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Magnetic resonance imaging detects improvements of pulmonary and paranasal sinus abnormalities in response to elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis

  • Lena Wucherpfennig
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Simon M.F. Triphan
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Sabine Wege
    Affiliations
    Department of Pulmonology and Respiratory Medicine, Cystic Fibrosis Center, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Hans-Ulrich Kauczor
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Claus P. Heussel
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Niclas Schmitt
    Affiliations
    Department of Neuroradiology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
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  • Felix Wuennemann
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
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  • Victoria L. Mayer
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany
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  • Olaf Sommerburg
    Affiliations
    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Translational Pulmonology and Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, University of Heidelberg, Heidelberg, Germany
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  • Marcus A. Mall
    Affiliations
    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Translational Pulmonology and Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, University of Heidelberg, Heidelberg, Germany

    Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    German Center for Lung Research (DZL), Associated partner site, Berlin, Germany

    Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
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  • Author Footnotes
    1 These authors contributed equally as last authors.
    Monika Eichinger
    Footnotes
    1 These authors contributed equally as last authors.
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally as last authors.
    Mark O. Wielpütz
    Correspondence
    Corresponding author at: Department of Diagnostic and Interventional Radiology, University Hospital of Heidelberg, and Translational Lung Research Center (TLRC), German Lung Research Center (DZL), Im Neuenheimer Feld 420, 69120 Heidelberg, Germany.
    Footnotes
    1 These authors contributed equally as last authors.
    Affiliations
    Department of Diagnostic and Interventional Radiology, Subdivision of Pulmonary Imaging, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany

    Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Im Neuenheimer Feld 156, 69120 Heidelberg, Germany

    Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Röntgenstr. 1, 69126 Heidelberg, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally as last authors.
Published:April 08, 2022DOI:https://doi.org/10.1016/j.jcf.2022.03.011

      Highlights

      • The chest MRI global score showed a long-term stability in patients under standard therapy without elexacaftor/tezacaftor/ivacaftor.
      • The chest MRI global score improved in patients under Elexacaftor/Tezacaftor/Ivacaftor, mainly due to reduction of bronchiectasis/wall thickening and mucus plugging.
      • The improved chest MRI global score correlated with proportional improvements in FEV1%.
      • The chronic rhinosinusitis MRI sum score improved under elexacaftor/tezacaftor/ivacaftor therapy through a reduction of mucopyoceles.

      Abstract

      Background

      Therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was recently approved for adult cystic fibrosis (CF) patients with at least one F508del mutation. However, its effects on structural and functional lung abnormalities and chronic rhinosinusitis have not been studied by imaging.

      Methods

      19 adults with CF (mean age 31±9y, range 19–55y) underwent standardized chest magnetic resonance imaging (MRI), and nine also same-session sinonasal MRI, before (MRI1) and after (MRI2) at least one month (mean duration 5 ± 3mon) on ETI. 24 control CF patients (30±7y, range 20–44y) without ETI underwent longitudinal chest MRI, and eleven also sinonasal MRI, twice (mean interval 40±15mon). MRI was assessed using the validated chest MRI score and chronic rhinosinusitis (CRS)-MRI score. Forced expiratory volume in 1 s percent predicted (FEV1%) was measured in all patients.

      Results

      In controls, the chest MRI global score and CRS-MRI sum score were stable from MRI1 to MRI2. In patients under ETI, the chest MRI global score improved (-11.4 ± 4.6, P<0.001), mainly due to reduction of bronchiectasis/wall thickening and mucus plugging subscores (-3.3 ± 2.2 and -5.2 ± 1.5, P<0.001, respectively). The improvement in chest MRI score correlated well with improved FEV1% (r=-0.703, P<0.001). The CRS-MRI sum score also improved in patients under ETI (-6.9 ± 3.0, P<0.001), mainly due to a reduction of mucopyoceles in the maxillary and ethmoid sinus (-50% and -39%, P<0.05, respectively).

      Conclusions

      MRI detects improvements of chest MRI and CRS-MRI scores in adult CF patients who first received ETI, demonstrating reversibility of structural lung and paranasal sinus abnormalities in patients with established disease.

      Keywords

      Abbreviations:

      CF (cystic fibrosis), CFTRm (cystic fibrosis transmembrane conductance regulator modulator), CT (Computed tomography), CRS (chronic rhinosinusitis), ETI (Elexacaftor/Tezacaftor/Ivacaftor), FEV1% (Forced expiratory volume in 1 s percent predicted), MRI (magnetic resonance imaging)
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      References

        • Gibson R.L.
        • Burns J.L.
        • Ramsey B.W.
        Pathophysiology and management of pulmonary infections in cystic fibrosis.
        Am J Respir Crit Care Med. 2003; 168: 918-951
        • Welsh M.J.
        • Ramsey B.W.
        • Accurso F.
        • Cutting G.R.
        Cystic Fibrosis.
        (editors)in: Valle DL Antonarakis S Ballabio A Beaudet AL Mitchell GA The online metabolic and molecular bases of inherited disease. McGraw-Hill Education, New York, NY2019
        • Mainz J.G.
        • Naehrlich L.
        • Schien M.
        • Kading M.
        • Schiller I.
        • Mayr S.
        • et al.
        Concordant genotype of upper and lower airways P aeruginosa and S aureus isolates in cystic fibrosis.
        Thorax. 2009; 64: 535-540
        • Berkhout M.C.
        • Rijntjes E.
        • El Bouazzaoui L.H.
        • Fokkens W.J.
        • Brimicombe R.W.
        • Heijerman H.G
        Importance of bacteriology in upper airways of patients with Cystic Fibrosis.
        J Cyst Fibros. 2013; 12: 525-529
        • De Boeck K.
        • Amaral M.D.
        Progress in therapies for cystic fibrosis.
        Lancet Respir Med. 2016; 4: 662-674
        • Mall M.A.
        • Mayer-Hamblett N.
        • Rowe S.M.
        Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications.
        Am J Respir Crit Care Med. 2020; 201: 1193-1208
        • Heijerman H.G.M.
        • McKone E.F.
        • Downey D.G.
        • Van Braeckel E.
        • Rowe S.M.
        • Tullis E.
        • et al.
        Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.
        Lancet. 2019; 394: 1940-1948
        • Middleton P.G.
        • Mall M.A.
        • Drevinek P.
        • Lands L.C.
        • McKone E.F.
        • Polineni D.
        • et al.
        Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele.
        N Engl J Med. 2019; 381: 1809-1819
        • Nichols D.P.
        • Paynter A.C.
        • Heltshe S.L.
        • Donaldson S.H.
        • Frederick C.A.
        • Freedman S.D.
        • et al.
        Clinical effectiveness of elexacaftor/tezacftor/ivacaftor in people with cystic fibrosis.
        Am J Respir Crit Care Med. 2021;
        • DiMango E.
        • Overdevest J.
        • Keating C.
        • Francis S.F.
        • Dansky D.
        • Gudis D.
        Effect of highly effective modulator treatment on sinonasal symptoms in cystic fibrosis.
        J Cyst Fibros. 2021; 20: 460-463
        • Wielpütz M.O.
        • Puderbach M.
        • Kopp-Schneider A.
        • Stahl M.
        • Fritzsching E.
        • Sommerburg O.
        • et al.
        Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease.
        Am J Respir Crit Care Med. 2014; 189: 956-965
        • Wielpütz M.O.
        • Eichinger M.
        • Biederer J.
        • Wege S.
        • Stahl M.
        • Sommerburg O.
        • et al.
        Imaging of cystic fibrosis lung disease and clinical interpretation.
        Röfo. 2016; 188: 834-845
        • Stahl M.
        • Wielpütz M.O.
        • Graeber S.Y.
        • Joachim C.
        • Sommerburg O.
        • Kauczor H.U.
        • et al.
        Comparison of lung clearance index and magnetic resonance imaging for assessment of lung disease in children with cystic fibrosis.
        Am J Respir Crit Care Med. 2017; 195: 349-359
        • Wielpütz M.O.
        • Eichinger M.
        • Wege S.
        • Eberhardt R.
        • Mall M.A.
        • Kauczor H.U.
        • et al.
        Midterm reproducibility of chest magnetic resonance imaging in adults with clinically stable cystic fibrosis and chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2019; 200: 103-107
        • Stahl M.
        • Wielpütz M.O.
        • Ricklefs I.
        • Dopfer C.
        • Barth S.
        • Schlegtendal A.
        • et al.
        Preventive inhalation of hypertonic saline in infants with cystic fibrosis (PRESIS). A randomized, double-blind, controlled study.
        Am J Respir Crit Care Med. 2019; 199: 1238-1248
        • Stahl M.
        • Steinke E.
        • Graeber S.Y.
        • Joachim C.
        • Seitz C.
        • Kauczor H.U.
        • et al.
        Magnetic resonance imaging detects progression of lung disease and impact of newborn screening in preschool children with cystic fibrosis.
        Am J Respir Crit Care Med. 2021;
        • Graeber S.Y.
        • Boutin S.
        • Wielpütz M.O.
        • Joachim C.
        • Frey D.L.
        • Wege S.
        • et al.
        Effects of lumacaftor-ivacaftor on lung clearance index, magnetic resonance imaging, and airway microbiome in phe508del homozygous patients with cystic fibrosis.
        Ann Am Thorac Soc. 2021; 18: 971-980
        • Bui S.
        • Masson A.
        • Enaud R.
        • Roditis L.
        • Dournes G.
        • Galode F.
        • et al.
        Long-term outcomes in real life of lumacaftor-ivacaftor treatment in adolescents with cystic fibrosis.
        Front Pediatr. 2021; 9744705
        • Beswick D.M.
        • Humphries S.M.
        • Balkissoon C.D.
        • Strand M.
        • Vladar E.K.
        • Lynch D.A.
        • et al.
        Impact of cystic fibrosis transmembrane conductance regulator therapy on chronic rhinosinusitis and health status: deep learning CT analysis and patient-reported outcomes.
        Ann Am Thorac Soc. 2022; 19: 12-19
        • Sommerburg O.
        • Wielpütz M.O.
        • Trame J.P.
        • Wuennemann F.
        • Opdazaite E.
        • Stahl M.
        • et al.
        Magnetic resonance imaging detects chronic rhinosinusitis in infants and preschool children with cystic fibrosis.
        Ann Am Thorac Soc. 2020; 17: 714-723
        • Rosenstein B.J.
        • Cutting G.R.
        The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel.
        J Pediatr. 1998; 132: 589-595
        • Quanjer P.H.
        • Tammeling G.J.
        • Cotes J.E.
        • Pedersen O.F.
        • Peslin R.
        • Yernault J.C.
        Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European community for steel and coal. Official statement of the european respiratory society.
        Eur Respir J Suppl. 1993; 16: 5-40
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • Burgos F.
        • Casaburi R.
        • Coates A.
        • et al.
        Standardisation of spirometry.
        Eur Respir J. 2005; 26: 319-338
        • Rosenfeld M.
        • Ratjen F.
        • Brumback L.
        • Daniel S.
        • Rowbotham R.
        • McNamara S.
        • et al.
        Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial.
        JAMA. 2012; 307: 2269-2277
        • Eichinger M.
        • Optazaite D.-E.
        • Kopp-Schneider A.
        • Hintze C.
        • Biederer J.
        • Niemann A.
        • et al.
        Morphologic and functional scoring of cystic fibrosis lung disease using MRI.
        Eur J Radiol. 2012; 81: 1321-1329
        • Triphan S.M.F.
        • Stahl M.
        • Jobst B.J.
        • Sommerburg O.
        • Kauczor H.U.
        • Schenk J.P.
        • et al.
        Echo time-dependence of observed lung t1 in patients with cystic fibrosis and correlation with clinical metrics.
        J Magn Reson Imaging. 2020; 52: 1645-1654
        • Chung J.
        • Wünnemann F.
        • Salomon J.
        • Boutin S.
        • Frey D.L.
        • Albrecht T.
        • et al.
        Increased inflammatory markers detected in nasal lavage correlate with paranasal sinus abnormalities at mri in adolescent patients with cystic fibrosis.
        Antioxidants (Basel). 2021; : 10
        • Burgel P.R.
        • Durieu I.
        • Chiron R.
        • Ramel S.
        • Danner-Boucher I.
        • Prevotat A.
        • et al.
        Rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis and advanced pulmonary disease.
        Am J Respir Crit Care Med. 2021; 204: 64-73
        • Graeber S.Y.
        • Vitzthum C.
        • Pallenberg S.T.
        • Naehrlich L.
        • Stahl M.
        • Rohrbach A.
        • et al.
        Effects of elexacaftor/tezacaftor/ivacaftor therapy on CFTR function in patients with cystic fibrosis and one or two F508del alleles.
        Am J Respir Crit Care Med. 2021;
        • van Beek E.J.
        • Hill C.
        • Woodhouse N.
        • Fichele S.
        • Fleming S.
        • Howe B.
        • et al.
        Assessment of lung disease in children with cystic fibrosis using hyperpolarized 3-Helium MRI: comparison with Shwachman score, Chrispin-Norman score and spirometry.
        Eur Radiol. 2007; 17: 1018-1024
        • Eggesbo H.B.
        • Sovik S.
        • Dolvik S.
        • Eiklid K.
        • Kolmannskog F.
        Proposal of a CT scoring system of the paranasal sinuses in diagnosing cystic fibrosis.
        Eur Radiol. 2003; 13: 1451-1460