Egyptian Pediatric Guidelines for the Management of Children with Isolated Thrombocytopenia Using the Adapted ADAPTE Methodology-A Limited-Resource Country Perspective.

BACKGROUND: Thrombocytopenia is a prevalent presentation in childhood with a broad spectrum of etiologies, associated findings, and clinical outcomes. Establishing the cause of thrombocytopenia and its proper management have obvious clinical repercussions but may be challenging. This article provides an adaptation of the high-quality Clinical Practice Guidelines (CPGs) of pediatric thrombocytopenia management to suit Egypt's health care context. METHODS: The Adapted ADAPTE methodology was used to identify the high-quality CPGs published between 2010 and 2020. An expert panel screened, assessed and reviewed the CPGs and formulated the adapted consensus recommendations based on the best available evidence. DISCUSSION: The final CPG document provides consensus recommendations and implementation tools on the management of isolated thrombocytopenia in children and adolescents in Egypt. There is a scarcity of evidence to support recommendations for various management protocols. In general, complete clinical assessment, full blood count, and expert analysis of the peripheral blood smear are indicated at initial diagnosis to confirm a bleeding disorder, exclude secondary causes of thrombocytopenia and choose the type of work up required. The International Society of Hemostasis and thrombosis-Bleeding assessment tool (ISTH-SCC BAT) could be used for initial screening of bleeding manifestations. The diagnosis of immune thrombocytopenic purpura (ITP) is based principally on the exclusion of other causes of isolated thrombocytopenia. Future research should report the outcome of this adapted guideline and include cost-analysis evaluations.

Transfusion of blood components in pediatric age groups: an evidence-based clinical practice guideline adapted for the use in Egypt using 'Adapted ADAPTE'.

Pediatric transfusion is a complex area of medicine covering a wide age range, from neonates to young adults. Compared to adult practice, there is a relative lack of high-quality research to inform evidence-based guidelines. We aimed to adapt the pre-existing high-quality practice guidelines for the transfusion of blood components in different pediatric age groups to be available for national use by general practitioners, pediatricians, and other health care professionals. The guideline panel included 17 key leaders from different Egyptian institutions. The panel used the Adapted ADAPTE methodology. The panel prioritized the health questions and recommendations according to their importance for clinicians and patients. The procedure included searching for existing guidelines, quality appraisal, and adaptation of the recommendations to the target context of use. The guideline covered all important aspects of the indications, dosing, and administration of packed red cells, platelets, and fresh frozen plasma. It also included transfusion in special situations, e.g., chronic hemolytic anemia and aplastic anemia, management of massive blood loss, malignancies, surgery, recommendations for safe transfusion practices, and recommendations for modifications of cellular blood components. The final version of the adapted clinical practice guideline (CPG) has been made after a thorough review by an external review panel and was guided by their official recommendations and modifications. A set of implementation tools included algorithms, tables, and flow charts to aid decision-making in practice. This adapted guideline serves as a tool for safe transfusion practices in different pediatric age groups.

Efficacy and safety of early-start deferiprone in infants and young children with transfusion-dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double-blind, placebo-controlled, clinical trial (START).

Children with transfusion-dependent thalassemia (TDT) require regular blood transfusions that, without iron-chelation therapy, lead to iron-overload toxicities. Current practice delays chelation therapy (late-start) until reaching iron overload (serum ferritin ≥1000 µg/L) to minimize risks of iron-depletion. Deferiprone's distinct pharmacological properties, including iron-shuttling to transferrin, may reduce risks of iron depletion during mild-to-moderate iron loads and iron overload/toxicity in children with TDT. The early-start deferiprone (START) study evaluated the efficacy/safety of early-start deferiprone in infants/young children with TDT. Sixty-four infants/children recently diagnosed with beta-thalassemia and serum ferritin (SF) between 200 and 600 µg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF-threshold (≥1000 µg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF-threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron-shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 µg/L, placebo: 451.7 µg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone-treated patients were iron-depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo (p = .045). Deferiprone-treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early-start deferiprone was well-tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.

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.

Deferiprone for transfusional iron overload in sickle cell disease and other anemias: open-label study of up to 3 years.

Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST (Ferriprox in Patients With Iron Overload in Sickle Cell Disease Trial), a 1-year, randomized noninferiority study of deferiprone vs deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary end point was safety. Secondary end points were change in liver iron concentration (LIC), cardiac T2∗, serum ferritin (SF), and the proportion of responders (≥20% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0%) and abdominal pain (7.5%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1, -2.64 [4.64]; year 2, -3.91 [6.38]; year 3, -6.64 [7.72], all P < .0001). Mean SF levels (µg/L) decreased significantly after year 2 (-771, P = .0008) and year 3 (-1016, P = .0420). Responder rates for LIC and SF increased each year (LIC: year 1, 46.5%; year 2, 57.1%; year 3, 66.1%; SF: year 1, 35.2%; year 2, 55.2%; year 3, 70.9%). Cardiac T2∗ remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. The trial was registered at www.clinicaltrials.gov as #NCT02443545.

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Abdominal lymphadenopathy in children with Gaucher disease: Relation to disease severity and glucosylsphingosine.

Few case reports and series reported abdominal lymphadenopathy (ALN) in people with Gaucher disease (GD). However, it's prevalence among Gaucher population, clinical implications and potential biomarkers are unknown. Hence this study aims to assess the prevalence of ALN among children with GD & to correlate it to neutrophil-lymphocytic-ratio (NLR), platelet-lymphocytic-ratio (PLR) and glucosylsphingosine (Lyso-GL1). Fifty children with GD (14 type-1 and 36 type-3) on enzyme-replacement therapy (ERT) were compared to 50 matched healthy controls, focusing on history of pressure manifestations by ALN (diarrhea, constipation, abdominal pain, intestinal obstruction), and history of splenectomy, with calculation of severity scoring index (SSI). NLR, PLR and Lyso-GL1 were measured. Abdominal-ultrasound was done with assessment of liver and spleen volumes and ALN. CT-scan was done for those having significant lymphadenopathy. Twenty-six children with GD had ALN (52%). The most common presentations were abdominal-pain (22%) & constipation (18%), with intestinal-obstruction in 3 children (6%). Children with GD had significantly higher NLR (p < .001) and decreased PLR (p = .024) compared to controls. Interestingly, children with GD having ALN had significantly higher SSI (.012), Lyso-GL1 (p = .002) and NLR (p = .001) than those without ALN. Multivariate-logistic regression showed that ALN was independently related to Lyso-GL1 (p = .027), NLR (p = .023) and SSI (p = .032). Thus, ALN is a prevalent GD morbidity with wide clinical-spectrum ranging from asymptomatic cases to intestinal obstruction. ALN is related to SSI, NLR and Lyso-GL1 in children with GD.HighlightsChildren with GD had significantly higher NLR and lower PLR compared to controls.Children with GD having ALN had significantly higher SSI, Lyso-GL1 and NLR than those without ALN.ALN was independently related to Lyso-GL1, NLR and SSI in children with GD.

Management of children with glucose-6-phosphate dehydrogenase deficiency presenting with acute haemolytic crisis during the SARs-COV-2 pandemic.

BACKGROUND AND OBJECTIVES: Shortage of blood during the severe acute respiratory syndrome-COV-2 (SARs-COV-2) pandemic impacted transfusion practice. The primary aim of the study is to assess management of acute haemolytic crisis (AHC) in glucose-6-phosphate dehydrogenase(G6PD)- deficient children during SARs-COV-2 pandemic, and then to assess blood donation situation and the role of telemedicine in management. METHODS: Assessment of G6PD-deficient children attending the Emergency Department (ER) with AHC from 1 March 2020 for 5 months in comparison to same period in the previous 2 years, in three paediatric haematology centres. AHC cases presenting with infection were tested for SARs-COV-2 using RT-PCR. Children with Hb (50-65 g/L) and who were not transfused, were followed up using telemedicine with Hb re-checked in 24 h. RESULTS: A 45% drop in ER visits due to G6PD deficiency-related AHC during SARs-COV-2 pandemic in comparison to the previous 2 years was observed. 10% of patients presented with fever and all tested negative for COVID-19 by RT-PCR. 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up. A restrictive transfusion strategy was adopted and one of the reasons was a 39% drop in blood donation in participating centres. CONCLUSION: Fewer G6PD-deficient children with AHC visited the ER during SARs-COV-2 and most tolerated lower Hb levels. Telemedicine was an efficient tool to support their families. A restrictive transfusion strategy was clear in this study.

Coenzyme Q10 administration has no effect on sICAM-1 and metabolic parameters of pediatrics with type 1 diabetes mellitus.

Background: Endothelial dysfunction (ED) plays a key role in the development and progression of microvascular and macrovascular complications in pediatrics with type 1 diabetes mellitus (T1DM). Coenzyme Q10 (CoQ10) is a nutraceutical with a known anti-inflammatory and anti-oxidant activity. This study was conducted to evaluate the potential effect of CoQ10 on ED and various metabolic parameters. Methods: This prospective randomized open-label pilot study was conducted on 49 T1DM pediatric patients. Seven healthy non-diabetic pediatric subjects who didn't receive treatment were included as a control group. Eligible patients were randomly allocated into either group I (n = 25); received 100 mg of CoQ10 in addition to standard treatment or group II (n = 24); received standard treatment only. The levels of; soluble intracellular adhesion molecule-1 (sICAM-1), glycated hemoglobin (HbA1c), fasting blood glucose (FBG), lipid profile, serum creatinine and liver function tests were assessed for both groups at baseline and after 3 months of treatment. Results: At baseline, compared to an age-matched healthy control group sICAM-1 levels were significantly elevated in group II diabetic patients (276.5 (231.6-320.66) vs 221.8 (177.9-267.1 ng/ml), p = 0.042. After 3 months of treatment no significant difference was observed in sICAM-1, HbA1c, FBG, lipid profile, serum creatinine and liver function tests between the two study groups. A positive correlation was found between sICAM-1 and HbA1c throughout the study (r = 0.308, p = 0.0054). Conclusion: Administration of CoQ10 for 3 months in T1DM pediatric patients was well tolerated but had no favorable effect on ED or metabolic parameters.

Ganglion Cell Complex Thinning in Young Gaucher Patients: Relation to Prodromal Parkinsonian Markers.

BACKGROUND: Patients with Gaucher disease (GD) have an increased risk for parkinsonism. Retinal thinning has been described in parkinsonism as an early nonmotor feature. Scarce reports have addressed retinal thickness changes in GD. OBJECTIVES: The objectives of this study were to compare ganglion cell complex (GCC) thickness in adolescents and young adults (AYAs) with GD with healthy control subjects, and to correlate it with the presence of parkinsonian features (PFs), clinical prodromal markers of parkinsonism, severity score index (SSI), and glucosylsphingosine (Lyso-GL-1). METHODS: This study included 48 AYAs with GD (11-29 years), 11 with manifest PFs (Group 1) and 37 with no PFs (Group 2), and 48 matched healthy control subjects (Group 3). Age of GD onset, disease duration, medication history, history of constipation, SSI, and hematological assessment were done. Neurocognitive evaluation included Parts I, II, and III of the Unified Parkinson's Disease Rating Scale (UPDRS), Wechsler Adult and Intelligence Scale and Wechsler Intelligence Scale for Children, Beck Depression Inventory (BDI), rapid eye movement sleep behavior disorder (RBD) scale, Munich Parasomnia Screening scale, and the olfactory dysfunction scale. Molecular analyses of the acid GBA gene and Lyso-GL-1 were done. Participants underwent full ophthalmological examination and optical coherence tomography with GCC thickness measurement. RESULTS: GCC was significantly thinner in Group 1 than in Groups 2 and 3 (P < 0.001), whereas no significant difference was found between Groups 2 and 3 (P = 0.977). In addition, a significant interocular GCC thickness difference was found among the studied AYAs with GD (P = 0.007). GCC correlated positively with total intelligence quotient (P < 0.001) and negatively with Lyso-GL-1 (P = 0.019), UPDRS (P = 0.004), and BDI (P = 0.029), but not with SSI (P = 0.874), GD type (P = 0.85), or genotype (P = 0.842). A significant negative relationship was found between GCC thickness and PFs (P = 0.001), parasomnia (P = 0.003), constipation (P = 0.031), RBD (P = 0.044), and hyposmia (P = 0.033). CONCLUSIONS: GCC thinning may be a promising biomarker for central nervous system neurodegeneration that has the potential to monitor early PFs among people with GD. © 2020 International Parkinson and Movement Disorder Society.

Serum progranulin levels in paediatric patients with Gaucher disease; relation to disease severity and liver stiffness by transient elastography.

BACKGROUND: Non-invasive screening for liver fibrosis using transient elastography (TE) could be of value in the management of Gaucher disease (GD). Progranulin (PGRN) is a novel disease modifier in GD and an independent marker of liver fibrosis. OBJECTIVES: We determined PGRN levels in paediatric patients with GD and assessed its role as a potential marker for disease severity and relation to liver stiffness by TE. METHODS: Fifty-one GD patients (20 had type 1 and 31 had type 3) with a median age of 9.5 years were compared to 40 age- and sex-matched healthy controls and were studied focusing on visceral manifestations, neurological disease, haematological profile and PGRN levels as well as abdominal ultrasound and TE. Patients were on enzyme replacement therapy (ERT) for various durations and those with viral hepatitis infection were excluded. RESULTS: By TE, 14 GD patients (27.5%) had elevated liver stiffness ≥7.0 kPa. Liver stiffness was significantly higher in type 1 GD patients than type 3 (P = .002), in splenectomized patients (P = .012) and those with dysphagia (P < .001). Liver stiffness was positively correlated with age of onset of ERT (P < .001). PGRN levels were significantly lower in GD patients compared with controls (P < .001). PGRN was significantly lower in GD patients with squint (P = .025), dysphagia (P = .036) and elevated liver stiffness (P = .015). PGRN was positively correlated with white blood cell count (r = .455, P = .002) and haemoglobin (r = .546, P < .001), while negatively correlated with severity score index (r = -.529, P < .001), liver volume (r = -.298, P = .034) and liver stiffness (r = -.652, P < .001). CONCLUSIONS: Serum PGRN levels were associated with clinical disease severity and elevated liver stiffness in paediatric GD patients.

Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients.

Evidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of parkinsonism. Anthropometric measures, complete neurological assessment, and SSI were examined. Neuropsychiatric evaluation included parts I, II, III, and V of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Wechsler Intelligence Scale for Children (WISC-children). Molecular analysis of the acid GBA gene was performed, and SSI was calculated. Sixteen GD patients (66.6%) had parkinsonian features with a male to female ratio of 1:1. Their mean age was 15.69 ± 5.62 (range, 12-26). They were all on enzyme replacement therapy (ERT) with a dose of 60 U/kg/2 weeks. Twelve GD patients were phenotypically type 3 (75%). Thirteen GD patients with parkinsonian features (81.25%) had L483P mutation. GD patients with parkinsonian features had higher SSI (P < 0.001), lower cognitive functions (P = 0.007), and more significant depressive symptoms (P = 0.031). Logistic regression analysis revealed that GD genotype (P = 0.003), GD type (P = 0.006), and cognitive functions (P = 0.03) were the only significant independent factors for the development of parkinsonian features among GD patients. With the increased life span and improved somatic manifestations of type 3GD on ERT, these patients can live to develop parkinsonism. Cognitive decline and depression can be early predictors of parkinsonism among GD population.

Pulmonary manifestations in young Gaucher disease patients: Phenotype-genotype correlation and radiological findings.

BACKGROUND: Although pulmonary involvement is important orbidity in Gaucher disease (GD), it is previously reported to be rare. Moreover, no epidemiological studies described its prevalence specifically in children. The clinical spectrum and risk determinants for this complication and its long-term response to therapy are unknown. AIM: To assess the prevalence of clinical and radiological pulmonary involvement in pediatric GD patients and its relation to Gaucher severity and genotype. METHODS: Forty-eight GD patients were studied focusing on pulmonary and neurological manifestations with assessment of severity scoring index (SSI; a Gaucher specific scale). Detailed enzyme replacement therapy (ERT) history was taken regarding dose, duration, and effect on pulmonary manifestations. Genotype was performed to 30 patients. Radiological investigations included plain chest-radiography (CXR), high-resolution CT (HRCT), and hepatic and splenic volumes. RESULTS: Fifteen patients had type 1 (31.2%) and 33 patients had type 3 GD (68.8%). The most common mutation was L483P detected in 25 patients (83.3%). Sixteen patients had recurrent chest wheeze (33%). CXR showed pulmonary findings in 17 patients (35.4%) while HRCT-chest showed affection in 31 patients (64.6%). The ground-glass pattern was present in 14 patients (29.1%), reticulonodular infiltration in 9 patients (18.8%), air trapping in 6 patients (12.5%), and bronchiectatic changes in two patients (4.2%). Univariate logistic regression analysis for predictors of abnormal HRCT-chest was negatively correlated with platelets (P = .01) and hemoglobin (P = .018) and positively correlated with recurrent chest wheezing (P = .019), abnormal CXR (P = .007), and SSI (P = .009). CONCLUSION: Pulmonary involvement is a prevalent morbidity of GD with variable presentations. CXR for early detection of pulmonary involvement in GD is safe and highly predictive.

Psychiatric manifestations in Egyptian Gaucher patients on enzyme replacement therapy.

OBJECTIVES: Gaucher disease (GD) may include psychiatric symptoms as a part of its wide spectrum of manifestations, with several reports describing its association with mood or psychotic symptoms. We investigated the presence of psychiatric manifestations in an Egyptian sample of Gaucher Disease (GD) patients. METHODS: Our sample consisted of 22 GD patients (diagnosed by low glucocerebrosidase (GBA) activity in leukocytes or fibroblasts and molecular analysis by full (GBA) gene sequencing). 13 patients were classified as GD type 1 and 9 patients as GD type 3. We assessed the presence of psychiatric symptoms using the Mini-international neuropsychiatric interview (M.I.N·I) and the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) tools. Arabic versions were used. RESULTS: The results showed that 41% of the sample had psychiatric disorders, with the most common being depression. None was receiving any form of psychiatric treatment. We found no statistically significant association between the presence of psychiatric disorders and any of the clinical variables of GD, its phenotype, or genotype. CONCLUSION: The current results suggest that GD patients are susceptible to psychiatric disorders. However, these results need to be replicated on a wider scale. These findings are of ultimate importance, considering the lack of integrated services addressing both the medical and psychological aspects of inborn errors of metabolism in many countries.

Surfactant protein D as a marker for pulmonary complications in pediatric patients with sickle cell disease: Relation to lung function tests.

BACKGROUND: Surfactant protein D (SP-D) is considered a candidate biomarker for lung integrity and for disease progression. AIM: We determined the level of SP-D in children and adolescents with SCD and assessed its possible relation to pulmonary complications and lung function. METHODS: Serum SP-D levels were assessed in 50 SCD patients compared with 30 healthy controls. High-resolution computerized tomography (HRCT) of the chest was done. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1 ), FEV1 /FVC% and forced expiratory flow rate during 25-75% of expiration (FEF25-75%) were determined. RESULTS: SP-D was significantly higher in SCD patients than controls, particularly patients with sickle cell anemia than those with sickle ß-thalassemia. SP-D levels were significantly associated with increasing severity of interstitial lung disease. The highest SP-D levels were observed among patients with restrictive lung disease followed by mixed type then obstructive lung disease. SP-D was positively correlated to HbS and serum ferritin while negatively correlated to duration of hydroxyurea treatment and parameters of pulmonary functions. ROC curve analysis revealed that SP-D cutoff value 720 ng/mL could significantly detect the presence of abnormal pulmonary function among SCD patients with 82% sensitivity and 88% specificity. Logistic regression analysis showed that SP-D is an independent factor related to abnormal pulmonary function in SCD. CONCLUSIONS: SP-D may be a promising biomarker for screening of SCD patients for risk of later pulmonary complications.

Predictors of future microalbuminuria in children and adolescents with type 1 diabetes mellitus in Egypt.

INTRODUCTION: The present study was designed to assess the validity and efficacy of urinary markers (NAG, RBP, transferrin, α1-microglobulin, and plasma homocysteine) as early predictors of microalbuminuria in diabetic nephropathy in children and adolescents with type-1 diabetes, and its relation with haemoglobin glycated (HbA1c), serum lipid profile, and blood pressure. MATERIAL AND METHODS: This study is a follow-up study to the 2002 study by Salem et al. The present study included 35 type 1 diabetes mellitus (T1DM) children and adolescents recruited from regular attendees of the specialised Diabetology Clinic, Children's hospital, Ain Shams University, with previously measured urinary N-acetyl-ß-glucosaminidase (13) or homocysteine (11) or transferrin (28) or α1-microglobulin (27) or retinol binding protein (13) as an early predictor of diabetic nephropathy in T1DM. Thirty-five patients with type 1 diabetes mellitus were enrolled, and 24 patients were normoalbuminuric at baseline. The patients were tested for markers other than urinary microalbumin, to predict diabetic nephropathy and early renal impairment in children and adolescents with type 1 diabetes mellitus. RESULTS: Regarding the metabolic control between the studied groups, we found that there is significant difference in HbA1c between the microalbuminuric patients and the normoalbuminuric patients. According to the number of positive markers of diabetic nephropathy, the only parameter that was higher in patients with more than one elevated marker was mean systolic blood pressure. Although mean diabetic blood pressure was higher, it was not statistically significant. Regarding to the predictability of urinary markers, urinary N-acetyl-ß-glucosaminidase is the most predictable marker with high sensitivity and specificity. The least sensitivity noticed was urinary RBP and the least specificity noticed was urinary α1-microglobulin. CONCLUSIONS: Regarding the predictability of urinary markers, urinary NAG is the most predictable marker with both high sensitivity and specificity, with a sensitivity of 60%, specificity 75%, positive predictive value 60%, negative predictive value 75%, and a diagnostic accuracy of 0.58%. Urinary RBP is another marker with low sensitivity but high specificity. Urinary α1-microglobulin is a valid marker with high sensitivity but low specificity. Contrary to previous markers, plasma homocysteine has high specificity but low sensitivity.

Evaluation of continuous glucose monitoring system for detection of alterations in glucose homeostasis in pediatric patients with ß-thalassemia major.

BACKGROUND: Disturbances of glucose metabolism are common in ß-thalassemia major (ß-TM). AIM: This study was conducted to assess the pattern of glucose homeostasis in pediatric ß-TM patients comparing oral glucose tolerance test (OGTT) and continuous glucose monitoring system (CGMS). METHODS: Two-hundred ß-TM patients were studied and those with random blood glucose (RBG) ≥7.8 mmol/L (140 mg/dL) were subjected to OGTT, insertion of CGMS and measurement of fasting C peptide, fasting insulin, and hemoglobin A1c (HbA1c). RESULTS: Twenty patients (10%) had RBG ≥ 7.8 mmol/L. Using OGTT, 6 out of 20 patients (30%) had impaired glucose tolerance (IGT) while 7 (35%) patients were in the diabetic range. CGMS showed that 7/20 (35%) patients had IGT and 13 (65%) patients had diabetes mellitus (DM); 10 of the latter group had HbA1c readings within diabetic range. The percentage of diabetic patients diagnosed by CGMS was significantly higher than that with OGTT (P = 0.012). Serum ferritin was the only independent variable related to elevated RBG. All ß-TM patients with DM were non-compliant to chelation therapy. CONCLUSIONS: The use of CGMS in the diagnosis of early glycemic abnormalities among pediatric patients with ß-TM appears to be superior to other known diagnostic modalities.

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.

Management of Children With ß-Thalassemia Intermedia: Overview, Recent Advances, and Treatment Challenges.

Our knowledge of the various clinical morbidities that thalassemia intermedia (TI) patients endure has substantially increased over the past decade. It is mandatory to grasp a solid understanding of disease-specific complications in order to tailor management. The optimal course of management for TI patients has been hard to identify, and several controversies remain with regard to the best treatment plan. Although advances in TI are moving at a fast pace, many complications remain with no treatment guidelines. Studies that expand our understanding of the mechanisms and risk factors, as well as clinical trials evaluating the roles of available treatments, will help establish management guidelines that improve patient care. Novel therapeutic modalities are now emerging. This article focuses on the management of children with ß-TI. We present various clinical morbidities and their association with the underlying disease pathophysiology and risk factors. All therapeutic options, recent advances, and treatment challenges were reviewed.

Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial.

Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to "early start deferiprone" (.ES-DFP) at a low dose (50 mg/kg/day) or to "delay chelation" (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 µg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES-DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES-DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group.