ABSTRACT
Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.
ABSTRACT
(1) Background: Vitamin K (VK) is a fat-soluble compound with a common chemical structure, a 2-methyl-1,4-naphthoquinone ring, and a variable aliphatic side-chain. VK is involved in the synthesis of blood-clotting proteins, bone stability, anti-oxidative, and immune inflammatory-modulatory functions. Vitamin K also activates protein S, which acts as an antioxidant and anti-inflammatory. The fact that cytokine overproduction, oxidative stress, and disturbed microcirculation by thrombogenicity play a central role in severe COVID-19 prompted us to analyze this vitamin. (2) Methods: We analyzed by a validated liquid-chromatography tandem mass-spectrometry method serum vitamin K1, MK4, MK7, and VK epoxide levels in 104 healthy controls, 77 patients with non-COVID-19 pneumonia, and 135 hospitalized COVID-19 patients with potentially fatal outcomes admitted to our University Hospital between April and November 2020. We included the quotient between VK and triglyceride (TG, nmol/mmol/L) values in the analyses with respect to the TG transporter function for all VK subtypes. Additionally, we assessed anthropometric, routine laboratory, and clinical data from the laboratory and hospital information systems. (3) Results: The COVID-19 patients had significantly lower MK7 levels than non-COVID-19 pneumonia patients and healthy controls. COVID-19 and non-COVID-19 pneumonia patients had significantly lower vitamin K1 and significantly higher MK4 compared to healthy controls, but did not differ significantly from each other. Between COVID-19 non-survivors (n = 30) and survivors (n = 105) no significant differences were seen in all vitamin K subtypes, despite the fact that non-survivors had higher peak concentrations of IL-6, CRP, d-dimer, and higher oxygen needs, respectively. (4) Conclusions: The present data identified significantly decreased vitamin K1, K2 (MK7), and increased MK4 levels in patients with COVID-19 compared to healthy controls. Vitamin K2 (MK7) was lowest in COVID-19 patients irrespective of potentially fatal courses, indicating consumption of this VK subtype by COVID-19 immanent effects, most probably inflammatory and oxidative stress factors.
ABSTRACT
(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods: We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised KYN, Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results: At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071-1.319) followed by age (1.041, 95% CI: 1.011-1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66-95%) and a specificity of 72% (95% CI: 65-82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions: Kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons.
ABSTRACT
Understanding immune reactivity against SARS-CoV-2 is essential for coping with the COVID-19 pandemic. Herein, we discuss experiences and open questions about the complex immune responses to SARS-CoV-2. Some people react excellently without experiencing any clinical symptoms, they do not get sick, and they do not pass the virus on to anyone else ("sterilizing" immunity). Others produce antibodies and do not get COVID-19 but transmit the virus to others ("protective" immunity). Some people get sick but recover. A varying percentage develops respiratory failure, systemic symptoms, clotting disorders, cytokine storms, or multi-organ failure; they subsequently decease. Some develop long COVID, a new pathologic entity similar to fatigue syndrome or autoimmunity. In reality, COVID-19 is considered more of a systemic immune-vascular disease than a pulmonic disease, involving many tissues and the central nervous system. To fully comprehend the complex clinical manifestations, a profound understanding of the immune responses to SARS-CoV-2 is a good way to improve clinical management of COVID-19. Although neutralizing antibodies are an established approach to recognize an immune status, cellular immunity plays at least an equivalent or an even more important role. However, reliable methods to estimate the SARS-CoV-2-specific T cell capacity are not available for clinical routines. This deficit is important because an unknown percentage of people may exist with good memory T cell responsibility but a low number of or completely lacking peripheral antibodies against SARS-CoV-2. Apart from natural immune responses, vaccination against SARS-CoV-2 turned out to be very effective and much safer than naturally acquired immunity. Nevertheless, besides unwanted side effects of the currently available vector and mRNA preparations, concerns remain whether these vaccines will be strong enough to defeat the pandemic. Altogether, herein we discuss important questions, and try to give answers based on the current knowledge and preliminary data from our laboratories.
ABSTRACT
(1) Background: Vitamin D, a well-established regulator of calcium and phosphate metabolism, also has immune-modulatory functions. An uncontrolled immune response and cytokine storm are tightly linked to fatal courses of COVID-19. The present retrospective study aimed to inves-tigate vitamin D status markers and vitamin D degradation products in a mixed cohort of 148 hospitalized COVID-19 patients with various clinical courses of COVID-19. (2) Methods: The serum concentrations of 25(OH)D3, 25(OH)D2, 24,25(OH)2D3, and 25,26(OH)2D3 were determined by a validated liquid-chromatography tandem mass-spectrometry method in leftover serum samples from 148 COVID-19 patients that were admitted to the University Hospital of the Medical Uni-versity of Graz between April and November 2020. Anthropometric and clinical data, as well as outcomes were obtained from the laboratory and hospital information systems. (3) Results: From the 148 patients, 34 (23%) died within 30 days after admission. The frequency of fatal outcomes did not differ between males and females. Non-survivors were significantly older than survivors, had higher peak concentrations of IL-6 and CRP, and required mechanical ventilation more frequently. The serum concentrations of all vitamin D metabolites and the vitamin D metabolite ratio (VMR) did not differ significantly between survivors and non-survivors. Additionally, the need for res-piratory support was unrelated to the serum concentrations of 25(OH)D vitamin D and the two vitamin D catabolites, as well as the VMR. (4) Conclusion: The present results do not support a relevant role of vitamin D for the course and outcome of COVID-19.