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Observational Study
. 2025 Dec 4;66(6):2500150.
doi: 10.1183/13993003.00150-2025. Print 2025 Dec.

Reduction of systemic inflammation by elexacaftor/tezacaftor/ivacaftor correlates with lung function improvement in cystic fibrosis

Olga Halle  1   2   3 , Simon Y Graeber  4   5   6   7   3 , Julia Kontsendorn  1   2 , Claudia Kessemeier  1   2 , Jan-Niklas Falke  1   2 , Jannik Schwabe  1   2 , Katharina Schütz  1   2 , Sophia T Pallenberg  1 , Rebecca Dalferth  1 , Ruth Grychtol  1   2 , Felix C Ringshausen  2   8 , Mirjam Stahl  4   5   6   7 , Stephanie Thee  4   5   6   7 , Jobst F Roehmel  4   5   6   7 , Zulfiya Syunyaeva  4   5   6 , Julia Duerr  4   5   6 , Jaehi Chung  9   10 , Stephanie Hirtz  11 , Tatjana Uselmann  9   10 , Iris Kühbandner  9   10 , Claudia Rückes-Nilges  12   13 , Azadeh Bagheri-Pothoff  12   13 , Sandra Barth  12   13 , Bianca Schaub  14 , Folke Brinkmann  15   16 , Stefanie Weber  17 , Silke van Koningsbruggen-Rietschel  18   19 , Mustafa Abdo  20 , Markus Weckmann  15   16   21 , Stefanie Widder  22 , Gesine Hansen  1   2   23 , Burkhard Tümmler  1   2 , Olaf Sommerburg  9   10 , Lutz Naehrlich  12   13 , Marcus A Mall  4   5   6   7   24 , Anna-Maria Dittrich  25   2   23   24
Affiliations
Observational Study

Reduction of systemic inflammation by elexacaftor/tezacaftor/ivacaftor correlates with lung function improvement in cystic fibrosis

Olga Halle et al. Eur Respir J. .

Abstract

Background: The triple cystic fibrosis transmembrane conductance regulator modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) rapidly improves airway and systemic inflammation in people with cystic fibrosis. However, longitudinal effects on systemic inflammation and their relationship to lung function remain unknown.

Methods: In this prospective, observational, multicentre study, we analysed peripheral blood neutrophil counts, C-reactive protein (CRP) and six pro-inflammatory serum cytokines in a cohort of 198 people with cystic fibrosis aged ≥6 years at baseline and follow-up visits 3, 12 and 24 months after initiation of ETI, compared to 74 age-matched healthy control participants.

Results: Neutrophil counts and CRP, granulocyte colony-stimulating factor, interleukin (IL)-1β, IL-6 and IL-8 were reduced to 71%, 40%, 41%, 63%, 46% and 81% of median baseline values, respectively, after 3 months of therapy (all p<0.05), whereas monocyte chemotactic protein-1 reached 82% of baseline levels at 12 months only (p<0.05). Change from baseline to 3 months correlated with improvements in percent predicted forced expiratory volume for all systemic inflammation parameters except IL-8 (Spearman's r -0.17 to -0.42, p<0.05). All cytokines reached healthy control levels at or before 24 months. Decreased inflammation levels were sustained until 24 months for all parameters (p<0.05) except IL-6.

Conclusions: Our results demonstrate that ETI exerts rapid and sustained effects on systemic inflammation associated with lung function improvements in children, adolescents and adults with cystic fibrosis in a real-world, post-approval setting. However, our data also show that individual markers of systemic inflammation remain at levels above those of healthy controls, particularly in certain subgroups, suggesting persistence or resurgence of residual systemic inflammation.

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Conflict of interest statement

Conflict of interest: S.Y. Graeber reports grants and honoraria from Vertex, honoraria from Chiesi, and participating on advisory or data monitoring boards for Vertex and Chiesi. K. Schütz reports honoraria or travel reimbursements from Vertex and Octapharma. S.T. Pallenberg reports travel funds from Vertex. F.C. Ringshausen reports institutional funding from IMI (EU/EFPIA) and iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), the Mukoviszidose Institute, Novartis, Insmed Germany, Arcturus, AstraZeneca, Boehringer Ingelheim, Parion, ReCode and Vertex Pharmaceuticals Inc., consulting fees or honoraria from Parion Sciences, Boehringer Ingelheim, Insmed, Chiesi, I!DE Werbeagentur GmbH, Grifols, AstraZeneca and Sanofi, and participating on advisory or data monitoring boards for Insmed, Boehringer Ingelheim, Parion Sciences and Chiesi. M. Stahl reports payments for clinical studies and honoraria for presentations from Vertex, and participating on the Vertex Pharmaceuticals advisory board. S. Thee reports honoraria from Vertex Pharmaceuticals and Viatris PARI GmbH. B. Schaub reports consulting fees and/or honoraria from GlaxoSmithKline, Novartis, Sanofi, Astra Zeneca and has participated on advisory/monitoring boards for Sanofi and AstraZeneca. S. van Koningsbruggen-Rietschel has received consulting fees or honoraria from BiomX, PureIMS and Vitalograph. G. Hansen reports consulting fees and/or honoraria from Sanofi GmbH, MedUpdate and Abbvie. B. Tümmler reports honoraria from and participating on advisory/monitoring boards of Vertex Pharmaceuticals Inc. O. Sommerburg reports payments to institution for participation in clinical trials and honoraria for lectures from Vertex. L. Naehrlich reports institutional fees for study participation from Vertex Pharmaceuticals and Mukoviszidose Institute, participating on the trial steering committee for CF STORM, and being medical lead of the German CF-registry and pharmacovigilance study manager of the ECFSPR. M.A. Mall reports payments to institution for participation in clinical trials from Vertex Pharmaceuticals, Boehringer Ingelheim and Enterprise Therapeutics, consulting fees, honoraria or travel reimbursements from Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Splisense and Vertex Pharmaceuticals, and participating on advisory/monitoring boards for Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex. A-M. Dittrich reports clinical study funding (paid to institution) from Vertex Pharmaceuticals Inc. for execution of clinical studies, consulting fees from GSK, Oxford University and Novartis via the c4c consortium, and personal remuneration for scientific advice on textbooks and online educational materials. The remaining authors declare no conflict of interests.

Figures

FIGURE 1
FIGURE 1
Visit sequences and follow-up rates for study participants with cystic fibrosis.
FIGURE 2
FIGURE 2
Correlation of baseline percent predicted forced expiratory volume in 1 s (ppFEV1) with baseline peripheral blood neutrophil counts and concentrations of C-reactive protein (CRP), serum granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-1β, IL-6, IL-8 and monocyte chemotactic protein (MCP)-1 in adults, adolescents and children with cystic fibrosis. One dot indicates one study participant. r indicates Spearman's correlation coefficient. p-values were adjusted for false discovery rate using the Benjamini–Hochberg correction. ns: nonsignificant (p>0.05).
FIGURE 3
FIGURE 3
Systemic inflammation markers in healthy controls (HC) and in adults, adolescents and children with cystic fibrosis at baseline (BL) and under elexacaftor/tezacaftor/ivacaftor (ETI) therapy. Peripheral blood neutrophil counts and concentrations of C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-1β, IL-6, IL-8 and monocyte chemotactic protein (MCP)-1 at BL, and at time points 3, 12 and 24 months after initiation of ETI treatment. One dot indicates one study participant; horizontal lines indicate the median. Green-filled rectangles indicate interquartile range of HC values. Ref.: laboratory reference thresholds (supplementary methods). ANOVA with p-value adjustment for false discovery rate using the Benjamini–Hochberg correction. Nonindicated pairwise comparisons are not significant (p>0.05). Note that no pairwise comparisons were performed between time points 3, 12 and 24 months.
FIGURE 4
FIGURE 4
Comparison of markers of systemic inflammation between adolescents and adults (≥12 years) and children (6–11 years) with cystic fibrosis at baseline and after 3 months of elexacaftor/tezacaftor/ivacaftor. Peripheral blood neutrophil counts and concentrations of C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-1β, IL-6, IL-8 and monocyte chemotactic protein (MCP)-1 in indicated age groups. One symbol per study participant. Ref.: laboratory reference thresholds (supplementary methods). Two-way ANOVA; p-values were adjusted for false discovery rate using the Benjamini–Hochberg correction. Nonindicated pairwise comparisons are not significant (p>0.05). Horizontal lines indicate median.
FIGURE 5
FIGURE 5
Correlation between changes in systemic inflammation and changes in lung function in people with cystic fibrosis under elexacaftor/tezacaftor/ivacaftor treatment. Correlation between change in percent predicted forced expiratory volume in 1 s (ppFEV1) and change in peripheral blood neutrophil counts and concentrations of C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-1β, IL-6, IL-8 and monocyte chemotactic protein (MCP)-1 from baseline to 3 months. Changes were calculated by subtracting the baseline time point values from the 3-month time point values; so positive changes indicate increase, and negative changes indicate decrease of the respective parameter. One dot indicates one study participant. r indicates Spearman's correlation coefficient. p-values were adjusted for false discovery rate using the Benjamini–Hochberg correction. ns: nonsignificant (p>0.05).
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