Thromboprophylaxis Outcome in Childhood SARS-CoV-2 Infection: A Single-Center Experience.

BACKGROUND: The SARS-CoV-2 infection has been associated with potentially endothelial damage and coagulation cascade activation that cause thrombosis. There is limited information on thrombosis and anticoagulant therapy in children with coronavirus disease 2019 (COVID-19). AIMS: This study evaluates the outcome of thromboprophylaxis in children younger than 18-year old with COVID-19 infection. METHODS: A retrospective study was conducted on 184 hospitalized pediatric patients with confirmed COVID-19 infection. A designed questionnaire was made to collect all demographic, clinical, and laboratory data. According to World Health Organization, the patients were classified as asymptomatic/mild, moderate, severe, and critically ill. RESULTS: The mean age of the patients was 7.04±5.9 (1 wk to younger than 18 y). Overall, 33 patients received anticoagulant therapy. All patients who passed away (n=19) belonged to the critical group. One patient (1.28%) was complicated with deep vein thrombosis despite taking thromboprophylaxis, and 1 (1.28%) with pulmonary thromboembolism while the patient did not take an anticoagulant. CONCLUSIONS: Our data showed a lower rate of thrombosis (1.4%) than adult patients with COVID-19. It may underline the role of anticoagulants in moderate to severe/critically ill children with COVID-19 infection. Expert opinion and personal experience are necessary, while we have a significant knowledge gap in understanding COVID-19-associated coagulopathy and thrombotic risk in children.

The The use of oral glucose-lowering agents (GLAs) in ß-thalassemia patients with diabetes: Preliminary data from a retrospective study of ICET-A Network.

OBJECTIVE: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations. STUDY DESIGN AND METHOD: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network. RESULTS: Eight  thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%).  In 68 (61.2) patients  GLAs was prescribed as monotherapy, while the remaining  49  (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients  of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12- 120 months), required insulin therapy for better metabolic control. CONCLUSION: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time.

Efficacy and Safety of Sinopharm Vaccine for SARS-CoV-2 and breakthrough infections in Iranian Patients with Hemoglobinopathies: A Preliminary Report.

Background: The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to high morbidity and mortality worldwide. Vaccination against SARS-CoV-2 is a leading strategy to change the course of the COVID-19 pandemic. Aims of the study: Our aim was to investigate the efficacy and side effects of the Sinopharm vaccine in patients with hemoglobinopathies in Iran and the frequency of breakthrough infection after a full course of vaccination. Methods: A multicenter cross-sectional study of 434 patients with hemoglobinopathies (303 ß-thalassemia major, 118 ß-thalassemia intermedia, and 13 sickle-thalassemia) were conducted from March to July 2021 in IRAN. All patients have received the first dose of the China Sinopharm vaccine and received the second dose of the vaccine 28 days apar. Antibody testing: Detection of immunity after vaccination was evaluated by commercial enzyme-linked immunosorbent assay (Pishtazteb ELISA commercial kit), including a surrogate virus neutralization test (sVNT), for detection of SARS-CoV-2 immunoglobulins (IgA, IgM, IgG), total neutralizing antibody (NAb). Results: The mean age of patients was 35.0 ± 8.5 (from 18 to 70) years, and 55.6% were positive for the antibody. Overall, 48.2% of the studied population had at least one side effect after vaccination. The most frequent side effects were fever and chills, dizziness, and body pain. A total of 90 (20.7%) vaccinated patients developed breakthrough infections after two doses of Sinopharm vaccination. Disease severity was recorded, and it was classified as mild in 77.8%, moderate in 13.6%, and severe in 7.4% of patients. One 28-year-old woman with ß-thalassemia major died eight days after diagnosing a breakthrough SARS-CoV-2 infection. Conclusion: No safety concerns were identified in patients who received two doses of the Sinopharm vaccine. Its efficacy was not optimal due to the lack of effect on new variations of the virus. However, our data show that it seems to be protective against the severity of COVID-19 infection in patients with hemoglobinopathies. The frequency of breakthrough infections after two doses of Sinopharm vaccination supports the evolving dynamic of SARS-CoV-2 variants requiring special challenge since such infection may represent a risk for vulnerable patients.

Effectiveness of myofascial therapy on hemophilic arthropathy: A systematic review and meta-analysis of clinical trials.

Background: Recurrent hemarthrosis is one of the major complications affecting joint functions, and causing chronic pain in hemophilia patients. Objective: To summarize the existing evidence of the effects of myofascial therapy (MFT) on joint status, joint pain, and hemarthrosis in hemophilic arthropathy. Methods: This systematic review and meta-analysis was done according to PRISMA checklist. Finally, four clinical trials included and were pooled using STATA 13. Standardized mean difference (SMD) considered as the effect size. Results: All patients in the case group received 3 interventions of MFT over a 3-week period and were evaluated for 1-5 months. Joint pain with and without load was significantly decreased after three weeks in the intervention group compared to controls (SMD: -0.61, 95% CI: -1.02, -0.21 and 0.58, 95% CI: -0.88, -0.28 respectively). Also, joint status significantly improved three weeks later in patients with MFT compared to controls. (SMD: -0.49, 95% CI: -0.79, -0.19) and this improvement remained until the end of the follow-up period (SMD: -0.54, 95% CI: -0.84, -0.24). Conclusion: This meta-analysis showed that MFT can be an effective intervention improving the joint status and decreasing pain perception in patients with hemophilic arthropathy. Consequently, it can play an important role in achieving higher functionality and quality of life in these patients. However, due to the small number of studies and other limitations, further well-designed trials and updated meta-analysis are needed for more accurate results and interpretation.

The Outcome of Children With Malignant Bone Tumors: A Single-Center Experience.

Malignant bone tumors (MBT) account for 3% to 5% of cancers in children younger than 15 years. We aimed to report the outcome of children with MBT in 10 years in Southern Iran. During the study period, 100 patients (57 Osteosarcoma, 43 Ewing sarcoma) with an M/F ratio of 1.56 and a median age of 13.8 years (3.8-17.9) were diagnosed. Metastasis occurred in 27% of patients, mostly in the first 3 months of diagnosis. The mean survival time of MBT altogether was 94.1 months (95% CI: 86.5-101.7). The 5-year overall survival and event-free survivals were 85.2% (95% CI: 74%-91.8%) and 69.2% (95% CI: 56%-79%), respectively. Metastasis was the only independent risk factor of death in our study cohort (Hazard ratio 36.7, 95% CI: 4.8-282.6, P = .001) MBT in children mostly occur in adolescent boys. About one-third of them become metastatic, which is significantly associated with poor outcomes.

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent ß-thalassemia: a comprehensive single-center experience.

Over the past 20 years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent ß-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. ß-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15 mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or ß-globin gene mutations with HU response was observed in this geographic area of the world.

Association Between Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Torque Teno Virus Infection After Hematopoietic Stem Cell Transplantation.

OBJECTIVES: An association between costimulatory molecule gene polymorphisms and viral infection after hematopoietic stem cell transplantation may be related to clinical outcomes, especially acute graft-versus-host disease. Cytotoxic T-lymphocyte antigen 4 has been suggested as a crucial negative regulator of the immune system. In this study, our objective was to investigate the association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms (including -1722 T/C, -1661 A/G, -318 C/T, and +49 A/G) and torque teno virus infection after hematopoietic stem cell transplantation in patients with and without acute graft-versus-host disease. MATERIALS AND METHODS: Our study included 71 recipients. We evaluated cytotoxic T-lymphocyte antigen 4 gene polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Our results showed that the GG genotype of the cytotoxic T-lymphocyte antigen 4 +49 A/G was significantly more frequent in transplanted patients infected with torque teno virus, whereas the AG genotype was more common in transplanted patients who did not have this infection. In addition, the -1661 AA and GA genotypes and -318 TC genotypes were significantly more frequent in transplanted patients infected with the virus and who had low-grade (grades I and II) acute graft-versus-host disease. Among those with grade I graft-versus-host disease, the GG genotype of the cytotoxic T-lymphocyte antigen 4+49 A/G was more frequent in transplanted patients with torque teno virus infection, whereas the AG genotype was higher in transplanted patients who did not have this infection. CONCLUSIONS: This is the first report indicating that cytotoxic T-lymphocyte antigen 4 gene polymorphism may be implicated in prevalence of torque teno virus infection after stem cell transplant. Further larger studies and evaluation of other costimulatory molecules are suggested.

Prevalence and severity of Coronavirus disease 2019 (COVID-19) in Transfusion Dependent and Non-Transfusion Dependent ß-thalassemia patients and effects of associated comorbidities: an Iranian nationwide study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreak is a global and challenging disease that is accompany with mortality and morbidity. AIM OF STUDY: We evaluated the prevalence and the impact of comorbidities in thalassemia Iranian patients affected by COVID-19.  Methods: A multicenter, retrospective, cross-sectional study was conducted across all comprehensive thalassemia centers in Iran, from January to June 15th, 2020. RESULTS: Forty-three confirmed COVID-19 thalassemia patients (32 TDT, and 11 NTDT) were detected. The mean age of patients was 35.3 ± 11.5 years (range 9 - 67); 21 females and 22 males. Overall, 78.1% of TDT and 90.9% of NTDT patients were complicated with at least one comorbidity (P: 0.656). The overall mortality rate of thalassemia patients with COVID-19 was 18.6% while 27.3% was in NTDT patients compared to 15.6% in TDT patients (P:0.401). The dead group had a non-significant higher frequency of endocrinopathies compared to the recovered group (62.5% versus 45.7% P:0.457). Ten female thalassemia patients with positive COVID-19 had hypogonadism, six patients were receiving hormone replacement therapy and all of them recovered (zero death) compared to two deaths from 4 patients who were not receiving hormone replacement therapy (P:0.133). Furthermore, the prevalence of COVID-19 in NTDT patients was significantly higher than the general population (45 per 10,000 versus 22.29 per 10,000 respectively, P:0.018) while the prevalence of TDT was almost similar to the normal population (P:0.539). The mortality rate of COVID-19 was 4.71% in the normal Iranian population compared to 18.6% in ß-thalassemias (P: <0.001) at the same date. CONCLUSIONS: It is important to acknowledge that ß-thalassemia patients, especially young adults/adults, have a chronic condition which may contribute to increase susceptibility to SARS-CoV-2 infection. A higher susceptibility to the infection was observed in patients with NTDT and in untreated hypogonadal female thalassemic patients. However, to confirm these data, more accurate designed studies are needed.

A comprehensive update of ICET-A Network on COVID-19 in thalassemias: what we know and where we stand.

A review of the literature on COVID-19 pandemic in patients with thalassemias is presented. Globally, the prevalence of COVID-19 among  ß-thalassemia patients seems to be lower than in general population; associated co-morbidities aggravated the severity of  COVID- 19, leading to a poorer prognosis, irrespective of age. A multicenter registry will enhance the understanding of COVID-19 in these patients and will lead to more evidence-based management recommendations.

Preliminary Data on COVID-19 in Patients with Hemoglobinopathies: A Multicentre ICET-A Study.

OBJECTIVES: This study aims to investigate, retrospectively, the epidemiological and clinical characteristics, laboratory results, radiologic findings, and outcomes of COVID-19 in patients with transfusion-dependent ß thalassemia major (TM), ß-thalassemia intermedia (TI) and sickle cell disease (SCD). DESIGN: A total of 17 Centers, from 10 countries, following 9,499 patients with hemoglobinopathies, participated in the survey. MAIN OUTCOME DATA: Clinical, laboratory, and radiologic findings and outcomes of patients with COVID-19 were collected from medical records and summarized. RESULTS: A total of 13 patients, 7 with TM, 3 with TI, and 3 with SCD, with confirmed COVID-19, were identified in 6 Centers from different countries. The overall mean age of patients was 33.7±12.3 years (range:13-66); 9/13 (69.2%) patients were females. Six patients had pneumonia, and 4 needed oxygen therapy. Increased C-reactive protein (6/10), high serum lactate dehydrogenase (LDH; 6/10), and erythrocyte sedimentation rate (ESR; 6/10) were the most common laboratory findings. 6/10 patients had an exacerbation of anemia (2 with SCD). In the majority of patients, the course of COVID-19 was moderate (6/10) and severe in 3/10 patients. A 30-year-old female with TM, developed a critical SARS-CoV-2 infection, followed by death in an Intensive Care Unit. In one Center (Oman), the majority of suspected cases were observed in patients with SCD between the age of 21 and 40 years. A rapid clinical improvement of tachypnea/dyspnea and oxygen saturation was observed, after red blood cell exchange transfusion, in a young girl with SCD and worsening of anemia (Hb level from 9.2 g/dl to 6.1g/dl). CONCLUSIONS: The data presented in this survey permit an early assessment of the clinical characteristics of COVID 19 in different countries. 70% of symptomatic patients with COVID- 19 required hospitalization. The presence of associated co-morbidities can aggravate the severity of COVID- 19, leading to a poorer prognosis irrespective of age.

Antithrombotic prophylaxis in children and adolescents' patients with SARS-CoV-2 (COVID-19) infection: A practical guidance for clinicians.

Severe coronavirus disease 2019 (COVID-19) is often associated with features of hypercoagulable state which can manifest as venous thromboembolism (VTE) and/or microthrombosis. Given the high risk of VTE in critically ill COVID-19 patients, appropriate VTE prophylaxis seems to be an important part of managing these patients. Although many protocols regarding venous thromboembolism (VTE) prophylaxis or therapeutic (full-dose) anticoagulation have been conducted worldwide, primarily in hospitalised adult patients, details on paediatric patients, if included, are limited or incomplete. The current evidences suggest that anticoagulation therapy with low molecular weight heparins (LMWH) appears to be associated with better prognosis in patients with moderate to severe COVID-19 induced coagulopathies or elevated D-dimer levels.  Our recommendations are intended to offer guidance for anticoagulation prophylaxis and treatment in COVID-19 children and adolescent patients and not intend to supersede the clinician judgement. We are also conscious that several clinical questions deserve further studies and clarifications because this area is rapidly evolving.

Evaluation of endocrine complications in beta-thalassemia intermedia (ß-TI): a cross-sectional multicenter study.

BACKGROUND: Data on the prevalence and type of endocrine disorders in ß-thalassemia intermedia (ß-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of ß-TI patients. METHODS: In this cross-sectional multicenter study, 726 ß-TI patients, aged 2.5-80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5-80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. RESULTS: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729-13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944-13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217-140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012-2.977, P = 0.045). Hydroxyurea was identified as a "protective factor" for NIDDM (Odds ratio: 0.259, 95% CI: 0.074-0.902, P = 0.034). CONCLUSIONS: To the best of our knowledge, this is the largest cohort of ß-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with ß-TI compared with ß-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in ß-TI patients.

Efficacy and safety of resveratrol, an oral hemoglobin F-augmenting agent, in patients with beta-thalassemia intermedia.

Recently, resveratrol showed induction of γ-globin mRNA synthesis in human erythroid precursors and reducing oxidative stress in red cells of thalassemia patients in many in vitro studies. We aimed to investigate the efficacy and safety of resveratrol, for the first time, in non-transfusion-dependent beta-thalassemia intermedia (B-TI) in Southern Iran. In this double-blind randomized clinical trial, 54 patients with B-TI were investigated during 6 months between October 2016 and March 2017. Patients were randomly allocated into three groups by simple randomization method. Group 1 (hydroxyurea (HU) and placebo, 18 patients), group 2 (resveratrol/piperine and placebo, 16 patients), and group 3(HU and resveratrol/piperine, 20 patients). Primary end point was considered as change in hemoglobin (Hb) levels and need for blood transfusion. Drug safety was considered as a secondary end point. Mean age of the patients was 28.2 ± 5.6 (18-42) years. Response rate was not significantly different among the three groups (P > 0.05). Higher percentages of adverse events were detected in groups 2 (31.3%) and 3 (25%) compared to group 1 (5.6%). However, the difference was not statistically significant (P > 0.05). All reported adverse events were gastrointestinal symptoms. Resveratrol showed a similar efficacy with HU in the small population of non-transfusion B-TI patients during a 6-month follow-up. Complications, mostly gastrointestinal, were observed more frequently in resveratrol groups compared to the HU group. Although it was not statistically significant, more attention should be given to safety and efficacy of resveratrol as an oral HbF-augmenting agent.

Investigating the bone mineral density in children with solid tumors in southern Iran: a case-control study.

Along with increasing childhood cancer survival, there is increasing concern about its chronic complications. We showed that 20.5 and 45.9% of children with solid tumors in southern Iran had low bone mass for chronological age in lumbar and femoral area, which was associated with serum ferritin and hemoglobin. 52.4% of these children had vitamin D deficiency, as well. PURPOSE/INTRODUCTION: Along with increasing the childhood cancer survival, there is increasing concern about the chronic complications of the disease and the related therapies. This study aims to compare the vitamin D status and bone mineral apparent density (BMAD) of these children with healthy ones and assess some possible associated factors. METHOD: This case-control study enrolled 50 children with solid tumors and their age- and sex-matched controls. Dual-energy X-ray absorptiometry was used to assess bone mineral density. Body mass index, puberty, physical activity, sun exposure, and biochemical data were assessed. RESULTS: 52.4% of children with solid tumors had vitamin D deficiency, and there was no significant difference between the prevalence of vitamin D deficiency in patients and controls (P = 0.285). The prevalence of low bone mass for chronological age in lumbar area was 20.5 and 12.5% in patients and controls, respectively (P = 0.399). Lumbar spine BMD was associated with hemoglobin level (r = 0.468, P = 0.049), while low bone mass in femoral neck was associated with serum ferritin (859 ± 1037 in low bone mass vs. 178 ± 264 in without low bone mass, P = 0.039). CONCLUSION: Vitamin D deficiency and low bone mass are prevalent among Iranian children with solid tumors. Future studies are warranted to investigate the best strategies to prevent and treat vitamin D deficiency and low bone mass in children surviving cancer.

Evaluation of bone mineral density in children with sickle-cell anemia and its associated factors in the south of Iran: a case-control study.

Sickle-cell anemia is a hereditary hemoglobin disorder among children. We showed that the low bone mass is prevalent among these children, and it has a negative association with hemoglobin. In spite of using supplementary 200 IU/day vitamin D, 59.6% of children with sickle-cell anemia are vitamin D deficient. We suggest that early diagnosis and treatment of this problem could improve the bone health in them.

Relationship Between Some Single-nucleotide Polymorphism and Response to Hydroxyurea Therapy in Iranian Patients With ß-Thalassemia Intermedia.

OBJECTIVE: To evaluate the possible relationship between hydroxyurea (HU) response and some single-nucleotide polymorphism (SNP) in patients affected by ß-thalassemia intermedia. MATERIALS AND METHODS: In this cross-sectional study, 100 ß-thalassemia intermedia patients who were taking HU with a dose of 8 to 15 mg/kg body weight per day for a period of at least 6 months were randomly selected between February 2013 and October 2014 in southern Iran. HU response was defined based on decrease or cessation of the blood transfusion need and evaluation of Hb level. RESULTS: In univariate analysis, from all evaluated SNPs, only rs10837814 SNP of olfactory receptors (ORs) OR51B2 showed a significant association with HU response (P=0.038) and from laboratory characteristics, only nucleated red blood cells showed significant associations (116%±183%) in good responders versus (264%±286%) in poor responders (P=0.045). In multiple logistic regression, neither laboratory variables nor different SNPs, showed significant association with HU response. Three novel nucleotide variations (-665 [A→C], -1301 [T→G],-1199 delA) in OR51B2 gene were found in good responders. CONCLUSIONS: None of the evaluated SNPs in our study showed significant association with HU response. Further larger studies and evaluation of other genes are suggested.

A Number of Cases in Iran Presenting with Coinheritance of Hemoglobin-H Disease and Beta-Thalassemia Minor.

Thalassemias are a group of inherited hematological disorders caused by defects in the synthesis of one or more of the hemoglobin (Hb) chains. The ß- and α-thalassemias are widespread throughout the Mediterranean region, the Middle East, and Southeast Asia including Iran. In this study, we report five patients known to carry a coinheritance of Hb H (ß4) disease and ß-thalassemia (ß-thal) minor. There is a high prevalence of consanguineous marriages in our population and the high rate of thalassemia determinants can cause coinheritance of α- and ß-thal. Therefore, it is of special interest to report coinheritance of Hb H disease and ß-thal minor which could lead to misdiagnosis.