Temporal Kinetics of RNAemia and Associated Systemic Cytokines in Hospitalized COVID-19 Patients

Debby van Riel; Carmen W.E. Embregts; GJ (George) Sips; Johannes P.C. van den Akker; Henrik Endeman; Els van Nood; Mathijs Raadsen; Lisa Bauer; Jeroen van Kampen; Richard Molenkamp; Marion Koopmans; David van de Vijver; Corine H. GeurtsvanKessel

doi:10.1128/mSphere.00311-21

Temporal Kinetics of RNAemia and Associated Systemic Cytokines in Hospitalized COVID-19 Patients

Debby van Riel^*, Carmen W.E. Embregts, GJ (George) Sips, Johannes P.C. van den Akker, Henrik Endeman, Els van Nood, Mathijs Raadsen, Lisa Bauer, Jeroen van Kampen, Richard Molenkamp, Marion Koopmans, David van de Vijver, Corine H. GeurtsvanKessel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

COVID-19 is associated with a wide range of extrarespiratory complications, of which the pathogenesis is currently not fully understood. However, both systemic spread and systemic inflammatory responses are thought to contribute to the systemic pathogenesis. In this study, we determined the temporal kinetics of viral RNA in serum (RNAemia) and the associated inflammatory cytokines and chemokines during the course of COVID-19 in hospitalized patients. We show that RNAemia can be detected in 90% of the patients who develop critical disease, compared to 50% of the patients who develop moderate or severe disease. Furthermore, RNAemia lasts longer in patients who develop critical disease. Elevated levels of interleukin-10 (IL-10) and MCP-1-but not IL-6-are associated with viral load in serum, whereas higher levels of IL-6 in serum were associated with the development of critical disease. In conclusion, RNAemia is common in hospitalized patients, with the highest frequency and duration in patients who develop critical disease. The fact that several cytokines or chemokines are directly associated with the presence of viral RNA in the circulation suggests that the development of RNAemia is an important factor in the systemic pathogenesis of COVID-19. IMPORTANCE Severe COVID-19 can be considered a systemic disease as many extrarespiratory complications occur. However, the systemic pathogenesis is poorly understood. Here, we show that the presence of viral RNA in the blood (RNAemia) occurs more frequently in patients who develop critical disease, compared to patients with moderate or severe disease. In addition, RNAemia is associated with increased levels of inflammatory cytokines and chemokines, like MCP-1 and IL-10, in serum during the course of disease. This suggests that extrarespiratory spread of SARS-CoV-2 contributes to systemic inflammatory responses, which are an important factor in the systemic pathogenesis of COVID-19.

Original language	English
Article number	e00311-21
Journal	mSphere
Volume	6
Issue number	3
Early online date	28 May 2021
DOIs	https://doi.org/10.1128/mSphere.00311-21
Publication status	Published - May 2021

Bibliographical note

Funding Information:
Debby van Riel is supported by the Netherlands Organization for Scientific Research (VIDI 91718308) and a EUR fellowship. In addition, this work was supported by funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 101003589 (RECoVER). We declare no competing interests.

Publisher Copyright:
Copyright © 2021 van Riel et al.

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mSphere.00311-21Final published version, 772 KBLicence: CC BY

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van Riel, D., Embregts, C. W. E., Sips, GJ., van den Akker, J. P. C., Endeman, H., van Nood, E., Raadsen, M., Bauer, L., van Kampen, J., Molenkamp, R., Koopmans, M., van de Vijver, D., & GeurtsvanKessel, C. H. (2021). Temporal Kinetics of RNAemia and Associated Systemic Cytokines in Hospitalized COVID-19 Patients. mSphere, 6(3), Article e00311-21. https://doi.org/10.1128/mSphere.00311-21

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title = "Temporal Kinetics of RNAemia and Associated Systemic Cytokines in Hospitalized COVID-19 Patients",

abstract = "COVID-19 is associated with a wide range of extrarespiratory complications, of which the pathogenesis is currently not fully understood. However, both systemic spread and systemic inflammatory responses are thought to contribute to the systemic pathogenesis. In this study, we determined the temporal kinetics of viral RNA in serum (RNAemia) and the associated inflammatory cytokines and chemokines during the course of COVID-19 in hospitalized patients. We show that RNAemia can be detected in 90% of the patients who develop critical disease, compared to 50% of the patients who develop moderate or severe disease. Furthermore, RNAemia lasts longer in patients who develop critical disease. Elevated levels of interleukin-10 (IL-10) and MCP-1-but not IL-6-are associated with viral load in serum, whereas higher levels of IL-6 in serum were associated with the development of critical disease. In conclusion, RNAemia is common in hospitalized patients, with the highest frequency and duration in patients who develop critical disease. The fact that several cytokines or chemokines are directly associated with the presence of viral RNA in the circulation suggests that the development of RNAemia is an important factor in the systemic pathogenesis of COVID-19. IMPORTANCE Severe COVID-19 can be considered a systemic disease as many extrarespiratory complications occur. However, the systemic pathogenesis is poorly understood. Here, we show that the presence of viral RNA in the blood (RNAemia) occurs more frequently in patients who develop critical disease, compared to patients with moderate or severe disease. In addition, RNAemia is associated with increased levels of inflammatory cytokines and chemokines, like MCP-1 and IL-10, in serum during the course of disease. This suggests that extrarespiratory spread of SARS-CoV-2 contributes to systemic inflammatory responses, which are an important factor in the systemic pathogenesis of COVID-19.",

author = "{van Riel}, Debby and Embregts, {Carmen W.E.} and Sips, {GJ (George)} and {van den Akker}, {Johannes P.C.} and Henrik Endeman and {van Nood}, Els and Mathijs Raadsen and Lisa Bauer and {van Kampen}, Jeroen and Richard Molenkamp and Marion Koopmans and {van de Vijver}, David and GeurtsvanKessel, {Corine H.}",

note = "Funding Information: Debby van Riel is supported by the Netherlands Organization for Scientific Research (VIDI 91718308) and a EUR fellowship. In addition, this work was supported by funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 101003589 (RECoVER). We declare no competing interests. Publisher Copyright: Copyright {\textcopyright} 2021 van Riel et al.",

year = "2021",

month = may,

doi = "10.1128/mSphere.00311-21",

language = "English",

volume = "6",

journal = "mSphere",

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AU - van Riel, Debby

AU - Embregts, Carmen W.E.

AU - Sips, GJ (George)

AU - van den Akker, Johannes P.C.

AU - Endeman, Henrik

AU - van Nood, Els

AU - Raadsen, Mathijs

AU - Bauer, Lisa

AU - van Kampen, Jeroen

AU - Molenkamp, Richard

AU - Koopmans, Marion

AU - van de Vijver, David

AU - GeurtsvanKessel, Corine H.

N1 - Funding Information: Debby van Riel is supported by the Netherlands Organization for Scientific Research (VIDI 91718308) and a EUR fellowship. In addition, this work was supported by funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 101003589 (RECoVER). We declare no competing interests. Publisher Copyright: Copyright © 2021 van Riel et al.

PY - 2021/5

Y1 - 2021/5

N2 - COVID-19 is associated with a wide range of extrarespiratory complications, of which the pathogenesis is currently not fully understood. However, both systemic spread and systemic inflammatory responses are thought to contribute to the systemic pathogenesis. In this study, we determined the temporal kinetics of viral RNA in serum (RNAemia) and the associated inflammatory cytokines and chemokines during the course of COVID-19 in hospitalized patients. We show that RNAemia can be detected in 90% of the patients who develop critical disease, compared to 50% of the patients who develop moderate or severe disease. Furthermore, RNAemia lasts longer in patients who develop critical disease. Elevated levels of interleukin-10 (IL-10) and MCP-1-but not IL-6-are associated with viral load in serum, whereas higher levels of IL-6 in serum were associated with the development of critical disease. In conclusion, RNAemia is common in hospitalized patients, with the highest frequency and duration in patients who develop critical disease. The fact that several cytokines or chemokines are directly associated with the presence of viral RNA in the circulation suggests that the development of RNAemia is an important factor in the systemic pathogenesis of COVID-19. IMPORTANCE Severe COVID-19 can be considered a systemic disease as many extrarespiratory complications occur. However, the systemic pathogenesis is poorly understood. Here, we show that the presence of viral RNA in the blood (RNAemia) occurs more frequently in patients who develop critical disease, compared to patients with moderate or severe disease. In addition, RNAemia is associated with increased levels of inflammatory cytokines and chemokines, like MCP-1 and IL-10, in serum during the course of disease. This suggests that extrarespiratory spread of SARS-CoV-2 contributes to systemic inflammatory responses, which are an important factor in the systemic pathogenesis of COVID-19.

AB - COVID-19 is associated with a wide range of extrarespiratory complications, of which the pathogenesis is currently not fully understood. However, both systemic spread and systemic inflammatory responses are thought to contribute to the systemic pathogenesis. In this study, we determined the temporal kinetics of viral RNA in serum (RNAemia) and the associated inflammatory cytokines and chemokines during the course of COVID-19 in hospitalized patients. We show that RNAemia can be detected in 90% of the patients who develop critical disease, compared to 50% of the patients who develop moderate or severe disease. Furthermore, RNAemia lasts longer in patients who develop critical disease. Elevated levels of interleukin-10 (IL-10) and MCP-1-but not IL-6-are associated with viral load in serum, whereas higher levels of IL-6 in serum were associated with the development of critical disease. In conclusion, RNAemia is common in hospitalized patients, with the highest frequency and duration in patients who develop critical disease. The fact that several cytokines or chemokines are directly associated with the presence of viral RNA in the circulation suggests that the development of RNAemia is an important factor in the systemic pathogenesis of COVID-19. IMPORTANCE Severe COVID-19 can be considered a systemic disease as many extrarespiratory complications occur. However, the systemic pathogenesis is poorly understood. Here, we show that the presence of viral RNA in the blood (RNAemia) occurs more frequently in patients who develop critical disease, compared to patients with moderate or severe disease. In addition, RNAemia is associated with increased levels of inflammatory cytokines and chemokines, like MCP-1 and IL-10, in serum during the course of disease. This suggests that extrarespiratory spread of SARS-CoV-2 contributes to systemic inflammatory responses, which are an important factor in the systemic pathogenesis of COVID-19.

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Temporal Kinetics of RNAemia and Associated Systemic Cytokines in Hospitalized COVID-19 Patients

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