Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 10, pp 2625–2631 | Cite as

C-reactive protein as an early marker of immune-related adverse events

  • Amir-Reza Abolhassani
  • Gerold Schuler
  • Michael Constantin Kirchberger
  • Lucie HeinzerlingEmail author
Original Article – Clinical Oncology



Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs.


In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables.


At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1–70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (P < 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms.


CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.


Adverse events C-reactive protein Immune checkpoint inhibitors Melanoma 



The present work was performed in the fulfillment of the requirements for obtaining the degree “Dr. med.”. We thank Sabine Schüpferling (Department of Dermatology) for laboratory assistance.

Compliance with ethical standards

Study participants gave written consent for anonymous analyzation of data. This study was approved by the institutional review board of the medical faculty of the University Erlangen and all procedures performed in studies were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declarations.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Andersson B-Å, Lewin F, Lundgren J et al (2014) Plasma tumor necrosis factor-α and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 140:515–519. CrossRefGoogle Scholar
  2. Atallah-Yunes SA, Kadado AJ, Kaufman GP, Hernandez-Montfort J (2019) Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases. J Cancer Res Clin, OncolGoogle Scholar
  3. Balar AV, Castellano D, O’Donnell PH et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. Google Scholar
  4. Bamias G, Delladetsima I, Perdiki M et al (2017) Immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy. Cancer Invest. Google Scholar
  5. Brahmer JR, Tykodi SS, Chow LQM et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. CrossRefGoogle Scholar
  6. Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol 36:1714–1768. CrossRefGoogle Scholar
  7. Callahan MK, Yang A, Tandon S et al (2011) Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis. J Clin Oncol. Google Scholar
  8. Cheng R, Cooper A, Kench J et al (2015) Ipilimumab-induced toxicities and the gastroenterologist. J Gastroenterol Hepatol 30:657–666. CrossRefGoogle Scholar
  9. Chuzi S, Tavora F, Cruz M et al (2017) Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res. Google Scholar
  10. Ciubotaru I, Potempa LA, Wander RC (2005) Production of modified C-reactive protein in Uf937-derived macrophages. Exp Biol Med. Google Scholar
  11. Daly LE, Power DG, O’Reilly Á et al (2017) The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer 116:310–317. CrossRefGoogle Scholar
  12. Damuzzo V, Solito S, Pinton L et al (2016) Clinical implication of tumor-associated and immunological parameters in melanoma patients treated with ipilimumab. Oncoimmunology. Google Scholar
  13. 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. Google Scholar
  14. Fang S, Wang Y, Sui D et al (2015) C-reactive protein as a marker of melanoma progression. J Clin Oncol. Google Scholar
  15. Garon EB, Rizvi NA, Hui R et al (2015) Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J Med. Google Scholar
  16. Haas M, Heinemann V, Kullmann F et al (2013) Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol 139:681–689. CrossRefGoogle Scholar
  17. Heppt MV, Roesch A, Weide B et al (2017a) Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma. Eur J Cancer. Google Scholar
  18. Heppt MV, Roesch A, Weide B et al (2017b) Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma. Eur J Cancer 81:36–44. CrossRefGoogle Scholar
  19. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. CrossRefGoogle Scholar
  20. Hogan SA, Levesque MP, Cheng PF (2018) Melanoma immunotherapy: next-generation biomarkers. Front Oncol 8:1–10. CrossRefGoogle Scholar
  21. Hopkins AM, Rowland A, Kichenadasse G et al (2017) Predicting response and toxicity to immune checkpoint inhibitors using routinely available blood and clinical markers. Br J Cancer 117:913–920. CrossRefGoogle Scholar
  22. Indini A, Di Guardo L, Cimminiello C et al (2018) Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J Cancer Res Clin Oncol 145:511–521. CrossRefGoogle Scholar
  23. Jacquelot N, Pitt JM, Enot DP et al (2017) Immune biomarkers for prognosis and prediction of responses to immune checkpoint blockade in cutaneous melanoma. Oncoimmunology. Google Scholar
  24. Joshi S, Pantalena L-C, Liu XK et al (2011) 1,25-Dihydroxyvitamin D3 Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A. Mol Cell Biol. Google Scholar
  25. Landskron G, De La Fuente M, Thuwajit P et al (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. Google Scholar
  26. Langdon A, Crook N, Dantas G (2016) The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med 8(1):39CrossRefGoogle Scholar
  27. Lankes K, Hundorfean G, Harrer T et al (2016) Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology 5:e1128611. CrossRefGoogle Scholar
  28. Le Gall C, Desideri-Vaillant C, Nicolas X (2011) Significations of extremely elevated C-reactive protein: about 91 cases in a French hospital center. Pathol Biol. Google Scholar
  29. Martens A, Wistuba-Hamprecht K, Foppen MG et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22:2908–2918. CrossRefGoogle Scholar
  30. Mysler E, Psioni C, Tate P, Tate G (2004) Influence of corticosteroids on C-reactive protein in patients with rheumatoid arthritis. Arthritis Res Ther 6:57CrossRefGoogle Scholar
  31. Nakayama T, Saito K, Kumagai J et al (2018) Higher serum C-reactive protein level represents the immunosuppressive tumor microenvironment in patients with clear cell renal cell carcinoma. Clin Genitourin Cancer. Google Scholar
  32. Nghiem PT, Bhatia S, Lipson EJ et al (2016) PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. New Engl J Med. 374:2542–2552. CrossRefGoogle Scholar
  33. Okuhira H, Yamamoto Y, Inaba Y et al (2018) Prognostic factors of daily blood examination for advanced melanoma patients treated with nivolumab. Biosci Trends 12:412–418. CrossRefGoogle Scholar
  34. Puzanov I, Diab A, Abdallah K et al (2017) Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. Google Scholar
  35. Ricciuti B, Genova C, De Giglio A et al (2018) Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol 145:479–485. CrossRefGoogle Scholar
  36. Robert C, Schachter J, Long GV et al (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532. CrossRefGoogle Scholar
  37. Roy S, Trinchieri G (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17:271–285CrossRefGoogle Scholar
  38. Schadendorf D, Wolchok JD, Stephen Hodi F et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase II and III trials. J Clin Oncol. 35:3807–3814. CrossRefGoogle Scholar
  39. Schindler K, Harmankaya K, Kuk D, Mangana J, Michielin O, Hoeller C, Dummer R et al (2014) Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. ASCO Annual meeting, abstracts, meeting library. In: J Clin Oncol 325Google Scholar
  40. Schuetz P, Albrich W, Mueller B (2011) Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med 9:107. CrossRefGoogle Scholar
  41. Shrotriya S, Walsh D, Bennani-Baiti N et al (2015) C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS One. Google Scholar
  42. Simeone E, Gentilcore G, Giannarelli D et al (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683. CrossRefGoogle Scholar
  43. Sproston NR, Ashworth JJ (2018) Role of C-reactive protein at sites of inflammation and infection. Front Immunol 9:754. CrossRefGoogle Scholar
  44. Stucci S, Palmirotta R, Passarelli A et al (2017) Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management. Oncol, LettGoogle Scholar
  45. Su Q, Zhu EC, Wu JB et al (2019) Risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors for solid tumors: a systematic review and meta-analysis. Front Immunol. Google Scholar
  46. Tarhini AA, Lin Y, Yeku O et al (2014) A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med 12:19. CrossRefGoogle Scholar
  47. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. CrossRefGoogle Scholar
  48. Vanderschueren S, Deeren D, Knockaert DC et al (2006) Extremely elevated C-reactive protein. Eur J Intern Med 1:5–9. Google Scholar
  49. Vétizou M, Pitt JM, Daillère R et al (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079–1084. CrossRefGoogle Scholar
  50. Weide B, Martens A, Hassel JC et al (2016) Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res 22:5487–5496. CrossRefGoogle Scholar
  51. Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of DermatologyUniversitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-NürnbergErlangenGermany

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