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Despite advances, few therapeutics have shown efficacy in severe coronavirus disease 2019 (COVID-19). In a different context, virus-specific T cells have proven safe and effective. We conducted a randomized (2:1), open-label, phase 1/2 trial to evaluate the safety and efficacy of off-the-shelf, partially human leukocyte antigen (HLA)-matched, convalescent donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells (CoV-2-STs) in combination with standard of care (SoC) in patients with severe COVID-19 compared to SoC during Delta variant predominance. After a dose-escalated phase 1 safety study, 90 participants were randomized to receive CoV-2-ST+SoC (n= 60) or SoC only (n= 30). The co-primary objectives of the study were the composite of time to recovery and 30-d recovery rate and the in vivo expansion of CoV-2-STs in patients receiving CoV-2-ST+SoC over SoC. The key secondary objective was survival on day 60. CoV-2-ST+SoC treatment was safe and well tolerated. The study met the primary composite endpoint (CoV-2-ST+SoC versus SoC: recovery rate 65% versus 38%, P= 0.017; median recovery time 11 d versus not reached, P= 0.052, respectively; rate ratio for recovery 1.71 (95% confidence interval 1.03–2.83, P= 0.036)) and the co-primary objective of significant CoV-2-ST expansion compared to SοC (CoV-2-ST+SoC versus SoC, P= 0.047). Overall, in hospitalized patients with severe COVID-19, adoptive immunotherapy with CoV-2-STs was feasible and safe. Larger trials are needed to strengthen the preliminary evidence of clinical benefit in severe COVID-19.

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P= 0.01) and glycerol (340 vs. 169 mol/L, P= 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P= 0.008), glycerol (P= 0.004), and pyruvate (P= 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio OR, 1.075; 95% confidence interval CI, 1.004-1.150; P= 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043-2.312; P= 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001-1.012; P= 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor.

The present study aimed to determine whether amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) predicts intensive care unit (ICU) mortality in a cohort of general, noncardiac, critically ill patients. To this end, a total of 233 consecutive mechanically ventilated patients (109 men) having a median age of 60 years and a wide range in admitting diagnoses, including medical (n = 118), surgical (n = 83), and multiple trauma (n = 32) cases were prospectively studied. Median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores on ICU admission were 16 and 9, respectively. The study end point was ICU outcome. Blood samples were drawn on admission in the ICU and on postadmission days 1 and 2 to determine NT-pro-BNP levels. In a subgroup (n = 77), admission proinflammatory and anti-inflammatory cytokine levels, including TNF-, IL-6, and IL-10, were also measured. Nonsurvivors (n = 98) had significantly higher NT-pro-BNP levels than survivors (n = 135) on admission in the ICU (2,074 vs. 283 pg/mL; P< 0.001), on day 1 (2,197 vs. 221 pg/mL; P< 0.001), and on day 2 (2,726 vs. 139 pg/mL; P< 0.001). Median values for TNF-, IL-6, and IL-10 were 3.70, 131.57, and 111.88 pg/mL, respectively. Receiver operating characteristic analysis showed that the area under the receiver operating characteristic curve in predicting ICU mortality was 0.70 for APACHE II and 0.77 for admission NT-pro-BNP (P= 0.08). The cutoff in admission NT-pro-BNP that best predicted outcome was 941 pg/mL. Multiple logistic regression analysis revealed that APACHE II score (odds ratio, 1.06; P= 0.007) and the best cutoff point in admission NT-pro-BNP (odds ratio, 7.74; P< 0.001) independently predicted ICU mortality, even if cytokines were entered in the analysis. In conclusion, plasma NT-pro-BNP is frequently raised in noncardiac, mixed, critically ill patients, and nonsurvivors have consistently higher levels than survivors. Elevated admission NT-pro-BNP represents an independent predictor for poor ICU outcome in the presence of clinical severity scores.