Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2021-09-08 , DOI: 10.1016/j.jaci.2021.08.021 Grace C Lee 1 , Marcos I Restrepo 2 , Nathan Harper 3 , Muthu Saravanan Manoharan 4 , Alisha M Smith 5 , Justin A Meunier 3 , Sandra Sanchez-Reilly 6 , Aamir Ehsan 7 , Anne P Branum 3 , Caitlyn Winter 8 , Lauryn Winter 8 , Fabio Jimenez 3 , Lavanya Pandranki 4 , Andrew Carrillo 3 , Graciela L Perez 3 , Antonio Anzueto 6 , Hanh Trinh 7 , Monica Lee 7 , Joan M Hecht 9 , Celida Martinez-Vargas 7 , Raj T Sehgal 6 , Jose Cadena 6 , Elizabeth A Walter 2 , Kimberly Oakman 7 , Raymond Benavides 10 , Jacqueline A Pugh 2 , 7 , Scott Letendre 11 , Maristella Steri 12 , Valeria Orrù 12 , Edoardo Fiorillo 12 , Francesco Cucca 13 , Alvaro G Moreira 8 , Nu Zhang 14 , Elizabeth Leadbetter 14 , Brian K Agan 15 , Douglas D Richman 16 , Weijing He 3 , Robert A Clark 2 , Jason F Okulicz 17 , Sunil K Ahuja 18
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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.
中文翻译：
免疫弹性和 COVID-19 生存优势
背景
2019 年严重冠状病毒病 (COVID-19) 的风险在相似年龄的人群中存在显着差异，男性更高。对严重 COVID-19 的易感性与年龄无关、性别偏向的差异可能归因于我们称之为免疫弹性 (IR) 的性二态性保护属性的缺陷。
客观的
我们试图检查先于严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染或由其诱发的 IR 缺陷是否独立预测 COVID-19 死亡率。
方法
IR 水平通过 2 个新指标进行量化：免疫健康等级（IHG-I [最佳] 至 IHG-IV）以衡量 CD8 +和 CD4 + T 细胞计数平衡，以及血液基因表达特征。在前瞻性 COVID-19 队列（n = 522）中检查了 IR 指标；主要结果是 30 天死亡率。IR 指标与非 COVID-19 队列（n = 13,461）结果的关联提供了将 COVID-19 前 IR 状态与 COVID-19 期间的 IR 以及 COVID-19 结果联系起来的框架。
结果
IHG-I 跟踪 CD8 +和 CD4 + T 细胞计数之间的高级平衡，是健康成年人中最常见的级别 (73%)，尤其是女性。SARS-CoV-2 感染与 IHG-I 的代表性不足（21%）与 IHG-II 或 IHG-IV 的代表性过高（77%）相关，尤其是在男性与女性中（P <.01). 在控制了年龄和性别后，IHG-I 与死亡率降低 88% 相关；降低住院和呼吸衰竭的风险；降低血浆 IL-6 水平；快速清除鼻咽部 SARS-CoV-2 负担；以及与生存相关的基因表达特征，表示免疫能力和受控炎症。在非 COVID-19 队列中，IR 保持指标与对进行性流感或 HIV 感染的抵抗力以及弗雷明汉心脏研究中较低的 9 年死亡率相关，尤其是在女性中。
结论
在抗原挑战期间通过受控炎症保持免疫能力是 IR 的标志，并且与长寿和抗艾滋病相关。与年龄无关，在 SARS-CoV-2 感染之前和/或期间，男性偏向于降低 IR 的倾向容易导致严重的 COVID-19。
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