Immunologic resilience and COVID-19 survival advantage

Abstract

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.

Keywords: AIDS; Aging; COVID-19; HIV; SARS-CoV-2; biomarkers; immune; inflammation; influenza.

Graphical abstract

Fig 1

IHG associations in study cohorts. A and B, IHG features. Ratio, CD4:CD8 ratio. C,Left: IHG prevalence in SardiNIA cohort by sex and age strata and females with SLE. Middle: IHG at presentation in the COVID-19 cohort by sex, hospitalization and survivor status, and nonsurvivors by age. Right: IHG in therapy-naive HIV⁺ participants (with known dates of seroconversion) at entry into the Natural History Study by entry viral load (VL; <1K, 1-10K, 10-100K, ≥100K copies/mL; K, ×10³). Rightmost: IHGs before and after at least 5 years of antiretroviral therapy (ART). D, IHG prevalence (top) and OR with 95% CI for prevalence of IHG-I (bottom) by sex within age strata. E, HRs with 95% CI of developing AIDS (1987 criteria⁵¹) in HIV⁺ participants by entry IHG. H, High; L, low. F,Top-left: IHG prevalence by age strata. P_IHG-I and P_IHG-IV is for the proportion of IHG-I vs rest and IHG-IV vs rest across age strata. Top-right: Age strata distribution by IHG subgrades. Middle-left and right: OR with 95% CI for hospitalization. OR by age strata (left) adjusted by baseline IHG status and OR by baseline IHG status (right) adjusted by age strata. Bottom: Median values of CD4⁺ and CD8⁺ counts and CD4:CD8 ratio by hospitalization status (yes/no) and (left) age strata and (right) IHG subgrades. F, Female; M, male. †P = .06. ∗P < .05. ∗∗P < .01. ∗∗∗P < .001.

Fig 2

Association of IHGs at presentation (baseline) with hospitalization status and reconstitution of IHG during convalescence in the COVID-19 cohort. A,Top: IHG prevalence at baseline by hospitalized (H) and nonhospitalized (NH) status and age strata. Bottom: OR with 95% CI for having IHG-I or IHG-II at baseline by hospitalization status. Percent hospitalized shown by age strata. B, Paired IHG distributions at baseline and during convalescence among 206 COVID-19 survivors overall and stratified by age. C, Distribution of IHG subgrades (as in 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 = .07. ∗P < .05. ∗∗P < .01. ∗∗∗P < .001.

Fig 3

COVID-19 outcomes by baseline IHG status. A,Top 3 plots: Kaplan-Meier curves for 30-day all-cause mortality from days since presentation by baseline IHG status (top), IHG-I and IHG-II subgrades (middle), and IHG-I and IHG-IV subgrades (bottom). Middle: Number at risk (No.) indicates patients who had not died or been censored before that time point. Bottom: Age-adjusted HRs (aHRs) with 95% CIs (reference: IHG-I). B,Top 3 plots: Cumulative hospital discharge estimates within 30 days of presentation among hospitalized patients by baseline IHG status (top), IHG-I and IHG-II subgrades (middle), and IHG-I and IHG-IV subgrades (bottom). Middle: Number at risk (No.) indicates patients who had not been discharged or been censored before that time point. Bottom: Age-adjusted RRs (aRRs) with 95% CIs (reference: IHG-I). C, Peak plasma IL-6 levels by hospitalization status, survivorship status in hospitalized patients, and baseline IHG status. D, Levels of SARS-CoV-2 viral transcript burden proxied by log₁₀-normalized counts of SARS-CoV-2 nucleoprotein “N” gene sequence in nasal transcriptomes of hospitalized patients by baseline IHG status, depicted as mean ± SEM (bands). H, Hospitalized; H-S, hospitalized survivor; H-NS, hospitalized nonsurvivor; NH, nonhospitalized; SEM, standard error of mean.

Fig 4

Beneficial and detrimental traits in the COVID-19 cohort and the FHS. A,Center: HRs (95% CI) of mortality in the COVID-19 cohort (30-day) and the FHS (survival over 9 years adjusted by age as a continuous variable). HRs are depicted for 34 of the 52 traits identified in baseline peripheral blood transcriptome from 48 patients that were significantly associated with progressive COVID-19. GO-BP terms (left) were classified as detrimental (#1-26) or beneficial (#27-34) traits, and representative genes (right) in each trait are shown. The association of these traits was analyzed in the FHS for 9-year survival. Forest plots are categorized and color-coded to represent shared and unique significant associations (FDR < 0.1) in these 2 cohorts. Fig E9 and Table E8 depict the entire list of traits. B, Gene expression scores for a representative detrimental and beneficial trait in baseline peripheral blood transcriptomes (n = 48) by hospitalization and survivorship status (NH-S, nonhospitalized survivors; H-S, hospitalized survivors; NS, nonsurvivors), age strata, and baseline IHG status. FDR, False-discovery rate.