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Analysis of pulmonary features and treatment approaches in the COPA syndrome

Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, Anthony K. Shum
ERJ Open Research 2018 4: 00017-2018; DOI: 10.1183/23120541.00017-2018
Jessica L. Tsui
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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Oscar A. Estrada
2Dept of Medicine, Division of Pulmonary and Critical Care, University of California Los Angeles, Los Angeles, CA, USA
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Zimu Deng
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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Kristin M. Wang
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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Christopher S. Law
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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Brett M. Elicker
3Dept of Radiology, University of California San Francisco, San Francisco, CA, USA
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Kirk D. Jones
4Dept of Pathology, University of California San Francisco, San Francisco, CA, USA
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Sharon D. Dell
5Dept of Pediatrics, The Hospital for Sick Children, Toronto, Canada
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Gunnar Gudmundsson
6Dept of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland
7Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Sif Hansdottir
6Dept of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland
7Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Simon M. Helfgott
8Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA
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Stefano Volpi
9Clinica Pediatrica e Reumatologia, Centro per le Malattie Autoinfiammatorie e Immunodeficienze, Instituto Giannina Gaslini, Genoa, Italy
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Marco Gattorno
9Clinica Pediatrica e Reumatologia, Centro per le Malattie Autoinfiammatorie e Immunodeficienze, Instituto Giannina Gaslini, Genoa, Italy
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Michael R. Waterfield
10Dept of Pediatrics, University of California San Francisco, San Francisco, CA, USA
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Alice Y. Chan
10Dept of Pediatrics, University of California San Francisco, San Francisco, CA, USA
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Sharon A. Chung
11Russell/Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, USA
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Brett Ley
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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Anthony K. Shum
1Dept of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, San Francisco, CA, USA
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  • For correspondence: anthony.shum@ucsf.edu
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  • FIGURE 1
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    FIGURE 1

    Serial imaging while on immunosuppressive therapy (two subjects). Axial computed tomography images from subject 5 demonstrate radiographic stability (a) baseline and b) 6 years later) in contrast to subject 4, who developed more cysts and ground-glass opacities over time (c) baseline and d) 14 years later). Yellow arrows indicate cysts and blue arrows indicate ground-glass opacity.

  • FIGURE 2
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    FIGURE 2

    Lung histopathology from two subjects demonstrating either capillaritis or prior alveolar haemorrhage. Subject 2: a) low-power view shows diffuse alveolar haemorrhage with filling of alveolar spaces by red blood cells. Focal lymphoid hyperplasia is present. Scale bar=500 µm. b) High-power view shows alveolar haemorrhage and prominent septal neutrophils (arrows) consistent with alveolar capillaritis. Scale bar=100 µm. Subject 4: c) low-power view shows bronchiolocentric airspace enlargement/cystic change, prominent lymphoid hyperplasia and increased haemosiderin-filled intra-alveolar macrophages. Scale bar=1 mm. d) High-power view shows lymphoid hyperplasia and haemosiderin-filled macrophages, indicative of prior alveolar haemorrhage. Scale bar=200 µm.

  • FIGURE 3
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    FIGURE 3

    Impact of immunosuppressive therapy on pulmonary function, recurrence of diffuse alveolar haemorrhage (DAH) and chest computed tomography (CT) findings over time (four subjects). a) Subject 5 demonstrated decline in pulmonary function as indicated by % predicted forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) but had radiographic stability while on treatment, while in contrast, her sibling, b) subject 4, struggled with medication noncompliance and developed multiple episodes of DAH as well as radiographic decline based on serial CT scans. Both c) subject 6 and d) subject 11 experienced physiological decline but radiographic stability and/or improvement with immunosuppression. Time axis is years from initial study. Vertical arrows within the plots indicate episodes of DAH; numbers in boxes indicate the episode number. Major chest CT scan findings and treatment regimen are indicated below. Dotted line represents 80% predicted FEV1, FVC and DLCO, which are the cut-offs for normal.

Tables

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  • TABLE 1

    Subject characteristics

    CharacteristicsPatients
    Subjects14
    Sex
     Male3 (21%)
     Female11 (79%)
    Age at presentation years
     <11 (7%)
     2–910 (71%)
     10–123 (21%)
    Disease manifestations
     Lung disease
      Diffuse alveolar haemorrhage7 (50%)
      DPLD14 (100%)
     Arthritis14 (100%)
     Renal disease3 (21%)

    DPLD: diffuse parenchymal lung disease.

    • TABLE 2

      Initial pulmonary function tests (PFTs)

      SubjectAge yearsFEV1 % predictedFVC % predictedFEV1/FVC %TLC % predictedPFT patternDLCO % predicted
      13155617268Restrictive37
      32335486256Mixed17
      42056588362Restrictive45
      51357727567Restrictive69
      65585695NARestrictiveNA
      73532436363MixedNA
      8767649867RestrictiveNA
      108827691NANormalNA
      112867698376Restrictive68
      123569698069Restrictive41
      1315899179101Obstructive58
      14959618972Restrictive48

      FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; NA: not available.

      • TABLE 3

        Lung histopathological findings

        FeaturesSubjects (n with finding/n tested)
        Number of biopsies available for review10 (10/11)
        Type of biopsy
         Open lung biopsy8 (8/10)
         Transbronchial biopsy2 (2/10)
        Follicular bronchiolitis7 (7/10)
        Alveolar haemorrhage4 (4/10)
        Airspace enlargement/cystic changes2 (2/10)
        Acute lung injury with capillaritis2 (2/10)#
        Interstitial fibrosis2 (2/10)¶
        Nondiagnostic1 (1/10)

        #: both subjects with this finding were related (father and daughter); ¶: both biopsies demonstrated non-usual interstitial pneumonitis.

        • TABLE 4

          Current immunosuppression maintenance regimens

          Type of immunomodulationSubjects#
          Low-dose corticosteroids9 (75%)
          Mycophenolate mofetil5 (42%)
          Hydroxychloroquine4 (33%)
          Azathioprine3 (25%)
          Rituximab2 (16%)
          Etanercept2 (16%)
          Methotrexate2 (16%)
          IVIG2 (16%)
          Combination therapies
           One agents4 (33%)
           Two agents3 (25%)
           More than two agents5 (42%)

          IVIG: intravenous immunoglobulin. #: N=12.

          • TABLE 5

            When to consider genetic testing for COPA syndrome

            Pulmonary features
             Evidence of follicular bronchiolitis or cysts
             Diffuse alveolar haemorrhage
            Extrapulmonary features
             Early age of onset (<12 years)
             Family history of disease
             Positive for ANA or ANCA, ±RF
             Arthritis

            Consider targeted sequencing for exons 8–9 of COPA in patients with one pulmonary feature and two extrapulmonary features, and strongly consider sequencing in patients with one pulmonary and three extrapulmonary features. ANA: anti-nuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody; RF: rheumatoid factor.

            Supplementary Materials

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              Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

              TABLE S1 Subject characteristics (detailed) 00017-2018_tableS1

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            Analysis of pulmonary features and treatment approaches in the COPA syndrome
            Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, Anthony K. Shum
            ERJ Open Research Apr 2018, 4 (2) 00017-2018; DOI: 10.1183/23120541.00017-2018

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            Analysis of pulmonary features and treatment approaches in the COPA syndrome
            Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, Anthony K. Shum
            ERJ Open Research Apr 2018, 4 (2) 00017-2018; DOI: 10.1183/23120541.00017-2018
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