Gastrointestinal toxicities associated with immune checkpoint inhibitors: a disproportionality analysis leveraging VigiBase, the WHO Adverse Drug Reaction Database

与免疫检查点抑制剂相关的胃肠道毒性: 利用 WHO 药物不良反应数据库 VigiBase 进行的不成比例分析



免疫检查点抑制剂 (ICIs) 可以显著提高某些晚期恶性肿瘤的生存率, 但是, ICIs 治疗也可能导致许多免疫相关的不良反应事件. 我们的研究旨在鉴定和表征与 ICIs 相关的胃肠道不良反应事件.


鉴定和表征与 ICIs 相关的胃肠道不良反应事件, 提高对 ICIs 所致胃肠道不良事件的认识.


从世界卫生组织 (WHO) 药物不良反应数据库 VigiBase 获得 2011 年 1 月 1 日至 2019 年 3 月 6 日的药物不良反应数据, 将接受 ICIs 治疗报告的胃肠道不良反应事件与整个数据库报告进行比较. 通过计算信息成分 (IC) 和报告优势比 (ROR) 评估 ICIs 与胃肠道不良反应事件之间的关联.


ICIs 治疗可导致多种胃肠道不良反应事件, 甚至可发生严重巨结肠. 对于晚期恶性肿瘤患者进行 ICIs 临床诊疗时, 需要考虑 ICIs 相关胃肠道不良反应事件.


  1. Abu-Sbeih H, Wang YH, 2020. Gastrointestinal tract adverse events. In: Naing A, Hajjar J (Eds.), Immunotherapy. Springer, Cham, p.247–253.

    Google Scholar 

  2. Afzal MZ, Mercado RR, Shirai K, 2018. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer, 6:64.

    Article  Google Scholar 

  3. Baxi S, Yang A, Gennarelli RL, et al., 2018. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ, 360:k793.

    Article  Google Scholar 

  4. Cho JH, Choi JH, 2020. Cytomegalovirus ileo-pancolitis presenting as toxic megacolon in an immunocompetent patient: a case report. World J Clin Cases, 8(3):552–559.

    Article  Google Scholar 

  5. de Malet A, Antoni G, Collins M, et al., 2019. Evolution and recurrence of gastrointestinal immune-related adverse events induced by immune checkpoint inhibitors. Eur J Cancer, 106:106–114.

    CAS  Article  Google Scholar 

  6. Derosa L, Hellmann MD, Spaziano M, et al., 2018. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol, 29(6):1437–1444.

    CAS  Article  Google Scholar 

  7. Doroshow DB, Sanmamed MF, Hastings K, et al., 2019. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res, 25(15):4592–4602.

    CAS  Article  Google Scholar 

  8. Gu LH, Khadaroo PA, Su H, et al., 2019. The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis. BMC Cancer, 19:559.

    Article  Google Scholar 

  9. Haanen JBAG, Carbonnel F, Robert C, et al., 2017. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 28(Suppl_4):iv119–iv142.

    CAS  Article  Google Scholar 

  10. Leppkes M, Ganslmayer M, Strauß R, et al., 2015. Das toxic megacolon. Med Klin Intensivmed Notfmed, 110(7):500–505.

    CAS  Article  Google Scholar 

  11. Madden K, Kasler MK, 2019. Immune checkpoint inhibitors in lung cancer and melanoma. Semin Oncol Nurs, 35(5):150932.

    Article  Google Scholar 

  12. Rodriguez-Vida A, Perez-Gracia JL, Bellmunt J, 2018. Immunotherapy combinations and sequences in urothelial cancer: facts and hopes. Clin Cancer Res, 24(24):6115–6124.

    CAS  Article  Google Scholar 

  13. Sangro B, Chan SL, Meyer T, et al., 2020. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol, 72(2):320–341.

    CAS  Article  Google Scholar 

  14. Song M, Li ZL, Zhou YJ, et al., 2020. Gastrointestinal involvement of COVID-19 and potential faecal transmission of SARS-CoV-2. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(9):749–751.

    CAS  Article  Google Scholar 

  15. Tandon P, Bourassa-Blanchette S, Bishay K, et al., 2018. The risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis. J Immunother, 41(3):101–108.

    Article  Google Scholar 

  16. Wang DY, Ye F, Zhao SL, et al., 2017. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology, 6(10):e1344805.

    Article  Google Scholar 

  17. Wang DY, Salem JE, Cohen JV, et al., 2018. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol, 4(12):1721–1728.

    Article  Google Scholar 

  18. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al., 2017. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med, 377(14):1345–1356.

    CAS  Article  Google Scholar 

  19. Xu C, Chen YP, Du XJ, et al., 2018. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ, 363:k4226.

    Article  Google Scholar 

  20. Yuan ZH, Yang HK, Wei YM, 2019. Combined induction with anti-PD-1 and anti-CTLA-4 antibodies provides synergistic antitumor effects in DC-CIK cells in renal carcinoma cell lines. Int J Clin Exp Pathol, 12(1): 123–132.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang J, Li HH, Chen YF, et al., 2020. Microencapsulation of immunoglobulin Y: optimization with response surface morphology and controlled release during simulated gastrointestinal digestion. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(8):611–627.

    CAS  Article  Google Scholar 

  22. Zhang ML, Neyaz A, Patil D, et al., 2020. Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies. Histopathology, 76(2):233–243.

    Article  Google Scholar 

  23. Zhao SZ, Reynolds MW, Lefkowith J, et al., 2001. A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database. Clin Ther, 23(9):1478–1491.

    CAS  Article  Google Scholar 

Download references


The supplied data come from various sources from VigiBase, and the probability that the suspected adverse effect is drug-related is not the same in all cases. The information does not represent the opinion of the Uppsala Monitoring Center or the WHO. Camilla Westerberg of the custom search team at the Uppsala Monitoring Centre (Uppsala, Sweden) research department is thanked for his help with the data extraction.

Author information




The study design was created by Xiahong LIN. Data collection and analysis was performed by Sifu HUANG, Xuefeng BAI, and Kainan ZHENG. Taiyong FANG and Yanta GUO conducted the literature search. Sifu HUANG and Xuefeng BAI wrote and edited the manuscript, and they contributed equally to this study. Xiahong LIN, Sifu HUANG, and Xuefeng BAI were responsible for the final modification of the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Xiahong Lin.

Ethics declarations

Sifu HUANG, Xuefeng BAI, Taiyong FANG, Yanta GUO, Kainan ZHENG, and Xiahong LIN declare that they have no conflicts of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huang, S., Bai, X., Fang, T. et al. Gastrointestinal toxicities associated with immune checkpoint inhibitors: a disproportionality analysis leveraging VigiBase, the WHO Adverse Drug Reaction Database. J. Zhejiang Univ. Sci. B 22, 156–164 (2021).

Download citation


  • 免疫检查点抑制剂
  • 胃肠道毒性
  • VigiBase
  • 信息成分
  • 报告优势比