Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.

evere infection with COVID-19 has been linked to immune dysregulation, including impaired or delayed production of type I and type III interferons 1-5 , marked lymphopenia [6][7][8][9][10] and a paradoxical increase in pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6 1,4,6,[11][12][13] . Alteration of T cell compartments include increases in effector and activated CD4 and CD8 T cells [14][15][16][17] , CD8 + T cells contribute to survival in patients with COVID-19 and hematologic cancer

Rationale: The epidemiology of post-acute care use and hospital readmission after sepsis remains largely unknown.Objectives: To examine the rate of post-acute care use and hospital readmission after sepsis and to examine risk factors and outcomes for hospital readmissions after sepsis. Methods:In an observational cohort study conducted in an academic health care system (2010-2012), we compared post-acute care use at discharge and hospital readmission after 3,620 sepsis hospitalizations with 108,958 nonsepsis hospitalizations. We used three validated, claims-based approaches to identify sepsis and severe sepsis.Measurements and Main Results: Post-acute care use at discharge was more likely after sepsis, driven by skilled care facility placement (35.4% after sepsis vs. 15.8%; P , 0.001), with the highest rate observed after severe sepsis. Readmission rates at 7, 30, and 90 days were higher postsepsis (P , 0.001). Compared with nonsepsis hospitalizations (15.6% readmitted within 30 d), the increased readmission risk was present regardless of sepsis severity (27.3% after sepsis and 26.0-26.2% after severe sepsis). After controlling for presepsis characteristics, the readmission risk was found to be 1.51 times greater (95% CI, 1.38-1.66) than nonsepsis hospitalizations. Readmissions after sepsis were more likely to result in death or transition to hospice care (6.1% vs. 13.3% after sepsis; P , 0.001). Independent risk factors associated with 30-day readmissions after sepsis hospitalizations included age, malignancy diagnosis, hospitalizations in the year prior to the index hospitalization, nonelective index admission type, one or more procedures during the index hospitalization, and low hemoglobin and high red cell distribution width at discharge.Conclusions: Post-acute care use and hospital readmissions were common after sepsis. The increased readmission risk after sepsis was observed regardless of sepsis severity and was associated with adverse readmission outcomes.

PURPOSE: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate based on experimental and observational evidence. We used genetic causal inference methods – Mendelian Randomization and mediation – to infer potential effects of plasma ANG2. METHODS: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically-predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. RESULTS: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n=404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09 – 0.36, p=0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p=0.042. No significant QTL were identified in African ancestry subjects. Genetically-predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06 – 4.78), p=0.035. Plasma ANG2 mediated 34% of the rs2442608C - ARDS risk. CONCLUSIONS: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant associates with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals.We identified broad changes in neutrophils, NK cells, and monocytes during severe COVID-19, suggesting excessive mobilization of innate lineages. We found marked activation within T and B cells, highly oligoclonal B cell populations, profound plasmablast expansion, and SARS-CoV-2specific antibodies in many, but not all, severe COVID-19 cases. Despite this heterogeneity, we found selective clustering of severe COVID-19 cases through unbiased analysis of the aggregated immunological phenotypes. Our findings demonstrate broad immune perturbations spanning both innate and adaptive leukocytes that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.One Sentence Summary: Broad immune perturbations in severe COVID-19 surrogates, as well as the medical personnel in charge of patient care.

Objective Septic shock is associated with increased long-term morbidity and mortality. However, little is known about the use of hospital-based acute care in survivors after hospital discharge. The objectives of the study were to examine the frequency, timing, causes, and risk factors associated with Emergency Department (ED) visits and hospital readmissions within 30 days of discharge. Design Retrospective cohort study. Setting Tertiary, academic hospital in the United States. Patients Patients admitted with septic shock (serum lactate ≥ 4 mmol/L or refractory hypotension) and discharged alive to a non-hospice setting between 2007 and 2010. Interventions None. Measurements and Main Results The co-primary outcomes were all-cause hospital readmission and ED visits (treat-and-release encounters) within 30 days to any of the three health system hospitals. Of 269 at-risk survivors, 63 (23.4%, 95% confidence interval (CI): 18.2, 28.5) were readmitted within 30 days of discharge and another 12 (4.5%, 95% CI: 2.3, 7.7) returned to the ED for a treat-and-release visit. Readmissions occurred within 15 days of discharge in 75% of cases and were more likely in oncology patients (p=0.001) and patients with a longer hospital length of stay (p=0.04). Readmissions were frequently due to another life-threatening condition and resulted in death or discharge to hospice in 16% of cases. The reasons for readmission were deemed potentially related to the index septic shock hospitalization in 78% (49/63) of cases. The most common cause was infection-related, accounting for 46% of all 30-day readmissions, followed by cardiovascular or thromboembolic events (18%). Conclusions The use of hospital-based acute care appeared to be common in septic shock survivors. Encounters often led to readmission within 15 days of discharge, were frequently due to another acute condition, and appeared to result in substantial morbidity and mortality. Given the potential public health implications of these findings, validation studies are needed.

These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.