both in the short and long term. We encourage future studies of modulator effects in other CF childhood populations, particularly those treated with ETI, to assess generalizability of our findings. This group comparison study, while offering opportunity for new insights, has several potential limitations. The comparison group, while closely matched in other respects, was younger by an average of 1.4 years at the time of body composition measurement. While all patients were assessed before their 12th birthday, several older participants, particularly girls, may have experienced early pubertal changes and related increased fat accretion. Given the retrospective study design and lack of thorough documentation regarding pubertal status, we were unable to assess pubertal maturation in this population. Most of the participants, however, were less than 10 years of age and likely prepubertal or in early stages of puberty. Further, expected mean percent body fat increase for boys and girls is less than a percentage point per year at ages 6–11 and cannot explain a greater than an 8-percentage point differential for percent body fat in the two groups.9 Second, our comparison group was relatively small. Assembling a large comparison group with like-genotype that has not been treated with a modulator is difficult given the current treatment options for CF. Our comparison group was large enough to demonstrate significant differences in body mass and composition for the modulator treatment group. Limited numbers in our control group could have obscured a small but statistically significant increase in skeletal muscle mass and strength with modulator therapy. Additionally, only upper extremity muscle strength was measured and thus does not represent lower extremity, core, or respiratory muscle strength. Our observations suggest a need for comprehensive study of the feasibility and outcomes of potentially effective, family focused nutritional and physical activity interventions for children with CF, particularly at the time of modulator therapy initiation. Failure to achieve healthier weight gain may blunt the impressive multisystem benefits of modulators. Future studies should target skeletal muscle growth and limitation of fat accretion as key components of healthy weight gain, starting early in life, in efforts to augment lifespan health of children, many of whom are now projected to live into middle age and beyond. Carolyn Dress: Data collection and curation; formal analysis; original draft writing; review and editing; final approval of submitted manuscript. Elizabeth Hente: Conceptualization; funding acquisition; review and editing; project administration; final approval of submitted manuscript. Md M. Hossain: Data analysis; review and editing; final approval of submitted manuscript. William Hardie: Conceptualization; funding acquisition; review and editing; final approval of submitted manuscript. Michelle Hjelm: Conceptualization; funding acquisition; review and editing; final approval of submitted manuscript. Thomas Boat: Conceptualization; funding acquisition; formal analysis; original draft writing; review and editing; supervision; final approval of submitted manuscript. This work was supported in part by Vertex Pharmaceuticals (grant number CTA0001313, 2022). Vertex had no role in collection, analysis or interpretation of data, or writing of this report. The authors declare no conflict of interest. All subjects gave their informed consent for inclusion before they participated in this study. This study was approved by the local Institutional Review Board.","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38116856","pmcid":null,"openalex_id":"https://openalex.org/W4389998979","authors":[],"funders":[{"funder_name":"Vertex Pharmaceuticals","grant_id":"2022","title":null},{"funder_name":"Vertex Pharmaceuticals","grant_id":"CTA0001313","title":null}],"total_grants":2,"fwci":0.8222,"citation_percentile":0.74303544,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ppul.26797","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ppul.26797","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ppul.26797","host_type":"publisher"},{"url":"https://doi.org/10.1002/ppul.26797","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38116856","host_type":"repository"}],"fields_of_study":["Cystic Fibrosis Research Advances","Neonatal Respiratory Health Research","Tracheal and airway disorders","Child","Humans","Cystic Fibrosis","Cystic Fibrosis Transmembrane Conductance Regulator","Aminophenols","Aminopyridines","Body Composition","Mutation"],"mesh_terms":["Aminophenols","Aminopyridines","Body Composition","Child","Cystic Fibrosis","Humans","Mutation","Cystic Fibrosis Transmembrane Conductance Regulator"],"keywords":["Medicine","Cystic fibrosis","Overweight","Ivacaftor","Body mass index","Spirometry","Cystic fibrosis transmembrane conductance regulator","Percentile","Internal medicine","Pulmonary function testing","Sarcopenia","Lung","Endocrinology","Cardiology","Gastroenterology","Physiology","Asthma","Body composition","BMI","Modulator Therapy","Children With Cf"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T00:28:20.910181Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}