Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.
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.
['Franklin|Cindy|C|', 'Rooms|Isabelle|I|', 'Fiedler|Melanie|M|', 'Reis|Henning|H|', 'Milsch|Laura|L|', 'Herz|Saskia|S|', 'Livingstone|Elisabeth|E|', 'Zimmer|Lisa|L|', 'Schmid|Kurt Werner|KW|', 'Dittmer|Ulf|U|', 'Schadendorf|Dirk|D|', 'Schilling|Bastian|B|']
D000293:Adolescent D000328:Adult D000368:Aged D000369:Aged, 80 and over D000914:Antibodies, Viral D000074322:Antineoplastic Agents, Immunological D000998:Antiviral Agents D003092:Colitis D003587:Cytomegalovirus D003586:Cytomegalovirus Infections D004279:DNA, Viral D005260:Female D015774:Ganciclovir D005858:Germany D006785:Hospitals, University D054884:Host-Pathogen Interactions D006801:Humans D016867:Immunocompromised Host D007166:Immunosuppressive Agents D008297:Male D008545:Melanoma D008875:Middle Aged D009894:Opportunistic Infections D011237:Predictive Value of Tests D012307:Risk Factors D012878:Skin Neoplasms D013997:Time Factors D016896:Treatment Outcome D014775:Virus Activation D055815:Young Adult
Colitis Melanoma CMV Checkpoint inhibition