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1.
Nature ; 2022 Jul 28.
Article in English | MEDLINE | ID: covidwho-1960390

ABSTRACT

Anorexia and fasting are host adaptations to acute infection, inducing a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB) 1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). CD4+ T cell function is impaired in COVID-19 and BHB promotes both survival and production of Interferon-γ from CD4+ T cells. Using metabolic tracing analysis, we uncovered that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we demonstrate that ketogenic diet (KD) and delivery of BHB as ketone ester drink restores CD4+ T cell metabolism and function in respiratory infections, ultimately reducing the mortality of SARS-CoV-2 infected mice. Altogether, our data reveal BHB as alternative carbon source promoting T cell responses in pulmonary viral infections, highlighting impaired ketogenesis as a potential confounder of severe COVID-19.

2.
Intensive Care Med ; 48(7): 975-976, 2022 07.
Article in English | MEDLINE | ID: covidwho-1935757
3.
Crit Care Med ; 50(7): e651-e652, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1927450
5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327137

ABSTRACT

Hyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Functional proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.

6.
Crit Care Med ; 50(6): e526-e538, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1621691

ABSTRACT

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage. DESIGN: Multicenter, retrospective analysis between January 2010 and May 2021. SETTING: Three tertiary care ECMO centers in Germany and Switzerland. PATIENTS: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%. CONCLUSIONS: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Respiratory Distress Syndrome , Anticoagulants/therapeutic use , COVID-19/complications , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/methods , Humans , Intracranial Hemorrhages/drug therapy , Intracranial Hemorrhages/epidemiology , Intracranial Hemorrhages/etiology , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/therapy , Retrospective Studies
8.
Cell Rep ; 35(13): 109320, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1275189

ABSTRACT

Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of coronavirus disease 2019 (COVID-19). Compared with severely ill individuals, those who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we identify CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Antibodies, Viral/immunology , CD40 Ligand/immunology , CD40 Ligand/metabolism , Cross Reactions , Humans , Immunologic Memory , Interleukins/immunology , Interleukins/metabolism
9.
Transfus Med Hemother ; 48(3): 154-160, 2021 May.
Article in English | MEDLINE | ID: covidwho-1247451

ABSTRACT

BACKGROUND: The SARS-CoV-2 pandemic has challenged many of our current routine practices in the treatment and care of patients. Given the critical importance of blood donation and transfusion we analyzed 92 blood samples of individuals infected with SARS-CoV-2 stratified by symptoms. STUDY DESIGN AND METHODS: We therefore tested blood samples for SARS-CoV-2 via RT-PCR targeting the E gene. In addition, we tested each blood sample for anti-SARS-CoV-2 IgG antibodies via ELISA and performed plaque reduction neutralization tests. RESULTS: SARS-CoV-2 RNA was absent in the blood of mild to asymptomatic patients (57 individuals) and only detectable in individuals with severe COVID-19 who were admitted to the intensive care unit (35 individuals) (n = 6/92 [6.5%]; p = 0.023 Fisher's exact test). Interestingly, anti-spike IgG antibodies were not significantly higher in intensive care unit patients compared to mild patients, but we found that their neutralizing capacity was disproportionately increased (p < 0.001). CONCLUSION: Our observations support the hypothesis that there are no potential hazards from blood or plasma transfusion of SARS-CoV-2-positive individuals with mild flu-like symptoms and more importantly of asymptomatic individuals.

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