Global patterns of antigen receptor repertoire disruption across adaptive immune compartments in COVID-19.

Whereas pathogen-specific T and B cells are a primary focus of interest during infectious disease, we have used COVID-19 to ask whether their emergence comes at a cost of broader B cell and T cell repertoire disruption. We applied a genomic DNA-based approach to concurrently study the immunoglobulin-heavy (IGH) and T cell receptor (TCR) ß and δ chain loci of 95 individuals. Our approach detected anticipated repertoire focusing for the IGH repertoire, including expansions of clusters of related sequences temporally aligned with SARS-CoV-2-specific seroconversion, and enrichment of some shared SARS-CoV-2-associated sequences. No significant age-related or disease severity-related deficiencies were noted for the IGH repertoire. By contrast, whereas focusing occurred at the TCRß and TCRδ loci, including some TCRß sequence-sharing, disruptive repertoire narrowing was almost entirely limited to many patients aged older than 50 y. By temporarily reducing T cell diversity and by risking expansions of nonbeneficial T cells, these traits may constitute an age-related risk factor for COVID-19, including a vulnerability to new variants for which T cells may provide key protection.

Two-year prospective cohort of intensive care survivors enrolled on a digitally enabled recovery pathway focussed on individualised recovery goal attainment.

BACKGROUND: Despite substantial evidence documenting physical, psychological, and cognitive problems experienced by intensive care unit (ICU) survivors, few studies explore interventions supporting recovery after hospital discharge. Individualised recovery goal setting, the standard of care across many rehabilitation areas, is rarely used for ICU survivors. Digital health technologies may help to address current service fragmentation and gaps. We developed and implemented a digital ICU recovery pathway using the aTouchaway e-health platform. OBJECTIVES: The objective of this study was to explore recovery barriers and challenges; recovery goals set and achieved; self-reported patient outcomes; and healthcare costs of patients enrolled on a 12-week digital ICU recovery pathway after hospital discharge. METHODS: We conducted a prospective observational single-centre cohort study (June 2021 to May 2023) at a 90-bed tertiary critical care service in London, UK. We enrolled adults ventilated for ≥3 days who were able to participate in recovery activities. We ascertained baseline recovery challenges and identified recovery goals and achievement over 12 weeks. We collected patient-reported outcomes at 2-4, 12-14, 26-28 weeks and healthcare utilisation monthly for 28 weeks. RESULTS: We enrolled 105 participants (35% of eligible patients). Common rehabilitation challenges were standing balance (60%), walking indoors (56%), and washing (64%) and dressing (47%) abilities. Of 522 home recovery goals, 63% weekly, 48% monthly, and 38% aspirational goals were achieved. Most goals related to self-care: ability to move outside (91 goals, 55% achieved) and inside (45 goals, 47% achieved) the home and community access (65 goals, 48% achieved). Nottingham Extended Activities of Daily Living Scale scores improved from timepoints 1 to 2 (median [interquartile range]: 15 [7, 19] versus 19 [15, 21], P = 0.01). Total healthcare costs were £240,017 (median [interquartile range] cost per patient: £784 [£125, £4419]). CONCLUSIONS: This study found multiple ongoing functional deficits, challenges achieving recovery goals, and limited improvements in self-reported outcomes, with moderate healthcare costs after hospital discharge indicate substantial ongoing rehabilitative needs.

Development of a menu of recovery goals to facilitate goal setting after critical illness.

OBJECTIVE: To develop an expert-informed (including end users) recovery goal menu for adults recovering from critical illness applicable to the community/home setting. RESEARCH METHODOLOGY/DESIGN: Stage 1 Item generation: iterative development of domains, sub-domains, and goals in consultation with former intensive care patients, family members and expert clinicians. Stage 2 Content validity assessment: cognitive interviews and the content validity index. SETTING: Virtual consultation meetings facilitated by the research team at King's College London and Guy's and St Thomas' NHS Foundation Trust. MAIN OUTCOME MEASURES: Content validity as assessed by: the Item-Content Validity Index (I-CVI), Scale Level-Content Validity Index/Universal Agreement (S-CVI/UA) score, the Scale Level-Content Validity Index/Average (S-CVI/Ave) score and Average Content Validity Ratio (CVR). RESULTS: Item generation resulted in a goal menu comprising 4 domains, 22 sub-domains and 95 goals assigned as follows: Self-care: 9 sub-domains with 37 goals, Productivity: 7 sub-domains with 13 goals, Leisure: 3 sub-domains with 25 goals, and Person domain 3 sub-domains with 20 goals. Cognitive interviews resulted in addition of 79 goals and modification of 7, addition of 4 new sub-domains and modification of 4, thus resulting in 4 domains, 26 sub-domains with a total of 174 goals. Twenty-four sub-domains (169 goals) were deemed relevant with Item-Content Validity Index (I-CVI) scores ranging from 0.72 to 1. Two sub-domains (5 goals) did not meet the 0.7 cut-off and were removed. The Scale Level-Content Validity Index/Universal Agreement (S-CVI/UA) score was 0.46; the Scale Level-Content Validity Index/Average (S-CVI/Ave) 0.91. Average Content Validity Ratio (CVR) was 0.93. CONCLUSION: An expert informed recovery goal menu for former intensive care patients has been developed with excellent content validity. The final goal menu comprises 169 goals within 24 sub-domains grouped under 4 domains. IMPLICATIONS FOR CLINICAL PRACTICE: This menu will help patients to set goals and increase our understanding of how individuals recover from critical illness.

A dynamic COVID-19 immune signature includes associations with poor prognosis.

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.

Author Correction: A dynamic COVID-19 immune signature includes associations with poor prognosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: A dynamic COVID-19 immune signature includes associations with poor prognosis.

A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01186-5.