Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Zika virus and autoimmunity. One-step forward

Zika virus (ZIKV) infection has been associated with the development of Guillain-Barré syndrome (GBS) and idiopathic thrombocytopenic purpura (ITP). Whether ZIKV infection is related to other autoimmune diseases is unknown. Therefore, an association study to evaluate rheumatic and thyroid autoimmunity in patients with ZIKV disease was conducted through a panel of 14 autoantibodies. In addition, a literature review on ZIKV, and GBS and ITP was performed. Our results disclosed a lack of association of rheumatoid and thyroid autoimmunity with ZIKV disease. A total of 272 cases of GBS related to ZIKV were retrieved from the literature, the majority of them being males (54.8%). Electrophysiological findings indicated acute inflammatory demyelinating polyneuropathy as the most frequent subphenotype (75.7%). Up to date, twenty-four cases of ITP in patients with ZIKV disease have been published. Although a few fatal cases have been observed, most of the reported patients responded well to immunomodulatory treatment. A review of the mechanisms incriminated into the development of autoimmune phenomenon in ZIKV disease indicates molecular mimicry as the most plausible one. Nevertheless, more research aimed at deciphering ZIKV disease pathogenesis and its relationship with autoimmunity is warranted

Bystander activation and autoimmunity

The interaction over time of genetic, epigenetic and environmental factors (i.e., autoimmune ecology) increases or decreases the liability an individual would have to develop an autoimmune disease (AD) depending on the misbalance between risk and protective effects. Pathogens have been the most common antecedent events studied, but multiple other environmental factors including xenobiotic chemicals, drugs, vaccines, and nutritional factors have been implicated into the development of ADs. Three main mechanisms have been offered to explain the development of autoimmunity: molecular mimicry, epitope spreading, and bystander activation. The latter is characterized by auto-reactive B and T cells that undergo activation in an antigen-independent manner, influencing the development and course of autoimmunity. Activation occurs due to a combination of an inflammatory milieu, co-signaling ligands, and interactions with neighboring cells. In this review, we will discuss the studies performed seeking to define the role of bystander activation in systemic and organ-specific ADs. In all cases, we are cognizant of individual differences between hosts and the variable latency time for clinical expression of disease, all of which have made our understanding of the etiology of loss of immune tolerance difficult and enigmatic. © 2019 Elsevier Lt

Autonomic symptoms following Zika virus infection

Purpose: To determine if autonomic symptoms are associated with previous Zika virus infection. Methods: Case–control study including 35 patients with Zika virus infection without evidence of neurological disease and 105 controls. Symptoms of autonomic dysfunction were assessed with the composite autonomic symptom scale 31 (COMPASS-31). Results: Patients with previous Zika virus infection had significantly higher COMPASS-31 score than controls regardless of age and sex (p = 0.007). The main drivers for the higher scores where orthostatic intolerance (p = 0.003), secretomotor (p = 0.04) and bladder symptoms (p  less than  0.001). Conclusion: Zika virus infection is associated with autonomic dysfunction. The mechanisms remain to be elucidated. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature

Progress towards precision medicine for lupus: The role of genetic biomarkers

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease (AD). Precision medicine gives clinicians and society access to the information needed to create individually tailored programs to predict, prevent, and treat SLE. Although several biomarkers have been described for SLE, current expansion of knowledge on lupus genetics makes the implementation of genetic biomarkers possible. Herein, a comprehensive description of relevant SLE genetic biomarkers from the precision medicine perspective is offered. National inception cohorts should be created and the implementation of translational programs for the control of ADs such as SLE should be put into practice. Factors that are predictive of developing these conditions should be examined at the population level in order to establish preventive measures in at-risk individuals for whom healthcare should be personalized/precise and participatory. The implementation of such a program will allow the discovery of new mechanisms and a new taxonomy of ADs. The translational model should also involve educational and training programs together with digital participatory surveillance systems. Healthcare’s one-size-fits-all approach to treating patients will be replaced with a personalized/precision approach to medicine that focuses on individuals and each family member. © 2018 Informa UK Limited, trading as Taylor and Francis Group

Bystander activation and autoimmunity

The interaction over time of genetic, epigenetic and environmental factors (i.e., autoimmune ecology) increases or decreases the liability an individual would have to develop an autoimmune disease (AD) depending on the misbalance between risk and protective effects. Pathogens have been the most common antecedent events studied, but multiple other environmental factors including xenobiotic chemicals, drugs, vaccines, and nutritional factors have been implicated into the development of ADs. Three main mechanisms have been offered to explain the development of autoimmunity: molecular mimicry, epitope spreading, and bystander activation. The latter is characterized by auto-reactive B and T cells that undergo activation in an antigen-independent manner, influencing the development and course of autoimmunity. Activation occurs due to a combination of an inflammatory milieu, co-signaling ligands, and interactions with neighboring cells. In this review, we will discuss the studies performed seeking to define the role of bystander activation in systemic and organ-specific ADs. In all cases, we are cognizant of individual differences between hosts and the variable latency time for clinical expression of disease, all of which have made our understanding of the etiology of loss of immune tolerance difficult and enigmatic. © 2019 Elsevier Lt

Progress towards precision medicine for lupus: The role of genetic biomarkers

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease (AD). Precision medicine gives clinicians and society access to the information needed to create individually tailored programs to predict, prevent, and treat SLE. Although several biomarkers have been described for SLE, current expansion of knowledge on lupus genetics makes the implementation of genetic biomarkers possible. Herein, a comprehensive description of relevant SLE genetic biomarkers from the precision medicine perspective is offered. National inception cohorts should be created and the implementation of translational programs for the control of ADs such as SLE should be put into practice. Factors that are predictive of developing these conditions should be examined at the population level in order to establish preventive measures in at-risk individuals for whom healthcare should be personalized/precise and participatory. The implementation of such a program will allow the discovery of new mechanisms and a new taxonomy of ADs. The translational model should also involve educational and training programs together with digital participatory surveillance systems. Healthcare’s one-size-fits-all approach to treating patients will be replaced with a personalized/precision approach to medicine that focuses on individuals and each family member. © 2018 Informa UK Limited, trading as Taylor and Francis Group

Autoimmunity in Guillain-Barré syndrome associated with Zika virus infection and beyond

Autoimmune diseases share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities among them as well as their familial clustering. Guillain-Barré syndrome (GBS), an autoimmune peripheral neuropathy, has been recently associated with Zika virus (ZIKV) infection. Based on a series of cases, this review article provides a comparative analysis of GBS associated with ZIKV infection, contrasted with the general characteristics of GBS in light of the autoimmune tautology, including gender differences in prevalence, subphenotypes, polyautoimmunity, familial autoimmunity, age at onset, pathophysiology, ecology, genetics, ancestry, and treatment. © 2017 Elsevier B.V