Genetic clues to COVID-19 severity: exploring the stromal cell-derived factor-1/CXCL12 rs2839693 polymorphism in adult Egyptians.

BACKGROUND: A novel corona virus called SARS-CoV-2 was identified at the end of December 2019, and the illness induced by it was designated as coronavirus disease 2019 (COVID-19). Severity of the disease could vary significantly since most of the infected individuals experience mild to moderate respiratory symptoms and recover without specialized care. Genetic polymorphisms have implications in influencing the varying degrees of COVID-19 severity. This study aims to assess the potential association between the CXCL12 rs2839693 polymorphism and the severity of COVID-19 in Assiut University Quarantine Hospital during the period from May 2022 to August 2022. METHODS: The present study is a cross-sectional study and is applied to 300 COVID-19 patients confirmed by RT-PCR admitted to Assiut University Quarantine Hospital from May 2022 to August 2022. Based on the clinical symptoms, the recruited participants had been divided into two groups. Group I involved mild or moderate cases; Group II involved severe or critical conditions. The rs2839693 polymorphism was detected by real time PCR using TaqMan assay probe. RESULTS: The frequency of the T allele and the TT genotype was significantly higher in the severe or critical group compared with the mild or moderate group (p value < 0.001). C-reactive protein (CRP) and D-dimers are significantly elevated in the combined variants (CT + TT) and the TT compared with the CC (P value 0.006 and 0.017 respectively) and the CC,CT genotypes (p value 0.019 and 0.002 respectively). The combined variants (CT + TT) of CXCL12 were found to be independent predictors to severe or critical COVID-19 risk with P value = < 0.001, OR = 3.034& 95% CI = 1.805-5.098. CONCLUSION: Our findings revealed that CXCL12 rs2839693 had a role in the development and seriousness of COVID-19. Patients with the TT genotype or the T allele at increased risk developed severe or critical rather than mild or moderate disease.

Therapeutic Outcomes of High Dose-Dexamethasone versus Prednisolone + Azathioprine, Rituximab, Eltrombopag, and Romiplostim Strategies in Persistent, Chronic, Refractory, and Relapsed Immune Thrombocytopenia Patients.

BACKGROUND: Primary immune thrombocytopenia (ITP) is an inflammatory autoimmune disease that can be managed with several treatment options. However, there is a lack of comparative data on the efficacy of these options in different phases of the disease. AIM OF THE STUDY: This study aimed to evaluate the efficacy of high-dose Dexamethasone (HD-DXM), Prednisolone + Azathioprine, Rituximab, Eltrombopag, and Romiplostim schedules in persistent, chronic refractory or relapsed Egyptian ITP patients with a platelet count ≤30 × 109/L. The primary outcome measure was a sustained increase in platelet counts over 50 × 109/L for an additional 12 months without additional ITP regimens. The study also aimed to identify a suitable treatment regimen with a long remission duration for each phase of ITP. RESULTS: Prednisolone + Azathioprine was significantly more effective in achieving an overall response in persistent patients than Romiplostim, high-dose Dexamethasone, and Rituximab. (90.9% vs. 66.6, [Odds ratio, OR: 5; confidence interval, CI 95% (0.866-28.86)], 45%, [OR: 0.082, CI 95% (0.015-0.448)] and, 25%, [OR: 30, CI 95% (4.24-211.8)], respectively, p-value < 0.01). Eltrombopag was significantly more effective in achieving a durable response in refractory ITP than HD-DXM, Rituximab, and Prednisolone; (80% compared to 32.2% [OR: 0.119, CI 95% (0.035-0.410)], 22.2% [OR:0.071, CI 95% (0.011-0.455)], and 18.1% [OR: 0.056, CI 95% (0.009-0.342)], respectively, p-value < 0.01). CONCLUSIONS: Finally, Eltrombopag following HD-DXM showed the highest percentage of patients with complete treatment-free survival times of at least 330 days. These findings could help clinicians choose the most appropriate treatment for their patients with ITP based on the phase of the disease. This trial is registered in clinicaltrials.gov with registration number NCT05861297.

Clinical Care Team's Guide for Awareness on Risk Assessment of Eltrombopag Complicating Acute Kidney Injury in Relapsed Immune Thrombocytopenic Patients: A Case Report.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by antigen-specific T cells and antiplatelet autoantibodies that inhibit platelet production in the bone marrow or destroy platelets in the spleen. ITP is a form of autoimmunity and is closely associated with inflammation. Corticosteroids are the first-line therapy for ITP, with a total response rate of 53-80%. However, corticosteroid therapy is associated with significant side effects and is often ineffective in patients with corticosteroid-resistant or -intolerant disease. Eltrombopag has been validated as a second-line option in ITP therapy. Despite several studies demonstrating the efficacy and safety of Eltrombopag in immune thrombocytopenia patients, the prevalence of Eltrombopag-induced acute kidney injury has been observed. This case report describes a patient who experienced acute kidney injury during Eltrombopag therapy. A sudden increase in serum creatinine to 6.7 mg/dL and metabolic acidosis occurred after eight weeks of Eltrombopag. The patient's renal failure had worsened, proteinuria was detected, and emergency hemodialysis was initiated. With vigilant kidney function screening and prompt treatment, the patient's renal function improved remarkably following cessation of Eltrombopag and initiation of hemodialysis. This case highlights the importance of comprehensive medication history-taking and vigilant kidney function screening in patients receiving Eltrombopag.

The Outcomes and Adverse Drug Patterns of Immunomodulators and Thrombopoietin Receptor Agonists in Primary Immune Thrombocytopenia Egyptian Patients with Hemorrhage Comorbidity.

Immune thrombocytopenia (ITP) treatment has evolved recently. However, none of the treatments have only benefits without drawbacks. This study aimed to compare the clinical outcomes and adverse drug patterns of Eltrombopag, Romiplostim, Prednisolone + Azathioprine, High Dose-dexamethasone (HD-DXM) (control group), and Rituximab in primary ITP Egyptian patients. All patients were initiated with corticosteroids, HD-DXM, as a first-line treatment for the first month immediately following diagnosis. Four hundred sixty-seven ITP patients were randomly assigned to five groups. The outcome measures were judged at baseline, at the end of treatment (6 months), and after an additional 6-month free treatment period. The follow-up period for which relapse is noted was 6 months after the end of treatment. Eltrombopag and Romiplostim resulted in a significantly higher incidence of sustained response than Rituximab, HD-DXM, and Prednisolone + Azathioprine (55.2% and 50.6% vs. 29.2%, 29.1%, and 18%, respectively; p-value < 0.001). More patients on immunomodulators (Prednisolone+ Azathioprine, HD-DXM, and Rituximab) relapsed than those on Romiplostim and Eltrombopag (81.9%, 70.8%, and 70.7% vs. 49.3%, and 44.7%, respectively; p-value < 0.01). We also describe 23 reports of pulmonary hypertension with Prednisolone+ Azathioprine and 13 reports with HD-DXM. The thrombotic events occurred in 16.6% and 13% of patients who received Eltrombopag and Romiplostim treatment, respectively. Most patients had at least one or two risk factors (92.8% of cases). Corticosteroids are effective first-line therapy in primary ITP patients. However, relapse is frequent. Eltrombopag and Romiplostim are safer and more effective than Prednisolone, HD-DXM, and Rituximab. They might be reasonable beneficial options after a one-month HD-DXM regimen.

The Association Between Plasma MicroRNA-451 Expression Levels and Chronic Kidney Disease in Children with ß-Thalassemia Major.

INTRODUCTION: Patients with ß -thalassemia major (ß -TM) had a high rate of glomerular dysfunction due to chronic anemia, iron overload, and chelation therapy. There is also evidence of proximal tubular damage, as almost all patients have various amounts of proteinuria. MicroRNAs are non-coding RNA molecules that regulate gene expression. In diabetes, a relative increase in renal microRNA-451 appeared to protect against diabetic kidney injury. This study aimed to investigate the association between miRNA-451 and the development of chronic kidney disease (CKD) in children with ß-TM. METHODS: This study included 60 pediatric patients with ß-TM and 30 healthy children as controls. We categorized patients into two groups according to the presence of CKD. Complete blood and reticulocyte counts, serum levels of ferritin, creatinine and glucose, and urine albumin/creatinine ratio (ACR) were measured. Plasma miRNA-451 expression level was measured by real-time quantitative reversed transcription PCR in all included children. RESULTS: miRNA-451 levels were significantly higher in ß-TM (25.326 ± 12.191) as compared with controls (9.453 ± 5.753) (P < .001). Patients with ß-TM and CKD had significantly lower miRNA-451 levels (19.72 ± 13.023) than those without CKD (30.933 ± 8.23). MiRNA-451 levels had significantly positive correlated with eGFR (r = 0.385 P < .05) and reticulocyte counts (r = 0.27, P < .05). Linear logistic regression analysis showed that low plasma microRNA-451 was a significant independent predictor of CKD. CONCLUSION: miRNA-451 has a protective role against CKD development, and low plasma expression levels are associated with CKD in children with ß-TM  DOI: 10.52547/ijkd.6756.

Intracranial hemorrhage in primary immune thrombocytopenia (ITP): 20 years' experience in pediatrics.

Incidence of intracranial hemorrhage (ICH) among children with primary immune thrombocytopenia (ITP) varies among different studies. We published data during the period of 1997-2007 of ICH in children with primary ITP, addressing risk factors and outcome. The aim of this study is to assess changes in incidence, risk factors, and outcome of ICH in children with ITP from last decade and to report the overall 20 years' experience. We compared 2008-2018 with the decade before it. Data of children with ITP and ICH during study period and ITP control cases were analyzed. Neurosurgical intervention and outcome were also reported. A total of 4340 children with primary ITP were evaluated. Twenty-five (0.63%) ICH events were reported over 2 decades. Head trauma, hematuria, and platelet counts < 10 × 109/L were the risk factors mostly associated with ICH. Overall mortality was 24%, and a further 28% had neurologic sequelae. Neurosurgical intervention was done in 12% of cases with good outcome.Conclusion: Persistent platelet counts < 10 × 109/L were a significant risk factor for ICH in both time periods, while head trauma and hematuria were more reported in the period of 2008-2018 as significant risk factors for ICH. Outcome was comparable in both periods. What is Known: • ICH is a rare complication of ITP; however, early recognition of risk factors and aggressive treatment might lead to complete recovery without sequalae. Platelet counts less than < 10 × 109/L are the main risk factor for ICH. Few studies reported other significant risk factors. What is New: • Hematuria and head trauma are significant risk factors for ICH in ITP, in addition to having a persistently low platelet count < 10 × 109/L. (more than 90 days in chronic ITP, 45 days in persistent and 21 days in acute ITP) • Combined treatment with IVIG and HDMP followed by platelet transfusion was associated with complete recovery without sequelae in almost 50% of patients.

WITHDRAWN:Randomized controlled trial of effect of N-acetylcysteine as an antioxidant on iron overload in children with thalassemia major.

Ahead of Print article withdrawn by publisher.

Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response.

Background: Deferasirox is the first line of treatment in iron overload. In spite of the many studies concerning the efficacy of deferasirox, some patients remain unresponsive to deferasirox.Methods: One hundred and sixty patients were enrolled in stratified-randomized controlled study. Patients were randomly divided into four regimens, group I (n = 40) received 30 mg/kg deferasirox, group II (n = 40) received 20 mg omeprazole and 30 mg/kg deferasirox, group III (n = 40) received 400 mg vitamin E and 30 mg/kg deferasirox and group IV (n = 40) received 420 mg silymarin and 30 mg/kg deferasirox. Blood specimens were collected from each patient for up to 24 h, and then plasma deferasirox concentrations were inspected.Results: Silymarin, Vitamin E, and omeprazole significantly increased the peak plasma concentration of deferasirox (P < 0.001) by 27.9, 14.9 and 2.4 fold, respectively, as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57, and 4.98-fold, respectively, following administration of omeprazole, vitamin E, and silymarin compared to deferasirox alone.Conclusion: Silymarin, vitamin E, and omeprazole represent promising adjuvant therapy to improve the chelation efficacy of deferasirox that might also be further applied to enhance the pharmacokinetics of deferasirox to overcome the lack of response.

Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia.

Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis - the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.

Frequency of icaA and icaD determinants and biofilm formation among coagulase-negative staphylococci associated with nasal carriage in neonatal intensive care units.

INTRODUCTION: Nasal colonization with coagulase-negative staphylococci (CoNS) may be a preliminary risk factor for systemic infection. The aim of this study was to assess the frequency of ica A and D genes and biofilm formation among hospital-acquired nasal colonizing CoNS strains isolated from neonates in the neonatal intensive care units (NICUs). Antibiotic sensitivity patterns and some relevant risk factors were estimated. METHODS: This study assessed nasal colonization with CoNS among neonates at days one and three of admission to NICUs of Beni-Suef University Hospital and Beni-Suef General Hospital from November 2015 to May 2016. The isolates were screened and identified; susceptibility testing was performed. Biofilm formation was examined using the Congo red agar method. Isolates identified as CoNS were tested by polymerase chain reaction (PCR) for the presence of mecA and icaA and icaD genes. RESULTS: A total of 340 nasal swabs were collected from 170 neonates. The incidence of nasal colonization with CoNS was 50%. The species most frequently isolated were S. haemolyticus and S. epidermidis. Multidrug resistance (MDR) was detected in 86% of isolates. It was found that there was a strong association between the presence of mecA gene and phenotypic resistance to methicillin and also the presence of the icaA gene and biofilm formation. CONCLUSIONS: Neonates admitted to NICUs can become reservoirs for CoNS strains, leading to potential dissemination of MDR strains into the community.

A randomized multicenter study: safety and efficacy of mini-pool intravenous immunoglobulin versus standard immunoglobulin in children aged 1-18 years with immune thrombocytopenia.

BACKGROUND: Because there is a global shortage of intravenous immunoglobulin, there is a need for new products to fill the gap. STUDY DESIGN AND METHODS: This was a multicenter, open-label study investigating the safety and efficacy of a newly developed mini-pool intravenous immunoglobulin G for children with immune thrombocytopenia. Seventy-two patients ages 1 to 18 years with newly diagnosed (<1 month) immune thrombocytopenia who had platelet counts from 5 to 20 × 109 /L with no serious bleeding were recruited from four centers in Egypt. Eligible patients were randomized into three groups 1:1:1. Group A (n = 24) received blood group-specific mini-pool intravenous immunoglobulin in a dose equivalent to immunoglobulin 1 g/kg over 6 to 8 hours, Group B (n = 24) received standard intravenous immunoglobulin (approximately 1g/kg) as a single dose, and Group C (n = 24) did not receive any platelet-enhancing therapy. Parents signed informed consent. RESULTS: Of the patients who received mini-pool intravenous immunoglobulin, 14 achieved a complete response (CR) (58.8%), and four had a response (16.6%). Of the patients who received intravenous immunoglobulin G, 16 achieved a complete response (66.6%), and four had a response (16.6%). In Group C, eight patients achieved a complete response (33.3%), and four had a response (16.6%). The median time to response was 8, 9, and 21 days in Group A, B, and C, respectively, which was significantly higher in Group C than Groups A and B (p < 0.001). Patients in Groups A and B reported 16 adverse drug reactions. CONCLUSION: Mini-pool intravenous immunoglobulin G was well tolerated, presented no safety issues, and was effective in the treatment of immune thrombocytopenia, with efficacy comparable to that of the standard intravenous immunoglobulin G group, and it was significantly more effective than no treatment.

Autoimmune thrombocytopenia: flow cytometric determination of platelet-associated CD154/CD40L and CD40 on peripheral blood T and B lymphocytes.

BACKGROUND AND OBJECTIVES: The CD40-CD40L system has pleiotropic effects in a variety of cells and biological processes including the immune response. Within the immune system, these molecules represent a critical link between its humoral and cellular arms. Immune or idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by antibody-induced platelet destruction and clearance due to anti-platelet autoantibodies, which bind to circulating platelets resulting in their destruction by the reticuloendothelial system. Despite its clinical importance, the diagnosis of ITP is one of exclusion, thus, inevitably associated with potential difficulties. CD40 is a cell surface receptor that belongs to the tumor necrosis factor-receptor (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. CD40-ligand (CD40L/CD154), a member of the TNF superfamily, is a cell membrane molecule expressed on activated CD4 + T lymphocytes and is essential for the T cell-dependent activation of B lymphocytes. Therefore it is now thought that CD40-CD40L interactions play a more important role in ITP immune regulation. DESIGN AND METHODS: The expressions of CD154 and CD40 on peripheral blood (PB) T and B lymphocytes, respectively, were measured using flow cytometry (FCM). An antigen-specific assay for platelet-associated CD154 (CD40L) on CD4 + T lymphocytes and for CD40 on CD19 + B lymphocytes was tested in 30 pediatric patients with acute ITP, 30 adult patients with chronic ITP, and in 20 age- and sex-matched healthy controls. RESULTS: The expression of CD4 + CD154+ and CD4 + CD154+/CD4+ on PB T lymphocytes, and CD19 + CD40+ and CD19 + CD40+/CD19+ on PB B lymphocytes were significantly higher in acute and chronic ITP patients compared to controls, and in acute patients compared to chronics (p < 0.001). CONCLUSIONS: CD40-CD40L interaction plays an important role in the pathology of certain autoimmune diseases. ITP is an autoimmune disease characterized by increased platelet destruction caused by anti-platelet autoantibodies, which mainly target a platelet surface antigen. It is speculated that platelet-associated CD154 is competent to induce the CD40-dependent proliferation of B lymphocytes. Therefore, platelet-associated CD154 expression is increased in ITP patients and is able to drive the activation of autoreactive B lymphocytes in this disease. These findings are particularly useful for clarifying the pathogenic process in ITP patients and for developing a therapeutic approach that blocks pathogenic anti-platelet antibody production. Blockade of the CD40/CD154 signal is a potential immunomodulatory strategy for T cell-mediated diseases, and many findings suggest that CD40/CD154 blockade therapy is potentially effective for ITP through selective suppression of autoreactive T and B lymphocytes to platelet antigens.