Autoimmune Hemolytic Anemia in the Pediatric Age Group: The Egyptian Experience.

Autoimmune hemolytic anemia (AIHA) is a common disease entity among adults; however, it is rare among the pediatric age group. Evidence is scarce regarding pediatric AIHA in the literature. The objective of this study is to assess the frequency of AIHA and describe the clinical and laboratory characteristics and treatment outcomes of a cohort of children with AIHA in Egypt. A retrospective study was conducted on 50 children with AIHA who were registered and followed up at the New Children's Hospital in Cairo, Egypt, between January 2010 and January 2021. The study group comprised 60% females and 40% males. Their median age was 8.25 years. All patients showed low hemoglobin levels with a mean of 5.40 ± 1.34 g/dl and a median reticulocyte count of 10 (IQR: 8-15). Twelve (24%) patients were diagnosed with Evans syndrome, and a positive Coombs test was detected in 46 patients (92%). The frequency of primary AIHA was 40%, whereas it was 60% for secondary AIHA. The first line of therapy for acute attacks was high-dose IV steroids which responded well in 38 (76%) patients. Secondary AIHA was more common among our children (60%). AIHA is more prevalent in females (60%). The clinical and laboratory characteristics matched previous reports.

Genotype-phenotype associations in familial Mediterranean fever: a study of 500 Egyptian pediatric patients.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, caused by recessively inherited MEFV gene mutations. The most frequent MEFV mutations differ in penetrance and disease severity. We investigated the genotype-phenotype associations of the three most frequent MEFV gene mutations (M680I, M694V, and V726A) in Egyptian FMF children, regarding clinical features, severity, and colchicine response. METHODS: We conducted a retrospective analysis of the medical registries of 500 FMF pediatric patients from Metropolitan Cairo between 2010 and 2015. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method. RESULTS: Males represented 54% and ages ranged from 2 to 18 years. The most frequent symptoms were abdominal pain, fever, and arthralgia. Clinical features mostly associated with M694V mutation either homozygous or heterozygous whether simple, double, or triple. Of the patients, 94.6% completely responded to colchicine. Among patients benefiting from colchicine, 42.5% had M694V/V726A, 21.6% had M694V/V726A/M680I, and 21.1% had M694V genotype. Simple heterozygous M694V or V726A mutations conveyed a moderate phenotype in 57.1% and 50% of cases, respectively. Homozygous M694V mutation showed moderate and severe phenotypes in 21.7% and 65.2% of cases, respectively. Compound M694V/V726A mutation associated with moderate or severe disease in 48.3% and 33.8% of cases, respectively. CONCLUSION: This study encompasses the largest group of Egyptian pediatric FMF up to date to explore their genotype-phenotype associations. Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response. KEY POINTS: • This study encompasses the largest group of Egyptian pediatric patients affected by FMF up to date to explore their genotype-phenotype associations. • Our results support the notion that the genotype influences the phenotype as regards the clinical manifestations, the disease severity, and the response to colchicine treatment.

Clinical Characteristics, Molecular Background, and Survival of Egyptian Patients With Gaucher Disease Over a 20-Year Follow-up.

This study analyzes the general disease characteristics, impact of enzyme replacement therapy (ERT), and overall survival (OS) of 156 Egyptian patients with Gaucher disease (GD) enrolled on hormone replacement from 1998 to 2017. The mean age at diagnosis was 32.46±12.68 months. Anemia was noted at diagnosis in 50%, thrombocytopenia in 30.7%, severe splenomegaly in 58.7%, severe hepatomegaly in 11.9%, and skeletal findings were detected in 24.3% of the patients. The most prevalent GD type was type 3 (54.5%). Twenty-two of type 3 patients had no neurological manifestations at diagnosis, and 12 developed variable central nervous system manifestations during follow-up. The most common neurological features were limited eye movements, oculomotor apraxia, and squint. Of the 60 patients for whom genotypes were obtained, homozygous L444P was the most common (n=35/60, 58.3%). Treatment with ERT (imiglucerase) revealed significant improvements in blood indices, organ volumes, and growth parameters (P<0.05). Ten (11.7%) type 3 patients did not develop any neurological manifestations under ERT over 20 years. Mortality was 16%, and the 20-year OS was 73.3%. We conclude that in Egypt, type 3 is the most prevalent phenotype of GD, and homozygous L444P is the predominant GBA genotype of GD. Early age at diagnosis and treatment with ERT over 20 years revealed significant improvements in disease manifestations, with an OS of 73.3%.

Polyneuropathy Associated with Severe Iron Overload and Oxidative Stress in ß-Thalassemia Patients.

To investigate the frequency of peripheral neuropathy in patients with ß-thalassemia, and to assess its relation to iron overload and oxidative stress. Sixty ß-thalassemia patients with mean age of 19 ± 4.9 years were recruited. Serum ferritin was quantitatively assessed by enzyme-linked immunoassay and biomarkers of oxidative stress were estimated calorimetrically. Electrophysiological studies using NEMUS 2, Galileu Software were carried out. The patients were separated into two groups: those with abnormal nerve conduction studies (NCS) {Group A; N = 38} and those with normal NCS {Group B; N = 22}. Thirty-eight (63.3%) patients had axonal motor neuropathy as evidenced by abnormal NCS (group A), they showed higher mean serum ferritin (p < 0.01), higher mean malondialdehyde (MDA) (p < 0.01), and lower mean nitrous oxide, total antioxidant capacity, paraoxonase-1 (PON1) (p < 0.01) compared to group B. Bivariate analysis of NCS data demonstrated that abnormal NCS were more frequent in splenectomized patients (p = 0.002), and poorly-chelated patients with serum ferritin ≥ 2000 ng/ml (p = 0.001). Significant variables associated with abnormal motor NCS were entered in stepwise regression analysis and only elevated serum ferritin (p = 0.01) was independently associated with abnormal motor NCS (p = 0.02; 95% CI 1.433-51.791). None of the studied patients had sensory neuropathy or myopathy. Peripheral motor neuropathy may occur in ß-thalassemia patients at a high frequency, regardless of their age and gender. Severe iron overload may contribute to the pathogenesis of neuropathy. Other factors including chelation therapy, splenectomy, and oxidative stress might have an enhancing effect that couldn't be proved in this study.

Carotid Doppler ultrasonography as a screening tool of early atherosclerotic changes in children and young adults with ß-thalassemia major.

PURPOSE: ß-thalassemia major (ß-TM) patients had an increased incidence of cardiovascular complications secondary to iron overload. They showed early carotid atherosclerosis as showed by increased carotid intima media thickness (CIMT) that may occur early even when significant iron overload is absent. We aimed to test the diagnostic performance of CIMT measurement by Doppler ultrasonography as a structural indicator for premature atherosclerosis in ß-TM patients. METHODS: Case-control study included 42 ß-TM patients (24 males and 18 females) aged from 3 to 30 years and 36 age- and sex-matched healthy controls. Carotid Duplex was used for measurement of CIMT in all subjects. RESULTS: The frequency of abnormal CIMT among patients was 19%. Mean CIMT of right anterior wall was 0.8 ± 0.16 (range 0.5-1.2) mm, of right posterior wall was 0.80 ± 0.17 (range 0.5-1.2), of right lateral wall was 0.8 ± 0.17 (range 0.5-1.1) mm. CIMT of left anterior wall ranged from 0.5 to 1.2 with mean 0.81 ± 0.17, CIMT of left posterior wall ranged from 0.5 to 1.1 with mean 0.80 ± 0.17 mm. Mean CIMT of left lateral wall was 0.81 ± 0.18 mm (range 0.5-1.2). CIMT of right anterior, right posterior and left anterior walls were thicker in patients compared to controls (P = 0.003, 0.015, < 0.001, respectively). There was no observable difference in CIMT between males and females, splenectomised and non-splenectomised, or well and poorly chelated subgroups (P > 0.05). CIMT of right lateral wall correlated with the disease duration (r = 0.3, P = 0.04). CONCLUSIONS: Carotid ultrasound was a useful tool to detect subclinical atherosclerosis thorough CIMT evaluation in B-thalassemia major patients. B-thalassemia major children proved to have an increased CIMT regardless the state of iron overload.

Enhancing Effect of Hydroxyurea on Hb F in Sickle Cell Disease: Ten-Year Egyptian Experience.

Patients with sickle cell disease experience hemolytic anemia and vaso-occlusions that result in pain, organ injury, and premature mortality. Several prospective studies have verified the efficacy and tolerability of hydroxyurea (HU), and demonstrated its efficacy in reducing painful vaso-occlusive crises (VOCs) in addition to its ability to increase Hb F levels. We aimed to evaluate the long-term effects of HU therapy on Hb F and assess its long term efficacy and safety in sickle cell disease patients. A retrospective study on 60 sickle cell disease patients was conducted. We studied the laboratory changes, frequency of VOCs per year, frequency of hospital admisions per year and number of transfusions per year, both before and after HU therapy. The follow-up period was 4 to 120 months. Hb F levels after HU therapy positively correlated with the duration of HU therapy, baseline Hb F levels and baseline total hemoglobin (Hb) (r = 0.4, p = 0.04; r = 0.45, p = 0.001; r = 0.5, p = 0.019, respectively) and inversely correlated with baseline total leucocyte count (r = -0.33, p = 0.034). Hydroxyurea therapy was associated with an increase in the total Hb and mean corpuscular volume (MCV) (p = 0.009, p = 0.000; respectively) and with a decrease in total leucocyte count, platelet count and reticulocyte count (p = 0.00, p = 0.03, p = 0.02, respectively). Moreover, a significant reduction in the frequency of VOCs, transfusion frequency and hospital admissions per year after HU therapy was shown in the studied subjects. Hydroxyurea induced an increase in Hb F level, which was maintained over time and was associated with clinical efficacy and acceptable safety.

Serum Hepcidin as a Diagnostic Marker of Severe Iron Overload in Beta-thalassemia Major.

OBJECTIVES: To investigate potential usefulness of serum hepcidin in the diagnosis of iron overload in children with ß-thalassemia. METHODS: A study was conducted on 30 thalassemia major (TM), 30 thalassemia intermedia (TI) and 60 healthy children as controls. Serum hepcidin was measured by Human Hepcidin, ELISA Kit. RESULTS: ß-thalassemia patients had a higher serum hepcidin compared to the controls (p < 0.001). TM group had higher hepcidin and ferritin compared to the TI group (p = 0.034; < 0.001, respectively). Among controls, hepcidin did not correlate with age (r = 0.225, p = 0.084). Among ß-thalassemia patients, it correlated positively with age (r = 0.4; p = 0.001), disease duration (r = 0.5; p < 0.001), transfusion frequency (r = 0.35; p = 0.007), total number of transfusions (r = 0.4; p = 0.003), and ferritin (r = 0.3; p = 0.027). Total hemoglobin and serum ferritin were significantly related to hepcidin, which tended to increase by 0.514 ng/ml with each 1 g/dl rise in hemoglobin (p = 0.023) and by 0.002 ng/ml with each 1 ng/ml rise in serum ferritin (p = 0.002). Iron overload [serum ferritin (SF) ≥ 1500 ng/ml] was independently associated with TM (p = 0.001) and elevated serum hepcidin (p = 0.02). The overall predictability of serum hepcidin in severe iron overload was statistically significant when compared to hepcidin to serum ferritin ratio. CONCLUSIONS: Serum hepcidin is elevated in children with ß-thalassemia; but this elevation is more evident in TM patients with severe iron overload. Thus, hepcidin can be a potential marker of severe iron overload in patients with TM. Further studies are recommended to compare serum hepcidin and serum ferritin in the prediction of severe iron overload in steady state and during infection or inflammation.

Response to hydroxycarbamide in pediatric ß-thalassemia intermedia: 8 years' follow-up in Egypt.

Hydroxycarbamide (hydroxyurea or HU) has been shown to increase fetal hemoglobin (HbF) in patients with ß-thalassemia intermedia (TI). The reported effects of HU in increasing the total hemoglobin (Hb) have been inconsistent. Studies of long-term therapy with HU in pediatric TI are rather uncommon. A retrospective observational study was carried out to evaluate the clinical responses to HU in Egyptian patients with ß-TI. One hundred patients; children (n = 82, mean age 9.9 ± 4.1 years) and adults (n = 18) were studied for the mean Hb, HbF%, median serum ferritin, transfusion history, and splenic size before and after HU therapy (mean dose 20.0 ± 4.2 mg/kg/day, range 10-29 mg/kg/day) over a follow-up period 4 to 96 months (mean 35.4 ± 19.2 months). Molecular studies were also done for group of patients (n = 42). The overall response rate to HU was 79 %; 46 % were minor responders (with a reduction in transfusion rate by 50 % or more and/or an increase in their total hemoglobin level by 1-2 g/dl) and 33 % major responders (becoming transfusion-free and/or having an increase in total hemoglobin level by >2 g/dl). Mean hemoglobin increased among responders from 6.9 ± 0.9 g/dl to 8.3 ± 1.4 g/dl (p < 0.001). A significant rise in mean HbF (27.0 vs. 42.5 %; p < 0.011) and a decrease in median serum ferritin (800 vs. 644 ng/ml; p < 0.001) were also observed among responders (n = 45). Transfusions stopped in 44 % of pretreatment frequently transfused responders (n = 11/25). Splenic size decreased in 37 % of patients (n = 30/81). The predominant ß-thalassemia mutation was 1-6 (T > C) in 32/42 (76 %) of studied patients; 28/32 were responders. Bivariate analysis showed no predictors of response as regards sex, pediatric and adult age, splenic status, or genotype. Hydroxycarbamide is a good therapeutic modality in the management of pediatric as in adult TI patients. It can minimize the need for blood transfusion, concomitant iron overload, and blood-born viral transmission especially in developing countries like Egypt.

Oxidant-antioxidant status in Egyptian children with sickle cell anemia: a single center based study / Estado oxidante-antioxidante em crianças egípcias com anemia falciforme: estudo baseado em um único centro

OBJECTIVE: the present study was conducted to investigate the oxidant-antioxidant status in Egyptian children with sickle cell anemia. METHODS: the serum levels of total antioxidant capacity (TAO), paraoxonase (PON), vitamin E, nitrite, and malondialdehyde (MDA) were measured in 40 steady state children with homozygous sickle cell anemia (24 males and 16 females) and 20 apparently healthy age- and gender-matched controls. RESULTS: mean serum TAO, PON, vitamin E, and nitrite levels were significantly lower in the group with sickle cell anemia, whereas mean serum MDA was significantly higher in these children compared to controls. No significant differences in mean levels of TAO, PON, nitrite, vitamin E, and MDA were found in sickle cell anemia patients receiving hydroxyurea when compared with those not receiving hydroxyurea. A significant negative correlation between serum nitrite and the occurrence of vaso-occlusive crises (VOC) was observed (r = -0.3, p = 0.04). PON level was found to be positively correlated with patients' weight and BMI (r = -0.4, p = 0.01; r = -0.7, p < 0.001, respectively), but not with frequency of VOC. The area under the curve of serum nitrite in predicting occurrence of VOC was 0.782, versus 0.701 for PON, and 0.650 for TAO (p = 0.006). Serum MDA was not correlated with nitrite, PON, TAO, or vitamin E levels. No significant correlations were detected between serum nitrite and hemoglobin or antioxidant enzymes. CONCLUSION: children with sickle cell anemia have chronic oxidative stress that may result in increased VOC, and decreased serum nitrite may be associated with increases in VOC frequency. A novel finding in this study is the decrease in PON level in these patients, which is an interesting subject for further research. .

OBJETIVO: o presente estudo foi realizado com o objetivo de investigar o estado oxidante-antioxidante em crianc¸as egípcias com anemia falciforme. MÉTODOS: dosamos os níveis séricos da capacidade antioxidante total (CAT), paraoxonase (PON), vitamina E, nitrito e malondialdeído (MDA) em 40 crianças estáveis com anemia falciforme homozigótica (24 meninos e 16 meninas), e 20 controles pareados por idade/sexo aparente-mente saudáveis. RESULTADOS: os níveis séricos médios da CAT, PON, vitamina E e nitrito foram significativamente menores, ao passo que o nível sérico médio de MDA foi significativamente maior em crianças com anemia falciforme (AF), em comparação aos controles. Não foram encontradasdiferenças significativas nos níveis médios de CAT, PON, nitrito, vitamina E e MDA em pacientescom AF em tratamento com hidroxiureia, em comparação aos que receberam hidroxiureia. Encontramos uma correlação negativa significativa entre o nitrito sérico e a ocorrência decrises vaso-oclusivas agudas (CVO) (r = -0,3, p = 0,04). Descobrimos que o nível de PON está correlacionado positivamente com o peso e o IMC dos pacientes (r = -0,4; p = 0,01; r = -0,7; p < 0,001, respectivamente), porém não com a frequência de CVO. A área sob a curva (ASC) donitrito sérico na previsão da ocorrência de CVO foi 0,782, em comparação a 0,701 para PON e 0,650 para CAT (p = 0,006). O MDA não está correlacionado a nitrito, PON, CAT ou vitamina E. Não foram detectadas correlações significativas entre nitrito sérico e hemoglobina ou enzimas antioxidantes. CONCLUSÃO: crianças com AF apresentam estresse oxidativo crônico que pode resultar emaumento das CVO. Em crianças com AF, a redução nos níveis de ...

Oxidant-antioxidant status in Egyptian children with sickle cell anemia: a single center based study.

OBJECTIVE: the present study was conducted to investigate the oxidant-antioxidant status in Egyptian children with sickle cell anemia. METHODS: the serum levels of total antioxidant capacity (TAO), paraoxonase (PON), vitamin E, nitrite, and malondialdehyde (MDA) were measured in 40 steady state children with homozygous sickle cell anemia (24 males and 16 females) and 20 apparently healthy age- and gender-matched controls. RESULTS: mean serum TAO, PON, vitamin E, and nitrite levels were significantly lower in the group with sickle cell anemia, whereas mean serum MDA was significantly higher in these children compared to controls. No significant differences in mean levels of TAO, PON, nitrite, vitamin E, and MDA were found in sickle cell anemia patients receiving hydroxyurea when compared with those not receiving hydroxyurea. A significant negative correlation between serum nitrite and the occurrence of vaso-occlusive crises (VOC) was observed (r=-0.3, p=0.04). PON level was found to be positively correlated with patients' weight and BMI (r=-0.4, p=0.01; r=-0.7, p<0.001, respectively), but not with frequency of VOC. The area under the curve of serum nitrite in predicting occurrence of VOC was 0.782, versus 0.701 for PON, and 0.650 for TAO (p=0.006). Serum MDA was not correlated with nitrite, PON, TAO, or vitamin E levels. No significant correlations were detected between serum nitrite and hemoglobin or antioxidant enzymes. CONCLUSION: children with sickle cell anemia have chronic oxidative stress that may result in increased VOC, and decreased serum nitrite may be associated with increases in VOC frequency. A novel finding in this study is the decrease in PON level in these patients, which is an interesting subject for further research.

Study of thyroid function in Egyptian children with ß-thalassemia major and ß-thalassemia intermedia.

BACKGROUND: Thyroid dysfunction is a known complication of transfusion-dependent ß-thalassemia. However, information on its frequency and risk factors among Egyptian Children is still unclear. OBJECTIVE: We aimed to determine the frequency of functional thyroid abnormalities among young patients with ß-thalassemia and compare the thyroid function status among patients with ß-thalassemia major (TM) and ß-thalassemia intermedia (TI). MATERIALS AND METHODS: This was a cross-sectional study that included 52 ß-thalassemia children [27 boys and 25 girls; 34 (65.4%) with TM and 18 (34.6%) with TI]. Their mean age was 16.0±1.91 (range: 12-18) years. Thyroid function and iron load status were assessed by measurement of free tetraiodothyronine, free triiodothyronine, thyroid stimulating hormone (TSH), and serum ferritin concentrations. RESULTS: Serum TSH of the studied cases ranged from 0.28 to 25 µIU/ml with a mean of 4.5±4.8 µIU/ml. None of the studied cases had overt primary hypothyroidism and the frequency of subclinical hypothyroidism was 19.2%. No risk factors for thyroid dysfunction could be identified among our cases. The thyroid profile was comparable in TM and TI patients (P>0.05) and the frequency of subclinical hypothyroidism among TM cases was 20.6% and it was comparable to the 16.7% found among TI patients (P>0.05). No correlations were found between TSH, serum ferritin, chelation therapy, and frequency of blood transfusion. CONCLUSION AND RECOMMENDATIONS: Both TM and TI patients are at risk for subclinical thyroid failure regardless of their iron overload status. Early evaluation of thyroid function in ß-thalassemia children and thyroid replacement therapy for subclinical hypothyroidism should be introduced in the treatment protocols.