Skip to main content

Advertisement

SpringerLink
Log in

Elevated risk of opportunistic viral infection in patients with Crohn’s disease during biological therapies: a meta analysis of randomized controlled trials

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Biological agents have been widely used in the treatment of Crohn’s disease (CD). These drugs carry the risk of excessive immunosuppression, indicating possible opportunistic infections including opportunistic viral infections, but no meta analysis has ever focused on this issue.

Purpose

To evaluate whether there is an association between biological agents therapy and the risk of opportunistic viral infections and serious infections in patients with CD.

Methods

A search of online databases was performed and literature selection was carried out according to the inclusion and exclusion criteria by reading titles, abstracts and full texts. Study heterogeneity and publication bias were assessed. Whether to choose a fixed effects model or a random effects model depended on the result of heterogeneity test.

Results

There was a statistical significance in opportunistic viral infection events between the biological agents group and the placebo group. However, our analysis didn’t observe statistically significant differences between the two groups when combined analyses were carried out for herpes zoster and herpes simplex separately. A risk trend in the biological agents group was observed in the analysis for herpes zoster. More analyses aimed at the outcome measures and including influenza and serious infection were carried out separately, but no statistical significance was found in them.

Conclusion

Biological agents use might increase the risk of opportunistic viral infections in patients with CD, but not the risk of herpes simplex and serious infections. More randomized controlled trials (RCTs) are needed to draw the conclusion of whether they could elevate the risk of herpes zoster.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, Gendre JP (2002) Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis 8(4):244–250

    Article  PubMed  Google Scholar 

  2. Baumgart DC, Sandborn WJ (2012) Crohn’s disease. Lancet 380(9853):1590–1605

    Article  PubMed  Google Scholar 

  3. Gionchetti P, Calabrese C, Tambasco R, Brugnera R, Straforini G, Liguori G, Fornarini GS, Riso D, Campieri M, Rizzello F (2011) Role of conventional therapies in the era of biological treatment in Crohn’s disease. World J Gastroenterol 17(14):1797–1806

    Article  PubMed  Google Scholar 

  4. Burger D, Travis S (2011) Conventional medical management of inflammatory bowel disease. Gastroenterology 140(6):1827–1837

    Article  PubMed  Google Scholar 

  5. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, Langholff W, Londhe A, Sandborn WJ (2012) Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol 107(9):1409–1422

    Article  PubMed  CAS  Google Scholar 

  6. Viget N, Vernier-Massouille G, Salmon-Ceron D, Yazdanpanah Y, Colombel JF (2008) Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis. Gut 57:549–558

    Article  PubMed  CAS  Google Scholar 

  7. Lin Z, Bai Y, Zheng P (2011) Meta-analysis: efficacy and safety of combination therapy of infliximab and immunosuppressives for Crohn’s disease. Eur J Gastroenterol Hepatol 23(12):1100–1110

    Article  PubMed  CAS  Google Scholar 

  8. Higgins JPT, Green S (updated March 2011) Cochrane handbook for systematic reviews of interventions: version 5.1.0. www.handbook.cochrane.org

  9. Ruemmele FM, Lachaux A, Cézard JP, Morali A, Maurage C, Giniès JL, Viola S, Goulet O, Lamireau T, Scaillon M, Breton A, Sarles J, Groupe Francophone d’Hépatologie, Gastroentérologie et Nutrition Pédiatrique (2009) Efficacy of infliximab in pediatric Crohn’s disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy. Inflamm Bowel Dis 15(3):388–394

    Article  PubMed  Google Scholar 

  10. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D’Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P, SONIC Study Group (2010) Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 362(15):1383–1395

    Article  PubMed  CAS  Google Scholar 

  11. Van Assche G, Vermeire S, Ballet V, Gabriels F, Noman M, D’Haens G, Claessens C, Humblet E, Vande Casteele N, Gils A, Rutgeerts P (2012) Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut 61(2):229–234

    Article  PubMed  Google Scholar 

  12. Feagan BG, Sandborn WJ, Wolf DC, Coteur G, Purcaru O, Brabant Y, Rutgeerts PJ (2011) Randomised clinical trial: improvement in health outcomes with certolizumab pegol in patients with active Crohn’s disease with prior loss of response to infliximab. Aliment Pharmacol Ther 33(5):541–550

    Article  PubMed  CAS  Google Scholar 

  13. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 337(15):1029–1035

    Article  PubMed  CAS  Google Scholar 

  14. Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, Mayer L, Van Hogezand RA, Braakman T, DeWoody KL, Schaible TF, Van Deventer SJ (1999) Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 117(4):761–769

    Article  PubMed  CAS  Google Scholar 

  15. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ (1999) Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 340(18):1398–1405

    Article  PubMed  CAS  Google Scholar 

  16. Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Schölmerich J, Panés J, Sandborn WJ, PRECiSE 2 Study Investigators (2010) Increased response and remission rates in short-duration Crohn’s disease with subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial data. Am J Gastroenterol 105(7):1574–1582

    Article  PubMed  CAS  Google Scholar 

  17. Winter TA, Wright J, Ghosh S, Jahnsen J, Innes A, Round P (2004) Intravenous CDP870, a PEGylated Fab’ fragment of a humanized antitumour necrosis factor antibody, in patients with moderate-to-severe Crohn’s disease: an exploratory study. Aliment Pharmacol Ther 20(11–12):1337–1346

    Article  PubMed  CAS  Google Scholar 

  18. Sands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, Katz S, Goldblum R, Harrigan R, Hilton D, Hanauer SB (2007) Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis 13(1):2–11

    Article  PubMed  Google Scholar 

  19. Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, Wolf DC, Baker JP, Hawkey C, Archambault A, Bernstein CN, Novak C, Heath PK, Targan SR, CDP571 Crohn’s Disease Study Group (2001) An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial. Gastroenterology 120(6):1330–1338

    Article  PubMed  CAS  Google Scholar 

  20. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S, Natalizumab Pan-European Study Group (2003) Natalizumab for active Crohn’s disease. N Engl J Med 348(1):24–32

    Article  PubMed  CAS  Google Scholar 

  21. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P, International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial Group, Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group (2005) Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 353(18):1912–1925

    Article  PubMed  CAS  Google Scholar 

  22. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OØ, Innes A, CDP870 Crohn’s Disease Study Group (2005) A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 129(3):807–818

    Article  PubMed  CAS  Google Scholar 

  23. Sandborn WJ, Schreiber S, Feagan BG, Rutgeerts P, Younes ZH, Bloomfield R, Coteur G, Guzman JP, D’Haens GR (2011) Certolizumab pegol for active Crohn’s disease: a placebo-controlled, randomized trial. Clin Gastroenterol Hepatol 9(8):670–678

    Article  PubMed  CAS  Google Scholar 

  24. Lémann M, Mary JY, Duclos B, Veyrac M, Dupas JL, Delchier JC, Laharie D, Moreau J, Cadiot G, Picon L, Bourreille A, Sobahni I, Colombel JF, Groupe d’Etude Therapeutique des Affections Inflammatoires du Tube Digestif (GETAID) (2006) Infliximab plus azathioprine for steroid-dependent Crohn’s disease patients: a randomized placebo-controlled trial. Gastroenterology 130(4):1054–1061

    Article  PubMed  Google Scholar 

  25. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M, Wolf DC, Hernandez C, Bornstein J, Sandborn WJ, International Efficacy of Natalizumab in Crohn’s Disease Response and Remission (ENCORE) Trial Group (2007) Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology 132(5):1672–1683

    Article  PubMed  CAS  Google Scholar 

  26. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF (2007) Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132(1):52–65

    Article  PubMed  CAS  Google Scholar 

  27. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B, Li J, Pollack PF (2007) Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 56(9):1232–1239

    Article  PubMed  CAS  Google Scholar 

  28. Colombel JF, Schwartz DA, Sandborn WJ, Kamm MA, D’Haens G, Rutgeerts P, Enns R, Panaccione R, Schreiber S, Li J, Kent JD, Lomax KG, Pollack PF (2009) Adalimumab for the treatment of fistulas in patients with Crohn’s disease. Gut 58(7):940–948

    Article  PubMed  CAS  Google Scholar 

  29. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D’Haens G, Li J, Rosenfeld MR, Kent JD, Pollack PF (2007) Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 146(12):829–838

    Article  PubMed  Google Scholar 

  30. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, Bloomfield R, Schreiber S, PRECISE 1 Study Investigators (2007) Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 357(3):228–238

    Article  PubMed  CAS  Google Scholar 

  31. Hanauer SB, Panes J, Colombel JF, Bloomfield R, Schreiber S, Sandborn WJ (2010) Clinical rial: impact of prior infliximab therapy on the clinical response to certolizumab pegol maintenance therapy for Crohn’s disease. Aliment Pharmacol Ther 32(3):384–393

    Article  PubMed  CAS  Google Scholar 

  32. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, Panaccione R, Wolf D, Pollack P (2006) Human anti-tumor necrosis factor monoclonal antibody adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 130(2):323–333

    Article  PubMed  CAS  Google Scholar 

  33. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ (2004) Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 350(9):876–885

    Article  PubMed  CAS  Google Scholar 

  34. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P, ACCENT I Study Group (2002) Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359(9317):1541–1549

    Article  PubMed  CAS  Google Scholar 

  35. Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, McColm J, Bloomfield R, Sandborn WJ, PRECISE 2 Study Investigators (2007) Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 357(3):239–250

    Article  PubMed  CAS  Google Scholar 

  36. Schreiber S, Lawrance IC, Thomsen OØ, Hanauer SB, Bloomfield R, Sandborn WJ (2011) Randomised clinical trial: certolizumab pegol for fistulas in Crohn’s disease—subgroup results from a placebo-controlled study. Aliment Pharmacol Ther 33(2):185–193

    Article  PubMed  CAS  Google Scholar 

  37. Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P, Ustekinumab Crohn’s Disease Study Group (2008) A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 135(4):1130–1141

    Article  PubMed  CAS  Google Scholar 

  38. Kimball AB, Gordon KB, Fakharzadeh S, Yeilding N, Szapary PO, Schenkel B, Guzzo C, Li S, Papp KA (2012) Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol 166(4):861–872

    Article  PubMed  CAS  Google Scholar 

  39. Hutchinson M, Kappos L, Calabresi PA, Confavreux C, Giovannoni G, Galetta SL, Havrdova E, Lublin FD, Miller DH, O’Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, AFFIRM and SENTINEL Investigators (2009) The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol 256(3):405–415

    Article  PubMed  CAS  Google Scholar 

  40. Probert CS, Hearing SD, Schreiber S, Kühbacher T, Ghosh S, Arnott ID, Forbes A (2003) Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 52(7):998–1002

    Article  PubMed  CAS  Google Scholar 

  41. Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA (2002) Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology 41(10):1133–1137

    Article  PubMed  CAS  Google Scholar 

  42. Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF, Egan LJ (2008) Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 134(4):929–936

    Article  PubMed  Google Scholar 

  43. Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D’Inca R, Bossa F, Angelucci E, Biancone L, Gionchetti P, Ardizzone S, Papi C, Fries W, Danese S, Riegler G, Cappello M, Castiglione F, Annese V, Orlando A (2011) Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 9(1):30–35

    Article  PubMed  CAS  Google Scholar 

  44. Plevy SE, Landers CJ, Prehn J, Carramanzana NM, Deem RL, Shealy D, Targan SR (1997) A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 159(12):6276–6282

    PubMed  CAS  Google Scholar 

  45. van Deventer SJ (1999) Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn’s disease–the mechanisms of action of infliximab. Aliment Pharmacol Ther 13(Suppl 4):3–8

    Article  PubMed  Google Scholar 

  46. Lobb RR, Hemler ME (1994) The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest 94(5):1722–1728

    Article  PubMed  CAS  Google Scholar 

  47. Rüegg C, Postigo AA, Sikorski EE, Butcher EC, Pytela R, Erle DJ (1992) Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol 117(1):179–189

    Article  PubMed  Google Scholar 

  48. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A, Butcher EC (1993) Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74(1):185–195

    Article  PubMed  CAS  Google Scholar 

  49. Utsugi M, Dobashi K, Ono A, Ishizuka T, Matsuzaki S, Hisada T, Shimizu Y, Kawata T, Aoki H, Kamide Y, Mori M (2009) PI3K p110beta positively regulates lipopolysaccharide-induced IL-12 production in human macrophages and dendritic cells and JNK1 plays a novel role. J Immunol 182(9):5225–5231

    Article  PubMed  CAS  Google Scholar 

  50. Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH (1998) The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 16:495–521

    Article  PubMed  CAS  Google Scholar 

  51. Hall MA, McGlinn E, Coakley G, Fisher SA, Boki K, Middleton D, Kaklamani E, Moutsopoulos H, Loughran TP Jr, Ollier WE, Panayi GS, Lanchbury JS (2000) Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. Genes Immun 1(3):219–224

    Article  PubMed  CAS  Google Scholar 

  52. Stallmach A, Marth T, Weiss B, Wittig BM, Hombach A, Schmidt C, Neurath M, Zeitz M, Zeuzem S, Abken H (2004) An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo. Gut 53(3):339–345

    Article  PubMed  CAS  Google Scholar 

  53. Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Takayama T, Kitazume MT, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T (2010) TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn’s disease. Inflamm Bowel Dis 16(4):568–575

    Article  PubMed  Google Scholar 

  54. Sarra M, Pallone F, Macdonald TT, Monteleone G (2010) IL-23/IL-17 axis in IBD. Inflamm Bowel Dis 16(10):1808–1813

    Article  PubMed  Google Scholar 

  55. Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F (2010) Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33(2):279–288

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study is supported by research grants from the Public health project of China (No. 201002020).

Conflicts of interest

The authors declare that they have nothing to disclose.

Authorship

Guarantor of the article: Bing Xia.

Author contributions: All the authors contributed to the design of the study. Xiaobing Wang, Junzhang Zhao were responsible for writing of the manuscript. Xiaobing Wang, Rui Zhou, Meifang Huang, Jin Li and Shufang Xu took part in the literature search and quality assessment and the data extraction. Xiaobing Wang and Wei Wang performed the statistical analysis. All authors approved the final version of the manuscript.

Author information

Authors and Affiliations

  1. Department of Gastroenterology /Hepatology, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan, 430071, People’s Republic of China

    Xiaobing Wang, Feng Zhou, Junzhang Zhao, Rui Zhou, Meifang Huang, Jin Li, Wei Wang, Shufang Xu & Bing Xia

  2. The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, 430071, People’s Republic of China

    Xiaobing Wang, Feng Zhou, Junzhang Zhao, Rui Zhou, Meifang Huang, Jin Li, Wei Wang, Shufang Xu & Bing Xia

Authors
  1. Xiaobing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junzhang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meifang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shufang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bing Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bing Xia.

Additional information

Xiaobing Wang, Feng Zhou and Junzhang Zhao contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM FigureS1

The forest plot of randomized controlled trials of biological agents versus placebo in herpes zoster events in CD (JPEG 47 kb)

High resolution image (TIFF 8285 kb)

ESM FigureS2

The forest plot of randomized controlled trials of biological agents versus placebo in herpes simplex events in CD (JPEG 51 kb)

High resolution image (TIFF 9122 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Zhou, F., Zhao, J. et al. Elevated risk of opportunistic viral infection in patients with Crohn’s disease during biological therapies: a meta analysis of randomized controlled trials. Eur J Clin Pharmacol 69, 1891–1899 (2013). https://doi.org/10.1007/s00228-013-1559-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1559-8

Keywords

Search

Navigation