Immunologic resilience and COVID-19 survival advantage

The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immu...

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Published in:	Journal of allergy and clinical immunology Vol. 148; no. 5; pp. 1176 - 1191
Main Authors:	Restrepo, Marcos I., Manoharan, Muthu Saravanan, Sanchez-Reilly, Sandra, Ehsan, Aamir, Branum, Anne P., Winter, Caitlyn, Winter, Lauryn, Pandranki, Lavanya, Carrillo, Andrew, Perez, Graciela L., Anzueto, Antonio, Lee, Monica, Martinez-Vargas, Celida, Sehgal, Raj T., Walter, Elizabeth A., Oakman, Kimberly, Benavides, Raymond, Pugh, Jacqueline A., Abdalla, Mohamed I., Adams, Sandra G., Agnew, Joseph, Barker, Jennifer, Birdwell, Angela, Bradford, Stephen, Briggs, Heather, Marin Corral, Judith, Dacus, Jennifer J., Danaher, Patrick J., DePaul, Scott A., Dickerson, Jill, Elbel, Samantha, Escamilla, Corina, Farrar, Robert, Feldman, David, Flynn, Julianne, Ford, Delvina, Galley, Samantha, Garza, Maritza, Gilman, Sherraine, Gomez, Jennifer, Grassmuck, Sally, Hanson, Joshua, Hastings, Gabrielyd, Haywood, Audrey, Hinojosa, Cecilia, Ho, Tony T., Jewell, Pamela, Lester, Chadwick S., Levine, Stephanie M., Louder, Angel, Maldonado, Rachel, McElligott, Neil, Medlin, Laura, Mireles, Myra, Morneau, Kathleen, Nambiar, Anoop, Nathanson, Robert, Pascual-Guardia, Sergi, Patterson, Marisa, Perez, Rogelio, Phillips, Robert E., Polk, Patrick B., Pomager, Michael A., Preston, Kristy J., Rangel, Michelle, Reichelderfer, Renee L., Renz, Evan M., Ross, Jeanette, Rudd, Teresa, Sanchez, Maria E., Sanders, Tammy, Schindler, Kevin C., Schmit, David, Solorzano, Claudio, Soni, Nilam, Tam, Win S., Tovar, Edward J., Tyler, Anna R., Veloso, Maria C., Venticinque, Steven G., Villalpando, Jorge A., Villanueva, Melissa, Villegas, Lauren, Wallace, Andrew, Wang, Emily, Williamson, Andreia, Trammell Velasquez, Sadie A., Yunes, Andrea, Letendre, Scott, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Cucca, Francesco, Moreira, Alvaro G., Zhang, Nu, Agan, Brian K., He, Weijing, Clark, Robert A., Okulicz, Jason F., Ahuja, Sunil K.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2021 Mosby
Subjects:	Adult Aged Aging AIDS biomarkers Cohort Studies COVID-19 COVID-19 - epidemiology COVID-19 - immunology COVID-19 - mortality Disease Resistance Female HIV HIV Infections - epidemiology HIV-1 - physiology Humans immune Immunocompetence inflammation influenza Interleukin-6 - blood Longitudinal Studies Male Middle Aged Prospective Studies Respiratory Insufficiency - epidemiology SARS-CoV-2 SARS-CoV-2 - physiology Severity of Illness Index Sex Factors Survival Analysis T-Lymphocytes - immunology Transcriptome - immunology United States - epidemiology Viral Load United States influenza RR immune OR biomarkers AIDS IHG IR HR IQR CMV SLE N COVID-19 FHS SARS-CoV-2 HIV inflammation Aging IC IF GO-BP
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Summary:	The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non–COVID-19 cohorts (n = 13,461) provided the framework for linking pre–COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non–COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 For additional list of authors from the South Texas Veterans Health Care System COVID-19 Team, please see the Acknowledgment section at the end of the article. These authors contributed equally as first authors to this work. Contributed equally as second authors. South Texas Veterans Health Care System COVID-19 Team. Key cohort contributors.
ISSN:	0091-6749 1097-6825
DOI:	10.1016/j.jaci.2021.08.021