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Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients

Martin-Vicente et al., medRxiv, doi:10.1101/2021.03.08.21253121

Mar 2021

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Retrospective 92 ICU patients with almost all treated with HCQ and only one non-HCQ treated patient that died, showing unadjusted non-statistically significant lower mortality with treatment.

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risk of death, 59.3% lower, RR 0.41, p = 0.41, treatment 37 of 91 (40.7%), control 1 of 1 (100.0%), NNT 1.7.

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Martin-Vicente et al., 8 Mar 2021, retrospective, Spain, preprint, 38 authors.

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Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients

María Martin-Vicente, Raquel Almansa, Isidoro Martínez, Ana P Tedim, Elena Bustamante, Luis Tamayo, César Aldecoa, José Manuel Gómez, Gloria Renedo, Jose Ángel Berezo, Jamil Antonio Cedeño, Nuria Mamolar, Pablo García Olivares, Rubén Herrán, Ramón Cicuendez, Pedro Enríquez, Alicia Ortega, Noelia Jorge, Amanda De La Fuente, Juan Bustamante-Munguira, María José Muñoz-Gómez, Milagros González-Rivera, Carolina Puertas, Vicente Más, Mónica Vázquez, Felipe Pérez-García, Jesús Rico-Feijoo, Silvia Martín, Anna Motos, Laia Fernandez-Barat, Jose María Eiros, Marta Dominguez-Gil, Ricard Ferrer, Ferrán Barbé, David J Kelvin, Jesús F Bermejo-Martin, Salvador Resino, Antoni Torres

doi:10.1101/2021.03.08.21253121

Purpose: to evaluate the association between anti-SARS-CoV-2 S IgM and IgG antibodies with viral RNA load in plasma, the frequency of antigenemia and with the risk of mortality in critically ill patients with COVID-19. Methods: anti-SARS-CoV-2 S antibodies levels, viral RNA load and antigenemia were profiled in plasma of 92 adult patients in the first 24 hours following ICU admission. The impact of these variables on 30-day mortality was assessed by using Kaplan-Meier curves and multivariate Cox regression analysis. Results: non survivors showed more frequently absence of anti-SARS-CoV-2 S IgG and IgM antibodies than survivors (26.3% vs 5.6% for IgM and 18.4% vs 5.6% for IgG), and a higher frequency of antigenemia ( 47 .4% vs 22.2%) (p <0.05). Non survivors showed lower concentrations of anti-S IgG and IgM and higher viral RNA loads in plasma, which were associated to increased 30-day mortality and decreased survival mean time. [Adjusted HR (CI95%), p]: [S IgM (AUC ≥60): 0.48 (0.24; 0.97), 0.040]; [S IgG (AUC ≥237): 0.47 (0.23; 0.97), 0.042]; [Antigenemia (+): 2.45 (1.27; 4.71), 0.007]; [N1 viral load (≥ 2.156 copies/mL): 2.21 (1.11; 4.39),0.024]; [N2 viral load (≥ 3.035 copies/mL): 2.32 (1.16; 4.63), 0.017]. Frequency of antigenemia was >2.5-fold higher in patients with absence of antibodies. Levels of anti-SARS-CoV-2 S antibodies correlated inversely with viral RNA load. Conclusion: absence / insufficient levels of anti-SARS-CoV-2 S antibodies following ICU admission is associated to poor viral control, evidenced by increased viral RNA loads in plasma, higher frequency of antigenemia, and also to increased 30-day mortality.

Funding: This work was supported by awards from the Canadian Institutes of Health Research, the Canadian 2019 Novel Coronavirus (COVID-19) Rapid Research Funding initiative (CIHR OV2 -170357) (DJK) and the "Subvenciones de concesión directa para proyectos y programas de investigación del virus SARS-CoV2, causante del COVID-19", FONDO -COVID19, Instituto de Salud Carlos III (COV20/00110, CIBERES, 06/06/0028), (AT) and finally by the "Convocatoria extraordinaria y urgente de la Gerencia Regional de Salud de Castilla y León, para la financiación de proyectos de investigación en enfermedad COVID-19" (GRS COVID 53/A/20) (CA). APT was funded by the Sara Borrell Research Grant CD018/0123 funded by Instituto de Salud Carlos III and co-financed by the European Development Regional Fund (A Way to Achieve Europe programme). The funding sources did not play any role neither in the design of the study and collection, not in the analysis, in the interpretation of data or in writing the manuscript. Consent to participate: Informed consent was obtained orally when clinically possible. In the remaining cases, the informed consent waiver was authorized by the Ethics committee. Consent for publication: not applicable Acknowledgements: we thank the IBSAL and CIBER administrative support to run this study.

References

Ali, Luxmi, Anjum, Hyperimmune anti-COVID-19 IVIG (C-IVIG) Therapy for Passive Immunization of Severe and Critically Ill COVID-19 Patients: A structured summary of a study protocol for a randomised controlled trial, Trials, doi:10.1186/s13063-020-04839-5

Asif, Frithiof, Lipcsey, Weak anti-SARS-CoV-2 antibody response is associated with mortality in a Swedish cohort of COVID-19 patients in critical care, Critical Care, doi:10.1186/s13054-020-03362-y

Bermejo-Martin, González-Rivera, Almansa, Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19, Crit Care, doi:10.1186/s13054-020-03398-0

Birra, Benucci, Landolfi, COVID 19: a clue from innate immunity, Immunol Res, doi:10.1007/s12026-020-09137-5

Deb, Mdma, Rahman, An update to monoclonal antibody as therapeutic option against COVID-19, Biosaf Health, doi:10.1016/j.bsheal.2021.02.001

Hagman, Hedenstierna, Gille-Johnson, SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study, Clin Infect Dis, doi:10.1093/cid/ciaa1285

Hashem, Algaissi, Almahboub, Early Humoral Response Correlates with Disease Severity and Outcomes in COVID-19 Patients, Viruses, doi:10.3390/v12121390

Hingrat, Visseaux, Laouenan, Detection of SARS-CoV-2 N-antigen in blood during acute COVID-19 provides a sensitive new marker and new testing alternatives, Clin Microbiol Infect, doi:10.1016/j.cmi.2020.11.025

Hsieh, Goldsmith, Schaub, Structure-based design of prefusionstabilized SARS-CoV-2 spikes, Science, doi:10.1126/science.abd0826

Li, Huang, Wu, Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19, Nat Commun, doi:10.1038/s41467-020-19943-y

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Ogata, Maley, Wu, Ultra-sensitive Serial Profiling of SARS-CoV-2 Antigens and Antibodies in Plasma to Understand Disease Progression in COVID-19 Patients with Severe Disease, Clin Chem, doi:10.1093/clinchem/hvaa213

Röltgen, Powell, Wirz, Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome, Sci Immunol, doi:10.1126/sciimmunol.abe0240

Salazar, Christensen, Graviss, Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG, Am J Pathol, doi:10.1016/j.ajpath.2020.10.008

Veyer, Kernéis, Poulet, Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value, Clin Infect Dis, doi:10.1093/cid/ciaa1196

Wrapp, Wang, Corbett, Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science, doi:10.1126/science.abb2507

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The impact of these variables on ' '30-day mortality was assessed by using Kaplan-Meier curves and multivariate Cox regression ' 'analysis.Resultsnon survivors ' 'showed more frequently absence of anti-SARS-CoV-2 S IgG and IgM antibodies than survivors ' '(26.3% vs 5.6% for IgM and 18.4% vs 5.6% for IgG), and a higher frequency of antigenemia ' '(47.4% vs 22.2%) (p <0.05). Non survivors showed lower ' 'concentrations of anti-S IgG and IgM and higher viral RNA loads in plasma, which were ' 'associated to increased 30-day mortality and decreased survival mean time. [Adjusted HR ' '(CI95%), p]: [S IgM (AUC ≥60): 0.48 (0.24; 0.97), 0.040]; [S IgG ' '(AUC ≥237): 0.47 (0.23; 0.97), 0.042]; [Antigenemia (+): 2.45 (1.27; 4.71), 0.007]; [N1 viral ' 'load (≥ 2.156 copies/mL): 2.21 (1.11; 4.39),0.024]; [N2 viral load (≥ 3.035 copies/mL): 2.32 ' '(1.16; 4.63), 0.017]. Frequency of antigenemia was >2.5-fold higher in patients with ' 'absence of antibodies. Levels of anti-SARS-CoV-2 S antibodies correlated inversely with viral ' 'RNA load.Conclusionabsence / ' 'insufficient levels of anti-SARS-CoV-2 S antibodies following ICU admission is associated to ' 'poor viral control, evidenced by increased viral RNA loads in plasma, higher frequency of ' 'antigenemia, and also to increased 30-day ' 'mortality.Take-home ' 'messageabsent or low levels of antibodies against the S protein of ' 'SARS-CoV- 2 at ICU admission is associated to an increased risk of mortality, higher ' 'frequency of antigenemia and higher viral RNA loads in plasma. 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