Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.


Journal

The Lancet. Microbe
ISSN: 2666-5247
Titre abrégé: Lancet Microbe
Pays: England
ID NLM: 101769019

Informations de publication

Date de publication:
27 May 2024
Historique:
received: 24 08 2023
revised: 08 01 2024
accepted: 11 01 2024
medline: 31 5 2024
pubmed: 31 5 2024
entrez: 30 5 2024
Statut: aheadofprint

Résumé

Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. US National Institutes of Health.

Sections du résumé

BACKGROUND BACKGROUND
Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes.
METHODS METHODS
In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery.
FINDINGS RESULTS
The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors.
INTERPRETATION CONCLUSIONS
Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment.
FUNDING BACKGROUND
US National Institutes of Health.

Identifiants

pubmed: 38815595
pii: S2666-5247(24)00015-6
doi: 10.1016/S2666-5247(24)00015-6
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Investigateurs

David Sahner (D)
John Tierney (J)
Susan E Vogel (SE)
Betsey R Herpin (BR)
Mary C Smolskis (MC)
Laura A McKay (LA)
Kelly Cahill (K)
Page Crew (P)
Ratna Sardana (R)
Sharon Segal Raim (SS)
Lisa Hensely (L)
Johsua Lorenzo (J)
Rebecca Mock (R)
Judith Zuckerman (J)
Negin Atri (N)
Mark Miller (M)
David Vallee (D)
Lucy Chung (L)
Nayon Kang (N)
Kevin Barrett (K)
Stacey J Adam (SJ)
Sarah Read (S)
Ruxandra Draghia-Akli (R)
Judy Currier (J)
Eric Hughes (E)
Rachel H Harrigan (RH)
Laura Amos (L)
Amy Carlsen (A)
Anita Carter (A)
Gary Collins (G)
Bionca Davis (B)
Eileen Denning (E)
Alain DuChene (A)
Kate Eckroth (K)
Nicole Engen (N)
Alex Frase (A)
Greg Gandits (G)
Birgit Grund (B)
Merrie Harrison (M)
Nancy Hurlbut (N)
Payton Kaiser (P)
Joseph Koopmeiners (J)
Gregg Larson (G)
Sue Meger (S)
Shweta Sharma Mistry (SS)
Thomas Murray (T)
Ray Nelson (R)
Kien Quan (K)
Siu Fun Quan (SF)
Cavan Reilly (C)
Lianne Siegel (L)
Greg Thompson (G)
David Vock (D)
Jamie Walski (J)
Annetine C Gelijns (AC)
Alan J Moskowitz (AJ)
Emilia Bagiella (E)
Ellen Moquete (E)
Karen O'Sullivan (K)
Mary E Marks (ME)
Evan Accardi (E)
Emily Kinzel (E)
Sarah Burris (S)
Gabriela Bedoya (G)
Lola Gupta (L)
Jessica R Overbey (JR)
Milerva Santos (M)
Marc A Gillinov (MA)
Marissa A Miller (MA)
Wendy C Taddei-Peters (WC)
Kathleen Fenton (K)
Uriel Sandkovsky (U)
Robert L Gottlieb (RL)
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Clara Salgado (C)
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Fleur Hudson (F)
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Anna L Goodman (AL)
None Dphil
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S Bhagani (S)
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Cissy Kityo (C)
Henry Mugerwa (H)
Francis Kiweewa (F)
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Henry Mugerwa (H)
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Aniongo Fred (A)
Alice Alupo (A)
Doryn Ebong (D)
Edson Monday (E)
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Milton Kainja (M)
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Jeniffer Alaba (J)
Geoffrey Magombe (G)
Harriet Tino (H)
Emmanuel Obonya (E)
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Martin Onyango (M)
Tukamwesiga Naboth (T)
Hadijah Naluyinda (H)
Regina Nanyunja (R)
Muttiibwa Irene (M)
Biira Jane (B)
Kyobejja Wimfred (K)
Ssemazzi Leonard (S)
Tkiinomuhisha Deus (T)
Namasaba Babra (N)
Paul Taire (P)
Joseph Lutaakome (J)
Evelyn Nabankema (E)
Joseph Ogavu (J)
Oscar Mugerwa (O)
Ivan Okoth (I)
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Anthony Makhoba (A)
Phiona Arikiriza (P)
Nabuuma Theresa (N)
Hope Nakayima (H)
Kisuule Frank (K)
Patrícia Ramgi (P)
Kássia Pereira (K)
Anu Osinusi (A)
Huyen Cao (H)
Paul Klekotka (P)
Karen Price (K)
Ajay Nirula (A)
Suzette Osei (S)
Craig Tipple (C)
Angela Wills (A)
Amanda Peppercorn (A)
Helen Watson (H)
Rajesh Gupta (R)
Elizabeth Alexander (E)
Erik Mogalian (E)
Leo Lin (L)
Xiao Ding (X)
David Margolis (D)
Li Yan (L)
Jean-Luc Girardet (JL)
Ji Ma (J)
Zhi Hong (Z)
Quing Zhu (Q)
Seth Seegobin (S)
Michael Gibbs (M)
Mickel Latchman (M)
Katarzyna Hasior (K)
Jerome Bouquet (J)
Jianxin Wei (J)
Katie Streicher (K)
Albert Schmelzer (A)
Dennis Brooks (D)
Jonny Butcher (J)
Dimitar Tonev (D)
Douglas Arbetter (D)
Philippe Damstetter (P)
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Michael Stumpp (M)
Susana Goncalves (S)
Krishnan Ramanathan (K)
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Beth Baseler (B)
Marc Teitelbaum (M)
Adam Schechner (A)
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Shirley Jankelevich (S)
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Nancy Becker (N)
Suzanne Dolney (S)
Debbie Hissey (D)
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Mi Ha Kim (MH)
Joy Beeler (J)
Liam Harmon (L)
Mabel Asomah (M)
Yvonne Jato (Y)
April Stottlemyer (A)
Olivia Tang (O)
Sharon Vanderpuye (S)
Lindsey Yeon (L)
Molly Buehn (M)
Vanessa Eccard-Koons (V)
Sadie Frary (S)
Leah MacDonald (L)
Jennifer Cash (J)
Lisa Hoopengardner (L)
Jessica Linton (J)
Marylu Schaffhauser (M)
Michaela Nelson (M)
Mary Spinelli-Nadzam (M)
Calvin Proffitt (C)
Christopher Lee (C)
Theresa Engel (T)
Laura Fontaine (L)
C K Osborne (CK)
Matt Hohn (M)
Michael Galcik (M)
DeeDee Thompson (D)
Stacey Kopka (S)
Denise M Shelley (DM)
Gregg Mendez (G)
Shawn Brown (S)
Sara Albert (S)
Abby Balde (A)
Michelle Baracz (M)
Mona Bielica (M)
Shere Billouin-Frazier (S)
Jay Choudary (J)
Mary Dixon (M)
Carolyn Eyler (C)
Leanne Frye (L)
Jensen Gertz (J)
Lisa Giebeig (L)
Neelam Gulati (N)
Liz Hankinson (L)
Debi Hogarty (D)
Lynda Huber (L)
Gary Krauss (G)
Eileen Lake (E)
Meryan Manandhar (M)
Erin Rudzinski (E)
Jen Sandrus (J)
Connie Suders (C)
Ven Natarajan (V)
Adam W Rupert (AW)
Michael Baseler (M)
Danielle Lynam (D)
Tom Imamichi (T)
Sylvain Laverdure (S)
Ashley McCormack (A)
Sharada Paudel (S)
Kyndal Cook (K)
Kendra Haupt (K)
Ayub Khan (A)
Allison Hazen (A)
Yunden Badralmaa (Y)
Kenneth Smith (K)
Bhakti Patel (B)
Amanda Kubernac (A)
Robert Kubernac (R)
Marie L Hoover (ML)
Courtney Solomon (C)
Marium Rashid (M)
Joseph Murphy (J)
Craig Brown (C)
Nadine DuChateau (N)
Sadie Ellis (S)
Adam Flosi (A)
Lisa Fox (L)
Les Johnson (L)
Rich Nelson (R)
Jelena Stojanovic (J)
Amy Treagus (A)
Christine Wenner (C)
Richard Williams (R)

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests ALG reports receiving institutional funding from Novavax, institutional partnership with AstraZeneca, and being personally named as inventor on a patent used by AstraZeneca. DDM reports receiving grants from the Danish National Research Foundation. DL reports participation in a study funded by Gilead with no salary support. EM reports payments to his institution received from SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs and KODA Therapeutics, and Cidara, and payment for participating in an advisory board for Basilea. KW reports honorarium for Acute Respiratory Distress Syndrome (ARDS) International Conference in 2023, and travel support from University of California San Francisco. MAM reports institutional funding by the US Department of Defence, Roche-Genetech, and Quantum Health, and personal consulting fees from Gilead, Novartis, and Johnson & Johnson. MKJ reports grants received from Regeneron, Laurent, and Gilead, honoraria from Gilead, and a leadership role with the HIV Medicine Association Board of Directors. PC reports consulting fees from Eli Lilly and Regeneron. All other authors declare no competing interests. All authors were not precluded from accessing data in the study.

Auteurs

Tomas O Jensen (TO)

Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: tomas.jensen@regionh.dk.

Thomas A Murray (TA)

Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.

Greg A Grandits (GA)

Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA.

Mamta K Jain (MK)

UT Southwestern Medical Center, Dallas, TX, USA.

Birgit Grund (B)

School of Statistics, University of Minnesota, Minneapolis, MN, USA.

Kathryn Shaw-Saliba (K)

National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

Michael A Matthay (MA)

Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.

Mahsa Abassi (M)

Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA.

Magdalena Ardelt (M)

Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA, USA.

Jason V Baker (JV)

Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA; Division of Infectious Diseases, Hennepin Healthcare, Minneapolis, MN, USA.

Peter Chen (P)

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Robin L Dewar (RL)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Anna L Goodman (AL)

The Medical Research Council Clinical Trials Unit, University College London, London, UK; Department of Infectious Diseases, Guy's and St Thomas' National Health Service Foundation Trust, London, UK.

Timothy J Hatlen (TJ)

Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.

Helene C Highbarger (HC)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Mark Holodniy (M)

VA Palo Alto Health Care System, Palo Alto, CA, USA; Department of Medicine, Infectious Diseases, Stanford University, Stanford, CA, USA.

Perrine Lallemand (P)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Sylvain Laverdure (S)

Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Bradley G Leshnower (BG)

Emory School of Medicine, Atlanta, GA, USA.

David Looney (D)

VA San Diego Healthcare Center, San Diego, CA, USA; Division of Infectious Diseases and Global Public Health, University of California San Diego, San Diego, CA, USA.

Charalampos D Moschopoulos (CD)

National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Henry Mugerwa (H)

Joint Clinical Research Centre, Kampala, Uganda.

Daniel D Murray (DD)

Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Eleftherios Mylonakis (E)

Department of Medicine, Houston Methodist Hospital, Houston, TX, USA; Infectious Diseases Division, Brown University, Providence, RI, USA.

Stephanie Nagy-Agren (S)

Salem Veterans Affairs Medical Center, Salem, VA, USA; Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA.

M Tauseef Rehman (MT)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Adam Rupert (A)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Randy Stevens (R)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Stuart Turville (S)

The Kirby Institute, Sydney, Australia.

Amy Weintrob (A)

Washington DC Veterans Affairs Medical Center, Washington, DC, USA.

Katherine Wick (K)

Department of Internal Medicine, University of California Davis, Davis, CA, USA.

Jens Lundgren (J)

Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Emily R Ko (ER)

Division of General Internal Medicine, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Classifications MeSH