CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma

      Background

      Intraluminal contributor(s) to airflow obstruction in severe asthma are patient-specific and must be evaluated to personalize treatment. The occurrence and functional consequence of airway mucus in the presence or absence of airway eosinophils remain undetermined.

      Objective

      The objective of this study was to understand the functional consequence of airway mucus in the presence or absence of eosinophils and to identify biomarkers of mucus-related airflow obstruction.

      Methods

      Mucus plugs were quantified on CT scans, and their contribution to ventilation heterogeneity (using MRI ventilation defect percent [VDP]) was evaluated in 27 patients with severe asthma. Patients were dichotomized based on sputum eosinophilia such that the relationship between mucus, eosinophilia, and ventilation heterogeneity could be investigated. Fractional exhaled nitric oxide (F eno) and related cytokines in sputum were measured.

      Results

      Mucus plugging was present in 100% of asthma patients with sputum eosinophils and 36% of those without sputum eosinophils ( P = .0006) and was correlated with MRI VDP prebronchodilator ( r = 0.68; P = .0001) and postbronchodilator ( r = 0.72; P < .0001). In a multivariable regression, both mucus and eosinophils contributed to the prediction of postbronchodilator MRI VDP ( R 2 = 0.75; P < .0001). Patients with asthma in whom the mucus score was high had raised F eno ( P = .03) and IL-4 ( P = .02) values. Mucus plugging correlated with F eno ( r = 0.63; P = .005).

      Conclusions

      Both airway eosinophils and mucus can contribute to ventilation heterogeneity in patients with severe asthma. Patients in whom mucus is the dominant cause of airway obstruction have evidence of an upregulated IL-4/IL-13 pathway that could be identified according to increased F eno level.

      Key Words

      Abbreviations:

      EB ( eosinophilic bronchitis), Feno ( fractional exhaled nitric oxide), 3He ( helium-3), N2 ( nitrogen), VDP ( ventilation defect percent)
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      References

        • Kuyper L.M.
        • Pare P.D.
        • Hogg J.C.
        • et al.
        Characterization of airway plugging in fatal asthma.
        Am J Med. 2003; 115: 6-11
        • Hays S.R.
        • Fahy J.V.
        The role of mucus in fatal asthma.
        Am J Med. 2003; 115: 68-69
        • Kuperman D.A.
        • Huang X.
        • Koth L.L.
        • et al.
        Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma.
        Nat Med. 2002; 8: 885-889
        • Wenzel S.
        • Castro M.
        • Corren J.
        • et al.
        Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.
        Lancet. 2016; 388: 31-44
        • Hanania N.A.
        • Korenblat P.
        • Chapman K.R.
        • et al.
        Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials.
        Lancet Respir Med. 2016; 4: 781-796
        • Brightling C.E.
        • Chanez P.
        • Leigh R.
        • et al.
        Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.
        Lancet Respir Med. 2015; 3: 692-701
        • Rabe K.F.
        • Nair P.
        • Brusselle G.
        • et al.
        Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma.
        N Engl J Med. 2018; 378: 2475-2485
        • 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
        • 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
        • Mummy D.G.
        • Kruger S.J.
        • Zha W.
        • et al.
        Ventilation defect percent in helium-3 magnetic resonance imaging as a biomarker of severe outcomes in asthma.
        J Allergy Clin Immunol. 2018; 141 (e4): 1140-1141
        • Svenningsen S.
        • Eddy R.L.
        • Lim H.F.
        • Cox P.G.
        • Nair P.
        • Parraga G.
        Sputum eosinophilia and MRI ventilation heterogeneity in severe asthma.
        Am J Respir Crit Care Med. 2018; 197: 876-884
        • 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
        • Kirby M.
        • Heydarian M.
        • Svenningsen S.
        • et al.
        Hyperpolarized 3He magnetic resonance functional imaging semiautomated segmentation.
        Acad Radiol. 2012; 19: 141-152
        • Kirby M.
        • Owrangi A.
        • Svenningsen S.
        • et al.
        On the role of abnormal DLCO in ex-smokers without airflow limitation: symptoms, exercise capacity and hyperpolarised helium-3 MRI.
        Thorax. 2013; 68: 752-759
        • Capaldi D.P.
        • Zha N.
        • Guo F.
        • et al.
        Pulmonary imaging biomarkers of gas trapping and emphysema in COPD: (3)He MR imaging and CT parametric response maps.
        Radiology. 2016; 279: 597-608
        • Adams C.J.
        • Capaldi D.P.I.
        • Di Cesare R.
        • McCormack D.G.
        • Parraga G.
        • Canadian Respiratory Research Network
        On the potential role of MRI Biomarkers of COPD to guide bronchoscopic lung volume reduction.
        Acad Radiol. 2018; 25: 159-168
        • Mukherjee M.
        • Bulir D.C.
        • Radford K.
        • et al.
        Sputum autoantibodies in patients with severe eosinophilic asthma.
        J Allergy Clin Immunol. 2018; 141: 1269-1279
        • Tanizaki Y.
        • Kitani H.
        • Okazaki M.
        • Mifune T.
        • Mitsunobu F.
        • Kimura I.
        Mucus hypersecretion and eosinophils in bronchoalveolar lavage fluid in adult patients with bronchial asthma.
        J Asthma. 1993; 30: 257-262
        • Cohn L.
        • Homer R.J.
        • MacLeod H.
        • Mohrs M.
        • Brombacher F.
        • Bottomly K.
        Th2-induced airway mucus production is dependent on IL-4Ralpha, but not on eosinophils.
        J Immunol. 1999; 162: 6178-6183
        • Mummy D.
        • Dunican E.
        • Lampkins T.
        • et al.
        Ventilation defects in asthma on hyperpolarized gas MRI are associated with airway mucus plugs on CT.
        Am J Respir Crit Care Med. 2018; 197: A6376
        • Dunican E.
        • Fahy J.V.
        • Mummy D.G.
        • et al.
        Regional ventilation defects measured on hyperpolarized 3He MRI are associated with mucus plugging measured on CT in asthma.
        Am J Respir Crit Care Med. 2016; 193: A1052
        • Guo F.
        • Svenningsen S.
        • Kirby M.
        • et al.
        Thoracic CT-MRI coregistration for regional pulmonary structure-function measurements of obstructive lung disease.
        Med Phys. 2017; 44: 1718-1733
        • Kay A.B.
        The role of T lymphocytes in asthma.
        Chem Immunol Allergy. 2006; 91: 59-75
        • Grunig G.
        • Warnock M.
        • Wakil A.E.
        • et al.
        Requirement for IL-13 independently of IL-4 in experimental asthma.
        Science. 1998; 282: 2261-2263
        • Gavett S.H.
        • O'Hearn D.J.
        • Karp C.L.
        • et al.
        Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice.
        Am J Physiol. 1997; 272: L253-L261
        • Chibana K.
        • Trudeau J.B.
        • Mustovich A.T.
        • et al.
        IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells.
        Clin Exp Allergy. 2008; 38: 936-946
        • Qin Y.
        • Jiang Y.
        • Sheikh A.S.
        • Shen S.
        • Liu J.
        • Jiang D.
        Interleukin-13 stimulates MUC5AC expression via a STAT6-TMEM16A-ERK1/2 pathway in human airway epithelial cells.
        Int Immunopharmacol. 2016; 40: 106-114
        • Wills-Karp M.
        • Luyimbazi J.
        • Xu X.
        • et al.
        Interleukin-13: central mediator of allergic asthma.
        Science. 1998; 282: 2258-2261
        • Russell R.J.
        • Chachi L.
        • FitzGerald J.M.
        • et al.
        Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.
        Lancet Respir Med. 2018; 6: 499-510
        • Dabbagh K.
        • Takeyama K.
        • Lee H.M.
        • Ueki I.F.
        • Lausier J.A.
        • Nadel J.A.
        IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo.
        J Immunol. 1999; 162: 6233-6237
        • Wills-Karp M.
        • Finkelman F.D.
        Untangling the complex web of IL-4- and IL-13-mediated signaling pathways.
        Sci Signal. 2008; 1: pe55
        • Wenzel S.
        • Ford L.
        • Pearlman D.
        • et al.
        Dupilumab in persistent asthma with elevated eosinophil levels.
        N Engl J Med. 2013; 368: 2455-2466

      Linked Article

      • CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma
        CHESTVol. 156Issue 4
        • In Brief
          With great interest, we read the article by Svenningsen et al in a recent issue of CHEST (June 2019) on CT scanning and functional MRI to evaluate airway mucus in severe asthma.1 We understand their results, but would like to ask the authors two questions. First, the authors included as study subjects “patients with severe asthma.” It takes time to perform MRI; the subjects should be patients who could be in the resting position during the time required for MRI. We would like to ask the authors whether all the patients with “severe asthma” could maintain the resting position during the MRI time.
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      • Response
        CHESTVol. 156Issue 4
        • In Brief
          We thank Drs Okauchi, Yamada, and Satoh for their pertinent questions in response to our multimodality imaging study designed to better understand the functional consequence of intraluminal contributors to airway obstruction in patients with severe asthma.1
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