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.

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.

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.

Outcomes of Extracorporeal Life Support in Children with Meningococcal Septicemia: A Retrospective Cohort Study.

Meningococcal disease is associated with high mortality despite aggressive antibiotic therapy and intensive care support. Patients may develop refractory hypotension and acute respiratory distress syndrome in which extracorporeal membrane oxygenation (ECMO) could serve as a life-saving rescue therapy. However, there is limited data regarding the outcomes of ECMO support in the setting of meningococcal disease. This retrospective analysis of prospectively collected data from Extracorporeal Life Support Organization registry (1989-2019) enrolled children (29 days-18 years old) with Neisseria meningitidis infection receiving ECMO for any support type and mode. A total of 122 patients underwent a single course of ECMO support, equating to 122 ECMO runs. The overall survival-to-discharge rate was 46.7%. Patients receiving pulmonary venovenous (VV) ECMO had the highest survival-to-discharge of 85.7%, while those receiving venoarterial (VA) ECMO for pulmonary indications had a survival of 32.4%. Patients receiving VA ECMO support for cardiac indications had a survival-to-discharge rate of 60.9%. Those needing extracorporeal cardiopulmonary resuscitation (ECPR) had a poor survival (14.3%). Hemorrhagic complications were common, occurring in 43.4% of patients, but not found to be associated with mortality (complication was present in 47.7% of deceased and 38.6% of survivors, p = 0.31). Multivariable logistic regression analysis revealed that neurologic complications were associated with increased odds of mortality (odds ratio: 44.11; 95% confidence interval: 4.95-393.08). ECMO can be utilized as rescue therapy in children with refractory cardiopulmonary failure in setting of meningococcemia. Patients who require pulmonary VV or cardiac ECMO have the best ECMO outcomes. However, the use of ECMO in those suffering cardiac arrest (ECPR) should be undertaken with caution.

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.

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.

Characteristics of Phase IV Clinical Trials in Oncology: An Analysis Using the ClinicalTrials.gov Registry Data.

The present study analyzed the characteristics of phase IV clinical trials in oncology using data from the ClinicalTrials.gov registry. The included trials were conducted between January 2013 and December 2022 and were examined for key characteristics, including outcome measures, interventions, sample sizes, and study design, different cancer types, and geographic regions. The analysis included 368 phase IV oncology studies. An amount of 50% of these studies examined both safety and efficacy, while 43.5% only reported efficacy outcome measures, and 6.5% only described safety outcome measures. Only 16.9% of studies were powered to detect adverse events with a frequency of 1 in 100. Targeted therapies accounted for the majority of included studies (53.5%), with breast (32.91%) and hematological cancers (25.82%) being the most frequently investigated malignancies. Most phase IV oncology studies lacked sufficient power to detect rare adverse events due to their small sample sizes and instead focused on effectiveness. To ensure that there is no gap in drug safety data collection and detection of rare adverse events due to limited phase IV clinical trials, there is a significant need for additional education and participation by both health care providers and patients in spontaneous reporting processes.

Humoral Response in Hemodialysis Patients Post-SARS-CoV-2 mRNA Vaccination: A Systematic Review of Literature.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has infected over 600 million individuals and caused nearly 7 million deaths worldwide (10 January 2023). Patients with renal disease undergoing hemodialysis are among those most adversely affected, with an increased predisposition to SARS-CoV-2 infection and death. This systematic review aimed to pool evidence assessing the humoral response of hemodialysis patients (HDP) post-mRNA SARS-CoV-2 vaccination. A systematic search of the literature was performed through MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers up to 10 January 2023. Cohort and case-control studies were included if they reported an immune response in one group of patients undergoing hemodialysis who received mRNA SARS-CoV-2 vaccination compared with another group of patients receiving the same vaccine but not on hemodialysis. The methodological quality was assessed using the Newcastle-Ottawa Scale. Meta-analysis was not deemed appropriate due to the high heterogeneity between studies. From the 120 studies identified, nine (n = 1969 participants) met the inclusion criteria. Most studies (n = 8/9, 88%) were of high or medium methodological quality (≥6/9 stars). The results revealed that HDP developed lower antibody levels across all timepoints post-vaccination when compared with controls. Patients with chronic kidney disease elicited the highest antibody immune response, followed by HDP and, lastly, kidney transplant recipients. Overall, post-vaccination antibody titers were comparatively lower than in the healthy population. Current results imply that robust vaccination strategies are needed to address waning immune responses in vulnerable populations.

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.

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.

Long-COVID Symptoms in Individuals Infected with Different SARS-CoV-2 Variants of Concern: A Systematic Review of the Literature.

The association of SARS-CoV-2 variants with long-COVID symptoms is still scarce, but new data are appearing at a fast pace. This systematic review compares the prevalence of long-COVID symptoms according to relevant SARS-CoV-2 variants in COVID-19 survivors. The MEDLINE, CINAHL, PubMed, EMBASE and Web of Science databases, as well as the medRxiv and bioRxiv preprint servers, were searched up to 25 October 2022. Case-control and cohort studies analyzing the presence of post-COVID symptoms appearing after an acute SARS-CoV-2 infection by the Alpha (B.1.1.7), Delta (B.1.617.2) or Omicron (B.1.1.529/BA.1) variants were included. Methodological quality was assessed using the Newcastle-Ottawa Scale. From 430 studies identified, 5 peer-reviewed studies and 1 preprint met the inclusion criteria. The sample included 355 patients infected with the historical variant, 512 infected with the Alpha variant, 41,563 infected with the Delta variant, and 57,616 infected with the Omicron variant. The methodological quality of all studies was high. The prevalence of long-COVID was higher in individuals infected with the historical variant (50%) compared to those infected with the Alpha, Delta or Omicron variants. It seems that the prevalence of long-COVID in individuals infected with the Omicron variant is the smallest, but current data are heterogeneous, and long-term data have, at this stage, an obviously shorter follow-up compared with the earlier variants. Fatigue is the most prevalent long-COVID symptom in all SARS-CoV-2 variants, but pain is likewise prevalent. The available data suggest that the infection with the Omicron variant results in fewer long-COVID symptoms compared to previous variants; however, the small number of studies and the lack of the control of cofounders, e.g., reinfections or vaccine status, in some studies limit the generality of the results. It appears that individuals infected with the historical variant are more likely to develop long-COVID symptomatology.

Age, Sex and Previous Comorbidities as Risk Factors Not Associated with SARS-CoV-2 Infection for Long COVID-19: A Systematic Review and Meta-Analysis.

Identification of predictors of long COVID-19 is essential for managing healthcare plans of patients. This systematic literature review and meta-analysis aimed to identify risk factors not associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, but rather potentially predictive of the development of long COVID-19. MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were screened through 15 September 2022. Peer-reviewed studies or preprints evaluating potential pre-SARS-CoV-2 infection risk factors for the development of long-lasting symptoms were included. The methodological quality was assessed using the Quality in Prognosis Studies (QUIPSs) tool. Random-effects meta-analyses with calculation of odds ratio (OR) were performed in those risk factors where a homogenous long COVID-19 definition was used. From 1978 studies identified, 37 peer-reviewed studies and one preprint were included. Eighteen articles evaluated age, sixteen articles evaluated sex, and twelve evaluated medical comorbidities as risk factors of long COVID-19. Overall, single studies reported that old age seems to be associated with long COVID-19 symptoms (n = 18); however, the meta-analysis did not reveal an association between old age and long COVID-19 (n = 3; OR 0.86, 95% CI 0.73 to 1.03, p = 0.17). Similarly, single studies revealed that female sex was associated with long COVID-19 symptoms (n = 16); which was confirmed in the meta-analysis (n = 7; OR 1.48, 95% CI 1.17 to 1.86, p = 0.01). Finally, medical comorbidities such as pulmonary disease (n = 4), diabetes (n = 1), obesity (n = 6), and organ transplantation (n = 1) were also identified as potential risk factors for long COVID-19. The risk of bias of most studies (71%, n = 27/38) was moderate or high. In conclusion, pooled evidence did not support an association between advancing age and long COVID-19 but supported that female sex is a risk factor for long COVID-19. Long COVID-19 was also associated with some previous medical comorbidities.

Improving Nasal Protection for Preventing SARS-CoV-2 Infection.

Airborne pathogens, including SARS-CoV-2, are mainly contracted within the airway pathways, especially in the nasal epithelia, where inhaled air is mostly filtered in resting conditions. Mucosal immunity developing after SARS-CoV-2 infection or vaccination in this part of the body represents one of the most efficient deterrents for preventing viral infection. Nonetheless, the complete lack of such protection in SARS-CoV-2 naïve or seronegative subjects, the limited capacity of neutralizing new and highly mutated lineages, along with the progressive waning of mucosal immunity over time, lead the way to considering alternative strategies for constructing new walls that could stop or entrap the virus at the nasal mucosa surface, which is the area primarily colonized by the new SARS-CoV-2 Omicron sublineages. Among various infection preventive strategies, those based on generating physical barriers within the nose, aimed at impeding host cell penetration (i.e., using compounds with mucoadhesive properties, which act by hindering, entrapping or adsorbing the virus), or those preventing the association of SARS-CoV-2 with its cellular receptors (i.e., administering anti-SARS-CoV-2 neutralizing antibodies or agents that inhibit priming or binding of the spike protein) could be considered appealing perspectives. Provided that these agents are proven safe, comfortable, and compatible with daily life, we suggest prioritizing their usage in subjects at enhanced risk of contagion, during high-risk activities, as well as in patients more likely to develop severe forms of SARS-CoV-2 infection.

Quantitative analysis of RT-PCR test results for SARS-CoV-2 diagnostics across Poland during COVID-19 pandemic: Comparison between early stage and major pandemic waves in 2020 and 2021 with reference to SARS-CoV-2 variants.

PURPOSE: From April to September 2020, Poland was minimally affected by COVID-19 compared to other EU countries. We aimed to investigate the risks of false reverse transcription polymerase chain reaction (RT-PCR) results during the first wave (compared to later waves), that rises when cycle threshold (Ct) of positive result is close to limit of detection (LOD). MATERIALS/METHODS: We analyzed Ct values of SARS-CoV-2 positive RT-PCR results of 7726 patients in Poland from April-September 2020. SARS-CoV-2 positive RT-PCR results of 14,534 patients in the 2nd-3rd wave and 10,861 patients in the 4th-5th pandemic waves were used. Statistical analysis was based on one-way analysis of variance. To verify, 95% confidence intervals with Bonferroni correction were computed. Incidence of SARS-CoV-2 variants in Poland was analyzed using Whole Genome Sequencing from 923 (3.6%) patients. RESULTS: The mean Ct of RT-PCR positive test results analyzed ranged between 22.89 and 26.71 depending on the month of the results collection. The differences between months were significant (p â€‹< â€‹0.001). Differences in Ct were observed between age groups, with younger patients displaying higher Ct values, however, major trends over time were paralleled between age groups. CONCLUSIONS: The mean Ct of the tested RT-PCR positive test results was lower than 35 which is considered an upper borderline for reliable positive results of the assay. Therefore, most COVID-19 cases recorded in Poland from April to September 2020 were detected with minor risks of inaccuracy. Data from a single center exhibited greater consistency for both virus Ct level and SARS-CoV-2 virus variant identification.

Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review.

Background: Although COVID-19 vaccination decreases the risk of severe illness, it is unclear whether vaccine administration may impact the prevalence of long-COVID. The aim of this systematic review is to investigate the association between COVID-19 vaccination and long-COVID symptomatology. Methods: MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to June 20, 2022. Peer-reviewed studies or preprints monitoring multiple symptoms appearing after acute SARS-CoV-2 infection either before or after COVID-19 vaccination collected by personal, telephone or electronic interviews were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Findings: From 2584 studies identified, 11 peer-reviewed studies and six preprints were included. The methodological quality of 82% (n=14/17) studies was high. Six studies (n=17,256,654 individuals) investigated the impact of vaccines before acute SARS-CoV-2 infection (vaccine-infection-long-COVID design). Overall, vaccination was associated with reduced risks or odds of long-COVID, with preliminary evidence suggesting that two doses are more effective than one dose. Eleven studies (n=36,736 COVID-19 survivors) investigated changes in long-COVID symptoms after vaccination (infection-long-COVID-vaccine design). Seven articles showed an improvement in long-COVID symptoms at least one dose post-vaccination, while four studies reported no change or worsening in long-COVID symptoms after vaccination. Interpretation: Low level of evidence (grade III, case-controls, cohort studies) suggests that vaccination before SARS-CoV-2 infection could reduce the risk of subsequent long-COVID. The impact of vaccination in people with existing long-COVID symptoms is still controversial, with some data showing changes in symptoms and others did not. These assumptions are limited to those vaccines used in the studies. Funding: The LONG-COVID-EXP-CM study supported by a grant of Comunidad de Madrid.

Transient spontaneous osteonecrosis of the knee (SONK) shortly after SARS-CoV-2 infection: A report of 2 cases.

BACKGROUND: This article describes 2 cases of post-coronavirus disease 2019 (COVID-19) transient spontaneous osteonecrosis of the knee (PCT-SONK) observed in patients who had previously recovered from COVID-19 without corticosteroid administration. OBJECTIVES: The possible pathomechanisms by which a recent SARS-CoV-2 infection may contribute as a causative factor for osteonecrosis are reviewed, and the differential diagnosis and treatment are discussed. MATERIAL AND METHODS: Two patients (males, 45- and 47-year-old) presented with sudden onset knee pain with no trauma history. The pain persisted during rest and at night. On magnetic resonance imaging (MRI), no subchondral bone thickening was observed; bone edema was diffusely distributed in the whole femoral condyle, in contrast to the more focal edema that is typically concentrated mainly around the subchondral region in classic SONK. Both patients were treated nonoperatively with no weight bearing and pharmacological agents, and complete resolution of symptoms was achieved. RESULTS: A follow-up MRI 10 weeks after presentation revealed a near-complete loss of signal in the medial femoral condyle in both patients. CONCLUSION: Orthopedic surgeons should be cautious when sudden knee pain without concurrent trauma or a history of injury occurs shortly after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even with mild COVID-19 illness. While some studies report the development of post-COVID-19 osteonecrosis after lower doses of corticosteroids and sooner after their administration than in comparable non-COVID-19 cases, our study is the first to report 2 cases with no corticosteroid administration at all. Therefore, the authors believe it adds to the body of knowledge on the potential connections between COVID-19 and PCT-SONK. The transient nature of symptoms and radiological findings suggest that aggressive surgical treatment of non-injury local bone edema occurring shortly after SARS-CoV-2 infection should be avoided.

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.