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Immunologic resilience and COVID-19 survival advantage

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 (IR)-dependent COVID-19 phenotypes (independent of age)
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 1 and CD4 1 T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n 5 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n 5 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 1 and CD4 1 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. (J Allergy Clin Immunol 2021;148:1176-91.) Key words: Aging, AIDS, biomarkers, COVID-19, HIV, immune, inflammation, influenza, SARS-CoV-2 Despite significant progress in the identification of host factors that influence coronavirus disease 2019 (COVID-19) outcomes, 1-7 the reasons why persons of similar ages vary in their susceptibility to developing progressive COVID-19, characterized by hospitalization, respiratory failure, and death, are unclear. We sought to identify persons with this susceptibility through the articulation of a parsimonious basis for 3 conundrums. First, although the risk of progressive COVID-19 increases with age, some older persons resist progression, manifesting asymptomatic or mild (ie, nonprogressive) COVID-19, 1,2 whereas some younger persons manifest progressive COVID-19. 3,4 Second, females appear to resist progressive COVID-19 more effectively than males. 5,6,8,9 This resistance aligns with evidence that females often manifest features of superior immunocompetence (IC) (resistance to some infections, longevity [10][11][12][13][14][15][16][17]. Third, clearance rates of nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vary, with delays contributing to progressive COVID-19. 18,19 We reasoned that a parsimonious basis for these conundrums is that, among persons of similar ages, progressive COVID-19 is ascribable to a deficit in a sexually dimorphic, immunityoptimizing attribute that antedates infection or is induced by SARS-CoV-2 infection. We termed this attribute as àSouth Texas Veterans Health Care System COVID- 19 Team. §Key cohort contributors. kContributed equally as second authors.  In this context, we hypothesized that individuals of similar ages may differ in their capacity to preserve IR before and during COVID-19, defining 3 major IR-dependent COVID-19 phenotypes (Table I). In SARS-CoV-2-negative persons, a deficit in IR is characterized by an immunosuppressive, proinflammatory state (IC low -IF high ) that is more common in males and predisposes to a shorter lifespan, as well as a progressive disease course during viral infections, such as influenza and HIV. If such persons acquire SARS-CoV-2 infection, the preexisting deficit in IR may increase susceptibility to development of progressive COVID-19 as well as amplify SARS-CoV-2-induced deficits in IR (phenotype 3; Table I). In contrast, resistance to developing deficits in IR before and during SARS-CoV-2 infection associates with nonprogressive COVID-19 (phenotype 1; Table I). Thus, persons with the IR-dependent  COVID-19 phenotype 3 may manifest 2 distinct IC low -IF high states:  one antedating infection and one induced by SARS-CoV-2. To test our hypothesis, we developed novel laboratory (lymphocyte equilibrium-based) and transcriptomic (gene expression-based) metrics of IR. We juxtaposed the distributions and associations of IR metrics in a prospective COVID-19 cohort with those in cohorts of SARS-CoV-2-negative persons. This juxtaposition provided empiric evidence in support of 3 IRdependent COVID-19 phenotypes (Table I). In addition, we evaluated the utility of IR metrics in the early prediction of all-cause 30-day COVID-19 mortality, the primary outcome of this study. We also examined secondary outcomes that track clinical indicators (eg, hospitalization and hospital length of stay) and biomarkers (eg, plasma IL-6 and nasopharyngeal SARS-CoV-2 levels) of progressive COVID-19.

Study design
Cohort details and analytical plan are available in this article's Online Repository at www.jacionline.org. A prospective observational cohort of 522 SARS-CoV-2-positive adults was evaluated at the South Texas Veterans Health Care System from March 20, 2020, to October 15, 2020 (cohort features in Fig   E1, A, and Table E1 in this article's Online Repository at www.jacionline.org  and Table II). Hospitalized and nonhospitalized patients were included, and a subset was studied through to the convalescence phase of the infection. The distribution patterns of IR metrics and their associations with outcomes in non-COVID-19 cohorts provided the framework for understanding the contributions of pre-COVID-19 IR status to COVID-19 outcomes. We evaluated previously well-characterized non-COVID-19 cohorts of persons exposed to 4 types of antigenic stimulation: (1) varied causes across lifespan (4 cohorts; total n 5 8201), including the community-based SardiNIA aging cohort (n 5 3896 20 ) and the Offspring cohort of the Framingham Heart Study (FHS; n 5 2306 21 ); (2) acute influenza infection (influenza virus challenge cohort of younger adults 22 and 2 adult cohorts of natural infection 23,24 ; total n 5 218); (3) self-antigen-associated antigenic stimulation in younger adults with systemic lupus erythematosus (SLE) 25

Procedures
Clinical and laboratory assessments (eg, scores of a clinical ordinal scale, 32 CD4 1 and CD8 1 T-cell counts, and plasma IL-6 levels) were recorded (see this article's Methods section in the Online Repository). These assessments were evaluated at baseline (presentation to the hospital or home visit) as well as prospectively (daily) during hospitalization and at least once in the convalescence phase. Cytomegalovirus (CMV) serostatus was evaluated at baseline. RNA from nasal cells collected from hospitalized patients was sequenced (RNA-Seq) to quantify SARS-CoV-2 levels as well as identify human genes whose expression levels were associated with SARS-CoV-2 levels and survival (see this article's Methods section in the Online Repository). RNA from peripheral blood cells was also sequenced.

Definitions and outcomes
Progressive COVID-19 was defined as progression along the continuum from hospitalization to need for any respiratory support and/or death. The primary outcome was all-cause 30-day COVID-19 mortality. Secondary outcomes included hospitalization, requirement of any respiratory support or mechanical ventilation; progression quantified by an increase in an 8-category clinical ordinal scale (see this article's Methods section in the Online Repository); hospital length of stay (recovery rate); all-cause 120-day mortality; plasma IL-6 levels (biomarker of IF and mortality [33][34][35][36][37]; and nasal SARS-CoV-2 clearance, defined as time to achievement of fewer than 10 counts of the viral nucleoprotein (N) gene. Clinical indicators of nonprogressive versus progressive COVID-19 disease course were nonhospitalized versus hospitalized patients, as well as survivors versus nonsurvivors within 120 days of presentation. Prespecified outcomes in the non-COVID-19 cohorts were allcause age-adjusted mortality over 9 years in the FHS, severity of influenza infection, and hazard of AIDS. A lower hazard of mortality in the COVID-19 cohort or the FHS was defined as a survival advantage.
RNA obtained from peripheral blood samples was sequenced and transcriptomic metrics of IR comprised gene expression signatures associated with mortality hazards during COVID-19 (Fig E1, B; see this article's Methods section in the Online Repository); bioinformatic approaches were similar to our previous studies. 52,53 Genes with significantly higher expression levels in study groups signifying nonprogressive COVID-19 were defined as beneficial, whereas genes with higher levels in study groups signifying progressive COVID-19 were defined as detrimental. Significantly enriched gene ontology biologic process (GO-BP) terms were derived on the basis of differentially expressed genes. Correspondingly, the GO-BP terms were defined as beneficial and detrimental traits. Gene scores were computed by averaging the z-score-normalized expression of all genes comprising the GO-BP term. Gene scores of the traits (GO-BP terms) that associated with 30-day mortality hazards during COVID-19 were examined for their associations with mortality in the FHS. Traits that associated with mortality in the COVID-19 cohort and FHS were examined for their associations with influenza infection severity.

Statistical analyses
On the basis of chi-square distribution, 522 patients provided 92% power to detect a moderate effect size (w 5 0.17) based on the incidence of death within 30 days of presentation with baseline IHG status at a significance level of .05. The statistical tests used for each panel in the figures are detailed in this article's Online Repository at www.jacionline.org. Kaplan-Meier survival curves were derived to illustrate cumulative events. Cox proportional hazards models were used to calculate hazard ratios (HRs) for mortality in the COVID-19 cohort and the FHS, and rate ratios (RRs) for recovery rates (hospital length of stay) as well as nasal SARS-CoV-2 clearance in the COVID-19 cohort. Multivariable logistic and linear regression models were used to compare secondary outcomes. RNA-sequencing analysis was performed using DESeq. 54 All P values are 2-sided and shown without adjustment for multiple testing unless specified. All analyses were performed using R, v3.5.0.

IHG distributions and associations in non-COVID-19 cohorts
Based on median CD8 1 and CD4 1 counts, the IHGs tracked distinct CD8-CD4 equilibrium/disequilibrium profiles: IHG-I tracked lower CD8-higher CD4, IHG-II tracked lowest CD8lower CD4, IHG-III tracked highest CD8-higher CD4, and IHG-IV tracked higher CD8-lowest CD4 (Fig E1, D). In a general population cohort (SardiNIA), across all age ranges, IHG-I was the most common grade and IHG-I was uniformly underrepresented in males (Fig 1, C and D). The overall prevalence of IHG-I in the SardiNIA cohort was 73%. IHG-I frequency declined progressively with age (84% and 46% in 18-24 and > _80 years age strata, respectively). Reciprocally, the prevalence of the other IHGs, especially IHG-II and IHG-IV, increased substantially with age (Fig 1, C, left). The IHG distribution patterns in younger women with SLE mirrored those of older persons (> _80 years) in the SardiNIA cohort. In therapy-naive HIV-seropositive adults, higher plasma HIV viral loads induced IHG-IV (Fig 1, C, right).
§Scores on the clinical ordinal scale are as follows: 1, not hospitalized, no limitations of activities; 2, not hospitalized, limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care; 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19-related or other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, receiving noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation; and 8, death.  The hierarchy of the hazard of developing AIDS according to the IHG at presentation was IHG-IV > IHG-III ; IHG-II > IHG-I, despite IHG-I and IHG-III marking higher CD4 1 counts and IHG-II and IHG-IV marking lower CD4 1 counts (Fig 1, E; Fig  E1, E). Initiation of antiretroviral therapy was associated with reconstitution of IHG-I (Fig 1, C, far-right). Thus, the juxtaposition of the IHG distributions from 3 non-COVID-19 cohorts suggested that IHG-I is the primordial IHG from which the other IHGs emerged in settings of increased antigenic stimulation (eg, SLE, HIV, and aging). Correspondingly, in HIV-seropositive persons, preservation of IHG-I was an indicator of superior IR (ie, resistance to AIDS progression). Our finding that mitigation of antigenic stimulation was associated with reconstitution of IHG-I (Fig 1, C, far-right) corroborated that degradation of IHG-I was related to increased antigenic stimulation rather than chronologic age per se. Instead, age may serve as an imperfect proxy for cumulative antigenic experience throughout life. This framework was used to examine whether (1) SARS-CoV-2 infection-associated antigenic stimulation induced similar shifts in IHG distributions across age ranges, and (2) mitigation of SARS-CoV-2 infection-associated antigenic stimulation was associated with reconstitution of IHGs to levels observed in age-matched persons in the SardiNIA cohort.
Akin to the SardiNIA cohort, IHG-I was overrepresented in females versus males in the COVID-19 cohort (35% vs 20%; P 5 .01 ; Fig 1, C). Conversely, a lower proportion of females versus males presented with IHG-II (48% vs 66%; P 5 .01 ; Fig 1, C). As in the SardiNIA cohort (Fig 1, C, left), IHG-I frequency declined and IHG-II and IHG-IV frequencies increased with age in the COVID-19 cohort (Fig 1, F, upper-left stacked bars). However, at both the overall cohort level and within comparable age ranges, IHG-I was underrepresented, whereas IHG-II and IHG-IV were overrepresented in the COVID-19 versus SardiNIA cohort (Fig 1, C; Fig 1, F, upper-left stacked bars). Overall cohortlevel differences in proportions were 21% versus 73% for IHG-I, 64% versus 22% for IHG-II, and 13% versus 3% for IHG-IV (P < .001 for COVID-19 vs SardiNIA intercohort differences). In addition, although hospitalization rates increased with age, within each age stratum, hospitalized patients were more likely to have IHG-II and IHG-IV at presentation (Fig 2, A). Conversely, nonhospitalized patients were more likely to have IHG-I (Fig 2,  A). IHG distributions were similar in younger and older patients who required respiratory support and/or died (Fig 1, C; Fig E1, F).
The underrepresentation of IHG-I versus overrepresentation of IHG-II and IHG-IV was attributable to SARS-CoV-2 infection because, during convalescence, younger and older COVID-19 survivors reconstituted IHG frequencies to levels found in their corresponding age groups in non-COVID-19 cohorts (SardiNIA cohort and health care workers; Fig 2, B, vs Fig 1, C; see Fig E2, A, in this article's Online Repository at www.jacionline.org). The IHG reconstitution patterns assigned patients to the IRdependent COVID-19 phenotypes (Table I). Phenotype 1 corresponded to preservation of superior IR (IHG-I) before and during early COVID-19. Phenotype 2 corresponded to presentation with a deficit in IR (IHG-II or IHG-IV) but reconstitution of IHG-I (reflecting a diathesis to degrade IHG-I during COVID-19). Phenotype 3 corresponded to presentation with and maintenance of IHG-II or IHG-IV during convalescence, suggesting that these grades may have antedated COVID-19.
The age-adjusted OR for hospitalization associated with IHG-II subgrades, and IHG-IVb/c versus IHG-I at baseline were comparable to or greater than the IHG-adjusted OR of hospitalization associated with older age (Fig 1, F; Fig E2, D). Although the probability of presenting with IHG-I declined with age ( Fig  E2, E), the modeled probability of hospitalization for a 30-year-  I   II   III   IV   IHG   I   II   III   IV   IHG Fig 1, B) in HIV-seronegative persons in the COVID-19 cohort categorized as hospitalized (H) and nonhospitalized (NH). D, Distribution of IHGs reconstituted during convalescence by baseline IHG status. E, The probability (with 95% confidence bands) of hospitalization according to age and baseline IHG. Overall IHG-IV was used in this model because all patients with IHG-IVc were hospitalized and numbers of patients in the other IHG-IV subgrades were small. P 5 .07. *P < .05. **P < .01. ***P < .001.   old patient presenting with IHG-IIc (80%; 95% CI, 48%-95%) was similar to that modeled for a 95-year-old patient with IHG-I (81%; 95% CI, 67%-90% ; Fig 2, E). Presentation with IHG-IV showed a similar increased probability of hospitalization but lower than that associated with IHG-IIc (Fig 2, E). The ageindependent prognostication of hospitalization by baseline IHG status was attributable to our finding that, unlike aggregated lymphocyte values by age, lymphocyte values by IHG status are range-bound across age (Fig 1, F). Hence, IHGs provide a uniform metric of IR across age.
The age-adjusted hazard of 30-day mortality was increased by a factor of 19.00 (95% CI, 2.47-146.28) with baseline IHG-IIc and 12.15 (95% CI, 1.33-111.15) with baseline IHG-IVc compared with baseline IHG-I (Fig 3, A;  Compared with baseline IHG-I, recovery rates were slowest with IHG-IVc (adjusted RR, 0.12; 95% CI, 0.04-0.30) followed by IHG-IIc (adjusted RR, 0.33; 95% CI, 0.20-0.55; Fig 3, B; Fig  E3, B). In addition, the likelihood of (1) hospitalization, (2) manifesting as an increase in the clinical ordinal scale, (3) need for any respiratory support, and (4) dying within 30 or 120 days of presentation, was lowest to highest in patients presenting with IHG-IVa followed by IHG-IVb, IHG-IIb, IHG-IVc, and IHG-IIc (see Fig  E3, C, and Fig E4, A-C, in this article's Online Repository at www.jacionline.org; Table E1, B and G). The strength of the associations between baseline IHG status and these outcomes was comparable to or greater than those of older age and was independent of age and body mass index (see Online Repository Notes 1 and 2 and Table E1, F and G, in this article's Online Repository at www.jacionline.org).
Correspondingly, although peak IL-6 levels during the disease course were higher in hospitalized patients and nonsurvivors, IL-6 levels were highest with baseline IHG-IIb/c and IHG-IVb/c (Fig 3, C; see Online Repository Note 3 in this article's Online Repository at www.jacionline.org). In addition, daily monitoring of IHGs revealed varied IHG reconstitution patterns, and improvements in IHG status presaged declines in plasma IL-6 levels during recovery (see Figs E5 and E6 and Online Repository Note 4 in this article's Online Repository at www. jacionline.org).
Seropositivity for CMV has been associated with the immunosenescence of age as well as changes in CD4 1 and CD8 1 lymphocyte levels (eg, the immune risk phenotype that tracks an inverted ratio and CMV seropositivity). [55][56][57][58] Because of these associations, we examined whether the associations of IHGs with outcomes were attributable to CMV seropositivity. Predictably, CMV seropositivity rates increased with age in the COVID-19 cohort; however, CMV serostatus did not independently associate with the outcomes of mortality, hospitalization, or respiratory support (see Online Repository Note 5 in this article's Online Repository at www.jacionline.org). In contrast, baseline IHGs were associated with these outcomes independent of CMV serostatus (Online Repository Note 5). This independent association may relate to our finding that CMV seropositivity was differentially distributed between IHG-II and IHG-IV (Online Repository Note 5). A greater proportion of individuals presenting with IHG-II (61%) were CMV-seronegative, whereas a greater proportion of persons presenting with IHG-IV (74%) were CMV-seropositive, and nearly 50% with IHG-I were CMVseropositive (Table II).

Baseline IHG, nasal SARS-CoV-2 levels, and local host response
Baseline IHG-I, IHG-II, and IHG-IV were associated with relatively rapid, intermediate, and delayed clearance, respectively, of nasal SARS-CoV-2 levels (Fig 3, D; see Fig E7, A, and Table E4 in this article's Online Repository at www.jacionline. org). Compared with baseline IHG-I, SARS-CoV-2 clearance rates were significantly slower by 87% (RR, 0.13; 95% CI, 0.02-0.82) with IHG-IV and trended to be slower by 72% (RR, 0.28; 95% CI, 0.05-1.44) with IHG-II (Fig E7, B). Correspondingly, SARS-CoV-2 levels were higher in nonsurvivors and patients requiring mechanical ventilation (Fig E7, C). Genes in the nasal transcriptome whose expression levels were associated with both lower SARS-CoV-2 levels and increased survival related to preservation of epithelial integrity as well as robust antiviral immune responses and controlled inflammatory responses (see Fig E8, Tables E5, A-C, and E6, A, and Online Repository Note 6 in this article's Online Repository at www.jacionline. org). Genes associated with higher SARS-CoV-2 levels also correlated with higher levels of ACE2, the SARS-CoV-2 receptor 59 ; these genes related to virus-induced inflammation (see Fig E8, B, in this article's Online Repository at www.jacionline. org; Table E5, D).

Unique and shared traits influencing mortality
Comparisons of study groups signifying nonprogressive and progressive COVID-19 identified 42 detrimental and 9 beneficial traits (GO-BP terms) and 28 beneficial genes (see Fig E8, A, and Tables E6, B, and E7 in this article's Online Repository at www. jacionline.org). These traits/genes segregated into 4 categories, depending on whether higher levels of detrimental traits and lower levels of the beneficial traits/genes associated with increased mortality hazards in either, both, or neither the COVID-19 cohort and the FHS (Fig 4, A; see Fig E9 and Table  E8, A and B, in this article's Online Repository at www. jacionline.org). Category 1 comprised 17 detrimental and 6 beneficial traits, along with 28 beneficial genes whose levels defined a unique IC low -IF high state associated with increased mortality   (Table E8, A and B). The unique IC low state related to lower levels of the beneficial traits/ genes linked to MHC class II-dependent antigen processing/presentation, the tyrosine signaling pathway, and HLA genes involved in T-cell costimulation (eg, GO-BP terms 28, 29, and 33, respectively; Fig 4, A). The unique IF high state related to higher levels of the detrimental traits linked to the inflammatory response to virus (eg, GO-BP terms 1, 5, and 15 corresponding  IFI6/35, IFIT1/3, IFITM1/3, IRF7, ISG15, MX1, OASL  CCL2, CDK1, CDKN1A, FLT3, GAS6   AXL, GAS6, IFIT2/3, IFNAR1, OAS1, STAR   APOBEC3A/B, DHX58, HERC5, IFITM1/3, MX1  CCL2/8,   to type I interferon signaling pathway, response to virus, and IFNg-mediating signaling pathway, respectively; Fig 4, A). Category 2 comprised 12 detrimental and 3 beneficial traits whose levels defined a shared IC low -IF high state associated with mortality hazards in both the COVID-19 cohort and the FHS (Table E8, C). The shared IC low state related to lower levels of shared beneficial traits linked to T-cell costimulation, T-cell signaling, and immune responses with genes (eg, CCR5, CCR7, and IL7R) essential for the integrity of T-cell homeostasis (eg, GO-BP terms 30, 31, and 32). The shared IF high state related to higher levels of shared detrimental traits related to inflammatory responses commonly elicited during antigenic challenges experienced during aging (eg, GO-BP terms 4 and 13 corresponding to defense response to gram-positive bacteria and response to LPS, respectively; Fig 4, A; see Fig E10 in this article's Online Repository at www.jacionline.org; Table E8, C). Category 3 comprised 8 detrimental traits associated with an increased mortality hazard that achieved statistical significance only in the FHS (eg, GO-BP terms 24 and 25; Fig 4, A; Fig E8, A). Category 4 comprised 5 detrimental traits that did not achieve statistical significance for mortality hazards in either the COVID-19 cohort or the FHS (Fig E9).

Peripheral blood GO-BP Terms
The unique and shared IC low -IF high states were associated with nonsurvivors, patients requiring mechanical ventilation, older individuals, and those presenting with IHG-II or IHG-IV (Fig 4, B; see Fig E11 and Table E9, A, in this article's Online Repository at www.jacionline.org,). Similar associations were observed with trait levels measured during the disease course (see Fig E12 in this article's Online Repository at www.jacionline.org; Table  E9, B and C). In addition, baseline levels of 48 of the 51 traits and the 28 beneficial genes were associated with baseline IHG status after controlling for age (Table E9, D).
Our discovery of a shared IC high -IF low state that was associated with a survival advantage in both the COVID-19 cohort and the FHS was congruent with 4 additional salutary associations in non-COVID-19 cohorts. First, akin to our findings in the COVID-19 cohort (Fig 4, B; Fig E11), in non-COVID-19 cohorts (see Fig E13 in this article's Online Repository at www.jacionline.org), the shared IC high -IF low state that was associated with COVID-19 survival marked individuals with IHG-I, whereas the shared IC low -IF high state that was associated with COVID-19 mortality marked persons with IHG-IIc and IHG-IVc. Second, the shared IC high -IF low state was overrepresented in females versus males across age in the FHS (see Fig E14, A, in this article's Online Repository at www.jacionline.org). In both sexes, levels of the shared IC high -IF low state declined proportionately during aging; however, comparable levels of this state were associated with a greater survival benefit in females (Fig E14, B; Table E8, D). Third, beneficial traits that defined the shared IC high state coclustered at high correlation levels with a gene signature (termed IMM-AGE [immune age]) 38 associated with lower hazards of cardiovascular disease and mortality in the FHS (see Fig E15 in this article's Online Repository at www.jacionline.org). Correspondingly, higher expression levels of the IMM-AGE signature were associated with a lower mortality hazard in the COVID-19 cohort (HR, 0.91; 95% CI, 0.84-0.98). Notably, higher levels of the IMM-AGE signature 38 were associated with a lower abundance of immune markers signifying immunosenescence in the FHS. Fourth, the shared IC high -IF low state was associated with lesssevere influenza infection, including after nasal inoculation of influenza virus in otherwise-healthy younger adults (see Fig  E16 in this article's Online Repository at www.jacionline.org).

DISCUSSION
Through evaluations of COVID-19 and non-COVID-19 cohorts, we uncovered the conserved features of a suspected but previously uncharacterized sexually dimorphic, antigenactivated, immunologic program that associates independently with lower IC and increased IF at any age. We propose that relative resistance to activation of this immunologic program is more common in females and signifies IR. Laboratory (CD8-CD4 equilibrium/disequilibrium-based) and transcriptomic (gene expression signatures) metrics signifying preservation of IR were associated with salutary outcomes: a survival advantage in persons either with or without COVID-19, as well as resistance to development of a progressive disease course during infections with SARS-CoV-2, influenza viruses, or HIV. We report on 3 observations relevant to understanding the basis for the ageindependent and sex-biased differences in susceptibility to developing severe COVID-19, as well as improving clinical care and identifying therapeutic targets for mitigation of progressive COVID-19.
First, we derived readily measurable metrics of IR that predicted all-cause, 30-day COVID-19 mortality independent of age, sex, body mass index, and CMV serostatus. Correspondingly, use of these metrics predicted secondary outcomes that included clinical indicators (eg, hospitalization and mechanical ventilation) and biomarkers (eg, plasma IL-6 and nasopharyngeal SARS-CoV-2 levels) indicative of progressive COVID-19. Second, we distinguished and quantified the individual contributions to COVID-19 outcomes of age versus age-independent deficits in IR that antedated SARS-CoV-2 infection versus age-independent deficits in IR that are uniquely induced in response to infection. These findings provide support for 3 novel, IR-dependent COVID-19 phenotypes linked to differential survival risks (Table I), predicated on whether persons had the proclivity to preserve IR before and during COVID-19, at any age. Across age strata, persons preserving metrics indicative of superior IR before and during early COVID-19 were more likely to manifest a survival advantage and nonprogressive COVID-19 (phenotype 1; Table I). Females were more likely to manifest phenotype 1. The distinction between the negative effects of age and preinfection or infection-induced deficits in IR at any age has clinical implications for the prediction and prevention of progressive COVID-19, as well as for the personalization of care (see Online Repository Note 7 and Figs E17 and E18 in this article's Online Repository at www.jacionline.org). Third, we identified 2 sets of IR-associated traits linked to IC or IF that were associated with survival: one set comprised traits that were uniquely associated with survival during COVID-19, whereas the other set comprised shared traits that were associated with mortality in persons with or without COVID-19. Both sets of traits may proffer therapeutic targets for mitigation of COVID-19 mortality, whereas the latter set of traits points to therapeutic targets for extending longevity.
IHG-I signifies high-grade CD8-CD4 equilibrium and represents the primordial IHG from which other IHGs emerge during antigenic challenges (see Online Repository Note 7). The relative prevalence of the various IHGs in a study group is unique to the type and level of antigenic experience or exposures.
Consequently, IHG distribution patterns across cohorts differed: SardiNIA (IHG-I > II > IV > III), SLE (IHG-II > IV > I > III),  COVID-19 (IHG-II > I > IV > III), and HIV1 therapy-naive patients with low HIV viral load (IHG-IV > II > I;III). Hence, HIVassociated and SARS-CoV-2-associated antigenic stimulation preferentially induce CD8-CD4 profiles corresponding to IHG-IVand IHG-II, respectively. Underscoring that IHG-I marks superior IR, in the HIV cohort, presentation with IHG-I, IHG-II, and IHG-IV was associated with the lowest, intermediate, and highest AIDS susceptibility, respectively. Paralleling these HIV-related associations, presentation with IHG-I versus IHG-II or IHG-IV was associated in an age-independent manner with a survival advantage versus disadvantage, as well as other features of nonprogressive versus progressive COVID-19.
The intercohort differences in IHG distributions underscore that age is an imperfect proxy for antigenic experience. In response to antigenic experience, the prevalence of IHG-I declines with age, increasing the pool of at-risk persons with IHG-II and IHG-IV. Thus, at any age, the presence of IHG-II or IHG-IV versus IHG-I before COVID-19 likely heightens the risk of developing progressive COVID-19. This is a parsimonious basis for our finding that although hospitalization rates increased with age, irrespective of age, patients who were hospitalized, required respiratory support, and/or died were more likely to present with IHG-II or IHG-IV versus IHG-I. Moreover, presentation with IHG-II or IHG-IV versus IHG-I was associated with delayed nasal SARS-CoV-2 clearance, a feature associated with mortality in our cohort. In a general HIV-seronegative community population, nearly 12% versus 27% of younger versus older adults (age <30 vs > _60 years) had IHG-II, and about 1 in 25 older adults had IHG-IV. Thus, we suggest that irrespective of age, persons with a diathesis to develop IHG-II or IHG-IV, before or during COVID-19, likely contribute the most to the overall burden of progressive COVID-19.
SARS-CoV-2 infection is unique in that, in the susceptible host, it may transiently perturb preexisting IR status to levels observed in HIV-seropositive persons. To metricize these perturbations and their contributions to COVID-19 outcomes, we evaluated IHG-II and IHG-IV subgrades, with IHG-IIc and IHG-IVc corresponding to CD8-CD4 profiles linked to profound CD4 1 lymphopenia (< _200 cells/mm 3 ) and IHG-IVc reflecting the profile of AIDS. In HIV-seronegative non-COVID-19 contexts, most persons with IHG-II or IHG-IV manifest the IHG-IIa or IHG-IVa subgrades; in the setting of COVID-19, some persons degrade preexisting IHG-I, IHG-IIa, or IHG-IVa to lower grades/subgrades. However, some persons resisted this degradation, accounting for our finding that, independent of age, baseline IHG status predicted survival and secondary outcomes, generally following a hierarchical pattern (better to worse): IHG-I > IHG-IIa > IHG-IVa > IHG-IVb > _ IHG-IIb > IHG-IVc > _ IHG-IIc. The extremes of this spectrum, that is, IHG-I versus IHG-IIc or IHG-IVc, represent persons with high-grade resistance versus susceptibility to degrade IR (phenotypes 1 vs 3, respectively). During COVID-19, these extremes were associated with lower versus higher plasma IL-6 levels. Nearly 40% of the individuals who died presented with IHG-IIc or IHG-IVc.
Persons presenting with IHG-IIc and IHG-IVc differed. Compared with persons presenting with IHG-I, presentation with IHG-IIc or IHG-IVc was associated with an approximately 19-fold or approximately 12-fold higher hazard of death in 30 days, respectively, and recovery times that were 67% and 88% longer, respectively. Persons presenting with IHG-IVc versus IHG-IIc tended to be older, have more comorbidities, were CMVseropositive, and displayed contrasting IHG reconstitution patterns during convalescence. Although CMV seropositivity increased with age, CMV serostatus was not associated with mortality. Thus, the IHG at presentation was not stochastic, but likely reflected the antigenic experience of the host before COVID-19 and response to SARS-CoV-2 infection.
Four findings highlight the substantial impact of baseline IHG status on COVID-19 outcomes: (1) compared to presentation with IHG-I, presentation with IHG-IIc increased the absolute risk of 30-day mortality by 28 additional deaths per 100 persons, (2) compared to presentation with IHG-IIa, presentation with IHG-IIc was associated with an excess of 26 additional deaths per 100 persons, (3) although more older persons presented with IHG-IIc or IHG-IVc, the age-adjusted associations of these grades with COVID-19 outcomes were at least as strong as those associated with older age, and (4) the associations of IHG status with COVID-19 mortality were independent of both age and CMV serostatus, as well as body mass index, a risk factor for severe COVID-19. 60,61 Transcriptomic data support that a switch from IHG-I to IHG-II or IHG-IV before or during COVID-19 may associate with an immunosuppressive, proinflammatory state that contributes to mortality. We identified 2 distinct IC low -IF high states that were associated with COVID-19 mortality. The shared IC low -IF high state likely antedated COVID-19, because it was associated with mortality not only in persons with COVID-19 but also in participants in the FHS, independent of age. In addition, trait features of the shared IC low -IF high state corresponded to maladaptive host responses to antigenic challenges typically experienced throughout life. The unique IC low -IF high state corresponded to unregulated host responses to SARS-CoV-2 infection and was associated with a survival disadvantage exclusively in patients with COVID-19. The unique and shared IC low -IF high states were enriched in persons with IHG-II or IHG-IV. Conversely, the shared IC high -IF low state was associated with a survival advantage in both the COVID-19 cohort and the FHS, and was enriched in persons with IHG-I, regardless of COVID-19 status. The shared IC high -IF low state was also associated with less-severe influenza infection.
Thus, irrespective of COVID-19 status, superior IR was indicated by IHG-I linked to a shared IC high -IF low state, whereas deficits in IR were indicated by IHG-II or IHG-IV linked to shared IC low -IF high states. Females were more successful than males in preserving indicators of superior IR, as well as in manifesting a longevity advantage compared with males in the FHS, even after correction for differences in the levels of IR between the sexes. Congruently, during COVID-19, more females presented with IHG-I, potentially explaining why the risk of developing progressive COVID-19 is lower in females.
Because the baseline IHGs independently predict COVID-19associated mortality and recovery, balancing IHG status across trial intervention versus placebo arms may reduce confounding in clinical studies (see Online Repository Note 7; Fig E18). Moreover, assessment of IHGs may allow for individualized care and tailoring therapies. During COVID-19, levels of the unique and shared IC low -IF high states were highest in persons presenting with IHG-IIc or IHG-IVc and corresponded to an immunodeficient-hyperinflammatory state characterized by uncontrolled inflammation, inadequate MHC class II responses, deficits in T-cell costimulation/signaling, higher plasma IL-6 levels, and higher nasal SARS-CoV-2 levels (see Online Repository Note 7; Fig E18). Gene expression analysis suggests that the failure to mount effective antiviral immune responses coupled with loss of epithelial integrity in the nasal compartment may underlie both higher SARS-CoV-2 burden and increased mortality, as well as correlate with higher expression of ACE2, the receptor for SARS-CoV-2 59 (see Online Repository Note 6). Thus, presentation with or rapid advancement to IHG-IIc or IHG-IVc serves as an early indicator of progressive disease, even before worsening respiratory function. Early targeting of the IC low -IF high state in persons presenting with or advancing to IHG-IIc and IHG-IVc states may mitigate disease progression. This can potentially be achieved via combinatorial therapies with immunomodulators (eg, baricitinib) and anti-inflammatory agents (eg, IL-6 signaling inhibitors).
The IHGs were more precise measures of immune status versus conventional metrics (CD4 1 count or CD4:CD8 ratio used alone; see Online Repository Note 8). This observation in conjunction with the strength of the associations of IHGs with COVID-19 outcomes suggest that IHGs hold promise as a pragmatic clinical tool to assess, monitor, and predict clinical outcomes and inflammatory status during COVID-19. Daily monitoring of IHGs (eg, Fig E6) was implemented at our institution to support algorithms in conjunction with clinical assessment for admission, anticipating levels of care and duration, and directing therapies. Based on our findings, examples of clinical utility of the IHGs include (1) initial staging of COVID-19 severity, (2) monitoring progress of COVID-19 severity, (3) improved differential diagnosis of worsening oxygenation status attributable to COVID-19 versus other sources (eg, patients with improving IHG status would suggest COVID-19 was less likely the cause, suggesting alternative possibilities such as pulmonary embolism or hospital-acquired pneumonia), (4) identification of patients with poor recovery or persistent COVID-19 (eg, persistently poor oxygenation, unresolved radiographic findings consistent with COVID-19, positive PCR test result for SARS-CoV-2 with low cycle threshold values, and failure to improve IR metrics). We found that all patients in our cohort with presumed persistent COVID-19 had persistent IHG-IIc or IHG-IVc, suggesting that a failure to clear SARS-CoV-2 burden, possibly due to deficits in IR, may contribute to this persistence. In such patients, IHGs were used to help identify those more likely to have persistent COVID-19, warranting aggressive/alternative therapeutic approaches including prolongation or reinitiation of remdesivir, corticosteroids, and/or initiation of immunomodulators (eg, baricitinib).
At the time of this article, the US Food and Drug Administration is strategizing COVID-19 vaccine booster doses for those who are ''immunocompromised'' and face a greater risk from infection or reinfection. 62 Yet, identifying persons who are ''immunocompromised'' beyond qualifying comorbidities (eg, history of cancer, transplant recipients, and receiving immunosuppressant medications), or those with advanced age, remains obscure and limited. IHGs track IC and IF status independent of age. For example, up to 14% of a general population manifested IHG-IV, a grade that is highly prevalent in therapy-naive HIV 1 persons. Hence, assessment of IHG status may provide a means to accurately and precisely gauge ''immunocompromised'' status relevant for prioritization of booster doses and other preventative therapies, regardless of age.
There are limitations of our study. The COVID-19 cohort comprised mostly male veterans, many of whom were older and had comorbidities; these features may not be generalizable. Second, therapies for COVID-19 could confound associations. Treatment decisions in our cohort were not dictated by participation in any concomitant clinical trials, and baseline IHG status was used for defining associations. Third, we were unable to obtain viral cultures. Fourth, defining the association of IHG status with postacute sequelae of SARS-CoV-2 infection was beyond the scope of this study.

CONCLUSIONS
We identified age-independent, female-biased processes linked to higher IC and lower IF, signifying IR that bridge longevity, COVID-19 survival, and resistance to AIDS and severe influenza. Thus, the IR metrics have value for precision immune health monitoring across lifespan, irrespective of COVID-19 status.
Our data favor a mechanistic model wherein gain of detrimental function (higher IF) and loss of beneficial functions (lower IC) signifying IR deficits independently and synergistically contribute to mortality in persons with or without COVID-19 (see Online Repository Note 7). Across all age ranges, the relative burden of progressive COVID-19 is dependent on the prevalence of individuals with a proclivity to preserve versus degrade IR before and during COVID-19, with males having a diathesis to degrade IR. The magnitude of the absolute risk differences for 30-day mortality associated with IHG status at presentation underscores the need for a combinatorial approach with immunomodulators and antiinflammatory agents to mitigate progression of preexisting IR deficits and/or promote the rapid restoration of the IR status that antedated SARS-CoV-2 infection.