Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups.

Introduction: While complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood. Methods: We therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome. Results: We show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p<0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID. Conclusion: In conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted.

Poor Preoperative Nutritional Status, but Not Hormone Levels, Are Associated With Mortality After Cardiac Surgery.

OBJECTIVES: The authors' aim was to examine the preoperative hormone and nutritional status in patients undergoing elective cardiac surgery. DESIGN AND SETTINGS: The authors' research was a single-center, prospective, observational study (ClinicalTrials.gov: NCT03736499). PARTICIPANTS & INTERVENTIONS: The authors examined 252 patients who underwent elective cardiac surgery. Preoperative thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), prolactin, and testosterone levels were collected and analyzed after the surgery. The Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status (CONUT), and Prognostic Nutritional Index (PNI) were all calculated as a sum and groups. Frailty was calculated based on the modified Frailty Index-11. The primary outcome was overall mortality. MEASUREMENTS AND MAIN RESULTS: The mean age of the patients was 64.23 years (standard deviation: 11.07 years). Thirty-three patients (13.01%) died during the median follow-up time of 20.48 months (interquartile range: 18.90-22.98 months). Thyroid hormones were examined as continuous variables and also in 3 groups based on low, normal, and high hormone levels. Continuous TSH (p = 0.230), continuous fT3 (p = 0.492), and continuous fT4 (p = 0.657) were not significantly associated with total mortality. After adjustment for the European System for Cardiac Operative Risk Evaluation II and postoperative complications, the following nutritional scores were associated with total mortality: GNRI < 91 (adjusted hazard ratio [AHR]: 4.384; 95% confidence interval [CI]: 1.866-10.303, p = 0.001), the higher CONUT group (AHR: 1.736; 95% CI: 1.736-2.866, p = 0.031), and a PNI < 48 points (AHR: 3.465; 95% CI: 1.735-6.918, p < 0.001). The modified Frailty Index-11 was not associated with mortality. CONCLUSIONS: Before cardiac surgery, nutritional status should be assessed because the findings may help to decrease mortality. The hormone levels were not associated with mortality.

Implantación de un protocolo de ensayos exhaustivo para un respirador mecánico de fabricación rápida Implementation of a comprehensive testing protocol for a rapidly manufactured mechanical ventilator

Introducción: La pandemia de COVID-19 ha puesto de manifiesto que las sobrecargas en los cuidados intensivos pueden desbordar las infraestructuras sanitarias existentes, que fue evidente en la escasez inmediata de respiradores mecánicos observada en todo el mundo. A pesar de las tentativas de alentar la autorización urgente de respiradores de emergencia recién desarrollados, los protocolos de ensayos existentes no están aceptados en todo el mundo, no están normalizados y ninguno trata los ensayos en entornos clínicos. El objetivo de este estudio fue recopilar y ejecutar un protocolo de ensayos clínicos exhaustivo para un respirador de emergencia recién desarrollado. Métodos: Aplicando las directrices previas, recopilamos un protocolo secuencial de ensayos con: 1. estudio preclínico, 2. estudio de seguridad, 3. ensayo de operabilidad por los facultativos, y 4. fase clínica con participación de pacientes con insuficiencia respiratoria. Se analizó el protocolo con el respirador Luca, un respirador mecánico con configuraciones sofisticadas desarrollado rápida y específicamente para responder a la pandemia de la COVID-19. Resultados: Durante las fases preclínicas/de seguridad, los cambios de presión y volumen que produjo el respirador se consideraron aceptables según la directriz Rapidly Manufactured Ventilator System. Asimismo, nuestro protocolo permitió identificar varios problemas que se resolvieron fácilmente con mínimos ajustes de software. La operabilidad resultó excelente (puntuación total de la escala de operabilidad del sistema = 90,5). Los ensayos clínicos revelaron que una muestra de 15 pacientes graves presentaba suficiente potencia estadística para detectar todas las diferencias significativas de interés clínico entre el respirador Luca y un respirador de UCI ordinario. Conclusiones: El respirador resultó exacto, fiable, seguro y fácil de usar. La implantación de un protocolo de ensayos preclínicos y clínicos exhaustivo y normalizado es factible y puede habilitar la autorización de emergencia oportuna de respiradores mecánicos de desarrollo rápido, cruciales en situaciones pandémicas.

Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study.

Background: Dysregulation of complement system is thought to be a major player in development of multi-organ damage and adverse outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement system activity and development of severe acute kidney injury (AKI) among hospitalized COVID-19 patients. Materials and Methods: In this multicenter, international study, complement as well as inflammatory and thrombotic parameters were analyzed in COVID-19 patients requiring hospitalization at one US and two Hungarian centers. The primary endpoint was development of severe AKI defined by KDIGO stage 2+3 criteria, while the secondary endpoint was need for renal replacement therapy (RRT). Complement markers with significant associations with endpoints were then correlated with a panel of inflammatory and thrombotic biomarkers and assessed for independent association with outcome measures using logistic regression. Results: A total of 131 hospitalized COVID-19 patients (median age 66 [IQR, 54-75] years; 54.2% males) were enrolled, 33 from the US, and 98 from Hungary. There was a greater prevalence of complement over-activation and consumption in those who developed severe AKI and need for RRT during hospitalization. C3a/C3 ratio was increased in groups developing severe AKI (3.29 vs. 1.71; p < 0.001) and requiring RRT (3.42 vs. 1.79; p < 0.001) in each cohort. Decrease in alternative and classical pathway activity, and consumption of C4 below reference range, as well as elevation of complement activation marker C3a above the normal was more common in patients progressing to severe AKI. In the Hungarian cohort, each standard deviation increase in C3a (SD = 210.1) was independently associated with 89.7% increased odds of developing severe AKI (95% CI, 7.6-234.5%). Complement was extensively correlated with an array of inflammatory biomarkers and a prothrombotic state. Conclusion: Consumption and dysregulation of complement system is associated with development of severe AKI in COVID-19 patients and could represent a promising therapeutic target for reducing thrombotic microangiopathy in SARS-CoV-2 infection.

Associations between the von Willebrand Factor-ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality.

BACKGROUND: Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated. OBJECTIVES: We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19. METHODS: Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records. RESULTS: VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio-indicating complement overactivation and consumption-was a strong independent predictor of in-hospital mortality. CONCLUSION: Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.

The efficacy of virtual distance training of intensive therapy and anaesthesiology among fifth-year medical students during the COVID-19 pandemic: a cross-sectional study.

BACKGROUND: The coronavirus disease (COVID-19) brought several challenges in medical education. The aim of our study was to investigate whether virtual distance trainings (VDT) organized during the COVID-19 pandemic at our university were effective in replacing in-person bed-side education in intensive therapy and anaesthesiology among fifth-year medical students, both from students' and instructors' perspectives. METHODS: This was a cross-sectional study consisting of three parts: a 20-item students' questionnaire filled out by students participating in VDT, a 22-item instructors' questionnaire filled out by instructors taking part in virtual distance education and a 20-item knowledge test completed by students participating in VDT, as well as by students visiting bed-side trainings (BT) during the same semester, before COVID-19 pandemic. The questionnaires focused on effectiveness, content, self-preparedness, technical background and interactivity of VDT. Instructors' and students' responses given to the common questions, as well as the knowledge test results were compared. Mann-Whitney U test was used for group comparisons and binary logistic regression was performed to analyze the influence of previous health-care experience on students' feeling of self-preparedness. RESULTS: One hundred thirthen students (response rate {RR}: 68%) and 29 instructors (RR: 97%) filled out the questionnaires. The majority of students found our VDT useful and effective; however, a considerable number of participants felt disadvantaged by taking VDT instead of BT sessions and would recommend keeping virtual distance education methods combined with BT. Instructors found VDT overall effective and deemed the transfer of their knowledge satisfactory; however, they described worse interactivity and contact with students during virtual sessions compared to in-person teaching. Instructors showed a clearer consensus that VDT should not replace BT in the future, while students' answers were more divided in this regard. Previous health-care experience did not influence students' feeling of self-preparedness. One hundred and twenty-seven students (56 after VDT {RR: 34%}; 71 after BT {RR: 67%}) completed the end-of-semester knowledge test. Students attending VDT performed better than students visiting BT (median score VDT:83.5 vs BT:77.3; p = 0.015). CONCLUSIONS: Virtual distance learning incorporating virtual practice sessions was effective in maintaining continuous education of intensive therapy and anaesthesiology among fifth-year medical students during the COVID-19 outbreak.

Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection.

Objectives: Uncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19. Methods: In this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records. Results: Increased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55-8.45, 95% CI) and 6.1 (2.1-17.8), respectively]. Conclusion: Increased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.

Challenges of intensive care and anesthesiology related to COVID-19 pandemic. Practical considerations / [Az aneszteziológiai és intenzív ellátás kihívásai a COVID­19-fertozéssel kapcsolatban. Gyakorlati ajánlás]

Due to the coronavirus epidemic, healthcare systems face growing challenges all around the world nowadays. These challenges are the most critical in the field of intensive treatment and anesthesiology. One of the most important prerequisites of effective critical care treatment is preserving the involved healthcare workers from the infection, by providing them with detailed practical advices on the preventive measures and treatment strategies. The aim of the present review is to summarize the most important related knowledge available from previous experiences. Orv Hetil. 2020; 161(17): 652­659.