Infectious Risks Associated with Biologics

  • David IsaacsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 764)


Biologics are generally either custom-designed monoclonal antibodies against specific target cells (e.g. B-cells) or target cytokines (e.g. tumour necrosis factor, TNF) or they are receptor constructs (fusion proteins) based on naturally-occurring cytokine or cell receptors. Biologics are mostly used in adult rheumatology but are increasingly used in paediatrics. There are significant concerns about safety and also about cost. The main safety concerns are about increased risk of infection and malignancy.

The use of TNF antagonists is associated with increased risk of serious infections with intracellular organisms, particularly mycobacteria, but also intracellular bacteria, fungi and Pneumocystis. B-cell antagonists like rituximab can cause progressive multifocal leukoencephalopathy. IL-6 antagonists are associated with increased rates of common bacterial infections and the complement pathway antagonist eculizumab with meningococcal infection.

The risk of some infections associated with biologics can be reduced, by screening patients starting TNF antagonists for latent tuberculosis and giving them cotrimoxazole prophylaxis against Pneumocystis, and by immunising against VZV, hepatitis B, meningococci and pneumococci. However, the risk of the biologics causing serious infection in children is unknown and needs study. Children should not be started on the biologics without careful consideration of the risks and without fully informed consent.


Progressive Multifocal Leukoencephalopathy Paroxysmal Nocturnal Haemoglobinuria Progressive Multifocal Leukoencephalopathy Macrophage Activation Syndrome Membrane Attack Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    FDA Center for Biologics Evaluation and Research (2007–10-29) (2011) What are “biologics” questions and answers. Accessed 1 Nov 2011 (Last updated 4/30/2009)
  2. 2.
    Beresford MW, Baildam EM (2009) New advances in the management of juvenile idiopathic arthritis—2: the era of biologicals. Arch Dis Child Educ Pract Ed 94:151–156CrossRefGoogle Scholar
  3. 3.
    Singh JA, Christensen R, Wells GA et al (2009) Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev 2009(4):CD007848. doi:10.1002/14651858.CD007848.pub2Google Scholar
  4. 4.
    Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501CrossRefGoogle Scholar
  5. 5.
    Bouwmeester T, Bauch A, Ruffner H et al (2004) A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6:97–105 (England)CrossRefGoogle Scholar
  6. 6.
    Marino MW, Dunn A, Grail D et al (1997) Characterization of tumor necrosis factor-deficient mice. Proc Natl Acad Sci USA 94:8093–8098CrossRefGoogle Scholar
  7. 7.
    Flynn J, Goldstein MM, Chan J et al (1995) Tumor necrosis factor -  a is required in the protective immune response against M. tuberculosis in mice. Immunity 2:561–572CrossRefGoogle Scholar
  8. 8.
    Rothe J, Lesslauer W, Lötscher H et al (1993) Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364:798–802CrossRefGoogle Scholar
  9. 9.
    Wellmer A, Gerber J, Ragheb J et al (2001) Effect of deficiency of tumor necrosis factor alpha or both of its receptors on Streptococcus pneumoniae central nervous system infection and peritonitis. Infect Immun 69:6881–6886CrossRefGoogle Scholar
  10. 10.
    Navarro-Sarabia F, Ariza-Ariza R, Hernandez-Cruz B, Villanueva I (2005) Adalimumab for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005(3):CD005113. doi:10.1002/14651858.CD005113.pub2Google Scholar
  11. 11.
    Keystone EC, Kavanaugh AF, Sharp JT et al (2004) Radiographic, clinical, and functional outcomes of treatment with Adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy. A randomized, placebo-controlled, 52-week trial. Arth Rheumat 50:1400–1411CrossRefGoogle Scholar
  12. 12.
    Singh JA, Noorbaloochi S, Singh G (2010) Golimumab for rheumatoid arthritis. Cochrane Database Syst Rev 2010(1):CD008341. doi:10.1002/14651858.CD008341Google Scholar
  13. 13.
    Food, Drug Administration (2011) FDA: Manufacturers of TNF-blocker drugs must highlight risk of fungal infections. FDA, 2008. Accessed 1 Nov 11
  14. 14.
    Skripak JM, Rodgers GL, Martucci C, Goldsmith DP (2011) Disseminated simplex (HSV) infection precipitating macrophage activation syndrome (MAS) in a child with systemic juvenile idiopathic arthritis (SJIA) undergoing therapy with infliximab. Pediatric Rheumatology Online Journal. #Abstract 58. 2003. Link: Accessed 1 Jun 2011Google Scholar
  15. 15.
    Komano Y, Harigai M, Koike R et al (2009) Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with infliximab: a retrospective review and case-control study of 21 patients. Arthritis Rheum 61:305–312CrossRefGoogle Scholar
  16. 16.
    Evens AM, Jovanovic BD, Su YC et al (2010) Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol (29 Nov 2010, Epub ahead of print)Google Scholar
  17. 17.
    Carson KR, Evens AM, Richey EA et al (2009) Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113:4834–4840CrossRefGoogle Scholar
  18. 18.
    Kean JM, Rao S, Wang M, Garcea RL (2009) Seroepidemiology of human polyomaviruses. PLoS Pathog 5:e1000363. Link: Scholar
  19. 19.
    Egli A, Infanti L, Dumoulin A et al (2009) Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors. J Infect Dis 199:837–846CrossRefGoogle Scholar
  20. 20.
    Van Der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF (1997) Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis 176:439–444CrossRefGoogle Scholar
  21. 21.
    Singh JA, Beg S, Lopez-Olivo MA (2010) Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev 2010(7):CD008331. doi:10.1002/14651858.CD008331.pub2Google Scholar
  22. 22.
    Campbell L, Chen CV, Bhagat SS, Parker RA, Ostor AJK (2010) Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology. doi:10.1093/rheumatology/keq343Google Scholar
  23. 23.
    Mertens M, Singh JA (2009) Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev 2009(1):CD005121. doi:10.1002/14651858.CD005121.pub3Google Scholar
  24. 24.
    Ross SC, Densen P (1984) Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine 63:243–273CrossRefGoogle Scholar
  25. 25.
    Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R (2008) FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 13:993–1000 (Epub 2008 Sep 10)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Infectious Disease and MicrobiologyChildren’s Hospital at WestmeadWestmeadAustralia

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