Serum Proteomics in COVID-19 Patients: Altered Coagulation and Complement Status as a Function of IL‑6 Level

  1. Angelo D’Alessandro
  2. Tiffany Thomas
  3. Monika Dzieciatkowska
  4. Ryan C. Hill
  5. Richard O. Francis
  6. Krystalyn E. Hudson
  7. James C. Zimring
  8. Eldad A. Hod
  9. Steven L. Spitalnik
  10. Kirk C. Hansen

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Abstract

Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.

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    SciScore for 10.1101/2020.05.29.20116889: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Blood collection and processing: This observational study was conducted according to the Declaration of Helsinki, in accordance with good clinical practice guidelines, and approved by the Columbia University Institutional Review Board.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Pathway analyses were performed with the DAVID software and Ingenuity Pathway Analysis.
    DAVID
    suggested: (DAVID, RRID:SCR_001881)
    Ingenuity Pathway Analysis
    suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)
    Graphs and statistical analyses were prepared with GraphPad Prism 8.0 (GraphPad Software, Inc, La Jolla, CA), GENE E (Broad Institute, Cambridge, MA, USA), and MetaboAnalyst 4.0.28
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    MetaboAnalyst
    suggested: (MetaboAnalyst, RRID:SCR_015539)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Nonetheless, there are several limitations that affect the interpretation of the results of the present study. First, the analyses presented herein were performed on residual samples obtained for routine clinical laboratory testing. Serum samples were tested here, which clearly impacts any conclusion related to coagulation cascades. In this view, it is worthwhile to note that any conclusion on coagulation phenotype here drawn based on the measurement of protein levels, not direct determination of enzymatic activity. Although these samples were refrigerated and stored for < 24 hours before initial preparation for analysis, future studies on freshly collected samples will determine whether bias was introduced by these sample collection procedures. In addition, the COVID-19 patients studied herein were mostly male (75%) and older (median age 56), as compared to the controls (62% female, median age 33). Although these sex and age-related biases are consistent with what is observed in clinical cohorts, especially with respect to the most severely ill patients, the relatively limited number of younger, female COVID-19 patients studied here prevented any post-hoc analysis based on age and sex as biological variables; nonetheless, samples are now being prospectively collected to perform these additional studies in newly enrolled cohorts. Moreover, all the COVID-19 patients in this study were inpatients and, as such, they were significantly ill. Future studies will investigate whether...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04292899CompletedStudy to Evaluate the Safety and Antiviral Activity of Remde…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1021/acs.jproteome.0c00365
  3. Version published to 10.1101/2020.05.29.20116889 on medRxiv