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. 2020 Oct 27;4(20):5174-5183.
doi: 10.1182/bloodadvances.2020002592.

Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children

Caroline Diorio  1   2 , Pamela A Shaw  3 , Edward Pequignot  4 , Alena Orlenko  3 , Fang Chen  4   5   6 , Richard Aplenc  1   2   5 , David M Barrett  1   2 , Hamid Bassiri  7 , Edward Behrens  2   8 , Amanda M DiNofia  1   2 , Vanessa Gonzalez  4   5   6 , Natalka Koterba  4   5   6 , Bruce L Levine  3   4   5   6 , Shannon L Maude  1   2 , Nuala J Meyer  9 , Jason H Moore  3 , Michele Paessler  6 , David L Porter  5   10 , Jenny L Bush  11 , Don L Siegel  4   5   6 , Megan M Davis  4 , Donglan Zhang  11 , Carl H June  4   5   6 , Stephan A Grupp  1   2   5 , J Joseph Melenhorst  4   5   6 , Simon F Lacey  4   5   6 , Scott L Weiss  11   12   13   14 , David T Teachey  1   2   5
Affiliations

Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children

Caroline Diorio et al. Blood Adv. .

Abstract

Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.

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Conflict of interest statement

Conflict-of-interest disclosure: S.L.M. is a consultant for Novartis Pharmaceuticals and Kite Pharma and reports receiving commercial research support from Novartis Pharmaceuticals. S.A.G. reports personal fees and grants from Novartis and CRISPR/Vertex; personal fees from Allogene, Cellular Biomedicine Group (CBMG), Adaptimmune, TCR2 Therapeutics, Juno, Jazz, Eureka, Cellectis, La Roche, GlaxoSmithKline, Cure Genetics, Humanigen, Janssen, and Johnson & Johnson; and grants from Kite and Servier. C.H.J. has ownership interest (including patents) in Tmunity and Novartis. D.L.P., B.L.L., S.F.L., and J.J.M. hold patent applications (US 20180258149, US 20180140602, US 20150283178) related to CAR T cell therapy. S.F.L. and J.J.M. receive research funding from Novartis. S.F.L. also receives research funding from Tmunity Therapeutics. B.L.L. and C.H.J. are cofounders and equity holders in Tmunity Therapeutics. B.L.L. is a consultant for Novartis as well as CRC Oncology and is a member of the scientific advisory boards of Avectas, Brammer Bio, Cure Genetics, and Incysus. J.J.M. is a consultant for Shanghai Unicar-Therapy Bio-medicine Technology Co. Ltd, Simcere of America Inc., IASO Biotherapeutics, and Poseida Therapeutics, and is a member of the scientific advisory board of IASO Biotherapeutics. D.T.T., J.J.M., and S.F.L. hold patent application (US 20180252727) related to toxicities after CAR T cell therapy. D.T.T. serves on the advisory board for Amgen, Janssen, La Roche, and Humanigen. D.L.P. has employment or spouse employment with Roche and Genentech; holds stock in Genentech and Roche; acts as a consultant for Novartis, Kite/Gilead, Incyte, Gerson Lehrman Group, Glenmark, Janssen, and Adepcet Bio; holds patents with Novartis and Tmunity; receives research funding from Novartis; and serves on the National Marrow Donor Program Board of Directors, and the American Board of Internal Medicine (Former, Hematology board exam writing committee member through October 2019). H.B. holds stock in CSL Behring, and acts as a consultant for Kriya Therapeutics. D.L.P. is a patent inventor for use of CAR T cells in CD19+ malignancies. D.M.B. is a consultant and have received research funding from Tmunity Therapeutics, a consultant and member on scientific advisory board for Cellares Corporation, received royalties/milestones from patents from Tmunity Therapeutics and Novartis Institute for Biomedical Research. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Cytokines with significant difference between CRS (N = 16) and sepsis (N = 80) at ICU admission. Cytokines that were significantly higher in CRS are shown first in black, followed by cytokines that were significantly higher in sepsis in red; graphs are ordered with respect to decreasing significance within each group. Group medians are noted with horizontal bars. Wilcoxon rank-sum test with Holm correction was used for multiple comparisons.
Figure 2.
Figure 2.
Training and testing accuracy and classification tree modeling of cytokines. (A) Feature importance for discrimination between sepsis (N = 80) and CRS (N = 16) cohorts. Cytokines are listed in terms of decreasing feature importance (right axis), and the performance of the model is shown (training and testing accuracy) when predictors are added to the model 1 at a time (left axis). (B) Classification tree model for discrimination between sepsis (N = 80) and CRS (N = 16) cohorts.
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References

    1. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64-73. - PMC - PubMed
    1. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541-1552. - PubMed
    1. Maude SL, Laetsch TW, Buechner J, et al. . Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. - PMC - PubMed
    1. Maude SL, Frey N, Shaw PA, et al. . Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517. - PMC - PubMed
    1. Grupp SA, Maude SL, Rives S, et al. . Tisagenlecleucel for the treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia: updated analysis of the ELIANA clinical trial. Biol Blood Marrow Transplant. 2019;25(3):S126-S127.

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