Chronic Obstructive Pulmonary Disease Patients Have Increased Levels of Plasma Inflammatory Mediators Reported Upregulated in Severe COVID-19

  1. Nathalie Acevedo
  2. Jose Miguel Escamilla-Gil
  3. Héctor Espinoza
  4. Ronald Regino
  5. Jonathan Ramírez
  6. Lucila Florez de Arco
  7. Rodolfo Dennis
  8. Carlos A. Torres-Duque
  9. Luis Caraballo

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Abstract

Chronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.

Methods

Ninety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the “COVID-19 Drug and Gene Set Library” and with experimentally tested protein biomarkers of severe COVID-19.

Results

Forty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19.

Conclusions

COPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.

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  1. Version published to 10.3389/fimmu.2021.678661
  2. Version published to 10.1101/2021.01.23.21250370v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.01.23.21250370: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the ethical committees of the University of Cartagena (nr. 4169722017) and the “Fundación Neumológica Colombiana” (nr. 232-07122017) and written informed consent was obtained from all participants.
    Consent: Inclusion criteria were no exacerbation in the last eight weeks, age 40 or more, with a clinical diagnosis of asthma or COPD confirmed by a pneumologist and signed informed consent.
    RandomizationQuantification of plasma proteins: For plasma profiling the samples were randomly distributed in 96-well plates and protein levels were measured by the Proximity Extension Assay (PEA) [18] using the Target 96 Inflammation Panel (
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    IgE antibodies were measured by ImmunoCAP following manufacturer instructions (Thermo Fisher, Uppsala, Sweden)
    IgE
    suggested: None
    Software and Algorithms
    SentencesResources
    (https://www.r-project.org/).
    https://www.r-project.org/
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)
    Functional annotation: The list of proteins with differences between patients and healthy controls were analysed for pathways, ontologies, diseases/drugs in the Enrichr web tool (https://maayanlab.cloud/Enrichr/) [31].
    Enrichr
    suggested: (Enrichr, RRID:SCR_001575)
    The induced network analysis was constructed in Consensus PathDB (http://cpdb.molgen.mpg.de/) using an intermediate nodes z-score threshold of 30 and including binary protein-protein interactions of high confidence and biochemical reactions [33].
    http://cpdb.molgen.mpg.de/
    suggested: (ConsensusPathDB, RRID:SCR_002231)
    The search engine Geneshot (https://amp.pharm.mssm.edu/geneshot/) was used to systematically retrieve known markers associated with SARS infection and to calculate the probability of detecting overlap due to chance with the protein list resulting from this study.
    Geneshot
    suggested: (Geneshot, RRID:SCR_017582)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2021.01.23.21250370v1 on medRxiv