Is antiviral treatment at the acute phase of COVID-19 effective for decreasing the risk of long-COVID? A systematic review.

PURPOSE: Preliminary evidence suggests a potential effect of antiviral medication used during the acute COVID-19 phase for preventing long-COVID. This review investigates if having received pharmacological treatment during acute SARS-CoV-2 infection may reduce the risk of long-COVID. METHODS: MEDLINE, CINAHL, PubMed, EMBASE, Web of Science databases, as well as medRxiv/bioRxiv preprint servers were searched up to July 15th, 2023. Articles comparing the presence of long-COVID symptoms between individuals who received or not a specific medication, particularly antivirals, during the acute phase of SARS-CoV-2 infection were included. Methodological quality was assessed using the Newcastle-Ottawa Scale or Cochrane's Risk of Bias (Rob) tool. RESULTS: From 517 studies identified, 6 peer-reviewed studies and one preprint met all inclusion criteria. The sample included 2683 (n = 4) hospitalized COVID-19 survivors and 307,409 (n = 3) non-hospitalized patients. The methodological quality was high in 71% of studies (n = 5/7). Two studies investigating the effects of Nirmaltrevir/Ritonavir and three studies the effect of Remdesivir reported conflicting results on effectiveness for preventing long-COVID. Three studies investigating the effects of other medication such as Dexamethasone (n = 2) or Metformin (n = 1) found positive results of these medications for preventing long-COVID. CONCLUSION: Available evidence about the effect of medication treatment with antivirals during acute COVID-19 and reduced risk of developing long-COVID is conflicting. Heterogeneous evidence suggests that Remdesivir or Nirmaltrevir/Ritonavir could have a potential protective effect for long-COVID. A limited number of studies demonstrated a potential benefit of other medications such as Dexamethasone or Metformin, but more studies are needed.

Platelet distribution width (PDW) as a significant correlate of COVID-19 infection severity and mortality.

SARS-CoV-2 infection may cause a wide spectrum of symptoms, from asymptomatic, to mild respiratory symptoms and life-threatening sepsis. Among the clinical laboratory biomarkers analyzed during COVID-19 pandemic, platelet indices have raised great interest, due to the critical involvement of platelets in COVID-19-related thromboinflammation. Through an electronic literature search on MEDLINE, CINAHL, PubMed, EMBASE, Web of Science, and preprint servers we performed and updated a systematic review aimed at providing a detailed analysis of studies addressing the potential clinical utility of platelet distribution width, platelet distribution width (PDW), in laboratory medicine, exploring the possible association between increased PDW levels, disease severity, and mortality in COVID-19. Our systematic review revealed a wide heterogeneity of COVID-19 cohorts examined and a lack of homogenous expression of platelet indices. We found that 75 % of studies reported significantly elevated PDW values in COVID-19 infected cohorts compared to healthy/non-COVID-19 controls, and 40 % of studies reported that patients with severe COVID-19 showed increased PDW values than those with less-than-severe illness. Interestingly, 71.4 % of studies demonstrated significant increased PDW values in non survivors vs. survivors. Overall, these results suggest that platelets are critically involved as major players in the process of immunothrombosis in COVID-19, and platelet reactivity and morphofunctional alterations are mirrored by PDW, as indicator of platelet heterogeneity. Our results confirm that the use of PDW as prognostic biomarkers of COVID-19 sepsis still remains debated due to the limited number of studies to draw a conclusion, but new opportunities to investigate the crucial role of platelets in thrombo-inflammation are warranted.

To Anticoagulate or Not to Anticoagulate in COVID-19: Lessons after 2 Years.

A hypercoagulable state associated with coronavirus disease 2019 (COVID-19) has been well documented and is believed to be strongly supported by a proinflammatory state. The hypercoagulable state in turn results in increased incidence of arterial and venous thromboembolism (VTE) seen in hospitalized COVID-19 when compared with hospitalized non-COVID-19 patient cohorts. Moreover, patients with arterial or VTE and COVID-19 have higher mortality compared with COVID-19 patients without arterial or VTE. Prevention of arterial or VTE thus remains an essential question in the management of COVID-19 patients, especially because of high rates of reported microvascular and macrovascular thrombosis. This has prompted multiple randomized control trials (RCTs) evaluating different anticoagulation strategies in COVID-19 patients at various stages of the disease. Herein, we review findings from RCTs in the past 2 years of antithrombotic therapy in critically ill hospitalized patients, noncritically ill hospitalized patients, patients postdischarge from the hospital, and outpatients. RCTs in critically ill patients demonstrated therapeutic dose anticoagulation does not improve outcomes and has more bleeding than prophylaxis dose anticoagulant in these patients. Trials in noncritically ill hospitalized patients showed a therapeutic dose anticoagulation with a heparin formulation might improve clinical outcomes. Anticoagulation with a direct oral anticoagulant posthospital discharge may improve outcomes, although there is a large RCT in progress. Nonhospitalized COVID-19 patients have an insufficient burden of events to be candidates for antithrombotic therapy. Anticoagulation in pregnant and lactating patients with COVID-19, as well as antiplatelet therapy for COVID-19, is also reviewed.

Infusion reactions to adeno-associated virus (AAV)-based gene therapy: Mechanisms, diagnostics, treatment and review of the literature.

The use of adeno-associated virus (AAV) vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion-associated reactions (IARs) pose a significant challenge to the safety and efficacy of AAV-based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll-like receptor activation and subsequent production of pro-inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies (Nabs) and T-cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre-existing Nabs, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu-like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre- and postadministration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV-based gene therapy.

Discontinuity of marginal artery at splenic flexure and rectosigmoid junction: A systematic review and meta-analysis.

AIM: The aim of this study was to provide comprehensive evidence-based assessment of the discontinuity of the marginal artery at the splenic flexure (SF) and the rectosigmoid junction (RSJ). METHOD: A systematic review was conducted of literature published to 26 December 2022 in the electronic databases PubMed, SCOPUS and Web of Science to identify studies eligible for inclusion. Data were extracted and pooled into a meta-analysis using the Metafor package in R. The primary outcomes were the pooled PPEs of the marginal artery at the SF and the RSJ. The secondary outcome was the size of vascular anastomoses. RESULTS: A total of 21 studies (n = 2,864 patients) were included. The marginal artery was present at the splenic flexure in 82% (95% CI: 62-95) of patients. Approximately 81% (95% CI: 63-94%) of patients had a large macroscopic anastomosis, while the remainder (19%) had small bridging ramifications forming the vessel. The marginal artery was present at the RSJ in 82% (95% CI: 70-91%) of patients. CONCLUSION: The marginal artery may be absent at the SF and the RSJ in up to 18% of individuals, which may confer a higher risk of ischaemic colitis. As a result of high interstudy heterogeneity noted in our analysis, further well-powered studies to clarify the prevalence of the marginal artery at the SF and the RSJ, as well as its relationship with other complementary colonic collaterals (intermediate and central mesenteric), are warranted.

Outcomes of extracorporeal life support for respiratory failure in children with primary immunodeficiencies.

OBJECTIVE: Extracorporeal Membrane Oxygenation (ECMO) may serve as a life-saving rescue therapy in critically ill children with respiratory failure. While survival rates of ECMO in children with secondary immunodeficiency is considered relatively poor, survival rates in children with primary immunodeficiencies (PID) has yet to be thoroughly investigated. DESIGN: Retrospective analysis of prospectively collected data from children (29 days-18 years old). PID patients were identified by using International Classification of Diseases (ICD) codes. SETTING: Data were retrieved from Extracorporeal Life Support Organization Registry (1989-2018). INTERVENTIONS: ECMO for a pulmonary support indication. The survival-to-discharge rate was calculated and factors influencing outcomes were compared between survivors and non-survivors. MEASUREMENTS AND MAIN RESULTS: A total of 73 eligible ECMO runs were included. The survival-to-discharge rate in pediatric PID patients was 45.2%. No differences were noted in survival based on type of immunodeficiency (p = 0.42) or decade of support (p = 0.98). There was no difference in the rate of pre-ECMO infection in survivors versus non-survivors (p = 0.69). The survival-to-discharge rate in patients with a culture positive infection during the ECMO run was 45.0% versus 45.3% in those with no infection (p = 0.98). In multivariate analysis, only cardiac complications (OR 5.09, 95% CI: 1.15-22.53), pulmonary complications (OR: 13.00, 95% CI: 1.20-141.25), and neurologic complications (OR: 9.86, 95% CI: 1.64-59.21) were independently associated with increased mortality. CONCLUSION: Children with a PID who require extracorporeal life support due to respiratory failure have a reasonable chance of survival and should be considered candidates for ECMO. The presence of a pre-ECMO infection should not be considered an ECMO contraindication.

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes' Structure.

This study investigated the biological effects on circulating monocytes after challenge with SARS-CoV-2 recombinant spike protein. Whole blood collected from seven ostensibly healthy healthcare workers was incubated for 15 min with 2 and 20 ng/mL final concentration of recombinant spike protein of Ancestral, Alpha, Delta, and Omicron variants. Samples were analyzed with Sysmex XN and DI-60 analyzers. Cellular complexity (i.e., the presence of granules, vacuoles and other cytoplasmic inclusions) increased in all samples challenged with the recombinant spike protein of the Ancestral, Alpha, and Delta variants, but not in those containing Omicron. The cellular content of nucleic acids was constantly decreased in most samples, achieving statistical significance in those containing 20 ng/mL of Alpha and Delta recombinant spike proteins. The heterogeneity of monocyte volumes significantly increased in all samples, achieving statistical significance in those containing 20 ng/mL of recombinant spike protein of the Ancestral, Alpha and Delta variants. The monocyte morphological abnormalities after spike protein challenge included dysmorphia, granulation, intense vacuolization, platelet phagocytosis, development of aberrant nuclei, and cytoplasmic extrusions. The SARS-CoV-2 spike protein triggers important monocyte morphological abnormalities, more evident in cells challenged with recombinant spike protein of the more clinically severe Alpha and Delta variants.

Effects of age, sex, serostatus, and underlying comorbidities on humoral response post-SARS-CoV-2 Pfizer-BioNTech mRNA vaccination: a systematic review.

With the advent of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, several vaccines have been developed to mitigate its spread and prevent adverse consequences of the Coronavirus Disease 2019 (COVID-19). The mRNA technology is an unprecedented vaccine, usually given in two doses to prevent SARS-CoV-2 infections. Despite effectiveness and safety, inter-individual immune response heterogeneity has been observed in recipients of mRNA-based vaccines. As a novel disease, the specific immune response mechanism responsible for warding off COVID-19 remains unclear at this point. However, significant evidence suggests that humoral response plays a crucial role in affording immunoprotection and preventing debilitating sequelae from COVID-19. As such, this paper focused on the possible effects of age, sex, serostatus, and comorbidities on humoral response (i.e. total antibodies, IgG, and/or IgA) of different populations post-mRNA-based Pfizer-BioNTech vaccination. A systematic search of literature was performed through PubMed, Cochrane CENTRAL, Google Scholar, Science Direct, medRxiv, and Research Square. Studies were included if they reported humoral response to COVID-19 mRNA vaccines. A total of 32 studies were identified and reviewed, and the percent differences of means of reported antibody levels were calculated for comparison. Findings revealed that older individuals, male sex, seronegativity, and those with more comorbidities mounted less humoral immune response. Given these findings, several recommendations were proposed regarding the current vaccination practices. These include giving additional doses of vaccination for immunocompromised and elderly populations. Another recommendation is conducting clinical trials in giving a combined scheme of mRNA vaccines, protein vaccines, and vector-based vaccines.

COVID-19 and Antiphospholipid Antibodies: Time for a Reality Check?

Antiphospholipid antibodies (aPL) comprise a panel of autoantibodies that reflect a potential prothrombotic risk in several autoimmune conditions, most notably antiphospholipid (antibody) syndrome (APS). aPL can be divided into those that form part of the laboratory criteria for APS, namely, lupus anticoagulant (LA), as well as anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I antibodies (aß2GPI) of the immunoglobulin G and M classes, and those that form a group considered as "noncriteria antibodies." The noncriteria antibodies include, for example, antiphosphatidylserine antibodies (aPS), antiprothrombin antibodies (aPT), and antiphosphatidylserine/prothrombin complex antibodies (aPS/PT). COVID-19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of various aPL being present in COVID-19 patients. There have also been similarities drawn between some of the pathophysiological features of COVID-19 and APS, in particular, the most severe form, catastrophic APS (CAPS). In this review, we critically appraise the literature on aPL and COVID-19. This is a companion piece to a separate review focused on LA. In the current review, we primarily concentrate on the so-called solid phase identifiable aPL, such as aCL and aß2GPI, but also reflect on noncriteria aPL. We conclude that aPL positivity may be a feature of COVID-19, at least in some patients, but in general, identified "solid-phase" aPL are of low titer and not able to be well-linked to the thrombotic aspects of COVID-19. Also, most publications did not assess for aPL persistence, and where persistence was checked, the findings appeared to represent transient aPL. Importantly, high-titer aPL or multiple aPL positivity (including double, triple) were in the minority of COVID-19 presentations, and thus discount any widespread presence of APS, including the most severe form CAPS, in COVID-19 patients.

Is Lupus Anticoagulant a Significant Feature of COVID-19? A Critical Appraisal of the Literature.

The term "lupus anticoagulant (LA)" identifies a form of antiphospholipid antibodies (aPLs) causing prolongation of clotting tests in a phospholipid concentration-dependent manner. LA is one of the laboratory criteria identified in patients with antiphospholipid (antibody) syndrome (APS). The presence of LA in patients with APS represents a significant risk factor for both thrombosis and pregnancy morbidity. There have been several reports of similarities between some of the pathophysiological features of COVID-19 and APS, in particular the most severe form, catastrophic APS. There have also been many reports identifying various aPLs, including LA, in COVID-19 patients. Accordingly, a very pertinent question arises: "Is LA a feature of COVID-19 pathology?" In this review, we critically appraise the literature to help answer this question. We conclude that LA positivity is a feature of COVID-19, at least in some patients, and potentially those who are the sickest or have the most severe infection. However, many publications have failed to appropriately consider the many confounders to LA identification, being assessed using clot-based assays such as the dilute Russell viper venom time, the activated partial thromboplastin time (aPTT), and the silica clotting time. First, most patients hospitalized with COVID-19 are placed on anticoagulant therapy, and those with prior histories of thrombosis would possibly present to hospital already on anticoagulant therapy. All anticoagulants, including vitamin K antagonists, heparin (both unfractionated heparin and low-molecular-weight heparin), and direct oral anticoagulants affect these clot-based assays. Second, C-reactive protein (CRP) is highly elevated in COVID-19 patients, and also associated with severity. CRP can also lead to false-positive LA, particularly with the aPTT assay. Third, persistence of aPL positivity (including LA) is required to identify APS. Fourth, those at greatest risk of thrombosis due to aPL are those with highest titers or multiple positivity. Most publications either did not identify anticoagulation and/or CRP in their COVID-19 cohorts or did not seem to account for these as possible confounders for LA detection. Most publications did not assess for aPL persistence, and where persistence was checked, LA appeared to represent transient aPL. Finally, high titer aPL or multiple aPL positivity were in the minority of COVID-19 presentations. Thus, at least some of the reported LAs associated with COVID-19 are likely to be false positives, and the relationship between the detected aPL/LA and COVID-19-associated coagulopathy remains to be resolved using larger and better studies.

Characterization of the significant decline in humoral immune response six months post-SARS-CoV-2 mRNA vaccination: A systematic review.

Accumulating evidence shows a progressive decline in the efficacy of coronavirus disease 2019 (COVID-19) (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) messenger RNA (mRNA) vaccines such as Pfizer-BioNTech (mRNA BNT161b2) and Moderna (mRNA-1273) in preventing breakthrough infections due to diminishing humoral immunity over time. Thus, this review characterizes the kinetics of anti-SARS-CoV-2 antibodies after the second dose of a primary cycle of COVID-19 mRNA vaccination. A systematic search of the literature was performed and a total of 18 articles (N = 15 980 participants) were identified and reviewed. The percent difference of means of reported antibody titers was then calculated to determine the decline in humoral response after the peak levels postvaccination. Findings revealed that the peak humoral response was reached at 21-28 days after the second dose, after which serum levels progressively diminished at 4-6-month postvaccination. Additionally, results showed that regardless of age, sex, serostatus, and presence of comorbidities, longitudinal data reporting antibody measurement exhibited a decline of both anti-receptor binding domain immunoglobulin G (IgG) and anti-spike IgG, ranging from 94% to 95% at 90-180 days and 55%-85% at 140-160 days, respectively, after the peak antibody response. This suggests that the rate of antibody decline may be independent of patient-related factors and peak antibody titers but mainly a function of time and antibody class/molecular target. Hence, this study highlights the necessity of more efficient vaccination strategies to provide booster administration in attenuating the effects of waning immunity, especially in the appearance of new variants of concerns.

Outcomes of Multiple Runs of Extracorporeal Membrane Oxygenation: An analysis of the Extracorporeal Life Support Registry.

OBJECTIVE: When patients deteriorate after decannulation from extracorporeal membrane oxygenation (ECMO), a second run of extracorporeal support may be considered. However, repeat cannulation can be difficult and poor outcomes associated with multiple ECMO runs are a concern. The aim of this study was to evaluate outcomes and identify factors associated with survival and mortality in cases of multiple runs of extracorporeal membrane oxygenation. DESIGN: Retrospective cohort analysis of the Extracorporeal Life Support Organization Registry. SETTING: The Extracorporeal Life Support Organization's registry was queried for neonates, children, and adults receiving 2 or more runs of ECMO during the same hospitalization, for any indication, from 1998 to 2015. PATIENTS: 1,818 patients from the Extracorporeal Life Support Organization Registry. RESULTS: Of the 1,818 patients, 1,648 underwent 2 runs and 170 underwent 3 or more runs of ECMO. The survival to discharge rate was 36.7% for 2 runs and 29.4% for 3 or more runs. No significant differences in survival were detected in analysis by decade of ECMO run (p = 0.21). Pediatric patients had less mortality than adults (OR: 0.45, 95%CI: 0.24-0.82). Cardiac support on the first run portrayed worse mortality than pulmonary support regardless of final run indication (OR:1.38, 95%CI: 1.09-1.75). Across all age groups, patients receiving pulmonary support on the last run tended to have higher survival rates regardless of support type on the first run. The only first run complication independently predictive of mortality on the final run was renal complications (OR: 1.60, 95%CI: 1.28-1.99). CONCLUSIONS: Though the use of multiple runs of ECMO is growing, outcomes remain poor for most cohorts. Survival decreases with each additional run. Patients requiring additional runs for a pulmonary indication should be considered prime candidates. Renal complications on the first run significantly increases the risk of mortality on subsequent runs, and as such, careful consideration should be applied in these cases.

The role of lipoprotein(a) in coronavirus disease 2019 (COVID-19) with relation to development of severe acute kidney injury.

Lipoprotein(a) (Lp(a)) is a prothrombotic and anti-fibrinolytic lipoprotein, whose role has not been clearly defined in the pathogenesis of coronavirus disease 2019 (COVID-19). In this prospective observational study, serum Lp(a) as well as outcomes were measured in 50 COVID-19 patients and 30 matched sick controls. Lp(a) was also assessed for correlation with a wide panel of biomarkers. Serum Lp(a) did not significantly differ between COVID-19 patients and sick controls, though its concentration was found to be significantly associated with severity of COVID-19 illness, including acute kidney failure stage (r = 0.380, p = 0.007), admission disease severity (r = 0.355, p = 0.013), and peak severity (r = 0.314; p = 0.03). Lp(a) was also positively correlated with interleukin (IL)-8 (r = 0.308; p = 0.037), fibrinogen (r = 0.344; p = 0.032) and creatinine (r = 0.327; p = 0.027), and negatively correlated with ADAMTS13 activity/VWF:Ag (r = - 0.335; p = 0.021); but not with IL-6 (r = 0.241; p = 0.106). These results would hence suggest that adverse outcomes in patients with COVID-19 may be aggravated by a genetically determined hyper-Lp(a) state rather than any inflammation induced elevations.

Factors Associated with Falls During Hospitalization for Coronavirus Disease 2019 (COVID-19).

BACKGROUND During the current Coronavirus Disease 2019 (COVID-19) pandemic, falls have been identified as a potential presenting symptom in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, data on factors increasing fall risk in this patient population are limited. This study aimed to examine the factors that may predispose hospitalized COVID-19 disease patients to falls. MATERIAL AND METHODS In this retrospective observational study, hospitalized COVID-19 disease patients were examined for fall incidence, as well as demographics, comorbidities, and clinical and laboratory data. Patients were stratified according to their fall status and their characteristics were compared using Fisher's exact test or Mann-Whitney U test. A total of 312 hospitalized COVID-19 disease patients were enrolled (median age, 75 years; males, 51.3%), of whom 11 (3.5%) fell. RESULTS There was a greater prevalence of falls among patients who experienced arrhythmias than those that did not (28.6% vs 1.7%; P<0.001). Additionally, a significantly greater proportion of those that were discharged to the internal ward and to the intensive care unit fell (10.3% and 10.0%, respectively) compared to those that were discharged home (1.6%, P=0.008). Thyroid-stimulating hormone (TSH) was significantly elevated in patients who fell (5.3 vs 0.97 µIU/mL, P=0.013), while alanine aminotransferase (ALT) was significantly lower in those who fell (17.1 vs 33.5 IU/L, P=0.041). CONCLUSIONS Arrhythmias may be an important predisposing factor for falls in COVID-19 disease patients and fall prevention programs should prioritize interventions directed at this vulnerable patient population.

Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis.

von Willebrand factor (VWF) is a large adhesive multimeric protein involved in hemostasis. The larger the size (or number of VWF multimers), the greater the functionality of the protein. A deficiency or defect of VWF can lead to von Willebrand disease (VWD) and cause bleeding. Conversely, an increase in VWF may create an environment that promotes thrombosis. ADAMS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), sometimes called VWF-cleaving protease, is primarily responsible for controlling the size of VWF. The most severe deficiency (<10% of normal levels) of ADAMTS-13 arises in thrombotic thrombocytopenic purpura, a condition characterized by the presence of ultralarge VWF and clinically resulting in enhanced risk of thrombosis. However, ADAMTS-13 deficiency may result from other pathological processes. Of relevance is the recent finding that COVID-19 (coronavirus disease 2019) is associated with both increased levels and activity of VWF as well as generally decreased (or occasionally normal) activity levels of ADAMTS-13. Thus, in COVID-19 there is an alteration in the VWF/ADAMTS-13 axis, most often described by increased VWF/ADAMTS-13 ratio (or reduced ADAMTS-13/VWF ratio). COVID-19 is also associated with high prothrombotic risk. Thus, the imbalance of VWF and ADAMTS-13 in COVID-19 may be providing a milieu that promotes (micro)thrombosis, in a clinical picture resembling a secondary thrombotic microangiopathy in some patients. This review therefore assesses the literature on VWF, ADAMTS-13, and COVID-19. Whenever reported in COVID-19, VWF has always been identified as raised (compared with normal reference ranges or control populations). Reports have included VWF level (i.e., VWF antigen) and in some cases one or more VWF "activity" (e.g., collagen binding; platelet glycoprotein Ib [GPIb] binding, using ristocetin cofactor or more modern versions including VWF:GPIbR [recombinant] and VWF:GPIbM [mutant]). Whenever reported, ADAMTS-13 has been reported as "normal" or reduced; however, it should be recognized that "normal" levels may still identify a relative reduction in individual cases. Some reports also discuss the raised VWF/ADAMTS-13 (or reduced ADAMTS-13/VWF) ratio, but very few provide actual numerical data.

Protective Effects of Statins Administration in European and North American Patients Infected with COVID-19: A Meta-Analysis.

Severe acute respiratory syndrome coronavirus 2 has spread rapidly throughout the world, becoming an overwhelming global health emergency. The array of injuries caused by this virus is broad and not limited to the respiratory system, but encompassing also extensive endothelial and systemic tissue damage. Since statins effectively improve endothelial function, these drugs may have beneficial effects in patients with coronavirus disease 2019 (COVID-19). Therefore, this investigation aimed to provide an updated overview on the interplay between statins and COVID-19, with particular focus on their potentially protective role against progression toward severe or critical illness and death. A systematic electronic search was performed in Scopus and PubMed up to present time. Data on statins use and COVID-19 outcomes especially in studies performed in Europe and North America were extracted and pooled. A total of seven studies met our inclusion criteria, totaling 2,398 patients (1,075 taking statins, i.e., 44.8%). Overall, statin usage in Western patients hospitalized with COVID-19 was associated with nearly 40% lower odds of progressing toward severe illness or death (odds ratio: 0.59; 95% confidence interval: 0.35-0.99). After excluding studies in which statin therapy was started during hospital admission, the beneficial effect of these drugs was magnified (odds ratio: 0.51; 95% confidence interval: 0.41-0.64). In conclusion, although randomized trials would be necessary to confirm these preliminary findings, current evidence would support a favorable effect of statins as adjuvant therapy in patients with COVID-19. Irrespective of these considerations, suspension of statin therapy seems highly unadvisable in COVID-19 patients.

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID-19) severity state.

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.

The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19).

OBJECTIVES: Severe coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes. METHODS: Adult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit. RESULTS: A total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8. CONCLUSIONS: The hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

A systematic review and meta-analysis of variants of the branches of the superior mesenteric artery: the Achilles heel of right hemicolectomy with complete mesocolic excision?

AIM: Dissection with subsequent ligation and resection of arteries at their origin (central vascular ligation) is essential for adequate oncological resection during right hemicolectomy with complete mesocolic excision. This technique is technically demanding due to the highly variable arterial pattern of the right colon. Therefore, this study aims to provide a comprehensive evidence-based assessment of the arterial vascular anatomy of the right colon. METHODS: A thorough systematic literature search through September 2020 was conducted on the electronic databases PubMed, Scopus and Web of Science to identify studies eligible for inclusion. Data were extracted and pooled into a meta-analysis using MetaXl software. RESULTS: A total of 41 studies (n = 4691 patients) were included. The ileocolic artery (ICA), right colic artery (RCA) and middle colic artery (MCA) were present in 99.7% (95% CI 99.4%-99.8%), 72.6% (95% CI 61.3%-82.5%) and 96.9% (95% CI 94.2%-98.8%) respectively of patients. Supernumerary RCA and MCA were observed in 3.2% and 11.4% respectively of all cases. The RCA shared a common trunk with the ICA and MCA in 13.2% and 17.7% respectively of patients. A retro-superior mesenteric vein course of the ICA and RCA was observed in 55.1% and 11.4% respectively of all cases. CONCLUSION: The vascular anatomy of the right colon displays several notable variations, namely the absence of some branches (RCA absent in 27.4% of cases), supernumerary branches, common trunks, and retro-superior mesenteric vein courses. These variations should be taken into consideration during right hemicolectomy with complete mesocolic excision to ensure adequate oncological resection while minimizing intra-operative complications.