Advertisement

Effects of Anti-T2 Biologic Treatment on Lung Ventilation Evaluated by MRI in Adults With Prednisone-Dependent Asthma

      Background

      The functional consequence of airway obstruction in asthma can be regionally measured using inhaled gas MRI. Ventilation defects visualized by MRI persist post-bronchodilator in patients with severe asthma with uncontrolled sputum eosinophilia and may be due to eosinophil-driven airway pathology that is responsive to “anti-T2” therapy.

      Research Question

      Do anti-T2 therapies that clear eosinophils from the airway lumen decrease ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma?

      Study Design and Methods

      Inhaled hyperpolarized gas MRI was performed before and after bronchodilation in 10 prednisone-dependent patients with asthma with uncontrolled eosinophilic bronchitis (sputum eosinophils ≥3%) at baseline and 558 (100-995) days later when their eosinophilic bronchitis had been controlled (sputum eosinophils <3%) by additional anti-T2 therapy. The effect of anti-T2 therapy on ventilation defects, quantified as the MRI ventilation-defect-percent (VDP), was evaluated before and after bronchodilation for all patients and compared between patients dichotomized based on the median percentage of sputum eosinophils at baseline (15.8%).

      Results

      MRI VDP was improved pre- (ΔVDP+anti-T2: -3% ± 4%, P = .02) and post-bronchodilator (ΔVDP+anti-T2: -3% ± 4%; P = .04) after additional anti-T2 therapy that controlled eosinophilic bronchitis (n = 2 mepolizumab, n = 2 reslizumab, n = 3 benralizumab, n = 1 dupilumab, n = 2 increased daily prednisone). A greater post-bronchodilator ΔVDP+anti-T2 was observed in those patients with median or higher percentage of sputum eosinophils at baseline (≥15.8%; P = .01). In 7 of 10 patients with asthma, residual ventilation defects persisted despite bronchodilator and anti-T2 therapy.

      Interpretation

      Controlling sputum eosinophilia with anti-T2 therapies improves ventilation defects, measured by inhaled gas MRI, in adults with prednisone-dependent asthma.

      Key Words

      Abbreviations:

      ACQ (asthma control questionnaire), MCID (minimal clinically important difference), TCV (thoracic cavity volume), VDP (ventilation defect percent)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Altes T.A.
        • Powers P.L.
        • Knight-Scott J.
        • et al.
        Hyperpolarized 3He MR lung ventilation imaging in asthmatics: preliminary findings.
        J Magn Reson Imaging. 2001; 13: 378-384
        • Aysola R.
        • de Lange E.E.
        • Castro M.
        • Altes T.A.
        Demonstration of the heterogeneous distribution of asthma in the lungs using CT and hyperpolarized helium-3 MRI.
        J Magn Reson Imaging. 2010; 32: 1379-1387
        • Svenningsen S.
        • Kirby M.
        • Starr D.
        • et al.
        What are ventilation defects in asthma?.
        Thorax. 2014; 69: 63-71
        • Costella S.
        • Kirby M.
        • Maksym G.N.
        • McCormack D.G.
        • Paterson N.A.
        • Parraga G.
        Regional pulmonary response to a methacholine challenge using hyperpolarized (3)He magnetic resonance imaging.
        Respirology. 2012; 17: 1237-1246
        • Svenningsen S.
        • Kirby M.
        • Starr D.
        • et al.
        Hyperpolarized (3) He and (129) Xe MRI: differences in asthma before bronchodilation.
        J Magn Reson Imaging. 2013; 38: 1521-1530
        • Kruger S.J.
        • Niles D.J.
        • Dardzinski B.
        • et al.
        Hyperpolarized helium-3 MRI of exercise-induced bronchoconstriction during challenge and therapy.
        J Magn Reson Imaging. 2014; 39: 1230-1237
        • Samee S.
        • Altes T.
        • Powers P.
        • et al.
        Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge.
        J Allergy Clin Immunol. 2003; 111: 1205-1211
        • de Lange E.E.
        • Altes T.A.
        • Patrie J.T.
        • et al.
        Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry.
        Chest. 2006; 130: 1055-1062
        • Svenningsen S.
        • Nair P.
        • Guo F.
        • McCormack D.G.
        • Parraga G.
        Is ventilation heterogeneity related to asthma control?.
        Eur Respir J. 2016; 48: 370-379
        • Tzeng Y.S.
        • Lutchen K.
        • Albert M.
        The difference in ventilation heterogeneity between asthmatic and healthy subjects quantified using hyperpolarized 3He MRI.
        J Appl Physiol. 2009; 106: 813-822
        • Hahn A.D.
        • Cadman R.V.
        • Sorkness R.L.
        • Jarjour N.N.
        • Nagle S.K.
        • Fain S.B.
        Redistribution of inhaled hyperpolarized 3He gas during breath-hold differs by asthma severity.
        J Appl Physiol. 2016; 120: 526-536
        • Campana L.
        • Kenyon J.
        • Zhalehdoust-Sani S.
        • et al.
        Probing airway conditions governing ventilation defects in asthma via hyperpolarized MRI image functional modeling.
        J Appl Physiol. 2009; 106: 1293-1300
        • Svenningsen S.
        • Eddy R.L.
        • Lim H.F.
        • Cox P.G.
        • Nair P.
        • Parraga G.
        Sputum eosinophilia and magnetic resonance imaging ventilation heterogeneity in severe asthma.
        Am J Respir Crit Care Med. 2018; 197: 876-884
        • Svenningsen S.
        • Haider E.
        • Boylan C.
        • et al.
        CT and functional MRI to evaluate airway mucus in severe asthma.
        Chest. 2019; 155: 1178-1189
        • Dunican E.M.
        • Elicker B.M.
        • Gierada D.S.
        • et al.
        Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.
        J Clin Invest. 2018; 128: 997-1009
        • Pizzichini E.
        • Pizzichini M.M.
        • Efthimiadis A.
        • et al.
        Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements.
        Am J Respir Crit Care Med. 1996; 154: 308-317
        • D’Silva L.
        • Hassan N.
        • Wang H.Y.
        • et al.
        Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice.
        Can Respir J. 2011; 18: 144-148
        • Fleming L.
        • Tsartsali L.
        • Wilson N.
        • Regamey N.
        • Bush A.
        Sputum inflammatory phenotypes are not stable in children with asthma.
        Thorax. 2012; 67: 675-681
        • Fleming L.
        • Tsartsali L.
        • Wilson N.
        • Regamey N.
        • Bush A.
        Longitudinal relationship between sputum eosinophils and exhaled nitric oxide in children with asthma.
        Am J Respir Crit Care Med. 2013; 188: 400-402
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • et al.
        Standardisation of spirometry.
        Eur Respir J. 2005; 26: 319-338
        • Kirby M.
        • Heydarian M.
        • Svenningsen S.
        • et al.
        Hyperpolarized 3He magnetic resonance functional imaging semiautomated segmentation.
        Acad Radiol. 2012; 19: 141-152
        • Eddy R.L.
        • Svenningsen S.
        • McCormack D.G.
        • Parraga G.
        What is the minimal clinically important difference for helium-3 magnetic resonance imaging ventilation defects?.
        Eur Respir J. 2018; 51
        • Jones P.W.
        • Beeh K.M.
        • Chapman K.R.
        • Decramer M.
        • Mahler D.A.
        • Wedzicha J.A.
        Minimal clinically important differences in pharmacological trials.
        Am J Respir Crit Care Med. 2014; 189: 250-255
        • Juniper E.F.
        • Svensson K.
        • Mork A.C.
        • Stahl E.
        Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.
        Respir Med. 2005; 99: 553-558
        • Fahy J.V.
        Type 2 inflammation in asthma: present in most, absent in many.
        Nat Rev Immunol. 2015; 15: 57-65
        • Dente F.L.
        • Bacci E.
        • Bartoli M.L.
        • et al.
        Effects of oral prednisone on sputum eosinophils and cytokines in patients with severe refractory asthma.
        Ann Allergy Asthma Immunol. 2010; 104: 464-470
        • Nair P.
        • Pizzichini M.M.
        • Kjarsgaard M.
        • et al.
        Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.
        N Engl J Med. 2009; 360: 985-993
        • Castro M.
        • Mathur S.
        • Hargreave F.
        • et al.
        Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study.
        Am J Respir Crit Care Med. 2011; 184: 1125-1132
        • Sehmi R.
        • Lim H.F.
        • Mukherjee M.
        • et al.
        Benralizumab attenuates airway eosinophilia in prednisone-dependent asthma.
        J Allergy Clin Immunol. 2018; 141: 1529-1532
        • Hughes P.J.C.
        • Smith L.
        • Chan H.F.
        • et al.
        Assessment of the influence of lung inflation state on the quantitative parameters derived from hyperpolarized gas lung ventilation MRI in healthy volunteers.
        J Appl Physiol. 2019; 126: 183-192
        • Mukherjee M.
        • Lacy P.
        • Ueki S.
        Eosinophil extracellular traps and inflammatory pathologies: untangling the web!.
        Front Immunol. 2018; 9: 2763
        • Moore W.C.
        • Bleecker E.R.
        • Curran-Everett D.
        • et al.
        Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.
        J Allergy Clin Immunol. 2007; 119: 405-413
        • Darquenne C.
        • van Ertbruggen C.
        • Prisk G.K.
        Convective flow dominates aerosol delivery to the lung segments.
        J Appl Physiol. 2011; 111: 48-54
        • Sa R.C.
        • Zeman K.L.
        • Bennett W.D.
        • Prisk G.K.
        • Darquenne C.
        Regional ventilation is the main determinant of alveolar deposition of coarse particles in the supine healthy human lung during tidal breathing.
        J Aerosol Med Pulm Drug Deliv. 2017; 30: 322-331
        • Brown J.S.
        • Zeman K.L.
        • Bennett W.D.
        Regional deposition of coarse particles and ventilation distribution in healthy subjects and patients with cystic fibrosis.
        J Aerosol Med. 2001; 14: 443-454
        • Verbanck S.
        • Ghorbaniasl G.
        • Biddiscombe M.F.
        • et al.
        Inhaled aerosol distribution in human airways: a scintigraphy-guided study in a 3D printed model.
        J Aerosol Med Pulm Drug Deliv. 2016; 29: 525-533
        • Greenblatt E.E.
        • Winkler T.
        • Harris R.S.
        • et al.
        What causes uneven aerosol deposition in the bronchoconstricted lung? a quantitative imaging study.
        J Aerosol Med Pulm Drug Deliv. 2016; 29: 57-75
        • Poorbahrami K.
        • Mummy D.G.
        • Fain S.B.
        • Oakes J.M.
        Patient-specific modeling of aerosol delivery in healthy and asthmatic adults.
        J Appl Physiol. 2019; 127: 1720-1732
        • Choi J.
        • LeBlanc L.J.
        • Choi S.
        • et al.
        Differences in particle deposition between members of imaging-based asthma clusters.
        J Aerosol Med Pulm Drug Deliv. 2019; 32: 213-223
        • Burgess G.
        • Boyce M.
        • Jones M.
        • et al.
        Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942.
        EBioMedicine. 2018; 35: 67-75
        • Lightwood D.
        • Tservistas M.
        • Zehentleitner M.
        • et al.
        Efficacy of an inhaled IL-13 antibody fragment in a model of chronic asthma.
        Am J Respir Crit Care Med. 2018; 198: 610-619
        • Eddy R.L.
        • Svenningsen S.
        • Licskai C.
        • McCormack D.G.
        • Parraga G.
        Hyperpolarized helium 3 MRI in mild-to-moderate asthma: prediction of postbronchodilator reversibility.
        Radiology. 2019; 293: 212-220
        • Svenningsen S.
        • Guo F.
        • Kirby M.
        • et al.
        Pulmonary functional magnetic resonance imaging: asthma temporal-spatial maps.
        Acad Radiol. 2014; 21: 1402-1410
        • Barnes P.J.
        Corticosteroid effects on cell signalling.
        Eur Respir J. 2006; 27: 413-426