Background: Interleukin-6 (IL-6) is a pleiotropic cytokine with a multitude of pro-inflammatory effects. Serum C-reactive protein (CRP) is an acute phase protein induced mainly by IL-6 in response to inflammatory conditions, particularly infection. The biological functions of CRP include opsonisation, induction of phagocytosis, complement activation, or chemotaxis enhancement. Factors interfering with IL-6-mediated recruitment of innate immune responses, such as the presence of anti-IL6 antibodies, may therefore compromise the host resistance to microbial pathogens. This has major implications for the use of IL-6-targeting biologics, such as tocilizumab or sarilumab in rheumatologic, immune dysregulation diseases, and cancer. Case presentation: 20-month-old Czech female developed severe septic shock with clinical and laboratory signs of systemic inflammation but no increase of CRP or IL-6. The offending pathogen was most likely Staphylococcus aureus, detected in a throat swab; the response to antibiotic treatment was prompt. A defect in the integrity of IL-6/CRP axis was suspected and verified by the detection of neutralizing IL-6 antibodies in the serum of the child. Conclusion: We report a first case of systemic bacterial infection in a patient with anti-IL6 autoantibodies. Disturbed IL-6 signaling, whether iatrogenic by targeted IL-6 blockade or endogenous due to the presence of autoantibodies against IL-6, represents a risk factor for increased infectious susceptibility. Patients with severe bacterial infection without elevation of CRP should be examined for the presence of anti-IL6 autoantibodies.

Department of Clinical Chemistry 1st Faculty of Medicine Thomayer's Hospital and Charles University Prague Czechia

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czechia

Department of Pediatrics 1st Faculty of Medicine Thomayer's Hospital and Charles University Prague Czechia

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Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. (1993) 53:1–78. 10.1016/S0065-2776(08)60532-5 PubMed DOI

Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. (2014) 70:11–20. 10.1016/j.cyto.2014.05.024 PubMed DOI

Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. (2018) 9:754. 10.3389/fimmu.2018.00754 PubMed DOI PMC

Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. (2003) 111:1805–12. 10.1172/JCI18921 PubMed DOI PMC

Vijayan AL, Vanimaya, Ravindran S, Saikant R, Lakshmi S, Kartik R, G M. Procalcitonin: a promising diagnostic marker for sepsis and antibiotic therapy. J Intensive Care. (2017) 5:51 10.1186/s40560-017-0246-8 PubMed DOI PMC

Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. (2005) 6:2–8. 10.1097/01.PCC.0000149131.72248.E6 PubMed DOI

Singer M, Deutschman CS, Seymour C, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. (2016) 315:801–10. 10.1001/jama.2016.0287 PubMed DOI PMC

Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity. (2019) 50:1007–23. 10.1016/j.immuni.2019.03.026 PubMed DOI

Puel A, Picard C, Lorrot M, Pons C, Chrabieh M, Lorenzo L, et al. . Recurrent Staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J Immunol. (2008) 180:647–54. 10.4049/jimmunol.180.1.647 PubMed DOI

Nanki T, Onoue I, Nagasaka K, Takayasu A, Ebisawa M, Hosoya T, et al. . Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. Ann Rheum Dis. (2013) 72:1100–2. 10.1136/annrheumdis-2012-202768 PubMed DOI

Spencer S, Köstel Bal S, Egner W, Lango Allen H, Raza SI, Ma CA, et al. . Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med. (2019) 216:1986–98. 10.1084/jem.20190344 PubMed DOI PMC

Schwerd T, Twigg SRF, Aschenbrenner D, Manrique S, Miller KA, Taylor IB, et al. . A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med. (2017) 214:2547–62. 10.1084/jem.20161810 PubMed DOI PMC

Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am. (2008) 28:277–91. 10.1016/j.iac.2008.01.005 PubMed DOI PMC

Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, et al. . Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. (1994) 368:339–42. 10.1038/368339a0 PubMed DOI

Barcenas-Morales G, Cortes-Acevedo P, Doffinger R. Anticytokine autoantibodies leading to infection early recognition, diagnosis and treatment options. Curr Opin Infect Dis. (2019) 32:330–6. 10.1097/QCO.0000000000000561 PubMed DOI PMC

Galle P, Svenson M, Bendtzen K, Hansen MB. High levels of neutralizing IL-6 autoantibodies in 0.1% of apparently healthy blood donors. Eur J Immunol. (2004) 34:3267–75. 10.1002/eji.200425268 PubMed DOI

Rutherford AI, Subesinghe S, Hyrich KL, Galloway JB. Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. (2018) 77:905–10. 10.1136/annrheumdis-2017-212825 PubMed DOI

Pawar A, Desai RJ, Solomon DH, Santiago Ortiz AJ, Gale S, Bao M, et al. . Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann Rheum Dis. (2019) 78:456–64. 10.1136/annrheumdis-2018-214367 PubMed DOI

Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. (2010) 20:222–32. 10.1007/s10165-010-0279-5 PubMed DOI

Kojima T, Yabe Y, Kaneko A, Hirano Y, Ishikawa H, Hayashi M, Miyake H, Takagi H, Kato T, Terabe K, et al. . Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. Mod Rheumatol. (2013) 23:977–85. 10.3109/s10165-012-0782-y PubMed DOI

Bari SF, Khan A, Lawson T. C reactive protein may not be reliable as a marker of severe bacterial infection in patients receiving tocilizumab. Case Reports. (2013) 2013:bcr2013010423 10.1136/bcr-2013-010423 PubMed DOI PMC