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[Preprint]. 2023 Feb 16:2023.02.13.23285855.

doi: 10.1101/2023.02.13.23285855.

Early Treatment, Inflammation and Post-COVID Conditions

Kelly A Gebo¹, Sonya L Heath², Yuriko Fukuta³, Xianming Zhu⁴, Sheriza Baksh⁵, Alison G Abraham⁶, Feben Habtehyimer¹, David Shade⁵, Jessica Ruff⁴, Malathi Ram⁷, Oliver Laeyendecker⁸, Reinaldo E Fernandez¹, Eshan U Patel⁵, Owen R Baker¹, Shmuel Shoham¹, Edward R Cachay⁹, Judith S Currier¹⁰, Jonathan M Gerber¹¹, Barry Meisenberg¹², Donald N Forthal¹³, Laura L Hammitt¹⁴, Moises A Huaman¹⁵, Adam Levine¹⁶, Giselle S Mosnaim¹⁷, Bela Patel¹⁸, James H Paxton¹⁹, Jay S Raval²⁰, Catherine G Sutcliffe¹⁴, Shweta Anjan²¹, Thomas Gniadek²², Seble Kassaye⁷, Janis E Blair²³, Karen Lane²⁴, Nichol A McBee²⁴, Amy L Gawad²⁴, Piyali Das²⁴, Sabra L Klein²⁵, Andrew Pekosz⁷, Arturo Casadevall⁷, Evan M Bloch⁴, Daniel Hanley²⁴, Aaron A R Tobian⁴, David J Sullivan⁷

Affiliations

¹ Department of Medicine, Division of Infectious Diseases, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
² Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL.
³ Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX.
⁴ Department of Pathology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁶ Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora CO.
⁷ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁸ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
⁹ Department of Medicine, Division of Infectious Diseases, University of California, San Diego, San Diego, CA.
¹⁰ Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA.
¹¹ Department of Medicine, Division of Hematology and Oncology, University of Massachusetts, Worchester, MA.
¹² Luminis Health, Annapolis, MD.
¹³ Department of Medicine, Division of Infectious Diseases, University of California, Irvine, Irvine, CA.
¹⁴ International Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
¹⁵ Department of Medicine, Division of Infectious Diseases University of Cincinnati, Cincinnati, OH.
¹⁶ Department of Emergency Medicine, Rhode Island Hospital Warren Alpert Medical School of Brown University, Providence, RI.
¹⁷ Division of Allergy and Immunology, Department of Medicine, Northshore University Health System, Evanston, IL.
¹⁸ Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Texas Health Science Center, Houston, TX.
¹⁹ Department of Emergency Medicine, Wayne State University, Detroit, MI.
²⁰ Department of Pathology, University of New Mexico, Albuquerque, NM.
²¹ Department of Medicine, Department of Medicine, Division of Infectious Diseases, University of Miami, Miller School of Medicine, Miami, FL.
²² Department of Pathology, Northshore University Health System, Evanston, IL.
²³ Department of Medicine, Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, AZ.
²⁴ Department of Neurology, Brain Injury Outcomes Division, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
²⁵ Division of Infectious Diseases, Medstar Georgetown University Hospital, Washington, D.C.

PMID: 36824860
PMCID: PMC9949202
DOI: 10.1101/2023.02.13.23285855

Early Treatment, Inflammation and Post-COVID Conditions

Kelly A Gebo et al. medRxiv. 2023.

[Preprint]. 2023 Feb 16:2023.02.13.23285855.

doi: 10.1101/2023.02.13.23285855.

Authors

Affiliations

¹ Department of Medicine, Division of Infectious Diseases, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
² Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL.
³ Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX.
⁴ Department of Pathology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁶ Department of Epidemiology, University of Colorado, Anschutz Medical Campus, Aurora CO.
⁷ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
⁸ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
⁹ Department of Medicine, Division of Infectious Diseases, University of California, San Diego, San Diego, CA.
¹⁰ Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA.
¹¹ Department of Medicine, Division of Hematology and Oncology, University of Massachusetts, Worchester, MA.
¹² Luminis Health, Annapolis, MD.
¹³ Department of Medicine, Division of Infectious Diseases, University of California, Irvine, Irvine, CA.
¹⁴ International Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
¹⁵ Department of Medicine, Division of Infectious Diseases University of Cincinnati, Cincinnati, OH.
¹⁶ Department of Emergency Medicine, Rhode Island Hospital Warren Alpert Medical School of Brown University, Providence, RI.
¹⁷ Division of Allergy and Immunology, Department of Medicine, Northshore University Health System, Evanston, IL.
¹⁸ Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Texas Health Science Center, Houston, TX.
¹⁹ Department of Emergency Medicine, Wayne State University, Detroit, MI.
²⁰ Department of Pathology, University of New Mexico, Albuquerque, NM.
²¹ Department of Medicine, Department of Medicine, Division of Infectious Diseases, University of Miami, Miller School of Medicine, Miami, FL.
²² Department of Pathology, Northshore University Health System, Evanston, IL.
²³ Department of Medicine, Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, AZ.
²⁴ Department of Neurology, Brain Injury Outcomes Division, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
²⁵ Division of Infectious Diseases, Medstar Georgetown University Hospital, Washington, D.C.

PMID: 36824860
PMCID: PMC9949202
DOI: 10.1101/2023.02.13.23285855

Abstract

Background: Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC.

Methods: Among 883 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of CCP vs. control plasma with available biospecimens and symptom data, the association between early COVID treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay (Mesoscale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between COVID treatment, cytokine levels and PCC were examined using multivariate logistic regression models.

Results: One-third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and loss of smell (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis including diabetes, body mass index, race, and vaccine status, female sex (adjusted odds ratio[AOR]=2.70[1.93-3.81]), older age (AOR=1.32[1.17-1.50]), and elevated baseline levels of IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC.There was a trend for decreased PCC in those with early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment.

Conclusion: Increased IL-6 levels were associated with the development of PCC and there was a trend for decreased PCC with early CCP treatment in this predominately unvaccinated population. Future treatment studies should evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Keywords: COVID-19; COVID-19 serotherapy; chemokines; cytokines; interleukin-6; post COVID conditions (PCC); post-acute sequelae of COVID (PASC).

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Conflict of interest statement

Conflicts of Interest: Kelly Gebo- Consults for the Aspen Institute, Teach for America, served as a non-paid member of scientific advisory board for Pfizer and writes COVID management guidelines for UpToDate which are out of scope of paper. Sonya L. Heath- Nothing to disclose Yuriko Fukuta- Nothing to disclose Xianming Zhu- Nothing to disclose Sheriza Baksh- Nothing to disclose Alison G. Abraham- Consultant for Implementation Group Inc, Hirslanden Klinik, Zurich CH, & ELSEVIER, Feben Habtehyimer- Nothing to disclose David Shade- Nothing to disclose Jessica Ruff- Nothing to disclose Malathi Ram- Nothing to disclose Oliver Laeyendecker- Nothing to disclose Reinaldo E. Fernandez- Nothing to disclose Eshan U. Patel- Nothing to disclose Owen R. Baker- Nothing to disclose Shmuel Shoham- Served on a CCP guideline panel Edward R. Cachay- has received unrestricted research grants from Gilead and Merck paid to the Regents of the University of California. He also participated in an advisory board to Theratechnologies for an unrelated topic. Judith S. Currier- Consulted for Merck and Company in 2021, currently not on any guidelines panel Jonathan M. Gerber- Nothing to disclose Thomas J. Gniadek- Currently employed by Fenwal, Inc., a Fresenius Kabi Company. Barry Meisenberg- Nothing to disclose Donald N. Forthal- nothing to disclose Laura L. Hammitt- research funding to my institution from AstraZeneca, CDC, Merck, NIH, and Pfizer. Moises A. Huaman- M.A.H. reports contracts from Gilead Sciences Inc, Insmed Inc, AN2 Therapeutics, Inc to the University of Cincinnati, outside the submitted work. Adam Levine- Nothing to disclose Giselle S. Mosnaim- Received research grant support from Teva, Alk-Abello, and Genentech and currently receives research grant support from Novartis, GlaxoSmithKline, and Sanofi-Regeneron. Serves as Immediate Past President of the American Academy of Allergy Asthma and Immunology and Co-Chair of the Continuous Assessment Program Examination for the American Board of Allergy and Immunology Bela Patel- Part of COVID trials and PAH trials, no disclosures relevant to CP James H. Paxton- Research funding from MindRhythm, Inc Jay S. Raval- Consultant and Advisor with Sanofi Genzyme; Board of Directors Member with the American Society for Apheresis, no overlap with CP Catherine G. Sutcliffe- Nothing to disclose Shweta Anjan- Nothing to disclose Seble Kassaye- Helped to produce educational materials related to HIV with Integritas Communications, LLC and Vindico Medical Education, LLC Janis E. Blair- Nothing to disclose Karen Lane- nothing to disclose Nichol A. McBee- Nothing to disclose Amy L. Gawad- Nothing to disclose Piyali Das- Nothing to disclose Sabra L. Klein- Nothing to disclose Andrew Pekosz- Nothing to disclose Arturo Casadevall- Serve on the scientific advisory board of SAB Therapeutics Evan M. Bloch- EMB reports personal fees and non-financial support from Terumo BCT, Abbott Laboratories, Tegus and UptoDate, outside of the submitted work. EMB is a member of the United States Food and Drug Administration (FDA) Blood Products Advisory Committee. Served on a CCP guideline panel Daniel Hanley- Dr. Hanley reports personal fees from Neurelis, Neurotrope, and medicolegal consulting. Aaron A.R. Tobian- Served on a CCP guideline panel David J. Sullivan- Founder and Board member with stock options (macrolide for malaria) DJS reports AliquantumRx, Hemex Health malaria diagnostics consulting and royalties for malaria diagnostic test control standards to Alere- all outside of submitted work

Figures

**Figure 2.. Trajectory of the cytokines during study period**
Abbreviation: PCC: Post COVID 19 condition. SCR: screening visit. D14: Day 14 visit. D90: day 90 visit. Note: Each dot represents a sample, and each line represents a person.

**Figure 3.. Comparison of cytokines at screening between study participants with PCC and without PCC**
Abbreviation: PCC: Post COVID-19 condition. Note: P values were determined by Wilcoxon rank sum test. *IL-6 were significantly different after adjusting multiple comparison using Benjamini-Hockberg correction with a false discovery rate of 0.05.

See this image and copyright information in PMC

References

1. Centers for Disease Control and Prevention. COVID Data Tracker. Available at: https://covid.cdc.gov/covid-data-tracker/#datatracker-home. Accessed 11 February 2023.
1. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Condition WHOCCDWGoP-C-. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022; 22(4): e102–e7. - PMC - PubMed
1. Centers for Disease Control and Prevention. Long COVID or Post-COVID Conditions. Available at: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects. Accessed 11 February 2023.
1. Centers for Disease Control and Prevention. Post-COVID Conditions: Overview for Healthcare Providers. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-c.... Accessed 11 February 2023.
1. Groff D, Sun A, Ssentongo AE, et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open 2021; 4(10): e2128568. - PMC - PubMed

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This is a preprint.

Early Treatment, Inflammation and Post-COVID Conditions

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Early Treatment, Inflammation and Post-COVID Conditions

Authors

Affiliations

Abstract

Conflict of interest statement

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