Monoclonal antibody levels and protection from COVID-19

Multiple monoclonal antibodies have been shown to be effective for both prophylaxis and therapy for SARS-CoV-2 infection. Here we aggregate data from randomized controlled trials assessing the use of monoclonal antibodies (mAb) in preventing symptomatic SARS-CoV-2 infection. We use data on the in vivo concentration of mAb and the associated protection from COVID-19 over time to model the dose-response relationship of mAb for prophylaxis. We estimate that 50% protection from COVID-19 is achieved with a mAb concentration of 96-fold of the in vitro IC50 (95% CI: 32—285). This relationship provides a tool for predicting the prophylactic efficacy of new mAb and against SARS-CoV-2 variants. Finally, we compare the relationship between neutralization titer and protection from COVID-19 after either mAb treatment or vaccination. We find no significant difference between the 50% protective titer for mAb and vaccination, although sample sizes limited the power to detect a difference

Definitions of massive transfusion in adults with critical bleeding: a systematic review.

BACKGROUND: Definitions for massive transfusion (MT) vary widely between studies, contributing to challenges in interpretation of research findings and practice evaluation. In this first systematic review, we aimed to identify all MT definitions used in randomised controlled trials (RCTs) to date to inform the development of consensus definitions for MT. METHODS: We systematically searched the following databases for RCTs from inception until 11 August 2022: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Cumulative Index to Nursing and Allied Health Literature, and Transfusion Evidence Library. Ongoing trials were sought from CENTRAL, ClinicalTrials.gov, and World Health Organisation International Clinical Trials Registry Platform. To be eligible for inclusion, studies had to fulfil all the following three criteria: (1) be an RCT; (2) include an adult patient population with major bleeding who had received, or were anticipated to receive, an MT in any clinical setting; and (3) specify a definition for MT as an inclusion criterion or outcome measure. RESULTS: Of the 8,458 distinct references identified, 30 trials were included for analysis (19 published, 11 ongoing). Trauma was the most common clinical setting in published trials, while for ongoing trials, it was obstetrics. A total of 15 different definitions of MT were identified across published and ongoing trials, varying greatly in cut-offs for volume transfused and time period. Almost all definitions specified the number of red blood cells (RBCs) within a set time period, with none including plasma, platelets or other haemostatic agents that are part of contemporary transfusion resuscitation. For completed trials, the most commonly used definition was transfusion of ≥ 10 RBC units in 24 h (9/19, all in trauma), while for ongoing trials it was 3-5 RBC units (n = 7), with the timing for transfusion being poorly defined, or in some trials not provided at all (n = 5). CONCLUSIONS: Transfusion of ≥ 10 RBC units within 24 h was the most commonly used definition in published RCTs, while lower RBC volumes are being used in ongoing RCTs. Any consensus definitions should reflect the need to incorporate different blood components/products for MT and agree on whether a 'one-size-fits-all' approach should be used across different clinical settings

Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis

Background: Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome. Methods: In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy. Findings: We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1. Interpretation: Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. Funding: The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government

Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial.

BACKGROUND: There is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage. METHODS: We conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo. RESULTS: Twenty-seven of 39 participants (69%; 95% CI, 52-83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8-50.8%) overall, with no difference between arms. CONCLUSIONS: In this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using 'off-the-shelf' fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers. TRIAL REGISTRATION: ISRCTN67540073 . Registered on 5 August 2015

Improving outcomes for patients with lymphoma: design and development of the Australian and New Zealand Lymphoma and Related Diseases Registry

Background Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. Methods The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. Results To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, which we describe, along with approaches used to overcome them. Several confirmed international collaborations are now in place, and the registry is providing valuable data for clinicians, researchers, industry and government, including through presentations of results at major national and international conferences. Conclusion Challenges in establishing the LaRDR have been successfully overcome and the registry is now a valuable resource for lymphoma clinicians, researchers, health economists and others in Australia, New Zealand and globally

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

How should we use convalescent plasma therapies for the management of COVID-19?

Convalescent plasma (CP) from blood donors with antibodies to severe acute respiratory syndrome coronavirus 2 may benefit patients with COVID-19 by providing immediate passive immunity via transfusion or by being used to manufacture hyperimmune immunoglobulin preparations. Optimal product characteristics (including neutralizing antibody titers), transfusion volume, and administration timing remain to be determined. Preliminary COVID-19 CP safety data are encouraging, but establishing the clinical efficacy of CP requires an ongoing international collaborative effort. Preliminary results from large, high-quality randomized trials have recently started to be reported

Blood donation by African migrants and refugees in Australia

Changing population demographics have important implications for the ability of transfusion services to meet the transfusion requirements of minority groups. In Western countries, differences in red-blood-cell (RBC) antigens between predominantly Caucasian blood donors and recipients from different demographic backgrounds may result in higher RBC alloimmunization rates, particularly in those who are chronically transfused, and can make it more difficult to source compatible blood. Ensuring blood donors are representative of the general population is particularly relevant for patients of African descent, who have a number of important blood group differences from Caucasians. However, there are challenges in ensuring a representative donor population, especially when the national population is very multicultural. Research in African migrants and refugees living in Australia has identified blood donation knowledge, misconceptions about blood donation from experiences prior to migration, and perceptions or experiences of discrimination within the host country as important determinants of blood donation. Therefore, promotion of knowledge and awareness of blood donation and blood and health service processes should be considered to assist with the recruitment of migrant donors