Increased levels of plasma cytokines and correlations to organ failure and 30-day mortality in critically ill Covid-19 patients

Sara Bülow Anderberg, Tomas Luther, Malin Berglund, Rolf Larsson, Sten Rubertsson, Miklos Lipcsey, Anders Larsson, Robert Frithiof, Michael Hultström, Sara Bülow Anderberg, Tomas Luther, Malin Berglund, Rolf Larsson, Sten Rubertsson, Miklos Lipcsey, Anders Larsson, Robert Frithiof, Michael Hultström

Abstract

Background: The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients.

Method: 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality.

Results: A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality.

Conclusion: The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission.

Keywords: Acute kidney injury; Biomarkers; COVID-19; Cytokine storm; Inflammation; Intensive care.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
A heatmap showing hierarchical clustering of individual patients according to the detectable plasma concentration of 24 out of 27 analyzed cytokines (A). The clustering of patients in the general heatmap is largely driven by the relatively high concentrations of IP-10 and RANTES (A). The cytokines were further separated into subgroups and shown in separate heatmaps; Th1-cytokines (B), Th2-cytokines (C), Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing Proteins (NLRP) associated cytokines (D) and chemokines (E). IL-12, IL-2, IFN γ and TNF α were categorized as Th1-cytokines. Th1 cytokines participate in cell mediated immunity, promotes inflammation and tissue damage . IL-10, IL-4, IL-13, IL-7 and IL-9 were categorized as Th2-cytokines (C). Th2-cytokine expression plays a role in humoral immunity and may act anti-inflammatory . NLPR-associated mediators (D) IL-1β, IL-6, IL-8 and IL-1ra take part in the innate immune response including promoting immune cell infiltration of infected tissues. Notably, these cytokines clustered the groups perfectly , . MIP-1a, eotaxin, MCP-1, MIP-1b, IP-10 and RANTES were grouped as chemokines . The color key of the calculated z-score represents a scale of −4 to 4 SD where the individual value departs from the group mean as shown in the figure.
Fig. 2
Fig. 2
Plasma concentrations of IL-8 at admission to intensive care in Covid-19 patients is associated with 30-day mortality (A), respiratory failure presented as PaO2/FiO2 (B) and acute kidney injury (AKI) stratified by Kidney Disease: Improved Global Outcome (C). Plasma concentrations of IL-8 demonstrated the strongest correlation with 30-day mortality (r = 0.503, p = 0.002) among the 27 cytokines analyzed in our panel. Increased plasma expression of IL-8 in Covid-19 correlated well with both respiratory failure (r = −0.681) as well as AKI development (r = 0.728, p = 0.000). Data shown as logarithmically transformed plasma concentration preoperatively in controls (filled triangles) and at admission to intensive care in Covid-19 patients (filled circles).

References

    1. Grasselli G., Zangrillo A., Zanella A. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020
    1. Mehta P., McAuley D.F., Brown M. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 2020;395(10229):1033–1034.
    1. McGonagle D., Sharif K., O'Regan A. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun. Rev. 2020;102537
    1. Qin C., Zhou L., Hu Z. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. 2020
    1. Zhang W., Zhao Y., Zhang F. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin. Immunol. 2020;214:108393.
    1. Reiss L.K., Schuppert A., Uhlig S. Inflammatory processes during acute respiratory distress syndrome: a complex system. Curr. Opin. Crit. Care. 2018;24(1):1–9.
    1. Steinberg K.P., Hudson L.D., Goodman R.B. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N. Engl. J. Med. 2006;354(16):1671–1684.
    1. Rhodes A., Evans L.E., Alhazzani W. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304–377.
    1. Moreno R.P., Metnitz P.G., Almeida E. SAPS 3–From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31(10):1345–1355.
    1. Vincent J.L., Moreno R., Takala J. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22(7):707–710.
    1. Section 2: AKI Definition. Kidney Int. Suppl. (2011) 2012; 2(1):19-36.
    1. Kany S., Vollrath J.T., Relja B. Cytokines in Inflammatory Disease. Int. J. Mol. Sci. 2019;20(23):6008.
    1. Matsumoto H., Ogura H., Shimizu K. The clinical importance of a cytokine network in the acute phase of sepsis. Sci. Rep. 2018;8(1):13995.
    1. Bozza F.A., Salluh J.I., Japiassu A.M. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit. Care. 2007;11(2):R49.
    1. Wang C., Fei D., Li X. IL-6 may be a good biomarker for earlier detection of COVID-19 progression. Intensive Care Med. 2020
    1. Chishti A.D., Shenton B.K., Kirby J.A. Neutrophil chemotaxis and receptor expression in clinical septic shock. Intensive Care Med. 2004;30(4):605–611.
    1. Behrens E.M., Koretzky G.A. Review: cytokine storm syndrome: looking toward the precision medicine era. Arthrit. Rheumatol. 2017;69(6):1135–1143.
    1. Kox M., Waalders N.J.B., Kooistra E.J. Cytokine levels in critically Ill patients with COVID-19 and other conditions. JAMA. 2020
    1. Tsurumi A., Que Y.-A., Ryan C.M. TNF-α/IL-10 ratio correlates with burn severity and may serve as a risk predictor of increased susceptibility to infections. Front. Public Health. 2016;4(216)
    1. Cavaillon J.M. Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol. Biol. (Noisy-le-grand) 2001;47(4):695–702.
    1. S. Wan, Q. Yi, S. Fan et al., Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv 2020:2020.2002.2010.20021832.
    1. Channappanavar R., Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars Immunopathol. 2017;39(5):529–539.
    1. Force* TADT: Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA 307(23) (2012) 2526-2533.
    1. Fujishima S. Pathophysiology and biomarkers of acute respiratory distress syndrome. J. Intensive Care. 2014;2(1):32.
    1. Terpstra M.L., Aman J., van Nieuw Amerongen G.P. Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis*. Crit. Care Med. 2014;42(3):691–700.
    1. Bautista E., Arcos M., Jimenez-Alvarez L. Angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to A/H1N1 virus infection. Exp. Mol. Pathol. 2013;94(3):486–492.
    1. Quint J.K., Donaldson G.C., Goldring J.J.P. Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of COPD. Chest. 2010;137(4):812–822.
    1. Liu M., Guo S., Hibbert J.M. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 2011;22(3):121–130.
    1. Hu Y., Sun J., Dai Z. Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis. J. Clin. Virol. 2020;127:104371.
    1. Wang L., Li X., Chen H. Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China. Am. J. Nephrol. 2020:1–6.
    1. Ronco C., Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies. Nat. Rev. Nephrol. 2020:1–3.
    1. Pei G., Zhang Z., Peng J. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J. Am. Soc. Nephrol. 2020
    1. Panitchote A., Mehkri O., Hastings A. Factors associated with acute kidney injury in acute respiratory distress syndrome. Ann. Intensive Care. 2019;9(1):74.
    1. Hultström M., von Seth M., Frithiof R. Hyperreninemia and low total body water may contribute to acute kidney injury in COVID-19 patients in intensive care. J. Hypertens. 2020;38(8):1613–1614.
    1. Cheng Y., Luo R., Wang K. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829–838.
    1. McNicholas B.A., Rezoagli E., Pham T. Impact of early acute kidney injury on management and outcome in patients with acute respiratory distress syndrome: a secondary analysis of a multicenter observational study. Crit. Care Med. 2019;47(9):1216–1225.
    1. Darmon M., Clec'h C., Adrie C. Acute respiratory distress syndrome and risk of AKI among critically ill patients. Clin. J. Am. Soc. Nephrol. 2014;9(8):1347–1353.
    1. Malek M., Hassanshahi J., Fartootzadeh R. Nephrogenic acute respiratory distress syndrome: A narrative review on pathophysiology and treatment. Chin. J. Traumatol. 2018;21(1):4–10.
    1. Russo R.C., Garcia C.C., Teixeira M.M. The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases. Expert Rev. Clin. Immunol. 2014;10(5):593–619.
    1. Raphael I., Nalawade S., Eagar T.N. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17.
    1. Torre D., Speranza F., Giola M. Role of Th1 and Th2 Cytokines in immune response to uncomplicated <em>Plasmodium falciparum</em> Malaria. Clin. Diagn. Lab. Immunol. 2002;9(2):348–351.
    1. Kelley N., Jeltema D., Duan Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 2019;20(13)
    1. Lamkanfi M., Dixit V.M. Mechanisms and functions of inflammasomes. Cell. 2014;157(5):1013–1022.
    1. Zlotnik A., Yoshie O. The chemokine superfamily revisited. Immunity. 2012;36(5):705–716.

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