Vitamin D deficiency and COVID-19 severity - plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis
Journal of Internal Medicine. 2022;289(1):97-115
Background: SARS-CoV-2 coronavirus infection ranges from asymptomatic through to fatal COVID-19 characterized by a 'cytokine storm' and lung failure Vitamin D deficiency has been postulated as a determinant of severity Objectives: To review the evidence relevant to vitamin D and COVID-19
Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection
Nature Communications. 2021;12(1):3189
In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.
ABO blood group and COVID-19: an updated systematic literature review and meta-analysis
Blood Transfusion = Trasfusione Del Sangue. 2021
BACKGROUND Following the first reports in the literature, the association between the ABO blood group and SARS-CoV-2 infection has been investigated by a number of studies, although with varying results. The main object of this systematic review was to assess the relationship between the ABO blood group and the occurrence and severity of COVID-19. MATERIALS AND METHODS A systematic literature search using appropriate MeSH terms was performed through Medline and PubMed. The outcomes considered were the prevalence of the blood group O vs non-O types in SARS-CoV-2 infected and non-infected subjects, and the severity of SARS-CoV-2 infection according to ABO group. The methodological quality of the studies included in the analysis was assessed with the Newcastle-Ottawa Scale, and the overall quality of the available evidence using the GRADE system. Benchmarks used to evaluate the effect size were odd ratios (ORs) for case control studies and risk ratios (RRs) for cohort studies. RESULTS Twenty-one studies were included in the analysis. Overall, individuals with group O had a lower infection rate compared to individuals of non-O group (OR: 0.81; 95% CI: 0.75, 0.86). However, the difference in the effect size was significantly lower in cohort studies compared to case control studies. No evidence was found indicating an effect of the O type on the disease severity in the infected patients. DISCUSSION We have found low/very low evidence that group O individuals are less susceptible to SARS-CoV-2 infection compared to those in the non-O group. No evidence was found indicating an effect of the O type on disease severity in SARS-CoV-2 infection.
COVID-19 Convalescent Plasma: from donation to treatment - A Systematic Review & Single Center Experience
Missouri medicine. 2021;118(1):74-80
Convalescent plasma is an old treatment for a new disease. The coronavirus disease 2019 (COVID-19) pandemic caused the analysis of convalescent plasma to reemerge as a possible treatment. First, a systematic review summarizes the available research examining the use of convalescent plasma for the treatment of patients with COVID-19. Second, we describe our experience in establishing a single-center convalescent plasma donation program.
Prospective individual patient data meta-analysis: Evaluating convalescent plasma for COVID-19
Statistics in Medicine. 2021
As the world faced the devastation of the COVID-19 pandemic in late 2019 and early 2020, numerous clinical trials were initiated in many locations in an effort to establish the efficacy (or lack thereof) of potential treatments. As the pandemic has been shifting locations rapidly, individual studies have been at risk of failing to meet recruitment targets because of declining numbers of eligible patients with COVID-19 encountered at participating sites. It has become clear that it might take several more COVID-19 surges at the same location to achieve full enrollment and to find answers about what treatments are effective for this disease. This paper proposes an innovative approach for pooling patient-level data from multiple ongoing randomized clinical trials (RCTs) that have not been configured as a network of sites. We present the statistical analysis plan of a prospective individual patient data (IPD) meta-analysis (MA) from ongoing RCTs of convalescent plasma (CP). We employ an adaptive Bayesian approach for continuously monitoring the accumulating pooled data via posterior probabilities for safety, efficacy, and harm. Although we focus on RCTs for CP and address specific challenges related to CP treatment for COVID-19, the proposed framework is generally applicable to pooling data from RCTs for other therapies and disease settings in order to find answers in weeks or months, rather than years.
COVID-19 Associated Thrombocytopenia in Children: An Emerging Issue
International Journal of Pediatrics-Mashhad. 2021;9(6):13635-13642
Thrombocytopenia is a risk factor for increased mortality and morbidity during the Coronavirus Disease 2019 (COVID-19) In patients with COVID-19, the mechanisms lead to thrombocytopenia seems to be multifactorial Thrombotic consumption of platelets in microvasculature, cytokine release, sepsis, and drug induced, direct infection of megakaryocytes and autoimmune destruction of platelets are the leading etiologies in COVID-19 and thrombocytopenia In this overview, the research was conducted by screening the relevant articles evaluating the COVID-19 associated thrombocytopenia in children An electronic search was performed in online databases of Scopus, EMBASE, Cochrane, Web of Science and Medline (via PubMed) with English language from December 2019 up to September 2020 Thrombocytopenia at admission in patients with SARS-CoV-2 infection is common, but delayed phase thrombocytopenia (occurring 2 weeks after beginning of symptoms) is uncertain The delayed phase thrombocytopenia in COVID-19 is more prevalent in infected case with low lymphocyte count at admission and has a significant correlation with higher mortality rate In majority of cases with COVID-19 and thrombocytopenia, the platelet count is mildly decreased Severe thrombocytopenia or a prompt decline in number of platelets often indicates immune mediated thrombocytopenia or in late terminal stages of this infection Thrombocytopenia is a significant finding in patients with severe type of COVID -19 Immune mediated platelet destruction might account for the delayed-phase thrombocytopenia in a group of patients, and can manifest as severe thrombocytopenia It is important for practitioners to be vigilant and aware of this hematologic abnormality
Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021
BACKGROUND SARS-CoV-2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor would reduce COVID-19 progression. METHODS Adults (N=497) symptomatic with mild COVID-19 and at high-risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N=246) or placebo-equivalent (N=251) for 21 days and followed to Day 35. Primary endpoints were safety and progression to moderate or severe disease, per the Gates MRI scale. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS The study was terminated after 497 of target 600 participants were enrolled due to a pre-specified interim analysis of the first 200 participants which crossed the futility boundary for the primary efficacy endpoint in the Intent to Treat population. Enrollees were 85% aged < 65 years old, 60% female, 27% Hispanic, Black or other minorities and 69% with ≥2 comorbidities. Rivaroxaban was well-tolerated. Disease progression rates were 46/222 (20.7%) in rivaroxaban vs. 44/222 (19.8%) in placebo groups, with a risk difference of -1.0, 95% CI, -6.4 to 8.4; P = 0.78. CONCLUSIONS Our study did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.
Symptomatic adult patients with mild COVID-19 and at high-risk for COVID-19 progression (n= 497).
Oral rivaroxaban (n= 246).
Placebo-equivalent (n= 251).
Rivaroxaban was well-tolerated. Disease progression rates were 46/222 (20.7%) in rivaroxaban vs. 44/222 (19.8%) in placebo groups, with a risk difference of -1.0.
Efficacy and safety of current treatment interventions for patients with severe COVID-19 infection: a network meta-analysis of randomised controlled trials
Journal of medical virology. 2021
This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19 infection. We searched databases for randomized controlled trials (RCTs) published up to April 30, 2021, with Chinese or English language restriction, of medications recommended for patients (aged 18 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). We identified 1,855 abstracts and of these included 15 RCTs comprising 3,073 participants through database searches and other sources. In terms of efficacy, compared with the standard of care (SOC) group, no significant decrease in ACM was found in α-Lipoic acid, convalescent plasma (CP), azithromycin, tocilizumab, methylprednisolone, interferon beta, CP/SOC, high dosage sarilumab, low dosage sarilumab, remdesivir, lopinavir-ritonavir, auxora and placebo group. Compared with placebo, we found that a significant decrease in ACM was only found in methylprednisolone [odds ratio (OR) 0.16, 95% confidence interval (CI) 0.03-0.75]. With respect to TEAEs, the CP group showed lower TEAEs than placebo (OR 0.07, 95% CI 0.01-0.58) or SOC (OR 0.05, 95% CI 0.01-0.42) group for the therapy of severe COVID-19 patients. This study only demonstrated that methylprednisolone was superior to placebo in treating patients with severe COVID-19 infection. Meanwhile, this further confirmed that the safety of other treatment interventions might be inferior to CP for the therapy of severe COVID-19 patients. This article is protected by copyright. All rights reserved.
Therapeutic strategies in patients with coagulopathy and disseminated intravascular coagulation: awareness of the phase-dependent characteristics
Minerva Medica. 2021
INTRODUCTION Disseminated intravascular coagulation (DIC) has long been understood as a condition where both thrombotic and hemostatic abnormalities coexist. DIC is a difficult complication for clinicians to manage as it is due to multiple underlying complications of pathophysiologic abnormalities in diverse disease states. Ongoing research continues to define the meaning of DIC, evaluate therapeutic options, and how it presents with the complex paradigm of systemic activation of coagulation. In this review we introduce the current topis regarding this tough situation. EVIDENCE ACQUISITION Online search of published medical literature through MEDLINE and Web of Sience using the term "disseminated intravascular coagulation", "coagulopathy", "coagulation disorder", "hemostasis", "fibrinolysis", "thrombus" and "anticoagulants". EVIDENCE SYNTHESIS Articles were chosen for inclusion based on their relevance to disseminated intravascular coagulation, coagulopathy, hemostasis and thrombosis in sepsis, COVID-19, trauma, and obstetrics. Reference lists were reviewed to identify additional relevant articles. CONCLUSIONS DIC is recognized as a pathologically triggered and dysregulated systemic activation of coagulation in response to various noxious stimuli. DIC's phenotype and clinical manifestations can vary from prothrombotic to hemorrhagic, depending on the underlying diseases. However, the fundamental mechanisms of systemic and vascular endothelial dysfunction can be explained as different phases of the acute response, with an initial prothrombotic phase that can commonly change to hemostatic insufficiency. Thrombin is the key initiator of the pathophysiologic process along with endothelial injury and initially fibrinolysis activation followed by fibrinolysis suppression. There is no established approach for managing DIC beyond initially treating the underlying disease and replacement therapy for the management of coagulopathy. Targeting anticoagulation therapy with antithrombin concentrates and recombinant thrombomodulin for the prevention of microthrombus formation, and antifibrinolytic therapy using tranexamic acid for the coagulopathy after massive bleeding, continue to be studied as therapeutic options.
Is Microthrombosis the Main Pathology in Coronavirus Disease 2019 Severity?-A Systematic Review of the Postmortem Pathologic Findings
Critical Care Explorations. 2021;3(5):e0427
This systematic review attempts to retrieve and report the findings of postmortem studies including the histopathologic data of deceased coronavirus disease 2019 patients and to review the manifestations of coronavirus disease 2019-associated thrombotic pathologies reported in the recent literature. DATA SOURCES PubMed, Excerpta Medica Database, and Cochrane library between December 1, 2019, and August 26, 2020. STUDY SELECTION Investigators screened 360 unique references, retrieved published autopsy series, and report on the postmortem histopathologic information on patients who had died of coronavirus disease 2019. DATA EXTRACTION Investigators independently abstracted all available data including study design, participant demographics, key histopathologic findings, disease severity markers, duration of hospital stay, and cause of death. DATA SYNTHESIS From the 65 eligible studies, 691 total completed autopsies were included in evidence synthesis. Histopathologic evaluation of the lungs revealed presence of diffuse alveolar damage in 323 of 443 patients and pulmonary microthrombi in 242 of 326 patients. Deep venous thrombosis and pulmonary embolism were found in 41% and ~15%, respectively, of the cadavers examined for thromboembolic events. d-dimer levels were generally higher in patients with severe clinical course of coronavirus disease 2019. Plasma levels of ferritin, lactate dehydrogenase, interleukin-6, and C-reactive protein were higher in nonsurvivors when compared with survivors. Overall, microthrombi and extensive angiogenesis of lung vasculature were the most common pathologic findings in the lungs and microthrombi in most of the assessed organ-tissue. CONCLUSIONS Diffuse alveolar damage was the most predominant feature in the lungs of coronavirus disease 2019 patients who underwent postmortem assessment. Widespread pulmonary microthrombosis and extensive pulmonary angiogenesis, in addition to frequent pulmonary and extrapulmonary microthrombotic and thromboembolic findings in patients with coronavirus disease 2019, appear to be consistent with the disease-specific hypercoagulability. Further discovery efforts in assessing the link between coronavirus disease 2019, hypercoagulable state, and immunothrombosis are warranted. In the interim, increased attention to anticoagulant treatment approaches in coronavirus disease 2019 patients is needed.