Anti-IL6 Autoantibodies in an Infant With CRP-Less Septic Shock

Abstract

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.

IL-6 signalling pathway inactivation with siltuximab in patients with COVID-19 respiratory failure: an observational cohort study

“…The siltuximab antibody IL-6 complex neutralizes the activity of IL-6 to prevent acute-phase expression of CRP. Therefore, serum CRP levels provide an indirect measure of siltuximab efficacy in neutralizing IL-6 (Bloomfield et al 2019;EUSA 2019), which is a recognised component of the cytokine storm associated with COVID-19 (Mehta P et al 2020;Xu X et al 2020). Five days following treatment with siltuximab, serum CRP was reduced to within the normal range in all patients with available data, and levels stabilized through to Day 7 of follow-up suggesting that inflammation levels were reduced in response to treatment.…”

Recognition and management of respiratory co-infection and secondary bacterial pneumonia in patients with COVID-19

“…Co-infection and secondary bacterial infection • Viral co-infection incidence varies based on case series (0% to 15%) [2][3][4][5][6][7] • Combine bacterial and viral infection is rare in COVID-19 patients 3,8-10 • Secondary bacterial infection is not uncommon and leads to signifi cant morbidity and mortality, especially in the elderly 4,9,16 Procalcitonin • Detectable in 2 to 4 hours, peaks at 12 to 24 hours, and has a half-life of 25 to 30 hours • Levels are normal (< 0.5 μg/L) in COVID-19 patients with mild disease and may be elevated (≥ 0.50 μg/L) in patients with severe disease 10,14 • Elevated levels are correlated to a nearly 5-fold higher risk for severe SARS-CoV-2 infection 17 • Elevated levels are not specifi c to bacterial infection because they can also be raised in patients with acute respiratory distress syndrome, end-stage renal disease, cardiogenic shock, and multi-organ failure 18 • A normal level makes bacterial infection less likely and can guide antibiotic discontinuation 19,20 • In bacterial infection, levels may be less affected by IL-6 inhibitors than C-reactive protein (CRP) [21][22][23]…”

“…34,37,38 Exactly how long this effect lasts with 1 or 2 doses is unclear. Procalcitonin may be less affected by IL-6 inhibitors, [21][22][23] but the data to differentiate bacteria from viral pneumonia in this context is limited and should be further evaluated.…”

Autoantibodies against cytokines: phenocopies of primary immunodeficiencies?

“…Four patients with autoantibodies against IL-6 who developed severe bacterial infections have been published to date (Bloomfield et al 2019;Nanki et al 2013;Puel et al 2008). Further, patients with autoantibodies against IL-6 and severe bacterial infections have been identified (Doffinger and von Bernuth unpublished data).…”