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1.
Front Cell Infect Microbiol ; 11: 795026, 2021.
Article in English | MEDLINE | ID: covidwho-1686455

ABSTRACT

Objective: To develop and validate a prognostic model for in-hospital mortality after four days based on age, fever at admission and five haematological parameters routinely measured in hospitalized Covid-19 patients during the first four days after admission. Methods: Haematological parameters measured during the first 4 days after admission were subjected to a linear mixed model to obtain patient-specific intercepts and slopes for each parameter. A prediction model was built using logistic regression with variable selection and shrinkage factor estimation supported by bootstrapping. Model development was based on 481 survivors and 97 non-survivors, hospitalized before the occurrence of mutations. Internal validation was done by 10-fold cross-validation. The model was temporally-externally validated in 299 survivors and 42 non-survivors hospitalized when the Alpha variant (B.1.1.7) was prevalent. Results: The final model included age, fever on admission as well as the slope or intercept of lactate dehydrogenase, platelet count, C-reactive protein, and creatinine. Tenfold cross validation resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.92, a mean calibration slope of 1.0023 and a Brier score of 0.076. At temporal-external validation, application of the previously developed model showed an AUROC of 0.88, a calibration slope of 0.95 and a Brier score of 0.073. Regarding the relative importance of the variables, the (apparent) variation in mortality explained by the six variables deduced from the haematological parameters measured during the first four days is higher (explained variation 0.295) than that of age (0.210). Conclusions: The presented model requires only variables routinely acquired in hospitals, which allows immediate and wide-spread use as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system. Clinical Trial Registration: Austrian Coronavirus Adaptive Clinical Trial (ACOVACT); ClinicalTrials.gov, identifier NCT04351724.


Subject(s)
COVID-19 , SARS-CoV-2 , Hospital Mortality , Hospitalization , Humans , Retrospective Studies
2.
Cardiovasc Res ; 117(14): 2807-2820, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1596913

ABSTRACT

AIMS: Anticoagulation was associated with improved survival of hospitalized coronavirus disease 2019 (COVID-19) patients in large-scale studies. Yet, the development of COVID-19-associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low-molecular-weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence. METHODS AND RESULTS: Data of 586 hospitalized COVID-19 patients from three different regions of Austria were evaluated retrospectively. Of these, 419 (71.5%) patients received LMWH and 62 (10.5%) received non-vitamin-K oral anticoagulants (NOACs) during hospitalization. Plasma was collected at different time points in a subset of 106 patients in order to evaluate markers of thromboinflammation (H3Cit-DNA) and the cell death marker cell-free DNA (cfDNA). Use of LMWH was associated with improved survival upon multivariable Cox regression (hazard ratio = 0.561, 95% confidence interval: 0.348-0.906). Interestingly, neither LMWH nor NOAC was associated with attenuation of D-dimer increase over time, or thromboinflammation. In contrast, anticoagulation was associated with a decrease in cfDNA during hospitalization, and curtailed viral persistence was observed in patients using LMWH leading to a 4-day reduction of virus positivity upon quantitative polymerase chain reaction [13 (interquartile range: 6-24) vs. 9 (interquartile range: 5-16) days, P = 0.009]. CONCLUSION: Time courses of haemostatic and thromboinflammatory biomarkers were similar in patients with and without LMWH, indicating either no effects of LMWH on haemostasis or that LMWH reduced hypercoagulability to levels of patients without LMWH. Nonetheless, anticoagulation with LMWH was associated with reduced mortality, improved markers of cell death, and curtailed viral persistence, indicating potential beneficial effects of LMWH beyond haemostasis, which encourages use of LMWH in COVID-19 patients without contraindications.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , /virology , Aged , Anticoagulants/pharmacology , Austria/epidemiology , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/mortality , Female , Hemostasis , Heparin, Low-Molecular-Weight/pharmacology , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , SARS-CoV-2/drug effects , /prevention & control
3.
J Am Soc Nephrol ; 32(3): 708-722, 2021 03.
Article in English | MEDLINE | ID: covidwho-1496675

ABSTRACT

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Graft Rejection/therapy , Interleukin-6/antagonists & inhibitors , Kidney Transplantation/adverse effects , Adult , Allografts , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Female , Glomerular Filtration Rate , Graft Rejection/immunology , Graft Rejection/physiopathology , Humans , Infections/etiology , Interleukin-6/immunology , Isoantibodies/blood , Male , Middle Aged , Tissue Donors , Treatment Outcome , Young Adult
4.
Cardiovasc Res ; 117(14): 2807-2820, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1450385

ABSTRACT

AIMS: Anticoagulation was associated with improved survival of hospitalized coronavirus disease 2019 (COVID-19) patients in large-scale studies. Yet, the development of COVID-19-associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low-molecular-weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence. METHODS AND RESULTS: Data of 586 hospitalized COVID-19 patients from three different regions of Austria were evaluated retrospectively. Of these, 419 (71.5%) patients received LMWH and 62 (10.5%) received non-vitamin-K oral anticoagulants (NOACs) during hospitalization. Plasma was collected at different time points in a subset of 106 patients in order to evaluate markers of thromboinflammation (H3Cit-DNA) and the cell death marker cell-free DNA (cfDNA). Use of LMWH was associated with improved survival upon multivariable Cox regression (hazard ratio = 0.561, 95% confidence interval: 0.348-0.906). Interestingly, neither LMWH nor NOAC was associated with attenuation of D-dimer increase over time, or thromboinflammation. In contrast, anticoagulation was associated with a decrease in cfDNA during hospitalization, and curtailed viral persistence was observed in patients using LMWH leading to a 4-day reduction of virus positivity upon quantitative polymerase chain reaction [13 (interquartile range: 6-24) vs. 9 (interquartile range: 5-16) days, P = 0.009]. CONCLUSION: Time courses of haemostatic and thromboinflammatory biomarkers were similar in patients with and without LMWH, indicating either no effects of LMWH on haemostasis or that LMWH reduced hypercoagulability to levels of patients without LMWH. Nonetheless, anticoagulation with LMWH was associated with reduced mortality, improved markers of cell death, and curtailed viral persistence, indicating potential beneficial effects of LMWH beyond haemostasis, which encourages use of LMWH in COVID-19 patients without contraindications.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , /virology , Aged , Anticoagulants/pharmacology , Austria/epidemiology , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/mortality , Female , Hemostasis , Heparin, Low-Molecular-Weight/pharmacology , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , SARS-CoV-2/drug effects , /prevention & control
5.
Vaccines (Basel) ; 9(9)2021 Aug 27.
Article in English | MEDLINE | ID: covidwho-1374551

ABSTRACT

We report the case of a 19-year-old male who complained of myalgia, muscle weakness, and darkened urine two days after receiving his Ad26.COV2.S (Johnson & Johnson, New Brunswick, New Jersey, United States) COVID-19 vaccination. Blood examination revealed an increased creatine kinase (CK) level, and his urinary dipstick tested positive for blood, indicative of acute rhabdomyolysis. Serum creatinine levels were normal. Rhabdomyolysis due to strenuous physical activity was ruled out and further diagnostics excluded an autoimmune cause. Under repeated treatment with intravenous fluid resuscitation (outpatient treatment), his symptoms resolved and peak CK levels of 44,180 U/L returned to almost normal levels within two weeks. Rhabdomyolysis is a rare, potentially fatal vaccine-induced reaction. Further research is needed to better understand the underlying pathomechanism and to investigate whether subcutaneous injection of vaccines may be able to prevent rhabdomyolysis.

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