COVID-19 und Lebererkrankungen COVID-19 and liver diseases

Bis zu 53 % der PatientInnen mit Coronavirus Disease 2019 (COVID-19) weisen eine hepatische Beteiligung auf. Durch die Expression der Hauptzielstruktur für „severe acute respiratory syndrome coronavirus type 2" (SARS-CoV-2), des Angiotensin-converting-Enzym-2(ACE2)-Rezeptors, auch auf Cholangiozyten, sinusoidalen Endothelzellen und Hepatozyten kann es zu einer direkten Schädigung der Leber kommen. Ferner spielt eine indirekte (nicht durch Rezeptoren vermittelte) Schädigung der Leber im Rahmen von COVID-19 durch eine schwere systemische Inflammation mit Zytokinsturm, hepatischen Thrombosen und einer systemischen Hypoxie eine wichtige Rolle. Bei COVID-19 gelten Leberwerte als wichtige Prädiktoren für die Prognose der PatientInnen. Wichtig ist es hierbei Differenzialdiagnosen für die Leberwerterhöhung, wie andere Virusinfektionen, medikamentös-toxisch induzierte Leberschädigung sowie autoimmune, metabolische und andere Lebererkrankungen, abzuklären. Von hoher klinischer Relevanz für die Behandlung kritisch kranker PatientInnen auf der Intensivstation ist das Krankheitsbild der „secondary sclerosing cholangitis in critically ill patients" (SSC-CIP). Hierfür sind unter anderem hochdosierte Katecholamine, eine Beatmung mit hohem positivem endexspiratorischem Druck (PEEP) und die extrakorporale Membranoxygenierung (ECMO) Risikofaktoren. Eine frühe Diagnose dieser Erkrankung und Behandlung mittels interventioneller endoskopischer retrograder Cholangiographie (ERC) ist hierbei von entscheidender Bedeutung. Auch sollte eine Lebertransplantation evaluiert werden. Bei einer COVID-19-Erkrankung treten Fälle mit SSC, sog. COVID-SSC, auf. Die COVID-SSC und die SSC-CIP sind im klinischen Phänotyp, Risikofaktoren, Prognose und transplantatfreien Überleben vergleichbar. PatientInnen mit vorbestehender Lebererkrankung haben kein erhöhtes Risiko für eine Infektion mit SARS-CoV‑2, erkranken jedoch schwerer an COVID-19 als PatientInnen ohne Lebervorerkrankungen. Bei PatientInnen mit einer vorbestehenden Leberzirrhose kann eine SARS-CoV-2-Infektion ein akut-auf-chronisches Leberversagen (ACLF) induzieren. Hierbei handelt es sich um ein Krankheitsbild mit einer sehr hohen Mortalität, das im Rahmen einer intensivmedizinischen Behandlung therapiert werden muss.

Prognostic factors for favorable outcomes after veno-venous extracorporeal membrane oxygenation in critical care patients with COVID-19.

BACKGROUND: Patients with COVID-19 and severe acute respiratory failure may require veno-venous extracorporeal membrane oxygenation (VV ECMO). Yet, this procedure is resource-intensive and high mortality rates have been reported. Thus, predictors for identifying patients who will benefit from VV ECMO would be helpful. METHODS: This retrospective study included 129 patients with COVID-19 and severe acute respiratory failure, who had received VV ECMO at the University Medical Center Regensburg, Germany, between 1 March 2020 and 31 December 2021. Patient-specific factors and relevant intensive-care parameters at the time of the decision to start VV ECMO were investigated regarding their value as predictors of patient survival. In addition, the intensive-care course of the first 10 days of VV ECMO was compared between survivors and patients who had died in the intensive care unit. RESULTS: The most important parameters for predicting outcome were patient age and platelet count, which differed significantly between survivors and non-survivors (age: 52.6±8.1 vs. 57.4±10.1 years, p<0.001; platelet count before VV ECMO: 321.3±132.2 vs. 262.0±121.0 /nL, p = 0.006; average on day 10: 199.2±88.0 vs. 147.1±57.9 /nL, p = 0.002). A linear regression model derived from parameters collected before the start of VV ECMO only included age and platelet count. Patients were divided into two groups by using receiver operating characteristics (ROC) analysis: group 1: 78% of patients, mortality 26%; group 2: 22% of patients, mortality 75%. A second linear regression model included average blood pH, minimum paO2, and average pump flow on day 10 of VV ECMO in addition to age and platelet count. The ROC curve resulted in two cut-off values and thus in three groups: group 1: 25% of patients, mortality 93%; group 2: 45% of patients, mortality 31%; group 3: 30% of patients, mortality 0%.

Evaluation of models for prognosing mortality in critical care patients with COVID-19: First- and second-wave data from a German university hospital.

BACKGROUND: In a previous study, we had investigated the intensive care course of patients with coronavirus disease 2019 (COVID-19) in the first wave in Germany by calculating models for prognosticating in-hospital death with univariable and multivariable regression analysis. This study analyzed if these models were also applicable to patients with COVID-19 in the second wave. METHODS: This retrospective cohort study included 98 critical care patients with COVID-19, who had been treated at the University Medical Center Regensburg, Germany, between October 2020 and February 2021. Data collected for each patient included vital signs, dosage of catecholamines, analgosedation, anticoagulation, and antithrombotic medication, diagnostic blood tests, treatment with extracorporeal membrane oxygenation (ECMO), intensive care scores, ventilator therapy, and pulmonary gas exchange. Using these data, expected mortality was calculated by means of the originally developed mathematical models, thereby testing the models for their applicability to patients in the second wave. RESULTS: Mortality in the second-wave cohort did not significantly differ from that in the first-wave cohort (41.8% vs. 32.2%, p = 0.151). As in our previous study, individual parameters such as pH of blood or mean arterial pressure (MAP) differed significantly between survivors and non-survivors. In contrast to our previous study, however, survivors and non-survivors in this study showed significant or even highly significant differences in pulmonary gas exchange and ventilator therapy (e.g. mean and minimum values for oxygen saturation and partial pressure of oxygen, mean values for the fraction of inspired oxygen, positive expiratory pressure, tidal volume, and oxygenation ratio). ECMO therapy was more frequently administered than in the first-wave cohort. Calculations of expected mortality by means of the originally developed univariable and multivariable models showed that the use of simple cut-off values for pH, MAP, troponin, or combinations of these parameters resulted in correctly estimated outcome in approximately 75% of patients without ECMO therapy.

SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia with Venous Thrombosis, Pulmonary Embolism, and Adrenal Haemorrhage: A Case Report with Literature Review.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) with venous thrombosis is a rare complication of SARS-CoV-2 vaccination with ChAdOx1 (AstraZeneca) and AD26.COV2.S (Johnson & Johnson, New Brunswick, NJ, USA) associated with high mortality. At present, there are no known differences in the pathophysiology or risk factors of VITT with the AstraZeneca vaccine (ChAdOx1) compared with the Johnson & Johnson vaccine (AD26.COV2.S). Herein, we present the case of a healthy 39-year-old patient with VITT after having received the vaccine Ad26.COV2.S. Ten days after vaccination, the patient developed a deep vein thrombosis and subsequent pulmonary embolism. A computed tomography scan of the abdomen showed adrenal gland bleeding and an adrenocorticotrophic hormone stimulation test diagnosed adrenal insufficiency. Therapy with intravenous immunoglobulin, argatroban and hydrocortisone was initiated immediately after diagnosis. The patient left the hospital 22 days after admission with the diagnosis of adrenal insufficiency but otherwise in good health. To the best of our knowledge, five cases of VITT and adrenal bleeding have been described to date in the literature but the presented case was the first to occur after immunisation with the vaccine of Johnson & Johnson. In summary, VITT-associated adrenal dysfunction is a very rare complication of vaccination with an adenoviral vector-based COVID-19 vaccine.

Interprofessional Collaboration between ICU Physicians, Staff Nurses, and Hospital Pharmacists Optimizes Antimicrobial Treatment and Improves Quality of Care and Economic Outcome.

(1) Background: Antibiotic resistance is a worldwide health threat. The WHO published a global strategic plan in 2001 to contain antimicrobial resistance. In the following year, a workshop identified crucial barriers to the implementation of the strategy, e.g., underdeveloped health infrastructures and the scarcity of valid data as well as a lack of implementation of antibiotic stewardship (ABS) programs in medical curricula. Here, we show that interprofessional learning and education can contribute to the optimization of antibiotic use and preserving antibiotic effectiveness. We have initiated interprofessional rounds on a medical intensive care unit (MICU) with a focus on gastroenterology, hepatology, infectious diseases, endocrinology, and liver transplantation. We integrated ICU physicians, hospital pharmacists, nursing staff, and medical students as well as students of pharmacy to broaden the rather technical concept of ABS with an interprofessional approach to conceptualize awareness and behavioral change in antibiotic prescription and use. Methods: Clinical performance data and consumption figures for antibiotics were analyzed over a 10-year period from 2012 to 2021. The control period covered the years 2012-2014. The intervention period comprised the years 2015-2021, following the implementation of an interprofessional approach to ABS at a MICU of a German university hospital. Data from the hospital pharmacy, hospital administration, and hospital information system were included in the analyses. A specific electronic platform was developed for the optimization of documentation, interprofessional learning, education, and sustainability. The years 2020 and 2021 were analyzed independently due to the SARS-CoV-2 pandemic and the care of numerous COVID-19 patients at the MICU. Results: Implementation of an interprofessional ABS program resulted in the optimization of antibiotic management at the MICU. The suggestions of the hospital pharmacist for optimization can be divided into the following categories (i) indication for and selection of therapy (43.6%), (ii) optimization of dosing (27.6%), (iii) drug interactions (9.4%), (iv) side effects (4.1%), and (v) other pharmacokinetic, pharmacodynamic, and pharmacoeconomic topics (15.3%). These suggestions were discussed among the interprofessional team at the MICU; 86.1% were consequently implemented and the prescription of antibiotics was changed. In addition, further analysis of the intensive care German Diagnosis Related Groups (G-DRGs) showed that the case mix points increased significantly by 31.6% during the period under review. Accordingly, the severity of illness of the patients treated at the ICU as measured by the Simplified Acute Physiology Score (SAPS) II increased by 21.4% and the proportion of mechanically ventilated patients exceeded 50%. Antibiotic spending per case mix point was calculated. While spending was EUR 60.22 per case mix point in 2015, this was reduced by 42.9% to EUR 34.37 per case mix point by 2019, following the implementation of the interprofessional ABS program on the MICU. Through close interprofessional collaboration between physicians, hospital pharmacists, and staff nurses, the consumption of broad-spectrum antibiotics, e.g., carbapenems, was significantly reduced, thus improving patient care. In parallel, the case mix and case mix index increased. Thus, the responsible use of resources and high-performance medicine are not contradictory. In our view, close interprofessional and interdisciplinary collaboration between physicians, pharmacists, and nursing staff will be of outstanding importance in the future to prepare health care professionals for global health care to ensure that the effectiveness of our antibiotics is preserved.

Contribution of High Viral Loads, Detection of Viral Antigen and Seroconversion to Severe Acute Respiratory Syndrome Coronavirus 2 Infectivity.

BACKGROUND: From a public health perspective, effective containment strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be balanced with individual liberties. METHODS: We collected 79 respiratory samples from 59 patients monitored in an outpatient center or in the intensive care unit of the University Hospital Regensburg. We analyzed viral load by quantitative real-time polymerase chain reaction, viral antigen by point-of-care assay, time since onset of symptoms, and the presence of SARS-CoV-2 immunoglobulin G (IgG) antibodies in the context of virus isolation from respiratory specimens. RESULTS: The odds ratio for virus isolation increased 1.9-fold for each log10 level of SARS-CoV-2 RNA and 7.4-fold with detection of viral antigen, while it decreased 6.3-fold beyond 10 days of symptoms and 20.0-fold with the presence of SARS-CoV-2 antibodies. The latter was confirmed for B.1.1.7 strains. The positive predictive value for virus isolation was 60.0% for viral loads >107 RNA copies/mL and 50.0% for the presence of viral antigen. Symptom onset before 10 days and seroconversion predicted lack of infectivity with negative predictive values of 93.8% and 96.0%. CONCLUSIONS: Our data support quarantining patients with high viral load and detection of viral antigen and lifting restrictive measures with increasing time to symptom onset and seroconversion. Delay of antibody formation may prolong infectivity.

Lower blood pH as a strong prognostic factor for fatal outcomes in critically ill COVID-19 patients at an intensive care unit: A multivariable analysis.

BACKGROUND: Data of critically ill COVID-19 patients are being evaluated worldwide, not only to understand the various aspects of the disease and to refine treatment strategies but also to improve clinical decision-making. For clinical decision-making in particular, prognostic factors of a lethal course of the disease would be highly relevant. METHODS: In this retrospective cohort study, we analyzed the first 59 adult critically ill Covid-19 patients treated in one of the intensive care units of the University Medical Center Regensburg, Germany. Using uni- and multivariable regression models, we extracted a set of parameters that allowed for prognosing in-hospital mortality. RESULTS: Within the cohort, 19 patients died (mortality 32.2%). Blood pH value, mean arterial pressure, base excess, troponin, and procalcitonin were identified as highly significant prognostic factors of in-hospital mortality. However, no significant differences were found for other parameters expected to be relevant prognostic factors, like low arterial partial pressure of oxygen or high lactate levels. In the multivariable logistic regression analysis, the pH value and the mean arterial pressure turned out to be the most influential prognostic factors for a lethal course.

Secondary hemophagocytic lymphohistiocytosis and severe liver injury induced by hepatic SARS-CoV-2 infection unmasking Wilson's disease: Balancing immunosuppression.

A 21-year-old woman was hospitalized due to coronavirus disease 2019 (COVID-19)-associated respiratory and hepatic impairment concomitant with severe hemolytic anemia. Upon diagnosis of secondary hemophagocytic lymphohistiocytosis, immunosuppression with anakinra and steroids was started, leading to a hepatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viremia. Subsequent liver biopsy revealed virus particles in hepatocytes by electron microscopy and SARS-CoV-2 virus could be isolated and cultured. Immunosuppression was stopped and convalescent donor plasma given. In the differential diagnosis, an acute crisis of Wilson's disease was raised by laboratory and genetic testing. This case highlights the complexity of balancing immunosuppression to control hyperinflammation versus systemic SARS-CoV-2 dissemination.

A highly specific and sensitive serological assay detects SARS-CoV-2 antibody levels in COVID-19 patients that correlate with neutralization.

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels. METHODS: In our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated. RESULTS: The RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%; N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection; N = 53) in serum. CONCLUSIONS: With the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.