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Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis

  • Author Footnotes
    1 These authors contributed equally.
    Cindy Franklin
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany

    Department of Dermatology, Inselspital Bern, Bern University Hospital, University of Bern, Switzerland
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  • Author Footnotes
    1 These authors contributed equally.
    Isabelle Rooms
    Footnotes
    1 These authors contributed equally.
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Melanie Fiedler
    Affiliations
    Department of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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  • Henning Reis
    Affiliations
    German Cancer Consortium (DKTK), Heidelberg, Germany

    Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
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  • Laura Milsch
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Saskia Herz
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Elisabeth Livingstone
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Lisa Zimmer
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Kurt Werner Schmid
    Affiliations
    German Cancer Consortium (DKTK), Heidelberg, Germany

    Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
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  • Ulf Dittmer
    Affiliations
    Department of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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  • Dirk Schadendorf
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany
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  • Bastian Schilling
    Correspondence
    Corresponding author: Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider Str. 2, 97080 Würzburg, Germany.
    Affiliations
    Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    German Cancer Consortium (DKTK), Heidelberg, Germany

    Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally.
Published:October 19, 2017DOI:https://doi.org/10.1016/j.ejca.2017.09.019

      Highlights

      • Checkpoint inhibitors can cause immune-related colitis (irColitis).
      • IrColitis can be refractory to immunosuppressive and immunomodulatory therapies.
      • Refractory irColitis is often caused by reactivation of cytomegalovirus (CMV).
      • CMV colitis can resolve after the application of ganciclovir.
      • Different repetitive diagnostic measures are needed to detect CMV colitis.

      Abstract

      Objectives

      Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches.

      Methods

      Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected.

      Results

      We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053).

      Conclusions

      This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.

      Keywords

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