Immunologic resilience and COVID-19 survival advantage

Lee, G. C.; Restrepo, M. I.; Harper, N.; Manoharan, M. S.; Smith, A. M.; Meunier, J. A.; Sanchez-Reilly, S.; Ehsan, A.; Branum, A. P.; Winter, C.; Winter, L.; Jimenez, F.; Pandranki, L.; Carrillo, A.; Perez, G. L.; Anzueto, A.; Trinh, H.; Lee, M.; Hecht, J. M.; Martinez-Vargas, C.; Sehgal, R. T.; Cadena, J.; Walter, E. A.; Oakman, K.; Benavides, R.; Pugh, J. A.; Abdalla, M. I.; Adams, S. G.; Agnew, J.; Ali, S.; Barker, J.; Birdwell, A.; Bradford, S.; Briggs, H.; Marin Corral, J.; Dacus, J. J.; Danaher, P. J.; Depaul, S. A.; Dickerson, J.; Doanne, J.; Elbel, S.; Escamilla, C.; Farrar, R.; Feldman, D.; Flynn, J.; Ford, D.; Foy, J. D.; Freeman, M.; Galley, S.; Garza, M.; Gilman, S.; Gomez, J.; Goyal, V. K.; Grassmuck, S.; Hanson, J.; Harris, B.; Hastings, G.; Haywood, A.; Hinojosa, C.; T. T., Ho; Hopkins, T.; Jewell, P.; Johnson, T. B.; Kotogiannes, V.; Lawler, A. C.; Lester, C. S.; Levine, S. M.; Lewis, H. V.; Louder, A.; Mainor, C.; Maldonado, R.; Martinez, Y.; Mcelligott, N.; Medlin, L.; Mireles, M.; Morneau, K.; Munro, S. B.; Nambiar, A.; Nassery, D.; Nathanson, R.; O'Rorke, J.; Padgett, C.; Pascual-Guardia, S.; Patterson, M.; Perez, R.; Phillips, R. E.; Polk, P. B.; Pomager, M. A.; Preston, K. J.; Proud, K. C.; Rangel, M.; Ratcliffe, T. A.; Reichelderfer, R. L.; Renz, E. M.; Ross, J.; Rudd, T.; Sanchez, M. E.; Sanders, T.; Schindler, K. C.; Schmit, D.; Solorzano, C.; Soni, N.; Tam, W. S.; Tovar, E. J.; Tyler, A. R.; Vasquez, A.; Veloso, M. C.; Venticinque, S. G.; Villalpando, J. A.; Villanueva, M.; Villegas, L.; Wallace, A.; Wang, E.; Williamson, A.; Trammell Velasquez, S. A.; Yunes, A.; Zentner, K. H.; Letendre, S.; Steri, M.; Orru, V.; Fiorillo, E.; Cucca, F.; Moreira, A. G.; Zhang, N.; Leadbetter, E.; Agan, B. K.; Richman, D. D.; He, W.; Clark, R. A.; Okulicz, J. F.; Ahuja, S. K.

doi:10.1016/j.jaci.2021.08.021

Background: 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). Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Immunologic resilience and COVID-19 survival advantage / Lee, G. C.; Restrepo, M. I.; Harper, N.; Manoharan, M. S.; Smith, A. M.; Meunier, J. A.; Sanchez-Reilly, S.; Ehsan, A.; Branum, A. P.; Winter, C.; Winter, L.; Jimenez, F.; Pandranki, L.; Carrillo, A.; Perez, G. L.; Anzueto, A.; Trinh, H.; Lee, M.; Hecht, J. M.; Martinez-Vargas, C.; Sehgal, R. T.; Cadena, J.; Walter, E. A.; Oakman, K.; Benavides, R.; Pugh, J. A.; Abdalla, M. I.; Adams, S. G.; Agnew, J.; Ali, S.; Barker, J.; Birdwell, A.; Bradford, S.; Briggs, H.; Marin Corral, J.; Dacus, J. J.; Danaher, P. J.; Depaul, S. A.; Dickerson, J.; Doanne, J.; Elbel, S.; Escamilla, C.; Farrar, R.; Feldman, D.; Flynn, J.; Ford, D.; Foy, J. D.; Freeman, M.; Galley, S.; Garza, M.; Gilman, S.; Gomez, J.; Goyal, V. K.; Grassmuck, S.; Hanson, J.; Harris, B.; Hastings, G.; Haywood, A.; Hinojosa, C.; Ho, T. T.; Hopkins, T.; Jewell, P.; Johnson, T. B.; Kotogiannes, V.; Lawler, A. C.; Lester, C. S.; Levine, S. M.; Lewis, H. V.; Louder, A.; Mainor, C.; Maldonado, R.; Martinez, Y.; Mcelligott, N.; Medlin, L.; Mireles, M.; Morneau, K.; Munro, S. B.; Nambiar, A.; Nassery, D.; Nathanson, R.; O'Rorke, J.; Padgett, C.; Pascual-Guardia, S.; Patterson, M.; Perez, R.; Phillips, R. E.; Polk, P. B.; Pomager, M. A.; Preston, K. J.; Proud, K. C.; Rangel, M.; Ratcliffe, T. A.; Reichelderfer, R. L.; Renz, E. M.; Ross, J.; Rudd, T.; Sanchez, M. E.; Sanders, T.; Schindler, K. C.; Schmit, D.; Solorzano, C.; Soni, N.; Tam, W. S.; Tovar, E. J.; Tyler, A. R.; Vasquez, A.; Veloso, M. C.; Venticinque, S. G.; Villalpando, J. A.; Villanueva, M.; Villegas, L.; Wallace, A.; Wang, E.; Williamson, A.; Trammell Velasquez, S. A.; Yunes, A.; Zentner, K. H.; Letendre, S.; Steri, M.; Orru, V.; Fiorillo, E.; Cucca, F.; Moreira, A. G.; Zhang, N.; Leadbetter, E.; Agan, B. K.; Richman, D. D.; He, W.; Clark, R. A.; Okulicz, J. F.; Ahuja, S. K.. - In: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. - ISSN 0091-6749. - 148:5(2021), pp. 1176-1191. [10.1016/j.jaci.2021.08.021]