Elexacaftor/tezacaftor/ivacaftor influences body composition in adults with cystic fibrosis: a fully automated CT-based analysis

Abstract

A poor nutritional status is associated with worse pulmonary function and survival in people with cystic fibrosis (pwCF). CF transmembrane conductance regulator modulators can improve pulmonary function and body weight, but more data is needed to evaluate its effects on body composition. In this retrospective study, a pre-trained deep-learning network was used to perform a fully automated body composition analysis on chest CTs from 66 adult pwCF before and after receiving elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Muscle and adipose tissues were quantified and divided by bone volume to obtain body size-adjusted ratios. After receiving ETI therapy, marked increases were observed in all adipose tissue ratios among pwCF, including the total adipose tissue ratio (+ 46.21%, p < 0.001). In contrast, only small, but statistically significant increases of the muscle ratio were measured in the overall study population (+ 1.63%, p = 0.008). Study participants who were initially categorized as underweight experienced more pronounced effects on total adipose tissue ratio (p = 0.002), while gains in muscle ratio were equally distributed across BMI categories (p = 0.832). Our findings suggest that ETI therapy primarily affects adipose tissues, not muscle tissue, in adults with CF. These effects are primarily observed among pwCF who were initially underweight. Our findings may have implications for the future nutritional management of pwCF.

Figure 1

Unadjusted results from CT-based body composition analysis before (T0) and after (T1) elexacaftor/tezacaftor/ivacaftor therapy. Significant increases of muscle, IMAT, EAT, PAT, SAT and TAT ratios were observed between baseline (T0) and follow-up (T1) analysis of body composition. Bone volume was stable and utilized as the denominator for calculating body size-adjusted ratios. Statistics: Line at median. P-value was determined using Wilcoxon signed rank test. * p < 0.05; ** p < 0.01; *** p < 0.001. TAT, total adipose tissue; IMAT, intra- and intermuscular adipose tissue; EAT, epicardial adipose tissue; PAT, paracardial adipose tissue; SAT, subcutaneous adipose tissue.

Figure 2

Adjusted results from CT-based body composition analysis (BCA) before (T0) and after (T1) elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Estimated mean BCA outcome ratio (pre/post-ETI) by BMI category. Underweight pwCF (n = 20, BMI < 18.5 kg/m²) exhibited pronounced increase of TAT ratio (p = 0.013). Statistics: Generalized equation estimation models, estimated mean and standard deviation. P-value shown for interaction effect. Interaction effect time(pre/post)*BMI category adjusted for age at ETI start, biological sex and duration of ETI therapy. BMI, body mass index; TAT, total adipose tissue; IMAT, intra- and intermuscular adipose tissue; EAT, epicardial adipose tissue; PAT, paracardial adipose tissue; SAT, subcutaneous adipose tissue.

Figure 3

Study flow diagram showing inclusion criteria and analyzed cohort. Initially, 204 people with CF (pwCF) receiving elexacaftor/tezacaftor/ivacaftor (ETI) were screened. After filtering out 40 pwCF without available chest CT scans and 98 pwCF obtaining CT scans independent of ETI therapy initiation and/or with missing follow-up CT scan, 66 pwCF remained as the final cohort.

Figure 4

Exemplary in- and output of fully automated CT-based body composition analysis (BCA). (A) Visualization of feature extraction for BCA and marker aggregation. BCA network detects the different BCA features within the chest CT scan. Those raw features are combined with bone to calculate body size-adjusted biomarkers. The tissues are encoded in colors as follows: pink: bone, yellow: muscle, orange-brown: subcutaneous adipose tissue (SAT), purple: epicardial adipose tissue (EAT), light blue: paracardial adipose tissue (PAT) and turquoise: inter- and intramuscular adipose tissue (IMAT). (B) Exemplary chest CT in axial view before (left) and after (right) elexacaftor/tezacaftor/ivacaftor therapy showing decreasing bronchiectasis wall thickening and regredient mucus impaction. (C) Exemplary chest CT in axial view showing increased proportion of subcutaneous adipose tissue (SAT, orange-brown) and increased inter- and intramuscular adipose tissue (IMAT, turquoise) after elexacaftor/tezacaftor/ivacaftor therapy.