Safety and efficacy of L-Glutamine in reducing the frequency of acute complications among patients with sickle cell disease: A randomized controlled study.

To evaluate the safety and efficacy of L-glutamine in reducing vaso-occlusive crisis (VOC) and improving cerebral arterial blood flow in children with sickle cell disease (SCD). This is an interventional randomized controlled trial that recruited sixty SCD patients, aged 9.2 ± 3.7 years, who had at least two VOCs during the last 12 months and on a stable dose of hydroxyurea. They were randomly assigned in a 1:1 ratio to receive glutamine (0.3 gm/kg/dose/12h) orally for 24 weeks or the standard of care (SOC). All patients had VOCs in the last year > 3, those on glutamine had a higher number of VOCs and hospitalization for VOC in the last year. There was a decreasing trend in the number, severity, and hospitalization of VOC and a significantly lower cumulative number of VOCs and hospitalizations in the glutamine group than in SOC (p = 0.008, p < 0.001 respectively). Time-averaged mean maximum velocity for the glutamine group had a marginal increase in both middle cerebral arteries, all values remained normal within a normal range, and in both internal carotid arteries, values increased from abnormally low to normal ranges at week 24. Glutamine reduced the number of VOCs and severity and may have a potentially favorable impact on the cerebral arterial flow velocities.

Endothelin-1 gene polymorphism (G8002A) and endothelial monocyte-activating polypeptide II: Role in vascular dysfunction in pediatric patients with ß-thalassemia major.

BACKGROUND: Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, stimulates production of reactive oxygen species. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide. AIM: To assess ET-1 gene polymorphism (G8002A) in pediatric patients with ß-thalassemia major (ß-TM) as a potential genetic marker for vascular dysfunction and its possible relation to EMAP II, oxidative stress and vascular complications. METHODS: ß-TM patients (n = 95) without symptomatic cardiac or renal disease were compared with 95 healthy controls. Markers of hemolysis, serum ferritin, urinary albumin-to-creatinine ratio, serum EMAP II, malondialdehyde (MDA) and antioxidant enzymes; superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase and catalase were measured. ET-1 gene polymorphism (G8002A) was determined using polymerase chain reaction­restriction fragment length polymorphism. RESULTS: ß-TM patients had significantly higher EMAP II than healthy controls. EMAP II was significantly higher among patients with cardiac disease, pulmonary hypertension (PH) risk, nephropathy, poor compliance to therapy and ferritin ≥ 2500 µg/L. There were significant correlations between EMAP II and transfusion index, LDH, ferritin and oxidative stress markers. The AA genotype of ET-1 gene polymorphism (G8002A) was significantly higher among ß-TM patients than controls. The number of patients with cardiac disease, PH risk or nephropathy was significantly higher among AA genotype compared with GG and GA genotypes. Lactate dehydrogenase (LDH), serum ferritin, EMAP II, MDA, SOD and GPx were significantly higher in AA genotype. CONCLUSION: ET-1 gene polymorphism (G8002A) could be a possible genetic marker for prediction of increased susceptibility to cardiopulmonary and renal complications among pediatric patients with ß-TM.

The implementation of automated red blood cell exchange (erythrocytapheresis) as a treatment modality in sickle cell disease patients: Single center experience.

BACKGROUND: Improvements of health infrastructure, preventive care and clinical management is important to reduce the morbidity and mortality of sickle cell disease (SCD). OBJECTIVE: This prospective, investigator-initiated non-randomized open-label intervention, single centre study describes the implementation of the automated erythrocytapheresis in low-middle income country as a treatment modality for SCD patients to improve the standard of care and highlights its benefits and challenges. METHODOLOGY: Eligible patients with SCD who had overt stroke, abnormal/conditional transcranial doppler (TCD), or other indications were subjected to regular automated erythrocytapheresis program. RESULTS: From 18th Dec 2017 till 17th Dec 2022, 21 subjects were enrolled; seventeen (80.9 %) were Egyptian and four (19.1 %) were non-Egyptian (three Sudanese and one Nigerian). Totalling 133 sessions had been performed mainly in working hours with fluctuating frequency per month. All sessions maintained isovolumic status and were performed using central venous access. The target HbS concentration was set from the start; the mean final FCR % fraction was 51, most of the session (n = 78, 58.7 %) were able to achieve target FCR. The majority of session pass smoothly with no adverse event (n = 81, 60.9 %), except for certain challenges as shortage of the required blood (n = 38), hypotension (n = 2), hypocalcaemia (n = 2). CONCLUSION: Automated erythrocytapheresis is safe and effective modality for management of patients with sickle cell disease.

Hidden brain iron content in sickle cell disease: impact on neurocognitive functions.

Children with sickle cell disease (SCD) are at a high risk for neurocognitive impairment. We aim to quantitatively measure cerebral tissue R2* to investigate the brain iron deposition in children and young adults with SCD in comparison to beta thalassemia major (BTM) and healthy controls and evaluate its impact on neurocognitive functions in patients with SCD. Thirty-two SCD, fifteen BTM, and eleven controls were recruited. Multi-echo fast-gradient echo sequence brain MRI was performed, and brain R2* values of both caudate and thalamic regions were calculated. SCD patients were examined for the neurocognitive functions. SCD had high iron overload 0.30 ± 0.12 mg/kg/day. 68.9% of SCD had under-threshold IQ, 12.5% had moderate to severe anxiety, and 60.8% had depression. There were no differences between SCD, BTM, and controls in brain MRI except that left thalamus R2* higher in BTM than both SCD and controls (p = 0.032). Mean right caudate R2* was higher in female than male (p = 0.044). No significant association between brain R2* and LIC or heart R2* values in SCD. Left caudate R2* directly correlate with age and HbS%, and negatively correlate with HbA% while right thalamus R2* negatively correlate with transfusion index and among SCD patients.Conclusion: Neurocognitive dysfunction in SCD could not be explained solely by brain iron overload. What is Known: • Children with sickle cell disease are at great risk of brain damage due to their irregularly shaped red blood cells that can interrupt blood flow to the brain. • There are a number of factors that have negative brain effects that result in learning difficulties, and this not only due to increase brain iron content. What is New: • Assessment of quantitative brain iron content using MRI R2* in children and young adults with SCD in comparison to beta thalassemia major and healthy controls. • Impact of brain iron content on neurocognitive functions of children and young adults with SCD.

Angiotensinogen M235T Gene Polymorphism is a Genetic Determinant of Cerebrovascular and Cardiopulmonary Morbidity in Adolescents with Sickle Cell Disease.

BACKGROUND: Cerebrovascular stroke is a common critical complication of sickle cell disease (SCD). Angiotensinogen (AGT) M235T gene polymorphism is associated with risk of ischemic stroke and cardiovascular disease. AIM: We investigated the potential association between angiotensinogen M235T gene polymorphism and susceptibility to cerebrovascular and cardiopulmonary complications in adolescents with SCD. METHODS: Forty-six patients with SCD in steady state were studied stressing on history of stroke, hydroxyurea/chelation therapy, hematological profile, and echocardiographic findings. Polymerase chain reaction-based restriction fragment length polymorphism analysis was used to detect AGT M235T gene polymorphism. Fifty sex- and age-matched healthy controls were enrolled for assessment of M235T gene polymorphism pattern. RESULTS: The distribution of AGT M235T gene polymorphism was similar between SCD patients and healthy controls. The frequency of T allele of AGT M235T gene polymorphism (TT and MT genotypes) was significantly higher among patients with history of manifest stroke (P < .001). Patients with TT and MT genotypes had higher incidence of cardiopulmonary complications (P = .041) as well as higher percentage of HbS (P < .001) and lower hemoglobin level (P = .008) compared with those with MM genotype. Serum ferritin, liver iron concentration, and cardiac T2* were not related to T alleles or genotypes. Logistic regression analysis revealed that M235T genotype was a significant independent factor related to the occurrence of stroke among patients with SCD (Odds Ratio 14.05, 95% confidence interval 3.82-28.91; P = .001). CONCLUSION: AGT M235T gene polymorphism may represent a genetic modifier to vascular morbidities in Egyptian patients with SCD.

Early detection of myocardial iron overload in patients with ß-thalassemia major using cardiac magnetic resonance T1 mapping.

BACKGROUND: The T2* technique, used for quantifying myocardial iron content (MIC), has limitations in detecting early myocardial iron overload (MIO). The in vivo mapping of the myocardial T1 relaxation time is a promising alternative for the early detection and management of MIO. METHODS: 32 ß-thalassemia major (ßTM) patients aged 11.5 ± 4 years and 32 healthy controls were recruited and underwent thorough clinical and laboratory assessments. The mid-level septal iron overload was measured through T1 mapping using a modified Look-Locker inversion recovery sequence with a 3 (3 s) 3 (3 s) 5 scheme. Septum was divided at the mentioned level into 3 zones corresponding to segments 8 and 9 in the cardiac segmentation model. RESULTS: 21.9 % of ßTM had clinical cardiac morbidity. The cut-off of T1 mapping of hepatic and myocardium to differentiate between the patients and control groups was ≤466 and ≥ 923 ms respectively. The T1 technique was able to detect 4 patients with high MIC, two of them were not detected by the T2* technique. There was a statistically significant correlation between the average T1 values of the studied zones in patients with ßTM and the liver iron content (LIC), the T1 values within segment 8 of the liver, age of patients, the age at first transfusion, age of splenectomy and serum ferritin value. CONCLUSION: The addition of the T1 mapping sequence to the conventional T2* technique was able to increase the efficacy of the MIC detection protocol by earlier detection of MIO. This would guide chelation therapy to decrease myocardial morbidity.

Epistaxis in a Pediatric Outpatient Clinic: Could It be an Alarming Sign?

Introduction Epistaxis is a common presentation among children. Objective To investigate the suitability of a simple tool of assessment for patients with epistaxis that could guide in subgrouping those with possible bleeding tendencies who may need further assessment. Methods Children who presented to a tertiary outpatient clinic with epistaxis of an unknown cause were recruited. They underwent thorough clinical assessment and answered the pediatric bleeding questionnaire and the epistaxis severity score. All patients underwent complete blood count as well as coagulation profile, and confirmatory diagnostic tests were performed as needed. Results Among the 30,043 patients who presented to the outpatient clinic over a year, 100 children had epistaxis, with an estimated annual frequency of 1 in 300. A total of 84% of the patients were younger than 12, and nearly half of these were younger than 6 years. Seventy-six patients had recurrent epistaxis, and 12 had systemic comorbidities. A significant higher percentage of patients presented with epistaxis in the hot months of the year. A total of 90% of the patients presented anterior bleeding, and the majority were treated with nasal compression only. Forty-three patients presented with epistaxis only; 37 of them were diagnosed as idiopathic epistaxis, and 6 had local causes. Fifty-seven patients presented with other bleeding manifestations, 47 of whom had a definite bleeding disorder and the other 10 had undiagnosed bleeding tendency. Those with other bleeding manifestations showed a higher frequency of positive family history of epistaxis; of being referred from a primary care physician; of having alarming low platelet count, and of presenting less seasonal variability. A bleeding score ≥ 2 showed significant value in suspecting an underlying systemic pathology as a cause of epistaxis. Conclusion The pediatric bleeding questionnaire is a useful and simple tool in the identification of pediatric patients who need further diagnostic testing to detect any underlying bleeding tendency.

The role of MRI-R2* in the detection of subclinical pancreatic iron loading among transfusion-dependent sickle cell disease patients and correlation with hepatic and cardiac iron loading.

OBJECTIVES: Pancreatic reserve could be preserved by early assessment of pancreatic iron overload among transfusion-dependent sickle cell disease (SCD) patients. This study aimed to measure pancreatic iron load and correlate its value with patients' laboratory and radiological markers of iron overload. MATERIALS AND METHODS: Sixty-six SCD children and young adults underwent MRI T2* relaxometry using a simple mathematical spreadsheet and laboratory assessment. RESULTS: The results indicated moderate-to-severe hepatic iron overload among 65.2% of studied cases. None had cardiac iron overload. Normal-to-mild iron overload was present in the pancreas in 86% of cases, and 50% had elevated serum ferritin > 2500 ug/L. There was no significant correlation between pancreatic R2* level, serum ferritin, and hepatic iron overload. Patients with higher levels of hemolysis markers and lower pre-transfusion hemoglobin levels showed moderate-to-severe pancreatic iron overload. CONCLUSION: Chronically transfused patients with SCD have a high frequency of iron overload complications including pancreatic iron deposition, thereby necessitating proper monitoring of the body's overall iron balance as well as detection of extrahepatic iron depositions.

COVID-19 effect on clinical research: Single-site risk management experience.

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic is extensively impacting new and ongoing clinical trials of various medical products irrespective of indication. It has the potential to adverse effect not only in terms of recruitment and immediate patient care but is also likely to affect the data collection and analysis in the months to come. AIM: The aim was to illustrate the effect of COVID-19 on the clinical research in one of the research centers in low limited-resource country as Egypt and the management plan performed to decrease this adverse impact. METHODOLOGY: Secondary data were collected anonymously about the measures implemented to deal with the challenges of conducting the nine ongoing and new clinical researches during COVID-19 pandemic at Faculty of Medicine, Ain Shams University Research Institute-Clinical Research Center. RESULTS: Out of the 47 enrolled participants, thirty participants required investigational product (IP) dispensation during the remaining study period; 27 of them had their IP dispensed at site, and six participants who were from far away Governorate were not able to come to the center due to the partial lockdown and had their IP deliver through courier to their home. Safety laboratory assessment had performed at the site or local laboratory at their hometown. Virtual visit alternatives to in-person visits for communication and patient evaluation had been performed. Recruitment of new participants and opening new sites were stopped in many trials. In order to reduce the on-site activities, in particular, on-site monitoring, all monitoring visits were performed virtually. CONCLUSION: The adverse impact of COVID-19 pandemic on clinical trials could be lessening by active management plan.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4+CD28null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4+CD28null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4+CD28null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4+CD28null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4+CD28null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4+CD28null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4+CD28null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Renal iron deposition by magnetic resonance imaging in pediatric ß-thalassemia major patients: Relation to renal biomarkers, total body iron and chelation therapy.

BACKGROUND: The reciprocal of multiecho gradient-echo (ME-GRE) T2* magnetic resonance imaging (MRI) R2*, rises linearly with tissue iron concentration in both heart and liver. Little is known about renal iron deposition in ß-thalassemia major (ß-TM). AIM: To assess renal iron overload by MRI and its relation to total body iron and renal function among 50 pediatric patients with ß-TM. METHODS: Serum ferritin, serum cystatin C, urinary albumin creatinine ratio (UACR), and urinary ß2-microglobulin (ß2 M) were measured with calculation of ß2 M/albumin ratio. Quantification of liver, heart and kidney iron overload was done by MRI. RESULTS: Serum cystatin C, UACR and urinary ß2 microglobulin as well as urinary ß2m/albumin were significantly higher in ß-TM patients than the control group. No significant difference was found as regards renal R2* between Patients with mean serum ferritin above 2500 µg/L and those with lower serum cutoff. Renal R2* was higher in patients with poor compliance to chelation therapy and positively correlated to indirect bilirubin, LDH, cystatin C and LIC but inversely correlated to cardiac T2*. CONCLUSION: kidney iron deposition impairs renal glomerular and tubular functions in pediatric patients with ß-TM and is related to hemolysis, total body iron overload and poor compliance to chelation.

Epistaxis in a Pediatric Outpatient Clinic: Could It be an Alarming Sign?

Abstract Introduction Epistaxis is a common presentation among children. Objective To investigate the suitability of a simple tool of assessment for patients with epistaxis that could guide in subgrouping those with possible bleeding tendencies who may need further assessment. Methods Children who presented to a tertiary outpatient clinic with epistaxis of an unknown cause were recruited. They underwent thorough clinical assessment and answered the pediatric bleeding questionnaire and the epistaxis severity score. All patients underwent complete blood count as well as coagulation profile, and confirmatory diagnostic tests were performed as needed. Results Among the 30,043 patients who presented to the outpatient clinic over a year, 100 children had epistaxis, with an estimated annual frequency of 1 in 300. A total of 84% of the patients were younger than 12, and nearly half of these were younger than 6 years. Seventy-six patients had recurrent epistaxis, and 12 had systemic comorbidities. A significant higher percentage of patients presented with epistaxis in the hot months of the year. A total of 90% of the patients presented anterior bleeding, and the majority were treated with nasal compression only. Forty-three patients presented with epistaxis only; 37 of them were diagnosed as idiopathic epistaxis, and 6 had local causes. Fifty-seven patients presented with other bleeding manifestations, 47 of whom had a definite bleeding disorder and the other 10 had undiagnosed bleeding tendency. Those with other bleeding manifestations showed a higher frequency of positive family history of epistaxis; of being referred from a primary care physician; of having alarming low platelet count, and of presenting less seasonal variability. A bleeding score ≥ 2 showed significant value in suspecting an underlying systemic pathology as a cause of epistaxis. Conclusion The pediatric bleeding questionnaire is a useful and simple tool in the identification of pediatric patients who need further diagnostic testing to detect any underlying bleeding tendency.